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A delicate balance: thyroid and renal function

Vaske HH, Schermerhorn T, Grauer GF.  Effects of hyperthyroidism on kidney function:  a review.  J Feline Med Surg 2016;18(2):55-59.

Many older feline patients are affected by chronic kidney disease (CKD), hyperthyroidism, or both.  Over 30% of cats over 15 years of age have CKD associated with nephron damage of various etiologies, and frequently of unknown etiology. CKD is considered irreversible and progressive, as the damaged nephrons are ultimately replaced by fibrous scar tissue.  Hyperthyroidism is the most common endocrinopathy found in older cats, and affects at least 6% of cats older than 9 years of age. Since thyroid hormone affects the function of many organ systems, the hypermetabolic syndrome that occurs with production of excess thyroid hormone significantly affects the kidneys as well as the heart, intestines, liver, and nervous system, among other target organs.  Cats with hyperthyroidism alone have a median survival time of 1.6-4.0 years, while those who have developed CKD prior to treatment of hyperthyroidism have survival times of only 0.5-2.0 years.

The renin-angiotensin-aldosterone system (RAAS) is upregulated in hyperthyroid cats. The ultimate result of this upregulation is an increase in cardiac output of > 60%.  Additional increases in cardiac output beyond this may occur due to increased responsiveness and activation of β-adrenergic receptors  within cardiac tissue and the renal cortex; this in turn can result in increased sympathetic nervous system activity and further increases in RAAS activity.  In unregulated hyperthyroidism, increased renal blood flow (RBF), increased glomerular capillary hydrostatic pressure, and increased glomerular filtration rate (GFR) result from the increased cardiac output, decreased systemic vascular resistance, and increased blood volume associated with this endocrinopathy.  Renal proteinuria can occur in cats with CKD or hyperthyroidism, and is a risk factor for the development of azotemia or progression of azotemic CKD.  At least in the case of proteinuria associated with hyperthyroidism, the degree of proteinuria tends to decrease once the patient is rendered euthyroid.

Since the hyperthyroid state tends to cause increases in RBF and GFR, it can be difficult to interpret the quality of renal function in unregulated hyperthyroid cats using common biomarkers such as blood urea nitrogen (BUN) and creatinine, since these parameters are affected by GFR, and reflect GFR.  In addition, as the production of serum creatinine is affected by muscle mass, hyperthyroid cats, who often have sarcopenia secondary to their hyperthyroid-associated hypermetabolic state, may have apparently better renal function than they truly have due to decreased serum creatinine.  CKD may therefore be unmasked in some cats only after euthyroidism is restored.  About 10-23% of hyperthyroid cats have pre-treatment azotemia, while 15-49% of hyperthyroid cats demonstrate post-treatment azotemia.

Many options exist for the treatment of feline hyperthyroidism; regardless of the treatment modality used, when hyperthyroidism is successfully treated, there will be a decrease in renal excretory function, a decrease in the GFR, and an increase in serum creatinine.  This increase in serum creatinine may be somewhat delayed. Serum creatinine can continue to increase for 6 months after the cat becomes euthyroid, while GFR can decrease for up to one month following attainment of euthyroidism, and then will stabilize.  Therefore, it is important for clinicians to monitor serum creatinine for at least 6 months after the patient is rendered euthyroid.  Studies have shown that hyperthyroid cats who develop post-treatment azotemia do not have decreased survival times compared with those who do not develop post-treatment azotemia.  Hyperthyroid cats with pre-treatment azotemia, however, do appear to have decreased survival times post-treatment relative to those without pre-treatment azotemia.

Iatrogenic hypothyroidism subsequent to treatment of hyperthyroidism has adverse effects on kidney function. It is well known that hypothyroidism is associated with decreased GFR in dogs, and the same is likely to be true in cats.  Cats with iatrogenic hypothyroidism are more likely to develop post-treatment azotemia than those cats who are euthyroid post-treatment.  Moreover, azotemic hypothyroid cats have a significantly shorter survival time than non-azotemic hypothyroid cats. Resolution of azotemia was noted in 50% of hypothyroid cats in which the hypothyroidism was corrected by reducing the dose of anti-thyroid medication.  Therefore, thyroid hormone supplementation of cats rendered hypothyroid by I131 treatment, or reduction in the dosage of anti-thyroid medication to achieve euthyroidism, is recommended to help improve renal function.  It is essential to identify cats who have developed iatrogenic hypothyroidism and treat them accordingly, so that kidney function is preserved and protected.

Hypothyroidism may take 3-6 months to develop post-radioiodine therapy, so not only creatinine, but total T4, should be monitored for at least 6 months post-treatment.  As total T4 is easily lowered in euthyroid sick patients, confirmation of a true hypothyroid state must be accomplished through evaluation of serum TSH (thyroid stimulating hormone).  The combination of low total T4 and and elevated TSH concentration confirms the diagnosis of hypothyroidism, and then the cat should either be supplemented with levothyroxine or have its dosage of anti-thyroid medication adjusted, depending on how the hyperthyroidism was originally treated.  At this time, the canine TSH assay is the only available method of evaluating TSH levels in the cat, and is considered reliable for diagnosing feline hypothyroidism; no feline-specific TSH assay is available.

There are currently no completely dependable ways to predict development of post-treatment azotemia in newly diagnosed hyperthyroid cats. Pre-treatment evaluation of BUN, creatinine, and urine specific gravity, as well as other parameters such as GFR and urine protein:creatinine ratio has not been shown to reliably predict the development of post-treatment azotemia. No studies evaluating the use of the newly developed biomarker symmetric dimethylarginine (SDMA) in the prediction of post-treatment azotemia in hyperthyroid cats were cited in the article, and none may have been published yet.  As SDMA reflects GFR, it also may not reliably predict development of post-treatment azotemia.

In treating feline hyperthyroidism, the target total T4 should be in the lower half of the reference interval, without actually creating hypothyroidism.  Monitoring of renal function as well as T4 for a minimum of 6 months following attainment of euthyroidism is essential in all hyperthyroid cats.  Owners of hyperthyroid cats demonstrating evidence of pre-treatment CKD should be counseled that the animal may have decreased survival time, and that long-term monitoring of renal function is required.  Due to the poor prognosis of cats with iatrogenic hypothyroidism, this condition needs to be anticipated, screened for, and treated whenever necessary. [PJS]

See also:
Williams TL, Elliot J, Syme HM.  Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism.  J Vet Intern Med 2014;28:1251-5.

Williams TL, Peak KJ, et al.  Survival and the development of azotemia after treatment of hyperthyroid cats.  J Vet Intern Med 2010;24:863-9.