Laila Bruun

Increase in percent free prostate-specific antigen in men with chronic kidney disease

BACKGROUND Prostate-specific antigen (PSA) occurs in different molecular forms in serum: free PSA (fPSA) and complexed PSA (cPSA), the sum of which corresponds to total PSA (tPSA). In addition to tPSA, percent fPSA is widely used in the detection of prostate cancer. Free PSA, approximately 28 kDa, is eliminated by glomerular filtration. Previous data showed that men with end-stage renal dysfunction requiring chronic dialysis have increased percent fPSA. In this study, we evaluated whether moderate-to-severe chronic renal dysfunction, but with no need for dialysis, also importantly affects percent fPSA. METHODS The study group consisted of 101 men (median age 57 years, interquartile range 46-68) with chronic kidney disease and no diagnosis of prostate cancer. Their median glomerular filtration rate (GFR) was 23 mL/min/1.73 m(2) (interquartile range 16-33; range 8-83), determined by iohexol clearance. Controls included 5264 men (median age 57 years, interquartile range 54-62) attending a prostate cancer screening program with no diagnosis of prostate cancer during 8 years of follow-up. RESULTS With adjustment for age, median fPSA levels and percent fPSA were significantly higher (P < 0.001) in patients with renal dysfunction, 0.45 microg/L and 47.2%, respectively, compared to controls, 0.29 microg/L and 29.9%, respectively. Regression analysis in the study group showed a significant association between GFR and percent fPSA (P = 0.036). CONCLUSIONS The percent fPSA is importantly influenced by moderately impaired renal function in men with chronic kidney disease. For such men, use of the current clinical decision limits for percent fPSA could cause some men with prostate cancer to be misdiagnosed as having benign disease, and therefore fPSA should not be used to diagnose prostate cancer in these patients.

Evaluation of a new immunoassay for cystatin C, based on a double monoclonal principle, in men with normal and impaired renal function

Background. Elevated cystatin C in blood reflects impaired glomerular filtration rate (GFR), but current cystatin C assays, based on polyclonal antibodies and immunoturbidimetric or nephelometric detection, have several limitations. We evaluated a new immunoassay based on monoclonal antibodies in samples from patients with and without chronic kidney disease (CKD). Methods. The study enrolled 170 men without known CKD (Group A) and 104 men with CKD (Group B). All patients were assessed with iohexol clearance, plasma creatinine and plasma cystatin C by a conventional particle-enhanced immunoturbidimetric assay (PETIA) and by the new double monoclonal assay. In Group A, three serial blood draws were performed at median intervals of 4 h and 12 days between samples, to also allow assessments of the variability in cystatin C values with the new assay. Concordance correlation coefficients and the 95% limits of agreement were used to estimate the agreement of reciprocal cystatin C and reciprocal creatinine with iohexol clearance. Results. Median iohexol clearance (mL/min/1.73 m2) was 81 [interquartile range (IQR) 70, 92] in Group A and 23 (IQR 16, 34) in Group B. The concordance correlation with GFR for the new cystatin C assay compared to the established assay was similar in Group A (0.441 versus 0.465) but higher in Group B (0.680 versus 0.593). Cystatin C measured by both assays exhibited closer agreement with GFR than creatinine. The agreement between the two cystatin C assays was high, with concordance correlations of 0.815 in Group A and 0.935 in Group B. Compared to the conventional assay, the new assay tended to yield lower values of cystatin C at the low end of the range in Group A. The new cystatin C assay exhibited small intraindividual variability across serial samples (coefficient of variation ≤6%). Conclusions. In this first clinical evaluation, the new cystatin C assay performed similarly to the established PETIA in patients with normal GFR and better in patients with CKD. The new assay may offer an alternative to current commercial assays to detect and monitor impaired kidney function.

Intra-individual short-term variability of prostate-specific antigen and other kallikrein markers in a serial collection of blood from men under evaluation for prostate cancer.

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

Anti-Müllerian hormone, a Sertoli cell-derived marker, is decreased in plasma of male patients in all stages of chronic kidney disease.

Male patients with terminal renal failure are often infertile and exhibit an abnormal sex hormone pattern in plasma. We studied patients in all chronic kidney disease (CKD) stages to determine plasma levels of anti‐Müllerian hormone (AMH), a Sertoli cell‐derived marker, and other sex hormones. Seventy‐eight male patients with CKD stages 1–5 and a median age of 40 years (22–50 years), as well as 20 healthy controls with a median age of 37 years (26–44 years), were enrolled. The CKD patients were evenly distributed; 18 with CKD stages 1–2, 19 with CKD stage 3, 19 with CKD stage 4, and 22 with CKD stage 5. Cystatin C, follicle‐stimulating hormone, luteinizing hormone, prolactin, sex hormone‐binding globulin, testosterone, and AMH levels in plasma were analysed. AMH was analysed using the Ansh Labs UltraSensitive AMH assay. Several changes occurred in plasma levels of sex hormones in male patients with CKD. Plasma AMH levels were lower in CKD stages 1–4 by 30% (p = 0.041) and by 70% (p < 0.001) in CKD stage 5 compared with controls. Plasma luteinizing hormone and prolactin levels were higher and testosterone levels were lower compared with controls. The pathophysiological role of this reduction in AMH is unclear, but can be linked to altered Sertoli cell function.

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.


The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome

The application of proteomics in chronic kidney disease (CKD) can potentially uncover biomarkers and pathways that are predictive of disease.

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.