In the past 30 years there have been major improvements in the care of children with chronic kidney disease (CKD). However, most of the available epidemiological data stem from end-stage renal disease (ESRD) registries and information on the earlier stages of pediatric CKD is still limited. The median reported incidence of renal replacement therapy (RRT) in children aged 0–19 years across the world in 2008 was 9 per million of the age-related population (4–18 years). The prevalence of RRT in 2008 ranged from 18 to 100 per million of the age-related population. Congenital disorders, including congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary nephropathies, are responsible for about two thirds of all cases of CKD in developed countries, while acquired causes predominate in developing countries. Children with congenital disorders experience a slower progression of CKD than those with glomerulonephritis, resulting in a lower proportion of CAKUT in the ESRD population compared with less advanced stages of CKD. Most children with ESRD start on dialysis and then receive a transplant. While the survival rate of children with ERSD has improved, it remains about 30 times lower than that of healthy peers. Children now mainly die of cardiovascular causes and infection rather than from renal failure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00467-011-1939-1) contains supplementary material, which is available to authorized users

The development of donor‐specific HLA antibodies (DSA) is associated with worse renal allograft survival in adult patients. This study assessed the natural history of de novo DSA, and its impact on renal function in pediatric renal transplant recipients (RTR). HLA antibodies were measured prospectively using single‐antigen‐bead assays at 1, 3, 6 and 12 months posttransplant followed by 12‐monthly intervals and during episodes of allograft dysfunction. Of 215 patients with HLA antibody monitoring, 75 (35%) developed DSA at median of 0.25 years posttransplant with a high prevalence of Class II (70%) and HLA‐DQ (45%) DSA. DSA resolved in 35 (47%) patients and was associated with earlier detection (median, inter‐quartile range 0.14, 0.09–0.33 vs. 0.84, 0.15–2.37 years) and lower mean fluorescence intensity (MFI) (2658, 1573–3819 vs. 7820, 5166–11 990). Overall, DSA positive patients had more rapid GFR decline with a 50% reduction in GFR at mean 5.3 (CI: 4.7–5.8) years versus 6.1 (5.7–6.4) years in DSA negative patients (p = 0.02). GFR decreased by a magnitude of 1 mL/min/1.73 m2 per log10 increase in Class II DSA MFI (p < 0.01). Using Cox regression, independent factors predicting poorer renal allograft outcome were older age at transplant (hazard ratio 1.1, CI: 1.0–1.2 per year), tubulitis (1.5, 1.3–1.8) and microvasculature injury (2.9, 1.4–5.7). In conclusion, pediatric RTR with de novo DSA and microvasculature injury were at risk of allograft failure.

Solid organ transplantation has transformed the lives of many children and adults by providing treatment for patients with organ failure who would have otherwise succumbed to their disease. The first successful transplant in 1954 was a kidney transplant between identical twins, which circumvented the problem of rejection from MHC incompatibility. Further progress in solid organ transplantation was enabled by the discovery of immunosuppressive agents such as corticosteroids and azathioprine in the 1950s and ciclosporin in 1970. Today, solid organ transplantation is a conventional treatment with improved patient and allograft survival rates. However, the challenge that lies ahead is to extend allograft survival time while simultaneously reducing the side effects of immunosuppression. This is particularly important for children who have irreversible organ failure and may require multiple transplants. Pediatric transplant teams also need to improve patient quality of life at a time of physical, emotional and psychosocial development. This review will elaborate on the long-term outcomes of children after kidney, liver, heart, lung and intestinal transplantation. As mortality rates after transplantation have declined, there has emerged an increased focus on reducing longer-term morbidity with improved outcomes in optimizing cardiovascular risk, renal impairment, growth and quality of life. Data were obtained from a review of the literature and particularly from national registries and databases such as the North American Pediatric Renal Trials and Collaborative Studies for the kidney, SPLIT for liver, International Society for Heart and Lung Transplantation and UNOS for intestinal transplantation.

Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.

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Human leukocyte antigen (HLA) sensitisation occurs after transfusion of blood products and transplantation. It can also happen spontaneously through cross-sensitisation from infection and pro-inflammatory events. Patients who are highly sensitised face longer waiting times on organ allocation programmes, more graft rejection and therefore more side effects of immunosuppression, and poorer graft outcomes. In this review, we discuss these issues, along with the limitations of modern HLA detection methods, and potential ways of decreasing HLA antibody development. We do not discuss the removal of antibodies after they have developed.

IntroductionWe have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes.MethodsA total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan–Meier estimator.ResultsOf 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R 2 0.072; C3d: adjusted R 2 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q−) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q−) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30–1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d−); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d−) years; HR 0.38; 95% CI 0.15–0.97; p = 0.04].ConclusionAssessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction.Electronic supplementary materialThe online version of this article (10.1007/s00467-017-3772-7) contains supplementary material, which is available to authorized users.

Atypical haemolytic uraemic syndrome (aHUS) is frequently associated with mutations in the gene encoding complement factor H (CFH). The clinical response to plasma therapy in aHUS is variable. We present here our experience of plasma therapy in three aHUS patients with CFH mutations. Three children presented aged 4, 22 and 6 months (patients 1-3 respectively) in acute kidney injury requiring dialysis. Plasma therapy consisting of plasma filtration (patient 1) or plasma exchange (PEX; patients 2 and 3) was commenced early following presentation. This resulted in aHUS remission and cessation of dialysis after 2 weeks, 9 days and 2 weeks respectively. Relapses were common and associated with increasing the interval between PEX, but all responded to intensification of PEX therapy. Patient 1 recovered 50% of renal function after first presentation. She had four relapses and started peritoneal dialysis 41 months after presentation. Mutation screening of CFH showed a missense mutation (c.3546 G > T, p.Arg1182Ser) in exon 23. PEX in patient 2 was slowly tapered over 4 months to fortnightly sessions, but she relapsed when PEX was extended to every 4 weeks. Renal function remained normal 12 months post-presentation. Mutation screening of CFH showed a mutation in exon 23 (c.3590 T > C, p.Val1197Ala) and two additional sequence variants in exons 3 and 4. Patient 3 had two relapses associated with intercurrent illnesses concurrent with reducing PEX to weekly doses. Renal function was normal 5 months post-presentation. All three patients showed a good response to PEX with improved renal function both initially and following a relapse. Further research is necessary to determine the best maintenance strategy to delay or prevent end-stage kidney disease.