Study design
This study was designed as a retrospective, cross-sectional study. The local ethical committee approved the study protocol (07.07.2020/1601), and the study was conducted following the ethical principles stated in the Declaration of Helsinki.
The study included patients who were reviewed in our hospital between January 2015 and April 2021 and had primary hypothyroidism with thyroid stimulating hormone (TSH) levels of more than 50 mIU/L. At the time of presentation, each patient’s demographic information (gender and age), medication history and atherosclerotic risk factors (history of smoking, alcohol use, dyslipidaemia, hypertension (HT) and diabetes mellitus (DM)) were documented. Patients were excluded if they were currently pregnant or under 18 years of age, with myxedema coma, had an GFR<15 mL/min/1.73 m2, were receiving maintenance renal replacement therapy, had chronic liver disease, concomitant malignancies, stroke, pulmonary embolism, immunological disease or chronic heart failure, or had recently received treatments known to affect renal function, such as nonsteroidal anti-inflammatory drugs, diuretics, contrast agents or certain antibiotics. The height and weight of the participants were recorded, and the body mass index (BMI) was calculated by dividing the weight (kg) by the square of their height (m).
All blood samples were taken after eight or more hours of fasting. All laboratory analyses were performed in the same laboratory. Free thyroxine (FT4), free triiodothyronine (FT3) and TSH were analysed using the electrochemiluminescence immunoassay method (Roche Diagnostics GmbH, D-68298 Mannheim, Germany). The GFR was estimated using the National Kidney Foundation’s simplified Modification of Diet in Renal Disease (MDRD) calculation, as follows (6,7):
GFR = 175 × (serum creatinine)-1.154 × (age)-0.203 × (0.742 if female) × (1.212 if African American).
where units for GFR are mL/min/1.73 m2 and creatinine mg/dL.
Acute kidney injury was defined as an increase in creatinine levels of 0.3 mg/dL (26.4 µmol/L) or 50% from baseline in less than 48 hours, or a reduction in urine output to less than 0.5 mL/kg/h for more than six hours (6). Patients with AKI were included in the case group and patients without AKI in the control group.
Statistical analysis
Kolmogorov-Smirnov and Shapiro-Wilk tests were used to test for normality. Correlation of risk factors with outcome were analysed independently (univariate analysis) by either Student’s t-test or Mann-Whitney U-test where applicable. The differences in proportions between groups were compared by using the chi-squared or Fisher’s exact test, where appropriate. Descriptive statistics were used to summarise the data and are presented as median (interquartile range (IQR) or odds ratio (OR)) for skewed continuous variables, and count with the percentage of total for categorical variables. In order to define risk factors for AKI secondary to severe hypothyroidism, univariate and multivariate binary logistic regression analyses were performed; ORs and confidence intervals (CI) were calculated. All statistical analyses were carried out on Windows using the SPSS v23 programme (SPSS Inc., Chicago, IL, USA). A p value of less than 0.05 was taken as statistically significant.
RESULTS
Between January 2015 and April 2021, 2226 patients with TSH > 50 mIU/L were identified. A total of 100 patients, with complete retrospective demographic and laboratory data were included in our study. Twenty patients (11 males (M), 9 females (F)) were included in the AKI group (cases) and 80 (23 M, 57 F) were included in the control group. The median age of the AKI group was 56 years (IQR 44.3–68.5), and the median age of the control group 49 years (IQR 32.3–60). The median age, the median age at diagnosis of hypothyroidism and the proportion of males were significantly higher in the cases than in the control group (p = 0.027, p = 0.001 and p = 0.001 respectively). There was no difference between the groups in weight, BMI, duration of hypothyroidism, rate of newly diagnosed or daily levothyroxine dose per kg. The rate of treatment (TH replacement therapy) discontinuation and treatment discontinuation time were significantly higher in the case group (p = 0.040 and p = 0.049 respectively). While there was no difference in the rates of cardiovascular disease (CVD), heart failure, obstructive sleep apnoea or hyperlipidemia, the rates of HT and DM were significantly higher in the case group (p < 0.001 and p = 0.002 respectively). Alcohol consumption, cigarette use, fibrate use as risk factors for rhabdomyolysis and AKI did not differ between the groups, but the rate of statin use was found to be higher in the case group (p = 0.002) (Table 1).
There was a significant difference between the groups in levels of urea, creatinine, GFR, creatine kinase (CK), uric acid, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, FT4, FT3 and potassium (p = 0.001, p < 0.001, p < 0.001, p = 0.010, p < 0.001, p = 0.036, p = 0.047, p = 0.001, p < 0.001 and p = 0.027 respectively) (Table 2).
The binary logistic regression analyses are shown in Table 3. In the univariate logistic regression analyses, male gender (OR 0.330, 95% CI 0.121–0.902; p = 0.031), age > 60 years (OR 0.222, 95% CI 0.080–0.621; p = 0.004), hypothyroidism diagnosed after age 60 years (OR 0.127, 95% CI 0.035–0.511; p = 0.462), presence of DM (OR 0.156, 95% CI 0.042–0.580; p = 0.006), presence of HT (OR 0.074, 95% CI 0.023–0.235; p  0.001), hyperuricaemia (OR 0.110, 95% CI 0.024–0.503; p  = 0.004), CK > 1000 U/L (OR 0.246, 95% CI 0.082–0.739; p  = 0.012), FT4 < 0.2 ng/dL (OR 0.241, 95% CI 0.083–0.700; p  = 0.009), FT3 < 1.3 pg/mL (OR 0.080, 95% CI 0.019–0.345; p  = 0.001) and statin use (OR 0.120, 95% CI 0.026–0.557; p  = 0.007) were statistically significant predictors for the occurrence of AKI due to severe hypothyroidism. Multivariate logistic regression analyses showed that age greater than 60 when diagnosed with hypothyroidism (OR 59.674, 95% CI 5.955–598.031; p = 0.001), FT3 < 1.3 pg/mL (OR 17.151, 95% CI 2.491–118.089; p = 0.004), CK > 1000 U/L (OR 11.522, 95% CI 1.602–82.848; p = 0.015) were predictors for the development of AKI associated with severe hypothyroidism.