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Abstract

Objectives

The aims of this study were to evaluate concentrations of symmetric dimethylarginine (SDMA) in hyperthyroid cats before and after radioiodine treatment, and to compare results with other variables used to assess kidney function in cats (creatinine, urine specific gravity [USG] and glomerular filtration rate [GFR] measured by renal scintigraphy).

Methods

Thirteen cats diagnosed with hyperthyroidism based on clinical signs and increased serum total thyroxine (TT4) were included in this prospective study. Study design included physical examination, complete blood count, serum chemistry, TT4, urinalysis and SDMA before treatment (T0) and at 1 month (T1) and 3 months post-treatment (T3). GFR was quantified by renal scintigraphy at T0 and T3.

Results

Median GFR decreased significantly from baseline (3.18 ml/kg/min; range 1.35–4.87) at T3 (2.22 ml/kg/min; range 1.81–3.42 [P = 0.005]). While median creatinine and serum urea nitrogen increased post-treatment (creatinine: T0 = 0.8 mg/dl [range 0.4–1.1], T1 = 1.3 mg/dl [range 0.9–2]; T3 = 1.65 mg/dl [range 0.8–2.8]; P <0.001; serum urea nitrogen: T0 = 23 mg/dl [range 15–26]; T1 = 27 mg/dl [range 20–40]; T3 = 27.5 mg/dl [range 20–36]; P <0.001), SDMA and USG did not change significantly (SDMA: T0 = 11 µg/dl [range 7–15]; T1 = 12 µg/dl [range 6–16]; T3 = 10.5 µg/dl [range 8–21]; P = 0.789; USG: T0 = 1.030 [range 1.011–1.059]; T1 = 1.035 [range 1.012–1.044]; T3 = 1.030 [range 1.007–1.055]; P = 0.792).

Conclusions and relevance

Our data suggest that factors other than GFR may affect serum SDMA in hyperthyroid cats and that SDMA does not offer an advantage over other biomarkers traditionally used to predict changes in renal function following radioiodine therapy.

Keywords

Hyperthyroidism symmetric dimethylarginine renal biomarkers chronic kidney disease glomerular filtration rate renal scintigraphy

Introduction

Though chronic kidney disease (CKD) is a common comorbidity in hyperthyroid cats, it is often only diagnosed after treatment and restoration of a euthyroid state due to thyroxine’s catabolic effect on muscle mass and its positive effect on renal blood flow.^1–8

Symmetric dimethylarginine (SDMA) has garnered considerable interest as a possible predictor of post-treatment azotemia in hyperthyroid cats because it is correlated with glomerular filtration rate (GFR), is more sensitive than creatinine in the detection of feline CKD and is not affected by muscle mass.^9–12 Recent studies have found a significant increase in SDMA following hyperthyroid treatment but low sensitivity of this biomarker to predict post-treatment azotemia.^1,3 Additional recent studies have looked at GFR in addition to SDMA in hyperthyroid cats. One study found that, while both creatinine and urea nitrogen increased following treatment with radioiodine, SDMA did not. Furthermore, SDMA did not significantly correlate with GFR.¹³ In contrast, another study looking at cats treated with an iodine-restricted diet found that SDMA was better correlated with GFR than creatinine; however, the majority of cats in this study remained hyperthyroid after 6 months of iodine restriction.¹⁴

These studies suggest that, while SDMA can be a helpful biomarker of pre-existing CKD in hyperthyroid cats, its concentrations can be influenced by altered metabolic states that are independent of renal function. To further elucidate this, we prospectively evaluated changes in renal biomarkers, as well as GFR, as measured by nuclear scintigraphy, in a population of cats undergoing radioiodine therapy. We hypothesized that, in contrast to creatinine, SDMA values would not increase significantly post-treatment or correlate with GFR or thyroxine values.

Materials and methods

Hyperthyroid cats presenting to the Iowa State University Lloyd Veterinary Medical Center for radioiodine treatment were enrolled. Informed owner consent was obtained and the study protocol was approved by the Iowa State University Institutional Animal Care and Use Committee (IACUC 19-047). Diagnosis of hyperthyroidism was based on compatible clinical signs, examination findings and a high serum total thyroxine (TT4). Cats were excluded if they had received methimazole in the previous 2 weeks, were on an iodine-restricted diet in the past month or if they had underlying comorbidities making them poor candidates for radioiodine therapy.

Baseline (T0) assessment included a physical examination, complete blood count, serum biochemistry profile, urinalysis, SDMA, TT4 and systolic blood pressure. These parameters were repeated at 1 month (T1) and 3 months (T3) post-treatment. GFR was quantified by renal scintigraphy using ^99mTechnetium-diethylenetriaminepentaacetic acid (DTPA) 24 h prior to treatment and again at T3.

Serum urea nitrogen, creatinine and phosphorus were measured with an automated clinical analyzer (Vitros; Ortho Clinical Diagnostics) using colorimetric (urea nitrogen and phosphorus) and two-point rate (creatinine) assays validated for use in cats. Serum TT4 was measured using a solid-phase, chemiluminescent competitive assay validated for use in cats (Immulite 1000; Siemens Healthcare Diagnostics).¹⁵ Serum SDMA was measured using a high-throughput chemistry analyzer validated for use in cats by IDEXX.¹⁶ Indirect blood pressure was measured using Doppler.¹⁷ Azotemia was defined as a creatinine above the laboratory reference interval (RI: >2.1 mg/dl). Additionally, cats with a creatinine ⩾1.6 mg/dl but still below the laboratory creatinine RI were also considered to have abnormal kidney function and considered separately from cats with creatinine <1.6 mg/dl.

Nuclear imaging determination of GFR was performed within 48 h of obtaining blood samples for biomarker analysis. GFR measurement was accomplished using 2.5 mCi ^99mTechnetium-DTPA injected intravenously in cats anesthetized with intravenous (IV) butorphanol and alfaxalone and maintained with isoflurane. A 20% window on the pulse height analyzer was centered on the 140 keV photopeak of ^99mTechnetium. The cats were positioned in dorsal recumbency on the surface of the gamma camera, centered over the kidneys. A dynamic, frame mode acquisition of images was initiated immediately prior to injection of the radiopharmaceutical and consisted of 64 × 64 × 16 matrix array at 6 s/frame for 6 mins. The net counts of radioisotope for each kidney during the 1–3-min post-injection interval was determined by the dynamic acquisition. The GFR was calculated from the 1–3-min post-injection interval as a percentage of dose data using a dedicated computer workstation with Mirage software. Global GFR >2.5 ml/kg/min was considered to be normal.¹⁸ Thyroid scintigraphy was performed immediately following GFR determination.¹⁸

Cats were treated with a mean dose of 3.91 mCi Na–¹³¹Iodine (range 3.62–4.26) by subcutaneous injection. The radioiodine dose for each cat was selected following combined assessment of TT4, severity of clinical signs, physical examination and nuclear scintigraphy findings.

Data were analyzed using R version 3.6.2. The Friedman test was used to determine if there were any differences across visits for all responses of interest (biomarkers, GFR, thyroid and body condition parameters). Pairwise comparisons were calculated using Conover’s post-hoc test, and P values were adjusted using the Bonferroni correction. Additionally, correlations between biomarkers at each visit were evaluated using Spearman’s rank correlation. Significance was set at P <0.05.

Results

Thirteen cats were included in this study. Demographic information is included in file 1 in the supplementary material. Laboratory work was available for all time points for 10/13 cats and GFR data for both T0 and T3 were available for 8/13 cats. Urea nitrogen and creatinine increased significantly post-treatment while SDMA and urine specific gravity (USG) did not (Table 1).

Table 1

Results of variables evaluated at baseline (T0) and at 1 month (T1) and 3 months (T3) post-radioiodine treatment in hyperthyroid cats

Variable	T0 (n = 13)	T1 (n = 13)	T3 (n = 10)	P value
Weight (kg)	4.4 (2.98–6.68)^a	4.35 (3.1–6.53)*,^b	4.75 (3.67–7.73)^†,a,b	0.015
TT4 (µg/dl)	8.42 (3.83–21.33)^a	1.36 (<0.5–3.37)^a	1.92 (0.5–3.24)^a	<0.001
GFR (ml/kg/min)	3.18 (1.35–4.87)^a	–	2.22 (1.81–3.42)^‡,a	0.005
Phosphorus (mg/dl)	4.7 (2.6–7.3)^a,b	4 (2.8–5.8)^a	3.4 (2.8–5.5)^b	0.002
Serum urea nitrogen (mg/dl)	23 (15–26)^a,b	27 (20–40)^a	27.5 (20–36)^b	<0.001
Creatinine (mg/dl)	0.8 (0.4–1.1)^a	1.3 (0.9–2)^a	1.65 (0.8–2.8)^a	<0.001
SDMA (µg/dl)	11 (7–15)	12 (6–16)	10.5 (8–21)	0.789
USG	1.030 (1.011–1.059)^§	1.035 (1.012–1.044)	1.030 (1.007–1.055)	0.792

Data are expressed as median (range). Significant differences between time points are indicated by the same superscript letter

n = 11

†

n = 9

‡

n = 8

n = 12

TT4 = total thyroxine; GFR = glomerular filtration rate; SDMA = symmetric dimethylarginine; USG = urine specific gravity

Of the 10 cats with laboratory data for T3, one developed azotemia (creatinine >2.1 mg/dl) and four cats had a creatinine ⩾1.6 mg/dl but within the RI. Creatinine increased from the baseline value post-treatment in all cats (Figure 1).

Figure 1

Baseline (T0), 1 month (T1) and 3 months (T3) post-treatment creatinine values. Dotted line indicates the upper limit of the reference interval

There was substantial variation in SDMA between cats and time points (Figure 2). One had an SDMA above the RI (>14 µg/dl) at T0 and 3/10 had an SDMA above the RI at T3. SDMA in 4/10 cats decreased from T0 to T3, increased in 5/10 and stayed the same in one cat. In the cat with an SDMA above the RI at T0 (15 µg/dl), SDMA increased to 16 µg/dl at T1 and 21 µg/dl at T3. This cat had a normal creatinine at T0 and a creatinine of 2.1 mg/dl at T3. Of the four cats developing a creatinine ⩾1.6 mg/dl but within the RI at T3, two had SDMA values that decreased or remained the same between T0 and T3, and two had SDMA values that were within the RI at T0 and above the RI at T3. SDMA and creatinine did not correlate at T0; following treatment, there was a significant positive correlation between SDMA and creatinine (Table 2).

Figure 2

Baseline (T0), 1 month (T1) and 3 months (T3) post-treatment symmetric dimethylarginine (SDMA) values. Dotted line indicates the upper limit of the reference interval

Table 2

Correlation coefficients and P values for correlation comparisons at baseline (T0), 1 month (T1) and 3 months (T3) post-radioiodine treatment in hyperthyroid cats

Variables	T0	T1	T3
GFR + creatinine	ρ = –0.173; P = 0.573	–	ρ = –0.424; P = 0.295
GFR + SDMA	ρ = –0.277; P = 0.359	–	ρ = –0.627; P = 0.096
Creatinine + SDMA	ρ = 0.398; P = 0.215	ρ = 0.690; P = 0.009*	ρ = 0.673; P = 0.033*
SDMA + TT4	ρ = 0.053; P = 0.864	ρ = –0.503; P = 0.080	ρ = –0.509; P = 0.133

Statistically significant result

GFR = glomerular filtration rate; SDMA = symmetric dimethylarginine; TT4 = total thyroxine

Median GFR decreased significantly from baseline at T3 (P = 0.005; Table 1). Of the eight cats with T3 GFR data, one had a subnormal GFR (<2.5 ml/kg/min) pretreatment and five had a subnormal GFR post-treatment (Figure 3). Of the five cats with a subnormal post-treatment GFR, one had a post-treatment creatinine above the RI, four had a post-treatment creatinine ⩾1.6 mg/dl, and three had a post-treatment SDMA above the RI. None of the cats with a normal post-treatment GFR had a post-treatment creatinine ⩾1.6 mg/dl or SDMA above the RI. Neither SDMA nor creatinine correlated with GFR at either time point (Table 2).

Figure 3

Baseline (T0) and 3 months (T3) post-treatment glomerular filtration rate (GFR) values. Dotted line indicates the normal cut-off for this method of GFR measurement

Median TT4 concentrations significantly decreased after treatment (Table 1). Nine of 10 cats that completed the study had a TT4 within the RI (1–4 µg/dl) at T3. Of these nine cats, four had a TT4 at the low end of the RI (1–2 µg/dl; Figure 4). The remaining cat had a low TT4 (<0.5 µg/dl). Correlation between TT4 and SDMA was insignificant at all time points (Table 2). The analyses were repeated with the eight cats that had full data sets (pre- and post-GFR studies) and statistical outcomes were unchanged (analyses are included in file 2 in the supplementary material).

Figure 4

Baseline (T0), 1 month (T1) and 3 months (T3) post-treatment total thyroxine (TT4) values. Dotted lines indicate the limits of the reference interval

Discussion

We identified significant decreases in GFR and concurrent increases in serum creatinine following hyperthyroid treatment, similar to previous studies.^{3,5,6,13,19,20} However, in our study population, median SDMA did not increase post-treatment. While SDMA did appear to be helpful in predicting decreased kidney function post-treatment in some cats, the variability in SDMA from baseline in individual cats suggested that extrarenal influences play a role in altering serum SDMA concentrations in hyperthyroid cats.

In this study, changes in individual SDMA values varied greatly with almost as many cats experiencing decreases in SDMA values as cats experiencing increases. Similarly, in a study of 47 cats undergoing radioiodine therapy, SDMA decreased in 49% of cats post-treatment. Moreover, 4/6 cats with high pretreatment SDMA values had normalization of SDMA post-treatment.¹³ In another study that looked at SDMA and creatinine in 80 cats before and after oral radioiodine treatment, it was reported that, though the mean SDMA did increase significantly post-treatment, individual SDMA values decreased after treatment in nearly a third of cats.²¹

These results suggest that SDMA may be influenced by factors independent of GFR, including thyroid hormone status. In one study that looked at SDMA in cats before and after bilateral thyroidectomy, investigators found a significant influence of thyroid status on SDMA, with hyperthyroid cats tending to have a higher SDMA than euthyroid or hypothyroid cats.²² In a population of humans without kidney disease, SDMA was also found to be increased in hyperthyroid individuals relative to euthyroid controls, which was suspected to be due to upregulation of SDMA production.²³ As a biomarker of GFR, SDMA is expected to correlate positively with creatinine;¹⁰ however, multiple studies have found either a lack of correlation between SDMA and creatinine pretreatment or a positive correlation that became stronger post-treatment.^1,3,21 Similarly, we found that SDMA and creatinine did not correlate pretreatment but positively correlated post-treatment. We speculate that the lack of correlation in hyperthyroid cats may be due to the metabolic changes attributable to the hyperthyroid state, with positive correlation between SDMA and creatinine developing in the non-hyperthyroid state due to resolution of these changes. Additionally, since creatinine is influenced by muscle mass and SDMA is not, better muscle condition following treatment may also help explain the stronger correlation between these two biomarkers.

It is important to note that these preliminary data are limited by the small sample size, which reduced the statistical power to detect significant correlations and changes in biomarkers between treatments, and not all cats were studied at all three time points; in particular, while there was no correlation between GFR and SDMA, we unexpectedly found no correlation between GFR and creatinine, which opposed our hypothesis, making it possible that a correlation between GFR and SDMA went undetected owing to the sample size. In addition, muscle condition score was not recorded consistently, making accurate interpretation of creatinine difficult. It is possible that the 3-month study duration was inadequate to evaluate the full effect of radioiodine treatment on the kidney as creatinine has been shown to continue to rise for 6 months after treatment of hyperthyroidism.²⁴ We also did not measure thyroid-stimulating hormone in this study, which may have resulted in a failure to detect iatrogenic hypothyroidism in some cats.

Conclusions

The data from this study suggest that SDMA is influenced by non-renal factors attributable to hyperthyroidism in radioiodine-treated cats. When SDMA is included in the pretreatment workup of hyperthyroid cats, it should be interpreted in the context of other factors such as urea nitrogen, creatinine, USG, history and physical examination parameters.

Supplemental Material

Supplementary file 1

Demographic information for included cases

Supplemental Material

Supplementary file 2

Results of variables evaluated at baseline and 1- and 3-months post-radioiodine treatment in cats with completed data sets (n = 8)

Footnotes

Acknowledgements

The authors wish to thank Lauren McKeen for statistical advice and analysis.

Accepted: 8 February 2023

Author note

These data were presented, in part, in abstract form at the 2018 ACVIM Forum, Seattle, WA, USA.

Supplementary material

The following files are available online:

Supplementary file 1: Demographic information for included cases.

Supplementary file 2: Results of variables evaluated at baseline and 1- and 3-months post-radioiodine treatment in cats with completed data sets (n = 8).

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The work described in this manuscript involved the use of non-experimental (owned or unowned) animals and procedures that differed from established internationally recognized high standards (‘best practice’) of veterinary clinical care for the individual patient. The study therefore had prior ethical approval from an established (or ad hoc) committee as stated in the manuscript.

Informed consent

Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.

ORCID iD

Laura R Van Vertloo

Jean-Sébastien Palerme

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Supplementary Material

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Changes in symmetric dimethylarginine and glomerular filtration rates in hyperthyroid cats undergoing radioiodine therapy

Abstract

Objectives

Methods

Results

Conclusions and relevance

Keywords

Introduction

Materials and methods

Results

Discussion

Conclusions

Supplemental Material

Supplementary file 1

Supplemental Material

Supplementary file 2

Footnotes

Acknowledgements

Author note

Supplementary material

Conflict of interest

Funding

Ethical approval

Informed consent

ORCID iD

References

Supplementary Material