General and Comparative Endocrinology 160 (2009) 205–215

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General and Comparative Endocrinology

journal homepage: www.elsevier.com/locate/ygcen

Review

Interactions between thyroid and kidney function in pathological

conditions of these organ systems: A review
Ingrid van Hoek *, Sylvie Daminet
Department of Medicine & Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Thyroidal status affects kidney function already in the embryonic stage. Thyroid hormones influence
Received 23 June 2008 general tissue growth as well as tubular functions, electrolyte handling and neural input. Hyper- and
Revised 2 December 2008 hypo-functioning of the thyroid influences mature kidney function indirectly by affecting the cardiovas-
Accepted 3 December 2008
cular system and the renal blood flow, and directly by affecting glomerular filtration, electrolyte pumps,
Available online 24 December 2008
the secretory and absorptive capacity of the tubuli, and the structure of the kidney.
Hyperthyroidism accelerates several physiologic processes, a fact which is reflected in the decreased
Keywords:
systemic vascular resistance, increased cardiac output (CO), increased renal blood flow (RBF), hypertro-
Thyroid
Kidney
phic and hyperplastic tubuli, and increased glomerular filtration rate (GFR). Renal failure can progress
Human due to glomerulosclerosis, proteinuria and oxidative stress.
Animal Hypothyroidism has a more negative influence on kidney function. Peripheral vascular resistance is
Cats increased with intrarenal vasoconstriction, and CO is decreased, causing decreased RBF. The influence
on the different tubular functions is modest, although the transport capacity is below normal. The GFR
is decreased up to 40% in hypothyroid humans. Despite the negative influences on glomerular and tubular
kidney function, a hypothyroid state has been described as beneficial in kidney disease.
Kidney disease is associated with decreased thyroid hormone concentrations caused by central effects
and by changes in peripheral hormone metabolism and thyroid hormone binding proteins. Geriatric cats
form an animal model of disease because both hyperthyroidism and chronic kidney disease (CKD) have
high prevalence among them, and the link between thyroid and kidney affects the evaluation of clinical
wellbeing and the possible treatment options.
Ó 2008 Elsevier Inc. All rights reserved.

1. Introduction described more specifically in geriatric cats. Geriatric cats can be

The thyroidal status influences kidney function both during
embryonic development and in the mature functioning of the kid-
ney, indirectly by affecting the cardiovascular system through its
influence on renal blood flow (RBF), and directly by affecting glo-
merular function, the tubular secretory and absorptive capacities,
electrolyte pumps and kidney structure (den Hollander et al.,
2005). When the thyroid is either hyper- or hypo-functioning,
changes in different clinical renal parameters such as glomerular
filtration rate (GFR), urine specific gravity (USG), urinary protein/
creatinine ratio (UPC) and markers of tubular function can occur.
Vice versa, kidney disease influences circulating thyroid hormones.
This review describes the link between thyroid and kidney func-
tion in pathological conditions of these organ systems. The effects
of hyper- and hypothyroidism on different parts of the nephron, as
well as the effects of kidney disease on the thyroid parameters, will
be described in general in humans, rodents and dogs, and will be
* Corresponding author. Fax: +32 92647791.
E-mail address: Ingrid.vanHoek@ugent.be (I. van Hoek).
an animal model of disease regarding the link between thyroid
and kidney function in pathological conditions of the thyroid
and/or kidneys.
2. Influence of thyroid hormones on kidney development
Once intact protein synthesis is present in the developing kid-
ney of rats (Braunlich, 1984), thyroid hormones influence general
tissue growth, the different tubular functions, electrolyte handling,
mitochondrial enzymes and neural input. Hyperthyroidism in-
creases protein turnover, with a net result of renal atrophy in the
kidneys of neonatal rats. Hypothyroidism decreases protein syn-
thesis and cellular development, which leads to decreases in cell
number, density and size in the kidney (Slotkin et al., 1992; Canavan
et al., 1994). The effects of thyroid hormones on kidney function
have been investigated extensively in neonatal rats. Thyroid hor-
mones accelerate development, as well as increasing the activity
of renal Na+ cotransported phosphate (NaPi) in the proximal tubule
(Euzet et al., 1995; Alcalde et al., 1999), of cortical Na+/H+ exchanger
(NHE) (Baum et al., 1998) and of Na+–K+-adenosinetriphosphatase

0016-6480/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygcen.2008.12.008
206 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215
(Na+–K+-ATPase) (Nakhoul et al., 2000). A pre- and peri-natal
depletion in thyroid hormones leads to deficits in the mitochon-
drial enzymes 3-ketoacid-CoA transferase, citrate synthase, carni-
tine acetyltransferase (Wijkhuisen et al., 1995). It also leads to
deficits in a  1 adrenergic receptors implicated in the transduc-
tion of neurotrophic signals (Tan et al., 1997), and to only slight
deficits in the b-adrenergic receptors and the activity of adenylate
cyclase in the kidney (Pracyk and Slotkin, 1992). Hyperthyroidism
slightly increases the numbers of b-receptor binding sites, as well
as the activity of adenylate cyclase and ornithine decarboxylase
(Pracyk and Slotkin, 1991).
3. Influence of hyperthyroidism on healthy mature kidney
function
Thyrotoxicosis is a clinical syndrome of hypermetabolism and
hyperactivity which is caused by increased serum concentrations
of the thyroidal hormones free thyroxine (fT4) and free triiodothy-
ronine (fT3). Thyrotoxicosis is associated with increased thyroid
hormone synthesis and secretion by the thyroid gland (hyperthy-
roidism). Thyrotoxicosis causes acceleration of physiologic pro-
cesses in the kidney, which is reflected in changes in the clinical
parameters (Braverman and Utiger, 2005a).
3.1. Hemodynamic and vascular changes
Thyroid hormones have a positive chronotropic effect caused by
their influence on the electrophysiological parameters, by their
shortened atrio-ventricular conduction time and by up regulated
b-receptors in cardiac tissue (Kaptein et al., 1984), which results
in tachycardia (Hammond et al., 1987). They also have a positive
inotropic effect caused by changes in several sodium, potassium
and calcium channels, as well as by changes in the activity of myo-
sin isoenzymes (Walker et al., 1994; Kienle et al., 1994).
Systemic vascular resistance is decreased in the hyperthyroid
state. Muscle tissue has a greater number of capillary vessels (Capo
and Sillau, 1983; Celsing et al., 1986) and its contractility is re-
duced due to decreased response to norepinephrin and the direct
effect of thyroid hormones on vascular smooth muscle cells (Ishik-
awa et al., 1989; Ojamaa et al., 1996; Zwaveling et al., 1997). A
higher number of vascular smooth muscle cells are relaxed due
to the increased local release of vasodilators (Scivoletto et al.,
1986) and responsiveness to the endothelium-dependant vasodila-
tor acetylcholine (Ach) (Vargas et al., 1995; Napoli et al., 2001),
while the activity of the endogenous renal vasoconstrictor endo-
thelin is decreased (Singh et al., 1994). The activity of atrial natri-
uretic factor (ANF) is increased in humans, rats, rabbits and dogs
due either to the higher cardiac preload or the direct effect of T4
on gene expression (Zimmerman et al., 1987, 1988; Hwu et al.,
1993; Yegin et al., 1997; Koukoulis et al., 2002). The activity of
nitric oxide synthase (NOS) and the production of endothelium-de-
rived relaxing factor nitric oxide (NO) is increased in the renal
cortex and medulla (Napoli et al., 2001; Quesada et al., 2002;
Bussemaker et al., 2003). This can be regarded as a protective
homeostatic effect in target organs of hypertensive disease and
can be due to the direct effect of thyroid hormones on NOS activity.
The indirect effects can include a response to high arterial pressure,
hyperdynamic circulation with shear stress on the endothelium
that causes expression of NOS (Xiao et al., 1997), or increased re-
lease of vaso-active substances (Quesada et al., 2002). The
decreased systemic vascular resistance, combined with the
changes in b-adrenergic activity caused by the increased number
of b-adrenergic receptors in the renal cortex (Atlas et al., 1977;
Churchill et al., 1983; Haro et al., 1992), causes increased activity
of the renin–angiotensin–aldosterone system (RAAS). The direct
effect of T3 on renin gene expression also enhances the RAAS activ-
ity, which means an increase in the concentrations of plasma renin,
plasma angiotensin II and serum angiotensin converting enzyme
(ACE), as well as an increase in the synthesis of angiotensinogen
in the liver, an increase in the density of angiotensin receptors
and an increase of renin release in humans, rats, rabbits an dogs
(Resnick and Laragh, 1982; Montiel et al., 1984; Ruiz et al., 1987;
Marchant et al., 1993; Sernia et al., 1993; Asmah et al., 1997; Yegin
et al., 1997; Koukoulis et al., 2002).
The increased cardiac output (CO) caused by positive chrono-
tropic and inotropic effects, decreased vascular resistance and
increased blood volume due to RAAS activation (Klein and Ojamaa,
2001) leads to increased renal blood flow (RBF) in hyperthyroid
rats, humans and cats (Singh et al., 1994; Adams et al., 1997a; Sing-
er, 2001).
3.2. Glomerular changes
Hyperthyroidism increases GFR up to 18% in hyperthyroid rats
(Katz and Lindheimer, 1973; Capasso et al., 1999) and humans
(den Hollander et al., 2005) by several mechanisms. It leads to
the decreased resistance of afferent arterioles in the kidney, which
increases the glomerular hydrostatic pressure and subsequently
the GFR (Conger et al., 1989), though it also increases the chance
of hypoperfusion of the proximal tubule. The intrarenal feedback
mechanism increases the GFR to cope with the threatening hypo-
perfusion and the escape of urine entering the distal tubule, which
has to be replaced by the delivery of proximal tubule fluid (Straub,
1977). Thyroid hormones increase mRNA expression of chloride
channels (ClC) in a dose-dependent way (Shirota et al., 1992; San-
tos et al., 2003) and also increase the activity of ClC and Cl absorp-
tion in the proximal tubule and Henle’s loop. Tubulo-glomerular
feedback adjusts GFR after a decreased chloride load is sensed
within the distal tubule by the macula densa (Graves et al.,
1994). The increased GFR is reversed after treatment of hyperthy-
roidism in humans (den Hollander et al., 2005).
Serum creatinine concentration is an indirect estimate of the
GFR and is often significantly decreased in humans with hyperthy-
roidism due to the increased GFR, increased clearance and in-
creased tubular secretion of creatinine, but also due to the
decreased muscle mass (Bradley et al., 1974; Ford et al., 1989;
Verhelst et al., 1997; Manetti et al., 2005). Serum creatinine con-
centration increases after therapy for hyperthyroidism (Ford
et al., 1989; den Hollander et al., 2005). Serum concentration of
cystatin C (CysC) is another estimator of the GFR (Almy et al.,
2002) because it is freely filtered by the glomerulus and because
there is no catabolization in the tubuli (Grubb, 1992). Serum CysC
is independent of age, sex, malignancy or inflammation (Laterza
et al., 2002). However, intra-individual variability is high (Keevil
et al., 1998) and thyroid hormones influence the general metabo-
lism, thereby increasing the production rate of CysC in humans
(Fricker et al., 2003; Wiesli et al., 2003; Manetti et al., 2005) and
rats (Schmitt and Bachmann, 2003).
Proteinuria with an increased total UPC and urinary albumin/
creatinine ratio is often present in hyperthyroid humans and rats
(Conger et al., 1989; Ford et al., 1989; Suher et al., 2005). It is not
related to RAAS activity, blood pressure or oxidative stress (Rodri-
guez-Gomez et al., 2003; Moreno et al., 2005), though it can be a
reflection of glomerular hypertension and hyperfiltration, changes
in tubular protein handling, or changes in the structure of the glo-
merular barrier (Vargas et al., 2006). Proteinuria resolves quickly
after the treatment of hyperthyroidism in humans (Ford et al.,
1989).
The effects of hyperthyroidism on different aspects of kidney
and heart function, with their direct or indirect effects on the
 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215 207

Table 1 lar transport processes through increased gene expression and the
Effects of hypo- or hyperthyroidism on different aspects of kidney function described synthesis and activity of carrier proteins (Braunlich, 1985; Braun-
in different species (superscript) with the direct or indirect effect on renal blood flow
(RBF) and glomerular filtration rate (GFR). The effects are schematically outlined in
lich et al., 1987) such as Na+–K+-ATPase across the basolateral
Figs. 1 and 2. membrane. They also stimulate NHE activity in brush border mem-
brane vesicles, which leads to increased uptake of Na+ in exchange
Hypothyroidism Hyperthyroidism
for H+ (Kinsella and Sacktor, 1985). More specifically, NHE-2 and
RBF Decreased rat, dog, human
Increased rat, cat, human
NHE-3 isoform mRNA levels increase after transition from the
Chronotropic effect Decreased human Increased pig
Inotropic effect Decreased human Increased pig
hypothyroid to the hyperthyroid state (Azuma et al., 1996). The
Systemic vascular Increased Decreased increased tubular reabsorption of sodium, combined with the
resistance decreased load of filtered sodium, causes a decreased pressure–
Vascular contractility Increased rat Decreased rat, rabbit, human diuresis–natriuresis response (Vargas et al., 1994, 2006) and
ANF Decreased rat, dog, human Increased rat, rabbit, dog, human
enhanced Na+Ca+ exchange activity and Ca+ reabsorption (Kumar
NOS Decreased rat Increased rat, human
b-Adrenergic receptor Decreased rat, human Increased rat, human and Prasad, 2002) in the basolateral membrane through modula-
RAAS Decreased rat, rabbit, dog, human Increased rat, rabbit, human, dog tion of the uptake of Ca+ in brush border membrane vesicles.
CO Decreased rat Increased rat, cat, human Tubular cells can be damaged due to the hypertrophy and
GFR Decreased rat, dog, human Increased rat, cat, human hyperplasia, or they can be decrepitated due to the increased func-
Glomerular Increased efferent arterioles dog
Decreased afferent arterioles rat
tional level. Urinary markers such as retinol binding protein (RBP)
vasoconstriction and N-acetyl-b-glucosaminidase (NAG) will appear in the urine
rat rat, human
Chloride channels Decreased Increased
rat cat when there is tubular damage (Price, 1992). The urinary RBP/creat-
Tubulo-glomerular Decreased Increased
feedback inine ratio in humans is higher in hyperthyroidism than in euthy-
Serum creatinine Increased human
Decreased rat, human
roidism, but it varies widely and does not differ from values in
concentration control subjects (Ford et al., 1989). It is therefore unlikely to indi-
rat, human rat, human
Proteinuria Increased Increased
cate tubular damage in humans, though a possible cause could be
ANF, atrial natriuretic factor; NOS, nitric oxide synthase; RAAS, renin–angiotensin– either the decreased plasma RBP concentration in humans (Suraci
aldosterone system; CO, cardiac output. et al., 1983; Aktuna et al., 1993) or the increased RBP turnover
combined with the normal RBP synthesis reported in chickens
(Bhat and Cama, 1978). Tubular damage leads to increased NAG
concentrations in urine. Damage to the glomerular basement
RBF and the GFR, are described in Table 1 and schematically out- membrane, which is caused by degranulation of granulocytes or
lined in Figs. 1 and 2. active infection of the urinary system, can also lead to increased
NAG concentrations in urine (Marchewka et al., 1994). Urinary
3.3. Tubular changes NAG is increased in humans with Graves’ disease or thyroiditis
(Nakamura et al., 1991), and serum NAG decreases after treatment
Renal tubules are hypertrophic and hyperplastic in hyperthy- of hyperthyroidism (Pinto et al., 1989).
roidism, which leads to increased tubular mass, kidney weight, mi- Human patients with thyrotoxicosis can have a decreased abil-
totic index, DNA content (with a constant protein/DNA ratio) ity to concentrate urine (Cutler et al., 1967), though without clini-
(Stephan et al., 1982), renal expression of renin mRNA (Kobori cal significance (Katz et al., 1975). Suggested reasons for the
et al., 1998), metabolic level, and tubular secretory and re-absorp- impairment of urine concentration are disturbances in the metab-
tive capacity (Pisi and Cavalli, 1955; Katz et al., 1975; Kobori et al., olization of or sensitivity to vasopressin in the distal nephrons
1998). Thyroid hormones stimulate active, carrier-mediated tubu- (Weston et al., 1956), reduced sodium concentration secondary

Fig. 1. Hemodynamic changes in hypo- and hyperthyroidism that have an effect on renal blood flow.
208 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215

Fig. 2. Changes in kidney function in hypo- and hyperthyroidism that have an effect on the glomerular filtration rate.

to increased RBF (Cutler et al., 1967), or osmotic diuresis caused by 2000). Hypothyroidism is rare in cats unless it is iatrogenic after
increased filtered solute (Leaf et al., 1952). treatment of hyperthyroidism (Nykamp et al., 2005) or spontane-
The effects of hyperthyroidism on tubular kidney function are ous in congenital hypothyroidism (Jones et al., 1992) and lympho-
described in Table 2. cytic thyroiditis (Schumm-Draeger et al., 1996).

4. Influence of hypothyroidism on healthy mature kidney
function
Hypothyroidism in humans can be primary/thyroidal with de-
creased thyroidal production and secretion of thyroxine and triio-
dothyronine, or secondary/central with decreased thyroidal
stimulation by thyroid stimulating hormone (TSH) (Braverman
and Utiger, 2005b). Most of the effects of hypothyroidism on kid-
ney function are the opposite of the changes caused by hyperthy-
roidism, and the decreased serum concentration of thyroid
hormones slows many physiologic processes. More than 95% of
the clinical cases of hypothyroidism in dogs are the result of
destruction of the thyroid gland itself (i.e. primary hypothyroid-
ism) caused by lymphocytic thyroiditis or idiopathic thyroid atro-
phy (Benjamin et al., 1996), while secondary hypothyroidism can
be caused by thyroid neoplasia, which accounts for 5% of the clin-
ical cases of hypothyroidism (Scott-Moncrieff and Guptill-Yoran,
4.1. Hemodynamic and vascular changes
The increase of peripheral vascular resistance in hypothyroid-
ism is caused by intrarenal vasoconstriction (Singer, 2001).
Although the plasma concentration of catecholamines is increased
(Diekman et al., 2001), the response to vasodilators in the kidney
is reduced (Klein and Ojamaa, 2001). Sensitivity to a- and b-
adrenergic stimulants such as norepinephrin, phenylephrine
(PHE) and ATP is decreased; sensitivity to stimulants of G-protein
coupled receptors, to non-specific stimulants of receptors in vas-
cular smooth muscle, to endothelium dependent vasodilatation,
to NO in the kidney and to isoprenalin in the aorta and mesen-
teric vascular bed is also decreased (Rahmani et al., 1987; Takig-
uchi et al., 1988; Vanhoutte, 1989; Gunasekera and Kuriyama,
1990; Sabio et al., 1994; Vargas et al.,1995, 1996, 2006). Reduced
sensitivity of b-adrenergic receptors to catecholamines and stim-
ulation of the b-adrenergic function decreases plasma renin re-

Table 2
Changes in characteristics of tubular functions in hypo- and hyperthyroidism, described in several species (superscript).

Tubular characteristics Hypothyroidism Hyperthyroidism

rat rat
All-over characteristics Atrophic Hypertrophic and hyperplastic
DNA content Unchanged rat Increased rat
Protein/DNA ratio Increased rat Unchanged rat
Kidney weight Decreased rat Increased rat
Na+–K+-ATPase activity across basolateral Decreased rat, rabbit Activated rat
membrane
Na+ reabsorbtion through Na+/H+ exchanger Decreased rat
Increased rat

(NHE)
Urine concentrating ability Impaired rat Decreased human
Due to: Due to:
 Decreased osmotic driving force rat  Disturbed metabolization or sensitivity of distal tubuli to
 Decreased response of vasopressin to osmotic vasopressin
stimuli rate  Reduced sodium concentration human
 Impaired water handling human  Osmotic diuresis human
 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215
lease and activity (Atlas et al., 1977; Bouhnik et al., 1981; Chur-
chill et al., 1983; Haro et al., 1992; Vargas et al., 2006), which, to-
gether with the decreased concentration of plasma AII and of the
angiotensinogen synthesized in the liver, and with the decreased
density of the angiotensinogen receptors, reduces RAAS activity in
humans, rats and rabbits (Ruiz et al., 1987; Marchant et al., 1993;
Asmah et al., 1997; Yegin et al., 1997). RAAS activity normalizes
after treatment of hypothyroidism in humans and rats (Montiel
et al., 1984; Hwu et al., 1993; Koukoulis et al., 2002).
The cardiac output is decreased in hypothyroidism (Katz et al.,
1975). This decrease is caused by bradycardia, by decreased ven-
tricular filling and by decreased cardiac contractility (Crowley
et al., 1977; Wieshammer et al., 1989; Diekman et al., 2001).
The decreased CO leads to decreased RBF in rats, humans, and
dogs (White et al., 1947; Bradley et al., 1972; Villabona et al.,
1999). Glomerular lesions seen in hypothyroidism, such as thick-
ening of the basement membrane and increased mesangial matrix
(Katz et al., 1975; Lafayette et al., 1994), contribute to the de-
creased RBF. It has been suggested that the decreased NOS activ-
ity in the aorta contributes to the increased total peripheral
vascular resistance reported in hypothyroid rats (Quesada et al.,
2002).
4.2. Glomerular changes
The glomerular filtration rate can be reduced up to 40% in
hypothyroid humans (Capasso et al., 1999; Karanikas et al.,
2004; den Hollander et al., 2005; Suher et al., 2005) and up to
30% in hypothyroid rats (Katz and Lindheimer, 1973). The GFR
is reported to have decreased in dogs after thyroidectomy (White
et al., 1947), and to have significantly decreased in dogs diag-
nosed with thyroid deficiency (White et al., 1947; Gommeren
et al., 2008). The decreased GFR is corrected after treatment with
thyroid hormone in humans with normal renal function (Monte-
negro et al., 1996; Villabona et al., 1999; Karanikas et al., 2004;
den Hollander et al., 2005), which is suggestive of only functional
renal changes that do not cause permanent histological damage
(Montenegro et al., 1996).
The decreased GFR has several causes. Firstly, hypothyroidism is
associated with decreased CO and circulating volume, impaired
activity of the RAAS, and a decreased ANF level (Gillum et al.,
1987; Zimmerman et al., 1987; Suher et al., 2005), which could
lead to decreased renal perfusion (den Hollander et al., 2005). Sec-
ondly, the glomerular surface area can be decreased by growth
retardation in the parenchyma of the kidney (Bradley et al.,
1982). Thirdly, a filtrate overload caused by deficient sodium and
water reabsorption in the proximal tubule could lead to an adap-
tive preglomerular vasoconstriction (Zimmerman et al., 1988).
Fourthly, renal expression of the chloride channel ClC-2 is
decreased in hypothyroid rats, and the tubulo-glomerular feedback
mechanism decreases GFR when an increased chloride load
is sensed in the distal tubuli. Finally, hypothyroidism causes a
decrease in insulin-like growth factor 1 (IGF-1). However, in re-
sponse to thyroxin replacement, the IGF-1 is increased, along with
the vascular endothelial growth factor (VEGF) (Schmid et al., 2004).
IGF-1 is known to increase creatinine clearance in humans and
VEGF increases the activity of NOS, thereby improving the relaxing
capacity of the renal vasculature. Hence, both IGF-1 and VEGF
could influence RBF and GFR in hypothyroidism before and after
thyroxin replacement.
The increase of serum creatinine in hypothyroidism is caused
by the reduced glomerular function and creatinine generation from
possible myopathy and rhabdomyolysis (Sekine et al., 1993; Lafay-
ette et al., 1994), though not from the impaired creatinine metab-
olism (Karanikas et al., 2004). It is reversible after treatment with
209
thyroid hormone supplementation (Kreisman and Hennessey,
1999; den Hollander et al., 2005).
Hypothyroid humans and rats can have an increased transcap-
illar leaking of the plasma proteins such as albumin, which leads
to mild proteinuria and albuminuria (Wheatley and Edwards,
1983; Tilton et al., 1989; Villabona et al., 1999). The albuminuria
is considered to be present before the decrease in GFR in hypothy-
roid patients (Suher et al., 2005).
The effects of hypothyroidism on different aspects of kidney
function with a direct or indirect effect on RBF and GFR are
described in Table 1 and schematically outlined in Figs. 1 and 2.
4.3. Tubular changes
The influence of short-term hypothyroidism on the tubular
functions is only modest (Karanikas et al., 2004), even though the
tubular transport capacity is below normal (White et al., 1947)
and the phosphate reabsorption rate is reduced in the proximal tu-
bule (Bommer et al., 1979). The influence of hypothyroidism on
Na+–K+-ATPase depends on the duration of the hypothyroidism.
With short-term hypothyroidism, in rats the Na+–K+-ATPase activ-
ity is decreased in the proximal convoluted tubule, and in rabbits it
is decreased in the proximal convoluted tubule as well as in the
straight tubule and in the cortical and medullar collecting tubules,
though not in other nephron segments (Barlet et al., 1985; Garg
and Tisher, 1985). In long-term hypothyroidism, the Na+–K+-ATP-
ase activity is decreased in all segments of the nephron in the rab-
bit and in the proximal convoluted and straight tubules in the rat
(Capasso et al., 1985; Barlet and Doucet,1986a,b). Sodium transport
is restored after thyroid hormone supplementation, though Na+–
K+-ATPase activity is delayed for more than 7 days, possibly by
an additional effect of thyroid hormones on the potassium conduc-
tive pathways in the basolateral membrane of the tubuli (Capasso
et al., 1985).
Urinary acidification is impaired with increased sodium and
bicarbonate excretion rates (Michael et al., 1976). Hypothyroidism
causes a decreased backflux of H+ across the epithelium and H+
permeability with subsequent inhibition of bicarbonate reabsorp-
tion. It also causes decreased NHE activity and density in the apical
membrane (Marcos et al., 1996), and disturbances in the vacuolar
H+-ATPase which are partly responsible for proximal H+ secretion
(Ulate et al., 1993). Hypothyroidism causes a decreased kidney-
to-body weight ratio, though there is compensatory renal hyper-
trophy and increased protein/DNA ratio without changes in the
DNA content of the renal cells (Stephan et al., 1982). Thyroid sup-
plementation and the subsequent doubling of the kidney mass
(Ismail-Beigi and Edelman, 1971) show the reversibility of the
decreased kidney mass, and tubular damage is therefore not
suspected.
The ability to concentrate urine is impaired in hypothyroidism
(Holmes and Discala, 1970; Michael et al., 1972). This is reversible
with thyroid hormone replacement and is not associated with a
decrease in GFR, serum urea, solute excretion or plasma argi-
nine–vasopressine (AVP) concentration. It could be linked to a
diminished medullar osmotic driving force in the collecting duct
(Cadnapaphornchai et al., 2003) or to the responsiveness of AVP
to osmotic stimuli (Vargas et al., 1991). A decreased atrial natri-
uretic factor (ANF) is described in humans, rats, rabbits and dogs
(Zimmerman et al., 1987, 1988; Hwu et al., 1993; Yegin et al.,
1997; Koukoulis et al., 2002), although is unlikely that it plays an
important role (Sahun et al., 2001). Direct impaired renal water
and electrolytes handling could also account for the decreased ur-
ine concentration (Ota et al., 1994).
The effects of hypothyroidism on tubular kidney function are
described in Table 2.
210 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215
5. The effects of thyroid dysfunction on chronic kidney disease
(CKD)
5.1. Hyperthyroidism
Renal failure progresses in hyperthyroidism due to the damage
caused by glomerulosclerosis, proteinuria and oxidative stress.
Glomerular capillary hydrostatic pressure is increased due to the
decreased preglomerular arteriolar resistance (Conger et al.,
1989), resulting in intra-glomerular hypertension and glomerular
hyperfiltration, thereby contributing to glomerulosclerosis and
the progression of renal disease in rats (Hostetter et al., 1981; Ol-
son et al., 1982). Proteinuria directly injures the kidney, because
the trafficking of protein through the tubulo-interstitium causes
interstitial inflammation with upregulation of various inflamma-
tory mediators and pro-fibrotic cytokines (Abbate and Remuzzi,
1999). Thyroid hormones regulate energy metabolism and mito-
chondria, which are a source of free radicals in the cells (Mogulkoc
et al., 2005a, 2006), and anti-oxidant enzymes are down regulated
by a quantitative deficiency of intracellular superoxide dismutase
(SOD) (Mori and Cowley, 2004). The development of renal insuffi-
ciency is aided by the oxidative stress from superoxide and other
reactive oxygen species. Oxidative stress is suggested to participate
in T4 induced hypertension (Vargas et al., 2006).
5.2. Hypothyroidism
Despite the negative influences of hypothyroidism on glomeru-
lar and tubular function described earlier, a hypothyroid state has
been described as beneficial in CKD. Rats with induced renal insuf-
ficiency that underwent thyroidectomy showed reduced protein-
uria and slower deterioration of renal function (Tomford et al.,
1981; Conger et al., 1989). This can be caused by alteration in prox-
imal tubular protein reabsorption, prevention of oxidative stress
with lower levels of the oxidant malondialdehyde (MDA) in renal
tissue of hypothyroid rats (Tenorio-Velazquez et al., 2005; Mog-
ulkoc et al., 2005b), or changes in the glomerular hemodynamics
(Syme, 2007). The same factors could account for the reduced renal
compensatory hypertrophy subsequent to the subtotal nephrec-
tomy seen in methimazole treated rats (Andrade et al., 1992). On
the other hand, treatment of hypothyroidism in a patient with pro-
gressive renal failure can lead to significant improvement of renal
function (van Welsem and Lobatto, 2007).
6. The effect of CKD on thyroid function
6.1. Euthyroid sick syndrome
The decreased serum thyroid hormone concentrations in
patients with non-thyroidal diseases like CKD are referred to as
the euthyroid sick syndrome. The lower serum concentration of
TT4, fT4 and T3 is associated with increased severity of non-thyroi-
dal illness in cats (Peterson and Gamble, 1990; Mooney et al.,
1996; Wakeling et al., 2008) and dogs (Kantrowitz et al., 2001),
as well as increased mortality in dogs (Schoeman et al., 2007a,b;
Mooney et al., 2008; Schoeman and Herrtage, 2008).
Differentiation between hypothyroidism and non-thyroidal ill-
ness can be performed by evaluation of thyroidal 99mTcO uptake
(Diaz Espineira et al., 2007) or TSH stimulation (Daminet et al.,
2007). Concomitant non-thyroidal illness can suppress serum TT4
concentration into the reference ranges, even in a cat with hyper-
thyroidism (Peterson and Gamble, 1990). The decrease in thyroid
hormones is caused by changes in peripheral hormone metabo-
lism, thyroid hormone binding proteins and central effects. Extra
thyroidal conversion of T4 to T3 is decreased due to decreased
delivery of T4 to intracellular deiodinases and the activity of these
deiodinases. At the tissue level there is decreased uptake of T4 and
T3, impaired activity of nuclear receptors to T3, and post-receptor
actions of T3. The production of thyroid hormone binding proteins
(thyroxin binding globulin, transthyretine and albumin) and their
affinity for thyroid hormones is decreased, which explains the nor-
mal serum concentration of freeT4 (fT4) in non-thyroidal illness.
However, elevated fT4 concentration has been reported in 6–12%
of cats with non-thyroidal illness (Mooney et al., 1996; Peterson
et al., 2001). Thyrotropin (TSH) secretion is decreased, which
causes decreased thyroidal secretion of T3 and decreased availabil-
ity of T4 for peripheral conversion to T3. The hypothalamic–pitui-
tary axis is intact in patients with CKD, because TSH can elevate in
patients with CKD and primary hypothyroidism, and TSH is sup-
pressed in patients with CKD and hyperthyroidism (Utiger, 1995;
De Groot, 1999; Lim, 2001). The decrease in TSH secretion despite
the low level of circulating thyroid hormone explains the euthyroid
sick syndrome as a host’s defense mechanism against protein
wasting, and therefore treatment with thyroid hormone supple-
mentation remains debatable due to the controversy in human
medicine (Lim et al., 1985; De Groot, 2006).
6.2. Thyroid function and volume
Among a representative sample of adult humans in the USA, re-
duced GFR was associated with a higher prevalence of hypothy-
roidism, with many subclinical cases. The cause of this is unclear,
but auto-immune disorders, iodine excess and the potential effects
of retained solutes in the kidney on thyroid function could play a
role (Lo et al., 2005). Also, an increased prevalence of goiter and
thyroid gland volume has been reported in patients with CKD
(Lim et al., 1977; Hegedus et al., 1985). This could result from in-
creased TSH stimulation related to excessive iodine accumulation
or the presence and/or retention of goitrogens. A palpable thyroid
gland has also been described in euthyroid cats with non-thyroidal
illness (Peterson and Gamble, 1990). These cats had higher TT4
concentrations (though still within reference ranges) than euthy-
roid cats with non-thyroidal illness that did not have a palpable
thyroid gland. It is believed that these cats had mild hyperthyroid-
ism, though less than 10% of them developed clinical hyperthyroid-
ism, so there could still be other factors influencing thyroid
volume, as in humans with CKD and goiter.
7. Considerations in geriatric cats
Hyperthyroidism is the most diagnosed endocrine disorder in
middle-aged to older cats, with a median age at diagnosis of 13
years (Gerber et al., 1994). It is reported to affect 0.3% of all cats,
with no apparent sex or breed predilection (Peterson et al.,
1983). It is caused by benign adenomatous hyperplasia of the thy-
roid gland in 98% of the cases (Meeking, 2005). CKD affects 7.7% of
cats over 10 years of age and 15.3% of cats over 15 years of age
(DiBartola et al., 1987; Lulich et al., 1992). Indeed, the prevalence
of pre-existing CKD in hyperthyroid cats in different studies has
been reported to be 14% (n = 167) (Milner et al., 2006), 23%
(n = 202) (Broussard et al., 1995), 27% (n = 22) (Bucknell, 2000)
and 40% (n = 22) (Adams et al., 1997b). The results of treatment
on kidney function in hyperthyroid cats are outlined in Table 3.
It is important to mention that pre-existing renal disease is associ-
ated with shorter survival after treatment of hyperthyroidism
(Milner et al., 2006).
The evaluation of kidney function in a cat with thyroid dysfunc-
tion is important, but also difficult, because the clinical signs of
hyperthyroidism and CKD overlap, and hyperthyroidism can mask
and in some cases even worsen CKD. Systemic hypertension can be
 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215 211

Table 3
Effect of treatment on kidney function in hyperthyroid cats.

Number of hyperthyroid Evaluation USG USG after GFR before GFR after Creatinine Creatinine after N = cats developing
cats per treatment period after before treatment treatment treatment before treatment treatment azotemia after
method treatment treatment ml/min/kg ml/min/kg mg/dl (mg/dl) treatment (%)
Graves et al. (1994) Thyroidectomy: n = 13 30 days 1.038 1.030 2.51 ± 0.69 1.4 ± 0.41 1.26 ± 0.34 2.05 ± 0.60 5 (39)
Controls: n = 11 — 1.058 1.058 2.02 ± 0.27 2.18 ± 0.5 1.45 ± 0.2 1.54 ± 0.27 —
131
DiBartola et al. (1996) I: n = 27 90 days 1.046 1.043 — — 1.3 ± 0.4 2.0 ± 0.6 —
Methimazole: n = 9 90 days 1.042 1.037 — — 1.7 ± 0.9 2.7 ± 2.5 —
Thyroidectomy: n = 22 90 days 1.033 1.033 — — 1.7 ± 0.6 2.4 ± 0.8 —
131
Adams et al. (1997b) I: n = 22 6 days 1.032 1.031 2.25 2.1 1.3 ± 0.6 1.2 ± 0.5 —
30 days 1.028 — 1.9 ± 0.7
Becker et al. (2000) Methimazole: n = 12 42 days 1.041 1.033 3.83 ± 1.82 2.02 ± 0.81 1.32 ± 0.2 1.8 ± 0.96 2 (17)
Controls: n = 10 — 1.057 1.056 1.83 ± 0.56 2.05 ± 0.3 1.63 ± 0.13 1.65 ± 0.16 —
131
Boag et al. (2007) I: 27 6 months Not shown Not shown 3.79 ± 1.3 2.29 ± 0.98 Not shown Not shown 10 (37)
131
van Hoek et al., 2008b I: 21 24 weeks 1.037 1.040 3.3 ± 1.2 1.6 ± 0.6 0.81 ± 0.24 1.54 ± 0.51 5 (24)

transmitted onto the glomeruli when there is failure of autoregula-
tion (DiBartola et al., 1996). However, systemic hypertension is less
common in hyperthyroid cats than previously presumed and is not
the most important mediator of progressive renal injury (Kobay-
ashi et al., 1990; Elliott et al., 2001). A geriatric cat presented with
weight loss, vomiting, polyuria and polydipsia can present clinical
signs of both hyperthyroidism and co-existing CKD (Langston and
Reine, 2006). Proteinuria is frequently present in hyperthyroid
cats, regardless of whether they are developing azotemia or main-
taining healthy renal function (Syme and Elliott, 2001), therefore a
change in the glomerular barrier is less likely (Syme, 2007). USG is
lower in cats with hyperthyroidism compared to healthy cats
(Graves et al., 1994; Becker et al., 2000), and it decreases (Graves
et al., 1994; Adams et al., 1997b) or remains the same (DiBartola
et al., 1996; Becker et al., 2000) after treatment, hence USG after
treatment stays lower compared to USG in healthy cats (Graves
et al., 1994; Becker et al., 2000). The diagnosis of mild hyperthy-
roidism in cats with CKD can also pose difficulties, because CKD
can suppress the serum TT4 concentration into the reference range
values (Peterson and Gamble, 1990; Wakeling et al., 2008). Other
methods of less diagnostic value include the analysis of fT4, which
in these cats is only of limited value (Mooney et al., 1996), the T3
suppression test, which has not yet been evaluated in cats with
concurrent hyperthyroidism and CKD (Peterson et al., 1990b), or
the TRH stimulation test, which could not confirm hyperthyroid-
ism in sick cats that were believed to be hyperthyroid (Tomsa
et al., 2001). A recent study described TSH measurement in hyper-
thyroid cats with CKD. The combined measurement of serum TSH
and fT4 could be of merit in diagnosing hyperthyroidism in any cat
with mild or previously diagnosed CKD (Wakeling et al., 2008).
However, the assay used was a canine TSH assay and it was there-
fore not species specific. Moreover, it is a 1st generation assay with
low sensitivity. The diagnostic value of TSH stimulation and/or thy-
roid scintigraphy in cats with CKD and suspected hyperthyroidism
has not yet been investigated in cats.
Hyperthyroidism can mask co-existing CKD, which becomes
apparent after treatment of hyperthyroidism. GFR and plasma cre-
atinine describe a reverse relationship in hyperthyroid cats before
and after treatment. Plasma creatinine concentration is decreased
in hyperthyroid cats and healthy cats supplemented with thyroxin
(Graves et al., 1994; Adams et al., 1997a), but values increase after
treatment of hyperthyroidism (Graves et al., 1994; DiBartola et al.,
1996; Adams et al., 1997b). The GFR increases in cats with hyper-
thyroidism, and decreases after treatment. This is inversely related
to the increase in serum creatinine concentration after treatment
(Graves et al., 1994; Adams et al., 1997b; Becker et al., 2000). A
proposed cause for the decreased GFR is renal hypertrophy caused
by hyperthyroidism, which reverses after treatment and causes
normalization of the GFR per gram of renal tissue (Syme, 2007).
This is less likely, however, because the GFR is already decreased
6 days after treatment (Adams et al., 1997b). The unmasking of re-
nal failure with the development of post-treatment renal azotemia
is present in 39% (n = 13) (Graves et al., 1994), 17% (n = 12) (Becker
et al., 2000), 37% (n = 67) (Milner et al., 2006) and ±30% of cats
(Langston and Reine, 2006).
Cats with hyperthyroidism and pre-existing renal disease should
be submitted to treatment for hyperthyroidism, which is reversible
with respect to treatment modalities of the thyroid, but also with re-
spect to renal changes caused by the treatment for hyperthyroidism
(Bucknell, 2000). The effects of methimazole treatment on renal
function are reversible because discontinuation of methimazole in
hyperthyroid cats developing post-treatment renal azotemia in-
creases the GFR and decreases the serum creatinine concentration
(Becker et al., 2000). When euthyroidism is achieved and maintained
for at least 4 weeks, a definitive decision can be made regarding
maintenance of renal function after treatment of hyperthyroidism
and an irreversible treatment can be implemented (Langston and
Reine, 2006; van Hoek et al., 2008b). A recent study showed for
the first time in an evidence-based way that an accurate evaluation
of kidney function can be performed from 4 weeks after 131I treat-
ment (van Hoek et al., 2009). A significant decrease in the GFR has
been described in hyperthyroid cats until 4 weeks after treatment
with radioiodine, with no significant decline thereafter (van Hoek
et al., 2008b). When the renal function is evaluated in a methima-
zole-treated hyperthyroid cat suspected of renal failure, it is
important to avoid hypothyroidism. Hypothyroidism could falsely
increase the serum creatinine concentration in cats as it does in
humans (Karanikas et al., 2004), and this could influence the deci-
sion regarding definitive treatment.
A diagnostic challenge can arise in cats developing azotemia
and a serum TT4 concentration below the reference range after
irreversible treatment of hyperthyroidism. Indeed, some cats can
have iatrogenic hypothyroidism, which could contribute to declin-
ing kidney function (Peterson and Becker, 1995; Chun et al., 2002;
Karanikas et al., 2004; Nykamp et al., 2005) or to the CKD suppress-
ing serum TT4 below the reference ranges (Peterson and Gamble,
1990; Wakeling et al., 2008), or both. The differentiation between
these two pathological conditions has not yet been investigated
in cats, in contrast to dogs, for which the quantitative measure-
ment of thyroidal 99mTcO4 uptake has the highest discriminatory
power with regard to differentiating between primary hypothy-
roidism and non-thyroidal illness (Diaz Espineira et al., 2007).
It would be ideal if pre-existing though masked renal failure
could be detected in hyperthyroid cats for the purpose of predict-
212 I. van Hoek, S. Daminet / General and Comparative Endocrinology 160 (2009) 205–215
ing post-treatment renal azotemia. Early detection of CKD before
the onset of CKD and azotemia is crucial for good management
of these patients (Grauer, 2005). Pre-treatment assessment of the
GFR (Adams et al., 1997b; Becker et al., 2000) is predictive for
the development of CKD, though the pre-treatment baseline values
of serum creatinine, BUN and urinary protein or USG have not been
proven to be predictive for CKD (Adams et al., 1997b; Syme and
Elliott, 2001; Jepson et al., 2006). A recent study proved that the
development of post-treatment renal azotemia could possibly be
predicted by the pre-treatment measurement of serum TT4, GFR
and USG (van Hoek et al., 2009). CysC is not correlated to the
GFR and is not influenced by the state of the thyroid or its treat-
ment in hyperthyroid cats, and is therefore not useful for the detec-
tion of early renal disease in hyperthyroid cats (Jepson et al., 2006).
New urinary markers that could hold promise for the future are
urinary NAG and urinary RBP. RBP has been detected in the urine
of cats with hyperthyroidism, regardless of developing CKD after
treatment for hyperthyroidism, and this urinary RBP is not sug-
gested to be correlated to serum RBP concentrations (van Hoek
et al., 2007, 2008a, 2009, 2008d). Hyperthyroid cats have increased
urinary NAG concentration compared to healthy controls, though
this does not change after treatment. Urinary NAG is higher before
treatment in cats developing post-treatment renal azotemia com-
pared to cats maintaining healthy kidney function (Lapointe
et al., 2008). Nevertheless, the usefulness of NAG in hyperthyroid
cats for the detection of tubular damage remains unclear from
these preliminary data, and all the more because hyperthyroid cats
have an increased prevalence of urinary tract infection, which can
falsely increase the urinary NAG (Mayer-Roenne et al., 2007).
8. Conclusion
There is extensive linkage between thyroid and kidney function
already in the embryonic stage. This linkage becomes clearer in hy-
per- and hypothyroidism, which lead to hemodynamic and vascu-
lar changes in the kidney, as well as to changes in the tubular and
glomerular structure and function. CKD acts as a non-thyroidal ill-
ness, thereby influencing the thyroidal hormone concentration. A
special group of interest is formed by geriatric cats, where there
is an increased prevalence of hyperthyroidism and CKD. These
can serve as an animal model of disease because the linkage be-
tween thyroid and kidney has strong implications for the evalua-
tion of clinical wellbeing and the consideration of treatment
options.
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