In an 8-year longitudinal study of Pima Indians with type 2 diabetes and nephropathy, we used statistical techniques that are novel and depend on minimal assumptions in order to compare longitudinal measurements of GFR. Individuals enrolled with new-onset microalbuminuria either progressed to macroalbuminuria (progressors, n=13) or did not progress (non-progressors, n=13) during follow-up. Subjects with new-onset macroalbuminuria at screening were also followed (n=22). Patients had their GFR determined serially by urinary iothalamate clearances (average 11 clearances; range 6-19). GFR courses of individuals were modeled using an adaptation of smoothing and regression cubic B-splines. Group comparisons were based on 5-component vectors of fitted GFR values using a permutation approach to a Hotelling's T² statistic. GFR profiles of initially microalbuminuric progressors differed significantly from those of non-progressors (P=0.003). There were no significant baseline differences between progressors and non-progressors with respect to any measured clinical parameters. The course of GFR in the first 4 years following progression to macroalbuminuria in initially microalbuminuric subjects did not differ from that in newly screened macroalbuminuric subjects (P=0.27). Without imposing simplifying models on the data, the statistical techniques used demonstrate that the courses of decline of GFR in definable subgroups of initially microalbuminuric diabetic Pima Indians, although generally progressive, follow distinct trajectories that are related to the extent of glomerular barrier dysfunction, as reflected by the evolution from microalbuminuria to macroalbuminuria.