Introduction

Renal secondary hyperparathyroidism is a common finding in canine and feline patients with chronic kidney disease (CKD). A prospective study of 80 cats found that 84% of cats with CKD demonstrated hyperparathyroidism.¹ This group was stratified into compensated, uremic, and end-stage CKD, and when compared with age-matched controls, the latter two groups showed significantly higher values for parathyroid hormone (PTH) and phosphorus. In fact, it has been demonstrated that cats are often hyperparathyroid before they have developed azotemia.² Similar results were shown in a study in which 75.9% of dogs with CKD were diagnosed with hyperparathyroidism, with 100% of dogs with advanced CKD demonstrating hyperparathyroidism.³ Despite the fact that hyperparathyroidism is prevalent in companion animals, complex mechanisms work to restore calcium homeostasis, and bloodwork derangements or pathology are seldom witnessed until late in the disease process.

During CKD progression, as functional nephrons are lost, glomerular filtration rate diminishes, leading to hyperphosphatemia. Excess phosphorus complexes with ionized calcium, lowering its blood concentration. Additionally, with CKD, lower levels of 25-hydroxycholecalciferol are produced by the kidneys, decreasing calcium absorption at the level of the kidney and intestine. In an attempt to improve calcium balance, PTH levels rise. Initially, this rise helps the kidney excrete phosphorus. However, as additional nephrons are lost and the kidneys cannot excrete phosphorus appropriately, the phosphaturic effect of PTH is diminished and the negative feedback on PTH is lost, leading to hyperparathyroidism.

Under the effect of increased PTH, calcium and phosphorus are liberated from the bone. In humans, an established link exists between oral pathology and renal secondary hyperparathyroidism. Osseous lesions are uncommon but well documented in dogs. In canines, a hierarchy of bone loss has been demonstrated, with an affinity for jaw/alveolar bone, followed by other skull bones, the ribs, vertebrae, and finally long bones.⁴ Loss of mandibular mineralization and replacement with fibrous connective tissue can produce jaw flexibility, leading to the descriptor “rubber jaw.”⁵ Clinical findings can include mobile teeth despite normal probing findings, pathological fractures, and malocclusion.⁶ Radiographic findings include teeth that appear to be “floating in space” owing to loss of supporting bone and a ground glass appearance of mandibular bone.⁶ No similar feline cases of fibrous osteodystrophy due to renal secondary hyperparathyroidism have been reported.

Case Report

A 6 yr old neutered male mixed-breed cat was referred to a veterinary teaching hospital for renal transplantation (RTx), after medical management of International Renal Interest Society Stage 4 CKD failed to provide a suitable quality of life.⁷ At 4 yr of age, the cat was diagnosed with acute kidney injury, after suspected ingestion of a lily petal. The cat was decontaminated and treated supportively for resulting CKD for several years. Nine months before presentation for RTx, abdominal ultrasound revealed mild bilateral renomegaly with poor corticomedullary definition, mild to moderate renal pelvis dilation, and absence of ureteral dilation. Urine culture yielded Escherichia coli. Antibiotic therapy resulted in negative urine cultures, although the cat remained persistently severely azotemic (creatinine 5.3 mg/dL; reference 0.3–2.1/blood urea nitrogen [BUN] 133 mg/dL; reference 10–30), hyperphosphatemic (11.9 mg/dL; reference 3.4–8.5), isosthenuric (urine specific gravity 1.012), and anemic (packed cell volume 22%) before presentation (Table 1). Parathyroid hormone levels were not assessed before evaluation for the planned RTx.

TABLE 1 Summary of Pertinent Laboratory Parameters Before and After RTx

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Concurrent medical conditions included moderate periodontal disease, diabetes mellitus controlled by diet, chronic intermittent pancreatitis, suspected inflammatory bowel disease, and early hypertrophic cardiomyopathy (based on the presence of a grade II/VI parasternal heart murmur and mild equivocal left ventricular wall thickening on echocardiogram). Blood pressure could not be evaluated because of temperament. The cat consumed a variety of commercial cat foods, some of which were grain free. Preoperative infectious disease screening included retroviral testing (negative for feline immunodeficiency virus and feline leukemia virus) and toxoplasmosis titers (immunoglobulin G negative, immunoglobulin M 1:64). Life-long clindamycin therapy was instituted because of the potential for clinical toxoplasmosis with immune suppression. The cat was prescribed a cyclosporine trial at 4 mg/kg orally q 12 hr for 1 mo before presentation. Urine culture following the cyclosporine trial was negative.

Upon evaluation for the RTx, 1 wk before surgery, the cat was quiet, alert, and responsive with an aural temperature of 102.1°F, heart rate of 240 beats per min, and respiratory rate of 36 breaths per min. A grade I/VI parasternal heart murmur was appreciated with normal lung sounds in all quadrants. Palpation of abdomen and peripheral lymph nodes was unremarkable. Initial bloodwork revealed severe azotemia (creatinine 5.5 mg/dL; reference 0.3–2.1/BUN 133 mg/dL; reference 10–30), hyperphosphatemia (10.8 mg/dL; reference 3.4–8.5), and normocalcemia (11.0 mg/dL; reference 8.0–11.8; Table 1). Preoperative abdominal ultrasound revealed kidney changes consistent with previous findings. Owing to the immunosuppressive protocols required for RTx, a comprehensive oral health assessment and treatment procedure was recommended to remove the bacterial burden from the oral cavity.

Oral examination under anesthesia revealed severe dental calculus and gingivitis associated with the majority of the remaining teeth. Subtle mobility was noted in all teeth, with significant mobility detected in several. Feline odontoclastic resorptive lesions were present on numerous teeth, and the pulp canals appeared narrowed in all teeth with the exception of the canine teeth. Retained root fragments were detected radiographically. The most notable findings of intraoral dental radiographs (Figure 1) included a diffuse, severe bone demineralization across the mandible and maxilla including the orbit, with thinning of the cortices. The mandibular bone demonstrated a ground glass appearance, and the mandibular canal was difficult to visualize owing to lack of bony definition. Nasal concha were easily visualized with decreased opacity of maxillary bone. Generalized resorption of alveolar bone left teeth to appear free of boney attachment. Occlusion of the jaw was neutral with no palpable laxity. Because of the severe periodontal disease affecting the remaining teeth, all were extracted along with the retained root fragments. The cat recovered from anesthesia uneventfully, and pain was well controlled with analgesics. Aftercare for the cat included hospitalization with 0.03 mg/kg buprenorphine IV q 8 hr and 10 mg/kg clindamycin IV q 12 hr.

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The severe osseous changes witnessed on dental radiographs along with the history of chronic kidney disease prompted evaluation of the cat’s parathyroid glands with a Vitamin D panel^a and an ultrasound examination. Results indicated an intact PTH of 215.6 pmol/L (reference 0.4–2.5), 25-Hydroxyvitamin D value of 134 nmol/L (reference 65.0–170.0), and ionized calcium level of 1.22 mmol/dL (reference 1.00–1.40). On ultrasound examination, in the midbody of both lobes of the thyroid gland, there were hypoechoic nodules (right side = 0.28 × 0.41 cm, left side = 0.28 × 0.76 cm). These nodules had moderate peripheral vascularity indicating they were not thyroid cysts. The sizes of the external parathyroid glands were not recorded. The thyroid gland was normal. A diagnosis of renal osteodystrophy due to secondary hyperparathyroidism was established.

After continued monitoring in hospital for 7 days, a heterotopic kidney transplantation was performed. A cortical wedge biopsy was taken from the body of the left native kidney. Histopathology indicated chronic tubulointerstitial disease characterized by moderate, chronic diffuse tubular atrophy; marked, multifocal, interstitial fibrosis with lymphohistiocytic inflammation and free lipid; and moderate focal, segmental glomerulosclerosis, without signs of infection. Blood transfusions were performed from crossmatch compatible donors intraoperatively and 2 days postoperatively owing to persistent anemia. At 1 and 7 days after RTx, abdominal ultrasounds were completed to assess the viability of the allograft. Five days after RTx, the cat became persistently hyperglycemic and treatment for diabetes mellitus was initiated with subcutaneous regular insulin (1 unit q 6 hr).

Six days after RTx, the cat developed a gallop rhythm, along with an increased respiratory rate and effort with expiratory crackles. Thoracic radiographs revealed generalized cardiomegaly and pulmonary edema, consistent with congestive heart failure. Echocardiogram confirmed mild pericardial effusion and scant pleural effusion. The cat responded well to treatment with furosemide and oxygen, along with adjustments in IV fluid therapy. Despite cautious fluid therapy, it was concluded that the congestive heart failure resulted from iatrogenic fluid overloading. The cat was discharged from the teaching hospital 10 days postoperatively, with resolved azotemia (creatinine 1.2 mg/dL; reference 0.3–2.1/BUN 23 mg/dL; reference 10–30; Table 1). Therapies included oral prednisolone (0.2 mg/kg q 12 hr), mycophenolate (8 mg/kg q 12 hr), cyclosporine (4 mg/kg q 12 hr), clopidogrel (3 mg/kg q 24 hr), and clindamycin (4 mg/kg q 12 hr) as well as subcutaneous glargine insulin (1 unit q 12 hr). Continued ultrasound examinations, bloodwork monitoring, and assessment of trough cyclosporine levels were completed with the referring veterinarian.

After 5 wk of continued care, the cat developed acute azotemia (creatinine 6.6 mg/dL; reference 0.3–2.1; Table 1) and renomegaly of the allograft. Rejection was suspected, although infection could not be ruled out. The patient was hospitalized and treated with enhanced immunosuppressive therapy (increased oral prednisolone at 1.5 mg/kg q 12 hr and cyclosporine at 8 mg/kg q 12 hr) and broad-spectrum antibiotics, resulting in moderate improvement in azotemia (creatinine 2.8 mg/dL; reference 0.3–2.1). Serial increases in subcutaneous glargine to 4 units q 12 hr were required to maintain glycemic control. Two months after RTx, the referring veterinarian reported plaque-like lesions on the dorsal neck bearing the appearance of calcinosis cutis. Cytology interpretation by a credentialed clinical pathologist supported this suspicion. The calcium × phosphorus product at this time was 125.4 mg²/dL². At this visit, the dosage of prednisolone was 1 mg/kg orally q 12 hr. Over the next 2 wk, the cat’s quality of life improved and his creatinine decreased (1.7 mg/dL; reference 0.3–2.1). Bloodwork was repeated to evaluate the cat’s PTH level 3.5 mo after RTx. Results indicated an intact PTH value of 27.2 pmol/L (reference 0.4–2.5; Table 1). Results remained consistent with renal secondary hyperparathyroidism, although a marked decrease was noted in the PTH level after transplantation.

Discussion

A literature review yielded limited examples of clinical changes related to presumed renal secondary hyperparathyroidism in cats. One report documented hyperparathyroidism (PTH 10.0 pmol/L; reference 0.5–5.8) in an 18 yr old domestic shorthair with a 5 yr history of CKD.⁸ Notable findings in this case included enlarged parathyroid glands with a lack of the predicted hyperphosphatemia and hypocalcemia expected with hyperparathyroidism. Osseous structures were not evaluated in this cat. Another publication describes an azotemic 10 yr-old domestic shorthair who presented with histopathologically diagnosed metastatic calcifications of the footpads in conjunction with renal secondary hyperparathyroidism (PTH 75.8 pg/mL; reference 3.3–22.5).⁹ That cat demonstrated a calcium × phosphorus product of 73.5 mg²/dL² at diagnosis. The calcification resolved with feeding a phosphorus- and protein-restricted diet over the course of 105 days. The PTH level and calcium × phosphorus product normalized with treatment. Bone lesions were not reported on thoracic and abdominal radiographs. The final documented manifestation of feline renal secondary hyperparathyroidism describes an azotemic 5 mo old domestic shorthair who suffered from multifocal osteolytic lesions in the cortical region of long bones and the skull.¹⁰ The most significant changes were identified in the femoral diaphysis, where a massive substitution of fibrous connective tissue for bone and increase in osteoblast activity was diagnosed with histopathology. Osteolytic changes were noted in the calvarium, maxilla, and mandible with thinned cortices. Parathyroid hormone level was not documented in this cat owing to euthanasia; hyperparathyroidism was suspected as a result of parathyroid hyperplasia. Kidney histopathology revealed evidence of chronic glomerulonephritis with metastatic mineralization. The calcium × phosphorus product in this cat was 93.6 mg²/dL².

In a study that examined histologic sections of bone from 93 necropsied cats with CKD, mild osteoclastic resorption of cortical and trabecular bone and replacement with fibrous connective tissue was identified in cats with the most severe renal disease.¹¹ This group also demonstrated the greatest parathyroid weight. Signs of gross osteomalacia were not witnessed in any necropsied cat, and a hierarchy of bone preference was not documented. Another study compared femoral and vertebral bone quality of 13 cats with advanced naturally occurring CKD with normal controls and found increased bone resorption, lower cortical bone mineral density, and increased fragility in the bones of cats with CKD.¹²

Interestingly, the clinical findings and distribution of lesions associated with renal secondary hyperparathyroidism described in the current cat demonstrate expected manifestations of a canine patient and to the authors’ knowledge are novel findings in the feline species. The classic appearance of fibrous osteodystrophy in dogs involves teeth that appear to be “floating in space” because of alveolar and trabecular bone loss.⁶ Additionally these patients may exhibit mobile teeth despite normal probing depths, tendency toward fracture, mobile bone, and malocclusion. The cat described in this case demonstrated similar radiographic lesions and tooth mobility. Similar to the cat in this report, narrowed dental pulp canals have been reported in human patients with renal secondary hyperparathyroidism.¹³ Histopathology of the alveolar bone would have been an interesting addition to this report, but fear of fracture with further osseous compromise deterred this diagnostic test.

Following continued care, the patient developed cutaneous lesions consistent with calcinosis cutis. Although this was not verified with histopathology because of quality of life concerns, the finding is plausible given the calcium × phosphorus product of 125.4 mg²/dL² at the time. A calcium × phosphorus product greater than 70 mg²/dL² has been associated with metastatic soft tissue calcification in human patients with uremia.¹⁴ Immunosuppressive doses of glucocorticoids also may have contributed to this finding.

The relatively long chronicity of the cat’s CKD before admission for RTx may explain the development of clinical findings in this case. A meta-analysis of a 50 yr span of veterinary literature yielded 42 examples of dogs with renal secondary hyperparathyroidism resulting in renal osteodystrophy.⁶ The median age of these patients was 35.6 mo, with 62% of the patients 2 yr of age or younger. Young, growing dogs affected with renal disease are susceptible to osseous changes because of sensitivity of growing bone to the effects of PTH. The advanced age of the current patient compared with the veterinary literature yields another interesting facet to this report.

To date, there are no reports concerning the effect of RTx on renal secondary hyperparathyroidism in domestic species. Another novel finding includes the significant decrease in PTH concentration from 215.6 to 27.2 pmol/L, 3.5 mo after RTx. Tracking parathyroid gland size measurements over this period would have been of interest. Although additional imaging to assess bone quality was not acquired 3.5 mo after RTx, significant remineralization would not be expected based on results from human studies. Continued presence of renal secondary hyperparathyroidism occurs in approximately 50% of human kidney transplant recipients, as was demonstrated in the current case.¹⁵ Bone disease progression after restoring normal renal function is dependent on the degree of loss at the time of transplantation, and pre-existing osseous changes were severe in this cat’s oral cavity.¹⁶

Conclusion

This report brings to light potential sequelae of CKD and renal secondary hyperparathyroidism. Although bone has been discussed as a target organ for damage in relation to these conditions, PTH has been identified as a uremic toxin affecting the heart, brain, muscle, lung, erythrocytes, leukocytes, pancreas, and adrenal glands.¹⁷ Hyperparathyroidism is a common sequela to chronic kidney disease in cats and dogs but often goes unrecognized owing to the compensatory mechanisms of the body to achieve calcium homeostasis and normalize blood analyte values. As elevated PTH levels can exist before azotemia, it could possibly serve not only as a bio-marker but as a disease process warranting earlier intervention. Typical management of CKD includes restriction of dietary phosphorus as well as administration of a phosphorus binder in patients in the later stages of disease. These therapies also have shown to be rewarding in improving survival and treating manifestations of hyperparathyroidism in companion animals.¹⁸ Calcitriol supplementation has been explored as an avenue to reduce PTH concentrations with mixed results.^19,20 Awareness of potential bone fragility in affected patients is essential to prevent pathologic bone fracture. Veterinary dentists, in particular, should be mindful of evaluation for osseous lesions involving the mandibular and maxillary bone.⁶