An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Clinical and Histopathologic Characteristics of Pediatric Patients With Primary Membranous Nephropathy.

Introduction: Primary membranous nephropathy (PMN) is uncommon in children. Therefore, data on the clinical course of affected children are scarce. In recent years, several novel antigens have been implicated in the pathogenesis of PMN. However, the histopathologic characteristics of pediatric patients with PMN remain poorly represented in the literature. Methods: We have retrospectively analyzed the clinical presentation and outcomes data of 21 children with PMN from 3 centers in the United States. In addition, we have identified novel antigens in biopsy specimens from these patients and correlated their presence or absence to clinical outcomes. Finally, we compared the results of the novel antigen staining from our clinical cohort to a validation cohort of 127 biopsy specimens from children with PMN at Arkana Laboratories. Results: The data from the 2 cohorts demonstrated similar overall antigen positivity rates of 62% to 63%, with phospholipase A2 receptor (PLA2R) and exostosin 1 (EXT1) being the most commonly found antigens. Results from the clinical cohort showed that overall, the kidney prognosis for children with PMN was good, with 17 of 21 patients entering a complete or partial remission. Children who were positive for PLA2R or EXT1 were significantly more likely to enter remission than those in the antigen negative group. Conclusion: Approximately 60% of pediatric membranous cases are positive for a novel antigen on kidney biopsy and the clinical prognosis is generally favorable. More studies are needed to understand the clinical implications of each specific novel antigen.

BK DNAemia in pediatric kidney transplant recipients: Predictors and outcomes.

BACKGROUND: Pediatric data on risk factors and the clinical course of BK DNAemia are limited. We aimed to determine the effects of BK DNAemia on transplant outcomes and delineate the safety and efficacy of various treatment approaches. METHODS: This retrospective-cohort study included 161 transplants (age ≤ 21 years) performed at a single center between 1/1/2012 and 1/1/2020. We used Cox proportional models to evaluate the effects of BK DNAemia on patient survival (PS), graft survival (GS), and acute rejection (AR), using BK as a time-dependent covariate. We also assessed the effects of pharmacological intervention on BK DNAemia duration using intervention as a time-dependent covariate. RESULTS: BK-free survival was 69.1% at 1-year and 54.6% at 3-year posttransplant. After multivariate adjustment, BK DNAemia was associated with young age at transplant (aHR, age 5-<12 vs. ≥12 (years): 2.5 (1.4-4.5); p = .001) and steroid-based immunosuppression (IS) (aHR: 2.2 [1.1-4.5]; p = .03). We found no effect of DNAemia on AR (aHR: 1.25; p = .5), PS (aHR: 2.85; p = .22), and GS (aHR: 0.56; p = .41). Of 70 patients with DNAemia, 22 (31.4%) received no treatment, 20 (28.6%) received IS reduction alone, and 28 patients (40%) received treatment with at least one pharmacological agent (leflunomide, IVIG, ciprofloxacin, cidofovir). Sixty-three patients (90%) cleared DNAemia with median time to resolution of 2.4 months (IQR:1.4-5.6). We found no significant effect of BK-directed pharmacological treatment on time to resolution (aHR: 0.64;p = .13). BK-directed agents were well tolerated. CONCLUSIONS: BK DNAemia is associated with a young age at transplant and steroid-based maintenance IS. We found no effect of BK DNAemia on AR, GS, and PS.

Anemia in Pediatric Kidney Transplant Recipients-Etiologies and Management.

Posttransplant anemia (PTA) is a common complication of pediatric kidney transplantation, with a prevalence ranging from 22 to 85%. PTA is categorized as early (within 6 months posttransplant) and late (>6 months posttransplant). Early PTA is typically associated with surgical blood losses and iron deficiency. Late PTA primarily results from graft dysfunction; however, iron deficiency, drug toxicity, and posttransplant inflammation also play a role. PTA is more severe compared with the anemia in glomerular-filtration-rate matched patients with native chronic kidney disease. Treatment of PTA is directed toward the underlying cause. Erythropoiesis stimulating agents (ESA) are effective; however, their use is limited in the transplant setting. Timely diagnosis and treatment of PTA are vital to prevent long-term adverse outcomes in pediatric transplant recipients.

Steroid avoidance/withdrawal and maintenance immunosuppression in pediatric kidney transplantation.

BACKGROUND: Corticosteroids have been an integral part of maintenance immunosuppression for pediatric kidney transplantation. However, prolonged steroid therapy is associated with significant toxicities resulting in several SW/avoidance strategies in recent years. METHOD/OBJECTIVE: This comprehensive review aims to discuss steroid-related toxicities and the safety, efficacy, and benefit of steroid avoidance/withdrawal immunosuppression in pediatric kidney transplant recipients. RESULTS: Initial studies of SW/avoidance conducted in the setting of CSA and AZA showed an increased incidence of AR but no increase in graft loss or mortality with SW/avoidance maintenance immunosuppression. Studies performed under modern immunosuppression (induction therapy, Tac, and MMF) show no significant increase in AR or graft loss with SW/avoidance immunosuppression. Furthermore, SW/avoidance immunosuppression is associated with significant improvement in growth, BMI, BP control, and lipid profile in pediatric kidney transplant recipients. Despite these data, SW/avoidance remains controversial, and only 40% of pediatric kidney transplant recipients in the United States are currently on SW/avoidance maintenance immunosuppression. CONCLUSION: SW/avoidance maintenance immunosuppression is safe and associated with fewer side effects compared with steroid-inclusive maintenance immunosuppression in pediatric kidney transplant recipients.

Antineutrophilic cytoplasmic antibody-associated vasculitis and the kidney.

PURPOSE OF REVIEW: The purpose of this review is to highlight recent studies that have emerged on the topic of ANCA-associated vasculitis with some historical context. The review also discusses how the adult data is relevant to pediatric patients. RECENT FINDINGS: Pediatric studies on AAV are lacking. Therapies targeted to the inflammatory cascade specifically implicated in AAV, such as MPO inhibitors and complement mediators, are emerging. The PEXIVAS study recently called into question the routine use of plasma exchange (PLEX) in severe AAV, with no difference in ESKD or mortality found between patients who did or did not receive PLEX. Longer maintenance duration of nearly 48 months is preferred as compared with shorter duration in patients who are not on dialysis because of higher relapse rates in children with AAV. SUMMARY: Current treatment in AAV includes corticosteroids, rituximab, and cyclophosphamide for induction. Maintenance therapy commonly consists of azathioprine or rituximab. Plasma exchange (PLEX) is no longer recommended for induction therapy for AAV but some experts still consider this as an option for patients who are not responding to therapy or have severe disease at presentation. However, emerging novel therapies may be on the horizon.

Induction and maintenance immunosuppression in pediatric kidney transplantation-Advances and controversies.

Advances in immunosuppression have improved graft survival in pediatric kidney transplant recipients; however, treatment-related toxicities need to be balanced against the possibility of graft rejection. Several immunosuppressive agents are available for use in transplant recipients; however, the optimal combinations of agents remain unclear, resulting in variations in institutional protocols. Lymphocyte-depleting antibodies, specifically ATG, are the most common induction agent used for pediatric kidney transplantation in the US. Basiliximab may be used for induction in immunologically low-risk children; however, pediatric data are scarce. CNIs and antiproliferative agents (mostly Tac and mycophenolate in recent years) constitute the backbone of maintenance immunosuppression. Steroid-avoidance maintenance regimens remain controversial. Belatacept and mTOR inhibitors are used in children under specific circumstances such as non-adherence or CNI toxicity. This article reviews the indications, mechanism of action, efficacy, dosing, and side effect profiles of various immunosuppressive agents available for pediatric kidney transplantation.

Cardiovascular disease in children with chronic kidney disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in children with chronic kidney disease (CKD). The cause of CVD in children with CKD is multifactorial and there are new and emerging data regarding prevalence and risk factors for CVD in this population. RECENT FINDINGS: A number of recent publications from longitudinal cohort studies of children with CKD have greatly increased our knowledge about the prevalence and risk factors for CVD including hypertension, obesity and dyslipidaemia. Masked hypertension and isolated nocturnal hypertension both correlate with surrogate markers of CVD in children. Obesity and adiposity are associated with an increased risk of CVD. Markers other than BMI such as waist to height ratio and fat-free tissue to fat tissue ratio better correlate with the presence of CVD in children. Dyslipidaemia is extremely prevalent in the paediatric CKD population, but there is a lack of consensus on treatment. More data on the relationship between bone mineral disease and CVD continue to emerge including an association between hyperparathyroidism and isolated nocturnal hypertension. SUMMARY: Children with CKD have multiple potentially modifiable risk factors for CVD. Research focused on CVD outcomes in children is needed.

Diagnostic Utility of Galactose-Deficient Immunoglobulin A1 Immunostaining in the Differentiation of Lupus Nephritis and Immunoglobulin A Nephropathy.

Background: Renal biopsy plays an important role in the establishment of the diagnosis and the management of patients with lupus nephritis. Immunoglobulin A (IgA) nephropathy rarely has been reported in kidney biopsy of lupus patients. Lupus nephritis and IgA nephropathy can be readily diagnosed on renal biopsy when the classic patterns are present. However, atypical patterns can become a diagnostic challenge. Galactose-deficient IgA1 (Gd-IgA1) is a key element in the pathogenesis of primary IgA nephropathy. Glomerular Gd-IgA1 deposits, detected by immunofluorescent staining of KM-55 (a Gd-IgA1-specific monoclonal antibody), are consistently identified in the mesangium of IgA nephropathy but are significantly less or absent in lupus nephritis accompanied by significant IgA deposition. Case Presentation: Here we report the case of an 11-year-old girl who was recently diagnosed with systemic lupus erythematosus (SLE) and was found to have hematuria and proteinuria. Renal biopsy showed focal mesangial hypercellularity with IgA dominant, "full house" like pattern of mesangial deposition. The biopsy findings present a diagnostic dilemma with the differential diagnosis of IgA nephropathy versus lupus nephritis with atypical immunofluorescence, and IgA nephropathy is favored, in the absence of strong straining of C1q or C3, extraglomerular deposits, tissue antinuclear antibodies, and endothelial tubuloreticular inclusions. However, no detectable glomerular KM-55 staining was seen in the kidney biopsy. Conclusions: We demonstrate the unique diagnostic utility of immunostaining for KM-55 in a challenging kidney biopsy of an SLE patient with features suggestive of IgA nephropathy. The absence of KM-55 staining excludes IgA nephropathy, supporting a diagnosis of lupus nephritis with atypical immunofluorescence in this patient with SLE.

Evaluation of T2Candida Panel for detection of Candida in peritoneal dialysates.

Fungal peritonitis in the peritoneal dialysis population is difficult to diagnose promptly due to the inherently slow cultivation-based methods currently required for identification of peritonitis pathogens. Because of the moderate risk for severe complications, the need for rapid diagnostics is considerable. One possible solution to this unmet need is the T2Candida Panel, a new technology designed to detect the most common pathogenic Candida spp. directly from whole blood specimens in as little as a few hours. We hypothesized that this technology could be applied to the detection of Candida in peritoneal dialysate, a matrix not currently approved by the Food and Drug Administration for testing by this system. Remnant dialysate samples from three healthy (noninfected) pediatric peritoneal dialysis patients were spiked with Candida glabrata, serially diluted, and tested in triplicate with unaltered dialysate specimens. The assay detected C. glabrata in 100% of spiked dialysate samples across the full spectrum of dilutions tested, and no assay inhibition or cross-reactivity was noted. These findings suggest one of possibly more applications of this technology. The positive clinical implications of this test will continue to be realized as its use is validated in peritoneal dialysate and other patient specimen types.

Clinical presentation and outcome of pediatric ANCA-associated glomerulonephritis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a small- and medium-sized vasculitis classically seen in adult patients, with peak onset near the fifth to seventh decade of life. There is little data on ANCA-associated vasculitis in pediatric patients, and most studies have limited follow-up. METHODS: This is a retrospective chart review of 22 patients with ANCA-positive glomerulonephritis in a single institution from 1991 to 2013. RESULTS: Of the 22 patients, eight (36 %) required renal replacement therapy (RRT) at diagnosis; four of these patients recovered sufficient renal function to initially discontinue dialysis. Five patients (23 %) were treated with plasmapheresis at presentation. The median time from presentation until first clinical or serologic relapse was 1.7 ± 1.2 years. After a median follow-up of 5.8 years, just over half of our patients had chronic kidney disease (CKD) stages 1-3 (55 %). Seven (32 %) patients progressed to end-stage renal disease (ESRD) and eventually required kidney transplant. CONCLUSION: ANCA-associated glomerulonephritis is a rare disorder in children. Presentation and outcomes vary significantly among patients. More research is required to follow these patients who are diagnosed in childhood to further characterize the long-term outcome of the disease.