The Reninangiotensinaldosterone System And Proteinuria

It is recognized that many patients, including those with type 2 diabetes, require multiple drug therapy in order to achieve optimal blood pressure control [80]. In order to reduce the risk of progression to end-stage renal disease, this treatment regimen should include an agent that inhibits the angiotensin II type 1 receptor.

While the angiotensin converting enzyme inhibitor captopril has been shown to reduce the incidence of end-stage renal disease or death in patients with type 1 diabetes [81], similar beneficial results of angiotensin converting enzyme inhibitor therapy have not been replicated in type 2 diabetes. Studies of the effect of angiotensin converting enzyme inhibitors on proteinuria beyond blood pressure control have been relatively small and inconsistent, with some trials demonstrating a reduction in proteinuria [82-85], while others, including United Kingdom Prospective Diabetes Study (UKPDS) [80] and Appropriate Blood pressure Control in Diabetes study (ABCD) [86], failing to demonstrate these benefits beyond blood pressure control. Data in support of prevention of end-stage renal disease with the use of angiotensin converting enzyme inhibitors in patients with type 2 diabetes do not exist [80, 82-86]. When renoprotection is a goal, patients with type 2 diabetes should have an angiotensin receptor antagonist as part of their antihypertension regimen. Angiotensin receptor blockers have been efficacious in overt hypertensive type 2 diabetic nephropathy (RENAAL and IDNT), and diabetic microalbuminuria with [87] and without hypertension [88]. Agents that provide angiotensin II type-1 receptor blockade are more effective that other antihypertensive agents, even for comparable levels of blood pressure control, in reducing proteinuria and slowing progression to end-stage renal disease. In patients with type 2 diabetes, strict blood pressure control is not sufficient for maximal reduction of the decline in glomerular filtration rate. The antiproteinuric action of renin-angiotensin-aldosterone system blockade cannot be completely attributed to reduction in blood pressure [88-90]. It is common to use diuretics to potentiate the antihypertensive and antiproteinuric effect of renin-angiotensin-aldosterone system agents [91, 92].

Angiotensin II can cause endothelial dysfunction and promote vascular disease [93, 94]. Angiotensin II has receptor-mediated effects on renal hemodynamics and glomerular permeselectivity [81, 95]. Other actions are on transforming growth factor-beta-1 and plasminogen activator inhibitor (PAI) synthesis, and on inflammation via protein kinase C in mesangial and proximal tubular renal cells [96, 97]. Hyperglycemia may activate the intrarenal renin system [98] and stimulate angiotensin II production in mesangial cells [99]. It also contributes to endothelial dysfunction, probably due to decreased nitric oxide generation [100] and protein kinase C and reactive oxygen species [101].

The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study was a multinational, double-blind, randomized, placebo-controlled study that evaluated the renoprotective effects of losartan in 1513 patients with type 2 diabetes and nephropathy [89]. The primary efficacy measure was the time to first event of the composite endpoint of a doubling of serum creatinine, the onset of end-stage renal disease, or death. End-stage renal disease was defined as the need for chronic dialysis or renal transplantation. The three secondary endpoints included 1) the time to first event of cardiovascular morbidity and mortality (a composite of myocardial infarction, stroke, cardiovascular-related death, coronary or peripheral revascularization procedures, or first hospitalization for heart failure or unstable angina); 2) changes in the level of proteinuria; and 3) progression of renal disease (slope of the reciprocal of serum creatinine). The effects of losartan on proteinuria were evident at Month 3 (-29.1%, p<0.001) and persisted throughout the remainder of the mean 3.4-year follow-up: Year 1 35% and end-of study 39% (both p<0.001) [79]. Treatment with losartan resulted in a significant risk reduction of 16% in risk of the primary composite endpoint; P=0.02. The decrease in risk remained essentially unchanged after correction for blood pressure. For the components of the primary endpoint, losartan significantly reduced the risk of progression to end-stage renal disease by 29% (P=0.002), and significantly reduced the risk of doubling of serum creatinine by 25% (P=0.006). The risk of death was not significantly different between study groups. Losartan significantly reduced the risk of end-stage renal disease or death by 20%; P=0.01. There was no significant difference in the secondary composite endpoint of cardiovascular morbidity and mortality between the two treatment groups. An exception was first hospitalization for heart failure, a component of the cardiovascular composite endpoint, which was significantly reduced by 32% in the group treated with losartan; P=0.005.

The study also showed that losartan compared to the placebo significantly reduced proteinuria (the urinary albumin:creatinine ratio) by 34.3% (P<0.001), and reduced the rate of decline in renal function (as measured by the reciprocal of the serum creatinine concentration over time) by 18.5%; P=0.01. As an element of its prospective design, the RENAAL study included populations in whom the prevalence of type 2 diabetes is high, including Asian, Black, and Hispanic patients. There were no interactions between ethnicity/race and treatment benefit in the RENAAL study, indicating that the beneficial effects of treatment with losartan were applicable to the racial groups studied. The reduction of proteinuria in the RENAAL study accounted for approximately one-half of the effect of losartan on the reduction of risk of end-stage renal disease: when proteinuria was adjusted as a time-varying covariant, the risk reduction for end-stage renal disease was reduced from 28.1 to 14.1%.

Thus, reduction of proteinuria does not completely explain the impact of intervention on outcomes such as end-stage renal disease. However, reduction of proteinuria must remain an important consideration when treating patients with type 2 diabetes and nephropathy. Furthermore, future studies in this patient group should include reduction of risk for end-stage renal disease or death as the treatment goal [79].

The Irbesartan Diabetic Nephropathy Trial (IDNT) was a multinational, randomized, double-blind, placebo-controlled study that evaluated the renoprotective effects of irbesartan compared to amlodipine or conventional antihypertensive therapy in 1715 hypertensive patients with type 2 diabetes and nephropathy [90]. The primary efficacy measure was the time to first event of the composite endpoint of a doubling of serum creatinine, end-stage renal disease, or death. End-stage renal disease was defined as the need for chronic dialysis, renal transplantation, or a serum creatinine of > 6 mg/dL. The secondary efficacy measure was the time to first event of the composite endpoint of death from cardiovascular causes, non-fatal myocardial infarction, hospitalization for heart failure, a permanent neurologic deficit caused by cerebrovascular event, or lower limb amputation above the ankle. Treatment with irbesartan significantly reduced the risk of reaching the composite primary endpoint by 20% compared to placebo (P=0.02), and by 23% compared to amlodipine (P=0.006); the effect was independent of blood pressure. Irbesartan significantly reduced the risk of doubling of serum creatinine by 33% compared to placebo (P=0.003), and by 37% compared to amlodipine (P<0.001). The risk of end-stage renal disease and death were not significantly different between study groups. There were no significant differences among the treatment groups in the secondary composite cardiovascular outcome.

Some researchers believe that doses of angiotensin converting enzyme inhibitors or angiotensin receptor blockers higher than those needed for blood pressure optimization should be employed to achieve additional reduction of urine protein excretion [102]. In the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (iRMA-2) study, the 300-mg (70%, p <0.001), but not the 150-mg (39%, P=ns) dose of irbesartan was associated with a statistically significant risk reduction in progression from incipient to overt diabetic nephropathy (urinary albumin excretion rate > 200 microg/min and at least 30% higher than baseline) [87].

Combination angiotensin converting enzyme inhibitor - angiotensin receptor blocker therapy has been suggested, on the theory that it is advantageous to reduce the amount of angiotensin II available for binding to the angiotensin type 1 receptor, and to block the binding of available angiotensin II (e.g., what has escaped angiotensin converting enzyme inhibition by being produced by alternative pathways such as chymase) to the receptor site. Concomitant use of an angiotensin type 1-selective angiotensin receptor blocker might completely block the reduced level of angiotensin II that reaches receptor [97, 103-106]. For example, in a study of 199 patients with hypertension and type 2 diabetes who received 12 weeks of monotherapy with candesartan 16 mg daily or lisinopril 20 mg daily followed by 12 weeks of monotherapy or combination treatment, mean (95% confidence interval) reductions in diastolic blood pressure were 9.5 mm Hg (7.7-11.2 mm Hg, p<0.001) and 9.7 mm Hg (7.911.5, p<0.001), respectively, and in urinary albumin:creatinine ratio were 30% (15-42, p<0.001) and 46% (35-56, p<0.001) for candesartan and lisinopril, respectively. At 24 weeks the mean reduction in diastolic blood pressure with combination treatment (mean 16.3 mm Hg, 13.6-18.9, p<0. 001) was significantly greater than that with candesartan (10.4 mm Hg, 7.7-13.1, p<0.001) or lisinopril (mean 10.7 mm Hg, 8.0 mm Hg to 13.5 mm Hg, p<0.001). Furthermore, the reduction in urinary albumin:creatinine ratio with combination treatment (50%, 36-61, p<0.001) was greater than with candesartan (24%, 0-43, P=0.05) or lisinopril (39%, 20-54, p<0.001) monotherapy [107].

It remains unclear whether the demonstrated effects of combined angiotensin receptor antagonists and angiotensin converting enzyme inhibitors are a result of greater blood pressure reduction and or the effect of combined therapy on the renin-angiotensin-aldosterone system [108]. More studies are necessary before conclusions can be reached.

Although one might postulate that there would be an advantage to inhibiting renin [109], current renin inhibitors are large molecules and are limited by their poor bioavailability.

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