Nonsteroidal anti-inflammatory drugs (NSAIDs) induced Nephrotoxicity
Introduction :-

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the class of drugs which provide anti-pyretic, analgesic and anti-inflammatory effects.  The term non steroidal separates it from other steroids which have range of other similar effects. Aspirin, naproxen and ibuprofen are the most common and prominent members of this group. These are all available over the counters in most countries (Stuart, 2010).  The widespread and in certain population daily use of these drugs have become increasingly prevalent. Commonly two main adverse drug reactions associated with Nonsteroidal anti-inflammatory drugs (NSAIDs) are the effects on renal tubules and gastrointestinal (GI) tract. In the 1980s clinical consequences of Nonsteroidal anti-inflammatory drugs (NSAIDs) were well documented (Dunn et al., 1980, 1984).  In America only approximately 43% deaths, emergency hospitalization and adverse drug reaction cases every year are due to the Nonsteroidal anti-inflammatory drugs (NSAIDs) (Green, 2001).  The controversies regarding their usage led to the discovery of selective cyclo-oxygenase 2 (COX-2) inhibitors.

Clinical Manifestations in Human due to Nonsteroidal anti-inflammatory drugs (NSAIDs):-
Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with the renal adverse reactions.  Common renal adverse drug reactions include:-

Hypertension or high blood pressure is the chronic medical condition in which the pressure of the blood in the arteries is elevated. It causes heart to work harder than normal to circulate blood through the body.  This condition may arise due to adverse drug reactions involving anti-inflammatory drugs like ibuprofen and including cyclo-oxygenase 2 (COX-2) inhibitors as well (Black HR et al., 2003). It can result in myocardial infarction and stroke.

Chronic analgesic nephritis: -
Analgesic nephropathy is a term used to describe the injury to the kidney caused by the use of combinations of analgesic medications like paracetamol, aspirin, and phenacetin. It may arise due to the chronic use of single medication as well. Analgesic drugs affect the blood flow to the kidney and causes oxidative damage to the kidney (McLaughlin et al., 1998).

Obstructive nephropathy:-
This type of adverse drug reaction is mainly associated with the administration of sulphonamides. Sulphonamides the antibacterial drugs are more likely to precipitate in urine, particularly when urine is more acidic. The acetylated forms of drug like sulfadiazine are the least soluble. Crystals of sulphonamide are formed in the renal tubules causing crystalluria (Daudon et al., July 2003).

Allergic Nephropathy:-
Nonsteroidal anti-inflammatory drugs (NSAIDs) like cephalosporins, penicillin’s can cause renal injury by an allergic reaction. It is delayed type of response when reaction occurs after few days of initial drug therapy.

Glomerular nephritis:-
It is a renal disease in which glomeruli or small blood vessels in the kidney (usually both) are damaged in response to inflammation (Couser et al., 1999).

Mechanism of NSAIDs Nephrotoxicity:-
Kidney have high metabolic requirement than any other organ in the body as it receives 20% of cardiac output. Kidney is an active site for prostaglandin production. Prostaglandin, Thromboxanes and Leucotreine are the various inflammatory mediators derived and regulated by the phospholipids in the plasma membrane via lipo-oxygenase and cyclo-oxygenase pathways (Figure 3).

Figure 3 Prostaglandin production (Source: - Maroon et al., 2010)

Kidneys are also major route of excretion to many drug metabolites. Hence kidney tubules are exposed to high concentrations of the drug and drug metabolites. When there is renal compromise for example during dehydration, renal dysfunction, electrolyte depletion. Kidney is dependent on cyclo-oxygenase 1 and 2 (COX 1, COX2) for prostaglandin synthesis to auto regulate water balance, renal blood flow and tubular functions. NSAIDs (for example flunixin, ibuprofen) associated renal toxicity is characterized by sodium and fluid retention, decreased renal function and perfusion.  These NSAIDs inhibit the renal prostaglandin synthesis ability by interrupting in between cyclo-oxygenase pathway. Other than Inflammatory mediator’s, the prostaglandins are involved in the regulation and modulation of haemodynamics, gastric mucosal enzymes integrity, tubular salt and water reabsorption, rennin release. Hence when those administered nephrotoxicity is rather inevitable. It can result in renal ischemia.  The combination of other drug and NSAIDS can also increase the risk of renal injury. For example combination of anaesthesia and NSAIDs increases risk to renal injury (Gambaro & Perazella, 2003).Persons having any other chronic renal disease or dehydration are at great risk of acute renal failure while taking NSAIDs.  According to National Kidney Foundation report nearly 10 % cases are directly correlated to the over use of NSAIDs.  The cyclo-oxygenase 2(COX-2) inhibitors like Vioxx have been reported for major gastrointestinal (GI) tract side effects in past few years. Particularly older populations group are at higher risk of gastrointestinal (GI) tract complications. Aspirin is now believed to be responsible for inhibition of both cyclo-oxygenase and NF-kB pathway. NF-kB is transcriptional factor, which controls Deoxy ribose nucleic acid (DNA) transcription during inflammatory immune response. It has ability to detect damaging stimuli for example infectious agents, free radicals and cell injuries. After detection it directs the Deoxy ribose nucleic acid (DNA) to produce inflammatory cytokines and chemokines (Wang et al., 2004).

The risk of nephrotoxic injury can be reduced by taking proper precautions and by reducing the dosage of antibiotics. Populations which are at high risk for example elderly persons and infants should be closely monitored to prevent overdose.


  • ATSDR. (2005). Toxicological Profile for Arsenic. Draft for public comment. Agency for Toxic Substances and Disease Registry, Atlanta, GA. 29–182.
  • Carbrey JM, Song L, Zhou Y, Yoshinaga M, Rojek A. Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice. Proc Natl Acad Sci U S A 2009;106:15956-60.
  • Chen, C. J., Hsueh, Y. M., Chiou, H. Y., et al. (1997b). In“Arsenic: Exposure and Health Effects.” (C. O. Abernathy, R. L. Cal-deron, and W. R. Chappell, Eds.), pp. 232–242. Chapman & Hall, London.
  • Chobanian AV, Bakris GL, Black HR et al. (December 2003). "Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure". Hypertension 42 (6): 1206–52.
  • Couser WG (May 1999). "Glomerulonephritis". Lancet 353 (9163): 1509–15. doi:10.1016/S0140-6736(98)06195-9. PMID 10232333.
  • Daudon M, Cohen-Solal F, Barbey F, Gagnadoux MF, Knebelmann B, Jungers P (July 2003). "Cystine crystal volume determination: a useful tool in the management of cystinuric patients". Urol. Res. 31 (3): 207–11. doi:10.1007/s00240-003-0319-0. PMID 12748836.
  • Dunn MJ, Zambraski EJ: Renal effects of drugs that inhibit prostaglandin synthesis. Kidney Int 18:609-622, 1980.
  • Dunn MJ: Nonsteroidal anti-inflammatroy drugs and renal function. Annu Rev Med 35:411-428, 1984.
  • Sabath Ernesto, 2012. Renal health and the environment: heavy metal nephrotoxicity. Spanish Nephrology Society. 32, 279-86 [Online] Available at: [Accessed 02 December 2012].
  • Ellenhorn MJ, Barceloux DG. Arsenic in medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier. 1988: 1012-6.
  • Gambaro G, Perazella MA: Adverse renal effects of anti-inflammatory agents: Evaluation of selective and nonselec-tive cyclooxygenase inhibitors. J Intern Med 253: 643–652, 2003.
  • Glodny B, Unterholzner V, Taferner B, et al. (2009). "Normal kidney size and its influencing factors - a 64-slice MDCT study of 1.040 asymptomatic patients". BMC Urology 9: 19. doi:10.1186/1471-2490-9-19. PMC 2813848. PMID 20030823.
  • Green, Ga (2001). "Understanding NSAIDs: from aspirin to COX-2". Clinical cornerstone 3 (5): 50–60. doi:10.1016/S1098-3597(01)90069-9. ISSN 1098-3597. PMID 11464731.
  • Huang M, Choiu SJ, Kim DW, Kim NY, Park CH, Yu SD et al. Risk assessment of low-level cadmium and arsenic on the kidney. J Toxicol Environ Health A 2009; 72:149.
  • IARC Monographs. (2004). “Evaluation of Carcinogenic Risks to Humans: Some Drinking-water Disinfectants and Contaminants, including Arsenic.” Vol. 84. 512 pp. International Agency for Re-search on Cancer, Lyon.
  • IARC Monographs. (2006). “Evaluation of the Carinogenic Risks to Humans: Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphide and Vanadium Pentoxide.” Vol. 86. 330 pp. International Agency for Research on Cancer, Lyon.
  • Jarup L. Hazards of heavy metal contamination. British Medical Bulletin. 2003. 68:167-182.
  • Maroon J C, Bost JW, Maroon A, Natural anti-inflammatory agents for pain relief Surg Neurol Int 2010,I:80. 
  • McLaughlin JK, Lipworth L, Chow WH, Blot WJ (September 1998). "Analgesic use and chronic renal failure: a critical review of the epidemiologic literature". Kidney Int. 54 (3): 679–86. doi:10.1046/j.1523-1755.1998.00043.x. PMID 9734593
  • Warden, Stuart J. (April 2010). "Prophylactic Use of NSAIDs by Athletes: A Risk/Benefit Assessment". The Physician and Sports Medicine 38 (1): 132138. doi:10.3810/psm.2010.04.1770. PMID 20424410.
  • Wang C, Chung M, Lichtenstein A, Balk E, Kupelnick B, DeVine D, Lawrence A, Lau J. Effects of omega-3 fatty acids on cardiovascular disease. Evid Rep Technol Assess (Summ). 2004 Mar;(94):1-8. Review. PubMed PMID: 15133888.
  • WHO. (1981). “Environmental Health Criteria, Arsenic.” pp. 1–174.  World Health Organization, Geneva.
  • WHO. (2001). “Environmental Health Criteria, 224, Arsenic and Arsenic Compounds.” 2nd ed. pp. 385–392. World Health Organi-zation, Geneva.



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