Harriet M. Syme

Background: Chronic kidney disease (CKD) is a common sequela of ureteral obstruction, but many cats are non-azotemic after subcutaneous ureteral bypass (SUB) placement. Objectives: Compare CKD progression rates after SUB placement with idiopathic CKD (iCKD), and explore variables associated with progression. Animals: Seventy-one referred cats after SUB placement for ureteral obstruction and 89 primary care cats with iCKD. Methods: Retrospective observational longitudinal study. Baseline (3–6 months after SUB or at CKD diagnosis for iCKD cases) clinicopathological data and CKD progression (≥ 25% increase in creatinine concentration [Cr]) rates were compared between iCKD and SUB cats. Univariable logistic regression identified variables associated with SUB cat CKD progression. Results: Baseline Cr was lower in the SUB group (SUB, 2.0 mg/dL; iCKD, 2.3 mg/dL; p = 0.01). For SUB cats with a ≥ 25% increase in Cr within 1 year, 45% (9/20) had SUB obstruction. Of the remaining 11 cats, 35% had a positive urine culture. Only SUB blockage was associated with CKD progression in SUB cats (odds ratio, 33.33; confidence interval [CI], 3.80–292.60; p = 0.002). Progression of CKD within 1 year did not differ between groups (iCKD, 29.5%; SUB, 28.1%; p = 0.85), even after exclusion of obstructed cases (iCKD, 29.5%; SUB, 17.7%; p = 0.12). Median time to CKD progression was not different between groups (iCKD, 833 days; range, 21–2141; SUB, 653 days; range, 43–1662; p = 0.80). Conclusions and Clinical Importance: Progression of CKD after SUB placement occurs with similar frequency and time frame as in cats with iCKD, but should prompt assessment for SUB blockage and pyelonephritis.

Background: Early diagnosis of hypertension remains an important problem in cats. Lack of routine blood pressure screening in primary care practice, and the possibility of white coat artifact mean the discovery of a new diagnostic test, if less sensitive to short-term changes in blood pressure associated with veterinary care, would be useful. Identification of metabolomic changes in hypertensive cats could advance understanding of the pathogenesis of hypertension in cats, as well as identify novel biomarkers. Objectives: Use untargeted metabolomics to identify biochemical changes in cat plasma and urine between normotensive controls (NT) and hypertensive cats before treatment (HTpre); HTpre and hypertensive cats treated with amlodipine (HTtx). Animals: Biobanked surplus plasma and urine samples were selected from client-owned cats (> 9 years old) that were NT (urine n = 17, plasma n = 19), HTpre (urine n = 13, plasma n = 19), or HTtx (urine n = 12, plasma n = 19). Methods: Samples were profiled using flow infusion electrospray—high-resolution mass spectrometry, and differences assessed using univariate (paired or two sample t-tests) and multivariate (partial least squares discriminant analysis) methods using the R-based MetaboAnalyst platform. Tentative identifications of metabolites then were made using the MZedDb database. Results: Significant (false discovery adjusted < 0.01) biochemical differences were observed between each of the sample groups. Biochemical changes in urine between HTpre and NT animals were linked to the tricarboxylic acid cycle, oxidative stress, steroid hormones, taurine metabolism, and phosphatidylinositol-3,4,5-trisphosphate. Conclusions: Metabolites altered in hypertensive cats were similar to those observed in other species.

Background: Multi-steroid profiles are proven to help with the diagnostic approach to adrenal disorders in humans. Objectives: Compare liquid chromatography tandem mass spectrometry (LC–MS/MS) and radioimmunoassay (RIA) measurement of aldosterone in feline blood samples. Evaluate multi-steroid profiles in cats with hyperaldosteronism. Animals: Client-owned cats with low/normal aldosterone by RIA (low aldo, n = 15), high aldosterone by RIA (high aldo, n = 6) and overt primary hyperaldosteronism (PHA, n = 6). Methods: Exploratory retrospective case–control study. Feline blood multi-steroid profiles were analyzed with LC–MS/MS and compared with results from a commercially available RIA in widespread clinical use. Results: Aldosterone measurement by LC–MS/MS and RIA was strongly correlated (r = 0.93, p < 0.001) but showed a bias of 56 (95% CI: 104–7) pmol/L, with RIA giving higher values. Creatinine concentration was not significantly associated with the discrepancy between methods (p = 0.95). Cats with PHA had significantly lower serum concentrations of cortisol and glucocorticoid precursors (17-hydroxyprogesterone, 11-deoxycortisol), testosterone, and significantly higher dihydrotestosterone and 5α-dihydroprogesterone concentrations than the low aldo group. Pregnenolone concentrations were significantly lower in the PHA group than in the high aldo group. Conclusion and Clinical Importance: Quantification of aldosterone by either LC–MS/MS or RIA is adequate for PHA diagnosis in the clinical setting, with appropriate method-specific reference intervals. Cats with PHA had different concentrations of some steroids compared with the control groups, but overt steroid excess (other than aldosterone) was not observed.

BACKGROUND: Primary aldosteronism (PA) is a common cause of human hypertension. Somatic mutations in KCNJ5 , CACNA1D , ATP1A1 , and ATP2B3 are found in at least 80% of aldosterone-producing adenomas, which cause unilateral PA in humans. Somatic mutations have been identified infrequently in 7 other genes; few of these were known to play a role in aldosterone secretion before the discovery of their mutations. Interrogating somatic mutations in the domestic cat, in which spontaneous PA is also known to occur, might improve the understanding of normal adrenal gland physiology and the pathophysiology of PA. METHODS: DNA and RNA extracted from tissue from 13 cats with unilateral aldosterone-secreting tumors, including 8 carcinomas and 5 adenomas, underwent whole genome sequencing, targeted Sanger sequencing, and RNA sequencing. Single-nucleotide substitution variants were filtered to select those with a predicted deleterious effect on protein function and a suspected role in aldosterone secretion. RESULTS: Probable functional somatic single-nucleotide polymorphisms (n=8) were found in 3 adenomas and 2 carcinomas. Mutations with predicted significant effects were identified in 2 genes also mutated in human PA; GNAQ and CTNNB1 , and in a residue of CACNA1C analogous to a common CACNA1D mutation. In contrast to humans, CACNA1C expression was much greater than CACNA1D in both feline tumor and nontumor adrenal tissue. No mutations were identified in KCNJ5 , CACNA1D , ATP1A1 , or ATP2B3. CONCLUSIONS: Similar mutations were identified in cats to those found in humans. It is, therefore, likely that both species have shared underlying selection pressures for mutations that increase aldosterone secretion.

Background: Functionality of human adrenal tumors is inferred by CYP11B1 (cortisol synthase) expression, CYP11B2 (aldosterone synthase) expression, or both. Hypothesis/Objectives: Nonfunctional canine adrenal tumors have low expression of steroidogenic enzymes, whereas aldosterone-producing tumors express CYP11B, and cortisol-producing tumors express both CYP11B and CYP17. Animals: Twenty-two client-owned dogs with adrenocortical tumors (ACT) (8 nonfunctional, 7-cortisol producing, 2 aldosterone-producing and 5 functional noncortisol producing) and 2 dogs with normal adrenal glands. Methods: Retrospective case series. Adrenal functionality was determined from clinical signs and endocrine testing. CYP11A1, CYP11B, CYP17, and HSD3B2 expression was detected by immunohistochemistry on formalin-fixed paraffin-embedded adrenal tissue. Protein expression was semiquantified by 2 blinded observers using H-scoring (results reported as median [range]) and compared in nonfunctional and cortisol-producing adrenal tumors by Mann-Whitney U tests. Results: CYP11A1, CYP11B, and HSD3B2 were present within all cortical layers of normal adrenal glands, and CYP17 was expressed within the zona fasciculata and zona reticularis. Expression of CYP11A1 (191.25 [97.5-270] vs. 175 [102.5-295] P = .69), CYP11B (190 [130-265] vs. 147.5 [95-202.5]; P = .07), CYP17 (177.5 [87.5-240] vs. 247.5 [55-292.5]; P = .40), and HSD3B2 (230 [47.5-295] vs. 277.5 [67.5-295]; P = .34) were not significantly different between cortisol-producing and nonfunctional ACT. Conclusions and Clinical Importance: Our findings suggest it is not possible to determine functionality of canine ACT by immunohistochemistry for steroidogenic enzymes. Tumor size cannot be used to infer functionality of adrenal tumors.

Background: Knowledge of additional risk factors for thrombotic disease (TD) among dogs with renal proteinuria is limited; these might differ for TD affecting the systemic arterial (AT), systemic venous (VT), and pulmonary circulation (PT). Hypothesis/Objectives: To compare signalment and clinicopathological data between dogs with renal proteinuria with or without TD, and between dogs with AT, VT, and PT. Animals: One hundred fifty client-owned dogs with renal proteinuria, 50 of which had TD. Methods: Retrospective case-controlled study. A database search (2004-2021) identified proteinuric dogs (UPC > 2) with and without TD. Clinicopathological data were obtained from the records. TD and non-TD (NTD) groups were compared by binary logistic regression, and AT, VT, and PT groups by multinomial regression. Normal data presented as mean ± SD, non-normal data presented as median [25th, 75th percentiles]. Results: Cavalier King Charles Spaniels were overrepresented in the TD group (OR = 98.8, 95% CI 2.09-4671, P = .02). Compared to NTD cases, TD cases had higher concentration of neutrophils (11.06 [8.92, 16.58] × 109/L vs 7.31 [5.63, 11.06] × 109/L, P = .02), and lower concentration of eosinophils (0 [0, 0.21] × 109/L vs 0.17 [0.04, 0.41] × 109/L, P = .002) in blood, and lower serum albumin (2.45 ± 0.73 g/dL vs 2.83 ± 0.73 g/dL, P = .04). AT cases had higher serum albumin concentrations than VT cases (2.73 ± 0.48 g/dL vs 2.17 ± 0.49 g/dL, P = .03) and were older than PT cases (10.6 ± 2.6 years vs 7.0 ± 4.3 years, P = .008). VT cases were older (9.1 ± 4.2 years vs 7.0 ± 4.3 years, P = .008) and had higher serum cholesterol concentration (398 [309-692 mg/dL] vs 255 [155-402 mg/dL], P = .03) than PT cases. Conclusions and Clinical Importance: Differences between thrombus locations could reflect differences in pathogenesis.

Background: GS-441524 has been successfully used to treat feline infectious peritonitis (FIP) in cats. However, the use of its prodrug, remdesivir, in combination with a PO GS-441524 containing product for the treatment of FIP has not yet been described. Objectives: Describe treatment protocols, response to treatment and outcomes in cats with FIP treated with a combination of PO GS-441524 and injectable remdesivir. Animals: Thirty-two client-owned cats diagnosed with effusive or non-effusive FIP including those with ocular and neurological involvement. Methods: Cats diagnosed with FIP at a single university hospital between August 2021 and July 2022 were included. Variables were recorded from time of diagnosis, and subsequent follow-up information was obtained from the records of referring veterinarians. All surviving cats were observed for the entire 12-week treatment period. Results: Cats received treatment with different combinations of IV remdesivir, SC remdesivir, and PO GS-441524 at a median (range) dosage of 15 (10-20) mg/kg. Clinical response to treatment was observed in 28 of 32 cats (87.5%) in a median (range) of 2 (1-5) days. Twenty-six of 32 cats (81.3%) were alive and in clinical and biochemical remission at the end of the 12-week treatment period. Six of 32 cats (18.8%) died or were euthanized during treatment with 4 of the 6 cats (66%) dying within 3 days of starting treatment. Conclusions: We describe the effective use of injectable remdesivir and PO GS-441524 for the treatment of FIP in cats. Success occurred using different treatment protocols and with different presentations of FIP including cats with ocular and neurological involvement.

Background: Cats presenting with upper urinary tract uroliths (UUTUs) and ureteral obstruction (“obstructive UUTU”) are typically younger than cats with idiopathic CKD that often have incidental nephroliths. Hypothesis: Cats with upper urinary tract urolith have 2 clinical phenotypes; a more aggressive phenotype at risk of obstructive UUTU at a young age and a more benign phenotype in older cats, with reduced risk of obstructive UUTU. Objectives: Identify risk factors for UUTU and for obstructive UUTU. Animals: Eleven thousand four hundred thirty-one cats were referred for care over 10 years; 521 (4.6%) with UUTU. Methods: Retrospective VetCompass observational cross-sectional study. Multivariable logistic regression models were performed to identify risk factors for a diagnosis of UUTU vs no UUTU and additionally, obstructive UUTU vs nonobstructive UUTU. Results: Risk factors for UUTU included female sex (odds ratio [OR] 1.6, confidence interval [CI] 1.3-1.9; P < .001), British shorthair, Burmese, Persian, Ragdoll or Tonkinese (vs non-purebred ORs 1.92-3.31; P < .001) breed and being ≥4 years (ORs 2.1-3.9; P < .001). Risk factors for obstructive UUTU were female sex (OR 1.8, CI 1.2-2.6; P = .002), having bilateral uroliths (OR 2.0, CI 1.4-2.9; P = .002) and age, with the odds of obstructive UUTU increasing as age at diagnosis of UUTU decreased (≥12 years, reference category; 8-11.9 years, OR 2.7, CI 1.6-4.5; 4-7.9 years, OR 4.1, CI 2.5-7.0; 0-3.9 years, OR 4.3, CI 2.2-8.6; P < 0.001). Conclusions and Clinical Importance: Cats diagnosed with UUTU at a younger age have a more aggressive phenotype with higher risk of obstructive UUTU compared to cats over 12 years of age diagnosed with UUTU.

Background: Ionized calcium concentration ([iCa]) is more sensitive for detecting calcium disturbances than serum total calcium concentration but literature on ionized hypercalcemia in cats is limited. Urolithiasis is a possible adverse consequence of hypercalcemia. Hypothesis/Objectives: To describe clinical details of diagnoses associated with ionized hypercalcemia in cats and association with urolithiasis. Animals: Cats (238) seen between 2009 and 2019 at a referral hospital with [iCa] above the normal reference interval. Methods: Observational cross-sectional study. Signalment, serum biochemical and imaging findings were reviewed for cats with ionized hypercalcemia considered to be clinically relevant (>1.41 mmol/L). Data were summarized by cause of hypercalcemia (i.e., diagnosis). Results: Diagnoses for the 238 cats with [iCa] >1.41 mmol/L included: acute kidney injury (AKI; 13%), malignancy-associated (10.1%), idiopathic hypercalcemia (IHC; 10.1%), chronic kidney disease/renal diet-associated (8.4%), iatrogenic (5.5%), primary hyperparathyroidism (2.1%), vitamin D toxicity (2.1%) and granulomatous disease (1.7%). In 112 cases (47.1%), no cause for ionized hypercalcemia could be determined (n = 95), hypercalcemia was transient (n = 12), or the cat was juvenile (<1 year; n = 5). Urolithiasis was identified in 83.3% of AKI, 72.7% of iatrogenic, 61.1% of CKD/renal diet-associated and 50% of IHC cases that were imaged (<50% for other diagnoses). Diagnoses with a high proportion of concurrent total hypercalcemia included primary hyperparathyroidism (100%), vitamin D toxicity (100%), malignancy-associated (71.4%), granulomatous disease (66.7%) and IHC (65.2%). Conclusions and Clinical Importance: Ionized hypercalcemia was most commonly associated with kidney diseases, neoplasia or IHC. The proportion of urolithiasis cases varied by diagnosis.