Feline Hyperthyroidism and Renal Function

Chapter 43


Feline Hyperthyroidism and Renal Function




Physiology


Hyperthyroidism has numerous effects on both glomerular and renal tubular function. Thyroid hormones increase glomerular filtration rate (GFR) partly as a result of direct renal actions and partly secondary to cardiovascular and systemic hemodynamic effects that act to increase renal blood flow. When hyperthyroid patients are treated, GFR decreases and some cats become azotemic. Chronic kidney disease (CKD) is “unmasked” in some treated hyperthyroid cats; the renal disease is preexisting but is hidden by the increased GFR that accompanies the hyperthyroid state. Changes in GFR occur with all treatment modalities and should be considered the result of resolution of the hyperthyroid state and not a side effect of treatment.


The most significant hemodynamic effect of thyrotoxicosis is a profound decline in systemic vascular resistance secondary to dilation of resistance arterioles in the peripheral circulation. The decline occurs as a result of thyroid hormone–induced increases in tissue metabolism, release of locally acting vasodilators, and direct effects of the thyroid hormone triiodothyronine (T3) on vascular smooth muscle. As a result of the decrease in systemic vascular resistance, effective arterial filling volume decreases, causing stimulation of the sympathetic and renin-angiotensin-aldosterone systems. Activation of this system stimulates renal sodium reabsorption, leading to an increase in plasma volume; this increases stroke volume and along with the increase in heart rate that occurs with hyperthyroidism enhances cardiac output. This renal tubular effect is augmented by impaired response of the renal tubules to natriuretic peptides associated with thyrotoxicosis. Taken together, these mechanisms explain how plasma volume increases and sodium excretion decreases in the hyperthyroid state despite increases in renal blood flow and GFR. The normal pressure-diuresis-natriuresis response of the kidneys is altered by direct and indirect actions of thyroid hormones. Tubular reabsorption of other electrolytes, including phosphorus, also is enhanced.



Epidemiology


In most published studies, about 10% of hyperthyroid cats are azotemic at the time of diagnosis. A further 15% to 49% of cats become azotemic in the first few months after starting treatment. The number of cats that develop azotemia depends on various factors but particularly on how well hyperthyroidism is controlled. If treatment results in a borderline hyperthyroid state, the change in GFR is not as great as for a patient that is well controlled; the cat may not become azotemic. However, adverse consequences of thyrotoxicosis may be persistent. Conversely, if a cat is rendered hypothyroid during treatment, the likelihood of developing azotemia is increased.


CKD is highly prevalent in geriatric cats. The prevalence of azotemia increases with age, and hyperthyroid cats tend to be elderly. Even so, it is unclear whether the very high prevalence of azotemic CKD in cats that are diagnosed and treated for hyperthyroidism can be explained simply by demographics. One commonly asked question that has yet to be resolved is whether the high prevalence of azotemic CKD in cats treated for hyperthyroidism is due to the fact that hyperthyroidism is damaging to the kidneys. The hyperthyroid state causes glomerular hyperfiltration, hyperphosphatemia, and proteinuria, all of which have been associated with progression of CKD in cats and other species. At the present time, direct evidence that the hyperthyroid state is injurious to the kidneys is lacking.



Diagnosis of Hyperthyroidism with Chronic Kidney Disease


Diagnosis of hyperthyroidism is usually straightforward; in a cat that shows compatible clinical signs, demonstration of elevated serum total thyroxine (T4) concentration is all that is required. However, in patients with nonthyroidal illness, total T4 concentration can be suppressed, often to within or below the laboratory reference range. This is a relatively common occurrence in cats with previously diagnosed azotemic CKD. In the author’s clinics, hyperthyroidism is often suspected in cats with CKD many months before the diagnosis is confirmed by laboratory testing. Although these cats may exhibit classic signs of hyperthyroidism, the owner is unaware of any problem in many instances. The clinical suspicion arises when the cat is noted to lose weight while the serum creatinine concentration is decreasing secondary to enhanced GFR. Together with palpation of a goiter, these changes, although often subtle, are highly suggestive of hyperthyroidism.


Numerous testing strategies are possible in this situation. One option is to wait and repeat total T4 measurement in the hope that values will eventually be outside the reference range. An alternative option is to use a combination of diagnostic tests to confirm the diagnosis. A total T4 measurement in the upper half of the laboratory reference range together with either an undetectable thyroid-stimulating hormone (TSH) concentration (<0.03 ng/ml using the canine Diagnostic Products Corporation [DPC] assay) or an increased free T4 concentration is supportive of the diagnosis of hyperthyroidism, even though either of these tests (TSH, free T4) when performed in isolation has relatively low specificity (i.e., results in many false-positive diagnoses). Other options include the use of provocative endocrine tests (i.e., T3 suppression test or thyrotropin-releasing hormone stimulation test) or thyroid scintigraphy, but these tests have disadvantages including the need for specialist facilities, collection of multiple blood samples, tablet administration, and potential side effects.



Renal Function in Hyperthyroidism


In the hyperthyroid state GFR increases, causing decreases in serum or plasma concentrations of urea and creatinine. However, the changes in urea and creatinine that occur are not proportional to one another; the urea-to-creatinine ratio increases with hyperthyroidism, and it is common for hyperthyroid cats to have urea concentrations above the laboratory reference range. Elevated urea concentrations are found even in cats with good underlying renal function that do not go on to develop azotemia when treated. The reasons for the change in the urea-to-creatinine ratio are multifactorial. Urea may be relatively increased in the hyperthyroid state because of failure to fast the (polyphagic) patient before blood sampling and increased protein catabolism. Creatinine may also be relatively decreased, independent of the effects of GFR, because of a reduction in muscle mass.


Studies performed in hyperthyroid cats treated with radioactive iodine show that GFR decreases rapidly after establishment of euthyroidism with detectable changes in 1 week and that after 1 month little further change in GFR occurs. However, creatinine concentration takes longer to plateau after treatment, typically stabilizing after about 3 months. The urea concentration may increase slightly with treatment for hyperthyroidism, but this change is inconsistent.


Hyperthyroid cats may exhibit polydipsia and polyuria and consequently have relatively low urine specific gravity (USG). This finding was thought to be more common in cats with severe thyrotoxicosis, and the prevalence of these clinical signs is believed to have decreased in recent years as a result of earlier diagnosis. The cause of the polyuria and polydipsia is poorly understood. In experimental studies in rodents, hyperthyroidism was shown to inhibit the insertion of aquaporins, the channels through which water is absorbed in the renal distal tubules and collecting ducts, resulting in a form of nephrogenic diabetes insipidus. It also has been proposed that heat intolerance results in a psychogenic polydipsia in hyperthyroid animals. These effects are independent of any underlying renal dysfunction. Treatment of hyperthyroidism, despite the resulting decline in GFR, has very unpredictable effects on USG except in cats that become overtly azotemic.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Feline Hyperthyroidism and Renal Function

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