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Anesth Analg 1999;89:999
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Renal Dysfunction Associated with the Perioperative Use of Diclofenac

Haimee Kim, FANZCA*, Manli Xu, MMBS*, Yiguang Lin, PhD*, Michael J. Cousins, MD, FANZCA*, Robert P. Eckstein, FRCPA{dagger}, Vicki Jordan, FRCPA{dagger}, Ian Power, MD, FRCA*, and Laurence E. Mather, PhD, FANZCA*

Departments of *Anaesthesia and Pain Management and {dagger}Anatomical Pathology, University of Sydney at Royal North Shore Hospital, St Leonards, Australia

Address correspondence to Professor Laurence E. Mather, Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Address e-mail to lmather{at}med usyd.edu.au.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Postoperative renal dysfunction in rats is induced by ketorolac dosed concurrently with gentamicin. Herein, we report the renal effects of diclofenac in four groups of rats: control (C = anesthesia, surgery); diclofenac (D = anesthesia, surgery, diclofenac 18 mg · kg–1 · d–1); gentamicin (G = anesthesia, surgery, gentamicin 20 mg · kg–1 · d–1); and diclofenac and gentamicin (DG = anesthesia, surgery, diclofenac, gentamicin). Renal function, after three treatment days, was assessed using histology, p-aminohippurate (PAH), and iothalamate (IOT) clearances, serum and urine electrolytes, osmolality, urea, and creatinine. Urine output was increased (from 5.2 to 12.5 mL/24 h), and urine osmolality was decreased (from 2121 to 883 mOsm/kg) in the DG group. PAH and IOT clearances were decreased in the G and DG groups (PAH by 18%, IOT by 22%; PAH by 38%, IOT by 43%, respectively); there were no changes in the C and D groups. Urea and creatinine clearances were decreased by 61% and 43%, respectively, in the DG group. Kidney sections showed the most severe pathologic changes in the DG group. Our data indicate that the perioperative combination of diclofenac and gentamicin was deleterious to renal function.

Implications: Diclofenac alone does not result in significant perioperative renal dysfunction, but the combination of gentamicin and diclofenac is deleterious to renal function. Considering this and previous findings, the evidence suggests that treatment with aminoglycosides may be a significant risk factor for inducing perioperative renal failure during treatment with nonsteroidal antiinflammatory drugs.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the management of mild-to-moderate postoperative pain. Their opioid-sparing effect and availability in parenteral forms make them ideal for day-only and short-stay admissions for elective surgery (1–4). The rationale for their use is that they produce inhibition of peripheral hyperalgesia mediated by their antiinflammatory properties (5), possibly supplemented by centrally mediated actions that attenuate central sensitization (6–9). However, reports of serious postoperative renal dysfunction, especially associated with the use of parenteral ketorolac, has created concern about the use of NSAIDs in postsurgical patients (10,11).

The overall mechanism of renal dysfunction associated with chronic NSAID use is principally caused by inhibition of cyclooxygenase enzymes, resulting in decreased synthesis of eicosanoids, which are important autacoids in the regulation of renal function (12,13). However, relatively little is known about the acute renal effects of NSAIDs when used in postoperative pain management (14).

A recent study performed in our laboratory examined the renal effects of ketorolac in rats undergoing anesthesia and surgery, gentamicin treatment, and dehydration (15). No change in renal function was found when ketorolac was used alone or with dehydration, but severe renal dysfunction associated with widespread histologic changes was found when ketorolac was given with gentamicin. This suggests that the coadministration of aminoglycoside is a risk factor and is consistent with the results of other investigations (15–17).

Our study tested the hypothesis that diclofenac, a NSAID of a different chemical class from ketorolac, when coadministered with and without gentamicin in the perioperative setting, would cause renal effects similar to those of ketorolac. In testing this hypothesis, we studied kidney histopathology, along with the renal handling of electrolytes, nitrogenous end-metabolites, water, iothalamate (IOT), and p-aminohippurate (PAH), in a rat model previously shown to be sensitive to nephrotoxic drugs (15).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by our animal care and ethics committee of the Royal North Shore Hospital. Four groups of 10 rats were studied: the control (C) group underwent anesthesia and surgery; the diclofenac (D) group underwent anesthesia, surgery, and diclofenac (18 mg · kg–1 · d–1) treatment; the gentamicin (G) group underwent anesthesia, surgery, and gentamicin (20 mg · kg–1 · d–1) treatment; the gentamicin and diclofenac (DG) group underwent anesthesia, surgery, and treatment with diclofenac (18 mg ·kg–1 · d–1) and gentamicin (20 mg · kg–1 · d–1). The study drugs were given by subcutaneous (sc) injection in divided doses, twice daily for seven injections. Surgery, blood sampling, and baseline clearance studies were performed under anesthesia (Day 0). Arterial blood samples were analyzed for baseline serum osmolality and concentrations of Na+, K+, creatinine, urea, PAH, and IOT. Surgery comprised incision in the neck and cut-down implantation of chronic indwelling cannulae into the carotid artery and jugular vein to allow simultaneous venous infusion, arterial blood sampling, and blood pressure monitoring. The study-drug injections were commenced on Day 0, after completion of clearance studies; the last dose was given 2 h before the clearance studies being repeated on Day 3. The diclofenac dose was consistent with antinociceptive doses in a rat model of acute inflammatory joint pain (18). The gentamicin dose approaches borderline renal toxicity in the Fischer 344 rat (15); larger doses have been found to exert a greater (19) and longer lasting effect (20). The three-day duration of dosing was consistent with clinical practice.

Adult male Fischer 344 rats were housed in metabolic cages with free access to food and water in a controlled environment of 19°C and a 12-h light/dark cycle. Preoperative body weight, 24-h urine output, and water intake were monitored daily for each animal. Urine was collected under 1 mL of paraffin oil to prevent evaporation; samples were analyzed for osmolality and Na+, K+, creatinine, and urea concentrations.

Anesthesia was induced with isoflurane and maintained with midazolam (1 mg/kg sc) and with spontaneous ventilation of 2% to 3% isoflurane in O2 via a modified Ayre’s T-piece system with a humidifier. Rectal temperature was monitored and core body temperature was maintained at 36.5°C to 37.5 with a heating pad. Surgery comprised a longitudinal incision in the neck and blunt dissection to expose the carotid artery and jugular vein. Silastic laboratory tubing was used to cannulate the internal jugular vein (0.025-in. inside diameter, 0.047-in. outside diameter) and the carotid artery (0.020-in. inside diameter, 0.037-in. outside diameter). The mean arterial blood pressure was maintained at 90 to 110 mm Hg by manipulation of the inspired isoflurane concentration. Blood samples were taken, and renal clearance studies were performed. The blood loss was replaced by Hartmann’s solution in a volume ratio of 3:1 (Hartmann’s solution:blood). The cannulae were tunneled sc and externalized to the midscapula region. The dead space of each cannula was filled with a solution of 6-g polyvinyl pyrrolidone in 5 mL 1000 U/mL sodium heparin to maintain patency. The incision was sutured, and the animals were allowed to recover. Each animal was given 8 mL of Hartmann’s solution sc to compensate for intraoperative and postoperative fluid losses. On Day 3, the animals were again anesthetized, and blood sampling and renal clearance studies were repeated by accessing the vascular cannulae. Anesthesia was deepened at the conclusion of clearance studies before killing the animals by exsanguination.

The clearances of PAH (20% sodium salt; Merck, West Point, PA) and IOT (70%; Rhone-Poulenc, Collegeville, PA), ClPAH and ClIOT, respectively, were used to approximate renal plasma flow (RPF) and glomerular filtration rate, respectively, using a urineless technique developed in our laboratory (21). Briefly, a steady-state of IOT and PAH arterial plasma concentrations was achieved within 30 min by a two-stage IV infusion (1 mg PAH and 0.5 mg IOT in 0.5 mL 0.9% saline infused for 1 min, immediately before a continuous infusion of 1.0 mg/h PAH and 0.25 mg/h IOT in 0.9% saline). Arterial blood samples (0.1 mL) were collected at 38, 44, 50, and 60 min after commencement of infusion and analyzed by high-performance liquid chromatography (21). ClPAH and ClIOT were calculated from the ratio of the constant infusion rate to the respective median arterial PAH and IOT concentrations (21). Total body clearances of urea and creatinine (Clurea and Clcr, respectively) were determined from the respective ratios of the amounts excreted into urine to median plasma concentrations.

Both kidneys from each rat were bisected, and any gross abnormality was noted. The fresh tissue was fixed in 10% buffered formalin. A full cross-sectional face of each kidney was processed and stained with hematoxylin and eosin stains. The kidneys were identified by a study number, and the code was not known to the research pathologist who made histologic assessments and scores. The kidneys were assessed on two criteria: 1) evidence of tubular necrosis, and 2) evidence of regeneration. For the diagnosis of tubular necrosis, identification of necrotic nuclear and cytoplasmic debris within proximal tubular lumens was required. Regeneration was identified by the presence of proximal tubular dilation, flattening of epithelial lining cells, and regenerative nuclear features. Necrosis and regeneration were both scored on the scale 0 to 3 (0 = no evidence of change from normal, 3 = the most severe in the spectrum of changes noted), giving a combined histology score for each rat from 0 to 6.

The data were found to be normally distributed (Wilk-Shapiro test). The differences for the relevant variables between Day 0 and Day 3 were analyzed with one-way analysis of variance (ANOVA). Preliminary studies indicated that for a 25% change in ClPAH (a primary study variable), the power of the study would be 80% with groups of 10 animals. Subsequent post hoc power analysis indicated that the one-sided power for detecting a difference between the C and DG groups with a type error of 0.05 was 86% for a significantly changed ClPAH, 58% for ClIOT, and 99% for urinary osmolality. A one-sided test was considered to be justified on the basis that impaired performance was the only logical outcome.

Where significant group differences for treatments were found by ANOVA, the least significant difference method was used to determine homogeneity of group means. The histologic scores for the treatment group, being nonparametric data, were described by the median and range. The histologic scores for the four treatment groups were analyzed using the Kruskal-Wallis test; if this showed statistical significance, then pairwise comparisons were made among treatment groups using Mann-Whitney U-tests. The significance level was set at 0.05 for all procedures. Analyses were performed using Statistix for Windows (version 1.0; Analytical Software, Tallahassee, FL) on a personal computer.


   Results
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 Methods
 Results
Discussion
 References
 
Tables 1–3 show the means and SD values of the data obtained on Days 0 and 3 along with the 95% confidence intervals of the changes between the days. Changes within the groups between Day 0 and Day 3 were not significant if the 95% confidence interval for the mean of the differences for Day 0 to Day 3 included zero. Results of the ANOVA indicated whether there were significant differences between treatment groups for the differences Day 0 – Day 3. Differences between the treatment groups, for which the mean values of the changes from Day 0 to Day 3 could not be shown to be significantly different (least significant difference method), were placed in homogenous groups labeled "a," "b," and "c."


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  		Table 1. Body Weight, Serum Electrolytes, Urea, Creatinine, and Urine Osmolality
 
Body weight decreased (5%–7%) in all groups; there was no difference in weight loss among the groups. Serum Na+ and osmolality did not change significantly for any of the groups. Serum K+ was decreased significantly in the G group, but did not change significantly in the other treatment groups. Both serum urea and creatinine were unchanged in the C group, although both were increased in all the other groups, with the largest increase being in the DG group (Table 1).

Urine output was markedly increased for the DG group only, although there was not a higher water intake in this group. Urinary Na+ excretion was decreased in all treatment groups, the maximum change being in the DG group. Likewise, urinary K+ excretion was markedly decreased in the DG group, whereas it remained unchanged in the other treatment groups. Urine osmolality was also markedly decreased in the DG group (Table 2).


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  		Table 2. Urine Volume, Electrolytes, Osmolality
 
ClPAH was decreased in the G and DG groups, with the greatest decrease being in the DG group. ClIOT was decreased in the D and DG groups, with the greatest change again being in the DG group. Clurea and Clcr were decreased in the DG group only (Table 3).


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  		Table 3. Renal Cl of ClPAH, ClIOT, Clcr, and Clurea
 
Kidney sections of the DG group consistently showed the most severe and widespread changes, with frequent foci of tubular necrosis and regeneration (Figures 1 and 2). Similar, but less severe, changes were present in the G group. There were minimal changes in the C and D groups. The median (range) of the histology scores were: C group = 1 (0–1), D group = 1 (0–2), G group = 2 (0–3), and DG group = 4 (2–4). There was a significant difference between the treatment group scores (P < 0.00001). DG and G groups had significantly higher scores than the C group, but there was no significant difference among the G, D, and C groups. Specifically, the DG group had a significantly higher score than the D group (P = 0.0001) or the G group (P = 0.007).



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  		Figure 1. Rat renal cortex (hematoxylin and eosin staining) of the control rat, the renal tubules are lined by normal epithelial cells.

 


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  		Figure 2. Rat renal cortex (hematoxylin and eosin staining) of a rat from DG group (diclofenac and gentamicin) showing the focal areas of tubular necrosis.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Consistent deleterious effects on renal histology and function were found only in the DG group. Although this group had a generally lower body weight, the change in body weight was not different from the other groups. Also, the fact that the effects associated with the drug treatments were greater in virtually all respects in the DG group indicates that the greater effects in this group are related to the drug treatment rather than the animals’ differences in weight. Accordingly, this finding mimics that of our previous study in which the most notable changes were found in an analogous group of rats treated with the combination of ketorolac and gentamicin (15). Thus, the common feature between the studies in this perioperative rat model is that the combination of a subtoxic dose of NSAID with a subtoxic dose of gentamicin provokes renal dysfunction.

Inhibition of renal prostaglandin synthesis by NSAIDs, in individuals dependent on increased renal prostaglandin synthesis for maintenance of renal perfusion, can lead to renal dysfunction (22,23). The products of arachidonic acid metabolism have diverse roles in the kidney, including the regulation of RPF (prostaglandins PGI2 and PGE2 vasodilate; thromboxane A2 vasoconstricts), salt and water handling, and renin release by the juxtaglomerular apparatus. Renal prostaglandin synthesis is low in healthy subjects and plays a minor role in the maintenance of RPF. Under these conditions, inhibition of prostaglandin synthesis by NSAIDs appears to cause no clinically significant adverse effects. A recent study showed diclofenac in therapeutic doses had no effect on inulin clearance, Clcr, or ClPAH in healthy unanesthetized human volunteers (24). However, in subjects dependent on increased prostaglandin synthesis for maintenance of RPF and fluid and electrolyte homeostasis, inhibition of cyclooxygenases by NSAIDs may have profound adverse renal effects. Thus, the risk of adverse renal effects is increased by any condition that results in low circulating blood volume or increased renin production, e.g., plasma volume contraction, congestive cardiac failure, cirrhosis and ascites, diabetes mellitus, and old age (22). During anesthesia and surgery, renal blood flow may be reduced by approximately 30% in humans (25). In this study, we replicated the conditions of anesthesia and surgery in the rat to assess the renal effects of diclofenac and gentamicin in the perioperative setting.

As in our previous study, which examined the renal effects of ketorolac (15), we used Fischer 344 rats because, for some nephrotoxins, their susceptibility parallels that of humans (19,20). The dose of gentamicin chosen for our study was known to be borderline nephrotoxic in this model (19,20), and this was confirmed by the decreased ClPAH found in the G group.

With the exception of a small decrease in ClIOT, other markers of renal function were not significantly altered in the D group, suggesting that diclofenac treatment alone did not result in significant renal dysfunction. This is consistent with previous studies (15,17). A study of the renal effects of human perioperative diclofenac treatment showed changes consistent with renal prostaglandin inhibition on the first postoperative day but there were no lasting adverse effects (26).

In a study of diclofenac and ibuprofen treatment on gentamicin-induced nephrotoxicity in rats, Farag et al. (17) found that simultaneous treatment with diclofenac and gentamicin for five days resulted in changes in renal function that were not significantly different from those caused by gentamicin alone. Rats treated with the combination for 27 days, however, had significantly greater renal dysfunction than those treated with gentamicin alone. They proposed that in contrast to acute NSAID treatment, chronic treatment results in inhibition of renal prostaglandin synthesis, which, in the setting of gentamicin-induced nephrotoxicity, results in a significant decrease in RPF, ultimately contributing to potentiation of nephrotoxicity. In our study, the markers indicating renal dysfunction were consistently greatest in the DG group; the largest decrease in Clurea, urine K+ and osmolality, the production of large volumes of dilute urine, and the greatest increase in serum urea and creatinine were found after three days of treatment. The dose of diclofenac used in our study, based on antinociceptive doses in rats, was larger than that by Farag et al. (17), which was extrapolated from human therapeutic doses. This may partly account for the increased nephrotoxicity during the three-day treatment period in the DG group in our study. The decreased ClPAH in the G group was not distinguishable from that in the DG group, suggesting that the coadministration of diclofenac and gentamicin does not lead to a further decrease in RPF compared with that caused by gentamicin alone. Thus, decreased RPF as a result of NSAID-induced renal prostaglandin inhibition may not fully explain the nephrotoxicity associated with combined diclofenac and gentamicin treatment (26,27).

The results of this study are consistent with our previous study, which examined the effects of ketorolac and gentamicin in a rat perioperative model (15). The combination of ketorolac and gentamicin was associated with the most marked changes in renal function with a similar pattern of decreased urine osmolality, production of large volumes of urine, decreased RPF, increased serum K+, urea and creatinine, and histologic changes consistent with acute tubular necrosis. In a human postoperative study (28), diclofenac produced decreased renal excretion of K+, whereas in this study, urinary K+ was not significantly decreased in the D group. The only significant decrease in K+ excretion was in the DG group, suggesting that the combination of diclofenac and gentamicin may lead to decreased urinary K+ excretion and a tendency to hyperkalemia.

In conclusion, in this perioperative rat model, with drug administration for three days, diclofenac alone did not result in significant renal dysfunction, but the combination of gentamicin and diclofenac was deleterious to renal function. In consideration of our previous finding that ketorolac with gentamicin is deleterious to renal function in the same model, the evidence suggests that aminoglycosides may be a significant risk factor for inducing perioperative renal failure during treatment with NSAIDs.


   Acknowledgments
 
This work was supported by grants from Roche-Syntex Pty. Ltd. (Australia) and from the University of Sydney.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 28, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press