The Inexorable Rise of AKI
Authors: Edward D. Siew, Jonathan Himmelfarb
Journal: Journal of the American Society of Nephrology (2012)

The treatment of anuria should be conservative. If circulatory failure is present, appropriate steps should be taken to correct it. Otherwise, therapy is limited to the balanced maintenance of the patient until the kidneys have a chance to effect recovery. Homer Smith 19511 This year marks the 60th anniversary of application of the Kolff-Brigham dialyzer to Korean War casualties with trauma-related AKI. This medical marvel, implemented in the field under extreme conditions, substantially reduced the mortality associated with anuric renal failure.2 The use of dialysis has benefited countless hospitalized patients with AKI since; yet continued celebration of this achievement must be tempered by lack of similar progress in the prevention and treatment of accompanying parenchymal kidney injury. The latter remains one of the great challenges for kidney disease researchers and clinicians in the 21st century. In this issue of JASN,3 Hsu and colleagues leverage data from a large, nationally representative sample of hospital databases to examine secular trends in the incidence of dialysis-requiring AKI. Identifying over a million cases between 2000 and 2009, the authors uncover increases in population-based incidence rates of >10% per year with a near tripling in the absolute number of annual cases. Subgroup analyses indicate that increases appear to be most robust among elderly individuals (aged >65 years), men, and non-Hispanic blacks. Attempting to pinpoint underlying causes for these alarming trends, the investigators adjust for changes in demographics, parallel increases in known AKI precipitants including acute heart failure, sepsis, and critical illness, and more liberal application of cardiac catheterization. Yet the aggregate effect of these factors only account for a fraction of the increase in rates of dialysis-requiring AKI observed. Of importance, the authors demonstrate that although the human toll of this disease has risen proportionally to the increase in incidence (as reflected in absolute number of hospital deaths), the individual risk for death during hospitalization appears to be modestly decreasing. Hsu and colleagues should be commended for effectively examining and updating national trends in AKI among hospitalized patients. The use of reimbursement-linked procedure codes, although perhaps not fully validated, nevertheless likely captured the main outcome with high fidelity and low misclassification. Coupling findings to US Census data also allows for further estimates of the population-based incidence of disease, thus helping to frame the important public health implication of these findings. Results from this study are congruent with earlier observations.4 Although the reasons for this trend are incompletely understood, the authors' current and previous findings suggest that the observed increases are not completely attributable to rising inpatient acuity or changes in coding practices. It is notable that a previous study using a similar dataset also revealed continuing declines in mortality from as high as 41.3% in 1988 to 28.1% in 2002,4 which decreased further to 23.5% by 2009 in this study. However, attributing the magnitude of such an improvement to a revolution in supportive care alone, rather than to a significant change in case-mix, should be viewed with healthy skepticism. For example, because CKD is the predominant premorbid risk factor for AKI,5 an increase in the prevalence of CKD in the hospitalized population would be a plausible explanation for both the increasing use of dialysis and the observed decline in mortality. Although the authors point out that only modest increases in the population-based prevalence of CKD have occurred, it is not clear if the same holds true for hospitalized populations. Appreciation for the role of other expanding risk factors including obesity and proteinuria is also warranted.5,6 Regardless, these findings reinforce calls for greater translational research that challenges older assumptions of disease mechanism and support recent collaborative efforts to reevaluate the approach to clinical trials where progress has been lacking.7,8 In 2002, Sutton et al. described four distinct phases of AKI including initiation, extension, maintenance, and recovery.9 Despite considerable effort and resources, few interventions directed at the initiation or extension of injury have translated to human efficacy. Simultaneously, dialysis continues to remain the backbone of therapy for cases of severe injury. However, recent well executed trials suggest that we may already be approaching a therapeutic plateau in the value of dialytic therapy during the maintenance phase of injury.10,11 Collectively, these observations impart critical challenges upon the health care system including how to: optimally care for a clearly and rapidly growing population of AKI survivors at risk for long-term loss of kidney function, and how to effectively extend effort and resources beyond the early phases of injury to identify factors that can reduce irreversible loss of kidney function and its attendant complications. Preclinical data indicate that injured kidneys are increasingly vulnerable to further injury due to underlying loss of myogenic autoregulation, medullary hypoxia, and chronic inflammation.12 Accumulating data extending these findings to the clinical setting reveal that severe AKI is a major and independent accelerant of long-term loss of kidney function.13 A concerning implication of the findings is that dialysis-requiring AKI, while remaining the most visible and recognizable form of AKI to consulting nephrologists, represents only a minority of the increasing public health burden from AKI. A convergence of data are now emerging from both the AKI and CKD literature suggesting that progression of kidney disease in the modern era is often nonlinear and frequently punctuated by repeated episodes of nondialysis-requiring AKI.14,15 These more insidious AKI events underscore that from the public health standpoint, the accelerated path to ESRD may be an outcome as equally important as the shorter-term effects on morbidity and mortality. The further we draw the curtain back on the longitudinal effect of AKI, the greater the importance of identifying factors that increase the risk for worsening long-term injury. Little is currently known about processes of care that positively or negatively influence the rate of decline in kidney function after AKI. We need strategies to better identify those with a high likelihood of recovery and to develop optimal outpatient dialysis and supportive strategies to augment that recovery. In patients unlikely to recover, needed areas of improvement include facilitation of timely access placement and transplant referral for those who are eligible as well as better communication over long-term goals of care. The importance of the latter occurring before hospitalization, particularly among those with or experiencing premorbid decline in functional status, may be especially relevant in elderly individiuals,16 one of the fastest growing groups highlighted in this work. In the greater population of patients with nondialysis-requiring AKI, improving recognition that an AKI event has occurred and identifying modifiable care elements that can impair recovery or predispose to further injury are warranted. Recently launched prospective studies that target a better understanding of the mechanisms and markers that govern outcomes after AKI will be instrumental in this regard.17 In summary, AKI represents one of the most common problems encountered by nephrologists in the clinical care of hospitalized patients, yet the true effect on the public health has been underestimated, and is growing. The sage advice offered a half-century ago by Homer Smith, which has been time tested, will not suffice for the 21st century. We desperately need earlier and better diagnostics, and most important, proven preventative and early therapeutic therapies that can be delivered to the vulnerable kidney parenchyma at a time when disease processes are reversible. Lessening the future burden from this condition will require galvanizing ongoing efforts to translate novel approaches into routine treatment and prevention strategies. Disclosures E.D.S. reports being a consultant for Alere Inc. J.H. reports being a consultant for Abbott, Affymax, and Thrasos. E.D.S. is supported by National Institutes of Health Grant 5K23 DK088964-02. J.H. is supported by National Institutes of Health Grants UO1 DK082179, RO1 HL065193, RO1 HL070938, UO1 DK084012, RO1 DK091584, UH2 TR000504, and RO1 HL030946.