- From the results obtained it is concluded that abnormal peripheral metabolism of

T4 seems to be the primary cause of altered plasma concentrations of thyroid

hormones in patients with
ARF.

-In contrast to T3 and T4, the concentration of serum reverse triiodothyronine

(rT3) was elevated in the oliguric/anuric phase and normal in the polyuric phase.

- Serum thyroxine (T4) and triiodothyronine (T3) concentrations were significantly

decreased in the oliguric/anuric phase, as compared with the mean values obtained
in the postpolyuric
phase and with controls.

-In kidney disease patients, some TSH alterations may be observed such as altered
clearance, blunted response to TRH, decreased pulsatility, increased half-life and
impaired glycosylation
leading to reduced bioactivity

-TSH is a more reliable measure of thyroid function in kidney disease

-Kidney disease may alter thyroid hormone transport into peripheral tissues, as
well as intracellular thyroid hormone nuclear action

-Exposure to uremic serum from patients inhibited the cellular uptake of T4 by rat
hepatocytes, which may potentially result in low tissue levels of T3

-In the general population, hypothyroidism is associated with impaired cardiac

contractility, endothelial dysfunction, atherosclerosis and possibly higher
cardiovascular mortality

-Of even greater uncertainty are the risks and benefits of thyroid hormone
replacement, which bear a narrow therapeutic-to-toxic window and are frequently
prescribed to CKD and ESRD
patients.

-The synthesis and secretion of thyroid hormones [e.g. triiodothyronine (T3) and
T4] are stimulated by TSH from the pituitary gland, which is regulated by
thyrotropin-releasing
hormone (TRH) from the hypothalamus. In turn, TRH and TSH are regulated by feedback
inhibition from circulating T4, which is converted to T3 in the hypothalamus and
pituitary
by type 2 5'-deiodinase 2 (D2) [43, 44]. D2 activity increases as T4 levels fall.
In peripheral tissues, T4 is converted to T3 via type 1 5'-deiodinase enzymes (D1)
and D2 [45, 46].
It is now thought that in humans, D2 is the primary contributor to the peripheral
production of T3

-The kidney plays a key role in the metabolism, degradation and excretion of
thyroid hormone and its metabolites (Table 2) [3]. Kidney disease may predispose to
alterations in regulation
of the hypothalamic–pituitary–thyroid axis, as well as changes in thyroid hormone
uptake and action. The uremic milieu may also influence the performance of thyroid
hormone assays

- These collective data suggest that low T3 may be a marker of malnutrition,

inflammation and nonthyroidal illness in CKD and ESRD

-reversible,urine output,bloodpressure, blood urea.

-In kidney disease patients, rT3 levels are typically normal. This stands in
contrast to: (i) nonthyroidal illness in which rT3 levels are typically high (due
to increased generation
of rT3 from T4 and decreased clearance of rT3 to T2) and (ii) hypothyroidism in
which rT3 levels are typically low

-Early studies suggested that low thyroid hormone levels may be a physiologic
adaptation in ESRD patients who are prone to hypercatabolism, malnutrition and
dialytic protein and amino
acid losses

-However, recent studies in CKD and ESRD patients suggest that low T3 and/or T4
levels are associated with adverse cardiovascular surrogates, including
atherosclerosis, vascular
calcification, arterial stiffness, impaired flow-mediated vasodilation,
intravascular volume deficits, abnormal ventricular conduction and impaired cardiac
function.

-Levothyroxine is the 4th and 12th most commonly prescribed medication in CKD and
ESRD Medicare Part D enrollees, respectively, but the therapeutic benefits of
thyroid hormone
replacement in these populations remain unclear

-Treatment with exogenous thyroid hormone has been associated with decreased
progression or reversal of impaired kidney function in hypothyroid CKD patients

-In contrast to T4 which is largely produced by the thyroid gland, 80% of T3 is

produced by peripheral deiodination of T4 to T3

-Essentially 99.98% of circulating T4 is bound to carrier proteins (mostly to

thyroid-binding globulin, followed by transthyretin, albumin and lipoproteins)
[55]. Thus total T4
assays, which measure both free and protein-bound hormone, may result in reduced T4
levels in low-protein states frequently observed in advanced CKD and ESRD patients.

-Low T3 levels are the most frequently observed biochemical thyroid alteration in
CKD

-The levels of serum total thyroxine (TT4), triiodothyronine (TT3), free T3, (FT3)
free T4 (FT4) and thyrotropin (TSH) were measured in 127 clinically euthyroid
patients with
varying grades of chronic renal failure (CRF); and 97 healthy individuals. They
were grouped as: Group I containing 93 patients on conservative management; Group
II containing
34 patients on regular dialysis therapy; and Group III (normals). Group I patients
showed significant decrease in TT3, TT4 and FT3 levels (p less than 0.001) as
compared to Group III,
whereas FT4 and TSH values in group I were not significantly altered. TT3, TT4 and
FT3 levels reduced as the severity of renal damage increased. Variations in TT3,
TT4, FT3, FT4 and TSH
levels in Group II patients were similar to those in Group I, except for a decrease
in TSH levels (p less than 0.05) as compared to normals. Several thyroid function
tests are abnormal
in CRF patients, however, finding of normal FT4 and TSH levels would indicate
functional euthyroid status.

-High TSH was independently associated with the decreased eGFR in patients with T2D
without overt thyroid dysfunction. Our findings indicate that doctors who treat T2D
patients should
routinely measure the thyroid function

-It has been suggested that GFR may increase following thyroid hormone supplement
in hypothyroidism [18–22], while GFR may be reduced after treatment for
hyperthyroidism [21] or
after withdrawal of T4 treatment [23]. These findings suggest that low thyroid
function may cause reduction in GFR

- The prevalence of subclinical hypothyroidism increases consistently in patients

who have a decline in GFR. Low T3, normal to reduced T4 levels, and normal TSH
often result in
increased thyroid gland volume. In turn, a decrease in renal function also accounts
for an ineffective clearance of abnormal serum constituents, inflammatory
cytokines, iodide excretion,
and an increase of nitrogen conservation. All of these factors have been clinically
proven to affect the normal physiology and metabolism of thyroid hormones.

- Patients who receive appropriate treatment for their thyroid disease have a
decreased chance of developing or exacerbating renal dysfunction. However, treating
patients with a mild
elevation of TSH (less than 20?IU/mL) results in a negative nitrogen balance by
increased muscle catabolism. Clinicians should look for low T3 levels in patients
prior to renal transplant
as low levels are associated with renal graft loss.

-Low T3 levels are the most common laboratory finding followed by subclinical
hypothyroidism in CKD patients

-The thyroid produces hormones (T3 and T4) that have many actions including
metabolism, development, protein synthesis, and the regulation of many other
important hormones

-A search for articles was done using PubMed, Google Scholar, Cochran Review,

- Risk factors for CKD include diabetes, hypertension, hyperlipidemia, and thyroid
disorders.

-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 [7]. A decreased clearance of
goitrogenic substances like aryl acid due to CKD may also be a factor

-In uremia, the pituitary receptor response to TRH is blunted causing a decrease in
TSH release. The response of TSH to TRH is delayed because of the decreased
clearance
and the increase of half-life of TSH

-Transient increases in T4 levels are usually seen after hemodialysis. This effect
is mainly due to the use of heparin as an anticoagulant which inhibits T4 binding
to
proteins and leads to an increase in T4 levels

-Low T3 levels in CKD may be due to the iodothyronine deiodinase (helps in T3

synthesis from T4) affected by fasting, chronic metabolic acidosis, and chronic
protein
malnutrition seen in CKD. Such factors influence the proteins binding to T3 [7].
Low T3 levels in CKD may also be due to the decreased peripheral (extra thyroidal)
conversion from
T4 to T3 due to decreased clearance of the inflammatory cytokines such as TNF-alpha
and IL-1.

-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

-Most patients on hemodialysis (HD) are euthyroid [12]. Systemic acidosis, time on
dialysis, markers of endothelial damage, and inflammation from HD are associated
with low
T3 levels [12]. 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 [7]. HD
affects the cellular transport of TSH which might act as a compensatory mechanism
for maintaining
an euthyroid status

-Peritoneal dialysis (PD) is usually associated with low T3 levels and subclinical
hypothyroidism.Low T3 levels might be due to inflammation and malnutrition in PD,
as there
is an association between free T3, CRP, and serum albumin [28]. Subclinical
hypothyroidism may be due to a decrease in iodide clearance.The T4 and T3 losses
are minor
(10% and 1%, resp.) and easily compensated in PD.Thyroid hormone supplementation is
not necessary in patients on PD

-Renal transplantation is known to normalize thyroid hormone levels.

-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 [12].
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

- The pathophysiology links between thyroid dysfunction and glomerulonephritis

involve proteinuria and formation of immune complexes

-The study also finds dyslipidemia as a common disorder in CKD. The study reveals
that CKD patients with elevated lipid parameters have strong risk for developing
CVD,
so early treatment for lipid abnormalities in CKD patients may lower the chance of
developing CVD later

-Stage 4 and 5 CKD patients had significantly higher risk of having thyroid
dysfunction as compared to stage 3 patients

-Chronic renal failure affects thyroid function in multiple ways, including low
circulating thyroid hormone concentration, altered peripheral hormone metabolism,
disturbed
binding to carrier proteins, possible reduction in tissue thyroid hormone content,
and increased iodine store in thyroid glands. Both plasma triiodothyronine (T(3))
and thyroxine (T(4))
are reduced. The low serum T(3) is not due to increased T(3) degradation or to
decreased thyroidal T(3) secretion but is a result of impaired extrathyroidal T(4)
to T(3) conversion.
The reduction in T(4) is attributed to the presence of circulating inhibitors,
which impair binding of T(4) to thyroxine-binding globulin. Despite decreased
circulating T(4) and T(3),
thyroid-stimulating hormone (TSH) is not elevated. This absence of TSH elevation is
not due to dysfunction of the hypothalamo-pituitary axis, because truly
hypothyroid renal failure patients can mount a high TSH response. Thyroid hormone
losses during hemodialysis and peritoneal dialysis are trivial and do not require
replacement

-Stage 1 with normal or high GFR (GFR > 90 mL/min)

Stage 2 Mild CKD (GFR = 60-89 mL/min)
Stage 3A Moderate CKD (GFR = 45-59 mL/min)
Stage 3B Moderate CKD (GFR = 30-44 mL/min)
Stage 4 Severe CKD (GFR = 15-29 mL/min)
Stage 5 End Stage CKD (GFR <15 mL/min)

-
Test From To Units
TSH
0.4 4.0 mU/l (milliunits per litre)
FT4
9.0 25.0 pmol/l (picomoles per litre)
FT3
3.5 7.8 pmol/l (picomoles per litre)

-TSH 0.2 - 4.0 miu/L

free T4 10 - 20 pmol/L
total T3 0.9 - 2.5 nmol/L

-Thyroid Stimulating Hormone (TSH)

An indicator of thyroid function.

Normal range for an adult: 0.4 – 5.5 mU/mL

-Thyroxine (T4)
Normal range for an adult: 5 – 11 µg/dL

- The normal range of TSH levels is 0.4 to 4.0 milli-international units per liter

- total T4 test in adults generally range from 5.0 to 12.0 micrograms per deciliter
(µg/dL)

-Typically, normal results range from 100 to 200 nanograms per deciliter (ng/dL). A
normal T3 test result doesn't necessarily mean that your thyroid is functioning
perfectly.
Measuring your T4 and TSH can help your doctor figure out if you have a thyroid
problem despite a normal T3 result