DISCUSSION
This is the first study in the literature to examine the risk factors
for AKI due to severe hypothyroidism. Male gender, age greater than 60
years, age at diagnosis of hypothyroidism greater than 60, statin use,
presence of DM, presence of HT, hyperuricaemia, CK >
1000 U/L, FT4 < 0.2 ng/dL, FT3 < 1.3 pg/mL were
identified as possible contributing factors to the development of AKI in
the univariate analyses. In the multivariate analyses, age at diagnosis
of hypothyroidism > 60 years, CK > 1000 U/L
and FT3 < 1.3 pg/mL were observed as predictors for
development of AKI.
Severe hypothyroidism can have various effects on the biological
structure and functioning of the kidneys. In severe hypothyroidism,
histological abnormalities such as thickening of both tubular and
glomerular basement membranes have been observed (7). In some studies,
proteinuria has been observed in hypothyroid patients and is associated
with the severity of hypothyroidism (8). In addition, hypothyroidism has
been linked to a variety of glomerulopathies, including membranous
glomerulopathy, minimum-change nephropathy and membranoproliferative
glomerulonephritis, with thyroxine therapy alleviating urine protein
loss (9,10).
Rhabdomyolysis is an important and life-threatening complication of
severe hypothyroidism. Cases of AKI due to rhabdomyolysis caused by
hypothyroidism have been reported in the literature (11). The risk of
rhabdomyolysis increases with a CK value of >1000 U/L
(12,13), and that CK > 1000 U/L increases the risk of AKI
three-fold (14). Supporting this, in our study, CK values were
significantly higher in the AKI group, and CK > 1000 U/L
was observed as a risk factor for the development of AKI.
Male gender was shown to be another factor that increased the risk of
AKI due to severe hypothyroidism in our study. Epidemiological studies
have observed that chronic kidney disease is more common in females
(15). This is because females have a longer life expectancy than males
and that GFR decreases with age. However, the risk of AKI and the
proportion of patients with chronic kidney disease receiving renal
replacement therapy were found to be higher in males in epidemiological
studies . Possible reasons for this include the protective effects of
oestrogen in women, the harmful effects of testosterone, and an
unhealthy lifestyle and busy work-life in males (15,16,17).
Studies have reported that TSH levels increase with age, and follow-up
is recommended until high TSH levels are <8 mIU/L, especially
in older patients (18). As age increases, renal function decreases;
patients become more susceptible to prerenal AKI, and GFR may decrease
(19). Hypothyroidism has been linked to decreased renal plasma flow
(RPF), and inadequate effective RBF. The hypodynamic condition of the
vascular system caused by hypothyroidism is hypothesised to be the cause
of the reduction in GFR and RBF (20). High TSH levels have been found to
be negatively correlated with RPF, RBF and GFR due to high vascular
resistance in afferent renal arterioles. It has also been shown that the
TH relaxes arteries and reduces arterial resistance (3). The elderly are
at risk of renal dysfunction due to the hypodynamic circulation caused
by severe hypothyroidism. In support of this, our study showed that
being over 60 years old or age
greater than 60 at the time of diagnosis of hypothyroidism were risk
factors for development of AKI due to severe hypothyroidism.
Although the TSH levels in the AKI and control groups were not different
in our study, other studies has shown that an increase in TSH is related
to a decrease in RBF and a decline in GFR (3). The fact that all of the
patients in this study had severe hypothyroidism may explain for the
lack of differences in TSH values. Besides, it has been observed that
FT4 levels are strongly associated with changes in renal function
changes, including after treatment with levothyroxine (21). Peripheral
TH may cause activation of the renin-angiotensin and sympathetic
systems, and affect renal vascular compliance through actions on the
nuclear receptor (22). TH, especially FT3, are particularly associated
with renal tubular function, which induces increased expression of mRNA
encoding alpha and beta subunits of the Na+/K+-ATPase enzyme (23). Since
there are no studies on this subject in the literature, it is not
possible to define the level of FT3 or FT4 that increases the risk of
AKI. In our study, it was observed that FT3 below the median value in
both the univariate and multivariate analyses was a statistically
significant risk factor for the development of AKI secondary to severe
hypothyroidism.
The length of time that a patient has been hypothyroid, independent of
the TSH level, may also increase the risk of renal dysfunction. In our
study, treatment discontinuation time in the AKI group was found to be
statistically higher than in the control group. Although the
discontinuation time does not appear to affect the development of AKI,
the authors believe that a longer time of treatment discontinuation has
a greater effect on the decrease in RBF and GFR. The hypodynamic
circulation due to TH deficiency may also be implicated in AKI formation
in the chronic period.
There are many studies in the literature regarding the relationship
between serum uric acid levels and kidney function. A negative
association has been found in most studies, but not confirmed in others
(24). Furthermore, as an inflammatory marker, high blood uric acid
levels have various physiological effects on renal function,
hypertension, and CVD development, including endothelial dysfunction
(24,25). In the current study, hyperuricaemia, in addition to the
vascular and renal implications of severe hypothyroidism, was discovered
to be a risk factor for AKI in the univariate analysis.
Due to the effects of hypothyroidism on the renal glomerular and
vascular structure, the presence of a disease that may affect kidney
baseline function may increase the risk of AKI. Hypertension and
diabetes are the most common causes of chronic kidney disease and are
associated with poor renal outcomes, including in patients with
hypothyroidism (26). In diabetic patients, a reduction in GFR is seen in
parallel with an increase in TSH. In addition, the incidence of diabetic
nephropathy increases with increasing TSH values (27). It is already
predictable that the presence of traditional AKI risk factors such as DM
and HT will increase the risk of AKI due to severe hypothyroidism , as
in our study.
Myopathy due to severe hypothyroidism, elevated CK, hypovolaemia and
electrolyte abnormalities increases the risk of rhabdomyolysis (11). In
cross-sectional studies, statin therapy increases the risk of
rhabdomyolysis due to the possibility of inducing immune-mediated
necrotising myopathy and CK elevation, and via other mechanisms (28,29).
For these possible reasons, in our study, statin use was one of the
factors affecting the development of AKI due to severe hypothyroidism.
The present study, being retrospective, and investigating a rare
disease, has several limitations. First, all the patients were recruited
from a single centre, and the sample size was relatively small. Second,
several potentially relevant factors, such as the duration of chronic
illness, genetic predisposition and race, were not investigated.
However, there is little research on severe hypothyroidism; our study
focused on patients with AKI due to severe hypothyroidism, which is
rarer. Randomized prospective studies with more patients participating
in terms of risk factors for AKI due to severe hypothyroidism
independent of classical AKI risk factors (such as DM and HT) will
contribute to the literature.
AKI due to severe hypothyroidism is an important and life-threatening
complication. We recommend close follow-up and monitoring in hypothyroid
patients who are diagnosed at age > 60 years, or whose CK
is greater than 1000 U/L, or FT3 less than 1.3 pg/mL.