Suspected contrast-induced nephropathy in three sequential patients undergoing computed tomography angiography and transarterial embolization for nonresectable neoplasia

Maureen A. Griffin From the William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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William T. N. Culp Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Carrie A. Palm Department of Medicine & Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Robert H. Poppenga Department of Food Safety Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Abstract

CASE DESCRIPTION

During the same week, 3 sequential patients (a 10-year-old 8.7-kg spayed female poodle cross [dog 1], 13-year-old 2.6-kg spayed female domestic longhair cat, and 13-year-old 9.0-kg castrated male mixed-breed dog [dog 2]) underwent CT-angiography (day 0) and transarterial embolization (day 1) for nonresectable hepatocellular carcinoma (n = 2) or prostatic carcinoma (1).

CLINICAL FINDINGS

Contrast-induced nephropathy (CIN) was suspected in all animals on the basis of higher serum creatinine concentrations after contrast medium administration (exposure), compared with baseline concentrations before exposure, consistent with CIN definitions. The total dose of contrast medium was < 3 mL/kg for each exposure. For all 3 patients, creatinine concentration peaked at a median of 3 days (range, 2 to 3 days) after the first exposure (day 0), and the median absolute and relative increases in creatinine concentration after exposure (vs baseline concentrations before exposure) were 2.9 mg/dL (range, 2.2 to 3.7 mg/dL) and 410% (range, 260 to 720%), respectively.

TREATMENT AND OUTCOME

The patients received individually tailored supportive care for acute kidney injury. Serum creatinine concentrations began to improve at a median of 4 days (range, 3 to 4 days) and returned to within reference limits at a median of 7 days (range, 3 to 13 days) following initial exposure.

CLINICAL RELEVANCE

CIN should be considered as a potential complication following IV administration of contrast medium. Short-term outcome following CIN can be excellent with supportive care.

Abstract

CASE DESCRIPTION

During the same week, 3 sequential patients (a 10-year-old 8.7-kg spayed female poodle cross [dog 1], 13-year-old 2.6-kg spayed female domestic longhair cat, and 13-year-old 9.0-kg castrated male mixed-breed dog [dog 2]) underwent CT-angiography (day 0) and transarterial embolization (day 1) for nonresectable hepatocellular carcinoma (n = 2) or prostatic carcinoma (1).

CLINICAL FINDINGS

Contrast-induced nephropathy (CIN) was suspected in all animals on the basis of higher serum creatinine concentrations after contrast medium administration (exposure), compared with baseline concentrations before exposure, consistent with CIN definitions. The total dose of contrast medium was < 3 mL/kg for each exposure. For all 3 patients, creatinine concentration peaked at a median of 3 days (range, 2 to 3 days) after the first exposure (day 0), and the median absolute and relative increases in creatinine concentration after exposure (vs baseline concentrations before exposure) were 2.9 mg/dL (range, 2.2 to 3.7 mg/dL) and 410% (range, 260 to 720%), respectively.

TREATMENT AND OUTCOME

The patients received individually tailored supportive care for acute kidney injury. Serum creatinine concentrations began to improve at a median of 4 days (range, 3 to 4 days) and returned to within reference limits at a median of 7 days (range, 3 to 13 days) following initial exposure.

CLINICAL RELEVANCE

CIN should be considered as a potential complication following IV administration of contrast medium. Short-term outcome following CIN can be excellent with supportive care.

Introduction

Three client-owned animals (2 dogs and 1 cat) were presented to the University of California-Davis Veterinary Medical Teaching Hospital (UCD-VMTH) for transarterial embolization (TAE) of nonresectable neoplasia. Each animal first underwent CT-angiography (day 0 for each patient), followed by fluoroscopically guided TAE the following day (day 1 for each patient). The 3 animals were treated sequentially within the same week.

The first animal was a 10-year-old 8.7-kg spayed female Poodle cross (dog 1) with hepatocellular carcinoma referred for treatment with TAE. The dog was initially presented to its primary veterinarian for evaluation of episodic tachypnea and lethargy, at which point results of hematologic assessments indicated an inflammatory leukogram, high liver enzyme activities, and hypoglycemia; abdominal ultrasonography revealed a large hepatic mass; and laparotomy revealed that the mass was nonresectable. Results of histologic examination of a liver biopsy sample obtained during laparotomy were consistent with hepatocellular carcinoma.

On referral examination, dog 1 had a body condition score of 5/9, hepatomegaly, and cardiac arrhythmia with a grade 3/6 left apical systolic heart murmur. The remainder of the findings from the physical examination were unremarkable. Results of a CBC and serum biochemical analyses indicated mild thrombocytosis (462,000 platelets/mL; reference range, 150,000 to 400,000 platelets/mL), marked hypoglycemia (21 mg/dL; reference range, 86 to 118 mg/dL), metabolic acidosis (serum bicarbonate concentration, 16 mmol/L [reference range, 20 to 29 mmol/L]; anion gap, 28 mmol/L [reference range, 12 to 20 mmol/L]), hyperglobulinemia (3.4 g/dL; reference range, 1.7 to 3.1 g/dL), mildly high activities of aspartate transaminase (AST; 56 U/L [reference range, 20 to 49 U/L]) and g-glutamyltransferase (825 U/L; reference range, 0 to 5 U/L), and low creatinine concentration (0.6 mg/dL; reference range, 0.8 to 1.5 mg/dL); however, the dog's serum alanine amino-transferase activity (ALT; 68 U/L [reference range, 21 to 72 U/L]) and SUN concentration (12 mg/dL; reference range, 11 to 33 mg/dL) were within reference limits. Urinalysis revealed a urine specific gravity of 1.016, and thoracic radiography revealed no evidence of pulmonary metastasis or cardiomegaly. Findings from cardiac consultation involving echocardiography and ECG included mild myxomatous mitral valve disease, a thickened left ventricle, and frequent atrial ectopy. Blood pressures were within reference limits, and serum troponin concentration was mildly high (0.5 ng/mL; reference range, 0 to 0.2 ng/mL).

Dog 1 underwent general anesthesia for CT-angiography. Anesthesia was induced with etomidate (0.5 mg/kg, IV) and midazolam (0.2 mg/kg, IV), and after intubation, general anesthesia was maintained with isoflurane delivered in oxygen. To maintain appropriate hydration and perfusion, lactated Ringer solution (LRS; 10 mL/kg/h, IV) was administered throughout anesthesia. Perfusion parameters and blood pressures were monitored throughout the anesthetic event, and no hypotension (defined as mean arterial pressure < 60 mm Hg, systolic blood pressure < 80 mm Hg, or both) or other abnormalities were identified during anesthesia. Helical CT (Lightspeed 16; GE Medical Systems) images were obtained before and after administration of contrast medium (iopamidol [Isovue-370], 370 mg I/mL; 2.9 mL/kg, IV), and a large (8.4 × 8 × 9.5-cm) vascular, cavitated hepatic mass was identified. The mass appeared to have arisen from the central region of the liver, distorted the entire left aspect of the liver, and was deemed nonresectable owing to its extent and hilar location. Additional findings included a mildly enlarged dorsally located hepatic lymph node, a nodule (approx 4-mm diameter) on the right adrenal gland, and pinpoint renal cortical cysts bilaterally. Hematologic analyses performed approximately 20 minutes after induction of anesthesia revealed that the dog remained hypoglycemic (blood glucose concentration, 39 mg/dL). Recovery from anesthesia was unremarkable.

The following day (day 1), dog 1 underwent general anesthesia for TAE. The dog was premedicated with butorphanol (0.2 mg/kg, IV) and atropine sulfate (0.02 mg/kg, SC), and general anesthesia was induced with etomidate (1.0 mg/kg, IV) and midazolam (0.2 mg/kg, IV). After the dog was intubated, general anesthesia was maintained with isoflurane delivered in oxygen, and hydration and perfusion were maintained with the administration of LRS (4 mL/kg/h, IV) throughout anesthesia. Hepatic TAE was performed with a 0.014-inch microwire (RUNTHROUGH NS; Terumo Corp) and microcatheter (Progreat; Terumo Corp) combination via an access point in the right femoral artery and advanced under fluoroscopic guidance into a hepatic arterial branch that supplied the tumor. During this process, multiple small injections of contrast medium (iopamidol) were injected through the catheter so that the dog's vasculature and the catheter's location could be visualized with fluoroscopy. Once the catheter had been advanced to the proper location, a slurry of contrast medium, saline (0.9% NaCl) solution, and embolization particles (polyvinyl alcohol beads; Boston Scientific) was made and, with closely monitored fluoroscopic guidance, was injected slowly in short, repeated cycles to prevent retrograde flow. When cessation of blood flow through that arterial supply to the tumor was achieved, injection of the slurry was discontinued, and a second arterial tumoral blood supply was selected from a branch of the splenic artery. The embolization procedure was similarly performed at this location as well. Afterward, selective and non-selective arteriography was performed to assess the efficacy of the procedure and to verify patency of the main hepatic artery, celiac artery, and gastroduodenal artery; patency was confirmed. Given the nature of arterial treatment within branches of the celiac artery, inadvertent embolization of the renal arteries could not have occurred. All instruments were removed and the right femoral artery was ligated. No procedure-related complications were observed, and dog 1 recovered from anesthesia without complication. Overall, the total duration of the TAE procedure was 143 minutes, duration of anesthesia was 320 minutes, and volume of iopamidol administered was 17.4 mL (2 mL/ kg). Intraoperatively, dog 1 was not hypotensive but was intermittently hypo- or hyperglycemic (range, 22 to 149 mg/dL). Dog 1 was hospitalized overnight for monitoring and treatment with 2 mL/kg/h of LRS IV and 0.1 mg/kg/h of fentanyl at a constant rate infusion.

The next day, serum biochemical analyses were repeated, and abdominal ultrasonography and thoracic radiography were performed. Serum biochemical analyses revealed azotemia (creatinine concentration, 1.9 mg/dL; SUN concentration, 52 mg/dL) and markedly increased liver enzyme activities (ALT, 1710 U/L; AST, 8,748 U/L; alkaline phosphatase (ALP), 220 U/L [reference range, 14 to 91 U/L]; and γ-glutamyltransferase, 511 U/L), compared with previous results. The dog's glycemic status spontaneously normalized after recovery from anesthesia; however, the dog had developed evidence of pancreatitis (on the basis of findings from abdominal ultrasonography combined with a serum canine pancreas-specific lipase concentration of > 2,000 μg/L [reference range, 0 to 200 μg/L]), aspiration pneumonia (on the basis of thoracic radiographic evidence), and hypercoagulability (on the basis of results from thromboelastography) with thromboembolic disease (evidence noticed during abdominal ultrasonographic examination). Dog 1 remained hospitalized and continued to receive LRS (2 mL/kg/h, IV).

On day 3 (2 days after TAE), abdominal ultrasonography was repeated and revealed findings consistent with acute kidney injury (hyperechoic and mildly thickened renal cortices) and secondary retroperito-neal effusion and inflammation; appropriate venous and arterial blood flow was present in both kidneys. Urinalysis revealed isosthenuria (urine specific gravity, 1.011) with proteinuria (75 mg/dL), glycosuria (50 mg/ dL) without hyperglycemia, hematuria (6 to 8 RBCs/ hpf; reference range, 0 to 2 RBCs/hpf), rare hyaline casts, and no WBCs or bacteriuria. Aerobic bacterial culture performed on a urine sample yielded no growth. Medical management included LRS (2 mL/ kg/h, IV) to maintain hydration and prevent overhydration; broad-spectrum antimicrobials, including enrofloxacin (10 mg/kg, IV, q 24 h) and ampicillin-sulbactam (50 mg/kg, IV, q 8 h), for treatment of aspiration pneumonia; nasogastric tube feedings; capromorelin (3 mg/kg, PO, q 24 h), pantoprazole (1 mg/kg, IV, q 12 h), and ondansetron (0.5 mg/kg, IV, q 12 h) for gastro-supportive effects; and clopidogrel (2.2 mg/kg, PO, q 24 h) to prevent blood clot formation. The dog's serum concentrations of creatinine (Figure 1) and SUN, estimated urine output, and body weight were monitored during hospitalization. Changes in body weight and estimated urine output were unremarkable, and by day 4 (3 days after TAE), the dog's serum creatinine concentration began to decrease. On day 8 (7 days after TAE), dog 1 had a serum creatinine concentration of 1.2 mg/dL and was discharged with prescriptions of amoxicillin trihydrate–clavulanate potassium (15 mg/kg, PO, q 12 h for 28 days), enrofloxacin (10 mg/kg, PO, q 24 h for 28 days), omeprazole (1 mg/kg, PO, q 12 h for 7 days), ondansetron (0.5 mg/kg, PO, q 12 h for 7 days), clopidogrel (2 mg/kg, PO, q 24 h for 14 days), and capromorelin (3 mg/kg, PO, q 24 h). In addition, the client was instructed to monitor for any signs of systemic illness and limit activity until after undergoing a recheck examination. At 1 year after TAE, dog 1 was reportedly clinically normal with no outward signs of disease.

Figure 1
Figure 1

Line graphs of progressive serum creatinine concentrations in 3 sequential patients (dog 1 [blue], cat [gray], and dog 2 [orange]) that underwent CT-angiography (day 0) and transarterial embolization treatment (day 1) for nonresectable neoplasia during the same week. All 3 patients had an increase in serum creatinine concentration, consistent with the definition of contrast-induced nephropathy, with a peak concentration observed on day 2 or 3 after CT-angiography; subsequent improvement with supportive care was noted before hospital discharge on day 8 for dog 1 and day 5 for dog 2 and the affected cat. Breaks in the line graphs for dog 1 (between days 8 and 18) and dog 2 (between days 5 and 13) represent interims between the point of hospital discharge and recheck evaluation when concentrations of serum creatinine were not obtained.

Citation: Journal of the American Veterinary Medical Association 259, 10; 10.2460/javma.20.02.0058

The second animal was a 13-year-old 2.6-kg spayed female domestic longhair cat with hepato-cellular carcinoma referred for treatment with TAE. Previously, the cat had been presented to its primary veterinarian for evaluation of hematuria, pollakiuria, and weight loss. The referring veterinarian performed blood work that revealed thrombocytosis, high liver enzyme activities, hypocalcemia (both total and ionized calcium), and a total T4 concentration within reference limits; abdominal ultrasonography that revealed a large hepatic mass on the right side with possible invasion into the caudal vena cava; and fine-needle aspiration and cytologic examination of the mass that yielded findings consistent with hepatocellular carcinoma. In addition, the cat had a previous history of hyperthyroidism secondary to thyroid carcinoma, for which the cat underwent unilateral thyroidectomy at the UCD-VMTH approximately 3.3 years before the present referral examination; cervical and mediastinal recurrent and ectopic thyroid carcinoma with subsequent surgical excision, during which the left cranial lung lobe appeared abnormal, was removed, and had evidence of fibrosis and emphysema on histologic examination (approx 2.4 years before the present referral examination); and hypocalcemia and suspected hypoparathyroidism treated with calcium carbonate and calcitriol following a second surgery to excise recurrent thyroid carcinoma.

On referral examination for the recently detected hepatic mass, the cat had a grade 2/6 left parasternal systolic heart murmur, hepatomegaly, and a body condition score of 3/9. The remaining findings on physical examination were unremarkable. Results of a CBC indicated normocytic, normochromic, nonre-generative anemia (Hct, 28.7%; reference range, 30% to 50%), and thrombocytosis (758,000 platelets/μL; reference range, 180,000 to 500,000 platelets/μL). Serum biochemical analyses revealed hypocalcemia (total calcium concentration, 5.7 mg/dL [reference range, 9.0 to 10.9 mg/dL]; ionized calcium concentration, 0.73 mmol/L [reference range, 1.14 to 1.35]); high activities of ALT (724 U/L; reference range, 27 to 101 U/L), AST (176 U/L; reference range, 17 to 58 U/L), and ALP (370 U/L; reference range, 14 to 71 U/L); hypocholesterolemia (70 mg/dL; reference range, 89 to 258 mg/dL); and low concentrations of creatinine (0.7 mg/dL; reference range, 1.1 to 2.2 mg/ dL) and SUN (17 mg/dL; reference range, 18 to 33 mg/dL). Urinalysis revealed a urine specific gravity of 1.059, proteinuria (75 mg/dL), and hematuria (> 100 RBCs/hpf) but no pyuria or bacteriuria. Thoracic radiography revealed generalized cardiomegaly but no evidence of pulmonary metastatic disease. Results from cardiac consultation with echocardiography and ECG were unremarkable, with the cat's heart murmur reported to have been physiologic in nature.

On day 0, the cat underwent general anesthesia for CT-angiography. The cat was premedicated with atropine (0.02 mg/kg, SC), then general anesthesia was induced with propofol (2.7 mg/kg, IV) and midazolam (0.2 mg/kg, IV). After intubation, general anesthesia was maintained with isoflurane delivered in oxygen. Helical CT images were obtained before and after administration of iopamidol (370 mg I/mL; 3.0 mL/kg, IV). To maintain appropriate hydration and perfusion, LRS (5 mL/kg/h, IV) was administered throughout anesthesia. In addition, perfusion parameters and blood pressures were monitored throughout the anesthetic event, and no hypotension was observed. Computed tomography revealed a large (4.7 × 5.1 × 5.4-cm) mass in the right side of the liver. The mass was deemed nonresectable owing to its hilar location in the liver and its association with vascular structures. Findings consistent with cholangitis, reactive abdominal lymph nodes, and splenomegaly were also evident. The cat recovered from anesthesia without complication and was hospitalized overnight.

On day 1 after CT-angiography, the cat underwent general anesthesia for TAE. The cat was premedicated with butorphanol (0.3 mg/kg, IV) and atropine (0.02 mg/kg, SC), and general anesthesia was induced with alfaxalone (1.2 mg/kg, IV) and midazolam (0.2 mg/kg, IV) and, after intubation, was maintained with isoflurane delivered in oxygen. To maintain appropriate hydration and perfusion, LRS (5 mL/kg/h], IV) and dopamine (3 to 10 mg/kg/min, IV) were administered throughout the anesthetic event. The procedure for TAE was performed as described earlier for dog 1, except that polyvinyl alcohol hydrogel beads (Bead Block; Boston Scientific Corp) were used for embolization in the cat and there was no tumoral blood supply arising from a splenic arterial branch, such that only hepatic arterial branches supplying the tumor were embolized. No procedure-related complications were observed, and recovery from anesthesia was unremarkable. Overall, the total duration of the TAE procedure was 173 minutes, duration of anesthesia was 275 minutes, and volume of iopamidol administered was 5.2 mL (2 mL/kg). No hypotension was observed during anesthesia.

The following day (day 2), serum biochemical analyses were repeated and revealed azotemia (creati-nine concentration, 2.9 mg/dL; SUN concentration, 73 mg/dL) and marked increased liver enzyme activities (ALT, 17,302 U/L; AST, 20,069 U/L; and ALP, 858 U/L), compared with the cat's earlier results. The cat's hypocalcemia had improved (total calcium concentration, 9.5 mg/dL); however, hyperphosphatemia (10.7 mg/ dL; reference range, 3.2 to 6.3 mg/dL) had developed. Fluid therapy was initiated with LRS (2 mL/kg/h, IV). The cat's serum concentrations of creatinine (Figure 1) and SUN, estimated urine output, and body weight were monitored. Findings from urinalysis on day 2 (1 day after TAE) included a urine specific gravity of 1.015, proteinuria (75 mg/dL), hematuria (> 100 RBCs/ hpf), and no casts, glycosuria, pyuria, or bacteriuria. No meaningful changes in body weight or estimated urine output occurred, and the cat's serum creatinine concentration improved. On day 5 (4 days after TAE), the cat had a serum creatinine concentration of 1.4 mg/ dL and was discharged with prescriptions of amoxicillin trihydrate–clavulanate potassium (15 mg/kg, PO, q 12 h for 28 days) and omeprazole (1 mg/kg, PO, q 12 h for 7 days). In addition, the client was instructed to reduce activity for approximately 2 weeks and monitor for any signs of systemic illness. Eight months after TAE, the cat had a serum creatinine concentration of 0.8 mg/dL, and 1 year after TAE, the cat was reportedly doing well and had no clinical signs of disease.

The third animal was a 13-year-old 9.0-kg castrated male mixed-breed dog (dog 2) with prostatic carcinoma referred for treatment with TAE, which is also referred to as prostatic artery embolization when involving the prostate. The dog had a history of pituitary-dependent hyperadrenocorticism and degenerative mitral valve disease with severe dilation of the left atrium and had been presented to its primary veterinarian for evaluation of hemorrhagic preputial discharge and, later, tenesmus. Results of urinalysis performed by the referring veterinarian indicated hematuria with no pyuria or bacteriuria, and subsequent bacterial culture performed on a sample of urine collected approximately 2 weeks before referral examination yielded no growth. In addition, abdominal ultrasonography had revealed an enlarged, mineralized prostatic mass that extended into the trigone region of the urinary bladder, multifocal nodules in the wall of the urinary bladder, severe bilateral degenerative renal changes, and hepatomegaly with a hepatic mass. Results of cytologic examination of fine-needle aspirate samples of the prostatic mass and hepatic mass were consistent with prostatic carcinoma and benign hepatic changes. Dog 2 was prescribed meloxicam (dosage not reported) and referred to the UCD-VMTH.

On referral examination, dog 2 had a grade 5/6 left apical systolic heart murmur, an enlarged, firm prostate on rectal examination, and a body condition score of 5/9. Results of a CBC were unremarkable. Serum biochemical analyses revealed mild azotemia (creatinine concentration, 1.8 mg/dL; SUN concentration, 40 mg/dL), mildly high ALP activity (172 U/L), and mild hyperkalemia (5.3 mmol/L; reference range, 3.6 to 4.8 mmol/L). Thoracic radiography revealed mild generalized cardiomegaly with enlargement of the left side of the heart and no evidence of pulmonary metastatic disease. Abdominal ultrasonography revealed polypoid mucosal masses in the urinary bladder, a prostatic mass with mineralization, bilateral severe renal degenerative changes with pyelectasia combined with cavitations in the papilla, choledocholithiasis, an isoechoic hepatic mass, and nonspecific splenic nodules.

Dog 2 underwent general anesthesia for CT-angiography. The dog was premedicated with butorphanol (0.3 mg/kg, IM) and atropine (0.02 mg/kg, SC). Anesthesia was induced with etomidate (0.8 mg/kg, IV) and midazolam (0.1 mg/kg, IV), and after intubation, general anesthesia was maintained with isoflurane delivered in oxygen. Fluid therapy and patient monitoring were performed as described earlier for dog 1. Helical CT images were obtained before and after administration of iopamidol (370 mg I/mL; 3.0 mL/kg, IV), and findings included a prostatic mass with extension into the trigone without ureteral obstruction, polypoid structures in the ventral aspect of the urinary bladder wall, an enlarged right medial iliac lymph node, hepatomegaly with a mass in the right side of the liver, cholelithiasis, cholestasis, and bilateral marked degenerative renal changes. No hypotension was observed during anesthesia, and recovery was unremarkable.

The following day (day 1), dog 2 underwent general anesthesia for prostate TAE. The dog was premedicated with meperidine (5 mg/kg, IM) and atropine (0.02 mg/ kg, SC). General anesthesia was induced with etomidate (1.1 mg/kg, IV) and midazolam (0.2 mg/kg, IV) and, after intubation, was maintained with isoflurane delivered in oxygen. To maintain appropriate hydration and perfusion, LRS (3 mL/kg/h, IV) and dobutamine (3 to 5 μg/ kg/min, IV, to effect) were administered throughout anesthesia. Prostatic artery embolization was performed with similar equipment as described for dog 1; however, the equipment was introduced from an access point in the dog's left carotid artery. After the guidewire and catheter were advanced into the aorta, small volumes of iopamidol were injected to fluoroscopically map the blood supply to the prostate; the microwire and micro-catheter were advanced into the left prostatic artery, and the vascular supply to the prostate was identified. A slurry of contrast medium mixed with polyvinyl alcohol beads (Bead Block, Boston Scientific) was injected until vascular stasis was observed. The microwire and microcatheter combination was then repositioned into the right prostatic artery, and the process was repeated. After bilateral embolization, iopamidol was injected at the level of aortic trifurcation and revealed no further fluoroscopic evidence of blushing of the prostate, signifying cessation of blood flow to the prostate and tumor. The prostate TAE equipment was removed from dog 2, and the dog's left carotid artery, which was used in the approach for prostate TAE, was ligated. No hypotension or procedure-related complications were observed, and dog 2 recovered from anesthesia without complication. The total duration of prostate TAE was 70 minutes, duration of general anesthesia was 245 minutes, and amount of iopamidol administered was 18.0 mL (2.0 ml/kg). Dog 2 was hospitalized overnight.

On day 2 (1 day after prostate TAE), results of serum biochemical analyses for dog 2 indicated that its azotemia had worsened (creatinine concentration, 4.0 mg/dL; SUN concentration, 68 mg/ dL). Therefore, dog 2 received supportive treatment with LRS (2 mL/kg/h, IV), and its serum concentrations of creatinine (Figure 1) and SUN, estimated urine output, and body weight were monitored during hospitalization. A focused recheck ultrasono-graphic examination of the dog's urinary system revealed unchanged renal degenerative findings from before prostate TAE and verified appropriate venous and arterial blood flow for both kidneys. Urinalysis performed on a free-catch sample of urine revealed a urine specific gravity of 1.026, proteinuria (25 mg/ dL), hematuria (25 to 50 RBCs/hpf), pyuria (11 to 20 WBCs/hpf), and no casts or glycosuria.

On day 3 (2 days after prostate TAE), urethral catheterization was performed to obtain a sterile urine sample, and the sample was submitted for aerobic bacterial culture. On day 4 (3 days after prostate TAE), the dog's azotemia began to improve. On day 5, the dog had a serum creatinine concentration of 2.1 mg/dL and was discharged with a prescription of omeprazole (1 mg/kg, PO, q 12 h for 7 days).

On day 7 (6 days after prostate TAE), results of aerobic bacterial culture performed on urine indicated growth of Mycoplasma sp, and doxycycline (5.6 mg/ kg, PO, q 12 h for 2 weeks) was prescribed. Administration of doxycycline began the following day; thus, dog 2 had improvement in azotemia 3 days before antimicrobial administration, suggesting an alternative explanation, such as contrast-induced nephropathy (CIN), for the dog's acute kidney injury. Repeated aerobic bacterial culture performed on urine samples collected 2 and 4 weeks after prostate TAE yielded no growth. At 1 year after prostate TAE, dog 2 was reportedly doing well with no clinical signs of disease.

When the 3 patients were considered collectively, creatinine concentration peaked at a median of 3 days (range, 2 to 3 days) after the first exposure (day 0) to contrast medium, and the median absolute and relative increases in creatinine concentration after exposure (vs baseline concentrations before exposure) were 2.9 mg/dL (range, 2.2 to 3.7 mg/dL) and 410% (range, 260% to 720%). Following peak serum creatinine concentrations, the measurements began to improve at a median of 4 days (range, 3 to 4 days) and returned to within reference limits at a median of 7 days (range, 3 to 13 days) following the initial exposure. The contrast medium used for all 3 procedures was obtained from the same lot. Given the development of marked azotemia in patients that underwent contrast medium administration sequentially within a single week, samples of contrast medium from the pharmacy stock of the same lot as that used in the 3 procedures of the present report were tested to confirm an appropriate iopamidol concentration and to look for potential contaminants. For untargeted contaminant testing, gas chromatography–mass spec-trometry and liquid chromatography–mass spectrometry screens were performed; however, no contaminants were identified. In addition, the concentration of iopamidol was determined with high-performance liquid chromatography–mass spectrometry and a commercially available iopamidol standard. The iopamidol concentration was consistent with the labeled concentration.

Discussion

Contrast-induced nephropathy has been documented in human medicine and is defined as an absolute (≥ 0.5 mg/dL) or relative (≥ 25%) increase in a patient's serum creatinine concentration above baseline for that patient 48 to 72 hours following exposure to a contrast medium wherein alternative explanations for renal impairment have been excluded.1 Although not part of the strict definition or criteria for CIN, serum creatinine concentration typically peaks between 3 to 5 days after contrast medium administration and returns to near baseline within 1 to 3 weeks.1,2 Definitive documentation of CIN as a cause for acute kidney injury can be challenging in many patients because of concurrent comorbidities and risks for nephropathies in these patients. In humans, the risk of renal function impairment associated with radiologic procedures is low overall (2.3% in one study3]); however, patient-specific risk factors and the volume of contrast medium administered can alter this incidence.1,3,4,5

Multiple risk factors for CIN have been documented in people, including older age, preexisting kidney disease, cardiac disease, hypotension, dehydration, volume of contrast media administered, and use of medications that affect renal perfusion or function.1,6 The risk for CIN has been described as cumulative, in which the risk for development of CIN is greater when multiple risk factors are present with a synergy among risk factors.1 Moreover, protocols have been recommended in people to reduce the risk for CIN.6,7 For instance, nephrotoxic drugs (eg, angiotensin-converting enzyme inhibitors) should be discontinued ≥ 24 hours before contrast medium exposure.6,8,9 Prehydration has also been shown to be effective in reducing the risk for CIN, and it is recommended to begin IV fluid therapy with an isotonic crystalloid ≥ 12 hours before contrast medium exposure and continue this fluid therapy for 6 to 12 hours following exposure; however, forced diuresis with mannitol or furosemide is not recommended and is associated with an increased risk of CIN in people.6,8,9 Vasodilators (eg, theophylline) may be used in high-risk human patients but are not recommended for routine use.6,9 The role of antioxidants (eg, ascorbic acid and N-acetylcysteine) in CIN in humans is not well documented.6,9,10

In veterinary medicine, CIN is not well documented. A retrospective study11 of 86 dogs with 92 IV administrations of contrast medium expanded the time frame in the definition of CIN to 7 days post-exposure, and 7 (8%) dogs developed parameters that met the definition for CIN. However, those investigators were unable to determine risk factors for or clinical progression of CIN in dogs because long-term follow-up was only reported for 2 dogs.11 Although risk factors for CIN have not yet been identified in dogs or cats, it is important to consider that risk factors similar to those documented in people may also be associated with CIN in veterinary patients. In a retrospective study12 of 280 dogs that underwent general anesthesia and IV administration of various contrast media, no significant alterations in serum markers for renal function were detected; however, the authors reported that only a small number of dogs had preand post-exposure serum biochemical results in their medical records and that intervals for hematologic assessments may not have been appropriate to detect the changes, some of which could have been mild or transient. Because of the paucity of information on CIN in veterinary patients, recommendations to reduce the risk of CIN (especially in animals with comorbidities that may increase the risk of this disease) have not been reported.

The pathophysiologic processes associated with CIN are complex, multifactorial, and incompletely understood. Multiple mechanisms have been proposed by which iodinated contrast agents cause acute tubular necrosis and CIN syndrome.13 These include vasoconstriction at the renal corticomedullary junction, which can occur up to 3 to 4 hours following contrast medium administration; impaired renal autoregulatory ability in the outer medullary region through a loss of nitric oxide production; oxidative stress; and toxic effects directly impacting the renal tubules.13 The osmolarity and ionic nature of contrast media appear to contribute to the pathogenesis of CIN.13 Higher osmolar, ionic compounds (vs lower osmolar, nonionic compounds) have relatively good attenuation with enhanced visualization on imaging modalities but also result in increased risk for nephrotoxicity.13 Therefore, low osmolar, nonionic contrast agents (eg, iohexol and iopamidol) are generally preferred in human and veterinary medicine. For patients at high risk for CIN (eg, those with chronic kidney disease or cardiac disease), administration of iso-osmolar contrast agents may be associated with a lower risk of CIN.13

The 3 animals of the present report had increases in serum creatinine concentrations that peaked at a median of 3 days (range, 2 to 3 days) after the first contrast medium administration (during CT-angiogram). The median absolute increase in creatinine concentration was 2.9 mg/dL (range, 2.2 to 3.7 mg/dL), and the median relative increase in creatinine concentration was 410% (range, 260% to 720%) from baseline. These increases and the temporal association with administration of contrast medium were consistent with the definition for CIN in humans. However, for each animal, other differential diagnoses for azotemia were considered. Prerenal causes were deemed unlikely because modifiable factors that affect renal perfusion (eg, mean and systolic arterial blood pressure, perfusion parameters, and hydration status) were assessed to have been adequate in all 3 patients; no animals developed hypovolemia, had evidence of poor cardiac function, or had signs of dehydration, and all 3 animals were provided fluid therapy over the course of hospitalization. Although dog 1 developed pancreatitis, the dog maintained adequate perfusion and hydration. Postrenal causes were also excluded, as there was no evidence of urinary obstruction in any of these patients. A renal source of azotemia was subsequently considered most likely. Primary differential diagnoses included pyelonephritis, procedure-related renal injury, general anesthesia-related renal injury (associated with renal ischemia), and CIN. No definitive evidence of pyelonephritis was detected in any of these patients; however, dog 2 had a urinary tract infection diagnosed after prostate TAE. Although bacterial culture performed on urine obtained from dog 2 yielded growth of a Mycoplasma sp, recheck ultrasonographic examination revealed no changes in renal structure from before versus after exposure to contrast medium, the dog's pyuria resolved, and results were negative for recheck bacterial cultures performed on urine samples obtained at 2 and 4 weeks after prostate TAE and antimicrobial treatment. Moreover, azotemia in dog 2 began to improve 3 days before antimicrobial treatment was started. However, findings from diagnostic imaging and laboratory analyses indicated that all 3 animals had evidence of at least stage 1 chronic kidney disease when assessed with guidelines14 from the International Renal Interest Society, and chronic kidney disease may be considered a risk factor for acute kidney injury. No known direct effect of the TAE procedures causing renal impairment (eg, nontarget embolization or clotting secondary to catheter placement) was detected. Furthermore, in all 3 animals, blood pressure was closely monitored throughout general anesthesia and recovery for CT-angiography and TAE. Although 2 of the animals required vasopressors for cardiovascular support, such treatment was initiated to prevent hypotension, and hypotension during anesthesia was not observed in any of the 3 animals. Moreover, testing of the iopamidol lot revealed no evidence of toxicants or inadvertent overdose of contrast medium administration. Therefore, CIN was suspected in these 3 patients, given that each met the criteria for CIN, as defined in humans, with the time course of disease and exclusion of other causes of sudden onset or progressive azotemia. As is typically observed in people with CIN, all 3 animals of the present report also showed resolution or improvement of azotemia with supportive care within 4 to 12 days following the procedure. This supports the potential for good outcomes in veterinary patients with suspected CIN, provided the condition is recognized early and appropriate treatment and supportive care for acute kidney injury are initiated.

It is also important to consider comorbidities that may predispose animals to CIN to improve early detection and prevent this condition. Each animal in the present report had ≥ 1 predisposing risk factor reported in people for CIN, including older age, cardiac disease, and preexisting renal disease. Moreover, because CIN is a diagnosis of exclusion, it is important to consider alternative differential diagnoses for azotemia following contrast medium administration that may influence treatment and prognosis. These 3 patients were thoroughly assessed, and although pancreatitis in dog 1 and pyelonephritis in dog 2 could not be ruled out as contributing factors for sudden onset or progression of azotemia, these conditions were deemed less likely causes than CIN because of the reasons previously discussed, the temporal nature of azotemia relative to contrast medium exposure, and the fact that all 3 instances occurred sequentially within a week. In these 3 patients, high concentrations of serum markers for renal function were seen following contrast medium administration, despite measures taken to help reduce the risk of nephropathy with general anesthesia and contrast medium administration. Conservative doses of nonionic, iodinated contrast medium were used in all 3 patients, and administration did not exceed the recommended dose (generally considered < 3 mL/kg, with a safe dose not yet documented in dogs).15 Contrast medium administration for CT-angiography and TAE were separated by approximately 24 hours to decrease the duration of general anesthesia per day and total contrast medium dose per day, with supportive fluid therapy in the interim of these 2 procedures for each of the 3 patients of the present report. Additionally, appropriate patient monitoring and support were performed during anesthesia in all 3 animals during CT-angiography and TAE, and blood pressure was monitored and maintained within reference limits with fluid therapy and administration of vasopressors as indicated. Periprocedural fluid therapy was also provided to all 3 patients. Although the 3 instances of suspected CIN described in the present report were temporally sequential with the same lot of contrast medium used for each procedure, our testings of the lot detected no abnormalities, such as nephrotoxins.

A limitation of the present clinical report involves the retrospective nature of data collection with a subsequent inability to document cause and effect. Although CIN was strongly suspected in the 3 animals of the present report, CIN could not be definitively proven. In addition, our findings cannot be extrapolated to other contrast media or lots of iopamidol.

In conclusion, CIN should be considered as a possible complication following the use of injectable iodinated contrast medium. Active monitoring for CIN may improve outcomes in veterinary patients, and thoughtful periprocedural patient monitoring and medical management (eg, fluid therapy spanning from at least 12 hours before to 6 to 12 hours after administration of contrast medium in patients at risk) should be performed. In conjunction, possible nephrotoxic drugs should be discontinued at least 24 hours before administration of contrast medium in patients that can tolerate the change. It is also very important to monitor serum creatinine concentrations before and after administration of contrast medium in patients at increased risk for CIN, and small increases in creatinine concentration should be documented and addressed promptly.

Acknowledgments

The authors declare that there were no conflicts of interest.

References

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    Hossain MA, Costanzo E, Cosentino J, et al. Contrast-induced nephropathy: pathophysiology, risk factors, and prevention. Saudi J Kidney Dis Transpl. 2018;29(1):19. doi:10.4103/1319-2442.225199

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    Azzalini L, Spagnoli V, Ly HQ. Contrast-induced nephropathy: from pathophysiology to preventive strategies. Can J Cardiol. 2016;32(2):247255.

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    Solomon R, Deray G, Consensus Panel for CIN. How to prevent contrast-induced nephropathy and manage risk patients: practical recommendations. Kidney Int Suppl. 2006;69(100):S51S53. doi:10.1038/sj.ki.5000375

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    Stacul F, Adam A, Becker CR, et al. Strategies to reduce the risk of contrast-induced nephropathy. Am J Cardiol. 2006;98(6A):59K77K.

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    Briguori C, Marenzi G. Contrast-induced nephropathy: pharmacological prophylaxis. Kidney Int Suppl. 2006;69(100):S30S38.

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    Goic JB, Koenigshof AM, McGuire LD, Klinger AC, Beal MW. A retrospective evaluation of contrast-induced kidney injury in dogs (2006–2012). J Vet Emerg Crit Care (San Antonio). 2016;26(5):713719.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Pollard RE, Puchalski SM, Pascoe PJ. Hemodynamic and serum biochemical alterations associated with intravenous administration of three types of contrast media in anesthetized dogs. Am J Vet Res. 2008;69(10):12681273.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Tumlin J, Stacul F, Adam A, et al. Pathophysiology of contrast-induced nephropathy. Am J Cardiol. 2006;98(6A): 14K20K.

  • 14. IRIS staging of CKD. International Renal Interest Society. Accessed April 10, 2020. www.iris-kidney.com/guidelines/staging.html

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  • Figure 1

    Line graphs of progressive serum creatinine concentrations in 3 sequential patients (dog 1 [blue], cat [gray], and dog 2 [orange]) that underwent CT-angiography (day 0) and transarterial embolization treatment (day 1) for nonresectable neoplasia during the same week. All 3 patients had an increase in serum creatinine concentration, consistent with the definition of contrast-induced nephropathy, with a peak concentration observed on day 2 or 3 after CT-angiography; subsequent improvement with supportive care was noted before hospital discharge on day 8 for dog 1 and day 5 for dog 2 and the affected cat. Breaks in the line graphs for dog 1 (between days 8 and 18) and dog 2 (between days 5 and 13) represent interims between the point of hospital discharge and recheck evaluation when concentrations of serum creatinine were not obtained.

  • 1.

    Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and patients at risk. Kidney Int Suppl. 2006;69(100):S11S15.

  • 2.

    McCullough PA, Sandberg KR. Epidemiology of contrast-induced nephropathy. Rev Cardiovasc Med. 2003;4(suppl 5):S3S9.

  • 3.

    Lasser EC, Lyon SG, Berry CC. Reports on contrast media reactions: analysis of data from reports to the US Food and Drug Administration (Erratum published in Radiology. 1997;204[3]:876). Radiology. 1997;203(3):605610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Marenzi G, Marana I, Lauri G, et al. The prevention of radiocontrast-agent–induced nephropathy by hemofiltration. N Engl J Med. 2003;349(14):13331340.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Hossain MA, Costanzo E, Cosentino J, et al. Contrast-induced nephropathy: pathophysiology, risk factors, and prevention. Saudi J Kidney Dis Transpl. 2018;29(1):19. doi:10.4103/1319-2442.225199

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Walsh SR, Tang T, Gaunt ME, Boyle JR. Contrast-induced nephropathy. J Endovasc Ther. 2007;14(1):92100.

  • 7.

    Azzalini L, Spagnoli V, Ly HQ. Contrast-induced nephropathy: from pathophysiology to preventive strategies. Can J Cardiol. 2016;32(2):247255.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Solomon R, Deray G, Consensus Panel for CIN. How to prevent contrast-induced nephropathy and manage risk patients: practical recommendations. Kidney Int Suppl. 2006;69(100):S51S53. doi:10.1038/sj.ki.5000375

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Stacul F, Adam A, Becker CR, et al. Strategies to reduce the risk of contrast-induced nephropathy. Am J Cardiol. 2006;98(6A):59K77K.

  • 10.

    Briguori C, Marenzi G. Contrast-induced nephropathy: pharmacological prophylaxis. Kidney Int Suppl. 2006;69(100):S30S38.

  • 11.

    Goic JB, Koenigshof AM, McGuire LD, Klinger AC, Beal MW. A retrospective evaluation of contrast-induced kidney injury in dogs (2006–2012). J Vet Emerg Crit Care (San Antonio). 2016;26(5):713719.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Pollard RE, Puchalski SM, Pascoe PJ. Hemodynamic and serum biochemical alterations associated with intravenous administration of three types of contrast media in anesthetized dogs. Am J Vet Res. 2008;69(10):12681273.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Tumlin J, Stacul F, Adam A, et al. Pathophysiology of contrast-induced nephropathy. Am J Cardiol. 2006;98(6A): 14K20K.

  • 14. IRIS staging of CKD. International Renal Interest Society. Accessed April 10, 2020. www.iris-kidney.com/guidelines/staging.html

  • 15. Weisse C. Fundamentals of interventional radiology and interventional endoscopy. In: Johnston S, Tobias K, eds. Veterinary Surgery: Small Animal. 2nd ed. Elsevier; 2018:309317.

    • Search Google Scholar
    • Export Citation

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