Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.

Preserved renal function during long-term follow-up in children with chronic liver disease.

AIM: We have previously found well-maintained renal function in children with new-onset chronic liver disease. In this study, we investigated their renal function during long-term follow-up of the disease. METHODS: In a study of 289 children with chronic liver disease, renal function was investigated as glomerular filtration rate (GFR) measured as clearance of inulin or iohexol. Yearly change in GFR was calculated based on a linear mixed model. The data were analysed with regard to different subgroups of liver disease and with regard to the outcome. RESULTS: The initially well-preserved renal function remained so in most patients during the observation period, even in children with progressive liver disease leading to decompensation. The greatest fall in GFR occurred in patients with initial hyperfiltration. Cholestasis seemed to have a nephroprotective effect. CONCLUSION: Chronic liver disease in childhood seems to have less impact on renal function than believed earlier, at least as long as the liver function remains compensated. Regular renal check-ups remain an essential tool for optimal patient care. Hyperfiltration seems to predict decline in renal function. Otherwise no further reliable prognostic markers were found in patients whose liver disease was not decompensated.

Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment.

AIM: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing. METHODS: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR) and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages. RESULTS: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5-25 kg/m2 , all equations performed similarly, and for BMI < 18.5 kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m2 ). The four more recent equations also classified mGFR stages better than CG. CONCLUSIONS: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations.

Comparison of cystatin C, creatinine, and iohexol clearance in pediatric liver transplantation-a retrospective cohort study.

Impaired renal function after pediatric (LT) is a recognized problem. Accurate monitoring of (GFR) is imperative to detect declining renal function. GFR can be estimated via s-creatinine and/or p-cystatin C or measured by inulin and or/iohexol clearances. We retrospectively compared eGFRcrea and eGFRcyst, to mGFRiohex after LT. Data from 91 children with 312 concomitant measurements of s-creatinine, p-cystatin C, and iohexol clearance, obtained between 2007 and 2015, were analyzed. eGFR was calculated by using the p-cystatin C-based CAPA and CKD-EPI formulas, and the s-creatinine-based Schwartz-LYON, FAS, revised Schwartz and MDRD formulas. Also, the arithmetic means of cystatin C-based and creatinine-based equations were used. Every calculated eGFR was compared to mGFRiohex in statistical correlation, accuracy, precision, bias, and misclassifications. Among the different equations, p-cystatin C-based formulas (CAPA and CKD-EPI) as well as the s-creatinine-based Schwartz-LYON formula showed the most correct estimates regarding accuracy (84-87.5%), bias (0.19-4.0 ml/min/1.73 m2 ), and misclassification rate (24.7-25%). In patients with renal function <75 ml/min/1.73 m2 , cystatin C-based formulas were significantly more accurate and less biased than creatinine-based formulas. In conclusion, S-creatinine could be used in a clinical setting on a regular basis in liver transplanted pediatric patients, with reliable results, if eGFR is calculated by the Schwartz-LYON formula. When suspected renal dysfunction, cystatin C-based eGFR should be calculated, since it gives more accurate and less biased estimates than creatinine-based eGFR, and should be confirmed by mGFR (iohexol).

Well Preserved Renal Function in Children With Untreated Chronic Liver Disease.

OBJECTIVES: On the basis of studies with hepatorenal syndrome, it is widely regarded that renal function is impacted in chronic liver disease (CLD). Therefore, we investigated renal function in children with CLD. METHODS: In a retrospective study of 277 children with CLD, renal function was investigated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), measured as clearance of inulin and para-amino hippuric acid or clearance of iohexol. The data were analyzed with regard to different subgroups of liver disease and to the grade of damage. RESULTS: Hyperfiltration (>+2 SD of controls) was found in the subgroups of progressive familial intrahepatic cholestasis (44%), glycogenosis (75%), and acute fulminant liver failure (60%). Patients with biliary atresia, most other patients with metabolic disease and intrahepatic cholestasis, and those with vascular anomalies and cryptogenic cirrhosis had normal renal function. Decreased renal function was found in patients with Alagille's syndrome (64% < -2 SD). Increased GFR and ERPF was found in patients with elevated transaminases, low prothrombin level, high bile acid concentration, and high aspartate-aminotransferase-to-platelet ratio. CONCLUSIONS: Most children with CLD had surprisingly well preserved renal function and certain groups had even hyperfiltration. The finding that children with decompensated liver disease and ongoing liver failure had stable kidney function suggests that no prognostic markers of threatening hepatorenal syndrome were at hand. Moreover, estimation of GFR based on serum creatinine fails to reveal hyperfiltration.

Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules.

How the kidney prevents urinary excretion of plasma proteins continues to be debated. Here, using unfixed whole-mount mouse kidneys, we show that fluorescent-tagged proteins and neutral dextrans permeate into the glomerular basement membrane (GBM), in general agreement with Ogston's 1958 equation describing how permeation into gels is related to molecular size. Electron-microscopic analyses of kidneys fixed seconds to hours after injecting gold-tagged albumin, negatively charged gold nanoparticles, and stable oligoclusters of gold nanoparticles show that permeation into the lamina densa of the GBM is size-sensitive. Nanoparticles comparable in size with IgG dimers do not permeate into it. IgG monomer-sized particles permeate to some extent. Albumin-sized particles permeate extensively into the lamina densa. Particles traversing the lamina densa tend to accumulate upstream of the podocyte glycocalyx that spans the slit, but none are observed upstream of the slit diaphragm. At low concentrations, ovalbumin-sized nanoparticles reach the primary filtrate, are captured by proximal tubule cells, and are endocytosed. At higher concentrations, tubular capture is saturated, and they reach the urine. In mouse models of Pierson's or Alport's proteinuric syndromes resulting from defects in GBM structural proteins (laminin ß2 or collagen α3 IV), the GBM is irregularly swollen, the lamina densa is absent, and permeation is increased. Our observations indicate that size-dependent permeation into the lamina densa of the GBM and the podocyte glycocalyx, together with saturable tubular capture, determines which macromolecules reach the urine without the need to invoke direct size selection by the slit diaphragm.

New standardized cystatin C and creatinine GFR equations in children validated with inulin clearance.

BACKGROUND: This study compares glomerular filtration rate (GFR) equations in children based on standardized cystatin C (CYSC) and creatinine (CREA) and their combinations with renal clearance of inulin (C-inulin). METHODS: A total of 220 children with different renal disorders were referred for C-inulin (median 84 ml/min/1.73 m(2)). Bias, precision (interquartile range, IQR), and accuracy (percentage of estimates ±30 % of C-inulin; P30) were evaluated for two cystatin C equations, CAPACYSC and BergCYSC, for creatinine equations, SchwartzCREA and GaoCREA, the arithmetic mean of CAPACYSC and SchwartzCREA (MEANCAPA+Schwartz), BergCYSC and SchwartzCREA (MEANBERG+SCHWARTZ) and the composite equation ChehadeCYSC+CREA. RESULTS: Overall results of CAPACYSC, BergCYSC, SchwartzCREA, GaoCREA, MEANCAPA+Schwartz, MEANBERG+SCHWARTZ and ChehadeCYSC+CREA were: median bias -7.6/-4.9/-3.7/-2.3/-4.6/-4.0/-10.1 %, IQR 20.0/19.9/21.7/22.4/21.0/20.9/23.3 ml/min/1.73 m(2) and P30 86/86/80/83/89/91/83 %. The cystatin C equations, MEANCAPA+Schwartz and MEANBERG+SCHWARTZ had a more stable performance across subgroups compared with SchwartzCREA, GaoCREA and ChehadeCYSC+CREA. CONCLUSIONS: Cystatin C was the preferred filtration marker for GFR estimation in children, while the benefit of combining cystatin C and creatinine deserves further investigations.

Measuring GFR: a systematic review.

BACKGROUND: No comprehensive systematic review of the accuracy of glomerular filtration rate (GFR) measurement methods using renal inulin clearance as reference has been published. STUDY DESIGN: Systematic review with meta-analysis of cross-sectional diagnostic studies. SETTING & POPULATION: Published original studies and systematic reviews in any population. SELECTION CRITERIA FOR STUDIES: Index and reference measurements conducted within 48 hours; at least 15 participants studied; GFR markers measured in plasma or urine; plasma clearance calculation algorithm verified in another study; tubular secretion of creatinine had not been blocked by medicines. INDEX TESTS: Endogenous creatinine clearance; renal or plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), diethylenetriaminepentaacetic acid (DTPA), iohexol, and iothalamate; and plasma clearance of inulin. REFERENCE TEST: Renal inulin clearance measured under continuous inulin infusion and urine collection. RESULTS: Mean bias <10%, median bias <5%, the proportion of errors in the index measurements that did not exceed 30% (P30) ≥80%, and P10 ≥50% were set as requirements for sufficient accuracy. Based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, the quality of evidence across studies was rated for each index method. Renal clearance of iothalamate measured GFR with sufficient accuracy (strong evidence). Renal and plasma clearance of 51Cr-EDTA and plasma clearance of iohexol were sufficiently accurate to measure GFR (moderately strong evidence). Renal clearance of DTPA, renal clearance of iohexol, and plasma clearance of inulin had sufficient accuracy (limited evidence). Endogenous creatinine clearance was an inaccurate method (strong evidence), as was plasma clearance of DTPA (limited evidence). The evidence to determine the accuracy of plasma iothalamate clearance was insufficient. With the exception of plasma clearance of inulin, only renal clearance methods had P30 >90%. LIMITATIONS: The included studies were few and most were old and small, which may limit generalizability. Requirements for sufficient accuracy may depend on clinical setting. CONCLUSIONS: At least moderately strong evidence suggests that renal clearance of 51Cr-EDTA or iothalamate and plasma clearance of 51Cr-EDTA or iohexol are sufficiently accurate methods to measure GFR.

An observational cohort study of the effect of hypertension on the loss of renal function in pediatric kidney recipients.

BACKGROUND: Post-transplant hypertension impacts negatively on renal graft survival. Our primary objective was to analyze the effect of hypertension on the glomerular filtration rate (GFR) slope. METHODS: All clinical charts of children who underwent renal transplantation since the introduction of the routine use of ambulatory blood pressure monitoring (ABPM) were reviewed. Eligibility criteria for inclusion were measurement of GFR at 3 months, at 1 year post-transplant, and thereafter at yearly intervals; ABPM performed annually after transplantation; and functioning graft for a minimum of 2 years. RESULTS: Sixty-eight (39 males) of 79 patients, aged 9.1±5.3 years, met the inclusion criteria. The mean follow-up was 6.2±2.8 years. Twenty-four patients had normotension or controlled hypertension throughout their follow-up (normotensive group). Forty-four patients had hypertension or noncontrolled hypertension at some point(s) during the follow-up period (hypertensive group). GFR slope was -1.6ml/min/1.73 m(2) per year (95% confidence interval (CI = -3.7 to 0.4) in the normotensive group and -2ml/min/1.73 m(2) per year (95% CI = -3 to -1.1) in the hypertensive group (P = 0.42). There was no difference between groups with regard to the change in GFR values from 3 months to 1 year and to last control (P = 0.87). At most recent control, the overall prevalence of controlled hypertension was 78.2% (95% CI = 63.6-89.1). CONCLUSIONS: Although the results of our study are encouraging, they need to be confirmed in a larger prospective study using the same post-transplant follow-up protocol.

Renal transplantation in infants and small children.

There are still concerns about renal transplantation in small children. The aim of this study was to identify prenatal data, underlying diseases, patient and graft survival, graft function and growth in young renal transplant recipients at our center. A retrospective analysis was performed on 50 kidney transplants performed during the period 1981-2008 in children weighing <13 kg. Their median age at transplantation was 1.4 (range 0.4-3.7) years and the median weight was 9.5 (3.4-12.1) kg. The underlying diseases were congenital in 88% of the patients and acquired in 12%. Ten-year patient survival was 88% (82% before 1998 and 95% since 1998). Ten-year graft survival was 82% (75 and 95%, respectively). Graft function (glomerular filtration rate) deteriorated from a mean of 75-48 ml/min/1.73 m(2) within 10 years. There was rapid catch-up growth within the first years post-transplant, from a median height of -2.44 standard deviation score (SDS) at transplantation to -0.74 SDS after 3 years. In small children, patient and graft survival were as good as those in older children. Renal function deteriorated during the first years post-transplant but stabilized within a few years. In most children, there was a substantial improvement in growth within the first years after transplantation.

Predictors of outcome in paediatric IgA nephropathy with regard to clinical and histopathological variables (Oxford classification).

BACKGROUND: There has been a lack of international consensus on the classification and the predictive value of the histopathology findings in IgA nephropathy (IgAN). Recently, the International IgA Nephropathy Network has developed the Oxford classification in which four histological variables with the most prognostic importance are identified (MEST score). Our objective was to validate these findings and to assess their predictive power in our cohort and to compare them to identified clinical predictors. METHODS: Ninety-nine children with a follow-up time >5 years were included and investigated with clearances of inulin or iohexol for glomerular filtration rate (GFR), proteinuria and blood pressure at biopsy and during follow-up. Biopsies (90/99) were re-evaluated and scored according to the Oxford classification. RESULTS: Eighteen patients progressed to a poor outcome [end-stage renal disease (ESRD) or GFR reduction >50%]. In the univariate analysis, we found that mesangial hypercellullarity score >0.5, presence of endocapillary hypercellularity or tubular atrophy/interstitial fibrosis of >25% were each associated with a poor outcome, and also presence of cellular or fibrocellular crescents and of global glomerulosclerosis, but segmental glomerulosclerosis did not reach statistical significance. The clinical predictors of a poor outcome were a low GFR, a high mean arterial blood pressure and a high amount of albuminuria (log Ualb/c) at time of biopsy and low GFR and a high log Ualb/c during follow-up. CONCLUSION: We found that three of the four histology lesions identified in the Oxford classification, as well as presence of crescents, were valid in predicting a poor outcome in our cohort of patients.

Use of annual ABPM, and repeated carotid scan and echocardiography to monitor cardiovascular health over nine yr in pediatric and young adult renal transplant recipients.

In adult hypertensive patients, increased cIMT and LVH are independent risk factors for cardiovascular events. We have previously observed that in pediatric RTRs with tight control of BP, cIMT did not progress over time. This investigation is an extension of the aforementioned study aimed at re-examining cIMT and also reporting serial echocardiography results. Twenty-two RTRs aged 9.4 ± 3.3 yr at their baseline carotid scan underwent two additional vascular ultrasounds during a follow-up of 9.1 ± 0.9 yr. Carotid scan and echocardiography examinations were carried out simultaneously with ABPM. Antihypertensive therapy was determined according to the recipient's ABPM results, which were performed at yearly intervals. Baseline cIMT was significantly greater in RTRs than in healthy controls. There was no statistical evidence of systematic changes in cIMT over time. At the last examination, 14 of 17 RTRs with treated hypertension had controlled hypertension (prevalence 82%; 95% CI, 56.5-96.2), and the overall prevalence of LVH was 4.5% (95% CI, -0.01 to 23.5). The lack of progression of cIMT over time and the low prevalence of LVH might reflect the effect of long-standing BP control.

ABO-incompatible kidney transplantation in children.

We designed a new protocol to enable safe ABO-incompatible kidney transplantation. The new protocol utilizes antigen-specific immunoadsorption rather than unspecific plasma exchange to remove existing anti A/B antibodies and rituximab rather than splenectomy to prevent rebound of antibodies. Sixty patients have so far been successfully transplanted with this protocol and 10 of those have been children. When compared with ABO-compatible transplantations, we could not find any differences in success rate, renal function, or adverse events.

Comparison of plasma clearance of iohexol and urinary clearance of inulin for measurement of GFR in children.

BACKGROUND: Very few studies have been published that compare plasma clearance of iohexol (Cio) with renal clearance of inulin (Cin). STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 60 children aged 11.6 ± 4.5 years with different kidney disorders were investigated. INDEX TEST: Plasma Cio calculated from the slope and a single point. REFERENCE TEST: Renal Cin with continuous infusion during water diuresis. Results were compared with the correlation coefficients, bias and precision, accuracy percentage, root mean square error, and intraclass correlation. OTHER MEASUREMENTS: Measured creatinine clearance and estimated glomerular filtration rate based on serum creatinine level and height. RESULTS: Mean Cin was 70.7 ± 41.3 (SD) mL/min/1.73 m². Mean differences between Cio and Cin were 2.65 and 2.00 mL/min/1.73 m² for the slope and single-point methods, respectively. Precision was ±16 mL/min/1.73 m² and intraclass correlation was 0.92 in both methods. Proportions of Cio within 30% of Cin were 83.3% and 86.7% for the slope and single-point methods, respectively. LIMITATIONS: A limited number of patients; no adults were studied. CONCLUSIONS: Plasma Cio shows good agreement with renal Cin.

Predictors of outcome in Henoch-Schönlein nephritis.

Factors predictive of renal outcome were studied in 78 children with Henoch-Schönlein nephritis followed up for as long as 17 (mean 5.2) years. Patients with a good outcome (74%) were healthy or had microalbuminuria or mild proteinuria at the final follow-up (FU), and those with poor outcome (26%) had active renal disease or chronic kidney disease at stages IV-V. Patients with mild symptoms at onset (hematuria + or - mild proteinuria) had a poor outcome in 15% of cases versus 41% of those with severe symptoms (nephritic or nephrotic syndrome or nephritic-nephrotic picture) (p = 0.011). However, among patients with mild proteinuria at onset, 18% showed a poor prognosis; non-nephrotic proteinuria with a urine albumin/creatinine ratio at a cut-off value of >144 mg/mmol at the 1-year FU was predictive of a poor outcome. Among 59 biopsied patients, 37% of those with advanced histological findings [International Study of Kidney Disease in Children (ISKDC) stages III-V] had a poor outcome compared to none of those with mild findings (ISKDC stages I-II) (p = 0.0015). Patients with a poor outcome were older at onset, had more proteinuria, and lower glomerular filtration rate at the 1-year FU compared with patients with a good outcome. Multivariate analysis showed that proteinuria at the 1-year FU and the ISKDC grading score of the renal biopsy were the two most discriminant factors of a poor prognosis.

Risk markers of future microalbuminuria and hypertension based on clinical and morphological parameters in young type 1 diabetes patients.

BACKGROUND: Nephropathy is a severe complication of type 1 diabetes and develops in 30% of patients. Currently, it is not possible to identify young patients at risk prior to the development of microalbuminuria (MA) and/or hypertension (HT). OBJECTIVE: To study predictors of MA and/or HT in young normoalbuminuric (NA) patients with type 1 diabetes. SUBJECTS AND METHODS: Forty-six NA and normotensive (NT) type 1 diabetes patients, regularly followed since onset with checks on metabolic control, kidney function, and MA, were investigated with kidney biopsies and 24-h ambulatory blood pressure measurements (ABPMs) after 10.6 yr of diabetes. The patients were followed another six and a half years with regard to the development of MA and HT. RESULTS: Fifteen patients developed MA and/or HT during follow-up. The strongest risk markers were poor metabolic control after puberty, high day-time systolic blood pressure (BP), and increased BMT at 10 yr, which explained 62% of the outcome for MA and/or HT at 17 yr duration with 77% sensitivity and 65% specificity. The threshold values were long-term postpubertal HbA(1c) > 8.2%, day-time systolic BP > 130 mmHg, and BMT > 490 nm/1.73 m(2). CONCLUSIONS: Normoalbuminuric and NT patients at risk of developing MA and HT could be identified and might benefit from an early start of antihypertensive therapy and improvement of metabolic control.

Treatment of severe Henoch-Schönlein and immunoglobulin A nephritis. A single center experience.

Our aim was to report the effect of two treatment regimens in 43 cases of severe Henoch-Schönlein nephritis (HSN) and immunoglobulin A nephritis (IgAN) (24 HSN, 19 IgAN). Group A, 11 HSN and 7 IgAN, 88% with an International Study of Kidney Disease in Children (ISKDC) biopsy grade > or = III and severe clinical features, were treated with corticosteroids, cyclophosphamide (CYC-P) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB). Group B, 12 HSN and 13 IgAN, 72% with biopsy findings as above and 52% with severe clinical features, were treated with ACEi/ARB +/- corticosteroids. The outcome classification was: (a) healthy; (b) mild proteinuria, normal glomerular filtration rate (GFR); (c) active renal disease; (d) chronic renal failure. Twenty-six patients had a good outcome (a + b). The 17 children with poor outcome (c + d) had lower GFR at onset and at follow-up, higher albumin excretion at follow-up, and higher percentage of segmental glomerulosclerosis in the renal biopsy, than those with good outcome. Treatment with corticosteroids, CYC-P and ACEi/ARB was effective in increasing GFR, reducing proteinuria and decreasing the disease activity index. The proteinuria had decreased at follow-up in both groups. In group A, GFR increased and histopathological activity index declined after treatment. The outcome did not differ between groups A and B. The effects of treatment did not differ between HSN and IgAN.

The impact of sodium chloride and volume depletion in the chronic kidney disease of congenital chloride diarrhea.

Congenital chloride diarrhea is due to mutations in the intestinal Cl(-)/HCO(3)(-) exchange (SLC26A3) which results in sodium chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital chloride diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital chloride diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that diarrhea-related sodium chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.