ABSTRACT
Introduction
Spermatogenic dysfunction is a side effect of valganciclovir, which is commonly used to treat cytomegalovirus infections. Here, we report the case of a reproductive man who underwent kidney transplantation and was diagnosed with azoospermia after valganciclovir treatment for cytomegalovirus infection.
Case Presentation
A 30‐year‐old man underwent an ABO‐compatible living‐donor kidney transplantation. Two months after the kidney transplant, the patient was diagnosed with cytomegalovirus infection and gastritis. Therefore, valganciclovir treatment was initiated. Two months after completion of valganciclovir treatment, the patient was diagnosed with azoospermia. Azoospermia induced by valganciclovir was suspected, and careful monitoring was performed. Nine months after azoospermia diagnosis, the sperm concentration improved to normal range (43.3 × 106/mL). Subsequently, the patient's wife conceived.
Conclusion
During valganciclovir treatment, careful monitoring and adequate informed consent are needed to support patients of reproductive age.
Keywords: azoospermia, cytomegalovirus, kidney transplantation, spermatozoa, valganciclovir
Abbreviations
- CMV
cytomegalovirus
- GCV
ganciclovir
- KT
kidney transplant
- VGCV
valganciclovir
Summary.
Spermatogenic dysfunction, including azoospermia, is a side effect of valganciclovir treatment for cytomegalovirus infection; therefore, careful induction and adequate informed consent are needed to support patients of reproductive age after kidney transplantation.
1. Introduction
Kidney transplant (KT) is regarded as the best treatment for improving the quality of life and prognosis of patients with end‐stage renal disease [1]. However, several problems, including cytomegalovirus (CMV) infection, need to be resolved in clinical practice. Reportedly, CMV infections are associated with a high risk of acute rejection, graft loss, and mortality in patients who undergo KT [2, 3, 4]. Valganciclovir (VGCV) plays an important role in decreasing these risks in patients undergoing KT; otherwise, recipients with a CMV‐seronegative status are at a high risk during KT from a CMV‐seropositive donor. In > 60% of cases, the recipients have been reported to be diagnosed with CMV infection within 100 days after KT without prophylaxis [5, 6].
Spermatogenic dysfunction has been reported as a side effect of VGCV [7, 8]. VGCV is an L‐valyl ester prodrug of ganciclovir (GCV) that is rapidly converted to GCV after oral administration. The mechanism of effect is to attack and inhibit rapidly dividing cells; therefore, sperm count is decreased [7]. Animal experiments have shown that GCV's effect on male fertility appears to be reversible 24 weeks after termination of GCV [8]. A prospective study conducted in North America showed that improvement in semen parameters after KT was delayed in men with VGCV, while sperm concentration and sperm motility/morphology were comparable between men with VGCV and men without VGCV 6 months after VGCV treatment [7]. Here, we report the case of a reproductive man who underwent KT and was diagnosed with azoospermia after VGCV treatment for CMV infection.
2. Case Presentation
A 30‐year‐old man underwent ABO‐compatible living‐donor KT with his father as the donor 13 months after the introduction of hemodialysis owing to end‐stage renal disease secondary to IgA nephropathy. The patient's CMV serostatus indicated a high risk of infection (recipient seronegative/donor seropositive), and CMV prophylaxis was considered. However, because the patient had a strong desire to have a child, we decided to provide preemptive treatment, in which VGCV therapy is initiated upon CMV infection, instead of prophylactic treatment, considering the possibility of spermatogenesis disorders. Two months after KT, the patient visited our hospital because of stomach discomfort. A proton pump inhibitor was prescribed, and CMV antigenemia was checked. The stomach discomfort did not improve, and the CMV antigenemia test result was positive (C10/C11 13/7). Furthermore, upper gastrointestinal endoscopy revealed diffuse gastritis and duodenitis induced by CMV (Figure 1A,B). However, histological findings from both hematoxylin and eosin staining and in situ hybridization were insufficient for the diagnosis of CMV infection (Figure 1C,D). Considering CMV antigenemia and clinical symptoms, preemptive VGCV treatment was initiated. Two weeks after treatment, the patient's stomach discomfort resolved. Three weeks later, we confirmed that the CMV antigenemia test was negative, and VGCV treatment was completed. Two months after the VGCV treatment, the patient was diagnosed with azoospermia by a gynecologist during his infertility treatment visit. Endocrine tests revealed elevated levels of luteinizing hormone (10.5 U/mL), follicle‐stimulating hormone (12.3 U/mL), and prolactin (15.9 ng/mL). Free testosterone level was within the normal range for his age (10.1 pg/mL). Palpation and ultrasonography did not reveal varicoceles. Therefore, the condition was considered to be non‐obstructive azoospermia, and transient azoospermia induced by VGCV was strongly suspected. The patient was carefully monitored. Nine months after azoospermia diagnosis, the sperm concentration, semen volume, and total sperm motility improved to 43.3 × 106/mL, 1.5 mL, and 55.3%, respectively, which are within the normal ranges. Subsequently, the patient's wife conceived, and it was her first pregnancy at the age of 32. During this period, graft function remained unchanged, and the serum creatinine level was around 1.5 mg/dL (Figure 2).
FIGURE 1.
Representative images of upper gastrointestinal endoscopy and pathological examination. No obvious ulcers or other remarkable lesions are observed; however, slight redness is observed in the lower part of the gastric lordosis (A) and duodenum (B). Gastric biopsy reveals few inflammatory cell infiltrations, and no findings suggestive of graft‐versus‐host disease, such as apoptotic figures, are noted on hematoxylin and eosin staining (C). In situ hybridization results are negative for cytomegalovirus (D).
FIGURE 2.
Serum creatinine levels and sperm concentrations during the course of clinical treatment for cytomegalovirus infection. Stomach pain disappeared 10 days after the initiation of VGCV, and the dose of VGCV was reduced to 450 mg. VGCV administration was discontinued on Day 29 after confirming that the CMV antigenemia test result was negative. Semen analysis on Day 61 revealed azoospermia. On Day 343, the sperm concentration improved to within the normal range. CMV, cytomegalovirus; EVR, everolimus; MMF, mycophenolate mofetil; PSL, prednisone; Tac, tacrolimus; VGCV, valganciclovir.
3. Discussion
We encountered a rare case of azoospermia in a reproductive man treated with VGCV. CMV infection is common in solid organ transplant recipients, and VGCV is a common prophylactic and therapeutic drug against CMV infection. In this case, considering the spermatogenic dysfunction induced by VGCV, a preemptive treatment strategy was selected despite the high risk of CMV infection (donor: positive/recipient: negative). Preemptive treatment was initiated when the patient was diagnosed with CMV infection (and/or CMV gastritis). This treatment course is often prescribed; however, azoospermia, but not oligospermia or asthenospermia, is not expected in reproductive recipients. Therefore, adequate informed consent is required when using VGCV in recipients of reproductive age.
Generally, in men with end‐stage renal disease, spermatogenesis dysfunction and fertility are common, and the occurrence of sexual dysfunction is approximately 50%–70% in male patients on maintenance dialysis [9]. However, successful KT has been reported to improve sexual dysfunction, which is a major concern in reproductive patients [10, 11, 12]. A prospective observational study showed that the increase in sperm concentration was greater in untreated patients than in VGCV‐treated patients after KT, whereas VGCV‐treated patients experienced a greater increase after the termination of VGCV than untreated patients. A similar pattern was observed for the other sperm parameters. In the study, patients with azoospermia were observed at baseline, and none showed recovery to normal sperm concentration levels at the termination of VGCV or follow‐up; moreover, no patient experienced a shift from normal to abnormal between baseline and the end of follow‐up, regardless of VGCV treatment [7]. Therefore, unless patients have azoospermia at baseline, spermatogenic dysfunction induced by VGCV may be improved after the termination of VGCV, whereas patients with azoospermia at baseline need to be monitored. Screening baseline sperm parameters is uncommon in clinical practice; however, screening should be considered in patients with a strong desire to have children before VGCV administration, regardless of preemptive or prophylactic treatment.
There are very few reports on VGCV‐induced spermatogenic dysfunction, and the underlying mechanism remains unclear. The cytotoxicity is reportedly caused by the metabolic product of VGCV (GCV), resulting in the inhibition of dividing cells. The levels of hormones, including luteinizing hormone, follicle‐stimulating hormone, and testosterone, are not affected by VGCV administration [7, 8]. This theme is relatively complicated because remarkable changes occur after KT. Uremia induces spermatogenic or hormonal dysfunction, and successful KT considerably resolves these conditions. Therefore, careful interpretation of our findings and further research are needed to elucidate the mechanisms underlying VGCV‐induced spermatogenic dysfunction. To the best of our knowledge, there is no report on the prevalence of GCV‐ or VGCV‐induced spermatogenic disorders. Therefore, it is important to accumulate cases and report comprehensive data.
Recently, letermovir, a CMV DNA terminase complex inhibitor globally approved for the prophylaxis of CMV infection and disease in adult allogeneic hematopoietic stem cell transplant recipients [13, 14, 15], has been approved for the prophylaxis of CMV infection after KT. Its efficacy and safety have been verified in a Japanese cohort [16]. However, spermatogenic dysfunction has not been reported. Therefore, careful induction and adequate informed consent are required to support patients of reproductive age.
In summary, VGCV treatment for CMV infection can cause azoospermia as a side effect. Careful monitoring should be performed, and screening for baseline sperm parameters and sperm preservation should be considered to avoid the worst situation before VGCV use in patients of reproductive age undergoing KT.
Disclosure
The authors have nothing to report.
Consent
Consent to participate and consent for publication were acquired from the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors would like to thank the recipient for their important contribution to this study.
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