Successful management of proteinuria and systemic hypertension in a dog with renal cell carcinoma with surgery, telmisartan, and amlodipine

Abstract

An 11-year-old neutered male Yorkshire terrier dog was presented with a 3-week history of hematuria and anorexia. A unilateral renal mass was detected and surgically removed. The renal mass was diagnosed on histopathologic examination as a renal carcinoma. Supportive medical therapy was carried out and persistent systemic hypertension was managed using telmisartan.

Renal cell carcinoma is an uncommon neoplasia of the kidney in dogs, but it is also the most common type of primary renal tumor in dogs (1). The prevalence of primary renal neoplasia is estimated to be 0.3% to 1.5% of all canine neoplasias (2). German shepherd dogs are known to be predisposed to renal tumors (3). Dogs with renal cell carcinoma frequently present with hematuria, anorexia, and weight loss (4); anemia and fever are also common clinical findings, but are rarely present concurrently (5). A biochemistry panel may detect renal azotemia and increased liver enzyme concentrations, but blood test results are often within normal limits, especially if the tumor is unilateral (4,6,7). Urinalysis may be normal, but the patient can present with proteinuria and/or gross or microscopic hematuria (4,5). The size and location of the mass can be identified by abdominal radiography. Thoracic radiographs may help identify any evidence of metastases to thoracic organs, with the lungs most frequently implicated; this finding may influence the treatment protocol (5). Abdominal ultrasonography or intravenous urography helps clinicians recognize the kidney mass more reliably than radiography alone (4). Computed tomography (CT) scanning helps identify evidence of metastasis and adhesion to surrounding structures (caudal vena cava, lumbar musculature, adrenal glands) in more detail (8).

A definitive diagnosis requires post-operative histopathological identification of neoplastic cells in the affected tissue (5). Nephroureterctomy is the mainstay of treatment of renal cell carcinoma in cases with unilateral kidney involvement in which contralateral kidney function is normal and metastases are not evident (5,7). In several studies, chronic renal failure occurred after nephroureterectomy; therefore, regular monitoring to determine whether patients have complications associated with chronic renal insufficiency (CRI) is essential, and appropriate therapy should be administered (9,10). This case describes the diagnostic work-up of a dog with unilateral renal cell carcinoma and successful medical management after nephroureterectomy.

Case description

An 11-year-old, neutered male Yorkshire terrier dog with a 3-week history of intermittent hematuria and sustained anorexia was referred to our facility. On physical examination, the dog was alert and the body temperature, pulse rate, and respiratory rate were normal, but systemic hypertension was identified. Blood pressure was 170 mmHg as measured using an ultrasonic Doppler flow detector. As part of the diagnostic work-up, a complete blood (cell) count (CBC), biochemical panel, electrolytes and gases, coagulation tests, urinalysis, and urine culture were conducted. Thrombocytosis [546 × 10⁹/L; reference interval (RI): 148 to 484 × 10⁹/L] was detected on CBC and an increased blood urea nitrogen (BUN) concentration (14.6 mmol/L; RI: 2.5 to 9.6 mmol/L) was identified on the biochemistry panel, which was likely due to decreased renal function. Prothrombin time (PT) was normal (15 s), activated partial thrombin time (aPTT) was delayed (114 s), and the D-dimer value was normal. Urinalysis revealed relatively good concentration ability (specific gravity 1.032; RI: 1.008 to 1.012), hematuria, and a high urine protein-creatinine ratio (UPC) (> 12.5). The urine culture was negative.

Thoracic radiographs showed no remarkable findings, and an abdominal radiograph showed a mass that occupied most of the right middle abdomen; its estimated size was 4.5 × 7.5 cm on the ventroabdominal view. On the right lateral view, the mass was suspected to originate from the retroperitoneum. The abdominal ultrasonograph revealed a 5-cm mass in the right kidney (Figure 1A). Most of the mass consisted of multifocal cysts, which had distinct demarcations, and some parts of the mass had hyperechoic parenchyma. The left kidney was normal (Figure 1 B,C). A presumptive diagnosis of a mixed echogenic mass originating from the right kidney was made, which included unilateral renal neoplasia, renal abscess, or pyonephrosis.

Figure 1.

Ultrasonographic images of the abdomen of a dog with renal cell carcinoma. A — The affected right kidney; B, C — The normal left kidney. D — A computed tomography (CT) image of both kidneys. Most of the parenchymal structure of the right kidney has been replaced by hypoechoic fluid (A, D star). The left kidney had a normal structure and blood flow on ultrasonography. Apparent contrast enhancement was identified in the left kidney on CT scanning.

A CT scan confirmed the mass in the right kidney but did not identify metastases to other organs (Figure 1 D). Most of the parenchyma of the mass could not be visualized with the exception of a cranial section of the right kidney, and the mass was full of fluid (16 HU). There was a small possibility that the fluid was a suppurative or bloody effusion. The mass was suspected to be a primary cancer, as both kidneys were asymmetric and there was no mesenteric edema surrounding the mass. Unilateral primary renal neoplasia was tentatively diagnosed.

A nephroureterectomy was performed and a large, heterogeneous mass and other affected tissues, including the caudal vena cava and adrenal gland, were removed from the right kidney. The diameter of the mass was 5.5 × 8 cm (Figure 2 A,B) and the mitotic index was < 10.

Figure 2.

Images of the right kidney with renal cell carcinoma. A — Enlarged and amorphic right kidney measuring 5.5 × 8 cm. B — Cross section of the right kidney. It was filled with fluid and there was no demarcation between the cortex and medulla. C — Pleomorphic, faintly basophilic, and occasionally vacuolated neoplastic cells invaded the right kidney. Normal architecture was extensively compressed. D — The caudal vena cava and surrounding tissues. Inflammation extended into the perivascular connective tissue and fat; neoplastic populations were observed.

After surgery, histopathology revealed an invasive renal carcinoma. Within the kidney, the normal architecture was extensively compressed, resulting in bands of connective tissue surrounding atrophic renal tubules or glomerular structures, and neoplastic cell infiltration was observed (Figure 2 C). The neoplastic cells were moderately pleomorphic and were characterized by a variable amount of basophilic, occasionally vacuolated cytoplasm, hyperchromatic anisokaryotic round/ovoid nuclei, and often, prominent nucleoli. The renal cell carcinoma had spread into the adjacent perirenal connective tissue, accompanied by secondary inflammation and hemorrhage (Figure 2 D).

After surgery, the patient had a urinary catheter and oliguria [< 2 mL/kg body weight (BW) per hour] was detected. The values of BUN and creatinine were 10 mmol/L (RI: 2.5 to 9.6 mmol/L) and 70.7 μmol/L (RI: 44.2 to 159.1 μmol/L), respectively. Because the patient might have been hypovolemic and acute renal failure could occur, aggressive fluid therapy was administered. Hartmann’s Solution (Hartmann’s Sol; CJ Health Care, Eumsung, Chungbuk, Korea) was administered at a rate based on 5% dehydration, and furosemide (Lasix; Handok, Seoul, Korea), 1 mg/kg BW per hour, IV, was administered for 6 h. Polyuria (> 5 mg/kg BW per hour) was identified 3 h after the first furosemide administration. Urinalysis was performed and the urine specific gravity was 1.035 and the UPC was 0.5. The patient received intensive care, including monitoring of body temperature, pulse rate, respiratory rate, and blood pressure. To prevent bacterial infection and sepsis, cefotaxime sodium (Wooridul; Hwasung, Gyeong-gi, Korea), 30 mg/kg BW, IV, was administered every 8 h. D-dimer concentration increased (1.5 mg/L, reference range: 0 to 0.3 mg/L), possibly due to blood loss, and dalteparin sodium (Fragmin; Pfizer Belgium, Puurs, Belgium), 150 IU/kg BW, SC, was administered every 8 h for 24 h before d-dimer concentration returned to normal (0.1 mg/L). Nonregenerative anemia [hematocrit (HCT) = 24] was managed by administering recombinant human erythropoietin (Epokine prefilled injection; CJ Health Care, I-cheon, Gyeong-gi, Korea), 100 IU/kg BW, SC, q48h. Anemia had improved after 1 wk, so erythropoietin was discontinued; other blood test results were normal. Systemic hypertension was initially managed with amlodipine maleate (Novalopine tab; JW Pharmaceutical Corporation, DangJin, Chungnam, Korea), 0.3 mg/kg BW, PO, q12h, for 1 wk, but the hypertension was not controlled and increased over time to 180 mmHg. Therefore, an angiotensin II type1 receptor blocker (ARB), telmisartan (Semintra; Boehringer Ingelheim Promeco, Mexico City, Mexico), 0.43 mg/kg BW, PO, q24h, was prescribed; blood pressure improved to 130 mmHg after 1 wk. The dog had no clinical signs at the 1-year follow-up, and blood pressure has been maintained in the normal range using telmisartan.

Discussion

This report describes the successful management of a renal cell carcinoma with surgical removal and supportive medical treatment. As the patient had unilateral renal carcinoma and the contralateral kidney was considered functional on the basis of blood tests and abdominal ultrasonography, nephroureterectomy was indicated.

Dogs with renal cell carcinoma sometimes show metastasis to lung, liver, regional lymph nodes, and local invasion into the surrounding structures (caudal vena cava, lumbar musculature, and adrenal glands) of the affected kidney (11,12). In our case, adhesion to the caudal vena cava and adrenal glands surrounding the affected right kidney was observed. In dogs with unilateral renal cell carcinoma, nephroureterectomy has been associated with a mean survival time of 16 mo (13), and 1 study suggests survival times of up to 4 y (14). Histopathologic evaluation showed that the mitotic index was < 10 and the patient was expected to survive for about 1180 d (14). The patient has been followed for more than a year. This patient showed signs of complication after surgery, including azotemia, non-regenerative anemia, and systemic hypertension. Azotemia and anemia improved soon after initiation of supportive medical therapy, but the systemic hypertension was difficult to control. Thorough monitoring and management of systemic hypertension is important for patients with a unilateral kidney because they might have refractory hypertension caused by CRI (9,15). Essential or idiopathic hypertension is rare in cats and dogs compared with humans and systemic hypertension is most often associated with other diseases or conditions (16). Renal disease is the most common cause of hypertension in veterinary patients. As activation of the rennin-angiotensin-aldosterone (RAA) system is one of the main causes of hypertension in dogs with CRI, angiotensin-converting enzyme inhibitors such as benazepril and enalapril are usually recommended as the initial antihypertensive agents of choice (17,18). Combination therapy with different classes of antihypertensive agents is often necessary for dogs with refractory hypertension; these agents include calcium channel blockers, direct arterial dilators, and ARBs (19,20). In 1 study of ARBs, telmisartan was administered to a dog with persistent hypertension and proteinuria and the problems resolved successfully, but there are few reports of telmisartan in veterinary medicine (20). Telmisartan may have another benefit, as it can act as an anticancer agent (21,22). Telmisartan is thought to modulate the development and progression of cancer by selectively blocking the activation of angiotensin II type1 receptors (AT1Rs), thereby suppressing the RAA system. The RAA system signaling has been shown to increase cancer cell proliferation in malignancy by enhancing the activation of AT1R in malignant cells, which promotes pro-survival signaling and caspase activity (22,23). In human medicine, it is suggested that telmisartan is a potential agent for the prevention and treatment of renal cell carcinoma (24). A case report showed that 1487 human patients with renal cell carcinoma who received angiotensin system inhibitors had improved overall survival (25). It is also possible that renal cell carcinoma in dogs might be improved with administration of telmisartan, but additional studies are needed to determine its efficacy.

In conclusion, a case of canine renal cell carcinoma was successfully managed with medical therapy after surgery. To the authors’ knowledge, this is the first case of persistent systemic hypertension after nephroureterectomy in a dog that was controlled using telmisartan.