Thyroid disorder in CKD

1. Thyroid Disorder in
Chronic Renal Failure

2. Content
1. Thyroid
• Physiology
• Synthesis of thyroid hormones
• Thyroid hormone metabolism
• Sick euthyroid syndrome
• Effects of thyroid hormones
2. CKD
3. Potential mechanisms linking thyroid and kidney disease
4. Kidney Disease as a Risk Factor for Thyroid Dysfunction
5. Thyroid Dysfunction as a Risk Factor for Altered Kidney Structure and Function
6. Thyroid functional test derangements in kidney disease
7. Treatment of thyroid dysfunction
8. Key points

3. Thyroid
Thyroid is an endocrine gland situated at the root of the neck on either side of the
trachea.
 It has two lobes, which are connected in the middle by an isthmus.
 It weighs about 20 to 40 g in adults.
Thyroid is larger in females than in males.
The structure and the function of the thyroid gland change in different stages of the
sexual cycle in females

4. Half-life Thyroid hormones
T4 has a long half life of 7 days.
Half-life of T3 is varying between 10 and 24 hours.
Rate of Secretion
Thyroxine = 80 to 90 µg/day
Tri-iodothyronine = 4 to 5 µg/day
Reverse T3 = 1 to 2 µg/day.
Plasma Level
•Total T3 = 0.12 µg/dL
•Total T4 = 8 µg/dL.
Metabolism of Thyroid Hormones Degradation of thyroid hormones occurs in muscles, liver and
kidney.

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Synthesis of thyroid hormones occurs in five stages: 1. Thyroglobulin synthesis 2. Iodide
trapping 3. Oxidation of iodide 4. Transport of iodine into follicular cavity 5. Iodination of
tyrosine 6. Coupling reactions

7. Thyroid hormone metabolism:
Peripheral metabolism of thyroid hormones involves the sequential removal of iodine
molecules, converting T4 into the more active T3 and inactivating thyroid hormones
before their excretion
Degradation of Thyroid Hormone
These steps occur in peripheral tissues:
1. Deiodination and decarboxylation
2. Glucuronidation/Sulfonation in liver
3. Excretion into bile ducts
4. Excretion of glucuronide conjugate in urine

8. In the peripheral tissues
•T4 is converted to T3 by 5’ iodinase (reverse T3 ). ‰
•T3 is more biologically active than T4 . ‰
•rT3 is inactive.

9. Type I deiodinase, which is located primarily in thyroid, liver, and kidneys, has a
relatively low affinity for T4 .
Type II deiodinase has a higher affinity for T4 and is found primarily in the
pituitary gland, brain, brown fat, and thyroid gland.
Expression of type II deiodinase allows it to regulate T3 concentrations locally,
a property that may be important in the context of levothyroxine (T4 )
replacement.
Type II deiodinase is also regulated by thyroid hormone; hypothyroidism
induces the enzyme, resulting in enhanced T4 → T3 conversion in tissues such
as brain and pituitary.
T4 → T3 conversion is impaired by fasting, systemic illness or acute trauma,
oral contrast agents, and a variety of medications (e.g., propylthiouracil,
propranolol, amiodarone, glucocorticoids).
Type III deiodinase inactivates T4 and T3 and is the most important source of
reverse T3 (rT3 ), including in the sick euthyroid syndrome.
In the sick euthyroid syndrome, especially with hypoperfusion, the type III
deiodinase is activated in muscle and liver.
Massive hemangiomas that express type III deiodinase are a rare cause of
consumptive hypothyroidism in infants

10. SICK EUTHYROID SYNDROME (NONTHYROIDAL ILLNESS)
Any acute, severe illness can cause abnormalities of circulating TSH or thyroid
hormone levels in the absence of underlying thyroid disease, making these
measurements potentially misleading.
The major cause of these hormonal changes is the release of cytokines such as IL-6.
Unless a thyroid disorder is strongly suspected, the routine testing of thyroid function
should be avoided in acutely ill patients.
The most common hormone pattern in sick euthyroid syndrome (SES), also called
nonthyroidal illness (NTI), is a decrease in total and unbound T3 levels (low T3
syndrome) with normal levels of T4 and TSH.
T4 conversion to T3 via peripheral 5′ (outer ring) deiodination is impaired, leading to
increased reverse T3 (rT3 ).
Since rT3 is metabolized by 5′ deiodination, its clearance is also reduced.
Thus, decreased clearance rather than increased production is the major basis for
increased rT3.

11. Teleologically, the fall in T3 may limit catabolism in starved or ill patients.
With decreased tissue perfusion, muscle and liver expression of the type 3 deiodinase
leads to accelerated T4 and T3 metabolism.
Any severe illness can induce changes in thyroid hormone levels, but certain disorders
exhibit a distinctive pattern of abnormalities.
Renal disease is often accompanied by low T3 concentrations, but with normal
rather than increased rT3 levels, due to an unknown factor that increases uptake of
rT3 into the liver.

13. Chronic Kidney Disease
Kidney damage for ≥3 months, as defined by structural or functional abnormalities of
the kidney, with or without decreased GFR.

15. Any dysfunction in the thyroid can affect the production of thyroid hormones (T3 and
T4) which can be linked to various pathologies throughout the body.
One of the most important conditions that has been less studied is thyroid hormone
levels and how they affect the progression of CKD.
Disorders in renal function have been seen to coexist with specific levels of thyroid
hormone.
This study is done to simplify the importance of interactions between thyroid function
and kidney disease.
POTENTIAL MECHANISMS LINKING THYROID AND KIDNEY DISEASE

18. Kidney Disease as a Risk Factor for Thyroid Dysfunction
It has been suggested that kidney disease may lead to thyroid dysfunction via multiple
pathways.
 It is hypothesized that iodine excess resulting from impaired clearance and
retention in CKD may lead to hypothyroidism via the Wolff–Chaikoff effect.
Although it is an essential element for thyroid hormone synthesis, exposure to excess
iodine may lead to transient inhibition of thyroid hormone synthesis, presumably due
to the generation of intrathyroidal iodolactones or iodolipids that inhibit TPO activity.
There is eventually an “escape” from the Wolff–Chaikoff effect, owing to iodine-
induced downregulation of the sodium–iodide symporter responsible for iodine
transport into thyroid follicular cells and subsequent reduction in intrathyroidal iodine
and iodine-induced inhibitors of thyroid hormone synthesis.
Conversely, exposure to excess iodine may also lead to hyperthyroidism via the Jod-
Basedow phenomenon, particularly among those with nodular goiters with
autonomously functioning thyroid tissue and/or those with endemic goiter residing in
iodine-deficient areas, although this phenomenon has also been described in those
without underlying thyroid disease living in iodine-replete regions.

19. In the dialysis population, frequent exposure to iodine-containing agents via
angiography procedures, contrast-enhanced computed tomography scans, fistulogram
procedures, povidone–iodine cleansing agents, and dietary sources may lead to
sustained high concentrations of iodine, and there are a number of case reports and
series documenting iodine induced thyroid functional disease in ESRD patients via
these routes
The vast majority of thyroid hormone is protein bound, it has been hypothesized
that heavy protein losses in nephrotic syndrome and peritoneal dialyzate may lead to
thyroid hormone depletion.
Indeed, limited data have shown that urinary protein losses are associated with serum
T3 and T4 reductions proportional to the degree of hypoalbuminemia and proteinuria.
Acid–base derangements may contribute to thyroid functional test aberrations in
CKD.
In healthy adults, induction of metabolic acidosis has been shown to lead to higher
TSH and lower T3 and T4 levels, and in hemodialysis patients correction of metabolic
acidosis with oral sodium citrate has normalized aberrant T3 levels.

20. Thyroid Dysfunction as a Risk Factor for Altered Kidney Structure and Function
There are considerable knowledge gaps with regard to the mechanistic link and
directionality of the association between thyroid and kidney diseases.
However, current evidence shows that hypothyroidism adversely affects kidney size
and structure in both development and adulthood.
For example, in animal studies hypothyroidism has been shown to result:
1. A reduced kidney size to body weight ratio;
2. Truncated tubular mass;
3. Various glomerular basement membrane changes including
•Reduced glomerular basement membrane volume and area,
•Glomerular basement membrane thickening,
•Mesangial matrix expansion, and
•Increased glomerular capillary permeability to proteins.

21. A growing body of evidence also suggests that hypothyroidism may lead to kidney
dysfunction, presumably due to:
1. Reduced cardiac output as a squeal of impaired systolic and diastolic function;
2. Decreased vasodilator synthesis and subsequent intrarenal vasoconstriction
leading to impaired renal perfusion;
3. Reduced renin–angiotensin–aldosterone production and activity resulting in
impaired autoregulation of renal perfusion; and
4. Alterations in chloride channel expression leading to increased distal chloride
delivery and increased tubuloglomerular feedback.

22. Multiple case series have also documented an association between severe
hypothyroidism and kidney dysfunction.
In a study of 24 patients with acute, severe iatrogenic hypothyroidism (i.e., 20 out of
24 patients with serum TSH values >40mIU/mL) induced before radioiodine scanning
for monitoring of thyroid carcinoma, comparison of preinduction euthyroid and
postinduction hypothyroid creatinine values available in a subset of 15 patients
demonstrated a 34% increase in mean serum creatinine values (1.17 vs. 0.87mg/dL,
respectively) following provocation of hypothyroidism.1
In a case series of 27 patients with acute hypothyroidism due to thyroidectomy (TSH
mean±SD 70±23mIU/mL), laboratory and isotopic kidney function studies using serum
creatinine and 51Cr-EDTA clearance, respectively, were conducted pre- and
postthyroid hormone replacement.
Following thyroid hormone replacement, there was a significant decline in serum
creatinine (1.30±0.44 vs. 1.04±0.32mg/dL)2
1Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med January
2Karanikas G, Schutz M, Szabo M, et al. Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy.
Am J Nephrol January–February 2004;24(1):41–5.

23. Goiter in CKD
There is an increased prevalence of goiter (0–9%) in patients with CKD.
This may be due to the decreased clearance of the inorganic iodides, causing a
hypertrophic effect on the thyroid gland tissue leading to goiter.
A decreased clearance of goitrogenic substances like aryl acid due to CKD may also be
a factor.
Research has shown that increased serum iodine levels can result in prolongation of
the Wolff-Chaikoff effect.

24. Subclinical Hypothyroidism
Subclinical hypothyroidism is defined as an elevation in serum TSH concentration
(normal range 5–10 μIU/mL) in conjunction with a normal serum free T4
concentration.
With the decline in GFR, the prevalence of subclinical hypothyroidism increases
consistently.
One study showed that approximately 18% of the patients with CKD not requiring
dialysis have subclinical primary hypothyroidism.
This finding is independently associated with a progressively lower estimated GFR. The
prevalence of subclinical primary hypothyroidism increased from 7% to 17.9% in
individuals whose GFR has decreased from ≥90 mL/min to 60 mL/min.

25. Hyperthyroidism
The prevalence of hyperthyroidism in CKD patients is the same as it is with the general
population; thus CKD is not directly associated with hyperthyroidism.
However, it is important to understand that aspects of hyperthyroidism can indeed
accelerate CKD.
These mechanisms are the following:
•increased renal blood flow seen in hyperthyroidism results in intraglomerular
hypertension, leading to increased filtration pressure and consequent hyperfiltration.
•Proteinuria seen in hyperthyroidism is known to cause direct renal injury;
•Increased mitochondrial energy metabolism along with downregulation of
superoxide dismutase, which occurs in hyperthyroidism, contributes to an increased
free radical generation that causes renal injury
•Oxidative stress also contributes to hypertension in hyperthyroidism, which
contributes to CKD progression

26. Thyroid Disorders in Glomerular Diseases
Thyroid diseases including both hypo- and hyperthyroidism are associated with several
types of glomerulonephritis.
The types of glomerulonephritis seen in thyroid disease are membranous, IgA,
mesangiocapillary, membranoproliferative, and minimal change glomerulonephritis.
Among these, the most frequent is membranous glomerulonephritis.
The two main histological changes seen:
1. A thickened glomerular basement membrane (GBM) due to immune complex
deposition
2. An increased mesangial and endocapillary cellularity.

27. The pathophysiology links between thyroid dysfunction and glomerulonephritis involve
proteinuria and formation of immune complexes.
This association is extremely common in autoimmune thyroiditis.
Approximately up to 50% of patients with autoimmune thyroiditis have the presence
of immune complexes.
These complexes are mainly responsible for the alteration of the renal function by
depositing on the basement membrane of the glomeruli.
Some studies have also reported a deposition of thyroglobulin in the basement
membrane of the glomeruli.
In addition to thyroid diseases, similar effects are also seen in other autoimmune
disorders such as systemic lupus erythematosus (SLE) and diabetes

28. Nephrotic Syndrome
Changes in the serum levels of thyroid hormone can affect nephrotic syndrome in
many ways.
Due to proteinuria, there is a loss of many binding proteins including thyroxine-
binding globulin (TBG), transthyretin or prealbumin, and albumin.
Due to losses of these proteins, there is a reduction in serum T4 and total T3 levels.
In most circumstances, patients are euthyroid because the thyroid is able to
compensate for the proteinuria and free T3 and T4 levels are normal.

29. Effects of Dialysis on Thyroid Hormones Hemodialysis
Most patients on hemodialysis (HD) are euthyroid.
Systemic acidosis, time on dialysis, markers of endothelial damage, and inflammation
from HD are associated with low T3 levels.
Low total T4 levels with increased free T4 levels are seen as heparin inhibits T4
binding to proteins, thereby increasing a free T4 fraction in these patients.
TSH is elevated in 20% of patients on HD usually in the range of 5–20 mU/L .
HD affects the cellular transport of TSH which might act as a compensatory
mechanism for maintaining an euthyroid status.

30. Nodules and Carcinoma
Patients with chronic kidney disease may have a slightly higher frequency of thyroid
nodules and thyroid carcinoma.
Why this might occur is not known

31. THYROID FUNCTIONAL TEST DERANGEMENTS IN KIDNEY DISEASE

32. Thyrotropin
In the general population, serum TSH is typically used for the screening, diagnosis, and
treatment monitoring of primary hypothyroidism.
It is the most sensitive and specific single metric of thyroid function given its negative
logarithmic association with serum T3 and T4 (i.e., small changes in T3 and T4 lead to
exponential changes in TSH).
Some TSH alterations may be observed in kidney disease including impaired
clearance, blunted response to TRH, reduced pulsatility, increased half-life, and
impaired glycosylation leading to altered function.
However, unlike T3 and T4, serum TSH levels typically remain normal in nonthyroid
illness, rendering it a more robust metric of thyroid function in chronic illness states.
In fact, in one clinical study of 38 dialysis patients who underwent studies of thyroid
function (TSH, total T3, total T4, and FT4) and metabolic testing, serum TSH and FT4
concentrations were found to be more reliable indicators of metabolic state as
compared with T3 concentrations.1
1Spector DA, Davis PJ, Helderman JH, Bell B, Utiger RD. Thyroid function and metabolic state in chronic renal failure. Ann Intern Med

33. Triiodothyronine
Reduced T3 levels are the most commonly observed thyroid functional test alteration
in CKD patients.
In a crosssectional analysis of 2284 CKD patients with normal TSH levels, there was a
graded increase in the prevalence of low T3 with progressively lower levels of kidney
function, such that 79% of patients with eGFRs 2
Reverse Triiodothyronine
Reverse T3 (rT3) is a metabolically inactive form of thyroid hormone, which is
generated from T4 via the type 3 5′-deiodinase enzyme.
In addition to producing rT3, the type 3 5′-deiodinase enzyme is also responsible for
decomposing rT3 into inactive diiodothyronine.
In hypothyroidism, rT3 levels are typically low due to reduced production of the
precursor (i.e., T4), although in mild hypothyroidism rT3 levels may sometimes be
normal or high.
In contrast, rT3 levels typically remain normal in kidney dysfunction(unknown
factor).
At this time, it is not known as to whether rT3 levels can be used to reliably distinguish
between thyroid functional test alterations arising from nonthyroidal illness versus
hypothyroidism versus kidney dysfunction
2Song SH, Kwak IS, Lee DW, Kang YH, Seong EY, Park JS. The prevalence of low triiodothyronine according to the stage of chronic kidney

34. Thyroxine
The vast majority of circulating T4 (>99.9%) is bound to proteins (e.g., thyroid-binding
globulin, transthyretin, albumin, and lipoproteins), and total T4 assays measure both
free and protein-bound hormone.
Hence, reduced total T4 levels may be observed in euthyroid CKD patients who have
low-protein states due to malnutrition, inflammation, nephrotic syndrome, and excess
protein losses via peritoneal dialysate.
FT4 assays that are routinely used in clinical practice measure the minute fraction of
nonprotein bound, biologically active hormone using “indirect” methods. For example,
the FT4 analog assay estimates FT4 concentrations based on antibody sequestration of
total T4 relative to FT4 levels.
Although generally accurate, the FT4 analog method is protein-dependent and may
thus result in spurious levels in the presence of low-protein concentrations and
pathologic conditions in which endogenous substances (e.g., uremic toxins) and
medications (e.g., heparin, furosemide) impair thyroid hormone–protein binding.

35. Antithyroid Peroxidase Antibodies
In the general population, the most common cause of primary hypothyroidism in
iodine-sufficient areas of the world is chronic autoimmune hypothyroidism
(Hashimoto’s thyroiditis), which is typically characterized by high serum concentrations
of autoantibodies to thyroid peroxidase (TPO).
Indeed, serum anti-TPO antibodies are elevated in over 90% of patients with chronic
autoimmune hypothyroidism.
There has been limited study of the distribution of anti-TPO antibody levels among
hypothyroid patients with impaired kidney function.
In one study of NHANES III participants with hypothyroidism, it was found that the
prevalence of elevated anti-TPO antibody levels decreased with incrementally lower
eGF3
3Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease.

36. TREATMENT OF THYROID DYSFUNCTION
United States Renal Data System data have shown that LEVOTHYROXINE is among the
most commonly prescribed medications in predialysis CKD and ESRD patients who are
Medicare Part D enrollees (i.e., 4th and 12th most commonly prescribed medications,
respectively).4
In the general population, thyroid hormone supplementation in hypothyroid patients
has been shown to reverse adverse cardiovascular surrogates such as diastolic
dysfunction, dyslipidemia, endothelial dysfunction, and atherosclerosis.
In terms of population-based analyses, Ravzi et al. examined the impact of
LEVOTHYROXINE treatment among 4735 patients with subclinical hypothyroidism
(defined as a TSH range of 5.0–10.0 mIU/L and normal FT4 levels) stratified by age.5
There are a paucity of data with regard to thyroid hormone replacement therapy and
outcomes in hypothyroid CKD patients.
4US Renal Data System USRDS. 2012 annual data report: atlas of end-stage renal disease in the United States Bethesda, MD. 2012
5Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and
mortality. Arch Intern Med May 28, 2012;172(10):811–7.

37. In one study of hemodialysis patients with low circulating total T3 levels, it was shown
that exogenous T3 supplementation led to greater protein degradation (ascertained by
a negative nitrogen balance, greater urea generation rate, and increase in leucine flux),
raising concern that thyroid hormone replacement therapy may aggravate catabolism
and protein-energy wasting in CKD patients, potent predictors of mortality for this
population.
In a placebo-controlled study of 39 euthyroid hemodialysis patients, treatment with
exogenous T4 over a period of 12–16 weeks led to reductions in LDL cholesterol and
lipoprotein levels without leading to symptoms of thyrotoxicosis.7
Emerging epidemiologic data have also indicated that administration of
LEVOTHYROXINE in CKD patients with subclinical hypothyroidism was also associated
with decreased progression of kidney dysfunction over time 6
Abnormal Thyroid Function tests become normalize after successful kidney transplantation
6Shin DH, Lee MJ, Lee HS, et al. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease
7Bommer C, Werle E, Walter-Sack I, et al. D-thyroxine reduces lipoprotein(a) serum concentration in dialysis patients. J Am Soc Nephrol January
1998;9(1):90–6

38. KEY POINTS
• Patients with advanced predialysis and dialysis-dependent chronic kidney disease
(CKD) have a fivefold higher prevalence of hypothyroidism compared to those with
normal kidney function.
• In the general population, serum thyrotropin (TSH) is the most sensitive and specific
single metric of thyroid function, and it may also be a more robust index of thyroid
function in CKD and other chronic illness states as compared with serum
triiodothyronine and thyroxine levels.
• A growing body of evidence suggests that hypothyroidism may be associated with
the development and progression of CKD, as well as higher mortality risk in dialysis-
dependent CKD patients.
• LEVOTHYROXINE is one of the most commonly prescribed medications in the
predialysis CKD and end-stage renal disease (ESRD) populations. However, there
remain knowledge gaps with regard to the safety and effectiveness of exogenous
thyroid hormone supplementation in hypothyroid CKD patients.

39. Reference
1. Textbook of Nephro-Endocrinology, Second Edition
2. Int J Nephrol. 2014; 2014: 520281
3. Harrison Principles of Internal Medicine
4. Davidson’s Principles & Practice of Medicine

40. THANK U
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