Introduction: Unlike idiopathic nephrotic syndrome (NS), hereditary podocytopathies are not expected to recur after kidney transplantation. However, some reports of posttransplant recurrence of NS in patients carrying variants in the NPHS2 gene have been described, notably with the p.Arg138Gln variant, which is more prevalent in Europe. The objective of this study was to assess the risk of recurrence after kidney transplantation in a large cohort of patients with biallelic NPHS2 pathogenic variants. Methods: Since January 2010, 61 patients identified at Necker-Enfants Malades Hospital and 56 enrolled in the PodoNet Registry with biallelic variants in the NPHS2 gene were transplanted and were compared with 44 transplanted children with steroid-resistant NS (SRNS) without any identified pathogenic variant. Results: Of the 117 patients, 23 carried the p.Arg138Gln variant in the homozygous state and 16 in the compound heterozygous state. The other 78 patients carried different variants in the homozygous (n = 44) or compound heterozygous state. Only 1 patient with NPHS2-related SRNS experienced posttransplant recurrence (median follow-up of cohort 8.5 years [2.5–15]). Conversely, 7 of 44 patients (16%) without any identified pathogenic variant recurred within a maximum of 7 days after transplantation (median follow-up 8.9 years [0.6–13.9]). Conclusion: In this large cohort, the risk of patients with causative variants in the NPHS2 gene to develop NS recurrence after kidney transplantation was extremely low. This is coherent with the pathophysiology of intrinsic slit-diaphragm disease. These data are reassuring and should be considered when counselling patients, making living kidney donation, whether related or not, a safe choice.

BackgroundIt is not known whether withdrawal of angiotensin-converting enzyme inhibitors (ACEIs) in children with advanced chronic kidney disease (CKD) is beneficial similar to adults. We report a case series of children with advanced CKD whose ACEIs were stopped.MethodsIn the last 5 years, we stopped ACEIs in seven consecutive children on ACEI therapy with rapidly declining CKD stage 4-5. The median age was 12.5 years (range 6.8-17.6); the median estimated glomerular filtration rate (eGFR) at stopping ACEIs was 12.5 ml/min/1.73 m(2) (range 8.8-19.9).ResultsSix to twelve months after stopping ACEIs, the eGFR increased in five children (71%). The median absolute increase of eGFR was 5.0 ml/min/1.73 m(2) (range -2.3 to +20.0) and relative increase of eGFR was 30% (range -34 to +99). The median follow-up after stopping ACEIs was 2.7 (range 0.5-5.0) years, either until the start of dialysis (n = 5) or until the last follow-up without dialysis (n = 2).ConclusionsThis case series showed that withdrawal of ACEIs in children with CKD stage 4-5 and rapidly declining kidney function may lead to an increase in eGFR.

Abstract Background Schimke immunoosseous dysplasia (SIOD) is an ultra-rare inherited disease affecting many organ systems. Spondyloepiphyseal dysplasia, T-cell immunodeficiency and steroid resistant nephrotic syndrome are the main symptoms of this disease. Case presentation We aimed to characterize the clinical, pathological and genetic features of SIOD patients received at tertiary Pediatric Nephrology Center, University Hospital Motol, Prague, Czech Republic during the period 2001–2021. The mean age at diagnosis was 21 months (range 18–48 months). All patients presented with growth failure, nephropathy and immunodeficiency. Infections and neurologic complications were present in most of the affected children during the course of the disease. Conclusions Although SIOD is a disease characterized by specific features, the individual phenotype may differ. Neurologic signs can severely affect the quality of life; the view on the management of SIOD is not uniform. Currently, new therapeutic methods are required.

Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m(2). uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m(2), and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m(2), or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.

Objectives Strict BP control can retard progression of CKD in children. This prospective 3-year randomized controlled trial is aimed to investigate whether strict BP control can retard progression of chronic allograft dysfunction. Methods Twenty-three pediatric patients were randomly selected to the standard BP group (STAND, target 24-hour MAP 50-95th percentile, n = 11) or the intensified BP group (INTENS, target 24-hour MAP <50th percentile, n = 12). The primary endpoint was an annual reduction in eGFR (Schwartz formula, mL/min/1.73 m(2)/y), secondary graft survival, BP, proteinuria, and safety. Results A total of 21 children (age at entry 11.2 (range 6.2-16.8) years) completed the study, with 73% of children in INTENS and 70% of children in STAND group reached their goal BP. Ambulatory indexed 24-hour MAP decreased significantly in INTENS group (from 0.94 (range 0.86-1.17) to 0.85 (range 0.79-1.01, P < 0.01)) but not in STAND group (from 0.93 (range 0.85-1.07) to 0.90 (range 0.84-1.01)). Proteinuria did not change significantly in either group (22.1 mg/mmol creatinine to 15.3 in STAND group vs 25.7 to 11.8 in INTENS group). The annual reduction in eGFR did not differ between the INTENS and STAND groups (-1.9 mL/min/1.73 m(2)/y (range +6.4 to -14.3) vs -0.9 (range +4.0 to -8.5)). Conclusion This first randomized controlled trial on strict BP control has demonstrated that strict BP control is feasible in 73% of children but the strict BP control does not lead to retardation of graft function decline in comparison with standard BP control. However, the results need to be interpreted with caution keeping the major limitation of the study, that is, small sample size in mind.

Background The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis. Methods We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis). Results RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ss = -0.67; P < 0.001) and intima media thickness (ss = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ss = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ss = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ss = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ss = 1.47; P = 0.01). Conclusions In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.

Meeting abtract IGA NEPHROPATHY IN CHILDREN IN THE CZECH REGISTRY OF RENAL BIOPSIES (CRRB).

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.

BACKGROUND:The aim of this prospective single center study was to investigate the ability of urinary neutrophil gelatinase-associated lipocalin (NGAL) to distinguish acute rejection from other causes of acute kidney injury (AKI) in children after renal transplantation.METHODS:Fifteen children fulfilled the inclusion criteria (acute kidney injury (AKI) with allograft biopsy, at least 21 days after renal transplantation, no sepsis) during 2013 - 2014 in our pediatric transplantation center. The mean age was 14.8  2.8, median time after renal transplantation was 0.4 years (range 0.1 - 3.8). Urinary NGAL was measured in spot urine by Chemiluminescent Microparticle Immunoassay technology.RESULTS:Four patients had biopsy proven acute rejection (rejection group), eleven children had AKI of other cause (non-rejection group). The median urinary NGAL concentration in the rejection group was not significantly different from NGAL in the non-rejection group (7.3 ng/mL, range 3.0 - 42.3 vs. 8.6 ng/mL, range 3.4 - 54.7, p = 0.48). There was a significant negative correlation between eGFR and urinary NGAL concentrations (r = -0.77, p < 0.001).CONCLUSIONS:Our small study suggests that in children after renal transplantation, urinary NGAL cannot be used as a specific marker for distinguishing acute rejection from other non-rejection causes of AKI. Urinary NGAL was mainly associated with graft function but not with the etiology of AKI.

Importance:Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults. Objective:To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD. Design, Setting, and Participants:Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016. Exposures:Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy. Main Outcomes and Measures:The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2. Results:Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007). Conclusions and Relevance:Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD.

BACKGROUND Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease, characterized by progressive renal function deterioration, nephrotic proteinuria, and risk of chronic renal failure. We present long-term results of 5 patients with primary FSGS and recurrence of nephrotic proteinuria after renal transplantation treated with plasma exchange (PE) and immunoadsorption (IA). METHODS We retrospectively investigated the relationship between the delay in initiation of the therapy and treatment outcomes, particularly achievement of remission of proteinuria. RESULTS Remission occurred in all three patients who started PE/IA in interval 3-7 days after diagnosis of recurrence of FSGS. Remission was achieved after 3-4 weeks in two patients with 3 days of delay to the start of PE. The third patient (PE started with 7 days of delay) reached complete remission after 6 months of PE/IA treatment. All these patients had remission sustainable for a long time. The remaining two patients with 14 and 406 days of delay to PE treatment did not achieve remission sustainable for a long time. The two patients who did not achieve remission developed end-stage renal disease with graft loss (1 and 6.7 years after transplantation). Patients who achieved remission of proteinuria during PE/IA treatment have still functioning grafts (2.8, 9.7 and 3.8 years after renal transplantation). All these patients are still treated with PE/IA. CONCLUSIONS The present 5 cases suggest that if recurrence of FSGS occurs, the probability of achieving remission is dependent on the early initiation of PE/IA therapy. Therefore, we suggest that PE/IA treatment might be started as soon as possible after recurrence of FSGS.

IgA nephropathy is currently the most frequently investigated glomerulonephritis. The disease is defined by the presence of dominant or co-dominant deposits of IgA1 in the glomerular mesangium. Circulating immune complexes are most likely the source of the deposited IgA1. However, it is also possible that the aggregates of structurally altered IgA1 or enhanced binding to IgA receptors expressed on mesangial cells lead to deposition. The cause of the formation of immune complexes responsible for IgA nephropathy lies in the incomplete O-linked oligosaccharide side chains, which, due to the deficiency of corresponding glycosyltransferases, lack terminal galactose residues leading to the exposure of N-acetylgalactosamine. Naturally occurring antibodies of the IgG or IgA1 isotype bind to this sugar antigen. In the clinical course, we differentiate between the early stage usually characterized by hematuria, and a variable late stage characterized either by a clinical remission, by persistence of hematuria, or by increasing proteinuria and blood pressure and decreasing renal function in one third of the patients. In the early stage, it is difficult to predict the prognosis of IgA nephropathy, either on the basis of clinical presentation and morphological findings, or according to the level of galactose-deficient IgA1 in the circulation. The reliable criteria of serious prognosis emerge only in the later stages of the disease and include proteinuria, hypertension, and histologically apparent tubular atrophy and interstitial sclerosis. The dominant trend in the treatment of IgA nephropathy is the emphasis on administration of ACE inhibitors/sartans, which are introduced into the treatment at the time of microalbuminuria. If proteinuria does not decrease below 1 g/24 h, treatment with prednisone is justifiable. New findings concerning the molecular/cellular mechanism involved in the pathogenesis of IgA nephropathy suggest the possible therapeutical interference with the generation of nephritogenic immune complexes by a selective blocking of the IgA1 molecules with altered glycan structures using monovalent reagents.

Proteinuria is a common manifestation of chronic kidney disease (CKD), and there is a high incidence of CDK and its complications following renal transplantation. However, little data are available on the association between proteinuria and graft/patient survival in the paediatric transplant population. The primary aim of this study was to investigate the associations between posttransplant proteinuria and graft/patient survival in children after renal transplantation.

BACKGROUND AND OBJECTIVES:Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS:Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS:The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

OBJECTIVES:The extent and relevance of altered bone metabolism for statural growth in children with chronic kidney disease is controversial. We analyzed the impact of renal dysfunction and recombinant growth hormone therapy on a panel of serum markers of bone metabolism in a large pediatric chronic kidney disease cohort.METHODS:Bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin and C-terminal FGF-23 (cFGF23) normalized for age and sex were analyzed in 556 children aged 6-18 years with an estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m2. 41 children receiving recombinant growth hormone therapy were compared to an untreated matched control group.RESULTS:Standardized levels of BAP, TRAP5b and cFGF-23 were increased whereas sclerostin was reduced. BAP was correlated positively and cFGF-23 inversely with eGFR. Intact serum parathormone was an independent positive predictor of BAP and TRAP5b and negatively associated with sclerostin. BAP and TRAP5B were negatively affected by increased C-reactive protein levels. In children receiving recombinant growth hormone, BAP was higher and TRAP5b lower than in untreated controls. Sclerostin levels were in the normal range and higher than in untreated controls. Serum sclerostin and cFGF-23 independently predicted height standard deviation score, and BAP and TRAP5b the prospective change in height standard deviation score.CONCLUSION:Markers of bone metabolism indicate a high-bone turnover state in children with chronic kidney disease. Growth hormone induces an osteoanabolic pattern and normalizes osteocyte activity. The osteocyte markers cFGF23 and sclerostin are associated with standardized height, and the markers of bone turnover predict height velocity.