J Clin Nephrol Ren Care

• Abstract
• Keywords
• Introduction
• Patients and Methods
• Statistical Analysis
• Results
• Discussion
• Conclusions
• Conflicts of Interest
• Table 1
• Table 2
• Table 3
• Table 4
• Table 5
• References

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Journal of Clinical Nephrology and Renal Care

¹Department of Internal Medicine, Al-Azhar University, Eygpt
²Department Clinical Pathology, Al-Azhar University, Eygpt
³Department Cardiology, Al-Azhar University, Eygpt

Abstract

Background and aim:The kidney is involved in the regulation of thyroid hormones metabolism. Numerous abnormalities of thyroid hormones in end-stage kidney disease (ESKD) have been described. The aim of our study was to estimate the prevalence of thyroid dysfunction and its relation to Echocardiologic abnormalities in patients with end stage kidney disease.

Material and method:60 patients with ESKD on regular hemodialysis were recruited for this study. All subjects were investigated with Transthoracic Echocardiography and laboratory tests to determine thyroid function, including: serum triiodothyronine (T3), free T3, serum thyroxine (T4), freeT4, thyroid-stimulating hormone (TSH). Results were compared with the same measurements in 20 normal control subjects.

Results:The prevalence of thyroid abnormalities (78.3%) and low T3 (70%). T3 and T4 were significantly low (68.6 ± 21.4 ng/dL, 5.1 ± 2.1 μg/dL) compared to control group (104.1 ± 20.2 ng/dL, 7.8 ± 2.0 μg/dL). The prevalence of Echocardiologic abnormalities (71.7%) and left ventricular hypertrophy (70%). There was significant low T3 in patients with Echocardiologic abnormalities. 90.7% in patients with Echocardiologic abnormalities and 90.5% of patients with left ventricular hypertrophy had thyroid abnormalities. T3 levels show negative correlations with LVMI, LVEDD, SWT and PWT and a positive correlation with LVEF. No significant correlations between FT3, FT4, TSH and Echocardiographic data can be observed detected.

Conclusion:Echocardiographic abnormalities were linked by thyroid abnormalities especially low T3. Screening for early detection of thyroid disorders is useful and important.

Keywords

Echocardiologic abnormalities, Thyroid abnormalities, ESKD

Introduction

The kidney plays an important role in the metabolism, degradation and excretion of several thyroid hormones. It is not surprising, therefore, that impairment in kidney function leads to disturbed thyroid physiology [1]. Chronic renal failure affects thyroid function in multiple way, including low circulating thyroid hormone concentration, altered peripheral hormone metabolism, disturbed binding to carrier proteins, possible reduction in tissue thyroid hormone content, and increase iodine store in thyroid glands. Both plasma triiodothyronine (T3) and thyroxin (T4) are reduced [2].

Thyroid function has been extensively evaluated in patients with chronic kidney disease, however the results are variable, primary hyperthyroidism is extremely rare, while the prevalence of hypothyroidism is increased in patients with chronic renal failure [3]. The prevalence of hypothyroidism was increased in persons with reduced glomerular filtration rate (GFR), ranging from 5.4% for persons with estimated GFR ≥ 90 mL/min/1.73 m² to more than 20% in persons with estimated GFR < 60 mL/min/1.73 m² [4]. In spite of a large number of previous investigations of thyroid function abnormalities in end stage kidney disease (ESKD) patients, the echocardiographic findings were not included in the analysis in most of these studies. Therefore, the aim of this study was to evaluate thyroid function abnormalities and its relation to echocardiographic abnormalities in ESKD patients.

Patients and Methods

Sixty clinically stable end stage kidney diseasepatients were enrolled in this cross sectional study. All patients were under regular hemodialysis at Al-Azhar University Hospital (Hussein Hospital) between October 2014 and Jun 2015 (4 hours session, thrice weekly), using polysulfone high flux dialyzer 1.6 m² surface area, with dialysate flow 500 ml/min and dialysate calcium concentration 1.25 mmol/l, using heparin as anticoagulant with tailored doses according to each case and bicarbonate based dialysate. The adequacy of dialysis was assessed using Kt/V formula. 20 normal individuals were used as control group.

Patients with the following criteria were excluded: patients younger than 18 year; patients with congestive heart failure, respiratory failure, and liver cirrhosis; patients who had a history of peritoneal dialysis or kidney transplantation prior to hemodialysis; patients who have been receiving thyroid hormone replacement or suppressive therapy due to overt thyroid disease; patients who have been receiving medications affecting thyroid hormone levels, such as amiodarone, glucocorticoids, and lithium; patients who have active malignancy.

Each patient underwent complete history and physical examination with special emphasis on age, gender, body mass index, primary renal disease, comorbidities, and medications. Measurement of thyroid hormones was performed. As heparin may interfere with competitive assays, blood was drawn just before the start of hemodialysis procedure from the inserted dialysis needle or from the arterial port of dialysis circuit, before contact of blood with dialyzer and before heparin administration. This ensured that there was an interval of at least 48 hours since the last heparin application. The battery of tests thus included: TSH determined by immune radiometric assay, reference range (RR) 0.17-4.05 μIU/mL; total T4, RIA RR 5.4-12.4 μg/dL; total T3, RIA, RR 78-182 ng/dL; freeT4 measured by RIA, RR 0.89-1.79 ng/dL; free T3, RIA, RR 1.6-3.77 pg/dL (IMMUNOTECH s.r.o. -Radiovo1-102 27, Prague-Czech Republic). Transthoracic Echocardiography was performed on a non-dialysis day, close to the time of discharge based on the imaging protocol recommended by American Society of Echocardiography [5]. All patients were informed about the content of the study and gave their written approvals before enrollment. All procedures were performed in accordance with the ethical standards of Al-Azhar University's committee on human experiments.

Statistical Analysis

Statistical analysis was performed using SPSS for Windows, version 20.0 (SPSS, Inc.). Values were expressed as mean ± Standard deviation (SD) and as percentage for categorical parameters. Independent t-test was applied for comparison between two independent groups with parametrical data. Chi-square test was applied for estimating the occurrence of categorical variables. Pearson's correlation coefficient was used to test the correlation between thyroid function tests and echocardiographic parameters. P-values < 0.05 were considered statistically significant.

Results

Characteristics of the 80 participants are summarized in the table 1, table 2 and table 3. The major etiology of ESKD is hypertension (31.7%) and the major comorbid disease is diabetes mellitus (30%). T3 and T4 levels are significantly low (68.6 ± 21.4 ng/dL, 5.1 ± 2.1 μg/dL) as compared to control (104.1 ± 20.2 ng/dL, 7.8 ± 2.0 μg/dL). No significant differences are detected as regards TSH, FT3, and FT4 levels. The left ventricular mass index (LVMI), septal wall thickness (SWT), posterior wall thickness (PWT) and left atrium diameter (LAD) are significantly high as compared to control. On the other hand, the left ventricular ejection fraction (LVEF) is significantly low (Table 2). Out of 60 patients, 43 patients (71.7%) haveechocardiographic abnormalities, 42 of them (70%) haveleft ventricular hypertrophy, 13 patients (21.7%) haveleft ventricular dilatation, 25 patients (41.7%) havesystolic dysfunction, 33 patients (55%) haveleft atrial dilatation and 19 patients (31.7%) haveaortic annulus dilatation. As regards thyroid functions, 78.3% of the patients have thyroid function abnormalities, 70% have low total T3, 60% have low T4 and 20% have elevated TSH (Table 1). Significant numbers of patients with echocardiographic abnormalities (39 out of 43) have thyroid function abnormalities (90.7%) with a P-value < 0.005. thirty eight out of forty two of patients with left ventricular hypertrophy (90.5%) have thyroid function abnormalities (P < 0.005), 30 out of 33 patients with left atrial dilatation (90.9%) have thyroid function abnormalities (P < 0.05) (Table 3). The patients with echocardiographic abnormalities have a significantly low T3 as compared to patients with normal echocardiographic studies (Table 4). T3 levels show negative correlations with LVMI, LVEDD, SWT and PWT and a positive correlation with LVEF. Moreover, T4 levels have a positive correlation with LVEF. No significant correlations between FT3, FT4, TSH and Echocardiographic data can be observed detected (Table 5).

Discussion

Most studies of thyroid hormones in clinically euthyroid patients with varying degrees of chronic renal failure showed significant decrease in total T3, total T4 and free T3 (FT3) levels compared with control [6,7]. A low T3 and T4 syndrome is evident when glomerular filtration rate (GFR) is reduced below 30 ± 16 ml/min [7]. Usually there is more distinct suppression of T3 than of T4 [8]. The concentrations of reverse T3 (rT3), the inactive metabolite of T4 in plasma are usually low but normal or even elevated values have been reported by some authors [8,9]. Similar to findings of this study, the previous studies have demonstrated that the most common thyroid imbalance in patients on hemodialysis was low T3 syndrome, while FT3 levels generally remain within the normal limits [6,10]. Ozen, et al. [11] demonstrated that up to 70% of stage 5 CKD patients have low T3. Soffer, et al. found that low serum levels of thyroxine in 69.5% of the patients studied and of triiodothyronine (T3) in 46.5% and 13.0% had high levels of TSH [12].

The reduction in thyroid hormone may be due to the effect of chronic renal failure on the thyroid hormones which include altered peripheral metabolism like impairment of peripheral deiodination of T4 which is the mainsource of T3. Due to reduced deiodinase activity, tissue and circulating levels of the active form of the thyroid hormone and T3are low in kidney failure [13]. Toxic uremic solute such as urea, creatinine, indoles and phenols inhibits protein binding of T4 [8]. Furthermore, systemic inflammation [14,15] and metabolic acidosis [14] may alter thyroid function in CKD patients.The concentration of serum iodine in patients with CKD is higher due to lower iodine clearance caused by reduced glomerular filtration. Elevated levels of serum inorganic iodine in patients with CKD may potentially block thyroid hormone synthesis (Wolff–Chaikoff effect) [16]. In contrast, the thyroid-pituitary feedback loop seems to remain intact, because steady-stateplasma TSH remains substantially normal [3]. The Reduced renal clearance may contribute to delayed recovery, since TSH and TRH are normally cleared by the kidney [17]. Low T3 associated with endothelial dysfunction, a harbinger of atherosclerosis, in stage 3 and 4 CKD patients [10], as well as cardiomyopathy [18] and with high risk of death in stage 5 CKD patients [19]. The cardiovascular mortality in these individuals is 10- to 20-fold more frequent than in the general population [20]. Although more than 50% of the individuals starting a dialysis program present some type of pre-existent cardiovascular disease, the traditional risk factors for cardiovascular disease do not completely explain this excess risk, which seems to be influenced by the so-called non-traditional risk factors associated with CKD. This set of factors accelerates the course of coronary artery disease (CAD) and is associated with a higher prevalence of ventricular hypertrophy, myocardial fibrosis, valvulopathies, arrhythmias and sudden death [21].

The cardiomiopathy of the patient undergoing dialysis is mainly due to the presence of ischemic cardiopathy and morphofunctional alterations of the left ventricle (LV) in response to pressure and volume overload. The physiopathology of the transformations induced by uremia in the left ventricular chamber is complex and multifactorial [22]. Arteriovenous fistula, which was used for vascular access in patients with ESRD, increases stroke volume load on the left ventricle and this may contributes to LVH and may results in LV systolic and diastolic dysfunction with time [23]. The left ventricular dysfunction and hypertrophy were most common echocardiographic findings and statistically correlated with anemia and presence of hypertension [24,25].

In current study, significant numbers of patients have echocardiologic abnormalities (71.7% of patients), majority of these patients have left ventricular hypertrophy (70%), 55% have left atrial dilatation and 41.7% have systolic dysfunction. Similar findings have been demonstrated by Foley, et al. [26] they reported that abnormalities of left ventricular structure and functions were very frequent on baseline echocardiography: 73.9% had left ventricular hypertrophy, 35.5% had left ventricular dilatation and 14.8% had systolic dysfunction in ESRD patients. Singh, et al. [27] reported that LVH in 76.92%, diastolic dysfunction in 72% but did not find systolic dysfunction in CKD patients. Zoccali, et al. [28] found 77% of patients had LVH and 22% had systolic dysfunction by in haemodialysis patients. Agarwal, et al. [29] had observed diastolic dysfunction in 60% and systolic dysfunction in 15% of patients. In addition, Laddha, et al. found that in hypertensive patients with ESRD LVH was present in 87.5%, diastolic dysfunction was present in 72.9% as measured by abnormal E/A ratio, systolic dysfunction as measured by reduced LVEF was present in 29.2% and pericardial effusion observed in 14.6%. In normotensive patient with ESRD LVH was present in 45.5%, diastolic dysfunction was present in 40.9%, and systolic dysfunction was present in 13.6% and pericardial effusion observed in 13.6% patients [25].

Left ventricular dysfunction and LVH are considered a maladaptive response to hypertension, volume overload, anaemia, hyperphosphataemia, inflammation and other risk factors [30]. It is important to recognize that part of the alteration in the geometry of LV in CKD patients can be related to the moment at which the echocardiogram was performed. Shortly after the dialysis session, it is common to see a reduction in diastolic diameter of the LV and an increase in the thickness of the LV wall as a pure consequence of volume depletion by ultrafiltration. While, examination shortly before beginning the session can shows LV dilatation that will be ‘converted' into concentric at the end of the session. Such fluctuation could be minimized by performing the echocardiogram during the interdialytic period [31].

Thyroid diseases can result in a wide range of cardiovascular manifestations and complications like atrial fibrillation, cardiomyopathy, and congestive heart failure. It is well known that T3 increases cardiac output by affecting tissue oxygen consumption, vascular resistance, blood volume, cardiac contractility, and heart rate [32]. Therefore, low T3, even in the normal range, has been suggested to be associated with various cardiovascular diseases in ESRD patients, which has been clarified by several previous studies [9,16,33,34]. Independently from the presence of primary thyroid hypofunction and differently from other organs, the heart is particularly vulnerable to reductions in biologically active T3 in plasma because cardiomyocytes have a negligible capability to generate T3 from locally converted precursor T4. Consequently, when circulating T3 is low, the myocardium may become relatively hypothyroid [35].

The large numbers of previous investigations were on the prognostic value of low T3 for all-cause and cardiovascular (CV) mortality in ESRD patients and echocardiographic findings were not included in the analysis in most of these studies. In this study, we have found majority of patients who have echocardiographic abnormalities (90.7%) have thyroid function abnormalities. The thyroid abnormalities are frequent among patients with left ventricular hypertrophy (90.5%). Moreover, in concordance with our observations previous studies [8,35-38] have been demonstrated that LV systolic function was depressed and LVMI was increased in the presence of low T3. Correction of malnutrition, anemia, acidosis, and thyroid hormone has associated with improvement of LVMI, LVEF [39,40]. Therapeutic use of thyroid hormone has not been adequately studied [41]. Finally, the small number of patients was the first limitation in this study. Diastolic dysfunctions are a frequent finding among ESKD patients who have thyroid abnormalities and must be included for better assessment.

Conclusions

The majority ofhemodialysis patients have echocardiographic abnormalities. The left ventricular hypertrophy and left atrial dilatation were the most common abnormalities. Echocardiographic abnormalities were linked by thyroid abnormalities especially low T3. Screening for early detection of thyroid disorders is useful and important. This is just a preliminary report regarding thyroid dysfunction and its cardiovascular complications and future studies with a larger sample size may be considered.

Conflict of Interest

There is no conflict of interest.

References

1. Levy J, Morgan J, Brown E (2004) Oxford Hand book of Dialysis. (2nd edn), Oxford University press.
   


2. De Rossi S, Cohen D (2008) Renal disease. In: Greenberg MS, Glick M, ship JA, Burket's oral Medicine. (11th edn), Hamilton, BC Decker, 363-383.
   


3. Gomez-Pan A, Alvarez-Ude F, Yeo PP, Hall R, Evered DC, et al. (1996) Function of the hypothalamo-hypophysial-thyroid axis in chronic renal failure. Clin Endocrinol 2: 567-574.
   


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


5. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, et al. (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28: 1-39.
   


6. Kayima JK, Otieno LS, Gitau W, Mwai S (1992) Thyroid hormone profiles in patients with chronic renal failure on conservative management and regular hemodialysis. East African Medical Journal 69: 333-336.
   


7. Rakesh Kumar, Singh MP, Mehdi MD (2015) Hospital Based Study On Thyroid Function In Patients With Chronic Kidney Disease In Kosi Region Of Bihar. International Journal of Recent Scientific Research 6: 3412- 3415.
   


8. Zoccali C, Tripepi G, Cutrupi S, Pizzini P, Mallamaci F (2005) Low triiodothyronine: a new facet of inflammation in end-stage renal disease. J Am Soc Nephrol 6: 2789-2795.
   


9. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P(2006) Low triiodothyronine and survival in end-stage renal disease. Kidney International 70: 523-528.
   


10. Kosowicz J, Malczewska B, and Czekaleski S (1980) Serum reverse triiodothyronine (3, 3, 5-L-triiodothyronin) in chronic renal failure. Nephron 26: 85-90.
    


11. Ozen KP, Asci G, Gungor O, Carrero JJ, Kircelli F, et al. (2011) Nutritional state alters the association between free triiodothyronine levels and mortality in hemodialysis patients. Am J Nephrol 33: 305-312.
    


12. Soffer O, Pelet D, Segal S, Bar-Khayim Y (1979) Thyroid function in hemodialysis. Isr J Med Sci 15: 836-839.
    


13. Kaptein EM (1996) Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocrine Rev 17: 45-63.
    


14. Wiederkehr MR, Kalogiros J, Krapf R (2004) Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients. Nephrol Dial Transplant 19: 1190-1197.
    


15. Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, et al. (2007) Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 262: 690-701.
    


16. Brough R, Jones C (2006) Iatrogenic iodine as a cause of hypothyroidism in infants with end-stage renal failure. Pediatric Nephrology 21: 400-402.
    


17. Biff F Palmer (2002) Metabolic Disturbances in Chronic Renal Failure. Saudi J Kidney Dis Transplant 13: 273-280.
    


18. Song SH, Kwak IS, Lee DW, Kang YH, Seong EY, et al. (2009) The prevalence of low triiodothyronine according to the stage of chronic kidney disease in subjects with a normal thyroid stimulating hormone. Nephrol Dial Transplant 24: 1534-1538.
    


19. Pagliacci MC, Pelicci G, Grignani F, Giammartino C, Fedeli L, et al. (1987) Thyroid function tests in patients undergoing maintenance dialysis: characterization of the “low T4 syndrome” in subject on regular hemodialysis and continuouse ambulatory peritoneal dialysis. Nephron 46: 225-230.
    


20. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, et al. (1996) The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease. Am J Kidney Dis 28: 53-61.
    


21. McCullough PA (2004) Cardiovascular disease in chronic kidney disease from a cardiologist's perspective. Curr Opin Nephrol Hypertens 13: 591-600.
    


22. Parfrey PS, Foley RN (1999) The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 10: 1606-1615.
    


23. Sood MM, Pauly RP, Rigatto C, Komenda P (2008) Left ventricular dysfunction in the haemodialysis population. NDT Plus 4: 199-205.
    


24. Shivendra S, Doley PK, Pragya P, Sivasankar M, Singh VP, et al. (2014) Echocardiographic Changes in Patients with ESRD on Maintenance Hemodialysis-A Single Centre Study. J Cardiovasc Dis Diagn 2: 165.
    


25. Laddha M, Sachdeva V, Diggikar PM, Satpathy PK, Kakrani AL (2014) Echocardiographic assessment of cardaic dysfunction in patients of end-stage renal disease on haemodialysis. Journal of the Association of Physicians of India 62: 28-33.
    


26. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, et al. (1995) Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 47: 186-192.
    


27. Singh NP, Chandrashekar MN, Nair M, Anuradha S, Kohli R, et al. (2000) The cardiovascular and hemodynamic effects of erythropoietin in CRF. JAPI 48: 301-306.
    


28. Zoccali C, Benedetto F, Mallamaci F, Tripepi G, Fermo I, et al. (2000) Inflammation is associated with carotid atherosclerosis in dialysis patients. Creed Investigators. Cardiovascular Risk Extended Evaluation in Dialysis Patients. Journal of Hypertension 18: 1207-1213.
    


29. Agarwal S, Dangri P, OP Kalra OP, S Rajpal (2003) Echocardiographic assessment of cardiac dysfunction in patients of chronic renal failure. JIACM 4: 296-303.
    


30. Zoccali C, Mallamaci F, Tripepi G (2003) Traditional and emerging cardiovascular risk factors in end-stage renal disease. Kidney Int Suppl 85: S105-S110.
    


31. Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray D, et al. (1996) Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int 49: 1428-1434.
    


32. Klein I, Danzi S (2007) Thyroid disease and the heart. Circulation 116: 1725-1735.
    


33. Tatar E, Kircelli F, Asci G, Carrero JJ, Gungor O, et al. (2011) Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients. Clin J Am Soc Nephrol 6: 2240-2246.
    


34. Tatar E, Sezis Demirci M, Kircelli F, Gungor O, Yaprak M, et al. (2012) The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. Int Urol Nephrol 44: 601-606.
    


35. Rohit R Arora (2012) Addressing Cardiovascular Risks in Thyroid Disorders. Physicans Weekly 6th Sep.
    


36. Ali L, Mohy U, Ahmed I, Rehan Riaz (2015) Thyroid disorders; and cardiovascular risks. Professional Med J 22: 1289-1297.
    


37. Koo HM, Kim CH, Doh FM, Lee MJ, Kim EJ, et al. (2013) The impact of low triiodothyronine levels on mortality is mediated by malnutrition and cardiac dysfunction in incident hemodialysis patients. Eur J Endocrinol 169: 409-419.
    


38. Meuwese CL, Dekker FW, Lindholm B, Qureshi AR, Heimburger O, et al. (2012) Baseline levels and trimestral variation of triiodothyronine and thyroxine and their association with mortality in maintenance hemodialysis patients. Clin J Am Soc Nephrol 7: 131-138.
    


39. Covic A, Mardare NG, Ardeleanu S, Prisada O, Gusbeth-Tatomir P, et al. (2006) Serial echocardiographic changes in patients on hemodialysis: an evaluation of guideline implementation. J Nephrol 19: 783-793.
    


40. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, et al. (2000) Serial change in echocardiographic parameters and cardiac failure in end-stage renal disease. Journal of the American Society of Nephrology 11: 912-916.
    


41. Gerdes AM, Iervasi G (2010) Thyroid Replacement Therapy and Heart Failure. Circulation 122: 385-393.