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Can glomerulosclerosis be reversed?

Nature Clinical Practice Nephrology volume 2, pages 290–291 (2006)Cite this article

Chronic kidney disease (CKD) is a major cause of morbidity and mortality, resulting in progressive scarring of renal parenchyma and culminating in the development of end-stage renal disease. In many other parenchymal diseases, such as left ventricular hypertrophy and atherosclerosis of coronary arteries, scarring can be at least partially reversed to restore more normal tissue structure and function. In humans, however, no new glomeruli can be generated after term birth. The apparent inexorable progression of renal scarring characteristic of CKD is postulated to start with disease-specific injury, which then activates compensatory but ultimately maladaptive changes, such as hemodynamic alterations and altered growth responses, in the remaining nephrons. Nevertheless, even advanced sclerotic glomeruli are not inert, but have ongoing cell turnover and, therefore, there is potential for modulation of these processes.

Recent data from both animals and humans have documented the potential reversibility and mechanisms of glomerulosclerosis, and examined mechanisms of glomerular remodeling.1 Interest has focused on angiotensin-converting-enzyme inhibitors (ACEIs), because of their efficacy in lowering glomerular pressure even beyond systemic pressures, by decreasing efferent arteriolar resistance. Early studies in the 5/6 NEPHRECTOMY MODEL, using delayed intervention starting at a point of established sclerosis, indicated that higher doses of ACEIs were more effective than normal antihypertensive doses in ameliorating development of glomerulosclerosis, despite having similar efficacy in normalizing systemic and glomerular blood pressures.1 In some rats, the extent and severity of sclerosis after this intervention was even less at autopsy than at biopsy 4 weeks earlier, indicating regression of glomerulosclerosis.1 More recent studies by the groups of Ritz, Remuzzi, Zatz, Chatziantoniou, and myself, have explored the mechanisms and potential for regression of glomerulosclerosis in rodent models.2,3,4,5,6,7 Ritz and co-workers sacrificed subgroups of rats at different times after subtotal nephrectomy and showed that a 4-week course of high-dose enalapril initiated 8 weeks after the initial injury decreased glomerulosclerosis, vascular lesions and tubulointerstitial fibrosis to levels lower than those seen at the start of treatment. In these studies, the number of podocytes per glomerulus was not changed by ACEI treatment, but the volume of the podocytes was increased. By contrast, mesangial and endothelial cell proliferation was reversed by an ACEI, with a corresponding reduction in glomerular volume and capillary number.3 In our recent preliminary studies in a different variant of the remnant kidney model, we have observed simplification of capillary branching in untreated sclerotic rats, with increased capillary branching occurring when ACEIs were used to induce regression of sclerosis. This observation indicates that increased capillary growth can take place when regression is induced.

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  1. Renal/Electron Microscopy Laboratory at Vanderbilt University Medical Center, Nashville, TN, USA

    Agnes B Fogo

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  1. Agnes B Fogo
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Correspondence to Agnes B Fogo.

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Fogo, A. Can glomerulosclerosis be reversed?. Nat Rev Nephrol 2, 290–291 (2006). https://doi.org/10.1038/ncpneph0200

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