Bidirectional Interaction of Thyroid-Kidney Organs in Disease States

Purpose Thyroid hormones play an important role in growth, development, and physiology of the kidney. The kidney plays a key role in the metabolism, degradation, and excretion of thyroid hormones and its metabolites. The aim of this study is to investigate the prevalence of disease states of thyroid-kidney organs and detecting the correlation between thyroid and kidney function abnormalities. Materials and Methods In this retrospective study, a total of forty-five patients with thyroid and kidney dysfunction were investigated. Clinical features, laboratory data at initial presentation, management, and outcomes were collected. The paper has been written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. Median, percentage, mean ± standard deviation (SD), and the two-tailed t-test were used for statistical analyses. The correlation between variables was assessed by Pearson's, Spearman's correlation tests and regression analyses. Results The mean ± SD of age of study patients was 48.2 ± 22.93 years (ranging from 1 to 90 years). There was no correlation between serum thyroid-stimulating hormone, free thyroxine levels with estimated glomerular filtration rate, and proteinuria. No association between antimicrosomal antibodies with estimated glomerular filtration rate was seen. Cardiovascular disease was the most common complication of overt hypothyroidism in kidney dysfunction patients. Conclusion The present study showed more prevalence of primary hypothyroidism in comparison with other thyroid dysfunctions in patients with kidney dysfunction. Reduced mean values of thyroid function profiles after treatment suggest that this thyroid disease should be considered and ameliorated with thyroid hormone replacement therapy in patients with kidney disease.


Description of Statement.
yroid hormones are necessary for the growth and development of the kidney and for the maintenance of water and electrolyte homeostasis. On the other hand, kidneys are involved in the metabolism and elimination of thyroid hormones. yroid dysfunction is common in patients with chronic kidney disease [1]. Documentation of this association has come from large, welldocumented clinical trials that found an inverse relationship between thyroid function (generally best assessed by measurement of serum thyrotropin levels) and estimated glomerular filtration rates [2]. Patients with chronic kidney disease exhibit a variety of endocrine disturbances, but the evidence of thyroid dysfunction exists only in laboratory parameters. Many of the patients are not associated with clinical signs and symptoms of disease. In other words, chronic kidney disease (CKD) is a well-known cause of nonthyroidal illness causing thyroid dysfunction, i.e., alteration in thyroid parameters in the absence of underlying thyroid disease [3].

Definition of Kidney Dysfunction.
Acute kidney injury (AKI), acute kidney disease (AKD), and CKD can form a continuum of disease, whereby initial kidney injury can lead to persistent injury eventually leading to CKD. AKI is defined as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistent of kidney disease for a period of >90 days. AKD is defined as acute or subacute damage and/or loss of kidney function for the duration of 7 days and 90 days after exposure to an AKI initiating event. Recovery from AKI within 48 h of the initiating event typically heralds rapid reversal of AKI (16th ADQI consensus report of 2017). CKD is classified into zero to seven stages (stages of 0, 1, 2, 3a, 3b, 4, and 5) according to estimated glomerular filtration rate (eGFR) and kidney damage such as proteinuria (>200 mg/day or protein to creatinine ratio >200 mg/g creatinine) or albuminuria (urinary albumin excretion ≥30 mg/day or albumin to creatinine ratio ≥30 mg/g creatinine).

Objectives
ere are many uncertainties about thyroid abnormalities in kidney diseases and vice versa in literature review that can expressed as questions in this study. Furthermore, the aim of this study is to investigate the prevalence of disease states of thyroid-kidney organs and detecting the correlation between thyroid and kidney function abnormalities. e questions which are suggested are as follows:

How is Study Might Work.
yroid functional disease is a risk factor for kidney disease, and some analyses suggest that even high-normal TSH levels may be a risk factor for kidney function. It has been suggested that hypothyroidism leads to kidney dysfunction via decreased cardiac output, altered intrarenal hemodynamics, reduced renin-angiotensin-aldosterone production and activation, and increased tubuloglomerular feedback in chloride channel and expression. Conversely, patients with CKD may be at higher risk for thyroid dysfunction via several pathways. Amelioration of risk factors prevents kidney disease progression, cardiovascular disease, and mortality. erefore, more studies for evaluating the clinical and biochemical association are needed to better understand the causal implications of this disorder in kidney disease.

Why It Must be Performed.
Because clinical studies in patients with the dysfunctional thyroid state is low and not much data are available on how thyroid dysfunction influences renal function in human beings, this study has been planned. Furthermore, this study has been performed in these patients to investigate the alterations in kidney function in the dysfunctional thyroid state and to correlate these values with thyroid profiles of patients. Development or progression of kidney disease, elevated serum creatinine (SCr), decrease of eGFR, and development or progression of thyroid dysfunction were primary endpoints in this study.

Criteria for
(2) Secondary Outcomes. Cardiovascular events, dyslipidemia, progression of subclinical hypothyroidism to primary hypothyroidism, and mortality were secondary endpoints in this study.

Electronic Search.
e paper has been written based on advanced searching via PubMed and Google Scholar databases to identify articles that were published since inception to January 2020. e mentioned search included the following search terms: chronic kidney disease and thyroid dysfunction, thyroid and kidney disease, and thyroid and chronic kidney disease.

Searching Other Resources.
e author reviewed references of all included articles and performed handsearching of related journals to identify the additional relevant studies.

Study Selection.
e search strategy was used to obtain titles and abstracts of studies that might be relevant to the review. e titles and abstracts were screened by the author who discarded studies that were not applicable; however, studies and reviews that might include relevant data or information on studies were retained initially. e author independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.

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International Journal of Nephrology

Data Extraction and Management.
Data extraction was carried out by the author, and studies reported in non-English language journals were to be translated before assessment. Where more than one publication of one study existed, reports were grouped together, and the publication with the most complete data was included.
3.5. Data Items. All patients of thyroid dysfunction with renal disorders and patients of renal dysfunction with thyroid disorders were investigated. Clinical features such as age, sex, different symptoms, and physical signs were extracted from this study. Furthermore, biochemical variables of TSH, fT4, fT3, SCr, eGFR, serum total creatine phosphokinase (CPK), serum total cholesterol, serum triglyceride, hemoglobin (Hb), urine protein, antithyroid autoantibodies at initial presentation, imaging, management, and outcomes were collected.

Assessment of Risk of Bias and Quality in Included Articles.
Case reports were analyzed using criteria developed by the Joanna Briggs Institute critical appraisal tool for case reports that have different assessment tools for each study design in question. e evaluation tool has 8 items for case reports.

Statistical Analysis. Data were entered in Microsoft
Excel 2010 software. Categorical variables are recorded as frequency (N) and percentage (%). e continuous variables were determined as to whether they were normally distributed using the Kolmogorov-Smirnov test. Continuous variables with normal distribution are reported as mean-± standard deviation (SD). Nonparametric variables are expressed as median and interquartile range (Q1, Q3, and IQR). Comparisons between continuous variables with normally distributed (ND) data were assessed by the Wilcoxon-matched pairs test, and variables with nonnormally distributed (NND) data were assessed by the two-tailed onesample t-test analysis. e correlation between continuous variables with normal distributed data was analyzed using product moment correlation (Pearson's correlation coefficient test) (r) and with nonnormally distributed data assessed with Spearman's rank correlation coefficient (rσ). When one variable was nonnormally distributed (X) and another was normally distributed data (Y), regression analyses were used. Significance was assessed with the p value of <0.05.

Study design
Nonrandomized data of randomized trials were planned with systematic review design in this retrospective study.

Sample sizes
Sample sizes ranged from 45 to 59 patients in this study and fourteen patients were excluded from this study.

Setting
Most patients in this study were referred to single centers but several reports indicated multicenter follow-up.

Participants
All patients are included in this study if they had thyroid function test abnormality and kidney failure including acute kidney injury, chronic kidney disease, glomerular disease, nephrotic syndrome, and tubular disease.

Excluded Studies (Criteria).
Patients were excluded from the study if they had renal or thyroid carcinoma in initial presentation. International Journal of Nephrology Distribution of age in male and female is described in Table 1 (Supplementary Table S2).

Patientsʼ
Complaints. Patient's history and physical examination are of paramount importance, especially in the setting of thyroid dysfunction in kidney disease and effect of kidney disease on thyroid disorders. e patients with primary hypothyroidism presented with muscle pain (9/30, 30%), as the most common symptom, fatique and generalized edema (11.1%), weight gain and lethargy (8.8%), tiredness and generalized weakness (6.6%), and dyspnea and poor appetite (4.4%) in the present study. Patients with primary hyperthyroidism presented with fatique and dyspnea (4.4%) and tiredness and increased appetite (2.2%). Patients with subclinical hypothyroidism presented with fatique and generalized weakness (2.2%) and patients with subclinical hyperthyroidism presented with fatique and muscle pain (2.2%) in this research. Patients with euthyroidism presented with dyspnea (2.2%) in the present study. Dry skin without edema has been seen in 12/30 (40%) patients as the most common sign in physical examination in the present study.
ere were hypokalemia and hyponatremia in four patients (4/45, 8.8%). Circulating antithyroid antibodies, specifically antimicrosomal (AMA) and antithyroglobulin antibodies (ATA), are usually present in patients with autoimmune thyroid disease that the prevalence of them in the present study is given (Supplementary Table S5). Distribution and mean values of serum autoantibodies in different stages of the estimated glomerular filtration rate (eGFR) are given in Table 3. Metabolic syndrome definition according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) is the diagnosed co-occurrence of greater than or equal to three of five metabolic abnormalities: abdominal obesity (waist circumference, hyperglycemia, hypertension (HTN), and dyslipidemia in combination). Several studies have demonstrated a close association between metabolic syndrome and thyroid dysfunction. ere was metabolic syndrome or syndrome X or insulin resistant syndrome in 2/30 (6.6%) of patients with overt hypothyroidism as the most common thyroid dysfunction in the present study. Prevalence of any risk factor of  International Journal of Nephrology 5 metabolic syndrome has been described in the present study ( , and mean value of decreased fT4 levels was 0.5 ± 0.5 ng/dl. ere was decreased fT3 in nine patients (9/45, 20%), and mean ± SD of this hormone was 1.93 ± 1.54 pg/ml (Table 5). ere was elevated serum creatine phosphokinase (CPK) in twelve patients (12/ 30, 40%) with a mean average of serum CPK of 18504.2 ± 31659.83 IU/l in primary hypothyroidism. e prevalence of high serum TSH, CPK, serum creatinine, and total cholesterol has been shown in this study ( Figure 2). ere was no correlation between serum TSH and fT4 levels and serum CPK in this study ( Figure 3).
ere was hypercholesterolemia in eleven patients (11/30, 36.6%) with a mean ± SD of 352.6 ± 20.19 mg/dl. ere was no correlation between serum TSH and serum total cholesterol seen with r � 0.13 (p value of 0.69) ( Figure 4). Moreover, there was no correlation between serum total cholesterol and fT4 with r � −0.01 (p value: NS).
ere was hypercreatininemia in twenty-two patients (22/30, 73.3%) of primary hypothyroidism with a mean value of 1.67 ± 0.27 mg/dl, and there was no correlation between serum TSH and fT4 levels and serum creatinine in this study. Furthermore, the impact of kidney dysfunction on thyroid function abnormalities has been assessed, and there was no correlation between serum creatinine and serum TSH and fT4 levels in accordance to statistical analyses ( Figure 5). ere was primary hypothyroidism in 2.2% of stage of 2, 3a, 3b, and 4 of CKD, and there was also euthyroidism in 1/45 (2.2%) of stages of 4 of CKD. Prevalence of low T4, T3, and elevated TSH in different stages of CKD has been shown in this study ( Figure 6). Moreover, there was no association between serum TSH and fT4 levels with different stages of CKD (eGFR) and between  Table S7). e correlation between elevated urine protein and serum TSH in this study was 0.85 (p value of 0.06), and really there was no significant relationship between proteinuria and primary hypothyroidism (Figures 8(a) and 8(b)). As previously mentioned, there was metabolic syndrome in 2/30 (6.6%) patients with primary hypothyroidism in the present study.
(3) Subclinical Hyperthyroidism. ere was subclinical hypothyroidism in three patients (3/45, 6.6%) that included normal fT4, fT3, and low serum TSH in three patients. e mean ± SD value of low serum TSH levels was 0.03 ± 0.02 mIU/ml. ere was metabolic syndrome in one patient of subclinical hypothyroidism in the current study.
(4) Subclinical Hypothyroidism. ere was subclinical hypothyroidism in one patient (1/45, 2.2%) that consisted high serum TSH levels of 11.89 mIU/ml.  ere was a statistical significance for serum TSH levels before and after treatment with THRT (p value of 0.003; w value � 0) (

Follow-Up.
In this study, serum TSH has been assessed in nineteen patients (19/45, 42.2%) after treatment. Median time of blood sampling for initial normal serum TSH after drug treatment in these patients has been calculated 4 months with an IQR of 5 months (Q3-Q1 � 6-1), minimum (Min) of 0.5 mo, maximum (Max) of 24 mo, midrange of 23.5 mo, and mean of 5.96 mo. Outcomes of thyroid dysfunction in renal disease include cardiovascular disease, dyslipidemia, progression of subclinical hypothyroidism to primary hypothyroidism, and death (Table 7) (Figure 9) (Supplementary Table S11).         Figure 7: Correlation between serum TSH and fT4 levels with different stages of CKD. a, b. Impact of abnormal TSH and fT4 levels on different stages of CKD in primary hypothyroidism. c, d. Impact of kidney dysfunction on serum TSH and fT4 levels in primary hypothyroidism. CKD, chronic kidney disease; fT4, free thyroxin; TSH, thyroid-stimulating hormone.  Figure 8: Correlation between proteinuria and serum TSH and fT4 levels in primary hypothyroidism in the current study. Impact of proteinuria on thyroid function tests has been shown accurately. fT4, free thyroxin; TSH, thyroid-stimulating hormone.

Discussion
yroid and kidney functions are known to interact, and thyroid dysfunction is known to cause significant changes in kidney function, especially to affect GFR. yroid hormones are involved in the growth, development, and physiology of the kidney. Decreased or elevated thyroid hormones affect glomerular filtration rate, renal blood flow, tubular function, water-electrolyte balance, and kidney structure [44]. yroidal functional disease and in particular hypothyroidism is highly prevalent among CKD and kidney failure patients. In the present study, 25/45 (55.5%) patients were female and 20/45 (20%) were male and the obtained results were in contrast with the study by Petimani and Adake that 77.7% of patients (35/45) were male and 22.2% of them (10/45) were female [45]. ese results were in agreement with the study by Rashead and Aryee et al. [46,47]. Low thyroid hormone levels (i.e., triiodothyronine) have been associated with adverse cardiovascular sequela in CKD and kidney failure, but these metrics are confounded by malnutrition, inflammation, and comorbid states and hence may signify nonthyroidal illness (i.e., thyroid functional test derangements associated with underlying ill health in the absence of thyroid pathology). It has hypothesized that hypothyroidism is an underrecognized, modifiable risk factor for the enormous burden of cardiovascular disease and death in CKD and kidney failure [48]. CKD has been known to affect the pituitary-thyroid axis and the peripheral metabolism of thyroid hormones. One of the most important links between thyroid disorders and CKD is uremia [49]. e author identified a significant association between thyroid dysfunction (both hypothyroidism and hyperthyroidism) and high mortality in patients with stage 3 CKD with an increased risk of death (17%−27% above the risk). ese results were identified in euthyroid patients with CKD over a median follow-up period of 5.5 years [2]. yroid functions have subtle clinical features associated with some forms of thyroid dysfunction. e clinicians must decide which test is best suiting to diagnose or exclude disorder. It is emphasized that a single thyroid function test (TFT) is not absolute in diagnostic accuracy, and thus, it must be a careful selection of such tests, so that their combination can give comprehensive data that would enhance the diagnostic accuracy. In the study by Rashead and Hamid, there was a significant difference between normal and abnormal values of creatinine, while there was a highly significant difference (P < 0.001) between normal and abnormal values of TSH, T3, and T4 [46]. Prevalence of fT4 and fT3 levels in our patients were 57.7% and 17.7%, respectively, in contrast with the study by Vivek Paul Benjamin et al. that these values were 68% and 24% in serum TSH levels of >10 mIU/ml, respectively [50]. Furthermore, the study by Fan et al. revealed the high prevalence of low T3 syndrome in nondialysis-dependent chronic kidney disease (NDD-CKD) patients even in early stages [51]. As we know, pallor is the first sign of hypothyroidism in these patients, while it occurs in greater than 20% of patients (as a second sign of primary hypothyroidism) in our patients. As previously known, over 40% of patients with CKD are anemic. So, suspicion of a relationship between thyroid dysfunction and anemia with CKD should be considered. In our study, there was anemia in 31.11% of patients, and 71.4% of anemic patients with CKD were presented with elevated TSH. Moreover, 57.1% and 35.7% of patients with anemia and CKD had low fT4 and fT3 levels, respectively. Conversely, the prevalence of anemia in low T3 syndrome and CKD was reported as 84.2% in Fan et al.' study.
is study was performed with Percentage (%) Figure 9: Distribution of various outcomes in thyroid-kidney disease. Dark gray column with three plus sign shows frequency of mortality in hypothyroidism patients, dark gray column with two plus sign is indicative of frequency of cardiovascular disease (CVD) in primary hypothyroidism and subclinical hyperthyroidism, dark gray column with one plus sign is indicative of hypertriglyceridemia in primary hypothyroidism, and light dark column shows hypercholesterolemia in hypothyroidism patients.
consideration that there was a positive correlation between serum total protein, prealbumin, and albumin levels and serum total triiodothyronine levels (TT3) levels according to the study by Fan et al. and a positive correlation between serum protein and albumin with serum TSH levels according to the study by Arora et al. [52], but it resulted in different findings. In this study, there was no relationship between serum TSH and fT4 levels and proteinuria, and that result was consistent with the result of the study by Gilles et al. [53], while in the study by Du et al., there was a positive correlation between serum total thyroxin levels (TT4) and fT4 levels with albuminuria, but albuminuria was not associated with TT3, fT3, and TSH [54]. Another study by Sridharan et al. documented a positive relationship between fT4 and fT3 levels with microalbuminuria [55]. e present study revealed no correlation between eGFR and serum fT4 and TSH levels that was in agreement with the study by Vivek Paul Benjamin et al. Another study by Khatiwada et al. concluded that stage 4 and stage 5 CKD patients had significantly higher risk of having thyroid dysfunction in comparison to stage 3 CKD [56]. While our study showed a higher prevalence of elevated TSH and low fT3 levels in stage 3b CKD and higher prevalence of low fT4 levels in stage IV CKD. Another keypoint that should be noticed in this study is attributed to the mortality rate of 2.2% in one patient with primary hypothyroidism, and the etiology of the unexpected death could not be established because the relatives refused a pathological postmortem biopsy. e serum fT4 level was within the normal range, although the TSH level was still high but lower than initial presentation, and serum creatinine was 209 μmol/l (laboratory tests at the time of death). Hypothyroidism may induce de novo AKI or CKD progression due to the hypodynamic circulatory state that was created by thyroid hormone deficiency. Moreover, paralyticus ileus due to autonomic neuropathy (due to hypokalemia) can be caused by urinary retention. erefore, clinicians must be alert from rare manifestations or complications of hypothyroidism such as acute kidney injury and paralyticus ileus due to untreated hypothyroidism as if mostly thyroxine deficiency may be missed and treatment can reverse the complications [34]. Consistent with this finding, the study by Rhee et al. suggested that hypothyroidism is associated with higher mortality in dialysis patients which may be ameliorated by THRT [57]. ere are several reports suggesting that metabolic syndrome is closely associated with thyroid dysfunction due to the impact of thyroid hormones on lipid metabolism, glucose, blood pressure, and cardiovascular dysfunction.
is study detected metabolic syndrome in 2/30 (6.6%) patients with primary hypothyroidism as the most common thyroid disease in this study. Conversely, thyroid dysfunction and hypothyroidism were seen in 28% and 69/432 (16%) of patients with metabolic syndrome in the study by Deshmukh et al., respectively. e predominance of hypothyroidism (primary and subclinical: 25.7%) suggests that metabolic syndrome could also be a consequence or sequela of various stages of hypothyroidism during the natural course of disease [58]. Moreover, Wolffenbuttel et al. in a cohort study concluded that higher plasma levels of fT3 were associated with several components of metabolic syndrome when corrected for possible confounding factors. Only in men, lower fT4 levels were related to metabolic syndrome. ere was a 50-80% increased risk of having metabolic syndrome compared to lowest quartile of the highest fT3 and fT3/fT4 ratio quartiles [59]. To end, there were some limitations in this study. First, insufficient data were seen in some of case reports. Second, there were low case numbers for the different clinical categories of thyroid dysfunction in patients with kidney dysfunction, e.g., thirty patients with primary hypothyroidism were included in this study.

Conclusions
e interplay between the thyroid and kidney in each other's function is known for many years. yroid function affects renal physiology and development, whereas kidney failure could result in thyroid dysfunction. e present study demonstrated that the prevalence of primary hypothyroidism was high in patients with kidney dysfunction. Prevalence of hypothyroidism, elevated CPK, hypercholesterolemia, and raised serum creatinine levels was high in stage 3b CKD patients. Moreover, prevalence of elevated TSH and low fT3 levels was high in stage 3b CKD, and low fT4 levels was higher in stage IV CKD. ere was no correlation between thyroid function tests (serum TSH and serum thyroxine levels) and decreased eGFR, hypercholesterolemia, and proteinuria in the present study.
e findings of the present study have a lot of clinical relevance, since a multisystem approach to treat patients with diseases affecting either of these organs (the thyroid or kidney) would prove vitality to avoid missing subtle but clinically relevant abnormalities.

Data Availability
e datasets used to support the findings of this study are included in additional supporting files.

Additional Points
Highlights. High prevalence of primary hypothyroidism in patients with kidney dysfunction. High prevalence of elevated CPK, hypercholesterolemia, and raised serum creatinine levels in stage 3b CKD patients. High prevalence of elevated TSH and low fT3 levels in stage 3b CKD and low fT4 levels in stage IV CKD. No correlation between thyroid function tests and decreased eGFR, hypercholesterolemia, and proteinuria.

Conflicts of Interest
e author declares that there are no conflicts of interest.

Authors' Contributions
e author contributed to study concept, design, data collection, definition of intellectual content, literature search, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript review, and he is the guarantor. Acknowledgments e author thanks the National University of Tehran Medical Sciences, College of Medicine and Imam Khomeini Hospital Complex. Table S1. JBI critical appraisal tool for case reports in included articles. Tables S2(a)-S2(c). Raw data of age, sex, and laboratory parameters in thyroid-kidney dysfunction. Table  S3. Raw data of symptoms and signs. Table S4. Prevalence of changes of TSH, fT4, and fT3 in CKD patients with anemia. Table S5. Distribution of positive thyroid autoantibodies in the current study. Table S6. Raw data of metabolic syndrome and its components in the present study. Table S7. Correlation between eGFR and serum TSH and fT4 in disease states. Tables S8(a)-S8(d). Raw data of laboratory findings in the present study. Tables S9(a)-S9(b). Raw data and frequency of imaging modalities in clinical studies. Tables S10(a)-S10(c). yroid function tests, serum creatinine, creatine phosphokinase, and total cholesterol before following treatment and follow-up in enrolled patients. Tables S11(a)-S11(c). Raw data and statistical analyses of laboratory parameters following thyroid hormone replacement therapy in hypothyroidism. (Supplementary Materials)