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Acute kidney injury: definition controversies and epidemiology
Clinical Queries: Nephrology 0101 (2012) 1–5
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Clinical Queries: Nephrology January–March 2012, Vol. 1/Issue 1
j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
ISSN No.: 2211-9477
Acute kidney injury: definition controversies and epidemiology Narayan Prasad*, Amresh Krishna Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – 226014, India.
a r t i c l e
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Article history: Received 6 November 2011 Accepted 14 November 2011
Keywords: Acute kidney injury Definition Epidemiology
a b s t r a c t
The term acute kidney injury (AKI) has now replaced the older term ‘acute renal failure’. Clinically AKI is characterized by a rapid reduction in kidney function resulting in a failure to maintain fluid, electrolyte, and acid–base homoeostasis. However, the definitions in published works of AKI is non-homogenous, ranging from severe to relatively modest observable increases in serum creatinine concentration. Changes in serum creatinine levels are relatively insensitive to small changes in glomerular filtration rate. The varying incidence and prevalence of AKI may also be the result of different definition employed and methods used for ascertainment of cases. To date there is a paucity of data on the incidence of AKI. The incidence of AKI also varies with the clinical setting, community-acquired, hospital-acquired, sepsis-induced, and ICU-associated AKI. The recent review is an attempt to find out the evidences for recent changes in definition and epidemiology of AKI. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction The term acute kidney injury (AKI) has now replaced the older term ‘acute renal failure’ (ARF).1 Himmelfarb and Ikizler et al has described changing lexicography of AKI in a mini review in 2007.2 The lexicography of AKI is related to some important historical periods in the history of kidney diseases.3 William Heberden first termed this modern AKI as the ischuria renalis in his Commentaries on the History and Cure of Diseases while describing the clinical course of AKI in 1802. The syndrome remained overlooked until World War II when Bywaters and Beal classically described anuric AKI after Crushsyndrome during the German bombing of London. Andre Cournand who was the winner of the 1956 Nobel Prize in Physiology or Medicine and his co-worker extensively studied the changes in kidney function associated with circulatory failure or shock in man during an investigation carried out during this war. In 1964, Homer W Smith introduced the term acute renal failure in his book titled The Kidney – Structure and Function in Health and Disease.4 This term ARF stood the test of the time until the new nomenclature AKI was introduced a few years back. Smith comprehensively reviewed data from animal models, as well as physiologic, pathologic, and clinical data from human cases of ARF. Smith provided clinical advice for the treatment of anuria which is still useful guide for clinicians in the management of anuria. The treatment of anuria should be conservative and the appropriate steps should be taken to correct it. The concept of renal support system should be applied to support the patient until the kidneys have a chance to recover. The overzealous administration of fluid in anuric patient *Corresponding author. E-mail address: [email protected]; [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(11)70002-4
may produce dangerous pulmonary edema and may promote the formation of renal edema. The different methods of renal replacement therapy (RRT) hemodialysis, peritoneal dialysis, and continuous RRT may be helpful in supporting the patient through a critical period of uremia. However, they cannot induce diuresis and their value in influencing the course of acute anuria is not established. Because each method involves an inherent physiologic burden, the application of any of them may handicap rather than promote spontaneous recovery. Clinically AKI is characterized by a rapid reduction in kidney function resulting in a failure to maintain fluid, electrolyte, and acid–base homoeostasis. Over recent years it has been observed that even a slight increase in serum creatinine is associated with increased mortality and morbidity.5–7 Previous studies have used an assortment of definitions for AKI, including those based on changes in serum creatinine, absolute levels of serum creatinine, changes in urine output (UO) or blood urea nitrogen (BUN) concentrations, or the need for dialysis. The wide variation in definitions has made it difficult to compare information across studies and populations. The definitions in published works of AKI is non-homogenous, ranging from severe (e.g. AKI requiring dialysis) to relatively modest observable increases in serum creatinine concentration (e.g. increase in serum creatinine of 0.3–0.5 mg/dL above baseline). At least 35 definitions of ARF are enlisted in the literature.2 Some of the definitions are extremely complex and could allow excessive subjectivity in AKI determination (Table 1). These would likely be impractical for prospective, multicentric investigations, and studies. Moreover, none of the definitions used to date take into account the modifying effects of age, gender, and race on creatinine generation. Changes in serum creatinine are not specific and are unable to discriminate the causes of renal injury (e.g. ischemic, nephrotoxic)
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Table 1 Definitions of acute kidney injury from several published studies. Authors
Definitions
Allgren et al8
1 mg/dL increase in serum creatinine over 2 days
Bates et al9
50% increase in serum creatinine to at least 2 mg/dL
Behrend and Miller10
0.9 mg/dL increase in serum creatinine if baseline serum creatinine is < 2.0 mg/dL to at least 2.0 mg/dL or 1.5 mg/dL increase in serum creatinine if baseline serum creatinine is > 2 mg/dL
Cochran et al11
More than 0.3 mg/dL and > 20% increase in serum creatinine
Eisenberg et al12
More than 1.0 mg/dL increase in serum creatinine or > 20 mg/dL increase in BUN
Hou et al13 0.5 mg/dL increase in serum creatinine if baseline serum creatinine is < 1.9 mg/dL or 1.0 mg/dL if baseline serum creatinine is 1.9 to 4.9 mg/dL or 1.5 mg/dL increase if baseline serum creatinine is 5 mg/dL or more Kurinik et al14
0.5 mg/dL or 25% increase in serum creatinine within 48 hr
Levy et al15
25% increase in serum creatinine to at least 2.0 mg/dL in 2 days
Liano and Pascual16 ‘Sudden’ rise of > 2 mg/dL in subjects with prior ‘normal’ renal function, or ‘sudden’ increase in serum creatinine of > 50% with ‘mild to moderate’ basal chronic renal failure with serum creatinine < 3.0 mg/dL, or ‘elevation of serum creatinine at admission with normal or increased renal size (except with myeloma or hydronephrosis with cortical atrophy)’ Lautin et al17 6 graded criteria More than 0.3 mg/dL and 20% increase in serum creatinine on days 1, 2, or 3, and days 5, 6, or 7, or > 0.3 mg/dL increase in serum creatinine on days 1, 2, or 3, or 0.3 mg/dL and 20% increase in serum creatinine on day 1 or 2, or > 2.0 mg/dL increase in serum creatinine on day 1 or 2, or 1.0 mg/dL increase in serum creatinine on day 1, or 20 mg/dL or 50% increase in BUN on day 1 Obialo et al18 0.5 mg/dL increase in serum creatinine to at least 2.0 mg/dL, or admission serum creatinine 2.0 mg/dL with no history of renal disease Parfey et al19
More than 50% increase in serum creatinine to at least 1.4 mg/dL
Shusterman et al20 0.9 mg/dL increase in serum creatinine if baseline serum creatinine < 2.0 mg/dL, or 1.5 mg/dL increase in serum creatinine if baseline serum creatinine > 2.0 mg/dL, and ‘remained elevated for at least one additional consecutive determination’ Taylor et al21
More than 0.3 mg/dL rise in serum creatinine
BUN: blood urea nitrogen.
Table 2 Comparative details of risk-injury-failure-loss-end-stage renal disease classification and acute kidney injury network staging.
Serum creatinine criteria
UO criteria
(A) The ADQI criteria for the definition and classification of AKI (i.e. RIFLE criteria) Risk Increase in serum creatinine ≥ 1.5 × baseline or decrease in GFR ≥ 25% < 0.5 mL/kg/hr for ≥ 6 hr Injury Increase in serum creatinine ≥ 2.0 × baseline or decrease in GFR ≥ 50% < 0.5 mL/kg/hr for ≥ 12 hr Failure Increase in serum creatinine ≥ 3.0 × baseline or decrease in GFR ≥ 75% or an < 0.3 mL/kg/hr ≥ 24 hr or absolute serum creatinine ≥ 354 mmol/L with an acute rise of at least 44 mmol/L anuria ≥ 12 hr
(B) The proposed AKIN criteria for the definition and classification of AKI Stage 1 Increase in serum creatinine ≥ 26.2 mmol/L or increase to ≥ 150–199% (1.5 to 1.9-fold) from baseline < 0.5 mL/kg/hr for ≥ 6 hr Stage 2 Increase in serum creatinine to 200–299% (≥ 2 to 2.9-fold) from baseline < 0.5 mL/kg/hr for ≥ 12 hr Stage 3 Increase in serum creatinine to ≥ 300% (≥ 3-fold) from baseline or serum < 0.3 mL/kg/hr ≥ 24 hr or creatinine ≥ 354 mmol/L with an acute rise of at least 44 mmol/L or initiation of RRT anuria ≥ 12 hr ADQI: acute dialysis quality initiative, AKI: acute kidney injury, AKIN: acute kidney injury network, GFR: glomerular filtration rate RIFLE: risk-injury-failure-loss-end-stage renal disease, RRT: renal replacement therapy, UO: urine output.
or the site and extent of glomerular or tubular injury, and levels are relatively insensitive to small changes in glomerular filtration rate (GFR).6 Moreover, changes in serum creatinine may lag behind changes (decline or recovery) in GFR by several days. Finally, because serum creatinine is influenced by one of the potential interventions for ARF (e.g. creatinine is removed by dialysis), its specificity for renal recovery is even more problematic. Several groups have recognized these limitations and have worked to identify the knowledge gaps and define the necessary steps to correct these deficiencies. These efforts have included consensus conferences and publications from the Acute Dialysis Quality Initiative (ADQI) group,6 the American Society of Nephrology (ASN) ARF Advisory group,22 the International Society of Nephrology (ISN), and the National Kidney Foundation (NKF), and KDIGO (Kidney Disease: Improving Global Outcomes) groups.23 This term enables healthcare workers to consider the disease as a spectrum of injury, which extends from less severe forms of injury with minimal rise of serum creatinine requiring no specific treatment to a more advanced injury when AKI may require RRT. The ADQI group consisted of experts from the discipline of nephrology as well as critical care medicine, published the RIFLE classification which is a consensus and evidence-based definition
of AKI (Table 2, panel A). The acronym RIFLE defines three grades of severity of AKI (risk, injury and failure) and two clinical outcomes (loss of renal function and end-stage of kidney injury) (Figure 1). Loss of renal function is defined as the irreversible or, persistent AKI for > 4 weeks. End-stage was defined as persistent renal injury for >3 months. The RIFLE classification has now been evaluated in a number of clinical studies of critically ill patients with AKI. In general, these criteria were found to have clinical relevance for the diagnosis of AKI, classifying the severity of AKI and for monitoring the progression of AKI, as well as having modest predictive ability for mortality.24–28 The details of classification based on serum creatinine and UO criteria are shown in Table 2, panel A. Acute kidney injury, as defined by the RIFLE criteria, is now recognized as an important intensive care unit (ICU) syndrome alongside other defined syndromes such as systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock29 and acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).30 It is worth noting that the RIFLE classification of AKI was originally intended to standardize the severity and definition of AKI, providing an important tool for research. Not with standing the ability to predict outcome, it is not intended to take into account the cause of AKI or the need for RRT. Other limitations include issues surrounding the differing sensitivity and specificity of the UO criteria compared with
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Non-oliguria
Oliguria
Risk
Abrupt (1–7) days decrease (>25% in GFR, or serum creatinine × 1.5 sustained
Decreased UO relative to fluid input UO <0.5 mg/kg/hr × 6 hr
Injury
Adjust creatinine or GFR decreased >50% serum creatinine × 2
UO <0.5 mg/kg/hr × 12 hr
Failure
Adjust creatinine or GFR decrease >75% serum creatinine × 3 or serum creatinine >4 mg% when acute increase >0.5 mg%
UO <0.5 mg/kg/hr × 12 hr Anuria × 12 hr
Loss
Irreversible AKI or persistent AKI >4 weeks
ESRD
End-stage renal disease >3 months
3
Specificity
AKI-earliest time point for provision of RRT
Figure 1 Risk-injury-failure-loss-end-stage renal disease classification of acute kidney injury. UO: urine output, GFR: glomerular filtration rate, AKI: acute kidney injury, RRT: renal replacement therapy.
the change in serum creatinine, although the former adds important information in the evaluation of patients.31 The validity of estimating baseline creatinine when this value is unavailable has also risen as a concern. More recently, the acute kidney injury network (AKIN) group, an international collaboration of nephrologists and intensivists, have proposed refinements to the RIFLE criteria.7 First, the AKIN group sought to increase the sensitivity of the RIFLE criteria by recommending that a smaller change in serum creatinine (≥ 26.2 mmol/L) be used as a threshold to define the presence of AKI and identify patients with stage 1 AKI (analogous to RIFLE-risk). Second, a time constraint of 48 hours for the diagnosis of AKI was proposed. The AKIN staging system for AKI stages 1, 2, and 3 corresponds to the risk, injury, and failure categories, respectively (Table 2, panel B). Slight modifications to the criteria for stage 1 would result in even greater sensitivity for the diagnosis of early AKI, and categories for loss and ESRD have been eliminated because these represent outcomes rather than course of AKI.32,33 Whether these modifications are an improvement to the existing RIFLE classification or will demonstrate a high false-positive rate requires further study. These definitions aimed to promote the earlier detection and recognition of AKI triggering appropriate treatment prior to progressive injury and kidney failure. The application of these definitions in > 500,000 patients has validated the increased risk of mortality associated with developing AKI.34,35 However, certain limitations for these definitions of AKI have been identified. First, the sensitivity and specificity may be lost when diuretics are been used. Second, the UO can be measured accurately only in catheterized patients. Third, the need of baseline serum creatinine to calculate the proportion decrease in renal function, and finally many other biomarkers including serum cystatine C that allow earlier detection of the kidney injury.36,37 Recently, the international guideline group, KDIGO has brought together international experts from various sub-specialties to produce a definition and staging system that harmonizes the previous definitions and staging systems proposed by both ADQI and AKIN.38 It is expected that this definition and staging system will be globally adopted and will be helpful for future comparison of incidence, outcome and effectiveness of therapeutic interventions for AKI. Patients should be staged according to whichever criteria (serum creatinine or UO) gives them the highest stage and only after they have been identified as meeting the criteria for the definition of AKI.
Epidemiology of acute kidney injury To date there is a paucity of data on the incidence of AKI whether community or hospital-acquired. The varying incidence and prevalence of AKI may be the result of different definition employed and methods used for ascertainment of cases. Epidemiological studies of AKI may underestimate the prevalence rate, as patients are not universally screened for changes in estimated GFR or UO in epidemiological studies. The incidence of AKI also varies with the clinical setting, community-acquired, hospital-acquired, sepsis-induced, and ICU-associated AKI. The reported prevalence of AKI from US data ranges from 1% (community-acquired) up to 7.1% (hospital-acquired) of all hospital admissions.39,40 The population (per million populations [pmp]) incidence of AKI from UK data ranges from 172 pmp/year from early data41 up to 486–630 pmp/year from more recent studies,42–44 again depending on definition. The incidence of AKI requiring RRT ranges from 22 pmp/year to 203 pmp/year.43 An estimated 5–20% of critically ill patients experience an episode of AKI during the course of their illness and AKI receiving RRT has been reported in 4.9% of all admissions to the ICUs.45 Data from the Intensive Care National Audit Research Center (ICNARC) suggests that AKI accounts for nearly 10% of all ICU bed days.46 We will deal with epidemiological aspects of community-acquired, hospital-acquired, and ICU-associated AKI in the present article.
Community-acquired acute kidney injury Only few systematic studies-related to the epidemiology of community-acquired AKI have been reported in literature. Overall, annual rates of the incidence of AKI vary from 22 pmp to 620 pmp. The definitional dependence of the incidence of community-acquired AKI is very obvious. A British study reported an annual incidence rate of 22 pmp using the need for RRT as a definition while 175 pmp using the definition of a serum creatinine > 5.7 mg/dL.47 Scotland study reported an annual incidence of 50 pmp using the need for RRT compared with 102 pmp with a serum creatinine > 5.7 mg/dL and 620 pmp using a serum creatinine > 3.4 mg/dL.48 Using the baseline serum creatinine and the rate of rise in serum creatinine, an annual incidence of 209 pmp has been reported from the Madrid region.49 Community-acquired AKI may account for 1% of hospital admissions in USA.50
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In tropical settings, the etiology of community-acquired AKI may vary, as diarrheal illnesses, infectious diseases, and snakebites are still common causes of AKI. Many changing trends in incidence of AKI with development have been observed in developing countries.51 Cerda et al mentioned contrasting characteristics of AKI in developed and developing countries.52 In developed countries, AKI occurs predominantly in urban ICUs and is associated with multiorgan failure and sepsis, high mortality, and occurrence in older populations. While cases of AKI in urban areas of the developing world have similar characteristics to those in the developed world, AKI in rural regions commonly develops in response to a single disease and specific conditions (e.g. gastroenteritis) or infections (e.g. severe malaria, leptospirosis, or hemolytic–uremic syndrome) and in younger otherwise healthy individuals. Many causes of AKI in rural settings, such as diarrhea, poisoning, malaria, or septic abortion, can be prevented by interventions at the individual, community, and regional levels. The herbal nephrotoxins and alternative medical therapies also contribute to AKI in these clinical settings. The incidence of pregnancy-associated AKI is still a problem in developing countries with illegal abortion is an important cause of it.53 Natural disasters such as earthquakes with resulting Crush-syndrome victims contribute to local and regional epidemics of AKI.54 There is a need of systematic study for the incidence of AKI caused by these alternative therapies in the northern region of India where this practice is not uncommon.
Hospital-acquired acute kidney injury It is generally believed that AKI may develop in > 5% of admitted patients, the heterogeneity of the condition and associated comorbidities make its study difficult. In the 1980s Huo et al reported the incidence of hospital-acquired AKI as 4.9%.13 However, the same group in 2002 showed an increased incidence of 7%55 again due to definitional differences. Chertow et al have shown the increasing odds ratio of mortality and cost of treatment in hospital-acquired AKI with increasing level of serum creatinine (Table 3).56 Several single center studies have reported that AKI occurs in 5–7% of hospitalized patients.57 These data suggest that hospital-acquired AKI exceeds the prevalence of a community-acquired AKI by 10-fold and that the major causes of hospital-acquired AKI are changing. The incidence of post-operative AKI is decreasing, whereas newer etiologies, including HIV nephropathy, AKI after solid organ transplantation and after cardiac resuscitation is increasing. Similarly, although the incidence of AKI because of antibiotic use is declining, cases of hospitalacquired AKI owing to the use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, chemotherapeutic agents, and antiviral agents is increasing. Two large studies from USA,58,59 which included > 5,000,000 hospital discharges in each study revealed that prevalence of AKI in hospitalized patients steadily increased over time, with a concomitant trend towards decreased mortality. The performance characteristics of the International Classification of Diseases, 9th revision, Clinical Modification codes (ICD-9-CM) for AKI were compared with serum creatinine-based definitions of AKI in nearly 100,000 discharges from three Boston hospitals.60 There was very high specificity (97.7%) for AKI with only modest sensitivity (35.4%). It appears that administrative and claims database-based evaluations of the prevalence of AKI in hospitalized patients possibly severely underestimate morbidity, mortality, and cost associated with AKI. The increase in the Table 3 Mortality and cost associated with selected changes in serum creatinine in hospitalacquired acute kidney injury. Increase creatinine Odds ratio (95% CI) (mg/dL) 0.3 0.5 1.0 2.0
Increase in cost ($)
4.1 (3.1–5.5) 4,886 6.5 (5.0–8.5) 7,499 9.7 (7.1–13.2) 13,200 16.4 (10.3–26) 22,023
prevalence of hospital-acquired AKI over time parallels the increased prevalence of sepsis in hospitalized patients, a major contributor to AKI in this setting. It is worth noting that with increasing prevalence of chronic kidney disease globally, the prevalence of acute on CKD is also increasing. Patients with CKD are 3 times more likely to develop AKI. It has been observed that acute on CKD accounts for the 36% cases of CKD in biopsied AKI patients.61 The incidence of AKI has sharply declined from 0.5 per 1000 pregnancies to one in 20,000 births in developed countries.62,63 Pregnancy-related AKI (PRAKI) is on the decline from 14.5% reported in 1987 to 4.3% in 2005 in India.64,65 However, pregnancy is still responsible for 15–20% of AKI in developing countries.66,67
Intensive care unit-associated acute kidney injury Acute kidney injury occurs frequently in the ICU setting.68 Despite of improved dialytic technology, including the development and refinement of continuous renal replacement therapies for the most critically ill patients, high mortality rates associated with AKI in ICU setting has not changed.16,69 The AKI complicating non-renal organ system failure in the ICU setting is associated with mortality rates of 50% to 70%, which has not changed for several decades. Given the excess mortality rates, much effort has been placed on accurately predicting in-hospital mortality in critically ill AKI patients. Such prediction models are important for clinical decision-making, quality improvement, and design of future clinical trials and research.20 Most predictive models are validated based on single center study and risk factors assessed at a single point of time in the study. Recently, the Program to Improve Care in Acute Renal Disease, a registry of critically ill patients with AKI across multiple US clinical sites, developed models for prognostic stratification and risk adjustment for mortality after AKI with analysis providing separate predictive models at three different time points during the course of AKI on day of AKI diagnosis, nephrology consultation, and finally day of initiation of RRT. There were remarkable differences in patient characteristics, processes of care, and outcomes across clinical sites.70 The predictors of mortality on time-dependent covariate are shown in Table 4. Sepsis status and organ system status were updated daily and last value carried forward wherever missing and dialysis status carried forward after initiation. The sepsis, age, central nervous system failure, liver failure, hematologic failure, and dialysis were the significant factors predicting mortality. Further studies are required to validate this model in different clinical settings. However, many uncomplicated AKI may be managed outside the ICU setting and carries a good prognosis, with mortality rates < 5–10%.20 Conclusion To sum up, it appears that the incidence of AKI varies in different studies perhaps due to definitional differences of AKI. The newer definitions of ADQI and AKIN will bring the uniformity in diagnostic criteria of AKI. However, certain limitations for these definitions of AKI still remain to be resolved. The use of diuretics before reporting to nephrologists may alter the diagnostic criteria based on UO and the sensitivity and specificity may be lost in that scenario and accurate measurement of UO may need urethral catheterization which may not be required for the management purpose in many patients. Table 4 Predictors of mortality using time-dependent covariates. Cox model
Age (per decade) Sepsis Central nervous system failure Liver failure Hematologic failure Dialysis
Parameter Relative risk
95% CI
1.13 1.87 4.58 1.90 1.46 1.79
1.01–1.26 1.33–2.63 3.30–6.35 1.34–2.71 1.01–2.10 1.21–2.66
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The need of baseline serum creatinine to calculate the proportion decrease in renal function may not be available in many patients and finally many other biomarkers including serum cystatine C, neutrophil gelatin associated lipocalin (NGAL) may allow earlier detection of the kidney injury. With increasing research in the field of AKI for its early recognition by novel biomarkers may further lead to refinement of the existing criteria. References 1. Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for change? J Am Soc Nephrol 2003;14:2178–87. 2. Himmelfarb J, Ikizler TA. Acute kidney injury: changing lexicography, definitions, and epidemiology. Kidney Int 2007;71:971–6. 3. Eknoyan G. Emergence of the concept of acute renal failure. Am J Nephrol 2002; 22:225–30. 4. Smith HJ. The Kidney: Structure and Function in Health and Disease. London, England: Oxford University Press 1964;v–vii. 5. Praught ML, Shlipak MG. 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mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care 1994;9:72–81. 31. Bagshaw SM, George C, Dinu I, Bellomo R. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant October 25, 2007 [epub ahead of print]. 32. Molitoris BA, Levin A, Warnock DG, et al. Acute Kidney Injury Network: improving outcomes from acute kidney injury. J Am Soc Nephrol 2007;18:1992–4. 33. Bagshaw SM, George C, Bellomo R, et al. A comparison of RIFLE and AKIN criteria for acute kidney injury. Nephrol Dial Transplant 2008;23:1569–74. 34. Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006;34:1913–7. 35. Thakar CV, Christianson A, Freyberg R, Almenoff P, Render ML. Incidence and outcomes of acute kidney injury in intensive care units: a Veterans Administration study. Crit Care Med 2009;37:2552–8. 36. Uchino S, Doig GC, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:1669–77. 37. Herget-Rosenthal S, Marggraf G, Husting J. Early detection of acute renal failure by cystatin C. Kidney Int 2004;66:1115–22. 38. Kidney Disease: Improving Global Outcomes. Clinical practice guideline on Acute Kidney Injury. 2011. www.kdigo.org. 39. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930–6. 40. Kaufman J, Dhakal M, Patel B, et al. Community-acquired acute renal failure. Am J Kidney Dis 1991;17:191–8. 41. Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: results of a living community based study. BMJ 1993;306:481–3. 42. Stevens PE, Tamimi NA, Al Hasani MK, et al. Non-specialist management of acute renal failure. QJM 2001;94:533–40. 43. Metcalfe W, Simpson KM, Khan IH, et al. Acute renal failure requiring renal replacement therapy: incidence and outcome. QJM 2002;95:579–83. 44. Hegarty J, Middleton R, Krebs M, et al. Severe acute renal failure. Place of care, incidence and outcomes. QJM 2005;98:661–6. 45. Metnitz PGH, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051–8. 46. Intensive-Care National Audit Research Centre, 2005. www.icnarc.org. 47. Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: results of a community based study. BMJ 1993;306:481–3. 48. Khan IH, Catto GR, Edward N, Macleod AM. Acute renal failure: factors influencing nephrology referral and outcome. QJM 1997;90:781–5. 49. Liano F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int 1996;50:811–8. 50. Kaufman J, Dhakal M, Patel B, Hamburger R. Community-acquired acute renal failure. Am J Kidney Dis 1991;17:191–8. 51. Chugh KS, Sakhuja V, Malhotra HS, Pereira BJG. Changing trends in acute renal failure in third-world countries — Chandigarh study. QJM 1989;73:1117–23. 52. Cerdá J, Arvind Bagga A, Kher V, Chakravarthi RM. The contrasting characteristics of acute kidney injury in developed and developing countries. Nature Rev Nephrol 2008;4:138–53. 53. Saleem Najar M, Rashid Shah A, Wani IA, et al. Pregnancy related acute kidney injury: a single center experience from the Kashmir Valley. Indian J Nephrol 2008; 18:159–61. 54. Ito J, Fukagawa M. Predicting the risk of acute kidney injury in earthquake victims. Nature Rev Nephrol 2009;5:64–5. 55. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930–6. 56. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365–70. 57. Lameire N, Van BW, Vanholder R. The changing epidemiology of acute renal failure. Nat Clin Pract Nephrol 2006;2:364–77. 58. Xue JL, Daniels F, Star RA, et al. Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992–2001. J Am Soc Nephrol 2006;17:1135–42. 59. Waikar SS, Curhan GC, Wald R, et al. Declining mortality in patients with acute renal failure, 1988–2002. J Am Soc Nephrol 2006;17:1143–50. 60. Waikar SS, Wald R, Chertow GM, et al. Validity of international classification of diseases, ninth revision, clinical modification codes for acute renal failure. J Am Soc Nephrol 2006;17:1688–94. 61. Zhang L, Wang M, Wang H. Acute renal failure in chronic kidney disease–clinical and pathological analysis of 104 cases. Clin Nephrol 2005;63:346–50. 62. Beaufils MB. Pregnancy. In: Clinical Nephrology 3rd ed. Davidson AM, Cameron JS, Grunfeld JP, et al, eds. New York: Oxford University Press 2005;1704–28. 63. Stratta P, Besso L, Canavase C, et al. Is pregnancy related acute renal failure a disappearing clinical entity? Ren Fail 1996;18:575–84. 64. Prakash J, Sen D, Kumar NS, et al. Acute renal failure due to intrinsic renal diseases: review of 1122 cases. Ren Fail 2003;25:225–33. 65. Kilari SK, Chinta RK, Vishnubhotla SK. Pregnancy related acute renal failure. J Obstet Gynecol India 2006;56:308–10. 66. Naqvi R, Akthar F, Ahmad E, et al. Acute renal failure of obstetrical origin during 1994 at one centre. Ren Fail 1996;18:681–3. 67. Selcuk NY, Onbul HZ, San A, Odabas AR. Changes in frequency and etiology of acute renal failure in pregnancy (1980–1997). Ren Fail 1998;20:513–7. 68. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813–8. 69. Liaño F, Pascual J. Outcomes in acute renal failure. Semin Nephrol 1998;18:541–50. 70. Chertow GM, Soroko SH, Paganini EP, et al. Mortality after acute renal failure: models for prognostic stratification and risk adjustment. Kidney Int 2006;70:1120–6.
Contents lists available at ScienceDirect
Clinical Queries: Nephrology January–March 2012, Vol. 1/Issue 1
j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
ISSN No.: 2211-9477
Acute kidney injury: definition controversies and epidemiology Narayan Prasad*, Amresh Krishna Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – 226014, India.
a r t i c l e
i
n f o
Article history: Received 6 November 2011 Accepted 14 November 2011
Keywords: Acute kidney injury Definition Epidemiology
a b s t r a c t
The term acute kidney injury (AKI) has now replaced the older term ‘acute renal failure’. Clinically AKI is characterized by a rapid reduction in kidney function resulting in a failure to maintain fluid, electrolyte, and acid–base homoeostasis. However, the definitions in published works of AKI is non-homogenous, ranging from severe to relatively modest observable increases in serum creatinine concentration. Changes in serum creatinine levels are relatively insensitive to small changes in glomerular filtration rate. The varying incidence and prevalence of AKI may also be the result of different definition employed and methods used for ascertainment of cases. To date there is a paucity of data on the incidence of AKI. The incidence of AKI also varies with the clinical setting, community-acquired, hospital-acquired, sepsis-induced, and ICU-associated AKI. The recent review is an attempt to find out the evidences for recent changes in definition and epidemiology of AKI. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction The term acute kidney injury (AKI) has now replaced the older term ‘acute renal failure’ (ARF).1 Himmelfarb and Ikizler et al has described changing lexicography of AKI in a mini review in 2007.2 The lexicography of AKI is related to some important historical periods in the history of kidney diseases.3 William Heberden first termed this modern AKI as the ischuria renalis in his Commentaries on the History and Cure of Diseases while describing the clinical course of AKI in 1802. The syndrome remained overlooked until World War II when Bywaters and Beal classically described anuric AKI after Crushsyndrome during the German bombing of London. Andre Cournand who was the winner of the 1956 Nobel Prize in Physiology or Medicine and his co-worker extensively studied the changes in kidney function associated with circulatory failure or shock in man during an investigation carried out during this war. In 1964, Homer W Smith introduced the term acute renal failure in his book titled The Kidney – Structure and Function in Health and Disease.4 This term ARF stood the test of the time until the new nomenclature AKI was introduced a few years back. Smith comprehensively reviewed data from animal models, as well as physiologic, pathologic, and clinical data from human cases of ARF. Smith provided clinical advice for the treatment of anuria which is still useful guide for clinicians in the management of anuria. The treatment of anuria should be conservative and the appropriate steps should be taken to correct it. The concept of renal support system should be applied to support the patient until the kidneys have a chance to recover. The overzealous administration of fluid in anuric patient *Corresponding author. E-mail address: [email protected]; [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(11)70002-4
may produce dangerous pulmonary edema and may promote the formation of renal edema. The different methods of renal replacement therapy (RRT) hemodialysis, peritoneal dialysis, and continuous RRT may be helpful in supporting the patient through a critical period of uremia. However, they cannot induce diuresis and their value in influencing the course of acute anuria is not established. Because each method involves an inherent physiologic burden, the application of any of them may handicap rather than promote spontaneous recovery. Clinically AKI is characterized by a rapid reduction in kidney function resulting in a failure to maintain fluid, electrolyte, and acid–base homoeostasis. Over recent years it has been observed that even a slight increase in serum creatinine is associated with increased mortality and morbidity.5–7 Previous studies have used an assortment of definitions for AKI, including those based on changes in serum creatinine, absolute levels of serum creatinine, changes in urine output (UO) or blood urea nitrogen (BUN) concentrations, or the need for dialysis. The wide variation in definitions has made it difficult to compare information across studies and populations. The definitions in published works of AKI is non-homogenous, ranging from severe (e.g. AKI requiring dialysis) to relatively modest observable increases in serum creatinine concentration (e.g. increase in serum creatinine of 0.3–0.5 mg/dL above baseline). At least 35 definitions of ARF are enlisted in the literature.2 Some of the definitions are extremely complex and could allow excessive subjectivity in AKI determination (Table 1). These would likely be impractical for prospective, multicentric investigations, and studies. Moreover, none of the definitions used to date take into account the modifying effects of age, gender, and race on creatinine generation. Changes in serum creatinine are not specific and are unable to discriminate the causes of renal injury (e.g. ischemic, nephrotoxic)
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2
Table 1 Definitions of acute kidney injury from several published studies. Authors
Definitions
Allgren et al8
1 mg/dL increase in serum creatinine over 2 days
Bates et al9
50% increase in serum creatinine to at least 2 mg/dL
Behrend and Miller10
0.9 mg/dL increase in serum creatinine if baseline serum creatinine is < 2.0 mg/dL to at least 2.0 mg/dL or 1.5 mg/dL increase in serum creatinine if baseline serum creatinine is > 2 mg/dL
Cochran et al11
More than 0.3 mg/dL and > 20% increase in serum creatinine
Eisenberg et al12
More than 1.0 mg/dL increase in serum creatinine or > 20 mg/dL increase in BUN
Hou et al13 0.5 mg/dL increase in serum creatinine if baseline serum creatinine is < 1.9 mg/dL or 1.0 mg/dL if baseline serum creatinine is 1.9 to 4.9 mg/dL or 1.5 mg/dL increase if baseline serum creatinine is 5 mg/dL or more Kurinik et al14
0.5 mg/dL or 25% increase in serum creatinine within 48 hr
Levy et al15
25% increase in serum creatinine to at least 2.0 mg/dL in 2 days
Liano and Pascual16 ‘Sudden’ rise of > 2 mg/dL in subjects with prior ‘normal’ renal function, or ‘sudden’ increase in serum creatinine of > 50% with ‘mild to moderate’ basal chronic renal failure with serum creatinine < 3.0 mg/dL, or ‘elevation of serum creatinine at admission with normal or increased renal size (except with myeloma or hydronephrosis with cortical atrophy)’ Lautin et al17 6 graded criteria More than 0.3 mg/dL and 20% increase in serum creatinine on days 1, 2, or 3, and days 5, 6, or 7, or > 0.3 mg/dL increase in serum creatinine on days 1, 2, or 3, or 0.3 mg/dL and 20% increase in serum creatinine on day 1 or 2, or > 2.0 mg/dL increase in serum creatinine on day 1 or 2, or 1.0 mg/dL increase in serum creatinine on day 1, or 20 mg/dL or 50% increase in BUN on day 1 Obialo et al18 0.5 mg/dL increase in serum creatinine to at least 2.0 mg/dL, or admission serum creatinine 2.0 mg/dL with no history of renal disease Parfey et al19
More than 50% increase in serum creatinine to at least 1.4 mg/dL
Shusterman et al20 0.9 mg/dL increase in serum creatinine if baseline serum creatinine < 2.0 mg/dL, or 1.5 mg/dL increase in serum creatinine if baseline serum creatinine > 2.0 mg/dL, and ‘remained elevated for at least one additional consecutive determination’ Taylor et al21
More than 0.3 mg/dL rise in serum creatinine
BUN: blood urea nitrogen.
Table 2 Comparative details of risk-injury-failure-loss-end-stage renal disease classification and acute kidney injury network staging.
Serum creatinine criteria
UO criteria
(A) The ADQI criteria for the definition and classification of AKI (i.e. RIFLE criteria) Risk Increase in serum creatinine ≥ 1.5 × baseline or decrease in GFR ≥ 25% < 0.5 mL/kg/hr for ≥ 6 hr Injury Increase in serum creatinine ≥ 2.0 × baseline or decrease in GFR ≥ 50% < 0.5 mL/kg/hr for ≥ 12 hr Failure Increase in serum creatinine ≥ 3.0 × baseline or decrease in GFR ≥ 75% or an < 0.3 mL/kg/hr ≥ 24 hr or absolute serum creatinine ≥ 354 mmol/L with an acute rise of at least 44 mmol/L anuria ≥ 12 hr
(B) The proposed AKIN criteria for the definition and classification of AKI Stage 1 Increase in serum creatinine ≥ 26.2 mmol/L or increase to ≥ 150–199% (1.5 to 1.9-fold) from baseline < 0.5 mL/kg/hr for ≥ 6 hr Stage 2 Increase in serum creatinine to 200–299% (≥ 2 to 2.9-fold) from baseline < 0.5 mL/kg/hr for ≥ 12 hr Stage 3 Increase in serum creatinine to ≥ 300% (≥ 3-fold) from baseline or serum < 0.3 mL/kg/hr ≥ 24 hr or creatinine ≥ 354 mmol/L with an acute rise of at least 44 mmol/L or initiation of RRT anuria ≥ 12 hr ADQI: acute dialysis quality initiative, AKI: acute kidney injury, AKIN: acute kidney injury network, GFR: glomerular filtration rate RIFLE: risk-injury-failure-loss-end-stage renal disease, RRT: renal replacement therapy, UO: urine output.
or the site and extent of glomerular or tubular injury, and levels are relatively insensitive to small changes in glomerular filtration rate (GFR).6 Moreover, changes in serum creatinine may lag behind changes (decline or recovery) in GFR by several days. Finally, because serum creatinine is influenced by one of the potential interventions for ARF (e.g. creatinine is removed by dialysis), its specificity for renal recovery is even more problematic. Several groups have recognized these limitations and have worked to identify the knowledge gaps and define the necessary steps to correct these deficiencies. These efforts have included consensus conferences and publications from the Acute Dialysis Quality Initiative (ADQI) group,6 the American Society of Nephrology (ASN) ARF Advisory group,22 the International Society of Nephrology (ISN), and the National Kidney Foundation (NKF), and KDIGO (Kidney Disease: Improving Global Outcomes) groups.23 This term enables healthcare workers to consider the disease as a spectrum of injury, which extends from less severe forms of injury with minimal rise of serum creatinine requiring no specific treatment to a more advanced injury when AKI may require RRT. The ADQI group consisted of experts from the discipline of nephrology as well as critical care medicine, published the RIFLE classification which is a consensus and evidence-based definition
of AKI (Table 2, panel A). The acronym RIFLE defines three grades of severity of AKI (risk, injury and failure) and two clinical outcomes (loss of renal function and end-stage of kidney injury) (Figure 1). Loss of renal function is defined as the irreversible or, persistent AKI for > 4 weeks. End-stage was defined as persistent renal injury for >3 months. The RIFLE classification has now been evaluated in a number of clinical studies of critically ill patients with AKI. In general, these criteria were found to have clinical relevance for the diagnosis of AKI, classifying the severity of AKI and for monitoring the progression of AKI, as well as having modest predictive ability for mortality.24–28 The details of classification based on serum creatinine and UO criteria are shown in Table 2, panel A. Acute kidney injury, as defined by the RIFLE criteria, is now recognized as an important intensive care unit (ICU) syndrome alongside other defined syndromes such as systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock29 and acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).30 It is worth noting that the RIFLE classification of AKI was originally intended to standardize the severity and definition of AKI, providing an important tool for research. Not with standing the ability to predict outcome, it is not intended to take into account the cause of AKI or the need for RRT. Other limitations include issues surrounding the differing sensitivity and specificity of the UO criteria compared with
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Non-oliguria
Oliguria
Risk
Abrupt (1–7) days decrease (>25% in GFR, or serum creatinine × 1.5 sustained
Decreased UO relative to fluid input UO <0.5 mg/kg/hr × 6 hr
Injury
Adjust creatinine or GFR decreased >50% serum creatinine × 2
UO <0.5 mg/kg/hr × 12 hr
Failure
Adjust creatinine or GFR decrease >75% serum creatinine × 3 or serum creatinine >4 mg% when acute increase >0.5 mg%
UO <0.5 mg/kg/hr × 12 hr Anuria × 12 hr
Loss
Irreversible AKI or persistent AKI >4 weeks
ESRD
End-stage renal disease >3 months
3
Specificity
AKI-earliest time point for provision of RRT
Figure 1 Risk-injury-failure-loss-end-stage renal disease classification of acute kidney injury. UO: urine output, GFR: glomerular filtration rate, AKI: acute kidney injury, RRT: renal replacement therapy.
the change in serum creatinine, although the former adds important information in the evaluation of patients.31 The validity of estimating baseline creatinine when this value is unavailable has also risen as a concern. More recently, the acute kidney injury network (AKIN) group, an international collaboration of nephrologists and intensivists, have proposed refinements to the RIFLE criteria.7 First, the AKIN group sought to increase the sensitivity of the RIFLE criteria by recommending that a smaller change in serum creatinine (≥ 26.2 mmol/L) be used as a threshold to define the presence of AKI and identify patients with stage 1 AKI (analogous to RIFLE-risk). Second, a time constraint of 48 hours for the diagnosis of AKI was proposed. The AKIN staging system for AKI stages 1, 2, and 3 corresponds to the risk, injury, and failure categories, respectively (Table 2, panel B). Slight modifications to the criteria for stage 1 would result in even greater sensitivity for the diagnosis of early AKI, and categories for loss and ESRD have been eliminated because these represent outcomes rather than course of AKI.32,33 Whether these modifications are an improvement to the existing RIFLE classification or will demonstrate a high false-positive rate requires further study. These definitions aimed to promote the earlier detection and recognition of AKI triggering appropriate treatment prior to progressive injury and kidney failure. The application of these definitions in > 500,000 patients has validated the increased risk of mortality associated with developing AKI.34,35 However, certain limitations for these definitions of AKI have been identified. First, the sensitivity and specificity may be lost when diuretics are been used. Second, the UO can be measured accurately only in catheterized patients. Third, the need of baseline serum creatinine to calculate the proportion decrease in renal function, and finally many other biomarkers including serum cystatine C that allow earlier detection of the kidney injury.36,37 Recently, the international guideline group, KDIGO has brought together international experts from various sub-specialties to produce a definition and staging system that harmonizes the previous definitions and staging systems proposed by both ADQI and AKIN.38 It is expected that this definition and staging system will be globally adopted and will be helpful for future comparison of incidence, outcome and effectiveness of therapeutic interventions for AKI. Patients should be staged according to whichever criteria (serum creatinine or UO) gives them the highest stage and only after they have been identified as meeting the criteria for the definition of AKI.
Epidemiology of acute kidney injury To date there is a paucity of data on the incidence of AKI whether community or hospital-acquired. The varying incidence and prevalence of AKI may be the result of different definition employed and methods used for ascertainment of cases. Epidemiological studies of AKI may underestimate the prevalence rate, as patients are not universally screened for changes in estimated GFR or UO in epidemiological studies. The incidence of AKI also varies with the clinical setting, community-acquired, hospital-acquired, sepsis-induced, and ICU-associated AKI. The reported prevalence of AKI from US data ranges from 1% (community-acquired) up to 7.1% (hospital-acquired) of all hospital admissions.39,40 The population (per million populations [pmp]) incidence of AKI from UK data ranges from 172 pmp/year from early data41 up to 486–630 pmp/year from more recent studies,42–44 again depending on definition. The incidence of AKI requiring RRT ranges from 22 pmp/year to 203 pmp/year.43 An estimated 5–20% of critically ill patients experience an episode of AKI during the course of their illness and AKI receiving RRT has been reported in 4.9% of all admissions to the ICUs.45 Data from the Intensive Care National Audit Research Center (ICNARC) suggests that AKI accounts for nearly 10% of all ICU bed days.46 We will deal with epidemiological aspects of community-acquired, hospital-acquired, and ICU-associated AKI in the present article.
Community-acquired acute kidney injury Only few systematic studies-related to the epidemiology of community-acquired AKI have been reported in literature. Overall, annual rates of the incidence of AKI vary from 22 pmp to 620 pmp. The definitional dependence of the incidence of community-acquired AKI is very obvious. A British study reported an annual incidence rate of 22 pmp using the need for RRT as a definition while 175 pmp using the definition of a serum creatinine > 5.7 mg/dL.47 Scotland study reported an annual incidence of 50 pmp using the need for RRT compared with 102 pmp with a serum creatinine > 5.7 mg/dL and 620 pmp using a serum creatinine > 3.4 mg/dL.48 Using the baseline serum creatinine and the rate of rise in serum creatinine, an annual incidence of 209 pmp has been reported from the Madrid region.49 Community-acquired AKI may account for 1% of hospital admissions in USA.50
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In tropical settings, the etiology of community-acquired AKI may vary, as diarrheal illnesses, infectious diseases, and snakebites are still common causes of AKI. Many changing trends in incidence of AKI with development have been observed in developing countries.51 Cerda et al mentioned contrasting characteristics of AKI in developed and developing countries.52 In developed countries, AKI occurs predominantly in urban ICUs and is associated with multiorgan failure and sepsis, high mortality, and occurrence in older populations. While cases of AKI in urban areas of the developing world have similar characteristics to those in the developed world, AKI in rural regions commonly develops in response to a single disease and specific conditions (e.g. gastroenteritis) or infections (e.g. severe malaria, leptospirosis, or hemolytic–uremic syndrome) and in younger otherwise healthy individuals. Many causes of AKI in rural settings, such as diarrhea, poisoning, malaria, or septic abortion, can be prevented by interventions at the individual, community, and regional levels. The herbal nephrotoxins and alternative medical therapies also contribute to AKI in these clinical settings. The incidence of pregnancy-associated AKI is still a problem in developing countries with illegal abortion is an important cause of it.53 Natural disasters such as earthquakes with resulting Crush-syndrome victims contribute to local and regional epidemics of AKI.54 There is a need of systematic study for the incidence of AKI caused by these alternative therapies in the northern region of India where this practice is not uncommon.
Hospital-acquired acute kidney injury It is generally believed that AKI may develop in > 5% of admitted patients, the heterogeneity of the condition and associated comorbidities make its study difficult. In the 1980s Huo et al reported the incidence of hospital-acquired AKI as 4.9%.13 However, the same group in 2002 showed an increased incidence of 7%55 again due to definitional differences. Chertow et al have shown the increasing odds ratio of mortality and cost of treatment in hospital-acquired AKI with increasing level of serum creatinine (Table 3).56 Several single center studies have reported that AKI occurs in 5–7% of hospitalized patients.57 These data suggest that hospital-acquired AKI exceeds the prevalence of a community-acquired AKI by 10-fold and that the major causes of hospital-acquired AKI are changing. The incidence of post-operative AKI is decreasing, whereas newer etiologies, including HIV nephropathy, AKI after solid organ transplantation and after cardiac resuscitation is increasing. Similarly, although the incidence of AKI because of antibiotic use is declining, cases of hospitalacquired AKI owing to the use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, chemotherapeutic agents, and antiviral agents is increasing. Two large studies from USA,58,59 which included > 5,000,000 hospital discharges in each study revealed that prevalence of AKI in hospitalized patients steadily increased over time, with a concomitant trend towards decreased mortality. The performance characteristics of the International Classification of Diseases, 9th revision, Clinical Modification codes (ICD-9-CM) for AKI were compared with serum creatinine-based definitions of AKI in nearly 100,000 discharges from three Boston hospitals.60 There was very high specificity (97.7%) for AKI with only modest sensitivity (35.4%). It appears that administrative and claims database-based evaluations of the prevalence of AKI in hospitalized patients possibly severely underestimate morbidity, mortality, and cost associated with AKI. The increase in the Table 3 Mortality and cost associated with selected changes in serum creatinine in hospitalacquired acute kidney injury. Increase creatinine Odds ratio (95% CI) (mg/dL) 0.3 0.5 1.0 2.0
Increase in cost ($)
4.1 (3.1–5.5) 4,886 6.5 (5.0–8.5) 7,499 9.7 (7.1–13.2) 13,200 16.4 (10.3–26) 22,023
prevalence of hospital-acquired AKI over time parallels the increased prevalence of sepsis in hospitalized patients, a major contributor to AKI in this setting. It is worth noting that with increasing prevalence of chronic kidney disease globally, the prevalence of acute on CKD is also increasing. Patients with CKD are 3 times more likely to develop AKI. It has been observed that acute on CKD accounts for the 36% cases of CKD in biopsied AKI patients.61 The incidence of AKI has sharply declined from 0.5 per 1000 pregnancies to one in 20,000 births in developed countries.62,63 Pregnancy-related AKI (PRAKI) is on the decline from 14.5% reported in 1987 to 4.3% in 2005 in India.64,65 However, pregnancy is still responsible for 15–20% of AKI in developing countries.66,67
Intensive care unit-associated acute kidney injury Acute kidney injury occurs frequently in the ICU setting.68 Despite of improved dialytic technology, including the development and refinement of continuous renal replacement therapies for the most critically ill patients, high mortality rates associated with AKI in ICU setting has not changed.16,69 The AKI complicating non-renal organ system failure in the ICU setting is associated with mortality rates of 50% to 70%, which has not changed for several decades. Given the excess mortality rates, much effort has been placed on accurately predicting in-hospital mortality in critically ill AKI patients. Such prediction models are important for clinical decision-making, quality improvement, and design of future clinical trials and research.20 Most predictive models are validated based on single center study and risk factors assessed at a single point of time in the study. Recently, the Program to Improve Care in Acute Renal Disease, a registry of critically ill patients with AKI across multiple US clinical sites, developed models for prognostic stratification and risk adjustment for mortality after AKI with analysis providing separate predictive models at three different time points during the course of AKI on day of AKI diagnosis, nephrology consultation, and finally day of initiation of RRT. There were remarkable differences in patient characteristics, processes of care, and outcomes across clinical sites.70 The predictors of mortality on time-dependent covariate are shown in Table 4. Sepsis status and organ system status were updated daily and last value carried forward wherever missing and dialysis status carried forward after initiation. The sepsis, age, central nervous system failure, liver failure, hematologic failure, and dialysis were the significant factors predicting mortality. Further studies are required to validate this model in different clinical settings. However, many uncomplicated AKI may be managed outside the ICU setting and carries a good prognosis, with mortality rates < 5–10%.20 Conclusion To sum up, it appears that the incidence of AKI varies in different studies perhaps due to definitional differences of AKI. The newer definitions of ADQI and AKIN will bring the uniformity in diagnostic criteria of AKI. However, certain limitations for these definitions of AKI still remain to be resolved. The use of diuretics before reporting to nephrologists may alter the diagnostic criteria based on UO and the sensitivity and specificity may be lost in that scenario and accurate measurement of UO may need urethral catheterization which may not be required for the management purpose in many patients. Table 4 Predictors of mortality using time-dependent covariates. Cox model
Age (per decade) Sepsis Central nervous system failure Liver failure Hematologic failure Dialysis
Parameter Relative risk
95% CI
1.13 1.87 4.58 1.90 1.46 1.79
1.01–1.26 1.33–2.63 3.30–6.35 1.34–2.71 1.01–2.10 1.21–2.66
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