Prognostic significance of persistent massive proteinuria in IgA nephropathy: 10‐year follow‐up study of 366 cases

This study was undertaken to clarify prognostic indices of a long-term clinical course in IgA nephropathy in large series. PATIENTS From 1972 to 1990, a total of 603 patients were diagnosed to have primary IgA nephropathy in our renal unit. Of these patients 366 patients were continuously followed up for 10 years or more. These patients were the subjects of this study. METHODS As predictive factors, several parameters were evaluated as follows: initial proteinuria; initial creatinine clearance (Ccr) values; initial hypertension; histological severity (eight parameters and total score); % duration of massive proteinuria (%DP); % duration of hypertension (%DH). %DP was defined as [(duration of proteinuria of 1.0g/day or more ÷ total duration of follow-up observation) × 100]. %DH was defined as [duration of hypertension ÷ total duration of follow-up observation] × 100]. As histological severity, eight parameters were evaluated according to the semiquantitative method of Pirani et al. Each of these lesions was graded from 0 to 3. A total score was defined as a total of all eight scores, graded from 0 to 24. During the 10-year follow-up observation, corticosteroid treatment was conducted in 112 patients. Most of the patients received antiplatelet drugs. Hypertensive patients were treated with antihypertensive therapy. Final outcome at 10 years since the initial renal biopsy was divided into three clinical courses as follows: a stable course was defined as no decrease of renal function for 10 years; a progressive course was defined as a decrease of 15% or more of initial Ccr values without going into HD; and haemodialysis (HD). Univariate analysis for these predictive factors was performed by using one-factor ANOVA corrected by Bonferroni/Dunn or Kruskal-Wallis test to determine the final outcome. A multivariate analysis was done by using a logistic model. RESULTS The age of the 366 patients was 33 ± 10 (range: 13–61); gender (M/F) 181/185; initial proteinuria 1.0 ± 1.0g/day (range: 0–6.6); initial Ccr values 85 ± 21 mL/min (range: 25–139); initial hypertension 63 cases (17%); total score as histological severity 7.7 ± 4.6. The final proteinuria was 0.9 ± 1.0 g/day (range: 0–5.7); final Ccr values 58 ± 38 mL/min (0–128); final hypertension 94 cases (25%); %DP 33 ± 39; %DH 18 ± 30. Numbers of patients having a stable course, a progressive course and haemodialysis were 192 (52%), 89 (25%) and 85 (23%), respectively. Clinical prognostic indices showed significant differences in age, initial proteinuria, initial Ccr, initial hypertension, %DO and %DH, respectively (P < 0.0001). Treatment with corticosteroids was significantly frequent in progressive and haemodialysis groups than a stable group (P < 0.0003). Histological prognostic indices showed significant differences in hypercellularity, active crescent, tuft adhesion, mesangial sclerosis, global sclerosis, tubular atrophy, interstitial fibrosis, vascular sclerosis and total score (P < 0.005). Multivariate analysis of clinical prognostic indices showed the highest relevance in %DP (relative risk 32.9, P < 0.0001), followed by %DH (relative risk 14.2, P < 0.0001). Multivariate analysis of histological prognostic indices showed the highest relevance in tubular atrophy (relative risk 9.2, P < 0.002), followed by interstitial fibrosis (relative risk 3.0, P < 0.05). Multivariate analysis of clinicohistological indices showed the highest relevance in %DP (relative risk 38.0, P < 0.0001), followed by %DH (relative risk 18.7, P < 0.0001). Patients with 30% or less in %DP underwent a favourable clinical course, while patients with 40% or more had a poor prognosis. %DH was one of the most reliable prognostic indices. However, there was no evidence of a turning point determining a long-term prognosis. COMMENT Thirty-three years have passed since IgA nephropathy was first reported in 1968. Many investigations have documented a long-term prognosis of the disease and predictive factors for a long-term clinical course. It is generally accepted that the renal survival rate of the disease is recognized to be 70–80% 10 to 20 years after clinical onset. Clinically, initial proteinuria and initial renal function are well related with a long-term prognosis. Histologically, interstitial fibrosis is a most reliable predictive factor for a poor prognosis as well. However, there are few reports evaluated by a large series with a long-term follow-up observation. In this study, all 366 patients have been continuously followed up for 10 years since the first renal biopsy. About 50% of the patients underwent a progressive course, with 25% of the total patients entering into chronic haemodialysis. Multivariate analyses of clinical and histological predictors at the time of the first renal biopsy indicated that not only initial proteinuria and initial renal function but also tubular atrophy and interstitial fibrosis are very important factors, as reported previously. However, in practical clinical observation, it is difficult to predict a long-term prognosis merely at the time of renal biopsy. Therefore, careful follow-up observation is needed to evaluate the disease activity. In the present study, the continuous examination of daily urinary protein excretion and blood pressure was performed during a follow-up period of 10 years. As the result, %DP of 1.0 g/day or more is clarified to be the most reliable independent predictor for a long-term prognosis, followed by %DH. Moreover, 40% or more of %DP is found to be well related with a poor prognosis. In conclusion, the most reliable, independent factor determining a long-term prognosis in IgA nephropathy is persistent massive proteinuria of 1.0 g/day or more.