Thyroid function and glomerular filtration—a potential for Grave errors

Theresa Claus, Saban Elitok, Roland Schmitt, Friedrich C. Luft and Ralph Kettritz

HELIOS Klinikum-Berlin, Franz Volhard Clinic, Medical Faculty of the Charité, Germany

Correspondence and offprint requests to: Ralph Kettritz, Franz Volhard Clinic, Wiltbergstrasse 50, D-13125 Berlin, Germany. Email: kettritz{at}fvk-berlin.de

Keywords: renal function; thyroid disease



   Introduction
 Top
 Introduction
 Cases
 Discussion
 Teaching points
 References
 
Endocrine disorders can have a profound influence on renal function. Hormones that directly regulate the kidney are well known. Sometimes the effects are subtle and less generally appreciated. We recently had two patients that underscore this state of affairs. We believe their presentations are worth sharing with other nephrophiles.



   Cases
 Top
 Introduction
 Cases
 Discussion
 Teaching points
 References
 
A 42-year-old female was referred for polyuria. She also had observed shortness of breath, sweating, palpitations and increased appetite that was coupled with a 3 kg weight loss from her basal weight of 65 kg. Her pulse pressure and heart rate were elevated. She had minimal exophthalmos; however, Stellwag's and Dalrymple's signs were present. Her thyroid gland was enlarged and smooth. A systolic murmur was audible over its surface. Her hands were moist and tremulous. The muscle stretch reflexes were brisk.

Hormonal studies quickly verified Graves' disease. We were interested to find a serum creatinine concentration of 27 µmol/l with a 24 h measured creatinine clearance of 254 ml/min. Of greater concern was a cystatin C concentration of 1.31 mg/l. The normal concentration is <1 mg/l. Treatment of her hyperthyroidism resulted in restoration of both values towards normal.

A 26-year-old male was referred due to an elevated creatine phosphokinase (CPK) value measured by his family doctor. He had gone to the doctor because of a tick bite 2 days earlier. The patient recalled having fallen on his back during a judo match 1 week earlier and had some vague aches but denied chronic pain. He was employed as a heating and air conditioning specialist and had no other complaints. In retrospect, he admitted to cold intolerance but could give no details. The physical examination, including neurological examination and Achilles muscle stretch reflex, were unremarkable. The patient weighed 70 kg.

The patient's serum creatinine concentration was 140 µmol/l. His 24 h measured creatinine clearance was 70 ml/min. The urinary sediment was normal; there was no proteinuria. CPK was 3910 U. Total cholesterol was 365 mg/dl, with a low-density lipoprotein cholesterol concentration of 281 mg/dl. The thyroid-stimulating hormone value was >100 U, while free T3 and free T4 were remarkably low. Autoantibodies consistent with Hashimoto's thyroiditis were detected in high titres, and scintigraphy was consistent with that diagnosis.

Questions

  1. What is the expected glomerular filtration rate in hyperthyroidism?
  2. What is the expected glomerular filtration rate in hypothyroidism?
  3. What is the effect of thyroid hormone on cystatin C?
  4. What is the mechanism of myopathy in both conditions and is there ever a risk of myoglobinuric acute renal failure?



   Discussion
 Top
 Introduction
 Cases
 Discussion
 Teaching points
 References
 
Our patients demonstrate a remarkable effect of thyroid function on glomerular filtration rate. The creatinine clearance of the patient with hyperthyroidism was doubled, while the creatinine clearance of the hypothyroid patient was halved. Both patients were treated, the hyperthyroid patient with ß blockade and methimazole, and the hypothyroid patient with thyroid hormone. After several months, the creatinine clearance of both patients had returned to normal.

Jayagopal et al. studied the effects of the hyperthyroid and hypothyroid state on changes in cystatin C and serum creatinine in 17 patients with hypothyroidism and 19 patients with hyperthyrodism [1]. All patients were newly diagnosed. The hypothyroid patients had a mean serum creatinine of 91 µmol/l while the hyperthyroid patients had a mean serum creatinine of 59 µmol/l. Creatinine fell by 13% in the hypothyroid patients after treatment, similar to our patient. The value increased in the hyperthyroid patients after treatment so that the groups were similar (78 µmol/l compared with 72 µmol/l). Cystatin C was lower in untreated hypothyroid patients than in those with untreated hyperthyroidism (0.76 mg/l compared with 1.12 mg/l). Treatment caused cystatin C to increase by 14% in the hypothyroid patients, compared with a 21% decrease in the hyperthyroid patients. The authors suggested that hyperthyroidism is associated with a reversible increase in cystatin C production, whereas in hypothyroidism the reverse is the case. Cystatins are endogenous cysteine protease inhibitors that modulate the turnover of intracellular and extracellular proteins. Cystatin C belongs to the type 2 cystatin superfamily and consists of 120 amino acid residues. Almost 99% of the protein is cleared from the circulation by glomerular filtration and tubular reabsorption followed by metabolization. In any event, cystatin C is not a reliable marker of the glomerular filtration rate in this common endocrine condition. Wiesli et al. made similar observations and drew the same conclusions [2]. Schmitt and Bachmann have raised the same caveat for the rat [3]. We measured creatinine clearence in our patient with hyperthyroidism and found increased values indicating an increased GFR. Increased glomerular filtration is characteristic of hyperthyroidism and is attributed to an enhanced cardiac output, decreased renal vascular resistance and elevated renal blood flow.

Hypothyroidism is associated with reversible acute renal failure [4]. In our patient, the effect on renal function was modest and disappeared with treatment. Hypothyroid myopathy is associated with proximal weakness and myalgias, muscle enlargement, slow relaxation of the reflexes and marked (up to 100-fold) increase in the creatine kinase level, as was the case in our patient. Elevated creatine kinase is regularly reported in hypothyroid patients. The mechanisms are most probably related to impaired glycogenolysis and impaired mitochondrial oxidative metabolism. Hypothyroidism can rarely cause rhabdomyolysis, precipitating parenchymal acute renal failure [5,6]



   Teaching points
 Top
 Introduction
 Cases
 Discussion
 Teaching points
 References
 

  1. Thyroid hormone can have clinically relevant effects on the glomerular filtration rate as reflected in the serum creatinine.
  2. Cystatin C fails as a marker of the glomerular filtration rate in patients with thyroid disease.
  3. Hypothyroidism belongs in the differential diagnosis of increased creatine kinase levels. Rarely, these may be sufficiently elevated to impact renal function directly.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Cases
 Discussion
 Teaching points
 References
 

  1. Jayagopal V, Keevil BG, Atkin SL, Jennings PE, Kilpatrick ES. Paradoxical changes in cystatin C and serum creatinine in patients with hypo- and hyperthyroidism. Clin Chem 2003; 49: 680–681[Free Full Text]
  2. Wiesli P, Schwegler B, Spinas GA, Schmid C. Serum cystatin C is sensitive to small changes in thyroid function. Clin Chim Acta 2003; 338: 87–90[CrossRef][ISI][Medline]
  3. Schmitt R, Bachmann S. Impact of thyroid dysfunction on serum cystatin C. Kidney Int 2003; 64: 1139–1140
  4. Mooraki A, Broumand B, Neekdoost F, Amirmokri P, Bastani B. Reversible acute renal failure associated with hypothyroidism: report of four cases with a brief review of literature. Nephrology (Carlton) 2003; 8: 57–60[CrossRef][Medline]
  5. Birewar S, Oppenheimer M, Zawada ET Jr. Hypothyroid acute renal failure. SD J Med 2004; 57: 109–110
  6. Barahona MJ, Mauri A, Sucunza N, Paredes R, Wagner AM. Hypothyroidism as a cause of rhabdomyolysis. Endocr J 2002; 49: 621–623[CrossRef][ISI][Medline]




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