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Nephrol Ther. Author manuscript; available in PMC 2017 June 19.
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Published in final edited form as:

Nephrol Ther. 2016 April ; 12(Suppl 1): S41–S48. doi:10.1016/j.nephro.2016.02.005.

Acute kidney injury and chronic kidney disease: from the

laboratory to the clinic
David A Ferenbach1,2 and Joseph V Bonventre1,3,4,5
1RenalDivision and Biomedical Engineering Division, Brigham and Women's Hospital,
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
2Centrefor Inflammation Research, Queen's Medical Research Institute, University of Edinburgh,
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Edinburgh, UK
3Harvard-MassachusettsInstitute of Technology, Division of Health Sciences and Technology,
Cambridge, Massachusetts, USA
4Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

Abstract
Chronic Kidney Disease and Acute Kidney Injury have traditionally been considered as separate
entities with different etiologies. This view has changed in recent years, with chronic kidney
disease recognized as a major risk factor for the development of new acute kidney injury, and
acute kidney injury now accepted to lead to de novo or accelerated chronic and end stage kidney
diseases. Patients with existing chronic kidney disease appear to be less able to mount a complete
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‘adaptive’ repair after acute insults, and instead repair maladaptively, with accelerated fibrosis and
rates of renal functional decline. This article reviews the epidemiological studies in man that have
demonstrated the links between these two processes. We also examine clinical and experimental
research in areas of importance to both acute and chronic disease: acute and chronic renal injury to
the vasculature, the pericyte and leukocyte populations, the signaling pathways implicated in
injury and repair, and the impact of cellular stress and increased levels of growth arrested and
senescent cells. The importance and therapeutic potential raised by these processes for acute and
chronic injury are discussed.

Keywords
kidney microvasculature; senescence; cell cycle arrest; fibrosis; kidney repair
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Introduction
Chronic kidney disease (CKD) and acute kidney injury (AKI) have been recognised as
important but distinct pathologies since their original descriptions by physicians such as
Bright (1), Heberden (2) and Abercrombie in the 19th century (3). Until recent years,
convention held that oliguric AKI was often fatal if untreated (4), but with the advent of

5
Corresponding author: Harvard Institutes of Medicine, Room 576, 4 Blackfan Circle, Boston MA 02115,
joseph_bonventre@hms.harvard.edu.
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dialysis complete recovery was often possible (5). CKD was considered a separate,
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irreversible and often progressive entity leading to end-stage renal disease.

Linking the epidemiology of AKI and CKD

In recent years standardized criteria have been adopted to allow consistent assessment of
degrees of AKI, and their impact on early mortality and subsequent renal function in
survivors (6, 7). With improved sample size, assessment criteria and length of follow-up
there are now strong data in support of three findings that: 1) pre-existing CKD is a major
risk factor for the development of AKI (8-10); 2) patients with CKD who develop AKI often
recover incompletely and experience worsened subsequent renal deterioration (8, 11, 12);
and 3) the survivors of de novo AKI are more likely to develop proteinuria, increased
cardiovascular disease risk and progressive CKD than matched non-AKI control patients (8,
12-14) (summarised in Table 1).
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Hence AKI and CKD are interlinked, with complete recovery from AKI far less common
than previously assumed, and pre-existing CKD priming the kidney for subsequent injury
and maladaptive repair. In this review we will discuss functions of the kidney implicated in
AKI and CKD, and examine the clinical and experimental evidence for their role in
determining levels of acute renal injury and adaptive vs maladaptive renal repair.

Functional and structural changes of acute kidney injury

Although AKI is a common clinical problem with high levels of morbidity and mortality,
renal biopsy is seldom undertaken in the acute phase of disease, and much of our
understanding is based on studies undertaken in experimental animals (15). From rodent
models such as ischemia-reperfusion injury (IRI) and the cecal ligation and puncture model
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of multi-organ failure it is understood that acute hypoperfusion and sepsis result in injury to
multiple cell populations (16). Early endothelial injury occurs, with obstruction and
paradoxical vasoconstriction potentiating reduced local oxygen delivery. In parallel with this
ligands are expressed promoting platelet aggregation, complement deposition via the
alternative pathway and the recruitment of inflammatory neutrophils and monocytes (17).
Consequent to altered oxygen availability there is tubular injury and necrosis causing tubular
dysfunction, oliguria and reduced glomerular filtration via tubulo-glomerular feedback.

Over subsequent days, a series of reparative steps ensue which if completed successfully
result in adaptive repair and a fully functional kidney. Tubular replacement starts, with
current data demonstrating a general dedifferentiation and proliferation of surviving mature
cells as responsible for repair (18-20). Monocytes replace neutrophils as the predominant
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infiltrating leukocyte, and switch phenotype from M1 (pro-inflammatory) to M2 (pro-repair)

to support the process of proliferation and regeneration, before exiting or undergoing
apoptosis to leave resident cells at similar levels to pre-injury (17). For true adaptive repair
to occur, after a period of several days kidney function should return to its previous level
(although clinical tools such as creatinine measurement lack sensitivity to detect small
changes). There should be no proteinuria and detailed histological assessment should show

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preserved tubules, glomeruli and microvasculature with no fibrosis or change in pericyte

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location or markers (Figure 1). In practice, however, such assessment is seldom undertaken.

Functional and structural changes of chronic kidney disease

CKD can occur through diverse pathologic mechanisms injuring one or several of the
compartments of the kidney: vasculature, the tubulointerstitium or the glomerulus. Several
features are seen in the kidney regardless of the initiating insult and are known to be
important for prognosis and progression to end stage renal disease. Microvascular loss
occurs along with increased fibrosis, leading to increased relative hypoxia within the kidney
and in particular within the outer medulla (21). This change is associated with and
potentially related to a change in pericyte location and behavior, with a loss of pericyte-
endothelial contact and pericyte migration to adopt a pro-fibrotic myofibroblast phenotype
(22, 23), which then deposit interstitial collagen. With chronic renal injury, there is also a
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progressive increase in cells expressing markers of senescence and cell-cycle arrest (24-27).
Irrespective of the initial insult, evidence of tubular cell loss and their replacement by
collagen scars and density of chronically infiltrating macrophages are associated with further
renal functional loss and progression towards end stage renal failure.

Changes to tubular cell survival and function, leukocyte and pericyte behaviour and
microvascular integrity are all features seem in both AKI and CKD (Figure 2). Evidence for
their involvement in the overlap between these two conditions will now be discussed.

Changes to the renal vasculature and oxygen delivery in acute kidney

injury
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A common feature of diverse processes causing AKI is a reduction in regional renal oxygen
delivery leading to inflammation, ischemia and necrosis (28). These features reflect an
imbalance between arterial pressure and vascular resistance, with areas of the kidney such as
the outer stripe of the outer medulla particularly vulnerable (29). Experimental work in rats
demonstrate that vascular function is abnormal for several days after IRI, with a failure of
nitric oxide generation from the blood vessels (30, 31) and increased vascular permeability
leading to tissue swelling (32). Concurrent with this the endothelium expresses adhesion
molecules resulting in the adhesion and recruitment of platelets and leukocytes- both also
capable of contributing to injury (33, 34). Studies using intra-vital microscopy have
demonstrated that with renal ischemia there is sluggish and even reversed flow in the early
phase after initial injury (35, 36).
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The transition between acute and chronic vascular injury

Work in both rats and mice demonstrate that experimental IRI results in a reduction in the
density of tubular capillaries even after apparently ‘adaptive’ complete repair (37, 38). It is
possible that signalling in early recovery which promotes tubular regeneration such as
increased TGF-β and reduced VEGF may oppose survival and recovery within the
microvasculature. The renal pericyte is now recognized as a key contributor to vascular
stability in development, in homeostasis and in response to kidney injury (22, 39). Defects in

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pericyte function result in vascular rarefaction and increased fibrosis- features that are both
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seen in clinical CKD (23).

Altered ability to respond to acute hemodynamic changes with CKD

There is now accumulating evidence demonstrating that even in the context of a normal
serum creatinine, changes persist in the kidney in the aftermath of AKI (11). Alterations
within the chronically damaged kidney lead to a state of relative hypoxia even in baseline
conditions, with reduced numbers of peritubular capillaries (40, 41) and increased deposition
of collagen leading to increased distances between the vessels and tubular cells (42).
Kidneys with CKD have increased activation of the renin-angiotensin system, and reduced
numbers of glomeruli lead to hyperfiltration and increased tubular oxygen consumption of
the corresponding tubules- further worsening imbalances between oxygen requirement and
delivery (43). New technologies such as blood oxygen level dependent (BOLD) MRI
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scanning now allows the detection of renal hypoxia non-invasively in patients, and in a
research setting has documented changes in response to blockers of the renin-angiotensin-
aldosterone system (44-46). Such drugs have actions on renal hypoxia and are documented
to improve outcome in CKD, though whether such effects contribute to protection remains
unproven. Ischemia in the kidney results in stabilization of hypoxia inducible factor 1-
α(HIF1α) and there is considerable interest in the potential for HIF-stabilizing agents as
therapeutic tools in renal injury (47, 48).

Altered tubular epithelial cell maturation in AKI and CKD

While evidence shows that tubular epithelial cells do not give rise to renal myofibroblasts in
response to acute or chronic injuries (39, 49), studies have shown that epithelial cells can
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upregulate mesenchymal surface markers in the context of both acute and chronic renal
injury (50). This is thought to be a transient upregulation, which in conjunction with
expression of the proliferative marker suggests that this reflects a de-differentiation of cells
undergoing active replication. (18, 51-53). The Wnt pathway is also induced in response to
AKI, while it is usually expressed only in embryogenesis and suppressed in the adult kidney
(54). There is evidence in both experimental models and in human disease implicating
activity of Wnt signaling genes and their downstream pathways such as β-catenin as
effectors of renal fibrosis (55, 56). Experimental IRI has been shown to result in Wnt4
induction, with return to baseline within 24h, contributing to de-differentiation of surviving
epithelial cells capable of responding to the various proliferative cues present in the injured
kidney (50, 57). There is also a burst of TGFβ signaling at this point which, if maintained,
may mediate later fibrosis. Studies, in vitro, have demonstrated a combination of Wnt
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downregulation and expression of matrix metalloproteinases as necessary for full

differentiation of renal tubules- but whether this is the case in vivo requires further study
(58, 59).

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Altered behaviour of leukocytes

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Macrophages
Macrophages have contrasting roles in renal injury and repair, augmenting early injury (60)
as M1 polarized cells, then switching to an M2 phenotype, clearing debris and supporting
epithelial cell repair (61, 62). Indeed whilst early depletion of macrophages is often
protective, depletion of M2 macrophages in mice with established AKI results in
prolongation of renal injury (63). While important in facilitating repair after AKI, the
presence of macrophages is also correlated with fibrosis and adverse outcome in both
humans and experimental models of renal disease (64, 65), with the persistence of M2 cells
shown to be deleterious.

Lymphocytes
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Studies in mice lacking lymphocyte subtypes support their involvement in the evolution of
renal injury (66). B cell deficient (μMT) and CD4/CD8 deficient mice are both protected
from AKI, but the RAG-1 strain demonstrates no alteration in susceptibility to injury
(67-69). Adding to the complexity of the field, in the RAG-1 strain, protection is restored by
adoptive transfer of either B or T cells alone only. Regulatory T cells have been reported to
limit tissue injury (70) with Treg depleted and deficient mice exhibiting worsened tissue
damage after experimental IRI (70).

Studies on μMT mice using bone marrow chimeras demonstrate that B cells appear to delay
tissue repair after injury (71), and adoptive transfer of lymphocytes from animals previously
exposed to severe IRI induce albuminuria in naïve recipients (72). If such findings are
replicated in man then the adaptive immune system and immunological memory play a
larger than expected role in the genesis of CKD and proteinuria after AKI.
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Alterations in pericyte number and activation status

Pericytes sit in close proximity to the endothelial cells within many organs where they
maintain vascular stability and release factors, including PDGF (73), angiopoetin (74), TGF-
β (75), VEGF (76) and sphingosine-1-phosphate (77). There is now an increasing
understanding of the role played by these cells in acute and chronic renal injury and fibrosis-
where they leave their perivascular locations in response to injury and differentiate to
become myofibroblasts (39, 78, 79). Thus in both AKI and CKD, injury activates pericytes
and induces their migration- contributing both to microcirculatory instability and loss (23).
Whether interventions targeting pericyte activation and survival could protect the renal
microcirculation and prevent the post-AKI loss of kidney vasculature is an important
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unanswered question.

Processes contributing to the development of CKD post AKI

Recurrent tubular injury as a stimulus to renal scarring
As clinical AKI impacts on multiple cell types including the vascular, epithelial,
mesenchymal and leukocyte lineages, it has been very difficult to establish which cell or
cells are responsible or involved with the scarring process. The role of the tubular epithelial

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cell on fibrosis has been investigated using a transgenic mouse expressing the simian
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diphtheria toxin receptor on the tubular epithelia, allowing their selective depletion in vivo
without injury to other cell types (80). These studies showed that a single round of injury led
to complete repair, but repeated sublethal injuries led to progressive fibrosis, loss of
capillaries and glomerulosclerosis. Thus, injury to the tubule alone is sufficient to produce
interstitial scarring and loss of glomeruli and capillaries- likely related to the release of
proinflammatory and vasoconstictive cytokines by the injured tubule.

KIM-1 as a potential surface receptor linking AKI to CKD

Kidney injury molecule 1 (KIM-1) is, an epithelial phagocytic receptor which is markedly
upregulated on the proximal tubule in various forms of acute and chronic kidney injury in
humans and many other species. Its ectodomain is released by metalloproteases and appears
in the urine and blood, serving as an excellent sensitive biomarker of proximal tubule injury
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and predicting progression of CKD (81). Acute KIM-1 is adaptive and protective with anti-
inflammatory effects (82-84). If expression of KIM-1 continues chronically it is possible
that this results in progressive uptake of noxious compounds from the intratubular lumen and
secondary cell injury over time with senescence, secretion of proinflammatory and
profibrotic cytokines. A transgenic mouse expressing KIM-1 developed CKD (85) and
zebrafish overexpressing KIM-1 have smaller kidneys and higher mortality rates (86).

Epigenetic Changes after AKI

The potential role for epigenetic changes in mediating the transition from AKI to CKD, and
in altering the response of the chronically damaged kidney to further AKI insults is an area
of active study (87),(88). Within clinical cohorts there is emerging evidence for alteration in
histones, DNA methylation and miRNA molecules within scarred kidneys (89). Similarly,
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changes in histones and in patterns of methylation have also been noted in AKI, and have
been reported to alter expression of pro-fibrotic genes such as MCP-1 and TNFα (90, 91).
With our tools to investigate these alterations improving, so will our ability to probe for
epigenetic cues which may prime ‘adaptively repaired’ kidneys to develop CKD or leave
them susceptible to recurrent AKI.

Senescence and cell cycle arrest in the acutely and chronically injured
kidney
While cellular senescence was first described as a feature of prolonged culture of cells in
vitro it is now recognized as a key feature of aging in vivo and degeneration in organs
including the kidney (92). With advancing age, with CKD or in response to interventions
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such as renal transplantation and immunosuppression there are increases in the numbers of
senescent cells within the kidney, and it is plausible but unproven that these cells may
contribute to the sensitivity of an aged or chronically damaged kidney to further acute injury.
Studies in progeroid mice have shown that depletion of p16INK4a expressing senescent cells
can delay age-associated pathologies, but this remains to be tested in naturally aged animals
to assess the importance of cells expressing p16INK4a (93). Data from human kidney
transplants demonstrates increased cellular senescence (94), with pre-implantation p16INK4a
levels predictive of graft survival (95, 96). Experimental murine transplantation of kidneys

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lacking the senescence trigger gene p16INK4a show increased survival rates and reduced
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fibrosis supporting a role for cellular senescence in the progression of renal fibrosis after
acute or chronic injury (96). This protection may reflect reductions in levels of factors such
as connective tissue growth factor (CTGF) and TGF-β which are both released from
senescent cells and can contribute to inflammation, vascular loss and fibrosis (25, 97, 98).
Senescent cells may also promote G2/M cell cycle arrest through release of the cytokine
IL-8 (99).

Our laboratory has demonstrated an important role for mitotic arrest at the G2/M phase of
the cell cycle in response to AKI, where it drives maladaptive repair and progressive fibrosis
(25-27) (Figure 3). Supporting this finding, additional studies using pharmacological
inhibition or potentiation of G2/M cell cycle arrest demonstrate reduced or increased levels
of fibrosis respectively (26, 27, 100). With age, AKI and CKD all associated with increased
levels of senescent cells (92), the potential for these cells to mediate crossover effects
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between chronic and acute renal pathologies merits further investigation.

Conclusions
Our understanding of the relationships between CKD and AKI remains incomplete, with
new data demonstrating more areas of overlap and inter-dependence. Both processes are
associated with major increases in patient morbidity and mortality, and new interventions to
lessen AKI susceptibility and reduce maladaptive repair leading to new or worsened CKD
are required. Our knowledge of the processes underlying vascular damage and loss, pericyte
migration, leukocyte activation, acute and chronic cellular senescence and tubular hypoxia
continues to advance. Increased understanding should lead to new, targeted therapies to
protect kidneys from these interrelated forms of kidney injury in the future.
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Figure 1. Chronic kidney disease and maladaptive repair after acute kidney injury
A kidney with chronic kidney disease is less likely to undergo complete adaptive repair after
an acute renal insult. In the context of pre-injury fibrosis, senescence and microvascular loss
the kidney is more likely to repair maladaptively with increased tubular loss and scarring.
While a normal kidney can respond to injury with adaptive repair it is also recognized that
with greater levels of injury and increasing age maladaptive repair to CKD is more likely.
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Figure 2. Inter-related features of chronic kidney disease and acute kidney injury
Features seen in chronic kidney disease are shown on the left and acute kidney injury on the
right. Solid lines demonstrate well established connections between these features, with
dotted lines indicating suspected or proposed connections.
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Figure 3. Cell cycle progression in acute and chronic kidney disease

Studies of models of renal injury have detected cells arrested at the G2/M checkpoint that
secrete pro-fibrotic factors promoting maladaptive repair and the transition from acute to
chronic kidney disease. Cell cycle arrest can also occur in the G1/S phase resulting in
p16INK4a positive senescent cells which, via the senescence-associated secretory phenotype
(SASP), also promote changes in aged and injured kidneys.
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Table 1
Clinical studies of interactions between acute kidney injury and chronic kidney disease
Several studies and meta-analyses have been performed in the last 10 years examining the impact of chronic kidney disease in rates of acute kidney injury
in hospital inpatients, and the impact of de novo acute kidney injury on subsequent kidney function and rates of end stage renal disease in survivors.

Study Population Sample/size Risk of AKI Effects of CKD on AKI Effects of AKI on CKD or Comments
ESRD
Ishani et al (8) n=233,803 Inpatients aged>67yrs. 3.1% in survivors 12% of total patients had 5.3 per 1000 developed ESRD. Relative risk of ESRD was
Ferenbach and Bonventre

JASN 2009 Medicare in year 2000 CKD. 34.3% of AKI 25% had prior AKI 41.2 in AKI+CKD patients,
patients had CKD 13.0 in AKI only patients

Xue et al (9) JASN n=5,403,015 Medicare discharges 23.8 cases per 1000 No data No data Risk of death at 90d was
2006 1992-2001 discharges Age, male 13.1% without AKI, 34.5%
gender and black race with AKI as the principal
associated with risk. diagnosis, and 48.6% with
AKI as a secondary
diagnosis

Coca et al (11) KI 13 studies, >1,000,000 participants No data No data AKI resulted in a pooled HR for Survivors of AKI had a
2012 new CKD of 8.82 and of ESRD of pooled HR for death of
3.1 1.98.

Wald et al (12) 3769 AKI patients, 13,598 controls No data No data Rate of ESRD in AKI patients of An episode of AKI resulted
JAMA 2009 (1996-2006) 2.63 per 100 person years, vs 0.9 in a HR for ESRD of 3.23.
in controls

Chawla et al (13) KI N=5351 AKI patients No data No data 13.6% of survivors developed Age of patient and severity
2011 CKD 4. of AKI both predicted
subsequent CKD

Chertow et al (101) N=19,982 total patients 1997-1998 13.1% of inpatients had Pre-existing CKD was a No data
AKI (by AKIN1 criteria) significant risk factor for
AKI

Coca et al (102) 8 studies total n=78,855 Creatinine increases of

AJKD 2007 10-24% increased RR of
30d mortality by 1.8×, rises

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of >50% increased RR by
6.9×.
Liano et al (5) KI N=187 ATN patients. Mean follow up of All patients had biopsy No previous nephropathies 11/57 patients followed up had
2007 7.2 years proven ATN were seen mild/moderate CKD

Vikse et al (14) N=570,433 females (1967-1991) 3.7% of pregnant ladies 1× prior Preeclampsia resulted in
NEJM 2008 developed pre-eclampsia RR of ESRD of 4.7. 2+ prior
preeclampsias had a RR of ESRD
of 15.5.

James et al (10) 8 control studies n=1,285,045 and 5 CKD In control patients, 0.2-6% Lower eGFF and higher No Data
AJKD 2015 studies n=79,519 developed AKI vs 2-25% albumin:creatinine ratio
In CKD studies conferred higher AKI risk

Heung et al (103), VA inpatients n=17,049 with AKI, No patients had documented Rate of recovery of AKI equated
AJKD 2015 n=87,715 without AKI. CKD prior to the study to a 2 year RR of new CKD3+: <3
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Study Population Sample/size Risk of AKI Effects of CKD on AKI Effects of AKI on CKD or Comments
ESRD
days RR 1.43 3-10 days RR 2.0
>10 days RR 2.65
Ferenbach and Bonventre

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