Retrospective studies reveal that only 13-20% of patients with IgAN will progress to end-stage renal failure (ESRF) within 10 years of biopsy diagnosis. It follows that to achieve adequate statistical power, and 5 yr trial using outcome measures of efficacy that are based on a declining GFR would require an enormous patient sample. Further, a majority of patients with IgAN are not at risk of developing ESRF, and thus, would be needlessly subjected to treatment. A major objective of this proposal therefore, is to identify the subset of patients who are at risk of ESRF, and to target it for future trials of therapy. To do this we propose to recruit 30 patients with IgAN of less equal to 3 year duration and to subject them to longitudinal study for 5 years. We will use a novel approach that we have devised to quantitate the extent and course of glomerular injury in humans, one which is based on a combination of physiological and morphometric techniques and mathematical modelling. We will perform serial determinations of GFR and its determinants, the sieving coefficients of polydisperse Ficoll, and a morphometric analysis of glomeruli and the interstitium in two biopsies separated by an interval of 304 yrs. Novel mathematical models will be used to compute intrinsic properties of glomerular capillary walls, including: - hydraulic permeability, filtration surface area, Kf, and the density and distribution of effective radii of functional pores. When derived from sieving of Ficoll, a rigid and spherical polymer of sucrose, the computed pore radii should replicate those encountered by endogenous proteins as they cross the glomerular barrier. In an effort to link the magnitude of the filtered protein load and interstitial abnormalities, respectively the strongest two predictors of progression to ESRF in IgAN, we will also estimate serially the delivery into urine of a chemotactic lipid product of protein-overloaded proximal tubules. We will then attempt to relate the delivery rate of this chemo- attractant for macrophages to interstitial cellularity and collagenization. At the end of the period of observation, we will use a novel adaptation of the technique of principal components analysis and canonical correlations to determine the strength of the relationships among the continuous variables, both individually an in groups (e.g. filtration capacity, barrier function, tubule protein overload and abnormalities of glomerular and interstitial structure). Our primary goal is to optimize the design for a future trial of therapy in IgAN by (i) defining the most sensitive outcome measures, whether functional or morphological, of a progressive renal injury; (ii) predicting from initial or early findings the subset of patients who are destined to progress, so that they can be targeted for therapy; and (iii) comparing the longitudinal findings in patients randomized to antiproteinuric treatment with enalapril to those randomized to a placebo, and to then perform an analysis of statistical power. A secondary goal is to elucidate the determinants of progression in the subset of patients who exhibit evidence of either increasing impairment of ultrafiltration capacity or ongoing destruction of nephrons during the period observation.
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