Acute kidney injury and chronic kidney disease - Kidney International

mini review

http://www.kidney-international.org & 2012 International Society of Nephrology

Acute kidney injury and chronic kidney disease: an integrated clinical syndrome Lakhmir S. Chawla1,2 and Paul L. Kimmel2,3 1

Department of Anesthesiology and Critical Care Medicine, George Washington University Medical Center, Washington, District of Columbia, USA; 2Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, Washington, District of Columbia, USA and 3National Institute of Diabetes, Digestive, and Kidney Disorders, National Institutes of Health, Bethesda, Maryland, USA

The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function. Kidney International (2012) 82, 516–524; doi:10.1038/ki.2012.208; published online 6 June 2012 KEYWORDS: acute kidney injury; acute on chronic; acute renal failure; chronic kidney disease; progression; risk factor

Correspondence: Lakhmir S. Chawla, Department of Anesthesiology and Critical Care Medicine, George Washington University Medical Center, 900 23rd Street, NW, RILF, G-105, Washington, District of Columbia, 20037, USA. E-mail: [email protected] Received 20 October 2011; revised 13 January 2012; accepted 21 February 2012; published online 6 June 2012 516

Acute kidney injury (AKI) is responsible for approximately 2 million deaths annually worldwide.1–3 AKI is increasingly common in critically ill patients, and those patients with the most severe form of AKI, requiring renal replacement therapy, have a mortality rate of 50–80%.3 Over the past 10 years, there has been substantial progress in the field of AKI. In particular, work on consensus definitions, epidemiologic and database studies, AKI biomarkers, and the appropriate dosing of renal replacement therapy has continued at a brisk pace. The classic teaching regarding patients who survive an episode of AKI, in particular acute tubular necrosis (ATN), was that those patients achieved full or nearly full recovery.4 This notion was based on studies that followed survivors of AKI after hospital discharge.4,5 The most recent comprehensive study of AKI survivors followed 187 patients with ATN for 10 years.5 The authors concluded that for those who survived ‘renal function is adequate in most patients’.5 However, the notion that most patients with AKI return to pre-morbid renal function is contradicted by a series of small but careful clinical studies conducted over 50 years ago.6,7 ‘Good clinical recovery, which is sustained, is the rule’ was reported by Lowe6 in his study of 14 selected patients who survived an episode of oliguria or anuria associated with ATN. Three patients (of the eight who had the assessment) in this series, however, had creatinine clearance of o80 ml/min. Lowe attributed any renal dysfunction to scarring or vascular damage. Finkenstaedt and Merrill7 reported inulin clearances of o70 ml/min in 6 of the 16 patients with no evidence of renal disease before occurrence of acute renal failure (ARF) 13–76 months after the episode. They concluded that the findings demonstrated that an episode of ARF ‘resulted in more chronic renal damage than would be expected’ and that ‘subnormal renal function late in the follow-up period occurred in the majority of cases studied.’ They attributed chronic dysfunction to rupture of basement membranes with abnormal epithelial regeneration, resulting in nephron loss. Up to 2007, however, when the epidemiology of AKI survivorship was assessed, there was a lack of large longitudinal studies to assess the effects of AKI on long-term renal function.8 More recently, from 2008 through 2012, multiple observational Kidney International (2012) 82, 516–524

LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease

studies assessing unique cohorts of patients, often using large administrative databases, demonstrated that patients who survive an episode of AKI have a significant risk for progression to advanced-stage chronic kidney disease (CKD).9–14 We review data suggesting that AKI is a cause of CKD and that prevalent CKD is a cause of incident AKI, and focus on the interrelationships between these two entities. We review the potential mechanistic factors underlying links between AKI and CKD, and offer clinical considerations based on these observations. AKI AS A RISK FACTOR FOR INCIDENT CKD

Ishani et al.10 assessed a random sample of Medicare beneficiaries and found that patients diagnosed with an episode of AKI were more likely to develop end-stage renal disease (ESRD) compared with patients without a history of either AKI or CKD. In their analysis, the risk of developing ESRD was eightfold higher in those with AKI compared with patients without a history of AKI or CKD. As this study used ICD-9 diagnostic codes, it is difficult to determine the proportion of patients who suffered AKI and then progressed directly to ESRD compared with patients who suffered AKI, recovered renal function, and then progressed to ESRD.10 Lo et al.,11 by using a Kaiser Permanente database in Northern California, retrospectively studied inpatient admissions. Patients with an episode of AKI treated with dialysis were compared with patients without an episode of AKI. Patients with a history of ESRD or a preadmission estimated glomerular filtration rate (eGFR) o45 ml/min per 1.73 m2 were excluded. In this study, the investigators found that an episode of dialysis-requiring AKI was associated with a 28-fold increased risk of developing advanced CKD, and a 2-fold increase in mortality. As patients who developed ESRD within 30 days of discharge were excluded from the long-term follow-up of advanced CKD, these data are consistent with a severe form of AKI followed by renal recovery and then progression to advanced-stage CKD.11 It should be noted that some patients assessed had pre-existing CKD. Wald et al.13 conducted a population-based cohort study in Ontario, Canada of AKI patients who required in-hospital dialysis and survived free of dialysis for at least 30 days after discharge. These patients were matched with patients without AKI or dialysis therapy during their index hospitalization. Patients with AKI requiring dialysis were over three times more likely to develop ESRD compared with control-matched patients. We and colleagues at the Veterans Affairs Medical Center in Washington, DC assessed a United States Department of Veterans Affairs database to ascertain long-term renal function in over 79,000 hospitalized patients with and without AKI.12 A particular focus was on the long-term outcome in patients with a diagnosis of ATN. Patients hospitalized for acute myocardial infarction or pneumonia without AKI were designated as controls. The remaining 5404 hospitalized patients who comprised the AKI group had diagnostic codes indicating ARF or ATN. Patients with pre-existing CKD were Kidney International (2012) 82, 516–524

mini review

excluded. Over the 5-year follow-up period, renal function deteriorated over time in all groups, but with significantly greater severity in those who had ATN and ARF compared with controls. Patients with AKI, especially those with ATN, with pre-existing normal renal function were more likely than controls to enter stage 4 or 5 CKD. We found that patients who had an episode of AKI were at high risk for the development of stage 4 CKD and had reduced survival time compared with control patients.12 Our studies in AKI survivors identified advanced age, the presence of diabetes mellitus, and decreased baseline eGFR as risk factors for the progression to advanced-stage CKD.12,15 In addition to these risk factors, along with our colleagues, we recently showed that low serum albumin concentration (SAlb) is a strong predictor of poor long-term renal outcome.9 The value of the SAlb as a predictor of CKD progression is not surprising, because this parameter has been associated with poor outcomes in both the general population and in a variety of diseases including ESRD, surgical illness, and acute stroke.16–18 Low SAlb levels can be a result of nutrition-related factors and/or high levels of inflammation.19,20 As several recent studies have shown that markers of inflammation predict AKI, it is likely that the relationship between SAlb level and CKD progression is based on a complex set of factors, including those related to diet, nutrition, and catabolism, as well as increased inflammation.15,21 Collectively, these studies underscore the strong association between AKI and the future development of CKD. SEVERITY, DURATION, AND FREQUENCY OF AKI AND CKD PROGRESSION

More recently, severity of AKI has been linked to CKD progression in survivors of AKI. Ishani et al.22 assessed patients who underwent cardiac surgery, and found that the magnitude of serum creatinine concentration during the postoperative hospital course was directly linked to progression. This effect was seen in patients with AKI with previously normal renal function (de novo AKI), as well as in patients with an episode of AKI superimposed on CKD (acute on chronic renal failure).22 The magnitude of increase in serum creatinine after cardiac surgery was associated in a graded manner with increased risk of CKD progression and mortality. This same trend has been demonstrated in patients who had percutaneous coronary revascularization. James et al.23 showed that patients undergoing percutaneous coronary revascularization who had AKI were at risk for future development of ESRD. Patients with AKIN stage I AKI were over 4 times more likely to develop ESRD, whereas patients with AKIN stage II/III were over 11 times more likely to develop ESRD.23 We have similarly shown that the severity of AKI is linked to CKD progression.9 We assessed a cohort of 11,589 patients with a spectrum of AKI from RIFLE stage R through F.9 Severity of AKI, assessed by peak serum creatinine, was associated with progression to advanced CKD (Figure 1). In particular, patients who required dialysis were at much higher risk for progression to CKD than patients with less 517

mini review


b

70

50

st

st ye a

rs

th s

po

po

st po

5

m

3 1–

12

m

1

5 1–

Time

1–

ye a

on

rp

l

st po

ye a

rs

th s

po 3–

12

m

on

th s m

3 1–

po

g in ur

on

D

pr ar ye

th s

30

Tertile 3: mean eGFR79.2

80

ita

2.0

90

on

2.5

100

sp

3.0

e

Mean Scr (mg/dI)

Tertile 1 (n = 767) Tertile 2 (n = 766) Tertile 3 (n = 767)

Ho

Mean eGFR 1–5 years post tertile

3.5

Mean eGFR

a

Time

9

Figure 1 | Effect of severity of acute kidney injury (AKI) on outcomes. AKI patients who survived for 1 year. (a) Mean eGFR over time (tertiles). (b) AKI patients who survived for 1 year. Mean serum creatinine (Scr) over time (tertiles). Tertiles were defined based on Scr at 1–5 years post admission. Error bars show the 95% confidence interval at each time point.

AKI AS AN ACCELERANT OF CKD

Hsu et al.27 showed that the incident growth of the ESRD population exceeded the prevalent CKD population. The 518

1

0.8 Proportion surviving

severe AKI.9 Although it is seemingly intuitive that the severity of AKI would be associated with progression to advanced CKD, these three studies are the first to show this link.9,22,23 These findings suggest that when the severity of AKI reaches a certain threshold the course of AKI is altered, initiating a chronic, progressive disease. In addition to severity, the duration of AKI has been linked to mortality but not to CKD progression. Coca et al.24 assessed a large cohort of patients with diabetes mellitus undergoing cardiac surgery in the Veterans Administration system. Both severity and duration of AKI were linked to long-term mortality. However, the duration of AKI was not linked to CKD progression.24 Consistent with these findings, Brown et al.25 assessed a separate cohort of US Veterans after cardiac surgery and confirmed that the duration of AKI was linked to worse long-term survival. Not surprisingly, patients who sustain multiple episodes of AKI as compared with a single episode of AKI have higher likelihoods of CKD progression. Thakar et al.26 have shown, in a cohort of US Veterans with diabetes, that those who experienced two or more episodes of AKI were much more likely to progress to stage 4 CKD than patients who experienced only one episode of AKI (Figure 2).26 These data are consistent with the hypothesis that for some patients a single episode of AKI has biologic ramifications beyond the acute event, engendering an ongoing state that predisposes to the development of further injury, manifested differentially in time as worsened AKI (short-term) or the development or worsening of CKD over longer periods (Figure 3). Some patients can fully recover from their initial AKI, but subsets of AKI survivors appear to go on to experience vicious cycles of intertwined AKI and CKD.26 It is likely that the severity of renal injury along with other clinical, treatment, and host risk factors mediate such processes.

0.6

No AKI

(P < 0.0001)

1 AKI 0.4

2 AKIs 3+AKIs

0.2

0

0

20

60 40 Months of follow-up from baseline

80

100

Figure 2 | Effect of acute kidney injury (AKI) frequency on outcomes.26 Survival to stage 4 chronic kidney disease (CKD) in no AKI vs. multiple AKI episode groups.

authors hypothesized that physician-related decisions to start chronic dialysis earlier might account for this discrepancy. We believe that the more likely explanation is the marked effect of AKI on the development and progression of CKD. CKD has consistently been shown to be a significant risk factor for the development of AKI.28,29 Probable explanations include the hemodynamic instability and failure of autoregulation30 in CKD patients, the ease of detection of small changes in GFR when renal function is impaired, and a predisposition to further injury in patients with diminished renal function.31,32 These consist of at least susceptibility to nephrotoxic agents, and the effects of ongoing humoral and renal pathologic mechanisms in the setting of CKD. Unfortunately, this risk appears to be bidirectional. Ishani et al.10 showed that patients with CKD who experienced an episode of AKI were 41 times more likely to develop ESRD than patients without kidney disease, whereas patients with CKD and no episodes of AKI had an 8.4-fold higher risk compared with patients without kidney disease. The risk of Kidney International (2012) 82, 516–524


100%

AKI

Repair

Chronic

GFR

0

Time

Figure 3 | Theoretical range of outcomes after acute kidney injury (AKI). The range of possible long-term outcomes after an episode of AKI comprises the entire spectrum of the glomerular filtration rate (GFR). The final GFR is determined by the level of GFR at the time of injury, the severity and duration of the injury, and responses across several phases over time. It is envisioned that repair and chronic phases have different and variable time frames, and different magnitudes of responses. Responses during repair and chronic phases are determined by the balance of processes that result in amelioration and worsening of GFR.

developing ESRD was enhanced almost fourfold by the superimposition of AKI in CKD patients. AKI enhanced the risk almost 10-fold compared with patients without either CKD or AKI, and astonishingly was associated with greater risk of developing ESRD than those identified with CKD in the Medicare population. Similarly, Hsu et al.33 showed that patients with an eGFR o45 ml/min per 1.73 m2 who experienced an episode of dialysis-requiring AKI were at very high risk for impaired recovery of renal function. In a population-based cohort in Scotland, Ali et al.1 showed that only 64% of patients with an episode of acute on chronic renal failure had full recovery of kidney function.1 In these studies, CKD was defined by an eGFR of 460 ml/min per 1.73 m2. In addition to low baseline eGFR, patients with CKD as assessed by proteinuria are at increased risk for AKI. James et al.29 showed in a cohort of over 920,000 patients that the level of proteinuria and diminished baseline eGFR were independent risk factors for developing AKI.29 The risk of progression to CKD in patients who develop AKI is not limited to adults but affects children as well.34,35 Large pediatric cohort studies suggest that certain subsets of children (such as bone marrow transplant patients) are at high risk for CKD progression. In contrast to adults, children tend to be less burdened with chronic disease. Thus, the evidence that AKI in children puts those patients at risk for CKD suggests processes subsequent to AKI that are integral to the acute episode, as opposed to simply changes that occur in an acute on chronic disease paradigm. Hui-Stickle et al.36 assessed pediatric intensive care unit patients upon discharge from a tertiary care center. In all, Kidney International (2012) 82, 516–524

mini review

34% had either reduced kidney function or were dialysis dependent upon discharge.36 The most compelling data regarding AKI and the risk of CKD in children came from a long-term follow-up of participants in the aforementioned study conducted by Askenazi et al.37 They followed up a cohort of children for 3 to 5 years after an episode of AKI. Mortality was 79.9%, with the majority of the deaths occurring within 2 years of the AKI episode. In all, 17 of 29 patients followed up in an outpatient clinic demonstrated evidence of CKD, manifested by hyperfiltration, reduced kidney function, hypertension, or microalbuminuria.37 Although this represents a small sample, it is consistent with animal and adult human studies showing that subsets of patients who develop AKI are at high risk for developing CKD and experiencing progression. These data suggest that for some patients AKI and CKD likely coexist in an intimate but vicious cycle. This concept is supported by the fact that CKD was thought to progress in a linear manner,38 but this is not always the case. Shah and Levey39 showed that as many as one-third of patients deviated from their reciprocal creatinine slope. The African American Study of Kidney Disease and Hypertension study has delineated several different courses in patients with CKD (personal communication, Tom Greene). Some of these courses are consistent with the notion of intermittent episodes of AKI complicating CKD, with varying levels of repair occurring. An episode of AKI that results in a decrement in GFR will necessarily affect the trajectory of GFR change; the course will ultimately be determined by whether the injury is reversible (volume-related changes in GFR and filtration fraction) and by the balance between effective and maladaptive repair mechanisms (Figure 4). The exact mechanism(s) by which AKI accelerates/initiates CKD in humans are unknown. Preclinical data, however, suggest that a variety of mechanisms may be operative. MECHANISMS UNDERLYING PROGRESSION OF AKI TO CKD

An important concept for understanding the course of CKD is that the progression to ESRD occurs via processes that may be independent of the original pathology of CKD.32,40 Such concepts were originally proposed for a variety of glomerular diseases,40 after follow-up studies in patients with poststreptococcal glomerulonephritis delineated long-term sequelae41 linked to current definitions of CKD, including decrements in GFR and the persistence of proteinuria, as well as the development of hypertension. Data from animal models suggest that kidneys after episodes of injury may be susceptible to progression to CKD, which is similarly independent of the initial cause of AKI. Key constructs regarding CKD progression are based on findings from the remnant kidney model in which nephron loss leads to glomerular hypertrophy in the remaining nephrons.42 Hypothesized mechanisms underlying CKD progression include effects of systemic and intrarenal hypertension and hyperfiltration, tubular hypertrophy, and hypertension resulting in arteriosclerosis, tubulointerstitial fibrosis, and glomerulosclerosis,43–45 as well as 519

mini review


c Normal repair and regeneration

a

b

ATN Neutrophils and monocytes

Interstitium

Endothelial injury

d

Maladaptive response

Interstitial fibrosis

Zones of hypoxia

Peri-tubular blood vessels Cells and casts Depleted blood supply Cell cycle arrest Epigenetic changes

Figure 4 | Tubule cross-section. (a) Cross section of normal renal tubule with intact epithelial cells, renal interstitium, and peri-tubular blood vessels. (b) Cross section of renal tubule with acute tubular necrosis (ATN) with epithelial cell necrosis, intra-tubular cast formation, endothelial injury of peri-tubular blood vessels, and migration of monocytes and macrophages into renal interstitium. (c) Cross section of renal tubule after normal repair and regeneration showing restoration of normal renal architecture. (d) Cross section of renal tubule after severe episode of AKI, resulting in maladaptive repair. Epithelial cells have evidence of cell cycle arrest and epigenetic changes that favor a fibrosis phenotype. Renal interstitium shows evidence of fibrosis. Post-injury vascular supply is less dense than baseline. The combination of decreased blood supply and fibrosis leads to zones of hypoxia wherein the combination of decreased vascular supply and fibrosis can initiate a vicious cycle leading to ongoing fibrosis.

the effects of derangements of the endocrine response and abnormalities in circulating mediators associated with decrements in renal function. The latter may affect cell structure and function, as well as physiologic responses. In the case of normal kidneys after an episode of injury, multiple injury pathways and maladaptive processes have been identified, which may contribute to determining the course of renal function after an initial insult. Nephron loss and glomerular hypertrophy

The pathophysiology of loss of nephron mass followed by glomerular hypertrophy has been well described in animal models.43 After an episode of AKI, it is possible that significant permanent loss of nephron mass results in a clinical state comparable to that of the remnant kidney model. After subtotal nephrectomy, single-nephron GFR increases via hyperfiltration and glomerular hypertrophy. Cellular proliferation ensues, ultimately resulting in tubulointerstitial fibrosis and progressive nephron loss.32 These processes are exacerbated by high-salt and high-protein diets.46,47 Increased tubular workload predisposes nephron segments to fibrosis and senescence, which can be mitigated by protein and calorie restriction.47,48 The lessons from animal studies have been successfully translated into patient-care paradigms. As an example, a cornerstone of CKD therapy is mitigation of glomerular 520

hypertrophy and hyperfiltration via hypertension control and renin–angiotensin–aldosterone system blockade. Interstitial inflammation and fibrosis

In human CKD and in the remnant kidney model, tubulointerstitial fibrosis predominates over glomerulosclerosis.32 As a consequence, human CKD often progresses without the need for continued glomerular injury.45,49–51 Further support of a pro-fibrotic effect in the setting of reduced renal mass is provided by experiments that show that the kidneys of animals exposed to ischemia–reperfusion (I–R) injury are more predisposed to developing fibrosis if nephron loss (e.g., unilateral nephrectomy) occurs before injury.52,53 In addition, inflammation after AKI can lead to interstitial immune cell infiltration followed by interstitial fibrosis. Inflammation has been shown to be an important feature of ischemic and septic AKI.15,54–56 Animal models of ATN consistently show an interstitial neutrophil infiltrate during the acute phase of ATN, often followed by monocytic– lymphocytic infiltration in later stages.32,55,57,58 Monocytes can exacerbate injury and promote fibrosis.59 The effects of tubulointerstitial fibrosis are critical, as tubulointerstitial fibrosis injury scores predict the decline of renal function better than glomerular injury scores.60,61 Reduced renal mass impairs recovery of experimental AKI and may predispose to the development of fibrosis.32 In most models Kidney International (2012) 82, 516–524


of experimental AKI, renal tubular regeneration occurs, but depending on the severity of the initial damage the recovery is often incomplete. Areas that do not complete full recovery may develop into focal areas of fibrosis.32,55,62 Both human and animal models link severity and frequency of AKI with worsening of long-term renal function.9,22,63 Multiple episodes of I–R-induced AKI have been shown to cause CKD and tubulointerstitial fibrosis in animal models. Thus, it is conceivable that subclinical episodes of AKI could both cause and worsen CKD.32 These data are consistent with the previously cited human data showing the effect of multiple episodes of AKI to enhance CKD progression.26 Endothelial injury and vascular rarefaction

Experimental models of AKI demonstrate endothelial involvement and vascular injury. Tubular repair after injury tends to be robust, but the vascular restorative capacity after AKI is more blunted.64 Various different injury models (e.g., I–R, folate, nitric oxide synthase inhibition, and ureteral obstruction) all demonstrate diminished vascular density after injury.65–68 The loss of vascular density varies between 30 and 50%.69 The loss of vascular reserve may be one of the key components of the development of fibrosis after injury. Injured tissue that has insufficient vascular supply becomes hypoxic, potentially setting into motion a self-propagating injury cascade. Rarefaction of capillaries initiates activation of hypoxia-inducible pathways that can promote inflammation and downstream fibrosis.32 Thus, capillary rarefaction in fibrotic foci can be both a cause and an effect of tissue hypoxia, in turn leading to activation of hypoxic signaling, inflammation, and activation of factors enhancing fibrosis. In experimental models, treatment with angiogenic factors such as vascular endothelial growth factor-121 ameliorates vascular dropout and endothelial damage.54 However, these compounds are only useful in the immediate post-injury period, and do not improve vascular dropout after AKI when administered 43 weeks after the insult.32 Cell cycle and maladaptive repair

Normal repair processes involve a host of growth factors and proliferative and other signaling cascades, which must be deployed, and function in coordinated, integrated temporal, and spatial manners. These mechanisms are critical for appropriate repair and regeneration.70 Cell cycle abnormalities affect the outcome of AKI. Preclinical studies demonstrate that p21, a cyclin-dependent kinase, is a critical checkpoint effector for induction of the cell cycle.71 In preclinical models of AKI, p21 antagonism worsens AKI, whereas p21 induction improves outcomes in AKI models.72,73 Cell cycle dysfunction can have effects at the point of injury and further downstream during repair. Pathways that affect the cell cycle can also activate fibroblasts and inflammation. Selected antiinflammatory therapies have been shown to decrease the severity of AKI during its acute phase.32,74 Recently, studies Kidney International (2012) 82, 516–524

mini review

involving the cell cycle of reparative cells have shed light on such processes.72,73 When AKI is severe, the corresponding tubular injury and interstitial inflammation are associated with proliferation of tubular epithelial cells. Yang et al.63 showed that when kidney damage was accompanied by fibrosis there were large numbers of proximal tubule epithelial cells arrested in the G2/M phase of the cell cycle. In contradistinction to proliferating epithelial cells, the arrested cells produced greater levels of transforming growth factor-b1 and connective tissue growth factor. These findings suggest that in response to injury a maladaptive repair process may ensue, causing fibrosis instead of repair of tubular epithelia. Cell cycle arrest causes tubular epithelial cells to convert to a phenotype that promotes the growth and activation of fibroblasts. Interestingly, in this same study, moderate I–R injury did not produce this maladaptive process. Only severe injury with I–R or aristolochic acid activated pro-fibrotic processes. Cell arrest was mitigated by agents, such as p53 inhibitors, that affect the cell cycle, and was exacerbated by agents that prolong cell cycle arrest.63 Animal studies support the notion that fibrosis is ongoing after AKI. Bechtel et al.69 investigated mechanisms of fibrosis that were temporally remote from the initiation of kidney injury. They showed that fibrosis continues owing to a failure of fibroblasts to return to their resting state. Epigenetic factors including hypermethylation of RASAL1 gene loci were involved. Both studies by Yang et al.63 and Bechtel et al.69 implicate the pathologic role of transforming growth factor-b in promoting fibrosis.63,69 When tubular epithelial cells arrest in the G2/M phase of the cell cycle, they produce transforming growth factor-b1. If transforming growth factor-b1 secretion and activation is sustained, epigenetic changes in fibroblasts may ensue, which can transform them into tumor-like myofibroblasts that proliferate in a growth factor–independent manner.74 Altogether, cell cycle arrest and epigenetic changes represent at least two maladaptive repair mechanisms that appear to have major roles in determining the post-AKI fibrotic phenotype. As cell cycle arrest and epigenetic changes appear to be sequential in nature, they may form pathways amenable to interruption.63,73,75,76 Identification of patients and risk factors for CKD progression

To help clinicians identify AKI survivors at increased risk for CKD development and progression, along with our colleagues, we developed three multivariable models. The most accessible (and therefore clinically useful) model is based on sentinel clinical events (i.e., RIFLE stage, need for dialysis, baseline eGFR, and sAlb).9 This model performed well, explaining 11% of the variance in the development of CKD (area under ROC curve ¼ 0.77). We validated this equation in a separate large cohort of hospitalized Veterans (Po0.001, c-statisticX0.81). As these end points are accessible and clinically relevant, clinicians could potentially use such equations to risk stratify AKI survivors at highest risk for 521

mini review

progression to CKD for therapeutic reasons or for inclusion in clinical trials.9 In addition to clinical models, novel AKI biomarkers show promise in improving risk assessment of patients with severe AKI. Srisawat et al.77 have shown that plasma neutrophil gelatinase–associated lipocalin improves the discrimination of clinical models to predict renal recovery. Future studies should incorporate plasma and urine biomarkers in risk assessment strategies to determine the best approach to identify patients at risk for CKD progression. Summary

The paradigm of AKI has markedly shifted over the past 5 years. The previous conventional wisdom that survivors of AKI tend to do well and fully recover renal function, perhaps based on indistinct recollections of early, limited studies, appears to be flawed.6,7 AKI can cause ESRD directly,8,10,78 and appears to increase the risk for incident CKD and worsen underlying CKD.12,22 In addition, severity and frequency of AKI appear to be important predictors of poorer outcomes.9,26 Experimental data support the clinical observations. Mechanistically, renal mass, vascular insufficiency, cell cycle disruption, and maladaptive repair appear to be important modulators of outcome, and these pathophysiologic processes are likely operative in mediating the poor outcomes observed in the clinical epidemiologic studies reviewed above. The public health impact of the long-term outcomes of AKI is significant. The population incidence of AKI is approximately 2100 per million population.1 Given the population of the developed world (USA, Canada, Western Europe, and Australia) of approximately 1 billion, there will be over 2 million cases of AKI this year, with an expected 1.5 million AKI survivors. Of these patients, approximately 15–20% will progress to advanced-stage CKD within 24 months, resulting in approximately 300,000 cases of advanced CKD per year. Given the increasing incidence of AKI in the aging population,8,79,80 the projected incidence is expected to increase. The National Institute of Diabetes, Digestive and Kidney Disease supports the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS AKI) study, which evaluates the long-term outcome of hospitalized patients, with and without CKD, who experience an episode of AKI, to determine the natural history of AKI and delineate risk factors for progression and development of complications, including cardiovascular disease.81 We propose a new model integrating acute and CKD. The separation of ARF and CKD into two distinct syndromes as taught in medical school is not in the best interest of an integrated approach to the long-term care of patients with kidney disease. Rather, we propose consideration of the state of diminution in GFR as a clinical entity, which has differential initiation and expression in time and along the spectrum of magnitude of GFR (Figure 3). Phases of disease include initiation, repair, and long-term outcomes (Figure 3 and/or 4). Differences in timing and severity of injury and the 522


balance of adaptive and maladaptive repair determine clinically apparent outcomes. The range of change in response to differential injury and the balance of adaptive and maladaptive repair in patients with different initial levels of renal function comprise the entire spectrum of GFR (Figure 3). Interventions to preserve function and enhance repair are presumably appropriate at several stages of the disease. Commonalities and differences in mechanisms mediating the different courses of long-term outcome must be delineated and translated into clinical trials and practice over the next decade. The giants, such as Lowe and Merrill, on whose shoulders we stand, were correct, even if their early findings were lost, misinterpreted, or incorrectly recalled. AKI and CKD comprise an intertwined clinical entity, a disease of diminished renal mass resulting in diminished GFR. Recommendations and future directions

We recommend that hospital survivors of AKI who experience severe AKI (AKIN stage III) be followed up by a nephrologist after discharge. Currently, this does not occur. At 30 days after discharge from the hospital with an episode of AKI, 74.5% of patients were seen by a primary physician compared with 11.9% and 29.5%, respectively, who were seen by a nephrologist or a cardiologist.82 Surprisingly, only about one-third of AKI patients requiring dialysis (AKIN stage III) are seen by a nephrologist within 30 days of discharge. This increases to 48.6% within 1 year of discharge, which is likely a result of a rising serum creatinine.82 Overall, a very small fraction of AKI patients are currently followed up by nephrologists after hospital discharge.82 To put this into context, an assessment of the nephrology follow-up of AKI survivors as compared with the cardiology follow-up of myocardial infarction survivors reveals a stark difference (11.9% vs. 76%, respectively).31,82 At the very least, we should continue to see our patients. Monitoring patients for blood pressure control, the use of drugs that interfere with the renin–angiotensin system, and avoidance of nephrotoxins may prove critical as public health measures, which may oppose current secular trends. DISCLOSURE

All the authors declared no competing interests. ACKNOWLEDGMENTS

We thank Paul Eggers and Richard Amdur for reviewing the manuscript. DISCLAIMER The views expressed in this article do not necessarily represent the views of the Department of Health and Human Services, the National Institutes of Health, the National Institute of Diabetes, Digestive and Kidney Diseases, or the United States Government. REFERENCES 1.

2.

Ali T, Khan I, Simpson W et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007; 18: 1292–1298. Murugan R, Kellum JA. Acute kidney injury: what’s the prognosis? Nat Rev Nephrol 2011; 7: 209–217. Kidney International (2012) 82, 516–524

mini review


3. Uchino S, Kellum JA, Bellomo R et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005; 294: 813–818. 4. Kjellstrand CM, Ebben J, Davin T. Time of death, recovery of renal function, development of chronic renal failure and need for chronic hemodialysis in patients with acute tubular necrosis. Trans Am Soc Artif Intern Organs 1981; 27: 45–50. 5. Liano F, Felipe C, Tenorio MT et al. Long-term outcome of acute tubular necrosis: a contribution to its natural history. Kidney Int 2007; 71: 679–686. 6. Lowe KG. The late prognosis in acute tubular necrosis; an interim followup report on 14 patients. Lancet 1952: 1086–1088. 7. Finkenstaedt JT, Merrill JP. Renal function after recovery from acute renal failure. N Engl J Med 1956; 254: 1023–1026. 8. Xue JL, Daniels F, Star RA et al. Mortality and advancing to end-stage renal disease in patients with hospital and non-hospital acquired renal failure. J Am Soc Nephrol 2007; 15: SA-PO965. 9. Chawla LS, Amdur RL, Amodeo S et al. The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int 2011; 79: 1361–1369. 10. Ishani A, Xue JL, Himmelfarb J et al. Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol 2009; 20: 223–228. 11. Lo LJ, Go AS, Chertow GM et al. Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease. Kidney Int 2009; 76: 893–899. 12. Amdur RL, Chawla LS, Amodeo S et al. Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis. Kidney Int 2009; 76: 1089–1097. 13. Wald R, Quinn RR, Luo J et al. Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. JAMA 2009; 302: 1179–1185. 14. Garg AX, Suri RS, Barrowman N et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 2003; 290: 1360–1370. 15. Chawla LS, Seneff MG, Nelson DR et al. Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis. Clin J Am Soc Nephrol 2007; 2: 22–30. 16. Engelman DT, Adams DH, Byrne JG et al. Impact of body mass index and albumin on morbidity and mortality after cardiac surgery. J Thorac Cardiovasc Surg 1999; 118: 866–873. 17. Gariballa SE, Parker SG, Taub N et al. Influence of nutritional status on clinical outcome after acute stroke. Am J Clin Nutr 1998; 68: 275–281. 18. Owen Jr WF, Lew NL, Liu Y et al. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993; 329: 1001–1006. 19. Friedman AN, Fadem SZ. Reassessment of albumin as a nutritional marker in kidney disease. J Am Soc Nephrol 2010; 21: 223–230. 20. Don BR, Kaysen G. Serum albumin: relationship to inflammation and nutrition. Semin Dial 2004; 17: 432–437. 21. Liu KD, Glidden DV, Eisner MD et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med 2007; 35: 2755–2761. 22. Ishani A, Nelson D, Clothier B et al. The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch Intern Med 2011; 171: 226–233. 23. James MT, Ghali WA, Knudtson ML et al. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation 2011; 123: 409–416. 24. Coca SG, King Jr JT, Rosenthal RA et al. The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans. Kidney Int 2010; 78: 926–933. 25. Brown JR, Kramer RS, Coca SG et al. Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann Thorac Surg 2010; 90: 1142–1148. 26. Thakar CV, Christianson A, Himmelfarb J et al. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol 2011; 6: 2567–2572. 27. Hsu CY, Vittinghoff E, Lin F et al. The incidence of end-stage renal disease is increasing faster than the prevalence of chronic renal insufficiency. Ann Intern Med 2004; 141: 95–101. 28. Thakar CV, Arrigain S, Worley S et al. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 2005; 16: 162–168. 29. James MT, Hemmelgarn BR, Wiebe N et al. Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study. Lancet 2010; 376: 2096–2103. 30. Bidani AK, Griffin KA, Williamson G et al. Protective importance of the myogenic response in the renal circulation. Hypertension 2009; 54: 393–398.

Kidney International (2012) 82, 516–524

31.

32.

33.

34. 35.

36.

37.

38. 39.

40.

41. 42. 43. 44.

45. 46. 47. 48.

49.

50.

51.

52.

53.

54.

55. 56.

57. 58.

Daugherty SL, Ho PM, Spertus JA et al. Association of early follow-up after acute myocardial infarction with higher rates of medication use. Arch Intern Med 2008; 168: 485–491 discussion 492. Venkatachalam MA, Griffin KA, Lan R et al. Acute kidney injury: a springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 2010; 298: F1078–F1094. Hsu CY, Chertow GM, McCulloch CE et al. Nonrecovery of kidney function and death after acute on chronic renal failure. Clin J Am Soc Nephrol 2009; 4: 891–898. Goldstein SL, Devarajan P. Acute kidney injury in childhood: should we be worried about progression to CKD? Pediatr Nephrol 2011; 26: 509–522. Goldstein SL, Devarajan P. Progression from acute kidney injury to chronic kidney disease: a pediatric perspective. Adv Chronic Kidney Dis 2008; 15: 278–283. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005; 45: 96–101. Askenazi DJ, Feig DI, Graham NM et al. 3–5 Year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006; 69: 184–189. Mitch WE, Walser M, Buffington GA et al. A simple method of estimating progression of chronic renal failure. Lancet 1976; 2: 1326–1328. Shah BV, Levey AS. Spontaneous changes in the rate of decline in reciprocal serum creatinine: errors in predicting the progression of renal disease from extrapolation of the slope. J Am Soc Nephrol 1992; 2: 1186–1191. Neugarten J, Feiner HD, Schacht RG et al. Aggravation of experimental glomerulonephritis by superimposed clip hypertension. Kidney Int 1982; 22: 257–263. Baldwin DS. Poststreptococcal glomerulonephritis. A progressive disease? Am J Med 1977; 62: 1–11. Ingelfinger JR. Disparities in renal endowment: causes and consequences. Adv Chronic Kidney Dis 2008; 15: 107–114. Hostetter TH. Progression of renal disease and renal hypertrophy. Annu Rev Physiol 1995; 57: 263–278. Hostetter TH, Olson JL, Rennke HG et al. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Jam Soc Nephrol 2001; 12: 1315–1325. Baldwin DS, Neugarten J. Hypertension and renal diseases. Am J Kidney Dis 1987; 10: 186–191. Shapiro JI, Elkins N, Reiss OK et al. Energy metabolism following reduction of renal mass. Kidney Int Suppl 1994; 45: S100–S105. Nath KA, Croatt AJ, Hostetter TH. Oxygen consumption and oxidant stress in surviving nephrons. Am J Physiol 1990; 258: F1354–F1362. Tapp DC, Wortham WG, Addison JF et al. Food restriction retards body growth and prevents end-stage renal pathology in remnant kidneys of rats regardless of protein intake. Lab Invest 1989; 60: 184–195. Risdon RA, Sloper JC, De Wardener HE. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 1968; 2: 363–366. Schainuck LI, Striker GE, Cutler RE et al. Structural-functional correlations in renal disease. II. The correlations. Hum Pathol 1970; 1: 631–641. Striker GE, Schainuck LI, Cutler RE et al. Structural-functional correlations in renal disease. I. A method for assaying and classifying histopathologic changes in renal disease. Hum Pathol 1970; 1: 615–630. Azuma H, Nadeau K, Takada M et al. Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney. Transplantation 1997; 64: 190–197. Azuma H, Nadeau K, Takada M et al. Initial ischemia/reperfusion injury influences late functional and structural changes in the kidney. Transplant Proc 1997; 29: 1528–1529. Liu KD, Glidden DV, Eisner MD et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury*. Crit Care Med 2007; 35: 2755–2761. Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 2006; 17: 1503–1520. Leelahavanichkul A, Huang Y, Hu X et al. Chronic kidney disease worsens sepsis and sepsis-induced acute kidney injury by releasing high mobility group box protein-1. Kidney Int 2011; 80: 1198–1211. Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 2003; 14: 2199–2210. Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol 2009; 130: 41–50.

523

mini review

59.

60. 61.

62. 63.

64.

65.

66.

67.

68.

69.

524

Castano AP, Lin SL, Surowy T et al. Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo. Sci Transl Med 2009; 1: 5ra13. Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 1992; 20: 1–17. Bohle A, von Gise H, Mackensen-Haen S et al. The obliteration of the postglomerular capillaries and its influence upon the function of both glomeruli and tubuli. Functional interpretation of morphologic findings. Klinische Wochenschrift 1981; 59: 1043–1051. Finn WF. Enhanced recovery from postischemic acute renal failure. Micropuncture studies in the rat. Circ Res 1980; 46: 440–448. Yang L, Besschetnova TY, Brooks CR et al. Epithelial cell cycle arrest in G2/ M mediates kidney fibrosis after injury. Nat Med 2010; 16: 535–543 531p following 143. Basile DP, Friedrich JL, Spahic J et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol 2011; 300: F721–F733. Basile DP, Donohoe D, Roethe K et al. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 2001; 281: F887–F899. Yuan HT, Li XZ, Pitera JE et al. Peritubular capillary loss after mouse acute nephrotoxicity correlates with down-regulation of vascular endothelial growth factor-A and hypoxia-inducible factor-1 alpha. Am J Pathol 2003; 163: 2289–2301. O0 Riordan E, Mendelev N, Patschan S et al. Chronic NOS inhibition actuates endothelial-mesenchymal transformation. Am J Physiol Heart Circ Physiol 2007; 292: H285–H294. Horbelt M, Lee SY, Mang HE et al. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am J Physiol Renal Physiol 2007; 293: F688–F695. Bechtel W, McGoohan S, Zeisberg EM et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 2010; 16: 544–550.


70. 71. 72.

73.

74. 75. 76.

77.

78.

79.

80. 81.

82.

Bonventre JV. Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol 2003; 14Suppl 1: S55–S61. Price PM, Safirstein RL, Megyesi J. The cell cycle and acute kidney injury. Kidney Int 2009; 76: 604–613. Hodeify R, Tarcsafalvi A, Megyesi J et al. Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol Renal Physiol 2011; 300: F1171–F1179. Megyesi J, Price PM, Tamayo E et al. The lack of a functional p21(WAF1/ CIP1) gene ameliorates progression to chronic renal failure. Proc Natl Acad Sci USA 1999; 96: 10830–10835. Wynn TA. Fibrosis under arrest. Nat Med 2010; 16: 523–525. Bechtel W, McGoohan S, Zeisberg EM et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 2010; 16: 544–550. Megyesi J, Udvarhelyi N, Safirstein RL et al. The p53-independent activation of transcription of p21 WAF1/CIP1/SDI1 after acute renal failure. Am J Physiol 1996; 271: F1211–F1216. Srisawat N, Murugan R, Lee M et al. Plasma neutrophil gelatinaseassociated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia. Kidney Int 2011; 80: 545–552. Lassnigg A, Schmidlin D, Mouhieddine M et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004; 15: 1597–1605. Chertow GM, Burdick E, Honour M et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–3370. Anderson S, Eldadah B, Halter JB et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011; 22: 28–38. Go AS, Parikh CR, Ikizler TA et al. The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods. BMC Nephrol 2010; 11: 22. USRDS Annual Report 2007 Department of Health and Human Services, NIDDK, United States Renal Data System (USRDS) (NIH publication no 07-3176) 2007; 1: 240–241.

Kidney International (2012) 82, 516–524