Impact of renal dysfunction on serum Prostate-Specific Antigen

Abstract: Measurement of prostate-specific antigen (PSA) in blood is an important tool in detection for prostate cancer. PSA occurs in several molecular forms in blood: mainly as a free form with a molecular mass of 28 kDa; and as PSA complexed to alpha-1-antichymotrypsin, complexed PSA, with a molecular mass of 90 kDa. Total PSA comprises the sum of free PSA and complexed PSA. The percentage of free-to-total PSA is frequently used due to its capacity to enhance the discrimination of prostate cancer from benign prostatic disorders. The assessed PSA concentration is, besides the production, also dependent on other factors such as the elimination and the intra-individual variability. Low-molecular-weight (LMW) proteins are extensively eliminated from plasma by glomerular filtration and as a consequence, plasma levels of these proteins are elevated in renal failure. The low molecular mass of free PSA, within the range of LMW proteins, and reported short half-life indicate elimination by glomerular filtration. The main interest in these studies was to describe the role of the kidneys in the elimination of free PSA, the effect of renal dysfunction on serum levels of PSA and percent free PSA, and to evaluate the intra-individual variation in PSA. We measured serum PSA in men with terminal renal failure on chronic dialysis treatment and demonstrated that patients on either hemodialysis or CAPD have increased percent free PSA but unaffected total PSA levels compared to controls. In men with terminal renal insufficiency, percent free PSA should be evaluated with caution in detection for prostate cancer as currently clinical cut-offs levels may not be applicable in uremic men. A high percent free PSA should not be considered as a sign of benign prostatic disorders in men with terminal renal failure. In order to study whether free PSA is eliminated by glomerular filtration, we investigated men undergoing renal transplantation. In this study we also included human kallikrein 2 (hK2), a new potential marker for prostate cancer. Plasma levels of free PSA and hK2 decreased rapidly after the transplantation, concluding that both proteins mainly are eliminated from the blood by glomerular filtration. We then evaluated whether moderate to severe renal dysfunction affects plasma levels of free PSA and percent free PSA. The studied men had a median glomerular filtration rate of 19.5 ml/min/1.73m2 (range; 8-54). We found significantly higher levels of free PSA and percent free PSA compared to controls. These findings show that renal function is an important factor to consider in the use of percent free PSA in detection of prostate cancer. The long-term intra-individual variation in PSA, over 2 years was evaluated in a cohort of men from the Göteborg screening study for prostate cancer. We included 2,571 men with total PSA less than 2 µg/l after 8 years of observation time. In seemingly healthy men, the long-term intra-individual variability in PSA was less than 14%, and with 95% probability, a change in total PSA greater than 30% indicates a change beyond normal variation.