Clinical outcome and Predictors of Acute Kidney Injury in Adult Patients Admitted to the Medical Ward of Jimma Medical Center, South West Ethiopia: A prospective Observational Study

Acute kidney injury is a major global public health problem occur both in community and hospital settings. It is expensive to manage, prolongs hospitalization and associated with high rates of in-hospital mortality. We aim to evaluate the clinical outcome and predictors of AKI in a single center hospitalized patients. Method A hospital based prospective observational study was employed. Patients were recruited using consecutive sampling technique after informed consent was secured from all patients. Data was cleaned, coded and entered in to Epi-data software version 4.4.2 and analyzed with SPSS version 21. Cox regression model was tted to identify predictors of mortality. Statistical signicance was considered at p-value of less than 0.05. This is a single center prospective observational study, investigated a total of 203 AKI patients. From these 203 patients, 69.5% had evidence of renal disease on admission, comparable with reports of community acquire AKI in developing countries; South Africa 72.4% ( 31 ), Sudan, 82.6% ( 46) , review of community acquired AKI in adults in Africa, 70–90% ( 47 ). high of patients


Background
Acute kidney injury (AKI) is a complex clinical syndrome arise in response to many etiologies such as hypovolemia, sepsis and nephrotoxins. It is a major global public health problem occur both in the community and hospital settings (1). Once occurred, AKI is expensive to manage, prolongs hospitalization and associated with increased mortality. The in-hospital mortality rate is reported 24% and increased with advanced stage of the disease ( 2,3 ). Based on United Kingdom National Institute for Health and Care Excellence (UK-NICE) published report on AKI, early identi cation and treatment with attention to hydration and medications could avoid up to 42,000 deaths each year ( 4 ).
AKI has a gradual and subtle presentation and impose a di cult challenge to healthcare professional ( 5 ). The risk increased with exposure to factors that cause or increase susceptibility to the disease. Although there is lack of su cient data regarding acute kidney injury in case of developing countries, diseases that are considered to be risk factors for AKI in developed world are increasing in prevalence in developing countries. Diabetes is believed to affect 9.4 million people in Africa, with a 6.1% prevalence of diabetic nephropathy in Ethiopia ( [6][7][8][9][10][11] ).
AKI is affects over 13 million people and results in 1.7 million deaths each year around the world. Even mild form of AKI is associated with a 50% high risk of death. It also impose a signi cant burden for society in terms of long-term consequences include; chronic kidney disease (CKD), kidney failure and death ( 12,22 ). A single exposure to AKI has a signi cantly higher risk of morbidity and mortality; with an episode of stage 1 AKI independently associated with an increase in 10-year mortality. The long-term impact of AKI is also extended to health care costs and in UK, it accounts about 1 % of the total health and social care budget ( 13,14 ). A recent study showed that; AKI has been associated with a 58% increased risk of heart failure and 40% increased risk of acute myocardial infraction particularly in patients with pre-existing cardiovascular diseases. Other than CKD and death, AKI is also a risk factor for cardiovascular disease events ( 10,15 ).
The burden of acute kidney injury is high in developing countries with limited resources for the care of these patients once the disease progresses to kidney failure ( 1 ).
The high morbidity and mortality associated with acute kidney injury in Ethiopia is challenging to community. Failure of early recognition of AKI with active monitoring of renal function lead to development of acute renal injury or end stage renal disease (ESRD). Patients with con rmed AKI are treated inappropriately and treatment itself is costly in resource limited settings especially; if progress to ESRD. These challenges are apparent in Ethiopia, where nephrology services are limited. Government run dialysis services in Ethiopia and access to dialysis is limited and some patients referred to private dialysis facilities where treatment is limited by the inability to cover cost of treatment ( 16,17 ).
Despite advances in AKI de nition considered a major step forward which represents a wide spectrum of patients and focusing attention on opportunities of prevention, renal replacement therapy and supportive measures, there is still high rate of in-hospital mortality. Lack of awareness of the disease and its long term impacts is still high among physicians, allied personnel and the lay public. Therefore, there is limited systematic effort and little resource allocation to inform health-care professionals and the public on the importance of the disease as a preventable and treatable ( 18 ).
In developing countries, late recognition of the disease is even more problematic in both community and hospital settings. Late recognition results in delayed management, where associated morbidity and mortality have worsened.
Most of the data on acute kidney injury are derived from high income countries, in low to moderate income countries; the long-term impact of AKI is almost completely unknown ( 19 ).
Limited data is available regarding renal function tests in hospitalized patients, risk factor recognition, outcomes and associated factors of AKI in Ethiopia ( 16,20 ). Therefore, the aim of this study was to evaluate clinical outcome and predictors of AKI in medical ward of Jimma medical center, Southwest Ethiopia.

Study design, Area and Period
A hospital based prospective observational study was conducted at medical ward of Jimma medical center, Southwest Ethiopia. The hospital is located in Jimma town, 350 kilometers Southwest of Addis Ababa; the capital city of Ethiopia. Currently; JMC is the only teaching and referral hospital in southwestern part of Ethiopia. It provides specialized health services through its nine medical and other clinical and diagnostic departments. The internal medicine department of the hospital has over 80 beds for inpatients and has two renal units ( 39 ). The study was conducted from April to August, 2019.

Study Population
All adult patients with diagnosis of acute kidney injury were recruited using consecutive sampling technique and followed till discharge or referral to facilities outside the hospital or death. Single population proportion formula was used to determine the sample size. Patients with age >18 years, patients with con rmed AKI diagnosed by physician and patients who were willing to sign written informed consent were included in the study. On the other hand; patients who can't able to give the required information, hospitalized for less than 48 hours and those patients with underlying CKD were excluded from the study. The baseline serum creatinine was determined for both hospital and community acquired acute kidney injury based on KIDGO AKI guideline and review of previous literatures. HA-KI: -The rst documented serum creatinine on admission or patients admitted with normal creatinine levels was used as the baseline for patients with hospital acquired AKI and an increase in creatinine equal to or greater than 0.3 mg/dL when compared with baseline creatinine was used to for patients who develop hospital acquired AKI as described in the KDIGO AKI Guideline( 1 ). CA-AKI: -(i) For patients with evidence of renal disease on admission; an increase ≥0.3mg/dL creatinine on admission compared with a prehospital record of creatinine within seven days to three months of hospital admission or (ii) Use of the minimum and or most recent value of admission Scr as a baseline kidney function was used based on review of previous studies ( 40,41,42 ). The clinical assessment (i.e., renal diagnostic imaging or ndings suggestive of CKD) was used to differentiate CA-AKI from CKD Ethical approval and consent to participate The study meet the ethical and scienti c standards outlined in national and international guidelines and approved by institutional review board (IRB) of institute of health, Jimma University research ethics unit (reference number: IHRPGA/574/2019), and a letter of permission was forwarded to the administration of Jimma medical center. Informed consent was secured from all participants and collected data was kept con dential.

Data collection and procedures
Data abstraction checklist was developed from review of literatures and National Con dential Enquiry into Patient Outcomes and Death (NCEPOD) AKI data collection tool to collect relevant information from patient chart about diagnosis, comorbidities, medications given, laboratory results and other investigation results. Data abstraction format and questionnaire was pretested to standardized and check suitability before actual data collection.

Statistical analysis
Epi data version 4.4.2 was used to enter, encode and clear data and SPSS version 21 was used for analysis. Descriptive statistics, such as frequency, percentage, mean, median and standard deviation was used to summarize patients' baseline characteristics. Frequency and proportion were used for categorical data, while mean and standard deviation for continuous variables. Crosstabs used for the comparison of proportions of categorical variables. Cox regression model was tted to determine independent predictors of mortality when the p-value is less than or equal to 0.25 on bivariate analysis. Statistical signi cance was considered at p-value of less than 0.05 on multivariate analysis.

Outcome measurement
Outcomes of patients with AKI were measured using poor and good outcome parameters. Poor outcomes include; deaths, non-recovery, self-discharge referral and recurrent AKI. Good outcome; patients discharged with complete recovery of renal function at hospital discharge. This was based on evaluating urine output and laboratory abnormality. Patients were followed starting from admission or diagnosis of AKI to discharge or occurrence of the event. The time was recorded from patient's admission or diagnosis of acute kidney injury to occurrence of the event or patients discharge from the hospital.
Operational de nitions and De nition of terms AKI was de ned according to KIDGO (2012) as any of the following: an increase in Scr by >3 mg/dl (>26.5 micromole/l) within 48 hours; OR increase in Scr to >1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; OR Urine volume < 0.5 ml/kg/h for 6 hours.
Clinical outcome: is the condition of the patient at the end of hospital stay.
Good clinical outcome: admitted patient discharged with improvement in kidney function which is evident by renal function tests and decided by physician Poor clinical outcome: in hospital death, self-discharge, referral and non-recovery were considered as poor clinical outcome.
Recovery--de ned as reversal at hospital discharge or return to baseline (43).
Late reversal---Reversal after seven days Sustained reversal ------Reversal within seven days Non-recovery-AKI not returned to premorbid/baseline kidney function Referral: Patients referred to other health facility for better management of the condition Self-discharge: Patients discharge themselves against medical care Comorbidities: -Chronic medical conditions that coexist and affects outcomes Duration of AKI-is de ned as the number of days AKI was present from the rst day the patient met the AKI criteria until they no longer did (44) Prolonged length of hospital stay-Hospital stay greater than or equal to seven days (45).

Sociodemographic and Clinical characteristics
A total of 234 AKI patients were enrolled to the study over a period ve months, 31 patients were excluded as per the exclusion criteria. Males' accounts 59.6% of all AKI admissions. Patients aged 60 years and above were 28.6%. The rest is summarized in table 1 below.      ( 12 ). The variation compared to these studies might be due to; difference in patients site of admission (i.e ICU vs general medical ward), underlying disease and study populations.
This study was done in two renal units of the medical ward; even though large number of critically ill patients were admitted to this ward; due to small number of beds in general ICU setting. On the other hand; this study exclude patients with underlying CKD; an important predictor of in hospital mortality in patients with AKI. The result of this study was comparable with ndings from other study in Egypt, 13%( 33 ) and one year study in Sanford-USA 10.8% ( 36 ). But there is still difference in duration of study compared to these studies.
In our study; age, sex, comorbidities and causes of AKI have no association with in-hospital mortality similar to ndings from India ( 51) ; but in other studies; in hospital mortality was signi cantly associated with cardiovascular disease and older age( 52 ), sepsis( 31 ), female sex( 53 ), hypertension and older age( 54 ).
In our study; stage of AKI (severity) was signi cantly associated with 30 day in hospital mortality. This might be due to patients delayed admission with advanced stage of the disease and missed attempts to prevent the progression of the disease and its consequences. Findings from this study are consistent with several other studies; in which Stage 3 AKI was associated with mortality; Egypt ( 33 ), India( 51 ), Brazil( 25 ). Other study also showed that; even pre stage AKI (pre AKI), de ned as a 25-50% increase in peak serum creatinine levels from baseline levels; is associated with increased mortality, longer hospital stay, and increased medical costs. So, clinicians should give emphasis to the clinical signi cance of pre-AKI ( 55 ). Stage of AKI is reported to be a predictor for mortality and decreased kidney function, correlate with short term and even longer-term outcomes. So, depending on the stage, the intensity of preventive and therapeutic measures should be performed( 1 ).
In this study; length of hospital stay was signi cantly associated with in hospital mortality; where patients with prolonged length of hospital stay greater than or equal to seven days had a 81% less risk of death compared to patients hospitalized for less than seven days. This might be due to patient's admission with severe and advanced stage of AKI with complications and died early on hospital admission. This is similar with ndings from Nigeria( 27 ). But report from other studies in Malawi and Colombia showed prolonged length of hospital stay was predictor of in hospital mortality (23,32) .
Duration of AKI had a stastically signi cant association with mortality in which; patients with AKI duration of greater than seven days had a seven times higher risk of mortality compared with patients with AKI duration of three to six days or less. This is similar to ndings from other studies where; AKI duration of greater > 2 weeks predicts mortality (33,56) .
Therefore; AKI duration should be used as an additional parameter for the prediction of in hospital mortality in critically ill patients and both KIDGO staging of AKI and AKI duration are strong predictor of mortality compared to KIDGO stage of AKI alone( 57 ). Persistent AKI was associated with worse clinical outcomes include increased ICU length of stay, time on the ventilator and days with cardiovascular failure. This showed the importance of identifying those patients and appropriate interventions( 58 ).
In this study it was found that; patients with hyperkalemia had a signi cantly associated higher risk of mortality compared with patients without hyperkalemia. This was similar from ndings of other studies( 51 ). Another study showed that; the in-hospital mortality rate of patients with hyperkalemia was 30.7%. The study revealed that; acute kidney injury (AKI) in patients with normal baseline renal function was a strong predictor of mortality, compared with AKI superimposed on CKD( 59 ). A study on predictors of hyperkalemia and death in patients with cardiac and renal diseases showed that; Compared to patients with normokalemia, those with hyperkalemia had a higher percentage of death. Hyperkalemic event, severity of renal disease and age were predictors of all-cause mortality( 60 ).
The result of this study identi ed that; need for RRT, which is predictor on bivariate analysis; had nearly signi cant association with in hospital mortality on multivariate analysis. Despite RRT was considered in 5% of patients and the other 5% were in need of dialysis, none of the patients were dialyzed due to various reasons include; referral to other institutions, self-discharged due to cost issues, patients late admission with advanced stage disease and complications lead patients to death before initiate dialysis. This is consistent with ndings from systematic review of AKI outcomes in sub-Saharan Africa which stated; acute kidney injury is severe in sub-Saharan Africa where, 70% of patients need dialysis and only 33% received; increase overall mortality rate from 33-86% (29,34) . Need for RRT is also revealed as predictor of mortality in other studies (25,33) . The variation with these studies might be due to; some patients admitted late with advanced stage disease and die before initating RRT; other patients self-discharged due to cost issues and also referred to other institutions for further investigation and management.

Limitations of the study
This study has several limitations. First, urine output assessment was done in around 70% of patients only, which might detect more cases and important to monitor outcomes. Second, patients with underlying CKD were excluded; because most patients have no routine renal function tests and di cult to know the baseline renal function. Furthermore, no outcome monitoring was performed beyond the period of hospitalization. Therefore, important information, including the incidence of CKD after AKI, mortality rate, and ESRD and other non-renal outcomes are unknown.

Conclusion
The study revealed that; about half of patients had improved renal function at hospital discharge. Twelve percent were died within 30 days of hospital admission. Severity of AKI, hyperkalemia duration of AKI and short length of hospital stay were predictors of 30 day mortality. Most of causes of AKI are preventable and patients would have been bene ted from early identi cation and treatment of these reversible causes. The institutional review board of Jimma University, institute of health, research ethics unit approved the study (reference number (IHRPGA/574/2019), and a letter of permission was forwarded to the administration of Jimma medical center. Informed consent was secured from all participants and the collected data was kept con dential.

Consent for publication "Not applicable"
Availability of data and materials. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request Competing interests." The authors declare that they have no competing interests" Funding. This study was sponsored by Jimma University. The funding body played no any role in study design, data collection, analysis and interpretation of data and writing of the manuscript or in the decision to submit the manuscript for publication. No funding or sponsorship was received for the publication of this article.
Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors' contributions. A.A contributed in design of the study, data collection, entry and perform analysis. K.K designed methodology and contributed her expertise in discussion and interpretation of results. M.B offered expert advice in methodology and the whole idea of the study. B.K assisted in discussion and editing the nal manuscript. All authors read and approved the nal manuscript. Kaplan-Meier estimated survival for severity of AKI. Long-rank test p=0.035