INTRODUCTION:

Hypothyroidism is the most common challenge of women in all age groups in India (1). The cases of hypothyroidism are usually diagnosed either independently or in combination with other medical and gynecological disorders (2). Primary hypothyroidism is typically characterized biochemically by raised serum TSH levels and lowered or undetectable free thyroxine (FT4) levels. An anterior pituitary hormone, TSH controls the thyroid gland to produce thyroid hormone. TSH, in turn, is controlled by a hypothalamic hormone, Thyrotropin-Releasing Hormone (TRH). Thyroid hormones have a wide range of functions affecting most of the tissues and organ systems in our body. With the further advent of our knowledge on hypothyroidism, it has been noticed that the renal function could be affected in such patients. The renal dysfunction may be due to complex mechanisms involving hemodynamic abnormalities of negative inotropic effect on the heart, reduced intravascular volume, and increased peripheral resistance with renal vasoconstriction (3). Thyroid hormones act on renal vasculature through growth factors like insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) improving renal blood flow. IGF-1 increases creatinine clearance in humans, which becomes deficient in hypothyroidism resulting in reduced clearance (4-6). VEGF relaxes the renal blood vessels mediated by endothelial nitric oxide synthase (7,8). In a study, higher levels of serum creatinine were observed before two weeks of hypothyroidism and got normalized after thyroid hormone replacement therapy (THRT) was started as early as possible (9). An inverse correlation had been shown between eGFR and TSH concentration in previous studies (10,11). The action of thyroid hormone is related to renin-angiotensin-aldosterone system (RAAS), levels of antidiuretic hormone (ADH) and plasma creatinine which is not dependent on renal function (12-15). In congenital hypothyroidism, there is increased occurrence of structural abnormalities of renal system like renal agenesis, dysplastic kidney, ectopic kidney, posterior urethral valves and also reduced renal mass (16). THRT reversed the structural abnormalities of decreased renal size and weight, decreased renal tubule length and diameter and reduced glomerular volume in hypothyroid neonatal rats (17-19). A strong correlation had been established between chronic kidney disease (CKD) and subclinical hypothyroidism in previous studies (20,21). Thyroid dysfunction had even been proved to cause renal failure (22).

As thyroid hormone plays a crucial role in renal function and GFR, it has to be given more importance. Serum creatinine levels and clearance measurements should be routinely performed to detect the renal dysfunction in hypothyroidism and also to check for the improvement after THRT. Hypothyroidism remains a neglected aspect of health of Indian women, especially in the reproductive age group making them suffer from all the corollaries associated with it like infertility, obesity, diabetes, dyslipidemia, atherosclerosis, etc (23). So, this study was planned in a North Indian suburb setup, where women's health is socially at neglect. We did the study to find the renal status in uncontrolled hypothyroid women in the reproductive age group.

MATERIALS AND METHODS:

A cross-sectional study was conducted in 30 hypothyroid cases. All cases were selected according to the widely accepted criteria of primary hypothyroidism, ie, low to undetectable serum thyroxine and elevated serum TSH levels. Serum samples of 30 females between 18-45 yearswhose TSH was more than 5mIU/L received in our immunology lab, Subharti Medical College, Meerut were chosen after clearance from the Institutional ethical committee. The samples were then analyzed for creatinine level in VITROS250 (Ortho Clinical Diagnostics) and the eGFR was calculated concerning for their age by using a standard equation, MDRD formula online. The serum creatinine concentration was estimated and eGFR was calculated in 30 healthy controls of the same gender and age group. Known cases of renal disorders, muscle disorders, diabetes, hypertension, pregnancy, patients on drugs for the treatment of thyroid disorders and any other systemic illness affecting the renal function were excluded from the study. Results were made explicit as mean ± standard deviation (SD) and correlated by statistical analysis using the student’s t-test. The p-value < 0.05 was treated statistically significant.

RESULTS:

The mean TSH level in cases was 8.15±2.5mIU/L and in controls was 3.11±0.88mIU/L. The difference between them was highly significant (p-value < 0.0001) as serum samples with high TSH concentration were purposefully selected. The mean of serum creatinine concentration in the hypothyroid cases was 0.9±0.13mg/dl and in controls was 0.67±0.07mg/dl. The difference between both was found to be highly significant (p-value < 0.0001), although the creatinine concentration was within the normal range in both the groups of cases and controls. The mean of calculated GFR was 108.32±13.41 mL/min/1.73m² in controls whereas in cases, it was 77.19±13.36mL/min/1.73m². The difference between them was highly significant (p-value <0.0001), (table 1).

Table 1: showing TSH, serum creatinine levels, eGFR in cases and controls.

Parameters	Cases	Controls	p value
Total number	30	30
Age (years)	36.2 ± 5.45	33.4 ± 6	0.3
TSH (mIU/L)	8.15 ± 2.5	3.11 ± 0.88	<0.0001
Serum creatinine (mg/dl)	0.9 ± 0.13	0.67 ± 0.07	<0.0001
eGFR (mL/min/1.73m²)	77.19 ± 13.36	108.32±13.41	<0.0001

DISCUSSION:

Our study showed distinct changes in serum creatinine, eGFR implying renal dysfunction in hypothyroid patients as compared to healthy controls. There was a significant change in the serum levels of creatinine concentration in hypothyroid patients when compared to healthy controls. Our study supports previous studies on renal dysfunction in hypothyroidism. Gagandeep Kaur Sidhu et al found serum urea, creatinine, and uric acid concentration levels were significantly higher in the hypothyroid group when compared to the euthyroid group (24). Mamatha B.V. et al also showed significantly elevated serum creatinine concentration in subclinical hypothyroid cases as compared to controls (p-value <0.001), (25). Our study further supports the observations in previous studies of Khan AH et al (26) and Vaneet Kaur et al (27) which showed significantly higher serum creatinine levels in hypothyroid cases as compared to controls. Hypothyroidism induced an elevated serum creatinine level which normalizes with THRT (28). The cause of elevated serum creatinine concentration in hypothyroidism may be due to increased synthesis or decreased clearance by the renal system (29). The deficiency or absence of thyroid hormone causes a reduction in cardiac output and an increase in systemic and renal vasoconstriction which results in reduced renal blood and plasma flow leading to decreased GFR (30). IGF-1 increases renal blood flow, which is found to be decreased in hypothyroidism and normalized by THRT (31,32). Decreased GFR should be responsible for increased creatinine levels in hypothyroid cases. Hypothyroidism induced myopathy may also elevate creatinine levels in the blood (26). So, hypothyroidism should be included as one of the differential diagnosis in patients with renal dysfunction and increased muscle enzymes.

In our study, there was a significant decrease in eGFR in hypothyroid patients as compared to healthy controls. A strong association and a negative correlation had been shown between eGFR and TSH concentration in previous studies (13,14). Yuji Hataya et al showed that eGFR rose rapidly over the first 6 months after THRT in CKD patients. Their observations stated that the decreased eGFR in hypothyroidism was due to deficient thyroid hormone and the renal dysfunction due to hypothyroidism could be mostly improved by THRT(33). As most of the hypothyroid cases are not worked up for renal dysfunction, the changes in serum urea, creatinine levels, and clearance measurements after THRT are not appreciated to a greater extent. Decreased GFR may be due to the generalized hypodynamic circulation in hypothyroidism due to thyroid hormone deficiency (34). We estimated GFR by MDRD formula, where the GFR is adjusted to body surface area and it is more accurate than other means of GFR estimation like creatinine clearance measurement from 24-hour urine collection and the Cockcroft-Gault formula (35). Various mechanisms have been described for reduced GFR in hypothyroidism which includes reduced sensitivity to β-adrenergic stimulus and decreased renin release resulting in decreased angiotensin II and defective RAAS activity (14). This invariably reduces GFR in hypothyroidism (36). There is also a reduced glomerular surface area available for filtration of blood because of defects in renal parenchymal growth (19). Also, VEGF, IGF-1 deficiency, reduced cardiac output due to negative chronotropic and negative inotropic effect, increased peripheral vascular resistance and intrarenal vasoconstriction in reduced thyroid hormone availability play a major role in the change of GFR in hypothyroidism. Untreated hypothyroidism may lead to adverse clinical consequences of proteinuria, glomerulonephritis (GN) and renal failure. In autoimmune thyroiditis, reversible proteinuria and biopsy-proven GN were reported in association with hypothyroidism and hyperthyroidism in animals, as well as children and adults (37). Defective metabolism of thyroid hormone had been proved to play a crucial role in renal failure (22). So, monitoring of renal parameters in hypothyroidism before and after treatment is very much needed.

Lesser sample size, lack of IGF-1 levels, lack of observations in serum creatinine and eGFR after THRT in the study groups are the limitations in our study.

CONCLUSION:

The mean serum creatinine was on the higher side of the reference range and the mean calculated GFR was low in untreated or poorly treated hypothyroid females as compared to healthy controls in Meerut, Uttar Pradesh which implies that hypothyroidism is associated with renal dysfunction. The elevation in the serum creatinine concentration may be due to a decrease in the GFR. This hypothyroid-induced renal dysfunction may lead to further complications and morbidity. So, hypothyroid women are suggested for renal assessment in the form of serum creatinine measurement, eGFR calculation regularly as a precautionary measure. The use of MDRD formula calculation should be routinely employed as a part of a regular checkup of the hypothyroid patients. As the renal dysfunction in hypothyroidism is reversible by THRT, the knowledge about the association between serum creatinine, eGFR and hypothyroidism may prevent unnecessary further scrutiny in-terms of costlier investigations and treatment modalities.

REFERENCES:

1. Subasree S. Prevalence of Thyroid Disroders in India: An Overview. Research J. Pharm. and Tech. 2014;7(10):1165-8.

2. Menon A, Thenmozhi MS. Correlation between Thyroid Function and Obesity. Research J. Pharm. and Tech. 2016; 9(10):1568-70.

3. Anandkumar S, Jessly Chacko, Theertha C. K, M. Usha. Thyroid Disorder: An Overview. Res. J. Pharmacology and Pharmacodynamics.2020; 12(1):01-04.

4. Copeland KC, Nair KS. Recombinant human insulin-like growth factor-I increases forearm blood flow. J ClinEndocrinol Metab.1994;79(1):230–2.

5. Guler HP, Schmid C, Zapf J, Froesch ER. Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. ProcNatlAcadSci U S A. 1989;86(8):2868–72.

6. Guler HP, Eckardt KU, Zapf J, Bauer C, Froesch ER. Insulin-like growth factor I increase glomerular filtration rate and renal plasma flow in man. ActaEndocrinol (Copenh). 1989;121(1):101–6.

7. Klanke B, Simon M, Rockl W, Weich HA, Stolte H, Grone HJ. Effects of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) on haemodynamics and permselectivity of the isolated perfused rat kidney. Nephrol Dial Transplant.1998; 13:875–85.

8. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. ProcNatlAcadSci U S A.2001; 98(5):2604–9.

9. Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med.1999; 159(1):79–82.

10. Asvold BO, Bjøro T, Vatten LJ. Association of thyroid function with estimated glomerular filtration rate in a population-based study: the HUNT study. EurJ Endocrinol.2011;164(1):101-5.

11. Shin DH, Lee MJ, Lee HS, Oh HJ, Ko KI, Kim CH, et al. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism. Thyroid.2013; 23:654-661.

12. Vargas F, Moreno JM, Rodriguez-Gomez I, Wangensteen R, Osuna A, Alvarez-Guerra M, et al. Vascular and renal function in experimental thyroid disorders. Eur J Endocrinol.2006; 154(2): 197-212.

13. Park CW, Shin YS, Ahn SJ, Kim SY, Choi EJ, Chang YS, et al. Thyroxine treatment induces upregulation of renin-angiotensinaldosterone system due to decreasing effective plasma volume in patients with primary myxoedema. Nephrol Dial Transplant.2001;16(9):1799-806.

14. Karanikas G, Schütz M, Szabo M, Becherer A, Wiesner K, Dudczak R, et al. Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy. Am J Nephrol.2004; 24(1):41-5.

15. Nakahama H, Sakaguchi K, Horita Y, Sasaki O, Nakamura S, Inenaga T, et al. Treatment of severe hypothyroidism reduced serum creatinine levels in two chronic renal failure patients. Nephron.2001;88(3):264-7.

16. Kumar J, Gordillo R, Kaskel FJ, Druschel CM, Woroniecki RP. Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism. J Pediatr.2009;154(2): 263–266.

17. Bradley SE, Coelho JB, Sealey JE, Edwards KD, Stéphan F. Changes in glomerulotubulardimensions, single nephron glomerular filtration rates and the renin-angiotensin system inhypothyroid rats. Life Sci.1982;30(7-8): 633–639.

18. Canavan JP, Holt J, Easton J, Smith K, Goldspink DF. Thyroid-induced changes in the growth of the liver, kidney, and diaphragm of neonatal rats. J Cell Physiol.1994; 161(1): 49–54.

19. Slotkin TA, Seidler FJ, Kavlock RJ, Bartolome JV. Thyroid hormone differentially regulates cellular development in neonatal rat heart and kidney. Teratology.1992; 45(3): 303–312.

20. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am SocNephrol. 2008; 3(5):1296-300.

21. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int.2005; 67(3):1047-1052.

22. Kaptein EM. Thyroid function in renal failure. ContribNephrol.1986; 50:64-72.

23. Maheshwari P, Mohan R, Shanmugarajan TS. KAP Study on Thyroid Disorders (Hypothyroidism and Hyperthyroidism) in a Tertiary Care Hospital. Research J. Pharm. and Tech. 2017; 10(1): 41-3.

24. Gagandeep Kaur Sidhu, Rahima.R.Malek, Asha Khubchandani, Sohil.H.Mansuri, Miku.S.Pate, Ruhan.H.Oza. A Study of Serum Urea, Creatinine and Uric Acid Levels InHypothyroid Patients. Int J Res Med.2016; 5(2); 115-118.

25. Mamatha B.V, Rakshitha M.N, Kashinath R.T, Laya Rose Thomas. Evaluation of serum urea and creatinine levels in subclinical hypothyroidism – A case control study. Medica Innovatica.2016; 5(2):3-6.

26. Khan A H, Majumder I. Serum creatinine and uric acid levels of hypothyroid patients. Bangladesh J Med Biochem.2010; 3(2):61-63.

27. Vaneet Kaur, Kamaljit Singh and MinniVerma. Changes in biochemical markers of renal function in subclinical and overt hypothyroidism. International Journal of Bioassays. 2015;4(04):3799-3802.

28. ChristophSchmid, MichaelBrandle, Cornelia Zwimpfer, Ju¨rgen Zapf, and Peter Wiesli. Effect of Thyroxine Replacement on Creatinine, Insulin-Like Growth Factor 1, Acid-Labile Subunit, and VascularEndothelial Growth Factor. Clinical chemistry.2004; 50(1):228-231.

29. Mohammmed GF, Sultan SM, Sadullah YQ. The relationship between Creatinine and patients with Renal Failure associated with anemia. Research J. Pharm. and Tech. 2020; 13(4):1633-5.

30. Thokada SS, Kandregula H, Mugada VK. Prevalence of Sub-Clinical Hypothyroidism among Diabetes Mellitus Patients with Vascular Complications. Asian J. Res. Pharm. Sci. 2018; 8(4): 253-7.

31. Kapadia KB, Bhatt PA, Shah JS. Association between altered thyroid state and insulin resistance. J PharmacolPharmacother. 2012; 3(2):156-60.

32. Valcavi R, Dieguez C, Preece M, Taylor A, Portioli I, Scanlon MF. Effect of thyroxine replacement therapy on plasma insulin-like growth factor 1 levels and growth hormone responses to growth hormone releasing factor in hypothyroid patients. ClinEndocrinol (Oxf).1987; 27(1):85–90.

33. Yuji Hataya, Shuta Igarashi, Takafumi Yamashita, Yasato Komatsu. Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients. Clinical and Experimental Nephrology.2013; 17(4):525–531.

34. Ajaykumar N, Shanthi M, Parameshwari R. The Effect of L-Thyroxine on Metabolic Parameters in Newly Diagnosed Primary Hypothyroidism. International Journal of Pharmaceutical Science Invention.2013; 2(8):14-8.

35. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.

36. Asmah BJ, Wan Nazaimoon WM, Norazmi K, Tan TT, Khalid BA. Plasma renin and aldosterone in thyroid diseases. HormMetab Res.1997; 29(11):580-3.

37. Iglesias P, Díez JJ: Thyroid dysfunction and kidney disease. Eur J Endocrinol.2009; 160(4): 503–515.

Received on 19.05.2020 Revised on 17.06.2020

Asian J. Pharm. Tech. 2020; 10(4):241-244.

DOI: 10.5958/2231-5713.2020.00040.9