Andrew Whelton

Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications

Although the prevalence of nephrotoxicity in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) is relatively low, the extensive use profile of these agents implies that many persons are at risk. At basal states of normal renal function, the role of renal prostaglandin production for maintenance of stable renal hemodynamic function is relatively limited. Nonetheless, in the clinical setting of reduced renal perfusion as seen in various forms of cardio-renal disease, dehydration, and the aging kidney, the adequacy of renal prostaglandin production mediated predominantly by cyclooxygenase-1 (COX-1) and, potentially, by COX-2 enzyme activity becomes of major significance in the activation of compensatory renal hemodynamics. Inhibition of renal prostaglandin production by the use of NSAIDs in these circumstances can potentially lead to the emergence of several distinct syndromes of disturbed renal function. These include fluid and electrolyte disorders, acute renal dysfunction, nephrotic syndrome/ interstitial nephritis, and renal papillary necrosis. In addition, by blunting the homeostatic renal effects of prostaglandins, NSAIDs can adversely influence blood pressure control, particularly during the use of angiotensin-converting enzyme (ACE) inhibitors, diuretics, and beta blockers. This is a matter of considerable public health concern, in that some 12 million US citizens are concurrently treated with NSAIDs and antihypertensive drugs. Finally, the risk of congestive heart failure is significantly increased when NSAIDs are given to patients receiving diuretic therapy who have cardiovascular risk factors. Physiologic factors, clinical presentations, diagnostic modalities, and clinical management strategies appropriate to these NSAID-induced renal syndromes are described.

Effects of celecoxib and rofecoxib on blood pressure and edema in patients ≥65 years of age with systemic hypertension and osteoarthritis

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase-2 (COX-2) specific inhibitors, with antihypertensive medication is common practice for many patients with arthritis. This study evaluated the effects of celecoxib 200 mg/day and rofecoxib 25 mg/day on blood pressure (BP) and edema in a 6-week, randomized, parallel-group, double-blind study in patients > or =65 years of age with osteoarthritis who were treated with fixed antihypertensive regimens. One thousand ninety-two patients received study medication (celecoxib, n = 549; rofecoxib, n = 543). Significantly more patients in the rofecoxib group compared with the celecoxib group developed increased systolic BP (change >20 mm Hg plus absolute value > or =140 mm Hg) at any time point (14.9% vs 6.9%, p <0.01). Rofecoxib caused the greatest increase in systolic BP in patients receiving angiotensin-converting enzyme inhibitors or beta blockers, whereas those on calcium channel antagonists or diuretic monotherapy receiving either celecoxib or rofecoxib showed no significant increases in BP. Clinically significant new-onset or worsening edema associated with weight gain developed in a greater percentage of patients in the rofecoxib group (7.7%) compared with the celecoxib group (4.7%) (p <0.05). Thus, in patients with controlled hypertension on a fixed antihypertensive regimen, careful monitoring of BP is warranted after the initiation of celecoxib or rofecoxib therapy.

Nonsteroidal anti-inflammatory drugs: Effects on kidney function

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are capable of inducing a variety of renal function abnormalities, particularly in high‐risk patients with decreased renal blood perfusion who depend on prostaglandin synthesis to maintain normal renal function. Fluid retention is the most common NSAID‐related renal complication, occurring to some degree in virtually all exposed individuals; however, clinically detectable edema occurs in less than 5% of patients and is readily reversible on discontinuation of the NSAID. Other electrolyte complications, notably hyperkalemia, are seen infrequently and occur in specific at‐risk patients. The next most worrisome complication is acute deterioration of renal function, which occurs in high‐risk patients and is also reversible. Nephrotic syndrome with interstitial nephritis is a rare problem of NSAID use and is reversible. Papillary necrosis is the only permanent complication of NSAIDs and is very rare. Altogether, these renal function abnormalities, with the exception of mild fluid retention, are clinically detectable in approximately 1% of exposed patients. Given the number of patients who take NSAIDs on a prescription or over‐the‐counter basis, the absolute number of at‐risk patients is relatively large. Consequently, an appreciation for the risk factors and pathophysiology of NSAID‐induced renal function abnormalities is required for optimal use of these drugs.

A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database

BACKGROUNDnTwo isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2-specific inhibitors inhibit only the COX-2 isoform.nnnOBJECTIVEnThis study sought to compare renal safety signals between the COX-2-specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000.nnnMETHODSnDisproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality.nnnRESULTSnAs with traditional NSAIDs, both COX-2-specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P < 0.01); abnormal renal function (2.38 vs 0.70; P < 0.01); renal failure (2.22 vs 1.09; P < 0.01); cardiac failure (2.39 vs 0.48; P < 0.01); and hypertension (2.15 vs 1.33; P < 0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen.nnnCONCLUSIONSnBased on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors.

In the clinical setting of reduced renal perfusion, as seen in patients with renal, cardiac, or liver disease, dehydration, or aging kidneys, renal prostaglandin production (mediated primarily by cyclooxygenase [COX]-1 and possibly by COX-2) plays a major role in compensatory renal hemodynamics. Inhibition of the synthesis of renal prostaglandins by conventional nonsteroidal anti-inflammatory drugs (NSAIDs) may result in several nephrotoxic syndromes, including fluid and electrolyte abnormalities, acute renal failure, nephrotic syndrome, and renal papillary necrosis. Moreover, NSAIDs may adversely influence blood pressure control in treated hypertensive individuals and also may decompensate the clinical stability of diuretic-treated patients with chronic heart failure. The recently approved COX-2–specific inhibitors celecoxib and rofecoxib offer the potential for sparing homeostatic COX-1 activity in the kidney while inhibiting COX-2–mediated pain and inflammation. Emerging clinical data are helping to quantify the renal and related cardiovascular risks associated with the use of COX-2–specific versus conventional NSAIDs. Although the risk of serious toxicity associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) is relatively low, nonetheless, up to approximately 5% of individuals exposed to NSAIDs may develop one or more forms of diverse “nephrotoxic” renal side effect syndromes. The number of at-risk individuals is high as a consequence of the fast consumption of these compounds either used at prescription strength or at over-the-counter dosing regimens. Hence, 500,000 to 2,500,000 individuals in the United States are estimated, on an annual basis, to potentially manifest an NSAID-related renal side-effect syndrome. The relevance of these clinical problems is particularly important in those NSAID users who become particularly “at risk” for nephrotoxic effects as a result of the clinical presence of volume-contracted states, low cardiac output, or other conditions that tend to compromise renal perfusion. The various NSAID-related renal syndromes that may become clinically apparent, after as little drug use as a single ingestion through to several weeks or months of drug consumption, will vary from the commonly encountered problems of edema formation through to the development of acute renal failure and the rare complication of acute papillary necrosis. –10 On the other hand, there are frequently encountered clinical NSAID-induced side effects that represent drug– drug– disease interactions and are manifest in treated hypertensive patients as an increase in blood pressure or seen in otherwise stable diuretic-treated individuals with chronic heart failure as a destabilization of their cardiac function. This review will summarize the known information defining the mechanisms by which these renal syndromes and related cardiovascular NSAID-induced side effects evolve and will characterize the “at-risk” NSAID consumer populations, together with approaches to the prevention and management of these diverse NSAID-related side effects. It will also summarize the currently available clinical information contrasting the development of renal and related cardiovascular NSAID-induced side effects in conventional versus COX-2–specific NSAID exposed individuals. It is clear that in conventional NSAID-treated individuals most of the nephrotoxic and related cardiovascular side effects are mediated as a result of the inhibition of renal prostaglandin synthesis.

Therapeutic Initiatives for the Avoidance of Aminoglycoside Toxicity

Aminoglycosides continue to be indispensable in the management of serious and life‐threatening aerobic gram‐negative infections. On an annual basis in the United States, they are used in the management of four million patients. Despite their clinical utility, they continue to manifest a high profile of toxic side effects such as nephrotoxicity and ototoxicity with the rare occurrence of neuromuscular toxicity. Animal experimental models have been invaluable in elucidating the pathophysiologic mechanisms by which aminoglycosides damage the kidney and the inner ear. However, it is from clinical therapeutic experience and prospective clinical trials that we have been able to solidly define the risk factors that accentuate the development of aminoglycoside‐related toxicity. The clinical toxicity of these agents can be kept to a minimum by ensuring the use of an appropriate dose, for periods of time not exceeding nine to ten days, in a well‐hydrated, normokalemic patient. Special subpopulation groups such as the elderly, the obese, those with preexisting renal disease, or patients who need the concurrent use of other nephrotoxins, require special care in the monitoring of their aminoglycoside therapy to ensure a safe and effective clinical outcome.

Preservation of Renal Function during Gout Treatment with Febuxostat: A Quantitative Study

Abstract Background: Hyperuricemia can accelerate renal decline associated with aging. Chronic kidney disease is frequently seen in patients with hyperuricemia and gout. Objectives: Assess the impact of urate–lowering therapy on renal function in subjects with gout who were treated with febuxostat for ≤ 48 months. Methods: Subjects from 2 phase 3 clinical studies were enrolled in the phase 3, long–term, open–label Febuxostat/Allopurinol Comparative Extension Long–Term (EXCEL) study. In the EXCEL study, 1086 subjects initially were treated with febuxostat 80 or 120 mg daily, or allopurinol 300 mg daily. The subjects were permitted to switch between doses of febuxostat and/or allopurinol during the first 6 months of treatment to achieve and maintain a serum uric acid (SUA) level ≥ 3 to < 6 mg/dL. For the analysis presented in this article, data from 551 subjects who received only febuxostat throughout the duration of both the phase 3 and EXCEL studies (≤ 48 months) were used to determine the impact of SUA reduction on estimated glomerular filtration rates (eGFRs). Results: At baseline of the 2 original phase 3 studies, subjects mean SUA level was 9.8 mg/dL. Greater sustained decreases in subjects SUA levels were associated with less renal function decline (P < 0.001)by statistical modeling. The study data predicted that for every 1 mg/dL of chronic reduction of SUA level in subjects with gout, there would be a preservation of 1.15 mL/min of eGFR. Conclusion: Sustained urate–lowering therapy with febuxostat appears to impede renal decline in patients with gout. The results discussed in this article support similar observations previously reported in 116 hyperuricemic subjects with gout who received febuxostat for ≤ 5 years.

Sulindac Kinetics and Effects on Renal Function and Prostaglandin Excretion in Renal Insufficiency

The purpose of this study was to evaluate the pharmacokinetics of sulindac, a purported “renal sparing” nonsteroidal anti‐inflammatory drug, and its effects on renal function and prostaglandin excretion in patients with reduced glomerular filtration rate.

Cholestyramine‐Induced Hyperchloremic Metabolic Acidosis

Cholestyramine is a nonabsorbable anion exchange resin that is used predominantly for the treatment of hypercholesterolemia in adults and the management of acute diarrhea in children. The authors report two cases of severe hyperchloremic nonanion gap metabolic acidosis associated with the use of cholestyramine therapy. The authors recommend that patients taking cholestyramine who have concomitant renal insufficiency or who are volume depleted or who are taking spironolactone be monitored carefully for the emergence of a hyperchloremic metabolic acidosis.

Rationale and design of the PREVENT-HIT study: A randomized, open-label pilot study to compare desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis

BACKGROUNDnDesirudin, a bivalent direct thrombin inhibitor (DTI), is approved by the US Food and Drug Administration for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing elective hip replacement surgery. It became available in the United States in March 2010.nnnOBJECTIVEnThe goal of the present article was to provide an overview of the rationale and design of the PREVENT-HIT study, a randomized, prospective, open-label, active drug-controlled, exploratory trial comparing the clinical and economic utility of desirudin versus argatroban in patients with suspected heparin-induced thrombocytopenia (HIT), with or without thrombosis.nnnSUMMARYnThe PREVENT-HIT study was designed to enroll approximately 120 patients from 20 to 25 US centers. All eligible patients were required to be aged >or=18 years. Patients with suspected HIT with or without thrombosis were divided into 2 treatment arms and randomized to receive treatment with desirudin or argatroban in a 1:1 ratio using a block randomization method. Arm A comprised patients who were naive to DTI therapy; arm B included patients whose condition was previously stabilized with intravenous argatroban. Desirudin was administered as a fixed-dose injection (15 or 30 mg SC q12h in patients without or with thrombosis, respectively). Argatroban was administered by continuous intravenous infusion in accordance with approved prescribing information or institutional prescribing guidelines at each study site. The primary efficacy outcome measure included the occurrence of any of the following up to 30 days after study drug discontinuation: new-onset or worsening thrombosis requiring discontinuation of study drug; amputation; or all-cause mortality. Other outcomes that were assessed included platelet recovery, bleeding, and pharmacoeconomic parameters. In addition, adverse events and other safety parameters were evaluated. Study enrollment began in November 2008 and ended in December 2009 due to slow enrollment (N = 16). The study results will be published separately.nnnCONCLUSIONnThe results from the PREVENT-HIT study should enhance understanding of the comparative clinical and economic utility of desirudin and argatroban in patients with HIT with or without thrombosis. ClinicalTrials.gov identifier: NCT00787332.