Protected: Methods for calculating the number of nephrons from ultrasound scans and kidney biopsies for nephrologists’ use

Abstract

The interest in determining the number of nephrons in the kidney dates back to the 1960s, when an influential laboratory method for determining ex vivo the number of nephrons in the kidneys was described by Bricker. Over the years, various methods have been developed to estimate the number of nephrons in living beings as accurately as possible. These modern methods combine data such as the glomerular density, the percentage of glomeruli in sclerosis calculated from biopsy samples, and the kidney volume, which can be precisely estimated from magnetic resonance, CT scan, or specific ultrasound methods. As the reduction in the number of functioning nephrons is closely connected with an increased risk of progression of renal disease (especially in patients with nephrotic syndrome) and hypertension, its introduction into clinical practice could allow a precise stratification of progression risk in patients with kidney disease and a better understanding of the mechanisms that contribute to the loss of functioning nephrons.

Keywords: nephrons number, kidney biopsy, CKD

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Finerenone for the treatment of patients with chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a clinical condition associated with a high risk of cardiovascular (CV) events, mortality and progression to most severe stage of the disease, also known as kidney failure (KF). CKD is characterized by a wide variability of progression, which depends, in part, on the variability of individual response to nephroprotective treatments. Thus, a consistent proportion of patients have an elevated residual risk both CV and renal events, confirmed by the evidence that about 70% of CKD patients followed by the nephrologist have residual proteinuria. Among the new therapeutic strategies, which have been developed precisely with the aim of minimizing this residual risk, a class of particular interest is represented by the new non-steroidal mineralocorticoid receptor antagonists (non-steroidal MRA). These drugs exert an important anti-fibrotic and anti-proteinuric effect and, unlike steroid MRAs, are associated with a much lower incidence of adverse effects. The non-steroidal MRA molecule for which the most data is available, which is finerenone, is potent and extremely selective, and this partly explains the differences in efficacy and safety compared to steroid MRAs. In clinical trials, finerenone has been shown to significantly reduce the risk of progression to KF. Furthermore, there is also evidence that the combination of non-steroidal MRAs together with SGLT2 inhibitors may represent a valid alternative to reduce the residual risk in CKD patients. Given this evidence, non-steroidal MRAs are gaining momentum in the care, and particularly in individualized care, of CKD patients.

 

Keywords: CKD, epidemiology, aldosterone, iperkalaemia, kidney failure, cardiovascular risk

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Introduzione

La malattia renale cronica (nota su larga scala come Chronic Kidney Disease, CKD) è una condizione clinica definita da una o più delle seguenti alterazioni confermate e persistenti per almeno 3 mesi: una riduzione del tasso di filtrazione glomerulare stimato (eGFR) <60 mL/min/1.73m2, un livello anomalo di albuminuria (o proteinuria) > 30 mg/die alla raccolta delle urine delle 24 ore (30 mg/g se misurata attraverso il rapporto albuminuria-creatininuria o ACR, sulle urine del mattino in estemporanea), una anomalia di funzione o struttura dei reni diagnosticata con esami strumentali o clinici [1, 2]. L’eGFR e la albuminuria sono cruciali nella definizione e quindi nella diagnosi della CKD e sono anche conosciute, data la loro importanza prognostica come “kidney measures” o “fattori di rischio non tradizionali” per distinguerle da altri fattori di rischio cardiovascolare tradizionale quali possono essere l’età, il fumo di sigaretta o i livelli di pressione arteriosa sistolica [3]. La presenza di CKD espone il paziente ad una prognosi sfavorevole, intesa come un aumento significativo del rischio di incidenza di eventi cardiovascolari (CV) fatali e non fatali (infarto del miocardio, ictus, scompenso cardiaco, vasculopatia periferica), rapida progressione del danno renale verso la kidney failure (KF) che viene definita come lo stadio più avanzato della CKD con ricorso alla terapia sostitutiva, e la mortalità da ogni causa [4, 5]. Tali eventi sono complessivamente considerati “eventi maggiori”, sia nella pratica che nella ricerca clinica, in quanto condizionano in modo sostanziale la qualità della vita. I pochi dati fin qui riportati acquistano ancora maggiore enfasi se si considera che la CKD ha una prevalenza in netto aumento nella popolazione generale a livello globale [6]. Per arginare tale fenomeno, il cui trend in ascesa è già da tempo evidente, un grande sforzo è stato rivolto all’individuazione di trattamenti farmacologici in grado di minimizzare il rischio sia di progressione renale che di eventi CV. I primi trattamenti che hanno portato ad una riduzione della progressione della CKD sono stati gli inibitori del sistema renina-angiotensina-aldosterone (RAASi), in particolare gli ACE inibitori ed i sartani [7]. Tuttavia, circa il 40% dei pazienti con CKD non risponde a questi farmaci, rimanendo ad un rischio elevato di eventi futuri sfavorevoli cardiovascolari e renali [8, 9].

 

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Which is the role of the oral iron therapies for iron deficiency anemia in non-dialysis-dependent chronic kidney disease patients? Results from clinical experience

Abstract

Iron deficiency afflicts about 60% of dialysis patients and about 30% of non-dialysis-dependent CKD patients (ND-CKD). The role of iron deficiency in determining anemia in CKD patients is so relevant that guidelines from the Kidney Disease Improving Global Outcomes (KDIGO) initiative recommend treating it before starting with erythropoiesis-stimulating agents. KDIGO guidelines suggest oral iron therapy because it is commonly available and inexpensive, although it is often characterized by low bioavailability and low compliance due to adverse effects.

A new-generation oral iron therapy is now available and seems to be promising. We therefore conducted a study to determine whether an association of iron sucrose, folic acid and vitamins C, B6, B12, can improve anemia in ND-CKD patients, stage 3-5. Our study shows that iron sucrose is a safe and effective oral iron therapy and that it is capable of correcting anemia in ND-CKD patients, although it does not seem to replete low iron stores.

Keywords: iron deficiency, chronic kidney disease, CKD, anemia, oral iron

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Introduzione

La carenza marziale, associata o meno all’anemia, rappresenta una delle condizioni più frequenti dei pazienti affetti da malattia renale cronica (MRC), siano essi in terapia conservativa o in terapia dialitica sostitutiva [1,2].

La carenza marziale è definita dalla Organizzazione Mondiale della Sanità come una condizione caratterizzata da una quantità di ferro insufficiente a mantenere la fisiologica funzione di sangue, cervello e muscoli. Essa non sempre si associa ad anemia, soprattutto se il deficit non è sufficientemente severo o è di recente insorgenza [3].

 

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Renal function performance in CKD stage 5: a sealed fate?

Abstract

Introduction and aims: Stages 4 and 5 of chronic kidney disease (CKD) have always been considered hard to modify in their speed and evolution. We retrospectively evaluated our CKD stage 5 patients (from 01/1/2016 to 12/31/2018), with a view to analyzing their kidney function evolution.

Material and Methods: We included only patients with longer than 6 months follow-up and at least 4 clinical-laboratory controls that included measured Creatinine Clearance (ClCr) and estimated GFR with CKD-EPI (eGFR). We evaluated: the agreement between ClCr and eGFR through Bland-Altman analysis; progression rate, classified as fast (eGFR loss >5ml/min/year), slow (eGFR loss 1-5 ml/min/year) and non-progressive (eGFR loss <1 ml/min/year or eGFR increase). We also evaluated which clinical-laboratory parameters (diabetes, blood pressure control, use of ACEi/ARBs, ischemic myocardiopathy, peripheral obliterant arteriopathy (POA), proteinuria, hemoglobin, uric acid, PTH, phosphorus) were associated to the different eGFR progression classes by means of bivariate regression and multinomial multiple regression model. Results: Measured CrCl and eGFR where often in agreement, especially for GFR values <12ml/min. The average slope of eGFR was -3.05 ±3.68 ml/min/1.73 m2/year. The progression of kidney function was fast in 17% of the patients, slow in 57.6%, non-progressive in 25.4%. At the bivariate analysis, a fast progression was associated with poor blood pressure control (p=0.038) and ACEi/ARBs use (p=0.043). In the multivariable model, only peripheral obliterative arteriopathy proved associated to an increased risk of fast progression of eGFR (relative risk ratio=5.97).

Discussion: Less than one fifth of our patients presented a fast GFR loss (>5 ml/min/year). The vast majority showed a slow progression, stabilisation or even an improvement. Despite the limits due to the small sample size, the data has encouraged us not to consider CKD stage 5 as an inexorable and short journey towards artificial replacement therapy.

 

Keywords: chronic kidney disease, CKD, disease progression, glomerular filtrate, chronic renal failure

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Introduzione

La malattia renale cronica (Chronic Kidney Disease, CKD) colpisce oltre 850 milioni di persone nel mondo (11% circa della popolazione mondiale) [1]; di questi, 37 milioni sono negli Stati Uniti (pari al 15% della popolazione) [2], 38 milioni in Europa (il 10% della popolazione) [3] e circa 4 milioni in Italia, pari a circa il 7% della popolazione [4]. Numerosi studi hanno approfondito i fattori di rischio e progressione del danno renale cronico, spesso includendo nel campione fasi di CKD estremamente polimorfe come fenotipo clinico, rischio cardiovascolare e complicanze in corso di malattia [58].

Agli inizi degli anni ’90, Maschio [10] considerava un valore di creatininemia di circa 2 mg/dl come un “punto di non-ritorno” della storia naturale della CKD,  al di là del quale si prevedeva un inevitabile e progressivo peggioramento della funzione renale, nonostante gli interventi di tipo dietetico e terapeutico messi in atto. Tutt’oggi si ritiene che la malattia renale cronica abbia un andamento prevalentemente lineare con una progressione più rapida nelle fasi più avanzate. Recenti studi osservazionali [11, 12] hanno evidenziato invece come nelle fasi avanzate della CKD la modalità di progressione possa essere variabile, mostrando spesso un andamento non lineare e fortemente eterogeneo.

 

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Screening and management of HCV-positive CKD outpatients

Abstract

Background: Hepatitis C Virus (HCV) disease, which is commonly underdiagnosed, in addition to the well-known effects on the liver is also a risk factor for Cronic Kidney Disease (CKD) and End Stage Renal Disease (ESRD). It worsens the outcome at every stage of CKD; around 400.000 people worldwide die from HCV-related causes each year. The KDIGO 2018 Guidelines recommend that all patients be evaluated for renal disease when HCV is diagnosed and be screened for HCV when CKD is diagnosed, as the prevalence may be higher than in the general population. Effective screening is therefore necessary in order to establish early treatment. Aims of the study: We ran a systematic program of screening and management of HCV in nephropathic outpatients in order to improve Sustained Virological Response 12 weeks after the end of treatment (SVR 12) and renal functions such as GFR and proteinuria. Materials and methods: We considered outpatients not in dialysis and older than 18. The systematic, prospective observational study of HCV infection run over a period of 18 months. Results: Of 2798 nephropathic outpatients that came to our attention during this period, we identified 108 HCV-positive patients (prevalence: 3.85%). The test for HCV-RNA resulted positive in 78 patients and, after hepatological evaluation and informed consent to treatment, 51 of them underwent therapy with the new direct-acting antivirals (DAAs). 34 patients concluded the treatment during the 18-month period, all of them with 100% SVR 12. The average pre-treatment GFR was 40.5 ml/m’; after treatment resulted equal to 45 ml/m’ (p=0.01). The average value of pre-treatment proteinuria was 1.18 g/24 h; it was reduced to 0.79 g/24 (p=0.015). The remaining 17 patients were still under treatment/evaluation at the end of the 18 months. Conclusions: Treatment with the new DAAs has been confirmed safe and effective and is associated with an improvement of renal functions. Systematic screening of nephropathic patients may therefore contribute to achieving the WHO target of eliminating HCV by 2030.

Keywords: Hepatitis C Virus, HCV, cronic kidney disease, CKD outpatients

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Introduzione

L’infezione da Virus C dell’Epatite (HCV) è comunemente sottodiagnosticata. Vi sono ben note ripercussioni sul fegato, che vanno da cambiamenti istologici minimi a fibrosi estesa e cirrosi con o senza carcinoma epatocellulare (HCC) [1], ma è ormai risaputo che esistono altre manifestazioni cliniche che vanno “oltre il fegato” ed è stato introdotto il concetto di “Malattia da HCV”. Le sue manifestazioni includono malattie cardiovascolari, compromissione del metabolismo del glucosio, disfunzione neurocognitiva, vasculite crioglobulinemica, linfoma non-Hodgkin a cellule B e malattia renale cronica [2].

La malattia renale in corso di HCV è raramente il risultato di una glomerulonefrite: glomerulonefrite membranoproliferativa di tipo I (Type I MPGN), poliarterite nodosa (PAN), nefropatia membranosa (MN), IgA nephropathy (IgAN), glomerulosclerosi focale e segmentaria (FSGS) costituiscono meno del 10% dei casi. La malattia renale in corso di HCV è dovuta per lo più a CKD, acute kidney injury (AKI), o sindrome epatorenale [3]. Sempre maggiori evidenze indicano il virus dell’epatite C come un fattore di rischio, influenzato tra l’altro dalla durata dell’infezione, per la comparsa di proteinuria, malattia renale cronica ed ESRD nella popolazione adulta generale, al di là dei fattori di rischio tradizionali quali diabete, ipertensione, obesità e dislipidemia [48]. Inoltre, l’infezione da HCV peggiora l’outcome dei pazienti in ogni stadio della CKD, accelerando il declino della funzione renale soprattutto negli stadi 4° e 5° [911]; anche la mortalità cumulativa risulta aumentata [9,12]. È per questo che le Linee Guida KDIGO 2018 per l’Epatite C raccomandano che tutti i pazienti siano valutati per la malattia renale al momento della diagnosi di HCV (Grado 1 A), ovvero di sottoporre a screening per HCV tutti i pazienti giunti all’osservazione per CKD, poichè in questi ultimi la prevalenza dell’infezione da HCV può essere maggiore rispetto alla popolazione generale (Grado 1 C) [13].

 

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Vascular dysfunction in Cardiorenal Syndrome type 4

Abstract

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

 

Keywords: arterial stiffness, cardiorenal syndrome, chronic kidney disease, inflammation, intima-media thickness, uremic toxins

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Chiave di lettura

Ragionevoli certezze: I pazienti con insufficienza renale cronica muoiono più spesso per un evento cardiaco che per la ridotta funzione renale. Il riconoscimento di questo link ha portato all’identificazione della Sindrome Cardiorenale di tipo 4. Nel corso dell’insufficienza renale cronica, con la progressiva riduzione della funzione renale, si assiste ad un aumento delle tossine uremiche ed alla comparsa di infiammazione cronica e stress ossidativo. L’ambiente uremico causa l’aumento della rigidità arteriosa, un riconosciuto fattore di rischio cardiovascolare ed un endpoint cardiovascolare intermedio. L’aumentata rigidità arteriosa provoca, infine, alterazioni emodinamiche e pressorie che causano la disfunzione cardiaca cronica. Nei pazienti con insufficienza renale cronica, riducendo la rigidità arteriosa migliora l’outcome.  

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Role of Ambulatory Blood Pressure Monitoring (ABPM) in chronic kidney patients: a review

Abstract

About 90%of patients with chronic kidney disease (CKD) have arterial hypertension; the main international guidelines recommend maintaining blood pressure (BP) values below 130/80 mmHg to reduce the cardio-renal risk in this population. Twenty-four-hour Ambulatory Blood Pressure Monitoring (ABPM) is the golden standard for the identification of the BP profiles and patterns, as well as for the assessment of the circadian rhythm and BP variability. The correct interpretation of ABPM allows to optimize anti-hypertensive treatment and to reduce cardio-renal risk in CKD patient.

In fact, in patients with CKD, the ABPM has a greater role in terms of renal and cardio-vascular prognosis when compared to clinical BP measurements. Patients with ABPM in target present a low cardio-renal risk, regardless of clinical BP values; on the contrary, if the clinical PA is normal and the ABPM not in target, this risk increases significantly. Moreover, in the CKD population, non-dipping is associated with a higher risk of cardiovascular events and end stage renal disease (ESRD), making identifying nocturnal hypertension greatly important.

Therefore, ABPM is an instrument of primary importance in the diagnostic and therapeutic work-out of renal patients.

 

KEYWORDS: ABPM, CKD, blood pressure

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Introduzione        

La malattia renale cronica (Chronic Kidney Disease, CKD) coinvolge in Italia circa 2 milioni di persone, con una prevalenza del 7% all’interno della popolazione generale, come osservato nello studio CARHES condotto in Italia nel 2010 [13]. 

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Temporal variation of Chronic Kidney Disease’s epidemiology

Abstract

Chronic Kidney Disease (CKD) is a major risk factor for mortality and morbidity, as well as a growing public health problem. Several studies describe the epidemiology of CKD (i.e. prevalence, incidence) by examining short time intervals. Conversely, the trend of epidemiology over time has not been well investigated, although it may provide useful information on how to improve prevention measures and the allocation of economic resources. Our aim here is to describe the main aspects of the epidemiology of CKD by focusing on its temporal variation. The global incidence of CKD has increased by 89% in the last 27 years, primarily due to the improved socio-demographic index and life-expectancy. Prevalence has similarly increased by 87% over the same period. Mortality rate has however decreased over the last decades, both in the general and CKD populations, due to a reduction in cardiovascular and infectious disease mortality. It is important to emphasize that the upward trend of incidence and prevalence of CKD can be explained by the ageing of the population, as well as by the increase in the prevalence of comorbidities such as hypertension, diabetes and obesity. It seems hard to compare trends between Italy and other countries because of the different methods used to assess epidemiologic measures. The creation of specific CKD Registries in Italy appears therefore necessary to monitor the trend of CKD and its comorbidities over time.

Keywords: chronic kidney disease, CKD, epidemiology, registers, socio-demographic index

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Introduzione

La malattia renale cronica (CKD) è una condizione patologica associata ad un alto rischio di mortalità e di morbidità. È stato infatti dimostrato, in studi di popolazione generale e di pazienti seguiti dalle unità nefrologiche, che la presenza di un valore di filtrato glomerulare stimato (eGFR) <60 ml/min/1,73m2 o di proteinuria si associa ad un alto rischio di sviluppare, nel tempo, eventi cardiovascolari (CV) maggiori (malattia coronarica, scompenso cardiaco, vasculopatia periferica), progressione del danno renale (riduzione del eGFR ed ingresso in dialisi) e mortalità da tutte le cause [15].  

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Challenges and results of the PIRP project (Prevenzione della Insufficienza Renale Progressiva) of the Emilia-Romagna Region

Abstract

The PIRP project was conceived in 2004; with the aim to face the increased prevalence of chronic kidney disease (CKD) associated with the aging and increased survival of the population. The first phase of the project consisted of training primary care physicians to identify people at risk of CKD and to implement intervention strategies that proved to be effective in preventing CKD it or delaying its progression once it is established. In the second phase of the project, dedicated ambulatories were opened in the nephrology units of Emilia-Romagna hospitals to provide an in-depth assessment and personalized care to CKD patients, following them up until renal failure or death or referring them back to general practitioners, according to the study protocol. A web-based registry was implemented to collect demographic and clinical data on PIRP patients. As of 30 June 2018, the registry included 26.211 CKD patients, with a median follow-up of 24.5 months. Over the 14 years of the PIRP the mean age of incident patients increased from 71.0 years to 74.2 years and the mean eGFR increased from 30.56 to 36.52 mL/min/1.73 m2, proving that the project was successful in recruiting older patients with a better renal function. At 5 years, the percentage of patients still active in the project was >45%.The implementation of the project has seen a reduction in the number of patients arriving every year to the dialysis treatment in E-R (about 100 units less from 2006 to 2016). The PIRP cohort is the largest in Italy and in Europe, which makes it ideal for research based on international comparisons and as a model for national registries.

Keywords: Renal insufficiency, CKD, GP, GFR, Proteinuria, Public Health Intervention

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INTRODUZIONE

La Malattia Renale Cronica (MRC) è, nell’ambito delle patologie croniche, una condizione molto diffusa, con una prevalenza crescente nella popolazione generale e con una stima a livello mondiale di circa il 10-15% (1). In Italia la prevalenza della MRC è stimata sull’ordine del 7,5% negli uomini e del 6,5% nelle donne sulla base dello studio CARHES (2). Questi dati di prevalenza italiana, sotto certi aspetti consolanti, sono però destinati ad aumentare per diversi ordini di fattori: i) invecchiamento della popolazione; ii) aumentata prevalenza nella popolazione generale di condizioni cliniche ad elevato rischio di danno renale (diabete mellito, sindrome metabolica, ipertensione arteriosa) (3), iii) aumentata sopravvivenza dei pazienti co-morbidi e complessi.

 

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Neprilysin inhibition and chronic kidney disease

Abstract

Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD)

Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD.

Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin – angiotensin – aldosterone (RAAS) system.

Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF).

The idea of ​​blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema.

Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria.

Key words: neprilysin, natriuretic peptides, sacubitril/valsartan, hypertension, heart failure, CKD

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INTRODUZIONE

I pazienti affetti da CKD presentano un rischio più elevato, rispetto alla popolazione generale, di progressione verso l’ESRD (1, 2), nonché un’incidenza particolarmente elevata di morbidità e mortalità cardiovascolare. Diversi fattori di rischio cardiovascolare, tradizionali e non, concorrono alla maggiore incidenza di eventi cardiovascolari nella popolazione affetta da CKD: aterosclerosi, infiammazione cronica, ipertensione arteriosa, iperattività del sistema nervoso simpatico ed un rimodellamento strutturale cardiaco (ad es. ipertrofia ventricolare sinistra) fattore quest’ultimo che può condurre ad una situazione di scompenso cardiaco (2).

Nella naturale evoluzione della CKD e delle sue complicanze, l’aterosclerosi, che rappresenta il primum movens nelle alterazioni a carico del sistema cardio-vascolare, perde man mano importanza nella genesi della mortalità cardio-vascolare. Allo stato attuale, le alterazioni strutturali presenti a livello cardiaco sono considerate le principali responsabili della maggiore incidenza di aritmie cardiache, quali la fibrillazione atriale e gli episodi di morte cardiaca improvvisa (3).
 

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