Male Infertility in Renal Failure and Transplantation

Scott D. Lundy; Sarah C. Vij

Disclosures

Transl Androl Urol. 2019;8(2):173-181. 

In This Article

ESRD and Spermatogenesis

Congenital Genitourinary Anomalies and ESRD/Infertility

Many young patients develop CKD at a young age secondary to congenital anomalies which may also predispose to male infertility by distinct mechanisms. For example, autosomal dominant polycystic kidney disease is associated with seminal vesicle cysts, megavesicles, and asthenozoospermia.[12] Prune belly syndrome is associated with near-universal refractory male infertility due to undescended testicles and prostatic hypoplasia,[13] and paternity is only achieved in approximately 5.0% of patients with exstrophy due to sexual dysfunction and abnormal genitalia.[14] Posterior urethral valves may confer increased risk of ED and/or ejaculatory dysfunction.[15] Congenital unilateral or bilateral absence of the vas deferens (CUAVD or CBAVD, respectively) is identified in 1% of men undergoing infertility workup (10% of those with azoospermia) and predisposes men to renal insufficiency later in life due to the associated prevalence of solitary kidney.[16] Interestingly, while 42% of men with CUAVD are found to have a solitary kidney, this rate falls to only 18% of men with CBAVD.[16] Presumably this is due to the fact that if the underlying mechanism bilaterally were to predispose to bilateral renal agenesis, then the developing embryo would have been nonviable. While management of these cases from a CKD perspective can be challenging, management of the infertility component is often equally challenging and requires careful patient-tailored management and in some cases assisted reproduction.

ESRD and Impaired Spermatogenesis

In addition to the association between a common congenital cause for ESRD and infertility, uremia itself strongly influences a man's ability to conceive. The mechanisms behind this are multifactorial and include (but are not likely limited to) direct effects on spermatogenesis, ED, and hormonal imbalances. Semen analysis in men with advanced CKD demonstrates decreased volume and oligoasthenozoospermia,[17] and testicular pathology can demonstrate Sertoli cell atrophy.[6] Xu and colleagues further characterized this phenomenon in patients on HD and noted a roughly 50% decrease in sperm viability, motility, concentration, and normal morphology in ESRD patients compared to controls.[18] Men on long-term dialysis have also been shown to have diminished testicular volume that continues to decrease with further time on HD. Biopsy of testicles from these patients has shown increased fibrosis with decreased germ cell proliferation.[19] Further mechanistic work demonstrated that sperm motility and normal morphology were the two basic semen parameters most affected by uremia.[20] The decrease in motility was directly correlated with the duration of HD. Ultrastructural analysis has shown significant morphological changes including a lack of acrosome with both head and tail abnormalities.[21] Biochemical analysis has also shown a downregulation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene below levels found in both healthy and in infertile men.[22] Taken together, the data suggests profound changes in spermatogenesis and sperm function in men with CKD.

Structural Reproductive Consequences of Renal Transplantation

The potential for reproductive consequences from transplant starts at the time of operation as the retroperitoneal exposure can result in damage to the spermatic cord structures including the vas deferens and testicular blood supply.[23] This operation can result in injury to the vas deferens[24] and predispose an already-subfertile man to further decline in fertility. If the man desires future fertility, care must be taken to mobilize the spermatic cord and preserve the testicular bloody supply and vas deferens. It is thus important to address the patient's fertility concerns preoperatively among the litany of other preoperative variables that are considered prior to renal transplantation.

Following transplantation, two groups[11,25] have characterized the changes in testicular architecture via testicular biopsy. Rodrigues Netto biopsied the testicles of 9 men before and renal transplant. The group quantitatively showed a robust increase in the number of spermatogonia, spermatocytes, spermatids, and spermatozoa, but no change in the number of Sertoli cells was appreciated.[25] Prem and colleagues later studied a cohort of 19 young men who underwent living donor renal transplantation; a subset of these men underwent testicular biopsy before and after transplantation with azathioprine-based immunosuppression.[11] Pretransplant testicular biopsy revealed late stage maturation arrest and decreased spermatogenesis. While post-transplant testicular biopsy showed improvement in spermatogenesis in a small portion of these patients, the majority continued to demonstrate signs of late stage maturational arrest.[11] This data suggests that while some functional recovery may occur with reversal of uremia, the underlying fibrosis and abnormal testicular architecture likely remains and will permanently affect fertility.

Semen Quality Following Renal Transplantation

Motivated by early reports of improvement in the hormonal panels of ESRD patients who received a kidney transplant, Lim and colleagues assessed semen parameters before and after transplant[8] in a small cohort of young men. As expected, they saw oligoasthenospermia and azoospermia in the pretransplant population with a gradual improvement in sperm count and motility over the course of ~12 months following transplant (Figure 1). Subsequent studies showed a statistically robust improvement in semen density, but this effect appeared to be limited to a subset of patients with a significant portion of men remaining azoospermic.[11] Interestingly, sperm motility in this study diminished significantly following transplantation. Follow-up work by Akbari et al. re-demonstrated the improvement in count, albeit with only modest improvements in motility and normal morphology.[9] They found that less than half of dialysis patients had normal semen analysis, whereas this improved to almost 75% after transplant.[9] At the 2-year mark, their data suggested that transplant patients demonstrate little-to-no difference in basic semen parameters when compared to healthy age-matched controls.

An elegant study by Eid and colleagues stratified young male renal transplant recipients into fertile and infertile categories and compared these groups to each other and to fertile and infertile patients in the general population.[26] They found that the fertile transplant group had sperm concentration and computer-aided sperm analysis (CASA) parameters that compared favorably to the fertile controls, supporting the possibility for complete spermatogenic recovery in some cases. In stark contrast, the infertile transplant cohort exhibited oligospermia and diminished motility that was strikingly similar to the infertile non-transplant control group. Interestingly, the transplant infertile group demonstrated poor flagellar coordination compared to infertile controls, suggesting fundamental mechanistic differences in sperm function. The group postulated that some of the effects may be related to a significant difference in cyclosporine levels, which may be gonadotoxic or spermatotoxic in a dose-dependent fashion.[26]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....