Hyperuricemia and gout following pediatric renal transplantation

Hyperuricemia and gout are common complications in adult renal transplant recipients. In pediatric recipients, however, hyperuricemia seems to be rare, but data are scarce. Thirty-two children (21 males, 11 females) were investigated for a median time of 4.8years (range: 0.4-11.2years) following renal transplantation. The median age of this pediatric study group was 13.9years (range: 5.7-20.3years), and the calculated glomerular filtration rate (GFR) was 61ml/min per 1.73m2 (range:12-88ml/min per 1.73m2). All patients were given calcineurin inhibitors, with 22 and ten children receiving cyclosporine A (CSA) and tacrolimus (TAC), respectively. The median plasma uric acid was 385μmol/l (range: 62-929μmol/l); 15 children (47%) were above the age-related normal range. Only one patient experienced gouty arthritis. There was a significant correlation between plasma uric acid concentration and both time span after transplantation and plasma creatinine, and an inverse correlation to GFR (p<0.05). No significant correlation was found between plasma uric acid and body mass index (BMI). Plasma uric acid concentrations were neither different among CSA- and TAC-treated children, nor did they correlate with drug exposure or blood trough levels of CSA or TAC. Plasma uric acid concentration was not different when compared to children with chronic renal failure (CRF) of a similar degree in native kidneys. We conclude that hyperuricemia is common among pediatric renal transplant recipients and rather a consequence of chronic renal transplant dysfunction than the use of calcineurin inhibitors. Gout, however, is rar

Impact of kidney biopsy on deciding when to initiate enzyme replacement therapy in children with Fabry disease

BACKGROUND Recommendations on when to start enzyme replacement therapy (ERT) in children with Fabry disease (FD) differ between guidelines. In this study, kidney biopsies of a cohort of 14 untreated children and one treated child were analyzed for their morphologic changes to determine whether early initiation of ERT is indicated. METHODS All pediatric FD patients (< 18 years old) diagnosed between 2003 and 2021 in our department who received a kidney biopsy were enrolled. Clinical symptoms; laboratory parameters regarding kidney function, such as eGFR, plasma urea, protein-creatinine, and albumin/creatinine ratio; and 14 kidney biopsies prior to ERT and one under treatment were retrospectively analyzed. RESULTS A total of 14 patients were enrolled, including 9 male and 5 female children, aged 3-18 years (median age 11). Seven of the enrolled children were 10 years old or younger. Histological analysis of kidney biopsy samples revealed severe vacuolization and accumulation of inclusions in podocytes and renal tubules. The majority of cases had no FD-specific clinical or laboratory features independent of age, gender, or genotype. The youngest FD patient presenting with isolated abnormal kidney biopsy was 3 years old. CONCLUSIONS We demonstrate that histological lesions, typical for FD, can be observed in kidney biopsies at a very young age in patients without classical clinical symptoms or laboratory abnormalities. Thus, we recommend kidney biopsies as a possible tool for early diagnosis of renal involvement in FD. As a consequence of these early biopsy findings without a clinical correlate, an early initiation of ERT should be considered. A higher resolution version of the Graphical abstract is available as Supplementary information

Successful long-term outcome after renal transplantation in a patient with atypical haemolytic uremic syndrome with combined membrane cofactor protein CD46 and complement factor I mutations

Background: Atypical haemolytic uremic syndrome (aHUS) is often associated with a high risk of disease recurrence and subsequent graft loss after isolated renal transplantation. Evidence-based recommendations for a mutation-based management after renal transplantation in aHUS caused by a combined mutation with complement factor I (CFI) and membrane cofactor protein CD46 (MCP) are limited. Case-diagnosis/Treatment: We describe a 9-year-old boy with a first manifestation of aHUS at the age of 9months carrying combined heterozygous mutations in the CFI and MCP genes. At the age of 5years, he underwent isolated cadaveric renal transplantation. Fresh frozen plasma was administered during and after transplantation, tapered and finally stopped after 3years. Conclusions: During the 5-year follow-up after transplantation there have been no signs of aHUS recurrence and graft function has remained good. The combination of heterozygous MCP and CFI mutations with aHUS might have a positive impact on the post-transplant course, possibly predicting a lower risk of aHUS recurrence after an isolated cadaveric renal transplantatio

Eculizumab in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: a systematic review

BACKGROUND: Infection-associated hemolytic uremic syndrome (IA-HUS), most often due to infection with Shiga toxin-producing bacteria, mainly affects young children. It can be acutely life-threatening, as well as cause long-term kidney and neurological morbidity. Specific treatment with proven efficacy is lacking. Since activation of the alternative complement pathway occurs in HUS, the monoclonal C5 antibody eculizumab is often used off-label once complications, e.g., seizures, occur. Eculizumab is prohibitively expensive and carries risk of infection. Its utility in IA-HUS has not been systematically studied. This systematic review aims to present, summarize, and evaluate all currently available data regarding the effect of eculizumab administration on medium- to long-term outcomes (i.e., outcomes after the acute phase, with a permanent character) in IA-HUS. METHODS: PubMed, Embase, and Web of Science were systematically searched for studies reporting the impact of eculizumab on medium- to long-term outcomes in IA-HUS. The final search occurred on March 2, 2022. Studies providing original data regarding medium- to long-term outcomes in at least 5 patients with IA-HUS, treated with at least one dose of eculizumab during the acute illness, were included. No other restrictions were imposed regarding patient population. Studies were excluded if data overlapped substantially with other studies, or if outcomes of IA-HUS patients were not reported separately. Study quality was assessed using the ROBINS-I tool for risk of bias in non-randomized studies of interventions. Data were analyzed descriptively. RESULTS: A total of 2944 studies were identified. Of these, 14 studies including 386 eculizumab-treated patients met inclusion criteria. All studies were observational. Shiga toxin-producing E. coli (STEC) was identified as the infectious agent in 381 of 386 patients (98.7%), effectively limiting the interpretation of the data to STEC-HUS patients. Pooling of data across studies was not possible. No study reported a statistically significant positive effect of eculizumab on any medium- to long-term outcome. Most studies were, however, subject to critical risk of bias due to confounding, as more severely ill patients received eculizumab. Three studies attempted to control for confounding through patient matching, although residual bias persisted due to matching limitations. DISCUSSION: Current observational evidence does not permit any conclusion regarding the impact of eculizumab in IA-HUS given critical risk of bias. Results of randomized clinical trials are eagerly awaited, as new therapeutic strategies are urgently needed to prevent long-term morbidity in these severely ill patients

Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997-2003

Hemolytic-uremic syndrome (HUS) is a leading cause of acute renal failure in childhood. In its typical presentation, it is preceded by an episode of diarrhea mostly due to Shiga-toxin-producing Escherichia coli. There is important geographical variation of many aspects of this syndrome. Nationwide data on childhood HUS in Switzerland have not been available so far. In a prospective national study through the Swiss Pediatric Surveillance Unit 114 cases (median age 21months, 50% boys) were reported between April 1997 and March 2003 by 38 pediatric units (annual incidence 1.42 per 105 children ≤16years). Shiga-toxin-producing E. coli were isolated in 32 (60%) of tested stool samples, serotype O157:H7 in eight. Sixteen children presented with only minimal renal involvement, including three with underlying urinary tract infection. Six patients presented with atypical hemolytic-uremic syndrome, and six with HUS due to invasive Streptococcus pneumoniae infection. Mortality was 5.3%, including two out of six children with S. pneumoniae infection. The severity of thrombocytopenia and the presence of central nervous system involvement significantly correlated with mortality. In conclusion, childhood HUS is not rare in Switzerland. Contrasting other countries, E. coli O157:H7 play only a minor role in the etiology. Incomplete manifestation is not uncommo

Membranoproliferative glomerulonephritis and C3 glomerulopathy in children: change in treatment modality? A report of a case series

Background Membranoproliferative glomerulonephritis (MPGN) with immune complexes and C3 glomerulopathy (C3G) in children are rare and have a variable outcome, with some patients progressing to end-stage renal disease (ESRD). Mutations in genes encoding regulatory proteins of the alternative complement pathway and of complement C3 (C3) have been identified as concausative factors. Methods Three children with MPGN type I, four with C3G, i.e. three with C3 glomerulonephritis (C3GN) and one with dense deposit disease (DDD), were followed. Clinical, autoimmune data, histological characteristics, estimated glomerular filtration rate (eGFR), proteinuria, serum C3, genetic and biochemical analysis were assessed. Results The median age at onset was 7.3 years and the median eGFR was 72 mL/min/1.73 m. Six children had marked proteinuria. All were treated with renin-angiotensin-aldosterone system (RAAS) blockers. Three were given one or more immunosuppressive drugs and two eculizumab. At the last median follow-up of 9 years after diagnosis, three children had normal eGFR and no or mild proteinuria on RAAS blockers only. Among four patients without remission of proteinuria, genetic analysis revealed mutations in complement regulator proteins of the alternative pathway. None of the three patients with immunosuppressive treatment achieved partial or complete remission of proteinuria and two progressed to ESRD and renal transplantation. Two patients treated with eculizumab revealed relevant decreases in proteinuria. Conclusions In children with MPGN type I and C3G, the outcomes of renal function and response to treatment modality show great variability independent from histological diagnosis at disease onset. In case of severe clinical presentation at disease onset, early genetic and biochemical analysis of the alternative pathway dysregulation is recommended. Treatment with eculizumab appears to be an option to slow disease progression in single cases

Prevalence and potential relevance of hyperuricemia in pediatric kidney transplant recipients—a CERTAIN registry analysis

Background: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. Methods: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. Results: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. Conclusion: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated. Keywords: gout; long-term outcome; pediatric kidney transplantation; uric acid; uric acid-lowering therapy

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations

Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood

Management des hämolytisch-urämischen Syndroms beim Kind

Das hämolytisch-urämische Syndrom (HUS) ist eine Krankheit, die sich bei den meisten Patienten im Kindes- und Jugendalter manifestiert. Sie ist gekennzeichnet durch das gleichzeitige Auftreten der Trias: mikroangiopathische hämolytische Anämie, Thrombozytopenie und akute Niereninsuffizienz. In diesem Artikel sollen neben den klinischen Merkmalen der einzelnen HUS-Formen auch Anleitungen zur Abklärung und Therapieoptionen bei Kindern mit HUS gegeben werden