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.