Daily compared with alternate-day levamisole in pediatric nephrotic syndrome: an open-label randomized controlled study.

BACKGROUND: Levamisole is less expensive and has a better toxicity profile compared to other steroid sparing agents used in nephrotic syndrome. It has a plasma half-life of 2.0 to 5.6 hours, but is conventionally administered on alternate days. We aimed to assess whether daily levamisole is safe and more effective than standard alternate-day therapy in maintaining remission in children with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). METHODS: An open-label randomized controlled trial was conducted in children with FR/SDNS. Group A received daily while Group B received alternate-day levamisole (2-3 mg/kg/dose) for 12 months. Prednisolone was tapered off by 3 months. Patients were monitored for relapses, further steroid requirement, and adverse effects. RESULTS: A total of 190 children with FR/SDNS (94 in Group A and 96 in Group B) were analyzed. Sustained remission for 12 months was observed in 36% of Group A and 27% of Group B patients (p = 0.18). Numbers completing 12 months in the study were 67% in Group A and 56% in Group B (p = 0.13). Time to first relapse, persistent FR/SDNS, and withdrawal due to poor compliance were statistically similar in both groups, while relapse rate and cumulative steroid dosage were significantly lower in Group A compared to Group B (p = 0.03 and p = 0.02, respectively). The incidence of adverse effects was comparable in both groups, with reversible leucopenia and hepatic transaminitis being the commonest. CONCLUSIONS: Daily levamisole therapy was not superior to alternate-day therapy in maintaining sustained remission over 12 months. Nevertheless, relapse rate and cumulative steroid dosage were significantly lower without increased adverse effects.

Antineutrophil cytoplasmic antibody in children with nephrotic syndrome treated with levamisole: a cross-sectional cohort study.

BACKGROUND: Levamisole is a commonly used steroid-sparing agent (SSA), but the reported incidence of antineutrophil cytoplasmic antibody (ANCA) positivity has been concerning. METHODS: Observational cross-sectional study wherein children aged 2 to 18 years with frequently relapsing/steroid dependent nephrotic syndrome (FRNS/SDNS) on levamisole for ≥ 12 months were tested for ANCA. RESULTS: A total of 210 children (33% female), median age of 7.3 (IQR: 5.6-9.6) years, and a median duration of levamisole exposure of 21 (IQR: 15-30) months were tested. ANCA was positive in 18% (n = 37): 89% (n = 33) perinuclear ANCA (pANCA), 3% (n = 1) cytoplasmic ANCA (cANCA), and 8% (n = 3) both. Of ANCA-positive children, none had reduced eGFR or abnormal urinalysis. The majority of these children were asymptomatic (81%, n = 30). Rash was more common among ANCA-positive children [6/37 (16%) vs. 3/173 (2%), p = 0.0001]. On multivariate analysis, higher age (OR = 1.02, [95th CI: 1.01 to 1.03], p = 0.007) and longer duration of levamisole exposure (OR = 1.05, [95th CI: 1.02 to 1.08], p = 0.0007) were associated with ANCA positivity. Levamisole was stopped in ANCA-positive children with the resolution of any clinical manifestations if present. Repeat ANCA testing was performed in 54% (20/37), and all were ANCA negative by 18 months. CONCLUSIONS: Children with FRNS/SDNS on longer duration of levamisole were associated with increasing prevalence of ANCA positivity, but most of these children were clinically asymptomatic. Prospective studies are required to determine the chronology of ANCA positivity and its clinical implication.

Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study.

BACKGROUND: Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. METHODS: This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative. RESULTS: There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2). CONCLUSION: WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Outcome of severe steroid-dependent nephrotic syndrome treated with mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) is used as a steroid-sparing agent in pediatric nephrotic syndrome (NS). However, data about its long-term efficacy and safety is limited. METHODS: We report the long-term outcome of MMF therapy in 46 NS patients who remained steroid dependent (SD) despite previous treatment with levamisole and cyclophosphamide. RESULTS: After 1 year of MMF initiation, 32 (70 %) patients had reduced steroid requirement: 12 with decreased threshold dose and 20 were able to stop steroids. At follow-up of mean 3.56 (standard deviation + 1.76) years, 25 (54 %) children required no further alternative immunosuppression (IS), having infrequent or no relapses, of which 14 stopped MMF after a mean 2.4 (standard deviation + 0.9) years; 11 are continuing on MMF for a median of 2.25 years (range 1.33-7.75 years). One patient had a psoriasis flare, and MMF was stopped. No other patient required permanent drug withdrawal due to side effects. The outcome of patients who did not require further alternate IS was significantly better than those who did, with 56 % vs. 10.5 %, respectively, being off regular medications at last follow-up. CONCLUSIONS: We conclude that MMF therapy is safe in the long term and allows >50 % of severe SDNS patients to avoid further toxic IS.

Recurrent meningitis in association with common variable immune deficiency.

Recurrent meningitis in children is unusual and usually associated with a predisposing factor like immune-deficiency disorder or cranio-spinal defect. We report a case of recurrent meningitis in association with Common Variable Immune deficiency.

BK virus-associated renal problems--clinical implications.

BK virus (BKV), a human polyomavirus, infects most of the human population, but clinically relevant infections are usually limited to individuals who are immunosuppressed. After primary infection, BKV remains latent in the kidneys and can be reactivated in immune deficiency conditions, including transplantation. As primary infection occurs in childhood, BKV may be particularly important in the pediatric transplant population. BKV is associated with tubulointerstitial nephritis and ureteric stenosis in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant recipients. There are increasing reports of BKV causing nephropathy and cystitis in non-renal solid organ transplant recipients and other immunodeficiency diseases. This might be related to the use of more potent immunosuppressive regimens or increasing awareness of BKV as an important pathogen. Diagnosis of BKV disease is by biopsy. Histopathological changes in renal biopsy specimens may mimic rejection or drug toxicity, but BKV nuclear inclusions can be seen. Treatment is by reduction of immunosuppression. Antiviral agents such as cidofovir are showing promise. BKV DNA polymerase chain reaction in blood or biopsy may be helpful in monitoring therapy. The impact of BKV disease in children is not well understood and prospective studies are needed to elucidate this further. This article reviews the current understanding of BKV-associated renal problems.

Neonatal nephrocalcinosis in association with glucose-galactose malabsorption.

We report a case of severe nephrocalcinosis related to hypercalcaemia in a newborn with glucose-galactose malabsorption. He presented with poor growth and was noted to have polyuria, which was later recognised to be severe watery diarrhoea. We discuss the possible aetiological factors for nephrocalcinosis in this condition.