Impact of de novo donor-specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function.

BACKGROUND: This retrospective multicenter long-term cohort study investigates de novo donor-specific HLA antibodies (dnDSA) impact on allograft survival in pediatric kidney transplantation (KTx), depending on allograft function at dnDSA detection. METHODS: Seventy patients with dnDSA screening in the context of acute allograft dysfunction (AAD) (>50% serum creatinine increase) or routine follow-up were included during a 20-year period. Number of dnDSA specificities and HLA total mean fluorescence intensity (MFI-sum) were collected. RESULTS: Median follow-up time was 8.6 years. Among the 22 dnDSA+ patients, 8 patients presented AAD. Compared with dnDSA- patients, allograft survival was shorter only in dnDSA+/AAD+ patients, regardless of dnDSA detection during the 5-year post-transplant period (9 patients) or later (13 patients) (log rank p < .001 and p < .001, respectively). One dnDSA+/AAD-, 7 dnDSA+/AAD+, and 5 dnDSA- patients lost their allograft. Allograft survival was shorter in dnDSA+/AAD+ patients compared with the 16 dnDSA-/AAD+ patients (log rank p < .001) but did not differ between dnDSA+/AAD- and dnDSA-/AAD- patients (log rank p = .157). dnDSA+/AAD+ and dnDSA-/AAD+ patients presented higher risk of allograft failure compared with the other patient groups after adjustment for recipient age at KTx, donor type, and incidence of delayed graft function (HR 11.322, 95% CI 3.094-41.429, p < .001). Concurrent MFI-sum >10 000 and multiple dnDSA specificities were more significantly associated with AAD, compared with each factor separately (p < .001). CONCLUSIONS: In pediatric KTx, AAD shortens allograft survival in dnDSA+ patients, regardless of dnDSA time detection, and is commonly observed when high MFI-sum concurs with multiple dnDSA specificities. dnDSA without AAD incidence does not determinately affect allograft survival.

Antibody-mediated rejection with the presence of glomerular crescents in a pediatric kidney transplant recipient: A case report.

Glomerular crescents in kidney transplantation are indicative of severe glomerular injury and constitute a hallmark of RPGN. Their concurrence with ABMR has been rarely described only in adult patients. We report a case of 10-year-old boy with compound heterozygous Fin-major Finnish-type congenital nephrotic syndrome, who had received a deceased-donor kidney transplant 5 years before onset of acute kidney injury and nephrotic range proteinuria without hematuria. Kidney allograft biopsy illustrated 6 glomeruli with global sclerosis and 6 with remarkable circumferential or segmental cellular crescents. Negative glomerular immunofluorescence for immune-complex deposits and the absence of serum ANCA eliminated the presence of immune-mediated and ANCA-positive pauci-immune crescentic glomerulonephritis. Diagnosis of ABMR was based on the high levels of HLA class II DSA and the histological evidence of glomerulitis, peritubular capillaritis, and acute tubular injury with positive linear peritubular capillary C4d staining. The patient despite plasmapheresis and enhanced immunosuppressive treatment progressed to end-stage renal disease. We conclude that glomerular crescents may represent a finding of AMBR and possibly a marker of poor allograft prognosis in pediatric patients.

Management of children with congenital nephrotic syndrome: challenging treatment paradigms.

BACKGROUND: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective. METHODS: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS. RESULTS: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3-8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1-8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2-9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7-16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died. CONCLUSION: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy.

Infants with congenital nephrotic syndrome have comparable outcomes to infants with other renal diseases.

BACKGROUND: Children with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children. METHODS: We conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS. RESULTS: Eighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6 months, 30 (68%) by 1 year, and 40 (91%) by 2 years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n = 5) or peritonitis (n = 4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6 months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months. CONCLUSIONS: Infants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data.

Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.

Background: Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods: Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results: Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions: CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Disparities in treatment rates of paediatric end-stage renal disease across Europe: insights from the ESPN/ERA-EDTA registry.

BACKGROUND: Considerable disparities exist in the provision of paediatric renal replacement therapy (RRT) across Europe. This study aims to determine whether these disparities arise from geographical differences in the occurrence of renal disease, or whether country-level access-to-care factors may be responsible. METHODS: Incidence was defined as the number of new patients aged 0-14 years starting RRT per year, between 2007 and 2011, per million children (pmc), and was extracted from the ESPN/ERA-EDTA registry database for 35 European countries. Country-level indicators on macroeconomics, perinatal care and physical access to treatment were collected through an online survey and from the World Bank database. The estimated effect is presented per 1SD increase for each indicator. RESULTS: The incidence of paediatric RRT in Europe was 5.4 cases pmc. Incidence decreased from Western to Eastern Europe (-1.91 pmc/1321 km, P < 0.0001), and increased from Southern to Northern Europe (0.93 pmc/838 km, P = 0.002). Regional differences in the occurrence of specific renal diseases were marginal. Higher RRT treatment rates were found in wealthier countries (2.47 pmc/€10 378 GDP per capita, P < 0.0001), among those that tend to spend more on healthcare (1.45 pmc/1.7% public health expenditure, P < 0.0001), and among countries where patients pay less out-of-pocket for healthcare (-1.29 pmc/11.7% out-of-pocket health expenditure, P < 0.0001). Country neonatal mortality was inversely related with incidence in the youngest patients (ages 0-4, -1.1 pmc/2.1 deaths per 1000 births, P = 0.10). Countries with a higher incidence had a lower average age at RRT start, which was fully explained by country GDP per capita. CONCLUSIONS: Inequalities exist in the provision of paediatric RRT throughout Europe, most of which are explained by differences in country macroeconomics, which limit the provision of treatment particularly in the youngest patients. This poses a challenge for healthcare policy makers in their aim to ensure universal and equal access to high-quality healthcare services across Europe.