NSAID Nephropathy and COX2 Inhibitors

1
NSAID Nephropathy and COX-2 Inhibitors

• Kellie A Goldsborough, MD
• Resident Grand Rounds
• November 2, 1999

2
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

3
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
• HEENT- PERRLA, EOMI
• 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

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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
• Didnt 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

5
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?

6
Introduction

• 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

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Types of NSAID 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)

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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

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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)

10
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

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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

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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

13
Pathophysiology of Vasomotor Acute Renal Failure-
cont
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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

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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

16
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

17
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

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Mistry et al - cont.

• RESULTS
• statistically significant fall in crt clearance
  (p
• prostaglandin production was decreased but not
  significantly (47.2 ng/h to 35 ng/h with wide
  CIs)
• CONCLUSIONS
• renal impairment with HTN ? more susceptible to
  kidney dysfunction
• In this population, sulindac affects renal
  function only marginally, has advantages over
  other NSAIDS

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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

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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

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Whelton et al - sulindac - cont

• RESULTS
• 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
• Suppression of urinary prostaglandin activity was
  observed for all three groups
• CONCLUSIONS
• cautioned the extrapolation that sulindac was
  renal sparing

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Whelton et al - sulindac - cont

• CONCLUSIONS-cont
• Worse renal function and longer therapy could be
  responsible
• IDd creatinine of 2 mg/dL to be cutoff, also
  recommend renal function check at 7 days
• WEAKNESSES
• small study of women, no placebo group
• pts who stopped ibuprofen not reflected in the
  final data

23
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 elytes, urine volume, crt, GFR, RPF,
  urinary 6 keto PGF1

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Eriksson et al - cont

• RESULTS
• 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

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Eriksson et al - cont.

• CONCLUSIONS
• short term treatment with sulindac doesnt
  suppress surrogate end points like naproxen does
• WEAKNESSES
• 9 pts, treatment period only 7 days
• 7 days of washout may not have been enough

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Summary of sulindac studies
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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

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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?

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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

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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

31
Stichtenoth et al - cont

• RESULTS
• Reduction of PGE2 by 43 (pin PGE-M by 36(p
  compared to baseline
• Reduction of PGE2 by 13 (ns) and PGE-M by
  22(p
• Indomethacin and meloxicam significantly
  different when looking at PGE2 excretion

32
Stichtenoth et al - cont

• CONCLUSIONS
• PGE2 excretion, reflecting PG production was not
  inhibited by meloxicam while indomethacin caused
  pronounced suppression
• WEAKNESSES
• women only, no placebo group
• measured surrogate endpoint only

33
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

34
Bevis et al - cont

• RESULTS
• No significant difference in the mean creatinine
  clearance from baseline at any time
• No rise in the BUN, creatinine or K levels
  throughout study
• CONCLUSIONS
• COX-2 selective inhibitors have minimal renal
  adverse effects

35
Bevis et al - cont

• WEAKNESSES
• They didnt 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?

36
Bosch-Marce 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 PGs

37
Bosch-Marce et al - cont

• RESULTS
• Ketorolac resulted in significant decreases in
  urine volume, GFR, RPF, and PGs when compared to
  baseline, SC-236 tx did not
• Assay found constitutive expression of COX-2
• CONCLUSION
• Although rats with cirrhosis and ascites showed
  constitutive COX-2 mRNA expression, selective
  inhibition was devoid of any significant effect
  on renal function

38
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

39
Whelton et al - elderly - cont

• RESULTS
• Significant reduction in GFR with naproxen
  (-7.53ml/min) as compared to celecoxib
  (-1.11ml/min) (p0.004)
• PGE2 significantly reduced with both naproxen (by
  76) and celecoxib (by 65) from baseline
• 6 keto PGF1 reduced to undetectable levels with
  both treatments

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Whelton et al - elderly - cont

• CONCLUSIONS
• Celecoxib does reduce urinary prostaglandins but
  doesnt affect GFR in healthy elderly adults
• WEAKNESSES
• The patients didnt have very significant renal
  dysfunction
• No placebo group, funded by drug company

41
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

42
Whelton et al - CRI - cont

• RESULTS
• There were no significant differences in GFR
  between treatment groups
• Both active agents reduced urinary PGs
• PGE2 ? by 88 with naproxen, 47 with celecoxib
  6 keto PGF1 ? by 82 and 48 but there was no
  statistical significance between groups

43
COX-2 Inhibitors - cont

• These studies demonstrate decrease in urinary
  PGs , but no change in GFR or creatinine
• Is there any demonstration of renal dysfunction
  related to these medicines?

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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 dcd, her renal
  failure resolved. She was discharged 4 days
  later, BUN/crt of 26/0.9.

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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 dcd, 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.

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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

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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.

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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.

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Acknowledgements

• 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