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review article
Julie R. Ingelfinger, M.D., Editor
F
From the Department of Medicine, Divi or more than 40 years, nephrologists have classified diminished
sion of Intensive Care Medicine, and the kidney function as two distinct syndromes acute and chronic kidney failure.
Division of Nephrology, Washington, DC,
Veterans Affairs Medical Center (L.S.C.), Whereas chronic kidney disease was recognized in the 19th century, acute
and the Department of Anesthesiology renal dysfunction became evident during the London Blitz of World War II, with the
and Critical Care Medicine (L.S.C.) and realization that crush injuries could cause dramatic but often reversible cessation of
Department of Medicine, Division of Renal
Diseases and Hypertension (L.S.C., P.L.K.), renal function. The disease states and stages of both acute and chronic renal syn-
George Washington University Medical dromes are delineated according to the serum creatinine concentration or the glo-
Center both in Washington, DC; and merular filtration rate (GFR), functional markers that were identified in the early
the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK), 20th century.1 Advanced renal impairment in both syndromes is treated with dialysis.
National Institutes of Health (NIH), Bethes During the past decade, separate conceptual models for chronic kidney disease2
da, MD (P.W.E., R.A.S., P.L.K.). Address re and acute kidney injury3 were developed to facilitate organized approaches to clinical
print requests to Dr. Kimmel at the NIDDK,
NIH, 6707 Democracy Blvd., Bethesda, MD research and trials. However, recent epidemiologic and mechanistic studies suggest
20892, or at kimmelp@extra.niddk.nih.gov. that the two syndromes are not distinct entities but rather are closely interconnected
N Engl J Med 2014;371:58-66. chronic kidney disease is a risk factor for acute kidney injury, acute kidney injury
DOI: 10.1056/NEJMra1214243 is a risk factor for the development of chronic kidney disease, and both acute kidney
Copyright 2014 Massachusetts Medical Society. injury and chronic kidney disease are risk factors for cardiovascular disease (Fig. 1).4
Until 2004, acute renal failure was generally defined, with some variations, as a sud-
den increase in the serum creatinine concentration, often accompanied by decreased
urine output.3 A time-honored differential diagnosis included prerenal azotemia,
postrenal urinary tract obstruction, and intrinsic renal diseases (usually categorized
anatomically), including renal vascular disease, glomerulonephritis, acute interstitial
nephritis, and acute tubular necrosis.3,5 Recently developed consensus functional
definitions on the basis of specific changes in the serum creatinine concentration
and urine volume now complement anatomical approaches to diagnosis.3,6 These
definitions have standardized the study of acute kidney injury,6 allowing the clas-
sification of patients into subgroups with graded outcomes (Table 1). However,
these definitions do not incorporate in the diagnostic schema the importance of the
various causes of acute kidney injury (e.g., prerenal azotemia vs. intrinsic acute
kidney injury).3 Potential biomarkers to predict risk, diagnosis, prognosis, and ther-
apeutic response in patients with acute kidney injury are being identified and evalu-
ated in clinical studies. Despite some progress, the promise of biomarkers that can
be used to classify and stratify patients according to risk has not yet been achieved.3,4
episode of acute kidney injury may be mediated do not return to their resting state38,40,43 owing
by the intervening development of chronic kid- in part to epigenetic factors.38 Some of these
ney disease, but the sequelae of acute kidney maladaptive processes are exacerbated by high-
injury may directly increase the risk of cardio- sodium and high-protein diets.27,44 However,
vascular disease by means of inflammatory or the role of individual cell types in kidneys, dur-
other pathways.33,34 ing ongoing stages of injury or recovery, in the
complex in vivo microenvironment in humans
is not completely understood.42,45
PRO GR E SSION OF CHRONIC
K IDNE Y DISE A SE A F TER The course of renal disease after an episode
ACU TE K IDNE Y INJ UR Y of acute kidney injury is determined by the ex-
tent of the decrement in GFR, the reversibility of
Although the mechanisms underlying progres- the injury, and the temporal balance among ef-
sion of renal dysfunction in humans are incom- fective and maladaptive repair and regenerative
pletely understood, studies in animals delineate mechanisms.4,27 Repetitive insults may cause
a number of causal pathways including mal- worsened long-term outcomes.24,46,47 Cell-cycle
adaptive repair, disordered regeneration, or both mechanisms and mediators such as heme oxygen-
that may potentiate ongoing organ dysfunc- ase 1, hypoxia-inducible factors, vascular endothe-
tion.4,27 Baldwin and colleagues in a series of stud- lial growth factor, and transforming growth fac-
ies first proposed that the progression of chronic tor 1 have been identified as protective factors
kidney disease might occur by means of processes in acute kidney injury, but some also may con-
independent of the initiating acute pathologic dis- tribute to the development of chronic kidney dis-
order or injury.35 Cascading mechanisms associ- ease.47-50 The chronic dysregulation of such fac-
ated with progressive injury include the effects of tors and the complex interactions between their
systemic and intrarenal hypertension and glomeru- expression and counterregulation over time may
lar hyperfiltration, tubular hypertrophy and atro- determine the character and extent of fibrotic
phy, tubulointerstitial fibrosis, progressive glomer- responses27,38,40,42,50 (Fig. 2). The roles of these
ular sclerosis, arteriosclerosis, genetic susceptibility, factors, as well as the roles of vasoactive media-
and the disordered humoral responses that are as- tors and mediators of progressive fibrosis such
sociated with chronic kidney disease.4,27,36 as transforming growth factor , are only begin-
Some pathologic processes (evaluated primarily ning to be delineated in animal models. These
in animal models) that persist after acute kidney mechanisms all have the capacity to interact,
injury are similar to those that have been thought synergistically accelerating loss of function. Many
to cause the progression of chronic kidney dis- of the mechanisms implicated in the develop-
ease. Endothelial injury, as part of tubulointer- ment and progression of chronic kidney disease
stitial damage, and vascular dropout may engen- and cardiovascular disease after an episode of
der vicious cycles of tissue hypoxia and ischemia, acute kidney injury may be targeted by conven-
in turn affecting renal cellular function.37 The tional therapies.26,27,50
combination of vascular insufficiency, glomerular
hypertension, and interstitial fibrosis is a perni-
CHRONIC K IDNE Y DISE A SE A S a R ISK
cious set of self-reinforcing mechanisms that per- FAC T OR FOR ACU TE K IDNE Y INJ UR Y
petuates injury, dampens repair, and causes pro-
gressive tissue damage (Fig. 2).4,27 Other factors The clinical consequences of acute kidney injury
initiated by acute kidney injury include dysreg- superimposed on chronic kidney disease, or
ulated apoptosis; abnormal cellular responses acute-on-chronic renal failure, have been recog-
including those of epithelial cells, pericytes, nized but poorly evaluated.51 Patients with chronic
myofibroblasts, and infiltrating immune and bone kidney disease may be at risk for the development
marrow cells; failed differentiation and sustained of transient decreases in renal function consistent
proinflammatory profibrotic signaling; progres- with acute kidney injury. The mechanisms by
sive capillary loss; perturbation of normal cell- which these decreases occur include failure of
cycle mechanisms; and epigenetic changes within autoregulation, abnormal vasodilatation, suscep-
renal epithelial and interstitial cells (Fig. 2).27,38-42 tibility to antihypertensive agents, and side ef-
Fibrosis may continue after acute kidney injury fects of medication (with drugs such as diuretic
resolves, presumably because fibrogenic cells agents, antihypertensive agents, including inhib-
Endothelial
Peritubular rarefaction
capillary
Myofibroblasts
Fibrocytes T lymphocyte Dendritic cell
Pericyte
Procollagen
Macrophage
Tubular
cells Stem cell
Cellular debris
Lumen of tubule
Widened interstitium
with fibrosis
Brush border
Cell-cycle
effects
Necrosis and
apoptosis
Vascular dropout
Angiogenesis
Tubular dropout
Appropriate inflammation
Fibrosis Thinned basement
Epigenetic changes
Epigenetic changes membrane
Heme oxygenase 1
Premature cell-cycle arrest
Limited TGF- expression
Persistent inflammation
Macrophage subsets
Nephrotoxins
T-cell subsets
Repetitive injury
Tregs
Unopposed TGF-
BMP-7
Macrophage subsets
Interleukin-10
T-cell subsets
Interferon-
Interleukin-13
COLOR FIGURE
62 Draft 6 6/12/14
n engl j med 371;1nejm.orgjuly 3, 2014
Author Kimmel
2 Fig #
The New England Journal of Medicine
Title Acute kidney injury and chronic kidney
Downloaded from nejm.org on September 18, 2015. For personal use only. No other uses without permission.
disease are interconnected syndromes
patients who do not have preexisting kidney injury. Such exquisite control, however, may be
disease but do have evidence of renal injury in- quite difficult to achieve with discrete single-agent
clude, first, do no harm, by avoiding nephro- therapies and may require broad-acting agents
toxic medications, including nonsteroidal anti- targeting final common pathways. Unfortunately,
inflammatory drugs and radiocontrast agents. the set of mediators of cellular processes of these
In addition, we need to determine the appropri- complex responses to injury are not yet available
ate treatment for important risk factors for for clinical trials. During the coming decade,
chronic kidney disease such as diabetes and translational scientists and clinical-trial investi-
hypertension. The preventive use of inhibitors of gators will be challenged to determine the dose
the reninangiotensinaldosterone system, low- and timing of drug intervention and the clinical
sodium diets, or both should be evaluated in characteristics of patients who will have a response
such patients.2-4 However, we do not know to such therapies.
whether these therapeutic approaches amelio- We need new therapeutic approaches to acute
rate or worsen outcomes in patients with acute kidney injury, evidence from well-designed, con-
kidney injury or in those with combinations of trolled prevention trials, and trials in specific
acute kidney injury and chronic kidney disease. patient populations. Attention to the stage, dura-
Patients who have had acute-on-chronic epi- tion, and clinical setting of acute kidney injury in
sodes of acute kidney injury and chronic kidney conjunction with coexisting conditions is essen-
disease should be followed by primary care tial for future interventional research and clin
physicians as well as nephrologists to ensure ical observation studies. Developing proteomic and
the highest standards of care.4,22,51 metabolomic approaches to diagnosis and prog-
Results from previous trials of dialysis and nosis, improving the phenotyping of patients with
pharmacologic therapies in patients with severe acute kidney injury (including complex clinical,
acute kidney injury that have focused on diverse environmental, and pharmacologic interactions),
vascular, regeneration, and inflammatory targets determining genetic links with disease suscepti-
have not generated useful, clinically meaningful bility and outcomes, and assessing, characteriz-
therapies.3 Intertwined molecular pathways are ing, and validating fit-for-purpose biomarkers
involved in repair, regeneration, and maladap- and functional stress tests in observational and
tive responses, which may culminate in fibrosis. clinical trials may enhance studies and aid the
Studies in animals regarding the pathophysio- translation of basic science results to bedside
logical features of acute kidney injury and poten- therapeutic approaches in order to improve out-
tial therapies generally have not considered the comes in patients with acute kidney injury in the
multiplicity of responses simultaneously in ex- presence or absence of chronic kidney disease.
perimental evaluations. Signals that are protec- The views expressed in this article do not necessarily reflect
tive in early stages may promote damage or im- those of the National Institute of Diabetes and Digestive and Kid-
ney Diseases (NIDDK), the National Institutes of Health, the De-
pede repair later in the course of acute kidney partment of Health and Human Services, or the U.S. government.
injury,39,47,48,50 suggesting the need for therapies Dr. Chawla reports receiving fees for serving on steering com-
that act at the correct location at the right time. mittees from AbbVie and AM-Pharma, fees for serving as an ad-
judicator for a clinical end-point study from Alere, fees for device
Current studies are evaluating the protective ef- development from Covidien, Gambro, Bard Medical, and NxStage
fects of antiinflammatory drugs, small interfer- Medical, fees for serving as a principal investigator for trials
ing RNAs, remote ischemic preconditioning sponsored by Astute Medical, fees for clinical-trial development
and planning from Ikaria, and grant support from Eli Lilly. He
(i.e., a brief period of ischemia in distant tissues, also reports providing expert testimony in a case of a patient
followed by a short interval of reperfusion), and with severe rhabdomyolysis and in a case of a patient who died
mesenchymal stem cells.57 after intubation. No other potential conflict of interest relevant
to this article was reported.
New approaches that are currently being de- Disclosure forms provided by the authors are available with
veloped may allow the selective targeting of cel- the full text of this article at NEJM.org.
lular therapy, increasing the locally active renal We thank Ms. Roberta Albert of the NIDDK for assistance in
the preparation of the original drafts of the figures and several
dose without increasing systemic side effects, to colleagues for providing critical reviews of an earlier version of
allow even the rescue of established acute kidney the manuscript.
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