Drug-Induced Acute Kidney Injury in Diabetes Mellitus

Background: Drug-induced acute kidney injury is a common situation in clinical practice. Many treatments are involved and they are even more aggressive when associated with a predisposing factor such as diabetes. We aimed to investigate clinical features of acute drug-induced kidney injury in diabetics in order to clarify renal prognosis. Methods: This was a descriptive and analytical retrospective study including diabetics who presented drug-induced acute kidney injury, conducted in our department during the period from 1986 to 2015. Acute kidney injury was classified according to Kidney Disease Improving Global Outcomes criteria. We analyzed medical records of patients. Results: 31 patients were included with mean age of 65.41 years and gender ratio M/F at 0.93. Diabetes was type 2 in 97% of cases. Mean previous creatinine clearance was 39.33 ml/min/1.73 m. Drugs involved were blockers of renin-angiotensin system (35%), aminoglycosides (16%), non-steroidal anti-inflammatory (16%), diuretics (13%), lipid-lowering agents (10%), rifampicin (6%) and ifosfamide (3%). Extracellular dehydration was present in nine cases (29%). Main drug combinations were with diuretics in 16 cases (52%) and with ACE inhibitor or ARB in eight cases (26%). Oligo anuria was observed in 5 cases (16%). Proteinuria with urine strips was objectified in 25 cases (81%). Acute kidney injury was grade 3 in 24 cases (77%), grade 2 in three cases (10%) and grade 1 in four cases (13%). Renal survival at 102 months was 57%. Identified renal prognosis factors were serum phosphorus >1.47 mmol/l (p = 0.01), proteinuria at urine strips (p = 0.042), dehydration (p = 0.013), oral antidiabetic treatment (p = 0.038), intravenous rehydration (p = 0.021) and insulin (p = 0.006). Conclusion: Drug-induced acute kidney injury is potentially serious in diabetics. Prevention is essential to improve the prognosis of this renal damage. How to cite this paper: Harzallah, A., Kaaroud, H., Hajji, M., Hamida, F.B., Khiari, K., Gorsane, I. and Abdallah, T.B. (2016) Drug-Induced Acute Kidney Injury in Diabetes Mellitus. Open Journal of Nephrology, 6, 176-187. http://dx.doi.org/10.4236/ojneph.2016.64023 Received: August 23, 2016 Accepted: December 25, 2016 Published: December 28, 2016 Copyright © 2016 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Introduction
Drug-induced acute kidney injury (AKI) is frequent in clinical practice [1].Indeed, the kidney is an organ particularly vulnerable to drug toxicity in the body by its own functions of filtration, concentration and disposal as well as its rich vascularization [2].
Involved drugs are numerous with multiple mechanisms.Drug nephrotoxicity may be related either to a specific effect of treatment, or to the induction of hypovolemia or by altering intrarenal hemodynamics.Treatments involved are even more aggressive when associated with one or more predisposing factors including diabetics [3].
Drug-induced AKI represents iatrogenic adverse events, mostly preventable, whose prognosis is typically better than other etiologies of AKI.They are potentially serious since they are associated with high morbidity and mortality and the risk of progression to end stage kidney disease (ESKD) [4].
Knowledge of risk factors and mechanisms of drug-induced nephrotoxicity are the basis for improved prevention and also for a better management of these patients [5].Pre-scription of potentially nephrotoxic drugs should be carried out in compliance with therapeutic indications.It must also take into account drug interactions and field of patients.
Diabetes mellitus is the single largest contributor to the growing prevalence of chronic kidney disease (CKD) worldwide and is one of the major risk factors for development of AKI [6].Meanwhile, literature is poor about prognostic factors of this condition in diabetic patients.
We conducted an analytic study with the purpose to establish prognostic factors of drug-induced AKI in these patients.

Patients and Methods
We performed a retrospective data analysis by reviewing the medical records of diabetic patients hospitalized at our department from January 1986 to June 2015 who presented an AKI after taking a drug with a compatible timeline from discovery of the AKI and drug intake.
We excluded individuals who were ≤18 years of age, critically ill patients and those who received iodinated contrast agents.
We collected data on demographics and past medical history, including baseline kidney function, hypertension, coronary artery disease, diabetic neuropathy, diabetic retinopathy and peripheral artery disease.
We noted dose, duration and frequency of administration of offending drug prior to AKI.
We also recorded the use of all other drugs administrated concomitantly with drug in question.The clinical and para-clinical data were collected from medical records.
Outcomes included renal recovery, length of hospital stay and mortality.
We defined complete renal recovery by a decrease in serum creatinine with return to baseline creatinine.
Local ethics committee had no objections against this study.Written consent was waived because of the retrospective observational nature of the study.Glomerular filtration rate was evaluated according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.Stages of CKD were defined according to the International Foundation Kidney disease Improving Global outcomes (KDIGO) [7].
AKI was defined as 26.5 µml/L or 1.5-fold increase in creatinine relative to baseline serum creatinine.Severity of AKI was classified on the basis of peak creatinine increment into three stages according to KDIGO criteria [8].
When baseline creatinine was unknown, it was estimated by the CKD-EPI equation assuming a glomerular filtration ratio of 75 ml/min/1.73m 2 as validated by Bagshaw et al. [4] [9].
ESKD has been defined by renal creatinine clearance below to 15 ml/min requiring maintenance dialysis.

Statistical Analysis
Statistical analyses were performed using SPSS 19.The results were presented as means ± SD for continuous variables and percentage for categorical variables.
Differences between groups were evaluated by Chi 2 test for percentages.In case of significance of chi-square test with non validity we used Fisher's bilateral test.
Comparison of independent groups was performed using the Student's t test for independent groups.
A p value less than 0.05 was considered statistically significant.
Quantitative variables were transformed into qualitative variables with two modalities.To determine the threshold at which it must "cut" quantitative variable, we have established ROC (Receiver Operating Characteristics) curve.After verifying that the area under the curve was significantly >0.500, we have chosen the threshold value of the variable as corresponding to the best couple "sensitivity-specificity".
A Kaplan-Meier method was used for comparison of survival.

Results
Among 182 diabetic patients presenting an AKI during the period of the study, we identified 31 cases of drug induced AKI (17%).
Thirty one patients were then included.The average age of patients was 65.41 years (39 -79 years).The age was over 65 years in 17 cases (55%).Gender ratio M/F was 0.93.
Ten patients (32%) were dependent to insulin therapy and 21 patients (68%) were on oral antidiabetic treatment.Hypertension was present at diagnosis in 25 cases (81%).
Intercurrent factor to drug intake was identified in 16 cases (52%).We found extracellular dehydration in nine cases (29%) and infectious episode in seven cases (23%).
Main drug combinations were with diuretics in 16 cases (52%) and with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) in eight cases (26%) (Table 3).Gentamicin was associated with an ACEi or ARB and a diuretic (furosemide) in two cases.NSAIDs were associated with a diuretic (furosemide) and an ARB in one case.
Oligo anuria was observed in 5 cases (16%  in 11 cases (35%) with lactic acidosis in one case that was under metformin.Elevated liver enzymes were noted in five cases (16%).Among these patients, three were under lipid lowering treatment and the others under rifampicin.
Rhabdomylosis was noted in two cases under lipid lowering treatment.Aseptic leukocyturia was observed in four cases (13%).
Renal ultrasound was made in 26 cases (84%) and has not found stenosis of renal artery in all cases.
Kidney biopsy was performed in one case presenting acute tubular necrosis after taking chemotherapy for cutaneous sarcoma without renal recovery after the usual time.
It confirmed diagnosis of acute tubular necrosis with chronic interstitial nephritis associated with diabetic glomerulosclerosis.
Offending drug has been stopped in all cases.Oral antidiabetics were stopped when taken and insulin was prescribed in 28 cases (90%).Rehydration was conducted in 19 cases (61%).That was oral in 7 cases (23%) and intravenous in 12 cases (42%).
Complete recovery was noted in 11 cases (35%) after a median period of 12.18 days Death occurred in three cases.Causes of death were hyperkalemia in one case and septic shock in two cases.

Discussion
Drug induced AKI represents 20% of all etiologies of AKI [10].Its incidence is increasing due to the emergence of new potentially nephrotoxic molecules and growing drug prescription.Pathophysiologic mechanism of drug-induced nephro toxicity is complex depending on type of drug involved [10].This is a serious event that is associated with increased morbidity and mortality [9].
Preventive measures require mainly understanding patients and drug-related risk factors.Diabetes which is currently expanding in the world is a major predisposing factor [11] [12].
Our study focused on clinical aspects of drug induced AKI in diabetic patients.Indeed, some patient characteristics can predispose to drug-induced nephrotoxicity.
Older age and female gender are associated with reduced muscle mass and lower total body water which can impact on drug dose [13] [14].Risk of drug nephrotoxicity is increased in the patient with CKD.Patient who is on diuretic therapy or has vomiting resulting in extracellular volume depletion is vulnerable also to toxic drug effects on the kidney [13].
BRAS were main causes of AKI in our study.AKI due to BRAS is increasing due to their large use in diabetics to slow progression of diabetic nephropathy.Furthermore, there are actually many evidence based indications for use of these molecules and several guidelines recommend their use for a number of chronic conditions like hypertension or CKD with proteinuria [15].
Our findings are consistent with other studies which have demonstrated an increasing incidence of AKI from treatment with BRAS.There is usually presence of an intercurrent illness and it is more common in patients with known renal failure [15].We found in our study an intercurrent factor in 52% of all cases.
AKI due to BRAS has been described primarily in patients with bilateral renal artery stenosis or with a single kidney and unilateral stenosis, and in some conditions like severe congestive heart failure and concomitant diuretic therapy [16].In our cases, renal ultrasound excluded renal artery stenosis but concomitant use of diuretics was present in 26% of all cases.Discontinuation of BRAS leads generally to recovery of renal function meanwhile exceptions has been reported [16].
Aminoglycosides and NSAIDs were either frequently observed in our study.Aminoglycosides are typically the most common drugs involved in the literature [17].They are responsible for about 25% of AKI [18].In our study, they were found in 16% of cases.
That was gentamicin in all reported cases.
The inhibition of prostaglandin synthesis by NSAIDs causes a reduction in renal blood flow and glomerular filtration [19].It is essentially in some pathological situations where renin-angiotensin system is strongly stimulated that the effect of NSAIDs promotes the onset of AKI.Then combination of BRAS with NSAIDs should be avoided especially in pre-existing renal insufficiency or extracellular volume depletion.
Lipid-lowering agents may lead to AKI via rhabdomyolysis [20].This risk is particularly increased in elderly diabetics.We reported two cases of rhabdomyolysis.
The other drugs found in our study were diuretics, rifampicin and cancer chemotherapy.Antituberculosis agents can induce AKI by immunoallergic mechanism [21] [22].
Hepatonephritis due to rifampicin was found in two cases in our study.
The presence of diabetes poses certain particular problems in the management of AKI.
Rapid institution of dialysis is important as the diabetic patient may tolerate uraemia less well [11].
Diabetes must be well controlled as uncontrolled ketosis may worsen hyperkalemia and metabolic acidosis, with increased risk of adverse effects of antidiabetic treatment.
Indeed, we reported one case of lactic acidosis in our study due to the use of metformin.
Patients with diabetes are then at increased risk of developing AKI [23].This condition carries a high mortality and management may be more complicated by the presence of diabetes.Some cases may be avoidable by reducing exposure of the diabetic patient to nephrotoxic agents.
Preventive measures are essential by assessing baseline renal function before initiation of therapy, adjusting the drug dosage and avoiding use of nephrotoxic drug combinations [5].
Non-recovery or incomplete recovery of renal function can translate into a need for long-term dialysis which is associated with low quality of life and representing a major burden for healthcare systems [24] [25].
Presence of factors such as elevated serum phosphorus, dehydration and proteinuria were associated with a poor prognosis in our study.
It is now well established that proteinuria is a progression factor of CKD.The degree of proteinuria is one of the most important predictors of progression of kidney disease, as well as the response to antiproteinuric treatment in almost all studies on CKD.
Dehydration and intravenous rehydration were identified as prognostic factors in our study.
Indeed, improvement of the hemodynamic status of patient with AKI and especially perfusion pressure has a beneficial effect on kidney function and helps to minimize the effect of further attacks on the already injured kidney.
AKI increases the risk of progression to advanced CKD in patients with diabetes regardless of the major risk factors for progression of CKD and each episode of AKI dual this risk.These data suggest that even moderate AKI in diabetics with preserved renal

Table 1 .
Clinical and biological parameters of patients.

Table 2 .
Type and dose of drugs.

Table 3 .
Combination of drugs in our study.

Table 4 .
Prognostic factors of drug-induced acute kidney injury.

Table 5 .
Evolution of patients depending on the drug type.