Synthroid Renal Protection or Renal Risk: What the Evidence Says About Levothyroxine and Kidney Function

Does levothyroxine protect the kidneys or threaten them?

Thyroid hormones affect renal growth, renal haemodynamics and salt and water metabolism, based largely on experimental work [4]. Hypothyroidism has been associated with increased serum creatinine and decreased glomerular filtration rate, and a review of the thyroid-kidney relationship notes that most renal manifestations of thyroid dysfunction are reversible with treatment [1]. That finding is consistent with improvement after treating thyroid dysfunction; it does not show that levothyroxine directly protects kidney tissue.

The levothyroxine sodium tablet label puts the risk side in the adverse reactions section, which it describes as primarily those of hyperthyroidism due to therapeutic overdosage: palpitations, tachycardia, arrhythmias, heart failure, angina, tremor, insomnia, heat intolerance, and decreased bone mineral density [3]. That list does not include kidney injury or reduced kidney function [3].

The direct evidence in people who already have kidney disease

The most relevant study enrolled 309 adults with stage 2-4 chronic kidney disease and subclinical hypothyroidism [2]. Of those, 180 took thyroid hormone replacement and 129 did not. Over a mean follow-up of 34.8 months, eGFR fell by 5.93 mL/min/1.73 m² per year in the untreated group and by 2.11 mL/min/1.73 m² per year in the treated group (P=0.04) [2]. In a multivariate Cox model, thyroid hormone replacement was an independent predictor of the combined renal outcome (a 50% fall in eGFR or end-stage renal disease), with a hazard ratio of 0.28 (95% CI 0.12 to 0.68) [2].

This compared patients who happened to be treated with patients who were not; it was not a randomized trial, so it cannot prove that the hormone preserved kidney function. Its direction favors treatment, but it is one study in one population.

Kidney disease makes hypothyroidism more common

The relationship runs both ways. In 14,623 adults in the Third National Health and Nutrition Examination Survey, the prevalence of hypothyroidism rose as estimated GFR fell: 5.4% with GFR at or above 90, 10.9% at 60 to 89, 20.4% at 45 to 59, 23.0% at 30 to 44, and 23.1% below 30 mL/min/1.73 m² [5]. Of those cases, 56% were subclinical [5]. A review describes thyroid dysfunction as highly prevalent in chronic kidney disease and notes that low T3 levels in these patients have been related to higher cardiovascular risk and all-cause mortality [1].

In 200 hemodialysis patients followed prospectively, 102 died, and lower free T3 predicted death: each 1 pg/mL higher free T3 was associated with a hazard ratio of 0.50 (95% CI 0.35 to 0.72) after adjustment for traditional and emerging risk factors [6]. That describes the prognostic weight of thyroid hormone status in dialysis; it does not establish that giving more levothyroxine changes survival.

Where the risk actually sits: over-replacement

The label is specific about what too much levothyroxine does. Over-treatment may cause an increase in heart rate, cardiac wall thickness and cardiac contractility, and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients [3]. For adults at risk of atrial fibrillation or with underlying cardiac disease, the label directs a starting dose below full replacement and titration every 6 to 8 weeks [3]. Over-replacement also increases bone resorption and decreases bone mineral density, particularly in postmenopausal women [3].

What happens to creatinine and eGFR after starting treatment

Hypothyroidism is associated with higher serum creatinine and lower GFR, and most of these renal manifestations are reversible with treatment [1]. A creatinine change after starting levothyroxine may therefore reflect the thyroid correction itself. The same review notes that the reverse effects have been reported in thyrotoxicosis [1].

Timing and interactions

The label says to take levothyroxine sodium tablets once daily on an empty stomach, one-half to one hour before breakfast with a full glass of water, and at least 4 hours before or after drugs known to interfere with absorption [3].

• Phosphate binders. The label lists calcium carbonate, ferrous sulfate, sevelamer and lanthanum as binders that may bind levothyroxine, and says to give levothyroxine at least 4 hours apart from them [3]. In 20 adults with hypothyroidism, 1,200 mg/day of elemental calcium as calcium carbonate taken with levothyroxine for 3 months lowered mean free T4 from 17 to 15 pmol/L and raised TSH from 1.6 to 2.7 mIU/L [7]. In 14 patients, ferrous sulfate 300 mg taken with thyroxine daily for 12 weeks raised mean TSH from 1.6 to 5.4 mU/L, and 9 patients had more hypothyroid symptoms [8]. Both studies were uncontrolled.
• Bile acid sequestrants and ion exchange resins. Colesevelam, cholestyramine, colestipol and Kayexalate decrease levothyroxine absorption; the label says to give levothyroxine at least 4 hours before these drugs or monitor TSH [3].
• Acid suppression. The label lists proton pump inhibitors, sucralfate and antacids as drugs that may reduce levothyroxine absorption through effects on gastric acidity, and says to monitor patients, without a fixed hour spacing [3]. In 10 patients taking levothyroxine, omeprazole raised TSH in all of them, an effect reversed by a 37% increase in thyroxine dose [9]. A retrospective study of 37 patients starting lansoprazole found a mean TSH change of 0.69 micro IU/mL, against 0.11 in 55 controls not on a PPI [10].
• Other forms. In 47 thyroidectomized patients on a PPI who switched from tablets to same-dose Tirosint soft gelatin capsules, mean TSH fell by 0.32 mIU/L at 6 weeks and 0.68 mIU/L at 12 weeks; 45 patients completed the open-label study, which had no control group [11]. In 24 patients whose tablet absorption was impaired by PPIs, switching to an oral solution lowered TSH in the replacement group from 5.4 to 1.7 mU/L [12].
• Testing. The label directs stopping biotin and biotin-containing supplements at least 2 days before TSH or T4 testing because of assay interference [3].

For dosing, the label gives a full replacement dose of 1.6 mcg/kg/day for adults with hypothyroidism, titrated in 12.5 to 25 mcg steps every 4 to 6 weeks until the patient is euthyroid, and says the peak effect of a given dose may take 4 to 6 weeks [3].

Dialysis and transplant

Patients on hemodialysis and peritoneal dialysis, and kidney transplant recipients, show thyroid hormone alterations and thyroid disease more often than the general population [1].