Efficacy of Urine Asymmetric Dimethylarginine Concentration to Predict Azotemia in Hyperthyroid Cats After Radio-Iodine Treatment

Abstract

Background: Hyperthyroidism can mask concurrent chronic kidney disease in cats, and no accurate biomarkers are available to predict which cats will develop renal azotemia after radioiodine (¹³¹I) treatment.

Hypothesis/objectives: To evaluate the potential of serum and urinary metabolites and metabolite ratios to predict post-¹³¹I renal azotemia in hyperthyroid cats.

Animals: Hyperthyroid cats (n = 31), before and (3-12 months) after treatment with ¹³¹I at the Faculty of Veterinary Medicine (Ghent University, Belgium).

Methods: Retrospective study. Optimized and validated feline extraction and analysis protocols were employed for metabolic profiling of urine and serum samples using ultra-high performance liquid chromatography-high-resolution mass spectrometry. A dual strategy of cross-validated univariate and penalized multivariate logistic regression was applied to determine predictivity (i.e., area under the curve [AUC], accuracy, sensitivity, and specificity) of individual biomarkers and panels.

Results: All hyperthyroid cats were non-azotemic before ¹³¹I administration. After ¹³¹I treatment, 7 cats became persistently (≥ 2 timepoints) azotemic while 24 remained non-azotemic. Urinary asymmetric dimethylarginine (ADMA) was identified as a pivotal predictor of post-¹³¹I azotemia in both univariate and multivariate modeling. When employed as a standalone biomarker, an AUC of 0.851, accuracy of 0.903, sensitivity of 0.714, and specificity of 0.958 were achieved. While pre-treatment USG was significantly different (P = 0.002) between both groups, it did not show enhanced prediction over ADMA, nor in multivariate modeling.

Conclusions and clinical importance: Urinary ADMA can accurately predict post-¹³¹I azotemia in hyperthyroid cats becoming euthyroid after ¹³¹I treatment. These findings can aid clinicians in managing owner expectations and modify treatment plans.

Keywords: 131I; biomarker; chronic kidney disease; feline; metabolic profiling.

FIGURE 1

Flowchart illustrating the number of included cats in each group. All cats were euthyroid after ¹³¹I treatment. For the cats developing post‐¹³¹I azotemia, the timepoint at which renal azotemia was detected for the first time is presented as well. All cats underwent at least two control visits after ¹³¹I treatment to confirm their azotemic or non‐azotemic status.

FIGURE 2

Alterations in serum and urinary metabolome of hyperthyroid cats remaining non‐azotemic (n = 24) and becoming azotemic (n = 7) after ¹³¹I treatment. PCA‐X plots show few outliers, and an overlap of the study groups can be noted before as well as after ¹³¹I treatment in both serum (A and B, respectively) and urine (E and F, respectively). Volcano plots show significantly altered metabolites and metabolite ratios before (n = 10) and after (n = 23) ¹³¹I treatment in urine (G and H, respectively), with no altered metabolites in serum before treatment (C) and only one metabolite after ¹³¹I treatment (D).

FIGURE 3

Longitudinal evolution and performance of urinary asymmetric dimethylarginine (ADMA) and the biomarker panel. (A) Boxplot representation of changing ADMA concentrations in hyperthyroid cats remaining non‐azotemic (n = 24) and becoming azotemic (n = 7) after ¹³¹I treatment. Statistical significance was evaluated using the Welch two‐sample t‐test. (B) Analysis of variable importance of included metabolites and metabolite ratios in urinary biomarker panel (n = 4). Each metabolite is assigned a weight between 0 and 100, with higher values indicating greater influence within the model. (C and D) Receiver operating characteristic (ROC) curve of ADMA and urinary panel for classification of post‐¹³¹I azotemia. The AUC with 95% CI is presented as well.