Is Regression of Chronic Nephropathies a Therapeutic Target?

[摘要] Most 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.

[学科分类] 泌尿医学

[关键词] Bone marrow necrosis;Sickle cell disease;Hyperhemolysis syndrome