Unmasking Kidney Disease In Hyperthyroid Cats after Treatment

I have two hyperthyroid cats that both had "completely normal" kidney function until we started treating with methimazole. On treatment, the serum T4 concentrations in both cats have come down nicely to 1.2 and 2.0 µg/dl, respectively (reference interval, 1.0-4.0 µg/dl), so these values are within the low-normal range, which is what I aim for after treatment.

In the first cat, the serum creatinine has increased from 1.2 mg/dl up to 2.0 mg/dl, whereas the serum creatinine value in the second cat rose from 1.5 mg/dl up to 2.5 mg/dl. Based on the IRIS staging system, both cats could be classified as having stage 2 chronic kidney disease (CKD).

How do I manage such hyperthyroid cats that develop "new" CKD after treatment? Should I lower the methimazole or stop it all together in order to help improve the kidney function?

My Response:

Hyperthyroidism and CKD are both very common problems of the older cat and may occur concurrently in the same patient (1,2). Because hyperthyroidism increases the glomerular filtration rate (GFR) and renal blood flow (RBF), the kidney disease may be masked and only revealed once the cat is rendered euthyroid (3-5). As you know, that's what happened in these two feline patients.

However, it is very important to understand that treatment of hyperthyroidism doesn't cause new kidney problems; the CKD was already present in your cats before the methimazole treatment, but the serum creatinine values were normal, in part due to the high GFR associated with hyperthyroidism. Now that you have the hyperthyroidism under control, the lowering of circulating thyroid hormone concentrations has also resulted in a drop in GFR, unmasking the underlying CKD that was already there.

Management of hyperthyroid cats that develop kidney disease after treatment
So what do we do with hyperthyroid cats like your two patients here— cats that develop mild CKD after treatment of hyperthyroidism with methimazole?

It was once thought that if azotemia developed following medical treatment, then it would be best to stop the methimazole and leave the hyperthyroidism untreated (or at least under-treat it) to maximize renal function. This recommendation has now been widely abandoned, with the realization that hyperthyroidism could actually be causing renal injury in these cats through the process of glomerular hyperfiltration (1,2,6). This increase in glomerular pressure has been associated with proteinuria and evidence of tubular damage, which could result in progressive renal injury. In other words, hyperthyroidism has the potential to exacerbate these processes and worsen, rather than help, renal function.

On the other hand, it's also important not to over control hyperthyroidism. In other words, we don't want the post-treatment T4 concentrations to go too low because iatrogenic hypothyroidism will make the azotemia worse (7). Even mild degrees of hypothyroidism can worsen the azotemia in susceptible cats. This means that the serum T4 value does not have to be below reference range — even a serum T4 in the lower third of the reference range may be too low, especially if the serum TSH is high, diagnostic for mild hypothyroidism (8).

Because of this association between development of iatrogenic hypothyroidism and worsening of azotemia, my "goal" in treating cats with hyperthyroidism is to reduce the total T4 concentration into the middle of the reference range (e.g., 2.0-3.0 µg/dl with your lab). So in your first cat, you may want to lower the methimazole dose and allow the serum T4 to come up into the mid-normal range. This may help increase GFR and improve kidney function in that cat. One recent study found that restoration of euthyroidism in cats with iatrogenic hypothyroidism resulted in a significant reduction in serum creatinine concentration, with azotemia resolving in half of the cats (9).

Finally, if you unmask kidney disease after treatment of a hyperthyroid cat, this also means that you should take steps to attempt to slow the progression of CKD, just as you would in a geriatric cat with CKD alone. These steps may include one or more of the following, depending on secondary factors and stage of the CKD (10,11):

• Antibiotics, if urinary tract infection
• Antihypertensives, if hypertensive
• Low-phosphate diet
• Phosphorus binders
• Calcitriol or ACE-inhibitors, if necessary
• Subcutaneous fluids

Survival times of hyperthyroid cats that develop mild CKD after treatment
In most cats that develop newly-diagnosed azotemia after treatment for hyperthyroidism, the CKD is mild (usually IRIS stage 2) and associated with few clinical signs other than mild polyuria and polydipsia. Owners of cats that have developed azotemia still report that treatment of the hyperthyroidism has improved the clinical condition of their cat, as shown by weight gain and resolution of other clinical signs of hyperthyroidism.

The survival time of cats that develop azotemia following treatment of hyperthyroidism does not differ from those that do not develop any azotemia (7). This fact may be surprising to many practicing veterinarians who naturally assume that the development of CKD is associated with a worse prognosis. However, CKD progresses relatively slowly in cats, and only about half of all cats diagnosed with mild CKD will ultimately succumb to the disease (12). Many CKD cats die because of unrelated causes.

Survival times of hyperthyroid cats that are azotemic prior to treatment
The situation is completely different in cats that are already clearly azotemic (serum creatinine >2 mg/dl), even before any treatment for hyperthyroidism has been given. In general the survival of this group of cats with azotemic CKD prior to treatment is poor. In one study, the median survival time for azotemic cats was only 178 days; however, survival times in that study was very variable,  ranged from 0 days up to 1,505 days (4.1 years) (13).

Bottom Line:

Hyperthyroid cats that develop "new" CKD after treatment are common, but the azotemia is generally mild and we should not withhold methimazole treatment in those cats. However, we don't want to induce iatrogenic hypothyroidism, and steps should be taken to address the underlying CKD. Unless prior azotemia was present, the prognosis of most treated cats with mild CKD is good to excellent.

References:

1. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clin Tech Small Anim Pract 2006;21:17-21.  
2. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.  
3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Res 1994;55:1745-1749.  
4. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Vet Rec 2007;161:711-715.  
5. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domest Anim Endocrinol 2009;36:45-56.  
6. Syme H. Are methimazole trials really necessary? In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
7. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092.  
8. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compendium 2013;35:E4. 
9. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
10. Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012;42:669-692.
11. Polzin DJ. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract 2011;41:15-30. 
12. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000;41:235-242.
13. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 

Top Endocrine Publications of 2013: Hypertension in Dogs and Cats

In my sixth compilation of the canine and feline endocrine publications of 2013, I’m moving on to endocrine hypertension. Listed below are 13 research papers written in 2013 that deal with a variety of hypertensive topics of clinical importance, many of which directly involve one or more hormones.

These range from a review of the hypertension associated with diabetic nephropathy (1) to an overview of guidelines for antihypertensive therapy in dogs and cats (2); from diagnostic testing of primary hyperaldosteronism in cats (3) to the use of plasma metanephrines for diagnosis of pheochromocytoma in dogs (5); and from a case study of a dog that develop severe hypertension secondary to an overdose of phenylpropanolamine (4) to a study of the relationship between the degree of hypertension and the development of ocular changes in cats with chronic kidney disease (6).

Other publications included are a comparison of indirect blood pressure measurements using a non-invasive method, high-definition oscillometry to direct measurements using a radio-telemetry device in awake cats (7) to a study of the effect of body position on indirect measurement of systolic arterial blood pressure in dogs (10);  from a report of a case series of dogs and cats with hypertensive encephalopathy (8) to a study of the effect of intra-abdominal hypertension on the adrenal gland secretion of cortisol, aldosterone, epinephrine, and norepinephrine in dogs (13); and finally, from a report of high dietary salt intake and blood pressure in cats (9) to an investigation of the renin-angiotensin-aldosterone system in the pathogenesis of hypertension associated with hyperthyroidism in cats (12).

References:

1. Bloom CA, Rand JS. Diabetes and the kidney in human and veterinary medicine. Vet Clin North Am Small Anim Pract 2013;43:351-365. 
2. Buoncompagni S, Bowles MH. Treatment of systemic hypertension associated with kidney disease. Compend Contin Educ Vet 2013;35:E1. 
3. Djajadiningrat-Laanen SC, Galac S, Boeve SAEB, et al. Evaluation of the oral fludrocortisone suppression test for diagnosing primary hyperaldosteronism in cats. J Vet Intern Med 2013;27:1493-1499. 
4. Ginn JA, Bentley E, Stepien RL. Systemic hypertension and hypertensive retinopathy following PPA overdose in a dog. J Am Anim Hosp Assoc 2013;49:46-53. 
5. Green BA, Frank EL. Comparison of plasma free metanephrines between healthy dogs and 3 dogs with pheochromocytoma. Vet Clin Pathol 2013;42:499-503. 
6. Karck J, von Spiessen L, Rohn K, et al. Interrelation between the degree of a chronic renal insufficiency and/or systemic hypertension and ocular changes in cats. Tierarztliche Praxis Ausgabe K, Kleintiere/Heimtiere 2013;41:37-45. 
7. Martel E, Egner B, Brown SA, et al. Comparison of high-definition oscillometry -- a non-invasive technology for arterial blood pressure measurement -- with a direct invasive method using radio-telemetry in awake healthy cats. J Feline Med Surg 2013; 15:1104-1115. 
8. O'Neill J, Kent M, Glass EN, et al. Clinicopathologic and MRI characteristics of presumptive hypertensive encephalopathy in two cats and two dogs. J Am Anim Hosp Assoc 2013;49:412-420. 
9. Reynolds BS, Chetboul V, Nguyen P, et al. Effects of dietary salt intake on renal function: a 2-year study in healthy aged cats. J Vet Intern Med 2013;27:507-515. 
10. Rondeau DA, Mackalonis ME, Hess RS. Effect of body position on indirect measurement of systolic arterial blood pressure in dogs. J Am Vet Med Assoc 2013;242:1523-1527. 
11. Tian Z, Shen Y, Liao H, et al. Carotid proliferative plaque formation in a canine model of chronic hypertension. J Investig Med 2013;61:995-1003. 
12. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 
13. Yu J, Fu X, Chang M, et al. The effects of intra-abdominal hypertension on the secretory function of canine adrenal glands. PLoS One 2013;8:e81795. 

Q & A: Calcitriol versus Vitamin D3: What's the Difference?

What is the difference between calcitriol and vitamin D3? They both appear to be 1,25-hydroxycholecalciferol.

How about vitamin D2? It that form active at all in dogs and cats with renal failure?

My Response:

Vitamin D is a fat-soluble vitamin that exists in various forms (1). The chemical structure of vitamin D was established in the early 1930's. The main forms are vitamin D2 (ergocalciferol), found in plants, yeasts and fungi and vitamin D3 (cholecalciferol) of animal origin. Vitamin D2 and D3 are not biologically active; rather, they must be modified in the body to have any effect.

Vitamin D2 or D3 must then be first hydroxylated in the liver and then in the kidneys to become active. At this point, as biologically active 1,25-OH-cholecalciferol (also called calcitriol), this form of vitamin D can exert its endocrine effects (1).

By the early 1970's, it had become clear that calcitriol was the active form of vitamin D. It is over 1,000 times as potent as Vitamin D2 and D3 in binding to the vitamin D receptor.

The sun
Vitamin D has long been considered an essential dietary ingredient, but in several species, including humans, sheep, cattle, horses, and pigs, vitamin D3 can be formed in the skin from a cholesterol metabolite (7-dehydrocholesterol) after exposure to natural sun light.

In dogs and cats, however, this skin production of vitamin D3 does not occur (2), so they are dependent entirely on a dietary source of vitamin D.

Food
Large amounts of vitamin D are not found in adequate amounts in most foods. It’s found in fish, cod liver oil, mushrooms, liver and eggs – but usually not in substantial amounts (except in cod liver oil). Thus, getting enough vitamin D naturally from whole foods is difficult.

Both vitamin D2 and D3 have been commercially synthesized and both forms seem to be effective at maintaining blood levels of vitamin D in the body.

Use of vitamin D in renal disease
In severe renal failure, the kidneys cannot produce adequate amounts of the biologically active vitamin D, and this commonly leads to abnormalities of calcium and phosphorus metabolism (3). Oral administration of active calcitriol to animals with chronic kidney disease helps compensate for the reduced production of the active hormone (4).

It is critical to understand that administration of vitamin D2 and D3 will not work to raise active vitamin D concentrations in these animals with renal disease. Active calcitriol must be used as the form of vitamin D to treat these animals (4).

References

1. Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006;92:4-8.
2. How KL, Hazewinkel HA, Mol JA. Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D. Gen Comp Endocrinol. 1994;96:12-18.
3. Gerber B, Hässig M, Reusch CE. Serum concentrations of 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol in clinically normal dogs and dogs with acute and chronic renal failure. Am J Vet Res. 2003;64:1161-1166.
4. Hostutler RA, DiBartola SP, Chew DJ, et al. Comparison of the effects of daily and intermittent-dose calcitriol on serum parathyroid hormone and ionized calcium concentrations in normal cats and cats with chronic renal failure. J Vet Intern Med. 2006;20:1307-1313.