Hormone-binding proteins and their associated hormones in patients with nephrotic syndrome

Abstract

AimIn the current study, we aimed to evaluate SHBG and TBG levels and their related hormone levels in patients with nephrotic syndrome and the control group.MethodsThe current study was conducted at Istanbul University Cerrahpaşa Faculty of Medicine, Department of Internal Medicine, with a total of 33 patients and 11 healthy controls. The study groups were divided into 3 groups: normal serum creatine level, high serum creatine level and control group. SHBG, TBG, T3, T4, fT3, fT4, TSH, testosterone, free testosterone, prolactin, FSH, and LH levels were determined in all groups. Proteinuria, hypoalbuminemia, and hyperlipidemia were present in the patient groups.ResultsThe mean age was 31.0 ± 11.0 years (Group 1), and 46 ± 15 years (Group 2) in patients with nephrotic syndrome. In the control group, the mean age was 29.0 ± 7.0 years. TBG, T3, T4, fT3, fT4 and TSH levels were found to be lower in the patient groups than in the control group. No statistically significant correlation was detected between SHBG and TGB and albumin, globulin and proteinuria, which are indicators of nephrotic syndrome.ConclusionNephrotic syndrome has important effects on the metabolism and regulation of protein or protein-protein-bound hormones and prohormones. This study indicates that individuals with nephrotic syndrome experience notable changes in SHBG, TBG, and related hormones. It can be said that this situation occurs as a result of the loss of both hormones and the proteins that bind these hormones from the kidneys.

Keywords

Introduction

Nephrotic syndrome is a kidney disorder characterized by a group of symptoms that result from damage to the small blood vessels in the kidneys.¹ The primary components of nephrotic syndrome include proteinuria, hypoalbuminemia, edema and hyperlipidemia.² The causes of nephrotic syndrome can vary, and it can be primary (idiopathic) or secondary to other underlying conditions.³ Common primary causes include minimal change disease, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy.⁴ Symptoms of nephrotic syndrome may include swelling, especially in the legs and around the eyes, fatigue, foamy urine (due to excess protein), and susceptibility to infections.⁵ Oxidative stress (OS) results from a disparity between the generation and buildup of reactive oxygen species (ROS) within cells and tissues, and the capacity of a biological system to effectively eliminate these reactive byproducts.^6-7 OS plays an important role in the pathophysiology of various diseases, including nephrotic syndrome.^8-14 Management of OS in nephrotic syndrome may involve strategies to enhance antioxidant defenses. This can include dietary measures (such as increasing intake of antioxidant-rich foods), supplementation with antioxidants, and addressing underlying causes of oxidative stress, such as inflammation.
Diagnosis involves a combination of clinical evaluation, laboratory tests (such as urine and blood tests), and sometimes a kidney biopsy to determine the underlying cause and guide treatment.¹⁵ Treatment aims to manage the underlying cause, control symptoms, and prevent complications. Medications such as corticosteroids, immunosuppressants, and diuretics may be prescribed, depending on the specific cause of nephrotic syndrome. It’s essential for individuals with nephrotic syndrome to receive ongoing medical care and monitoring to manage the condition effectively. Sex hormone binding globulin (SHBG) is a beta globulin that binds testosterone with a uniquely high affinity and limited capacity.¹⁶ SHBG is produced in the liver and, together with albumin, binds 97-99% of circulating testosterone. The primary function of SGBH is to regulate serum-free testosterone concentration. SHBG has the task of adjusting the blood level of free hormone against the fluctuating release of sex hormones.¹⁷ The transport system of thyroid hormones in humans is carried out through a group of serum transport proteins that show different concentrations, thyroid hormone activity and distribution rates.¹⁸ Thyroxin-binding globulin (TBG) is an unstable molecule with a molecular weight of 54 kilodaltons and is a member of the serine protease inhibitor family.¹⁹ TBG is a minor component of alpha globulins and accounts for 70% of T3 and T4 in human sera. In this study, we aimed to evaluate SHBG and TBG levels and their related hormone levels in patients with nephrotic syndrome and the control group.

Materials and Methods

In this study, serum SHBG and TBG-related hormone levels were compared in 33 patients with nephrotic syndrome and 11 healthy individuals who were followed up in the Department of Internal Medicine of Istanbul University Cerrahpasa Faculty of Medicine Hospital between 1999-2001. In the present study, the patient group was divided into two groups. The first group consisted of 20 patients whose ages ranged from 18 to 58 years and whose serum creatinine levels were within normal limits. The second group consisted of 13 patients whose ages ranged from 22 to 72 years and whose serum creatinine levels were high. The control group consisted of 11 healthy individuals aged between 22-48 years. Proteinuria, hypoalbuminemia, and hyperlipidemia were present in the patient groups. Serum SHBG, TBG, T3, T4, fT3, fT4 TSH, testosterone, free testosterone, prolactin, FSH, LH and E2 levels were measured in the patient groups and the control group. The data obtained as a result of the study was analyzed using the SPSS program.Ethical ApprovalThe study was conducted in accordance with ethical rules.Statistical AnalysisThe statistical analysis of the obtained data was analyzed using the SPSS program. P < .05 was considered statistically significant. Parameters in the study groups were expressed as mean and standard deviation. Mann-Whitney U test was used to compare study groups. ANOVA (Dunnet multiple comparison test) was used to compare the study group and control groups. The correlation between the parameters was checked with the Spearman correlation test. Multiple regression analysis was used to investigate the effects of albumin, globulin, proteinuria and creatinine on the changes in SHBG and TGB.

Results

The mean age was 31.0 ± 11.0 years (Group 1), and 46 ± 15 years (Group 2) in patients with nephrotic syndrome. In the control group, the mean age was 29.0 ± 7.0 years. The values of the parameters examined in the patient and control groups are shown in Table 1. TBG, T3, T4, fT3, fT4 and TSH levels were found to be lower in the patient groups than in the control group (Table 1). A notable statistical difference exists between Group 1 and the control group in terms of T. Protein, Albumin and T3 (P < .001). A statistically significant difference was detected in terms of T.Protein, Albumin, T3, fT3 and fT4 parameters in Group 2 and the control group. (P < .05). In addition, no statistically significant difference was detected between Group 2 and the control group in terms of FSH and LH, E2, prolactin and TBG parameters (P > .05) (Table 2). No statistically significant correlation was detected between SHBG and TGB and albumin, globulin and proteinuria, which are indicators of nephrotic syndrome. On the other hand, a significant correlation was detected between T4 and testosterone and albumin (P = .003, P = .049). In addition, a significant correlation was detected between prolactin and FSH and proteinuria. (P = .001, P = .049). A significant correlation was detected between T4 and TBG (P < .05). (Table 3).

Discussion

It is known that the main pathology in nephrotic syndrome is proteinuria , which results from the change in the permeability of the glomerular basement membrane. Almost all of the other components and metabolic complications of nephrotic syndrome develop due to urinary protein loss. Nephrotic syndrome has important effects on the metabolism and regulation of protein or protein-protein-bound hormones and prohormones. Although the loss of thyroxine-binding globulin in the urine and the resulting changes in thyroid functions in nephrotic syndrome are well known, there is no consensus on the changes in SHBG and other sex hormones and their mechanisms. There are many studies showing a decrease in the levels of serum TBG and related hormones in nephrotic syndrome, as well as a loss of TBG and related hormones in the urine.
In the study conducted by Ito et al.²⁰ in children with nephrotic syndrome who were untreated and had normal creatinine levels, they investigated TBG, T3, and T4 levels before treatment and in the remission period and found massive urinary TBG, T3, and T4 levels in the pre-treatment period compared to the remission period. They showed that there was a loss of fT3 and fT4. In addition, it has been determined that there is a positive correlation between urinary TBG excretion and proteinuria, and serum TBG levels have a negative correlation with urinary protein loss.
Serum TSH concentration was found to be statistically significantly higher in untreated patients than in those in the remission period of the same patients (P < .05).
In their study to examine urinary TSH concentrations in renal disease, primary hypothyroidism and normal groups, Yoshida et al.²¹ reported increased TSH excretion in the urine of patients with nephrotic syndrome. In addition, they found that urinary TSH excretion showed a significant correlation with both urinary protein excretion and β2-microglobulin excretion.
In another study, Capri et al.²² examined the changes in serum total and free thyroid hormones and TSH concentrations in patients with chronic nephrotic syndrome after intake of a low-protein diet.
Serum total T4 and total T3 concentrations increased significantly after diet treatment, while no significant changes were observed in mean serum fT4 and fT3 concentrations after diet. Based on these results, it is thought that the main mechanism here is the reduction in daily protein excretion in urine by giving a low-protein diet in nephrotic syndrome. In our study, similar results were obtained with the above studies, and lower TBG, T3, T4, Ft3, Ft4 and TSH levels were detected in the patient group compared to the control group.
In the literature, in a study conducted on boys with chronic renal failure at puberty,²³ serum SHBG and bound testosterone levels were investigated, and serum SHBG levels were found to be significantly higher than in control children of the same age (P < .005). They concluded that no significant change was detected in total testosterone level. Based on the results obtained, it is claimed that the reason for the pubertal delay in renal failure is due to changes in the testosterone fraction.
Maynar M et al.²⁴ in their study examining the urinary excretion of androgen hormones in professional athletes, they compared the levels of testosterone, epitestosterone, androsterone, 11-hydroxyandrosterone and SHBG after training and competition, and reported that while there was a decrease in the urinary concentrations of androgen hormones during training, they increased during the competition. These changes indicate that physical activity has an effect on the elimination of androgen hormones and the synthesis of their carrier protein, SHBG. Changes in SHBG excretion may occur even without renal pathology.
Shing et al’s study of 100 patients with idiopathic nephrotic syndrome reported that hypothyroidism is common in patients with nephrotic syndrome, especially in the SRNS subgroup. Therefore, they concluded that routine screening should be performed in patients with steroid-resistant nephrotic syndrome.²⁵

Conclusion

In conclusion, individuals with nephrotic syndrome experience substantial alterations in serum SHBG, TBG, and the associated hormones. Based on scientific research, the probable explanation for this phenomenon is the renal loss of both hormones and hormone-binding proteins.

Declarations

References

1. Politano SA, Colbert GB, Hamiduzzaman N. Nephrotic syndrome. Prim Care. 2020;47(4):597-613. doi:10.1016/j.pop.2020.08.002
   Article · PubMed · Google Scholar
2. Wang CS, Greenbaum LA. Nephrotic syndrome. Pediatr Clin North Am. 2019;66(1):73-85. doi:10.1016/j.pcl.2018.08.006
   Article · PubMed · Google Scholar
3. Campbell RE, Thurman JM. The immune system and idiopathic nephrotic syndrome. Clin J Am Soc Nephrol. 2022;17(12):1823-1834. doi:10.2215/cjn.07180622
   Article · PubMed · Google Scholar
4. Lamba P, Nam KH, Contractor J, Kim A. Nephritic syndrome. Prim Care. 2020;47(4):615-629. doi:10.1016/j.pop.2020.08.003
   Article · PubMed · Google Scholar
5. Zabala Ramirez MJ, Stein EJ, Jain K. Nephrotic syndrome for the internist. Med Clin North Am. 2023;107(4):727-737. doi:10.1016/j.mcna.2023.03.006
   Article · PubMed · Google Scholar
6. Erdal H, Demirtas MS, Kılıcbay F, Tunc G. Evaluation of oxidative stress levels and dynamic thiol-disulfide balance in patients with retinopathy of prematurity. Curr Eye Res. 2023;48(11):1026-1033. doi:10.1080/02713683.2023.2185569
   Article · PubMed · Google Scholar
7. Erdal H, Turgut F. Thiol/disulfide homeostasis as a new oxidative stress marker in patients with Fabry disease. J Investig Med. 2023;71(8):865-870. doi:10.1177/10815589231191966
   Article · PubMed · Google Scholar
8. Genc SO, Erdal H. Effect of mode of delivery on neonatal oxidative stress and dynamic thiol-disulfide homeostasis. J Int Med Res. 2023;51(10):3000605231202145. doi:10.1177/03000605231202145
   Article · PubMed · Google Scholar
9. Erdal H, Bekmezci M. Evaluation of dynamic thiol/disulfide homeostasis and ischemia-modified albumin levels in cord blood of newborns to patients with oxytocin-induced labor. Aksaray Univ J Sport Health Res. 2022;3:193-202.
   PubMed · Google Scholar
10. Gezici Güneş Ü, Turgut F, Erdal H, Dogan Serdar. Plasma apelin levels and thiol/disulfide balance in patients with type 2 diabetes mellitus. Turk J Nephrol. 2023;32:203-208.
    PubMed · Google Scholar
11. Erdal H, Demirtas MS, Tuncer SC, Ozcan O. Thiol/disulfide homeostasis as a new oxidative stress marker in patients with neonatal transient tachypnea. Ann Clin Anal Med. 2023;14(3):208-211. doi:10.4328/acam.21457
    Article · PubMed · Google Scholar
12. Demirtas MS, Erdal H. Evaluation of thiol-disulfide homeostasis and oxidative stress parameters in newborns receiving phototherapy. J Investig Med. 2023;71(3):183-190. doi:10.1177/10815589221140594
    Article · PubMed · Google Scholar
13. Demirtas MS, Kilicbay F, Erdal H, Tunc G. Oxidative stress levels and dynamic thiol-disulfide balance in preterm newborns with bronchopulmonary dysplasia. Lab Med. 2023;54(6):587-592. doi:10.1093/labmed/lmad010
    Article · PubMed · Google Scholar
14. Erdal H, Özcan O, Turgut F, et al. Evaluation of dynamic thiol-disulfide balance and ischemia-modified albumin levels in patients with chronic kidney disease. MKU Tip Derg. 2022;13:237-242. doi:10.17944/mkutfd.947113
    Article · PubMed · Google Scholar
15. Wang P, Yu ZH. Diagnosis and treatment of hereditary steroid-resistant nephrotic syndrome. Zhonghua Er Ke Za Zhi. 2019;57(8):646-649.
    PubMed · Google Scholar
16. Qu X, Donnelly R. Sex hormone-binding globulin as an early biomarker and therapeutic target in polycystic ovary syndrome. Int J Mol Sci. 2020;21(21):8191. doi:10.3390/ijms21218191
    Article · PubMed · Google Scholar
17. Simons PIHG, Valkenburg O, Stehouwer CDA, Brouwers MCGJ. Sex hormone-binding globulin: biomarker and hepatokine? Trends Endocrinol Metab. 2021;32(8):544-553. doi:10.1016/j.tem.2021.05.002
    Article · PubMed · Google Scholar
18. Salas-Lucia F, Bianco AC. T3 levels and thyroid hormone signaling. Front Endocrinol (Lausanne). 2022;13:1044691. doi:10.3389/fendo.2022.1044691
    Article · PubMed · Google Scholar
19. Rabah SA, Gowan IL, Pagnin M, Osman N, Richardson SJ. Thyroid hormone distributor proteins during development in vertebrates. Front Endocrinol (Lausanne). 2019;10:506. doi:10.3389/fendo.2019.00506
    Article · PubMed · Google Scholar
20. Ito S, Kano K, Ando T, Ichimura T. Thyroid function in children with nephrotic syndrome. Pediatr Nephrol. 1994;8(4):412-415. doi:10.1007/bf00856516
    Article · PubMed · Google Scholar
21. Yoshida K, Sakurada T, Kaise K, et al. Measurement of thyroid stimulating hormone in human urine. Endocrinol Jpn. 1988;35(5):733-739. doi:10.1507/endocrj1954.35.733
    Article · PubMed · Google Scholar
22. Carpi A, Romano F, Massitelli M, Ciardella F. Low protein supplemented diet corrects altered serum thyroid hormone and TSH concentrations in patients with chronic nephrotic syndrome. Thyroidology. 1990;2(2):89-92.
    PubMed · Google Scholar
23. Belgorosky A, Ferraris JR, Ramirez JA, Jasper H, Rivarola MA. Serum sex hormone-binding globulin and serum nonsex hormone-binding globulin-bound testosterone fractions in prepubertal boys with chronic renal failure. J Clin Endocrinol Metab. 1991;73(1):107-110. doi:10.1210/jcem-73-1-107
    Article · PubMed · Google Scholar
24. Maynar M, Caballero MJ, Mena P, Rodríguez C, Cortés R, Maynar JI. Urine excretion of androgen hormones in professional racing cyclists. Eur J Appl Physiol Occup Physiol. 1994;68(3):200-204. doi:10.1007/bf00376767
    Article · PubMed · Google Scholar
25. Singh S, Mishra OP, Mandal PP, et al. Thyroid function in patients with idiopathic nephrotic syndrome. Int Urol Nephrol. 2021;53(9):1859-1864. doi:10.1007/s11255-020-02778-3
    Article · PubMed · Google Scholar

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