To clarify the natural history of IgA nephropathy and to determine important factors in the progressive loss of renal function in affected patients, 121 patients with IgA nephropathy were followed for a median of 92 months. The cumulative probability of not progressing to end-stage renal failure (that is, of renal survival) was 0.87 at 15 years after the onset of 1st symptoms and 0.86 at 10 years after presentation and biopsy. Eight percent of patients progressed to end-stage renal failure, and 12% had a greater than 20% decline in renal function. A complete remission of disease activity was seen in 12% of patients, and the remaining 68% maintained stable renal function. When the final serum creatinine was expressed as a percentage of the initial serum creatinine for each patient and compared with all other variables, a number of factors were found to affect renal outcome. Of the presenting features, increased age, family history of nephritis, longer duration of symptoms, and presence of either nephrotic-range proteinuria or hypertension were all associated, by univariate analysis, with an adverse outcome, while a history of recurrent macroscopic hematuria and infection-associated exacerbations of disease activity were associated with a favorable outcome. Multivariate analysis showed that nephrotic-range proteinuria had an independent adverse effect. Of the initial laboratory findings, by univariate analysis, the number of hyaline casts, the degree of impairment of renal function, the degree of proteinuria, raised beta globulins on serum protein electrophoresis, and serum C4 concentrations were all associated with an adverse outcome, while the severity of initial hematuria and pyuria were associated with a favorable outcome. Renal biopsy findings associated with an adverse outcome by univariate analysis include, on light microscopy, the percentage of glomeruli with global sclerosis or segmental sclerosis or adhesions, the degrees of tubular atrophy or interstitial fibrosis, interstitial inflammation and blood-vessel thickening, and, on immunofluorescence, the intensity of IgA deposition. Multivariate analysis showed independent adverse effects on renal outcome of global glomerulosclerosis, segmental glomerulosclerosis or adhesions, and a combined mesangial and capillary wall deposition of IgM. Features at final assessment or during follow-up associated with an adverse outcome include, by univariate analysis, the number of hyaline casts, the degree of impairment of renal function, the degree of proteinuria, reduced serum IgG and IGM concentrations, reduced final IgA expressed as a percentage of the initial IgA concentration, transient decreases of creatinine clearance during follow-up of > 10% or > 20%, and persistence or development of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)