Toceranib phosphate-associated nephrotic syndrome in a dog: a case report.

BACKGROUND: Nephrotic syndrome (NS) is rare in dogs and is characterized by concurrent clinical findings of proteinuria, hyperlipidemia, hypoalbuminemia, and edema. NS has been reported in humans receiving tyrosine kinase inhibitors (TKI) and in dogs receiving masitinib. This is the first report of NS in a dog receiving toceranib phosphate. CASE PRESENTATION: An 8-year-old, female, spayed Labrador retriever was diagnosed with a 10 cm mast cell tumor on the left lateral abdomen. After completion of a 12-week vinblastine and prednisone protocol, she began treatment with toceranib phosphate (2.6 mg/kg by mouth, every other day). Proteinuria was documented prior to starting toceranib. On day 426 after diagnosis (day 328 of toceranib phosphate treatment), the dog was evaluated for diarrhea, lethargy and anorexia. On physical examination, dependent edema was noted on the ventral chest and abdomen, and sterile neutrophilic inflammation was aspirated from a 2.3 cm splenic nodule. The following laboratory values were reported: albumin < 1.5 g/dL; cholesterol 378 mg/dl and urine protein to creatinine ratio of 3.79. The patient was diagnosed with NS, and treatment with toceranib phosphate was discontinued. Low-dose aspirin was started in addition to an increased dosage of enalapril (0.47 mg/kg q12hr). No other therapy was instituted. The dog improved clinically, and laboratory values returned to near normal over the 8-week follow-up. She was euthanized 1399 days after discontinuing toceranib phosphate with progressive disease. CONCLUSIONS: Nephrotic syndrome is a potential adverse event associated with the drug toceranib phosphate which may be reversible with discontinuation of treatment. Careful monitoring of urine protein, serum biochemistry, blood pressure and patient weight is advisable during treatment with toceranib phosphate.

Presumed masitinib-induced nephrotic syndrome and azotemia in a dog.

Masitinib mesylate is a tyrosine-kinase inhibitor approved for the treatment of nonresectable or recurrent, Grade 2 or 3 mast cell tumors in dogs. This report describes nephrotic syndrome and acute kidney injury attributed to masitinib and illustrates the need for regular monitoring of serum creatinine concentration, urinalysis, and urine protein:creatinine ratio during its use.

Présomption de syndrome néphrotique et d'azotémie induits par le masitinib chez un chien. Le mésylate de masitinib est un inhibiteur de la tyrosine-kinase homologué pour le traitement des mastocytes non résécables ou récurrents de grade 2 ou 3 chez les chiens. Ce rapport décrit le syndrome néphrotique et une blessure aiguë au rein attribués au masitinib et illustre le besoin d'une surveillance régulière de la concentration sérique de créatinine, des analyses d'urine et du ratio protéine:créatinine urinaire durant son utilisation.(Traduit par Isabelle Vallières).

Progression of glomerulonephritis to end-stage kidney disease in a cat with nephrotic syndrome.

A percutaneous renal biopsy was performed on a 3-year-old female Japanese domestic cat with pleural effusion, mild azotemia, hypoalbuminemia, hypercholesterolemia, and proteinuria. Glomerular lesions included mild diffuse hypercellularity and numerous capsular adhesions with segmental sclerosis/hyalinosis of glomerular tufts. Electron microscopy revealed many subendothelial dense deposits with characteristic outer protrusion of glomerular basement membrane. Diffuse and global granular deposits of IgG and C3 were detected along the capillary walls. Tubulo-interstitial changes were mild at the time of biopsy, but progression of the disease was predicted because of the many capsular adhesions of the glomerular tufts. The cat was fed a prescription diet without any other specific or symptomatic therapy after renal biopsy, and died 43 weeks after the biopsy. At necropsy, extensive tubulo-interstitial fibrosis and mononuclear cell infiltration had developed throughout the cortex and outer medulla, and most glomeruli had extensive global sclerosis or obsolescence with less prominent depositions of IgG and C3.

Severe chemosis caused by nephrotic syndrome in a goat: a case report.

A 3-year old female goat with nephrotic syndrome was presented because of severe bilateral chemosis. The diagnosis was based on clinical findings, decreased packed cell volume, increased serum urea and creatinine, decreased serum protein and protein loss via the urinary tract. At post mortem examination, a chronic glomerulonephritis and interstitial nephritis were found. In addition to severe conjunctival oedema, ascites and subcutaneous oedema in the region of the larynx were noted. Immunohistochemistry for the detection of chlamydial antigen in the conjunctiva was negative. This is the first report of severe chemosis caused by nephrotic syndrome in a goat.

Nephrotic syndrome associated with administration of sulfadimethoxine/ormetoprim in a dobermann.

This case report describes sulphonamide-induced nephrotic syndrome in a young dobermann dog. The clinical signs and laboratory abnormalities resolved shortly after discontinuation of the sulphonamide antibiotic and with generalised supportive care. Since nephrotic syndrome typically carries a guarded prognosis in veterinary medicine and is poorly responsive to therapy, a thorough drug history should be an important part of the investigation of any animal with a protein-losing nephropathy.

The nephrotic syndrome in a heifer due to glomerulonephritis.

An 18-month-old Friesian heifer, which was admitted in November with a history of weight loss, diarrhoea and submandibular oedema, was found to have an enlarged left kidney and a massive proteinuria. Laboratory investigations revealed that there was a marked hypoalbuminaemia and that the range and the proportions of the individual proteins in the urine were almost identical to those in the serum. Consequently, the nephrotic syndrome was diagnosed. On gross and histopathological examination of the kidneys, there was evidence of pyelonephritis. However, immunofluorescence studies revealed a striking diffuse deposition of immunoglobulin in a predominantly linear pattern along the glomerular basement membranes. Abnormalities of the basement membranes. Abnormalities of the basement membranes were seen on ultrastructural examination and evidence of a flomerular protein leak was detected but changes typical of immune-complex deposition were absent. The immunofluorescence findings suggested a diagnosis of glomerulonephritis mediated by antiglomerular basement membrane antibody.

An immunohistological study of feline glomerulonephritis using the peroxidase-antiperoxidase method.

Twenty-two cases of feline glomerulonephritis were investigated for the presence of immune complexes within the glomerulus using the peroxidase-antiperoxidase (PAP) method. This method was used with formalin-fixed paraffin-wax embedded tissues which were pretreated with trypsin and with frozen sections of kidney tissue. Of a total of 25 kidney specimens examined (two cats had repeated biopsies) the composition of the deposits was 23/25 IgG, 17/25 C3, 11/25 IgM and 2/25 IgA. Serial studies of two cats showed a progression of the disease from initial nephrotic syndrome to chronic renal failure. With the more severe form of the disease there was a tendency for the deposition of complement and more than one class of immunoglobulin within the glomeruli.

Experimental immune complex glomerulonephritis and the nephrotic syndrome in cats immunised with cationised bovine serum albumin.

Membranous nephropathy was induced in four cats by repeated intravenous injections of 120 mg cationic bovine serum albumin (BSA, pI 9.5). All four cats developed diffuse granular deposits of IgG and C3 along the glomerular capillary walls as early as five weeks which persisted until the end of the experiment at 17 weeks. Ultrastructural studies revealed many subepithelial electron dense deposits. Two cats developed severe proteinuria and the nephrotic syndrome characterised by hypoalbuminaemia and oedema. An additional four cats received repeated injections of unmodified native BSA (pI 4.5) and remained basically normal. This is the first report of membranous nephropathy and the nephrotic syndrome in an experimental animal model which, unlike other animal models, is subject to the spontaneously occurring disease.

Treatment of membranoproliferative glomerulonephritis and nephrotic syndrome in a dog with a thromboxane synthetase inhibitor.

A 2-year-old spayed female Whippet with membranoproliferative glomerulonephritis and nephrotic syndrome was treated with a specific thromboxane synthetase inhibitor (3-methyl-2[3-pyridyl]-1-indoleoctanoic acid), resulting in decreased proteinuria and resolution of ascites and edema. Glomerular histology, however, appeared unaffected by treatment. Discontinuation of treatment for 10 weeks resulted in increased proteinuria and decreased serum albumin concentrations that were again attenuated when treatment was reinitiated. Thromboxane synthetase inhibitors have been used successfully to treat experimentally induced glomerulonephritis in several species and this treatment appears to hold promise for naturally occurring glomerulonephritis in dogs.

Characteristic changes in carbohydrate profile in the kidneys of hereditary nephrotic mice (ICGN strain).

The ICR-derived glomerulonephritis (ICGN) mice consist of heterozygous and homozygous groups and are considered to be a good model for human idiopathic nephrotic syndrome. To reveal changes in cell-surface carbohydrate construction, 24 lectins were applied to kidney sections of 10-, 30- and 50-week-old male heterozygous and homozygous ICGN mice and age-matched male ICR mice. Bandeiraea simplicifolia lectin-I (BSL-I), which specifically binds to alpha-D-galactopyranosyl groups, showed positive staining in the glomeruli of ICGN mice, but not in those of ICR mice. Positive BSL-I staining was observed only in distal tubules of homozygous ICGN mice. Lectin blotting for BSL-I demonstrated characteristic glycoproteins (45, 58 and 64 kD) in ICGN but not in ICR mice, and the levels of these molecules augmented in homozygous ICGN mice with the progression of renal failure. Moreover, succinylated wheat germ agglutinin, Dolichos biflorus agglutinin, Aleuria aurantia lectin and Ulex europaeus agglutinin-I showed positive staining only in the glomeruli of homozygous ICGN mice, but not in those of heterozygous ICGN or ICR mice. The staining intensities of Ricinus communis agglutinin-I, Phaseolus vulgaris agglutinin-E and -L, Lens culinaris agglutinin and Erythrina cristagalli agglutinin (ECL) in the glomeruli of homozygous ICGN mice were stronger than those of heterozygous ICGN and ICR mice. In conclusion, lectin histochemistry provided useful information for the diagnosis and prognosis of nephrotic lesions. Characteristic BSL-I binding glycoproteins may be pathogenic factors which cause renal disease in ICGN mice and are good tools to investigate the molecular mechanism of renal disorders in ICGN mice.

Idiopathic immune complex glomerulonephritis in dogs with multisystem involvement.

Renal specimens obtained by biopsy and/or at necropsy from 4 dogs with nephrotic syndrome were studied using light, immunofluorescence, and electron microscopies. The glomerulonephritis observed in these dogs was considered an idiopathic immune complex glomerulonephritis associated with multisystem involvement because causes of glomerulonephritis in these dogs could not be established. Immunoglobulin A was observed in granular deposits in the mesangial and subendothelial regions of the glomeruli. The relationship of the clinical and pathologic features of this disease in dogs to various renal syndromes in human beings are described.

Hypoalbuminemia-related platelet hypersensitivity in two dogs with nephrotic syndrome.

Platelet aggregation studies in 2 dogs with nephrotic syndrome disclosed increased platelet sensitivity to a low dose of adenosine diphosphate. Subsequent studies with isolated platelets and plasma indicated that a plasma factor was responsible primarily for inducing platelet hypersensitivity. The increased platelet aggregation response was corrected by increasing the albumin concentration of the plasma. The study suggested an important role for albumin in modulating platelet aggregation and may partially explain the tendency toward thrombosis noted in hypoalbuminemic dogs with nephrotic syndrome.

Natural remission of nephrotic syndrome in a dog with immune-complex glomerular disease.

A nephrotic syndrome caused by immune-complex glomerular disease was diagnosed in a 4-year-old male Great Dane. The syndrome was characterized by proteinuria, hypoproteinemia, hypoalbuminemia, hypercholesterolemia, and subcutaneous edema. Renal biopsy revealed segmental membranous glomerular disease. The edema underwent complete remission 18 days after admission. Two months after admission, there was no clinical or laboratory evidence of glomerular disease. Periodic reevaluation of the dog during the next 2 years revealed recurrence of proteinuria, but no other clinical or laboratory abnormalities. Serial renal biopsies revealed persistence, but no appreciable increase, in the severity of the segmental membranous glomerular disease. The natural course of the nephrotic syndrome and immune-complex glomerular disease has been associated with unpredictable variability. It was concluded that the widespread use of corticosteroid or immunosuppressant therapy in dogs with immune complex glomerular disease should be withheld until the natural course of the disease has been evaluated in a significant number of patients and until the results of well-controlled clinical studies confirm or deny their therapeutic value.

Nephrotic syndrome associated with renal amyloidosis in a colony of Syrian hamsters.

A 6% incidence of nephrotic syndrome was noted in a colony of 400 Syrian hamsters (Mesocricetus auratus) over a period of 2 years. Clinical findings consisted of severe ascites and anasarca, anorexia, cachexia, and papular dermatitis. Serum and urine chemical analysis revealed proteinuria and hypoalbuminemia in all animals tested; hypoproteinemia and high concentrations of serum cholesterol, triglycerides, and creatinine were detected in some of the affected hamsters. Demodex aurati was detected in skin scrapings from 4 of 8 hamsters. Necropsy findings included subcutaneous edema, ascites, and hydrothorax, as well as atrophic kidneys and testes. Extensive deposits of type AA amyloid were detected histologically in kidney, liver, spleen, and adrenal gland; smaller deposits were found in thyroid gland and intestine. Other histologic findings included periodontitis and hyalinization of the small arteries of the testes.

Hemostatic abnormalities in nephrotic syndrome.

Nephrotic syndrome is often associated with a hypercoagulable state and thrombotic complications. Thrombosis may be due to a number of abnormalities in blood, including AT III deficiency, increased concentrations of fibrinogen, factors V and VIII, and platelet hyperaggregability. The therapeutic approach to thrombosis in nephrotic syndrome is the use of anticoagulants as a preventive measure or an attempt at thrombolysis with streptokinase, urokinase, or stanozolol.

Membranous nephropathy in the cat: a clinical and pathological study.

A series of 13 cases of feline membranous nephropathy is presented. Two groups were distinguished clinically; eight cats had the nephrotic syndrome and five others were in renal failure but not nephrotic. The definitive diagnosis was based on histological, immunofluorescence and ultrastructural examinations of renal tissue obtained at renal biopsy or necropsy. Glomerular lesions were classified according to the degree of glomerular change into three distinct groups; mild, moderately severe and advanced. A relationship was established between the mild and moderately severe groups and cats with the nephrotic syndrome, and the advanced group and cats in renal failure. Diuretic therapy was satisfactory in initial control of oedema in the nephrotic cases. Monitoring of previously nephrotic cats for up to three years indicated that the disease is progressive, although in some cases it is sufficiently slow for a cat to live a relatively normal life without continuing treatment. The prognosis for cats presented in renal failure is hopeless.

Cranial edema associated with a protein-losing nephropathy in a golden-mantled flying fox (Pteropus pumilus).

An adult golden-mantled flying fox (Pteropus pumilus) was diagnosed with nephrotic syndrome on the basis of the findings of proteinuria, hypoalbuminemia, hypercholesterolemia, and cranial edema. Membranoproliferative glomerulitis and interstitial nephritis were confirmed antemortem by renal biopsy. The bat had received seven injections of oxytocin in the period immediately prior to presentation. The possible role of oxytocin in the development of the nephropathy is discussed. Supportive care and treatment with a single plasma transfusion, furosemide, and prednisone led to a gradual but complete resolution of the nephrotic syndrome in this animal.

Membranoproliferative glomerulonephritis in a calf with nephrotic syndrome.

A 2-month-old Japanese black calf was presented with a history of weight loss, exophthalmos and subcutaneous oedema of the brisket. Urinalysis and serum biochemistry showed proteinuria and hypoproteinaemia suggestive of nephrotic syndrome. Microscopically, lesions in the kidney were characterized by proliferation of mesangial cells and diffuse thickening of the glomerular basement membranes with the appearance of double contours. Immune complex deposits were confirmed by electron microscopy and immunofluorescence using reagents specific for bovine immunoglobulin G, complement factor C3 and bovine viral diarrhoea virus (BVDV). Consequently, the glomerular lesion in this case was diagnosed as membranoproliferative glomerulonephritis. BVDV type 1 was detected in serum by nested reverse transcriptase polymerase chain reaction. Viral antigen was also identified in the glomeruli by immunofluorescence. These results suggest that BVDV may have been the cause of immune complex glomerulonephritis in this calf.

Serum lipoprotein changes in dogs with renal disease.

BACKGROUND: People with renal disease develop a dyslipidemia that contributes to progression of renal injury and development of cardiovascular disease. Lipoproteins in dogs with renal disease have not been investigated. HYPOTHESIS: Dogs with chronic kidney disease (CKD) have dyslipidemia characterized by increased lower density lipoproteins and decreased high-density lipoproteins (HDLs). The degree of dyslipidemia is positively correlated with severity of disease, as reflected by serum creatinine concentration. ANIMALS: Prospective study of client-owned dogs presented to the Cornell University Hospital for Animals: 29 dogs with confirmed CKD, 5 dogs with nephrotic syndrome (NS), and 12 healthy control dogs presented for routine vaccinations, dental cleaning, or owned by students. METHODS: Lipoprotein electrophoresis was used to quantify relative proportions of the 3 main classes of lipoproteins in canine serum: low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and HDL. Serum cholesterol and creatinine concentrations; urinalysis and urine protein-to-creatinine ratio were measured by standard methods. RESULTS: Dyslipidemia was consistently found in dogs with CKD and NS and was characterized by a decrease in HDL and variable increases in LDL and VLDL. Dogs with NS had a proportionately greater increase in the VLDL fraction, as compared with dogs with CKD. CONCLUSION AND CLINICAL IMPORTANCE: Dyslipidemia similar to that documented in people with renal disease occurs in dogs with CKD, despite serum cholesterol concentrations often being within the reference interval. The contribution of altered lipoproteins to the pathogenesis of renal disease in dogs warrants additional study.