A targeted gene panel illuminates pathogenesis in young people with unexplained kidney failure.

BACKGROUND: Kidney failure in young people is often unexplained and a significant proportion will have an underlying genetic diagnosis. National Health Service England pioneered a comprehensive genomic testing service for such circumstances accessible to clinicians working outside of genetics. This is the first review of patients using this novel service since October 2021, following its introduction into clinical practice. METHODS: The 'Unexplained Young-Onset End-Stage Renal Disease' (test-code R257) gene panel uses targeted next generation sequencing to analyse 175 genes associated with renal disease in patients under 36 years of age. All tests undertaken between October 2021 and February 2022 were reviewed. Phenotypic data were extracted from request forms and referring clinicians contacted where additional details were required. RESULTS: Seventy-one patients underwent R257 testing over the study period. Among them, 23/71 patients (32%) were confirmed to have a genetic diagnosis and 2/71 (3%) had a genetically suggestive variant. Nephronophthisis and Alport syndrome were the most common conditions identified, (4/23 (17%) with pathogenic variants in NPHP1 and 4/23 (17%) with pathogenic variants in COL4A3/COL4A4). Positive predictors of a genetic diagnosis included a family history of renal disease (60% of positive cases) and extra-renal disease manifestations (48% of positive cases). CONCLUSION: This is the first study to evaluate the R257 gene panel in unexplained young-onset kidney failure, freely accessible to patients meeting testing criteria in England. A genetic diagnosis was identified in 32% of patients. This study highlights the essential and expanding role that genomic testing has for children and families affected by renal disease today.

Pharmacokinetics of Envarsus in pediatric kidney transplant recipients - phase 1 pilot conversion study.

INTRODUCTION: Tacrolimus is the standard immunosuppressant for pediatric kidney transplants and is routinely administered twice daily (BD-tac). Envarsus (LCP-tac), an extended-release formulation, is approved for adults but not for pediatric patients. METHODS: We conducted a pilot open-label phase 1 study in stable pediatric kidney transplant recipients (age < 18 at the time of study). Our primary objective was to compare the pharmacokinetics (Pk) of LCP-tac versus BD-tac. We conducted two 24-h Pk studies: pre-conversion (BD-tac) and 4 weeks post-conversion to LCP-tac. Patients were followed for 6 months, with the option to continue LCP-tac. RESULTS: Five patients completed the study, with no returns to BD-tac. Median age was 15 years (range 11-17). LCP-tac exhibited an extended-release profile versus the bimodal profile of BD-tac. Time to maximum concentration was delayed (5 h vs. 1 h), and maximum concentration was lower (9.9 ng/mL vs. 14.4 ng/mL). Tacrolimus area under the curve (24 h) was comparable (141 ± 46.5 ng/mL vs. 164 ± 27.8 ng/mL). No new safety concerns arose. There were no rejection and no difference in eGFR at the study's end (1.5 mL/min/1.73 m2 , range - 1.7 to 2.3 mL/min/1.73 m2 ). Concentration/dose ratio was higher in LCP-tac (1.8 ± 0.64 vs. 0.8 ± 0.39). The final conversion ratio was 0.6 (BD-tac: LCP-tac). CONCLUSION: Our pilot study confirms the extended-release Pk profile and improved absorption of LCP-tac compared to BD-tac. A larger study is needed to further evaluate the population Pk characteristics in children.

Optimizing the corticosteroid dose in steroid-sensitive nephrotic syndrome.

The use of corticosteroids in the treatment of steroid-sensitive nephrotic (SSNS) syndrome in children has evolved surprisingly slowly since the ISKDC consensus over 50 years ago. From a move towards longer courses of corticosteroid to treat the first episode in the 1990s and 2000s, more recent large, well-designed randomized controlled trials (RCTs) have unequivocally shown no benefit from an extended course, although doubt remains whether this applies across all age groups. With regard to prevention of relapses, daily ultra-low-dose prednisolone has recently been shown to be more effective than low-dose alternate-day prednisolone. Daily low-dose prednisolone for a week at the time of acute viral infection seems to be effective in the prevention of relapses but the results of a larger RCT are awaited. Recently, corticosteroid dosing to treat relapses has been questioned, with data suggesting lower doses may be as effective. The need for large RCTs to address the question of whether corticosteroid doses can be reduced was the conclusion of the authors of the recent corticosteroid therapy for nephrotic syndrome in children Cochrane update. This review summarizes development in thinking on corticosteroid use in SSNS and makes suggestions for areas that merit further scrutiny.

Double filtration plasmapheresis - 10-year pediatric experience as an alternative to plasma exchange.

BACKGROUND: Double filtration plasmapheresis (DFPP) is more selective at removing antibodies compared to plasma exchange (PE), thus reducing the need for replacement blood products. METHODS: We retrospectively analyzed the records of all pediatric patients whom DFPP had been performed. RESULTS: In total, 30 patients were treated with DFPP. Data were available for 436 sessions in 23 patients. Patients had a median of 6 (1-161) sessions. Age at start of treatment was 13.9 years (2.2-19.2) and weight 46 kg (13.4-82.8). Six patients were treated for antibody mediated rejection; 1 had full recovery, 1 CKD stage 4 and 4 required dialysis. Two patients were treated for recurrence of focal segmental glomerulosclerosis (FSGS) with good response. One successfully had an ABO-incompatible kidney transplantation. Five had anti-glomerular basement membrane disease; 3 had complete recovery, 1 CKD and 1 required transplantation. Three had granulomatosis with polyangiitis; 1 with full recovery, 1 had CKD and 1 required dialysis. Two had Type-2 Membrano-proliferative glomerulonephritis, 1 successfully treated, the other needing dialysis. One treated for rapidly progressive MPO-glomerulonephritis required dialysis. Other indications were Myasthenia Gravis, Guillain-Barré disease and autoimmune limbic encephalitis. Excluding FSGS patients (with >100 sessions), one patient had cryoprecipitate, 2 had blood transfusions, no other blood products were required. Minor complications were seen in 13 sessions (8.4%). No major complications were seen. CONCLUSION: DFPP is a safe, well tolerated form of apheresis that appears to have comparable outcomes to that of PE, without the routine need of replacement blood products.

Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome.

OBJECTIVE: Rituximab is an effective treatment for children with steroid dependent or frequently relapsing nephrotic syndrome. The optimum dosing schedule for rituximab has not been established. We hypothesized that a single low dose of 375 mg/m2 would have comparable outcomes to higher doses in reducing the frequency of relapse and time to B cell reconstitution. METHODS: We conducted a multicenter retrospective observational cohort study of children with steroid-sensitive frequently relapsing nephrotic syndrome. Data were extracted from clinical records including the dates of diagnosis, treatment, relapses, the use of concomitant immunosuppression, and lymphocyte subset profiling. Patients treated earlier received variable doses of rituximab, although typically two doses of 750 mg/m2. Later, patients received the current regimen of a single dose of 375 mg/m2. The primary outcome was an absence of clinically confirmed relapse 12 months following rituximab administration. Secondary outcomes were median time to relapse, probability of being relapse-free at 6 and 24 months and time to reconstitution of CD19+ B cells. RESULTS: Sixty patients received 143 courses of rituximab. Seven different dosing regimen strategies were used, ranging between 375 and 750 mg/m2 per dose, with administration of 1-4 doses. There was no significant difference in event-free survival at 12 months between dosing strategies. The median time to reconstitution of B cells was not significantly different between groups. CONCLUSIONS: Use of a single low-dose regimen of rituximab in the management of frequently relapsing nephrotic syndrome does not affect the probability of relapse at 12 months or time to B cell reconstitution compared to a conventional higher dose.

Peritoneal Dialysis Catheter Removal Post-Transplant - A Rare Case of Delayed Bowel Perforation.

Peritoneal dialysis (PD) is a well-established form of renal replacement therapy and the practice of leaving catheters in situ post-transplantation widely accepted. We present a rare complication: a child presenting with anal protrusion of the PD catheter.The patient is an 11-year-old boy with a background of renal dysplasia and congenital cutis laxa. Twenty-three weeks after dialysis was commenced, the patient underwent a renal transplant. Thirteen weeks post-transplant, the patient felt an unusual sensation after defecation. The curled end of the catheter was seen protruding from the anus. He was admitted, and investigations showed stable graft function, with abdominal X ray showing no free air.Intraoperative findings showed a small perforation of the sigmoid colon sealed off by adherence of several small intestinal loops. This was repaired laparoscopically after removal of the distal part of the catheter per rectum. No peritoneal contamination was seen. He was treated with 5 days of intravenous antibiotics and gradual introduction of enteral feeds. His graft function remained stable throughout.Timing of catheter removal varies, from the time of transplantation to over 3 months post-transplantation. Bowel perforation due to PD catheter insertion is rare and tends to occur at the time of insertion. Anal protrusion of a PD catheter in childhood is extremely rare and unrecorded in a pediatric patient with a connective tissue disorder. Our case highlights that serious complications can occur in the period between transplantation and elective PD catheter removal and that, in the immunocompromised patient, signs can be subtle.

Oral sildenafil as a rescue therapy in presumed acute pulmonary hypertensive crisis.

A 23-week-old baby, born at 26(+2) weeks, presented to the hospital with critical respiratory failure, which was impossible to stabilize. She had unstable oxygen saturations between 35% and 95%. A presumptive diagnosis of bronchopulmonary dysplasia with associated pulmonary hypertensive crisis was made. In the absence of inhaled nitric oxide, 2 oral doses of 1 mg/kg sildenafil were given, with a dramatic improvement 30 to 45 minutes later. Her oxygenation index fell from 43 to 14. She made a full recovery and was discharged from the hospital 2 weeks later.