Adattamento linguistico e culturale e validazione italiana del Renal iNUT, strumento di screening nutrizionale per pazienti ospedalizzati con malattia renale cronica

Pubblicato il Scarica PDF

Giovanni Cangelosi

DOI: 10.69097/43-02-2026-04

Sara Morales Palomares1,2*, Silvia Cappelletti2*, Gaetano Ferrara2,3, Stefano Mancin2, Giovanni Cangelosi2,4, Giada Vrenna2, Mauro Parozzi2,5, Domenica Gazineo2,6, Marco Sguanci2, Mattia Bozzetti7*, Elena Sandri8*
*Questi autori hanno contribuito in egual misura al lavoro

Sono stati utilizzati strumenti di intelligenza artificiale a supporto della revisione linguistica e della traduzione, ma i contenuti sono originali e interamente elaborati dagli autori. Nessun apporto dell’IA è stato introdotto senza supervisione umana.

1 Department of Pharmacy, Health and Nutritional Sciences (DFSSN), University of Calabria, 87036 Rende (CS), Italy
2 Italian Society of Nephrology Nurse (SIAN), Via Capotesta 1/30, 07026 Olbia, Italy
3 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Montpellier 1, 00128 Rome, Italy
4 School of Pharmacy, Experimental Medicine and “Stefani Scuri” Public Health Department, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino (MC), Italy
5 Medicine and Surgery Department, University of Parma, Via Gramsci 14, 43126 Parma, Italy
6 Governo Clinico e Qualità, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Giuseppe Massarenti 9, 40138, Bologna, Italy
7 Direction of Health Professions, ASST Cremona, Viale Concordia 1, 26100 Cremona, Italy
8 Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente Martir, 46001 Valencia, Spain

Corrispondenza a:
Dr. Giovanni Cangelosi
School of Pharmacy, Polo Medicina Sperimentale e Sanità Pubblica,
62032 Camerino, Italy
E-mail: giovanni01.cangelosi@unicam.it

 

Abstract

Contesto/obiettivo. La malattia renale cronica (MRC) è associata a un’elevata prevalenza di malnutrizione, condizione che incide negativamente sugli esiti clinici e sulla qualità di vita dei pazienti. Il Renal Inpatient Nutrition Screening Tool (Renal iNUT) è stato sviluppato nel Regno Unito per offrire uno strumento di screening nutrizionale rapido e specifico per i pazienti con MRC ospedalizzati. Sebbene esista un adattamento in lingua spagnola, non è ancora disponibile una versione italiana validata. Il presente studio si propone di tradurre, adattare culturalmente e validare psicometricamente il Renal iNUT per il contesto italiano.
Metodi.È stato realizzato un processo di adattamento e validazione transculturale in sette fasi, basato sulla metodologia di Sousa e Rojjanasrirat, volto a garantire l’equivalenza concettuale, linguistica e culturale con la versione originale. Dopo un test pilota condotto con professionisti sanitari per verificarne la chiarezza e la comprensibilità, è stata eseguita la validazione psicometrica su pazienti ospedalizzati affetti da MRC, valutando l’affidabilità inter- e intra-valutatore.
Risultati. Il test pilota ha confermato la chiarezza, la pertinenza e la facilità d’uso della versione italiana del Renal iNUT. La valutazione psicometrica ha evidenziato una buona affidabilità inter-valutatore (ICC = 0.83; IC 95%: 0.69–0.91) e un’eccellente affidabilità intra-valutatore (ICC = 0.90; IC 95%: 0.82–0.95). I punteggi totali sono risultati stabili tra le diverse valutazioni (mediana 2.0; IQR 1.0–3.0/2.5).
Conclusioni. La versione italiana del Renal iNUT dimostra un’elevata riproducibilità e una buona usabilità pratica, supportando l’implementazione di interventi nutrizionali precoci e di uno screening standardizzato nei reparti ospedalieri italiani. L’adozione di questo strumento può contribuire a migliorare la qualità dell’assistenza e gli esiti clinici nei pazienti con MRC.

Parole chiave: Malattia renale cronica, screening nutrizionale, Renal Inpatient Nutrition Screening Tool (Renal iNUT), adattamento transculturale, validità e affidabilità, Italia

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Chronic kidney disease (CKD) is becoming increasingly common and now affects around 10–11% of adults worldwide [1]. Among its many complications, malnutrition is one of the most relevant, as it strongly influences both disease progression and the patient’s overall well-being [2, 3]. According to recent systematic reviews, the global prevalence of malnutrition in CKD varies widely depending on clinical setting, disease stage, and the criteria or tools used to assess it [4]. Malnutrition in CKD has a multifactorial origin, resulting from several overlapping biological and clinical mechanisms [5]. A reduced dietary intake, often related to anorexia, nausea, or gastrointestinal symptoms, is one of the most common contributors. Metabolic and hormonal disturbances linked to chronic inflammation and the accumulation of uremic toxins further aggravate protein-energy wasting and muscle catabolism [6]. Changes in taste and smell perception can also lessen appetite and dietary variety, while dietary restrictions prescribed to control electrolyte or mineral imbalance, multiple medications, and the effects of repeated hospitalizations all play a role [7, 8]. Taken together, these factors not only raise the likelihood of malnutrition but also have a negative impact on patients’ overall clinical course. Individuals who are malnourished often respond less effectively to treatment, experience longer hospital stays, and are more likely to be readmitted, leading to greater healthcare costs [9]. As a result, their quality of life tends to decline, and long-term outcomes are poorer [10]. This issue becomes even more evident with advancing age and progressive kidney impairment, which highlights how essential regular nutritional screening and timely interventions are in this population [11]. To provide a clearer framework for describing nutrition-related disorders in CKD, the International Society of Renal Nutrition and Metabolism (ISRNM) proposed the concept of protein–energy wasting (PEW), a condition characterized by the loss of body protein and energy stores caused by metabolic and inflammatory disturbances [12]. Recent meta-analyses have shown that PEW occurs across all stages of CKD, with particularly high prevalence among dialysis patients [13]. In those undergoing hemodialysis, identifying nutritional risk and applying targeted interventions have been associated with improved outcomes [14], whereas persistent loss of appetite remains a powerful predictor of both hospitalization and mortality [15]. Common anthropometric indicators such as body mass index (BMI), triceps skinfold thickness (TSF), and mid-arm muscle circumference (MAMC) are often used to estimate nutritional status [16–18]. However, validated screening tools are still rarely applied in everyday practice [19]. The 2020 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines stress the need for more research to define optimal combinations of nutritional indicators for early detection and to standardize screening approaches for non-dialysis CKD populations [20]. In response to these needs, Jackson et al. developed the Renal Inpatient Nutrition Screening Tool (Renal iNUT), a concise screening instrument that showed high sensitivity and specificity when compared with the Subjective Global Assessment (SGA) [21]. Although the SGA remains the recognized gold standard for evaluating nutrition-related morbidity and mortality [22], the Renal iNUT offers clear advantages in terms of speed and usability, particularly for CKD inpatients [5, 9]. Its concise structure allows quick identification of at-risk patients and facilitates timely nutritional support [19]. The Renal iNUT has already been translated and validated in Spanish-speaking settings, confirming its reliability and ease of use [23]. Yet, no validated Italian version is currently available. Developing one could help healthcare professionals perform more consistent and standardized nutritional screening in Italian hospitals. Ultimately, an Italian adaptation might promote earlier dietary interventions, strengthen the integration of clinical nutrition within CKD care, and contribute to better long-term patient outcomes. Addressing this gap is crucial, since malnutrition continues to be a frequent but often underestimated complication that significantly impacts prognosis, complication rates, and quality of life in people with CKD.

Aim

This study aimed to translate, culturally adapt, and psychometrically validate the Renal iNUT tool for application in Italian hospital settings.

 

Methods

Study Design and Setting

This single-centre study focused on the translation, cultural adaptation, and psychometric validation of the Renal iNUT tool into Italian, following formal authorization from the original developers [21]. Briefly, the Renal INUT is a kidney-specific screening instrument developed to identify hospitalized patients with CKD who are at risk of malnutrition. It consists of a small set of items exploring key domains that are particularly relevant in this population: current BMI or clinical appearance of malnutrition, recent unintentional weight loss, changes in usual appetite and food intake, and the use of oral nutritional supplements. For each domain, predefined response options associated with nutritional risk are scored as positive, and the total number of “at-risk” responses generates an overall risk score (range 0–4), with higher scores reflecting a higher risk of malnutrition. This score is used to classify patients as low risk (0), at risk (1) or in need of dietetic referral (≥ 2). The tool also includes a brief follow-up section for weekly re-screening during hospitalization, in which weight, BMI and changes in appetite and food intake since admission are reassessed. The Renal iNUT is designed to be completed by ward nurses at the bedside in a few minutes using routinely available clinical information and a brief patient interview. The study followed a seven-phase cross-cultural adaptation protocol adapted from Sousa and Rojjanasrirat [24], ensuring rigorous methodology to preserve the conceptual, semantic, and cultural integrity of the tool. Phases 1–3 were conducted between March and April 2025, Phases 4–5 in May 2025, and Phases 6–7 from June to August 2025. Each phase is described below, to ensure the tool’s cultural and linguistic relevance and its applicability in clinical practice.

Ethical Considerations

The study was approved by the Bioethics Committee of Bologna (protocol no. 0390138). All participants provided written informed consent in accordance with the principles outlined in the Declaration of Helsinki. They were clearly informed about the voluntary nature of their participation and their right to withdraw at any stage without any negative consequences.

Translation and Cultural Adaptation Process

The Italian adaptation of the Renal iNUT followed a structured seven-phase process designed to ensure both linguistic accuracy and cultural relevance.

Translation of the Original Tool into Italian

During the first phase, two independent bilingual translators, both fluent in English and Italian, produced separate translations of the original tool. One translator specialized in healthcare terminology and was familiar with the conceptual basis of the questionnaire, while the other focused more on everyday language to maintain clarity and accessibility. This phase resulted in two Italian versions (IT1 and IT2), each reflecting a slightly different linguistic register.

Reconciliation of Translated Versions

In the next phase, an independent translator compared IT1 and IT2 to reconcile differences and produce a single harmonized version. Any inconsistencies were discussed and resolved to achieve the best possible balance between conceptual precision and linguistic naturalness. The resulting version was labeled Preliminary Italian Version 1 (PI-V1).

Blind Back-Translation

The reconciled Italian text was then translated back into English by two translators whose native language was English and who had no prior knowledge of the original instrument. This “blind” back-translation aimed to highlight any discrepancies or shifts in meaning that might have occurred during the translation process.

Multidisciplinary Committee Review

After the back-translation, a multidisciplinary panel composed of a methodologist, nephrology specialists, and all translators involved reviewed the materials side by side. The committee examined both semantic and conceptual equivalence, resolving any discrepancies and refining the Italian version to ensure it was consistent with the original content. This stage led to the creation of a pre-final Italian version of the Renal iNUT.

Content Validity Assessment

The pre-final version was then reviewed by the expert panel to evaluate item clarity, cultural appropriateness, and clinical relevance. The experts verified that all items maintained the intended meaning of the original version and that the instructions and response options were suitable for use in the Italian healthcare context.

Pre-Test of the Pre-Final Version

The pre-final version was pilot-tested with a group of 15 healthcare professionals, including nephrology nurses, dietitians, and physicians, working at Azienda Socio Sanitaria Territoriale (ASST) Lariana – Fermo della Battaglia, Como (Italy). Participants gave written informed consent and were asked to comment on the clarity of the instructions, the relevance of the items, and the ease of completing the questionnaire. Their feedback was incorporated to make minor adjustments and finalize the tool for clinical application.

Psychometric Testing

The final phase focused on evaluating the psychometric properties of the Renal iNUT tool in a representative sample of hospitalized patients with CKD. Healthcare professionals, including physicians and nurses from nephrology and internal medicine wards, were tasked with using the tool to assess the nutritional risk of patients. This phase was critical in determining the tool’s reliability and validity in clinical practice by assessing its consistency and accuracy across various patient scenarios.

Sample size for phase 7

The expected reliability for this study was based on the previously published validation of the Renal iNUT tool, which reported a Cohen’s kappa of 0.74 (95% CI [0.58, 0.90]), indicating substantial agreement. Assuming a similar level of agreement, an expected Intraclass Correlation Coefficients (ICC) of approximately 0.74 was considered. A simulation-based a priori power analysis indicated that for expected (ICC) values around 0.7–0.8, a sample of 30–40 patients with two raters is sufficient to obtain reliable and precise estimates, with a 95% confidence interval width of approximately 0.3 [25]. Accordingly, the inclusion of n = 35 patients in the present study can be regarded as adequate to assess inter- and intra-rater reliability. 

Data collection for phase 7

Data were collected between June and August 2025 in the tertiary nephrology department of ASST Lariana, Fermo della Battaglia (Como, Italy). Before data collection began, the participating healthcare professionals received specific training on how to administer and score the Renal iNUT, ensuring a uniform application of the tool across assessors. Patients diagnosed with CKD were recruited consecutively at the time of hospital admission, after signing written informed consent. The Renal iNUT was then administered by two independent raters following a structured schedule designed to test both intra- and inter-rater reliability:

Rater 1 (T0): Initial nutritional assessment performed at the time of patient admission.

Rater 1 (T6h): Repeat evaluation 6 hours later by the same professional to assess consistency within the same operator.

Rater 2 (T24h): Independent evaluation conducted within 24 hours of admission by another professional to assess inter-rater consistency.

All scores were assigned strictly according to the standardized Renal iNUT criteria to ensure objective and comparable evaluations of nutritional risk.

An overview of the entire process of translation, cultural adaptation, and validation is presented in Figure 1.

Flow diagram of the seven-phase cross-cultural adaptation and validation process
Figure 1. Flow diagram of the seven-phase cross-cultural adaptation and validation process of the Renal iNUT tool into Italian. Legend. CKD: Chronic Kidney Disease; ICC: Intraclass Correlation Coefficients; ASST: Azienda Socio Sanitaria Territoriale; PI-V1: Preliminary Italian Version 1; PF-IV: pre-final Italian version; BT1: Back Translation 1; BT2: Back Translation 2; I-CVI: Item-Content Validity Index; S-CVI: Scale-Content Validity Index.

Statistical Analysis

Descriptive statistics were produced for both demographic and clinical variables. Because continuous data were not normally distributed, they are presented as medians with interquartile ranges (IQR). Categorical variables, such as item-level responses, are expressed as absolute frequencies and percentages. Test–retest reliability (agreement between T0 and T6 h) was examined using the intraclass correlation coefficient [ICC (3, 1)] calculated through a two-way mixed-effects model (absolute agreement, single measures). Inter-rater reliability (agreement between T6 h and T24 h assessments) was analyzed with ICC (2,1) using a two-way random-effects model under the same agreement assumptions. Ninety-five-percent confidence intervals (CIs) were reported for all ICCs and interpreted according to conventional cut-offs: < 0.50 = poor, 0.50–0.75 = moderate, 0.75–0.90 = good, and > 0.90 = excellent reliability [26]. All analyses were conducted using R, version 4.5.0.

 

Results

The results of this study are presented according to the seven phases outlined in the Methods section, each representing a critical step in the linguistic and cultural adaptation and validation of the Renal iNUT tool for use in Italian clinical settings.

Translation and expert review (phases 1–5)

Phases 1–5 resulted in an Italian version of the Renal iNUT that was conceptually consistent with the original tool and suitable for use in Italian clinical settings. In phases 1–3, two independent forward translations were produced and reconciled into a single Italian draft, which was then blindly back-translated into English. Comparison of the back-translations with the original version showed good conceptual overlap, with no major discrepancies in meaning. During the multidisciplinary committee review (phase 4), nephrology experts, dietitians, a methodologist and the translators introduced only minor linguistic refinements to improve clarity and idiomatic flow, while preserving the original content and structure of the tool. In phase 5, content validity indices met a priori benchmarks I-CVI: Item-Content Validity Index (I-CVI) ≥ 0.78 and Scale-Content Validity Index (S-CVI) ≥ 0.80, indicating that the items were judged as clear, relevant and culturally appropriate by the expert panel and could be retained in the Italian version without substantial modification.

Pre-test with healthcare professionals (phase 6)

In phase 6, the pre-final Italian version (PF-IV) of the Renal iNUT was pre-tested with 15 healthcare professionals (nephrology nurses, dietitians and physicians) working in nephrology and internal medicine wards. Overall, participants considered the tool easy to understand, clinically relevant, and straightforward to administer. They also reported that it could be completed quickly and integrated into routine clinical assessments without affecting workflow, although the exact administration time was not formally measured in this study. Their feedback led to a few minor wording and layout adjustments, but no substantial changes to item content, resulting in the final Italian version used for psychometric testing (Supplementary File 1).

Phase 7: Psychometric Testing

Sample characteristics

A total of 35 hospitalized patients with CKD participated in psychometric testing. The median age of the sample was 71.4 years (IQR 56.7–80.9), and the median BMI was 23.6 kg/m² (IQR 21.2–25.6).

Renal-iNUT Scores

Across repeated assessments, total Renal iNUT scores remained stable, with median values of 2.0 at T0 (IQR 1.0–3.0), 2.0 at T6 h (IQR 1.0–2.0), and 2.0 at T24 h (IQR 1.0–2.5). The observed range was 0–4 at all time points (Table 1).

Item-level responses were consistent over time (Table 2). The domains most frequently endorsed were Food Intake (60.0% at T0; 48.6% at T6 h; 45.7% at T24 h) and Appetite (54.3%; 48.6%; 51.4%), followed by Weight Loss (37.1%; 40.0%; 38.2%). The items Malnutrition/BMI ≤ 20 (≈ 17%) and Nutritional Supplements (≈ 11–17%) appeared less frequently. Overall, these findings indicate a consistent response pattern across all assessment points. 

Timepoint n Median (IQR) Min Max
T0 35 2.0 (1.0–3.0) 0 4
T6h 35 2.0 (1.0–2.0) 0 4
T24h 35 2.0 (1.0–2.5) 0 4
Table 1. Total scores. Legend: n = number of participants; IQR = Interquartile Range; Min = Minimum; Max = Maximum; T0 = first evaluation; T6h = 6h evaluation; T24h = 24h evaluation. Note: Median (IQR) and range values for total Renal iNUT scores across the three assessment time points (T0, T6h, and T24h) in 35 hospitalized patients with chronic kidney disease (CKD).
Item T0

n (%)

 T6h

n (%)

 T24h

n (%)
Weight loss (involuntary) 13 (37.1%) 14 (40.0%) 13 (38.2%)
Malnutrition or BMI ≤ 20 6 (17.6%) 6 (17.1%) 6 (17.1%)
Nutritional supplements 4 (11.4%) 6 (17.1%) 5 (14.3%)
Food intake 21 (60.0%) 17 (48.6%) 16 (45.7%)
Appetite 19 (54.3%) 17 (48.6%) 18 (51.4%)
Table 2. Item response frequencies at T0, T6h, and T24h (only observed categories). Legend: BMI: body mass index; n = number of participants; T0 = first evaluation; T6h = 6h evaluation; T24h = 24h evaluation. Note: Frequencies and percentages of positive responses for each Renal iNUT item across the three assessment time points (T0, T6h, and T24h) in 35 hospitalized patients with CKD.

Reliability

Intra-rater Reliability (T0 vs T6h)

Intraclass correlation coefficients (ICC [3, 1]) for item-level agreement ranged from 0.78 to 1.00. The ICC for the total score was 0.83 (95% CI 0.69–0.91), indicating good reproducibility within the same rater (Table 3).

Item ICC 95% CI

(Lower)

 95% CI

(Upper)

 n
Item 1 0.82 0.67 0.91 35
Item 2 1.00 1.00 1.00 34
Item 3 0.78 0.60 0.88 35
Item 4 0.79 0.63 0.89 35
Item 5 0.78 0.60 0.88 35
Total 0.83 0.69 0.91 35
Table 3. Intraclass Correlation Coefficients [ICC (3, 1)] for Items and Total Score Between T0 and T6h. Legend: ICC = Intraclass correlation coefficients; n = number of participants; CI = Confidence Interval. Note: Intraclass correlation coefficients (ICC [3, 1]) and 95% confidence intervals (CI) for item-level and total scores obtained by the same rater at two time points (T0 and T6h).

Inter-rater reliability (T6h vs T24h)

Item-level ICC (2,1) values ranged from 0.83 to 1.00. The ICC for the total score was 0.90 (95% CI 0.82–0.95), indicating excellent agreement between different raters (Table 4).

Item ICC (2,1) 95% CI

(Lower)

 95% CI

(Upper)

 n
Item 1 0.94 0.88 0.97 34
Item 2 1.00 1.00 1.00 35
Item 3 0.90 0.80 0.95 35
Item 4 0.83 0.69 0.91 35
Item 5 0.83 0.69 0.91 35
Total 0.90 0.82 0.95 35
Table 4. ICC (2,1) (two-way random, absolute agreement) between T6h and T24h. Legend: ICC = Intraclass correlation coefficients; n = number of participants; CI = Confidence Interval. Note: Intraclass correlation coefficients (ICC [2, 1]) and 95% confidence intervals (CI) for item-level and total scores obtained by two different raters at T6h and T24h.

 

Discussion

This study set out to translate, culturally adapt, and psychometrically validate the Renal iNUT for use in Italian hospital settings, filling an important gap in renal-specific nutritional screening.

Malnutrition remains a common and complex complication in chronic kidney disease (CKD) [1, 2]. It contributes to higher morbidity, longer hospital stays, frequent readmissions, and rising healthcare costs [9]. Because of this, identifying nutritional risk early is essential to initiate prompt and effective interventions [27, 28]. The Renal iNUT was created to offer a concise, kidney-specific screening tool that combines anthropometric and dietary dimensions such as appetite, food intake, and oral nutritional supplement (ONS) use. These elements are highly relevant in CKD, where nutritional deterioration is often worsened by polypharmacy, uremic toxin buildup, gastrointestinal disturbances, and taste changes like dysgeusia, all of which reduce dietary intake [7, 8, 29]. By integrating these features, the tool allows for a more focused and clinically meaningful evaluation of nutritional risk. The process of translation, cultural adaptation, and validation followed a rigorous seven-phase protocol that has already been successfully applied in international studies [30]. This approach ensured that the Italian version maintained semantic alignment with the original tool while remaining appropriate for clinical use within the Italian healthcare system. The procedure included bilingual forward and back translations, review by a multidisciplinary committee, and an expert evaluation of each item’s clarity and cultural fit. Both the I-CVI and the S-CVI were above the recommended cutoffs, confirming the strength and reliability of the adapted version. Feedback gathered from 15 healthcare professionals, including nephrologists, dietitians, and nurses, confirmed that the Italian Renal iNUT was clear, practical, and easy to apply, with only minor wording adjustments required. Psychometric testing in a sample of 35 hospitalized CKD patients further supported its reliability, showing excellent reproducibility: intra-rater reliability (T0 vs T6 h) reached an ICC of 0.83 (95% CI 0.69–0.91), and inter-rater reliability (T6 h vs T24 h) achieved 0.90 (95% CI 0.82–0.95) [26]. These results are particularly noteworthy considering the difficulties inherent in assessing nutrition among CKD patients, where factors such as hydration status, inflammation, and metabolic alterations often interfere with anthropometric and biochemical measurements [31, 32]. From a clinical standpoint, the stable score distributions across repeated assessments, median 2.0 with consistent domain responses, underline the tool’s reliability for longitudinal monitoring. This is important because malnutrition in CKD is not static; it fluctuates with disease progression, dialysis regimens, comorbid conditions, and hospitalization episodes [33].

When compared with more general screening instruments such as the MUST [34] or the SGA [22], the Renal iNUT demonstrates several advantages [24, 35]. Traditional screening tools often rely heavily on body weight or BMI, yet these indicators can mask nutritional risk when patients present with fluid overload, sarcopenia, or protein–energy wasting [36]. The Renal iNUT offers a broader view: by including dietary intake, appetite, and the use of ONS, it captures CKD-specific conditions such as fluid imbalance and appetite loss, providing a more realistic picture of a patient’s nutritional status [24, 30]. Another advantage of the tool is the structured training offered to the professionals who use it. When staff receive standardized instruction, differences between observers tend to decrease, making the tool more consistent across units and professional roles [37, 38]. Incorporating this training into routine clinical practice could support wider and more reliable adoption of the Renal iNUT in nephrology settings [39]. The tool’s usefulness extends beyond nutritional screening alone. In older adults with CKD, malnutrition frequently overlaps with frailty, falls, longer hospital stays, and higher mortality rates [40]. Detecting nutritional risk early, through a CKD-specific tool like the Renal iNUT, can complement frailty assessments and help promote a more integrated and patient-centered model of care [24, 35]. Because nutritional decline and inflammation are closely linked, using the Renal iNUT alongside inflammatory or metabolic biomarkers may also enhance risk stratification and prognostic assessment [24, 41]. On a broader level, applying validated nutritional screening tools in a systematic way can contribute to shorter hospitalizations, fewer readmissions, and lower healthcare costs [42]. Embedding the Renal iNUT into standard care pathways could therefore benefit both patients and health systems [24]. Finally, as clinical nutrition becomes increasingly digitalized, there are growing opportunities to connect validated instruments like the Renal iNUT with electronic health records, mobile apps, and telemedicine systems. These integrations allow for real-time data entry, automatic scoring, and faster communication among multidisciplinary teams, ultimately supporting more efficient and coordinated nutritional care [43, 44]. In this context, artificial intelligence (AI) also holds promise: predictive algorithms trained on large clinical datasets could enhance risk prediction, personalize dietary strategies, and monitor trends over time. For CKD patients, whose nutritional trajectories often change rapidly, the combination of standardized screening instruments such as the Renal iNUT with AI-based technologies could represent a meaningful step toward precision nutrition and improved quality of care [45].

Future studies should also investigate how Renal iNUT scores relate to objective markers of nutritional status, such as serum albumin, inflammatory biomarkers, muscle strength, and body composition parameters, as well as to clinically meaningful outcomes including length of stay, readmissions, and mortality. Such evidence would provide a more comprehensive understanding of the clinical value of the tool and further support its use in routine nephrology practice.

Limitations

This study presents several limitations that should be acknowledged. First, it was carried out in a single Italian hospital, and therefore the findings may partly reflect local dietary habits, healthcare practices, and organizational models. While this setting enhances the cultural fit of the adaptation, it may restrict the broader applicability of the results to other regions or healthcare systems. The study sample was relatively small (n = 35). Although this number met the predefined requirements for estimating ICCs with adequate precision, it may not fully represent the diversity of the CKD population. Moreover, the short retest intervals (6–24 hours) helped to minimize clinical changes between assessments but could have introduced some degree of memory or learning bias among raters. Furthermore, we did not formally record the time required to complete each Renal iNUT assessment, and we were therefore unable to quantify its impact on workflow. In addition, we did not systematically collect biochemical and functional indicators of nutritional status (e.g., serum albumin, muscle strength, or muscle mass), which prevented us from evaluating the concurrent validity of the Renal iNUT against objective clinical markers. Finally, this investigation focused primarily on content validity and reliability. Other psychometric properties, such as construct, concurrent, and predictive validity, were not examined here and should be evaluated in future, larger-scale studies.

Relevance to clinical practice

The Italian adaptation of the Renal iNUT provides a fast, kidney-specific tool for detecting malnutrition in CKD patients and addresses a clear gap in daily clinical practice. By including key parameters such as appetite, food intake, and ONS use, the instrument captures nutritional risk more accurately than generic screening tools, which may fail in the presence of fluid overload or altered body composition. The Renal iNUT uses a standardized scoring system that helps nephrologists, dietitians, and nurses communicate more effectively and work toward a shared nutritional plan. The tool is easy to use, requires only a short period of training, and can be repeated several times during a patient’s hospital stay. This practicality makes it particularly useful for detecting early signs of nutritional decline and for triggering timely interventions aimed at preventing protein–energy wasting, reducing complications, and shortening recovery times. Thanks to its solid reproducibility, the Renal iNUT can be applied consistently from admission to discharge, ensuring continuity in the monitoring of nutritional status. Integrating the tool into electronic health records (EHRs) would make its use even smoother, automatic data capture and follow-up could be handled directly within the system. Beyond simplifying daily practice, this would enable real-time clinical decisions and generate valuable information for tracking hospital malnutrition at a national level. These datasets could in turn help health authorities refine care pathways and design more effective nutrition-related policies. In the near future, combining Renal iNUT data with artificial intelligence-based analytical platforms may further improve risk prediction and support more personalized nutritional care for patients with CKD. In summary, the Italian adaptation of the Renal iNUT stands out as a practical and reliable tool, one that promotes consistent screening, strengthens collaboration across disciplines, and contributes to better outcomes in nephrology care.

 

Conclusion

The Italian adaptation of the Renal iNUT resulted in a tool that remains true to the original version while being fully attuned to the linguistic and cultural characteristics of the Italian healthcare environment. Every domain, wording choice, and response option was carefully reviewed to reflect local dietary habits and clinical practice, making the instrument directly relevant to Italian patients and professionals. Clinically, having a renal-specific screening tool is a real step up from generic instruments. By focusing on appetite, actual food intake, and use of ONS, the Renal iNUT offers a more nuanced and sensitive picture of nutritional risk in CKD. Crucially, it can flag malnutrition even when usual markers, weight or BMI, are misleading because of fluid overload or altered body composition. Beyond accuracy, the tool helps standardize assessment across wards and roles, and it makes communication between nephrologists, dietitians, and nurses more consistent, bringing nutritional monitoring firmly into multidisciplinary CKD care. Because it is concise and easy to administer, it can be used routinely during a hospital stay to catch early decline and trigger timely action. Introducing a validated, kidney-specific screener into the Italian system addresses a clear gap: with malnutrition common in CKD and tightly linked to poor outcomes, the Renal iNUT could support earlier detection, better quality of care, and reductions in complications, length of stay, and costs. In summary, the Italian Renal iNUT is both a practical clinical tool and a step forward in nephrology care, promoting more proactive, standardized, and patient-centered nutritional management.

 

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Malattia renale metabolica: un nuovo concetto nell’interazione tra obesità, prediabete, diabete e disfunzione epatica

Pubblicato il Scarica PDF

Jorge Rico Fontalvo

DOI: 10.69097/43-01-2026-06

Jorge Rico Fontalvo1,2,6, Rodrigo Daza Arnedo3,6, María Raad Sarabia4, Javier Jiménez5, Juan Montejo-Hernández2,6, Tomas Rodríguez-Yánez7, María José Soler8, Maria Teresa Sciarrone-Alibrandi9, Rodolfo Fernando Rivera10

1. Facultad de Medicina, Departamento de Nefrología, Universidad Simón Bolívar de Barranquilla, Barranquilla, Colombia
2. Departamento médico, IPS Nephromedicall Medellín, Medellín, Colombia
3. IPS Caminos Cartagena, Cartagena, Colombia
4. Facultad de Medicina, Departamento de Medicina Interna, Universidad del Sinú, Cartagena, Colombia
5. Facultad de Medicina, Universidad Militar Nueva Granada, Bogotá, Colombia
6. Asociación Colombiana de Nefrología e HTA (ASOCOLNEF), Bogotá, Colombia
7. Facultad de Medicina, Departamento de Medicina Interna, Universidad de Cartagena, Cartagena, Colombia
8. Servicio de Nefrología, Hospital Universitario Vall de Hebron, Barcelona, España
9. Struttura Complessa Nefrologia e Dialisi, IRCCS Ospedale San Raffaele di Milano, Italia
10. Struttura Complessa Nefrologia e Dialisi, Ospedale Pio XI, Desio, ASST Brianza, Italia

Corrispondenza a:
Rodolfo Rivera,
E-mail: md.rfrivera@gmail.com

 

Abstract

Le alterazioni metaboliche quali obesità, insulino-resistenza, prediabete, diabete mellito di tipo 2 e la steatosi epatica associata a disfunzione metabolica (metabolic dysfunction-associated steatotic liver disease, MASLD) contribuiscono in misura crescente allo sviluppo della malattia renale cronica (chronic kidney disease, CKD). Sebbene spesso considerate entità separate, queste condizioni condividono meccanismi comuni, tra cui iperfiltrazione glomerulare, squilibrio delle adipochine, infiammazione cronica di basso grado, disfunzione endoteliale e accumulo lipidico, che avviano e sostengono il danno renale molto prima che la CKD classica diventi clinicamente evidente.

Il concetto di Malattia Renale Metabolica (Metabolic Kidney Disease, MKD) offre un quadro unitario in grado di descrivere il continuum del coinvolgimento renale lungo lo spettro metabolico. Le forme di MKD associate a obesità e prediabete spesso precedono la nefropatia diabetica, mentre la MASLD – secondo le più recenti linee guida EASL-EASD-EASO – rappresenta un disordine multisistemico con dirette conseguenze renali. I fenotipi metabolici misti amplificano ulteriormente lo stress metabolico, accelerando la progressione verso la CKD.

Il riconoscimento della MKD ha importanti implicazioni cliniche. Strategie di screening più ampie potrebbero consentire l’identificazione precoce di alterazioni renali in soggetti con vulnerabilità metabolica non intercettati dai criteri tradizionali di CKD. L’integrazione della valutazione metabolica nella pratica nefrologica potrebbe favorire interventi più precoci e olistici, con un potenziale miglioramento degli esiti cardiorenali.

Parole chiave: obesità, diabete mellito di tipo 2, prediabete, malattia renale cronica, disfunzione epatica, sindrome cardiorenale metabolica, albuminuria, iperfiltrazione glomerulare

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

List of Abbreviations:

ACR – Albumin-to-creatinine ratio
AGEs – Advanced glycation end-products
AKI – Acute kidney injury
CKD – Chronic Kidney Disease
CKM – Cardiovascular-kidney-metabolic syndrome
CRMS – Cardio-renal-metabolic syndrome
DKD – Diabetic kidney disease
eGFR – Estimated glomerular filtration rate
GLP-1 RA – Glucagon-like peptide-1 receptor agonist
HbA1c – Glycated haemoglobin
IL-6 – Interleukin 6
MASLD – Metabolic dysfunction–associated steatotic liver disease
MKD – Metabolic kidney disease
NAFLD – Non-alcoholic fatty liver disease (former term for MASLD)
NF-κB – Nuclear factor kappa-light-chain-enhancer of activated B cells
ORG – Obesity-related glomerulopathy
PKC – Protein kinase C
RAAS – Renin–angiotensin–aldosterone system
ROS – Reactive oxygen species
SGLT2 – Sodium–glucose cotransporter 2
T2DM – Type 2 diabetes mellitus
TGF-β – Transforming growth factor beta
TNF-α – Tumor necrosis factor alpha

 

Introduction

Cardiovascular diseases and other non-communicable conditions remain the leading cause of death worldwide, accounting for nearly 70% of global mortality [1]. Diabetes mellitus, arterial hypertension, obesity, and chronic kidney disease (CKD) constitute the most prevalent chronic conditions contributing to this burden. CKD affects an estimated 9-13% of the population, with prevalence increasingly driven by the global epidemics of diabetes and obesity [2, 3].

In parallel, the prevalence of diabetes has doubled from 1990 to 2022, reaching over 828 million adults globally [4]. Similar trends are observed in Latin America and other regions, where obesity and metabolic dysfunction are now major determinants of cardiovascular and renal risk [5–10]. Importantly, mounting evidence indicates that kidney injury can arise before overt diabetes develops, occurring across the entire spectrum of metabolic disturbances, including obesity, prediabetes, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD).

These interconnected processes form a continuum in which excess adiposity and adipose-tissue dysfunction induce systemic inflammation, endothelial injury, glomerular hyperfiltration, and neurohormonal activation. This “adipocentric” perspective has led to the recognition of the Cardio-Renal-Metabolic Syndrome (CRMS) as an integrated model encompassing cardiovascular, renal, and metabolic abnormalities [11–13].

Within this framework, the concept of Metabolic Kidney Disease (MKD) emerges as a unifying term describing kidney damage mediated primarily by metabolic dysfunction, even in the absence of sustained hyperglycaemia. MKD encompasses kidney injury associated with obesity, prediabetes, type 2 diabetes, MASLD, and mixed phenotypes. Its early recognition may be essential to interrupt disease progression and reduce cardiovascular and renal complications.

Importantly, metabolic dysfunction precedes and amplifies kidney injury across the entire continuum of adiposopathy, insulin resistance, impaired glucose tolerance, type 2 diabetes and MASLD, highlighting that renal damage often develops before overt hyperglycaemia becomes clinically detectable.

 

Cardio-Renal-Metabolic Syndrome (CRMS)

The Cardio-Renal-Metabolic Syndrome (CRMS) provides the essential pathophysiological context from which Metabolic Kidney Disease emerges. Evidence accumulated over the last decade shows that excess adiposity – particularly visceral and ectopic fat accumulation – drives a systemic inflammatory state that disrupts cardiovascular, renal, and metabolic homeostasis [14]. Rather than isolated diseases, these conditions form an interconnected continuum in which dysfunction in one organ system accelerates injury in the others.

The American Heart Association defines CRMS as a systemic disorder characterized by pathophysiological interactions between metabolic risk factors, CKD, and cardiovascular disease (CVD), leading to multiorgan dysfunction and increased cardiovascular events [12]. This framework emphasizes the bidirectional nature of these interactions: CVD increases the likelihood of renal dysfunction; CKD amplifies cardiovascular risk; and metabolic abnormalities – including adipose-tissue dysfunction, insulin resistance, and subclinical inflammation – drive both processes simultaneously [15–18].

Three major biological pathways underpin CRMS:

  1. Chronic low-grade inflammation, mediated by adipose-derived cytokines such as IL6 and TNFα, promoting endothelial dysfunction, oxidative stress, and vascular injury.
  2. Insulin resistance, contributing to altered podocyte signaling, increased sodium reabsorption, impaired nitric oxide bioavailability, and early glomerular hyperfiltration.
  3. Neurohormonal activation, including heightened activity of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS), fostering vasoconstriction, hypertension, fibrosis, and progressive organ damage.

To support clinical stratification, the AHA proposes a staging system encompassing the entire spectrum of metabolic and cardiorenal dysfunction [12, 15]:

  • Stage 0: No metabolic risk factors
  • Stage 1: Excess or dysfunctional adiposity, including prediabetes
  • Stage 2: Metabolic risk factors and/or moderate-to-high CKD risk
  • Stage 3: Subclinical CVD with overlapping metabolic or renal risk
  • Stage 4: Established CVD ± CKD (4a: without renal insufficiency; 4b: with renal insufficiency)

Within this continuum, the kidney is both target and mediator of metabolic injury. CRMS thus provides the conceptual foundation for MKD/ERM, clarifying how metabolic dysfunction – independent of glycaemic thresholds – initiates and amplifies renal injury.

 

Definition and Concept of Metabolic Kidney Disease (MKD/ERM)

Metabolic Kidney Disease (MKD), or Enfermedad Renal Metabólica (ERM), is an emerging and evolving concept that seeks to integrate the entire spectrum of renal injury associated with metabolic dysfunction. Rather than representing a single disease or a traditional histopathological entity, MKD reflects a continuum of pathophysiological alterations in which adipose-tissue dysfunction, insulin resistance, and chronic low-grade inflammation converge to drive early and progressive kidney damage. This view departs from classical models focused exclusively on hyperglycaemia or hypertension, and instead places the metabolic milieu – especially dysfunctional adiposity – at the centre of renal injury [13, 19] (Figure 1).

Common pathophysiological mechanisms in metabolic kidney disease (MKD)
Figure 1. Common pathophysiological mechanisms in metabolic kidney disease (MKD). 1. Inflammation: increased cytokine and adipokine signalling leading to endothelial dysfunction, tissue remodelling, and fibrosis. 2. Hyperfiltration: intraglomerular hypertension and haemodynamic stress, contributing to podocyte injury and glomerulosclerosis. 3. Endothelial dysfunction: impaired nitric oxide bioavailability leading to altered autoregulation and vascular stiffness. 4. Insulin resistance: disrupted insulin signalling in target tissues (e.g., podocytes, hepatocytes) promoting metabolic stress, lipotoxicity, and apoptosis.

Adipose-tissue dysfunction plays a pivotal mechanistic role. Excess visceral fat promotes secretion of proinflammatory cytokines (TNF-α, IL-6), dysregulated adipokines (reduced adiponectina, elevated leptina), increased oxidative stress, and activation of the renin–angiotensin–aldosterone system (RAAS). These mechanisms favour afferent arteriolar vasodilation, intraglomerular hypertension, podocyte stress, and alterations in glomerular permeability. Over time, these changes contribute to hypertrophy of glomerular structures, expansion of mesangial matrix, tubulointerstitial inflammation, and ultimately to a decline in glomerular filtration [20–24]. This continuum perspective aligns with current evidence, emphasizing that renal alterations frequently emerge during early metabolic imbalance, well before traditional diagnostic criteria for diabetes or CKD are met.

 

MKD as an Integrative Clinical Framework

The strength of the MKD concept lies in its ability to integrate metabolic phenotypes that traditionally have been described separately. Obesity, prediabetes, type 2 diabetes, MASLD, and their combinations share physiopathological pathways that converge on the kidney. Although the magnitude and temporal sequence of injury may differ, the kidney responds to metabolic stress in a largely stereotyped manner: early glomerular hyperfiltration, podocyte maladaptation, endothelial dysfunction, and progressive fibrosis.

This integrative framework does not negate existing terminology, such as Diabetic Kidney Disease (DKD) or CKD associated with metabolic syndrome, but rather seeks to connect them. DKD remains essential for describing renal injury in established diabetes. However, it does not encompass patients with obesity or prediabetes who show similar physiopathological patterns. Likewise, CKD associated with metabolic syndrome often remains an epidemiological description rather than a mechanistic one. MKD proposes a unifying perspective, highlighting the central role of metabolic dysfunction – whether hepatic, adipose, or pancreatic – in initiating and sustaining renal damage. Given its high prevalence and strong metabolic basis, MASLD should be formally recognised as a key determinant of renal vulnerability within the MKD spectrum, warranting systematic screening even in non-diabetic individuals.

 

Clinical Implications

Recognizing MKD as a distinct and broader clinical construct may help clinicians identify high-risk individuals who would not be screened under current CKD guidelines. It may also encourage early therapeutic interventions targeting adipose-tissue inflammation, insulin resistance, and metabolic stress before overt renal dysfunction becomes evident. Ultimately, MKD promotes a shift from reactive nephrology to a more preventive, metabolically informed approach, consistent with contemporary cardio-renal-metabolic frameworks.
Comparable patterns of early metabolic stress and altered body composition have been reported in kidney conditions characterised by organomegaly, where malnutrition and sarcopenia may develop despite preserved eGFR [25, 26], particularly in women due to the higher prevalence of hepatomegaly [27–29].
Furthermore, persistent inflammatory activation is a hallmark across CKD phenotypes. Evidence from anemia management [30], intravenous iron stewardship [31], and uremic toxin–driven vascular injury [32] highlights how metabolic and inflammatory disturbances can converge to amplify renal vulnerability, mirroring several mechanisms central to MKD.

 

Clinical Subtypes of Metabolic Kidney Disease

Metabolic Kidney Disease encompasses a spectrum of renal manifestations arising from distinct but interrelated metabolic disturbances. Although these conditions share common physiopathological pathways – such as insulin resistance, adipose-tissue dysfunction, chronic inflammation, and endothelial injury – each metabolic phenotype imprints a characteristic pattern of renal involvement (Figure 2). In the following sections, we describe the major clinical subtypes of MKD, highlighting their specific mechanisms, histopathological features, and implications for early detection and progression.

Figure 2. Proposed classification of metabolic kidney disease (MKD). Subtypes include obesity-related MKD, prediabetes-related MKD, T2DM-related MKD, MASLD-related MKD, and mixed MKD.

Obesity-Related- Metabolic Kidney Disease

Obesity represents one of the most consistent and well-established metabolic risk factors for the development and progression of kidney disease. Far from being a passive -energy storage compartment, adipose tissue – -particularly visceral fat accumulation – functions as an active endocrine and immunometabolic organ capable of modulating systemic inflammation, insulin sensitivity, oxidative stress, haemodynamics, and neurohormonal signalling [33–37]. These perturbations exert direct and indirect effects on renal structure and function, forming the basis of obesity-related- metabolic kidney disease.

From a haemodynamic standpoint, obesity is characterized by increased renal plasma flow, afferent arteriolar vasodilation, and elevated intraglomerular pressure. These early adaptations, largely mediated by hyperinsulinaemia, enhanced tubular sodium–glucose reabsorption, and heightened RAAS and sympathetic nervous system activity, culminate in glomerular hyperfiltration [36–38]. Persistent hyperfiltration contributes to enlargement of glomerular tuft volume and sets the stage for podocyte hypertrophy, detachment, and loss – events central to the initiation of proteinuria and progressive glomerulosclerosis.

Adipokines are central mediators of renal injury in obesity. Elevated leptin levels promote proliferation of mesangial cells, collagen deposition, and activation of profibrotic pathways, whereas reduced adiponectin impairs endothelial integrity and increases susceptibility to inflammation and oxidative stress [22, 37]. In parallel, secretion of cytokines such as IL6 and TNFα from dysfunctional adipose tissue fuels systemic lowgrade inflammation, promoting renal endothelial dysfunction, altered nitric oxide bioavailability, and microvascular injury.
Histopathological studies have described a recognizable phenotype in obesity-related kidney disease, known as obesity-elated glomerulopathy (ORG). Biopsies commonly reveal glomerulomegaly, mesangial expansion, podocyte -foot process widening, increased extracellular matrix deposition, thickening of the glomerular basement membrane, and variable degrees of tubulointerstitial inflammation and fibrosis [38–42]. Although traditionally considered a benign or slowly progressive condition, recent data suggest that ORG may lead to significant proteinuria and decline in kidney function, especially when metabolic risk factors coexist or remain uncontrolled.
Importantly, obesity also amplifies the impact of other metabolic abnormalities – prediabetes, MASLD, dyslipidaemia, and hypertension – enhancing their deleterious effects on the kidney. This synergistic behaviour explains why obesity serves not only as a primary driver of MKD but also as a critical component in mixed metabolic phenotypes.
The recognition of obesity-related MKD underscores the need for early clinical identification of renal stress in individuals with overweight or obesity, even in the absence of diabetes or overt CKD. Given the potential reversibility of early haemodynamic changes and the benefits of weight reduction, pharmacological metabolic modulation, and lifestyle interventions, early detection represents a crucial opportunity for prevention and disease-modifying therapy.

Prediabetes-Related Metabolic Kidney Disease

Prediabetes represents an intermediate metabolic state between normoglycaemia and overt diabetes, characterised by impaired fasting glucose, impaired glucose tolerance, or elevated glycated haemoglobin according to current diagnostic criteria [43]. Although traditionally viewed as a precursor stage with modest clinical implications, accumulating evidence indicates that prediabetes is not a benign condition. Rather, it constitutes a metabolically active and pathophysiologically relevant state capable of inducing early renal injury through mechanisms that parallel, but do not require, sustained hyperglycaemia [44–46].
Several epidemiological studies have demonstrated a consistent association between prediabetes and an increased risk of incident CKD, reduced eGFR, and elevated albuminuria. In a prospective cohort exceeding 7,000 individuals with nearly nine years of follow-up, both impaired glucose tolerance and elevated HbA1c were independently associated with new-onset CKD, with hazard ratios ranging from 1.13 to 1.39 [44]. These findings have been confirmed by larger population-based analyses, including the REACTION study involving more than 250,000 Chinese adults, where prediabetes was identified as an independent predictor of CKD, particularly among men [47]. Meta-analyses reinforce this association, suggesting that even modest elevations in glucose metabolism confer a measurable increase in renal risk [46].
From a mechanistic perspective, renal injury in prediabetes is driven primarily by insulin resistance, hyperinsulinaemia, and intermittent postprandial hyperglycaemia. These alterations impair podocyte insulin signalling, reduce nephrin expression, and promote cytoskeletal instability, rendering podocytes more vulnerable to detachment and apoptosis [45, 48]. Concurrently, increased proximal tubular sodium-glucose reabsorption diminishes sodium delivery to the macula densa, blunting tubuloglomerular feedback and favouring afferent arteriolar vasodilation – enhancing glomerular hyperfiltration in a pattern similar to early diabetic kidney disease [45, 48].
Oxidative stress also plays a central role. Elevated production of reactive oxygen species, accumulation of advanced glycation end-products, and activation of protein kinase C pathways contribute to endothelial dysfunction, mesangial expansion, and increased glomerular permeability [48]. These changes manifest clinically as low-grade albuminuria and may precede overt abnormalities in eGFR.
Despite this growing evidence, prediabetes is not currently included among the recommended indications for CKD screening in most clinical guidelines [49]. Given the substantial prevalence of prediabetes worldwide and its clear association with early renal injury, incorporating individuals with prediabetes into CKD risk stratification strategies could facilitate earlier detection of kidney involvement and prompt implementation of preventive interventions.

Diabetes-Related Metabolic Kidney Disease

Type 2 diabetes mellitus (T2DM) remains the most common metabolic condition associated with chronic kidney disease worldwide, and diabetic kidney disease (DKD) continues to represent a major cause of end-stage kidney disease [50]. However, within the conceptual framework of Metabolic Kidney Disease, diabetes-related renal injury is understood not as an isolated entity, but as the intensification and culmination of metabolic disturbances that often originate much earlier – during obesity, insulin resistance, and prediabetes. This perspective highlights the continuity of metabolic stress across the glycaemic spectrum and underscores the shared mechanisms that unite DKD with other MKD subtypes.
Hyperglycaemia initiates and amplifies several interrelated pathways that contribute to renal damage. Among the earliest alterations is glomerular hyperfiltration, driven by increased proximal tubular sodium-glucose reabsorption mediated by SGLT2. This reduces solute delivery to the macula densa, blunts tubuloglomerular feedback, and promotes afferent arteriolar vasodilation, thereby increasing intraglomerular pressure [51]. Persistent hyperfiltration accelerates podocyte hypertrophy and detachment – lesions central to the development of albuminuria.
Glucotoxicity exerts direct cellular effects. Chronic exposure to elevated glucose levels induces oxidative stress, mitochondrial dysfunction, and accumulation of advanced glycation end-products (AGEs). These processes trigger mesangial expansion, altered extracellular matrix turnover, and thickening of the glomerular basement membrane [52, 53]. Importantly, lipotoxicity – driven by elevated circulating free fatty acids and ectopic lipid accumulation – amplifies these pathways by promoting endoplasmic reticulum stress, inflammation, and apoptosis in podocytes and tubular cells [54].
Inflammatory and fibrotic pathways further contribute to disease progression. Activation of protein kinase C (PKC), nuclear factor-κB (NF-κB), and transforming growth factor-β (TGF-β) promotes epithelial–mesenchymal transition, interstitial fibrosis, and glomerulosclerosis [55]. These processes often evolve silently for years before clinical manifestations appear, explaining why many patients show evidence of renal structural injury even at the time of diabetes diagnosis.
Although DKD has traditionally been described as a distinct clinical entity, MKD emphasizes that diabetes-related renal injury represents a continuum of metabolic renal stress, rather than a binary state emerging only after hyperglycaemia surpasses diagnostic thresholds. This broader view aligns with epidemiological observations showing that albuminuria, reduced eGFR, and microvascular injury can be detected in a significant proportion of individuals with newly diagnosed diabetes or even during the prediabetic phase.
Recognising diabetes-related MKD within this continuum has practical implications: it highlights the importance of early interventions targeting hyperglycaemia, insulin resistance, RAAS activation, and metabolic inflammation. Moreover, therapies such as SGLT2 inhibitors and GLP-1 receptor agonists – initially developed for glycaemic control – have demonstrated significant renal and cardiovascular protection precisely because they modulate many of these shared metabolic pathways.

MASLD-Related Metabolic Kidney Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is now recognised as a multisystem metabolic disorder that extends well beyond the liver. The recent harmonized definitions and clinical practice guidelines issued jointly by EASL, EASD and EASO [56] underline the strong metabolic underpinnings of MASLD and its close association with insulin resistance, visceral fat accumulation, dyslipidaemia and systemic inflammation. This updated framework emphasizes that MASLD frequently coexists with other metabolic conditions and contributes to end-organ damage, including the kidney.
A growing body of evidence indicates that MASLD is independently associated with chronic kidney disease (CKD). A comprehensive and authoritative review by Bilson, [57] summarized epidemiological and mechanistic data supporting a strong association between MASLD and increased CKD risk, even after adjusting for obesity, diabetes and hypertension. These observations confirm that MASLD is not simply a marker of metabolic syndrome but a condition with its own pathophysiological impact on renal structure and function.
Mechanistically, MASLD promotes renal injury through multiple interconnected pathways. Hepatic steatosis triggers the release of hepatokines (e.g., fetuin-A) and other inflammatory mediators, which aggravate insulin resistance, endothelial dysfunction, and oxidative stress. These systemic disturbances impair glomerular autoregulation and increase susceptibility to hyperfiltration and podocyte stress. Disturbances in lipid metabolism characteristic of MASLD facilitate the accumulation of toxic lipid intermediates, contributing to mitochondrial dysfunction and activation of pro-fibrotic cascades within the kidney.
A further layer of complexity arises from genetic predisposition. Variants such as PNPLA3, TM6SF2 and MBOAT7 – well-established determinants of liver disease severity in MASLD – have been associated with increased renal vulnerability, suggesting shared metabolic and inflammatory pathways between hepatic steatosis and CKD [58]. These data reinforce the concept that renal involvement in MASLD is not solely a consequence of coexisting metabolic abnormalities, but reflects intrinsic pathobiological processes linked to the disease itself.
Meta-analytic data continue to support the association between MASLD and kidney dysfunction. The landmark systematic review by Musso and colleagues [59] remains a frequently cited foundational analysis demonstrating increased CKD prevalence and incidence among individuals with NAFLD. While older, its conclusions align with contemporary findings and highlight persistent mechanistic plausibility across diverse populations.
Recognizing MASLD as a distinct subtype within the broader spectrum of Metabolic Kidney Disease has important clinical implications. Given its high global prevalence and frequent underdiagnosis, incorporating MASLD into CKD risk stratification frameworks may facilitate earlier identification of renal involvement. Furthermore, therapeutic strategies targeting hepatic steatosis – such as GLP-1 receptor agonists, weight reduction and lifestyle interventions – may confer renal benefits even in the absence of overt diabetes. As recent guidelines emphasize [60, 61], a comprehensive approach addressing metabolic dysfunction across organ systems represents a crucial step toward improving long-term outcomes.

Mixed Metabolic Kidney Disease

Mixed Metabolic Kidney Disease represents the convergence of multiple metabolic derangements acting simultaneously on renal structure and function. In clinical practice, this phenotype is increasingly common, reflecting the overlap between obesity, insulin resistance, prediabetes, type 2 diabetes, hypertension, dyslipidaemia and MASLD. Rather than functioning as isolated risk factors, these conditions interact through shared mechanisms that amplify metabolic stress on the kidney, accelerating the transition from early functional changes to established chronic kidney disease [38].
From a pathophysiological standpoint, mixed MKD embodies a state in which haemodynamic, inflammatory, hormonal and lipid-related disturbances reinforce one another. Excess visceral fat accumulation fuels chronic low-grade inflammation and adipokine dysregulation, worsening insulin resistance and promoting hyperinsulinaemia [22]. In parallel, progressive impairments in glucose tolerance intensify tubular sodium-glucose reabsorption, stimulating afferent arteriolar vasodilation and glomerular hyperfiltration [45]. When MASLD coexists, the release of hepatokines and proinflammatory mediators further exacerbates endothelial dysfunction, oxidative stress and microvascular injury [50].
These synergistic mechanisms produce a renal phenotype that is often more severe than the sum of its individual components. Patients with obesity and MASLD, for example, exhibit higher rates of albuminuria and more pronounced declines in eGFR compared with individuals with either condition alone [62]. Similarly, the coexistence of prediabetes or early diabetes with hepatic steatosis and visceral fat accumulation results in more rapid structural changes – mesangial expansion, podocyte stress and tubulointerstitial fibrosis – even when glycaemic abnormalities remain modest [63].
Clinically, mixed MKD is frequently under-recognised. Traditional screening strategies tend to focus on single risk factors – most often diabetes – thereby missing individuals who harbour substantial renal risk due to the cumulative effect of multiple metabolic abnormalities. This oversight is particularly relevant in younger or non-diabetic individuals with obesity and MASLD, in whom early renal involvement may be subtle yet progressive.
Recognising mixed MKD as a distinct and increasingly prevalent phenotype underscores the importance of integrated metabolic assessment in the evaluation of CKD risk. A comprehensive approach – including assessment of adiposity, glycaemic status, hepatic steatosis, blood pressure and lipid profile – allows for earlier identification of individuals at high risk and supports targeted interventions aimed at modulating metabolic stress. Ultimately, the mixed MKD phenotype exemplifies the concept of Metabolic Kidney Disease: a continuum of renal injury shaped not by a single metabolic defect, but by the interplay of multiple overlapping disturbances acting across organ systems. Such multilayered interactions are increasingly documented across metabolic phenotypes, supporting the concept of mixed MKD as a clinically relevant and mechanistically distinct entity.

 

Screening and Clinical Implications

The recognition of Metabolic Kidney Disease (MKD) as a unified conceptual framework has important consequences for screening strategies, particularly in populations traditionally not considered at high risk for chronic kidney disease. Current screening algorithms [64] often prioritise individuals with established type 2 diabetes or long-standing hypertension, overlooking a substantial proportion of patients who exhibit renal involvement driven primarily by obesity, prediabetes, MASLD or combinations thereof. As a result, early stages of metabolic renal stress frequently remain undetected [12] until albuminuria or declines in eGFR become clinically evident.

Integrating MKD-oriented screening into routine nephrology workflows could meaningfully shift clinical practice toward earlier detection, streamlined risk stratification, and more timely initiation of preventive interventions, particularly in metabolically vulnerable individuals.

 

Who Should Be Screened?

Given the burden of metabolic dysfunction in modern populations, screening should extend beyond conventional high-risk groups. Individuals with the following characteristics merit evaluation for possible MKD (Figure 3):

  • Obesity with increased visceral fat accumulation, even in the absence of diabetes or hypertension
  • Prediabetes, particularly in those with impaired glucose tolerance or rising HbA1c
  • MASLD, regardless of glycaemic status, as emphasised by recent international guidelines [56]
  • Family history of type 2 diabetes, CKD or early cardiovascular disease [12]
  • Coexistence of multiple metabolic abnormalities, including dyslipidaemia, hyperuricaemia or elevated liver enzymes

In these individuals, glomerular hyperfiltration and endothelial dysfunction – hallmarks of early MKD – may precede measurable reductions in kidney function, highlighting the importance of timely assessment.

It is important to acknowledge that current CKD guidelines still do not formally recommend routine kidney screening in individuals with prediabetes or MASLD. The evidence supporting such an approach is growing, yet prospective validation and consensus-driven recommendations are still needed to define optimal screening thresholds and intervals.

 

What Tests Should Be Performed?

A pragmatic and clinically accessible initial evaluation may include:

  • Estimated glomerular filtration rate (eGFR) using creatinine or combined creatinine-cystatin C equations
  • Urine albumin-to-creatinine ratio (ACR) to detect early glomerular injury
  • Assessment of metabolic health, including fasting glucose, HbA1c, lipid profile, uric acid and markers of hepatic steatosis
  • Imaging, where appropriate, to evaluate hepatic steatosis or adipose distribution

Importantly, mild elevations in ACR or upward drifts in eGFR (suggesting glomerular hyperfiltration) should not be dismissed as normal variants in individuals with metabolic abnormalities, but rather considered potential markers of MKD.

 

Clinical Integration

Incorporating MKD into routine practice involves adopting a more comprehensive view of metabolic health, recognising that renal involvement can occur long before diagnostic thresholds for diabetes or CKD are reached. Early identification enables timely implementation of therapeutic strategies – such as weight optimisation, dietary interventions, metabolic modulation and blood pressure control – that mitigate renal stress and may alter longterm trajectories.

Screening includes estimated glomerular filtration rate (eGFR)
Figure 3. Recommended screening tests for chronic kidney disease (CKD). Screening includes estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR). These tests are recommended for individuals with obesity, prediabetes, hypertension, T2DM, cardiovascular disease, prior AKI, or age >60 years.

 

Conclusions

Metabolic Kidney Disease represents an important conceptual and clinical evolution in our understanding of the interplay between metabolic dysfunction and renal health. This framework offers clinicians a more actionable understanding of metabolic renal risk, promoting earlier recognition of kidney involvement and more timely implementation of prevention strategies. By integrating obesity, prediabetes, type 2 diabetes, MASLD and mixed phenotypes within a single conceptual framework, MKD offers a more coherent representation of the pathophysiological processes driving early kidney injury in contemporary populations. This approach emphasises the central role of adipose tissue dysfunction, insulin resistance, chronic low-grade inflammation and lipid dysregulation as shared mechanisms across the metabolic spectrum.

Recognising MKD broadens opportunities for earlier diagnosis, particularly in individuals who would not be captured by traditional CKD screening criteria. It also underscores the need for multidimensional management strategies that address metabolic dysfunction across organ systems, rather than focusing solely on glycaemic control or blood pressure.

As the prevalence of metabolic disorders continues to rise globally, incorporating the MKD framework into clinical practice may offer a path toward more effective prevention and improved longterm renal and cardiovascular outcomes. This review highlights the importance of a unified, metabolically informed approach to kidney health – an approach that aligns with modern evidence and reflects the complex, interconnected nature of metabolic disease.

 

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Trend dell’eGFR dopo l’inizio della terapia con empagliflozin in una coorte di pazienti con diabete e CKD stadio 3: è davvero un problema? TEMPOREALE real-world study

Pubblicato il Scarica PDF

Dr. Maria Elena Malighetti

DOI: 10.69097/42-06-2025-04

Maria Elena Malighetti1, Antonio Belviso2, Diana Donini3, Paolo Erpoli4, Marco Laneri5, Laura Molteni6, Eva Palmieri7, Giovanni Saccà8, Roberta Serra9

1 Casa di Cura Ambrosiana, Cesano Boscone (MI), Italy
2 Ambulatorio di diabetologia ASST Lecco, Lecco, Italy
3 Casa di Cura San Clemente, Fondazione Teresa Camplani (MN), Italy
4 SD Malattie Endocrine- Diabetologia ASST Valle Olona (VA), Italy
5 Clinica San Carlo, Paderno Dugnano (MI), Italy
6 Centro Ambulatoriale di Diabetologia, Endocrinologia e Malattie Metaboliche Ospedale di Erba (CO), Italy
7 UO di Medicina, Ospedale Saronno (VA), Italy
8 Ambulatorio di Diabetologia SC Medicina Interna, Ospedale di Melegnano (MI), Italy
9 Fondazione Giuseppina Brunenghi ONLUS, ASST Castelleone (CR), Italy

Corrispondenza a:
Dr. Maria Elena Malighetti
Casa di Cura Ambrosiana
Piazza Moneta, n°1
20090, Cesano Boscone (MI), Italy
Tel: 3474243484
E-mail: mariaelena.malighetti@gmail.com

 

Abstract

Introduzione. La malattia renale cronica (MRC) è una delle principali complicanze del diabete di tipo 2 (T2D), con conseguente aumento del rischio cardiovascolare. Empagliflozin, un inibitore del cotrasportatore sodio-glucosio di tipo 2 (SGLT2i), ha dimostrato benefici cardiorenali in studi clinici, ma i dati real-world nei pazienti con MRC moderata sono limitati.
Obiettivi. Valutare retrospettivamente le variazioni della velocità di filtrazione glomerulare stimata (eGFR) dopo avvio della terapia con empagliflozin in pazienti con T2D e MRC di stadio KDIGO 3A e 3B, con focus sull’insorgenza e sull’impatto del declino precoce dell’eGFR (“dip”) sugli esiti metabolici e sui fattori di rischio cardiovascolare associati.
Metodi. Studio multicentrico su pazienti adulti con T2D con eGFR 30-60 mL/min/1,73 m² che hanno iniziato la terapia con empagliflozin tra ottobre 2023 e aprile 2024. I parametri clinici sono stati raccolti al basale, a 1 mese e a 6 mesi. Analisi per sottogruppi sono state condotte in base allo stadio della MRC e al dip (declino eGFR >10% a 1 mese).
Risultati. Tra 166 pazienti, il 21,6% ha sperimentato il dip. Complessivamente, l’eGFR è aumentato di 2,75 mL/min/1,73 m² a 6 mesi (p<0,0001), con un miglioramento più pronunciato nei pazienti “non-dipper” e nei pazienti con MRC 3A. Nei pazienti “dipper”, l’eGFR ha registrato un parziale recupero. L’HbA1c è diminuita di circa 4 mmol/mol (nonostante l’uso concomitante di farmaci ipoglicemizzanti fosse diminuito all’inizio della terapia con empagliflozin), il peso di circa 2 kg e la pressione arteriosa sistolica di circa 4 mmHg. L’interruzione del trattamento con empagliflozin si è verificata nel 4,2% dei pazienti, principalmente a causa di infezioni genitourinarie. Discussione. Empagliflozin è risultato associato a stabilizzazione o miglioramento della funzionalità renale con moderati benefici metabolici nei pazienti con T2D e MRC di stadio 3. Il calo dell’eGFR è stato poco frequente e transitorio, a supporto dell’uso di empagliflozin in questa popolazione in contesti reali.

Parole chiave: diabete di tipo 2, malattia renale cronica, empagliflozin, calo dell’eGRF, normale pratica clinica

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Chronic kidney disease (CKD) is a pathological condition secondary to the loss of kidney function and is characterized by a slow and progressive evolution, with a reduction in estimated glomerular filtration rate (eGFR) and/or the appearance of albuminuria. CKD affects approximately 800 million people worldwide and it is associated with an increased risk of cardiovascular disease and mortality [1–3].

Cardiorenal complications are the main cause of mortality in patients with type 2 diabetes (T2D): the presence of shared cardiovascular risk factors, as well as the well-known neurohormonal activation, inflammation, and oxidative stress, may be part of the pathophysiology that explains this complex triad [4].

The management of CKD is complex due to the multifactorial nature of the disease and, in general, the aim of care is slowing its progression to avoid dialysis or kidney transplantation, responsible for a dramatic impact on quality of life, morbidity and mortality, as well as on the costs associated with renal replacement therapy [5, 6].

CKD, including its progression to end-stage renal disease, is independently associated with an increased risk of death, cardiovascular events, and hospitalization [7].

While CKD is generally considered progressive and irreversible, new evidence suggests that sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can slow or even potentially reverse certain aspects of CKD, particularly in patients with T2D [8–13].

These medications can reduce albuminuria, a key indicator of kidney damage, and improve overall kidney function. In particular, SGLT2i represent a new effective treatment option for kidney disease in patients with T2D, and its use is recommended in patients with diabetic and non-diabetic nephropathy, up to a GFR of 20 ml/min for the effect on albuminuria and the slowing of the decline in renal function [14–17].

Empagliflozin is currently regarded as one of the SGLT2 inhibitors with the most extensive evidence supporting its cardiovascular benefits, especially in lowering the risk of cardiovascular death and hospitalization due to heart failure [18, 19]. It is indicated as an adjunct to diet and exercise for the treatment of type 2 diabetes in adults and children aged 10 years and older. It can be used as monotherapy when glycemic control is inadequate and metformin is not suitable due to intolerance, or in combination with other glucose-lowering agents. It is also indicated in adults for the treatment of symptomatic chronic heart failure and for the treatment of CKD [19]. Indeed, in phase III clinical studies, empagliflozin has determined a significant reduction in the onset or worsening of kidney disease and in the relative risk of increased albuminuria compared to placebo. Therefore, the use of empagliflozin was associated with a slower progression of renal disease compared to placebo, when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events [19].

In addition, in a post hoc analysis of the EMPA-REG OUTCOME clinical trial, patients were divided into three groups based on the change in eGFR from baseline at four week; empagliflozin demonstrated that the decrease in eGFR, also called “eGFR dip”, which occurs soon after the start of treatment and which has often raised concerns in clinical practice as it may predispose patients to acute kidney injury, is indeed transient and did not have a significant impact on the treatment effect of empagliflozin on cardiovascular death, hospitalization for heart failure and renal disease. Even in T2D patients with more advanced renal disease and/or on diuretic therapy, despite being more likely to have a decrease in eGFR greater than 10% following treatment with empagliflozin, the reduction in cardiovascular and renal outcomes was not altered, supporting the treatment [20].

In the EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) trial, empagliflozin reduced cardiorenal outcomes by 28% in a diverse population of over 6,000 patients with CKD, of whom over 50% without T2D [21]. Data on chronic eGFR slopes were consistent with a benefit at any eGFR or urinary albumin:creatinine ratio level, potentially delaying kidney replacement therapy by 2-27 years, depending on baseline eGFR [21].

Following pivotal trials, it is important to assess transferability of results in the real world. Therefore, we conducted an observational study to assess slopes of eGFR levels after 1 and 6 months from the first prescription of empagliflozin in our patients. A cohort of adult T2D patients with stage 3 CKD according to KDIGO definitions was identified [2]. Clinical outcomes and modifications in type 2 diabetes therapy under routine clinical practice were also evaluated. The analysis was conducted not only on the overall population of patients treated with empagliflozin during the study period, but also with a focus on two distinct stages of CKD (stage 3A and 3B, as defined by KDIGO), and based on the presence of an “eGFR dip” (defined as a reduction in eGFR greater than 10% after initiating empagliflozin therapy).

 

Methods

This was a multicenter, retrospective, observational, pre-post cohort study conducted in 9 Italian diabetes outpatient clinics operating in the context of the national health system.

Eligibility criteria were: age ≥ 18 years; T2D diagnosis; eGFR values ranging between 30 and 60 ml/min (corresponding to KDIGO stage 3 CKD, measured and confirmed after a minimum of 3 months; and first prescription of empagliflozin between October 2023 and April 2024; signature of informed consent for authorizing the use of retrospective data according to Italian regulations.

The decision to start treatment with empagliflozin was based on clinical judgment and was independent of the subsequent decision to include patients in the retrospective study.

Diagnosis of Latent Autoimmune Diabetes in Adults (LADA) or type 1 diabetes, active neoplasms or treatment for malignant neoplasms in the previous 5 years, previous SGLT2i treatment, and lack of signed informed consent represented exclusion criteria.

All eligible patients were consecutively identified in the electronic medical records (EMRs) of each participating center. Patient data were extracted from EMRs.

Baseline was represented by the date of the first prescription of empagliflozin. Baseline data collected included: age, sex, ethnicity, duration of T2D, eGFR, glycated haemoglobin (HbA1c), body weight, body mass index (BMI), blood pressure, lipid profile, presence of comorbidities, glucose-lowering and antihypertensive therapy before and at the start of empagliflozin.

In terms of follow-up data, information on therapy discontinuation and eGFR was collected after 1 and 6 months. After 6 months, BMI, HbA1c, blood pressure, and changes in glucose-lowering therapy were also collected.

eGFR was calculated using the CKD-EPI formula (version 2021). According to KDIGO guidelines, CKD 3A was defined as eGFR values between 45 and 59 ml/min/1.73m2, while CKD 3B was defined as eGFR values between 30 and 44 ml/min/1.73m2.

Statistical methods

Due to the observational nature of this study, all patients meeting the inclusion criteria in the study period were considered, and no formal sample size calculation was performed.

The primary endpoint was represented by eGFR levels after 1 and 6 months of treatment with empagliflozin, administered according to clinical practice.

Secondary endpoints included: discontinuation of treatment with empagliflozin after 1 and 6 months from the start of therapy and reasons for discontinuation, changes from baseline to 6 months in the mean levels of creatinine, HbA1c, BMI, body weight, systolic (SBP) and diastolic (DBP) blood pressure, and changes in the likelihood of being treated with specific pharmacological classes of glucose-lowering drugs from baseline to 6 months.

Descriptive data were reported as mean and standard deviation in case of continuous variables, or proportions in case of categorical variables.

Paired t-test derived from linear mixed models for repeated measurements was applied for within-group pre-post comparisons. Results were expressed as estimated mean or estimated mean difference from T0 with their 95% confidence interval (95% CI). Proportions of patients treated with specific pharmacological classes were evaluated using mixed effects models. The results were expressed as probability of being treated and as Odds Ratio (OR) with relative 95%CI, expressing the likelihood of being treated after 6 months from the start of empagliflozin as compared to baseline.

Pre-post comparisons were performed on the overall population and in different predefined subgroups representing different renal impairment profiles:

– dippers (i.e. patients with at least 10% eGFR levels reduction after 1 month from the first prescription of empagliflozin)

– non-dippers

– CKD 3A stage

– CKD 3B stage

– dippers within CKD 3A stage

– non-dippers within CKD 3A stage

– dippers within CKD 3B stage

– non-dippers within CKD 3B stage

The primary analysis regarded the population overall and by dip phenomenon. Secondary exploratory analyses were focused on the other pre-defined subgroups.

 

Results

Overall, 166 subjects were identified, all starting empagliflozin between October 2023 and April 2024. All patients were treated with 10 mg according to the Summary of Product Characteristics.

Baseline patient characteristics, overall and by pre-defined subgroups, are reported in Table 1. Dippers were 35 (21.1% of cases with data available). Compared to non-dippers, dippers were more often female and had a higher prevalence of hypertension. Furthermore, higher proportions of dippers vs. non-dippers were treated with ACEi or diuretics (Table 1).

Overall, 96 subjects (57.8% of those with available data) had CKD stage 3A, while 70 (42.2%) had CKD stage 3B at baseline. Compared to individuals with CKD 3A, those with CKD 3B were older on average and showed a higher use of ACE inhibitors (Supplementary Table 1).

Mean estimated eGFR significantly improved by 2.75 ml/min/1.73m2 from baseline to 6 months in the overall population (p < 0.0001) (Table 2).

In the dippers’ subgroup, eGFR levels decreased from 45.2 to 37.5 ml/min/1.73m2 in the first month (p<0.0001), but then increased to 42.5 ml/min/1.73m2 after 6 months (Table 2) (p = 0.04).

In the non-dippers’ subgroup, eGFR levels increase was statistically significant both at 1 month (from 46.2 to 47.8; +1.62 ml/min/1.73m2; p = 0.001) and at 6 months (from 46.2 to 50.5; +4.26 ml/min/1.73m2; p < 0.0001) (Table 2).

In CKD 3A group eGFR levels significantly increased by 3.6 ml/min/1.73 m2 after 6 months of treatment with empagliflozin (p < 0.0001), while no significant changes were documented in CKD 3B group (p = 0.30) (Supplementary Table 2).

Among patients in the CKD 3A group, 20 out of 96 (20.8%) were classified as dippers, compared with 15 out of 70 (21.4%) in the CKD 3B group. Considering the dippers group, eGFR declined by 9.5 ml/min/1.73 m2 in CKD 3A (starting from estimated baseline levels of 49.7) and by 5.3 ml/min/1.73 m2 in CKD 3B (starting from estimated baseline levels of 39.2) after 1 month. In both groups eGFR levels showed a partial recovery at 6 month (Figure 1). No episode of acute kidney injury occurred. Small but consistent benefits were found in terms of metabolic control: HbA1c was reduced by about 3-4 mmol/mol in all subgroups (Table 2 and Supplementary Table 2). These results were obtained in spite of the likelihood of being treated with any glucose-lowering drugs was reduced by 58% (OR = 0.42; 95%CI 0.29-0.63) (Supplementary Table 3). In more details, significant reductions in the concomitant use of metformin and sulphonylureas were documented. Trends of reduction in the prevalence of use of DPP-IVi and basal insulin was also reported. Use of GLP-1 RA was unchanged. Other classes were prescribed in less than 10% of patients before starting empagliflozin and varied marginally (Supplementary Table 3).

Regarding cardiovascular risk factors, BMI, SBP, and DBP markedly decreased after 6 months of treatment with empagliflozin, although statistical significance was not always reached due to small size of the sample. The only exception was the CKD 3B group where BMI and blood pressure were unchanged after 6 months (Table 2 and Supplementary Table 2).

Patients who discontinued empagliflozin after 1 month were 3, all for genitourinary infections. After 6 months, 4 additional patients discontinued (2 for genitourinary infections, 1 for poor compliance, 1 for hospitalization). Overall, the incidence rate of treatment discontinuation for genitourinary infections was 0.15 patient-months.

Overall Dippers Non-dippers p-value
N 166 35 127
Age (years) 72.6 ± 9.5 74.2 ± 7.8 72.2 ± 10.0 0.29
Sex (%):
Men 99 (59.6) 14 (40.0) 82 (64.6) 0.009
Women 67 (40.4) 21 (60.0) 45 (35.4)
Ethnicity (%):
Caucasian 163 (98.2) 35 (100.0) 124 (97.6) 0.36
Afro-american 3 (1.8) 0 (0.0) 3 (2.4)
T2D duration (years) 12.1 ± 9.3 14.8 ± 10.2 11.4 ± 8.9 0.05
At least 1 glucose-lowering drug (except empagliflozin) (%) 117 (70.5) 30 (85.7) 83 (65.4) 0.02
Median [min-max] number of glucose-lowering drugs prescribed (N) 1 [0-4] 1 [0-2] 1 [0-4] 0.18
Treated with (%):
Diet Only 49 (29.5) 5 (14.3) 44 (34.6) 0.05
Oral Agents and/or GLP1 84 (50.6) 20 (57.1) 62 (48.8)
Insulin 12 (7.2) 5 (14.3) 6 (4.7)
Both 21 (12.7) 5 (14.3) 15 (11.8)
Hypertension (%) 138 (83.1) 33 (94.3) 101 (79.5) 0.04
At least 1 antihypertensive drug (%) 89 (53.6) 25 (71.4) 61 (48.0) 0.01
Median [min-max] number of antihypertensive agents prescribed (N) 1 [0-5] 2 [0-5] 0 [0-5] 0.006
Treated with (%):  
ACEi 33 (19.9) 12 (34.3) 20 (15.7) 0.01
ARBs 40 (24.1) 8 (22.9) 30 (23.6) 0.92
Beta-blockers 37 (22.3) 11 (31.4) 24 (18.9) 0.11
Ca-antagonists 38 (22.9) 12 (34.3) 24 (18.9) 0.05
Diuretics 49 (29.5) 17 (48.6) 29 (22.8) 0.003
Alpha-blockers 5 (3.0) 2 (5.7) 3 (2.4) 0.31
Others 16 (9.6) 4 (11.4) 12 (9.4) 0.73
Dyslipidemia (%) 107 (64.5) 23 (65.7) 81 (63.8) 0.83
Total cholesterol (mg/dl) 163.4 ± 41.7 158.5 ± 35.1 165.8 ± 43.6 0.43
LDL-cholesterol (mg/dl) 85.2 ± 36.3 82.8 ± 32.6 86.7 ± 37.7 0.62
HDL-cholesterol (mg/dl) 47.4±12.1 49.3±13.1 47.0±11.8 0.38
Triglycerides (mg/dl) 150.4±90.8 135.9±57.9 155.0±99.2 0.32
Heart failure (%) 40 (24.1) 10 (28.6) 30 (23.6) 0.55
Table 1. Baseline characteristics. Data are mean and standard deviation, median and min-max values, or frequency and proportion. *T-test or Mann-Whitney U-test (continuous variables) or chi-square test (categorical variables). 
Endpoints Visit OVERALL

(N = 166)

 DIPPERS

(N = 35)

 NON-DIPPERS

(N = 127)
    Estimated mean levels (95%CI) Estimated mean difference from T0 and 95% CI p-value Estimated mean levels (95%CI) Estimated mean difference from T0 and 95% CI p-value Estimated mean levels (95%CI) Estimated mean difference from T0 and 95% CI p-value
eGFR (ml/min/1.73m2) T0 45.88

(44.63;47.14)

 – – 45.2 (42.49;47.91) – – 46.22 (44.8;47.64) – –
T1 45.49

(43.75;47.22)

 -0.4

(-1.44;0.64)

 0.45 37.53

(34.05;41)

 -7.67

(-9.52;-5.83)

 <0.0001 47.84 (46.02;49.66) 1.62

(0.65;2.59)

 0.001
T6 48.63

(46.66;50.6)

 2.75

(1.49;4)

 <0.0001 42.57 (38.48;46.67) -2.63

(-5.13;-0.12)

 0.04 50.48 (48.32;52.63) 4.26

(2.93;5.58)

 <0.0001
Creatinine (mg/dl) T0 1.28

(1.21;1.35)

 – – 1.2

(1.05;1.35)

 – – 1.31

(1.23;1.38)

 – –
T1 1.34

(1.27;1.41)

 0.06

(0.02;0.1)

 0.006 1.44

(1.3;1.59)

 0.24

(0.16;0.33)

 <0.0001 1.31

(1.24;1.39)

 0.0

(-0.04;0.05)

 0.85
T6 1.35

(1.3;1.4)

 0.07

(0;0.13)

 0.05 1.45

(1.34;1.56)

 0.25

(0.12;0.39)

 0.0003 1.31

(1.25;1.37)

 0.0

(-0.07;0.08)

 0.89
HbA1c (mmol/mol) T0 55.56

(53.73;57.4)

 – – 53.63 (49.67;57.6) – – 55.81 (53.73;57.89) – –
T6 51.4

(50.09;52.71)

 -4.17

(-5.57;-2.77)

 <0.0001 50.88 (48.09;53.66) -2.76

(-5.74;0.22)

 0.07 51.4 (49.91;52.89) -4.41

(-6;-2.82)

 <0.0001
BMI (Kg/m2) T0 28.78

(28.04;29.52)

 – – 28.57 (26.97;30.18) – – 28.79 (27.95;29.64) – –
T6 28.17

(27.43;28.92)

 -0.6

(-0.96;-0.25)

 0.001 27.61 (25.99;29.22) -0.97

(-1.73;-0.21)

 0.01 28.3 (27.45;29.15) -0.5

(-0.9;-0.09)

 0.02
Body weight (kg) T0 79.54 (76.97;82.1) – – 77.32 (71.87;82.77) – – 79.81 (76.95;82.67) – –
T6 77.42 (75.02;79.81) -2.12

(-2.73;-1.51)

 <0.0001 74.3 (69.21;79.38) -3.02

(-4.32;-1.72)

 <0.0001 77.97 (75.3;80.64) -1.84

(-2.53;-1.15)

 <0.0001
SBP (mmHg) T0 134.57

(132.1;137.05)

 – – 138.86 (133.48;144.24) – – 133.06 (130.24;135.89) – –
T6 130.62

(128.32;132.92)

 -3.95

(-6.59;-1.32)

 0.003 133.71 (128.79;138.63) -5.15

(-10.87;0.57)

 0.08 129.61 (126.99;132.22) -3.45

(-6.48;-0.43)

 0.03
DBP (mmHg) T0 78.01

(76.64;79.37)

 – – 79.71 (76.75;82.68) – – 77.51 (75.96;79.07) – –
T6 76.16

(74.66;77.66)

 -1.85

(-3.61;-0.09)

 0.04 78.62 (75.45;81.8) -1.09

(-4.9;2.72)

 0.57 75.36 (73.68;77.05) -2.15

(-4.16;-0.13)

 0.04
Table 2. Continuous endpoints – Results of longitudinal linear mixed models for repeated measurements – Population overall and by dip phenomenon. p-values = paired t-test derived from linear mixed models for repeated measurements. Statistically significant p-values (p < 0.05) are in bold.
Figure 1. Trend of eGFR after 1 and 6 months of therapy with empagliflozin in T2D patients according to CKD class and presence of eGRF dip.
Figure 1. Trend of eGFR after 1 and 6 months of therapy with empagliflozin in T2D patients according to CKD class and presence of eGRF dip.

 

Discussion

Consistently with clinical trials, this real-world study confirms that empagliflozin treatment in patients with T2D and stage 3 CKD is associated with a stabilization or even improvement of eGFR over six months of follow-up. eGFR dip phenomenon regards about one fifth of patients attending Italian diabetes clinics, but renal function tends to recover and improve over time, according to findings deriving from trials such as EMPA-REG OUTCOME and EMPA-KIDNEY [10, 13, 19]. In our centers, empagliflozin was associated with a significant increase in eGFR mean levels of 2.75 l/min/1.73 m2 after 6 months. The analysis also documented that:

– the dip phenomenon was transient; after 6 months, even in these patients eGFR levels were higher than after 1 month of therapy.

– the eGFR dip was similarly frequent in the CKD 3A (21.3%) and in CKD 3B (22.1%).

– eGFR trend was similar after 6 months in the 3A and 3B KDIGO classes, despite the different mean levels recorded at baseline and at follow-up.

– eGFR trend of dippers and non-dippers was dissimilar in the two CKD classes: after 6 months, eGFR values in dippers returned to baseline levels and were similar to those of non-dippers in the CKD 3B subgroup, whereas they remained lower than baseline and markedly lower than non-dippers in the CKD 3A subgroup.

– Mild but consistent benefits were obtained in terms of secondary outcomes: after 6 months, HbA1c was reduced by about 4 mmol/mol, weight by 2 kg, SBP by 4 mmHg, and DBP by 2 mmHg (all p < 0.05).

Our findings suggest that patients experiencing an eGFR dip ≥ 10% within the first month of empagliflozin therapy may represent a clinically more vulnerable subgroup from a hemodynamic standpoint. In our cohort, dippers were more frequently of female gender and more frequently had hypertension. Furthermore, higher proportions of dippers vs. non-dippers patients were treated with ACEi or diuretics, i.e. factors that may reflect increased susceptibility to intraglomerular pressure shifts [19]. Nevertheless, the partial recovery of eGFR observed at 6 months in this group supports the interpretation of the dip as a functional and transient hemodynamic adjustment rather than a true renal injury. These observations highlight the importance of careful clinical assessment and monitoring in patients potentially more prone to hemodynamic fluctuations, without necessarily withholding the cardio-renal benefits of SGLT2 inhibition [19, 20].

When stratifying by CKD severity, patients with CKD stage 3A showed a statistically significant increase in eGFR, whereas those with stage 3B maintained stable kidney function without significant deterioration. These findings align with the known efficacy of empagliflozin across a broad range of baseline renal function and reinforce guideline recommendations endorsing its use down to eGFR levels of 20 mL/min/1.73m² [2, 10, 17, 22].

Beyond kidney function, empagliflozin use was associated with favourable metabolic and cardiovascular risk profiles: HbA1c was modestly but significantly reduced despite a decrease in concomitant use of other glucose-lowering agents, including metformin and sulphonylureas. It is known that in CKD, SGLT2i only modestly reduces HbA1c due to diminished effects on renal glucose excretion. Effects of SGLT2i on sodium excretion and plasma volume may be to some degree uncoupled from their glycemic effects, at least in the context of CKD [20].

Moreover, body weight and blood pressure tended to decrease, although changes were less evident in patients with more advanced CKD (stage 3B). These metabolic improvements further contribute to the cardiorenal benefits of empagliflozin observed in clinical trials [10–13].

In patients with T2D and chronic kidney disease (CKD) stage 3A or 3B, dedicated prospective clinical trials and meta-analyses reported that SGLT2i reduce SBP and DBP by a similar amount compared with patients with normal renal function [23].

In terms of implications for clinical practice, the study underlines that: it is important to start empagliflozin as early as possible, as also reported in the post hoc of EMPA-KIDNEY [21]; therapy with empagliflozin should be prescribed even if the eGFR is already reduced because it delays the progression of the decline in renal function; initial drop of eGFR regards a small proportion of patients and is generally transient [19, 20]. Furthermore, treatment discontinuation is low and mostly related to genitourinary infections, consistent with known safety profiles of SGLT2i. Importantly, no episodes of acute kidney injury were reported, even among dippers, highlighting the safety of empagliflozin in this population. Therefore, our study extends the evidence on empagliflozin’s beneficial effects on renal function and metabolic control in routine clinical practice in patients with T2D and moderate CKD. This supports the integration of empagliflozin into standard care to slow CKD progression, reduce cardiovascular risk, and potentially delay the need for renal replacement therapy [24, 25].

 

Strengths and limitations

The main strength of this study lies in the ability to evaluate outcomes of routine clinical practice in a multicenter real-world setting, using data collected from EMRs, and to assess their consistency – or discrepancy – with evidence from randomized clinical trials.

Limitations include retrospective design, small sample size, lack of longitudinal follow-up beyond 6 months, use of potentially confounding medications, and the lack of a control group.  In addition, the lack of follow-up data on albuminuria limited our ability to interpret the longitudinal results in terms of KDIGO classes. This was due to albuminuria being measured only once per year in usual care, whereas eGFR is assessed twice per year. In addition, only episodes of genitourinary symptoms resulting in treatment discontinuation were collected; less severe events were not recorded limiting the full evaluation of this important safety issue in our clinical practice. Future prospective studies with longer follow-up are warranted to confirm sustained renal benefits and to explore empagliflozin effects in more advanced CKD stages.

 

Conclusion

Despite reduced glucose-lowering efficacy at lower GFR levels, empagliflozin remains clinically valuable for patients with T2D and GFR between 30 and 60 ml/min/1.73m², primarily due to its proven cardiorenal protective effects. The eGFR dip phenomenon regards about one fifth of patients with CKD stage 3 and is transient, although eGFR values remain slightly lower than baseline after 6 months in patients with CKD 3A stage.

 

Supplementary Materials

 

Bibliography

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  13. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377:644-657. https://doi.org/10.1056/NEJMoa1611925.
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  25. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659-663. https://doi.org/10.1001/archinte.164.6.659.

Il progetto PIRP: un’intuizione di vent’anni fa, oggi più che mai attuale

Pubblicato il Scarica PDF

Antonio Santoro

DOI: 10.69097/42-05-2025-01

Antonio Santoro, Dino Gibertoni, Vittorio Albertazzi, Andrea Buscaroli, Simonetta Cimino, Gabriele Donati, Enrico Fiaccadori, Mariacristina Gregorini, Gaetano La Manna, Emanuele Mambelli, Renato Rapanà, Roberto Scarpioni, Alda Storari, Annalisa Zucchelli, Marcora Mandreoli, Comitato scientifico del progetto PIRP

Corrispondenza a:
Antonio Santoro
Casa di Cura Villa Toniolo, Via Toscana n. 34, Bologna
E-mail: a.santoro.nefro@gmail.com

 

Abstract

Il Progetto PIRP (Prevenzione Insufficienza Renale Progressiva), nato in Emilia-Romagna all’inizio degli anni 2000, nasceva con la finalità di creare una rete tra medici di medicina generale e nefrologi, volta a identificare precocemente la malattia renale cronica (MRC), rallentarne la progressione e migliorare gli esiti clinici.
Il progetto ha visto varie fasi: una fase formativa per i medici di base, la creazione di ambulatori dedicati e la realizzazione di un registro informatico regionale, che oggi include oltre 38.000 pazienti. I risultati hanno mostrato una riduzione della progressione della MRC, un minor accesso urgente alla dialisi e un miglior controllo delle comorbidità.
Il PIRP si distingue dal PDTA nazionale sulla MRC per il suo approccio operativo e territoriale, basato su dati reali e co-gestione multidisciplinare, mentre il PDTA rappresenta un quadro normativo generale.
Il progetto ha prodotto modelli predittivi (come il CT-PIRP), ha ispirato studi europei comparativi e oggi rappresenta un modello di sanità integrata, utile per l’applicazione di farmaci nefroprotettivi e intelligenza artificiale.
A vent’anni dalla sua nascita, il PIRP resta un esempio di medicina proattiva e collaborativa, anticipando i moderni paradigmi di “population health management”.

Parole chiave: Malattia Renale Cronica, Prevenzione, Integrazione territoriale, Registro clinico, Intelligenza artificiale

Introduzione

Quando, all’inizio degli anni Duemila, la Regione Emilia-Romagna decise di avviare il progetto Prevenzione Insufficienza Renale Progressiva (PIRP), l’idea era semplice ma rivoluzionaria: costruire una rete stabile tra medici di medicina generale (MMG) e nefrologi per intercettare precocemente la Malattia Renale Cronica (MRC), rallentarne la progressione e migliorare gli esiti clinici.
All’epoca, il concetto stesso di “chronic care model” era in fase di sperimentazione, e pochi sistemi sanitari avevano strumenti strutturati per la presa in carico del paziente nefropatico prima della dialisi.

A vent’anni di distanza possiamo dire che quell’intuizione è stata lungimirante e ha prodotto evidenze concrete, alcune delle quali hanno anticipato temi oggi al centro della nefrologia europea e mondiale.

 

Il progetto PIRP

Il progetto nasceva con un carattere prevalentemente clinico-assistenziale [1] e prevedeva tre diverse fasi: una progettuale, una formativa ed infine una attuativa (Figura 1).

La fase formativa veniva rivolta soprattutto ai MMG per il corretto e tempestivo riconoscimento della popolazione a rischio, e per l’implementazione delle varie strategie (modificazione stile di vita, correzione dei fattori di rischio modificabili) e terapie che si sono dimostrate efficaci nel ridurre lo sviluppo e l’evoluzione della MRC e prevenirne le complicanze. Venivano effettuati in tutte le province seminari volti a sottolineare tutti gli aspetti della patologia renale ed i fattori coinvolti nella progressione delle nefropatie. Si proseguiva con l’implementazione da parte dei Laboratori Analisi della Regione delle equazioni di calcolo per la valutazione del filtrato glomerulare e dei metodi per la determinazione dell’albuminuria/proteinuria, al fine di facilitare il riconoscimento dei pazienti con deficit funzionale renale anche iniziale e stadiarne lo stato di compromissione renale. Inoltre veniva realizzato un software dedicato alla raccolta dati e che servisse come Registro informatizzato (Registro PIRP) per seguire nel tempo l’evoluzione clinica dei pazienti che entravano nel progetto.

La fase attuativa che ha fatto seguito alla fase formativa ha visto l’apertura di ambulatori espressamente dedicati alla cura e alla gestione dell’insufficienza renale progressiva da parte delle UOC di Nefrologia. Agli ambulatori PIRP con accesso diretto tramite CUP vengono affidati diversi compiti: i) corretto inquadramento del paziente, ii) valutazione del grado di MRC; iii) valutazione delle comorbidità, iv) programmazione di indagini di completamento o ricovero specialistico; v) stima del ritmo di progressione individuale della nefropatia e analisi delle possibili soluzioni terapeutiche personalizzate. A seconda del grado di MRC e della presenza/assenza di fattori comorbidi il paziente veniva e viene riaffidato alle cure del MMG (pazienti con MRC ai primi stadi e assenza di comorbidità) oppure preso progressivamente in carico dall’équipe nefrologica (stadi di maggiore gravità). In ogni fase vi è sempre una co-gestione del paziente oltre che con il MMG anche con altri specialisti, cardiologi, diabetologi, ecc.

Fasi progettuali del progetto PIRP
Figura 1. Fasi progettuali del progetto PIRP: fase di progettazione, fase formativa e di sviluppo del software del Registro e fase attuativa che continua ancora ora nel 2025.

 

Un registro clinico-epidemiologico unico in Italia

Il PIRP non è solo un programma assistenziale, ma anche una piattaforma di dati clinici senza eguali in Italia.
Ad oggi oltre 38.000 pazienti con MRC in fase conservativa sono stati arruolati e seguiti nel tempo da 13 Unità di Nefrologia della Regione, per un totale di 178.000 visite nefrologiche e con il collegamento sistematico ai database amministrativi (per ricoveri ospedalieri, mortalità, evento dialisi, evento trapianto renale).
Questa infrastruttura ha permesso studi osservazionali che hanno evidenziato aspetti relativi alla MRC:

  • Eccesso di mortalità attribuibile alla CKD: usando la sopravvivenza relativa rispetto alla popolazione generale, Gibertoni et al. [2] hanno dimostrato che i pazienti MRC seguiti nel PIRP hanno una mortalità a 9 anni del 30% superiore, soprattutto se diabetici, proteinurici, anemici o con iperfosfatemia rispetto ai soggetti pari età della popolazione generale.
  • Iperfosfatemia e progressione renale: Bellasi et al. [3] hanno evidenziato che già nella fase conservativa della MRC, livelli di fosforo superiori o uguali a 4,3 mg/dl, raddoppiano il rischio di dialisi o di morte, sottolineando l’importanza di un controllo metabolico precoce in particolare della fosforemia.
  • Modelli prognostici innovativi: il CT-PIRP è un albero di classificazione che stratifica i pazienti in sette fenotipi clinici con differente rischio di declino del filtrato glomerulare, morte e inizio di terapia sostitutiva. Il modello è stato validato temporalmente e si propone come strumento pratico per personalizzare follow-up ed appropriati interventi terapeutici. Il modello permette di mettere in evidenza fenotipi clinici che caratterizzano momenti diversi di progressione e gravità della MRC [4, 5].
  • Evoluzione della MRC: l’ingresso in PIRP del paziente in genere porta ad un migliore controllo delle comorbidità e ad una riduzione della velocità di progressione della Malattia Renale con minore perdita annua del filtrato glomerulare [1]. A fronte di minore velocità di progressione si è osservato sin dai primi anni un minor rischio di arrivare alla necessità del trattamento dialitico, e questo in particolare nei pazienti seguiti dai primi stadi di Malattia Renale Cronica. Infatti osservando il trend dei pazienti incidenti alla dialisi in Emilia-Romagna (Figura 2) si osserva un andamento ondulante nell’incidenza in dialisi dal 2002 al 2006, con un successivo andamento decrescente che si protrae negli anni. In particolare, in questi ultimi anni si è ridotto il tasso grezzo di entrata in dialisi per i pazienti seguiti nel PIRP. Questi risultati non solo hanno migliorato la comprensione della storia naturale della CKD, ma hanno anche fornito strumenti predittivi applicabili nella pratica quotidiana.
Figura 2. Andamento del numero di pazienti entrati in dialisi in Emilia-Romagna dal 2005 al 2021, trend lineare dell’incidenza in dialisi e andamento del tasso grezzo (×100) di entrata in dialisi dei pazienti seguiti in PIRP.

 

Il PIRP ed i PDTA

Negli ultimi anni diverse Regioni italiane hanno prodotto dei PDTA sulla MRC. L’Emilia Romagna lo ha fatto nel 2018 [6] al fine di ottimizzare l’assistenza nefrologica al paziente con MRC, attraverso un approccio diagnostico e una presa in carico con percorsi omogenei e condivisi a livello regionale. Il 17 aprile 2025, la Conferenza Stato-Regioni ha approvato il “Documento di Indirizzo per il Percorso Preventivo Diagnostico Terapeutico Assistenziale della Malattia Renale Cronica, realizzato dal Ministero della Salute con la collaborazione della Società Italiana di Nefrologia (SIN), dei MMG, di altri specialisti e della Associazioni dei pazienti con malattie renali [7]. I PDTA, e in particolare quello nazionale, rappresentano un utilissimo strumento per indirizzare a un corretto approccio alla MRC. Rispetto però al PIRP, i PDTA hanno delle caratteristiche e anche degli scopi differenti.

Il PIRP nasce come espressione di una realtà loco-regionale ed ha come finalità principale quella di costruire una rete integrata tra MMG, nefrologi e altri specialisti al fine di intercettare precocemente i pazienti con MRC.

Il PDTA è volto a garantire equità di accesso e omogeneità delle cure nei riguardi della MRC. Il PIRP, oltre all’identificazione precoce della MRC, prevede un follow-up sistematico (con schede informatizzate condivise) ed ha come obiettivo quello di rallentare la progressione, ridurre le ospedalizzazioni e ottimizzare la transizione alla dialisi o al trapianto. Inoltre il PIRP ha una forte impronta sull’organizzazione di rete e sulla presa in carico multidisciplinare precoce.

Il PDTA è più ampio: definisce diagnosi, stadiazione, criteri di invio al nefrologo, monitoraggio, gestione delle complicanze e preparazione alla terapia sostitutiva. E quindi si propone come uno strumento di programmazione sanitaria e di appropriatezza clinica, meno legato a un modello operativo regionale. Include indicazioni anche su farmaci, comorbilità, terapia conservativa e palliative care.

Il PIRP utilizza una piattaforma informatica dedicata (condivisione di dati clinici tra MMG e nefrologi) e si basa su indicatori regionali di qualità, outcome (es. invio precoce al nefrologo, uso di farmaci nefro-protettivi, progressione GFR) e protocolli condivisi, ma con un impianto pragmatico, costruito sulla realtà emiliano-romagnola.

Il PDTA nazionale è un documento programmatico e normativo, non dispone di un proprio gestionale e fornisce raccomandazioni generali: ogni Regione deve declinarne i percorsi attuativi locali. In pratica è una ottima “cornice di riferimento”.

Infine il PIRP è stato una sorta di “laboratorio sperimentale”, che però ha già documentati outcome: maggiore invio precoce al nefrologo, riduzione degli accessi urgenti in dialisi, miglior controllo di diabete/ipertensione, impatto positivo su mortalità e progressione di malattia.

IL PDTA nazionale mira più a ridurre disomogeneità tra Regioni, però non è ancora supportato da outcome uniformi, perché molto dipende dalle applicazioni regionali.

 

PIRP e organizzazione delle cure: lezioni per il futuro

Uno degli aspetti più moderni del PIRP è l’integrazione tra medicina generale e specialistica.
L’analisi di Fiorentini et al. [6] ha mostrato come la compliance dei medici di base alle linee guida del programma sia influenzata da incentivi organizzativi e competitivi. Un richiamo importante per chi oggi disegna modelli di “population health management” [9]. In parallelo, studi recenti di confronto tra registri hanno dimostrato che la qualità dei flussi amministrativi (ad esempio le Schede di Dimissione Ospedaliera) è ancora insufficiente per identificare accuratamente la MRC [10]. Questo rafforza il valore di registri clinici come PIRP nelle valutazioni epidemiologiche e suggerisce che un vero governo clinico della CKD deve poggiare su dati validati e sulla collaborazione attiva tra livelli di cura.

 

Un modello che dialoga con l’Europa

Il PIRP è stato assunto come riferimento in studi europei comparativi: Brück et al. [11] hanno utilizzato il PIRP come coorte di confronto per valutare progressione e mortalità della CKD in diversi sistemi sanitari.
L’Italia, grazie a questa esperienza, si è potuta confrontare con realtà come Regno Unito, Belgio, Spagna e altri studi italiani, evidenziando come l’organizzazione precoce della presa in carico proposta con il PIRP può influenzare gli esiti in maniera favorevole, rispetto ad altri tipi di programmazione e sorveglianza della MRC.

 

Perché oggi il PIRP è più attuale che mai

La medicina sta vivendo un momento di forte transizione:

  • i nuovi farmaci nefroprotettivi (SGLT2-i, Finerenone, GLP1 agonisti, ecc.) richiedono un’identificazione precoce dei pazienti a rischio;
  • l’intelligenza artificiale promette di integrare modelli predittivi come il CT-PIRP nella pratica clinica;
  • i sistemi sanitari cercano soluzioni sostenibili per malattie croniche ad alta prevalenza.

In questo scenario, il PIRP rappresenta un laboratorio già funzionante di sanità integrata, capace di produrre evidenze, strumenti predittivi e indicazioni organizzative.
La sfida futura sarà integrare queste conoscenze con la sanità digitale, migliorare l’aderenza ai protocolli di referral, e usare i big data per interventi sempre più personalizzati e costo-efficaci.

 

Conclusione

Vent’anni fa il PIRP ha anticipato il bisogno di una gestione proattiva della MRC basata su prevenzione, stratificazione del rischio e collaborazione tra livelli di cura.
Oggi, con la pressione crescente della MRC sulla salute pubblica e con le nuove possibilità offerte da farmaci e intelligenza artificiale, quella visione appare non solo attuale, ma necessaria.

 

Bibliografia

  1. Santoro A, Gibertoni D, Rucci P, et al. The PIRP project (Prevenzione Insufficienza Renale Progressiva): how to integrate hospital and community maintenance treatment for chronic kidney disease. Journal of Nephrology (2019) 32:417–427. https://doi.org/10.1007/s40620-018-00570-2.
  2. Gibertoni D, Mandreoli M, Rucci P, et al. Excess mortality attributable to chronic kidney disease. Results from the PIRP project. J Nephrol. 2016. https://doi.org/10.1007/s40620-015-0239-4.
  3. Bellasi A, Mandreoli M, Baldrati L, et al. Chronic Kidney Disease Progression and Outcome According to Serum Phosphorus in Mild-to-Moderate Kidney Dysfunction. Clin J Am Soc Nephrol. 2011;6:883–891. https://doi.org/10.2215/cjn.07810910.
  4. Rucci P, Mandreoli M, Gibertoni D, et al. A clinical stratification tool for chronic kidney disease progression rate based on classification tree analysis. Nephrol Dial Transplant (2014) 29: 603–610. https://doi.org/10.1093/ndt/gft444.
  5. Gibertoni D, Rucci P, Mandreoli M, et al. Temporal validation of the CT-PIRP prognostic model for mortality and renal replacement therapy initiation in CKD. BMC Nephrol. 2019;20:177. https://doi.org/10.1186/s12882-019-1345-7.
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  10. Gibertoni D, Mandreoli M, De Amicis S, et al. L’accuratezza delle schede di dimissione ospedaliera nell’identificazione della MRC. G Ital Nefrol. Vol 5, 2019.
  11. Brück K, Jager KJ, Zoccali C, et al. Different rates of progression and mortality in CKD at outpatient nephrology clinics across Europe. Kidney Int. 2018;93:1432–1441. https://doi.org/10.1016/j.kint.2018.01.008.

Relazione tra obesità e salute renale nella popolazione generale e nelle ciliopatie

Pubblicato il Scarica PDF

Andrea Melluso

DOI: 10.69097/42-04-2025-07

Andrea Melluso1, Alessandra Perna2, Miriam Zacchia2

1 UO Nefrologia e Dialisi, Ospedale “don Tonino Bello”, ASL Bari, Molfetta, Italia
2 Dipartimento di Medicina Traslazionale, Università della Campania “Luigi Vanvitelli”, Napoli, Italia

Corrispondenza a:
Andrea Melluso
E-mail: andrea.melluso@virgilio.it

 

Abstract

La prevalenza dell’obesità è in progressivo aumento a livello globale e, tra le conseguenze negative sulla salute, vi è anche il danno renale. Quest’ultimo è dovuto ad alterazioni emodinamiche, metaboliche e infiammatorie.
Le ciliopatie sono un gruppo di patologie ereditarie causate dalla disfunzione del ciglio primario; tra queste rientrano la malattia del rene policistico autosomico dominante (ADPKD) e rari disordini sindromici come le sindromi di Alström e di Bardet-Biedl. Nell’ADPKD, l’obesità accelera la progressione della malattia renale. Nelle sindromi di Alström e di Bardet-Biedl la malattia renale è probabilmente dovuta alla combinazione di fattori intra-renali e sistemici; l’obesità rappresenta una delle manifestazioni cliniche più comuni e sono pertanto in corso studi che ne valutano il ruolo nella progressione della malattia renale cronica.
La gestione dell’obesità si avvale di interventi sullo stile di vita, farmaci e chirurgia. Interessanti novità farmacologiche sono oggi disponibili sia per l’obesità nella popolazione generale che per quella che si manifesta in alcune malattie genetiche. Il ruolo protettivo di molti di questi farmaci nella progressione della malattia renale cronica, che in diversi casi si osserva in maniera persino indipendente dalla perdita di peso, evidenzia ulteriormente l’intricato rapporto tra dismetabolismo e malattia renale.

Parole chiave: obesità, malattia renale cronica, ciliopatie, ADPKD, sindrome di Bardet-Biedl, sindrome di Alström

Obesità e salute renale. Epidemiologia

L’obesità negli adulti è definita dall’Organizzazione Mondiale della Sanità (OMS) come un indice di massa corporea (BMI) ≥30 kg/m², mentre il sovrappeso è associato a un BMI compreso tra 25 e 29,99 kg/m². In Europa, la prevalenza dell’obesità si attesta attorno al 20%, con alcune nazioni che superano il 30%, e si prevede che raggiunga il 24% a livello globale entro il 2035 [1, 2].

L’obesità è più frequente in individui con predisposizione genetica, che può avere una base monogenica, oligogenica o poligenica. Le forme monogeniche non sindromiche sono rare e tipicamente associate a mutazioni nei geni che regolano l’interazione tra cervello e tessuto adiposo, come quelli per la leptina, il suo recettore, il recettore della melanocortina 4, la proconvertasi 1 e la proopriomelanocortina, coinvolti nel pathway leptina-melanocortina. Le forme oligogeniche contribuiscono a circa il 3% dei casi, mentre la maggior parte delle obesità ereditarie ha una base poligenica, influenzata da fattori epigenetici [3].

Gli effetti negativi dell’obesità sulla salute renale sono ampiamente documentati. Una review sistematica e meta-analisi ha confermato che l’obesità costituisce un fattore di rischio indipendente per lo sviluppo di albuminuria (RR 1.51, IC: 1.36-1.67) e malattia renale cronica con velocità di filtrazione glomerulare stimata (eGFR) <60 mL/min/1.73m2 (RR 1.28, IC: 1.07–1.54) [4]. L’obesità costituisce inoltre un fattore di rischio per la nefrolitiasi [5].

Studi epidemiologici e osservazionali riportano che il 4-10% dei pazienti obesi presenta proteinuria. Tuttavia, determinare l’incidenza reale della glomerulopatia correlata all’obesità è più complesso a causa delle differenze nei protocolli adottati dai vari centri per l’esecuzione della biopsia renale [3].

Gli indici che misurano la distribuzione del grasso corporeo centrale, come il rapporto vita/fianchi, risultano più strettamente correlati al rischio di insufficienza renale terminale (ESKD) rispetto al BMI [6, 7]. Infatti il BMI, sebbene sia il parametro più utilizzato nella pratica clinica, ha diversi limiti, tra cui quello di non poter differenziare la composizione corporea (importante anche in ragione della possibile ritenzione di fluidi) e la distribuzione del grasso. Un rapporto vita/fianchi elevato (≥0,9 negli uomini e ≥0,8 nelle donne) è associato a un rischio maggiore di riduzione del filtrato renale, indipendentemente dal BMI. Questo perché l’adiposità centrale è correlata a una ridotta funzione renale anche in individui non obesi. Inoltre, tecniche avanzate come la risonanza magnetica (RM) o la tomografia computerizzata (TC) possono fornire misurazioni più accurate del grasso viscerale, metabolicamente attivo [1, 8–10]. La distribuzione dell’adipe sembra spiegare, almeno in parte, la differenza nel rischio di MRC tra uomini e donne [11].

Un altro indice promettente è il ‘weight-adjusted-waist index’ (WWI), misurato come circonferenza vita in cm/radice quadrata del peso corporeo in kg. Il WWI si è rivelato il miglior indicatore di obesità per la previsione della MRC e dell’albuminuria rispetto ad altri parametri come BMI, rapporto vita-altezza (WHTR) o circonferenza vita (WC) [12, 13].

Uno studio prospettico su 2711 partecipanti coreani con funzione renale normale e un follow-up medio di 11 anni ha riportato un’incidenza di MRC del 7%. Il rischio di malattia renale è maggiore nei pazienti con valori più elevati di BMI e, più significativamente, WHR (waist-to-hip ratio). Inoltre le curve di Kaplan-Meier mostrano che la riduzione dell’obesità migliora la prognosi renale [14].

Uno studio di Kanda et al. ha esaminato gli effetti della perdita di peso sulla funzione renale in persone sane, evidenziando differenze significative in base al sesso, alla velocità di perdita di peso e al BMI iniziale [15].

Un’analisi multivariata sui dati del CureGN non ha rilevato un aumento del rischio di eventi renali nei pazienti obesi con glomerulopatie. Tuttavia, lo studio presenta diversi limiti [16].

 

Il danno renale

Il danno renale associato all’obesità è il risultato di effetti diretti del tessuto adiposo sui reni e di complicanze sistemiche correlate a condizioni quali diabete, sindrome metabolica, dislipidemia, aterosclerosi e ipertensione. Questi effetti si traducono in alterazioni emodinamiche, metaboliche e infiammatorie che costituiscono i meccanismi alla base del danno renale [3] (Figura 1).

L’obesità è causa di alterazioni emodinamiche, infiammatorie e metaboliche
Figura 1. L’obesità è causa di alterazioni emodinamiche, infiammatorie e metaboliche che danneggiano il rene. A ciò possono sommarsi danni dovuti a fattori intrinseci, come mutazioni genetiche.
  • Iperfiltrazione e alterazioni emodinamiche [3, 4, 11, 17]. In presenza di insulino-resistenza, iperattività del sistema nervoso simpatico e attivazione del sistema renina-angiotensina (SRA), si verifica ipertensione glomerulare e aumento del tasso di filtrazione glomerulare.
    La dilatazione dell’arteriola afferente e la vasocostrizione dell’arteriola efferente, pur essendo un meccanismo inizialmente compensatorio, nel tempo porta a ipertrofia glomerulare, glomerulosclerosi e proteinuria (generalmente sub-nefrosica, raramente nefrosica). Inoltre, il grasso viscerale può esercitare una compressione meccanica su reni e vasi, contribuendo ulteriormente all’attivazione del SRA, mentre il tessuto adiposo produce direttamente componenti del SRA (come aldosterone e angiotensinogeno), inducendo ritenzione di sodio ed espansione del volume.
  • Tessuto adiposo [3, 11, 18]. Il grasso perirenale e del seno renale (RSF), localizzato nelle vicinanze delle arterie renali, comprime le strutture renali e secerne citochine e fattori angiogenici che influenzano la parete vascolare. Studi hanno evidenziato che un aumento della massa di RSF può aggravare la microalbuminuria, specialmente durante l’esercizio fisico, sebbene i dati disponibili siano ancora limitati. Inoltre, il tessuto adiposo rilascia citochine proinfiammatorie che determinano uno stato cronico di infiammazione e stress ossidativo mentre diminuisce la produzione di adiponectina, che ha proprietà antinfiammatorie e insulino-sensibilizzanti. L’iperleptinemia, osservata nei pazienti con MRC, aggrava l’infiammazione, stimola il tono simpatico, il riassorbimento di sodio, la proliferazione delle cellule glomerulari e aumenta la sintesi di collagene di tipo IV, favorendo la fibrosi e la glomerulosclerosi. Anche le cellule mesangiali rispondono alla leptina con un aumento dell’uptake di glucosio e ipertrofia, mentre sia esse sia le cellule endoteliali incrementano il rilascio di componenti della matrice extracellulare.
  • Insulino-resistenza e iperinsulinemia [1, 6, 11]. Questi fattori contribuiscono al danno renale attraverso meccanismi quali iperfiltrazione glomerulare, albuminuria, stress ossidativo e disfunzione endoteliale. È importante sottolineare che la predisposizione all’insulino-resistenza non è determinata esclusivamente dal BMI: anche soggetti con peso nella norma possono essere a rischio di sviluppare complicanze.

Il tessuto adiposo non è dunque solamente un deposito energetico, ma un organo endocrino che secerne adipochine, regolando processi come infiammazione, metabolismo, appetito, funzione cardiovascolare, immunità.

In realtà la tipologia e la quantità di adipochine rilasciate dal tessuto adiposo dipendono da diversi fattori, tra cui il tipo di adipociti (bianchi o bruni), la quantità, la localizzazione e le loro interazioni con altre cellule.

Gli adipociti si dividono principalmente in due categorie: quelli bianchi, i più numerosi negli adulti, che accumulano energia sotto forma di trigliceridi, e quelli bruni, presenti in quantità minori e più abbondanti nei neonati, che immagazzinano energia in piccole gocce lipidiche. Esiste inoltre un terzo tipo, adipociti beige, ovvero un sottotipo di adipociti bianchi che, in risposta al freddo o a specifici agenti farmacologici, acquisiscono caratteristiche simili a quelle dei bruni. L’attivazione del processo di beiging aumenta il dispendio energetico e migliora il metabolismo glucidico e lipidico [19].

Clinicamente il primo segno del danno correlato all’obesità è un lento aumento della proteinuria in range subnefrosico [18].

La riduzione del peso corporeo riduce anche i livelli delle citochine pro-infiammatorie legate all’obesità (es. TNF- α, MCP-1 e l’amiloide sierica) [11].

 

Alterazioni istopatologiche

Il rene dei pazienti obesi tende ad aumentare di volume [1, 6]. La diagnosi di glomerulopatia correlata all’obesità (ORG) si basa sull’esclusione clinica e istopatologica di altre patologie renali in soggetti con BMI ≥ 30 kg/m2. Dal punto di vista istopatologico, l’ORG si manifesta con glomerulomegalia, associata o meno a glomerulosclerosi focale segmentale secondaria, spesso localizzata nei glomeruli peri-ilari. Si possono osservare, inoltre, riduzione della densità dei podociti, aumento della larghezza dei processi pedicellari, ispessimento della membrana basale glomerulare, aumento della matrice mesangiale e sclerosi mesangiale.

Studi istologici hanno mostrato che anche i tubuli renali possono essere interessati, con ipertrofia delle cellule epiteliali del tubulo prossimale. Si possono talvolta osservare vacuoli lipidici intracellulari in queste cellule epiteliali, nei podociti e nelle cellule mesangiali [3, 18].

Un ruolo importante nello sviluppo di ORG lo hanno le condizioni predisponenti, quali un basso numero di nefroni alla nascita e anomalie renali, che, associate a una crescita compensatoria, possono ulteriormente favorire l’iperfiltrazione glomerulare. L’ipertrigliceridemia, di frequente associata all’obesità viscerale, è un altro fattore che peggiora l’outcome renale.

 

Trattamento dell’obesità

La gestione dell’obesità comprende modifiche dello stile di vita (attività fisica, nutrizione, terapia comportamentale), farmaci e chirurgia bariatrica.

L’attività fisica può ridurre il rischio di mortalità anche nei pazienti affetti da MRC, per i quali tuttavia non esistono ancora raccomandazioni definitive in termini di frequenza, intensità e durata; pertanto si consiglia un incremento graduale dell’attività. Nei soggetti policistici è sconsigliato effettuare attività che possano causare traumi tali da provocare la rottura delle cisti.

Gli interventi proposti sulla dieta dei pazienti con ADPKD sono stati vari (restrizione calorica, digiuno intermittente, assunzione di cibo ristretta in un determinato intervallo di tempo e dieta chetogenica): in questi pazienti, oltre ai vantaggi legati alla riduzione dell’adiposità viscerale, si ipotizza anche un beneficio dovuto al miglior controllo dei nutrienti e dello status energetico cellulare, che influisce sul pathway mTOR, attivato in modo anomalo nelle cisti renali [11, 20].

La prima scelta farmacologica per l’ipertensione correlata all’obesità è rappresentata dagli ACE inibitori e dai sartani perché riducono il rischio di glomerulopatia associata all’obesità e sono associati a una minore incidenza di diabete e a effetti positivi sull’ipertrofia del ventricolo sinistro [17]. Importante è anche la restrizione sodica.

Quando gli interventi sullo stile di vita non risultano sufficienti, si può ricorrere a un’ampia gamma di farmaci per il trattamento dell’obesità (indicati per BMI ≥ 30 kg/m2 o ≥ 27 kg/m2 in presenza di comorbidità legate al peso). Tra i farmaci approvati per la gestione del peso corporeo ci sono l’orlistat, naltrexone/bupropione a rilascio prolungato, fentermina/topiramato a rilascio controllato (combinazione di simpaticomimetico e inibitore dell’anidrasi carbonica, non approvato dall’EMA), setmelanotide, agonisti del recettore del GLP-1 (liraglutide e semaglutide), agonisti di GLP-1 e GIP (tirzepatide).

L’orlistat è un inibitore della lipasi intestinale, riduce l’assorbimento degli acidi grassi fino al 30% con perdita di peso intorno al 5%. Gli effetti collaterali più comuni includono meteorismo e malassorbimento, con conseguente riduzione dei livelli di vitamina D, vitamina E e beta-carotene, rendendo necessaria una supplementazione.

La combinazione bupropione-naltrexone agisce diminuendo l’appetito e il craving. Il bupropione è un inibitore del reuptake di noradrenalina e dopamina, che promuovono l’attivazione del pathway della melanocortina. Il naltrexone, antagonista dei recettori per gli oppiodi μ, riduce il feedback autoinibitorio attivato dal bupropione sui neuroni anoressigeni ipotalamici. Gli effetti collaterali più comuni sono nausea, vomito, cefalea, insonnia, secchezza delle fauci; va monitorata l’eventuale comparsa di pensieri suicidi.

La liraglutide è un agonista del recettore del GLP-1 (glucagon-like-peptide) che riduce l’appetito, ritarda lo svuotamento gastrico e bilancia la secrezione di insulina e glucagone. Alla dose di 3 mg/die, liraglutide è in grado di ridurre il peso corporeo del 5-10% e ritardare l’insorgenza del diabete nei soggetti prediabetici obesi, oltre a migliorare il controllo glicemico, la pressione arteriosa e il profilo lipidico. Una dose di 1,8 mg è associata a una diminuzione del rischio di eventi cardiovascolari gravi nei pazienti diabetici. Gli effetti indesiderati sono principalmente gastrointestinali (nausea, vomito, stitichezza, diarrea), mitigabili con un incremento graduale della dose. È controindicata in pazienti con storia di pancreatite, in donne in gravidanza e in soggetti con una storia personale o familiare di carcinoma midollare della tiroide o neoplasia endocrina multipla (MEN).
La semaglutide, agonista long-acting del GLP-1, è impiegata per ridurre il rischio di eventi cardiovascolari maggiori (MACE) in adulti con malattia cardiovascolare associata a obesità/sovrappeso, oppure per la perdita di peso nei pazienti obesi o sovrappeso con comorbidità correlate. Essa agisce rallentando lo svuotamento gastrico e producendo un effetto anoressigeno centrale. Gli effetti avversi principali sono gastrointestinali e, similmente a liraglutide, è controindicato in gravidanza e in pazienti a rischio di carcinoma midollare della tiroide o MEN.

La tirzepatide è un agonista dei recettori di GLP-1 e GIP, che, somministrato una volta a settimana, riduce l’appetito, aumenta la sensibilità all’insulina e l’assorbimento di glucosio e trigliceridi nel tessuto adiposo. Gli studi SURMOUNT hanno evidenziato una perdita di peso media del 20%, con effetti avversi principalmente gastrointestinali e bassi tassi di interruzione del trattamento.

La setmelanotide è un agonista del recettore per la melanocortina-4, che riduce l’appetito. Approvato per il trattamento di alcune forme di obesità monogenica e per pazienti con sindrome di Bardet-Biedl, è somministrato per via sottocutanea una volta al giorno. Gli effetti avversi principali sono reazioni locali al sito di iniezione, iperpigmentazione e nausea; c’è un warning del produttore per idee suicidarie e depressione.

Alcuni farmaci, sebbene non specifici per la gestione dell’obesità, mostrano effetti benefici sul peso corporeo, quali la metformina e gli inibitori di SGLT-2.

La metformina agisce riducendo la produzione epatica di glucosio e aumentando la sensibilità all’insulina. I meccanismi ipotizzati per la riduzione del peso includono l’attivazione di AMPK, l’incremento degli ormoni anoressizzanti e una maggiore sensibilità alla leptina. Studi clinici indicano una riduzione del peso a lungo termine intorno al 3%, con effetti collaterali principalmente gastrointestinali e il rischio, seppur raro, di acidosi lattica; l’uso prolungato può causare carenza di vitamina B12.

SGLT-2 è la proteina responsabile del riassorbimento della maggior parte del glucosio nei tubuli renali. Nei pazienti con diabete mellito (DM), si osserva spesso una sovraespressione di SGLT-2 durante la fase di iperfiltrazione, aggravando l’iperglicemia e lo stress renale. Questo ha portato allo sviluppo degli inibitori di SGLT-2, una classe di farmaci che bloccano questi cotrasportatori, aumentando l’escrezione di glucosio nelle urine. Gli inibitori di SGLT-2 migliorano il controllo glicemico, riducono la pressione arteriosa, la mortalità e la morbilità cardiovascolare, rallentano la progressione della MRC (riducendo iperfiltrazione, proteinuria, stress ossidativo e infiammazione) e provocano una perdita di peso di circa 2 kg, seppur questo effetto possa essere dovuto anche a riduzione dell’acqua corporea e in parte compensato da un aumento dell’appetito. Gli effetti avversi principali comprendono infezioni urinarie e genitali, disidratazione e, in casi rari, chetoacidosi diabetica per aumento della lipolisi e rilascio di acidi grassi liberi [3, 11, 17, 21, 22].

Per diversi dei farmaci citati è noto un effetto protettivo contro la progressione della malattia renale, in particolare per gli inibitori di SGLT-2, gli agonisti di GLP-1 e la tirzepatide (Tabella 1).

Classe Effetti principali
GLP-1 agonisti Riduzione di citochine proinfiammatorie e dello stress ossidativo, miglioramento del controllo glicemico e pressorio, riduzione della proteinuria e dell’iperfiltrazione (attraverso la natriuresi) nella nefropatia diabetica, perdita di peso, inibizione RAAS (probabilmente con meccanismo indiretto).
Tirzepatide Effetti simili ai GLP-1 agonisti, con un impatto più marcato sul peso corporeo e sul metabolismo, grazie all’azione sul GIP.
SGLT2i Riduzione dell’iperfiltrazione, natriuresi, riduzione della proteinuria, protezione cardiovascolare e renale indipendente dal controllo glicemico.
Tabella 1. Effetti principali di alcuni farmaci con azione protettiva sulla funzione renale.

Per quanto riguarda la chirurgia bariatrica/metabolica, le linee guida del National Institute for Health and Care Excellence (NICE) la raccomandano come opzione di trattamento per soggetti con un BMI ≥ 40 kg/m², o compreso tra 35 e 40 in presenza di comorbidità (ad es. diabete di tipo 2, ipertensione) che possano beneficiare del calo ponderale. Recentemente le nuove linee guida dell’ASMBS e dell’IFSO hanno proposto un ampliamento significativo delle indicazioni per la chirurgia, raccomandando di considerarla anche per soggetti con un BMI compreso tra 30 e 35 in presenza di malattie metaboliche come il diabete di tipo 2, qualora le terapie non chirurgiche abbiano prodotto risultati insufficienti. In alcuni casi, per pazienti di diverse origini etniche (ad esempio, asiatici con BMI > 27,5 kg/m²) o come “ponte” per trattamenti successivi (come il trapianto d’organo), la chirurgia bariatrica può essere indicata [23].

Le due procedure più comuni sono il bypass gastrico laparoscopico Roux-en-Y (LRYGB) e la sleeve gastrectomy laparoscopica (LSG). Una review sistematica ha riscontrato che, a un anno dall’intervento, la tecnica LRYGB ha mostrato una percentuale di perdita di peso totale (%TLW) leggermente superiore rispetto a LSG; a 5 anni invece le differenze tra le due tecniche non risultano rilevanti, con valori medi di 28.1% per LRYGB e 27.0% per LSG [24].

La perdita di peso riduce proteinuria e microalbuminuria nei pazienti con MRC. I meccanismi proposti includono il miglioramento del controllo pressorio, del profilo lipidico, della sensibilità all’insulina, la riduzione dei livelli di leptina, una minore attivazione del SRAA, la diminuzione dell’iperfiltrazione glomerulare e dei processi infiammatori.

Nuovi studi di maggiori dimensioni e durata saranno utili per ottenere ulteriori dati sull’effetto della perdita di peso sulla progressione della MRC [11].

 

Obesità e ciliopatie

Le ciglia sono strutture microtubulari classificate sulla base della struttura del loro assonema in mobili (9+2) e non-mobili (9+0). Queste ultime, dette ciglia primarie, sono diffusamente espresse nell’organismo e agiscono come sensori e trasduttori di segnali cellulari. Attraverso recettori quali Wnt, Hedgehog, TGFβ e PDGFR, le ciglia primarie partecipano alla trasduzione di segnali extracellulari [25].

Il termine “ciliopatie” indica un gruppo di patologie causate da disfunzioni del ciglio primario, come la malattia del rene policistico autosomico dominante, la sindrome di Bardet-Biedl (BBS), la sindrome di Alström (ALMS) e la sindrome di Senior-Løken.

ADPKD

La malattia del rene policistico autosomico dominante (ADPKD) colpisce oltre 10 milioni di persone in tutto il mondo ed è principalmente causata da varianti nei geni PKD1 e PKD2, che codificano rispettivamente per le proteine policistina 1 (PC1) e policistina 2 (PC2). Queste mantengono la funzione del ciglio primario e preservano l’integrità dei tubuli renali.

È interessante notare che esistono evidenze di una duplice funzione ciliare: nelle cellule renali normali il ciglio primario inibisce la formazione delle cisti, mentre nell’ADPKD, quando il complesso delle policistine è alterato, esso favorisce la crescita cistica [26–29].

L’accumulo di tessuto adiposo può aggravare i difetti metabolici associati all’ADPKD, influenzando diversi pathway del segnale cellulare.

Nello studio HALT-PKD A, un BMI elevato era associato a un maggiore incremento del volume renale totale (TKV) e a un declino più rapido dell’eGFR. Nei pazienti obesi, il rischio di progressione rapida del TKV (tasso di variazione annuale ≥7% rispetto a <5%) era circa quattro volte superiore e l’aumento percentuale annuale del TKV è stato più del 50% maggiore rispetto ai pazienti normopeso.

Nello studio TEMPO 3:4 si è confermata l’associazione tra BMI e incremento del TKV, mentre il declino dell’eGFR risultava correlato al BMI solo nelle donne. Per evitare il bias dovuto al peso delle cisti, in entrambi gli studi citati questo veniva calcolato sottraendo il peso stimato dei reni. Le discrepanze nei risultati potrebbero essere attribuibili alla mancata considerazione della distribuzione del grasso corporeo o ad altri fattori.

Dallo studio TEMPO 3:4 è emerso che l’efficacia del Tolvaptan, un farmaco per rallentare la progressione dell’ADPKD, era indipendente dal BMI. Tuttavia, un successivo studio di coorte retrospettivo ha evidenziato che l’aumento del grasso viscerale predice l’aumento di volume renale in modo più accurato del BMI nei soggetti magri e che l’efficacia del farmaco diminuisce col suo aumentare [11, 30–32].

L’obesità influisce sui livelli di ormoni e citochine, determinando un’aumentata attivazione del pathway PI3K/Akt che favorisce la sopravvivenza e la crescita cellulare. L’adiponectina, i cui livelli risultano ridotti nell’obesità, attiva l’enzima AMPK, che inibisce la via mTOR e riduce la proliferazione cellulare. Parallelamente, le citochine rilasciate dal grasso viscerale, come IL-6 e TNF-α, stimolano infiammazione e proliferazione cellulare, mentre l’insulina attiva le vie PI3K-AKT, mTOR e MAPK. Inoltre, gli acidi grassi saturi si legano alla fetuina, un ligando endogeno dei recettori TLR2/TLR4, attivando una risposta infiammatoria cronica di basso grado.

La perdita di peso nei soggetti obesi con ADPKD rappresenta un potenziale target terapeutico per migliorare l’assetto metabolico, ridurre l’aumento del TKV e la risposta pro-infiammatoria [11].

Ciliopatie sindromiche caratterizzate da obesità e malattia renale: Sindromi di Bardet-Biedl e di Alström

Le sindromi di Bardet-Biedl (BBS) e di Alström (ALMS) presentano sovente un quadro clinico che include obesità precoce e disfunzione renale. La sindrome di Bardet-Biedl è una malattia genetica rara a trasmissione autosomica recessiva, con una prevalenza stimata tra 1 caso ogni 120.000 e 1 ogni 160.000 in Nord America e in Europa, mentre in alcune comunità isolate la frequenza è significativamente più alta. La diagnosi si effettua sulla base dei criteri di Beales et al. e richiede la presenza di almeno 4 caratteristiche primarie o 3 primarie e 2 secondarie. La diagnosi precoce può essere difficile, poiché i segni clinici si manifestano in modo progressivo nel tempo, e lo studio genetico può risultare utile per confermare il sospetto [33].

L’obesità è una delle caratteristiche cliniche primarie della BBS e si manifesta precocemente: sebbene il peso alla nascita sia normale, il 90% dei pazienti sviluppa un aumento ponderale già nel primo anno di vita, con l’obesità che diventa evidente nei primi tre anni. Uno studio di Feuillan et al. ha mostrato che i pazienti con BBS hanno una maggiore adiposità viscerale rispetto ai controlli abbinati per BMI, anche dopo aver corretto per le covariate (età, sesso, razza e percentuale di grasso corporeo totale misurata tramite DEXA). Tuttavia, dopo aver aggiustato per età, sesso, razza, percentuale totale di grasso corporeo, testosterone libero ed estradiolo, la differenza nell’adiposità del grasso viscerale addominale diventa non significativa (p = 0,06).

I livelli di leptina risultano più alti rispetto ai controlli in base al grado di adiposità, suggerendo una resistenza a quest’ormone. Nel confronto tra gruppi con mutazioni in BBS10 e BBS1, è stato evidenziato che i primi avevano maggiori BMI-Z e obesità viscerale rispetto ai secondi. Altri studi genotipo-fenotipo suggeriscono che le mutazioni in BBS1 siano associate a un fenotipo di obesità più lieve rispetto ad altri genotipi BBS (una differenza che sembra ridursi nell’adolescenza) mentre le mutazioni in BBS9 e BBS4 si associano a un BMI più elevato. I bambini con mutazioni che comportano perdita di funzione hanno un rischio maggiore di sviluppare obesità grave [33–35].

La prevalenza della malattia renale nei pazienti con BBS varia a seconda degli studi, in parte a causa delle differenti definizioni adottate. Lo studio di Forsythe et al. su 350 pazienti ha rilevato che il 31% dei bambini e il 42% degli adulti presentavano MRC in stadio 2-5, mentre la MRC agli stadi 4-5 era presente nel 6% dei soggetti pediatrici e nell’8% degli adulti. Meyer et al., analizzando 607 pazienti BBS dal Clinical Registry Investigation of BBS (CRIBBS), hanno identificato uno stadio ESRD (più correttamente definito ‘Kidney Failure’) in 44 individui (7,2%).

Le alterazioni renali derivano sia da cause anatomiche che funzionali e la patogenesi della malattia renale è solo parzialmente nota. L’espressione delle proteine BBS nel rene suggerisce un contributo locale al danno renale. Uno studio su 54 pazienti ha evidenziato che l’ipostenuria è associata a un declino più rapido dell’eGFR. Questa ridotta capacità di concentrazione dell’urina potrebbe indicare un disturbo tubulointerstiziale. Inoltre, l’osservazione che anche i pazienti con eGFR conservato mostrino anomalie alla risonanza magnetica funzionale, soprattutto nella zona midollare, rafforza l’ipotesi di un disturbo tubulointerstiziale primitivo.

La frequente presenza di fattori come obesità, diabete e ipertensione evidenzia la necessità di analisi approfondite per quantificare il loro contributo al danno renale. Un nostro recente studio osservazionale condotto su 65 pazienti affetti da BBS ha evidenziato che un filtrato ridotto correla con l’ipertensione e mutazioni troncanti in qualsiasi gene BBS; inoltre, all’analisi multivariata, il BMI è risultato indipendentemente associato al declino dell’eGFR (β = -2,45; p < 0,0001), insieme all’età. La presenza di una significativa discordanza nel fenotipo renale nel 50% dei pazienti con le stesse varianti patogenetiche rafforza l’ipotesi di una compartecipazione di fattori intrinseci e secondari [33, 36, 37].

I meccanismi eziopatogenetici alla base dell’obesità in alcune ciliopatie non sono ancora completamente compresi e sembrano derivare da molteplici fattori, coinvolgendo il controllo del metabolismo energetico sia a livello centrale che periferico. Anche i neuroni e le cellule gliali possiedono ciglia e l’ipotalamo gioca un ruolo essenziale nell’omeostasi energetica. Nel nucleo arcuato ipotalamico, due popolazioni neuronali – neuroni AgRP e POMC – regolano l’appetito e il dispendio energetico: i neuroni AgRP si attivano in condizioni di deficit energetico e sono inibiti dall’insulina e dalla leptina mentre i neuroni POMC si attivano in condizioni di surplus energetico, contribuendo a ridurre l’assunzione di cibo e ad aumentare il dispendio energetico [2, 38].

Gli studi sull’obesità nella BBS si sono concentrati principalmente sul ruolo delle proteine BBS nel traffico intracellulare verso il ciglio primario o la membrana plasmatica.

Il ciglio primario è cruciale per la trasduzione del segnale della leptina nell’ipotalamo, la cui alterazione nei pazienti con BBS è testimoniata dal riscontro di livelli plasmatici di leptina maggiormente elevati rispetto ai controlli.

Alcuni studi suggeriscono che anomalie nel traffico dei recettori del neuropeptide Y e della serotonina (5-HT2C) siano tra i fattori che contribuiscono allo sviluppo dell’obesità. Un altro aspetto riguarda la disfunzione dell’adipogenesi: durante la fase di differenziazione, i preadipociti esprimono un ciglio primario che ospita recettori per le vie di segnalazione Wnt e Hedgehog, essenziali per il corretto sviluppo degli adipociti. Infine, le proteine BBS1 e BBS2 sono indispensabili per il corretto traffico del recettore dell’insulina verso la membrana plasmatica [33, 39].

Per quanto concerne la sindrome di Alström, studi su modelli murini con mutazioni del gene Alms1 evidenziano una riduzione della percentuale di neuroni ipotalamici ciliati, associata a una significativa diminuzione della spesa energetica. I dettagli molecolari di questo meccanismo rimangono ancora poco chiari [2].

La sindrome di Alström è una condizione autosomica recessiva caratterizzata da una vasta gamma di manifestazioni cliniche, tra cui obesità, insulino-resistenza o diabete mellito di tipo 2, ipertrigliceridemia, perdita dell’udito, cardiomiopatia, distrofia retinica, malattia renale ed epatica progressive. La sua prevalenza stimata varia da 1 a 10 casi ogni milione di persone. L’obesità e l’insulino-resistenza iniziano tipicamente a svilupparsi durante il primo anno di vita. Uno studio condotto da Waldman et al. su 38 pazienti con sindrome di Alström ha evidenziato che, su 25 bambini osservati, solo il 20% aveva un peso normale, mentre l’8% era in sovrappeso e il 72% era obeso. Nella popolazione adulta (13 pazienti), il 15% risultava in sovrappeso e l’85% obeso, con insulino-resistenza presente nel 100% dei casi. Mentre la BBS può essere causata da mutazioni in oltre 20 geni, la sindrome di Alström è causata da mutazioni del gene ALMS1 [33, 40, 41]. I pazienti con ALMS, ma non tutti quelli affetti da BBS, sono predisposti al diabete di tipo 2, suggerendo una complessità nella regolazione della funzione ciliare, con alcune alterazioni che potrebbero addirittura risultare protettive contro i disturbi metabolici (è interessante notare che la mancanza di BBS12 nei topi aumenta l’adipogenesi ma, paradossalmente, anche la sensibilità all’insulina) [42, 43].

La funzione renale tende a deteriorarsi con l’età, come evidenziato dallo studio di Waldman e, in precedenza, da quelli di Marshall et al.

Nello studio di Waldman et al, i criteri per la diagnosi di malattia renale cronica (MRC) erano soddisfatti in circa il 20% dei pazienti di età compresa tra i 20 e i 38 anni, con un danno renale probabilmente legato alla mancanza della proteina ALMS1, tuttavia non può essere escluso il contributo di condizioni associate, come la disfunzione metabolica [41].

L’approccio terapeutico per l’obesità nelle ciliopatie si basa su modifiche dello stile di vita, che includono una dieta ipocalorica e attività fisica aerobica adattata alle condizioni cliniche del paziente. Inoltre, migliorare l’igiene del sonno e aumentarne la durata potrebbe contribuire alla gestione dell’obesità. Un approccio ottimale prevede il supporto di un team multidisciplinare, composto da medici, dietisti, psicologi e fisioterapisti. Nei pazienti con obesità ad alto rischio, si può valutare la chirurgia bariatrica, sebbene i suoi effetti a lungo termine siano ancora in fase di studio. Una review ha evidenziato benefici meno duraturi nei soggetti con disturbi iperfagici [2, 33].

Nei pazienti diabetici, vanno privilegiati trattamenti che migliorino l’insulino-resistenza senza causare aumento di peso (es. metformina, incretine, SGLT2i) [36].

L’obesità è una delle caratteristiche cliniche della BBS e dell’Alström, per la quale ci sono interessanti novità terapeutiche. Setmelanotide, un agonista del recettore della melanocortina-4 (MC4R), è stato approvato negli Stati Uniti nel 2020 e in Europa nel 2021 per il trattamento dell’obesità causata da mutazioni di POMC, PCSK1 e LEPR nei soggetti di età superiore a 6 anni [33]. Nel 2022, la FDA ha esteso l’indicazione terapeutica di setmelanotide ai pazienti con sindrome di Bardet-Biedl (BBS), basandosi su uno studio di fase 3 che ha mostrato, dopo 52 settimane di trattamento, che circa il 30% dei partecipanti (con più di 12 anni) ha ottenuto una riduzione del peso corporeo ≥10%, con una riduzione del BMI medio di oltre il 9% in un anno [44, 45].

Un recente studio ha indagato l’efficacia di setmelanotide nei bambini con meno di 6 anni e, nel gruppo BBS, si è riscontrata una riduzione percentuale media del BMI del 10% alla cinquantaduesima settimana [44, 46]. Un abstract ha anticipato i risultati dell’estensione dello studio di fase 3, mostrando benefici clinici sostenuti dopo 3 anni di trattamento continuo col farmaco, con perdite medie di peso di circa 20 kg negli adulti e una riduzione del 19,4% nei percentili di BMI nei pazienti pediatrici [47].

Ganawa et al. hanno riportato un caso di utilizzo di agonisti di GLP-1 in una giovane donna con BBS con obesità insorta nell’infanzia e iperfagia. Dato il recupero del peso alla riduzione della dose, si è reso necessario mantenere il farmaco in terapia. Anche per l’Alström ci sono dati che suggeriscono la non inferiorità dei GLP-1 RAs in queste forme di obesità rispetto a quelle poligeniche [48].

Diversi effetti metabolici benefici di questi farmaci si sono riscontrati anche indipendentemente dalla riduzione del BMI [48, 49].

Attualmente non esistono interventi specifici per prevenire il danno renale. Il trapianto renale rappresenta la terapia di scelta dell’uremia terminale. È riportato un aumento del BMI mediano nella coorte dei pazienti trapiantati rispetto a quelli non trapiantati, per cui è consigliabile utilizzare regimi immunosoppressivi che consentano una riduzione dell’uso degli steroidi e, in particolare, valutare attentamente l’uso del tacrolimus, considerando il rischio maggiore di diabete post-trapianto (NODAT) in pazienti obesi [33, 36, 50].

 

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Innovazioni negli studi clinici randomizzati in nefrologia: dal disegno dello studio all’impegno attivo del paziente

Pubblicato il Scarica PDF

Giuseppe Pezzi

DOI: 10.69097/42-03-2025-02

Giuseppe Pezzi1, Roberta Arena2, Giuliana Papalia2, Raffaella Sbano3, Fiorella Iorio2, Chiara Summaria2, Angela Greco2, Rosita Greco2, Rocco Malivindi4, Pierangelo Veltri5, Gaetano La Manna6,7, Lilio Hu6,8, Gianluigi Zaza2, Michele Provenzano2

1 Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
2 Nephrology, Dialysis and Renal Transplant Unit, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende - Hospital 'SS. Annunziata', Cosenza, Italy
3 Radiology Unit, San Francesco di Paola Hospital, Paola, Cosenza, Italy
4 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende - Hospital 'SS. Annunziata', Cosenza, Italy
5 Department of Computer Science, Modeling, Electronics and Systems Engineering, University of Calabria, 87036 Rende, Italy
6 Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
7 Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
8 Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy

Corrispondenza a: 
Dr. Michele Provenzano
Nefrologia, Dialisi e Trapianto
Azienda Ospedaliera “SS. Annunziata”
Università della Calabria, Rende, Italia
Via Pietro Bucci, Arcavacata, Cosenza, Italia
e-mail: michele.provenzano@unical.it
Tel: +39-3407544146

 

Abstract

La pratica clinica attuale è guidata da nuove solide evidenze provenienti da studi clinici randomizzati (RCT). Questi studi seguono solitamente un disegno prospettico rigoroso, con visite predefinite ed esami pianificati durante il follow-up. In ambito nefrologico, gli RCT sono stati principalmente progettati per valutare l’efficacia di nuove terapie nel ridurre il rischio di insufficienza renale, la riduzione del tasso di filtrazione glomerulare stimato (eGFR), la mortalità o gli eventi cardiovascolari. I progressi informatici si riflettono inoltre in un miglioramento e in un’espansione delle tecnologie e delle innovazioni applicate agli RCT attuali e futuri. In questo contributo presentiamo alcune innovazioni e prospettive future degli RCT nei pazienti con malattia renale cronica.

Parole chiave: studi clinici randomizzati, malattia renale cronica, innovazione informatica, dispositivi medici, albuminuria

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Randomized clinical trials (RCTs) represent, to date, the most robust research tools for generating evidence on the efficacy and safety of new therapies for a given clinical condition [1]. The reliability of randomized studies lies in their prospective, ad hoc design, in which one group of subjects (controls) is assigned to the standard of care for the condition under investigation, while another group (active treatment arm) receives the standard of care plus the experimental treatment. The assignment to the control or active arm is random and occurs through randomization, which aims to create two groups of patients with similar characteristics (e.g. age, sex, prevalence of patients with type 2 diabetes, or those treated with diuretics), with the only difference being their assignment to either the active treatment or the control group. This randomization tool therefore allows for the optimal isolation and estimation of the effect of the “new” treatment compared to the standard of care in reducing the incidence of a specific clinical outcome (e.g., reduction in proteinuria or admission to dialysis) or in improving the symptoms of a disease (e.g., improving blood pressure or reducing fatigue).

In the field of kidney diseases, numerous randomized studies have been conducted over the past two decades. They have proven the effectiveness of drugs targeting different mechanisms, such as antihypertensives, erythropoiesis-stimulating drugs, and mineralocorticoid receptor antagonists, in terms of nephroprotection, as well as in reducing mortality and cardiovascular (CV) events, across different patient groups (e.g., diabetic, non-diabetic chronic kidney disease, glomerulonephritis) [2].

Recently, there has been an explosive and rapid increase in drugs available to treat kidney diseases, which has simultaneously led to a rise in the number of randomized studies in Nephrology [3]. In this scenario, with the progress and refinement of research tools in association with digital technologies, the design of randomized studies is undergoing innovations that involve the type of patients included, the methods of their inclusion, the monitoring or choice of treatment, the randomization sequence, and the study outcomes (endpoints). In this article, we describe the essential points of randomized studies in Nephrology and the innovations to consider for their accurate and timely interpretation.

 

Principal aspects of a randomized trial in Nephrology

Inclusion criteria

One starting point when designing a randomized study is to establish which type of patients should be included. This leads to the definition of inclusion criteria. The first inclusion criterion should define the disease setting, for example patients with Chronic Kidney Disease (CKD) with or without diabetes, or both. Such a decision may lead to the estimation of a treatment effect in both types of CKD conditions rather than restrict to one of them. For example, canagliflozin, a SGLT2 inhibitor that protects the kidneys from chronic failure, was tested in patients with CKD and diabetes in the CREDENCE trial, whereas similar agents, empagliflozin and dapagliflozin, were tested in both diabetic and non-diabetic CKD in the EMPA-KIDNEY and DAPA-CKD trials [4–7]. The extremely positive results from these studies influenced the guidelines and clinical practice, leading to changes in drug reimbursement [8].

The other major inclusion criteria in CKD trials are the so called “kidney measures” namely estimated Glomerular Filtration Rate (eGFR) and albuminuria levels. Such a biomarkers-based enrichment in clinical trials is due to the fact that eGFR and albuminuria represent two main predictors of clinical outcomes in patients suffering from CKD [9, 10].  Moreover, the presence of abnormal levels of eGFR and albuminuria allows to reach a significant number of clinical endpoints throughout the study. In previous trials, such as the first studies testing the efficacy of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), including the RENAAL and IDNT studies, serum creatinine was used instead of eGFR [11, 12]. For instance, in the RENAAL study, patients with a serum creatinine level of 1.3 to 3.0 mg/dL were included. Later on, serum creatinine was replaced by eGFR, that is considered a more accurate prognostic biomarker [13]. Another lesson from previous trials was the “flexibility” of inclusion criteria. In the DERIVE study, a phase 3 trial designed to test the efficacy and safety of dapagliflozin in early CKD, only patients with CKD stage 3A (eGFR between 45 and 60 mL/min/1.73 m2) on at least two visits were included. Such restriction, albeit of clinical relevance, was associated with a high percentage of screening failure and slowed the study completion. Similarly, the ALTITUDE study (Aliskiren in patients with CKD and diabetes) included patients with albuminuria > 200 mg/g in at least two out three first morning voids or eGFR between 30 and 60 mL/min [14].  A recent post-hoc analysis of the ALTITUDE database highlighted how adopting more flexible criteria, such as lowering thresholds for albuminuria (e.g. >160 mg/g at the second collection) and relaxing thresholds for eGFR (e.g. 25-75 mL/min), can significantly reduce screening failure rates. This approach not only increases the number of eligible patients participating in the study, but also maintains the integrity of the clinical endpoints, without compromising the statistical power of the study. In particular, the intrapatient variability of albuminuria and eGFR values, which can be influenced by factors such as diet, hydration and therapy adherence, suggests that more stringent screening criteria may not be necessary to predict clinical outcomes [15].

Owing to this evidence, recent RCTs have been designed by including CKD patients with lower levels of albuminuria and larger range of eGFR. For example, in the ROTATE-3 study, a 100 mg of 24h-albuminuria, stable on two visits, was considered sufficient to screen and randomize patients. The stability in this case was not interpreted as a value of at least 100 mg/day also on the second measurement, but rather as a difference in albuminuria from the first visit: less than 40 mg/24hr for subjects with albuminuria between 100 and 300 mg/24hr, and less than 20% difference for subjects with albuminuria between 300 and 3500 mg/24hr [16]. Such an implementation was used to warrant a reliable and appreciable evaluation of the treatment effect (eplerenone or dapagliflozin or the combination of both them) in reducing albuminuria after 4 weeks. A further element to take into consideration to enroll patients is the trajectory of the eGFR decline over time. A steeper decline means that patients are at increased risk for future kidney failure and thus are exactly those patients who need a more urgent treatment. A post-hoc analysis of the SONAR trial, a phase 3 trial showing the nephroprotection of atrasentan in CKD and diabetes, demonstrated that treatment effect of atrasentan in terms of kidney failure risk reduction was greater in patients with higher eGFR decline before the trial initiation [17]. Recent trials used the eGFR decline criterion (i.e. eGFR decline > 1 mL/min/year during the 2 years prior to entry in the study based on at least 3 eGFR measurements) to select patients [18].

Outcomes of clinical trials

The outcome or endpoint is defined as the event of interest on which a specific therapeutic intervention should act. In reference to the aforementioned RCTs, the randomization process creates two patient groups that are homogeneous with respect to factors such as gender, age, demographics and blood chemistry characteristics. Each group is assigned a therapeutic protocol to compare the effects of the experimental treatment with those of the standard of care or placebo. In some cases, depending on the study design, the same patient may receive different treatments over time, generally separated by washout periods (the so-called crossover design). What is observed at the end of the study period represents the primary outcome. The primary outcome is crucial in clinical trials because the entire study is designed around its incidence rate (in terms of sample size, duration). Other outcomes that can however be tested as pre-specified or post hoc analyses are the secondary outcomes. The difference in the incidence of the outcome between the treated group and the control group is generally expressed in the form of Relative Risk (RR), defined as the probability that a subject belonging to the group exposed to certain factors (i.e. experimental intervention) develops the outcome compared to the probability that a subject in the unexposed group (i.e. standard of care/placebo) develops the same outcome.

For years, the main hard endpoint evaluated in Nephrology trials was End Stage Kidney Disease (ESKD, that nowadays is also called Kidney Failure or KF), then differentiated into subgroups of persistence of CKD stage 5 (defined by the finding of eGFR < 15 ml/min confirmed on at least two occasions 15-30 days apart), entry into dialysis or arrival at kidney transplantation. The main trials in Nephrology, including the studies that demonstrated the effectiveness of ACEi and ARBs on slowing the progression of kidney damage, have adopted this primary endpoint.

However, it is known that the onset of ESKD may require a long observation period (even over 10 years), generally longer than the duration proposed in the study design [19]. This limit is added to the high rate of failures in the patient screening process, which is far higher than that of trials conducted in other areas of medicine and which, together, account for the important delay recorded in the panorama of scientific research in Nephrology.

To counter this trend, the identification of secondary endpoints or surrogate endpoints that could faithfully anticipate entry into dialysis was proposed as a workaround. Among these, we remember the main ones of reduction of eGFR and albuminuria. While on the first endpoint an eGFR decline of 57-40-30-20% within 3 years was tested, on proteinuria there is still no certain data on the expected reduction necessary to be able to speak of a good response to the treatment.

Despite the attempt by some authors to reduce the threshold of albuminuria among the inclusion criteria of a trial with the aim of increasing the sample of patients enrolled and reducing the study time, there was only a modest reduction in renal and cardiovascular events, contrary to what was expected.

This data was interpreted as a consequence of the variability in the measurement of albuminuria, confirming the importance of extending the inclusion criteria during the screening process to improve feasibility and efficiency of the study [20].

The use of eGFR and albuminuria as secondary outcomes could, on the other hand, reduce the generalizability of the trial results. One could, for example, incur the bias of excluding a given nosological entity such as non-albuminuric CKD, which is known to have an increased prevalence and a high risk of progression towards ESKD [21].

Regarding the reduction in eGFR, historically the main secondary endpoint identified has been an eGFR slope of -57%, generally represented in the form of a doubling of creatininemia. Also in this case, some authors have attempted to identify alternative endpoints with the aim of obtaining greater precision in estimating therapeutic efficacy at the cost, however, of recording a reduction thereof in the absence of a substantial increase in the statistical significance of the study [22]. In any case, the percentage reduction in filtration appears to be the best unit of measurement to estimate the temporal trend of renal function compared to the changes in eGFR in absolute value [19].

Furthermore, it was observed that reducing the percentage slope threshold of the eGFR from 57% to 40% increases the number of patients who develop the outcome, and this data also correlates with a high risk of evolution towards ESKD and mortality [23].

In light of what has been observed, the use of new potential surrogate outcomes such as an eGFR slope equal to – 30/40% on a sample of patients with baseline eGFR < 30 ml/min and a linear filtrate loss recorded in the run period equal to – 5 ml/min/year, could allow the achievement of the outcome and at the same time a reduction in study times.

Among the limitations identified, however, it should not be forgotten that some categories of patients, mainly elderly, non-proteinuric patients, with higher baseline eGFR, observe a non-linear trajectory of renal function which may reduce the predictability of the surrogate endpoints analyzed on the hard endpoints. Furthermore, the various formulas for estimating glomerular filtration take into account factors that can be modified over time, requiring optimization of the precision of the study with the integration of directly measured glomerular filtration values [19].

 

Innovations in the nephrology field of clinical trials

Role of the patient in treatment decisions

In recent decades, the role of the patient has undergone a significant transformation in decision-making processes within randomized clinical trials. In this context, a new doctor-patient relational model has gradually emerged, known as “Shared-Decision Making” (SDM), which involves the sharing of information and decisions between healthcare professionals and enrolled patients, empowering the latter with an increasingly active, informed, and autonomous role [24].

This model has found space since the end of the 1990s in the field of oncology, when various therapeutic options with uncertain outcomes emerged for terminally ill patients.

Thus, an increasingly broad exchange of communication began between the doctor and the patient, in order to involve them in decision-making and increase their awareness in the clinical field (Figure 1).

Figure 1. Innovations in the nephrology field of clinical trials and patients’ role.
Figure 1. Innovations in the nephrology field of clinical trials and patients’ role.

The SDM model is based on four fundamental pillars, as illustrated by some of its pioneers such as Charles and colleagues: 1) equal involvement of medical staff and patients; 2) sharing of information by both; 3) shared participation in drawing up consent to treatment; 4) reaching an agreement on the therapeutic path to follow [25].

The adoption of this model has allowed an ever-increasing participation of patients in trials, with better quality of the trials and construction of more solid evidence.

Greater therapeutic adherence and a reduction in losses during follow-up were also progressively documented, probably as a result of a greater degree of satistaction and psycho-physical well-being on the part of the patients enrolled in these types of trials.

The evidence shows that the use of SDM strategies also allows us to achieve better clinical, behavioral and psychological outcomes compared to those observed in trials with different strategies [26].

If the adoption of this model presents numerous positive implications on a scientific level, those on an ethical level are intuitive, as the priority of these trials is to place the will and needs of the patient at the centre.

However, guaranteeing greater information, awareness and decision-making autonomy implies a greater expenditure of energy and resources such as time and workload, giving more complexity to the decision-making process.

Conflicting circumstances can sometimes arise when the possibility of randomization in the control group or the blinding procedures do not reflect the patient’s wishes [27].

Patients with dementia, or any other type of cognitive dysfunction, also represent a real barrier [28].

Instead, in various circumstances, informing the patient about possible side effects and risks can lead to agitation and confusion, and it is easy to run into misunderstandings [29].

For these reasons, healthcare personnel have made use of Patients Decision Aids (PtDA), i.e. decision-making aids to support patients, consisting of educational materials or easy-to-consult media assistance. These come in the form of smartphone apps, web sources, videos or written documentation such as brochures. In some circumstances, healthcare personnel undergo professional training courses with the aim of acquiring greater communication skills [24].

An international cooperation, the International Patient Decision Aid Standards (IPDAS) Collaboration, was launched specifically to establish the criteria, on the basis of scientific evidence, according to which PtDAs should be drawn up and evaluated, guaranteeing the best possible information and supporting the sharing of decision-making processes [30].

Additionally, the use of questionnaires to assess patients’ preferences for different treatments in a crossover clinical trial is becoming more widespread, and collecting this information will assist clinicians in making personalized treatment decisions. An example is the upcoming FINESSE trial (EU trial number 2023-506434-69-00), in which digital questionnaires will be used to assess patients’ preferences of finerenone or semaglutide, as well as their perspectives on the feasibility of participation in a home-based trial.

New outcomes in current and future RCTs

In addition to monitoring treatment effect with eGFR and albuminuria changes over time (after treatment initiation), novel outcomes are gaining momentum in Nephrology nowadays. To this aim, the International Society of Nephrology is publishing a bi-monthly volume called Global Trial Focus (GTF) reporting the new RCTs related to kidney diseases (herein the link: https://www.theisn.org/in-action/research/clinical-trials-isn-act/). In the GTF, a number of studies tested the effect of treatment on new endpoints, such as quality of life, chronic pain, glycemic control, change in pruritus in different stages of CKD, and others.  The combination of an increasing number of RCTs (mirroring a more feasibility of these studies compared to the past) and more comprehensive endpoints may allow for deeper insights and improve the care of kidney diseases in the future.

Apps that remotely monitor blood pressure

Hypertension affects over a billion people in the world and constitutes a preponderant risk factor for the onset of various diseases, including cardiovascular and renal diseases [31].

It is estimated that approximately 12.8% of global deaths are attributable to this pathology, the treatment of which is based on lifestyle changes and medication.

However, despite the initiation of therapeutic and behavioral measures, hypertension control rates remain suboptimal, with only about half of patients achieving adequate blood pressure control [31–33].

Self-monitoring has allowed us to obtain some clinical benefits over time, favoring greater therapeutic adherence and the reduction of some problems such as masked hypertension or “white coat” hypertension [33].

However, further measures are necessary. The demand for health tools to support the problem has grown considerably, due to the significant impact it has on public health and economic resources. In recent years, there has been an ever-increasing interest in digital innovations, as an inexpensive method within everyone’s reach [31, 34].

The Health App market is constantly growing, and thousands of new ones are produced every year. The main fields of interest are, in fact, represented by chronic diseases such as arterial hypertension and diabetes [33].  The invention of sensors and wearable devices, such as Bluetooth bracelets or smartwatches, has made it possible to detect vital parameters such as heart rate, blood pressure, sleep quality and physical activity [35].

Apps that detect blood pressure also offer various additional functions, such as maintaining a daily blood pressure log, organizing records, and providing reminders for measurements and medication. They also provide the patient with basic information on disease, treatment, lifestyle management and how to self-monitor.

There are available also analysis tools that offer an overview of the trend in blood pressure over time, using graphs or tables. Readings and other recorded data can be exported, allowing healthcare professionals to view and analyze them remotely. Most of these apps are available for free [33, 36].

However, sufficient data is not yet available to evaluate the quality and accuracy of these applications. The results obtained so far must be interpreted with caution due to the variance between the sizes of the samples on which the studies were conducted (very often too small and with subjects coming from different populations), due to the heterogeneity of the studies themselves and the use of self-reported scales to measure adherence to treatments. Therefore, research should establish standardized protocols for measuring parameters and reporting adherence. But it is important not to overlook the potential of this type of intervention to implement knowledge of patients’ health status and support self-management towards a healthy lifestyle and adherence to therapy, especially given the ever-increasing role that artificial intelligence is acquiring, which could guarantee significant support [37].

Remote collection of blood and urine samples

One of the challenges in patient participation in clinical trials is the frequency of visits required for monitoring the progress of the study and for collecting biological samples (blood and urine) for analysis. The introduction of new technologies that allow patients to collect blood and urine samples without needing to visit the study center opens up new possibilities for remote protocol monitoring. Examples of validated devices for at-home blood and urine sampling are Hem-Col® and PeeSpot®, respectively. The Hem-Col® tool is an innovative blood collection microtube designed to facilitate capillary blood sampling through a finger prick; the presence of an anticoagulant and a preservation buffer enhances analyte stability in whole blood, allowing the device to be sent to the laboratory for analysis via regular post.  The PeeSpot® is a validated tool for collecting small amounts of urine (about 1.2 mL) through absorption onto a pad, which is held inside a tube. By adding various preservatives, the urine in the PeeSpot® can be preserved for up to 4 days in the refrigerator before being sent to the laboratory for the measurement of urinary albumin and creatinine. These devices represent a practical and efficient solution for both patients and healthcare professionals involved in clinical trials, lowering costs associated with frequent in-patient visits and optimizing the workflow. The FINESSE study (EU trial number 2023-506434-69-00), which will soon be launched, will use both devices for the remote monitoring of enrolled patients.

 

Conclusions

Many randomized studies have been published around kidney disease in the past few years. Taken together, results of randomized studies have allowed to improve guidelines and, at the end, to improve patients’ survival, time free from dialysis and to reduce the number of CV events. Significant progresses have also been made over the past decades in terms of inclusion criteria, outcomes, and patients’role, which will aid the future conduction of randomized studies worldwide.

 

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Ottimizzazione del trattamento e aderenza agli standard di cura nella gestione della CKD in medicina generale: il progetto TOSCA-CKD

Pubblicato il Scarica PDF

Francesco Pesce

DOI: 10.69097/42-02-2025-10

Francesco Pesce¹, Domenico Pasculli², Giuseppe Castellano³, Luca De Nicola⁴, Giovanni Gambaro⁵, Vincenzo Panichi6, Domenico Santoro7, Francesca Viazzi8, Monica Zanella9, Loreto Gesualdo10

1 Division of Renal Medicine “Ospedale Isola Tiberina – Gemelli Isola” Università Cattolica del Sacro Cuore, Rome Italy
2 ASL BA-SIMG Società Italiana Medici di Medicina Generale e delle Cure Primarie, Molfetta, Italy
3 Department of Nephrology, Dialysis, and Renal Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
4 Nephrology and Dialysis Div.,Dept. Advanced Medical and Surgical Sciences,University of Campania Luigi Vanvitelli, Naples, Italy
5 Division of Nephrology, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
6 Nephrology, Transplants and Dialysis Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
7 Nephrology and Dialysis Division, University of Messina, Messina, Italy
8 Division of Nephrology, Dialysis, and Transplantation, IRCCS Ospedale Policlinico San Martino, Genova, Italy
9 Department of Nephrology, Dialysis, and Transplantation, San Bortolo Hospital, 36100 Vicenza, Italy
10 Department of Precision and Regenerative Medicine and Ionian Area, Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy

Corrispondenza a:
Francesco Pesce
Division of Renal Medicine "Ospedale Isola Tiberina – Gemelli Isola" Università Cattolica del Sacro Cuore,
Via di Ponte Quattro capi, 39, 00186
Rome Italy
Tel/Fax: +39 06 6837540
E-mail: francesco.pesce@fbf-isola.it

 

Abstract

Background. Una collaborazione efficace tra medici di medicina generale (MMG) e nefrologi è fondamentale per ottimizzare la gestione della malattia renale cronica (CKD). Il progetto TOSCA-CKD (Treatment Optimization and Standard of Care Adherence in CKD Primary Care) ha avuto l’obiettivo di valutare l’implementazione delle linee guida e l’utilizzo di terapie nefroprotettive nella medicina generale.
Metodi. I dati clinici sono stati raccolti dalle cartelle elettroniche dei medici di base in 12 regioni italiane. Le informazioni sono state analizzate al basale (T0) e dopo 6 mesi (T6) di collaborazione con i nefrologi. Durante questo periodo osservazionale, i MMG hanno partecipato a programmi di formazione a distanza, che includevano webinar condotti da esperti e discussione di casi clinici.
Risultati. Hanno partecipato allo studio 76 MMG e 9 nefrologi, valutando una coorte di 124,759 pazienti. L’utilizzo del test uACR (rapporto urinario albumina/creatinina) è aumentato del 23.3% da T0 a T6 (dal 3.0% al 3.7%; p < 0.001). Analogamente, l’utilizzo del calcolo del eGFR è aumentato del 15.2% (dal 29.7% al 34.2%; p < 0.001). La diagnosi di CKD è aumentata del 17,5% tra i pazienti con eGFR < 60 mL/min/1,73 m² (dal 4% al 4.7%) e del 40% tra i pazienti con ACR > 30 mg/g (dallo 0.5% allo 0.7%). L’uso di ACEi/ARB si è mantenuto stabile intorno al 50%, mentre il trattamento con SGLT2i, il nuovo standard terapeutico secondo le attuali linee guida sulla CKD, è aumentato del 29.8% (dal 4.7% al 6.1%).
Conclusioni. Il progetto TOSCA-CKD ha dimostrato che la formazione a distanza dei MMG e un approccio strutturato di co-gestione con i nefrologi migliorano significativamente l’identificazione precoce e la gestione della CKD nella medicina generale.

Parole chiave: malattia renale cronica, medicina generale, terapia medica basata sulle linee guida, screening, SGLT2i

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Chronic kidney disease (CKD) is a prevalent and often underrecognized condition, affecting an estimated 700-840 million individuals worldwide [1]. It is characterized by persistent structural and/or functional kidney abnormalities, typically followed by progressive kidney damage. CKD is defined by the 2024 KDIGO guidelines as an estimated glomerular filtration rate (eGFR) of ≤60 mL/min/1.73 m², measured over a duration of at least three months, irrespective of the underlying etiology. CKD can also be diagnosed in the presence of kidney damage for a minimum of 3 months, indicated by structural abnormalities (e.g., detected through imaging or renal biopsy), persistent urine sediment abnormalities, or more frequently elevated urine albumin-to-creatinine ratio (ACR ≥30 mg/g).

The guidelines further classify CKD based on eGFR, divided into five stages (G1-G5), and on the degree of albuminuria, categorized into three stages (A1-A3). CKD is associated with an increased risk of cardiovascular disease and progression to end-stage kidney disease (ESKD). Currently, CKD is the 10th leading cause of death in the United States [2], with projections indicating it will become the 5th leading cause of death by 2040 [3].

Epidemiological data from the National Health and Nutrition Examination Survey III (NHANES III) report a global prevalence of CKD of approximately 10%. In Italy, the prevalence of CKD is estimated at 7.8% in women and 8.1% in men, based on data from the CARHES study [4]. This burden is expected to increase due to several factors, including population ageing, the rising incidence of comorbidities such as type 2 diabetes (T2D), heart failure (HF), and hypertension (HTN), as well as increased awareness of the importance of early CKD diagnosis, supported by the availability of simple, reliable, and cost-effective diagnostic tests.

The recent international REVEAL-CKD study highlighted the importance of early detection and prompt therapeutic intervention in CKD management. This study not only assessed the prevalence of undiagnosed early-stage CKD (stage 3), but also explored the associated risk factors (T2D, HTN, HF) and the impact of early diagnosis and appropriate therapeutic strategies on slowing disease progression. The REVEAL-CKD study found high rates of underdiagnosis, ranging from 61.6% to 95.5% across different countries, including the United States, Italy, Germany, Japan, and France. Specifically, the Italian cohort revealed that 77% of patients in stage 3 were undiagnosed (with 83.0% in stage 3a and 64.8% in stage 3b). Further analysis of the international cohort revealed that among patients who were diagnosed with stage 3 CKD, there was a notable reduction in the rate of eGFR decline, dropping from an average of -4.12 mL/min per year to just -0.30 mL/min per year over a two-year period. These findings emphasize that early diagnosis, followed by appropriate treatment and monitoring in accordance with clinical guidelines, can significantly slow the progression of CKD and potentially reduce the risk of adverse outcomes such as end-stage kidney disease [5].

The key role of GPs in the early identification of CKD was explored by the DANTE CKD pilot study (Disease Awareness Innovation Network for Chronic Kidney Disease Identification in General Practice) [6]. This study demonstrated the crucial role of early diagnosis and effective co-management between GPs and nephrologists in optimizing care pathways and potentially delaying disease progression. Through a regional experience, the study showed that targeted training and close collaboration between GPs and nephrologists significantly increased GPs’ awareness of CKD, facilitating earlier diagnosis, especially in high-risk patients, such as those with T2D, HTN, and HF, conditions that are strongly associated with kidney disease. The impact was evident in the increased proportion of patients tested for eGFR and uACR.

After the impressive results achieved through this regional experience within six months of collaboration between GPs and nephrology specialists, the national ENDORSE project (Early Chronic Kidney Disease Point of Care Screening) [7] was developed to evaluate, across Italy, the clinical and economic implications of GPs’ targeted training to enhance CKD early diagnosis. The ENDORSE project involved over 50 GPs and a cohort of more than 110,000 individuals, aiming to build a national collaborative network connecting nephrologists and primary care providers across 11 regions. After six months, the proportion of patients tested for eGFR increased by 44.7%, while testing for uACR rose by 95.2%. Overall, the number of patients screened according to KDIGO guidelines increased by 128.9%, demonstrating the effectiveness of medical networking and targeted training in improving early detection of CKD. In addition, to assess the potential economic benefits of early CKD diagnosis, a Budget Impact Analysis (BIA) was conducted within the enrolled cohort, considering a timeframe of 5 years and varying rates of eGFR decline. The analysis projected cumulative savings of €1.7 million over five years in the study cohort, and an estimated savings of €106.6 million when applied to the entire Italian CKD population.

Building on the evidence of these prior initiatives, the TOSCA-CKD project (Treatment Optimization and Standard of Care Adherence in CKD Primary Care) was designed to further enhance early identification of CKD patients and ensure timely referral to nephrologists for optimized treatment. While the DANTE and ENDORSE projects focused primarily on early diagnosis, TOSCA-CKD aimed to evaluate in primary care settings the implementation of clinical guidelines and the use of nephroprotective therapies, including RAAS inhibitors and SGLT2 inhibitors, to better manage disease progression. By reinforcing both diagnostic and therapeutic management, TOSCA-CKD aims to further reduce the burden of CKD and improve patient outcomes through a more integrated and coordinated approach to care.

 

Methods

The TOSCA-CKD project involved 76 General Practitioners (GPs) from 12 different Italian regions, supported by 9 nephrologists and 1 tutor who provided technical assistance on the use of the clinical information system. GPs were suggested by the panel of nephrologists based on several selection criteria, aiming to ensure a representative and balanced sample. A fundamental inclusion criterion was the use of the Millewin electronic health record (EHR), a Class I medical device (EU Regulation 2017/745) authorized by the Italian Ministry of Health (ID 1847935), which is employed for the registration and storage of clinical data within the Italian National Health Service (SSN). Further criteria included the geographic representation of GPs, with participants selected from different regions to reflect the diversity of healthcare settings across the country, and the matching of GPs for similar patient loads to minimize potential biases related to differences in practice volume.

GPs involved in the TOSCA-CKD project participated in a series of structured training sessions conducted by nephrologists. These sessions were designed to update GPs on the latest clinical guidelines for the diagnosis, monitoring, and management of CKD, as well as its common comorbidities. The primary goal of the training was to strengthen GPs’ skills in early CKD detection, improve their ability to manage the disease effectively, encourage collaborative networking with nephrologists, and ultimately ensure optimal care for patients.

At baseline (T0) and after 6 months (T6) of training and networking activities, participating GPs were asked to extract specific clinical data from their Millewin EHRs. The data collected included: number of patients evaluated, age, sex, comorbidities, estimated glomerular filtration rate (eGFR), albumin-to-creatinine ratio (ACR), ongoing pharmacological treatments, and the proportion of patients with eGFR < 60 mL/min/1.73m² and ACR> 30. All data collected were anonymized to ensure patient privacy and were then used for subsequent analysis.

 

Statistical analysis

The original dataset included 124,759 patients examined at baseline (T0) and 126,921 patients examined after six months (T6). A descriptive analysis was performed for patient demographics (age, gender) and the prevalence of comorbidities. Screening tests and the use of specific medications were assessed at both T0 and T6. The change (Delta) between T0 and T6 was calculated as the percentage difference.

Pearson’s Chi-square test was used to assess the statistical significance of differences observed between T0 and T6. An alpha significance level of 0.05 was set for all statistical analyses. Data were analyzed using IBM SPSS Statistics software, version 28.

 

Results

The baseline characteristics [T0] of the 124,759 patients included in the cohort, whose data were extracted from Electronic Medical Records (EMRs) of 76 GPs across 12 Italian regions, are summarized in Table 1. The mean age of the cohort was 53.21 years (SD ± 20.87), with 52.8% of patients being female. Regarding comorbidities commonly associated with CKD, 8% of patients had T2D, 23.9% had HTN, and 1% had HF.

At the 6-month follow-up (T6), the demographic profile remained largely unchanged, with a total of 126,921 patients. The mean age was 52.93 years (SD ± 20.94), and the proportion of female patients was 52.9%. The prevalence of T2D, HTN, and HF was 8.5%, 25.3%, and 1.1%, respectively (Table 1).

Overall, a significant increase in uACR and eGFR tests was observed after the educational intervention (Table 2 and 3). Specifically, the proportion of patients undergoing uACR screening rose from 3.0% at T0 to 3.7% at T6, reflecting a 23.3% increase in screening (p < 0.001). Similarly, eGFR testing increased from 29.7% at T0 to 34.2% at T6, representing a 15.2% increase in the rate of testing (p < 0.001).

When analyzed by subgroup, a 15% increase in uACR screening was found among T2D patients (p < 0.001), and a 14.6% increase was observed in patients with HTN (p < 0.001). In contrast, for patients with HF, the change in uACR screening was not statistically significant (p = 0.116). In terms of eGFR testing, the rate among patients with diabetes increased by 8.6% (p < 0.001), while it rose by 7.3% among hypertensive patients (p < 0.001). Similarly, the increase in eGFR testing for HF patients did not reach statistical significance (p = 0.129).

The overall increase in screening activity among GPs, prompted by the training intervention, resulted in a higher number of new CKD diagnoses. From T0 to T6, the proportion of patients with eGFR <60 mL/min/1.73m² increased by 17.5%, from 4% to 4.7% (p < 0.001) (Figure 1a), while the proportion of patients with uACR ≥30 mg/g expanded by 40%, from 0.5% to 0.7% (p < 0.001) (Figure 1b).

Regarding pharmacological treatments, the percentage of use of different classes of drugs in patients with CKD (e-GFR <60 mL/min/1.73 m²) was assessed. Overall, adherence to clinical guidelines was found to be low, with no significant global changes from T0 to T6, except for the use of SGLT2i (Table 4, Figure 2a). Specifically, around half of the patients with CKD were prescribed ACEi (50.5% at T0 and 49.9% at T6). Similarly, the proportion of patients on angiotensin receptor blockers (ARBs) was 48.4% at T0 and 48.7% at T6. The ACEi/ARB combination therapy was used by 22.2% of patients at T0 and 22.6% at T6. Additionally, 44.9% of patients were prescribed diuretics at T0 and at T6.

SGLT2i were prescribed to 4.7% of patients at T0 and 6.1% at T6, reflecting a 29.8% increase (p < 0.05) (Figure 2b). It is worth noting that, during the study period, dapagliflozin was the only SGLT2 inhibitor approved in Italy for the treatment of CKD, regardless of diabetes status. Dapagliflozin accounted for more than half of all SGLT2i prescriptions, both at baseline and at T6 (2.6% and 3.5%, respectively), representing a 34.6% increase (p < 0.05).

COVARIATE T0 (N=124759) T6 (N=126921)
AGE
Mean (SD) 53.21 (20.87) 52.93 (20.94)
SEX
Male 58.825 (47.2%) 59.767 (47.1%)
Female 65.934 (52.8%) 67.154 (52.9%)
T2D
Count (%) 9.951 (8) 10.725 (8.5)
HTN
Count (%) 29.849 (23,9) 32.144 (25.3)
HF
Count (%) 1.249 (1) 1.411 (1.1)
Table 1. Demographic and clinical characteristics of cohort population at T0 and T6. Type 2 Diabetes; HTN: Hypertension; HF: Hearth Failure; SD: Standard Deviation.
GROUP T0 T6 DELTA (%) p-value
OVERALL
Count N° (%) 3,743 (3.0) 4,695 (3.7) +23.3 <0.001¹
T2D
Count N° (%) 2,052 (20,6) 2,546 (23.7) +15.0 <0.001¹
HTN
Count N° (%) 2,855 (9.6) 3,543 (11.0) +14.6 <0.001¹
HF
Count N° (%) 177 (14.2) 231 (16.4) +15.5 = 0.116
Table 2. Variation in uACR test prescribed between T0 and T6. uACR: Urine albumin-creatinine ratio; T2D: Type 2 Diabetes; HTN: Hypertension; HF: Heart Failure; ¹Pearson’s Chi-square test was found to be statistically significant (p-value < 0.001).
GROUP T0 T6 DELTA (%) p-value
OVERALL
Count N° (%) 37,055 (29.7) 43,466 (34.2) +15.2 <0.001¹
T2D
Count N° (%) 5,662 (56.9) 6,631 (61.8) +8.6 <0.001¹
HT
Count N° (%) 15,901 (53.3) 18,378 (57.2) +7.3 <0.001¹
HF
Count N° (%) 735 (58.8) 871(61.7) +4.9 = 0.129
Table 3. Variation in e-GFR test prescribed between T0 and T6. e-GFR: Estimated Glomerular Filtration Rate; T2D: Type 2 Diabetes; HT: Hypertension; HF: Heart Failure; ¹Pearson’s Chi-square test was found to be statistically significant (p-value < 0.001).
DRUG T0 (%) T6 (%) DELTA (%) p-value
ACEi 50.5 49.9 -1.2 Ns
ARBs 48.4 48.7 +0.6 Ns
ARBs+ACEi 22.2 22.6 +1.8 Ns
SGLT2i 4.7 6.1 +29.8 p<0.05¹
MRA 14.5 14.8 +2.1 Ns
DIURETICS 44.9 44.9 0 Ns
BETA BLOCKERS 52.8 53.1 +0.6 Ns
CALCIUM ANTAGONISTS 40.2 40.3 +0.2 Ns
LIPID LOWERING DRUGS 60.7 60.6 -0.2 Ns
Table 4. Drugs utilization in CKD patients (e-GFR<60 mL/min/m2) between T0 and T6. e-GFR: Estimated Glomerular Filtration Rate; ACEi: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin Receptor Blockers; SGLT2i: Sodium-glucose cotransporter 2 inhibitors; MRA: Mineralcorticoid receptor antagonist. ¹Pearson’s Chi-square test was found to be statistically significant (p-value <0.05); ns:  statistically non-significant.
Figure 1. The proportion of patients diagnosed with CKD by 17.5% for patients with a glomerular filtration rate (e-GFR) < 60 mL/min/1.73 m² (a)
Figure 1. The proportion of patients diagnosed with CKD by 17.5% for patients with a glomerular filtration rate (e-GFR) < 60 mL/min/1.73 m² (a) and by 40% for patients with an albumin-to-creatinine ratio (ACR) ≥ 30 mg/g (b). CKD: Chronic Kidney Disease; e-GFR: estimated glomerular filtration rate; ACR: albumin-to-creatinine ratio.
Figure 2. Use of ACEi and ARBs remained almost stable between T0 and T6 at around 50%, with no significant difference
Figure 2. Use of ACEi and ARBs remained almost stable between T0 and T6 at around 50%, with no significant difference (a); use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) increased by 29.8% from 4.7% to 6.1%; the difference was statistically significant (p value < 0.05) (b). ACEi: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; SGLT2i: sodium-glucose cotransporter 2 inhibitors.

 

Discussion

CKD is a significant global health burden, associated with high morbidity, mortality, and substantial healthcare costs. A microsimulation model used in the INSIDE-CKD study assessed the clinical burden of CKD across eleven countries: Australia, Belgium, Brazil, Canada, China, Japan, Germany, Italy, France, Spain, the UK, and the US. It collected data on CKD prevalence, renal replacement therapy (RRT), comorbidities, and cardiovascular complications for each country [8].

For Italy, the model projected an increase in the CKD population from 3.9 million in 2021 to 4.4 million by 2026, representing a 14.7% rise in the estimated prevalence per 100,000 population. The profile of CKD is expected to shift towards more advanced stages (3b-5), with an estimated increase in RRT cases from 73,370 to 84,671. The financial impact on healthcare costs is projected to be significant, with an anticipated rise of 10.8%, of which 53% will be attributed to the costs of renal replacement therapy. In 2021, CKD accounted for 3.2% of Italy’s public healthcare spending, totaling approximately 4 billion euros.

In this context, GPs, who manage the majority of patients with or at risk of CKD, play a pivotal role in the early detection of the disease. Unfortunately, awareness among GPs remains suboptimal. In 2017, for example, the International Society of Nephrology’s Global Kidney Health Atlas survey, conducted across 125 countries (representing approximately 93% of the world’s population), found that 64% of respondents reported low or very low awareness of CKD in primary care settings [9]. To address this gap, Aminu K. Bello et al. stressed the importance of well-designed training programs, recommending hybrid models that combine webinars, face-to-face sessions, case study workshops, symposia, and online learning modules. These approaches aim to bridge knowledge gaps and facilitate the adoption of appropriate diagnostic and therapeutic pathways [10].

The TOSCA-CKD project, consistently with the results of the DANTE and ENDORSE studies, aimed to further demonstrate the value of training programs and GP-nephrologist networking in improving awareness and optimal management of CKD patients in the Italian real-world setting. The project successfully showed the effectiveness of educational programs in enhancing CKD awareness, leading to a significant increase in the routine use of diagnostic tests, particularly in high-risk populations. Specifically, the use of uACR and eGFR increased by 23.3% and 15.2%, respectively, over the study period, resulting in a corresponding rise in CKD diagnoses. In particular, the proportion of patients with eGFR <60 ml/min/1.73m² increased by 17.5%, while the proportion of patients with uACR ≥30 rose by 40%, with both changes being statistically significant.

In addition to early detection, timely implementation of appropriate therapeutic interventions, especially through specialist referral, is essential for effective CKD management. Significant pharmacological advancements have been made in the management of CKD in recent years, particularly with the introduction of SGLT2i. These medications have provided strong clinical evidence in slowing disease progression and reducing complications in CKD patients, irrespective of diabetes [11–13]. As a result, SGLT2i have become a cornerstone of CKD management, with international guidelines now recognizing them as the new standard of care for these patients.

The proven clinical benefits of SGLT2i may also lead to a reduction in healthcare costs, as outlined in previous studies. For example, an analysis conducted by McEwan et al., published in 2023, evaluated the economic impact of dapagliflozin treatment in addition to standard of care (SoC) compared to SoC alone, over a 3-year period. Specifically, applying the results of the DAPA-CKD study to a cohort of 100,000 patients, the economic analysis calculated the healthcare costs associated with managing end-stage kidney disease (ESKD), hospital admissions for heart failure (HHF), acute kidney injury (AKI), and all-cause mortality (ACM). The study found that treatment with dapagliflozin plus SoC resulted in a 33% reduction in total healthcare costs (equating to $264 million) over 3 years, due to a reduction in cardiorenal events [14].

Despite the robust evidence supporting their clinical and economic benefits, SGLT2i are still not widely adopted in clinical practice. A study conducted in the UK to assess the adoption of KDIGO 2024 guidelines and the appropriateness of CKD management in primary care revealed that only 17% of eligible patients were on SGLT2i treatment, most of whom were T2D patients. Importantly, patients at higher risk for adverse outcomes based on eGFR and albuminuria were less likely to receive SGLT2i therapy, as were non-diabetic patients. Although the time between the publication of KDIGO 2024 recommendations and the observational period of the project may have been too short to observe significant impact in clinical practice, these findings highlight the ongoing need for training and education for clinicians to ensure that patients at high risk of kidney disease progression receive the most appropriate treatments [15].

Further, the OPTIMIZE-CKD study by Tangri et al. highlighted the impact of treatment inertia in initiating nephroprotective therapies in patients with CKD [16]. This study specifically examined the use of SGLT2i in patients newly diagnosed with stages 3-4 CKD in Japan, Sweden, and the United States, after the approval of dapagliflozin in these countries. The results revealed that, more than 12 months post-approval, only 1.4%, 5.1%, and 1.3% of patients, respectively, had been treated with dapagliflozin. Notably, non-diabetic CKD patients, the majority of the cohort, were less likely to be prescribed dapagliflozin compared to those with T2D. This delay in the adoption of new therapies highlights the challenges associated with translating clinical evidence into practice and the persistence of treatment inertia, particularly in non-diabetic patients.

In Italy, a similar pattern of inertia in using nephroprotective therapies has been observed. The Annali AMD report from the Italian Associazione Medici Diabetologi (AMD) highlighted that, despite a general increase in the use of SGLT2i among patients with T2D (from 29% in 2022 to 35.8% in 2023), 62.5% of diabetic patients with concomitant CKD were still not receiving these medications. This finding points to the persistent gap in treatment, despite growing evidence of the SGLT2i efficacy in reducing kidney and cardiovascular events [17].

To further raise awareness among GPs and address the suboptimal management of CKD patients, the TOSCA-CKD study aimed to evaluate the use of nephroprotective drugs, such as RAASi and SGLT2i, in CKD patients (eGFR <60 mL/min/1.73m²) during the observation period. The results confirm the underutilization of guideline-directed medical therapies (GDMT). At baseline (T0), only half of the patients were prescribed an ACEi (50.5%) or an ARB (48.4%), with these rates remaining almost unchanged at T6 (ACEi 48.7%, ARBs 49.9%). Conversely, for SGLT2i, a significant increase in treatment adoption was observed from T0 to T6, rising from 4.7% of patients to 6.1%, reflecting a 29.8% increase (p < 0.05). Among SGLT2i, dapagliflozin was the most frequently used drug, particularly due to its prescribing eligibility by nephrologists during the project period, with a 34.6% increase from T0 to T6.

One possible explanation for the lack of increase in the use of ACE inhibitors and ARBs from T0 to T6, in contrast to the observed rise in the use of SGLT2 inhibitors, could be the significant focus placed on this novel class of drugs within the context of the study, as they are recommended as first-line therapy by the guidelines. Given this emphasis, it is likely that, in the first instance, SGLT2 inhibitors were prioritized and added to patients already receiving ACE inhibitors or ARBs, particularly those with comorbidities such as diabetes or heart failure. This strategy reflects a gradual approach to therapy optimization, which is consistent with the phenomenon of therapeutic inertia. Moreover, it is important to acknowledge that RAAS inhibitors have historically been underused and are still subject to high rates of discontinuation and suboptimal dosing. The high rate of discontinuation may have confounded the potential introduction of new ACE inhibitors or ARBs during the study period.

However, although the TOSCA-CKD study showed a positive trend in SGLT2i use, reflecting the effectiveness of the educational intervention and improved GP-to-nephrologist referrals, the absolute number of CKD patients receiving SGLT2i treatment is still too low and far from what is needed to achieve optimal care, especially given the proven benefits of these medications in improving cardiorenal outcomes and reducing mortality.

The relatively short observation period of this study may have been insufficient to fully capture the optimization of all nephroprotective therapies as many patients identified at the 6-month follow-up may not have yet undergone a specialist evaluation, and thus, their treatment may not have been fully optimized.

Nevertheless, the findings still highlight a persistent treatment gap, emphasizing the ongoing need to reduce delays and ensure CKD patients receive timely and appropriate care.

Conclusions

The TOSCA-CKD project, despite certain limitations, including the relatively short observation period, represents a clinically relevant initiative. The project demonstrated, in a real-world setting representative of Italian primary care settings, that remote GPs’ targeted educational programs, led by nephrologists, can effectively improve both the early identification and therapeutic management of CKD patients. However, CKD management remains suboptimal compared to guidelines’ recommendations. These results underscore the need for a structured care pathway with a well-defined co-management approach, including timely referrals to nephrology clinics, particularly for patients at higher risk of progression. A structured approach is essential for optimizing therapeutic management in line with KDIGO guidelines, especially as effective treatment options are now available to slow disease progression and manage comorbidities. Ultimately, these interventions could contribute to reducing the long-term healthcare burden associated with CKD.

 

Bibliography

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  5. Tangri N, Moriyama T, Schneider MP, et al. Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan, and the USA: results from the multinational observational REVEAL-CKD study. BMJ Open . 2023;13:e067386. https://doi.org/10.1136/bmjopen-2022-067386.
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Iohexolo è un metodo possibile per stimare la velocità di filtrazione glomerulare?

Pubblicato il Scarica PDF

Fabrizio Cristiano

DOI: 10.69097/42-02-2025-03

Fabrizio Cristiano1,2, Guillermo Rosa Diez4, Carlos Guido Musso3,4, Jenny Cristiano5

1 UOSD Nefrologia e Dialisi Ospedale di Ortona, Asl 2 Lanciano Vasto Chieti
2 Department of Neuroscience, Imaging and Clinical Science, University "G. d'Annunzio" Chieti - Pescara, 66100 Chieti, Italy
3 Servicio de Nefrología, Hospital Italiano, Buenos Aires, Argentina
4 Research Department, Hospital Italiano de Buenos Aires. Buenos Aires, Argentina
5 UOC Farmacia Ospedaliera – Ospedale Clinicizzato di Chieti – Asl 2 Lanciano Vasto Chieti

Corrispondenza a:
Fabrizio Cristiano
UOSD Nefrologia e Dialisi Ospedale di Ortona, Asl 2 Lanciano Vasto Chieti
Department of Neuroscience, Imaging and Clinical Science, University "G. d'Annunzio" Chieti - Pescara, 66100 Chieti, Italy
E-mail: fabrizio.cristiano@asl2abruzzo.it

 

Abstract

La misurazione della velocità di filtrazione glomerulare (GFR) è essenziale nella diagnosi e gestione della malattia renale cronica (CKD) e della malattia policistica renale autosomica dominante (ADPKD), entrambe condizioni che richiedono una valutazione precisa della funzione renale. Tradizionalmente, il GFR è stato stimato usando marcatori endogeni come creatinina e cistatina C, sebbene questi possano risultare inaccurati a causa di fattori non correlati alla funzione renale, come massa muscolare e dieta. Il metodo di clearance di iohexolo, un mezzo di contrasto non ionico e idrosolubile, rappresenta un’alternativa più accurata e meno invasiva rispetto ai marcatori tradizionali come inulina o marcatori radioattivi. Iohexolo viene eliminato esclusivamente tramite filtrazione glomerulare, rendendolo altamente adatto per una stima diretta del GFR. Questo articolo descrive le procedure per la clearance di iohexolo, che prevedono prelievi di sangue a intervalli definiti dopo somministrazione endovenosa. Nei pazienti con funzione renale normale, gli intervalli di campionamento sono più frequenti, mentre nei pazienti con CKD avanzata, inclusi quelli con ADPKD, l’eliminazione dell’iohexol è più lenta e richiede intervalli più ampi per garantire un’analisi accurata della clearance. Iohexolo ha dimostrato alta precisione e riproducibilità, anche rispetto ad altri marcatori. Vi sono numerose evidenze di come l’uso di iohexolo possa monitorare efficacemente la progressione di CKD e ADPKD. In particolare, nell’ADPKD, iohexol rileva variazioni sottili ma clinicamente significative del GFR, anche nelle fasi iniziali della malattia, rendendolo utile per valutare terapie mirate. Tuttavia, l’uso di iohexolo è limitato a centri specializzati a causa dei costi elevati e dei protocolli rigorosi. Purtroppo il suo utilizzo a tutt’oggi è ancora abbastanza limitato e non esportabile in tutte le realtà europee.

Parole chiave: velocità di filtrazione glomerulare, iohexolo, malattia renale cronica

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Glomerular filtration rate (GFR) assessment is a parameter in the diagnosis and management of chronic kidney disease (CKD), allowing an accurate estimation of renal function. Several methods have been proposed to measure GFR, including endogenous markers such as serum creatinine and cystatin C, as well as methods based on exogenous markers that are administered and subsequently quantified in plasma or urine [1]. Among exogenous markers, iohexol has recently gained attention due to its reliability, safety and accuracy in determining GFR. Iohexol is a nonionic, water-soluble, low-osmolal contrast agent, which has ideal characteristics for the assessment of GFR. Its elimination exclusively by the kidney, through glomerular filtration, makes it particularly suitable for this purpose [2].

 

GFR Analysis Methodology

The iohexol clearance method is a widely accepted approach to estimate glomerular filtration rate (GFR) due to its high accuracy and reproducibility. This method involves the administration of an exogenous tracer (iohexol) followed by serial blood sampling to monitor its plasma clearance. Below is a step-by-step description of the method. Iohexol is intravenously injected as a 5% solution (50 mg/mL), with the dose ranging from 5 to 10 mL (approximately 250 mg of iohexol). The precise dose is adjusted according to the patient’s body weight and renal function. Blood samples are collected at predetermined intervals based on the patient’s renal function. In patients with normal or mildly impaired renal function, blood samples are collected at shorter intervals, typically at 2, 4, and 6 hours. Patients with moderately to severely impaired renal function require extended sampling intervals, such as 2, 4, 6, 12, and 24 hours, to account for slower iohexol elimination. Plasma iohexol concentrations are measured using spectrophotometry or high-performance liquid chromatography (HPLC). The clearance rate of iohexol, directly proportional to GFR, is calculated from the plasma concentration decay curve. GFR is estimated using models such as the Brøchner-Mortensen formula, which considers the volume of distribution and elimination kinetics of iohexol. Protocol Adaptations: Specific protocols (e.g., 2-point or multi-point sampling) are tailored to optimize accuracy while reducing patient burden. Adjustments are made for variables like age, body mass, and comorbidities. This structured approach ensures a reliable estimation of GFR while accommodating physiological and pathological variations among patients. The iohexol clearance method has proven effective in clinical settings, particularly for patients with chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD), where precise GFR monitoring is crucial.

This is necessary to capture the slower elimination and obtain adequate data to correctly calculate the clearance [3]. Each patient may present physiological variations that affect the pharmacokinetics of iohexol, so protocols may be adapted based on factors such as age and body mass (e.g., elderly or underweight patients eliminate the tracer more slowly) and comorbid conditions (e.g., liver disease).   These adjustments are aimed at obtaining a detailed and accurate profile of GFR, especially in patients with impaired renal function or significant physiological variability [4]. The concentration of iohexol is determined in the laboratory by spectrophotometry or chromatography, and the data obtained are used to calculate the plasma clearance of iohexol. The clearance of iohexol (i.e. the rate at which it is eliminated from the plasma) is proportional to the GFR. In practice, the GFR can be calculated with formulas that consider the volume of distribution and the elimination time of iohexol [5].

Renal Function Level Tracer Dose Sampling Times Additional Notes
Normal renal function 5-10 mL (250 mg) 2, 4, 6 hours Frequent sampling captures rapid elimination
Mildly impaired function 5-10 mL (250 mg) 2, 4, 6 hours Protocols remain similar to normal function
Moderate impairment 5-10 mL (250 mg) 2, 4, 6, 12 hours Sampling extended to account for slower elimination
Severe impairment 5-10 mL (250 mg) 2, 4, 6, 12, 24 hours Comprehensive sampling ensures accurate calculation over prolonged clearance
Special populations Adjusted by weight Variable intervals Tailored protocols based on age, comorbidities (e.g., liver disease), and body mass
Table 1. Detailed description of the iohexol Method for GFR Estimation. Iohexol Sampling protocols based on renal function.

 

GFR Measurement: The Standard in Renal Functionality Assessment

Unlike other previously used contrast agents, such as inulin or 125I-iothalamate, iohexol has fewer side effects, is easy to handle, and does not require a specialized center for radioactivity management, as is the case with radioactive markers. Numerous studies have shown that iohexol offers high accuracy in estimating GFR. For example, comparison of iohexol clearance with inulin confirmed the accuracy of iohexol as a valid and less invasive alternative. GFR measurement with iohexol is based on blood sampling after marker injection and calculations that take into account the concentration of the marker in the plasma at defined intervals. Iohexol clearance has been shown to be useful in patients for whom creatinine is not always accurate in estimating renal function, particularly in conditions such as CKD, acute renal failure, and in pediatric patients or those with significant comorbidities, as this method is less influenced by variables such as muscle mass, age, and diet [6].

The ability to standardize a formula for accurate estimation of GFR and to use specific formulas for interpretation of clearance values ​​has reduced errors related to GFR measurement. However, the criticality of measuring GFR with iohexol is represented by rigorous protocols for blood sampling and laboratory analysis. Errors in sampling times and measurement techniques can influence the precision of the results. Many laboratories have adopted standardized protocols to minimize these fluctuations, making the use of iohexol more common and widespread in order to consolidate its role in clinical practice and in nephrology research, especially for those particulars that may present variability in estimating GFR [7].

Glomerular filtration rate (GFR) is the gold standard measure of kidney function and is critical to the diagnosis and management of kidney disease. An adequate estimation of GFR requires the measurement of renal clearance of an exogenous marker with the characteristic of being filtered by the kidney and that is not subject to reabsorption, metabolism or secretion. Although inulin represents an ideal marker of glomerular filtration, it cannot be used in clinical practice to estimate glomerular filtration. 125I-iothalamate and 99mTc-diethylenetriaminepentaacetic acid (DTPA) can represent an alternative, however, being difficult to handle and with safety limits, they cannot also be used in clinical practice. A possible alternative for estimating glomerular filtration could be represented by the use of non-radioactive contrast agents such as iothalamate (ionic) [8], which in terms of estimation and precision are comparable to inulin. However, they have limitations mainly represented by the collection method of urine and potential errors affected by delayed bladder emptying, such as obstructive causes in male patients or an excessive water load. The use of an appropriate exogenous marker (51Cr-EDTA, 125I-iothalamate, iohexol) has the advantage of estimating glomerular filtration precisely by evaluating the rate of elimination of the tracer after an intravenous infusion [9] and with blood samples repeated at intervals over time, however the procedure is complicated to implement. Thanks to the Bröchner-Mortensen formula it was possible to correlate iohexol with inulin clearance with data analysis with a simplified model with analysis of six blood samples (Figure 1).  This method is currently used to measure GFR in multicenter clinical trials [10]. The Bröchner-Mortensen formula is used to estimate creatinine clearance (or glomerular filtration rate, GFR) using iohexol, a contrast agent used in nuclear medicine and radiology to assess renal function. This method is useful for calculating GFR on a blood sample collected after iohexol administration [11].

GFR correction with iohexol using Bröchner-Mortensen formula.
Figure 1. GFR correction with iohexol using Bröchner-Mortensen formula.

Iohexol for CKD Patients

In order to give an accurate estimate of GFR, iohexol is considered a valid alternative to inulin but presents practical difficulties in the estimation and accuracy of the results. The accuracy of GFR estimation with iohexol was evaluated by administering the marker on three different occasions to 24 patients and measuring its plasma clearance. The results show a low intraindividual variability (5.59%) and a high reproducibility (6.28%), demonstrating that iohexol is reliable even in patients with moderate or severe renal insufficiency (GFR < 40 mL/min/1.73 m²) [12].

The accuracy of iohexol clearance is high and is not affected by gender and stage of chronic kidney disease, making the method applicable to different types of patients. Simplified iohexol clearance measurement methods exist to measure GFR in patients with CKD, comparing their accuracy with that of the standard 10-hour two-compartment method. The study evaluates the performance of several simplified models, including a population pharmacokinetic (popPK) model and 5-, 6-, and 7-hour single-compartment models, to reduce the complexity and cost of measurements [13].

The results indicate that compared to the 8-hour reference method, the abbreviated models tend to overestimate GFR, especially in patients with an eGFR less than 40 mL/min/1.73 m². Furthermore, the popPK model is less precise and less reliable in patients with advanced CKD (stage III-IV), while the 6- and 7-hour monocompartmental models provide a more accurate estimate but show limitations compared to the standard method [8].

Iohexol represents a valid alternative to inulin for the estimation of GFR, without the need for continuous infusion or urine collection required for inulin. The iohexol plasma clearance method initially requires multiple blood samples to accurately estimate GFR. However, abbreviated methods using a single plasma sample have also been developed, which certainly simplifies the procedure but may reduce accuracy for some patients, particularly those with advanced renal failure [14].

The reliability of the single-sample method has been evaluated. Their study demonstrated that, despite a strong correlation between the multiple and single clearance methods, the accuracy of the single sample method varies significantly according to the patient’s GFR, with acceptable results for approximately 75% of patients and more significant deviations for the remaining 25% [15].

Iohexol for ADPKD patients

Due to its unique characteristics, iohexol has been studied as a marker of GFR in patients with ADPKD. Iohexol clearance, measured by plasma sampling at specific times after contrast injection, represents a valid alternative to inulin and other traditional markers and has allowed to examine the progression of the disease and the effect of potential therapies in reducing the rate of GFR decline. ADPKD is characterized by a gradual replacement of the renal parenchyma with cystic formations resulting in a progressive decrease in GFR; accurate monitoring of this decline with iohexol allows a reliable estimate of residual renal function [16]. Iohexol is particularly useful in patients with ADPKD because it allows repeatable and reliable measurements with an accurate estimate of GFR over time, essential to monitor the evolution of the disease. It also detects changes in GFR even in the early stages of the disease, when creatinine values ​​are not yet significant [17]. Iohexol is an accurate marker for measuring GFR in patients with CKD and ADPKD. Due to its high accuracy, reliability and ease of use compared to traditional markers such as inulin, iohexol allows for accurate monitoring of the progression of chronic kidney disease. Iohexol clearance-based methods, including simplified protocols, reduce the need for extensive sampling, making the process less invasive and more suitable for frequent clinical use [18].

 

Discussion

The use of iohexol to measure GFR has several advantages over other methods, particularly those based on creatinine. Iohexol clearance provides an accurate and direct measurement of GFR without the limitations of factors unrelated to renal function (e.g. muscle mass) that influence creatinine. This makes it particularly useful for patients with variable characteristics, such as the elderly and children, or those with impaired muscle mass [19]. Unlike traditional methods such as inulin, which require continuous infusion and multiple urine collections, iohexol measurement is less invasive and more convenient for patients, as it requires only blood samples. Iohexol has low intraindividual variability, which makes repeat GFR measurements reliable over time, allowing effective monitoring of renal function in patients with chronic or progressive renal failure. The iohexol method is used in many European centers and is integrated into guidelines for GFR monitoring. In some countries, such as Sweden, it is used as part of standard care, demonstrating the efficacy and applicability of this technique at the clinical level. These advantages make iohexol a preferable choice for measuring GFR in clinical situations where greater accuracy is needed than creatinine-based estimates [20]. The use of iohexol has been particularly effective for comparing GFR data with other parameters, such as total kidney and cyst volume, allowing a holistic assessment of disease progression. Due to the accuracy of the iohexol-based method, it has been possible to demonstrate that some experimental drug treatments were able to slow down disease progression in selected patients [21]. However, this method still has some disadvantages. Iohexol itself and the analytical processes involved (e.g., spectrophotometry, chromatography) are costly. The method requires multiple blood samples, advanced laboratory equipment, and trained personnel, which increases operational costs.

The procedure presents a considerable complexity represented by sampling rigidity, because accurate GFR estimation depends on precise timing of blood samples. Even minor deviations in sampling times can lead to errors in clearance calculation; specialized training is required, because laboratory personnel need expertise in handling iohexol and analyzing plasma concentrations, which may not be available in all healthcare settings.

The method is often restricted to tertiary care centers or research facilities due to the need for specific equipment and expertise and regions with limited healthcare infrastructure may lack the resources to implement this method. The requirement for several blood samples over time makes the method invasive and potentially uncomfortable for patients. Elderly or pediatric patients, as well as those with compromised venous access, may face difficulties with repeated sampling. It is a method that is exposed to potential errors represented by a variability in the measurement, inconsistent sampling times or variations in laboratory analysis can affect the accuracy of the results. Following a precise protocol is essential, but this may not always be feasible in high-volume clinical settings. Differences in age, body weight, comorbidities (e.g., liver disease), and body composition can affect iohexol pharmacokinetics, necessitating protocol adjustments. In patients with severely impaired renal function, prolonged clearance times require extended sampling intervals, increasing the complexity and inconvenience. Although rare, the use of iohexol may pose risks, such as allergic reactions or mild nephrotoxicity in vulnerable patients. Close monitoring is necessary to minimize adverse effects, adding to the procedural demands. Methods like creatinine- or cystatin C-based eGFR estimates, while less accurate, are more practical for routine clinical use due to lower cost and invasiveness.

Newer non-invasive or minimally invasive approaches may overshadow iohexol clearance in certain settings [22]. To reduce the complexity, abbreviated kinetic profiles have been proposed, but these tend to decrease the precision of the results, especially in patients with advanced stages of CKD, as emerged from comparative studies between standard and simplified methods (iohexol).

 

Conclusions

The iohexol clearance method is a gold standard for GFR estimation in specific clinical and research contexts, providing unmatched accuracy. However, its high costs, procedural complexity, invasiveness, and dependency on specialized resources significantly limit its applicability in routine healthcare.

Simplified protocols and further technological advancements could help mitigate these barriers, broadening its accessibility. GFR estimation with iohexol involves some secondary difficulties, both in terms of high costs and the need to procure specific materials and handle a significant number of blood samples [23]. This limits the methodology to research settings or specialized centers. Unlike the gold standard creatinine-based method, which is less expensive and practicable in all healthcare settings, the use of iohexol requires advanced equipment and specifically trained personnel. The iohexol method, if not performed correctly, tends to overestimate GFR in patients with stage III and IV chronic kidney disease (eGFR < 40 mL/min/1.73 m²). Although iohexol is currently used in several research centers and specialized clinics in Europe, it remains poorly available in many healthcare settings due to staff training requirements. This logistical limitation reduces the applicability of the method in routine clinical settings, making regular monitoring of GFR with iohexol difficult in many peripheral regions. Countries such as Sweden have integrated the method as part of standard care, demonstrating the effectiveness of this approach in an advanced healthcare setting, but its use is still limited to specific cases or large clinical studies (iohexol). In conclusion, although the iohexol method is accurate and represents a valid alternative to traditional markers such as inulin, it still has significant disadvantages that limit its large-scale adoption, especially in settings with limited resources or in the absence of specialized laboratory technical staff.

 

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Diagnosi e gestione terapeutica della patologia ossea nel paziente con malattia renale cronica o portatore di trapianto di rene

Pubblicato il Scarica PDF

Simona Barbuto

DOI: 10.69097/41-06-2024-05

Simona Barbuto1*, Daniele Vetrano2*, Francesco Aguanno2, Carlo Minicucci2, Veronica Catalano2, Alessia Passaseo2, Serena Speciale2, Guido Zavatta3, Carla Serra4, Giulia Molinari5, Guido Marzocchi6, Giuseppe Cianciolo1,2

1. Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
2. Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
3. Unità Operativa di Endocrinologia e Cura e Prevenzione del Diabete, IRCCS Azienda Ospedialiero Universitaria di Bologna, Bologna, Italia
4. Unità Operativa di Ecografia Diagnostica e Terapeutica, IRCCS Azienda Ospedialiero Universitaria di Bologna, Bologna, Italia
5. Unità Operativa di Otorinolaringoiatria e Audiologia, IRCCS Azienda Ospedialiero Universitaria di Bologna, Bologna, Italia
6.Unità Operativa di Radiologia Cardio-Toraco-Vascolare, Oncoematologica, D’Urgenza e dell'Età Pediatrica, IRCCS Azienda Ospedialiero Universitaria di Bologna, Bologna, Italia
*Gli autori hanno contribuito egualmente al lavoro

Corrispondenza a:
Giuseppe Cianciolo
Unità Operativa di Nefrologia, Dialisi e Trapianto, IRCCS Azienda Ospedialiero Universitaria di Bologna, 40138 Bologna, Italia
Via Massarenti 14, 40138
Telefono: 0039 0512143255
e-mail: giuseppe.cianciolo@aosp.bo.it

 

Abstract

L’osteoporosi è una malattia scheletrica cronica caratterizzata dalla riduzione della densità minerale ossea e dal deterioramento della microarchitettura ossea, che aumenta il rischio di fratture. Nei pazienti con malattia renale cronica (CKD), la gestione dell’osteoporosi è complicata dalla presenza di alterazioni del metabolismo minerale (CKD-MBD) che influenzano negativamente la salute ossea. La diagnosi richiede un’approfondita valutazione clinica, che include la misurazione della densità minerale ossea tramite DEXA, la valutazione della microarchitettura ossea con TBS e l’analisi dei biomarcatori del turnover osseo. La gestione terapeutica deve essere personalizzata e può includere terapie con farmaci ad azione anti-riassorbitiva o osteoanabolica; infatti, è necessario tener conto dello stadio di CKD e del tipo di turnover osseo. Il Policlinico Sant’Orsola adotta un modello integrato di cura, che prevede il coinvolgimento di diversi specialisti (nefrologi, endocrinologi, radiologi, ecc..) nella gestione ottimale dell’osteoporosi del paziente nefropatico. Questo approccio multidisciplinare consente di affrontare in modo completo le complessità della CKD-MBD, migliorando la diagnosi e la terapia e, di conseguenza, la qualità della vita dei pazienti attraverso un piano di trattamento coordinato e personalizzato.

Parole chiave: CKD-MBD, malattia ossea, osteoporosi, malattia renale cronica, trapianto di rene

Introduzione

La prevalenza della malattia renale cronica (CKD) è aumentata considerevolmente negli ultimi decenni, di fatto trasformando questa patologia in un grave e crescente problema per la salute pubblica globale.  Nel 2017 l’incidenza era pari al 10% della popolazione generale con 800 milioni di individui affetti [1] e 3,9 milioni in terapia sostitutiva renale (KRT) nei pazienti con CKD in stadio terminale (ESRD) [2]. Inoltre, è stato stimato che entro il 2040 la CKD diventerà la quinta causa di mortalità nel mondo [1].

Come è ben noto, la CKD è caratterizzata da una serie di alterazioni del metabolismo minerale, incluse nella denominazione di Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) coniata, nel 2005, dalle linee guida Kidney Disease: Improving Global Outcomes (KDIGO) [3]. Le alterazioni del metabolismo minerale iniziano nelle fasi precoci della CKD; sebbene non sia noto quale sia il primum movens, si instaura una progressiva alterazione degli ormoni coinvolti nella regolazione del metabolismo minerale, ovvero la vitamina D 1-25(OH) il paratormone (PTH), il fattore di crescita dei fibroblasti-23 (FGF-23) e il suo recettore solubile Khloto [4, 5]. L’alterata omeostasi di tali ormoni rappresenta inizialmente una risposta adattativa dell’organismo, finalizzata al mantenimento nei range di normalità del calcio e del fosforo. Tuttavia, tale processo adattativo, se non corretto adeguatamente, parallelamente al declino della funzione renale, diventa maladattativo e con caratteristiche di irreversibilità [4, 5].

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La collagenosi perforante reattiva nel paziente emodializzato

Pubblicato il Scarica PDF

Francesco Iacono

DOI: 10.69097/41-05-2024-08

Francesco Iacono1, Angelo Ferrantelli1, Onofrio Schillaci1, Francesca Spica1, Carmela Zagarrigo1, Giuseppe Gigliotti2

1 ARNAS Civico Palermo, U.O.C. di Nefrologia e Dialisi abilitata ai trapianti
2 Presidio Ospedaliero Maria SS Addolorata Eboli, U.O.C. di Nefrologia e Dialisi

Corrispondenza a:
Francesco Iacono
U.O.C. di Nefrologia e Dialisi abilitata ai trapianti
Ospedale ARNAS Civico
Piazza Nicola Leotta n°4
90127 Palermo, Italia
Tel/Fax: 0916663540
E-mail: francesco.iacono@arnascivico.it

 

Abstract

Il prurito associato alla malattia renale cronica (Chronic Kidney Disease-associated Pruritus, CKD-aP) nell’emodialisi affligge circa il 38% dei nostri pazienti. Esso non è associato ad alcuna lesione dermatologica se non le comuni lesioni da grattamento, conseguenza dello stesso sintomo. Le cause associate al prurito sono state studiate in diverse trattazioni. Tuttavia, esiste una condizione relativamente rara che coinvolge il 10% dei pazienti emodializzati ovvero la collagenosi perforante reattiva. Questa è una condizione patologica secondaria alla terapia emodialitica cronica, dove si sviluppa un prurito diffuso associato ad una peculiare dermatosi reattiva con perforazione del derma e sviluppo di soluzioni di continuità dermo-epidermiche con estrusione di componenti della matrice dermica. In questo lavoro riporteremo una nostra esperienza con un caso diagnosticato di tale condizione.

Parole chiave: prurito, malattia renale cronica, dermatosi perforante, collagenosi perforante reattiva, emodialisi, emodiafiltrazione con reinfusione endogena

Epidemiologia e patogenesi del CKD-aP

Il prurito associato alla malattia renale cronica (CKD-aP) è definito come una sintomatologia pruriginosa direttamente correlata alla malattia renale cronica, non causato da altre eventuali condizioni patologiche concomitanti. Il CKD-aP possiede un’elevata variabilità clinica, rendendo la sua diagnosi difficoltosa. La severità di questa condizione può essere tale da compromettere notevolmente lo stile di vita dei pazienti affetti. Il sintomo potrà essere intermittente o persistente [1]. Questa è una caratteristica dei pazienti con Malattia renale cronica end-stage (ESRD) e tende a manifestarsi nei pazienti sia in terapia conservativa, indicando la progressiva necessità di ricorrere ad un trattamento sostitutivo, sia in terapia sostitutiva, legata ad una ridotta efficienza dialitica. Tuttavia, la persistenza del sintomo, nonostante il potenziamento della capacità depurativa dei trattamenti sostitutivi in alcuni pazienti, ha dimostrato la presenza di meccanismi patogenetici peculiari, determinati dalle alterazioni fisiopatologiche della malattia renale cronica.

In considerazione della vasta eterogeneità della sintomatologia pruriginosa e del mancato riferimento del sintomo da parte dei pazienti, l’epidemiologia del CKD-aP è in corso di definizione ed in costante aggiornamento.

Nei pazienti in terapia conservativa è stata valutata la prevalenza di tale condizione tramite uno studio osservazionale internazionale, il CKDopps (Chronic Kidney Disease  Outcomes and Practice Patterns Study), con un arruolamento di circa 3780 pazienti con malattia renale cronica (G3-G4-G5),  e successiva valutazione del sintomo tramite questionari multidimensionali autosomministrati per la valutazione della qualità di vita nella CKD, con riscontro di una prevalenza complessiva del 24% per pazienti affetti da prurito ad intensità moderata-severa, maggiormente presente nei pazienti con malattia renale cronica G5 [2-4].

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