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NSAID Nephropathy and COX-2 Inhibitors. Kellie A Goldsborough, MD Resident Grand Rounds November 2, 1999. Case Presentation. HPI- JS is a 69 yo bm, presents to the ER with a 2 week history of nausea, anorexia, and confusion. He was given Indomethacin 19 days earlier for a gout exacerbation

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nsaid nephropathy and cox 2 inhibitors

NSAID Nephropathy and COX-2 Inhibitors

Kellie A Goldsborough, MD

Resident Grand Rounds

November 2, 1999

case presentation
Case Presentation
  • HPI- JS is a 69 yo bm, presents to the ER with a 2 week history of nausea, anorexia, and confusion. He was given Indomethacin 19 days earlier for a gout exacerbation
  • PMHX- Dilated cardiomyopathy, EF 20-25%, hx of alcohol abuse, hypertension, gout
  • MEDS-
        • Lotensin 20 mg q day
        • Digoxin 0.125mg q day
        • Lasix 40mg q day
        • K-Dur 20meq q day
        • Indomethacin 25mg TID x 19days
case presentation cont
Case Presentation - cont.
  • All- NKDA
  • SH- no tobacco, no current ETOH
  • PE- 98.2 79 110/79 16 97% on RA
      • gen-thin bm, NAD, slow to respond
      • neck- no bruits or JVD
      • lungs- CTAB
      • heart- RRR, no M/G/R
      • abd- benign
      • ext-no C/C/E
      • neuro- overall depressed MS but nonfocal
case presentation cont1
Case Presentation - cont
  • Labs were significant for a BUN/crt of 147/4.7 (had been 13/1.1 19 days earlier)
  • Admitted, NSAID and ACE were discontinued
  • Negative UA, U/S, and duplex
  • Renal function improved, ACE was restarted, he was discharged 4 days later with BUN/crt of 54/1.0, advised against NSAIDS
  • Didn’t follow up, returned to the ER 22 days later, admitted to taking a “pain med”, his BUN/crt were 230/18.7
  • Negative SPEP/UPEP, ANCA, anti GBM
  • Consistent with NSAID nephropathy
  • Required MICU, hemodialysis, renal function did recover, discharged to a NH 11 days later with BUN /crt of 4/0.7
case presentation clinical questions
Case Presentation- Clinical Questions
  • Why did this happen?
  • Could it have been predicted or avoided?
  • Would the substitution of a different NSAID or a COX-2 inhibitor produce any less risk for this kind of NSAID nephropathy?
  • 1-5% of patients exposed to NSAIDS develop some kind of a nephropathy
  • NSAIDS have an extensive use profile
  • Estimate renal abnormality in 500,000 - 2.5 mil US citizens per year who use NSAIDS
  • Use is increasing due to aging, OTC availability, and advent of COX-2 inhibitors
types of nsaid nephropathy
Types ofNSAID Nephropathy
  • Abnormalities in sodium, water and potassium homeostasis
  • Vasomotor acute renal failure*
  • Nephrotic Syndrome
  • Interstitial Nephritis
  • Chronic renal failure most often due to papillary necrosis (acute or chronic)
objectives of presentation
Objectives of Presentation
  • Discuss the pathophysiology of the different forms of NSAID nephropathy focusing on the vasomotor ARF
  • Outline the risk factors for the development of ARF with NSAIDS
  • Discuss the differences between the traditional NSAIDS and the COX-2 inhibitors with regard to nephropathy
interstitial nephritis
Interstitial Nephritis
  • Difficult to estimate, less predictable and specific, related to other medicines, ie. beta lactams
  • Mechanism is unclear
    • delayed hypersensitivity response to the NSAID
    • inhibition of PG synthesis leads to increased proinflammatory substances
  • Patients afflicted are elderly, female, on NSAIDS for months
  • Clinical Presentation- heavy proteinuria, RBC &WBC in micro low FENa
  • Treatment- withdraw the NSAID, supportive care, steroids are debated, resolution weeks to months, chronic failure or ESRD can result (75%)
nephrotic syndrome
Nephrotic Syndrome
  • Approximately 10%-12% of patients who develop renal lesions on NSAIDS have minimal change nephrotic syndrome.
  • Patients are female, taking NSAIDS for months
  • Clinical presentation- nephrotic syndrome- heavy proteinuria, edema, low albumin, etc
  • Microscopic specimen- fusion of the epithelial cell foot processes
  • Treatment- withdraw NSAID, supportive, steroids more favored
renal papillary necrosis
Renal Papillary Necrosis
  • Least common, most serious, usually results in ESRD
  • Seen in massive NSAID o/d in a dehydrated patient
  • Acute
    • dehydration and massive NSAID ingestion elevated toxic metabolites and vasoconstriction  necrosis
  • Chronic
    • also known as analgesic nephropathy
    • present in 2% of the HD population
    • repetitive daily ingestion producing a syndrome of chronic renal failure, most often linked to phenacetin
pathophysiology of vasomotor acute renal failure
Pathophysiology of Vasomotor Acute Renal Failure
  • Most common, predictable nephropathy
  • directly related to prostaglandin synthesis suppression in the kidney
  • Prostaglandins-
    • unsaturated FA compounds derived from arachidonic acid
    • formation catalyzed by cyclooxygenase (COX) 2 isoforms (COX-1 and COX-2)
    • function as local hormones or autocoids
risk factors
Risk Factors
  • Mechanism is well established
  • Any state which results in a decreased effective arterial blood volume
    • congestive heart failure
    • cirrhosis
    • nephrotic syndrome
    • sepsis/hemorrhage/hypotension/diuretic
risk factors cont
Risk Factors - cont
  • Chronic Renal Failure
    • prostaglandins play an adaptive role
  • Elderly
    • decreased GFR, vasculature less responsive, decreased protein binding and decreased hepatic metabolism of drug
are all nsaids created equal sulindac
Are All NSAIDS Created Equal?Sulindac
  • Bunning et al, 1984
    • case report of 3 patients who developed ARF on traditional NSAIDS, but no adverse renal effects on sulindac
    • concluded that sulindac had less renal toxicity
    • sulindac is prodrug, converted to active form then converted to a sulfone which is inactive as a prostaglandin inhibitor
mistry et al
Mistry et al
  • More controlled study of sulindac
  • 9 patients, ages 35-45
  • CRI with creatinine clearance of 25-55 ml/min, HTN
  • Exclusion criteria: CHF, GI d/o, bleeding
  • all treated with sulindac 200 mg BID x 9days
  • End Points: creatinine, clearance, GFR RPF, urinary prostaglandins
  • Men were excluded from urinary PG measurements
mistry et al cont
Mistry et al - cont.
    • statistically significant fall in crt clearance (p<0.02) and rise in creatinine (p<0.02) with tx
    • prostaglandin production was decreased but not significantly (47.2 ng/h to 35 ng/h with wide CI’s)
    • renal impairment with HTN  more susceptible to kidney dysfunction
    • In this population, sulindac affects renal function only marginally, has advantages over other NSAIDS
mistry et al cont1
Mistry et al - cont.
  • Weaknesses
    • small study, only 9 days of treatment
    • urinary prostaglandins measured in only 5 patients
    • no comparison group
    • are changes really clinically significant?
      • creatinine change from 2.2 to 2.4 mg/dL
      • clearance change from 37 to 34 ml/min/m2
whelton et al sulindac
Whelton et al - sulindac
  • Prospectively randomized, triple crossover study
  • 12 women with chronic renal insufficiency (creatinine 1.5-3.1 mg/dL)
  • randomized to treatment for 11 days with ibuprofen, piroxicam, and sulindac
  • Endpoints: creatinine, RPF, GFR, urinary prostaglandin levels
whelton et al sulindac cont
Whelton et al - sulindac - cont
    • Ibuprofen withdrawn on day 8 because of increased creatinine in 2 pts and hyperkalemia in 1
    • There was a significant increase in creatinine level with sulindac tx (p<0.05)
    • Suppression of urinary prostaglandin activity was observed for all three groups
    • cautioned the extrapolation that sulindac was renal sparing
whelton et al sulindac cont1
Whelton et al - sulindac - cont
    • Worse renal function and longer therapy could be responsible
    • ID’d creatinine of 2 mg/dL to be cutoff, also recommend renal function check at 7 days
    • small study of women, no placebo group
    • pts who stopped ibuprofen not reflected in the final data
eriksson et al
Eriksson et al
  • Randomized, double blind, crossover design
  • 9 patients with rheumatologic disease and renal insufficiency (mean clearance 53ml/min)
  • randomized to tx with sulindac or naproxen with a placebo washout period
  • Followed e’lytes, urine volume, crt, GFR, RPF, urinary 6 keto PGF1
eriksson et al cont
Eriksson et al - cont
    • Treatment with naproxen significantly decreased the excretion of 6 keto PGF1 while sulindac had no such effect
    • naproxen caused a decrease in GFR and RPF while sulindac did not
    • There was no change in creatinine with either treatment
eriksson et al cont1
Eriksson et al - cont.
    • short term treatment with sulindac doesn’t suppress surrogate end points like naproxen does
    • 9 pts, treatment period only 7 days
    • 7 days of washout may not have been enough
cox 2 inhibitors intro
COX-2 inhibitors - intro
  • COX exists in 2 isoforms (COX-1 & COX-2)
  • COX-1 “constitutive”
    • producing thromboxane, PGE2 in the kidney, prostacyclin (anti-thrombogenic and cytoprotective)
  • COX-2 “inducible”
    • turned on by inflammatory stimuli
cox 2 inhibitors
COX-2 Inhibitors
  • Komhoff et al in 1997
    • Localized expression of COX-2 immunoreactive protein to endothelial and smooth muscle cells of vasculature in the human kidney
  • Does presence indicate a vital role?
cox 2 inhibitors cont
COX-2 Inhibitors - cont
  • Table 5 Influence on COX-1 and COX-2 activity of guinea-pig peritoneal macrophages for different NSAIDS
  • NSAID COX-1 IC50(mmol/L) COX-2 IC50 (mmol/L) Ratio
  • Flurbiprofen 15 4760 317
  • Indomethacin 0.21 6.4 30
  • Piroxicam 5.3 175 33
  • Meloxicam 5.8 1.9 0.33
  • SC-236 17.8 0.01 0.00056
stichtenoth et al
Stichtenoth et al
  • Randomized, crossover design comparing indomethacin and meloxicam
  • 14 women, healthy
  • exclusion criteria basically any diseases
  • randomized to meloxicam x 6 days or indomethacin x 3 days crossover with 5 day washout
  • Endpoints: urinary excretion of PGE2 and PGE-M
stichtenoth et al cont
Stichtenoth et al - cont
    • Reduction of PGE2 by 43% (p<0.05) and a reduction in PGE-M by 36%(p<0.001) with indomethacin compared to baseline
    • Reduction of PGE2 by 13% (ns) and PGE-M by 22%(p<0.05) with meloxicam compared to baseline
    • Indomethacin and meloxicam significantly different when looking at PGE2 excretion
stichtenoth et al cont1
Stichtenoth et al - cont
    • PGE2 excretion, reflecting PG production was not inhibited by meloxicam while indomethacin caused pronounced suppression
    • women only, no placebo group
    • measured surrogate endpoint only
bevis et al
Bevis et al
  • Open label, multicenter study
  • 25 pts with arthritic disease and renal insufficiency (crt clearance 25-60ml/min)
  • Exclusion criteria: severe disease, ulcers, hemodialysis, lithium, ACE, abnml labs
  • washout for 4 days, then tx with meloxicam for 28 days
  • Endpoints: creatinine clearance, creatinine and elytes at 14, 21, 28, 35 days
bevis et al cont
Bevis et al - cont
    • No significant difference in the mean creatinine clearance from baseline at any time
    • No rise in the BUN, creatinine or K levels throughout study
    • COX-2 selective inhibitors have minimal renal adverse effects
bevis et al cont1
Bevis et al - cont
    • They didn’t measure urinary prostaglandins which appears to be a good surrogate marker for renal dysfunction
    • No placebo group, or comparison drug
  • What about studies in the other people at risk from certain disease states?
bosch marc et al
Bosch-Marcĕ et al
  • Randomized study in rats, yes rats!
  • 22 rats with induced cirrhosis and ascites
  • Randomized to supratherapeutic ketorolac and SC-236 (highly selective COX-2)
  • Multiple endpoints: urine volume, GFR, RPF, urinary PG’s
bosch marce et al cont
Bosch-Marce et al - cont
    • Ketorolac resulted in significant decreases in urine volume, GFR, RPF, and PG’s when compared to baseline, SC-236 tx did not
    • Assay found constitutive expression of COX-2
    • Although rats with cirrhosis and ascites showed constitutive COX-2 mRNA expression, selective inhibition was devoid of any significant effect on renal function
whelton et al elderly
Whelton et al - elderly
  • Single center, single blind, randomized, crossover study- not published yet
  • 29 healthy elderly with GFR 67-127 ml/min
  • Randomized to celecoxib or naproxen for 10 days, then crossover with a 7 day washout
  • Endpoints: creatinine, GFR, urinary PGE2 and 6 keto PGF1
whelton et al elderly cont
Whelton et al - elderly - cont
    • Significant reduction in GFR with naproxen (-7.53ml/min) as compared to celecoxib (-1.11ml/min) (p=0.004)
    • PGE2 significantly reduced with both naproxen (by 76%) and celecoxib (by 65%) from baseline
    • 6 keto PGF1 reduced to undetectable levels with both treatments
whelton et al elderly cont1
Whelton et al - elderly - cont
    • Celecoxib does reduce urinary prostaglandins but doesn’t affect GFR in healthy elderly adults
    • The patients didn’t have very significant renal dysfunction
    • No placebo group, funded by drug company
whelton et al cri
Whelton et al - CRI
  • Multicenter, double blind, randomized, placebo controlled parallel group study
  • 75 pts with CRI (GFR 40-60 ml/min, and creatinine of 1.3-3.0 mg/dL)
  • Randomized to celecoxib, naproxen, or placebo x 7 days after washout
  • Endpoints: GFR, urinary PGE2 and 6 keto PGF1
whelton et al cri cont
Whelton et al - CRI - cont
    • There were no significant differences in GFR between treatment groups
    • Both active agents reduced urinary PG’s
    • PGE2  by 88% with naproxen, 47% with celecoxib; 6 keto PGF1  by 82% and 48% but there was no statistical significance between groups
cox 2 inhibitors cont1
COX-2 Inhibitors - cont
  • These studies demonstrate decrease in urinary PG’s , but no change in GFR or creatinine
  • Is there any demonstration of renal dysfunction related to these medicines?
local case series of cox 2 related nephropathies deterding
Local Case Series of COX-2 related nephropathies - Deterding
  • CASE 1- 65 yo wf with CML (dx 3/98), DM, HTN and previous episode of ARF thought to be due to TLS with resolution, baseline BUN/crt of 23/1.2. Started on Vioxx on 8/13, presented to the ER on 8/20 with a BUN/crt of 106/8.8. Also on accupril and lasix but had been for years. Work up included a negative urinalysis, ultrasound and duplex. The Vioxx and ACE were dc’d, her renal failure resolved. She was discharged 4 days later, BUN/crt of 26/0.9.
case series cont
Case Series - cont
  • CASE 2 - 72 yo wf with obesity, DM, and chronic venous insufficiency, prolonged hospitalization (5/28-6/17) for ?PE, pneumonia and bacteremia, improved with treatment. Started on lasix on 6/7, an ace on 6/9, then on celecoxib on 6/12. Labs on 6/16 showed nml renal function. Transferred to the TCU, next lab check on 6/23, BUN/crt of 25/2.9, then 29/3.6 on 6/25, and 29/3.9 on 6/26. The celecoxib and Ace were dc’d, work up = negative ultrasound and duplex, UA showed 1-5 WBC and few bacteria. Renal function improved after stopping the celecoxib, on 10/7 it was 17/1.0.
case series cont1
Case Series - cont
  • Cases are very suggestive for COX-2 related nephropathy
  • Only a case series
  • Other variables involved, most notably the Ace Inhibitor and the diuretic tx
  • Other studies are needed for verification of COX-2 related nephropathies
bottom lines
Bottom Lines
  • NSAID nephropathy is a significant health issue, prevalence may increase in the future due to aging of the population, increased availability, and the new COX-2 inhibitors.
  • Vasomotor acute renal failure is the most common and predictable NSAID nephropathy and also the most easily avoided by careful administration of NSAIDS.
  • Risk factors for acute renal failure related to NSAIDS are: volume depletion, congestive heart failure, cirrhosis, nephrotic syndrome, chronic renal insufficiency and advanced age.
bottom lines cont
Bottom Lines - cont
  • .When looking at traditional NSAIDS, sulindac may pose less of a risk for ARF if used for a short course.
  • .The COX-2 enzyme is constitutively expressed in the kidney, and COX-2 inhibitors, initially promising, appear to cause inhibition of prostaglandin synthesis and limited demonstration of acute renal dysfunction. However, this may be to a lesser degree than traditional NSAIDS, more studies are needed to delineate.
  • .No NSAID can be regarded as completely renal sparing, we must use these medicines more judiciously with careful monitoring of renal function in those who are at risk.
  • Richard Appel, MD helping pick articles
  • Liz Deterding, MD giving me cases
  • Christine Brandon-Bingham
  • Andrew Namen, MD , Todd Hulgan, MD , Linda Lee, MD for critiquing my work