A clinical study of drugs associated with acute kidney injury in the Chinese population

Purpose: To carry out a study aimed at comprehensive identificat6ion of classes of drugs which cause acute kidney injury (AKI). Methods: A total of 110,508 patients enrolled in Weihai Central Hospital, Weihai, Shandong, China between March 2014 to April 2018 were asked to provide information on comprehensive prescription drug coverage including antivirals, antibiotics, NSAIDs, diuretics and anti-cancer drugs. Only the active users of these classes of drugs were included in the study. Daily prescription dose, duration, date and time of each drug were recorded. Furthermore, the characteristics and other conditions of the patients such as hypertension, congestive heart failure, diabetes, liver disease, angiotensin receptor blockers (ARBs), alpha-receptor blockers, beta-receptor blockers, and calcium channel-blockers were included. Results: A total of 1230 patients presented with AKI during the first 60 days of follow-up, while 1546 (58 %) patients were diagnosed with AKI in the secondary endpoint. Indomethacin, valacyclovir, fluorouracil, levofloxacin, ibuprofen and rofecoxib produced higher frequencies of AKI than the control drug, celecoxib. Indomethacin (OR = 2.97 ; 95 % CI= 1.94 3.89) and valacyclovir (OR = 2.85 ; 95 % CI = 1.56 3.42) were mostly responsible for AKI, followed by rofecoxib (OR = 2.48 ; 95 % CI = 2.32 2.71), fluorouracil (OR = 2.58 ; 95 % CI = 1.94 3.11), ibuprofen (OR = 1.68 ; 95 % CI = 1.28 2.21) and levofloxacin (OR = 1.58 ; 95 % CI = 1.48 2.73), in that order Conclusion: This study has identified various classes of drugs which frequently induced AKI. Therefore, physicians should exercise caution in prescribing these drugs, and should consider other medicines to minimize the risk of AKI.


INTRODUCTION
Acute kidney injury (AKI) is defined as a sudden loss of renal function [1]. It is associated with high morbidity and mortality, especially in critically-ill patients [2]. The kidney performs various essential functions such as clearing of endogenous waste products, acid-base balance, electrolyte balance, and endocrine function. Thus, kidney injury may lead to complications such as metabolic acidosis, uremia, high potassium levels, imbalance in body fluids, multiple organ failure and ultimately death [3]. The causes of AKI vary from patient to patient, with a majority of cases due to damage to kidney tissue. Decreased blood flow to the kidney may be due to several factors such as inflammatory response, urinary tract infection, low blood pressure, and exposure to toxic substances which are injurious to the kidney [4]. The symptoms of AKI which arise due to urea accumulation, cause headache, loss of appetite, nausea, vomiting, and fatigue. Apart from urea, other nitrogenous substances also get accumulated in the bloodstream, and may cause disorientation [5]. In some cases, potassium also gets accumulated and causes an irregular heart rhythm which is a serious threat to patient's survival. There is also an increased risk of chronic kidney injury in future [6].
Acute kidney injury (AQKI) is diagnosed based on laboratory results for blood urea and nitrogen contents, level of serum creatinine, and abnormalities in urination [7]. The disease was considered a reversible syndrome, but results from animal model experiments and human studies have demonstrated that majority of AKI result in permanent kidney damage [8]. Antiinflammatory drugs and antibiotics are amongst the most widely prescribed medications in China. However, these drugs tend to have lots of side effects which include stomach ulcer, gastrointestinal bleeding and kidney injury. In some cases, antiviral and anti-cancer drugs cause various harmful side effects. There are also reports which suggest that NSAIDS are associated with an increased risk for chronic kidney disease [9]. Therefore, the objective of this study was to identify on a comprehensive basis, various classes of drugs which cause AKI.

Ethical approval and standards
All procedures in this study were carried out in accordance with the Declaration of Helsinki of 1964 and its later amendments [10]. Informed consent was obtained from all the patients and participants. Informed consent was also obtained from the parents, guardians or authorized representative of the participants. All the protocols and procedures were approved by the Hospital Ethical Research Committee (approval number: ERC/DICU/3546-R35A).

Study population and data source
The study started in March 2014 and was completed in April 2018. In this program, a total of 110508 patients who were enrolled in the Weihai Central Hospital, Weihai, Shandong, China provided information on comprehensive prescription drug coverage which included antiviral, antibacterial, NSAIDs, diuretic and anticancer drugs. The study selected only patients who had been active users of these drugs for more than one year, and were in the age range of 60 -75 years.

Main exposures
From the point of index prescription, the patients were categorized as users of antivirals (acyclovir and valacyclovir), NSAIDs (loxoprofen, ibuprofen and indomethacin), COX-2 inhibitors (celecoxib, diclofenac and rofecoxib); antibiotics (clarithromycin, levofloxacin and vancomycin), anti-cancer drug (fluorouracil) and diuretics (furosemide and spironolactone). The use of NSAIDs was defined as regular daily use of celecoxib, rofecoxib, ibuprofen, indomethacin and loxoprofen. Antibiotic use was defined as the use of drugs such as clarithromycin, levofloxacin, and vancomycin, whereas anticancer users were defined as those who used fluorouracil daily. Diuretic users were defined as patients on daily use of furosemide and spironolactone.
Daily prescription dose, duration, date and time for each drug were recorded. Patients who were prescribed more than one drug were not included during the study period. Track records on drug usage of all the patients were recorded until the patients were prescribed with different drugs, or until the completion of the follow-up period. There was more than 92% follow-up for the patients. Based on the enrollment files, the patients were characterized based on age-group and gender. Furthermore, the characteristics and other conditions of the patients such as hypertension, congestive heart failure, diabetes, liver disease, angiotensin receptor blockers (ARBs), alpha-receptor blockers, beta-receptor blockers, and calcium channel-blockers were recorded.

Assessment of health effects and LD 50
The health effects and lethal dose (LD 50 ) of the drugs were measured using iLab 2.0. (ACD Lab Inc, Toronto, Canada), to understand the toxic behavior of the investigated drugs.

Statistical analysis
Statistical analyses were carried out using SPSS Statistical Software 22.0 (SPSS Inc, USA). Frequencies for the different variables were calculated based on the category of drug usage. Characteristics of the patients were accessed for all the categories of drug exposure. Mean values for continuous variables such as age and BMI were calculated for each category and frequency of drugs used, and were compared using Student's t-test. Multivariable logistic regression was used to estimate the odds ratios (OR), and 95 % confidence intervals (CI) for the association between drug use, and AKI, adjusting for age (in years), sex, hypertension, diabetes, congestive heart failure, myocardial infarction and gout. The relative risk for AKI was estimated based on the adjusted and unadjusted drug proportional hazard model. Celecoxib was used as the reference or the control since it was widely used among the investigated subjects.

RESULTS
In this study, 15348 out of a total of 110508 patients between the ages of 60 -75 were identified as having been under prescription for NSAIDs, antivirals, antibiotics and other drugs for at least six months. The median age was 71 years for males, and 68 years for females. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most commonly prescribed medicines among the patients (73.18%). Other prescribed drugs were antivirals (7.4 %), antibiotics (7.17 %), anticancer drugs (6.37 %) and diuretics (5.88 %). Details of information on the characteristics and drug usage are presented in Table 1. During the first 60 days of the follow-up period, a total of 1230 patients experiencing AKI were identified, whereas a total of 1546 (58 %) patients were claimed to be diagnosed with AKI in the secondary endpoint. Overall, there were 2776 cases of AKI at the end of the study. The incidence of AKI varied from 5.78 % (for aciclovir) to 32.43 % (for rofecoxib) for the primary outcome, whereas the incidence of AKI for the control (celecoxib) was 9.8 % ( Table 2).
In the univariate analyses, indomethacin, valacyclovir, fluorouracil, levofloxacin, ibuprofen, and rofecoxib were associated with a higher risk of AKI than the control drug celecoxib. It was also observed that indomethacin and valacyclovir were associated with more than 60 % of the increased risk of AKI, when compared to celecoxib (95 % CI, 23 -81 %). As shown in On the other hand, the reference drug celecoxib did not produce any dose-dependent association with AKI.
Besides, results from the assessment of health effects and LD 50 revealed that most of these drugs resulted in negative effects on the blood, cardiovascular system, gastrointestinal tract, kidney, liver or lungs ( Table 4). As shown in Table 5, majority of the drugs appeared to have low LD 50 values which is an indication of their potential toxic effects.

DISCUSSION
In the present study, a comprehensive investigation was carried out on drugs which cause acute kidney injury. A total of 110508 patients were investigated during the study period, 15348 (13.89 %) of whom were diagnosed with kidney injury. Among the AKI cases, 1230 patients experienced AKI during the first 60 days of follow-up. In this study, elderly patients aged 60 -75 years were investigated for risk of AKI among users of anti-inflammatory, antibiotics, antivirals, diuretics and anticancer drugs. It was observed that 3 in every 500 patients were diagnosed with AKI during the 60 days of initial hospital admission. The study also observed that the risk of AKI varied among drug users. Rofecoxib, ibuprofen and indomethacin (NSAIDs), fluorouracil (anticancer), levofloxacin (antibiotic), and valacyclovir (antiviral) were associated with high risk for AKI. The results also revealed that the period from drug exposure to occurrence of AKI was between 45 -60 days. Furthermore, it was observed that the AKI patients were mostly above 70 years of age, especially the male population. This may be due to the fact that kidney function parameters were already elevated prior to exposure to these drugs. It was also observed that most of the AKI survivors recovered after the AKI episode.
A similar observation has also been reported in a study by Tonelli et al [11] which revealed that elderly male patients were more susceptible to AKI than other groups investigated. Studies have also shown that the incidence of AKI is rising among the elderly patients due to combinations of multiple diseases which include diabetes, vascular diseases and chronic kidney diseases [12,13].      These patients also have a higher degree of exposure to several nephrotoxic agents during the diagnostic procedures and drug administration [14]. The results of the present study indicate that the drug classes most frequently associated with AKI were NSAIDs, followed by antivirals and antibiotics. Among the NSAIDs, indomethacin, rofecoxib, and ibuprofen were associated with the highest incidents of AKI.
Valacyclovir (antiviral), fluorouracil (anticancer) and levofloxacin (antibiotic) were also associated with a high frequency of AKI. A similar report of acute renal failure among elderly patients due to valacyclovir has been made by Carlon et al, based on data from long-term use of valacyclovir [15]. Levofloxacin (antibiotic) was more associated with AKI than clarithromycin and vancomycin. Bird et al also reported risk of AKI associated with the use of levofloxacin, a fluoroquinolone [16]. Zhang et al reported the various effects of COX-2 inhibitors and their renal outcomes, including renal dysfunction, peripheral edema, and hypertension [17]. Their report revealed an increased risk of renal disease among rofecoxib users, when compared to celecoxib users. This is consistent with the results of the present study. Griffin et al [18] also reported elevated risk of AKI among elderly patients who used indomethacin and ibuprofen, when compared to other NSAIDs. This is also in agreement with the findings in this study. Moreover, Huerta et al [19] reported an association between NSAIDs and acute renal failure (ARF) among users of ibuprofen and diclofenac, especially among patients with hypertension, heart failure and diabetes [20].
Overall in this study, it is confirmed that a higher incidence of acute kidney injury is associated with the users of indomethacin, valacyclovir, rofecoxib, fluorouracil, ibuprofen, and levofloxacin. However, the other drugs such as celecoxib, aciclovir, diclofenac, loxoprofen, clarithromycin, vancomycin, furosemide, spironolactone produced high rates of remission and recovery.

CONCLUSION
The results obtained in this study indicate that NSAIDs viz, indomethacin, rofecoxib, and ibuprofen, and levofloxacin, fluorouracil and valacyclovir are associated with risk of AKI. These findings strongly suggest the need for caution by medical practitioners when prescribing these drugs to avoid risk of developing acute kidney injury.