Hypothyroidism has been identified as a comorbidity related to chronic kidney disease (CKD). The retrospective study investigated thyroid function and CKD and assessed the relationship between TSH and urine albumin/creatinine ratio (ACR), the slope of estimated glomerular filtration rate (eGFR), stratified by CKD grades.
This retrospective cohort study was conducted in a community nephrology clinic established with clinical and demographic data, from April 1, 2015, until December 30, 2019. Hypothyroidism prevalence, eGFR slope and ACR were the outcomes of interest and were analyzed by using unconditional and adjusted generalized linear (GLM) and logistic regression models.
The overall demographics of the 312 subjects were 58.3% were male, 12.8% had hypothyroidism and 43.3% had diabetes mellitus, with the median age of 73 years (IQR (interquartile range) 29-99). The hypothyroidism prevalence was 9.4%, 11.5%, 15%, and 17.5% for the CKD categories defined as Grade 1 and 2 combined, Grade 3, Grade 4, and Grade 5, respectively. The overall median eGFR slope was -0.0027 (IQR -0.158 - 0.602). With GLM models, the adjusted odds ratio of 1.052 (95% CI: 1.006-1.100) was calculated for TSH level > 5 µIU/L (Q2), per unit ml/min/day decline in eGFR slope. The overall median urine ACR was 10.2 mg/mmol (IQR 0.24-1414). In a multivariate logistic regression model with the 75th percentile for urine ACR, the adjusted odds ratio of TSH level of > 1.8 µIU/l (50th percentile) was 1.803 (95% CI: 0.986-3.296).
The prevalence of hypothyroidism increased with worsening eGFR grades from 9.4% to 17.4% at baseline. The higher TSH levels were associated with faster decline in eGFR and higher levels of albuminuria. Furthermore, prospective studies are needed to evaluate the effect of hypothyroidism treated on renal function.
Thyroid-stimulating hormone, Chronic kidney disease, Proteinuria, Estimated glomerular filtration rate
In the general population, there are 10-13.4 percent individuals diagnosed with chronic kidney disease (CKD) [1,2]. In addition to hypertension, anemia, cardiovascular disease and congestive heart failure, hypothyroidism has been identified as a comorbidity related to chronic kidney disease, which is usually accompanied by metabolic syndrome. The prevalence of hypothyroidism accompanied by CKD ranges between 3 and 25% [3]. TSH levels of 3 to 5 mIU/L, 5 to 10 mIU/L and greater than 10 mIU/L were associated with incrementally increased mortality risk of time-adjusted hazard ratios (95% CI) 1.27 (1.22-1.32) and 1.13 (1.02-1.25), respectively [4].
The primary objective of this study is to assess the relationship of hypothyroidism to urine albumin/creatinine ratio, slope of eGFR, hypothyroidism and different grades of CKD.
These objectives were met in a retrospective cohort, compiled from a nephrology clinic of a community hospital in Quebec. A random sample of 312 subjects was entered into an electronic database from the following data sources: Laboratory data from the Reflections database, clinical examination, medication list and demographical data from clinic charts, ECG data from Cardiology data management electronic database and radiological data from web-based PACs database.
The inclusion criteria for sample size were an age of ≥ 18, a diagnosis of CKD as represented by three eGFR readings of ≤ 90 ml/min/1.73 m2 and a life expectancy of more than 6 months. The subjects were excluded if the individuals were noted to have acute kidney injury, expected to require renal replacement therapy within 3 months, or transferred to another health care facility.
Age, gender, race, diabetes status, cause of renal disease, comorbidities, height, weight, blood pressure, baseline eGFR, baseline CKD grade, hemoglobin, sodium, potassium, calcium, phosphate, TSH, hemoglobin A1c, proteinuria and uric acid were the variables collected for the database. Absolute hemoglobin A1c was calculated by multiplying hemoglobin A1c by the hemoglobin in g/L [5].
For the calculation of sample size using logistic regression for albuminuria, the assumption of 10% hypothyroidism prevalence compared with 15% of hypothyroidism prevalence in the effect size of 0.5, power of 80% and alpha error of 0.05, the required sample size is 329. Similarly, if the effect size is 0.04, the power is set at 80%, alpha error of 0.05, for the desired linear regression analysis for slope of eGFR, with the anticipated TSH level above the 50th percentile (Q2) the required sample size is 274 [6].
The research team identified a random sample of 312 medical charts from a nephrology clinic of a community hospital were identified by the nephrology team and all data were collected and entered into an electronic excel database.
Estimated GFR slopes were calculated for individual patients using three or more eGFR values collected over time of follow up and the linear regression models. Significant urine albumin/creatinine levels at baseline were defined as 75th percentile (Q3).
Hypothyroidism was diagnosed as TSH level above 5 µIU/l (Q2). The TSH levels were categorized by greater than 50th (Q2) and 75th percentiles (Q3), as well.
Of the 312 subjects, 58.3% (182/312) were male, 12.8% had a diagnosis of hypothyroidism (40/312), 43.3% (135/312) of a diagnosis of diabetes mellitus, with a median age of 73 (IQR 29-99) (Table 1). Their baseline eGFR was 34 ml/min/1.73 m2 (IQR 9-93). The duration of the follow up period was 24.4 (IQR 0.93-103.5) months (Table 1). When the subjects were divided into CKD categories (less than 15 ml/min/1.73 m2, 15-30 ml/min/1.73 m2, 30-60 ml/min/1.73 m2 and > 60 ml/min/1.73 m2) a progressive increase in the proportion with the diagnosis of diabetes mellitus, diagnosis of dementia, proteinuria and ferritin was observed with statistical significance (Table 2). Conversely, there was a statistically significant progressive decline in eGFR, serum albumin and hemoglobin, also evident.
Table 1: Density grades in male group. View Table 1
Table 2: Density grades in female group. View Table 2
The overall median eGFR slope was -0.0027 (IQR -0.158 - 0.602) (Table 1). When generalized linear regression models were applied for the decline in eGFR slope, an odds ratio of 1.052 (95% CI: 1.006-1.100) was calculated for a TSH level greater than 5 µIU/l (Q2), after adjusting for systolic blood pressure, proteinuria, and baseline eGFR (Table 3A and Table 3B). Absolute hemoglobin A1c was not included due to not being an a priori objective.
Table 3a: Average range ratio of high frequency and low frequency in male group. View Table 3a
Table 3b: Average range ratio of high frequency and low frequency in male group. View Table 3b
The overall median urine albumin/creatinine ratio was 10.2 mg/mmol (IQR 0.24-1414) (Table 4). When the 75th percentile for urine ACR ratio was assessed in a multivariate logistic regression model, the TSH greater than 1.8 µIU/l (50th percentile) had an odds ratio of 1.803 (95% CI: 0.986-3.296), after adjusting for diabetes mellitus history, body mass index and chronic kidney disease grade at baseline presentation (Table 5A and Table 5B).
Table 4: Average range ratio of high frequency and low frequency in female group. View Table 4
Table 5a: Average value of energy in male group. View Table 5a
Table 5b: Average value of energy in male group. View Table 5b
It has been reported that the prevalence of hypothyroidism in CKD has ranged between 3 and 25% [2]. Our study findings show a similar progressive increase in the prevalence of hypothyroidism with worsening eGFR grades from 9.4% to 17.4%. Both the studies of Kalantar-Zadeh, et al. and Lo JC, Chertow GM, Go AS, et al. confirmed an increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease [7,8]. Their findings were again indicative of the progressive increase in the prevalence of hypothyroidism with the increasing CKD Grades [8].
Treatment for hypothyroidism resulted in a slower decline in renal function than untreated hypothyroidism [9]. Lower T3 levels in the renal transplant literature have shown to be linked with faster renal transplant graft loss [10]. Our study shows similar results but because of a small effect size, it marks an association of 5% increase in odds ratio of elevated TSH levels with a negative eGFR slope.
Proteinuria has been reported with both hyperthyroidism and hypothyroidism. Hyperthyroidism is associated with tubulointerstitial disease [3]. Immune complex renal disease and minimal change disease have also been reported in Hashimoto thyroiditis [3]. Nephrotic syndrome can cause thyroxine binding protein loss such as thyroglobulin binding protein, then can lead to higher TSH levels and subclinical hypothyroidism [11].
Hypothyroidism has multiple effects on renal tubules. It is linked to a decrease activity of the renin-angiotensin II - aldosterone axis, the proximal tubule Na/Phosphate pump, the Na - hydrogen pump and the sodium potassium ATPase pump [3]. The increased levels of ADH are noted in hypothyroidism, resulting in hyponatremia. Low thyroxine levels have been reported to decrease cardiac output and decreased renal blood flow which in turn lowers GFR [3]. Conversely, hyperthyroidism increases cardiac output, increases renal blood flow and results in renal hyperfiltration [3].
Another possible biological explanation for worsening renal function with hypothyroidism could be due to hypercalciuria and nephrocalcinosis. In both humans and animal models, there is a documented relationship with elevated TSH and hyperparathyroidism, resulting in hypercalcemia that can develop ultimately nephrocalcinosis [12].
The limitations of the study include retrospective bias, as well as the selection bias of sampling one nephrologist clinical practice. The study, like retrospective cohorts, is unable to account for all unperceived confounding factors. The results are limited in significance because of the relatively small sample size. Given the smaller effect size of TSH levels associated with eGFR slope, the results are limited in significance due to a relatively small sample size.
The tetraiodothyronine (T4) levels were not available for all subjects, because the institution did not include this thyroid function test.
In clinical practice, the thyroid tests for prognosis and/or renal function stabilization should be considered in the management chronic kidney disease. Further studies are needed to determine whether treatment of hypothyroidism reverses the progression of chronic kidney disease and improves the albuminuria.
• Ethics Approval obtained from the St. Mary's Hospital Research Ethics Board SMHC-20-03 in accordance to the Helsinki declaration.
• For a retrospective, database study individual patient consent was not required.
• There are no competing interests.
• There was no formal funding.
S Iqbal, C Scheede-Bergdahl and K Rafat Zand were involved in the conceptualization of the project, study design, and critical review of manuscript; S Iqbal and D Yang were key players for acquisition of data, and analysis and interpretation; S Iqbal wrote the main manuscript and prepared the tables; S Iqbal and D Barama critically reviewed the manuscript and completed the final approval.
Alyssa Shaw for the data entry and work diligence.