Renoprotection with Anti-Hypertensives: Reduction of Proteinuria and Improvement of Oxygenation via Inhibition of the Renin-Angiotensin System

Abstract

Hypertension is a common cause of chronic kidney disease (CKD) and even more common sequelae of CKD. While strict control of blood pressure is essential to preserve residual renal function, numerous clinical trials have demonstrated that inhibitors of the renin-angiotensin system (RAS), i.e. angiontensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), reduce the progression of CKD. These studies have examined type I and type II diabetic as well as non-diabetic nephropathies, utilizing end points such as serum creatinine, glomerular filtration rate, time to end-stage renal disease (ESRD), and death. These observations suggest that drugs blocking the RAS offer advantages beyond lowering blood pressure in diabetic and non-diabetic CKD. Therefore, guidelines recommend antihypertensives that block RAS in patients with CKD.Previous studies emphasized amelioration of glomerulosclerosis induced by glomerular hypertension as a renoprotective mechanism of inhibition of RAS. It should also be noted that progression to ESRD is mediated by two final common pathways; tubulointerstitial injury induced by proteinuria, and chronic hypoxia in the tubulointerstitium. Recent research indicates that reduction of proteinuria and improvement of oxygenation of the kidney are crucial mechanisms by which inhibition of RAS mediates renoprotection providing additional rationale for the use of ACEi and ARB to protect the kidney.

Circulating Renin Angiotensin System in Childhood Chronic Renal Failure: Marked Increase of Angiotensin-(1–7) in End-Stage Renal Disease

“…Experimental and clinical data have shown that Renin-Angiotensin System (RAS) is clearly involved in the pathogenesis of renal diseases (2,3). Acting on angiotensinergic type 1 (AT 1 ) receptors, Angiotensin (Ang) II induces progressive kidney injury via multiple mechanisms, including intraglomerular hypertension, sodium and water retention, stimulation of fibrogenic mediators, enhanced free radical formation, and contraction of mesangial cells (3,4). Moreover, clinical trials have demonstrated that RAS inhibitors, angiotensin-converting enzyme inhibitors (ACEi) and AT 1 receptor blockers reduce the rate of progression of CRF to ESRD (5,6).…”

Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

“…A large number of prospective, randomized, controlled studies have demonstrated the beneficial effects of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). These studies are covered in detail in our previous overview but, taken together, they ascribe the profound beneficial effects of blockade of RAS to reno-protection that goes beyond mere BP reduction (11). In particular, Weinberg et al reported that the BP-lowering effects of an ARB, candesartan cilexetil (approved dosage range in Japan up to 12 mg/day), reached a plateau when doses were increased to 96 mg/day.…”

“…Although HIF stimulation holds promise as a future therapy, at present the best modality for the treatment of kidney disease is blockade of the RAS (11). One important mechanism of the BP-independent renoprotective effect of this blockade is the preservation of peritubular capillary perfusion.…”

Pathophysiology of Arterial Hypertension: Insights from Pediatric Studies

“…Ang II constricts precapillary arterioles, leading to increased blood pressure, and also promotes renal sodium retention, which, in turn, causes expansion of circulating volume [22,23]. However, if this alteration is sustained, it will probably cause glomerular injury and an accelerated loss of kidney function over time [79]. At renal site, the locally produced Ang II constricts the efferent more than the afferent arteriole [22,23,81].…”