Endothelin-1 (ET-1), a potent endothelial growth–promoting and vasoconstrictor peptide, has been shown to play a central role in promoting proteinuria, a marker for renal injury, and glomerulosclerosis.36 ET-1 production can be enhanced by a variety of factors, including Ang II, aldosterone, reactive oxygen species, hypertension, and inflammation. ET-1–binding sites are present in podocytes, structural cells that line the glomerular filtration barrier, and Ang II, which induces renal ET-1 synthesis, can foster podocyte disruption and, in turn, glomerulosclerosis. In rats with experimentally induced microalbuminuria, which display pathologic features of renal injury similar to that seen in humans, the administration of telmisartan for 22 weeks yielded significant declines in intra-renal Ang II levels and markers for podocyte injury compared with hydralazine or placebo administration.37 These findings imply that Ang II blockade could slow the transition from microalbuminuria to overt nephropathy independent of changes in BP by blocking the growth-promoting and vasoconstricting actions of intrarenal Ang II, perhaps through the attenuation of ET-1 synthesis.
A study using cultured mouse tissue investigated how Ang II inhibition affects the interaction between podocytes and glomerular endothelial cells.38 Supernatant from normal mouse podocytes enhanced the sprouting of glomerular endothelial cells, whereas supernatant from mice with injured podocytes decreased it. This effect was associated with vascular endothelial growth factor A and angiopoietin-1 downregulation in the injured podocytes, a process that was reversed with administration of the ARB losartan. Thus, losartan may have the capacity to restore the sprouting of glomerular endothelial cells, capillary remodeling, and inhibition of renal disease progression independent of BP reduction.
Although antihypertensive therapy generally slows the progression of renal dysfunction, accumulating evidence suggests that both diabetic and nondiabetic renal disease may be especially responsive to agents that block Ang II.39 Major clinical trials such as the Irbesartan in Diabetic Nephropathy Trial (IDNT),40 Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL),41 Irbesartan Microalbuminuria II trial (IRMA II),42 and Microalbuminuria Reduction With Valsartan (MARVAL)43 studies have explored the effects of Ang II blockers in the management of renal disease.
In IDNT, 1715 hypertensive patients with diabetic nephropathy received treatment with irbesartan 300 mg, amlodipine 10 mg, or placebo for an average of 2.6 years.40 Although both active treatments yielded reductions in BP that were statistically greater than those achieved with placebo, no differences were seen between the active treatment groups. The incidence of the primary end point—a composite of doubling of baseline serum creatinine concentration, development of end-stage renal disease, or all-cause mortality—was significantly reduced with ARB treatment compared with placebo (20%) or amlodipine (23%) treatment. Moreover, with irbesartan treatment, the risk of doubling serum creatinine concentrations was significantly reduced (33% and 37%) vs placebo and amlodipine, respectively. The risk for end-stage renal disease also declined with irbesartan, but the 23% reduction seen vs that obtained with amlodipine or placebo did not achieve statistical significance.
The RENAAL trial also supports the use of an ARB in the setting of diabetic nephropathy.41 This study included 1513 hypertensive patients with diabetic nephropathy who were randomized to treatment with either losartan (50–100 mg) daily or placebo for an average of 3.4 years. Despite similar between-group BP reductions, losartan treatment reduced the risk of reaching the primary end point (composite of a doubling of the baseline serum creatinine concentration, end-stage renal disease, or death) by a significant 16%, and it reduced the risks of doubling of baseline serum creatinine and of end-stage renal disease by a significant 25% and 28%, respectively, compared with placebo.
The IRMA II trial included 590 patients with type 2 diabetes and hypertension but with less severe renal disease (persistent microalbuminuria) than patients in IDNT and RENAAL.42 In this 2-year study, patients received irbesartan 150 mg or 300 mg or placebo. Throughout the study, little variation was noted in absolute BP readings among groups. During the study, the development of diabetic nephropathy (primary end point)—defined as persistent albuminuria, with a urinary albumin excretion rate >200 μg/min and 30% higher than baseline—was reached by 5.2%, 9.7%, and 14.9% of patients treated with irbesartan 300 mg, 150 mg, or placebo, respectively. Compared with placebo treatment, significant reductions in the risk for diabetic nephropathy emerged for irbesartan 150 mg (39%) and 300 mg (70%). Irbesartan 150 mg and 300 mg also yielded significant dose-dependent reductions in urinary albumin excretion levels of 24% and 38%, respectively. In this study, irbesartan appeared to exert dose-dependent renal benefits in hypertensive diabetic patients independent of BP reductions.
The 24-week MARVAL trial compared daily doses of the ARB valsartan (80 mg) with the calcium channel blocker (CCB) amlodipine (5 mg) in normotensive and hypertensive patients with diabetes mellitus and persistent microalbuminuria.43 Compared with amlodipine treatment, valsartan yielded significant reductions in the primary end point—change in urinary albumin excretion rate (UAER) from baseline to week 24. Valsartan treatment also resulted in a progressive decline in UAER, culminating in a 44% decrease at week 24, compared with an 8% decline for amlodipine. In addition, significantly more patients reverted to normoalbuminuria with valsartan (29.9%) vs amlodipine (15%). These results suggest that valsartan 80 mg mitigates UAER more effectively than amlodipine 5 mg and that this beneficial effect is, to some degree, independent of BP reductions. Other studies have shown that in the mitigation of diabetic nephropathy, the efficacy of ARBs is similar to that of ACE inhibitors.44,45