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.

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.

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.

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.

Role of renal papillae in the regulation of sodium excretion during acute elevation of renal perfusion pressure in the rat.

We studied the role of renal papillae in the mechanism of increased sodium excretion during acute increase in mean arterial pressure (MAP). Sodium excretion increased dramatically in normal rats after acute increase in MAP by epinephrine (E) infusion (0.4 micrograms/min/100g). Glomerular filtration rate (GFR), renal blood flow (RBF), and papillary plasma flow (PPF) remained unchanged after the E administration. To define the role of the medulla in the mechanism of pressure-induced natriuresis, experiments were performed in a group of rats 8 to 12 days after the development of papillary necrosis induced by bromoethylamine hydrobromide. Urinary sodium and fractional sodium excretions were 2.00 +/- 0.34 microEq/min and 2.37 +/- 0.53% (n = 7), respectively, in papillary necrosis rats infused with saline. Administration of E to papillary necrosis rats, however, failed to increase both urinary sodium (2.89 +/- 0.61 microEq/min) and fractional sodium (FENa, 2.82 +/- 0.63%, n = 6) excretions despite a marked increase in MAP (129 vs 150 mm Hg, p less than 0.01). The RBF increased slightly after E infusion (4.42 vs 3.24 ml/min/100 g, p less than 0.05), but the GFR was not different between the control (0.39 +/- 0.05 ml/min/100g, n = 7) and the E-treated rats (0.43 +/- 0.06, n = 6). Failure to increase sodium excretion during acute increase in MAP was not due to the decreased GFR, since control rats with bilateral partial nephrectomy were able to increase sodium excretion from 1.92 +/- 0.33 to 7.76 +/- 1.63 microEq/min (p less than 0.01) after E infusion. These findings, therefore, suggest that renal papillae play a major role in the mechanism of natriuresis during acute increase in MAP.

Renal effects of prostaglandins and clinical adverse effects of nonsteroidal anti-inflammatory agents.

Non-steroidal anti-inflammatory agents ( NSAIA ) are increasingly used in clinical practice. They exert the majority of their therapeutic and adverse effects by inhibiting prostaglandin synthesis. A variety of clinically important side effects have been described following their administration. We review the renal complications, which include sodium retention, interference with the effectiveness of diuretics, impairment of water excretion, development of hyperkalemia, interference with the therapy of hypertension, and induction of at least four different forms of renal failure. The hemodynamic variety of renal failure and the side effects affecting fluid and electrolyte homeostasis are most likely to become manifest in the context of conditions leading to decreased renal perfusion. Guidelines for use of NSAIA , detection of patients at risk, and therapeutic approaches are provided.

Analgesic dilemma in chronic hemodialysis patients.

Analgesic drug abuse led to end-stage renal disease in 31% of 122 patients in a cross-sectional investigation at our center. Addiction to analgesics and tranquilizers remained a serious problem in these patients even after they were placed on chronic hemodialysis. There is strong evidence that drug addiction leading to end-stage renal disease and chronic hemodialysis correlates with a special type of personality typified by the 60-year-old depressive woman suffering from chronic headache.

Renal effects of antipyretic analgesics.

Most antipyretic analgesics can cause acute nephrotoxic effects, including acute tubular necrosis, acute interstitial nephritis, glomerular toxicity, and functional changes, such as "salicyl edema," following large doses of sodium salicylate. Most functional changes are related to acute suppression of prostaglandin synthesis, "the acute prostaglandin-effect," and have been primarily noted with the use of indomethacin. The association between prolonged and excessive consumption of compound analgesics and the development of renal disease and renal failure, characterized by renal papillary necrosis, is now well established. Studies in several countries have shown that the incidence of analgesic nephropathy as an indication for dialysis and transplantation corresponds to the per capita consumption of phenacetin in compound analgesics. Analgesic nephropathy, which is part of a wider clinical syndrome, the analgesic syndrome, is uncommon following the use of single analgesics. Analgesic nephropathy and the analgesic syndrome are discussed in detail, including the development of uroepithelial tumors.

Evolution of experimentally induced papillary necrosis to focal segmental glomerulosclerosis and nephrotic proteinuria.

Bromoethylamine (BEA)-induced papillary necrosis is a reproducible model for analgesic nephropathy. We induced this lesion in groups of male Sprague-Dawley rats and followed the functional and histological changes for 1 year. We found that by 1 month, necrosis of the papilla was complete, glomerular filtration rate was depressed, and urine albumin excretion was increased. There was an extensive interstitial fibrosis characterized by a mononuclear cell infiltrate and patchy tubular atrophy. By 6 months, there was re-epithelialization of the papillary stump accompanied by a marked increase in albuminuria and an improvement in concentrating ability. Changes seen at 9 months were more advanced. There was extensive cortical fibrosis manifested by pitting of the surface of the kidney. At 1 year, renal function remained impaired (creatinine clearance reduced by 65% to 0.26 mL/min/100 g), and the animals were now markedly nephrotic, with albuminuria of 254 mg of albumin/24 h. In the BEA rats, there was selective destruction of the deep nephrons leading to an increase in the volume-ratio of superficial to deep nephrons. Glomerular changes, affecting approximately 60% of the glomeruli, were characteristic of focal segmental glomerular sclerosis. This model of papillary necrosis/interstitial fibrosis is associated with chronic renal insufficiency and leads to the development of focal glomerular sclerosis and nephrotic proteinuria by 6 to 12 months after its induction.

Experimental renal papillary necrosis in rats: microangiographic and tubular micropuncture injection studies.

Proposed causes of renal papillary necrosis (RPN) include tubular toxicity due to hyperconcentration of toxins in the renal medulla and vasoconstriction of medullary vessels with ischemic necrosis. The authors studied these mechanisms in bromoethylamine hydrobromide-induced RPN in rats by microvascular and tubular micropuncture injection studies. During early stages of RPN, microvascular studies revealed reduced perfusion of vasa recta, and tubular injection studies showed unobstructed tubules and collecting ducts. In the late stage, medullary vascular obliteration and intratubular debris with tubular obstruction were seen. This evidence suggests that RPN in this model is initiated by vasoconstriction rather than direct tubular toxicity.

Analgesic nephropathy: is it caused by multi-analgesic abuse or single substance use?

Analgesic nephropathy is a slowly progressive renal disease, characterised by renal papillary necrosis. Recently, diagnostic criteria for this disease have been defined based on renal computed tomography scanning performed without contrast. The observation of a decreased renal mass of both kidneys, combined with either bumpy contours or papillary calcifications, has been found to have high diagnostic specificity and sensitivity. However, the question remains as to what kind of analgesics can cause analgesic nephropathy. In the majority of early reports about this condition, phenacetin was singled out as the nephrotoxic culprit. However, during the last decade the nephrotoxic potential of nonphenacetin-containing preparations has become apparent. It is clear that people who abuse analgesics prefer combination analgesics containing 2 analgesics combined with caffeine and/or codeine. In contrast, abuse of products containing only aspirin (acetylsalicylic acid) or paracetamol (acetaminophen) is seldom described and associated renal disease is only occasionally reported. Experimental evidence of the nephrotoxicity of analgesic preparations is not well established. The results of studies involving analgesic administration in animals remain contradictory. Clinical evidence linking high consumption of analgesic preparations with analgesic nephropathy is overwhelming. Most patients who admit to over-consuming analgesics have taken preparation containing more than one compound. In recent years, it has become more apparent that preparations not containing phenacetin also have the potential to cause nephrotoxicity manifesting as identical renal lesions. Further epidemiological evidence of the nephrotoxic potential of analgesic combinations has come from case-control studies published during the last decade and from 2 prospective cohort studies. Effective prevention of analgesic nephropathy consists of the prohibition of over-the-counter sales of preparation containing at least 2 analgesics associated with caffeine and/or codeine.

Phenacetin nephritis.

Prolonged ingestion of mixed analgesics containing phenacetin has been associated significantly with the development of a chronic interstitial nephritis frequently associated with papillary necrosis. This disease is frequently underdiagnosed. If an adequate history of headache and/or backache (of which most of these patients complain) is not taken, the central causative effect of phenacetin ingestion may never be appreciated. Laboratory tests show the usual abnormalities seen in any form of chronic interstitial nephritis such as poor urinary concentration, renal failure with large urine output, and no hypertension. Papillary necrosis is helpful but not pathognomonic. The type of medications ingested appears to be changing to prescription compounds. The with significant improvement in renal function.

Analgesic abuse syndrome: a frequently overlooked cause of reversible renal failure.

The incidence of analgesic nephropathy in the United States is greater than previously reported. Because of the characteristic radiographic features of papillary necrosis, this diagnosis may be made while it is still clinically unsuspected. Early diagnosis is extremely important because cessation of analgesic abuse may avert progressive renal damage. Uncovering the diagnosis calls for special care in obtaining the telltale history. This must be sought in patients with radiographic evidence of papillary necrosis when a history of diabetes mellitus, obstructive uropathy, or sicle cell anemia is absent, or in patients with unexplained nephrocalcinosis or nephrolithiasis.

Phenacetin-induced renal papillary necrosis: pyonephros, anuria, and bilateral ureteral obstruction.

A fifty-five-year-old man was seen with anuria. Retrograde pyelograms demonstrated bilateral ureteral obstruction subsequently shown to have resulted from sloughed renal papillae. A twenty-year history of phenacetin was obtained. Treatment included bilateral ureteral intubation, then ureterotomy on one side.

Analgesic abuse nephropathy.

Analgesic abuse nephropathy is seldom considered as a cause in patients presenting with chronic renal disease. In a three-year period 450 patients were seen with chronic renal failure. Of these 103 had interstitial renal disease as the cause of their failure. Twenty of these 103 were due to chronic analgesic abuse, which indicates that need for a greater awareness of this problem. The spectrum of clinical and roentgenographic aspects of analgesic abuse nephropathy are discussed. What constitutes analgesic abuse, helpful clinical findings, frequency of other medical illnesses, and the low incidence of documented renal infection prior to onset of renal failure are discussed. Intravenous pyelographic findings related to visualization, renal size, corticomedullary margins and pelvicalyceal changes are also discussed and demonstrated.

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.

Effect of 16,16-dimethyl PGE2 on renal papillary necrosis and gastrointestinal ulcerations (gastric, duodenal, intestinal) produced in rats by mefenamic acid.

Mefenamic acid, given orally to rats at a single dose of 1200 mg/kg, produced renal papillary necrosis (RPN) in 63% of animals. The incidence was reduced to 27% by 16,16-dimethyl PGE2 (dmPGE2), given at an oral dose of 0.75 mg/kg t.i.d. RPN is likely to be caused by the renal prostaglandin depletion elicited by mefenamic acid, an inhibitor of prostaglandin cyclooxygenase. Substitution with dmPGE2 reduces RPN presumably by preventing the prostaglandin depletion. We conclude that the prostaglandin used is cytoprotective for the kidney. Mefenamic acid, like most nonsteroidal anti-inflammatory compounds (NOSAC), produced ulcerations of the small intestine (jejunum and ileum). These were prevented by dmPGE2 (intestinal cytoprotection). Unlike most other NOSAC, however, mefenamic acid produced duodenal ulcers in nearly all animals (80%). Of these ulcers, 88% were perforated. Twenty-five of the twenty-six animals that died had a perforated ulcer. These duodenal ulcers were also prevented by dmPGE2. Mefenamic acid-induced ulcers could be used as an experimental model for testing agents with a potential for preventing or healing duodenal ulcers.

Changes in antioxidant enzyme activities and lipid peroxidation related to bromoethylamine-induced renal cytotoxicity.

BACKGROUND: The effect of bromoethylamine (BEA) administration on lipid peroxidation and on the activities of antioxidant enzymes was studied. METHODS: Adult rats received BEA at 1.2 mmol/kg, a dose that produces renal papillary necrosis. Lipid peroxidation assessed by maximal rate in MDA formation, the activities of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the levels of non-protein sulfhydryls (NPSH) were measured in renal cortex and papilla of control and BEA-treated animals. RESULTS: After BEA treatment, an increment in lipid peroxidation in papilla and cortex was found after 1.5 and 24 hours of treatment. Catalase activity decreased in both regions, but earlier in cortex. CONCLUSION: These data suggest some role of oxidative stress in the mechanism of BEA-induced papillary necrosis.

Pattern of renal cortical scarring after experimental papillary necrosis.

Three types of renal cortical damage were found in rats 2 mth after papillary necrosis had been induced by ethylenimine: (1) Circumscribed areas of interstitial nephritis affecting either deep or superficial nephrons. (2) Wedge-shaped or conical scars, extending from capsule to inner medulla. (3) Widespread tubular dilatation and cyst formation with a diffuse increase in interstitial tissue, usually associated with dense fibrous repair of the papillary remnant. The extent and character of the cortical changes did not appear to be determined by the severity of the papillary necrosis, and even the more severe cortical lesions were not accompanied by any major reduction in kidney size. Although these chronic experimental cortical lesions are the products of a less complex and less protracted natural history than end stage cortical damage in analgesic nephropathy, some of the factors influencing their evolution, such as infection, may also determine the natural history of the clinical lesion.