Renal microvascular dysfunction, hypertension and CKD progression

Abstract

Purpose of review: Despite apparent blood pressure (BP) control and renin-angiotensin system (RAS) blockade, the chronic kidney disease (CKD) outcomes have been suboptimal. Accordingly, this review is addressed to renal microvascular and autoregulatory impairments that underlie the enhanced dynamic glomerular BP transmission in CKD progression.

Recent findings: Clinical data suggest that failure to achieve adequate 24-h BP control is likely contributing to the suboptimal outcomes in CKD. Whereas evidence continues to accumulate regarding the importance of preglomerular autoregulatory impairment to the dynamic glomerular BP transmission, emerging data indicate that nitric oxide-mediated efferent vasodilation may play an important role in mitigating the consequences of glomerular hypertension. By contrast, the vasoconstrictor effects of angiotensin II are expected to potentially reduce glomerular barotrauma and possibly enhance ischemic injury. When adequate BP measurement methods are used, the evidence for BP-independent injury initiating mechanisms is considerably weaker and the renoprotection by RAS blockade largely parallels its antihypertensive effectiveness.

Summary: Adequate 24-h BP control presently offers the most feasible intervention for reducing glomerular BP transmission and improving suboptimal outcomes in CKD. Investigations addressed to improving myogenic autoregulation and/or enhancing nitric oxide-mediated efferent dilation in addition to the more downstream mediators may provide additional future therapeutic targets.

FIGURE 1

An overview of the pathogenesis of CKD progression. Although there is considerable interaction between BP-dependent and BP-independent initiating mechanisms, BP-dependent mechanisms predominate in hypertensive CKD states. BP-independent mechanisms may modulate hypertensive injury and also contribute to CKD progression in normotensive states. AR, autoregulation; BP, blood pressure; CKD, chronic kidney disease; NO, nitric oxide; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species.

FIGURE 2

(a) Summary of renal autoregulatory patterns obtained in rats with intact kidneys and normal autoregulation, vasodilated vascular bed and normal autoregulation (i.e. uninephrectomy) and vasodilated vascular bed and impaired autoregulation (i.e. 5/6 renal ablation model of CKD). Reproduced with permission from [49]. (b) Compilation of data obtained in our laboratory which demonstrates that the relationship between renal injury and average SBP parallels that of renal autoregulatory function in experimental rodent models of hypertension. Minimal injury is seen in SHR with intact autoregulation despite severe hypertension. Injury in the salt-sensitive SHRsp administered a high NaCl diet occurs at BPs that exceed the autoregulatory capacity, whereas the 5/6 renal ablation model, with impaired autoregulation, exhibits a much lower BP threshold for hypertensive injury than normal or SHR kidneys. CKD, chronic kidney disease; SHR, spontaneously hypertensive rat; SHRsp, stroke-prone spontaneously hypertensive rat. Reproduced with permission from [27].

FIGURE 3

Overview of the mechanisms regulating renal blood flow (RBF) autoregulation and glomerular BP transmission. Changes in the oscillating SBP are sensed and responded to by the myogenic mechanism. The ambient preglomerular tone is also influenced by neurohumoral agents, such as nitric oxide and angiotensin II. The dynamic autoregulation of RBF occurs at frequencies below the oscillating SBP (~6 Hz in rat) and includes a faster myogenic (~0.25 Hz) and a slower tubuloglomerular feedback (~0.04 Hz) component. BP, blood pressure; TGF, tubuloglomerular feedback. Reproduced with permission from [27].

FIGURE 4

Compilation of data obtained in our laboratory which illustrates the quantitative relationships between BP and glomerulosclerosis (GS) in rats with 5/6 renal ablation who were left untreated or received either calcium channel blockers or RAS blockade. The deleterious effects of calcium channel blockers on GS as compared to untreated or RAS blockade treated rats are evident. BP, blood pressure; DHP CCBs, dihydropyridine calcium channel blockers; RAS, renin–angiotensin system. Reproduced with permission from [49].