Long-term successful liver-kidney transplantation in a child with atypical hemolytic uremic syndrome caused by homozygous factor H deficiency.

BACKGROUND: Rational options for the treatment of end-stage renal disease (ESRD) due to atypical hemolytic uremic syndrome (aHUS) in children are still open to discussion. In the case of human complement factor H (CFH) deficiency, the choice is either kidney transplantation in combination with eculizumab, a humanized anti-C5 monoclonal antibody, or a combined liver-kidney transplantation. CASE-DIAGNOSIS/TREATMENT: A child with a homozygous CFH deficiency underwent a successful liver-kidney transplantation. CFH levels normalized within days. After 6 years of follow-up, the graft function (Cockroft clearance 100 ml min-1 1.73 m-2) and the liver functions were normal. RESULTS AND CONCLUSIONS: The results of this long-term follow-up confirm that combined liver-kidney transplantation remains a reasonable option in patients with ESRD due to aHUS when an identified genetic abnormality of the C3 convertase regulator synthesized in the liver has been identified.

Escherichia coli virulence patterns may help to predict vesicoureteral reflux in paediatric urinary tract infections.

AIM: Ultrasound and biological tools are used to predict high-grade vesicoureteral reflux, but other markers are needed to better select patients who need voiding cystography. Our aim was to determine whether studying Escherichia coli virulence factors would help to predict vesicoureteral reflux in patients with their first acute pyelonephritis. METHODS: We included children presenting with E. coli-related acute pyelonephritis or cystitis. Vesicoureteral reflux was assessed by voiding cystography. Virulence factors were identified by multiplex polymerase chain reaction. Statistical analysis was performed using logistic regression and the mean c-statistic test. RESULTS: We included 198 patients: 30 with cystitis and 168 with acute pyelonephritis, including 46 with vesicoureteral reflux. High-grade reflux was associated with acute pyelonephritis caused by the E. coli lacking virulence factors papGII (82% versus 47%, p < 0.001) or papC (85% versus 53%, p < 0.001) or belonging to phylogenetic group A or B1. When we added genetic data (lack of papGII, fyuA and phylogenetic groups) to classical predictors of vesicoureteral reflux (ultrasound examination, gender, age), the ability to predict high-grade reflux increased, with the c-statistic rising from 0.88 to 0.93. CONCLUSION: Bacterial virulence factors and clinical factors helped to predict high-grade reflux and may help to avoid unnecessary voiding cystographies.

Long-term results of combined liver-kidney transplantation for primary hyperoxaluria type 1: the French experience.

Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failure. The posttransplant recurrence of kidney disease can suggest a need for combined liver-kidney transplantation (LKT). However, the risk of LKT is theoretically far higher than the risk of kidney-alone transplantation (KAT). An unselected consecutive series of 54 patients with PH1 was analyzed according to the type of transplantation initially performed between May 1979 and June 2010 at 10 French centers. The duration of dialysis, extrarenal lesions, age, and follow-up were similar between the groups. Postoperative morbidity and mortality did not differ between the groups, and 10-year patient survival rates were similar for the LKT (n = 33) and KAT groups (n = 21; 78% versus 70%). Kidney graft survival at 10 years was better after LKT (87% versus 13%, P < .001) . Four patients (12.1%) lost their first kidney graft in the LKT group, whereas 19 (90%) did in the KAT group (P < .001). The recurrence of oxalosis occurred in 11 renal grafts (52%) in the KAT group but in none in the LKT group (P < .001). End-stage renal failure resulting from rejection was also higher in the KAT group (19% versus 9%, P < 0.0001). A second kidney transplant was performed for 15 patients (71%) in the KAT group versus 4 patients (12%) in the LKT group (P < 0.001). In conclusion, LKT for PH1 provides better kidney graft survival, less rejection, and similar long-term patient survival and is not associated with an increased short-term mortality risk. LKT must be the first-line treatment for PH1 patients with end-stage renal disease.

Acute metabolic acidosis in a GLUT2-deficient patient with Fanconi-Bickel syndrome: new pathophysiology insights.

Fanconi-Bickel syndrome is a rare autosomal-recessive disorder caused by mutations in the SLC2A2 gene coding for the glucose transporter protein 2 (GLUT2). Major manifestations include hepatomegaly, glucose intolerance, post-prandial hypoglycaemia and renal disease that usually presents as proximal tubular acidosis associated with proximal tubule dysfunction (renal Fanconi syndrome). We report a patient harbouring a homozygous mutation of SLC2A2 who presented a dramatic exacerbation of metabolic acidosis in the context of a viral infection, owing to both ketosis and major urinary bicarbonate loss. The kidney biopsy revealed nuclear and cytoplasmic accumulation of glycogen in proximal tubule cells, a lack of expression of GLUT2, and major defects of key proteins of the proximal tubule such as megalin, cubilin and the B2 subunit of H(+)-ATPase. These profound alterations of the transport systems most likely contributed to proximal tubule alterations and profound bicarbonate loss.

Childhood onset diabetes posttransplant in a girl with TCF2 mutation.

Heterozygous mutations of TCF2 (transcription factor 2) have been associated with maturity onset diabetes of the young, renal malformations, hyperuricemia, and occasionally internal genital malformations in female. We report a female patient with bilateral renal hypodysplasia and de novo heterozygous TCF2 gene mutation. At the age of 9 yr, she developed transient ketoacidosis immediately posttransplant, temporarily requiring insulin. During glucocorticoid tapering, impaired glucose tolerance persisted and overt insulin-dependent diabetes mellitus developed 1 yr later. Pathogenic factors which might have played a role in the acceleration of diabetes were (i) switch from cyclosporine to tacrolimus, (ii) weight excess, and (iii) cytomegalovirus infection. TCF2 analysis might, therefore, be of interest in patients with congenital abnormalities of the kidney and the urinary tract in order to improve posttransplant management in terms of steroid and tacrolimus exposure.

Adenine phosphoribosyltransferase deficiency in children.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 patients). The diagnosis was based on stone analysis and microscopic examination of urine and/or enzymatic determination of APRT on red blood cells. All children had null APRT enzyme activity in erythrocytes. APRT gene sequencing was performed on 18 patients, revealing six homozygous and 12 compound heterozygous mutations. At diagnosis, half of the patients had decreased kidney function, and two children presented with acute renal failure. Allopurinol treatment was given to all patients at a median dose of 9 mg/kg/day. After a median follow-up of 5 years, all patients showed stabilization or improvement of kidney function, normal growth and development, and six patients had recurrence of nephrolithiasis. Based on these results, we conclude that an excellent outcome can be achieved in children with APRT deficiency who receive the proper treatment.

Acute tubulointerstitial nephritis.

Acute tubulointerstitial nephritis (TIN) is a frequent cause of acute renal failure, characterised by the presence of inflammatory cell infiltrate in the interstitium of the kidney. Immuno-allergic reaction to certain medications, mainly non-steroidal anti-inflammatory drugs and antibiotics are by far the most important etiology for TIN today, but other situations such as infections, toxins, and vasculitis are known to induce TIN. Incidence of TIN is increasing, probably due to prescription habits and NSAID overuse, representing 3-7% of acute kidney injury in biopsies in children. Avoidance of the causal substance and rapid steroid therapy are hallmarks for patient care, but spontaneous initial recovery is very frequent and the general prognosis seems satisfactory. However, development of chronic TIN, without response to steroid or other immunosuppressive treatment, is possible. As the largest part of TIN is secondary to certain drugs, clear indications in particular for NSAID or antibiotics should be respected to reduce the number of TIN cases.

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial.

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. Little is known regarding the clinical presentation of APRT deficiency, especially in the white population. We retrospectively reviewed all 53 cases of APRT deficiency (from 43 families) identified at a single institution between 1978 and 2009. The median age at diagnosis was 36.3 years (range 0.5 to 78.0 years). In many patients, a several-year delay separated the onset of symptoms and diagnosis. Of the 40 patients from 33 families with full clinical data available, 14 (35%) had decreased renal function at diagnosis. Diagnosis occurred in six (15%) patients after reaching ESRD, with five diagnoses made at the time of disease recurrence in a renal allograft. Eight (20%) patients reached ESRD during a median follow-up of 74 months. Thirty-one families underwent APRT sequencing, which identified 54 (87%) mutant alleles on the 62 chromosomes analyzed. We identified 18 distinct mutations. A single T insertion in a splice donor site in intron 4 (IVS4 + 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 + 2insT mutation in two (0.98%) of 204 chromosomes of healthy newborns. This report, which is the largest published series of APRT deficiency to date, highlights the underdiagnosis and potential severity of this disease. Early diagnosis is crucial for initiation of effective treatment with allopurinol and for prevention of renal complications.

Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization.

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH2-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4+ T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon gamma expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction.

Vesicoureteral reflux in children with urinary tract infection: comparison of diagnostic accuracy of renal US criteria.

PURPOSE: To directly compare various renal ultrasonography (US) criteria for vesicoureteral reflux (VUR) with voiding cystography, the reference method, for diagnostic accuracy in helping to determine an intermediate strategy of screening children who require cystography. MATERIALS AND METHODS: Institutional review board approval and parental consent were obtained for this prospective hospital-based cohort study involving children with urinary tract infections (UTIs). Renal length, ureteral dilatation, pelvic dilatation, and corticomedullary differentiation were analyzed and compared. One hundred seventeen patients (median age, 0.8 year; age range, 0.0-13.9 years) were included: 46 (39%) boys (median age, 0.3 year; age range, 0.5-13.9 years) and 71 girls (median age, 1.2 years; age range, 0.0-11.5 years). A two-level logistic regression model was used to analyze data, and diagnostic accuracy calculations were performed. RESULTS: Thirty-two (27%) children had all-grade VUR, and eight (7%) had VUR of grade 3 or higher. Only ureteral dilatation was significantly related to all-grade VUR (odds ratio [OR], 7.5; 95% confidence interval [CI]: 1.0, 58.2; P = .05), with 25% sensitivity (95% CI: 15%, 39%) and 88% specificity (95% CI: 83%, 92%). Ureteral, pelvic, and urinary tract dilatations were significantly associated with VUR of grade 3 or higher, with ORs of 20.2 (95% CI: 3.5, 118.2; P = .001), 13.7 (95% CI: 4.1, 46.0; P < .001), and 20.0 (95% CI: 4.4, 90.1; P < .001), respectively. The best compromise between sensitivity and specificity was achieved by using the ureteral dilatation criterion, which had 73% sensitivity (95% CI: 43%, 90%) and 88% specificity (95% CI: 84%, 92%) for high-grade VUR. CONCLUSION: Ureteral dilatation may yield the best accuracy for the US-based diagnosis of both all-grade and high-grade VUR. This US criterion, perhaps in combination with other predictors, might find a place in an evidence-based selective strategy for limiting cystography in children with UTIs.

Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome.

AIMS: To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC(0-12)). METHODS: The pharmacokinetic model of MMF was described from 23 patients aged 7.4 +/- 3.9 years (range 2.9-14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTS: The population pharmacokinetic parameters were apparent oral clearance 9.7 l h(-1), apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h(-1), absorption rate constant 5.16 h(-1), lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC(0-12) was obtained using the combination of three MPA concentrations measured just before (T(0)), 1 and 4 h (T(1) and T(4)) after drug intake with a small error of 0.298 microg h(-1) ml(-1) between estimated and reference AUC(0-12). CONCLUSIONS: The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T(0), T(1) and T(4)h) Bayesian estimator of AUC(0-12) was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.

Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies.

It has been reported (this issue Pediatric Nephrology) that cyclosporine A (CyA) therapy in combination with corticosteroids, angiotensin-converting enzyme inhibitor, and an angiotensin receptor blocker decreased proteinuria in three patients with nephrotic syndrome (NS) due to WT1 mutations. Treatment with calcineurin inhibitors were found to induce a partial remission of proteinuria in several other children with genetic forms of NS, such as mutation in the podocine and in the phospholipase C epsilon gene. CyA therapy has also been reported to be beneficial to patients with Alport syndrome. Recent data have shown that the antiproteinuric effect of CyA in these cases may be due to a non-immunologic mechanism. CyA exerts an antiproteinuria effect by preventing the degradation of the actin organizing protein synaptodpodin and by a downregulation of TRPC6. This mechanism leads to the stabilization of the actin cytoskeleton in the kidney podocytes. This beneficial effect of CyA is interesting, but long-term results regarding function and nephrotoxicity are still missing.

L-carnitine supplementation and EPO requirement in children on chronic hemodialysis.

L-carnitine supplementation has been the subject of heated discussion in the context of the treatment of pediatric hemodialysis patients. The aim of this study was to analyze the effect of intravenous L-carnitine supplementation on the erythropoetin (EPO) requirement in six pediatric hemodialysis patients. All patients were on intravenous L-carnitine (2.5 g per session for patients >30 kg and 1 g for those <30 kg) for 9 months. The EPO dose was adapted monthly to maintain a target hemoglobin (Hb) level of 11-13 g/dl. Prior to the initiation of L-carnitine supplementation, the EPO requirement was 1.15 +/- 0.22 (range 0.37-1.75) microg/kg darbepoetin alpha. Free carnitine (FC) levels were measured before (40.4 +/- 4.9 micromol/l), immediately after the 9-month L-carnitine supplementation period (378.5 +/- 77.3 micromol/l), and 4 months after withdrawal of L-carnitine (95.6 +/- 4.0 micromol/l). After 9 months, the EPO dose was 0.47 +/- 0.10 microg/kg (p < 0.002). The Hb levels increased from 12.2 +/- 0.97 to 14.0 +/- 0.54 g/dl (p < 0.05) within the first 2 months, and the EPO dose was then decreased in a stepwise manner. In conclusion, following intravenous carnitine supplementation, FC levels were higher and persisted longer than expected. This rise was associated with increased Hb levels and decreased EPO requirement. Since controls were missing for this study, prospective long-term multi-center studies on a large number of patients are required to provide solid answers to the controversial question of L-carnitine supplementation in hemodialyzed children.

Tacrolimus nephrotoxicity: beware of the association of diarrhea, drug interaction and pharmacogenetics.

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition.

Impressive renal damage after acute pyelonephritis in a child.

Urinary tract infection (UTI) is one of the most common bacterial infections in children, and its role in the pathogenesis of scarred kidney is debated. We report on a 7-year-old child who presented with severe UTI. The early (day 4) renal computed tomography (CT) scan showed normal-sized kidneys (110 mm on the left, 105 mm on the right), whereas the control CT scan and dimercaptosuccinic acid (DMSA) scan, performed 1 and 2 months later, respectively, showed a small scarred right kidney (60 mm) with a 12% residual function. An intermittent right vesicoureteral reflux (VUR) was diagnosed by direct isotopic cystography and then treated by Cohen vesicoureteral reimplantation. The patient remained free of infectious recurrence, hypertension, or renal function decrease. This report demonstrates that one episode of acute pyelonephritis can lead to severe renal scarring. Whereas antenatal lesions are thought to have a stronger role in the causal pathway for reflux nephropathy than is UTI in addition to VUR, this observation reminds us that UTI can truly play an important role in damaging kidneys.

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).

Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish type--implication of EPO, transferrin and transcobalamin losses.

Congenital nephrotic syndrome of the Finnish type (CNF) is due to NPHS1 mutation and is responsible for a variety of urinary protein losses. We report the case of a 4-month-old girl with a particularly severe form (proteinuria approximately 150 g/l) of CNF. She developed severe non-regenerative anaemia requiring bi-monthly blood transfusions despite daily EPO (600 UI/kg) and iron supplementation. Epoetin pharmacokinetics revealed a urinary loss of 27% of the given dose within the first 24 h after IV injection. However, plasma levels remained increased after 24 h (228 UI/l). Plasma transferrin and transcobalamin levels were undetectable. Atransferrinaemia and atranscobalaminaemia seem to be responsible for disturbed erythropoiesis.

Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome.

BACKGROUND: Ante/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of Henle's loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype. METHODS: Charts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 [0.4-18.0] years. RESULTS: We describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life. CONCLUSIONS: We confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.