Dimitrios S. Emmanouel

Thyroid Hormone and the Kidney

Thyroid hormones affect both renal morphology and function. They are required for kidney growth and development, and thyroid deficiency results in decreased renal plasma flow and glomerular filtration rate and in impaired urinary concentration and dilution. Thyroid hormones also influence membrane transport and electrolyte metabolism, and alterations in mineral metabolism in hyperthyroidism frequently cause calcium nephropathy which affects renal function adversely. The kidney plays an important role in the peripheral metabolism of iodine and thyroid hormones, and thyroid function is altered in certain kidney diseases, particularly chronic renal failure. The pathogenesis of these alterations is currently under active investigation.

Mechanism of Impaired Water Excretion in the Hypothyroid Rat

The ability to excrete an oral water load and the renal diluting mechanism were studied in hypothyroid rats and in age-matched euthyroid controls. Hypothyroid animals excreted a significantly smaller fraction of a 50-ml/kg oral water load than controls, demonstrating the same limited ability to excrete free water as thyroid-deficient man. During hypotonic (0.45%) saline infusion, absolute sodium delivery to the diluting segment and free water clearance were markedly lower in hypothyroid rats. However, both fractional distal sodium delivery and fractional free water clearance were similar in hypothyroid and control animals, suggesting that the reduced absolute free water formation in hypothyroid rats was due to decreased net distal delivery. In support of this hypothesis was the observation that fractional distal sodium reabsorption was equal or higher in thyroid-deficient rats, which indicates that the sodium reabsorptive capacity of the diluting segment was preserved in these animals. The results cannot be attributed to incomplete suppression of antidiuretic hormone (ADH) since they were identical in diabetes insipidus rats, nor to different rates of non-ADH-dependent backflux of filtrate since tissue osmolality and solute concentrations in the cortex, medulla, and papilla were similar in hypothyroid and control rats of both Sprague-Dawley and Brattleboro strains. The functional integrity of the diluting segment in hypothyroid rats was further demonstrated in experiments in which distal delivery was increased by contralateral nephrectomy or by administration of carbonic anhydrase inhibitors which decrease proximal sodium reabsorption. In both studies, fractional free water clearance increased markedly reaching levels significantly greater than in euthyroid controls. These results demonstrate that the impaired ability of the hypothyroid rat to excrete a water load is not due to incomplete suppression of ADH or decreased reabsorptive capacity of the diluting segment but results from decreased filtrate delivery to this site secondary to reduced GFR.

Metabolism of Polypeptide Hormones by the Normal Kidney and in Uremia

Recent work from our laboratory on the mechanism of polypeptide hormone handling by the normal kidney and the pathogenesis of altered hormonal metabolism in renal failure is reviewed. The kidney extracts substantial amounts of low - and medium - molecular weight polypeptide hormones from the renal circulation by a process which probably involves both glomerular filtration plus luminal reabsorption and direct peritubular uptake, although the relative contribution of the two mechanisms under physiologic conditions is not known. The bulk of the extracted hormone is catabolized in the renal parenchyma since urinary excretion is negligible. Renal catabolism contributes an important fraction of the total metabolic clearance of polypeptide hormones, which accounts in part for their increased circulating levels in renal failure. Since certain hormones are heterogenous and a large proportion of their plasma immunoreactivity may consist of components of uncertain biologic activity, simple correlations between circulating hormone levels and endocrine abnormalities in uremia are hazardous.

Role of the kidney in hormone metabolism and its implications in clinical medicine

ZusammenfassungDie Urämie wird von verschiedenen metabolischen und endokrinen Störungen begleitet, die einerseits die Degradation hormonal aktiver Peptide in der erkrankten Niere behindern, andererseits durch direkte Auswirkungen des urämischen Milieus auf die extrarenale Degradation verschiedener Hormone, ihre Synthese oder Sekretion hervorgerufen sind. Es gelingt nicht immer, eine direkte Ursachen-Wirkung-Beziehung zwischen Änderungen des immunreaktiven Hormonspiegels und endokriner Funktionsstörung herzustellen, da in der Uramie die zirkulierende hormonale Immunreaktivität häufig kreuzreagierende Komponenten ohne biologische Aktivität einschließt und zusätzlich die Wirkung verschiedener Hormone auf ihre Zielorgane verändert ist. Abweichungen im Stoffwechsel der pankreatischen α- und β-Zellhormone und von Prolactin bei chronischem Nierenversagen sowie ihr Effekt auf den Stoffwechsel von Lipiden und Kohlenhydraten und auf die reproduktive Funktion werden in diesem Zusammenhang diskutiert.SummaryUremia is accompanied by a variety of metabolic and endocrine disorders, due in part to impaired degradation of hormonally active peptides by the diseased kidney, and in part to the fact that the uremic environment interferes with the extrarenal degradation of certain hormones, or with their synthesis or secretion. It is not always possible to establish a direct cause and effect relationship between alterations in immunoassayable hormone levels and endocrine abnormalities because in uremia the circulating hormonal immunoreactivity frequently includes crossreacting components without biological activity and, in addition, hormonal effects on target organs are often altered. Alterations in the metabolism of pancreatic alpha and beta cell hormones and of prolactin in chronic renal failure and their effect on the metabolism of lipids and carbohydrates and on reproductive function in this condition are discussed.