Nonsteroidal antiinflammatory drugs, cyclooxygenase-2, and the kidneys.

Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most commonly used classes of medications in the world, which function by inhibiting the cyclooxygenase (COX) enzymes and downregulating the inflammatory pathway. COX enzymes are constitutively expressed in the kidneys and function to maintain a homeostatic environment in terms of maintaining the glomerular filtration rate, blood pressure, sodium, water, and osmotic regulation. When the COX enzymes are inhibited by NSAIDs, a multitude of renal and vascular complications occur. This article aims to enlighten primary care physicians of the complications that arise with NSAIDs from a renal perspective and to present some management strategies.

Effects of 2-bromoethanamine on TonEBP expression and its possible role in induction of renal papillary necrosis in mice.

Chronic analgesic abuse has been shown to induce severe renal injury characterized by renal papillary necrosis (RPN), an injury detectable at late stage. While direct toxicity of the drug may exist, the molecular mechanisms underlying analgesics induction of RPN remain unknown. A major limitation to study the pathogenesis of RPN is the required chronic exposure before detection of injury. Here, we employed 2-bromoethanamine (BEA) to simulate rapid papillary toxicity using inner medullary collecting duct (IMCD3) cells. Although exposure to 10µM BEA had no effect on cellular viability under isotonic conditions, a 50% loss in cell viability was observed in the first 24 h when cells were subjected to sublethal hypertonic stress and nearly complete cell death after 48 h suggesting that BEA exerts cytotoxicity only under hypertonic conditions. Because TonEBP is a transcription factor critical for cell survival during hypertonic conditions, we undertook experiments to examine the effect of BEA on TonEBP expression and activity. Exposure of cells to 10µM BEA resulted in a substantial reduction in TonEBP protein expression after 24 h. In addition, TonEBP was not translocated to the nucleus in BEA-treated IMCD3 cells under acute hypertonic stress for transcription of target genes essential for osmolyte accumulation. Finally, we found a substantial decrease in TonEBP expression in medullary kidney tissues of mice injected with a single ip dose of BEA. Our data suggest that TonEBP is a potential target for BEA leading to the process of papillary necrosis in the settings of hypertonic stress.

Application of Dolichos biflorus in immunoassay detection of kidney collecting duct biomarkers.

Currently there are no biomarkers for detecting collecting duct damage in man. Antibodies to several collecting duct-specific antigens exist but sandwich assays have been difficult to establish due to the need for two different antibodies to the same protein. We hypothesized that a collecting duct-specific lectin could be used in combination with a collecting duct-specific antibody to negate the need for two different antibodies. The collecting duct specificity of selected antibodies (NiCa II 13C2, Pap XI 3C7, HuPaP VII 2B11 and aquaporin 2), was verified by immunohistochemistry. Aquaporin 2 and Pap XI 3C7 were used successfully in setting up assays with the lectin Dolichos biflorus, using the Meso Scale Discovery (MSD) platform. Antigen expression was highest in the papillae of rat and human kidney (corresponding to the greatest density of collecting ducts) and was also present in normal urine. We propose that further qualification and validation would lead to an assay for detecting collecting duct damage in man.

Characterization of renal papillary antigen 1 (RPA-1), a biomarker of renal papillary necrosis.

Renal papillary necrosis (RPN) is a relatively common toxicity observed in preclinical drug safety testing. It is also observed in a variety of human diseases. RPN is difficult to diagnose without expensive scanning methods or histopathology. A noninvasive biomarker that could be detected at early stages of kidney damage would be of great value both to preclinical drug safety testing and in the clinic. An antibody raised to an unknown epitope of an antigen in rat kidney papilla was found to be specific for collecting duct cells in the kidney; this was termed renal papillary antigen 1 (RPA-1). In this study, the authors show that RPA-1 is an early biomarker of RPN in two different rat models of toxicity: 2-bromoethanamine (BEA) and N-phenylanthranilic acid (NPAA). RPA-1 can be detected in urine at early stages of toxicity and correlates well with the histopathology observed. We also characterized the biochemical properties of RPA-1 and found that the antigen is a high molecular weight membrane bound glycoprotein, with the epitope likely to be carried on an N-linked carbohydrate structure. This study demonstrates that RPA-1 is an excellent marker of RPN that can be used to detect this toxicity in preclinical safety testing.

Bilateral ureteral obstruction from papillary necrosis secondary to household cleaner ingestion.

We report a case of a patient who developed bilateral hydroureteronephrosis from papillary necrosis secondary to ingestion of commercial toilet bowl cleaner. Eight days after her ingestion, acute renal failure prompted a renal ultrasound that showed bilateral hydroureteronephrosis. Emergent bilateral percutaneous nephrostomy tubes were placed and subsequent ureteroscopy revealed a large amount of obstructing necrotic material consistent with papillary necrosis. Ureteroscopic removal of the material and bilateral ureteral stents improved renal function. The etiology of this patient's papillary necrosis was likely due to a combination of hypovolemia, systemic acidosis from the ingestion, and direct toxicity of the substance on the renal vasculature. This case demonstrates the importance of early recognition of renal insults and the extra intestinal manifestations of toxic household ingestions.

Over-the-counter analgesic use.

Chronic analgesic nephropathy, particularly chronic interstitial nephritis and renal papillary necrosis, results from daily use for many years of mixtures containing at least two analgesics and caffeine or dependence-inducing drugs. Computed tomography scan can accurately diagnose this disease even in the absence of reliable information on previous analgesic use. The occasion to moderate regular use of aspirin and nonsteroidal anti-inflammatory drugs is without renal risk when renal function is normal. Paracetamol use is less clear although the risk is not great. The continued use of non-phenacetin-combined analgesics with or without nonsteroidal anti-inflammatory drugs is associated with faster progression toward renal impairment. As long as high-risk analgesic mixtures are available over the counter, analgesic nephropathy will continue to be a problem.

Indinavir-associated toxicity mimicking urinary tuberculosis in a patient with AIDS.

This case reported to a patient with AIDS who presented persistent sterile leukocyturia and hematuria, lower back pain, bladder suffering symptoms, and renal papillary necrosis which were thought to be secondary to urinary tuberculosis but were demonstrated to be indinavir-associated side effects. The intention of this report is to remind medical professionals involved in the care of HIV+ patients of this possible association in order to avoid unnecessary investigation and to stress the need of careful periodical assessment of renal function and urinalysis in patients treated with indinavir.

Indinavir-associated toxicity mimicking urinary tuberculosis in a patient with AIDS

This case reported to a patient with AIDS who presented persistent sterile leukocyturia and hematuria, lower back pain, bladder suffering symptoms, and renal papillary necrosis which were thought to be secondary to urinary tuberculosis but were demonstrated to be indinavir-associated side effects. The intention of this report is to remind medical professionals involved in the care of HIV+ patients of this possible association in order to avoid unnecessary investigation and to stress the need of careful periodical assessment of renal function and urinalysis in patients treated with indinavir.

[Bilateral papillary necrosis during indinavir treatment]. / Nécrose papillaire bilatérale lors d'un traitement par indinavir.

INTRODUCTION: Papillary necrosis results from ischemia of the renal medulla and papillae, induced by a variety of mechanisms. Papillary necrosis is a rare adverse effect of continuous protease-inhibitor therapy with indinavir. CASE: We describe the case of a patient who developed bilateral papillary necrosis. It was reversible after treatment interruption and increased hydration. CONCLUSION: This case shows the need to monitor kidney markers in patients under continuous treatment with indinavir.

Early pathophysiological features in canine renal papillary necrosis induced by nefiracetam.

To ascertain the early pathophysiological features in canine renal papillary necrosis (RPN) caused by the neurotransmission enhancer nefiracetam, male beagle dogs were orally administered nefiracetam at 300 mg/kg/day for 4 to 7 weeks in comparison with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), at 50 mg/kg/day for 5 weeks. During the dosing period, the animals were periodically subjected to laboratory tests, light-microscopic, immunohistochemical, and electron-microscopic examinations and/or cyclooxygenase (COX)-2 mRNA analysis. In laboratory tests, a decrease in urinary osmotic pressure and increases in urine volume and urinary lactate dehydrogenase (LDH) level were early biomarkers for detecting RPN. Light-microscopically, nefiracetam revealed epithelial swelling and degeneration in the papillary ducts in week 7, while ibuprofen displayed degeneration and necrosis in the papillary interstitium in week 5. In immunohistochemical staining with COX-2 antibody, nefiracetam elicited a positive reaction within interstitial cells around the affected epithelial cells in the papillary ducts (upper papilla) in week 7, and ibuprofen positively reacted within interstitial cells adjacent to the degenerative and/or necrotic lesions in week 5. Ultrastructurally, nefiracetam exhibited reductions of intracellular interdigitation and infoldings of epithelial cells in the papillary ducts, whereas ibuprofen showed no changes in the identical portions. Thus, the early morphological change in the papilla brought about by nefiracetam was quite different from that elicited by ibuprofen. By the renal papillary COX-2 mRNA expression analysis, nefiracetam exceedingly decreased its expression in week 4, but markedly increased it in week 7, suggesting an induction of COX-2 mRNA by renal papillary lesions. These results demonstrate that the epithelial cell in the papillary ducts is the primary target site for the onset of RPN evoked by nefiracetam.

Investigation on urinary proteins and renal mRNA expression in canine renal papillary necrosis induced by nefiracetam.

The occurrence of renal papillary necrosis (RPN), seen only in dogs after repeated oral administration of nefiracetam, a neurotransmission enhancer, at a relatively high dose, is because of inhibition of renal prostaglandin synthesis by the nefiracetam metabolite M-18. In this study, analyses of urinary proteins and renal mRNA expression were performed to investigate the possible existence of a specific protein expressing the characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins from male dogs given nefiracetam at 300 mg kg(-1) day(-1) over weeks 5-11, a protein of approximately 40 kDa, which was not seen in control urine, and protein of approximately 30 kDa emerged as distinct bands. Subsequently, clusterin precursor was identified in the former band and tissue kallikrein precursor in the latter by LC-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS). By quantitative real-time RT-PCR analysis with renal morphological aspects, individual findings showed that renal clusterin mRNA was increased in dogs with severe renal injury, and renal tissue kallikrein also increased, presumably related to hemodynamics. These results demonstrate that changes in renal clusterin mRNA may reflect the progression or severity of RPN, whereas upregulation of tissue kallikrein mRNA may subsequently play a compensating role in the prevention of RPN.

Comprehensive evaluation of canine renal papillary necrosis induced by nefiracetam, a neurotransmission enhancer.

The effects of nefiracetam, a neurotransmission enhancer, on renal biochemistry and morphology with toxicokinetic disposition were investigated in both in vivo and in vitro systems. In the in vivo studies with rats, dogs, and monkeys, only the dog exhibited renal papillary necrosis. Namely, when beagle dogs were orally administered with 300 mg/kg/day of nefiracetam over 11 weeks, decreased urinary osmotic pressure was noted from week 5, followed by increases in urine volume and urinary lactate dehydrogenase from week 8. The first morphological change was necrosis of ductal epithelia in the papilla in week 8. In toxicokinetics after 3 weeks of repeated oral administration to dogs, nefiracetam showed somewhat high concentrations in serum and the renal papilla as compared with rats and monkeys. As for metabolites, although metabolite-18 (M-18) concentration in the renal papilla of dogs was between that in rats and monkeys, the concentration ratios of M-18 in the papilla to cortex and papilla to medulla were remarkably high. In the in vitro studies, while nefiracetam itself showed no effects on the synthesis of prostaglandin E2 and 6-keto-prostaglandin F1alpha, a stable metabolite of prostaglandin I2, in canine renal papillary slices, only M-18 among the metabolites clearly decreased both prostaglandin syntheses. The basal prostaglandin synthesis in canine renal papillary slices was extremely low relative to those in rats and monkeys. Taken together, certain factors such as basal prostaglandin synthesis, M-18 penetration into the renal papilla leading to an intrarenal gradient, and inhibitory potential of M-18 on prostaglandin synthesis were considered to be crucial for the occurrence of renal papillary necrosis in dogs.

Celecoxib-related renal papillary necrosis.

Selective cyclooxygenase 2 (COX-2) inhibitors are known to affect renal prostaglandins (epoprostenol and dinoprostone), which are at least in part COX-2 dependent. Consequently, adverse events including hypertension, peripheral edema, hypercalemia, hyponatremia, and acute renal failure have been reported to occur with the new COX-2-specific inhibitors. This case report posits celecoxib as a likely cause of renal papillary necrosis and alerts physicians to the possibility of this additional renal complication with COX-2-specific inhibitors.

1H-Nuclear magnetic resonance pattern recognition studies with N-phenylanthranilic acid in the rat: time- and dose-related metabolic effects.

N-Phenylanthranilic acid (NPAA) causes renal papillary necrosis (RPN) in the rat following repeated oral dosing. Non-invasive early detection of RPN is difficult, but a number of potential biomarkers have been investigated, including phospholipid and uronic acid excretion. This study used 1H-nuclear magnetic resonance (NMR) spectroscopic analysis of urine to investigate urinary metabolic perturbations occurring in the rat following exposure to NPAA. Male Alderley Park rats received NPAA (300, 500 or 700 mg kg(-1) day(-1) orally) for 7 days, and urine was collected on days 7-8, 14-15, 21-22 and 28-29. In a separate study, urine was collected on days 1-2, 3-4, 5-6 and 7-8 from rats receiving 500 mg kg(-1) day(-1). Samples were analysed by 1H NMR spectroscopy combined with multivariate data analysis and clinical chemistry. Histopathology and clinical chemistry analysis of terminal blood samples was carried out following termination on days 4, 6, 8 and 29 (4 week time course) and days 2, 4, 6 and 8 (8 day study). Urine analysis revealed a marked, though variable, excretion of beta-hydroxybutyrate, acetoacetate and acetone (ketone bodies) seen on days 3-4, 5-6 and 7-8 of the study. It is postulated that the ketonuria might be secondary to an alteration in fatty acid metabolism due to inhibition of prostaglandin synthesis. In addition, an elevation in urinary ascorbate was observed during the first 8 days of the study. Ascorbate is considered to be a biomarker of hepatic response, probably reflecting an increased hepatic activity due to glucuronidation of NPAA.

Papillary necrosis associated with the HIV protease inhibitor indinavir.

The HIV protease inhibitor indinavir may cause nephrolithiasis and interstitial nephritis. The renal consequences of indinavir-associated nephrotoxicity are uncertain. We report a case of papillary necrosis in a patient treated with indinavir. An asymptomatic HIV-infected woman experienced right-sided renal colicky pain during treatment with indinavir. She passed a non-solid stone and continued indinavir treatment. Intravenous pyelogram performed 20 months later following an episode of left-sided colicky pain showed right-sided papillary necrosis. Indinavir-associated nephrolithiasis and chronic interstitial nephritis were the only possible causes identified in this patient. Physicians should be aware that indinavir nephrolithiasis may cause papillary necrosis.

Increased urinary uronic acid excretion in experimentally-induced renal papillary necrosis in rats.

We have evaluated the potential of urinary uronic acid measurement as an early indicator in the development of renal papillary necrosis (RPN). Urinary uronic acid was quantified with a range of other urinary biochemical parameters in rats given multiple doses of N-phenylanthranilic acid (NPAA) or mefenamic acid (MFA), each of which induces a dose-related papillary necrosis. In addition, histological examination was also carried out to confirm the development and presence of RPN. NPAA was administered to male wistar rats at p.o. doses of 100, 250, and 500 mg/kg and MFA at p.o. doses of 75, 150, and 300 mg/kg on days 1-4 and 8-11, and urine samples were collected for 16 hours each day. NPAA increased uronic acid excretion two-fold for both medium and high doses from day four. MFA increased uronic acid excretion to two and a half-fold by day 10 in the highest dose administered. Urinary creatinine was equally elevated in a dose-related manner following treatment with either NPAA or MFA. None of the other routine markers (urinary or serum) of nephrotoxicity showed any statistical changes. NPAA produced a dose- and time-related increase in excretion of uronic acid. Evidence of widespread papillary necrosis was seen histologically at the high doses of NPAA or MFA. The significant elevation of uronic acid in urine following treatment with either NPAA or MFA was well ahead of the development of RPN detectable by routine histology, suggesting that uronic acid measurement could serve as an early indicator of RPN. The assessment of urinary uronic acid may therefore provide a novel sensitive and selective marker of identifying the lesion earlier than is currently possible. An increase in urinary uronic acid following NPAA and MFA treatment supports the biochemical basis of these changes as a representative of acid mucopolysaccharides accumulation.

Renal and related cardiovascular effects of conventional and COX-2-specific NSAIDs and non-NSAID analgesics.

On a daily basis it appears that as many as one in five adults in the United States may consume an analgesic compound either on a prescription basis or by over-the-counter (OTC) purchase. This high profile of intermittent or repetitive analgesic use appears to be relatively similar throughout the developed world. Although analgesics generally have a good renal safety profile, the nonsteroidal anti-inflammatory drug (NSAID) analgesics may produce mild renal side effects, such as the generation of peripheral edema in up to 5% of the general population. Other more serious renal and related cardiovascular side effects tend to be more apparent in lesser numbers of clinically "at risk" NSAID analgesic users. In contrast, non-NSAID analgesics, such as paracetamol or tramadol, have essentially no renal or related cardiovascular side effects when used at recommended dosing schedules. This review characterizes the renal syndromes associated with the use of NSAID analgesics, identifies the risks inherent in the use of these compounds in treated patients with hypertension and congestive heart failure, summarizes the early comparable data available for the new COX-2-specific inhibitors, and profiles the scant acute and long-term clinical concerns attendant with the use of non-NSAID nonnarcotic analgesics. It is important that healthcare providers and practitioners are aware of the relative renal risks of different analgesics and that they use this knowledge to counsel the analgesic-consuming population appropriately.