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Chronic Renal Diseases: Renoprotective Benefits of Renin–Angiotensin System Inhibition

Giuseppe Remuzzi, MD; Piero Ruggenenti, MD; and Norberto Perico, MD
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From Mario Negri Institute for Pharmacological Research, Bergamo, Italy.

Requests for Single Reprints: Giuseppe Remuzzi, MD, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy; e-mail, gremuzzi@marionegri.it.

Current Author Addresses: Drs. Remuzzi, Ruggenenti, and Perico: Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.

Ann Intern Med. 2002;136(8):604-615. doi:10.7326/0003-4819-136-8-200204160-00010
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Progression to renal parenchymal damage and end-stage renal disease, which seems to be largely independent of the initial insult, is the final common pathway for chronic, proteinuric nephropathies in animals and humans. The key event is enhanced glomerular capillary pressure; this impairs glomerular permeability to proteins and permits excessive amounts of proteins to reach the lumen of the proximal tubule. The secondary process of reabsorption of filtered proteins can contribute to renal interstitial injury by activating intracellular events, including upregulation of the genes encoding vasoactive and inflammatory mediators. Both interstitial inflammation and progression of disease can be controlled by such drugs as angiotensin-converting enzyme inhibitors, which strengthen the glomerular permeability barrier to proteins and thereby limit proteinuria and filtered protein-dependent inflammatory signals. Clinical data strongly suggest that remission can now be achieved in some patients with chronic renal disease. Because of the current lag time between starting treatment and remission, however, a substantial proportion of patients still progress to end-stage renal disease before renal function begins to stabilize. A multimodal approach that centers on reducing or removing all risk factors associated with the progression of renal disease may decrease the time to remission of the disease for most patients with proteinuric nephropathies.


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Figure 1.
Effect of increased glomerular permeability to proteins on progressive renal injury.TGF-β

Compensatory glomerular hemodynamic changes in response to nephron loss caused by the original renal insult lead to increased intraglomerular capillary pressure, which impairs the size-selective function of the glomerular permeability barrier and causes protein ultrafiltration. Excessive reabsorption of proteins as a consequence of the increased glomerular permeability results in protein accumulation in proximal tubular cells. Congestion of endolysosomes and endoplasmic reticulum in proximal tubular cells may trigger the activation of genes encoding vasoactive and inflammatory mediators (endothelin, RANTES [regulated upon activation, normal T-cell expressed and secreted], monocyte chemoattractant protein-1, and other cytokines). In addition, enhanced generation of transforming growth factor-β ( ) causes tubular cell hypertrophy and collagen type IV production. Tubular cells may also become activated to transdifferentiate into myofibroblasts. Release of excessive vasoactive and inflammatory substances from the proximal tubular cells into the interstitium contributes to interstitial inflammation and fibroblast proliferation, eventually inducing increased synthesis of extracellular matrix and renal scarring. IGF-I = insulin-like growth factor-I; NF-κB = nuclear factor-κB.

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Figure 2.
Limiting protein traffic prevents progression of renal disease in animals.MWF/ZtmP

In experimental diabetes among rats with a remnant kidney and male Munich Wistar Fromter/Ztm ( ) rats (all animal models in which progressive proteinuria and renal injury develop with time), inhibition of angiotensin-converting enzyme with enalapril consistently exerts antiproteinuric and renoprotective properties. * < 0.01 versus control. In the top panel, white bars represent control rats and gray bars represent rats receiving enalapril. In the bottom three panels, each circle represents an individual rat. Diabetes = streptozotocin-induced diabetes; RMR = renal mass reduction.

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Figure 3.
Mean decline in glomerular filtration rate (GFR) during the Ramipril Efficacy in Nephropathy (REIN) core and follow-up study in patients with nondiabetic chronic proteinuric nephropathies.2

Solid lines indicate ramipril therapy and the dotted line indicates conventional therapy. Black circles indicate continued ramipril therapy during the core and follow-up study; black and white squares indicate a switch in treatment from conventional therapy (during the core study) to ramipril (during the follow-up study). The decline in GFR (in mL/min per 1.73 m per month) was significantly lower during the follow-up study than during the core study in the patients originally randomly assigned to ramipril or to placebo plus conventional antihypertensive therapy. The GFR was better preserved and the number of renal outcome events (for example, end-stage renal failure) was lower in patients receiving ramipril during the core and follow-up studies than in those who originally received conventional antihypertensive therapy and switched to ramipril in the follow-up phase.

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