T.L. Williams

Association of Iatrogenic Hypothyroidism with Azotemia and Reduced Survival Time in Cats Treated for Hyperthyroidism

BACKGROUND Iatrogenic hypothyroidism can occur after treatment of hyperthyroidism, and is correlated with a reduced glomerular filtration rate in humans and dogs. HYPOTHESIS Cats with iatrogenic hypothyroidism after treatment for hyperthyroidism will have a greater incidence of azotemia than euthyroid cats. ANIMALS Eighty client owned cats with hyperthyroidism. METHODS Two retrospective studies. (1) Longitudinal study of 12 hyperthyroid cats treated with radioiodine (documented as euthyroid after treatment), to assess changes in plasma thyroid stimulating hormone (TSH) concentration over a 6-month follow-up period, (2) Cross-sectional study of 75 hyperthyroid cats (documented as euthyroid) 6 months after commencement of treatment for hyperthyroidism to identify the relationship between thyroid status and the development of azotemia. Kaplan-Meier survival analysis was performed to identify relationships between thyroid and renal status and survival. RESULTS Plasma TSH concentrations were not suppressed in 7 of 8 cats with hypothyroidism 3 months after radioiodine treatment. The proportion of cats with azotemia was significantly (P= .028) greater in the hypothyroid (16 of 28) than the euthyroid group (14 of 47). Twenty-eight of 41 cats (68%) with plasma TT4 concentration below the laboratory reference range had an increased plasma TSH concentration. Hypothyroid cats that developed azotemia within the follow-up period had significantly (P= .018) shorter survival times (median survival time 456 days, range 231-1589 days) than those that remained nonazotemic (median survival time 905 days, range 316-1869 days). CONCLUSIONS AND CLINICAL IMPORTANCE Iatrogenic hypothyroidism appears to contribute to the development of azotemia after treatment of hyperthyroidism, and reduced survival time in azotemic cats.

Survival and the Development of Azotemia after Treatment of Hyperthyroid Cats

BACKGROUND Hyperthyroidism complicates the diagnosis of chronic kidney disease (CKD) as it increases glomerular filtration rate. No practical and reliable means for identifying those cats that will develop azotemia after treatment for hyperthyroidism has been identified. Hyperthyroidism is associated with proteinuria. Proteinuria has been correlated with decreased survival of cats with CKD and with progression of CKD. HYPOTHESIS Proteinuria and other clinical parameters measured at diagnosis of hyperthyroidism will be associated with the development of azotemia and survival time. ANIMALS Three hundred client owned hyperthyroid cats treated in first opinion practice. METHODS Retrospective, cohort study relating clinical parameters in hyperthyroid cats at diagnosis to the development of azotemia within 240 days of diagnosis and survival time (all cause mortality). Multivariable logistic regression analysis was used to identify factors that were predictive of the development of azotemia. Multivariable Cox regression analysis was used to identify factors associated with survival. RESULTS Three hundred cats were eligible for survival analysis and 216 cats for analysis of factors associated with the development of azotemia. The median survival time was 417 days, and 15.3% (41/268) cats developed azotemia within 240 days of diagnosis of hyperthyroidism. Plasma concentrations of urea and creatinine were positively correlated with the development of azotemia. Plasma globulin concentration was negatively correlated with the development of azotemia. Age, urine protein:creatinine ratio, and the presence of hypertension were significantly correlated with decreased survival time. Urine specific gravity and PCV were significantly correlated with increased survival time. CONCLUSIONS AND CLINICAL IMPORTANCE The proteinuria associated with hyperthyroidism is not a mediator of progression of CKD; however, it does correlate with all cause mortality.

Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension.

BACKGROUND Hypertension is present in some hyperthyroid cats at diagnosis or can develop after treatment for hyperthyroidism. Activation of the renin-angiotensin-aldosterone system (RAAS) could be involved in the pathogenesis of hypertension. HYPOTHESIS Hyperthyroid cats that develop hypertension before or after treatment for hyperthyroidism will have greater RAAS activation than normotensive cats. ANIMALS Ninety-nine hyperthyroid cats. METHODS Retrospective case-control study. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in untreated hyperthyroid hypertensive cats (HT-Pre group), initially normotensive hyperthyroid cats that develop hypertension after treatment (HT-Post group), and hyperthyroid cats that are normotensive (NT group). Data are presented as median [25th, 75th percentile]. RESULTS Baseline PRA was not significantly different among the 3 groups (HT-Pre group 1.50 [0.05, 2.37] ng/mL/h, HT-Post group 0.66 [0.17, 2.31] ng/mL/h, NT group 1.11 [0.57, 2.18] ng/mL/h; P = .44). PRA decreased significantly after treatment in the NT group (1.09 [0.53, 2.47] versus 0.22 [0.05, 0.76] ng/mL/h; P < .001) and the HT-Post group (0.71 [0.17, 2.33] versus 0.28 [0.07, 0.57] ng/mL/h; P = .006). Baseline PAC was not significantly different among the 3 groups (HT-Pre group 72.2 [40.0, 145.6] pg/mL, HT-Post group 69.7 [43.3, 142.6] pg/mL, NT group 109.0 [68.2, 184.6] pg/mL; P = .10). PAC decreased significantly after treatment in the NT group (114.4 [56.6, 204.1] versus 59.5 [32.4, 98.2] pg/mL; P < .001) but did not change significantly in the HT-Post group (61.2 [44.9, 124.0] versus 58.4 [42.0, 97.7] pg/mL; P = .59). CONCLUSIONS AND CLINICAL IMPORTANCE RAAS activation occurs in hyperthyroid cats, but is not associated with the development of hypertension. PAC is not influenced by changes in PRA in hyperthyroid cats that develop hypertension after treatment, perhaps indicating RAAS dysfunction in these cats.

Calcium and phosphate homeostasis in hyperthyroid cats - associations with development of azotaemia and survival time

OBJECTIVES To evaluate calcium and phosphate homeostasis in hyperthyroid cats and determine if plasma parathyroid hormone and fibroblast growth factor-23 are associated with the presence of -azotaemic chronic kidney disease and/or have prognostic significance. METHODS Retrospective cohort study. Logistic regression analysis and Cox regression analysis were performed to identify if parathyroid hormone and fibroblast growth factor-23 were predictors of development of azotaemia following treatment and survival time, respectively. RESULTS Two hundred and seven hyperthyroid cats were included. Elevated plasma parathyroid hormone concentrations, hyperphosphataemia, decreased plasma fibroblast growth factor-23 concentrations and hypocalcaemia were documented; however, all parameters returned to reference intervals following treatment of hyperthyroid cats without azotaemic chronic kidney disease. After adjustment for plasma creatinine concentration, baseline plasma parathyroid hormone and fibroblast growth factor-23 concentrations were not predictors of the development of azotaemia following treatment. Baseline plasma fibroblast growth factor-23 concentrations were associated with all-cause mortality; however, this association was not maintained after adjustment for packed cell volume. CLINICAL SIGNIFICANCE Changes in plasma parathyroid hormone and fibroblast growth factor-23 concentrations which occur in hyperthyroid cats are not mediators of progression of chronic kidney disease; however, fibroblast growth factor-23 would appear to have some prognostic significance in hyperthyroidism.

Effect on Renal Function of Restoration of Euthyroidism in Hyperthyroid Cats with Iatrogenic Hypothyroidism

Background Iatrogenic hypothyroidism is associated with an increased incidence of azotemia after treatment of hyperthyroidism, and decreased survival time in azotemic hyperthyroid cats. Hypothesis Restoration of euthyroidism will decrease plasma creatinine concentrations. Animals Nineteen client‐owned, methimazole‐ or carbimazole‐treated, hyperthyroid cats with documented iatrogenic hypothyroidism (based on subnormal plasma total thyroxine concentrations [TT4] and increased plasma thyroid‐stimulating hormone concentrations). Methods Prospective interventional study. Doses of antithyroid medication were reduced until euthyroidism was restored (TT4 10–40 nmol/L). Plasma creatinine concentration and selected other clinicopathologic variables were evaluated before and after restoration of euthyroidism and compared by nonparametric statistics. Data are presented as median [25th, 75th percentile]. Results Restoration of euthyroidism was associated with a significant decrease in plasma creatinine concentrations (2.61 [1.90, 3.26] mg/dL versus 2.07 [1.42, 2.82] mg/dL; P < .001) and body weight (4.03 [3.59, 4.53] kg versus 3.89 [3.34, 4.18] kg; P = .019), and a significant increase in packed cell volume (30 [28, 39]% versus 34 [29, 39]%; P = .038), heart rate (174 [163, 201] bpm versus 190 [164, 202] bpm; P = .009), and plasma alkaline phosphatase activity (26.6 [17.0, 33.0] IU/L versus 38.0 [23.5, 46.5] IU/L; P < .001). Conclusions and Clinical Importance Restoration of euthyroidism in medically treated hyperthyroid cats with iatrogenic hypothyroidism causes a reduction in plasma creatinine concentrations, and thus might improve renal function; however, this could be influenced by concurrent changes in body weight.

Urinary Exosomes Contain MicroRNAs Capable of Paracrine Modulation of Tubular Transporters in Kidney

Exosomes derived from all nephron segments are present in human urine, where their functionality is incompletely understood. Most studies have focused on biomarker discovery rather than exosome function. Through sequencing we identified the miRNA repertoire of urinary exosomes from healthy volunteers; 276 mature miRNAs and 345 pre-miRNAs were identified (43%/7% of reads). Among the most abundant were members of the miR-10, miR-30 and let-7 families. Targets for the identified miRNAs were predicted using five different databases; genes encoding membrane transporters and their regulators were enriched, highlighting the possibility that these miRNAs could modulate key renal tubular functions in a paracrine manner. As proof of concept, cultured renal epithelial cells were exposed to urinary exosomes and cellular exosomal uptake was confirmed; thereafter, reduced levels of the potassium channel ROMK and kinases SGK1 and WNK1 were observed in a human collecting duct cell line, while SPAK was unaltered. In proximal tubular cells, mRNA levels of the amino acid transporter gene SLC38A2 were diminished and reflected in a significant decrement of its encoded protein SNAT2. Protein levels of the kinase SGK1 did not change. Thus we demonstrated a novel potential function for miRNA in urinary exosomes.

Association between the findings on magnetic resonance imaging screening for syringomyelia in asymptomatic Cavalier King Charles spaniels and observation of clinical signs consistent with syringomyelia in later life

A questionnaire-based study was used to investigate the association between the findings on magnetic resonance imaging (MRI) screening for syringomyelia (SM) in 79 asymptomatic Cavalier King Charles spaniels (CKCS) and the subsequent development of clinical signs consistent with SM in later life. Owners reported clinical signs consistent with SM in 13/79 (16%) dogs at the time of the questionnaire. A significantly greater proportion of CKCS with a syrinx visible on MRI screening showed clinical signs in later life (9/25, 36%) than dogs without a visible syrinx (4/54, 7%; odds ratio 6.9). Whether the findings of MRI screening can be used to indicate the likelihood of an asymptomatic CKCS developing clinical signs consistent with SM in later life warrants further prospective study in a larger cohort of dogs.

Thromboelastography in healthy dairy cows

Thromboelastography is a whole blood-based coagulation assay that can be used to investigate hypocoagulability and hypercoagulability, as seen with thromboembolic diseases and disseminated intravascular coagulation. Numerous coagulopathies due to different causes are reported in cows. The objective was to establish reference intervals for thromboelastography using the TEG 5000 (Haemonetics GmbH, Munich, Germany) with citrated whole blood samples and kaolin activation in dairy cows and to investigate possible thromboelastographic changes between cows in different lactation periods. An additional objective was to test the stability of samples for up to 100h. Sixty blood samples from healthy Holstein-Friesian cows were examined. The samples were allocated to 3 different lactation groups (≤30 d postcalving, 31-99 d postcalving, ≥100 d postcalving). Thromboelastography was performed by using the TEG 5000 analyzer with citrated whole blood samples with kaolin activation. The calculated reference intervals were as follows: reaction time=2.2 to 6.2min, coagulation time=0.8 to 2.0min, angle α=58.2 to 81.8°, maximum amplitude=64.3 to 89.2mm, and clot rigidity=9.2 to 41.2 dyn/cm(2). The 3 different lactation groups showed no significant differences in TEG parameters. No significant difference was seen in samples stored for up to 48h at room temperature, which indicates that delays in processing samples, such as those arising during transit, are not an issue.

Investigation of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats

OBJECTIVE To investigate possible pathophysiological mechanisms (reduced plasma calcitriol concentrations and/or presence of concurrent or masked chronic kidney disease) for hypocalcaemiain hyperthyroid cats. METHODS Prospective cohort study. Routine plasma biochemical parameters, plasma parathyroid hormone and calcitriol concentrations, ionized calcium concentrations, and venous pH, were measured at diagnosis and following treatment of hyperthyroidism. Linear regression analysis was used to determine predictors of ionized calcium concentration. RESULTS Hyperthyroid cats (n=45) had lower ionized calcium concentrations than healthy geriatric cats (n=52), however, ionized calcium concentrations were higher in hyperthyroid cats with concurrent or masked chronic kidney disease than non-azotaemic hyperthyroid cats. Plasma calcitriol concentrations were higher in hyperthyroid cats than control cats. Plasma total thyroxine concentration and venous pH were independent predictors of ionized calcium concentration. Plasma total thyroxine concentration was also a predictor of ionized calcium concentration after adjustment for plasma parathyroid hormone and calcitriol concentrations. CLINICAL SIGNIFICANCE Hypocalcaemia in hyperthyroid cats is not associated with the presence of concurrent or masked chronic kidney disease or reduced plasma calcitriol concentrations. Increased thyroid hormone concentrations might influence ionized calcium concentrations through a mechanism, yet to be determined, that is independent of control by parathyroid hormone and calcitriol.

Validation of an automated enzyme immunoassay for the measurement of serum total thyroxine in cats

BACKGROUND Hyperthyroidism is common in older cats, which necessitates frequent screening of serum total thyroxine (TT4) concentrations. Fast, cheap, and reliable methods to measure TT4 in cats are needed. OBJECTIVES The purpose of the study was the validation of a human TT4 enzyme immunoassay (EIA) for use with feline serum, and derivation of a TT4 reference interval (RI) for cats aged 9 years and older. METHODS Assay precision, reproducibility, and linearity were evaluated. Interference by hemolysis was also assessed. Method comparison studies between the human EIA and a previously validated radioimmunoassay (RIA) and chemiluminescent-enzyme immunoassay (CEIA) were performed. Healthy cats (> 9 years) were recruited from 3 UK first opinion practices. RESULTS The human TT4 EIA demonstrated good precision and reproducibility, and adequate linearity. Hemolysis did not significantly alter measured TT4 concentrations until HGB > 8 g/L. Method comparison revealed proportional and constant errors between EIA and RIA/CEIA. The TT4 RI for cats (> 9 years) was calculated as 7.1-45.1 nmol/L (n = 49). CONCLUSIONS The human TT4 EIA was successfully validated for use with feline serum and offers a rapid, cheap, and reliable method for determination of serum TT4 concentrations in cats.