Is regression of chronic nephropathies a therapeutic target?

M ost kidney diseases lead to progressive deterioration of renal function, but the rate of progression differs among different disease types and even among individual patients with the same disease. Experimental studies and clinical research over the last few decades have identified several plausible mechanisms for progression of renal disease in various animal models and in human disease. These observations have led directly to studies establishing the fact that loss of renal function can be limited by certain antihypertensive medications (1). Thus, drugs that counteract the action of angiotensin II (AII)—the angiontensin-converting enzyme (ACE) inhibitors and the AII receptor antagonists—modify glomerular hemodynamics, lower proteinuria, and slow the rate of disease progression (2). Whether these drugs given in higher doses than those required to normalize BP can not only slow or halt progresssion but also induce regression of established glomerulosclerosis and tubular interstitial lesions has been debated. Evidence of reversal of proteinuria and glomerulosclerosis by combining a low-protein diet with an ACE inhibitor was first provided by Marinides et al. in 1990 in the puromycin aminonucleoside rat model (3). Ten years later, attention was again drawn to this topic by the work of Ma et al. (4). Although at that time glomerular structural changes were still considered irreversible, these authors showed regression of glomerulosclerosis in aging rats given an AII receptor antagonist. In this study, reversal of glomerular and vascular lesions was associated with modulation of plasminogen activator inhibitor-1 (PAI-1). The efficacy of AII antagonism in inducing regression of structural changes has also been demonstrated in a genetic model of progressive kidney disease, the male Munich Wistar Fromter (MWF) rat (5,6). In these rats, which develop proteinuria and glomerulosclerosis spontaneously with age, combined treatment with an ACE inhibitor and an AII receptor antagonist induced complete regression of proteinuria and favorably affected glomerulosclerosis. Thus, glomerular structural changes were ameliorated in those glomeruli with sclerosis involving 25% of the tuft area, while more extensive lesions remained unaltered. Interestingly, although GFR was not improved by treatment, the glomerular ultrafiltration coefficient increased (5). Recently, similar observations have also been reported in the renal ablation model by Adamczak and coworkers (7,8). In this classical model of glomerular disease progression, delayed treatment with an ACE inhibitor induced partial reversal of glomerular as well as interstitial and vascular lesions. Reversal of glomerular structural lesions was associated with remodeling of glomerular capillary microvasculature, as estimated by morphometric analysis, with a reduction in mean glomerular volume and reversal of the increase in total capillary surface area observed after renal mass ablation (8). Despite the beneficial effect of treatment on glomerulosclerosis in these animals, plasma creatinine levels did not decrease. In this issue of JASN, Ma and coworkers (9) report the results of a 4-wk trial of ACE inhibition and/or AII receptor antagonism, in subtotally nephrectomized rats, with treatment initiated 8 wk after induction of renal damage when extensive functional and structural changes had already developed. Following both treatments, or several combinations of them, sclerotic changes numerically decreased in only 4 wk from biopsy (8 wk) to autopsy (12 wk). This effect was attributed to the significant decrease in tissue inhibitor of metalloproteinase (TIMP-1). The limited effect on glomerular sclerosis was associated with reduced proteinuria, supporting the hypothesis that whenever a treatment is effective in reducing protein excretion, it is also effective in inducing regression of glomerulosclerotic changes. Evidence that regression of glomerulosclerosis can occur emerges also from clinical observations. In diabetic nephropathy, Mauer and coworkers have demonstrated that ten years after pancreas transplantation, signs of diabetic glomerulopathy were effectively reduced, likely as a consequence of normalization of hyperglycemia (10). However, renal function continued to deteriorate. In this context the results of the Ramipril Efficacy in Nephropathy (REIN) study (11) in proteinuric nondiabetic nephropathies are of some interest. Among 78 patients treated with the ACE inhibitor, 10% exhibited an increase in baseline GFR during 6 yr of continued treatment, indicating functional regression of renal disease. Sixteen additional patients had stabilization of GFRs. More recently, dual blockade of the renin-angiotensin system by ACE inhibitors and AII receptor antagonists up-titrated to maximum tolerated doses Published online ahead of print. Publication date available at www.jasn.org.