Diphenylamine-induced renal papillary necrosis and necrosis of the pars recta in laboratory rodents

The nephrotoxicity of diphenylamine, the parent compound of the mefenamate family of nonsteroidal anti-inflammatory drugs, was evaluated in male Syrian hamsters, male Sprague-Dawley rats, and male Mongolian gerbils. Total renal papillary necrosis was observed in four of ten, seven of ten, and six of ten male Syrian hamsters orally treated with diphenylamine at respective doses of 400 mg/kg body weight/day, 600 mg/kg body weight/day, and 800 mg/kg body weight/day. Total renal papillary necrosis was also observed in five of ten and four of ten male Syrian hamsters intraperitoneally treated with diphenylamine at respective doses of 600 mg/kg body weight/day and 800 mg/kg body weight/day. Focal intermediate renal papillary necrosis was induced in two hamsters orally given diphenylamine at 600 mg/kg body weight/day and in two of ten hamsters intraperitoneally given diphenylamine at 800 mg/kg body weight/day. Apex-limited necrosis of the medullary interstitial cells and vasa recta and degeneration of the renal interstitial matrix occurred in two Sprague-Dawley rats orally administered diphenylamine at 800 mg/kg body weight/day. Degeneration and necrosis of the pars recta was induced in seven of ten hamsters intraperitoneally given diphenylamine at 400 mg/kg body weight/day. Gross and microscopic renal lesions were not observed in any Mongolian gerbils. It was concluded that the Syrian hamster is more susceptible to the papillotoxic effects of diphenylamine than the Sprague-Dawley rat and the Mongolian gerbil. Renal papillary necrosis in the Syrian hamster treated orally with diphenylamine is reproducible, is of short onset, and is induced in a high proportion of the hamsters (70-90%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal medullary rim sign in 2 adult quarter horses.

This report describes a renal ultrasonographic abnormality (medullary rim sign), which was identified in 2 separate cases of spontaneously occurring disease associated with chronic and acute overdosage of phenylbutazone therapy. In horses, medullary rim sign has only been documented in neonatal foals experimentally administered large doses of phenylbutazone.     

Familial renal amyloidosis in Abyssinian cats

Medullary and glomerular amyloidosis, papillary necrosis, and secondary interstitial disease were diagnosed in eight related adult Abyssinian cats from two catteries. The lesions were similar to those in two unrelated mongrel cats with renal amyloidosis. Ultrastructurally, the patterns of amyloid deposition were as described in other species, although medullary deposition predominated. Potassium permanganate oxidation blocked Congo red staining of the deposits suggesting that they contained amyloid A protein (secondary amyloid). The disease may be a model of familial secondary amyloidosis and offers an opportunity to study the pathogenesis of both amyloid deposition and papillary necrosis. The histochemical characteristics of feline renal amyloid require careful attention to technique. Section thickness affects Congo red affinity and both dichroism as well as birefringence should be considered when interpreting staining reactions. Thioflavine-T may be the preferred stain for identification of small deposits of amyloid. Variation in section thickness markedly affected the degree of potassium permanganate oxidation.     

Characterization of renal defects in dogs with a syndrome similar to the Fanconi syndrome in man.

Ten adult dogs with multiple spontaneous defects of renal tubular reabsorption were studied. Clinical signs included polydipsia, polyuria, and glycosuria for 2 to 12 months. Eight of the dogs were Basenjis. Urinalyses revealed hyposthenuria, glycosuria, and amino aciduria in most dogs. Renal function was normal in 5 dogs and slightly reduced in the remainder. Moderate metabolic acidosis had developed in 3 dogs. Renal clearance studies revealed reduced tubular reabsorption of glucose, phosphate, sodium, potassium, and uric acid. Abnormal glucose tubular maximal curves were found. Results of oral glucose tolerance tests were normal. Two patterns of abnormal amino aciduria were evident: generalized amino aciduria and a pattern similar to that of cystinuria in dogs. Radiography of long bones and bone densitometry did not reveal any skeletal abnormalities. Five of the dogs died within 90 days of diagnosis; death was due to acute renal failure associated with profound dehydration, acidosis, and papillary necrosis. The other dogs remained stable without treatment after 18 months. Histopathology of kidneys did not reveal uniform abnormalities; some dogs had variable and nonspecific changes and others were normal. Electron microscopy did not reveal ultrastructural abnormalities in renal tubular cells. It was concluded that the syndrome in these dogs represents a new entity of renal disease in dogs, similar to idiopathic Fanconi syndrome in man.     

Generalized nodular dermatofibrosis in the absence of renal neoplasia in an Australian Cattle Dog

A 13-year-old, spayed, female Australian Cattle Dog had at least a 10-year history of numerous subcutaneous nodules for which fine-needle aspiration and cytologic evaluation were nondiagnostic. Abdominal ultrasound 3.5 months before necropsy detected a small left kidney but no cysts or neoplasms. At gross necropsy, innumerable, firm, round to oval, white, 0.25 to 2 cm masses were detected throughout the subcutaneous tissues of the axial and appendicular skeleton, epimysium of numerous muscles, and parietal peritoneum of the lateral abdominal body wall. The left kidney was approximately half the size of the right, and there was severe bilateral renal medullary (papillary) necrosis. Histologically, the subcutaneous nodules were well-demarcated masses of mature, hypocellular collagen that were consistent with previous reports of nodular dermatofibrosis and renal cystadenomas or cystadenocarcinomas. In addition to diffuse acute medullary necrosis, both kidneys were affected by severe chronic lymphoplasmacytic interstitial nephritis. This is the first known report of nodular dermatofibrosis in a dog without renal cysts, cystadenoma, or cystadenocarcinoma.     

Phenylbutazone and the horse--a review.

The clinical uses and side-effects of phenylbutazone in man, horses, and other animals are reviewed. The blood dyscrasias commonly described in man have not been reported in the horse, although several of the more minor side-effects have occasionally been seen (e.g. water retention, depression, transient staggering and phlebitis). Despite the lack of documented evidence, the toxicity of phenylbutazone in the horse is considered to be lower than that in man. This may be associated with the lower dose rates normally used, the more rapid plasma clearance rate and the comparatively younger age of most horses under treatment. The following guidelines for the use of phenylbutazone in practice are put toward. It should only be used under strict veterinary control and then only if there are clear clinical indications. It should not be given if there are signs of gastro-intestinal ulceration, clotting defects or any cardiac, renal or hepatic dysfunction. Dose rates should be kept to a minimum and the drug withdrawn immediately if any side-effects occur or if there is no clinical response within 4 days. If prolonged therapy is necessary, periodic haematological analyses should be carried out.     

Ultrasonographic evaluation of renal parenchymal diseases in dogs: 32 cases (1981-1986)

The medical records of 32 dogs with microscopically proven renal parenchymal disease were evaluated to characterize the associated ultrasonographic patterns and to assess the contribution of ultrasonography to the diagnosis and management in each case. Ultrasonography provided additional information on internal renal architecture in 18 dogs with radiographic evidence of structural abnormality. Ultrasonography determined the renal origin of 2 abdominal masses, defined the extent and distribution of neoplastic disease in 6 dogs, and identified kidneys not seen on survey radiographs or excretory urograms in 5 dogs because of decreased abdominal contrast or poor function. The ultrasonographic patterns were most specific for focal and multifocal or diffuse neoplasia. Ultrasonographic findings were least specific for diffuse parenchymal disease without architectural disruption such as glomerulo/interstitial nephritis, renal tubular necrosis, and nephrocalcinosis. In these cases, biopsy was recommended. Six interpretive errors were made. Four of these errors were related to the overestimation of renal pelvic and diverticular size because of confusion with medullary papilla. Two errors occurred in the diagnosis of renal lymphosarcoma, one of which was interpreted to be pyelonephritis. The other was an interpretive dilemma because of absence of hypoechoic multifocal nodules. Renal tubular necrosis was confirmed in this case.     

Renal amyloidosis in related English foxhounds

Renal amyloidosis was diagnosed in six related English foxhounds from two separate hunting kennels. There was no apparent age or sex predilection. All the dogs had clinical and laboratory findings compatible with renal disease. The onset of clinical signs was acute in all cases with death or euthanasia in five of the six affected dogs occurring within one week of presentation. The remaining dog was treated with diuresis which produced a temporary improvement. Histological examination of renal tissue from affected dogs identified the presence of both glomerular and interstitial amyloid, which was confirmed by immunohistochemical staining to be of the reactive type (amyloid A). There were occasional sclerosed glomeruli or glomeruli with thickened Bowman's capsules, in addition to interstitial and periglomerular infiltration with a predominance of plasma cells and lymphocytes and secondary changes including tubular eosinophilic casts. Renal papillary necrosis was identified in three dogs. One hound had concurrent multicentric lymphoma. Pedigree analysis of the affected dogs revealed that four individuals shared a common great grandsire and that the same dog was the grand-sire of a further case. Pedigree analysis of five additional dogs from one of the kennels, all of which had clinical signs of acute renal failure but from which renal tissue was not available, revealed a close relationship to those foxhounds with confirmed renal amyloidosis.     

Renal biopsy of dogs and cats

Renal diseases are common in dogs and cats. Renal biopsy may be required during the evaluation of the patient to establish a definitive diagnosis, determine the severity of the lesion and formulate an optimal treatment plan. Renal biopsy specimens can be collected via several methods. Percutaneous techniques are performed with ultrasound guidance in both dogs and cats or blindly in cats. If ultrasound guidance is not available, the keyhole technique can be used in dogs. Biopsy can also be performed using laparoscopy or surgery. While complications can arise with any of these techniques, complications are less frequent when an experienced operator uses proper technique. Renal biopsy specimens must be processed and evaluated appropriately if consistent and accurate diagnoses are to be rendered. The article summarizes patient selection and evaluation, renal biopsy techniques, expected complications of renal biopsy, and appropriate processing and evaluation of the renal biopsy specimen.     

ULTRASONOGRAPHIC EVALUATION OF RENAL SIZE IN DOGS WITH ACUTE ALLOGRAFT REJECTION

The purpose of this study was to determine the best method to ultrasonographically monitor renal size changes associated with acute allograft rejection in dogs. Qualitative changes in renal cortical and medullary echogenicity were also evaluated, although this was not a major focus of the study. Four unrelated, mixed-breed dogs underwent bilateral nephrectomies and heterotopic renal allograft transplantation. Ultrasound examinations of transplanted kidneys were initiated at 3 days after surgery and continued at 2–3 day intervals until death (38±2 days). Ultrasound measurements of kidney length, width, height, cross-sectional area, and estimated volume were used to assess relative changes in renal size associated with transplantation and rejection. Transplanted kidneys had a rapid increase in volume and cross-sectional area that averaged 103% and 83% above baseline levels, respectively, by 17 days after transplantation. The increased size was attributed to a combination of hypertrophy and acute rejection, the latter of which was confirmed at postmortem. Kidney volume decreased to approximately 35% above baseline volume by day 34 as rejection became more advanced. Qualitative changes associated with rejection included medullary enlargement with decreased echogenicity early in the study, followed by increased cortical thickness and echogenicity with poor cortical medullary definition in the latter stages of the survival period. It was concluded that relative changes in renal allograft size can be easily monitored with ultrasound. In regard to linear measurements, changes in renal width were more pronounced than changes in height or length with acute rejection. Therefore measurements that incorporate the width, namely volume or cross-sectional area, appear to be the most sensitive for monitoring changes in allograft size. Renal cross-sectional area measurements are preferred because they are simple to perform using the automated calculation capability of most newer ultrasound units.     

Renal adenoma in a cat

Renal adenoma, a benign tumor of epithelial origin, was diagnosed in a 10-year-old cat. Clinical signs included decreased appetite and weight loss. Nephrectomy resulted in clinical improvement. Seven months after surgery, the cat died, and pulmonary papillary adenocarcinoma was discovered. The pulmonary neoplasm differed markedly from the renal neoplasm.     

Attenuation by phenylbutazone of the renal effects and excretion of frusemide in horses.

The objectives of this study were to determine the effect of phenylbutazone premedication on the pharmacokinetics and urinary excretion of frusemide in horses; and on frusemide-induced changes in urinary electrolyte excretion. Six Standardbred mares were used in a 3-way crossover design. The pharmacokinetics and renal effects of frusemide (1 mg/kg bwt i.v.) were studied with and without phenylbutazone premedication (8.8 mg/kg bwt per os 24 h before, followed by 4.4 mg/kg bwt i.v. 30 min before frusemide administration). A control (saline) treatment was also studied. Administration of frusemide without phenylbutazone led to diuresis, natriuresis, kaliuresis and chloruresis, and altered the ratio of sodium:chloride excretion from 0.4 to 1.0 in the first hour of diuresis. When frusemide and phenylbutazone were administered, sodium and chloride excretion in the first hour were significantly (P<0.05) reduced by 40 and 32%, respectively, when compared to frusemide administrationwithout phenylbutazone. The fractional clearance of sodium and chloride was also significantly reduced. Potassium excretion, potassium fractional clearance and the ratio of sodium to chloride excretion were not affected by administration of phenylbutazone. During peak diuresis, phenylbutazone did not affect the efficiency of frusemide with respect to electrolyte excretion. The plasma disposition of frusemide was not affected by phenylbutazone. However, the renal excretion of frusemide decreased by approximately 25%. We conclude that the decreased urinary excretion of frusemide by phenylbutazone led to an attenuation of frusemide-induced increases in urinary excretion of sodium and chloride. Since the efficiency of frusemide was not affected by phenylbutazone, we conclude that phenylbutazone attenuates the renal excretion of frusemide without inhibiting the intrarenal activity of frusemide in horses.     

Renal (uremic) encephalopathy in a goat

Renal encephalopathy was diagnosed in a 2-year-old male boar goat with a history of chronic weight loss and ataxia. Histopathological examination of the brain revealed a striking myelin vacuolation distributed mainly in two patterns: (i) along the junction of the neocortex and corona radiata, and (ii) in the bundles of the internal capsule as it dissects through the basal nuclei. The kidneys had diffuse severe tubular and glomerular necrosis and degeneration. The neural lesions are consistent with renal (uremic) encephalopathy. To the authors' knowledge, this is the first report of renal encephalopathy in a goat.     

A case report of RccHanTM: WIST rat with multiple neoplastic and non-neoplastic proliferative lesions

It is extremely rare to have multiple spontaneous proliferative lesions in young adult rats. Here, we report the occurrence of different proliferative lesions in multiple tissues of a 7-week-old female rat in a 1-week repeated toxicity study. Grossly, multiple white patches and nodules in the bilateral kidneys, femoral and subcutaneous masses, and a nodule in the liver were observed. Renal lesions were diagnosed as renal mesenchymal tumors. One of the femoral subcutaneous masses was diagnosed as an adenolipoma consisting of mammary epithelial cells and mature adipocytes. The other femoral and abdominal subcutaneous masses were diagnosed as lipomas consisting of mature adipocytes. The liver nodule was diagnosed as non-regenerative hepatocellular hyperplasia, which was characterized by the proliferation of slightly hypertrophic hepatocytes. In the cauda equina, the growth of enlarged Schwann cells around the axon was observed, and this lesion was diagnosed as a neuroma.     

Copper salicylate and copper phenylbutazone as topically applied anti-inflammatory agents in the rat and horse

Topically applied copper phenylbutazone, phenylbutazone, copper salicylate, salicylate and dimethylsulfoxide glycerol (80:20) were investigated as anti-inflammatory agents in rats and horses. Dimethylsulfoxide and glycerol (80:20) or dimethylsulfoxide, ethanol and glycerol (60:20:20) were used as the drug solvents. Subcutaneously administered carrageenin was used to induce inflammatory oedema, either in the paws of rats or the alar fold of the horse. The severity of the oedema and the anti-inflammatory effect of the drugs were assessed by measuring changes in the paw or alar-fold diameters. Copper salicylate and copper phenylbutazone were effective inhibitors of the inflammatory oedema in both species, but dimethylsulfoxide:glycerol (80:20) was not. In the rat, copper salicylate and copper phenylbutazone were superior anti-inflammatory agents compared to either salicylate or phenylbutazone, respectively. Following the topical application of four times the recommended daily dose of copper phenylbutazone to the horse for 5 days, minor skin irritation occurred and trace concentrations of phenylbutazone (maximum 0.6 microgram/ml) and negligible concentrations of oxyphenbutazone and gamma-hydroxyphenylbutazone were detected in the plasma.     

Early renal ultrasonographic findings in dogs with experimentally induced ethylene glycol nephrosis

Renal ultrasonographic changes were evaluated in 5 dogs administered 10 ml of commercial antifreeze (95% ethylene glycol)/kg of body weight, PO, and in 2 dogs given placebos. Studies were made prior to and after ingestion on an hourly basis over a period of 8 to 10 hours. All dogs were anesthetized immediately after toxin or placebo ingestion for the duration of the study. Renal cortical echogenicity was evaluated in comparison with that of the adjacent liver and spleen. Echogenicity of the renal medulla and definition of the corticomedullary junction were assessed. Within 4 hours after ethylene glycol administration, renal cortical echogenicity of all intoxicated dogs increased from normal to surpass that of liver and approach or equal that of the spleen. Medullary echogenicity in all intoxicated dogs progressively increased over the course of the study, with changes recognized within 5 hours after ethylene glycol administration. An ultrasonographic pattern consisting of nearly equal, marked increase in cortical and medullary echogenicity and relatively hypoechoic corticomedullary junction and central medullary regions was recognized concurrent with the development of anuria in 3 of the 5 intoxicated dogs. Mild, transient increases in cortical and medullary echogenicity were observed in anesthetized control dogs. However, no statistical difference (P less than 0.05) was detected between baseline, peak, and terminal echogenicity values in these dogs. Blood and urine samples were collected hourly from intoxicated dogs to coincide with ultrasonographic studies. Most clinicopathologic values derived from these samples were not statistically different (P less than 0.05) from those reported in a study that used a similar intoxication protocol in nonanesthetized dogs.     

ULTRASONOGRAPHIC ANATOMY OF THE NORMAL CANINE KIDNEY*

Radiographic and ultrasonic examinations were performed in 12 normal dogs. Initial ultrasound examinations were performed in normally hydrated dogs. The ultrasonic appearance of the diuresed kidney was evaluated after excretory urography and intramuscular administration of furosemide. The dogs were euthanized for anatomic correlation with the sonographic appearance of the kidneys. Renal cortex, medulla, pelvic diverticula, intrarenal vessels, renal pelvis, and renal sinus fat were identified sonographically. Kidney enlargement during diuresis was due to increase renal medullary size. Veterinary Radiology, Vol. 25, No. 4, 1984; pp 173–178.     

Dynamic-interaction of vitamin K and levamisole on phenylbutazone activities

The results showed that co-administration of either vitamin K or levamisole along with phenylbutazone abolished the latter's anti-inflammatory and antipyretic activities and reduced its analgesic effect. Prolonged administration of phenylbutazone alone to rats for 21 days increased significantly serum glutamate oxalacetate transaminase (SGOT) activity, urea and creatinine concentrations, while it decreased with significance uric acid concentration in the serum. Vitamin K, when administered together with phenylbutazone, reduced its effect on SGOT activity and creatinine concentration. Levamisole antagonised the uricosuric effect of phenylbutazone, when both were concomitantly given. Histopathological examination of the liver of rats, given phenylbutazone alone, showed mild degenerative changes, whereas in combination with levamisole these changes were exacerbated. Kidney showed oedema, degeneration, congestion, and haemorrhage. These changes were severe in rats, given phenylbutazone alone, moderate in levamisole-treated animals, and mild in those given both drugs. Combination of levamisole with phenylbutazone not only decreased the congestion of gastric mucosa but also activated the gastric glands.     

Pharmacokinetics of phenylbutazone and oxyphenabutazone in the pig.

The kinetics of phenylbutazone (pbz) and its main metabolite oxyphenbutazone (oxpbz) were investigated in seven pigs in order to determine if this animal might serve as a model for human investigations. The study was performed in two stages, one as single dose experiments using intravenous injection, the second as infusion experiments. The rate of elimination for both compounds was demonstrated to be much faster than in man. Similar results have been observed in several other animal species. The degree of protein binding (pbz 98%, ox-pbz 97%), the apparent specific volume of distribution (pbz 0.18 1/kg, ox-pbz 0.28 1/kg) and the renal clearance were found to be similar to results obtained in man and rat. Ox-pbz had a higher renal clearance (0.13 ml/min/kg) than pbz (0.003 ml/min/kg) but still the renal excretion constituted only a small fraction of the total elimination (pbz 0.5%, ox-pbz 5%). Provided real steady state conditions were obtained during the infusion experiments calculations based on the results from the single dose experiments in the same animal revealed that between 20 and 60% of the injected pbz was metabolized to the ring-hydroxylation product (ox-pbz). It is concluded that the pig model is not superior to other animal models for studies of pbz/ox-pbz. The rapid elimination pattern is the main problem in relation to human investigations.     

Bilateral renal hypoplasia in four young horses

Three horses less than or equal to 3 years old were evaluated because of stunted growth, weight loss, anorexia, depression, and lethargy of at least 1 month's duration. A neonatal foal was examined after its death. In each case, gross and microscopic renal lesions were compatible with bilateral renal hypoplasia (ie, cortical hypoplasia with severe medullary hypoplasia). In young horses with renal failure, bilateral renal hypoplasia should be considered in the differential diagnosis, and may represent a congenital lesion.