Department of Medical and Surgical Sciences, Division of Nephrology, University Hospital, Padua, Italy
Keywords: COX-2; Coxib; COX-LOX; non-steroidal anti-inflammatory drugs
Introduction
A major expectation of cyclo-oxygenase-2 (COX-2) inhibitor therapy has been the (Coxib) reduction of untoward renal effects of non-steroidal anti-inflammatory drugs (NSAIDs). The idea that COX-isoform functions are mutually exclusive, with COX-1 involved in maintenance of normal renal physiology and COX-2 not normally expressed but rapidly induced in response to inflammation, inspired hopes of exciting new therapeutic possibilities. However, recent reports of acute renal failure [1] and interstitial nephritis [2] in patients taking celecoxib or rofecoxib has dampened enthusiasm for these inhibitors. Evolving knowledge of the activities of COX-1 and COX-2 has indicated that the original paradigm was an over-simplification. While it is true that COX-2 is induced at inflammation sites and plays a major role in prostanoid synthesis, COX-1 may also contribute to these mechanisms [3]. However, and more important, a critical role for COX-2 in renal function has recently come to light [4,5]. Indeed, in the kidney it plays an important role in the regulation of perfusion, water handling, and renin release in both normal and paraphysiological conditions [6,7]. Therefore, it is questionable whether Coxibs are benign for the kidney. As a matter of fact, celecoxib and rofecoxib interfere with fundamental renal processes including prostanoid synthesis [8]. Furthermore, their most frequent adverse renal effects are oedema, hypertension, and exacerbation of pre-existing hypertension, which represent a profile similar to that of conventional NSAIDs.
COX-2 in renal pathology
Abnormalities in renal prostanoids contribute to tissue injury dynamics and modulate the severity of inflammation and COX-2-derived prostanoids seem to play a crucial role in these mechanisms. Renal TxA2 production is increased and correlates with proteinuria, renal function, and renal histology in murine and human lupus nephritis, in immune-mediated mesangial cell injury and subtotal nephrectomy models in the rat, in human diabetic nephropathy, and in experimental and human cyclosporin nephrotoxicity. Furthermore, blockade of TxA2 improves proteinuria, glomerular filtration, and renal pathology [9]. Recent findings show or suggest that elevated renal synthesis of TxA2 or PGE2 is due to up-regulation of COX-2 in most conditions [1014]. Selective blockade of COX-2 improves the renal effects of kidney ablation [13], suggesting that COX-2 might be a target for therapeutic intervention. This may be especially useful in conditions such as lupus nephritis in which side effects of routine immunosuppression are a significant cause of morbidity and mortality. Indeed, Zoja et al. [14] recently demonstrated that treatment with a COX-2 inhibitor partially delayed proteinuria in murine lupus nephritis.
Leukotrienes in renal disease
Inflammation pathways are activated and coordinated by COX-derived prostanoids and by 5-lipoxygenase (LOX)-derived prostanoids, the leukotrienes (LT). In essentially all of the models and human diseases discussed previously, LTs play a pathogenic role. In the kidney, LTs are synthesized by infiltrating leukocytes or macrophages, and have biological actions that may be relevant to the pathogenesis of various nephropathies [15]. Peptidoleukotrienes (LTC4 and LTD4) cause renal vasoconstriction, mesangial cell contraction, and proliferation, as well as production of extracellular matrix proteins. LTB4 stimulates chemotaxis, leukocyte adhesion to endothelial cells, and modulates interleukin-1 production. LTs have been shown to decrease glomerular filtration rate (GFR) and contribute to damage in the anti-Thy-1 model of glomerulonephritis [16]. LTB4 plays a central role in post-ischaemic renal injury [17]. In murine lupus nephritis, LT production is significantly increased and is proportional to functional and histopathological derangements. In addition, LT receptor inhibition significantly improves renal haemodynamics [18]. In rat models of glomerulonephritis [19,20], increased renal levels of LTB4 have been found. Furthermore, specific LTD4 receptor antagonism prevented the deterioration of glomerular haemodynamics in a nephritis model [21]. In passive Heymann nephritis, LTD4 was shown to be a mediator of proteinuria and glomerular haemodynamic abnormalities [22], and its inhibition markedly improved both parameters. Peptidoleukotrienes play a role in the pathogenesis of experimental cyclosporin nephrotoxicity and blockade of their receptors prevents disease progression [23].
A role for LTs in mediating renal diseases in humans is supported by the discovery of LOX expression in biopsies from patients with glomerulonephritis [24], and by reductions in proteinuria and restoration of glomerular size permselectivity by inhibiting LT biosynthesis in patients with immune-mediated glomerulonephritis [25].
In summary, both COX- and LOX-derived prostanoids participate in the pathogenesis of renal disease and may also modulate renal function in certain renal disorders (Figure 1).
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Putative risks of selective inhibition of prostanoid synthetic pathways
Although speculative, recent observations following the introduction of Coxibs have raised concerns that the selective inhibition of prostanoid synthetic pathways may be dangerous. The following examples illustrate this concept.
COX activity and thrombosis (COX-1 and -2 inhibition vs COX-2 inhibition)
The delicate balance between platelet-induced TxA2 and endothelial-derived PGI2 (prostacyclin) maintains normal blood flow and modulates thrombogenic responses to injury. COX-2 seems to play a pivotal role in the production of endothelial prostacyclin [26]. Conversely, platelets produce TxA2 via the action of COX-1, which is the only COX isoform present therein [27]. A balancing of prothrombotic and antithrombotic effects can be proposed during NSAID administration as they inhibit both COX-1 and COX-2. Although this has not yet been explored, a potential imbalance induced by Coxibs (inhibiting endothelial PGI2 synthesis but not platelet TxA2 synthesis) may lead to increased risk of thrombosis. Because recent metanalysis indicated a potential increase in cardiovascular events with Coxibs, the authors urged caution in their use in patients at cardiovascular risk [28].
Aspirin-intolerant asthma and inflammatory renal disease induced by NSAIDs (COX inhibition and LT-related disorders)
A central role for COX inhibition in the sequence of events leading to aspirin-intolerant asthma is well established, and there is strong evidence suggesting that increased production of LTs is critical for this condition [29]. Although a shunt hypothesis, proposing a shunt of arachidonic acid from COX to LOX when the COX pathway is inhibited, has not yet received experimental support, the data from aspirin-intolerant asthma suggest an interplay between the two pathways. In certain individuals, this interrelationship may be critical and lead to asthma, to the rare interstitial nephritis [30], or to the more frequent NSAID-induced acute renal failure (Figure 1).
The data suggest that a balanced equilibrium exists between COX and LOX metabolites in inflammation, and that these molecules should be considered as a unique functional network. In most previous experimental models, administration of either TxA2, COX, or LOX inhibitors were only partially protective. However, co-administration of peptidoleukotriene antagonists with a TxA2 antagonist completely abrogated the renal derangement [31].
COX-LOX dual inhibition
Which strategies will safely interfere with these mediators and spare the kidney from adverse effects? The very selective inhibition of specific mediators may offer an interesting avenue. For instance, the modulation of distal effectors via TxA2 blockade or prostacyclin analogue has a favourable impact on functional derangement and slows the progression of renal disease in experimental models [9,32].
An attractive strategy for reducing renal risk associated with anti-inflammatory drug use could be the simultaneous inhibition of the COX and 5-LOX pathways, which may provide a less disruptive means of interfering with prostanoid-dependent inflammatory mechanisms with respect to COX-selective inhibition. In this way, the risk to the kidneys, especially when affected by inflammatory-immunological pathologies, may be reduced or abolished during the use of NSAIDS and related drugs. Whether the dual inhibition strategy also offers new opportunities to treat immuno-mediated or inflammatory renal diseases awaits investigation.
Several distinct agents that inhibit both LOX and COX have been synthesized. Some (tebufelone and tepoxalin) were discontinued because of liver toxicity due to their broad inhibition of redox enzymes. Others, including licofelone and darbufelone, are in different phases of clinical development [33,34]. Licofelone (previously named ML-3000 [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid) is in an advanced phase of development (a large phase III study has just been concluded). It is a pyrrolizine compound which was designed to overcome the broad inhibition of redox enzymes responsible for liver toxicity by mimicking arachidonic acid [34]. It has a dual and well balanced inhibitory action on COX and 5-LOX, and demonstrates anti-inflammatory, analgesic, antipyretic, anti-asthmatic, and antiplatelet aggregation activities. In addition, it shows excellent gastrointestinal tolerance and low liver and renal toxicity in both animal models and phase II clinical trials [35,36].
Unfortunately, neither experimental investigations of renal effects nor clinical studies with these agents have been published so far. Nevertheless, even though renal toxicity profiles need to be fully defined, the premises of these drugs are appealing.
Conclusion
The complexity and fundamental role of the prostanoid network in the kidney make it extremely difficult to safely interfere with this system. Risks range from: (i) modest but significant variations in blood pressure that may affect cardiovascular mortality in the long-term, to (ii) short-term but life-threatening conditions such as acute renal failure, and many other potentially serious side effects and disorders. Considering the physiological role of COX-2 in the kidney and the few but serious reports of side effects, Coxibs may not be as safe for the kidneys as initially hoped. Until specific clinical trials and analyses of adverse event reports on sufficiently large numbers of patients clarify the renal risk profile of these new agents, nephrologists should consider Coxibs equivalent to NSAIDs. More work is warranted to refine and test different strategies.
Acknowledgments
I wish to thank Professor Francesco Pugliese, Chair of Nephrology, University of Rome La Sapienza for his invaluable help in critically reading this paper.
Notes
Correspondence and offprint requests to: Dipartimento di Scienze Mediche e Chirurgiche, Divisione di Nefrologia, Policlinico Universitario, Università di Padova, Via Giustiniani 2, I-35128 Padova, Italy. Email: giga{at}unipd.it
References
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