Microvascular rarefaction and hypertension in the impaired recovery and progression of kidney disease following AKI in preexisting CKD states

Abstract

Acute kidney injury (AKI) is a major complication in hospitalized patients and is associated with elevated mortality rates. Numerous recent studies indicate that AKI also significantly increases the risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), hypertension, cardiovascular disease, and mortality in those patients who survive AKI. Moreover, the risk of ESRD and mortality after AKI is substantially higher in patients with preexisting CKD. However, the underlying mechanisms by which AKI and CKD interact to promote ESRD remain poorly understood. The recently developed models that superimpose AKI on rodents with preexisting CKD have provided new insights into the pathogenic mechanisms mediating the deleterious interactions between AKI and CKD. These studies show that preexisting CKD impairs recovery from AKI and promotes the development of mechanisms of CKD progression. Specifically, preexisting CKD exacerbates microvascular rarefaction, failed tubular redifferentiation, disruption of cell cycle regulation, hypertension, and proteinuria after AKI. The purpose of this review is to discuss the potential mechanisms by which microvascular rarefaction and hypertension contribute to impaired recovery from AKI and the subsequent progression of renal disease in preexisting CKD states.

Keywords: acute kidney injury; chronic kidney disease; hypertension; microvascular rarefaction.

Fig. 1.

Proposed mechanisms by which acute kidney injury (AKI) and chronic kidney disease (CKD) interact to impair recovery from AKI and accelerate the progression to end-stage renal disease (ESRD). Impaired recovery from AKI in preexisting CKD states is manifested by a greater percentage of tubules that fail to redifferentiate, which enhances nephron loss and tubulointerstitial fibrosis (TIF), as well as augmented microvascular rarefaction (indicated by black boxes). The potential mechanisms by which CKD–AKI interactions hinder tubule redifferentiation and promote capillary rarefaction are indicated by the dashed box. The presence of hypertension and impaired renal blood flow (RBF) autoregulation in CKD states alters peritubular capillary size and intracapillary forces that may synergize with AKI-induced endothelial injury to promote pericyte dysfunction and detachment, increase renal immune cell infiltration, and promote loss of capillaries. Moreover, tubule metabolic stress after AKI in preexisting CKD states may result in hypoxia, which could hinder normal cellular repair mechanisms. An important unanswered question is whether microvascular rarefaction drives failed tubule redifferentiation or vice versa. The progression of renal injury following AKI in preexisting CKD states is due to mechanisms that are independent of AKI. We propose that the development of hypertension following AKI in CKD states has a major role in the subsequent progression to ESRD. Augmented renal microvascular rarefaction and nephron loss both significantly increase the risk of hypertension. Even modest increases in blood pressure (BP) in the presence of CKD-associated impaired RBF autoregulation greatly increase the risk of barotrauma-mediated glomerulosclerosis (GS) and TIF, which could explain the rapid progression to ESRD in clinical AKI-CKD populations. Black boxes indicate processes involved in the impaired recovery from AKI, while red boxes indicate processes involved in the progression of CKD.