Acute kidney injury – improving outcomes with early risk assessment and intervention

Acute kidney injury (AKI) is being recognized around the world as a preventable and treatable cause of increasing morbidity and mortality. Epidemiological data from the developing world show an increasing trend in its incidence, though data from the developing world is still scarce. Causes for AKI differ among developed and developing countries with sepsis as the leading cause in the developed world while communicable diseases, toxin related acute kidney injuries as well as those associated with herbal medications still contribute to the incidence in the developing world. The mortality following AKI is between 20-60% with many needing intensive care unit (ICU) admissions and renal replacement therapy (RRT). There is increasing evidence that AKI may lead to chronic kidney disease (CKD). Early risk assessment and adoption of simple prevention strategies have shown to improve outcomes in AKI.


Introduction
Acute kidney injury (AKI) is emerging as an important cause of morbidity and mortality throughout the world.There is increasing evidence that even mild impairment of renal function can lead to serious consequences 1 .Possible explanations for this effect are volume overload, retention of uremic compounds, acidosis, electrolyte disorders, increased risk of infection and anaemia 2 .

Background
The first description of acute kidney injury was by William Heberden in 1802 where it was named ''ischuria renalis'' 3 .During the first world the syndrome was named ''war nephritis'' and again came in to light during the second world war following a publication on crush syndrome 4 .There have been several different definitions used in the literature until recently when two classification systems were introduced.More recently kidney disease improving global outcomes

Incidence and aetiologies
Epidemiological data on the incidence of AKI is mostly lacking.A recent publication by Hsu et al. revealed a 10% annual increase in dialysis requiring AKI in the United States.An adult cohort of beneficiaries of the health-care delivery system Kaiser Permanente of Northern California were evaluated over a 8-year period from 1996 till 2003, and found that the use of acute renal replacement therapy (RRT) increased from 195 patients per million population per year (pmp/y) in the period 1996-1997 to 295 pmp/y in the period 2002-2003.Between the years 1996-2003, there was also an increased incidence of AKI not requiring dialysis from 323 to 522 per 100 000 person-years 6 .
Etiologies for AKI differ among developed and developing countries.While sepsis remains the leading cause of AKI in developed countries, in the developing world infections remain the leading cause for AKI 7,8 .In sub-Saharan Africa diarrheal disease, malaria, nephrotoxic traditional medicines, post obstetric complications and HIV are the leading causes 8,9 .In Asia diarrheal disease, malaria, leptospirosis and snake bites constitute over 60% of AKI 8,10,11 .There is little epidemiological data from Latin America, however communicable diseases remain an important cause 12 .ICU-specific data from developed countries indicates an incidence of hospital-acquired AKI of between 5% and 20% of ICU admissions, corresponding to 66-80 per million population per year 13,14,15 .
Among infectious diseases causing AKI, malaria is an important cause.The incidence varies from 0.6% to 60% in various geographical regions 16 .Leptospirosis is a common cause of AKI in tropical and subtropical countries.It is the leading cause of AKI in Singapore and Thailand 17 .Acute glomerulo-nephritis (AGN) remains an important mechanism underlying AKI in the developing world.In areas such as southeast Anatolia in Turkey, AGN causes more than 60% of cases of AKI 18 .Herbal and non-herbal nephrotoxins are common causes of AKI in tropical regions including Africa.The toxicity of herbal products (e.g.Callilepis Vol.44, Nos. 1 & 2, 2013   Acute kidney injury -improving outcomes with early risk assessment and intervention laureola, known by Zulus as 'impila') often leads to liver failure, neurologic abnormalities, metabolic acidosis, AKI or respiratory failure 19,20 .

Prognosis
Many studies on AKI have been on ICU patients and reported outcomes have been poor.In one study, ICU mortality was 52 % with an overall mortality of 60.3%.Independent risk factors for hospital mortality included use of vasopressors (odds ratio [OR]  13 .In another study the mortality ranged from 8.8% to 26.3% with increasing severity of AKI.Patients with maximum RIFLE class R, class I and class F had hospital mortality rates of 8.8%, 11.4% and 26.3%, respectively, compared with 5.5% for patients without acute kidney injury.Additionally, acute kidney injury (hazard ratio, 1.7; 95% confidence interval, 1.28-2.13;P < 0.001) and maximum RIFLE class I (hazard ratio, 1.4; 95% confidence interval, 1.02-1.88;P = 0.037) and class F (hazard ratio, 2.7; 95% confidence interval, 2.03-3.55;P < 0.001) were associated with hospital mortality after adjusting for multiple covariates 21 .A study by Ostermann and Chang showed a hospital mortality rate ranging between 20.9% to 56.8% compared to 8.4% among patients without acute kidney injury 22 .
In a study conducted with data from the Australian New Zealand Intensive Care Society Adult Patient Database in 57 ICUs across Australia, AKI, defined by any RIFLE category, was associated with an increase in hospital mortality (OR 3.29, 95% CI 3.19-3.41,P < 0.0001).The crude hospital mortality stratified by RIFLE category was 17.9% for Risk, 27.7% for injury and 33.2% for failure.By multivariable analysis, each RIFLE category was independently associated with hospital mortality (OR: Risk 1.58, injury 2.54 and failure

3.22) 23 .
There is also increasing evidence to support that persistent renal dysfunction or CKD may be associated with AKI.Several studies support this.In the large multicenter BEST Kidney trial, 13% of patients still required RRT at hospital discharge 13 .Similar findings were reported in Sweden: 8.3% of patients on continuous RRT and 16.5% of patients on intermittent RRT developed end-stage kidney disease 24 .In Canada, 22% of surviving patients developed end stage kidney disease 25 .Finally, patients who already have chronic kidney disease are at much greater risk of developing end stage kidney disease.In the large Scottish database, 13% of patients with normal baseline kidney function developed end stage kidney disease, compared with 53% in patients who at baseline already had chronic kidney insufficiency 26 .

Situation in Sri Lanka
Though countrywide data is unavailable in Sri Lanka, a study (n=68) conducted at the National Hospital of Sri Lanka showed that sepsis and leptospirosis accounted for the majority of AKI presentations.Causes for sepsis were largely unidentified but urinary tract infection was the leading cause among those that were identified.Fifty eight (85.3%)patients required RRT with 46 (79.32%) receiving hemo-dialysis and 12 (20.68%)receiving acute peritoneal dialysis.Twenty patients (29.4%) made a complete recovery while 28 (41.2%) made partial recovery with a mortality of 24%.Of the patients who made a complete recovery 70% were below the age of 55 compared to 30% who were over 55 (p=0.13).The presence of co morbidities was associated with a worse outcome with only 5.9% achieving complete recovery (p< 0.01) 27 .

Risk assessment
There are many known exposures for AKI such as sepsis, critical illness, circulatory shock, burns, trauma etc; however the incidence varies even among individuals exposed to the same insult.Data from many large prospective studies have supported the presence of susceptibility factors for developing AKI.

Dehydration/volume depletion
Volume depletion is an important and reversible cause of AKI.This is accepted as a risk factor for development of AKI upon exposure to any insult.A systematic review of the literature to determine the ability of dynamic changes in arterial waveform-derived variables to predict fluid responsiveness and 56% of patients responded to a fluid challenge 28 .However, none of the existing guidelines have been designed to evaluate renal outcomes.Optimal fluid parameters and hemodynamic targets have not been established for AKI management 29 .

Age
Older age has been associated with the development of AKI both in hospital and in the community.The higher incidence in older age (>65) has been demonstrated with many insults such as radiocontrast, carotid surgery and nephrotoxic drugs.In a populationbased surveillance conducted among all adult residents of the Calgary Health Region, admitted to multidisciplinary and cardiovascular surgical intensive care units between May 1 1999 and April 30 2002, the highest incidence of AKI was among older patients Journal of the Ceylon College of Physicians N K Rathnamalala, S Rajapakse (>65years) 25 .In another study to identify and validate a risk prediction score for contrast induced nephropathy, age more than 75 years was an independent predictor of AKI in multivariate logistic regression with a p< 0.0001 30 .

Gender
Many studies have shown a higher occurrence of AKI in hospitalized females.This also has been seen with many different exposures such as contrast and drugs 30,31 .In a study to assess risk factors for developing AKI among patients undergoing cardiac surgery, of 32217 patients 1.7% developed AKI requiring dialysis.In the univariate comparison females were more likely to have AKI p <0.001 32 .However, Males consistently predominated in reports on the incidence of AKI complicating infection with HIV, malaria, and leptospirosis 33,34,35 .

Hypoalbuminemia
Hypoalbuminemia has been identified as a risk factor for developing AKI.It has also been demonstrated to be a predictor of death following the development of AKI.With each 10 g L-1 decrement in serum albumin the odds of AKI increased by 134% (pooled OR, 2.34; CI, 1.74-3.14).Among patients who had developed AKI, the odds of death rose 147% (pooled OR 2.47, 95% CI 1.51-4.05)with each 10 g L-1 serum albumin decrement 36 .

Chronic kidney disease (CKD)
CKD is the most consistent pre-existing condition associated with a high risk of AKI in almost every relevant study addressing hospital-or communityacquired AKI 37 .Pre-existing CKD increases the risk of non recovery from AKI.In a large, community based study in Northern California comprising 39,805 patients with CKD Stage 3B or higher, the risk for ESRD or death 30 days after hospital discharge was increased by 30% as a direct consequence of an episode of AKI 38 .

Diabetes mellitus
Diabetes mellitus is well-known for its deleterious effect of AKI superimposed on CKD.In a study undertaken in India, histological findings in patients with AKI showed underlying diabetic changes.In addition 27% had superimposed non diabetic changes responsible for AKI with diffuse proliferative changes being the commonest 39 .Diabetes mellitus is reported to be an important risk factor for AKI in hospital setting, particularly in association with cardiac surgery or exposure to radiocontrast media 37 .Diabetes mellitus is a risk factor for poor 1-year outcomes, including ESRD and death 25 .

Heart disease
Cardiac dysfunction has been identified as an important risk factor for AKI.In a case control study among hospitalized patients in Cleveland Ohio, heart failure was associated with an OR of 1.4 (CI 0.6-2.4) in multivariate analysis 40 .It is also associated with a higher incidence of induced AKI 30 .

Pre exposure medication
There is contrasting evidence on the impact of ACE inhibitors/ARBs on AKI.In a retrospective cohort study of 1358 adult patients undergoing cardiac surgery, it was found that preoperative use of ACE-I or angiotensin receptor blockers (ARB) was associated with a 27.6% higher risk for AKI postoperatively 41 .A propensity score-based analysis of 536 patients undergoing coronary artery bypass graft on cardiopulmonary bypass was conducted.In this study, the incidence of AKI was 6.4% in patients who received preoperative ACE inhibitors and 12.2% in patients who did not (P <0.02) 42 .In a study by Kiski et al. patients treated with renin-angiotensin aldosterone system blockade before exposure to radiocontrast agents developed significantly more contrast induced acute kidney injury (CI-AKI) within 72 hours and 30 days.Even after adjustment for confounding comorbidities, treatment with ACE-I or angiotensin II receptor type 1 blockers turned out to be an independent risk predictor 43 .

Nephrotoxic medication
The risk of AKI attributable to aminoglycosides is sufficiently high and varies with the definitions used for AKI and the study populations 44,45,46 .Some authors have called for elimination of amino glycosides from the standard antimicrobial agents for and use only for directed treatment of a number of severe gram positive and negative bacterial infections 47 .Older patients with pre existing renal dysfunction, septic patients with intravascular volume depletion may be at greater risk of aminoglycoside nephrotoxicity.Concomitant use of other nephrotoxic drugs, prolonged use and separate courses of aminoglycoside therapy over short time intervals also increase the risk of AKI 48 .

Contrast induced nephropathy
Contrast induced nephropathy (CIN) is defined as a rise in serum creatinine of > 0.5 mg/dl or a 25% increase from baseline value assessed at 48hrs after a radiological procedure with contrast administration 49 .However it is also noted in the literature that the increase in serum creatinine may occur until up to 5 days after contrast exposure 50 .It is accepted that in patients with normal renal functions even in the Vol.44, Nos. 1 & 2, 2013   Acute kidney injury -improving outcomes with early risk assessment and intervention presence of diabetes the risk of contrast induced AKI is low (1-2%) 51 .However the incidence may be as high as 25% in patients with pre existing renal impairment or in the presence of risk factors such as CKD, diabetes, CHF, advanced age, and concurrent administration of nephrotoxic drugs 52 .Contrast induced AKI was described as the third most common cause of new AKI in hospitalized patients and was responsible for 11% of cases 53 .

Prevention of AKI and early intervention strategies
Due to the heterogeneity of patients and the broad range of situations in which AKI is encountered, it is difficult to standardize the evaluation and management approach.The KDIGO clinical guidelines on the management of AKI provide a useful reference for this purpose 5 .KDIGO guidelines suggest the following in the high risk population • Discontinue all nephrotoxic agents • Ensure volume status and perfusion pressure • Consider functional hemo-dynamic monitoring • Monitor serum creatinine and urine output • Avoid hyperglycemia • Consider alternatives to radio contrast procedures.

Conclusion
Acute kidney injury is a common problem in medical, surgical, oncology and ICU settings in hospital.There is increasing evidence that irrespective of its nature AKI is a predictor of immediate and long term adverse outcomes.Individuals with CKD and other co-morbidities are especially susceptible to AKI and also AKI may be an independent risk factor for developing CKD.Research over the past decade has identified numerous preventable risk factors for AKI with the potential of improving the management and outcomes.A significant proportion of in hospital AKI is due to pre renal causes which is potentially reversible.Identifying those at risk and also those that are more prone to residual dysfunction enables aggressive and timely management.This is particularly relevant to Sri Lanka where there is a scarcity of resources for renal replacement therapy.