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Journal of Endocrinology & Metabolism

Original Article

Volume 12, Number 3, June 2022, pages 89-96

Thyroid-Stimulating Hormone and Estimated Glomerular Filtration Rate

In the general population, there are 10-13.4% 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 CKD, which is usually accompanied by metabolic syndrome. The prevalence of hypothyroidism accompanied by CKD ranges between 3% and 25% [3]. Thyroid-stimulating hormone (TSH) levels of 3 - 5, 5 - 10 and > 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 was to assess the relationship of hypothyroidism to urine albumin/creatinine ratio (ACR), slope of estimated glomerular filtration rate (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, electrocardiography (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, with 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. Ethics approval was obtained from the St. Mary’s Hospital Research Ethics Board SMHC-20-03 in accordance to the Helsinki declaration.

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 and all data were collected and entered into an electronic excel database.

The eGFR slopes were calculated for individual patients using three or more eGFR values collected over time of follow-up and the linear regression models. Baseline urine ACR was recorded to carry out linear regression models as well.

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) had a diagnosis of diabetes mellitus, with a median age of 73 (interquartile range (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 (< 15, 15 - 30, 30 - 60 and > 60 mL/min/1.73 m²), a progressive increase in the proportion with the diagnosis of diabetes mellitus, 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.

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Table 1. Baseline Characteristics

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Table 2. Baseline Characteristics by CKD Grades

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 (OR) of 1.052 (95% CI: 1.006 - 1.100) was calculated for a TSH level > 5 µIU/L (Q2), after adjusting for systolic blood pressure, proteinuria and baseline eGFR (Table 3). Absolute hemoglobin A1c was not included due to not being an a priori objective.

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Table 3. Unadjusted Odds Ratio and Adjusted Multivariate Model for eGFR Slope

The overall median urine ACR was 10.2 mg/mmol (IQR: 0.24 - 1,414). When baseline urine ACR ratio was assessed in a multivariate generalized linear regression model, the TSH > 1.8 µIU/L (50th percentile) had an OR of 1.1.02 (95% CI: 1.01 - 1.23), after adjusting for diabetes mellitus history, systolic blood pressure and eGFR at baseline presentation (Table 4).

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Table 4. Unadjusted Odds Ratio and Multivariate Adjusted GLM Model for Urine Albumin/Creatinine Ratio

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 Rhee et al [7] and Lo et al [8] confirmed an increased prevalence of subclinical and clinical hypothyroidism in persons with CKD [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 OR 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 decreased 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 antidiuretic hormone (ADH) are noted in hypothyroidism, resulting in hyponatremia. Low thyroxine levels have been reported to decrease cardiac output and decrease 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 CKD. Further studies are needed to determine whether treatment of hypothyroidism reverses the progression of CKD and improves the albuminuria.

Acknowledgments

We acknowledge Alyssa Shaw for the data entry and work diligence.

Financial Disclosure

There was no formal funding.

Conflict of Interest

No conflict of interest to report.

Informed Consent

For a retrospective, database study, individual patient consent was not required.

Author Contributions

SI, CSB and KRZ were involved in the conceptualization of the project, study design, and critical review of manuscript. SI and DY were key players for acquisition of data, and analysis and interpretation. SI wrote the main manuscript, and prepared the tables. SI and DB critically reviewed the manuscript and completed the final approval.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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