Acute Kidney Injury and Chronic Kidney Disease

C H A P T E R

26 Acute Kidney Injury and Chronic Kidney Disease Matthew T. Jamesa, Lakhmir S. Chawlab,c,d, Paul L. Kimmelc a

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; bDepartment of Anesthesiology and Critical Care Medicine, George Washington University Medical Center, Washington, DC, United States; cDivision of Kidney Diseases and Hypertension, Department of Medicine, George Washington University, Washington, DC, United States; dUniversity California of San Diego, San Diego, CA, United States

Abstract Previous conventional wisdom suggested patients who survived an episode of acute kidney injury (AKI) fully recovered renal function. AKI and chronic kidney disease (CKD) have been traditionally approached as separate clinical syndromes, mainly distinguished by criteria based on timing and duration of reduced kidney function. However, recent research demonstrates that AKI and CKD are closely related. CKD is an important risk factor for the development of AKI. In turn, AKI is associated with the development of CKD and progression of preexisting CKD in significant numbers of patients. Both AKI and CKD are associated with increased morbidity and mortality, particularly when they are seen in combination, including increased risks of major adverse cardiovascular events. AKI and CKD may be better considered as interconnected syndromes, rather than two disparate entities. This knowledge has implications for the longitudinal care of survivors of AKI and patients with CKD. Interventions that target the AKI to CKD continuum may improve outcomes of patients with kidney disease, although strong evidence identifying strategies that improve outcomes remains lacking. Improved strategies for identification of patients at risk could inform the design of clinical trials, but well-designed RCTs are needed to determine effective interventions and best care practices to mitigate the pathways of AKI to CKD and to ameliorate its progression.

INTRODUCTION Medical teaching has traditionally divided pathophysiology of disease into organ systems, and within these, into syndromic approaches.1,2 For more than a half century, nephrologists have taught limited and separate modules pertaining to acute renal failure Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00026-7

(ARF) and chronic renal disease to medical students. Over the last 15 years, in part to facilitate clinical recognition and research, conceptual definitions of chronic kidney disease (CKD)3 and acute kidney injury (AKI)4,5 have been developed and refined, categorizing disease states and stages according to measures based on long-term level and acute changes in S[Cr]. AKI is currently defined by decline in kidney function over one week or less, whereas CKD is defined as alterations of kidney function and structure for more than 3 months.6,7 Previous conventional wisdom suggested favorable long-term outcomes of patients with ARF, and acute tubular necrosis (ATN) in particular, if recovery occurred during hospitalization. In 1952, Lowe reported creatinine clearances ranging from 65.3 to 99 mL/min in a subset of 14 of 40 patients with oliguria or anuria and a diagnosis of ATN when followed 228 days to 2.9 years.8 Most of the values for creatinine clearance one to three years after the ATN episode remained below normal. Premorbid levels of renal function were not recorded. Lowe concluded “. once recovery has been made from the acute episode of ATN, a favorable prognosis can be given. the levels of renal function attained are compatible with normal expectation of life, although the renal reserve is diminished.” Finkenstaedt and Merrill described long-term outcomes of 16 patients with ARF who did not have cardiovascular disease (CVD) or kidney disease before the acute episode.9 In these patients as well, “clearance values obtained for the majority of the patients fell below the lower limit of normal.” Inulin clearances ranged from 35 to 120 mL/min/ 1.73 m2 at 1 to 76 months after the episode of ARF. Three

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of the patients had long-term values of inulin clearance less than or equal to 63 mL/min/1.73 m2. The lessons of these small seminal papers published in the Lancet and the New England Journal of Medicine regarding longterm outcomes of ATN more than a half century ago have been forgotten or misinterpreted.1 Recent evidence, however, from large well-designed observational studies shows a substantial proportion of patients with AKI, even those without a history of previous renal disease, progress to high stage CKD,1,2,10 and that AKI is an independent prognostic factor for the progressive loss of renal function in patients with CKD.1,10e12 Although the antecedents and clinical correlates of ARF have been known for many years, in the era of CKD and AKI classifications, CKD has emerged as the preeminent risk factor for AKI.1,2,13,14 Since 2007, the concept of AKI has been generally accepted by the kidney research and clinical communities.3,5 Several observational studies have documented ominous outcomes associated with small increases in S[Cr] in populations. Concepts and definitions of AKI (Table 26.1) demonstrate numerous similarities to those of CKD.1,3,7,15,16 The public health impact of the long-term outcomes of AKI is significant. AKI is associated with significant morbidity and mortality, and the incidence of AKI has nearly doubled over the past two decades.17,18 AKI is common, morbid, deadly, and costly.4 AKI has been linked with the development of subsequent CVD, CKD, and end-stage renal disease (ESRD) and is associated with high costs of care.1,2,10,18e20 Secular trends

TABLE 26.1

Putative Factors Associated with Progressive Loss of Renal Function in CKD and AKI

Systemic and intrarenal hypertension Hyperfiltration Tubular hypertrophy and atrophy Tubulointerstitial fibrosis Progressive glomerular sclerosis Arteriosclerosis Disordered physiologic, humoral, and biochemical responses associated with CKD PTH, FGF-23, inflammation, hyperphosphatemia, uremic toxins Endothelial injury and vascular dropout Interstitial infiltration Specific populations of immune cells including subpopulations of macrophages and T cells Dietary sodium and protein intake

suggest that while the incidence of AKI has increased, early mortality from AKI has diminished in highincome countries. As a result, the number of survivors who may live with sequelae of CKD has increased over time.20e22 The annual incidence of AKI has been estimated as approximately 2100 per million population.23,24 Given the population of the developed world, there are projected to be over 2 million cases of AKI yearly, with an expected 1.5 million AKI survivors.24,25 Of these patients, more than 15% of those without preexisting CKD will progress to advanced stage CKD within 24 months, resulting in an incidence of more than 300,000 cases of advanced CKD a year.24,25 Furthermore, episodes of AKI that are superimposed on CKD may hasten the progression to ESRD of additional patients with established CKD.20 These estimates demonstrate the significant population attributable risk of CKD associated with AKI. Given the higher incidence of AKI in older populations, the projected incidence of CKD and ESRD related to AKI is expected to increase.15,18,24,26 Observational studies show a large proportion of patients with AKI, even in the absence of concurrent or preexisting CKD, progress to advanced stages of CKD, even if not treated with RRT during the index hospitalization. Given the relationships between AKI and incident CKD, progression of preexisting CKD, increased risk of entry into ESRD programs, and higher mortality,1,2,20,27,28 AKI and CKD can be considered parts of an interdigitated syndrome (Figure 26.1). The individual components, AKI and CKD, differ in presentation both temporally and clinically. AKI involves rapid changes in glomerular filtration rate (GFR), while CKD is usually characterized by slowly progressive decline in GFR. Patients with AKI are at high risk of developing CKD, even when GFR recovers after the initial episode. Patients with CKD remain at risk for developing episodes of AKI, which may further contribute to progression toward kidney failure.1,2,14 The individual components of the syndrome and their combination are common and associated with adverse long-term outcomes. This syndrome can be expanded to include patients with acute kidney diseases and disorders when alterations in kidney function or structure are present for less than 3 months, which includes patients who do and do not strictly meet AKI criteria but also have similar relationships with increased risks of CKD and ESRD.7,29 CKD, however, is the obverse face of the AKI coin. For patients with reduced GFR, AKI and CKD are the twin prognostic profiles of Janus, the two-faced Roman god of doorways, beginnings and endings.

FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone.

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AKI AND DEVELOPMENT OF CKD, END-STAGE RENAL DISEASE, AND CARDIOVASCULAR EVENTS

AKI

CKD

MARCE

FIGURE 26.1

AKI and CKD are interconnected syndromes. AKI patients are at risk for developing long-term decrements in GFR, even if full recovery occurs after an episode. CKD patients are at the highest risk of developing AKI. Patients with AKI and CKD are at risk for developing major adverse renal and cardiovascular events (MARCE). AKI, acute kidney injury; CKD, chronic kidney disease; MARCE, major adverse renal and cardiovascular events.

AKI AND DEVELOPMENT OF CKD, ENDSTAGE RENAL DISEASE, AND CARDIOVASCULAR EVENTS Several retrospective studies have characterized the relationship between AKI and development of CKD. In an important early study, Vikse and colleagues showed the rate of entry into ESRD programs was 3.7 per 100,000 women per year, but women with a diagnosis of preeclampsia had a relative risk of ESRD that was 3.2- to 15-fold higher.30 Ishani et al. showed, in a retrospective, observational study of Medicare patients, with follow-up of two years, that a coded diagnosis of ARF was associated with a 13-fold increase in the risk of development of ESRD compared with hospitalized patients without such a diagnosis. Patients who had a diagnosis of both ARF and CKD had a 40-fold increased risk of entering the ESRD program compared with patients without either diagnosis, and their ESRD risk was almost five times as great as those with a diagnosis of CKD in the absence of AKI.20 The mortality rate for patients with a diagnosis of ARF was 57.7%, twice as high as that of comparable patients without a diagnosis of ARF. Patients who had diagnostic coding related both to ARF and CKD had a mortality rate 18% higher than those with only an ARF diagnosis, 70% higher than those with CKD alone, and 2.4-fold higher than those without either diagnosis. Newsome et al. showed similar increases in both ESRD and mortality among patients with acute myocardial infarction (MI) who sustained small increases in S[Cr].31 Lo et al. found, after controlling for potential confounders such as presence of diabetes mellitus and baseline level of estimated GFR (eGFR), that AKI necessitating dialysis was independently associated with an almost 30-fold increase in the risk of developing subsequent stage 4 or 5 CKD,

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and a more than doubled risk of death.28 Bucaloiu et al.11 showed, using propensity score matching techniques, an approximately 50% increased risk in mortality of patients with AKI, but without concomitant CKD, as well as an almost doubled risk of developing incident CKD in the Geisinger Health System in Pennsylvania. A strength of the study was the ability to ascertain information regarding urinary protein excretion, when present in the medical record. Of note, almost three quarters of the AKI patients only had stage 1 disease, by Acute Kidney Injury Network criteria, and the duration of AKI was less than 24 hours. Hsu et al. showed AKI had an incrementally adverse effect on patients with preexisting CKD in a cohort of patients from the Kaiser Permanente dataset. Compared with patients who had CKD and did not experience AKI, those who had AKI superimposed on CKD had a 30% higher long-term risk of death or ESRD.32 Wald et al. showed, in an administrative database study of a Canadian population of patients who required dialysis during hospitalization, but survived free of dialysis for at least a month after hospital discharge, that the group had a threefold increased risk of ESRD compared with the control group.27 In a cohort of Canadian patients identified from a prospective cardiac catheterization registration, patients who exhibited laboratory evidence of AKI following coronary angiography were at particular risk for subsequent loss of renal function and ESRD.14 Amdur and colleagues examined the long-term risk of patients diagnosed with ATN, as well as ARF, in the US Veterans Administration health system.24 Progression of loss of renal function in patients with ATN who did not have preexisting, concomitant CKD to stage 4 CKD or higher was similar to those who were diagnosed with CKD at study baseline. CKD and ATN patients had similar mortality, which was higher than that of the control group, which was comprised of patients with the serious hospital diagnoses of MI or pneumonia, acutely ill patients with a substantial burden of CVD and cardiovascular risk factors. Patients with ATN had approximately six times the risk of developing CKD compared with the control group, whereas those with ARF had a fourfold increase in risk. Approximately 20% of patients with a diagnosis of ATN, without preexisting CKD, entered stage 4 CKD after a follow-up of more than six years. More than 13% of patients with a diagnosis of ARF, without preexisting CKD, developed stage 4 CKD during the study observation period. The risk of developing stage 4 CKD in patients with a diagnosis of ATN or ARF was 5.6 and more than 3-fold greater, respectively, than that of a control group of hospitalized patients with MI or pneumonia. Nineteen retrospective cohort studies have characterized the relationships between AKI, based on the KDIGO criteria, and the risks of CKD and ESRD. Based

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on meta-analyses of these data, AKI carries an over twofold increased risk of new or progressive CKD (17.8 vs. 7.6 cases per 100 person-years for those with vs. without AKI) and an over fourfold increased risk of ESRD (0.47 vs. 0.08 cases per 100 person-years for those with vs. without AKI). More severe AKI stages are consistently associated with higher risks for both outcomes. These findings have recently been confirmed in a multicenter prospective study from the US. The Assessment Serial Evaluation and Subsequent Sequelae (ASSESS) AKI study compared outcomes following discharge of patients with AKI and matched hospitalized patients without AKI. Importantly, this study employed protocolized follow-up measurements of eGFR and proteinuria to ascertain CKD in a consistent manner during follow-up.33,34 The ASSESS AKI study reported that AKI was associated with an over threefold higher adjusted rate of development of CKD incidence and an over twofold higher adjusted rate of CKD progression. The risk of development of CKD and progression of CKD to and development of ESRD is enhanced after AKI, but is also negatively affected by the increased severity of and number of episodes of AKI.10,35,36 Risk factors that have been identified for developing CKD following AKI include older age, presence of a diagnosis of diabetes mellitus, heart failure, the magnitude of increase in S[Cr], provision of dialysis, lower baseline eGFR, level of RIFLE score, albuminuria, and hypoalbuminemia (Table 26.2).36,37 These findings have been confirmed in a systematic review, demonstrating an almost ninefold increased risk of developing CKD for patients with AKI, a threefold increased risk of developing ESRD, and a doubled risk of death.10 The study suggested increased risks of developing CKD and ESRD associated with severity of AKI as well.10 Table 26.2 outlines factors which may be associated with long-term outcomes in patients after an episode of AKI.

Several large observational cohort studies show patients who survive an AKI episode are at high risk for both progression to CKD and increased cardiovascular events.14,19,38 In a cohort of patients who received coronary angiography in Alberta Canada, AKI was independently associated with subsequent hospitalizations for heart failure and MI.14 In an analysis of the Veterans Administration hospital database, after a median follow-up of 1.4 years (interquartile range 0.5e3.4 years), patients with a diagnosis of ARF or with AKI had a cumulative incidence of major renal and cardiovascular events 37% higher than that of a comparison group of patients with a diagnosis of MI.19 More than 60% of patients with AKI had a major cardiovascular or kidney event during follow-up (Figure 26.1). The highest risk of death, kidney, and cardiovascular events was observed in patients with AKI and MI. In a meta-analysis of six studies with a minimum follow-up of 6 months, Odutayo et al. found AKI was associated with an approximately 86% higher risk of cardiovascular mortality, and 38% higher risk of a major cardiovascular event.39 Go et al. found that, among hospitalized patients from Kaiser Permanente in California, 20% of patients with AKI experienced a cardiovascular event in the year after hospital discharge, and that individuals with AKI were at 18% higher adjusted risk of developing acute coronary syndrome, peripheral arterial disease, ischemic stroke, or heart failure.40 However, AKI was most strongly and significantly associated with a 44% increased risk of heart failure, without significantly increased risks of atherosclerotic disease following adjustment. The prospective ASSESS AKI study showed similar findings when cardiovascular events following hospitalization were clinically adjudicated, with significantly higher adjusted risks of heart failure, but not major atherosclerotic events identified among those with AKI.33,34

AKI AS A SYNERGISTIC COMPLICATION OF PROGRESSION OF CKD TABLE 26.2

Clinical Factors Thought to be Associated with Long-Term Outcomes of AKI

Age Level of initial renal function Extent and severity of injury Albuminuria Diabetes mellitus Ethnicity Degree of early recovery of kidney function Lack of follow-up by physicians Genetic susceptibility

Patients with AKI superimposed on preexisting CKD present special challenges to clinicians and researchers.41 Analyses of repeated measures of kidney function suggest trajectories of CKD progression may include AKI episodes, but in a complex manner which makes analyses of the data problematic, and the formulation of definitive conclusions challenging.2,42,43 O’Hare and colleagues identified four distinct trajectories of eGFR in patients with CKD during the two years before onset of ESRD. The trajectories included relatively stable courses, progressive loss of renal function, and both aggressive and catastrophic decreases in GFR. Patients with more aggressive progression to ESRD were more likely to have been hospitalized and to have had a diagnosis of AKI.43

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AKI AS A SYNERGISTIC COMPLICATION OF PROGRESSION OF CKD

CKD is the most important risk factor for the development of AKI, and patients with CKD appear uniquely susceptible to the development of AKI.1,2,14,16 This was illustrated in a large cohort study from Alberta, Canada, that included almost 1 million participants with outpatient eGFR and albuminuria measurements to characterize their CKD stage. The risk of hospitalization with AKI was shown to increase progressively with both lower eGFR and greater albuminuria.44 The importance of CKD as a predictor of AKI is also apparent from the development of clinical risk scores for AKI after cardiac surgery and cardiac catheterization.45e47 Most risk scores for AKI include a history of CKD or baseline eGFR among the strongest predictors. More recently, some have also identified albuminuria as an additional independent predictor of AKI in multivariable models. Mechanisms by which patients with CKD may be at risk for developing transient decreases of renal function include failure of autoregulation, abnormal vasodilatation, lack of renal reserve, failure of adequate renal tubular mechanisms to reabsorb water and sodium, frequent hospitalizations with the potential for iatrogenic mishaps or exposure to nephrotoxins, treatment to achieve diuresis leading to volume depletion, susceptibility to effects of antihypertensives, overvigorous medication, the use of RAAS blockers, nephrotoxins, and age-related physiologic changes.1,2,14,16,26,48 Patients with congestive heart failure or those with cardiorenal syndrome would seem to be intrinsically at increased risk because of their decreased renal function, even in the absence of laboratory evaluations which suggest the presence of CKD.49e51 Some data suggest, however, the uremic milieu might be associated with protective factors, such as antiinflammatory responses that modify factors associated with progression of kidney disease.52 Of note, the data linking small changes in S[Cr] with adverse outcomes may have potential significance apart from traditional notions of disease states such as ATN, acute interstitial nephritis (AIN), acute glomerulonephritis, or renal vascular disease.15 If such findings are confirmed in prospective studies, the implication is that patients who experience changes in cardiac hemodynamics, such as those with congestive heart failure or one of the cardiorenal syndromes, may represent a population at risk, but not necessarily from kidney dysfunction as a prime determinant. In addition, commonly employed therapeutic maneuvers, theoretically applied by extrapolating from findings from RCTs conducted in patients with CKD, such as diuretic therapy, interventions to control level of blood pressure, salt restriction, and intervention with agents which affect the RAAS may have unintended adverse consequences in patients with AKI and CKD. The ramifications, especially regarding patients with prerenal hemodynamics, are wide-ranging. Although the clinical

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paradigm of “acute on chronic” kidney disease has been well-appreciated, it is only recently that observational data (frequently from administrative sources) have been effectively used to study such patients. The nephrology community’s therapeutic approach to patients with simultaneous AKI and CKD is limited to anecdotal approaches. In addition, whether temporal sequence (such as whether AKI preceded CKD or CKD was complicated by AKI) is associated with outcomes in patients with coexisting CKD and AKI is unknown. Although the large number of observational studies linking episodes of AKI to the development and progression of CKD has established consistent relationships, causal links cannot be inferred by these study designs. Observational studies, particularly those using administrative databases or conducted retrospectively, are subject to errors associated with confounding and selection bias.1,2,12,14,53 Findings linking small changes in S [Cr] to adverse outcomes may be affected by the clinical circumstances associated with receiving multiple laboratory tests, such as site of care, and linkages may be missed in those patients who do not have systematic or frequent ascertainment of S[Cr]. The assessment of renal disease using administrative data often does not have the granularity necessary to assess specific laboratory findings. The prospect of underestimation of the scope of the clinical problem is magnified when mild abnormalities, such as failure to maximally concentrate or acidify urine, in the presence or absence of a specific stressor, are considered as measures of CKD or tubular dysfunction. Only an RCT designed to test whether an intervention decreases the incidence of CKD or progressive loss of renal function after an episode of AKI can achieve a definitive conclusion regarding causality. In one of the few studies to explore this question, a randomized clinical trial testing off-pump vs. on-pump coronary artery bypass grafting surgery showed off-pump surgery reduced the incidence of AKI by 17%. There was no difference detected between the treatment groups in the risk of a 20% decline in renal function one year later in this trial.54 A lack of other effective early interventions for prevention and treatment of AKI has limited opportunities to further test causal pathways between AKI and long-term outcomes, and inferences continue to be drawn from several sets of extant data.2,53,55 Children usually do not have underlying comorbidities associated with risk for AKI or CKD, such as diabetes mellitus or hypertension. Several studies show children who sustain an episode of AKI develop signs of CKD, such as hypertension, decreased GFR, and urinary abnormalities, in the absence of comorbidities characterizing the adult population.56e58 In analyses in adult populations, when variation in the presence of

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comorbidities is considered, AKI emerges as an independent risk factor for the development of CKD, progressive loss of renal function, and development of ESRD. The severity of AKI has been associated with the development of adverse outcomes.10,36,59 Finally, the number and severity of episodes of AKI has been linked to adverse outcomes.35

MECHANISMS ASSOCIATED WITH PROGRESSIVE RENAL INJURY The long-term course after an episode of AKI is presumably determined by the extent of the decrement in GFR, the reversibility of the injury, and the temporal balance between effective and maladaptive repair mechanisms (Figure 26.2, Table 26.3).1,16 Although the mechanisms underlying progression of renal dysfunction in humans are incompletely understood, and are primarily derived from studies in animals and model systems, rather than from individual level clinical findings, data from animal studies delineate a number of possible mechanisms. Neugarten and Baldwin and colleagues first proposed that progression of chronic disease might occur by processes independent of the original pathology or injury, originally in glomerular diseases.60 The group showed evidence of renal dysfunction, consisting of incident hypertension, proteinuria, and hematuria, in addition to change in renal function characterized the long-term course of patients who recovered from an episode of poststreptococcal glomerulonephritis.61 They subsequently expanded these notions to patients with other glomerular diseases, and with decrements in renal function nonspecifically.62 These metrics are used today in analyses of CKD in children. A variety of mechanisms associated with progressive injury in AKI patients is similar to that proposed for progression in CKD (Table 26.1, Table 26.3).1,2,16 These include the effects of systemic and intrarenal hypertension and hyperfiltration, tubular hypertrophy and atrophy, tubulointerstitial fibrosis, progressive glomerular sclerosis, arteriosclerosis, and disordered physiologic, humoral, and biochemical responses associated with CKD (such as PTH, FGF-23, inflammation, and hyperphosphatemia [Table 26.1]). In addition, endothelial injury, as part of tubular interstitial injury, and vascular dropout may set up vicious cycles of hypoxia and ischemia, in turn affecting renal cellular function (Table 26.3).63 The state of the interstitium has been known to be associated with long-term outcomes in many glomerular and tubular diseases for many years.64 AKI has been associated with interstitial infiltration, mediated by chemokines, resulting in an influx of

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[

Short-term Repair

][

Long-term Regeneration or Maladaptive Response

][

Chronic Phase

]

90 80 GFR, ml/min/1.73m2

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70 60 50 40 30 20 10 0 Time

FIGURE 26.2 Renal functional changes after AKI. Previous investigators have outlined possible courses of AKI over time: complete resolution of renal functional decline, rapid, irreversible progression to ESRD, and intermediate long-term courses with progressive decline or maintenance of renal function. Findings from the African-American Study of Kidney Disease and Hypertension (AASK study) suggest the individual trajectories of renal functional changes over time in CKD patients are not simple linear slope relationships interrupted by the steep, rapid sloped declines of AKI, but are rather complicated higher order curves which render modeling difficult. The severity of injury and, most importantly, the baseline level of function at the beginning of the AKI episode, likely determine the long-term course. The Y axis depicts the range of GFR, and the X axis time, in months and years. Different colors indicate different individual patients, with similar GFR before the beginning of an episode of AKI. The time frame for the AKI episode is illustrated with an arrow. The individual lines indicate distinct patients, with varying changes in GFR over time after an episode of AKI. Dotted lines indicate repair and long-term regenerative phases. The scope of outcomes however theoretically includes the entire range of the GFR (right margin, Y axis). Responses after AKI and during the subsequent course of disease may vary over several phases, which may differ between patients in timing: repair and regeneration and chronic maladaptive periods. Individual factors such as age, genetic susceptibilities, the robust nature of repair and regenerative processes compared to those associated with fibrosis, and prescribed therapy may change the slope of decline differentially during the phases. Repetitive episodes of AKI during the course of illness in patients with diminished GFR will make analyses more difficult.

macrophages, T cells, and neutrophils (Table 26.1).65,66 Such cellular responses can culminate in facilitation of repair and regenerative mechanisms, or might be associated with maladaptive responses such as enhancing fibrosis, or interfering with cellular responses. Studies have assessed the roles of arrest of the normal cell cycle, and epigenetic changes within renal epithelial and interstitial cells. These processes might be exacerbated by diets rich in sodium and protein (Table 26.3).2,67,68 A balance of injury and restorative factors underlies outcomes for the kidneys in patients with AKI and

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CLINICAL CONSIDERATIONS

TABLE 26.3

Selected Putative AKI-Specific Factors Related to Progressive Loss of Renal Function

Arrest of normal cell cycle p21 Epigenetic changes within renal epithelial and interstitial cells Hypoxia-inducible factors Heme oxygenase Angiogenic factors Repetitive injury Failed differentiation and sustained proinflammatory profibrotic signaling Progressive capillary loss Specific populations of immune cells including subpopulations of macrophages and T cells

CKD, or the combination of the two entities (Table 26.3).2 It may also be that repetitive insults play meaningful roles.16,69 Various mediators (such as p21) have been outlined as protective factors in AKI, but may be contributors to ongoing fibrosis, inflammation, and CKD, depending on temporal regulation and expression.1,2,16 Other factors associated with long-term outcomes after an episode of AKI include failed differentiation, and sustained proinflammatory profibrotic signaling, progressive capillary loss, and endothelialemesenchymal transformation, G2 M cell cycle block, and epigenetic changes.1,2,16 Hypoxia-inducible factor-1-a (HIF-1-a) has been outlined as a protective factor in AKI but may be a contributor to CKD.16 Heme oxygenase-1 protects against acute insults, but also suppresses inflammation. Complex interactions between heme oxygenase and TGF-b1, over time, in specific cell subsets, may have ameliorative or maladaptive consequences.16,69,70 The lack of kidney tissue from patients with AKI and suitable controls has been identified as a barrier to enhancing our understanding of factors associated with outcomes in patients with AKI.2,71 The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) supports the Assessment, Serial Evaluation and Subsequent Sequelae of AKI (ASSESS AKI) study, which prospectively evaluated long-term outcomes of hospitalized patients, with and without CKD, after an episode of AKI, to determine the natural history of AKI and delineate risk factors for progression and development of complications, including CVD. This study also prospectively collected biological samples that will aid future evaluation of associations between selected biomarkers and long-term outcomes.33

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CLINICAL CONSIDERATIONS Few patients with AKI receive follow-up after hospital discharge, by generalists, cardiologists, or nephrologists.1,72,73 Siew et al. demonstrated a low rate of referral of patients with AKI to nephrologists after hospital discharge in the Veterans Administration system.73 Severity of renal disease did not affect referral rates. A survey study of Canadian nephrologists suggested a substantial gap between the opinions of nephrologists regarding patients who should receive follow-up and actual processes of nephrology care after hospitalization with AKI.74 Both patients and healthcare providers have described important challenges to care after a hospitalization with AKI, which may affect health outcomes.75,76 Despite the relationships between AKI and CKD, not all survivors of AKI go on to develop CKD. However, identification of patients at high risk of CKD following AKI could be used to target specialized care to individuals at greater risk. A predictive model for progression of AKI to stage 4 or 5 CKD was developed in over 14,000 survivors of an AKI hospitalization with a baseline eGFR >45 mL/min/1.73 m2 from Alberta, Canada. The model was validated in over 2700 patients from Ontario, Canada.37 Six independent variables associated with advanced CKD following AKI hospitalization were combined in the model: older age, female sex, higher baseline S[Cr], albuminuria, greater severity of AKI, and higher S[Cr] at the time of discharge. A multivariable model based on these predictors was well-calibrated and achieved good discrimination for predicting advanced CKD in the external validation cohort. This model could be used at the time of hospital discharge to identify patients at high risk warranting specialized follow-up after AKI. We suggest patients with AKI at risk of developing CKD following discharge from the hospital should have periodic assessment of renal function and urinary albumin:creatinine ratio (UACR), to assess prognosis and outcome. Patients at high risk or who sustain severe or persistent decrements in renal function should have follow-up with a nephrologist.2 How to treat patients who have survived an AKI episode whether or not they have CKD is unclear.1,2 Care for patients without preexisting CKD, who sustained an episode of AKI, should include avoidance of nephrotoxic medications, which may include nonsteroidal antiinflammatory drugs (NSAIDs) and contrast agents.2 However, because of lack of appropriate studies, we do not know whether current practices employed in CKD care slow or worsen the progression of renal disease in patients, with or without CKD, who

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survive an episode of AKI.1,2 Addressing factors associated with poor outcomes in CKD patients, by treating hypertension, and optimizing diabetes care would seem to be useful, but the efficacy and safety of these interventions in patients after an episode of AKI is unknown.2 For example, more intensive blood pressure lowering resulted in more frequent episodes of AKI in the Systolic Blood Pressure Intervention (SPRINT) Trial,77 and patients with diabetes who develop AKI have been reported to be at higher subsequent risk of hypoglycemia, particularly when they experienced partial or no recovery of kidney function.78 Use of RAAS blockers has been associated with lower mortality after AKI but may carry an increased risk of renal complications, including hospitalization for hyperkalemia or recurrence of AKI, suggesting cautious monitoring is warranted in this setting.79 Low sodium diets and other dietary interventions should be evaluated in such patients. Patients who have had an episode of AKI superimposed on CKD, a common clinical occurrence, should be followed by nephrologists to ensure optimal care.

FUTURE DIRECTIONS Although recent studies have focused on outcomes based on KDIGO AKI definitions, and changes in S [Cr], several areas need emphasis in future research. Little is known from prospective observational data regarding the long-term course of ATN. It is important that the long-term consequences of AKI be delineated in patients with specific renal diseases, such as ATN, or AIN, as well as prerenal azotemia, and renal vascular disease. The setting in which AKI occurs may be critical to outcome. We know little specifically about AKI which occurs in intensive care unit settings.80 Although sepsis is understood to be an important common etiologic factor in the development of AKI, relatively little is known about patients who develop AKI after sepsis.2,16,80e82 In addition, the elderly are particularly susceptible to the development of AKI.1,26,80 Finally, only recently have we begun to investigate the long-term sequelae of pediatric and neonatal AKI as well as AKI in low- and middle-income countries.57,71,83 Studies in children with AKI are particularly important regarding the scope of the problem of CKD in the US and worldwide. If AKI is associated with even small changes in renal function, and the development of chronic disease is dependent, at least in part on time, perinatal status, developmental stage, early nutritional experiences, and absence of diagnostic and therapeutic services, the potential for children with serious illness in the neonatal period or in early life to develop CKD, which is unnoticed until adulthood, perhaps first during a physical examination for the military, an

occupational-associated insurance evaluation or a medical encounter for acute illness or traumatic episode, is enormous. If AKI is fundamentally associated with the development of CKD, it is imperative that we understand the course of events in children who survive AKI and come to medical attention in adolescence or young adulthood. Biomarkers have been sought to predict the susceptibility to AKI, the course of the disease, and progression of CKD.84e86 It will be important to validate fit-for-purpose biomarkers to predict long-term outcomes of patients with AKI, in the presence or absence of CKD, to determine both prognosis, and therapeutic response to interventions. Nephrologists caring for patients with AKI, and with AKI superimposed on CKD, urgently need evidence from well-designed, controlled clinical trials to guide the therapy of their patients.2,82,87 However, initial evaluations suggest therapeutic trials will need to be large and costly, and prevention trials must include very large numbers of participants.87 The NIDDK has held workshops to facilitate design of clinical trials for AKI patients.87 Designs considered included prevention trials, trials in specific patient populations, such as those with sepsis, or hospitalized in an intensive care setting, and evaluation of the challenges encountered in developing new therapeutics. The most recent workshop discussed mechanisms that drive susceptibility to future CKD and cardiovascular events and characterized key knowledge gaps to facilitate new strategies to improve clinical outcomes of patients with AKI after hospitalization.88 The NIDDK has also sought suggestions regarding research in the field through an electronic medium, the Kidney Research National Dialogue.71 Responses encompassed developing clinical trial tools, including refining proteomic and metabolomic approaches to diagnosis and prognosis, improving AKI patient phenotyping, including complex clinical, environmental and pharmacologic interactions, determining genetic links with disease susceptibility and outcomes, assessing, characterizing, and validating fit-for-purpose biomarkers in observational and clinical trial settings, focusing on the interplay between repair and regenerative processes in association with mechanisms engendering fibrotic responses, developing better and more clinically relevant animal models, enhancing the evaluation of human renal tissue samples, building public/private partnerships, including academia, regulatory agencies and industry, and performing longitudinal studies.71 Attention to the AKI stage, setting, and characteristics of the patient population will be critical for research resulting in the improvement of outcomes for patients with AKI in the presence and absence of CKD due to a variety of causes.

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REFERENCES

CONCLUSIONS AKI and CKD are interconnected syndromes. To care for patients, nephrologists, pediatricians, internists, critical care specialists, and public health professionals, as well as policy makers, must appreciate the individual components of the syndrome, as well as their combined nature. Identification and implementation of effective interventions and models of care for patients with AKI, CKD, and AKI superimposed on CKD will be necessary to decrease the progression of CKD, and the incidence of ESRD, as well as the incidence and progression of CVD. More knowledge is needed regarding the interplay of AKI and CKD in distinct populations, in particular clinical settings. Like Janus, the two-profiled Roman god, we must evaluate AKI and CKD simultaneously in research, as well as in past and present studies, to advance the care and outcomes of patients with this complex interdigitated syndrome of decrement in renal function.

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52. Zager RA. Biologic memory in response to acute kidney injury: cytoresistance, toll-like receptor hyper-responsiveness and the onset of progressive renal disease. Nephrol Dial Transplant 2013; 28(8):1985e93. 53. Rifkin DE, Coca SG, Kalantar-Zadeh K. Does AKI truly lead to CKD? J Am Soc Nephrol 2012;23(6):979e84. 54. Garg AX, Devereaux PJ, Yusuf S, Cuerden MS, Parikh CR, Coca SG, et al. Kidney function after off-pump or on-pump coronary artery bypass graft surgery: a randomized clinical trial. JAMA 2014; 311(21):2191e8. 55. Hsu CY. Yes, AKI truly leads to CKD. J Am Soc Nephrol 2012;23(6): 967e9. 56. Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, RosasArellano MP, et al. Long-term renal prognosis of diarrheaassociated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. J Am Med Assoc 2003;290(10): 1360e70. 57. Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL. 3-5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006;69(1):184e9. 58. Mammen C, Al Abbas A, Skippen P, Nadel H, Levine D, Collet JP, et al. Long-term risk of CKD in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study. Am J Kidney Dis 2012;59(4):523e30. 59. Ishani A, Nelson D, Clothier B, Schult T, Nugent S, Greer N, 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(3): 226e33. 60. Baldwin DS, Neugarten J, Feiner HD, Gluck M, Spinowitz B. The existence of a protracted course in crescentic glomerulonephritis. Kidney Int 1987;31(3):790e4. 61. Baldwin DS. Poststreptococcal glomerulonephritis. A progressive disease? Am J Med 1977;62(1):1e11. 62. Baldwin DS. Chronic glomerulonephritis: nonimmunologic mechanisms of progressive glomerular damage. Kidney Int 1982;21(1): 109e20. 63. Basile DP. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int 2007;72(2): 151e6. 64. Bohle A, Strutz F, Muller GA. On the pathogenesis of chronic renal failure in primary glomerulopathies: a view from the interstitium. Exp Nephrol 1994;2(4):205e10. 65. Duffield JS. Macrophages and immunologic inflammation of the kidney. Semin Nephrol 2010;30(3):234e54. 66. Kinsey GR, Sharma R, Okusa MD. Regulatory T cells in AKI. J Am Soc Nephrol 2013;24(11):1720e6. 67. Spurgeon-Pechman KR, Donohoe DL, Mattson DL, Lund H, James L, Basile DP. Recovery from acute renal failure predisposes hypertension and secondary renal disease in response to elevated sodium. Am J Physiol Renal Physiol 2007;293(1): F269e78. 68. Kaushal GP, Shah SV. Challenges and advances in the treatment of AKI. J Am Soc Nephrol 2014;25(5):877e83. 69. Nath KA, Croatt AJ, Haggard JJ, Grande JP. Renal response to repetitive exposure to heme proteins: chronic injury induced by an acute insult. Kidney Int 2000;57(6):2423e33. 70. Zager RA, Johnson AC. Progressive histone alterations and proinflammatory gene activation: consequences of heme protein/ironmediated proximal tubule injury. Am J Physiol Renal Physiol 2010; 298(3):F827e37. 71. Bonventre JV, Basile D, Liu KD, McKay D, Molitoris BA, Nath KA, et al. AKI: a path forward. Clin J Am Soc Nephrol 2013;8(9):1606e8.

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72. 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. 73. Siew ED, Peterson JF, Eden SK, Hung AM, Speroff T, Ikizler TA, et al. Outpatient nephrology referral rates after acute kidney injury. J Am Soc Nephrol 2012;23(2):305e12. 74. Karsanji DJ, Pannu N, Manns BJ, Hemmelgarn BR, Tan Z, Jindal K, et al. Disparity between nephrologists’ opinions and contemporary practices for community follow-up after AKI hospitalization. Clin J Am Soc Nephrol 2017;12(11):1753e61. 75. Silver SA, Saragosa M, Adhikari NK, Bell CM, Harel Z, Harvey A, et al. What insights do patients and caregivers have on acute kidney injury and posthospitalisation care? A single-centre qualitative study from Toronto, Canada. BMJ Open 2018;8(6): e021418. 76. Phipps DL, Morris RL, Blakeman T, Ashcroft DM. What is involved in medicines management across care boundaries? A qualitative study of healthcare practitioners’ experiences in the case of acute kidney injury. BMJ Open 2017;7(1):e011765. 77. Rocco MV, Sink KM, Lovato LC, Wolfgram DF, Wiegmann TB, Wall BM, et al. Effects of intensive blood pressure treatment on acute kidney injury events in the systolic blood pressure intervention trial (SPRINT). Am J Kidney Dis 2018;71(3):352e61. 78. Hung AM, Siew ED, Wilson OD, Perkins AM, Greevy Jr RA, Horner J, et al. Risk of hypoglycemia following hospital discharge in patients with diabetes and acute kidney injury. Diabetes Care 2018;41(3):503e12. 79. Brar S, Ye F, James MT, Hemmelgarn B, Klarenbach S, Pannu N. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with outcomes after acute kidney injury. JAMA Intern Med 2018;178(12):1681e90. 80. Cohen SD, Kimmel PL. Long-term sequelae of acute kidney injury in the ICU. Curr Opin Crit Care 2012;18(6):623e8.

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81. Bonventre JV, Basile D, Liu KD, McKay D, Molitoris BA, Nath KA, Nickolas TL, Okusa MD, Palevsky PM, Schnellmann R, RysSikora K, Kimmel PL, Star RA. Kidney Research National Dialogue (KRND) AKI: a path forward. Clin J Am Soc Nephrol 2013; 8(9):1606e8. https://doi.org/10.2215/CJN.06040613. Epub 2013 Jul 18. 82. Star R. Design issues for clinical trials in acute renal failure. Blood Purif 2001;19(2):233e7. 83. Abitbol CL, Rodriguez MM. The long-term renal and cardiovascular consequences of prematurity. Nat Rev Nephrol 2012;8(5):265e74. 84. Liu KD, Glidden DV, Eisner MD, Parsons PE, Ware LB, Wheeler A, et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med 2007;35(12):2755e61. 85. Chawla LS, Seneff MG, Nelson DR, Williams M, Levy H, Kimmel PL, 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(1):22e30. 86. Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, Hamano T, et al. Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. Kidney Int 2013;83(5):909e14. 87. Molitoris BA, Okusa MD, Palevsky PM, Chawla LS, Kaufman JS, Devarajan P, et al. Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings. Clin J Am Soc Nephrol 2012;7(5): 856e60. 88. NIDDK workshop: improving care for patients after hospitalization with AKI. Bethesda, MD: Natcher Conference Center; 2019. Available from: https://www.niddk.nih.gov/news/meetings-workshops/ 2019/improving-care-patients-hospitalization-aki.

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QUESTIONS AND ANSWERS

Question 3

Question 1

Which of the following clinical factors are associated with poor long-term outcomes of AKI?

A 58-year-old man underwent coronary artery bypass surgery. Postoperatively he developed AKI. He was treated with HD over a two week period. S[Cr] on discharge was 1.2 mg/dL. Which ONE of the following statements in NOT TRUE regarding his future risk?

A. B. C. D. E.

A. He is at higher B. He is at higher C. He is at higher CKD D. He is at higher

Answer: E All of these factors are associated with poor renal outcomes following an episode of AKI. See Table 26.3 for a more comprehensive list.

risk of developing CVD risk of developing ESRD risk of developing advanced stage

Level of initial kidney function Extent and severity of AKI Older age Lack of follow-up by physicians All of the above

risk of developing a malignancy

Answer: D There is no evidence that he is at higher risk of developing a malignancy making Answer D not true and the correct answer to this question. AKI has been linked with the development of subsequent CVD, CKD, and ESRD making Answers A, B, and C true.1,10,18e20

Question 2 A 63-year-old woman with normal kidney function is admitted with sepsis secondary to a urinary tract infection. She developed AKI during the hospitalization but recovered kidney function and did not require treatment with HD. Which ONE of the following is true regarding her subsequent hospital course? A. She is NOT at higher risk of developing advanced stage CKD because there was no preexisting CKD before her episode of AKI B. She is NOT at higher risk of developing advanced stage CKD because her AKI episode did not require dialysis C. She has a higher mortality risk secondary to developing AKI D. She is NOT at higher risk of developing CVD Answer: C Answer C is true and the correct answer to this question. AKI leads to new CKD, progression of preexisting CKD, increased risk of entry into ESRD programs, and worsened mortality.1,20,27,28 Observational studies show a large proportion of patients with AKI, even in the absence of concurrent or preexisting CKD, progress to advanced stages of CKD, even if not treated with RRT during the index hospitalization, therefore Answers A and B are not true.1,10,24,28,32 Several large observational cohorts show patients who survive an AKI episode are at risk for both progression to CKD and increased cardiovascular events making Answer D not true.14,25,38

Question 4 Which of the following factors places CKD patients at higher risk for developing AKI? A. B. C. D.

Failure of autoregulation Abnormal vasodilatory responses Lack of renal reserve Failure of renal tubular mechanisms to reabsorb sodium and water E. All of the above

Answer: E All of these factors place CKD patients at higher risk for developing AKI. In addition, frequent hospitalizations with the potential for iatrogenic mishaps or exposure to nephrotoxins, treatment to achieve volume depletion, susceptibility to the use of antihypertensives, overvigorous medication, the use of RAAS blockers, the use of nephrotoxins, and age-related physiologic changes also increase the risk of developing AKI.1,16,26,48

Question 5 Which of the following factors have been proposed as factors associated with progressive loss of renal function following AKI? A. B. C. D. E.

Tubulointerstitial fibrosis Progressive glomerular sclerosis Endothelial injury and vascular dropout Tubular hypertrophy and atrophy All of the above

Answer: E All of these factors have been associated with progressive loss of renal function following AKI. See Table 26.1 for a comprehensive list of factors.

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QUESTIONS AND ANSWERS

Question 6 A 47-year-old man is discharged after a prolonged hospitalization for sepsis following an episode of severe pancreatitis. Baseline S[Cr] was 1.1 mg/dL. He required three weeks of treatment with HD and eventually recovered kidney function. Discharge S[Cr] was 2.1 mg/dL. Which ONE of the following should be part of his post discharge management? A. No renal follow-up is necessary because he is recovering from his episode of AKI and no longer requires dialysis B. Renal follow-up is needed to monitor his renal recovery C. The patient should be seen one year following discharge to recheck S[Cr]

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D. It is safe to use NSAIDs because he has recovered renal function Answer: B Answer B is correct. We suggest patients discharged from the hospital should have periodic assessment of renal function and UACR, to assess prognosis and outcome. Patients with severe decrement in renal function should have follow-up by a nephrologist, therefore Answer A is incorrect. Answer C is incorrect because one year follow-up is too late to assess his course. Answer D is incorrect as he has not fully recovered kidney function and is at higher risk for rehospitalization with recurrent AKI, which could result from NSAID use.

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