Progression to end-stage renal disease is common in chronic nephropathies, independent of the initial insult. While genetic factors may contribute to susceptibility and progression of renal disease, proteinuria has been documented as an independent predictor of outcome. Reduction of urinary protein levels by restoration of glomerular sieving function with renin-angiotensin system (RAS) blockers has been shown to limit renal function decline in individuals with non-diabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been observed in experimental animals and even in humans. In animal models, regression of glomerular structural changes is associated with remodeling of glomerular architecture. This review briefly describes our understanding of the mechanism of renal disease progression, the therapeutic advantages of ameliorating glomerular sieving dysfunction and proteinuria of RAS inhibitors and how remission/regression of renal injury can be achieved with multifactorial interventions.

1.
Zoja C, Abbate M, Remuzzi G: Progression of chronic kidney disease: insights from animal models. Curr Opin Nephrol Hypertens 2006;15:250-257.
2.
Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006;116:288-296.
3.
Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN group (gruppo Italiano di studi epidemiologici in nefrologia). Lancet 1997;349:1857-1863.
4.
Ruggenenti P, Perna A, Gherardi G, et al: Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. gruppo Italiano di studi epidemiologici in nefrologia (GISEN). Ramipril efficacy in nephropathy. Lancet 1998;352:1252-1256.
5.
Ruggenenti P, Perna A, Remuzzi G: ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril efficacy in nephropathy. J Am Soc Nephrol 2001;12:2832-2837.
6.
Catapano F, Chiodini P, De Nicola L, et al: Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression. Am J Kidney Dis 2008;52:475-485.
7.
Mann JF, Schmieder RE, McQueen M, et al: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-553.
8.
Palmer SC, Mavridis D, Navarese E, et al: Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015;385:2047-2056.
9.
Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal diseases. Lancet 2001;357:1601-1608.
10.
Ruggenenti P, Perna A, Benini R, et al: In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN group. Gruppo Italiano studi epidemiologici in nefrologia. J Am Soc Nephrol 1999;10:997-1006.
11.
Remuzzi A, Gagliardini E, Sangalli F, et al: ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease. Kidney Int 2006;69:1124-1130.
12.
Remuzzi A, Sangalli F, Macconi D, et al: Regression of renal disease by angiotensin II antagonism is caused by regeneration of kidney vasculature. J Am Soc Nephrol 2016;27:699-705.
13.
Sagrinati C, Netti GS, Mazzinghi B, et al: Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J Am Soc Nephrol 2006;17:2443-2456.
14.
Benigni A, Morigi M, Rizzo P, et al: Inhibiting angiotensin-converting enzyme promotes renal repair by limiting progenitor cell proliferation and restoring the glomerular architecture. Am J Pathol 2011;179:628-638.
15.
Rizzo P, Perico N, Gagliardini E, et al: Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat. Am J Pathol 2013;183:1769-1778.
16.
Romagnani P, Lasagni L, Remuzzi G: Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol 2013;9:137-146.
17.
Ruggenenti P, Perticucci E, Cravedi P, et al: Role of remission clinics in the longitudinal treatment of CKD. J Am Soc Nephrol 2008;19:1213-1224.
18.
Vegter S, Perna A, Postma MJ, et al: Sodium intake, ACE inhibition, and progression to ESRD. J Am Soc Nephrol 2012;23:165-173.
19.
Perico N, Amuchastegui SC, Colosio V, et al: Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. J Am Soc Nephrol 1994;5:1139-1146.
20.
Parving HH, Lehnert H, Bröchner-Mortensen J, et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-878.
21.
Ruggenenti P, Fassi A, Ilieva AP, et al: Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-1951.
22.
Ruggenenti P, Porrini E, Motterlini N, et al: Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes. J Am Soc Nephrol 2012;23:1717-1724.
23.
Schievink B, Kröpelin T, Mulder S, et al: Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes. Diabetes Obes Metab 2016;18:64-71.
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