Feline chronic kidney disease is associated with shortened telomeres and increased cellular senescence.

Telomeres are protective structures at the ends of chromosomes that have important implications for aging. To address the question of whether telomeres contribute to feline chronic kidney disease (CKD), we evaluated kidney, liver, and skin samples from 12 cats with naturally occurring CKD, 12 young normal cats, and 6 old normal cats. Telomere length was assessed using standard telomere fluorescent in situ hybridization (TEL-FISH) combined with immunohistochemistry (TELI-FISH) to identify proximal (PTEC) and distal tubular epithelial cells (DTEC), whereas senescence-associated ß-galactosidase (SABG) staining was used to evaluate senescence. Results revealed statistically significant decreases in the average telomere fluorescence intensity (TFI) of PTEC in CKD cats compared with young and geriatric normal cats, and in the DTEC of CKD cats compared with young normal cats. When histograms of individual TFI were compared, statistically significant decreases in the PTEC and DTEC of CKD cats were observed compared with young and geriatric normal cats. Concomitantly, a statistically significant increase in SABG staining was seen in CKD kidney samples compared with young normal cats. CKD cats tended to have increased SABG staining in the kidney compared with normal geriatric cats, but this did not reach statistical significance. No significant telomere shortening in liver or skin from any group was observed. Real-time quantitative telomeric repeat amplification protocol assessment of renal telomerase activity revealed comparable low levels of telomerase activity in all groups. Our results suggest that shortened telomeres and increased senescence in the kidneys of CKD cats may represent novel targets for interventional therapy.

Assessment of peritubular capillary rarefaction in kidneys of cats with chronic kidney disease.

BACKGROUND: Hypoxia is a key driver of fibrosis and is associated with capillary rarefaction in humans. OBJECTIVES: Characterize capillary rarefaction in cats with chronic kidney disease (CKD). ANIMALS: Archival kidney tissue from 58 cats with CKD, 20 unaffected cats. METHODS: Cross-sectional study of paraffin-embedded kidney tissue utilizing CD31 immunohistochemistry to highlight vascular structures. Consecutive high-power fields from the cortex (10) and corticomedullary junction (5) were digitally photographed. An observer counted and colored the capillary area. Image analysis was used to determine the capillary number, average capillary size, and average percent capillary area in the cortex and corticomedullary junction. Histologic scoring was performed by a pathologist masked to clinical data. RESULTS: Percent capillary area (cortex) was significantly lower in CKD (median 3.2, range, 0.8-5.6) compared to unaffected cats (4.4, 1.8-7.0; P = <.001) and was negatively correlated with serum creatinine concentrations (r = -.36, P = .0013), glomerulosclerosis (r = -0.39, P = <.001), inflammation (r = -.30, P = .009), and fibrosis (r = -.30, P = .007). Capillary size (cortex) was significantly lower in CKD cats (2591 pixels, 1184-7289) compared to unaffected cats (4523 pixels, 1801-7618; P = <.001) and was negatively correlated with serum creatinine concentrations (r = -.40, P = <.001), glomerulosclerosis (r = -.44, P < .001), inflammation (r = -.42, P = <.001), and fibrosis (r = -.38, P = <.001). CONCLUSIONS AND CLINICAL IMPORTANCE: Capillary rarefaction (decrease in capillary size and percent capillary area) is present in kidneys of cats with CKD and is positively correlated with renal dysfunction and histopathologic lesions.

Effect of repeated administration of a parenteral feline herpesvirus-1, calicivirus, and panleukopenia virus vaccine on select clinicopathologic, immunological, renal histologic, and immunohistochemical parameters in healthy adult cats.

OBJECTIVE: To assess whether hyperinoculation of cats with a feline herpesvirus-1, calicivirus, and panleukopenia virus (FVRCP) vaccine could be used as a model to study interstitial nephritis and to assess humoral and cell-mediated immune responses toward vaccinal α-enolase. ANIMALS: 6 healthy young adult purpose-bred research cats. PROCEDURES: Baseline renal cortical biopsies, whole blood, serum, and urine were collected prior to administration of a commercial FVRCP parenteral vaccine. Vaccine hyperinoculation was defined as a total of 8 vaccinations given at 2-week intervals over a 14-week period. Blood samples were collected immediately prior to each vaccination, and a second renal biopsy was performed 2 weeks after hyperinoculation (week 16). Renal histopathology, renal α-enolase immunohistochemistry, and assays to detect humoral and cell-mediated immune reactions against Crandell-Rees feline kidney (CRFK) cell lysates and α-enolase were performed. An α-enolase immunoreactivity score for renal tubules and glomeruli based on signal intensity was determined by a blinded pathologist. RESULTS: Hyperinoculation with the vaccine was not associated with clinicopathologic evidence of renal dysfunction, and interstitial nephritis was not recognized by light microscopy in the time studied. The mean serum absorbance values for antibodies against CRFK antigen and α-enolase were significantly (P < 0.001) higher at weeks 4, 8, and 16 versus week 0. Renal tubular and glomerular α-enolase immunoreactivity scores were higher at week 16 compared to baseline. CLINICAL RELEVANCE: Findings suggested that systemic immunological reactions occurred and renal tissues were affected by vaccine hyperinoculation; however, short-term FVRCP vaccine hyperinoculation cannot be used to study interstitial nephritis in cats.

Frequency of histologic lesions in the kidneys of cats without kidney disease.

OBJECTIVES: In humans, renal aging is associated with an increased frequency of glomerulosclerosis, interstitial fibrosis, inflammation and tubular atrophy. The purpose of this study was to describe the frequency of renal histopathologic lesions in cats without kidney disease. METHODS: A cross-sectional study of archival kidney tissue from 74 cats without kidney disease (serum creatinine <1.6 mg/dl; urine specific gravity >1.035) was carried out: 0-4 years (young, n = 18); 5-9 years (mature, n = 16); 10-14 years (senior, n = 34), 15+ years (geriatric, n = 6). Glomerulosclerosis, tubular atrophy, interstitial inflammation and fibrosis, and the presence or absence of lipid in the interstitium and tubules were scored by a pathologist masked to clinical data. Statistical analyses were performed as appropriate. RESULTS: Geriatric cats had significantly more glomerulosclerosis than mature (P = 0.01) and young cats (P = 0.004). Senior cats had significantly more glomerulosclerosis than young cats (P = 0.006). Glomerulosclerosis was weakly positively correlated with age (r = 0.48; P <0.0001). Geriatric cats had significantly more tubular atrophy than mature (P = 0.02) and young cats (P <0.0001). Senior cats had significantly more tubular atrophy than young cats (P <0.0001). Geriatric cats had significantly more inflammation than senior cats (P = 0.02), mature cats (P = 0.01) and young cats (P <0.0001). Senior cats had significantly more inflammation than young cats (P = 0.004). Geriatric and senior cats had significantly more fibrosis than young cats (P = 0.01 and P = 0.04, respectively). Frequency of tubular lipid increased with age (young: 28%; mature: 56%; senior: 79%; geriatric: 100%) as did the frequency of interstitial lipid (young: 22%, mature: 56%, senior: 85%, geriatric: 100%). CONCLUSIONS AND RELEVANCE: Evidence of renal aging exists in cats. These changes imply that the aging kidney may be more susceptible to injury and impaired healing.

Clinicopathologic and pathologic characteristics of feline proteinuric kidney disease.

OBJECTIVES: The aim of this study was to describe the causes, clinicopathologic features and outcomes of feline protein-losing nephropathy (proteinuria secondary to glomerular disease [PLN]). METHODS: Kidney biopsy/necropsy samples from proteinuric cats submitted to the International Veterinary Renal Pathology Service were retrospectively reviewed. Diagnoses based on histopathology were categorized by primary disease compartment. Clinicopathologic variables at diagnosis, development of hypoalbuminemia, anemia, hypertension, azotemia and effusion/edema, and survival were compared between cats with immune-complex glomerulonephritis (ICGN) and other causes of PLN. RESULTS: Fifty-eight percent (n = 31/53) of proteinuric cats had ICGN and 74% (n = 31/42) of cats with PLN had ICGN. Cats with glomerular diseases other than ICGN had a higher median urine protein:creatinine ratio than ICGN cats (14.5 vs 6.5; P <0.001). Onset of PLN occurred at a young age; median age at diagnosis was 3.5 years in ICGN cats vs 1.3 years in cats with other glomerular diseases (P = 0.026). Development of complications such as hypoalbuminemia, anemia, hypertension, azotemia and effusion/edema were common, regardless of the cause of PLN, and were not different between ICGN and cats with other glomerular diseases. Male cats were over-represented in the ICGN group (P = 0.003). Median survival time (MST) for all cats with PLN was 94 days (range 3-1848 days). Survival was not different between cats with ICGN and cats with other glomerular diseases. MST in ICGN cats that developed effusion was shorter (94 days) than cats that did not (700 days; P = 0.035). MST in IGCN cats that received immunosuppressive medications was longer (244 days) than cats that did not (17 days, P = 0.039). CONCLUSIONS AND RELEVANCE: Taken together, these data suggest that clinical suspicion for glomerular proteinuria should increase in young, male cats with higher degrees of proteinuria, and immune-mediated disease is common. Further studies are needed to determine the effect of immunosuppression on morbidity and mortality in cats with ICGN.

Subcutaneous fluid port-associated soft tissue sarcoma in a cat.

A 20-year-old male castrated domestic longhair cat was evaluated for assessment of its chronic kidney disease (CKD) and a non-healing ulcerated mass at the site of a previously placed and subsequently removed GIF tube. The cat had been diagnosed with CKD 10 years prior and two GIF tubes had been placed over a 5-year period, the second of which was associated with secondary infection. Biopsy of the non-healing ulcerated mass was consistent with grade 2 soft tissue sarcoma. At necropsy there was a discrete, serpentine, subcutaneous mass measuring approximately 8 mm in diameter that extended approximately 20 cm along the dorsum to the caudal thorax, following the path of the GIF tube, from the main intrascapular, ulcerated mass where the fluid port injection site was located. This is the first report of a fibrosarcoma arising at the site of a subcutaneous fluid port in a cat. Although the cat's owners were pleased with the 4 years of quality of life provided by this device, this complication should be considered when a decision to place ports for long-term management of disease is made.