Monday, November 14, 2011

Hyperthyroidism & Renal Disease: Is a "Tapazole Trial" Really Necessary?

Hyperthyroidism and chronic kidney disease (CKD) are both common disorders in older cats. Therefore, it should not be surprising that both disorders frequently develop together in the same cat. The prevalence of concurrent renal disease in cats with hyperthyroidism is estimated to be approximately 30–35% (1,2).

Hyperthyroidism & the Kidney: A Love-Hate Relationship

Hyperthyroidism tends to "artificially" increase the renal blood flow (RBF) as well as the glomerular filtration rate (GFR) (1–4). When the GFR is increased in a hyperthyroid cat with underlying CKD, it can mask renal insufficiency; serum concentrations of urea nitrogen and creatinine may be normal despite mild to moderate kidney disease (1–7). Decreased muscle mass and muscle wasting, a common feature of hyperthyroidism, also contribute to the lowered serum creatinine concentration in these cats (since creatinine is derived from muscle tissue) (1,2).

Treating hyperthyroidism restores the high serum T4 concentration to normal and, in cats without CKD, also returns the high GFR back to normal values. In cats with CKD, however, the GFR will fall to the low-normal or subnormal levels expected with moderate renal dysfunction. Therefore, this decrease in GFR can result in the apparent worsening of the serum kidney function tests or the development of renal disease.

It is important to remember, however, that treating the hyperthyroidism itself does not cause the CKD in these cats. The renal disease was already present before treatment but was masked by the hyperdynamic state of the hyperthyroidism.

Physiological Interactions Between Thyroid Hormones & Renal Function

Hyperthyroidism decreases peripheral vascular resistance by dilating the arterioles of the peripheral circulation. Because of this decrease in systemic vascular resistance, the effective circulating volume decreases, stimulating the renin-angiotensin-aldosterone system. This leads to renal sodium retention with a resultant increase in blood volume. Cardiac output may increase dramatically in cats with hyperthyroidism. In addition to the decrease in systemic vascular resistance, an increase in heart rate, increases in left ventricular contractility and ejection fraction, and increase in blood volume all contribute to this increase in cardiac output (1,2).

These systemic hemodynamic factors (i.e., the increased cardiac output) combined with intrarenal vasodilation lead to increases in renal blood flow (RBF), glomerular hydrostatic pressure, and glomerular filtration rate (GFR). Thyroid hormones also influence renal tubular function including electrolyte handling.

With time, hyperthyroidism can lead to renal changes including glomerular hypertension, glomerulosclerosis, proteinuria, and hyperplasia and hypertrophy of the renal tubules (1,2).

Hyperthyroidism Itself May Contribute to Chronic Kidney Disease

Recent research provides three lines of evidence that untreated hyperthyroidism itself contributes to the development or progression of CKD in cats.
  • First of all, a number of recent reports indicate that many untreated hyperthyroid cats develop proteinuria, which resolves within 4 weeks of successful treatment (8,9). This proteinuria, which reverses after treatment, could be a reflection of glomerular hypertension and hyperfiltration, changes in tubular protein handling, or a change in the structure of the glomerular barrier (1). Whatever the cause of the proteinuria, no treatment is generally needed other than treatment of the hyperthyroid state itself.
  • Secondly, cats with untreated hyperthyroidism have high levels of retinol binding protein (RBP), a urinary marker for tubular dysfunction or damage (10,11). This high urinary RBP excretion may reflect tubular damage or dysfunction resulting from the thyroid-induced hypertrophy and hyperplasia of the tubular cells. After treatment, these high urinary RBP levels fall in cats without azotemia but may remain slightly high in cats with pre-existing CKD. This too suggests that hyperthyroidism can cause reversible renal dysfunction; however, the renal tubular changes may become irreversible with time as CKD progresses.
  • Thirdly, many cats with untreated hyperthyroidism have high values for urinary N-acetyl-ß-D-glucosaminidase (NAG), a lysosomal glycosidase found primarily in epithelial cells of the proximal convoluted tubule (12). Like RBP, NAG is a specific marker of active proximal tubular damage. After treatment, these high urinary NAG levels decrease, again suggesting that these renal changes can be reversed, at least in cats without pre-existing CKD.
Overall, these studies all suggest that that leaving a hyperthyroid cat untreated (or poorly regulated with methimazole) may be detrimental to long-term kidney function. Treating and curing hyperthyroidism may help to both reverse renal damage and preserve remaining kidney function.

Clinical Implications in Hyperthyroid Cats

Decision-making with regard to treating cats with hyperthyroidism and CKD can be difficult. Clinicians can be confronted with two different scenarios concerning hyperthyroid cats with concurrent CKD.
  1. First of all, about 10% of hyperthyroid cats have known pre-existing CKD at time of diagnosis. These cats have obvious clinical and biochemical evidence of mild to moderate kidney disease, and do not present a diagnostic dilemma. However, hyperthyroid cats with pre-existing azotemia are more difficult to treat successfully, at least on a long-term basis. They have a worse prognosis than do cats that are not azotemic prior to treatment for hyperthyroidism.
  2. In the second scenario, cats are initially not azotemic but develop high serum concentrations of urea nitrogen or creatinine only after they have been treated for hyperthyroidism. These cats, which represent 20% to 25% of all hyperthyroid cats, are much more of a diagnostic dilemma because one may not even suspect that they have concurrent renal disease.
1. Pre-existing Azotemia in a Newly Diagnosed Hyperthyroid Cat
In hyperthyroid cats with overt CKD, we can predict that the GFR will fall once the euthyroidism is restored. Therefore, it is generally advised to try medical management prior to a more definitive treatment in cats with concurrent hyperthyroidism and pre-existing CKD. A low starting dose (i.e., 1.25 mg orally once daily) of methimazole with gradual dose escalation is prudent when starting a cat with CKD and hyperthyroidism on medical therapy. Cats should be monitored every 2 weeks with a CBC, biochemical profile, urinalysis, and serum T4 concentration.

Because the initial decline in GFR stabilizes after a month of successful resolution of the hyperthyroidism, one can decide at that time whether or not the cat's renal function is stable or worsening.

Hyperthyroid cat with overt CKD
and hypokalemia
Concurrent management of CKD is also extremely important these cats. If the renal function remains stable after a euthyroid state is established, a more definitive treatment, such as 131-I, should be strongly considered. If, on the other hand, renal function declines dramatically after antithyroid drug treatment, especially if accompanied by marked clinical deterioration of the cat's renal failure (to IRIS Stage 3 or 4), it may be best to maintain the cat on a reversible anti-thyroid therapy, decrease the dose, or stop it all together if need be.

In some of these cats with severe CKD, maintenance of a mild hyperthyroid state may give the best short-term clinical result. However, this course of action is far from ideal, and these cats have a very guarded to poor prognosis. Except in these extreme circumstances, the validity of maintaining a cat in a mildly hyperthyroid state is questionable given that uncontrolled hyperthyroidism, in itself, appears to be damaging to renal function (1,8,10–12)

2. Non-Azotemic Before Treatment of Hyperthyroidism; Development of Post-Treatment Azotemia
Hyperthyroidism is known to increase GFR, decrease circulating creatinine concentrations, and mask underlying renal disease. About 20% to 25% of hyperthyroid cats without known CKD develop azotemia after successful treatment of hyperthyroidism, irrespective of therapeutic modality (methimazole/carbimazole, surgical thyroidectomy, or radioiodine) (1).

Predicting which hyperthyroid cats will develop overt azotemia after treatment of hyperthyroidism can be difficult to impossible. The determination of GFR is clearly the best predictor of post-treatment CKD, with a low to low-normal GFR indicating that a hyperthyroid cat is at increased risk for post-treatment azotemia. However, techniques for assessment of GFR are not widely used in practice, and even GFR determinations are not a 100% perfect predictor of CKD. Routine pre-treatment parameters such as serum urea or creatinine concentrations, and urine specific gravity are certainly useful, but they cannot consistently predict impending azotemia (13).

Should Methimazole Trials be Performed in all Hyperthyroid Cats?

For years, it has been accepted practice to perform a methimazole trial in cats in which hyperthyroidism has been newly diagnosed to evaluate the impact of a euthyroid state on renal function.  Again, determining which untreated hyperthyroid cats have clinically significant underlying CKD can sometimes be difficult. Use of methimazole or carbimazole can provide a "preview" of how the cat will be after curing hyperthyroidism. Thus, many veterinarians attempt trial therapy with methimazole or carbimazole to help test what renal function might remain after treating the hyperthyroidism. If no marked deterioration occurs, then a more permanent therapeutic option for hyperthyroidism may be recommended.

Except for advanced (IRIS Stage 3–4) CKD, the necessity of this approach in cats without pretreatment azotemia is questionable, given that treatment for the hyperthyroidism is strongly recommended whatever the outcome. In support of this reasoning, the survival of cats that do develop azotemia is not shorter than those that do not develop azotemia after treatment of hyperthyroidism. In one study, the median survival time of cats that developed azotemia (595 days) was similar to that in cats that remained non-azotemic (584 days) after treatment (14).

Preventing Hypothyroidism after Treatment for Hyperthyroidism

Whatever treatment option for hyperthyroidism is considered, it is important to avoid hypothyroidism as it may have its own detrimental effects on GFR. Hypothyroidism in both humans and dogs has been showed to reduce GFR (15,16), and it is likely that similar changes occur in cats that develop iatrogenic hypothyroidism.

In a recent study by Williams et al (17), cats with iatrogenic hypothyroidism were more likely to develop azotemia in the 6 months after treatment than cats that remained euthyroid. Hypothyroid cats with azotemia also had shorter survival times than nonazotemic cats, whereas no difference in survival between euthyroid cats with or without azotemia could be detected. This suggests that the development iatrogenic hypothyroidism contributes to the development of azotemia, at least in cats with mild underlying CKD (IRIS Stage I or II) (17,18). More importantly, the hypothyroidism may shorten survival after treatment of hyperthyroidism.

If a cat with post-treatment azotemia develops a low T4 concentration, a serum TSH level should be measured to help exclude hypothyroidism (19). The finding of a high serum TSH concentration confirms hypothyroidism. A specific assay for feline TSH is not yet available. However, the commercially available canine TSH assay cross-reacts with feline TSH enough to enable its use as a diagnostic test for hypothyroid cats (19,20).

If iatrogenic hypothyroidism is diagnosed, treatment with L-thyroxine (0.1 mg once to twice daily) is indicated (20,21). The dosage should be adjusted based on post-pill serum T4 and cTSH determinations. Most cats treated will show improvement in their azotemia as the hypothyroidism resolves and euthyroidism is restored (18).

Long-Term Renal Function in Cats that Develop Azotemia after Treatment

In most cats that develop post-treatment azotemia, the CKD is not that severe or life threatening. It is also unusual to see a jump of more than one IRIS stage after treatment (22). In other words, hyperthyroid cats with IRIS Stage I–II CKD may develop overt azotemia after treatment, but one would not expect those cats' CKD to advance to more than IRIS Stage II–III after treatment (Figure 1).

Figure 1. Box plots of serum creatine concentrations in 45 hyperthyroid cats
before and after treatment. Prior to treatment 34 of the 45 cats were not azotemic, whereas 11 cats (Green Box) had IRIS stage 2 CKD.
After treatment, 12 of the 34 nonazotemic cats progressed to stage 2 CKD (Red Box).  All 11 cats with prior azotemia remained azotemic, but the the median value was not significantly different (Green Box).
Click image above to enlarge figure.
In addition, the decline in GFR after successful treatment of a cat's hyperthyroidism is not very progressive. Rather, the fall in GFR is detectable within 1 month but then remains stable at this level for months thereafter (1,6). The rise in serum urea nitrogen and creatinine values in cats with CKD follow the decrease in GFR, so that azotemia, when it does occur, would be expect to develop within 1 month of treatment but remain relatively stable over many months (6,22).

The Bottom Line

For years, conventional wisdom has been to perform a methimazole trial in cats in which hyperthyroidism has been newly diagnosed to evaluate the impact of a euthyroid state on renal function. In most cats without overt CKD, use of a methimazole trial prior to definitive therapy is not needed.

Remember that hyperthyroidism itself has long-term deleterious effects on renal function, and survival of cats that do develop azotemia after treatment for hyperthyroidism is no shorter than for those whose renal function remains stable. For those cats that do develop azotemia after their hyperthyroid state is corrected, the renal disease is not generally severe or life-threatening and usually stabilizes within the first month of therapy.

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