|Year : 2021 | Volume
| Issue : 3 | Page : 192-197
Retrospective pharmacovigilance analysis of nonsteroidal anti-inflammatory drugs-induced chronic kidney disease
Vardhipathi Sravana Swathi, Shrishti Saroha, Jai Prakash, Shashi Bhushan
National Co-ordination Centre-Pharmacovigilance Programme of India, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Government of India, Ghaziabad, Uttar Pradesh, India
|Date of Submission||24-Jul-2020|
|Date of Decision||31-Dec-2020|
|Date of Acceptance||17-May-2021|
|Date of Web Publication||22-Jun-2021|
Dr. Shashi Bhushan
National Coordination Centre-Pharmacovigilance Programme of India, Indian Pharmacopoeia Commission,
Raj Nagar, Sector-23, Ghaziabad - 201 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with kidney damage. In India, only a few reports related to the risk of chronic kidney disease (CKD) with NSAIDs are available. The present study highlights the prevalence and pattern of NSAIDs-induced CKD adverse drug reactions in the Indian population.
MATERIALS AND METHODS: The individual case safety reports (ICSRs) reported by the National Coordination Centre (NCC)-Pharmacovigilance Program of India to the Uppsala monitoring center Pharmacovigilance database system “VigiLyze” were analyzed by using the preferred term “Chronic Kidney Disease” and “NSAIDs” from July 1, 2011 to September 12, 2019. A total of 28 ICSRs of NSAIDs associated CKD ICSRs were analyzed retrospectively for age, gender, concomitant medication, seriousness, and other criteria.
RESULTS: About 82% of CKD cases due to NSAIDs were in the age group of 40–80 years, in which 54% belong to male. About 43% of the patients had CKD due to the use of diclofenac, and almost 96% of the patients had oral dosage forms of NSAIDs. The main indications of NSAIDs in these CKD cases were generalized body pain and joint pain. About 79% case of NSAID-induced CKD were serious, among which 54% led to the hospitalization and further use of NSAIDs discontinued in 86% of CKD cases.
CONCLUSION: The present study revealed that prolonged use of NSAIDs in chronic pain conditions was responsible for CKD. To reduce the risk of NSAIDs-induced CKD, health care professionals should take the necessary steps to improve patient safety.
Keywords: Chronic kidney disease, nonsteroidal anti-inflammatory drugs, pharmacovigilance, pharmacovigilance program of India, vigilize
|How to cite this article:|
Swathi VS, Saroha S, Prakash J, Bhushan S. Retrospective pharmacovigilance analysis of nonsteroidal anti-inflammatory drugs-induced chronic kidney disease. Indian J Pharmacol 2021;53:192-7
|How to cite this URL:|
Swathi VS, Saroha S, Prakash J, Bhushan S. Retrospective pharmacovigilance analysis of nonsteroidal anti-inflammatory drugs-induced chronic kidney disease. Indian J Pharmacol [serial online] 2021 [cited 2021 Sep 19];53:192-7. Available from: https://www.ijp-online.com/text.asp?2021/53/3/192/318978
| » Introduction|| |
Nonsteroidal anti-inflammatory drugs (NSAIDs) are anti-inflammatory drugs and analgesics which are the most commonly used medications in the world. More than 30 million people are taking NSAIDs daily. NSAIDs cause adverse effects like hyperkalemia, retention of sodium and water, acute kidney injury, nephritic syndrome, interstitial nephritis, papillary necrosis, and developmental effects. Chronic kidney disease (CKD) is one of the most critical causes of morbidity and mortality in the world. Hence, there is a significant risk of renal injuries/effect associated with the consumption of NSAIDs. Compared to other dosage forms like oral or topical of NSAIDs, parentral preparations of NSAIDS are having a high risk of the kidney. Selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxibcause more renal failure compared to nonselective COX-2 inhibitors. COX-2 selective NSAIDs are responsible for decreased glomerular filtration rate (GFR), increased serum creatinine, and hypertension. High and cumulative dose of NSAID is responsible for CKD but not the standard dose. NSAIDs like naproxen, celecoxib, meloxicam, nabumetone, and piroxicam having long half-life caused CKD. Decreased renal blood flow, tubular obstruction, and cell-mediated immune injury is the main mechanism of NSAIDs induced chronic renal disease. NSAID like phenacetin, which leads to papillary necrosis was banned from the Australia market. Piroxicam and ketorolac are responsible for renal injury by affecting renal perfusion. Long-term exposure of oxicams may cause CKD and analgesic nephropathy. NSAID-induced chronic renal failure is arduous to diagnose because symptoms are not initially visible. Several guidelines suggest avoiding NSAIDs in renal failure. Even though 9%–13% of patients with CKD are still using NSAIDs. The main reason for using NSAID in CKD patients is chronic pain, which further increases the risk of nephrotoxicity. CKD patients, who discontinued NSAIDs, improved their renal function after 6 months. NSAIDs interfere with the kidney's ability to auto regulate glomerular filtration pressure results in decrease in GFR and ultimately leads to kidney failure. NSAIDs can produce inflammatory changes in the nephron parts and leading to fibrosis and renal scarring. NSAIDs cause acute interstitial nephritis by acting as antigens, which stimulate immune reactions in the interstitium. Chronic interstitial nephritis is caused by the use of high and extended dose of NSAIDs and occurs in patients with preexisting kidney disease.
The widespread use of NSAIDs and a variety of deleterious effects on different organ systems prompted us to carry out this retrospective study of NSAIDs-induced CKD in the Indian population.
| » Materials and Methods|| |
Individual case safety reports (ICSRs) reported to the Uppsala monitoring centre Pharmacovigilance database system “VigiLyze” was analyzed. VigiLyze is a useful online search and analysis tool that provides access to ICSRs in VigiBase, a global database, containing ICSRs from more than 131 World Health Organization (WHO) member countries. It consists of pharmacovigilance data on allopathic, herbals, as well as biological medicines, including vaccines. The Indian Pharmacopoeia Commission is working as National coordination centre under Pharmacovigilance Program of India (PvPI) and has authorized access to VigiLyze. It provides global, national and regional information of suspected adverse drug events and is particularly valuable in cases where there are limited data available. It allows comparisons between the global and national pharmacovigilance information related to particular available drugs. We collated and analyzed the ICSRs from VigiLyze using the preferred term “Chronic Kidney Disease” and “NSAIDs”from July 1, 2011 to September 12, 2019. We filtered out the 28ICSRs of NSAIDs associated CKD, which were analyzed with respect to age, sex, type of reporter, type of NSAIDs, route of administration, indication, the seriousness of reaction, and year of ICSRs collection.
| » Results|| |
About 82% of CKD cases due to NSAIDs were in the age group of 40–80 year [Figure 1]. In this age group, generally, people suffer from arthritic pain and other illness and possibly have taken NSAIDs for symptomatic relief. About 14% of ICSRs were <40 years of age and 4% >80 years. Males were more prone to NSAIDs-induced CKD in comparison to females group. About 54% of the patients with NSAID-induced CKD were males and 46% females [Figure 1]. According to the literature, females were reported to show renoprotective action due to estrogen compared to males, hence less affected than males.
|Figure 1: Age and gender wise distribution of patients: The data were analysed from the individual case safety reports of chronic kidney disease associated with nonsteroidal anti-inflammatory drugs from VigiLyze|
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About 43% (12 ICSRs) of the patients got CKD due to the use of diclofenac, and 14% (4 ICSRs) of the patients got CKD due to ibuprofen [Figure 2]. Diclofenac and ibuprofen belong to nonselective COX inhibitors and could cause more adverse effects on the kidney in comparison to other selective COX inhibitors. The primary reason for the renal selectivity may be due to abnormal regulation of vasodilatation that occurs with these drugs, which is the main reason for NSAIDs-induced renal failure.
|Figure 2: Suspected nonsteroidal anti-inflammatory drugs causing chronic kidney disease: The data are representative of type of nonsteroidal anti-inflammatory drugs which cause chronic kidney disease in combination of nonsteroidal anti-inflammatory drugs or alone. The data were extracted from VigiLyze|
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Out of the 28 suspected NSAIDs-CKD ICSRs, 8 had a combination of two different NSAIDs such as diclofenac along ibuprofen, aceclofenac along paracetamol, diclofenac along aceclofenac, paracetamol along tramadol, and paracetamol along diclofenac [Figure 2]. The patients, who took a combination of NSAIDs, would have further increase risk of nephrotoxicity due to additive or synergistic effect. In two NSAIDs-CKD ICSRs pantoprazole, dopamine, trihexyphenidyl were concomitant drugs along with NSAIDs.
Analysis of these 28 ICSRs associated with NSAIDs-CKD revealed that 96% of the patients used oral dosage forms, while only 4% of patients used parenteral dosage forms of NSAIDs. In general, for chronic pain conditions, prescribers prefer to give oral forms of NSAIDs compared to parenteral forms. Moreover, patients prefer to use over-the-counter pain killers in tablet form, which are easy to administer as well as more economical compared to other dosage forms. The indication for NSAIDs use is summarized in [Figure 3], and it revealed that 25% and 10.71% of patients are using NSAIDs for generalized body pain and joint pains, respectively. About 7.14% of patients used NSAIDS for migraine, acute pain and unspecified pain and remaining 3.57% of patients used NSAIDs for rheumatoid arthritis, myalgia, gout, fever, and arthralgia.
|Figure 3: Percentage of nonsteroidal anti-inflammatory drugs use indications: The data are representative of therapeutic indication of nonsteroidal anti-inflammatory drugs induced chronic kidney disease - individual case safety reports, such as generalised body pain, joint pains, arthritis, myalgia, gout, fever etc., The data were extracted from VigiLyze|
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About 79% of suspected ICSRs of NSAIDs associated CKD were serious and remaining 21% nonserious [Figure 4]. According to WHO, there are six seriousness criteria of adverse drug reactions (ADRs), for example, suspected drugs lead to cause hospitalization or prolongation of hospitalization/death/life-threatening condition, disability, or other medically necessary condition. Fifty four percentage of NSAID-induced CKD ICSRs showed prolonged hospitalization or caused hospitalization of patients, 21% of ICSRs outcome was unknown, 14% of patients experienced life-threatening condition, 7% of patients had other medically important condition and 4% patients died [Figure 4].
|Figure 4: Severe cases of chronic kidney disease and Type of seriousness due to nonsteroidal anti-inflammatory drugs: The data represent the seriousness criteria of individual case safety reports of nonsteroidal anti-inflammatory drugs induced chronic kidney disease. The types of seriousness criteria are as per the World Health Organisation scale. The data were extracted from VigiLyze|
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After suspecting CKD due to NSAIDs, physician discontinued the suspected drug from the treatment regimen for preventing further risk. In 86% of ICSRs of NSAIDs associated CKD, after noticing the occurrence of ADR i.e., CKD, the NSAIDs were discontinued. In 7% of ICSRs action taken was unknown, action taken was not applicable in 4% and in 3% ICSRs doses were not changed [Figure 5]. The maximum reporting of suspected ICSRs of NSAIDs associated CKD were by the pharmacist (54%) followed by other healthcare professionals (32%) and physicians (14%) [Figure 5]. The highest contribution of ICSRs reporting by pharmacists is may be due to more interaction with the patient about the drug and its side effects; therefore, they have a better opportunity to report ADR to PvPI. The under-reporting of these ADR by physician might be due to lack of time or other reasons.
|Figure 5: Action taken by prescribers to manage chronic kidney disease and reporter qualification: The data are representative of action taken after the occurrence of adverse drug reactions as well as represent the qualification of the reporter who submits the adverse drug reactions. The data were extracted from VigiLyze|
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There was no significant rise in the number of NSAIDs-induced CKD ICSRs between the year 2012 and 2016, though, there was sharp and identical rise in the ICSRs in the year 2018 and 2019 [Figure 6]. We received one case in the year 2012 and 2013, two cases in the year 2014 and 2015, no case in the year 2016, 4 cases in the year 2017, 9 cases in the year 2018 and 2019. Although, the abrupt rise in the total number of NSAIDs-induced CKD ICSRs in the last 2 years reveals that healthcare professionals are more vigilant on pharmacovigilance for the sake of patient safety.
|Figure 6: Year-wise reporting trend of individual case safety reports: The data represent the number of nonsteroidal anti-inflammatory drugs-induced chronic kidney disease individual case safety reports, received in different years, starting from 2012 to 2019. The data were extracted from VigiLyze|
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| » Discussion|| |
ADR is the injurious and unintended reaction, which happens at the dose of drug usually used for prophylaxis, therapeutics, and the diagnosis of a disease. It grounds an enormous financial and societal distress on a nation due to the high incidence rate of morbidity and mortality. The postmarketing ADRs monitoring or postmarketing surveillance study of a drug is crucial because clinical trials conducted before the marketing authorization in the limited number and types of subjects. Therefore, a drug, found safe in the clinical trial might produce serious ADRs in future. Hence, ADRs monitoring or pharmacovigilance is necessary for better health care.
Most of the physicians would have prescribed NSAIDs as first-line treatment for any pain conditions making the patient use NSAIDs abundantly and become prone to ADRs and this became the base of our study. The current pharmacovigilance study shows the risk of CKD associated with NSAIDs. All results are interpreted based on pharmacovigilance data analyzed through VigiLyze.
In this retrospective study, CKD was mostly observed in the population of 40–80 years old people, which shows similar results of the study conducted by Koshy et al. They conducted a case-control study on the association between NSAIDs use and progression of CKD in elders and concluded that high cumulative doses of NSAIDs were associated with high risk of CKD. They analyzed the histo-pathological spectrum of kidney biopsies in the elderly population and mentioned NSAIDs were one of the causes of drug-induced tubule-interstitial nephritis. They stated that mostly the people of the mean age of 76 years had renal failure.
The present study highlighted that CKD risk was slight higher in males than females, confirming the finding by Nitsch et al. They conducted a meta-analysis study to assessed the relationship between gender and the risk of developing CKD and found that males have high-risk of mortality as compared to females. Estrogen have a renoprotective effect in a rat model as reported by Seliger et al.
In our study, diclofenac and aceclofenac were the leading cause to CKD, while Tan et al., reported indomethacin as the key cause of CKD. They mentioned decreased renal function with indomethacin is due to concomitant diuretic use which caused volume depletion. This difference might be due to the massive usage of indomethacin in comparison to diclofenac and aceclofenac during that period.
In our study, most NSAIDs responsible for CKD used in the oral dosage form, whereas, in the study conducted by Chang et al., showed that parenteral forms of NSAIDs have a higher risk of developing CKD rather than oral forms. Here, author conducted a nationwide cross-over study to investigate the relationship between short-term use of NSAIDs and the development of end-stage renal disease. They found the highest adjusted odd ratio with parenteral forms compared to oral dosage forms.
In our study, the use of NSAIDs leads to CKD, whereas, as per Go et al., use of NSAIDs leads to renal failure, cardiovascular side effects. They conducted a systemic review to identify the risk of acute renal failure in patients with CKD in community settings. They concluded that absolute risk with NSAIDs is higher in elders with CKD.
In our study, the main reason for NSAIDs use was generalized pain. In contrast, the study conducted by Wu et al., NSAIDs mostly used by the patient for chronic pain conditions. They conducted cohort study to examine the relationship between chronic pain in CKD patients and the use of NSAIDs, they found NSAIDs use in CKD patients is very common even though it is against to guidelines.
In the present study, the kidney function of the patient, physicians mostly stopped the use of NSAIDs after observing the CKD, Zhang et a., made a similar recommendation. Another study reported that there was a two-fold rise in the risk of kidney failure among individuals with lifetime use of more than 1000 paracetamol pills and eight-fold increased risk with a cumulative dose of more than 5000 NSAIDs pills. Therefore, previous studies emphasized an association between NSAIDs and the risk of chronic renal failure.
In the present study, most of the ICSRs were received from health-care professionals, signifying that healthcare professionals were taking keen interest in monitoring and reporting of safety data of NSAIDs. Nowadays, the role of healthcare professionals in Pharmacovigilance is increasing. Pharmacists, nurse, and physicians have primary contact with patients, acquire a good knowledge of the drugs, therefore, can quickly identify and report adverse effects of drugs to the concerned authorities. The contribution of Pharmacists and health-care professionals in ADR reporting is clearly reflected.
| » Conclusion|| |
We found that NSAIDs used by patients for chronic pain leads to CKD, males were more prone to CKD in compare to females, about 80% ICSRS were serious and lead to hospitalization in 54% of cases. Diclofenac contributes to more than half of cases of NSAIDs-induced CKD. To reduce risk with NSAIDs, health care professionals should take the necessary steps to improve patient safety like alternative pain management treatments, choosing drugs having relatively safer profile than drugs with high-risk, decreasing the dose of the drugs, regular monitoring of renal function tests and limiting the chronic use of NSAIDs. Although, the present study has some limitations such as lack of complete information in ICSRs, under-reporting or few number of reports and last but not the least all the ICSRs received on voluntary basis or as spontaneous report. Moreover, the present studies do not suggest any impending significant change in clinical/regulatory intervention of NSAIDs. However, a further focussed or active pharmacovigilance study will required to better evaluate the benefits and risk ratio related to the uses of NSAIDs.
Financial support and sponsorship
Conflicts of interest
All authors declare that there are no conflicts of interest in this study. The information of present study comes from a variety of sources. Likelihood of suspected adverse reaction with the drug is not the same in all cases. And information does not represent the opinion of the World Health Organization.
| » References|| |
Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl 1999;56:18-24.
Lafrance JP, Miller DR. Dispensed selective and nonselective nonsteroidal anti-inflammatory drugs and the risk of moderate to severe hyperkalemia: A nested case-control study. Am J Kidney Dis 2012;60:82-9.
Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, et al.
Evolving importance of kidney disease: From subspecialty to global health burden. Lancet 2013;382:158-69.
Chang YK, Liu JS, Hsu YH, Tarng DC, Hsu CC. Increased risk of end-stage renal disease (ESRD) requiring chronic dialysis is associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs): Nationwide case-crossover study. Medicine (Baltimore) 2015;94:e1362.
Nderitu P, Doos L, Jones PW, Davies SJ, Kadam UT. Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: A systematic review. Fam Pract 2013;30:247-55.
Whelton A, Schulman G, Wallemark C, Drower EJ, Isakson PC, Verburg KM, et al.
Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 2000;160:1465-70.
Adams DH, Howie AJ, Michael J, McConkey B, Bacon PA, Adu D. Non-steroidal anti-inflammatory drugs and renal failure. Lancet 1986;1:57-60.
Leonard CE, Freeman CP, Newcomb CW, Reese PP, Herlim M, Bilker WB, et al.
Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury. Pharmacoepidemiol Drug Saf 2012;21:1155-72.
Nanra RS. Analgesic nephropathy in the 1990s – An Australian perspective. Kidney Int Suppl 1993;42:86.
Davies NM, Skjodt NM. Choosing the right nonsteroidal anti-inflammatory drug for the right patient: A pharmacokinetic approach. Clin Pharmacokinet 2000;38:377-92.
Ingrasciotta Y, Sultana J, Giorgianni F, Fontana A, Santangelo A, Tari DU, et al.
Association of individual non-steroidal anti-inflammatory drugs and chronic kidney disease: A population-based case control study. PLoS One 2015;10:e0122899.
Kleinknecht D. Interstitial nephritis, the nephritic syndrome and chronic renal failure secondary to non-steroidal anti-inflammatory drugs. Semin Nephrol 1995;15:228-35.
Hull S, Mathur R, Dreyer G, Yaqoob MM. Evaluating ethnic differences in the prescription of NSAIDs for chronic kidney disease: A cross-sectional survey of patients in general practice. Br J Gen Pract 2014;64:e448-55.
Wu J, Ginsberg JS, Zhan M, Diamantidis CJ, Chen J, Woods C, et al.
Chronic pain and analgesic use in CKD: Implications for patient safety. Clin J Am Soc Nephrol 2015;10:435-42.
Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med 2002;347:1256-61.
Perazella MA. Drug-induced nephropathy: An update. Expert Opin Drug Saf 2005;4:689-706.
Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, et al.
Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 2001;345:1801-8.
Nitsch D, Grams M, Sang Y, Black C, Cirillo M, Djurdjev O, et al.
Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: A meta-analysis. BMJ 2013;346:f324.
Bhushan S, Ray RS, Prakash J, Singh GN. Global versus Indian perspective of pioglitazone-induced adverse drug reactions including bladder cancer: A comparative retrospective pharmacovigilance analysis. Clin Ther 2019;41:2252-62.
Blondell RD, Azadfard M, Wisniewski AM. Pharmacologic therapy for acute pain. Am Fam Physician 2013;87:766-72.
Koshy PJ, Parthsarathy R, Mathew M, Prabakaran R, Kuruvilla S, Abraham G. Interpretation of kidney biopsy in Indian patients older than 60 years: A tertiary care experience. Indian J Nephrol 2018;28:198-202.
] [Full text]
Seliger SL, Davis C, Stehman-Breen C. Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 2001;10:219-25.
Tan SY, Shapiro R, Kish MA. Reversible acute renal failure induced by indomethacin. JAMA 1979;241:2732-3.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.
Zhang X, Donnan PT, Bell S, Guthrie B. Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: Systematic review and meta-analysis. BMC Nephrol 2017;18:256.
Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, Gaziano JM. Analgesic use and renal function in men. JAMA 2001;286:315-21.
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