Alterations in Serum MicroRNA Profile During Hemodialysis - Potential Biological Implications.

BACKGROUND/AIMS: Hemodialysis implies significant alterations in the profile of serum components. microRNAs (miRNAs) are present in the human serum and are considered to target distant tissues where they can regulate gene expression, thus affecting homeostasis. Whether hemodialysis alters the profile of miRNAs in the serum is not known. METHODS: miRNA profiling in serum samples collected before and after hemodialysis was performed using miRNA qPCR arrays. The results were subsequently validated in an independent group of 10 hemodialyzed men. miRWalk database was used to identify mRNAs targeted by the miRNAs the levels of which changed after hemodialysis. The list of mRNAs was analyzed using the DAVID and PANTHER classification systems to identify pathways controlled by these miRNAs. RESULTS: miRNA profiling showed that the levels of the majority of circulating miRNAs were increased at least two-fold (115 out of 179 tested) while the levels of only five miRNAs were found at least two-fold lower after hemodialysis. Validation study confirmed the majority of the array results. Bioinformatics analysis of validated and significantly upregulated miRNAs revealed that gonadotropin-releasing hormone receptor, cell cycle and cell pluripotency-related pathways were targeted. CONCLUSION: Hemodialysis alters serum miRNA expression profile and this alteration may result in disruption of pathways contributing to subfertility and increased risk for cancer development being pathologies associated with hemodialysis.

Reproductive Health in Chronic Kidney Disease: The Implications of Sex and Gender.

Chronic kidney disease (CKD) is frequently accompanied by reproductive health challenges in females and males alike. Progression of CKD is associated with escalating impairment of the hypothalamic-pituitary-gonadal axis, which facilitates evolving ovarian, testicular, and sexual dysfunction. Common clinical reproductive health complications in CKD include abnormal menstruation, impaired sexual health, and reduced fertility. Though sex-specific factors, such as sex hormones and gonadal function, have a strong influence on reproductive health outcomes in CKD, a person's gender and gendered experience also have important implications. Institutionalized gender, gendered perceptions of health, and health care-seeking behaviors, as well as adherence to medical care, all have critical effects on reproductive health in CKD. This review endeavors to explore the implications of both sex and gender on overall reproductive health in individuals living with CKD.

Impact of Kidney Transplantation on Reproductive Hormone Levels in Males: A Longitudinal Study.

BACKGROUND/AIMS: Male patients with end-stage renal disease suffer from sexual disturbances and infertility. Disturbances in the hypothalamic-pituitary-gonadal axis are one of the causes of this. Decreased testosterone synthesis in Leydig cells of the testes and hyperprolactinemia are common. Kidney transplantation, unlike hemodialysis, normalizes these changes. However, how kidney transplantation affects Sertoli cell function is poorly understood. This study is aimed at investigating the changes in fertility-related hormones in men before, during, and after renal transplantation. METHODS: This longitudinal and prospective single center study enrolled 12 men undergoing living donor kidney transplantation. Plasma levels of creatinine, cystatin C, and serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, sex hormone-binding globulin, inhibin B, and anti-Müllerian hormone (AMH) were assayed at 10 different time points before, during, and after kidney transplantation. RESULTS: A rapid decrease in creatinine and cystatin C levels indicated successful renal transplantation. High pre-transplantation plasma levels of prolactin (mean 516 ± 306 mIE/L) and LH (9.4 ± 4.7 IU/L) were normalized after 7 days (248 ± 161 mIE/L and 6.1 ± 3.1 IU/L, respectively). Testosterone decreased rapidly during transplantation and increased again one week post-transplantation. Sertoli cell-derived hormone inhibin B decreased after transplantation, and there was a small non-significant trend of increased AMH after 12 months. CONCLUSION: Sertoli cell function, based on AMH and inhibin B levels, does not improve to the same extent or as fast as Leydig cell function after kidney transplantation, as determined by testosterone and LH levels.

MicroRNA-155 and Anti-Müllerian Hormone: New Potential Markers of Subfertility in Men with Chronic Kidney Disease.

BACKGROUND/AIMS: Men with terminal renal failure are often infertile. Anti-müllerian hormone (AMH), a marker of Sertoli cell function, is decreased among men with chronic kidney disease (CKD). Recently, a microRNA, miR-155, has been shown to be a potential marker for subfertility. We studied miR-155 and semen parameters in patients with CKD who were not yet on dialysis. We also aimed to study possible associations between AMH, miR-155, and semen parameters to evaluate them as markers of fertility. METHODS: Thirty male patients with CKD 1-4 as well as 18 healthy controls were enrolled. RESULTS: Serum levels of miR-155 were significantly higher among men with CKD stages 1-2 (4.51 ± 3.81 [p = 0.01]) and stages 3-4 (2.75 ± 1.77 [p = 0.006]) than in controls (1.09 ± 0.44). Sperm concentration was significantly lower among men with CKD 3-4 (42 ± 29) ×106/mL compared to controls (88 ± 42) ×106/mL (p = 0.011). High levels of miR-155 were associated with a relatively low sperm concentration (p = 0.02) and with a low total sperm number (p = 0.005). Low AMH levels were associated with a decreased percentage of motile sperm cells (p = 0.02). CONCLUSIONS: We conclude that men with stage 3-4 CKD had lower sperm concentrations than healthy fertile men and that increased serum miR-155 in men with stage 1-4 CKD was associated with semen parameters that indicate subfertility. Low AMH levels were associated with a low percentage of the total number of motile sperm cells. miR-155 and AMH may be potential markers of subfertility in men with CKD.

Male patients with terminal renal failure exhibit low serum levels of antimüllerian hormone.

Male reproductive function is impaired during end-stage renal disease (ESRD). Disturbance of the hypothalamic-pituitary-gonadal axis, and therefore the regulation of sex hormones, is one of the major causes. Our focus was to include antimüllerian hormone (AMH) and inhibin B concentrations. Twenty male patients on hemodialysis, median age 40 (26-48) years, were analyzed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, sex hormone-binding globulin (SHBG), testosterone, estradiol, AMH and inhibin B levels. We used 144 proven fertile men, median age 32 (19-44) years as a control group and analyzed differences using multiple linear regression. Males with ESRD demonstrated higher mean values for prolactin, 742 versus normal 210 mIE l-1 (95% confidence interval (CI): 60.3, 729), LH, 8.87 versus normal 4.5 IE l-1 (95% CI: 2.75, 6.14), and estradiol 89.7 versus normal 79.0 pmol l-1 (95% CI: -1.31, -0.15). Mean value for AMH was lower, 19.5 versus normal 47.3 pmol l-1 (95% CI: -37.6, -11.6). There were no differences found for FSH, SHBG, inhibin B and testosterone. The most important difference was found for AMH, a marker of Sertoli cell function in the testes, which decreased by close to 60% when compared with controls. Combined with an increase in LH, these findings may indicate a dysfunction of Sertoli cells and an effect on Leydig cells contributing to a potential mechanism of reproductive dysfunction in men with ESRD.

Nitric oxide (NO)--production and regulation of insulin secretion in islets of freely fed and fasted mice.

Production of nitric oxide through the action of nitric oxide synthase (NOS) has been detected in the islets of Langerhans. The inducible isoform of NOS (iNOS) is induced by cytokines and might contribute to the development of type-1 diabetes, while the constitutive isoform (cNOS) is thought to be implicated in the physiological regulation of insulin secretion. In the present study we have detected and quantified islet cNOS- and iNOS-derived NO production concomitant with measuring its influence on insulin secretion in the presence of different secretagogues: glucose, L-arginine, L-leucine and α-ketoisocaproic acid (KIC) both during fasting and freely fed conditions. In intact islets from freely fed mice both cNOS- and iNOS-activity was greatly increased by glucose (20 mmol/l). Fasting induced islet iNOS activity at both physiological (7 mmol/l) and high (20 mmol/l) glucose concentrations. NOS blockade increased insulin secretion both during freely fed conditions and after fasting. L-arginine stimulated islet cNOS activity and did not affect islet iNOS activity. l-leucine or KIC, known to enter the TCA cycle without affecting glycolysis, did not affect either islet cNOS- or iNOS activity. Accordingly, insulin secretion stimulated by L-leucine or KIC was unaffected by addition of L-NAME both during feeding and fasting. We conclude that both high glucose concentrations and fasting increase islet total NO production (mostly iNOS derived) which inhibit insulin secretion. The insulin secretagogues L-leucine and KIC, which do not affect glycolysis, do not interfere with the islet NO-NOS system.