The long-term outcome after acute kidney injury : a narrative review

Correspondência para: Daniela Ponce. Faculdade de Medicina de Botucatu-UNESP. Distrito de Rubião Junior, s/no. Botucatu, SP, Brazil. CEP: 18601-000. E-mail: dponce@fmb.unesp.br Esta revisão tem como objetivo focar o prognóstico em longo prazo de pacientes após episódio de lesão renal aguda (LRA). Pacientes sobreviventes à LRA apresentam maior mortalidade tardia quando comparados com aqueles internados sem LRA. Estudos recentes mostram mortalidade em logo prazo após LRA entre 15 e 74% e, de modo geral, são fatores que contribuem para essa mortalidade a idade avançada, a presença de comorbidades preexistentes e a recuperação incompleta da função renal. LRA também está associada com evolução para doença renal crônica, sendo a queda de função renal na alta hospitalar e número e intensidade dos episódios de LRA fatores associados com a evolução para DRC. A recuperação da função renal é definida pela maioria dos estudos como a não dependência de diálise e ocorre em 60 a 70% dos pacientes em até 90 dias. Futuros estudos são necessários para explorar o prognóstico tardio desses pacientes. Resumo


Resumo
This review will focus on long-term outcomes after acute kidney injury (AKI).Surviving AKI patients have a higher late mortality compared with those admitted without AKI.Recent studies have claimed that long-term mortality in patients after AKI varied from 15% to 74% and older age, presence of previous co-morbidities, and the incomplete recovery of renal function have been identified as risk factors for reduced survival.AKI is also associated with progression to chronic kidney (CKD) disease and the decline of renal function at hospital discharge and the number and severity of AKI episodes have been associated with progression to CKD.IN the most studies, recovery of renal function is defined as nondependence on renal replacement therapy which is probably too simplistic and it is expected in 60-70% of survivors by 90 days.Further studies are needed to explore the long-term prognosis of AKI patients.

IntRoductIon
Traditionally, most studies of severe acute kidney injury (AKI) in the critically ill have focused on short-term outcomes often assessed at hospital discharge.The risk of mortality associated with AKI is decreasing, but this mortality remains unacceptably high. 1,2Still, severe AKI should no longer simply be viewed as an indicator of overall severity of illness, but rather the failing kidney can exhibit important independent effects on outcome that may extend well beyond discharge from hospital. 3Thus, this review will focus on the long-term outcomes from AKI in the critically ill with an emphasis on survival and renal recovery.
In order to detect recent publications (2000 to present) on long-term outcome after AKI, an extensive literature search was performed using the Pubmed and MEDLINE.The key search terms used were acute kidney injury, long-term, mortality, renal recovery and prognosis, alone and in combination.All articles identified were English-language, full-text papers.We also searched the reference lists of identified articles for further relevant papers.

long-term mortAlity
Several studies have documented the long-term survival after severe AKI, in particular when coupled with admission to an ICU.Many studies reporting long-term outcome have limited generalizability as a result of selection bias due to inclusion of patients from a single institution, from either medical or surgical ICUs, or non-critically ill patients.Similarly, many of these studies were small or retrospective in design.Only one study was systematic review.Further, the development of severe AKI that would otherwise necessitate initiation of RRT can significantly influence decisions for life support withdrawal that can bias true estimates of mortality. 4hese factors contribute to the notable differences in long-term mortality rates across studies and thus need to be considered when making inferences regarding long term survival.
Survival rates post-discharge from 90 days to 10 years have been reported in almost 30 studies and ranged from 15-74%.  At 7][8][16][17][18][19][20] In a population based study of all episodes of severe AKI requiring RRT in all ICUs from a single health region, Bagshaw et al. 5 estimated a 90-day mortality of 60%. At 6 mont, the cumulative mortality has been reported between 55 and 73%.[7][8][9] In a large retrospective study, Morgera et al. 10 reported the long-term outcomes in a cohort of critically ill patients with severe AKI requiring RRT.The hospital mortality was 69%, and the probability of survival in the first 6 months after discharge was 77%.Estimates of mortality at 1 year have ranged from 15 to 65%.[5][6][7][8][9][10][11][12] Stevens et al. 29 found 2-year and 3-year mortality rates of 69% and 72%, respectively.Recently, Gallagher et al. 14 reported that there is no effect of differing RRT modalities on long-term outcome of AKI. A 2 and 3 years, 62% and 63% of patients had died in the lower and higher intensity dialysis groups, respectively (RR 1.04, 95% CI 0.96-1.12,p = 0.49).With follow-up to 5 years after admission to ICU, death had occurred in 55-70% of those diagnosed with severe AKI.8,17,20,25 Schiffl et al. 17 followed up 226 patients with severe AKI, (defined as need for dialysis) and absence of previous CKD and the observed mortality rate was 75% after 5 years, while Liano et al. 15 evaluated 177 patients surviving a moderate or severe acute tubular necrosis (ATN) episode and 50% were alive 10 years later.The difference in mortality depends on the setting and time period studied, and the severity of AKI.
5,17 Recent studies have suggested that long-term survival is associated with pre-existing chronic conditions and not with the severety of AKI episode. 11,275][36] While some studies 5,7 have suggested that use of continuous renal replacement therapy independently predicted death, this has not universally been found. 8,20,34,36Higher intensity of prescribed RRT has not been suggested to improve long-term outcome. 14n summary, the factors that contribute to AKIassociated mortality vary with time and differ in the early and long-term.Factors that modify the risk of early mortality occurring in less than 90 days after AKI include the primary diagnosis (such as sepsis), severity of acute illness and the burden of acute nonrenal organ dysfunction.Among early survivors, factors contributing to intermediate and long-term mortality include older age, pre-existing comorbid disease (CKD, cardiovascular disease or malignancy) and incomplete organ recovery with ongoing residual disease (Table 1).

RecoveRy of RenAl functIon
Nonrecovery of kidney function following an episode of AKI is a major morbid event with long-term implications for patients and health resources.The long term rates for complete or partial recovery of function are not well described and data related to the progression to chronic kidney disease (CKD) are conflicting.Data from studies including all etiologies of AKI are difficult to interpret as functional prognosis is known to be worse in some types of glomerulonephritis or vasculitis.
No consensus on a definition of renal recovery after AKI exists.The most frequent definitions are the weaning from dialysis, normalization of serum creatinine (sCr) or return to sCr baseline value.These criteria are associated with different rates of renal recovery depending on the cohort being evaluated.Studies including only dialyzed patients and considering recovery as weaning from dialysis can show higher rates of recovery than those evaluating patients with AKI based on baseline sCr.In addition, most of the studies left the ultimate decision to stop dialysis at the discretion of the treating physician, creating an outcome that is strongly influenced by individual physician and center practice patterns.These disparities in renal recovery definition are reflected on the different rates of reported renal recovery.
In large observational cohort studies of critically ill patients with severe ATN requiring RRT, the rate of dialysis dependence at hospital discharge was 13-29%. 2,5,37,38mong survivors of AKI, the rate of dialysis dependence seems to decrease at 6 months and 12 months after AKI onset; however, this result is often confounded by deaths that occur predominantly among those patients who remain on dialysis. 5,20everal patient-level susceptibilities modify the likelihood of nonrecovery from AKI and rapid progression to end stage renal disease (ESRD), in particular older age, [36][37][38] severity of CKD at baseline, female sex, presence of co-morbidities, parenchymal etiology of AKI, and late initiation of renal replacement therapy (RRT) or use of conventional intermittent RRT have all been associated with reduced recovery 5,8,21,25,[38][39][40][41][42][43] (Table 2).Both the severity of AKI and the number of AKI episodes are also associated with the development of incident CKD and ESRD. 18,39 Although no validated scoring systems that reliably predict recovery of kidney function after AKI are currently available, much effort is being focused on biomarkers of AKI that can make the diagnosis earlier and more accurately and possibly enable the use of strategies to prevent progression of this syndrome. 42In an experimental study in rats, ongoing inflammation and immune activity were found to be involved with the pathogenesis of CKD, and NGAL was upregulated, suggesting that it may be a valuable biomarker for the development of CKD after AKI. 43n addition, recent evidence suggests that NGAL may even be involved as a mediator of CKD progression. 44

IncIdent cKd And pRogRessIon to esRd
AKI is an independent risk for incident CKD and progression to ESRD [44][45][46][47] and the severity of AKI has been associated with recovery of renal function at the time of hospital discharge and progression to CKD.Studies performed by Pereira et al. 11 and Chawla et al. 45 showed that older age and the severity of AKI predicted progression to CKD.The most severe AKI patients evaluated by the RIFLE or AKIN criteria presented lower rate of recovery of renal function at the time of hospital discharge and higher progression to CKD.The risk of incident ESRD is reported to be 2.7-fold higher among critically ill patients with AKI who do not require RRT than among patients without AKI. 36These patients are also at increased risk of major cardiovascular events, rehospitalization and mortality. 35,43epending on the AKI etiology, 3-41% of patients could have end-stage renal disease and 3-24% could need chronic dialysis after discharge. 36The US Renal Data System 2010 Annual Data Report indicates that survivors of AKI are at risk of developing ESRD within the following year.This risk increases from less than 1% for those without previous CKD to 5% for those with previous CKD. 46rito et al. 27 described that the need for chronic dialysis was present in 4.7% after 60 months of follow up and all patients who progressed toward ESRD had previous CKD.Similar results were recently observed by Macedo et al. 18 showing that 4.7% progressed to ESRD; however, only one (1.1%)did so within the first year after AKI.In general, studies suggest a low rate of long term recurring need for RRT in those surviving an episode of critical illness, specifically with prior normal kidney function.
The risk of progression to CKD was higher in patients with previous CKD [glomerular filtration rate (GFR < 60 ml/min)] than those without it (GFR > 60 ml/min).In study of Brito et al. 27 less than 9% of patients without previous CKD progressed to CKD Stages 4 or 5 while 23% of patients with previous CKD progressed to CKD Stages 4 or 5.These results are similar to that found by Amdur et al. 47 where 20% of those with ATN progressed to CKD stage 4 or 5. Wu et al. 19 evaluated 9425 patients after severe AKI (with need for dialysis) and patients with previous CKD presented higher risk of progression to ESRD when compared with patients without previous CKD (17.8 x 0.15 patients/year).The risk of progression to ESRD was also higher when patients with previous CKD did not have total recovery of renal function at hospital discharge (RR = 212.7,95% CI 105.5-428.8,p < 0.001).
Thakar et al. 39 studied patients with diabetes and risk of progression to CKD after ATN episodes.
It was observed that an episode of AKI in diabetic patients compared with diabetic patients without ATN was associated with progression to CKD Stage 4 (RR = 3.56, 95% CI 2.76-4.61),and that each new episode of AKI led to increased risk (RR = 2.02, CI = 1.78-2.3).
In summary, progression to CKD is common and is associated with older age, presence of previous CKD and severity of AKI (Table 3).

conclusIon
It is increasingly recognized that AKI should not only be considered an acute syndrome, but it can be a risk condition for progression of CKD and late mortality.Several studies confirm that the long-term survival for patients with critical illness characterized by severe AKI is generally poor.Those who do survive, however, by and large enjoy high rates of renal recovery to independence from RRT.The long-term rates for complete or partial recovery of function are less well described and because of this the survivors of AKI deserve a careful and long-term medical follow-up.Further research is needed to explore the relationship between long-term survival and subsequent morbidity, specifically considering the recovery of kidney function.

tAble 1
However, no studies have specifically addressed what factors are predictive of long-term recovery of function.