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Abstract
Acute kidney injury (AKI) is associated with high mortality and morbidity risk. Factors predictive of mortality can guide in early identification of high-risk patients and escalation of therapy to improve outcomes. There is a paucity of data on AKI in Pakistan, and this study was done to determine in-hospital AKI mortality and the associated predictors of mortality. This was a prospective observational study conducted in the Acute Medical Unit and High Dependency Unit of Pak Emirates Military Hospital, Rawalpindi, from June to December 2018. Based on the Kidney Disease Improving Global Outcomes (KDIGO) AKI definition, 130 critically ill patients were included, while patients with chronic kidney disease were excluded. Data were collected on demographic profile-morbid conditions, etiology, laboratory values, and outcomes. The overall mortality was 45.4% (59/130) and varied with the stage of AKI, as it was 21.6%, 36.0%, and 61.8% in KDIGO stages 1, 2, and 3, respectively (P <0.05). There was a significant association (P <0.001) between sepsis, age >65 years, and mortality. Patients with inhospital mortality had higher median serum creatinine and mean potassium levels (P <0.01), with lower mean sodium levels and bicarbonate levels <10 mmol/L. However, on multivariate analysis using variables age >65 years, AKI stage 3, oliguria, bicarbonate <10 mmol/L, and sodium levels <130 mmol/L, only age [odds ratio (OR): 3.16, confidence interval (CI) 95%: 1.40−7.15), AKI stage 3 (OR: 3.12, CI 95%: 1.32−7.38], and low sodium levels <130 mmol/L (OR: 4.52, CI 95%: 1.40−14.61) were found to be independent predictors of mortality. Diabetes mellitus need for vasopressors, oliguria, hemodialysis requirement, and mean leukocyte counts had no significant association with mortality. AKI was associated with high in-hospital mortality in critically ill patients. Sepsis, hypertension, older age, Stage 3 AKI, higher mean creatinine, and potassium were predictive of increased mortality risk.
Introduction 
Acute kidney injury (AKI), formerly known as acute renal failure, is an abrupt decrease in kidney function, encompassing various etiologies.[1] AKI is a global health problem which is associated with considerable mortality, morbidity, and health-care costs, particularly in low-resource countries. It occurs in estimated 13.3 million people per year, and it contributes to some 1.7 million deaths annually;[2] 1.3 million, i.e., 85% of these deaths, occur in low-income and middle-income developing countries.
Epidemiological profile of AKI in developed countries is different from that of developing countries and even differs from center to center in the same country.[2],[3],[4] This is due to varying etiological factors, age groups, outcomes, higher mortality rates, and access to dialysis. Moreover, there is also a considerable difference in incidence of hospital-acquired and community-acquired AKI among regions. Low-income countries have a higher incidence of community-acquired AKI, and most studies showed a predominance of younger male patients as compared to the more elderly patients in high-income countries;[2],[5] however, urban centers in both had higher cases of hospital-acquired AKI. Furthermore, incidence of AKI is increasing with changing population dynamics and it has a varying mortality rate of 15%-60%.[2] Reasons for a varying reported mortality rate are variation in the treatment protocols and care, complications, AKI criteria, racial and cultural differences, and financial resources. The multicenter international crosssectional study AKI-Epidemiologic Prospective Investigation (AKI-EPI) study in critically ill patients also showed a significant variation in crude mortality rate across the various regions in the world. After adjustment for baseline risk, mortality rate becomes similar, which suggested that for a tertiary care academic hospital, AKI burden was not that different in various regions globally.[6] In the UK, almost 50% of patients who died from AKI had received suboptimal care according to the National Confidential Enquiry into Patient Outcome and Death in 2009.[7] The majority of deficiencies in care were seen in clinician management practices, highlighting the role of clinical awareness of prevalence and prognostic risk factors in AKI.[7]
The International Society of Nephrology (ISN) put forth the human rights case statement of 0 by 25.[3] The main goal of the 0 by 25 initiative is to eliminate or to at least reduce preventable AKI-related death worldwide by 2025. Accruing more data on the epidemiology of AKI and its outcomes is necessary, as data on the impact of AKI can guide policies in low-income countries. Identification of risk factors associated with poor prognosis can lead to earlier interventions, reduction in mortality rates, and implementation of evidence-based strategies. This can also assist in identifying high-risk patient subgroups who require counseling about prognosis. However, high-income countries disproportionately account for the published data in AKI, with over 84% of studies originating in high-income countries.[5] Lower middle-income countries face limited public funding for kidney care, lack of availability of surveillance systems, low workforce, and limited capacity to carry out research work to determine the burden of disease and outcomes.[8]
In developing countries such as Pakistan, epidemiological data are scarce, underreported, and not readily available. There is no nationwide registry, which shows a lack of focus, and therefore, Pakistan seems to be entirely off-track from achieving the 0 by 25 goal. Pakistan also falls in the category of countries having less than five nephrologists per one million population.[8] Considering paucity of data on AKI in Pakistan, the aim of this study was to determine etiologies, short-term outcomes, and predictors of mortality in critically ill AKI patients in a tertiary care hospital in Pakistan.
Method A prospective observational study was carried out in the Nephrology Department of Pak Emirates Military Hospital, Rawalpindi, Pakistan over a period of six months from June 2018 to December 2018. Approval was taken from the Ethical Review Committee. Considering inhospital prevalence of AKI 9% and margin of error 5%, sample size of patients was calculated to be 126 using the WHO calculator. Using nonprobability consecutive sampling, a total of 130 cases were included in the study. Critically ill patients admitted in the Acute Medical Unit (AMU) and High-Dependency Unit (HDU) under nephrology care were enrolled. AMU, a 16-bed ward, admits acute care patients who arrive mainly from the Emergency Department; similarly, HDU is a 12-bedded ward, in which critically ill patients who need continuous monitoring and care but do not require mechanical ventilation are admitted, often due to lack of bed availability in the Intensive Care Unit (ICU). Patients older than 18 years and having AKI as per the Kidney Disease Improving Global Outcomes (KDIGO) definition were included in the study and those with chronic kidney disease were excluded. Patients leaving against medical advice and those referred from other hospitals who had already undergone dialysis for AKI were also excluded.
AKI was defined as per the KDIGO as any of the following:
1. Increase in serum creatinine (SCr) by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 h; or
2. Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days; or
3. Urine volume <0.5 mL/kg/h for 6 h Severity of AKI was defined by the KDIGO staging and AKI was classified into the following stages:
1. Stage 1: Increase in SCr 1.5−1.9 times compared to baseline or ≥0.3 mg/dL ( ≥26.5 mmol/L) increase or urine output <0.5 mL/kg/h for 6-12 h.
2. Stage 2: Increase in SCr 2.0-2.9 times compared to baseline or urine output <0.5 mL/kg/h for ≥12 h.
3. Stage 3: Increase in SCr 3.0 times compared to baseline or increase in SCr to ≥4.0 mg/dL (≥353.6 mmol/L) or initiation of renal replacement therapy (RRT) or, in patients below 18 years of age, decrease in estimated glomerular filtration rate to <35 mL/min/1.73 m2 or anuria for ≥12 h.
Modality of dialysis used was intermittent hemodialysis (HD). Indications of initiation of dialysis were severe metabolic acidosis, refractory hyperkalemia, uremic encephalopathy, uremic pericarditis, and severe fluid overload. No specific cutoff for urea or Cr was used.
Data were collected on demographic profile, comorbid conditions, presence of oliguria, HD requirement, hypotension, etiology of AKI, and outcomes. Laboratory data included Admission serum creatinine levels, bicarbonate levels, serum potassium levels, serum levels, and total leukocyte count.
Data were entered and analyzed in IBM SPSS Statistics version 23.0 (IBM Corp., Armonk, NY, USA). Chi-square test was done for categorical data and percentage comparison, and t-test was done for comparison of mean values of continuous variables. Logistical regression was done to determine factors predictive of mortality. P-value <0.05 was considered statistically significant.
Results A total of 130 participants were included in the study based on the inclusion criteria. The mean age was 60.3 years with SD ±14.1. Majority 89.2% (116) were male and 10.8% (14) female.
The most common comorbid condition was diabetes mellitus in 48.5% (63), followed by hypertension (HTN) in 46.9% (61). Sepsis was the leading cause of AKI in 53.8% (70), and 40% (52) had oliguric AKI. Hypotension was seen in 38.5% (50) of cases. The etiological profile of AKI is summarized in [Table 1]. The mean length of stay was 5.29 ± 3.04 days.
Table 1. Clinical profile of patients with acute kidney injury.HD was carried out in 35.4% (46) of cases. The median Cr, mean bicarbonate, sodium, and potassium levels were 349.5 pmol/L, 15.15 ± 5.03 mmol/L, 134.45 ± 5.28 mmol/L, and 4.83 ± 0.79 mmol/L, respectively.
Overall, the mortality rate was 45.4%, as 59/130 died. Mortality rate varied with the stage of AKI, as it was 21.6%, 36.0%, and 61.8% in stages 1, 2, and 3, respectively, with P <0.05 [Figure 1].
Figure 1. Association between mortality and stages of acute kidney injury.65.7% of patients with sepsis died, and there was a statistically significant association on Chi-square test (P <0.001) between sepsis and mortality.
Patients having HTN also had a higher mortality rate (52.3% vs. 37.7%). There was no significant association between the presence of hypotension and mortality, and no significant difference between mortality rates in oliguric and non-oliguric AKI. 58.7% of patients who underwent dialysis died.
Patients with in-hospital mortality had higher mean SCr (P <0.001) and mean potassium levels (P = 0.012), with lower mean sodium levels. Although mean bicarbonate levels were not statistically different, there was a positive association of bicarbonate levels <10 mmol/L with mortality. The presence of diabetes had no effect on mortality rate, and mean leukocyte counts also did not significantly differ between the two groups [Table 2].
Table 2. Comparison between non-survivors and survivorsHowever, on multivariate analysis [Table 3] using variables age >65 years, AKI stage 3, oliguria, bicarbonate <10 mmol/L, and sodium levels <130 mmol/L; only age, AKI stage, and sodium levels were found to be independent predictors of mortality.
Discussion Clinical profile, epidemiology, and outcomes of AKI vary across the world. Differences in etiology, clinical practices, referral patterns, patient load, comorbid conditions, and delayed recognition and hospitalization perhaps account for these variations.
Majority of our patients were males; this difference may be due to the fact that the population which the hospital caters to is comprised mostly of current or former military soldiers. Although we found no statistically significant difference in this study, female gender was found to be an independent risk factor for mortality in a study by Hamzić- Mehmedbašić et al.[9] Among comorbid conditions, hypertension was associated with a poorer outcome in contrast to the study by Khalil et al [10] where it was associated with lower mortality rates. Elderly population was defined in different ways in various studies. In our study, individuals older than 65 years were considered the elderly group. Age was an independent predictor on multivariate analysis, elderly patients in our study had a higher mortality rate, and this was in agreement with various studies.[6],[11],[12],[13] Age was an independent predictor of death from AKI in the elderly in a multicenter retrospective study in China by Liu et al.[14] The elderly have less renal reserve due to either comorbid conditions or age-related functional changes.[12] Although most studies in developing countries show a higher proportion of younger patients, our study had a relatively higher proportion of elderly population as tertiary health-care centers in urban areas show a demographic profile similar to that of developed countries.[2]
The mortality rate of patients with AKI was 45.4% which was comparable to the reported 42% by Talib et al in a local study in Pakistan,[15] 46.8% by Emem-Chioma et al,[16] and 47.2% by Ahmed et al in Egypt.[17] However, this was considerably higher than 38.5% reported by Oluseyi et al.[13] The mortality was 39.1% in a study by Chaudhri et al,[18] 32.9% by Khalil et al in Pakistan,[10] and 29.5% in China.[19] Ulusoy et al[20] also reported a lower in-hospital mortality rate of 34.6% in Turkey. The crude in-hospital mortality rate was 27% in a multicenter study in the USA.[21] After adjusting for age, gender, and severity of illness, differences in outcomes of AKI were observed among different centers, and the authors recommended whether the variation was due to varying clinical practices and care, or other confounders required further research.[21] Considerably higher mortality rate of 51.9%[22] was observed in a study on elderly ICU population, 52.5% by Priyamvada et al in India,[23] and 66% mortality was observed in a study on AKI caused by ATN in Brazil.[11] This is in sharp contrast to the UK national average mortality of 18%[24] and 8.8% in one Chinese study.[25] In a meta-analysis, the overall pooled mortality rate in AKI was 21%, and it was attributed due to predominance of milder stages of AKI, and this was in comparable to 21.6% mortality rate of stage 1 AKI in our study. However, higher mortality rates of 42% and 46% were observed in patients with KDIGO stage 3 or those requiring RRT, respectively,[3] in the metanalysis and in comparison mortality rate in stage 3 AKI in our study was higher (66%). The mortality rate observed was perhaps higher in our study as the hospital is a referral center and most patients present with a higher stage of AKI and multiple comorbid conditions. The study population also consisted of critically ill patient population admitted in AMU and HDU. Furthermore, sepsis was the most common etiological factor and AKI due to sepsis has a very high mortality rate. One other observation was a high median Cr signifying delayed recognition and late presentation of patients in our study. Step-wise increase in mortality with increase in the stage of AKI was also seen in other studies,[5],[6],[26] and stage 3 AKI was a predictor of mortality in these studies in agreement with our study. Priyamvada et al,[23] however, reported similar mortality rates in all stages.
Sepsis was the leading cause of AKI in 52.3%; this was also observed in a study by Chaudhri et al[18] and among other studies from developing countries.[13],[23],[27],[28],[29] Septic AKI has higher inpatient mortality rates of up to 70%,[30] and it was also seen as an independent predictor of mortality in various studies;[9],[30] this was also observed in our study. In contrast, gastroenteritis was the most common cause in studies by Anvar and Raghavendra[28] and Ananth et al[31] in India.
In a recent systematic review, 41% of patients who underwent RRT died, whereas in our study, the mortality rate was higher (58.7%).[32] Although some studies showed increased mortality in patients undergoing RRT[19] making dialysis requirement an independent risk factor of mortality,[20] in a more recent study, RRT was associated with better survival in patients with AKI-related complications.[33]
There was a significant difference between mean creatinine levels among survivors and non-survivors; these findings were contrary to that observed by Talib et al.[15] Higher Cr levels were also paradoxically associated with better survival in another study by Cerda et al.[34] Possible explanations were that fluid overload often decreases Cr levels and is associated with greater mortality and perhaps earlier initiation of dialysis in patients presenting with higher Cr levels increases survival.[34] In adjusted analysis, higher creatinine concentration had lower overall mortality[35] in the University of Pennsylvania Health System-AKI cohort.
While oliguria was not a significant factor for mortality in our study, Teixeira et al and other studies found it to be an independent predictor of mortality.[9],[10],[36]
The limitations of our study include observational nature of this study; this was a singlecenter study and hence had a relatively smaller study population. The study population consisted mainly of critically ill patients who were admitted in AMU and HDU; however,ICU patients were excluded due to heterogeneous data and various studies already done on ICU patients in Pakistan. Due to incomplete data, some patients were excluded, resulting in selection bias. There was also a lack of control group of patients. Timing of dialysis initiation since hospital admission was not analyzed. The study also did not identify differences between outcomes of hospital-acquired AKI and community-acquired AKI. A long-term follow-up of outcomes was also not carried out. However, this is one of the few studies in Pakistan that has determined the epidemiological profile of AKI using the latest KDIGO staging of AKI and determined the predictors of outcomes in AKI patients.
Conclusion AKI was associated with high in-hospital mortality in critically ill patients. Sepsis, hypertension, older age, stage 3 AKI, higher mean Cr, and mean potassium were predictive of increased mortality risk. More multicenter regional studies are required to determine the epidemiological profile and outcomes of AKI in Pakistan.
Conflict of interest: None declared.
References 
Correspondence Address:
Taymmia Ejaz
Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan.
Pakistan
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.352436
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