Induction prednisone dosing for childhood nephrotic syndrome: how low should we go?

BACKGROUND: Historically, children with nephrotic syndrome (NS) across British Columbia (BC), Canada have been cared for without formal standardization of induction prednisone dosing. We hypothesized that local historical practice variation in induction dosing was wide and that children treated with lower doses had worse relapsing outcomes. METHODS: This retrospective cohort study included 92 NS patients from BC Children's Hospital (1990-2010). We excluded secondary causes of NS, age < 1 year at diagnosis, steroid resistance, and incomplete induction due to early relapse. We explored cumulative induction dose and defined dosing quartiles. Relapsing outcomes above and below each quartile threshold were compared including total relapses in 2 years, time to first relapse, and proportions developing frequently relapsing NS (FRNS) or starting a steroid-sparing agent (SSA). RESULTS: Cumulative prednisone was widely distributed with approximated median, 1st, and 3rd quartile doses of 2500, 2000, and 3000 mg/m2 respectively. Doses ≤ 2000 mg/m2 showed significantly higher relapses (4.2 vs 2.7), shorter time to first relapse (61 vs 175 days), and higher SSA use (36 vs 14%) compared to higher doses. Doses ≤ 2500 mg/m2 also showed significantly more relapses (3.9 vs 2.2), quicker first relapse (79 vs 208 days), and higher FRNS (37 vs 17%) and SSA use (28 vs 11%). Relapsing outcomes lacked statistical difference in ≤ 3000 vs > 3000 mg/m2 doses. CONCLUSIONS: Results strongly justify our development of a standardized, province-wide NS clinical pathway to reduce practice variation and minimize under-treatment. The lowest induction prednisone dosing threshold to minimize future relapsing risks is likely between 2000 and 2500 mg/m2. Further prospective studies are warranted.

Indications for kidney biopsy in idiopathic childhood nephrotic syndrome.

BACKGROUND: Most cases of childhood nephrotic syndrome (NS) are due to minimal change disease (MCD), while a minority of children have focal segmental glomerulosclerosis (FSGS) and an unfavorable clinical course, requiring a kidney biopsy to confirm diagnosis. We hypothesized that clinical characteristics at diagnosis and initial response to corticosteroid treatment accurately predict FSGS and can be used to guide consistent practice in the indications for kidney biopsy. METHODS: This was a case control study (1990-2012). Inclusion criteria included age 1-17 years, meeting the diagnostic criteria for NS, and having biopsy-proven FSGS or MCD. Clinical characteristics at diagnosis included age, kidney function [estimated glomerular filtration rate (eGFR)], hypertension, hematuria, nephritis (reduced eGFR, hematuria, hypertension), and response to steroids. RESULTS: From a total of 169 children who underwent kidney biopsy for NS we included 65 children with MCD and 22 with FSGS for analysis. There were no significant between-group differences in age, sex, or eGFR at the time of diagnosis. The FSGS group had a higher proportion of hypertension (40 vs. 15%; p = 0.02), hematuria (80 vs. 47%; p = 0.01), and nephritis (22 vs. 2%; p = 0.004) and was more likely to be steroid resistant after 6 weeks of treatment than the MCD group (67 vs. 19%; p < 0.001). As predictors of FSGS, hematuria had a high sensitivity of 0.80 [95% confidence interval (CI) 0.56-0.93] and low specificity of 0.53 (95% CI 0.39-0.66), nephritis had a low sensitivity of 0.22 (95% CI 0.07-0.48) and high specificity of 0.98 (95% CI 0.88-0.99), and steroid resistance had a low sensitivity of 0.67 (95% CI 0.43-0.85) and high specificity of 0.81 (95% CI 0.68-0.90). The combination of steroid resistance after 6 weeks of therapy and/or nephritis at diagnosis yielded the optimal sensitivity and specificity at 0.80 (95% CI 0.56-0.93) and 0.75 (95% CI 0.60-0.86), respectively, confirmed by the highest receiver operator characteristic area under the curve of 0.77. CONCLUSION: Steroid resistance after 6 weeks of therapy and/or nephritis at initial presentation is an accurate predictor of FSGS in children with NS and will be used as the indication for kidney biopsy in our newly developed clinical pathway. This approach will maximize the yield of diagnostic FSGS biopsies while minimizing the number of unnecessary MCD biopsies.