Low-Dose Rituximab in the Treatment of Primary Membranous Nephropathy – A Systematic Review and Meta-Analysis

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Gerry George Mathew

DOI: 10.69097/41-05-2024-04

Gerry George Mathew1, Shanmugam Sundaramurthy2, Prakash Muthuperumal3, V Jayaprakash4

1 Department of Nephrology, SRM Medical College Hospital And Research Centre, Kattankulathur, Tamil Nadu, India-603203
2 Department of Computing technologies, SRM Institute of science and Technology, Kattankulathur, Tamil Nadu, India-603203
3 School of Public Health, Division of Health Data Science, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
4 Department of Nephrology, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India-603203

Corrispondenza a:
Gerry George Mathew
Associate Professor Department of Nephrology, SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu, India-603203
Mobile: +91-8291077361
Fax: 044-24742845
E-mail: gerrygeorge007@gmail.com

 

Abstract

Introduction. Rituximab (RTX) holds promise as a treatment for idiopathic membranous nephropathy (IMN). While effective in standard regimens, the application of RTX is hampered by cost burdens and severe side effects. To address these issues, low-dose RTX has been proposed as an intervention strategy. Yet, the efficacy of this approach in treating IMN remain subject of debate. This systematic review and meta-analysis seek to examine the effectiveness of low-dose RTX in adult patients with IMN.
Methodology. A literature search was conducted using PubMed, Wiley Online Library, ScienceDirect, Cochrane Library, Springer and other sources, published between 2004 and 2024. Specifically, articles reporting the intravenous application of RTX at doses lower than four weekly infusions of 375 mg/m² or two infusions of 1 gram each on day 0 and day 15 were considered for inclusion. The primary outcomes were complete response (CR) and partial response (PR) rates at last follow-up. Secondary endpoints included serum creatinine levels, serum albumin levels, 24-hour proteinuria levels, protein-creatinine ratio (PCR), estimated glomerular filtration rate (eGFR) and anti-PLA2R antibody levels.
Results. Sixteen articles were included in this meta-analysis. The pooled analysis of odds ratios (OR) revealed that both main-line (OR = 0.48, 95% CI = 0.30-0.75, p = 0.001) and second-line (OR = 0.27, 95% CI = 0.11-0.67, p = 0.005) RTX treatments induced complete remission (CR) in IMN patients. At the last follow-up, patients treated with both main-line (mean difference [MD] = 1.45, 95% CI = 1.00-1.91, p < 0.00001) and second-line (MD = 0.88, 95% CI = 0.23-1.53, p < 0.00001) RTX treatments showed a significant increase in serum albumin levels. Conversely, in the analysed second line RTX therapy patients, low eGFR trend was noted in the post treatment arm compared to baseline levels (MD = 10.57, 95% CI = 0.30-20.83, p = 0.04). Moreover, RTX was found to be effective in reducing PCR (MD = 24.10, 95% CI= 1.07 to 47.13, p = 0.04) and depleting PLA2R antibody levels (MD = 127.36, 95% CI = 14.90-239.81, P = 0.03). However, RTX might be less effective in lowering proteinuria and serum creatinine levels in patients with nephrotic syndrome. Conclusion. Rituximab in a low-dose regimen is quite effective in treating adult patients with IMN. Therefore, it can be considered a promising treatment for both main-line and rescue therapy. More randomized controlled trials and research on optimizing the low-dose regimen, based on various health factors, are warranted.

Keywords: Low-dose rituximab, primary membranous nephropathy, systematic review, proteinuria, creatinine

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Introduction

Membranous nephropathy (MN) is an immune-mediated disorder that negatively affects the kidney glomerulus of humans [1]. Approximately 80% of MN occurs due to unidentifiable reasons, termed as either primary MN (PMN) or idiopathic MN (IMN) [2]. In the remaining 20% of individuals, MN develops secondarily due to various clinical conditions, such as bacterial or viral infections (hepatitis B and C, syphilis), malignancies, drug toxicities (penicillamine, gold salts) and other rheumatological or immunological diseases (rheumatoid arthritis, systemic lupus erythematosus) [3]. Annual prevalence rates vary globally, with higher incidences reported in North America and Europe [4], indicating greater tendencies among Caucasians followed by Asians, Blacks and Hispanics [5]. Although membranous glomerulopathy can affect individuals of any age, it predominantly manifests in adults than in children [6], with the average age occurring between 50 and 60 years [7]. Studies suggest a male preponderance in IMN cases, with a male-to-female ratio of 2:1, though the underlying reasons remain elusive [8].

PMN is characterized by B-cell abnormalities and the accumulation of immune complexes along the glomerular capillary walls, leading to membranous thickening [4, 9]. Several potential immunological mechanisms proposed include entrapment of preformed immune complexes in the subepithelial space, localization or implantation of circulating antigens in the subepithelial sites and binding of autoantibodies to podocyte membrane antigens (leading to the subepithelial deposition of immune complexes) [10]. Immune deposits consist of several components, including the immunoglobulin G (IgG) subclass of antigens and the membrane attack complex (MAC) formed from the complement components to create C5b–9 [11]. Figure 1 elaborates the treatment targets and immunological mechanisms in primary membranous nephropathy.

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Come valutare la velocità di filtrazione glomerulare e quale metodo è considerato il più affidabile?

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Fabrizio Cristiano

DOI: 10.69097/41-04-2024-02

Fabrizio Cristiano1,2, Cosima Posari1, Benito d’Angelo1, Alessandra Schiazza1, Anna Gigante1, Ludovico Caravelli1, Alessandra Piano1, Stefania Fulle2, Jenny Cristiano5, Ginevra di Matteo2, Guillermo Rosa Diez4, Vittore Verratti3

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 Department of Psychological, Health and Territorial Sciences, University “G. d’Annunzio” Chieti - Pescara, 66100 Chieti, Italy
4 Servicio de Nefrología, Hospital Italiano, 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 prevalenza della malattia renale cronica (CKD) continua ad aumentare a livello globale, sia per un aumento della morbilità e della mortalità associate sia per le implicazioni significative sulla qualità della vita dei pazienti e sulle economie nazionali. La malattia renale cronica spesso progredisce senza essere riconosciuta dai pazienti e dai sanitari, nonostante la diagnosi si basi su due semplici misure di laboratorio: velocità di filtrazione glomerulare stimata (eGFR) e analisi delle urine. La misura della GFR è correlata alla fisiologia renale, in particolare al concetto di clearance, con la creatinina identificata come un marcatore endogeno adatto per stimare la clearance della creatinina (CrCl). In base a questo principio sono state sviluppate varie equazioni per calcolare la CrCl o il GFR stimato (eGFR) utilizzando quattro variabili che incorporano la creatinina e alcune informazioni demografiche, come sesso ed età. Tuttavia, la misurazione della creatinina richiede la standardizzazione per ridurre al minimo la variabilità del dosaggio tra i laboratori. L’accuratezza di queste equazioni rimane controversa in alcuni sottogruppi di pazienti. Per questi motivi, sono stati ideati ulteriori modelli matematici per migliorare la stima della CrCl, in particolare quando la raccolta delle urine non è praticabile, in pazienti anziani o debilitati e in soggetti con traumi, diabete o obesità. Attualmente, l’eGFR negli adulti può essere immediatamente misurato e riportato utilizzando equazioni basate sulla creatinina tracciabili tramite spettrometria di massa con diluizione isotopica. In conclusione, sfruttando le conoscenze della fisiologia renale, l’eGFR può essere impiegato clinicamente per la diagnosi precoce e il trattamento della malattia renale cronica, nonché come strumento di sanità pubblica per stimarne la prevalenza.

Parole chiave: marcatori di filtrazione glomerulare, creatinine, cistatina C, inulina, iohexol

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Introduction

The prevalence of chronic kidney disease (CKD) continues to escalate globally, accompanied by an increase in morbidity, mortality, and significant implications for the quality of life of patients and the economies of nations. Any clinical condition resulting from a reduction in the number of functioning nephrons can progress into chronic renal failure, defined by the KDIGO guidelines as “abnormalities in kidney structure or function, present for 3 months, with health implications” [1].

In the real world, chronic kidney disease is a silent ailment often progressing unnoticed by patients and physicians, although the diagnosis relies on two simple laboratory measures: estimated GFR (eGFR) and urine analysis (screening for albuminuria/proteinuria). The glomerular filtration rate remains the premier comprehensive indicator of renal function as it assesses renal clearance and is directly related to the functioning renal mass, serving to classify CKD into stages, calculate medication dosages, and prepare for invasive studies with contrast medium. Early diagnosis of chronic kidney disease aids in delaying progression and reducing associated morbidity and mortality.

 

Identification of the Glomerular Filtration Process for GFR Measurement in Clinical Practice

Carl Ludwig (1816-1895), pioneered of glomerular filtration identified the glomerulus as a filter. This filtration is regulated by the hydrostatic pressure and modulated by the contraction and vasodilation of the afferent and efferent arterioles. He further hypothesized that the filtered volume decreased along the tubules due to reabsorption, thereby concentrating the end products in the urine [2]. However, to apply the concept of GFR in clinical settings, it was imperative to identify a solute removed solely by filtration, without reabsorption or secretion in the nephron. Later Paul Rehberg pinpointed creatinine as such a solute, given its endogenous production, filtration, and presumed lack of reabsorption or excretion.

Comparative summary of GFR estimation equations
Figure 1. Comparative summary of GFR estimation equations, including Cockcroft-Gault, simplified MDRD-4, CKD-EPI creatinine and cystatin C, and the FAS method. These formulas incorporate variables such as age, weight, serum creatinine, and patient demographics to determine renal function.

 

Estimation of GFR with Endogenous Markers

Creatinine-Based Glomerular Filtration Estimation

Creatinine remains the most widely utilized endogenous marker for estimating renal function in clinical practice, research, and animal models. It is a waste product of regular muscle metabolism. Creatinine, not being protein-bound, is freely filtered by the glomeruli; however, its synthesis is not constant, as it is determined by daily protein intake and muscle trophism. It is also subject to both secretory and reabsorptive mechanisms [3]. These conditions restrict the utility of creatinine as a renal function marker. Gender differences in tubular secretion have also been documented: males may secrete more creatinine than females, which could result in discrepancies in GFR estimation between male and female animals [4].

The initial method to measure creatinine, developed in 1886, was the alkaline picric acid reaction of Jaffé (a colorimetric method). This method’s interference with chromogens, such as bilirubin, glucose, or hemoglobin, led to inaccuracies in humans. In rodents, non-specific chromogens could overestimate creatinine by a factor of five. Different methods have been adapted to measure serum creatinine. The enzymatic determination, now considered the reference method in rodents, was validated in 2007 with various reactions with the aid of creatininase, creatinase, and sarcosine oxidase [5]. The measurement of creatinine in serum is prone to different types of error, interferences and imprecision. Serum creatinine certainly represents the most practical and least expensive measurement for stable glomerular filtration rate, however it presents some limitations in the interpretation of the results which may be secondary to both tubular secretion and the presence of muscle mass and protein intake. Even the absolute value of creatinine is subject to some variations such as the reference intervals of each analysis method of each laboratory with the risk of altering each glomerular filtration rate analysis equation. There are limitations in estimating creatinine secondary to muscle trophism because it is a product of muscle catabolism and results difficult in patients with extremely low or high muscular mass (e.g., anorexia, obesity or weight lifter). Creatinine is secreted by tubules and this explains why creatinine cleareance overestimates true GFR. Drugs, such as trimethoprim and cimetidine, also interfere with this tubular secretion and this explains why during their intake there is an increase in creatinine values ​​without evident alterations in GFR. The absolute value of creatinine could be altered in some pathological conditions such as liver failure and rhabdomyolysis. The absolute value of creatinine has physiological limits for an accurate estimate of the glomerular filtration rate [20].

Creatinine Clearance Over 24 Hours and Estimation of GFR Using Endogenous and Exogenous Markers

24-hour creatinine clearance has been a prevalent method for assessing GFR in animal models. Yet, it is crucial to acknowledge that the limitations of serum creatinine as a renal function marker impact the precision and accuracy of the 24-hour collection [6]. Blood samples are necessary to measure serum creatinine.

GFR Estimation Using Cystatin-C

Cystatin-C (CysC) is a low molecular weight protein (13KDa) of the family of cysteine ​​protease inhibitors. It is produced by all the nucleated cells of the body, filtered by the glomerulus, and then reabsorbed and metabolised by tubular epithelial cells, excluding its use for clearance on 24 hour urine. Like cratinine, the determination of cystatin C is influenced by factors such as sex, age and chronic inflammatory state [7], but it provides a more precise estimate of glomerular filtration as it is not affected by variables such as muscle mass and activity, or dietary protein intake.

 

GFR Estimation with Exogenous Markers: Inulin Clearance

The fructose polymer inulin has always represented a specific method for medical students for measuring glomerular filtration [8] due to the intrinsic characteristics of the molecule; in fact inulin is not metabolised, does not bind to plasma proteins and is freely filtered by the glomeruli without being reabsorbed or secreted by the tubular cells. However, considering inulin as the gold standard of the glomerular filtration method presents some limitations: the high cost and cumbersome methods for developing the process such as use with radioactive markers, poor solubility in water and demanding preparation for the solution to be injected (substance dissolve, filter and heat at high temperatures for many hours to remove inulin fragments). Once prepared, inulin is administered as a single intravenous bolus or continuous infusion and plasma and/or urine are collected at different times to calculate clearance. All these steps do not make this method universal.

 

Sinistrin: The New Inulin?

The measurement of GFR can also be obtained by evaluating the kinetics of Sinistrin FITC and in particular by estimating the half-life. Sinistrin has the advantage of having a lower molecular weight (3500 Da) compared to inulin, it is hightly soluble in aqueous solvents at room temperature, it can be used and labeled with FITC fluorescein [9]. Unlike inulin, it does not require any filtration and has the advantage of being able to be used using transcutaneous devices. An instrument composed of two LEDs is required for measuring fluorescence and transcutaneous GFR. The method consists in the intravenous infusion of Sinistrin with the FITC chromophore which emits the fluorescence captured by the instrument. Transcutaneous measurement has proven to be a good method for measuring renal function in murine models and has the advantage, especially in animals, of measuring glomerular filtration in the absence of particular traumas [21].

 

Transcutaneous Methods for GFR Measurement

To determine glomerular filtration, the intravenous injection of a sinister FITC molecule was studied and then the variation in fluorescence was studied using a device positioned on the skin. The change in fluorescence is used to calculate the elimination half-life of the marker and then convert the half-life data to GFR (ml/min). The main advantage of this method is its non-invasiveness, however it has limitations as it is an indirect method for measuring GFR and therefore requires conversion factors. The main advantage is its independence from blood/urine sampling and laboratory tests with real-time GFR examination, however a limitation to be evaluated is the high cost of the device ($1000) which makes it impractical for clinical practice [10].

 

Radiolabeled Tracers

The two most commonly used radiolabeled markers are ethylenediaminetetraacetic acid with radioactive chromium-51 (51Cr-EDTA) and diethylenetriamine pentaacetic acid with radioactive technetium-99 (99mTc-DTPA), both of which are low molecular weight and freely filtered by the glomerulus.

The method consists in measuring the plasma and urinary clearance of single intravenous injections of radiolabeled substances or alternatively intraperitoneal injection [11]. Blood and urine samples are taken and processed using a gamma counter that estimates GFR. 99mTc-DTPA has been used in healthy male Wistar rats and in animals with chronic kidney disease or doxorubicin-induced nephritic syndrome [12]. The main limitation of this technique derives from the use of radioisotopes, which are not easy to find and which require special authorization and specific conservation; furthermore it presents toxicity for operators who must use specific precautions and careful waste management.

99mTc can dissociate from DTPA and up to 13% of 99mTc-DTPA can bind to plasma proteins, resulting in an underestimate of GFR [13]. These markers could be useful for verifying GFR but are not preferable in clinical practice.

 

Non-Radiolabeled Contrast Agents in GFR Assessment

Among the various possibilities for measuring GFR is iothalamate, an ionic contrast agent derived from tri-iodobenzoic acid with a molecular weight of 637 Kda. Bell proposed a rapid HPLC method to detect iothalamate and para-aminohippuric acid in rat serum and urine [14], giving an estimate of both GFR and renal blood flow. This method is not easy to apply as it involves both central venous catheterization, a method not without serious side effects, and the simultaneous collection of blood and urine.

 

Iohexol/Iohexol-DBS

Iohexol (Omnipaque™, GE Healthcare) is a molecule used as a contrast agent. It is excreted unmetabolised by glomerular filtration, without reabsorption or secretion by renal tubular cells without undergoing hepatic metabolism or interference with blood cells. Its use as a reference method for measuring GFR was established almost 30 years ago in humans [15]. In recent years, the filtration of iohexol in mice has been studied by intravenous injection and subsequent blood sampling for pharmacokinetic analysis. Iohexol is measured by HPLC chromatographic analysis. Schultz et al. described the plasma clearance of iohexol in rats in 2014 using liquid chromatography-electrospray-mass spectrometry (LC-ESI-MS). They administered different doses of iohexol via the tail vein to male HsdRCCHan:WIS rats, and the animals were sacrificed at different times after infection with iohexol (15, 30, 60, and 90 minutes) to obtain blood samples. Passos et al. validated the plasma clearance of iohexol in rats [16] against the “classical” gold standard, inulin clearance, using capillary electrophoresis, observing a correlation between iohexol and inulin clearance (r = 0.792). However, the procedure required large amounts of blood. Carrara proposed the measurement of GFR through experiments on mice using the following scheme: administration of iohexol (129.4 mg) intravenously and subsequent determination on four blood samples after the infusion at times (20, 40, 120, 140 minutes) [17]. While Luis-Lima proposed a further simplified scheme with fewer side effects, always in mice; intravenous administration of 6.47 mg of iohexol and subsequent blood sampling (approximately 10 μL each) after the infusion at times (15, 35, 55 and 75 minutes) with determination of iohexol by HPLC-UV on the blood and with factor correction equal to 0.89. The advantage of both methods was represented by the fact that they were comparable in their results not only in mice with normal renal function but also in mice with CKD and with a single kidney following nephrectomy [16].

This method has the advantage of using a small quantity of blood, approximately 10 μL, offering the advantage of carrying out serial samples over time to evaluate the progress of renal function.

Rodríguez-Rodríguez AE et al. have proposed the possibility of using dried blood samples (DBS) while maintaining adequate precision in sample processing [16]. The method consisted of sampling 5 μL of blood with heparin tubes at times 15, 30, 45, 60, 75 minutes after the infusion of Iohexol and subsequent drying of the blood sample on filter paper (Whatman 903, GE Healthcare) to 24 hours and subsequent extraction with 5% perchloric acid with centrifuge [18]. The measurement of Iohexol was carried out with the HPLC method; this procedure showed high precision in the determination of GFR in mice.

Turner established a new method of determining GFR using Iohexol with two blood samples and compared it to better known methods such as inulin, creatinine and cystatin-C [19]. Intravenous infusion of 25 mg/kg of Iohexol was performed and blood samples were taken at times 2, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300 minutes; the result shawed that the samples taken at the 30 and 90 minute periods represented the average of the values ​​of all eleven blood samples. Thus, Iohexol was proposed as a method to determine GFR through a single intravenous infusion of 25 mg/kg of Iohexol, with subsequent measurements taken within 30 and 90 minutes.

Iohexol represents a precise method for measuring GFR however it may have measurement errors due to sample preparation.

 

Conclusions

The study of the various methods for calculating GFR is still a topic of study today so that we can achieve a simple, rapid and reproducible measurement in every peripheral structure. The ideal method should avoid 24-hour urine collection, reduce the amount of blood, avoid radiolabeled substances and speed in sample calculation. We have listed several types, each with potential disadvantages. Creatinine and cystatin-C, despite being widely used, sometimes have limitations in determining the real GFR. Radiolabeled markers (99mTc-DTPA and 51Cr-EDTA) are cheap but unsafe and should be replaced with an alternative method. Inulin represents the most precise method but is difficult to reproduce in a clinical environment due to the costs and complexity of the procedure. Iothalamate is less precise than inulin but more convenient and easier to use. Iohexol represents a precise and safe method but to date it has been studied in mouse models. An alternative may be represented by fluorescent markers such as FITC inulin or FITC sinistrin, also used in the transcutaneous method with the advantage of instantaneous measurement and no use of optimal methodical blood sampling in animals [6]. In conclusion, the method for measuring GFR should depend on the care setting, the resources available, the experience of the researcher and the safety and well-being of the animals.

 

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Too bad to be true: pseudo-AKI due to traumatic bladder rupture

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Marco Ruggeri

Marco Ruggeri1, Costanza Martino2, Antonio Giudicissi1, Sara Signorotti1, Giovanni Mosconi1

1 Nephrology and Dialysis Unit - Ospedale "M. Bufalini", Cesena, Italy
2 Intensive Care Unit - Ospedale "M. Bufalini", Cesena, Italia

Corresponding author:
Marco Ruggeri
U.O. Nefrologia e Dialisi, Ospedale "M. Bufalini", Cesena
Viale Giovanni Ghirotti 286
47521 Cesena, Italy
E-mail: marco.ruggeri@auslromagna.it

 

Abstract

Acute Kidney Injury (AKI) is described as a rapid decline in Glomerular Filtration Rate (GFR), reflected by an increase in serum creatinine (SCr) and/or contraction of diuresis. The traditional paradigm considers pre-renal, renal and post-renal causes of AKI. However, there are some settings in which an elevated SCr does not reflect a real decline in GFR. Here we describe the case of a pseudo-AKI, consequence of a massive intraperitoneal urinary leakage due to a traumatic bladder rupture. Besides the pathophysiological considerations, we want to raise awareness about this condition, especially in relation to patients presenting with oliguria, hematuria, apparent AKI, abdominal pain and ascites, particularly after trauma; we do this not only to prevent late diagnosis complications, but also to avoid costly and risky overtreatment.

Keywords: pseudo-AKI, creatinine, urinary ascites, bladder rupture, trauma

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Case report

A young adult, whose medical history includes favism, tabagism, alcohol drinking, drug addiction and no reports of kidney disease, was transported by helicopter to the emergency department after a road accident.

His arterial pressure was 190/80 mmHg, heart rate 103 beats per minute, peripheral oxygen saturation 100% with oxygen therapy, Glasgow Coma Scale 14/15.

Suspecting a seat belt trauma, a Focus Assessment with Sonography for Trauma (FAST) evidenced abdominal effusion, no display of the bladder and no signs of pneumothorax. Urine output was scarce and hematuric.

Laboratory findings (summarised in Table I) revealed no signs of bleeding, with white blood cells count 24040 x 106/L, hemoglobin 16.8 g/dL, platelets 307000 x 106/L; severe impairment of kidney function with serum creatinine (SCr) 6.94 mg/dL, estimated glomerular filtration rate (eGFR) 10 mL/min using CKD-EPI formula, unavailable azotemia, sodium 141 mmol/L, potassium 5.4 mmol/L, creatine phosphokinase 149 U/L, myoglobin 200 ug/L. Arterial blood gas analysis showed pH 7.22, pCO2 62.3 mmHg, pO2 570.4 mmHg, HCO3– 25.2 mmol/L, chloremia 103 mmol/L, anion gap 19.7 mmol/L. Urine drug test was positive for cocaine and opiates.

White blood cells 24040 x 106/L
Hemoglobin 16.8 g/dL
Platelets 307000 x 106/L
SCr 6.94 mg/dL
eGFR 10 mL/min
azotemia n/a
sodium 141 mmol/L
potassium 5.4 mmol/L
creatine phosphokinase 149 U/L
myoglobin 200 ug/L
pH 7.22
pCO2 62.3 mmHg
pO2 570.4 mmHg
HCO3– 25.2 mmol/L
Chloremia 103 mmol/L
anion gap 19.7 mmol/L
Table I: The patient’s laboratory results upon arrival to the emergency room

Because of a persistent psychomotor agitation and tendency to elevated blood pressure, sedation was enhanced, and the patient was subjected to oro-tracheal intubation.

A total body Computed Tomography (CT) scan with iodine contrast media was urgently performed (Fig. 1) and showed a burst breach of 6 cm of the superior-anterior bladder wall with massive spreading of urine in the peritoneal cavity, intact ureters without hydronephrosis and no lesions of other internal organs or bones.

Figure 1: Cross section of CT cystography showing a massive leakage of contrasted urine in the abdomen, originating from a large breach in the bladder dome
Figure 1: Cross section of CT cystography showing a massive leakage of contrasted urine in the abdomen, originating from a large breach in the bladder dome

The patient underwent an urgent exploratory laparotomy that detected, across all recesses of the peritoneal cavity, the aforementioned massive effusion of about 1 liter of urine mixed with blood. The liquid was aspirated in its entirety, the bladder rupture was surgically repaired and a 3-way bladder catheter for cystoclysis was placed. Then, he was transferred to the Intensive Care Unit for monitoring. Supporting treatment, besides sedation, included rehydrating electrolyte solution, clonidine for hypertension, methadone (because of history of drug addiction), enteral nutrition and enoxaparin.

A nephrological consultation was requested regarding the severe oliguric kidney impairment with electrolytes and metabolic anomalies. Because the starting level of SCr was disproportionately high and had grown very rapidly after the trauma (2-3 hours), and since we could exclude other causes of Acute Kidney Injury (AKI) such as hypovolemic or hemorrhagic shock, kidney lesions and rhabdomyolysis, we decided not to start Renal Replacement Therapy (RRT) immediately, but preferred a “wait and see” strategy, repeating a laboratory test soon after surgery (3 hours after the previous ones).

The results revealed a rapid improvement of AKI with SCr 5.1 mg/dl, eGFR 15 ml/min, urea 93 mg/dl (first detection), K+ 4.5 mmol/L, improved metabolic acidosis with reduction of the anion gap. The quantification of diuresis was hindered by bladder washouts during cystoclysis. The day after, SCr and urea were reduced to 1.35 mg/dl and 50 mg/dl respectively, while diuresis was effective, after stopping cystoclysis; on the third day of hospital stay, SCr returned to normal values (0.71 mg/dl).

The prompt improvement of biochemical parameters at the resolution of the uroperitoneum suggested a case of pseudo-AKI, in which the laboratory anomalies were not reflecting a real reduction in GFR, but were the result of the rapid diffusion, through the peritoneal membrane, of highly concentrated urinary waste (creatinine, potassium and acids) as in a reverse peritoneal self-dialysis.

 

Discussion

AKI is described as a rise in SCr concentration and/or a reduction of urine output over a short period of time, as defined by the AKIN criteria [1]. These parameters reflect an abrupt decline in GFR and in the ability to eliminate uremic toxins. Traditionally, AKI is divided in pre-renal, renal, and post-renal causes.

However, under certain conditions, SCr can increase acutely, independently of a decrease in the GFR and reflecting no real change in overall kidney function. This may be due to drug interference with the serum assay (eg. acetoacetate in diabetic ketoacidosis, cefoxitin, flucytosine [2–4]) or a decreased creatinine secretion (eg. cimetidine, trimethoprim, some antiviral drugs and some antitumoral agents such as tyrosine kinase inhibitors [5–9]).

Elevated SCr can also be a consequence of enhanced creatinine production, for example after a large meal comprising of cooked meat (muscle contains creatine, which is converted to creatinine by the heat while cooking); it then returns slowly to the baseline level [10]. It has also been suggested that SCr rises more rapidly with rhabdomyolysis (up to 2.5-3 mg/dL per day) than with any other causes of AKI, because of a massive release of creatinine from the injured muscle [11].

In all these settings, elevated SCr does not reflect a parallel decline in GFR, as is the case for another peculiar situation of pseudo-AKI: urinary ascites (UA). This condition is caused by intraperitoneal urinary effusion, originating from a bladder rupture. Compared to plasma, waste products in the urine (eg. creatinine, urea, acids, potassium) have a higher concentration; this drives a rapid diffusion gradient across the semipermeable membrane constituted by peritoneum, resembling the chemical-physical principle behind peritoneal dialysis, but obviously with a reverse gradient direction.

The clinical presentation of UA includes abdominal pain, peritoneal effusion, oliguria, hematuria and biochemical features of AKI (elevated SCr, azotemia and potassium, metabolic acidosis, hyponatriemia); in this setting, the simultaneous presence of ascites can suggest a superimposed hepatorenal syndrome, whereas the hematuria (or microscopic hematuria with proteinuria in urinary sample) can mimic a rapidly progressive glomerulonephritis [12]. Late presentations include ileus, peritonitis and sepsis [13, 14].

An ascites to serum creatinine ratio of >1.0 is suggestive of an intraperitoneal urinary leak [15]. Subdiaphragmatic lymph vessels are the main drainage routes of intraperitoneal fluid and macromolecules, at a flow rate of approximately 1 mL per minute [16, 17]; as urine production usually exceeds this value, any condition in which urine can freely access the peritoneal cavity would be expect to increase the ratio between ascites and serum creatinine.

Intraperitoneal infusion of urine is known to increase azotemia and SCr. The rapidity of this phenomenon is dependent on volume and time of infusion. For example, a bolus injection of 100 mL of urine into the abdominal cavity elevates SCr, acutely but transiently, from 0.77 to 1.26 mg/dL for 1 hour in normal dogs; surgical rupture of the canine empty bladder also gradually increases SCr to 1.45 mg/dL for 6 hours [18].

In our case, the disproportionately quick and elevated SCr rise (6.94 mg/dL) did not match the timing (2-3 hours earlier) or entity of the trauma, even in the case of a massive release of creatinine due to rhabdomyolysis. For example, in anephric patients on intermittent dialysis, the SCr increase seems to range from 1.3 to 2.0 mg/dl per day [11]. Therefore, in our patient, only the transperitoneal diffusion of about 1 liter of urine leakage could explain such a biochemical abnormality.

Alternative tests to support the diagnosis of UA include serum:urinary ascites albumin gradient >1.1 g/dL and the detection of mesothelial cells in urine cytology, suggesting the migration of mesothelial cells from the peritoneal cavity to the bladder [19].

Bladder rupture can be divided into extra-peritoneal, intra-peritoneal and combined. The first occurs in 54-56% of cases [13, 20] and almost exclusively in blunt traumas that fracture the pelvic bone [20]. Intraperitoneal bladder ruptures (38-40% of cases) are caused by a peak in the internal pressure of the bladder, resulting in the rupture of the dome, the most mobile and vulnerable part of the organ [13]. This typically occurs when the bladder is full, pushing its dome above the pelvic inlet and exposing it [20].

Pseudo-AKI due to bladder rupture is reported to be caused by trauma in 51% of cases, and by iatrogenic cause (gynecologic procedures, but also general surgical and urologic procedures) in 49% [21]. Spontaneous ruptures represent only <1% of cases and occur especially in patients with obstructive or retentive pathology, or history of substance abuse [22]. For example, alcohol abuse can predispose some patients to bladder rupture through an enhanced diuretic effect and an alteration in the perception of the need to void [22, 23]. The bladder-distending effects of alcohol can be strengthened by sympathomimetic agents such as cocaine and amphetamines, which increase flow resistance at the bladder neck [22].

The cause of bladder rupture in our case was of course a seat belt trauma, but the history of alcohol drinking and the detection of cocaine in the urine could suggest a distended bladder full of urine with a hypertonic bladder neck.

The diagnostic gold standard is CT cystography, whose sensitivity and specificity for diagnosing intraperitoneal bladder rupture is reported as 78% and 99% respectively in this study [24]. When diagnosis and treatment are prompt, the prognosis for bladder rupture is excellent. Indeed, normalization of biochemical values occurs <24 hours from the surgical repair, which is recommended for intraperitoneal rupture, although conservative therapy could be a treatment option for selected patients [25, 26].

 

Conclusions

Physicians should consider pseudo-AKI in any patient with blunt abdominal trauma, or who underwent genitourinary surgical procedures or radiation therapy, who develops anuria or oliguria, ascites and an elevated SCr. A delayed diagnosis can lead to several complications, such as ileus, peritonitis and sepsis, but also to the use of unnecessary and potentially harmful medications or hemodialysis.

We learnt from this experience that, even in the frantic context of emergency care, our goal should never be to resolve a laboratory abnormality without considering its causative origin first. We had all the reasons to initiate RRT in a “generic” post-trauma oliguric AKI patient with metabolic anomalies but, by realizing his SCr was “too bad to be true” we prevented costly and risky overtreatment.

 

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