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Rituximab and tacrolimus are therapies reserved for patients with frequently relapsing or steroid-dependent nephrotic syndrome who have failed conventional steroid-sparing agents. Given their toxicities, demonstrating non-inferiority of rituximab to tacrolimus may enable choice between these medications.This investigator-initiated, single-center, open-label, pilot randomized controlled trial examined the non-inferiority of two doses of intravenous (IV) rituximab given one-week apart to oral therapy with tacrolimus (1:1 allocation), in maintaining sustained remission over 12 months follow-up, in patients with difficult-to-treat steroid-sensitive nephrotic syndrome, defined as frequently relapsing or steroid-dependent disease that had failed ≥ 2 steroid-sparing strategies. Secondary outcomes included frequency of relapses, proportion with frequent relapses, time to relapse and frequent relapses, and adverse events (CTRI/2018/11/016342).Baseline characteristics were comparable for 41 patients randomized to receive rituximab (n = 21) or tacrolimus (n = 20). While 55% of patients in each limb were in sustained remission at 1 year, non-inferiority of rituximab to tacrolimus was not demonstrated (mean difference 0%; 95% CI - 30.8%, 30.8%; non-inferiority limit - 20%; P = 0.50). Frequent relapses were more common in patients administered rituximab compared to tacrolimus (risk difference 30%, 95% CI 7.0, 53.0, P = 0.023). Both groups showed similar reductions in relapse rates and prednisolone use. Common adverse events were infusion-related with rituximab and gastrointestinal symptoms with tacrolimus.Therapy with rituximab was not shown to be non-inferior to 12-months treatment with tacrolimus in maintaining remission in patients with difficult-to-treat steroid-sensitive nephrotic syndrome. Frequent relapses were more common with rituximab. While effective, both agents require close monitoring for adverse events. A higher resolution version of the Graphical abstract is available as Supplementary information.

Intradialytic hypotension (IDH) is a common adverse event resulting in premature interruption of hemodialysis, and consequently, inadequate fluid and solute removal. IDH occurs in response to the reduction in blood volume during ultrafiltration and subsequent poor compensatory mechanisms due to abnormal cardiac function or autonomic or baroreceptor failure. Pediatric patients are inherently at risk for IDH due to the added difficulty of determining and attaining an accurate dry weight. While frequent blood pressure monitoring, dialysate sodium profiling, ultrafiltration-guided blood volume monitoring, dialysate cooling, hemodiafiltration, and intradialytic mannitol and midodrine have been used to prevent IDH, they have not been extensively studied in pediatric population. Lack of large-scale studies on IDH in children makes it difficult to develop evidence-based management guidelines. Here, we aim to review IDH preventative strategies in the pediatric population and outlay recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup. Without strong evidence in the literature, our recommendations from the expert panel reflect expert opinion and serve as a valuable guide.

While patients with frequently relapsing nephrotic syndrome (FRNS) are initially treated with long-term alternate-day prednisolone, relapses and adverse effects are common. In an open-label randomized controlled trial, we compared the efficacy of therapy with low-dose daily to standard alternate-day prednisolone in reducing relapse rates over 12-month follow-up. Consecutive patients, aged 2–18 years, with FRNS were included. Following therapy of relapse, prednisolone was tapered to 0.75 mg/kg on alternate days. Stratifying for steroid dependence, patients were randomly assigned to prednisolone at 0.2–0.3 mg/kg daily or 0.5–0.7 mg/kg alternate day for 12 months. Relapses were treated with daily prednisolone, followed by return to intervention. Primary outcome was the incidence of relapses. Proportion with therapy failure (≥ 2 relapses in any 6 months or significant steroid toxicity) and sustained remission, cumulative prednisolone intake and adverse events were evaluated. Patients receiving daily prednisolone (n = 30) showed significantly fewer relapses than those on alternate-day therapy (n = 31) (0.55 relapses/person-year versus 1.94 relapses/person-year; incidence rate ratio 0.28; 95% CI 0.15, 0.52). Daily therapy was associated with higher rates of sustained remission at 6 months (73.3 versus 48.4%) and 1 year (60 versus 31.6%; log rank p = 0.013), lower rates of treatment failure at 6 months (3.3 versus 32.8%) and 1 year (6.7 versus 57.4%; p

Frasier syndrome is characterized by progressive glomerulopathy that is unresponsive to corticosteroids, male pseudohermaphroditism, and an increased risk of genitourinary tumors. Of 21 girls with steroid-resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) who were screened for mutations in the WT1 gene, two showed Frasier syndrome. Both patients had donor splice-site mutations in intron 9 of the WT1 gene and a male karyotype (46, XY). Long-term therapy with cyclosporine resulted in partial remission in both cases. One patient showed foci of gonadoblastoma in the excised dysgenetic gonads. This report highlights the need for screening for mutations in the WT1 gene in girls with steroid-resistant FSGS. Patients with Frasier syndrome might benefit from early gonadectomy.

We compared, in a randomized controlled trial, the efficacy of a regimen based on intravenous (i.v.) cyclophosphamide therapy with a combination of i.v. dexamethasone and oral cyclophosphamide therapy in inducing remission in patients with steroid-resistant nephrotic syndrome (SRNS). During April 2001 to December 2003, 52 consecutive patients with idiopathic SRNS, normal renal function and renal histology findings showing minimal change disease, focal segmental glomerulosclerosis or mesangioproliferative glomerulonephritis were enrolled into the study. Patients in group I received i.v. injection of cyclophosphamide once a month for 6 months and prednisolone on alternate days. Those in group II received i.v. treatment with dexamethasone (initially on alternate days, later fortnightly and monthly; total 14 doses), oral cyclophosphamide therapy (for 3 months) and prednisolone on alternate days. Data from 49 patients (26 in group I, 23 in group II) were analyzed; their clinical and biochemical features were similar at inclusion. Following treatment, complete remission was seen in 53.8% and 47.8% patients in groups I and II, respectively (P = 0.6). Long-term follow up showed favorable outcome in 14 (53.8%) patients in group I, and 9 (39.1%) in group II. Chief adverse effects, including cushingoid features and serious infections, were similar in both groups. Patients receiving i.v. dexamethasone therapy commonly showed hypertension and hypokalemia, while vomiting and reversible alopecia occurred in those receiving i.v. treatment with cyclophosphamide. In patients with SRNS, the efficacy of treatment intravenously with cyclophosphamide and orally with prednisolone was similar to the combination of dexamethasone intravenously, orally administered cyclophosphamide and prednisolone.

The concentration of cystatin C has been shown to be independent of age, gender and height, but the effect of malnutrition has not been studied. Levels of serum creatinine and cystatin C were estimated in 77 malnourished and 77 normally nourished boys between 2 years and 6 years of age without evidence of renal disease. The mean (95% confidence interval) serum creatinine level in the malnourished boys was significantly lower than that in the normally nourished boys [0.42 (0.38-0.45) mg/dl and 0.51 (0.48-0.55)] mg/dl, respectively, (P0.01)]. The mean level of serum cystatin C was 1.05 (0.94-1.17) mg/l and 1.12 (1.01-1.24) mg/l, respectively, in normally nourished and malnourished boys (P = 0.35). Mean glomerular filtration rate (GFR) estimated by the Schwartz equation in the malnourished boys was significantly higher than that in normally nourished children [141.8 (123.3-160.2) ml/min per 1.73 m(2) body surface area and 119.4 (109.3-129.5) ml/min per 1.73 m(2) body surface area], respectively (P = 0.04). However, the mean cystatin C-derived GFR was similar in the malnourished and normally nourished boys [99.70 (85.8-113.5) ml/min per 1.73 m(2) and 109.2 (94.4-124.0) ml/min per 1.73 m(2)], respectively (P = 0.35). The mean bias between GFR estimates using Bland and Altman analysis was greater in the malnourished children than in the normally nourished children (32.3% and 17.6%, respectively) (P = 0.15). Serum creatinine levels are lower in malnourished children and lead to overestimation of GFR, while cystatin C levels are unaffected.

Nail-patella syndrome (NPS) is a rare disorder with autosomal dominant mode of inheritance. We report a child with NPS and steroid-responsive, frequently relapsing nephrotic syndrome. The child had dystrophic nails, flexion contractures of both elbows and normal renal functions. X-rays of the knees and pelvis showed hypoplastic patellae and iliac horns. Renal histology was unremarkable with mild focal increase in mesangial cellularity compatible with minimal change disease. Ultrastructural features of NPS including thickening of the glomerular basement membrane with electron-lucent areas were not found.

During recent years, there has been an increasing demand for specialized care for children with kidney diseases, even in developing countries with limited resources. It is imperative to provide suitable facilities for appropriate and relevant training in pediatric nephrology to promote growth of pediatric nephrology in these areas. The training should give emphasis on preventive aspects, early diagnosis of common diseases and their optimum management with available resources. It should focus on locally prevalent renal diseases. The training programs should take into consideration the socioeconomic and cultural framework of the local community when designing curricula. To overcome the shortage of pediatric nephrology health professionals in the developing countries, the International Pediatric Nephrology Association has taken initiatives to support development of such training programs.

We have examined, in a randomized crossover trial, the antiproteinuric effect of treatment with low- (0.2 mg/kg daily) and high-dose (0.6 mg/kg daily) enalapril in 25 consecutive patients with steroid-resistant nephrotic syndrome (SRNS). Patients in group A ( n=11) received enalapril at low doses for 8 weeks, followed by 2 weeks of washout and then at high doses for 8 weeks. Those in group B ( n=14) initially received enalapril at high and then low doses. Patients continued to receive treatment with tapering doses of prednisolone; none received concomitant therapy with daily oral or intravenous steroids, alkylating agents, cyclosporine, non-steroidal anti-inflammatory drugs, and other antihypertensive medications. The urine albumin-to-creatinine (Ua/Uc) ratio and the percentage reduction were determined for each phase of therapy. Baseline clinical, biochemical, and histological features were comparable in the two groups. In the first phase, treatment with low-dose enalapril (group A) resulted in median 34.8% Ua/Uc reduction compared with 62.9% with high doses (group B) ( P0.01). High-dose enalapril was associated with a significant reduction in Ua/Uc ratio in both groups. The combined median Ua/Uc (95% confidence interval) reduction in the low-dose phase was 33% (-10.3% to 72.4%) and in the high-dose 52% (15.4%-70.4%) ( P0.05). The median Ua/Uc ratio at the end of 20 weeks was 1.1 and 1.8 in groups A and B, respectively ( P0.05). Systolic and diastolic blood pressure reductions were similar in both groups. No period or carry-over effect was found. Prolonged treatment with enalapril thus resulted in a dose-related reduction in nephrotic-range proteinuria. Titration of the dose of enalapril may be a useful strategy for achieving substantial reduction of proteinuria in children with SRNS.

We prospectively examined the effect of treatment with intravenous cyclophosphamide in patients with steroid-resistant nephrotic syndrome. Twenty-four patients (minimal change disease in 11, focal segmental glomerulosclerosis in 9, and mesangioproliferative glomerulonephritis in 4), who did not show remission of proteinuria despite treatment with 8 weeks of oral prednisolone and six intravenous pulses of dexamethasone, were studied. Cyclophosphamide was administered intravenously, at a dose of 750 mg/m(2) once a month for 6 months; therapy with alternate-day prednisolone was continued. The mean (SD) age at treatment was 7.8 (4.0) years; 18 patients had initial resistance and 6 had late resistance. At the end of 6 months treatment, 7 (29.2%) patients each had complete remission (absent proteinuria, normal serum albumin) and partial remission (1-2+ proteinuria, normal serum albumin). Ten (41.6%) patients showed no response to therapy. The mean time to complete or partial remission, after initiation of treatment with cyclophosphamide, was 2.4+/-1.7 months and 2.7+/-1.8 months, respectively. Most responders (85.8% complete and 57.2% partial responders) achieved remission by the third dose of pulse cyclophosphamide. More patients with late resistance (50%) compared with initial resistance (22.2%) achieved complete remission. Partial remission was transient and lasted for a mean duration of 6.4+/-3.5 months. Serious infections were observed during therapy in 5 patients. On long-term follow-up, 5 (20.8%) patients were in remission, while nephrotic-range proteinuria or end-stage renal disease was seen in 17 (70.8%). Findings from the present study suggest that therapy with intravenous cyclophosphamide has limited efficacy in inducing sustained remission in patients with initial corticosteroid resistance. Sustained remission is likely to occur in a significant proportion of patients with late resistance and those with absence of significant tubulointerstitial changes on renal histology.

Patients with steroid-resistant nephrotic syndrome often have an unsatisfactory long-term outcome and are at risk of developing chronic renal failure. We prospectively treated 65 children with idiopathic steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with intravenous pulses of corticosteroids and oral cyclophosphamide. Dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg) was administered intravenously, initially 6 pulses on alternate days, followed by 4 fortnightly and 8 monthly pulses. Oral cyclophosphamide therapy was given for 12 weeks and tapering doses of prednisolone were administered for 52 weeks. The mean age at treatment was 85.7± 44.9 months. Five patients developed serious infections during administration of initial alternate-day pulses and were excluded. Of 59 patients who completed initial alternate-day therapy, 17 had complete and 8 partial remission; 34 (57.6%) patients did not respond to treatment. The median urine protein to creatinine ratio decreased from 10.0 to 0.75 (P

Ellis-van Creveld (EvC) and Jeune's asphyxiating thoracic dystrophy (ATD) are related disorders characterized by narrow thoracic cage and short-limbed dwarfism. Some patients have overlapping features of both ATD and EvC, indicating that these syndromes may be a part of a disease spectrum. Nephronophthisis has been occasionally reported in patients with ATD, but not with EvC syndrome. We report a patient who was diagnosed with EvC syndrome at birth. He developed hypertension at 5 months of age and gradually progressive renal failure, requiring renal transplantation at 8 years. Histopathological findings in the nephrectomy specimen were indicative of nephronophthisis. The association of nephronophthisis in a patient with EvC syndrome has not been reported previously. This association further supports the hypothesis that ATD and EvC syndromes are related and represent a spectrum of disorders.

Relapses of nephrotic syndrome are usually treated with prednisolone, initially in three to four daily divided doses. The divided-dose regimen may cause poor patient compliance and greater adrenal suppression. In a prospective randomized controlled trial, we compared the efficacy of prednisolone in inducing remission of nephrotic syndrome, when given either as a single dose or in divided doses. Patients with steroid-responsive nephrotic syndrome with relapse were randomized to receive prednisolone 2 mg/kg per day, either as a single morning dose or in three divided doses for 2 weeks, followed by 1.5 mg/kg on every alternate day for 4 weeks. Parents tested the urine for protein daily until remission (nil proteinuria for 3 consecutive days). The duration between initiation of treatment and achievement of remission was recorded. Of 106 patients, 94 (47 each in single-dose and divided-dose groups) completed the study. The patients in the two groups were similar in relation to age, sex, number of relapses in the preceding year, and blood levels of creatinine, albumin, and cholesterol. The mean time for achievement of remission in the single- and divided-dose groups was 8.6 and 8.5 days, respectively (P = 0.94, power 96%). After 9 months' follow-up, there were no differences in the frequency of relapses and cumulative dose of prednisolone received in the two groups. The observations suggest that prednisolone administered in a single daily dose or in divided doses is equally effective in inducing remission in patients with relapsing nephrotic syndrome.

Urinary excretion of calcium, magnesium, phosphate, uric acid, oxalate, and creatinine was measured in 208 children (aged 8-15 years, 124 boys, 84 girls), living in a residential school near New Delhi. Levels were reduced compared with those reported from developed countries. The 95th percentile value of 24-h creatinine excretion was 33.4 mg/kg, calcium 2.2 mg/kg, magnesium 2.9 mg/kg, phosphate 9.4 mg/kg, uric acid 4.4 mg/kg, and oxalate 1.5 mg/kg. The 95th percentile value of the urine calcium/creatinine ratio was 0.15 and oxalate/creatinine 0.06. The dietary intake of proteins, calcium, and other nutrients in these children was less than recommended and explained the reduced urinary excretion observed. Physicians need to be aware of the regional patterns of normal urinary excretion of these constituents.

The aetiology of nephrolithiasis was investigated in 32 north Indian children (25 boys, 7 girls, mean age 7.9 +/- 3.3 years). An underlying disorder was detected in 16 (50%) patients and included idiopathic hypercalciuria (8 patients), hyperoxaluria (3 patients) and renal tubular acidosis, primary hyperparathyroidism and hyperuricosuria (1 patient each). Magnesium ammonium phosphate calculi were found in 2 patients with recurrent urinary tract infections, 1 of whom had a duplex pelvic collecting system. In 16 patients (50%) a cause for renal calculi was not identified. Our findings suggest that an underlying disorder is present in a large proportion of children with nephrolithiasis where appropriate treatment may be beneficial.

A 10-year-old girl with distal renal tubular acidosis (RTA) for 4 years (adequately treated for 3 years) developed clinical features suggesting systemic lupus erythematosus (SLE) with supportive laboratory evidence. She had heavy proteinuria and a decreased creatinine clearance (CCr). Renal biopsy showed diffuse proliferative and sclerosing glomerulonephritis with severe tubulointerstitial changes. Following treatment with corticosteroids and cyclophosphamide, she had a clinical remission, an increase in CCr and recovery from systemic acidosis. It is likely that distal RTA in this patient was a manifestation of SLE.

The efficacy of daily administration of a small dose of prednisolone was examined in 21 patients with corticosteroid-responsive, frequently relapsing nephrotic syndrome (FRNS). After induction of remission of a third or subsequent relapse with a 6-week course of prednisolone (standard therapy with prednisolone, STP), this drug was continued in a single daily dose of 0.25 mg/kg body weight (low-dose prednisolone, LDP) for 18 months. Relapses occurring during this period were treated with STP, following which LDP therapy was resumed. The historical controls comprised 14 patients with FRNS in whom relapses were treated with STP and who were observed over a minimum period of 30 months. The two groups were comparable for age at the onset of nephrotic syndrome and sex. Twenty patients completed LDP therapy, during which 12 had no relapse, 6 had infrequent and 2 frequent relapses (1 patient became steroid dependent and was taken off LDP). Twelve patients were followed for 12-42 months after stoppage of LDP; during this period 7 had no relapse, 4 had infrequent relapses and 1 showed steroid dependence. The number of relapses during LDP therapy (0.5/patient per year) was significantly less (P less than 0.001) than in the preceding 12 months (3.62/patient per year), and continued to remain low during the following 12 months (0.6/patient per year). Whereas the frequency of relapses in the LDP group was similar to that in the historical control group in the 1st year of comparison, it was significantly less during LDP therapy (0.5/patient per year versus 2.25/patient per year). No side effects were observed in patients on the LDP regimen, at the end of which the height percentiles improved in 6 patients and remained unchanged in 14. Our observations indicate that long-term therapy with a small daily dose of prednisolone can significantly reduce the number of relapses in patients with FRNS, and that the beneficial effect may continue even after its stoppage.