Chronic-on-acute kidney injury

Although older teaching suggested that patients who survived an episode of acute kidney injury (AKI) had a benign course, recent studies have demonstrated that AKI is strongly associated with increased risk for development of progressive chronic kidney disease (CKD) and longer-term mortality. Much as we understand that CKD predisposes to the development of AKI, we must recognize that the relationship is bidirectional and that our patients with AKI are at risk for chronic-on-acute kidney disease. Although older teaching suggested that patients who survived an episode of acute kidney injury (AKI) had a benign course, recent studies have demonstrated that AKI is strongly associated with increased risk for development of progressive chronic kidney disease (CKD) and longer-term mortality. Much as we understand that CKD predisposes to the development of AKI, we must recognize that the relationship is bidirectional and that our patients with AKI are at risk for chronic-on-acute kidney disease. The past decade has witnessed several paradigmatic shifts in our understanding of acute kidney disease. The first was the recognition that even small decrements in kidney function impacted clinical outcomes. For example, Chertow and colleagues demonstrated that increases in serum creatinine of as little as 0.3mg/dl were associated with an increase in in-hospital mortality of 80%.1.Chertow G.M. Burdick E. Honour M. et al.Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.J Am Soc Nephrol. 2005; 16: 3365-3370Crossref PubMed Scopus (2502) Google Scholar As a result, there has been a shift in nomenclature away from a primary focus on organ failure (acute renal failure) to a focus on lesser degrees of organ injury (acute kidney injury) and the development of new definitions and staging systems to describe acute kidney injury.2.Bellomo R. Ronco C. Kellum J.A. et al.Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Crit Care. 2004; 8: R204-R212Crossref PubMed Google Scholar,3.Mehta R.L. Kellum J.A. Shah S.V. et al.Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.Crit Care. 2007; 11: R31https://doi.org/10.1186/cc5713Crossref PubMed Scopus (5225) Google Scholar The second paradigmatic change was the recognition of the important interplay between acute kidney injury (AKI) and chronic kidney disease (CKD). While it was well recognized that patients with CKD are predisposed to the development of AKI, previous teaching held that the majority of patients who survived an episode of AKI recovered kidney function. Although it was known that a small percentage of patients surviving an episode of AKI might be left with chronic renal impairment, the renal prognosis for the vast majority of patients surviving an episode of AKI was generally believed to be good. As recently as 2005, an epidemiologic surveillance study reported that ‘although the majority of patients with (severe acute renal failure) will die, most survivors will become independent from renal replacement therapy within a year,’ but it was silent about the level of kidney function.4.Bagshaw S.M. Laupland K.B. Doig C.J. et al.Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study.Crit Care. 2005; 9: R700-R709Crossref PubMed Google Scholar More recently, however, multiple studies have highlighted the interplay among AKI, progressive CKD, and longer-term mortality risk.5.Ishani A. Xue J.L. Himmelfarb J. et al.Acute kidney injury increases risk of ESRD among elderly.J Am Soc Nephrol. 2009; 20: 223-228Crossref PubMed Scopus (885) Google Scholar, 6.Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 7.Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar, 8.Lafrance J.P. Miller D.R. Acute kidney injury associates with increased long-term mortality.J Am Soc Nephrol. 2010; 21: 345-352Crossref PubMed Scopus (432) Google Scholar, 9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar In one of the first analyses linking AKI to progression of CKD, Ishani and colleagues used a 5% random sample of US Medicare beneficiary claims data linked to the end-stage renal disease (ESRD) incidence database from the US Renal Data System.5.Ishani A. Xue J.L. Himmelfarb J. et al.Acute kidney injury increases risk of ESRD among elderly.J Am Soc Nephrol. 2009; 20: 223-228Crossref PubMed Scopus (885) Google Scholar They found that in hospitalized patients older than 67 years, AKI was associated with a nearly sevenfold increase in the hazard of developing ESRD during the ensuing 2 years in comparison with patients who did not develop AKI. When stratified on the basis of preexisting CKD, acute-on-chronic kidney disease was associated with a 41-fold increase in the hazard of ESRD, de novo AKI with a 13-fold increase, and CKD in the absence of AKI with a nearly 8.5-fold increase in comparison with patients without either acute or chronic kidney disease. AKI was also associated with a 2.4-fold increased hazard of death. Lo and colleagues evaluated the risk of progressive CKD in a cohort of 556,090 adult patients with baseline estimated glomerular filtration rates (eGFRs) of at least 45ml/min per 1.73m2 who were hospitalized in Kaiser Permanente of Northern California Health System over an 8-year period.6.Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar Patients who had dialysis-requiring AKI but were dialysis-independent 30 days after hospital discharge had a 28-fold higher risk of having an eGFR less than 30ml/min per 1.73m2 as compared with patients who did not have dialysis-requiring AKI. Dialysis-requiring AKI was also associated with a more than twofold increased risk of death. Similarly, using administrative databases from the Canadian province of Ontario, Wald and colleagues found an incidence rate of ESRD of 26.3 per 1000 person-years among 3769 people who survived an episode of AKI requiring dialysis and were dialysis-independent 30 days after hospital discharge as compared with an incidence of 9.1 per 1000 person-years among 13,598 matched controls who did not have AKI, for an adjusted hazard ratio of 3.2.7.Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar Unlike in the prior study, however, Wald and colleagues did not observe an increase in long-term mortality risk associated with AKI. Two additional studies used data from the US Department of Veterans Affairs Healthcare System to assess the impact of AKI on long-term mortality and progression of CKD.8.Lafrance J.P. Miller D.R. Acute kidney injury associates with increased long-term mortality.J Am Soc Nephrol. 2010; 21: 345-352Crossref PubMed Scopus (432) Google Scholar,9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar Lafrance and Miller identified 82,711 patients with non-dialysis-requiring AKI among 864,933 hospitalized patients.8.Lafrance J.P. Miller D.R. Acute kidney injury associates with increased long-term mortality.J Am Soc Nephrol. 2010; 21: 345-352Crossref PubMed Scopus (432) Google Scholar In this cohort, the adjusted mortality risk in patients with AKI who survived at least 90 days after hospital discharge was approximately 40% higher than that in patients without AKI. In addition, there was a graded relationship between mortality risk and severity of AKI. In a separate analysis, Chawla and colleagues observed a markedly increased risk of development of advanced CKD (eGFR <30ml/min per 1.73m2) in patients with a baseline eGFR greater than 60ml/min per 1.73m2 who were hospitalized with AKI as compared with patients without AKI who were hospitalized for pneumonia or myocardial infarction.9.Chawla L.S. Amdur R.L. Amodeo S. et al.The severity of acute kidney injury predicts progression to chronic kidney disease.Kidney Int. 2011; 79: 1361-1369Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar Risk factors for development of CKD included a diagnosis of acute tubular necrosis (as compared with other etiologies of AKI), need for renal replacement therapy, severity of AKI (graded on the basis of maximal increase in serum creatinine), serum albumin, and age. Extending these lines of investigation, Bucaloiu and colleagues10.Bucaloiu I.D. Kirchner H.L. Norfolk E.R. et al.Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury.Kidney Int. 2012; 81: 477-485Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar (this issue) analyze the impact of AKI on mortality and on progressive kidney disease in a cohort of patients with no evidence of preexisting CKD. In contrast to the earlier studies, however, they limit their analysis to patients who manifested complete recovery of kidney function on the basis of return of the eGFR to within 90% of the baseline value within 90 days. Patients with AKI were then matched, by the use of a propensity score for the development of AKI, with up to three contemporaneous controls. Of an initial cohort of 39,477 people, 1997 patients met the criteria for recovered AKI; 1610 of these AKI patients were able to be propensity-matched with 3652 control patients. During a median follow-up of slightly more than 3 years, the mortality rate was approximately 50% higher in patients who had AKI than in patients without AKI (2.8 deaths per 1000 patient-years vs. 1.9 deaths per 1000 patient-years). The risk of de novo CKD was increased more than twofold in the AKI cohort (incident rate of 28.1 per 1000 patient-years vs. 13.1 per 1000 patient-years). When incident CKD was added to the Cox proportional hazard model for mortality, the hazard ratio was attenuated from 1.50 (95% confidence interval, 1.21–1.85; P=0.0002) to 1.18 (95% confidence interval, 0.95–1.46; P=0.13). Thus, the authors suggest that the increased mortality risk following an episode of AKI is mediated by the development of CKD rather than the AKI event itself (Figure 1a). This conclusion is further suggested by the observation that mortality rates in patients with and without AKI who did not develop CKD were similar, while the mortality rate in patients with AKI who subsequently developed CKD was 3.6-fold greater. This elegant analysis by Bucaloiu and colleagues10.Bucaloiu I.D. Kirchner H.L. Norfolk E.R. et al.Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury.Kidney Int. 2012; 81: 477-485Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar represents the first demonstration that even in patients who manifest virtually complete recovery of kidney function, AKI is associated with a subsequent increased risk for development of CKD. However, several limitations must be considered in interpreting these findings. First, the authors were unable to propensity-match all of the AKI patients with non-AKI controls. The unmatched AKI patients represented a substantially different cohort—they were older, had a higher burden of comorbidities, were more likely to require critical care, and had longer hospitalization. Thus, the extrapolation of the study results to these patients must be undertaken with caution; however, this unmatched cohort was even more likely to develop CKD. Second, despite the careful propensity-score matching that was used, as with any observational study, there remains a risk of residual confounding and bias. In addition, because of reliance on non-protocolized laboratory testing, there is a further risk that bias may have been introduced. Finally, it is important to recognize that observational associations cannot confirm causality. The authors identify numerous predictors of de novo CKD, including increasing age, lower baseline eGFR, burden of comorbidities, hypertension, heart failure, hypoalbuminemia, and severity of AKI. With the exception of severity of AKI, these are also risk factors for the development of AKI. Thus, it remains possible that AKI is only a marker and not the mediator of the development of CKD (Figure 1b). Whether marker or mediator, these results reinforce the need for follow-up nephrologic care for patients who sustain an episode of AKI, even if they have virtually complete return to baseline kidney function. Much as we understand the risk of acute-on-chronic kidney disease, we must now recognize that the relationship is bidirectional and that our patients with AKI are at risk for chronic-on-acute kidney disease.