Long-Term Outcomes in IgA Nephropathy

Abstract

Background: IgA nephropathy can progress to kidney failure, and risk assessment soon after diagnosis has advantages both for clinical management and the development of new therapeutics. We present relationships among proteinuria, eGFR slope, and lifetime risks for kidney failure.

Methods: The IgA nephropathy cohort (2299 adults and 140 children) of the UK National Registry of Rare Kidney Diseases (RaDaR) was analyzed. Patients enrolled had a biopsy-proven diagnosis of IgA nephropathy plus proteinuria >0.5 g/d or eGFR <60 ml/min per 1.73 m 2 . Incident and prevalent populations and a population representative of a typical phase 3 clinical trial cohort were studied. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope.

Results: The median (Q1, Q3) follow-up was 5.9 (3.0, 10.5) years; 50% of patients reached kidney failure or died in the study period. The median (95% confidence interval [CI]) kidney survival was 11.4 (10.5 to 12.5) years; the mean age at kidney failure/death was 48 years, and most patients progressed to kidney failure within 10-15 years. On the basis of eGFR and age at diagnosis, almost all patients were at risk of progression to kidney failure within their expected lifetime unless a rate of eGFR loss ≤1 ml/min per 1.73 m 2 per year was maintained. Time-averaged proteinuria was significantly associated with worse kidney survival and more rapid eGFR loss in incident, prevalent, and clinical trial populations. Thirty percent of patients with time-averaged proteinuria of 0.44 to <0.88 g/g and approximately 20% of patients with time-averaged proteinuria <0.44 g/g developed kidney failure within 10 years. In the clinical trial population, each 10% decrease in time-averaged proteinuria from baseline was associated with a hazard ratio (95% CI) for kidney failure/death of 0.89 (0.87 to 0.92).

Conclusions: Outcomes in this large IgA nephropathy cohort are generally poor with few patients expected to avoid kidney failure in their lifetime. Significantly, patients traditionally regarded as being low risk, with proteinuria <0.88 g/g (<100 mg/mmol), had high rates of kidney failure within 10 years.

Graphical abstract

Figure 1

Outcomes and characteristics for the full-analysis population. (A) Kaplan–Meier survival curves of time to kidney failure/death event in adult versus pediatric patients. (B) Age at diagnosis by decade in adult versus pediatric patients. Dotted line highlights first year of recruitment of patients with IgA nephropathy into RaDaR (2013). (C) eGFR at diagnosis by year in adult patients. (D) eGFR at diagnosis by year in pediatric patients. (E) Kaplan–Meier survival curves of time to kidney failure/death event on the basis of age at diagnosis. (F) Scatter plot of eGFR at diagnosis against age at diagnosis for patients with IgA nephropathy. Reference lines showing rates of decline that reach eGFR=15 by age-sex standardized life expectancy of 81 years. Patients below a reference line will reach an eGFR of 15 ml/min per 1.73 m² before 81 years at the reference line rate of loss of eGFR. (G) Percentage of patients who will reach kidney failure during life expectancy on the basis of their eGFR at diagnosis. Life expectancy is based on year of birth and sex. IQR, interquartile range; RaDaR, UK National Registry of Rare Kidney Diseases.

Figure 2

Kaplan–Meier survival curves of time to kidney failure/death event in population 1. (A) Using total follow-up time-averaged proteinuria. (B) Using 24-month time-averaged proteinuria. 0.44 g/g=50 mg/mmol; 0.88 g/g=100 mg/mmol; 1.76 g/g=200 mg/mmol.

Figure 3

Kaplan–Meier survival curves of time to kidney failure/death event in population 4. (A) Using 6–12-month time-averaged proteinuria. (B) Using 6–24-month time-averaged proteinuria. 0.88 g/g=100 mg/mmol; 1.76 g/g=200 mg/mmol.

Figure 4

Forest plots of population 4. (A) Percentage of change in proteinuria at 6–12-month time-averaged proteinuria versus 6–30-month eGFR slope. (B) Percentage of change in proteinuria at 6–24-month time-averaged proteinuria versus total eGFR slope. (C) Percentage of change in proteinuria at 6–24-month time-averaged proteinuria versus hazard ratio of kidney failure/death event. (D) 6–30-month eGFR slope versus 5-year kidney survival rate. CI, confidence interval.