Renoprotection: A Matter of Blood Pressure Reduction or Agent-Characteristics?
Journal of the American Society of Nephrology
Data from recent clinical trials show that lowering of BP reduces the rate of renal function loss in chronic renal disease. There is evidence supporting the assertion that BP lowering obtained by intervention in the renin-angiotensinaldosterone system (RAAS) has an additive renoprotective effect in both diabetic and nondiabetic renal diseases. However, to dissociate BP-dependent and non-BP-dependent action of RAAS blockade, the relevant trials are in many cases flawed by design, resulting in BP
... differences between the comparative antihypertensive strategies. This review discusses whether the relevant literature allows for the conclusion that RAAS intervention has renoprotective effects in addition to its effects on BP. In particular, the main evidence for a specific renoprotective action of RAAS blockade is provided by its consistent antiproteinuric action, which cannot completely be attributed to the reduction in BP. Indeed, other strategies that lower proteinuria without having an antihypertensive effect, such as lowering dietary protein intake or the use of nonsteroidal antiinflammatory drugs, appear to have a renoprotective effect as well. Interestingly, a consistent finding across different intervention studies is that the more proteinuria is reduced the better the kidney appears to be protected. Therefore, it is concluded that agent-characteristics of RAAS intervention (i.e., antiproteinuric properties) independently influence renal function loss in addition to its BP-lowering effect. Future studies should further explore the renoprotective benefit of non-antihypertensive intervention measures, alone and in combination with antihypertensive strategies. Antihypertensive therapy has always been the cornerstone of renoprotective intervention. Recent large trials particularly indicate that intervention in the renin-angiotensin-aldosterone system (RAAS) appears to be effective in retarding the decline of renal function loss in both diabetic and nondiabetic renal diseases. In nondiabetic patients, the AIPRI (1) and REIN (2) studies showed that angiotensin-converting enzyme (ACE) inhibitors delay the progression of renal function loss. Lewis et al. (3) showed a renoprotective effect of ACE inhibitors in type 1 diabetic patients. Moreover, two recent studies, RENAAL (4) and IDNT (5), demonstrated angiotensin-II (AngII)-receptor (type 1) antagonists to be renoprotective in type 2 diabetics. The above-mentioned trials, comprising thousands of patients, can be taken as impressive evidence for RAAS intervention to be superior to other treatment strategies. However, whether the effects of RAAS intervention are due to the specific pharmacologic RAAS blockade as such or due to their antihypertensive potency is a crucial question. This issue is still open, because in many of the above trials, the obtained BP levels were lower in the patients treated with an agent that intervenes in the RAAS compared with the control groups. The current review focuses on this particular question, that is, is renoprotection obtained by a lower BP per se, or do the specific pharmacologic properties of the agent exert an independent renoprotective effect? Reduction of BP BP is an important risk factor for renal function loss. In the MFRIT study (6), BP was a strong predictor for the development of end-stage renal failure during 16-yr follow-up in middle-aged men. The study identified a strong graded relation between both systolic and diastolic BP and end-stage renal disease. Several other studies pointed out that a more aggressive BP control is beneficial on the course of renal function loss in renal patients. In patients with diabetic nephropathy, the importance of aggressive BP reduction for renal function preservation has been demonstrated (7,8). Early on, Parving et al. (7) demonstrated in an observational study that the long-term, aggressive antihypertensive treatment retards the rate of renal function loss in type 1 diabetic patients. Type 2 diabetic patients with nephropathy were studied in the ABCD study (9). In this study of 950 patients, the presence of hypertension was associated with nephropathy. Patients with hypertension were randomized to an intensive BP target (diastolic BP, 75 mmHg) versus a moderate BP target (diastolic BP, 80 to 89 mmHg). After 5-yr follow-up, an equally stabilizing effect on GFR decline was reported in both intervention groups (10). Also, in the nonhypertensive patients in this study, a more aggressive BP control did not influence GFR, although