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Iodine Research

Resource Network of The Iodine Movement

                        Iodine and the Body
Kidney                                                                                                  continued research: Kidney pg 2
                                                                                                                                                                                       Kidney pg 3

Given the importance of the kidney, it is surprising how little research looks at iodine and the kidney.

The NIS (Sodium-Iodide Symporter) has been found in the kidney -- primarily in the distal tubular
system, with less in the proximal tubules and none in the glomeruli.  The Pendrin transporter and
the AIT transporter have also been found in the kidneys.

Renal iodide transport appears to be, at least in part, an active process driven by the NIS.

Iodide clearance in the kidney varies with thyroid status, being lower in hypothyroidism and
increased in hyperthyroidism, which is mainly explained by changes of glomerular filtration.

Spitzweg, et al, have investigated the expression of the sodium iodide symporter in human kidney.

Kim, Porra, Suzuki, and Wall discuss the Pendrin, an iodide/chloride transporter found in the inner
ear, kidney, and thyroid.

Lacroix et al investigate both the NIS and the Pendrin in the kidney and other tissues.

Gopal and Ganapathy investigated the role of the AIT in the kidney.

Vadstrup has researched renal iodide excretion and the comparative aspects of iodine
conservation in mammals.

Matsushima researched iodide transport in the rabbit cortical collecting duct.

Escobar, et al, investigated the effects on thyroid hormones in different body tissues (including the
kidney) of various levels of iodine.

Katz has studied thyroid hormones and the kidney.

Vargas et al focus on the effects of thyroid hormones in vascular and renal systems, especially the
mechanisms by which thyroid hormones affect the regulation of body fluids.

Pavelka, Babicky, Vobecky look at the competition for excretion of bromide and iodide.

Mechanisms of adaptation to iodine deficiency in rats: thyroid status is tissue specific. Its relevance
for man.
Pedraza PE, Obregon MJ, Escobar-Morreale HF, del Rey FE, de Escobar GM.
Endocrinology. 2006 May;147(5):2098-108. Epub 2006 Feb 2.

Escobar, et al, investigated the effects on thyroid hormones in different body tissues (including the
kidney) of various levels of iodine.

Figure 5 summarizes the changes observed in T4 and T3 in cerebellum, pituitary, kidney, ovary,
adrenal, heart, and muscle with decreasing I availability. T4 decreased in all these tissues following
patterns similar to those of plasma T4 or FT4.

As already described above for the lung, the muscle and heart maintained normal T3
concentrations, even in LID animals. In these animals, T3 decreased only in the cerebellum,
pituitary, and kidney and did so only to 67–73% of C values, less than the decrease in circulating

The increase in T3 concentration in many of the tissues studied here, such as the liver, lung,
kidney, and muscle, were predictable from their known major dependency on plasma-derived T3.

[Thyroid and renal iodine clearance studied by means of radioactive iodine; review of theory and
Ferraris GM, Fregola G
Folia Endocrinol Mens Incretologia Incretoterapia. 1955 Jun;8(3):447-56. Italian.
[citation only]

[Thyroid and renal iodine clearance studied by means of radioactive iodine; clinical applications.]
Ferraris GM, Fregola G
Folia Endocrinol Mens Incretologia Incretoterapia. 1955 Jun;8(3):459-69. Italian.
[citation only]

Expression of SLC5A8 in kidney and its role in Na(+)-coupled transport of lactate.
Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, Smith SB, Prasad PD, Ganapathy V.
J Biol Chem. 2004 Oct 22;279(43):44522-32. Epub 2004 Aug 17.

We report here on the expression of slc5a8 in kidney and its relevance to Na(+)-coupled
reabsorption of lactate. slc5a8 is the murine ortholog of SLC5A8, a candidate tumor suppressor
gene, which we recently cloned from human intestine and demonstrated its functional identity as a
Na(+)-coupled transporter for short-chain fatty acids and lactate. The slc5a8 cDNA, cloned from
mouse kidney, codes for a protein consisting of 611 amino acids. When expressed heterologously
in mammalian cells or Xenopus oocytes, slc5a8 mediates Na(+)-coupled electrogenic transport of
lactate/pyruvate as well as short-chain fatty acids (e.g. acetate, propionate, and butyrate). The
Na+/fatty acid stoichiometry varies depending on the fatty acid substrate (2:1 for lactate and 4:1 for
propionate). This phenomenon of variable Na+/substrate stoichiometry depending on the fatty acid
substrate is also demonstrable with human SLC5A8. In situ hybridization with sagittal sections of
mouse kidney demonstrates abundant expression of the transcripts in the cortex as well as the
medulla. Brush border membrane vesicles prepared from rabbit kidney are able to transport lactate
in a Na(+)-coupled manner. The transport process exhibits the overshoot phenomenon, indicating
uphill lactate transport in response to the transmembrane Na+ gradient. The Na(+)-coupled lactate
transport in these membrane vesicles is inhibitable by short-chain fatty acids. We conclude that
slc5a8 is expressed abundantly in the kidney and that it plays a role in the active reabsorption of
lactate. slc5a8 is the first transporter known to be expressed in mammalian kidney that has the
ability to mediate the Na(+)-coupled reabsorption of lactate.

Assessing thyroid hormone status in a patient with thyroid disease and renal failure: from theory to
Kaptein EM, Wilcox RB, Nelson JC.
Thyroid. 2004 May;14(5):397-400.
[abstract only]

A 35-year-old Asian male, treated for hyperthyroidism, systemic lupus erythematosis, and uremia
presented with low serum total thyroxine (T4) and normal serum thyrotropin (TSH) levels. He had
been receiving prednisone and methimazole for 15 weeks. Free T4 measured by direct equilibrium
dialysis was in the hypothyroid range (0.3 ng/dL; normal, 0.8-2.7). Two possibilities were
considered: (1) a weakly bound dialyzable inhibitor in uremic serum that interfered with this serum
free T4 determination or (2) hypothyroidism with persistent TSH suppression because of prior
hyperthyroidism. To determine whether a weakly bound inhibitor was involved, the patient's serum
was serially diluted using two diluents: (1) an ultrafiltrate of the patient's serum, which would contain
any unbound inhibitor, as well as free T4 and (2) an inert diluent. Free T4 measurements were
similar with both, providing evidence against the presence of a dialyzable and ultrafilterable
inhibitor. In conclusion, this patient was hypothyroid because of antithyroid drug administration,
associated with prolonged central TSH suppression from preexisting hyperthyroidism.
Discontinuation of methimazole resulted in normalization of serum total T4 and TSH values. Thus,
paired, serial serum dilutions, using two different diluents, provided evidence for differentiation of
appropriately low free T4 measurements (because of hypothyroidism), from spuriously low free T4
measurements (because of an interfering inhibitor).

Radioiodine dosimetry in patients with end-stage renal disease receiving continuous ambulatory
peritoneal dialysis therapy.
Kaptein EM, Levenson H, Siegel ME, Gadallah M, Akmal M.
J Clin Endocrinol Metab. 2000 Sep;85(9):3058-64.

in patients with end-stage renal disease (ESRD), Na131I dosages for thyroid cancer may have to be
reduced to avoid excess radiation doses to red marrow, because radioiodine iree to five 2-L
exchanges daily) creatinine clearance rates are very low (mean, 7 mL/min), and radioiodine
clearance rates may be proportionately reduced. Thus, radioiodine kinetic studies were performed
in two hypothyroid CAPD patients with thyroid cancer, in eight euthyroid CAPD patients, and in eight
thyroid cancer patients with normal renal function. All received Na131I or Na123I orally, with serial
blood, urine, and/or dialysate sampling for 24-70 h. Dosimetry calculations were performed using
the MIRDOSE3 computer program. In CAPD patients, serum radioiodine half-times were 5 times
longer, and radioiodine clearance rates by urine plus dialysate were 20% of those in patients with
normal renal function. Na131I dosages for the two CAPD patients with thyroid cancer were reduced
from 150 mCi [5.6 gigabecquerels (GBq)] to 26.6 mCi (0.98 GBq) and 29.9 mCi (1.11 GBq),
respectively, resulting in radiation doses to red marrow and total body comparable to those in
patients with normal renal function who received a mean of 148 mCi (5.5 GBq) Na131I. Thus, in
patients receiving continuous ambulatory peritoneal dialysis therapy, 5-fold reductions in
radioiodine clearance rates require 5-fold decreases in Na131I dosages to avoid excessive
radiation doses to total body and red marrow.

Thyroid hormone metabolism and thyroid diseases in chronic renal failure.
Kaptein EM.
Endocr Rev. 1996 Feb;17(1):45-63.

Patients with ESRD have multiple alterations of thyroid hormone metabolism in the absence of
concurrent thyroid disease. These may include elevated basal TSH values, which may transiently
increase to greater than 10 mU/liter, blunted TSH response to TRH, diminished or absent TSH
diurnal rhythm, altered TSH glycosylation, and impaired TSH and TRH clearance rates. In addition,
serum total and free T3 and T4 values may be reduced, free rT3 levels are elevated while total
values are normal, serum binding protein concentrations may be altered, and disease-specific
inhibitors reduce serum T4 binding. Changes in T4 and T3 transfer, distribution, and metabolism
resemble those of other nonthyroidal illnesses, while changes in rT3 metabolism are disease
specific. Dialysis therapy minimally affects thyroid hormone metabolism, while zinc and
erythropoietin administration may partially reverse thyroid hormone abnormalities. Thyroid hormone
metabolism normalizes with renal transplantation; however, glucocorticoid therapy may induce
additional changes. ESRD patients may have an increased frequency of goiter, thyroid nodules,
thyroid carcinoma, and hypothyroidism. Goiter and hypothyroidism may be induced by iodide
excess, due to reduced renal iodide excretion, and may be reversed with iodide restriction in some
patients. The increased frequency of thyroid nodules and malignancies in ESRD may relate to
secondary hyperparathyroidism. After renal transplantation, the higher frequency of thyroid
malignancies may relate to the immunosuppressed state. Clinical symptoms and signs and
biochemical features of hypothyroidism and hyperthyroidism may be altered by concurrent ESRD.
ESRD patients with hyperthyroidism or follicular neoplasms require reduced dosages of Na 131-I
depending upon type, frequency, and duration of dialysis therapy.

Thyroid hormone and the kidney.
Katz AI, Emmanouel DS, Lindheimer MD.
Nephron. 1975;15(3-5):223-49. Review.
[abstract only]

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.

Regulated expression of pendrin in rat kidney in response to chronic NH4Cl or NaHCO3 loading.
Frische S, Kwon TH, Frokiaer J, Madsen KM, Nielsen S.
Am J Physiol Renal Physiol. 2003 Mar;284(3):F584-93. Epub 2002 Oct 22.

The anion exchanger pendrin is present in the apical plasma membrane of type B and non-A-non-B
intercalated cells of the cortical collecting duct (CCD) and connecting tubule and is involved in HCO
(3)(-) secretion. In this study, we investigated whether the abundance and subcellular localization of
pendrin are regulated in response to experimental metabolic acidosis and alkalosis with maintained
water and sodium intake. NH(4)Cl loading (0.033 mmol NH(4)Cl/g body wt for 7 days) dramatically
reduced pendrin abundance to 22 +/- 4% of control values (n = 6, P < 0.005). Immunoperoxidase
labeling for pendrin showed reduced intensity in NH(4)Cl-loaded animals compared with control
animals. Moreover, double-label laser confocal microscopy revealed a reduction in the fraction of
cells in the CCD exhibiting pendrin labeling to 65% of the control value (n = 6, P < 0.005).
Conversely, NaHCO(3) loading (0.033 mmol NaHCO(3)/g body wt for 7 days) induced a significant
increase in pendrin expression to 153 +/- 11% of control values (n = 6, P < 0.01) with no change in
the fraction of cells expressing pendrin. Immunoelectron microscopy revealed no major changes in
the subcellular distribution, with abundant labeling in both the apical plasma membrane and the
intracellular vesicles in all conditions. These results indicate that changes in pendrin protein
expression play a key role in the well-established regulation of HCO(3)(-) secretion in the CCD in
response to chronic changes in acid-base balance and suggest that regulation of pendrin
expression may be clinically important in the correction of acid-base disturbances.

Koutras DA.
Ann N Y Acad Sci. 2000;900:77-88. Review.
[abstract only]

Pregnancy affects thyroid physiology in many ways: (a) The renal iodide clearance rate is
increased, hence iodine requirements increase. (b) The fetal requirements for thyroid hormones
and iodide are an additional problem. (c) Serum thyroxine-binding globulin increases, thus
producing an increase in the levels of total T4 and T3. (d) Chorionic gonadotropin has a thyroid-
stimulating activity. This may be compensated for by a decrease in TSH, but in some cases
gestational thyrotoxicosis occurs. (e) Thyroid autoimmunity usually subsides during pregnancy, but
may rebound a few months after parturition, and postpartum thyroiditis may occur. Because
maternal antithyroid autoantibodies cross the placenta readily, fetal and neonatal hyperthyroidism
(or hypothyroidism) may develop. Pre-existing thyroid diseases are influenced. Nontoxic goiter
increases in size. Iodine and/or thyroxine may be required. Graves' disease may remit. If present,
antithyroid drugs should be given in small doses, and quite often they may be stopped altogether.
Hypothyroid patients may require a larger T4 dose.

Na(+)/I(-) symporter and Pendred syndrome gene and protein expressions in human extra-thyroidal
Lacroix L, Mian C, Caillou B, Talbot M, Filetti S, Schlumberger M, Bidart JM.
Eur J Endocrinol. 2001 Mar;144(3):297-302.

OBJECTIVE: The expression of two recently identified iodide transporters, namely the sodium/iodide
symporter (NIS) and pendrin, the product of the gene responsible for the Pendred syndrome (PDS),
was studied in a series of various extra-thyroidal human tissues, and especially in those known to
concentrate iodide.

METHODS: To this end, we used real-time kinetic quantitative PCR to detect NIS and PDS
transcripts and immunohistochemistry for the analysis of their protein products.

RESULTS: NIS gene and protein expression was detected in most tissues known to concentrate
iodine, and particularly in salivary glands and stomach. In contrast, PDS gene expression was
restricted to a few tissues, such as kidney and Sertoli cells. Interestingly, in kidney, pendrin
immunostaining was detected at the apical pole of epithelial cells of the thick ascending limb of the
Henle's loop and of the distal convoluted tubule.

CONCLUSION: This study provides new insights on the localization and expression of two genes
involved in iodide transport and emphasizes the interest of combining real-time quantitative PCR
and immunohistochemistry for the comparison of gene and protein expression in tissues.

Mechanism of iodide transport in the rabbit cortical collecting duct.
Matsushima Y, Muto S, Taniguchi J, Imai M.
Clin Exp Nephrol. 2006 Jun;10(2):102-10.

BACKGROUND: Pendrin, an anion exchanger known to participate in iodide transport in the apical
membrane of follicular cells of the thyroid gland, has recently been shown to exist in the apical
membrane of the beta- and gamma-intercalated (beta/gamma-IC) cells of the cortical collecting duct
(CCD). We examined mechanisms of iodide transport in the CCD.

METHODS: Rabbit CCD was perfused in vitro, and lumen-to-bath flux coefficients for both (125)I(-)
(K(I (lb))) and (36)Cl(-) (K(Cl (lb))) were measured simultaneously. The intracellular pH (pHi) of
beta/gamma-IC cells in the perfused CCD was measured by microscopic fluorometory, by loading 2',
7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein tetraacetoxy methylester (BCECF-AM), a fluorescent
marker for pHi. The effects on pHi of the replacement of NaCl with Na cyclamate, NaI, or NaBr in the
lumen or bath were observed.

RESULTS: K(I (lb)) was comparable to or slightly higher than K(Cl (lb)). Both iodide and chloride in
the lumen caused self- and cross-inhibitions to both fluxes. The addition of 5-nitro-2-(-3-
phenylpropylamino)-benzoate (NPPB), a Cl(-) channel inhibitor, to the bath significantly reduced K
(Cl (lb)), but not K(I (lb)). Replacement of luminal fluid NaCl with Na cyclamate, NaI, or NaBr caused
alkalization of pHi, no change in pHi, and slight acidification of pHi, respectively. Replacement of
bath NaCl with Na cyclamate, NaI, or NaBr caused alkalization, alkalization, and acidification of pHi,
respectively. Luminal NaI prevented the acidification of pHi caused by bath Na cyclamate.

CONCLUSIONS: The data are consistent with the model that iodide is transported via the Cl(-)/HCO
(3) (-) exchanger in the apical membrane of beta/gamma-IC cells and exits the basolateral
membrane via an electroneutral transporter that is distinct from the Cl(-) channel. We could not,
however, identify which type of beta/gamma-IC cell was mainly responsible.

The effect of acute doses of propylthiouracil on the renal excretion of iodide and other electrolytes
in the rat.
Matty AJ, Pye RG.
Experientia. 1968 Dec 15;24(12):1213-4.
[citation only]

Effect of diuretics on renal iodide excretion by humans.
Fregly MJ, McCarthy JS.
Toxicol Appl Pharmacol. 1973 Jun;25(2):289-98.
[citation only]

Effect of diuretics on renal iodide excretion by rats and dogs.
McCarthy JS, Fregly MJ, Nechay BR.
J Pharmacol Exp Ther. 1967 Nov;158(2):294-303.
[abstract only]

Diuretic studies were performed on rats and dogs after acute administration of hydrochlorothiazide,
aminophylline, ethacrynic acid, methazolamide and benzolamide. All chioruretic agents studied
increased the rate of urinary excretion of iodide. A significant correlation was noted between the
logarithms of the rates of chloride and iodide excretion by rats and dogs both prior to and during
drug administration. Apparently, drug administration does not alter tubular discrimination between
these two anions. The carbonic anhydrase inhibitors, methazolamide and benzolamide, increased
bicarbonate, but not chloride, excretion rate and had no significant effect on urinary iodide excretion
rate. The increased iodide loss accompanying administration of hydrochlorothiazide and
chlorothiazide to rats may explain the goitrogenic effect of these drugs reported earlier.

Thyroid function in chronic renal failure
Palmer BF, Henrich WL

The kidney normally contributes to the clearance of iodide, primarily by glomerular filtration. Thus,
iodide excretion is diminished in advanced renal failure, leading sequentially to an elevated plasma
inorganic iodide concentration and an initial increment in thyroidal iodide uptake. The ensuing
marked increase in the intrathyroidal iodide pool results in diminished uptake of radiolabeled iodide
by the thyroid in uremic patients. Increases in total body inorganic iodide can potentially block
thyroid hormone production (the Wolff-Chaikoff effect). Such a change may explain the slightly
higher frequency of goiter and hypothyroidism in patients with chronic renal failure.


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