In this large diverse contemporary cohort of patients receiving usual clinical care, we found that although most patients who suffered dialysis-requiring ARF and survived did recover sufficient kidney function to become dialysis independent in the short run, there was a greatly increased relative risk of developing progressive CKD (including ESRD) in the months to years after hospital discharge. Furthermore, ARF was independently associated with an increased risk of long-term mortality.
The underlying mechanism of the manner in which ARF leads to progressive CKD is not completely understood. But renal parenchymal injury sustained during episodes of ARF may lead to permanent tubulointerstitial fibrosis and a reduction in the number of functioning nephrons. Furthermore, an episode of ARF may—on the basis of animal models—lead to permanent damage to the renal micro-vasculature, and trigger inflammatory and fibrotic signaling pathways that predispose to future accelerated declines in GFR.17-23
As alluded to earlier, until last year, basically all previous studies of renal outcomes after ARF were limited by their case series design and lack of non-ARF comparison individuals.14,15
They also often had limited generalizability because of the nature of the patients studied (for example, only patients treated with continuous renal replacement therapies24
or only those who were in an intensive care unit).25,26
Recently, Ishani et al
showed among Medicare beneficiaries (aged
67 years) that ARF was independently associated with the future development of ESRD with an adjusted hazard ratio of 13 in the absence of documented CKD. However, both CKD and ARF were determined in that study using administrative diagnostic codes that are known to be insensitive and suffer from ‘code creep’ bias.28,29
Hence, it is not possible to assess the degree to which their observation was confounded by, for example, the level of pre-ARF renal dysfunction,30
as patients with lower GFR are more likely to develop both ARF31
Newsome et al
showed that among elderly Medicare patients suffering from acute myocardial infarction, in-hospital acute changes in serum creatinine (peak vs first inpatient serum creatinine) were independently associated with long-term risk of ESRD. However, residual confounding remains a concern, given their finding that seemingly minimal changes in serum creatinine concentration (0.1 mg per 100 ml) increased future risk of ESRD by as much as 45%, even after multivariable adjustment.
Our study extends this literature in several important ways. Our study population was more diverse in terms of age and underlying disease, and hence our results should be more generalizable. We used actual observed outpatient (calibrated) serum creatinine levels to define baseline kidney function. We were able to provide a more comprehensive view of the sequelae of ARF by obtaining data not only on ESRD27,33
but also on cases of progressive CKD (estimated GFR <30 ml/min per 1.73 m2
). The magnitude of renal injury was clearly defined and chart validation was performed to validate the ascertainment of ARF (100% positive predictive value). We chose to study ARF episodes of sufficient severity (requiring dialysis) in which there would be a pathophysiological likelihood of a permanent residual renal parenchymal damage. We used matching, in addition to regression, models to adjust for potential confounding.30
Finally, we conducted a series of sensitivity analyses that enhance our confidence in the robustness of the reported effect sizes.
Our findings have important public health and population epidemiology implications. The incidence of ARF has increased substantially over the past few decades.3-5
We previously documented the very high risk of ESRD after acute chronic renal failure16
and we now show that, among the much larger number of patients with a preexisting normal or near normal kidney function, dialysis-requiring ARF greatly increases the risk of subsequent progressive CKD. These trends may help to explain the somewhat paradoxical observation that growth in the incidence of treated ESRD in the United States has outpaced growth in the prevalence of CKD,34
as well as in the prevalence of risk factors for kidney failure such as diabetes mellitus.35
Our findings show that the array of clinical consequences of ARF extends long after hospitalization.36
Moreover, if successful strategies of ARF prevention could be developed, they may reduce the incidence of ESRD.37
From a research point of view, future studies of interventions in ARF should examine not only inpatient outcomes38-40
but also extend follow-up beyond discharge toevaluate the impact of different treatment strategies on the subsequent level of kidney function (beyond the absence of dialysis dependency). Our study also contributes toward a novel insight into risk factors for ESRD. It is noteworthy that over an 8-year period of follow-up, we did not observe any cases of ESRD among patients who had baseline-estimated GFR
45 ml/min per 1.73 m2
, unless there was superimposed dialysis-requiring ARF. Studies on ESRD risk factors in the past have not considered the role of ARF,32,41-43
but the very high relative risk associated with ARF merits it being included among other more established ESRD risk factors, such as hypertension or diabetes.
Our findings also have important clinical implications. Given these data, ARF should not be viewed as a transient, self-limited problem requiring no additional medical attention after hospital discharge. Currently, only a minority of patients who suffered ARF are being followed up by nephrologists or are undergoing testing for evidence of subtle kidney disease or of risk factors for future loss of kidney function (such as albuminuria).44
Changing this and early institution of preventive measures, such as strict blood pressure control or aggressive renin–angiotensin blockade, may reduce the high risk of progressive CKD documented after ARF. Preventing the development of progressive CKD may also ameliorate the increased risk of death observed among survivors of ARF, as CKD is a strong and independent risk factor for cardiovascular disease and overall mortality.45
The limitations of this study need to be mentioned. We only studied patients who suffered dialysis-requiring ARF. Hence, we are unable to ascertain the impact of less-severe degrees of ARF/acute kidney injury. The precise etiology that led to ARF was not always clear; but it would be unlikely for dialysis to be needed for reversible pre-renal or post-renal causes, and the most common cause of intrinsic ARF among hospitalized patients is acute tubular necrosis.1,2
Our chart review findings () are consistent with this. As our study was conducted among Kaiser health-plan enrollees, our results might not be entirely applicable to uninsured patients or to other health-care settings, although our cohort was diverse in terms of age, sex, race/ethnicity, and other factors. We did not obtain information on the graded severity of proteinuria, which was classified dichotomously. We did not analyze whether proteinuria or hypertension worsened after ARF. The observation that the adjusted relative risks for progressive CKD were greater for higher (
60 ml/min per 1.73 m2
) than for lower (46–59 ml/min per 1.73 m2
) estimated GFR is due to the low absolute risk of progressive CKD among those with a more preserved kidney function.
In summary, our findings underscore the important role of dialysis-requiring ARF in determining the likelihood of progressive CKD among persons with a normal or near normal kidney function. Although it has been long recognized that dialysis-requiring ARF is associated with short-term inpatient mortality and morbidity, more attention now needs to be focused on the long-term sequelae of ARF months to years after hospital discharge.