October 14, 2018
NSAIDS and renal complications cover

NSAIDS and Renal Complications

Previously, we have discussed NSAIDS and cardiovascular risk as well as NSAIDS and gastrointestinal complications. In this post, we’re going to review the literature on NSAIDS and renal complications. To summarize from the previous discussion, NSAIDS are one of the most commonly used drugs in the world and their use is increasing in the US and globally. In 2013, NSAIDs had accounted for more than 70 million prescriptions and 30 billion over-the-counter purchases. Sports medicine physicians should be cognizant of potential complications, especially nephrotoxicity. Acute kidney injury (AKI) is a major cause of morbidity and mortality. In individuals admitted to the hospital with AKI requiring emergent dialysis, mortality rates can exceed 50% [1]. Awareness can lead to better prescribing practices and increased safety for at-risk patients.
Cyclooxygenase enzymes, which regulate the conversion of arachidonic acid to prostaglandins, are abundantly present in the kidneys and play an important role in renal hemostasis, renin release, renal tubular salt and water reabsorption. COX-1 “predominates in vascular smooth muscle and collecting ducts, whereas COX2 predominates in the macula densa and nearby cells in the cortical thick ascending limb” [2]. In general, NSAIDs block the vasodilatory effects of prostaglandins.
Nearly all drugs are excreted via the kidneys, and the rate of drug induced nephropathy is increasing [3].  A decline in renal function can occur within days of initiation of NSAID therapy [4]. Non-selective NSAIDS and selective COX-2 inhibitors appear to carry similar risks [5]. In the UK, over 50% of elderly patients with CKD are prescribed NSAIDs with low-dose aspirin accounting for the majority of prescriptions [6].
It appears that NSAID use may be safe in healthy individuals without any underlying chronic kidney disease. In one cohort of approximately 2600 RA patients, NSAID use was an independent predictor of accelerated decline in renal function only in patients with advanced baseline renal impairment; patients with a normal baseline GFR had similar renal function at 3.2 years compared with non-NSAID users [7]. Other studies have found that patients with stage 4 or 5 CKD are more likely to have regular aspirin or NSAID use [8, 9].
pathophysiology of NSAIDS on GFR and kidney function

Image 1. Normal renal physiology and pathiophysiology of NSAID use on GFR (courtesy of tulane.edu)

NSAID use appears to promote progression of chronic kidney disease. Most studies record a decrease in mean GFR and CKD disease progression with NSAID use [10, 11]. Paradoxically, Evans et al found that regular aspirin users with stage 4–5 CKD had a slower rate of disease progression per year compared with non-users [12]. The dosing and frequency of use matter for disease progression as well, although there is no consensus on what constitutes ‘regular’ or ‘high’ use [10, 13].
NSAID use in patients with other comorbidities can contribute to CKD progression or the development of kidney disease. Individual patient risk factors include underlying kidney disease, volume depletion (overdiuresis, vomiting, diarrhea, etc), liver cirrhosis, congestive heart failure, diabetes, hypertension and elderly age. In individuals with hypertension, concurrent use of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) with NSAIDS was associated with an increased risk of AKI; the risk was greatest at initiation of treatment [14].
NSAID use can lead to multiple distinct renal syndromes. The first is renal insufficiency, which can be present acutely or, if unchecked, chronic with the end result of end stage renal disease. This appears to be caused by a decrease in glomerular filtration rate and renal vasoconstriction.
Sodium retention with hypertension and edema can be seen with NSAID use. COX inhibition can lead to decreased sodium excretion and increased sodium retention. This appears to occur via a variety of mechanisms including decreased GFR, direct inhibition of sodium absorption in the ascending limb collecting duct and reduction in renal medullary blood flow. Hyperkalemia can occur with NSAID use by suppression of the renin-angiotensin-aldosterone system in addition to diminished GFR. The significance of this is unknown. In one study of 1.2 million new NSAID users, NSAID use alone was not associated with developing a serum potassium ≥ 6 mEq/L [15].
renal effects of arachidonic acid inhibition from nsaid use

Image 2. Renal effects of arachidonic acid inhibition from nsaid use (courtesy of ajkd.org)

Papillary necrosis involves loss of the renal papilla, which normally facilitate urine accumulation for excretion into the ureter.  Acute tubular necrosis occurs from death of the epithelial cells in the renal tubules. Acute interstitial nephritis is inflammation of the interstitium or space between the renal tubules. This can occur acutely, sub-acutely or with chronic use. NSAID use may also increase the risk of renal cell cancer [16].
It is unclear which NSAIDS have the best renal safety profile. There are no large epidemiological studies comparing the majority of NSAIDS renal safety. In one study of 121,000 new NSAID users, meloxicam was the safted with an aRR of 1.27, followed by celecoxib (1.54, rofecoxib (2.31) and naproxen (2.42) [17].
In summary, NSAID use is safe in the general population when used at the lowest dose for the shortest period of time necessary. There is mixed evidence about whether regular NSAID use can contribute to the development of acute kidney injury or progression of underlying chronic kidney disease. High-dose NSAID use does appear to to contribute to CKD progression, although there is no consensus on what constitutes as ‘high dose.’ In patients with other comorbidities, especially hypertension, use of NSAIDS should be approached cautiously. There is no clear, evidence based recommendation on which NSAID is safest for the kidneys. The best available data would suggest the meloxicam and celebrex are the the least nephrotoxic.

References

1. Hsu CY, Chertow GM, et al. Nonrecovery of kidney function and death after acute on chronic renal failure. Clin J Am Soc Nephrol2009;4:891-8
2. Breyer MD, Harris RC. Cyclooxygenase 2 and the kidney. Curr Opin Nephrol Hypertens. 2001 Jan;10(1):89-98. Review.
3. Wu TY, Jen MH, et al. Ten-year trends in hospital admissions for adverse drug reactions in England 1999-2009. J R Soc Med2010;103:239-50.
4. Toto RD, Anderson SA, Brown-Cartwright D, et al. Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency. Kidney Int 1986;30:760–8.
5. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086.
6. Bhopal S, Chan J, Ellis O, et al. Non-steroidal anti-inflammatory drugs prescribing in chronic kidney disease: an observational study. Prim Health Care Res Dev 2010; 11(03): 280–84.
7. Möller B, Pruijm M, et al. Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study. Ann Rheum Dis. 2015 Apr;74(4):718-23.
8. Hippisley-Cox, Julia, and Carol Coupland. “Predicting the risk of Chronic Kidney Disease in Men and Women in England and Wales: prospective derivation and external validation of the QKidney® Scores.” BMC family practice 11.1 (2010): 49.
9. Fored, C. Michael, et al. “Acetaminophen, aspirin, and chronic renal failure.” New England Journal of Medicine 345.25 (2001): 1801-1808.
10. Yarger, S., et al. “Puk4 Cumulative exposure to nonsteroidal anti-inflammatory drugs (NSAIDS) and the progression of chronic kidney disease (CKD).” Value in Health 14.3 (2011): A74-A75.
11. Gooch, Katherine, et al. “NSAID use and progression of chronic kidney disease.” The American journal of medicine120.3 (2007): 280-e1.
12. Evans M, Fored CM, et al. Acetaminophen, aspirin and progression of advanced chronic kidney disease. Nephrol Dial Transplant. 2009 Jun;24(6):1908-18.
13. Nderitu P, Doos L, et al. Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Fam Pract. 2013 Jun;30(3):247-55.
14. Lapi F, Azoulay L, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013 Jan 8;346:e8525.
15. 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 Jul;60(1):82-9.
16. Cho E, Curhan G, Hankinson SE, Kantoff P, Atkins MB, Stampfer M, Choueiri TK. Prospective evaluation of analgesic use and risk of renal cell cancer. Arch Intern Med. 2011 Sep 12;171(16):1487-93.
17. Schneider V, Lévesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am J Epidemiol. 2006 Nov 1;164(9):881-9.
18. Whelton A. Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors. Am J Med. 2001 Feb 19;110 Suppl 3A:33S-42S. Review. PubMed PMID: 11173048.