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.

INTRODUCTION

End-stage renal disease (ESRD), or the permanent loss of kidney function, is a major health burden in the United States, which is associated with increased morbidity, mortality, and health care costs (51a). An emerging body of clinical data indicates that acute kidney injury (AKI) significantly increases the risk of ESRD (18, 20, 38). AKI, defined as an abrupt, but potentially reversible, loss of kidney function over a few days, is commonly observed in hospitalized patients and is associated with high mortality rates (51a). Common causes of AKI include prolonged renal ischemia, exposure to nephrotoxic agents, and sepsis (51a). Historically, the long-term renal outcome in patients surviving an episode of AKI was presumed to be good (18). However, several recent epidemiological studies indicate that AKI has major long-term consequences on kidney structure and function, morbidity, and mortality. For example, AKI substantially increases the risk of chronic kidney disease (CKD), or the permanent loss of individual nephrons, ESRD, cardiovascular disease, hypertension, and long-term mortality (16–18, 35–38, 47, 53). If AKI occurs in patients with CKD, the prognosis is significantly worse (38, 53, 66, 67). Clinical studies show that AKI accelerates the progression of established CKD and increases the risk of ESRD and mortality, above and beyond that observed in patients with either AKI or CKD (38). In light of these observations, AKI and CKD are now viewed as an interconnected clinical syndrome (18). The purpose of this review is to summarize the potential role of microvascular rarefaction and hypertension in contributing to impaired recovery from AKI in preexisting CKD states and the subsequent rapid progression to ESRD.

IMPAIRED RECOVERY AND ACCELERATED PROGRESSION OF KIDNEY DISEASE AFTER AKI IN PREEXISTING CKD STATES

Although there is strong evidence that AKI and CKD interact to promote ESRD in clinical populations, there is a paucity of animal models that recapitulate the AKI-CKD syndrome. For this reason, the development of AKI-CKD animal models that mimic clinical AKI-CKD populations has been recommended (23, 48, 74). It should be emphasized that there are numerous models being used to investigate the pathogenesis by which AKI directly leads to the permanent loss of nephrons (i.e., AKI-CKD transition) in animals without preexisting CKD (28). Moreover, several models exist in which animals are subjected to multiple AKI episodes over time to examine the subsequent mechanisms of CKD progression (28). However, only a couple of studies have examined renal function and structure several weeks after a single episode of AKI in animals with preexisting CKD associated with greater than 50% renal mass reduction (RMR) (45, 58), which is the focus of this review. We recently developed an AKI-CKD model using renal ischemia-reperfusion (IR) in rats with varying degrees of preexisting RMR to investigate whether decreased renal mass, per se, alters the severity of and recovery from IR-induced AKI (58). The surgical excision model of CKD (31) was used to create rats with different levels of normotensive RMR (75%, 50% and 0% RMR), and renal IR was performed two weeks after RMR surgery. While the severity of AKI was not different between groups, rats with 75% RMR exhibited impaired recovery four weeks after AKI, as evidenced by sustained elevations in plasma creatinine, a greater percentage of tubular epithelial cells (TEC) that failed to redifferentiate, and greater microvascular rarefaction and tubulointerstitial fibrosis (TIF) (Fig. 1). Of note, microvascular rarefaction and TIF are hallmarks of kidney disease, and the progression of CKD correlates best with the level of TIF (6, 51, 66, 67). Because the degree of injured, dedifferentiated tubules was similar among rats with different levels of RMR at 1 wk post-AKI, these data indicate that impaired recovery of injured TEC in rats with 75% RMR is manifest between weeks 1 and 4 following AKI. Evidence of impaired recovery following a single episode of AKI has also recently been reported in mice with preexisting CKD (45). It should also be noted that normotensive rats with 75% RMR spontaneously developed hypertension and proteinuria after AKI, major risk factors for CKD progression and ESRD, while those with 50% or 0% RMR did not.

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.

AUGMENTED MICROVASCULAR RAREFACTION AFTER AKI IN PREEXISTING CKD STATES

Renal microvascular damage and rarefaction are common after AKI and are thought to contribute to the AKI-CKD transition (6, 8, 9, 11, 21, 27, 30, 65, 67). We found that microvascular rarefaction was more severe in rats with preexisting CKD and was observed in close proximity to atrophic, vimentin-positive tubules 4 wk post-AKI (58). This raises the possibility that microvascular rarefaction directly impairs the ability of injured TEC to recover normal structure and function. A recent study by Kramann et al. (42), demonstrating that loss of peritubular capillaries promotes tubular injury, supports this concept. Loss of capillary density could predispose to hypoxia leading to growth arrest, oxidative stress, and aberrant cellular metabolism, which could hinder normal repair mechanisms (7, 27, 65, 67). Consistent with this concept, increased cell cycle arrest has been observed in mice with preexisting CKD during recovery from a single episode of IR-induced AKI (45).

An important, but unanswered question, is why does preexisting CKD promote capillary dropout after AKI? One possibility is altered mechanical forces within peritubular capillaries. CKD is associated with hypertension, impaired renal blood flow (RBF) autoregulation (12), endothelial dysfunction (72), inflammation (1), and increased peritubular capillary size and pressure (3, 15, 25, 34, 52). In conjunction with increased endothelial permeability and damage after AKI (5, 11, 63, 64), altered mechanical forces within peritubular capillaries could negatively impact cells that regulate capillary stability and TIF (Fig. 1). This is relevant given that pericytes, contractile cells adjoined to the outside of endothelial cells, play a major role in stabilizing capillaries, and regulating tissue fibrosis and signaling between TEC and endothelial cells (40, 41, 44, 50, 61, 67, 73). Altered mechanical forces within peritubular capillaries and impaired endothelial integrity can alter pericyte shape and function (24, 33, 60) and promote extravasation of immune cells to the interstitium and nearby TEC (33, 59, 69). Such inflammatory processes are thought to initiate or alter cellular pathways within pericytes, promote pericyte detachment, and ultimately lead to TIF (19, 26, 33, 41, 44, 46, 62, 67, 70).

Conversely, the exaggerated microvascular rarefaction after AKI in preexisting CKD states could be a result of the greater number of TEC that remain in a dedifferentiated state (Fig. 1). Such TEC are atrophic and growth-arrested but continue to secrete profibrotic and proinflammatory factors that are able to influence pericyte function and detachment (29, 66, 67). Supportive of this concept is evidence that specific injury to TEC promotes inflammation, fibrosis, and the loss of nearby capillaries (13, 67, 71). Of note, injured and dedifferentiated TEC are associated with decreased VEGF expression, which can also promote pericyte detachment and microvascular rarefaction (10, 46, 67, 71).

If the failure of more TEC to redifferentiate after AKI in preexisting CKD states is causing greater loss of capillaries, then what is driving failed TEC redifferentiation in such settings? As we have previously speculated (58, 66, 67), it is possible that the metabolic stress associated with CKD may impair the ability of injured TEC to regain normal structure and function. Alternatively, the presence of hypertension in AKI-CKD settings may also impair recovery of TEC. In the setting of hypertension and impaired RBF autoregulation in CKD states, increased renal blood pressure (BP) transmission can lead to additional, de novo, injury, which may impair the ability of previously injured TEC to recover from AKI. This concept is supported by a study in stroke-prone spontaneously hypertensive rats, in which repair of previously injured vasculature was greatly compromised by the presence of hypertension and new injury (32). De novo barotrauma-mediated injury to glomerular capillaries or peritubular capillaries could contribute to focal areas of inflammation and extracellular matrix production that may alter recovery of nearby previously injured TEC. Nevertheless, a fundamental question that remains to be answered is, does microvascular rarefaction predispose to impaired recovery of injured TEC or does the presence of more dedifferentiated TEC predispose to microvascular rarefaction?

AKI IN PREEXISTING CKD STATES PROMOTES HYPERTENSION AND CKD PROGRESSION

The TIF and loss of nephrons that result from AKI (i.e., the AKI-CKD transition) are separate processes from the subsequent progression of renal injury (43, 57, 67, 68). TIF resulting from AKI is a self-limiting process that circumscribes areas of dead tissue and results in a scar (39, 43, 67). Conversely, new pathological processes that injure cells that were either uninjured or had fully recovered from AKI are required for CKD progression (57, 67). In this respect, evidence from clinical (35) and experimental (30, 57, 58) studies showing that AKI results in hypertension is relevant, especially in preexisting CKD states.

Renal microvascular rarefaction after AKI increases the risk of hypertension by impairing the pressure-natriuresis mechanism (49, 56). Moreover, loss of additional nephrons following AKI in preexisting CKD states can diminish renal reserve and also promote hypertension (14). The development or worsening of hypertension after AKI in settings of CKD likely has major consequences (Fig. 1). Hypertension in settings of impaired RBF autoregulation increases renal BP transmission and the risk of barotrauma-mediated glomerulosclerosis (GS) (12). Of note, we found that rats with preexisting normotensive 75% RMR developed hypertension within 4 wk after AKI, and the rats with the most severe levels of hypertension within this group exhibited GS (58). In a more recent study, we found that significant levels of TIF 16 wk after IR-induced AKI in uninephrectomized rats was only observed in rats that developed hypertension, albeit modest, and GS (57). GS and TIF were minimal in rats that did not exhibit elevations in BP 16 wk after AKI. This is consistent with studies that have documented extensive levels of GS several months after AKI in uninephrectomized rats that also exhibited extensive levels of TIF (9, 22, 54, 55). Moreover, significant GS has also been observed after severe AKI in rats with intact kidneys (4), in which hypertension is likely present, although this has never been documented with BP radiotelemetry techniques. Despite the evidence to support this pathway of CKD progression after AKI, there are no studies that have addressed the role that even modest elevations in BP have in contributing to the progression of renal injury after AKI. Such studies would require careful monitoring of BP (24 h/day) via radiotelemetry for several months after AKI in rats treated with antihypertensive therapy vs. untreated rats. It is possible that modest increases in BP, even considered normotensive by current guidelines, may be the dominant factor in the progression to ESRD after AKI in preexisting CKD states. The recent evidence that AKI increases the risk of hypertension in clinical populations further supports the need for such studies (35). A better understanding of this important aspect of the AKI-CKD nexus could lead to new treatment strategies to reduce the risk of ESRD in this population.

CONCLUSIONS

Deleterious interactions between AKI and CKD are a major contributor to ESRD. The recent development of AKI-CKD models that mimic the clinical AKI-CKD syndrome will provide important insights into the underlying pathogenic mechanisms. These models show that preexisting CKD exacerbates renal microvascular rarefaction, impairs recovery of injured TEC, and alters cell cycle regulation after AKI (45, 58). Targeting these pathways may improve recovery and mitigate the subsequent rapid progression to ESRD after AKI in CKD patients. Moreover, recent studies suggest that even modest levels of hypertension after AKI in CKD states could play a major role in the subsequent progression of kidney disease. The development of additional AKI-CKD models that include preexisting hypertension, diabetes, and renal injury will provide even further insights into the clinical AKI-CKD nexus.

GRANTS

A. J. Polichnowski is currently supported by a Carl Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research, the American Heart Association (17AIREA33660433) and the NIH (C06RR0306551). The work presented in this review from A. J. Polichnowski has also been supported by grants from the Veterans Administration (IK2BX001285) and National Kidney Foundation of IL.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

A.J.P. prepared figure; drafted manuscript; edited and revised manuscript; and approved final version of manuscript.