AKI n CKD an Integrated Clinical Syndrome

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

    1Department 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 ofunderlying 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 acuteand 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, 516524; 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

    Acute kidney injury (AKI) is responsible for approximately2 million deaths annually worldwide.13 AKI is increasinglycommon in critically ill patients, and those patients with themost severe form of AKI, requiring renal replacement

    therapy, have a mortality rate of 5080%.3 Over the past 10years, there has been substantial progress in the field of AKI.In particular, work on consensus definitions, epidemiologicand database studies, AKI biomarkers, and the appropriatedosing of renal replacement therapy has continued at a briskpace. The classic teaching regarding patients who survive anepisode 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 ofAKI after hospital discharge.4,5 The most recent comprehen-sive study of AKI survivors followed 187 patients with ATNfor 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 topre-morbid renal function is contradicted by a series of smallbut careful clinical studies conducted over 50 years ago.6,7

    Good clinical recovery, which is sustained, is the rule wasreported by Lowe6 in his study of 14 selected patients whosurvived an episode of oliguria or anuria associated withATN. Three patients (of the eight who had the assessment) inthis series, however, had creatinine clearance ofo80 ml/min.Lowe attributed any renal dysfunction to scarring or vasculardamage. Finkenstaedt and Merrill7 reported inulin clearancesofo70 ml/min in 6 of the 16 patients with no evidence ofrenal disease before occurrence of acute renal failure (ARF)

    1376 months after the episode. They concluded that thefindings demonstrated that an episode of ARF resulted inmore chronic renal damage than would be expectedand that subnormal renal function late in the follow-upperiod occurred in the majority of cases studied. Theyattributed chronic dysfunction to rupture of basementmembranes with abnormal epithelial regeneration, resultingin nephron loss.

    Up to 2007, however, when the epidemiology of AKIsurvivorship was assessed, there was a lack of large longitudinalstudies to assess the effects of AKI on long-term renal function.8

    More recently, from 2008 through 2012, multiple observational

    m i n i r e v i e w http://www.kidney-international.org

    & 2012 International Society of Nephrology

    Received 20 October 2011; revised 13 January 2012; accepted 21

    February 2012; published online 6 June 2012

    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]

    516 Kidney International(2012) 82 , 516524

    http://dx.doi.org/10.1038/ki.2012.208http://www.kidney-international.org/mailto:[email protected]:[email protected]://www.kidney-international.org/http://dx.doi.org/10.1038/ki.2012.208
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    studies assessing unique cohorts of patients, often using largeadministrative databases, demonstrated that patients who survivean episode of AKI have a significant risk for progression toadvanced-stage chronic kidney disease (CKD).914

    We review data suggesting that AKI is a cause of CKD andthat prevalent CKD is a cause of incident AKI, and focus onthe interrelationships between these two entities. We reviewthe potential mechanistic factors underlying links betweenAKI and CKD, and offer clinical considerations based onthese observations.

    AKI AS A RISKFACTOR FOR INCIDENT CKD

    Ishani et al .10 assessed a random sample of Medicarebeneficiaries and found that patients diagnosed with anepisode of AKI were more likely to develop end-stage renaldisease (ESRD) compared with patients without a history ofeither AKI or CKD. In their analysis, the risk of developingESRD was eightfold higher in those with AKI compared withpatients without a history of AKI or CKD. As this study used

    ICD-9 diagnostic codes, it is difficult to determine theproportion of patients who suffered AKI and then progresseddirectly to ESRD compared with patients who sufferedAKI,recovered renal function, and then progressed to ESRD.10

    Lo et al.,1 1 by using a Kaiser Permanente database inNorthern California, retrospectively studied inpatient admis-sions. Patients with an episode of AKI treated with dialysis werecompared with patients without an episode of AKI. Patientswith a history of ESRD or a preadmission estimated glomerularfiltration rate (eGFR) o45 ml/min per 1.73m2 were excluded.In this study, the investigators found that an episode ofdialysis-requiring AKI was associated with a 28-fold increased

    risk of developing advanced CKD, and a 2-fold increase inmortality. As patients who developed ESRD within 30 daysof discharge were excluded from the long-term follow-up ofadvanced CKD, these data are consistent with a severe formof AKI followed by renal recovery and then progression toadvanced-stage CKD.11 It should be noted that some patientsassessed had pre-existing CKD.

    Wald et al.13 conducted a population-based cohort studyin Ontario, Canada of AKI patients who required in-hospitaldialysis and survived free of dialysis for at least 30 days afterdischarge. These patients were matched with patients withoutAKI or dialysis therapy during their index hospitalization.Patients with AKI requiring dialysis were over three times

    more likely to develop ESRD compared with control-matchedpatients.

    We and colleagues at the Veterans Affairs Medical Centerin Washington, DC assessed a United States Department ofVeterans Affairs database to ascertain long-term renal functionin over 79,000 hospitalized patients with and without AKI.12

    A particular focus was on the long-term outcome in patientswith a diagnosis of ATN. Patients hospitalized for acutemyocardial infarction or pneumonia without AKI were desig-nated as controls. The remaining 5404 hospitalized patientswho comprised the AKI group had diagnostic codes indicat-ing ARF or ATN. Patients with pre-existing CKD were

    excluded. Over the 5-year follow-up period, renal functiondeteriorated over time in all groups, but with significantlygreater severity in those who had ATN and ARF comparedwith controls. Patients with AKI, especially those with ATN,with pre-existing normal renal function were more likelythan controls to enter stage 4 or 5 CKD. We found thatpatients who had an episode of AKI were at high risk for thedevelopment of stage 4 CKD andhad reduced survival timecompared with control patients.12

    Our studies in AKI survivors identified advanced age, thepresence of diabetes mellitus, and decreased baseline eGFRasrisk factors for the progression to advanced-stage CKD.12,15 Inaddition to these risk factors, along with our colleagues, werecently showed that low serum albumin concentration (SAlb)is a strong predictor of poor long-term renal outcome.9 Thevalue of the SAlb as a predictor of CKD progression is notsurprising, because this parameter has been associated withpoor outcomes in both the general population and in a varietyof diseases including ESRD, surgical illness, and acute stroke.1618

    Low SAlb levels can be a result of nutrition-related factorsand/or high levels of inflammation.19,20 As several recentstudies have shown that markers of inflammation predictAKI, it is likely that the relationship between SAlb level andCKD progression is based on a complex set of factors,including those related to diet, nutrition, and catabolism, aswell as increased inflammation.15,21

    Collectively, these studies underscore the strong associa-tion 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 CKDprogression in survivors of AKI. Ishaniet al.22 assessed patientswho underwent cardiac surgery, and found that the magnitudeof serum creatinine concentration during the postoperativehospital course was directly linked to progression. This effectwas seen in patients with AKI with previously normal renalfunction (de novoAKI), as well as in patients with an episodeof AKI superimposed on CKD (acute on chronic renalfailure).22 The magnitude of increase in serum creatinine aftercardiac surgery was associated in a graded manner withincreased risk of CKD progression and mortality.

    This same trend has been demonstrated in patients whohad percutaneous coronary revascularization. James et al.23

    showed that patients undergoing percutaneous coronaryrevascularization who had AKI were at risk for future develop-ment of ESRD. Patients with AKIN stage I AKI were over 4times more likely to develop ESRD, whereas patients with AKINstage II/III were over 11 times more likely to develop ESRD. 23

    We have similarly shown that the severity of AKI is linkedto CKD progression.9 We assessed a cohort of 11,589 patientswith a spectrum of AKI from RIFLE stage R through F.9

    Severity of AKI, assessed by peak serum creatinine, wasassociated with progression to advanced CKD (Figure 1). Inparticular, patients who required dialysis were at muchhigher risk for progression to CKD than patients with less

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    severe AKI.9 Although it is seemingly intuitive that the

    severity of AKI would be associated with progression toadvancedCKD, these three studies are the first to show thislink.9,22,23 These findings suggest that when the severity ofAKI reaches a certain threshold the course of AKI is altered,initiating a chronic, progressive disease.

    In addition to severity, the duration of AKI has beenlinked to mortality but not to CKD progression. Coca et al.24

    assessed a large cohort of patients with diabetes mellitusundergoing cardiac surgery in the Veterans Administrationsystem. Both severity and duration of AKI were linked tolong-term mortality. However, the duration of AKI was notlinked to CKDprogression.24 Consistent with these findings,

    Brownet al.

    25

    assessed a separate cohort of US Veterans aftercardiac surgery and confirmed that the duration of AKI waslinked to worse long-term survival.

    Not surprisingly, patients who sustain multiple episodes ofAKI as compared with a single episode of AKIhave higherlikelihoods of CKD progression. Thakar et al.26 have shown,in a cohort of US Veterans with diabetes, that those whoexperienced two or more episodes of AKI were much morelikely to progress to stage 4 CKD than patients whoexperienced only one episode of AKI (Figure 2).26

    These data are consistent with the hypothesis that for somepatients a single episode of AKI has biologic ramificationsbeyond the acute event, engendering an ongoing state that

    predisposes to the development of further injury, manifesteddifferentially in time as worsened AKI (short-term) or thedevelopment or worsening of CKD over longer periods(Figure 3). Some patients can fully recover from their initialAKI, but subsets of AKI survivors appear to go on toexperience vicious cycles of intertwined AKI and CKD.26 It islikely that the severity of renal injury along with other clinical,treatment, and host risk factors mediate such processes.

    AKI AS ANACCELERANT OF CKD

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

    authors hypothesized that physician-related decisionsto start chronic dialysis earlier might account for thisdiscrepancy. We believe that the more likely explanation isthe marked effect of AKI on the development and progres-sion of CKD.

    CKD has consistently been shownto be a significant riskfactor for the development of AKI.28,29 Probable explanationsinclude the hemodynamic instability and failure of auto-

    regulation30 in CKD patients, the ease of detection of smallchanges in GFR when renal function is impaired, and apredispositionto further injury in patients with diminishedrenal function.31,32 These consist of at least susceptibility tonephrotoxic agents, and the effects of ongoing humoral andrenal pathologic mechanisms in the setting of CKD.Unfortunately, this risk appears to be bidirectional. Ishaniet al.10 showed that patients with CKD who experienced anepisode of AKI were 41 times more likely to develop ESRDthan patients without kidney disease, whereas patients withCKD and no episodes of AKI had an 8.4-fold higher riskcompared with patients without kidney disease. The risk of

    a b

    80

    90

    100

    70

    50

    60

    40

    30

    MeaneGFR

    Tertile 1: meaneGFR>79.2

    Tertile 2: meaneGFR 61-79.2

    Tertile 3: meaneGFR

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    developing ESRD was enhanced almost fourfold by thesuperimposition of AKI in CKD patients. AKI enhanced therisk almost 10-fold compared with patients without eitherCKD or AKI, and astonishingly was associated with greaterrisk of developing ESRD than those identifiedwith CKD in

    the Medicare population. Similarly, Hsu et al.

    33

    showed thatpatients with an eGFR o45ml/min per 1.73m2 whoexperienced an episode of dialysis-requiring AKI were atvery high risk for impaired recovery of renal function. In apopulation-based cohort in Scotland, Ali et al.1 showed thatonly 64% of patients with an episode of acute on chronicrenal failure had full recovery of kidney function.1

    In these studies, CKD was defined by an eGFR of460 ml/min per 1.73 m2. In addition to low baseline eGFR,patients with CKD as assessed by proteinuria are at increasedrisk for AKI. Jameset al.29 showed in a cohort of over 920,000patients that the level of proteinuria and diminished baselineeGFR were independent risk factors for developing AKI.29

    The risk of progression to CKD in patients who developAKI is not limited to adults but affects children as well. 34,35

    Large pediatric cohort studies suggest that certain subsets ofchildren (such as bone marrow transplant patients) are athigh risk for CKD progression. In contrast to adults, childrentend to be less burdened with chronic disease. Thus, theevidence that AKI in children puts those patients at risk forCKD suggests processes subsequent to AKI that are integralto the acute episode, as opposed to simply changes that occurin an acute on chronic disease paradigm.

    Hui-Stickle et al.36 assessed pediatric intensive care unitpatients upon discharge from a tertiary care center. In all,

    34% had either reduced kidney function or were dialysisdependent upon discharge.36 The most compelling dataregarding AKI and the risk of CKD in children came from along-term follow-up of participants in the aforementionedstudy conducted by Askenazi et al.37 They followed up acohort of children for 3 to 5 years after an episode of AKI.Mortality was 79.9%, with the majority of the deathsoccurring within 2 years of the AKI episode. In all, 17 of29 patients followed up in an outpatient clinic demonstratedevidence of CKD, manifested by hyperfiltration, reducedkidney function, hypertension, or microalbuminuria.37

    Although this represents a small sample, it is consistent withanimal and adult human studies showing that subsets ofpatients who develop AKI are at high risk for developingCKD and experiencing progression.

    These data suggest that for some patients AKI and CKDlikely coexist in an intimate but vicious cycle. This concept issupported by the fact that CKD was thought to progress in alinear manner,38 but this is not always the case. Shah and

    Levey39 showed that as many as one-third of patients deviatedfrom their reciprocal creatinine slope. The African AmericanStudy of Kidney Disease and Hypertension study has delinea-ted several different courses in patients with CKD (personalcommunication, Tom Greene). Some of these courses areconsistent with the notion of intermittent episodes of AKIcomplicating CKD, with varying levels of repair occurring.An episode of AKI that results in a decrement in GFR willnecessarily affect the trajectory of GFR change; the course willultimately be determined by whether the injury is reversible(volume-related changes in GFR and filtration fraction) andby the balance between effective and maladaptive repair

    mechanisms (Figure 4). The exact mechanism(s) by whichAKI accelerates/initiates CKD in humans are unknown.Preclinical data, however, suggest that a variety of mechanismsmay be operative.

    MECHANISMS UNDERLYING PROGRESSION OF AKI TO CKD

    An important concept for understanding the course of CKD isthat the progression to ESRD occurs via processes that maybe independent of the original pathology of CKD.32,40 Suchconceptswere originally proposed for a variety of glomerulardiseases,40 after follow-up studies in patients with post-streptococcal glomerulonephritis delineated long-term sequelae41

    linked to current definitions of CKD, including decrements

    in GFR and the persistence of proteinuria, as well as thedevelopment of hypertension. Data from animal modelssuggest that kidneys after episodes of injury may be sus-ceptible to progression to CKD, which is similarly indepen-dent of the initial cause of AKI. Key constructs regarding CKDprogression are based on findings from the remnant kidneymodel in which nephron loss leads to glomerular hypertrophyin the remaining nephrons.42 Hypothesized mechanismsunderlying CKD progression include effects of systemic andintrarenal hypertension and hyperfiltration, tubular hyper-trophy, and hypertension resulting in arteriosclerosis, tubu-lointerstitial fibrosis, and glomerulosclerosis,4345 as well as

    100%

    0

    GFR

    Time

    AKI Repair Chronic

    Figure 3 | Theoretical range of outcomes after acute kidneyinjury (AKI). The range of possible long-term outcomes after anepisode of AKI comprises the entire spectrum of the glomerularfiltration rate (GFR). The final GFR is determined by the level ofGFR at the time of injury, the severity and duration of the injury,and responses across several phases over time. It is envisionedthat repair and chronic phases have different and variable timeframes, and different magnitudes of responses. Responses duringrepair and chronic phases are determined by the balance ofprocesses that result in amelioration and worsening of GFR.

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    the effects of derangements of the endocrine response and

    abnormalities in circulating mediators associated with decre-ments in renal function. The latter may affect cell structure andfunction, as well as physiologic responses. In the case of normalkidneys after an episode of injury, multiple injury pathways andmaladaptive processes have been identified, which maycontribute to determining the course of renal function afteran initial insult.

    Nephron loss and glomerular hypertrophy

    The pathophysiology of loss of nephron mass followed byglomerular hypertrophy has been well described in animalmodels.43 After an episode of AKI, it is possible that signi-ficant permanent loss of nephron mass results in a clinical

    state comparable to that of the remnant kidney model. Aftersubtotal nephrectomy, single-nephron GFR increases viahyperfiltration and glomerular hypertrophy. Cellular prolif-eration ensues, ultimately resulting in tubulointerstitial fibrosisand progressive nephron loss.32 These processes are exacer-bated by high-salt and high-protein diets.46,47 Increasedtubular workload predisposes nephron segments to fibrosisand senescence, which can be mitigated by protein and calorierestriction.47,48

    The lessons from animal studies have been successfullytranslated into patient-care paradigms. As an example, acornerstone of CKD therapy is mitigation of glomerular

    hypertrophy and hyperfiltration via hypertension control and

    reninangiotensinaldosterone system blockade.

    Interstitial inflammation and fibrosis

    In human CKD and in the remnant kidney model,tubulointerstitial fibrosis predominates over glomerulo-sclerosis.32 As a consequence, human CKD often progresseswithout the need for continued glomerular injury.45,4951

    Further support of a pro-fibrotic effect in the setting ofreduced renal mass is provided by experiments that show thatthe kidneys of animals exposed to ischemiareperfusion (IR)injury are more predisposed to developing fibrosis if nephronloss (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 tobe an important feature ofischemic and septic AKI.15,5456 Animal models of ATNconsistently show an interstitial neutrophil infiltrate duringthe acute phase of ATN, often followed by monocyticlymphocytic infiltration in later stages.32,55,57,58 Monocytescan exacerbate injury and promote fibrosis.59 The effects oftubulointerstitial fibrosis are critical, as tubulointerstitialfibrosis injury scores predict the decline of renal functionbetter than glomerular injury scores.60,61 Reduced renalmass impairs recovery of experimental AKI and maypredispose to the development of fibrosis.32 In most models

    Peri-tubularblood vessels

    Interstitium

    c

    Normal repairand regeneration

    a b ATN

    Endothelialinjury

    Cellsand casts

    Cell cycle arrestEpigenetic changes

    Zones ofhypoxia

    d Maladaptiveresponse

    Interstitialfibrosis

    Depletedblood supply

    Neutrophils andmonocytes

    Figure 4 | Tubule cross-section. (a) Cross section of normal renal tubule with intact epithelial cells, renal interstitium, and peri-tubularblood 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 ofrenal tubule after normal repair and regeneration showing restoration of normal renal architecture. (d) Cross section of renal tubule aftersevere episode of AKI, resulting in maladaptive repair. Epithelial cells have evidence of cell cycle arrest and epigenetic changes that favor afibrosis phenotype. Renal interstitium shows evidence of fibrosis. Post-injury vascular supply is less dense than baseline. The combinationof decreased blood supply and fibrosis leads to zones of hypoxia wherein the combination of decreased vascular supply and fibrosis caninitiate a vicious cycle leading to ongoing fibrosis.

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    of experimental AKI, renal tubular regeneration occurs, butdepending on the severity of the initial damage the recoveryis often incomplete. Areas that do not complete full recoverymay develop into focal areas of fibrosis.32,55,62

    Both human and animal models link severity andfrequency of AKI with worsening of long-term renalfunction.9,22,63 Multiple episodes of IR-induced AKI havebeen shown to cause CKD and tubulointerstitial fibrosis inanimal models. Thus, it is conceivable that subclinicalepisodes of AKI could both cause and worsen CKD.32 Thesedata are consistent with the previously cited human datashowing the effect of multiple episodes of AKI to enhanceCKD progression.26

    Endothelial injury and vascular rarefaction

    Experimental models of AKI demonstrate endothelialinvolvement and vascular injury. Tubular repair after injurytends to be robust, but the vascular restorative capacity afterAKI is more blunted.64 Various different injury models (e.g.,

    IR, folate, nitric oxide synthase inhibition, and ureteralobstruction) all demonstrate diminished vascular densityafter injury.6568 The loss of vascular density varies between30 and 50%.69 The loss of vascular reserve may be oneof the key components of the development of fibrosisafter injury. Injured tissue that has insufficient vascularsupply becomes hypoxic, potentially setting into motion aself-propagating injury cascade. Rarefaction of capillariesinitiates activation of hypoxia-inducible pathways that canpromote inflammation and downstream fibrosis.32 Thus,capillary rarefaction in fibrotic foci can be both a cause andan effect of tissue hypoxia, in turn leading to activation of

    hypoxic signaling, inflammation, and activation of factorsenhancing fibrosis.In experimental models, treatment with angiogenic factors

    such as vascular endothelial growth factor-121 amelioratesvascular dropout and endothelial damage.54 However, thesecompounds are only useful in the immediate post-injuryperiod, and do not improve vascular dropout after AKI whenadministered43 weeks after the insult.32

    Cell cycle and maladaptive repair

    Normal repair processes involve a host of growth factors andproliferative and other signaling cascades, which must bedeployed, and function in coordinated, integrated temporal,

    and spatial manners. These mechanisms are critical forappropriate repair and regeneration.70 Cell cycle abnormalitiesaffect the outcome of AKI. Preclinical studies demonstratethat p21, a cyclin-dependent kinase, is a critical check-point effector for induction of the cell cycle.71 In preclinicalmodels of AKI, p21 antagonism worsens AKI, whereas p21induction improves outcomes in AKI models.72,73 Cell cycledysfunction can have effects at the point of injury and furtherdownstream during repair. Pathways that affect the cell cyclecan also activate fibroblasts and inflammation. Selected anti-inflammatory therapies have been shown to decrease theseverity of AKI during its acute phase.32,74 Recently, studies

    involving the cell cycle of reparative cells have shed light onsuch processes.72,73

    When AKI is severe, the corresponding tubular injury andinterstitial inflammation are associated with proliferation oftubular epithelial cells. Yanget al.63 showed that when kidneydamage was accompanied by fibrosis there were largenumbers of proximal tubule epithelial cells arrested in theG2/M phase of the cell cycle. In contradistinction to prolif-erating epithelial cells, the arrested cells produced greaterlevels of transforming growth factor-b1 and connective tissuegrowth factor. These findings suggest that in response toinjury a maladaptive repair process may ensue, causingfibrosis instead of repair of tubular epithelia. Cell cycle arrestcauses tubular epithelial cells to convert to a phenotype thatpromotes the growth and activation of fibroblasts. Interest-ingly, in this same study, moderate IR injury did notproduce this maladaptive process. Only severe injury with IRor aristolochic acid activated pro-fibrotic processes. Cell arrestwas mitigated by agents, such as p53 inhibitors, that affect the

    cell cycle, and was exacerbated by agents that prolong cellcycle arrest.63

    Animal studies support the notion that fibrosis is ongoingafter AKI. Bechtelet al.69 investigated mechanisms of fibrosisthat were temporally remote from the initiation of kidneyinjury. They showed that fibrosis continues owing to a failureof fibroblasts to return to their resting state. Epigeneticfactors including hypermethylation ofRASAL1gene loci wereinvolved. 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 activationis sustained, epigenetic changes in fibroblasts may ensue,which can transform them into tumor-like myofibroblaststhat proliferate in a growth factorindependent manner.74

    Altogether, cell cycle arrest and epigenetic changes representat least two maladaptive repair mechanisms that appear tohave major roles in determining the post-AKI fibroticphenotype. As cell cycle arrest and epigenetic changes appearto be sequentialin nature, they may form pathways amenableto interruption.63,73,75,76

    Identification of patients and risk factors for CKD progression

    To help clinicians identify AKI survivors at increased risk forCKD development and progression, along with our collea-gues, we developed three multivariable models. The mostaccessible (and therefore clinically useful) model is based onsentinel 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 0.77). We validated this equation ina separate large cohort of hospitalized Veterans (Po0.001,c-statisticX0.81). As these end points are accessible andclinically relevant, clinicians could potentially use suchequations to risk stratify AKI survivors at highest risk for

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    progression toCKD for therapeutic reasons or for inclusionin clinical trials.9

    In addition to clinical models, novel AKI biomarkers showpromise in improvingrisk assessment of patients with severeAKI. Srisawat et al.77 have shown that plasma neutrophilgelatinaseassociated lipocalin improves the discrimination ofclinical models to predict renal recovery. Future studiesshould incorporate plasma and urine biomarkers in riskassessment strategies to determine the best approach toidentify patients at risk for CKD progression.

    Summary

    The paradigm of AKI has markedly shifted over the past 5years. The previous conventional wisdom that survivors ofAKI tend to do well and fully recover renal function, perhapsbased 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 worsenunderlying CKD.12,22 In addition, severity and frequency of

    AKI appear to be important predictors of poorer out-comes.9,26 Experimental data support the clinical observa-tions. Mechanistically, renal mass, vascular insufficiency, cell cycledisruption, and maladaptive repair appear to be importantmodulators of outcome, and these pathophysiologic processesare likely operative in mediating the poor outcomes observedin the clinical epidemiologic studies reviewed above.

    The public health impact of the long-term outcomes ofAKI is significant. The population incidence of AKI isapproximately 2100 per million population.1 Given thepopulation of the developed world (USA, Canada, WesternEurope, and Australia) of approximately 1 billion, there

    will be over 2 million cases of AKI this year, with an expected1.5 million AKI survivors. Of these patients, approxi-mately 1520% will progress to advanced-stage CKD within24 months, resulting in approximately 300,000 cases ofadvanced CKD per year. Given the increasing incidence ofAKI in the aging population,8,79,80 the projected incidence isexpected to increase. The National Institute of Diabetes,Digestive and Kidney Disease supports the Assessment, SerialEvaluation, and Subsequent Sequelae of Acute Kidney Injury(ASSESS AKI) study, which evaluates the long-term outcomeof hospitalized patients, with and without CKD, whoexperience an episode of AKI, to determine the naturalhistory of AKI and delineate risk factors for progression and

    development of complications, including cardiovasculardisease.81

    We propose a new model integrating acute and CKD. Theseparation of ARF and CKD into two distinct syndromes astaught in medical school is not in the best interest of anintegrated approach to the long-term care of patients withkidney disease. Rather, we propose consideration of the stateof diminution in GFR as a clinical entity, which hasdifferential initiation and expression in time and along thespectrum of magnitude of GFR (Figure 3). Phases of diseaseinclude initiation, repair, and long-term outcomes (Figure 3and/or4). Differences in timing and severity of injury and the

    balance of adaptive and maladaptive repair determineclinically apparent outcomes. The range of change inresponse to differential injury and the balance of adaptiveand maladaptive repair in patients with different initial levelsof renal function comprise the entire spectrum of GFR(Figure 3). Interventions to preserve function and enhancerepair are presumably appropriate at several stages of thedisease. Commonalities and differences in mechanismsmediating the different courses of long-term outcome mustbe delineated and translated into clinical trials and practiceover the next decade.

    The giants, such as Lowe and Merrill, on whose shoulderswe stand, were correct, even if their early findings were lost,misinterpreted, or incorrectly recalled. AKI and CKDcomprise an intertwined clinical entity, a disease ofdiminished 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 nephrologistafter discharge. Currently, this does not occur. At 30 days afterdischarge from the hospital with an episode of AKI, 74.5% ofpatients were seen by a primary physician compared with11.9% and 29.5%, respectively, who were seen by a nephrologistor a cardiologist.82 Surprisingly, only about one-third of AKIpatients requiring dialysis (AKIN stage III) are seen by anephrologist within 30 days of discharge. This increases to48.6% within 1 year ofdischarge, which is likely a result of arising serum creatinine.82 Overall, a very small fraction of AKIpatients are currently followed up by nephrologists afterhospital discharge.82 To put this into context, an assessment

    of the nephrology follow-up of AKI survivors as compared withthe cardiology follow-up of myocardial infarction survivorsreveals a stark difference (11.9% vs. 76%, respectively).31,82 Atthe very least, we should continue to see our patients.Monitoring patients for blood pressure control, the use ofdrugs that interfere with the reninangiotensin system, andavoidance of nephrotoxins may prove critical as public healthmeasures, which may oppose current secular trends.

    DISCLOSURE

    All the authors declared no competing interests.

    ACKNOWLEDGMENTS

    We thank Paul Eggers and Richard Amdur for reviewing themanuscript.

    DISCLAIMERThe views expressed in this article do not necessarily represent theviews of the Department of Health and Human Services, the NationalInstitutes of Health, the National Institute of Diabetes, Digestive andKidney Diseases, or the United States Government.

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