Asiri Abeyagunawardena

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Increasing the dose of prednisolone during viral infections reduces the risk of relapse in nephrotic syndrome: a randomised controlled trial

Background: Relapses of nephrotic syndrome are often triggered by viral upper respiratory tract infections (URTIs), possibly mediated by cytokine release. Objective: To test, in a randomised double-blind placebo-controlled crossover trial, the hypothesis that a small short-term increase in the dose of prednisolone will reduce the release of cytokines and thereby reduce the risk of relapse. Methods: Sequential patients receiving low-dose (<0.6 mg/kg) prednisolone on alternate days as maintenance therapy were recruited. At the first sign of a presumed viral URTI, all children were examined and randomly allocated to take medicine A or B (containing either prednisolone (5 mg) or placebo) in the first viral URTI, and vice versa in the second. If the criteria for diagnosis of a viral URTI were met, the new medicine was prescribed on alternate days for 1 week at the same dose as that of the prednisolone being taken by the patient on an alternate-day basis. A freshly voided urine sample was tested each morning. The presence of 3+ proteinuria for 3 consecutive days was diagnostic of relapse. Results: 48 patients were recruited, and 40 completed the trial (29 male; 11 female). Age at entry ranged from 1.5 to 13.2 (median 5.3) years. The relapse rate after viral URTI was 19/40 (48%) in the placebo group and 7/40 (18%) in the prednisolone group (p = 0.014; two-sided probability using Fisher’s exact test). Conclusion: Prescribing prednisolone daily for 7 consecutive days at the same dose as that taken by the patient on an alternate-day basis at the onset of a presumed viral URTI significantly reduces the risk of relapse in children with steroid-dependent nephrotic syndrome.

The use of steroid-sparing agents in steroid-sensitive nephrotic syndrome

Childhood nephrotic syndrome (NS) is frequently characterized by a relapsing course. There is no uniform agreement about the precise stage at which a steroid-sparing agent should be introduced to control the disease. In order to evaluate the treatment strategies and outcome of steroid-sensitive NS over the last 2 decades, a retrospective notes review was undertaken in a cohort of children treated at Great Ormond Street Childrens Hospital between 1980 and 2000. From a population of 863 children with NS referred, 509 had frequently relapsing or steroid-dependent disease and 261 children received at least one steroid-sparing agent. Cyclophosphamide was the first choice in 178 patients and in 114 no further steroid-sparing agent was needed. Levamisole was prescribed as the first steroid-sparing agent for 65 children and disease control was achieved in 30%. Cyclosporin A was prescribed in 61 children and sustained remission was induced in 69%. It is concluded that cyclophosphamide is a potent agent in inducing sustained remission in steroid-sensitive NS. Levamisole and cyclosporin A have emerged as attractive steroid-sparing agents. Complications and major side effects of treatment are infrequent but occasionally fatal.

Risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome

In November, 1999, all children under age 18 years in the UK were offered immunisation with the newly introduced meningococcal C conjugate vaccine (MCCV). In a cohort of 106 patients with nephrotic syndrome, there were 63 relapses during the 12 months before vaccination, and 96 during the equivalent period postvaccination (p=0.009). The relapse rate of nephrotic syndrome increased significantly after administration of MCCV. Whether to vaccinate such children needs to be carefully considered.

Adrenocortical suppression increases the risk of relapse in nephrotic syndrome

Objective: Children with nephrotic syndrome (NS) are usually treated with long-term low dose alternate day prednisolone with or without glucocorticoid sparing therapy, such as levamisole or ciclosporin, to maintain remission. The degree of hypothalamic-pituitary-adrenal axis (HPA) suppression with such therapeutic strategies has not been studied systematically. HPA suppression could cause a relapse or adrenal crisis. Study design: To study the risks of HPA suppression, a modified low dose synacthen test (0.5 μg) was administered to 32 patients (22 male,10 female) with a mean age of 9.7 years (range 3.8–17.6 years) with NS receiving long-term alternate day prednisolone for over 12 months. Twelve patients received alternate day prednisolone, 11 alternate prednisolone+levamisole and nine alternate prednisolone+ciclosporin. All patients were followed up for 3 years and the relapse rate noted. Results: 20/32 (62.5%) patients had a peak serum cortisol concentration of <500 nmol/l, which suggested suboptimal cortisol secretion and possible HPA suppression. 10/12 children in the prednisolone group and 8/11 in the levamisole group had a suboptimal cortisol response compared with 2/9 in the ciclosporin group. During follow-up, the 20 children who had a suboptimal cortisol response had significantly more relapses (95 relapses) compared to the 12 children with a normal cortisol response who had 24 relapses (p = 0.01). Conclusions: Children with NS receiving long-term alternate day prednisolone therapy are at risk of developing HPA suppression and should be evaluated using the modified synacthen test. Children with evidence of HPA suppression are at a greater risk of relapse.

Immunosuppressive therapy of childhood idiopathic nephrotic syndrome.

Childhood nephrotic syndrome (NS) is a distressing chronic renal disorder with potentially life threatening complications. Over 80% of cases in children are due to minimal change disease and the majority will respond to corticosteroid therapy. Steroid-sensitive NS is considered a relatively benign condition, since progression to end stage renal failure (ESRF) is extremely rare and > 80% will enter spontaneous long-term remission in later childhood. However, the disease is characterised by a relapsing course, placing the child at risk of acute complications, such as infection, hypovolaemia and thrombosis. Frequent relapses can result in a not inconsequential corticosteroid burden or prescription of cytotoxic immunosupressive therapy to control the disease. In contrast, steroid-resistant and -refractory NS has an unfavourable outcome with a propensity to progress to ESRF. While these clinical entities have an unpredictable response to cytotoxic immunosupressive therapy, the favourable long-term renal survival associated with children who enter sustained remission has revived the enthusiasm to treat steroid-resistant NS with more aggressive immunosuppressive regimens.

Treatment of steroid sensitive nephrotic syndrome.

Childhood idiopathic nephrotic syndrome (NS) is a chronic glomerular disorder, and if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. The aim of the management of NS in children is to induce and maintain complete remission with resolution of proteinuria and edema without encountering serious adverse effects of therapy. Over 90% of cases in children are due to minimal change disease (MCD) and a majority of them will respond to corticosteroid therapy. Steroid sensitive NS is considered to be a relatively benign condition; progression to end stage renal failure is extremely rare and over 80% achieve spontaneous remission in later childhood. The early disease is characterized by a relapsing course, placing the child at risk of acute complications. The occurrence of frequent relapses necessitates clear therapeutic strategies in order to maintain sustained remission and minimize steroid toxicity. Numerous therapeutic regimens have been proposed utilizing steroid sparing agents such as alkylating agents, principally, cyclophosphamide and chlorambucil, calcineurin inhibitors namely cyclosporin A and immunomodulatory drug levamisole with variable success and associated side-effects. It is therefore important that the benefits and risks of these agents are weighed before considering their use in the treatment of patients with NS.

G376(P) Short course of daily prednisolone during upper respiratory tract infection reduces the risk of relapse in childhood nephrotic syndrome

Aims Relapses in childhood nephrotic syndrome (NS) are often precipitated by viral upper respiratory tract infections (URTI). This study was undertaken to ascertain the effect of a short course of low dose corticosteroids during URTI on relapse frequency in patients with steroid sensitive NS who are off corticosteroids. Method A placebo-controlled crossover trial was conducted on 48 patients with steroid dependant NS who had been off corticosteroids. Patients recruited were into one of two groups. Group A received 5 days of daily prednisolone at 0.5 mg/kg at the onset of an URTI while group B received 5 days of placebo. Both groups were followed up for one year and the URTI induced relapse frequency was noted. A cross over was performed for the next year with group A receiving placebo and group B receiving prednisolone. The student t-test was used to compare continuous variables. The Fishers exact test was used to compare categorical variables. Of the 48 patients recruited, 33 completed the study. The mean (SD) age at baseline was 12.0 ± 2.4 years for the treatment group and 10.0 ±2.9 years for the placebo group. In the treatment group 113 episodes of URTI led to 11 relapses while in the control group 101 episodes of URTI led to 25 relapses. There was no significant difference between the mean number of URTIs between the treatment and control groups (3.5 ± 1.5 and 3.2 ± 1.4, p = 0.31). The treatment group had a significantly lesser number of relapses compared to the control group (p = 0.014). The majority (65.6%) within the treatment group did not relapse whilst the remaining subjects had a single relapse. In contrast only 40.6% of the control group remained in remission whilst 40.6% suffered from a single relapse and 18.8% had two relapses. Conclusion Administration of a short course of daily corticosteroids during a presumed URTI significantly reduces the frequency of URTI induced relapses in patients with steroid sensitive NS who are off corticosteroids.

Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population

Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants. Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (χ2 p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS. Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease.

Pulsed Vincristine Therapy in Steroid-Resistant Nephrotic Syndrome

Steroid-resistant nephrotic syndrome (SRNS) poses a therapeutic challenge for the paediatric nephrologist. As relentless progression to renal failure occurs with continued proteinuria, such patients will be treated with different cytotoxic medications with variable success rates and side-effects. We present here our findings on administering the anticancer drug vincristine for SRNS patients at a single centre in Sri Lanka. Methods. Between 2002 and 2007, fifty-four children presenting with steroid and cyclophosphamide resistance were treated with vincristine at 1.5 mg/m2 in weekly intravenous pulses for 8 weeks along with a tapering steroid regimen of 6 months. All patients were closely followed up for 5 years. Results. Of the 54 patients 39 were males and 15 were females (age range 3.5–11.6 years, median 6.1 years). At the end of the treatment course, 21 patients achieved complete remission while 7 had partial remission and no response was seen in 26 patients. Sustained remission at 6, 12, 24, and 60 months were 15 (27.78%), 11 (20.37%), 9 (16.67%), and 7 (12.96%), respectively. Most side-effects observed were reversible and no serious side-effects were noted during vincristine therapy. Conclusion. Although its therapeutic mechanisms in nephrotic syndrome are still not elucidated, vincristine appears to be a potent alternative that could be considered for treating SRNS.