Introduction

Patients with end-stage kidney disease (ESKD) on dialysis have a special profile, including constant uremic status, frequent comorbidities, such as type 2 diabetes mellitus (T2DM), arterial hypertension, dyslipidaemia and coronary artery disease. Additionally, complications related to dialysis may occur, such as peritonitis in patients on continuous ambulatory peritoneal dialysis, access-related or hemodynamic in patients on haemodialysis. In addition, patients on dialysis have constant contact with the healthcare system, a lower quality of life, which can cause a range of neuropsychiatric disorders, such as depression, anxiety and distress. All these listed factors and the added comorbidities may influence or be the cause of sexual dysfunction in both men and women.

Erectile dysfunction (ED) is known to have a negative impact on the quality of life. The first epidemiological survey of sexual dysfunction in patients with chronic kidney disease (CKD) was conducted in 1972 [1] and since then several studies confirmed that the prevalence of sexual dysfunction in haemodialysis patients is high [2].

Erectile and kidney dysfunction share common risk factors associated with conditions that involve endothelial impairment such as coronary artery disease, dyslipidaemia, diabetes mellitus, hypertension, smoking and obesity [3, 4]. Increasing evidence suggests that CKD is frequently associated with psychosocial factors, such as anxiety, depression, and health-related poor quality of life, all of which can result in sexual dysfunction [5]. There’s a high incidence (70%) and prevalence (82%) of erectile dysfunction in men with CKD [2, 6].

Kidney transplant (KT) is recognized to be the best treatment for end-stage renal disease (ESRD), and the number of kidney transplants is increasing worldwide, with restoration of kidney function. Data regarding the state of erectile dysfunction after kidney transplantation is controversial: some studies show that erectile function improves after renal transplant (RT) [7,8,9,10,11,12,13] while other authors suggest that sexual parameters are not affected by renal transplantation [14,15,16,17]. Additionally, some studies have indicated that erectile dysfunction is worsened after kidney transplantation surgery [18,19,20,21].

In the twenty-first century, graft survival and survival of transplant recipients increased due to latest transplantation technology, as well as better evaluation of renal parameters and new immunosuppressive strategies that prevent graft rejection. In this new era of medicine, erectile function in the context of a better quality of life became an important concern for patients and doctors.

Aims

This review aims to evaluate the impact of renal transplantation on erectile dysfunction in men with end-stage chronic kidney disease.

Materials and methods

The updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to standardize data search, collection, synthesis, and reporting [22]. For our meta-analysis, we used a protocol registered at OSF Registries (Registration https://doi.org/10.17605/OSF.IO/JV2MQ).

Data sources and search strategy

Potentially relevant studies were searched in the following databases, from the inception until August 2022: MELDINE (PubMed), SCOPUS, Embase and Cochrane library. No language filters were applied in the search process. In addition to aforementioned sources, ClinicalTrials.gov database was also screened for additional citations. References from representative studies were also searched to retrieve further studies for eligibility assessment. Hand search for relevant articles was also performed from textbooks. We used different combinations of keywords and controlled vocabulary to create a comprehensive search strategy: “renal transplant and erectile dysfunction”, “CKD and erectile dysfunction”, “erectile dysfunction after kidney transplant”, “erectile dysfunction”.

Study selection

We conducted a systematic review and meta-analysis including observational cohort studies and randomized controlled trials (RCTs) in men with ESRD that evaluated the role of renal transplant on the impact of erectile dysfunction in men. In this analysis, only ESRD who had undergone renal transplantation were included and the IIEF questionnaire was used. The same group of patients were analyzed using the same questionnaire after surgery. We considered studies that explored the prevalence and predictors of any form of sexual dysfunction in patients with CKD. Studies were eligible if they compared the same group of population before and after renal transplantation. Studies with a population of patients without CKD were excluded, as were studies that compared groups of patients on dialysis with different groups of patients with renal transplant.

Data extraction and synthesis

Data extracted included identifying information, aim of the study, details of the study protocol and demographic data. We extracted characteristics of each study including baseline IIEF score (IIEF—5), IIEF domain (IIEF – 15) (erectile function, intercourse satisfaction, orgasmic function, sexual desire, overall satisfaction), baseline clinical characteristics of the study population, known comorbidities, type of donor, type of anastomosis used during renal transplantation, type of study design, and total duration of follow-up.

Risk of bias

Two reviewers (AM and IN) evaluated the quality of the selected studies independently without blinding to authorship or journal according to recommendations from the Cochrane Collaboration. For the observational studies, the quality was assessed using the Newcastle–Ottawa scale (NOS) [23] The scale used three categories to evaluate: selection of the study groups, the comparability of the groups and the assessment of outcome. Stars awarded for each quality item serve as a quick visual assessment. Stars are awarded such that the highest quality studies are awarded up to nine stars. Disagreements were resolved by consensus. Publication bias was assessed using the funnel plot technique[24].

Main outcomes and measures

The primary outcome of this analysis was to measure the impact of renal transplantation on sexual function using the International Index of Erectile Function (IEEF) score, sexual domains and also other questionaries. Secondary outcomes included: 1. establishing if mean IIEF-15 or IIEF-5 change from baseline in KTs, 2. Number of patients with improvement or worsening of ED on postoperative evaluation.

The International Index of Erectile Function (IIEF) is a widely used, multi-dimensional self-report instrument for the evaluation of male sexual function [25]. It has been recommended as a primary endpoint for clinical trials of ED and for diagnostic evaluation of ED severity [26], and it is now considered gold-standard for measurement of sexual function [27]. This questionnaire includes all aspects of male sexual functions (erection, orgasmic function, libido, and overall satisfaction) and can evaluate as objectively as possible sexual function in male patients [28].

Statistical analysis

We used a random-effects model for meta-analysis and expressed treatment effects as a risk ratio (RR) with 95% confidence intervals (CI). We used the I2 statistic to assess for inconsistency across individual studies. An I2 > 50% indicated large inconsistency across studies (heterogeneity) not explained by chance. We considered a p-value below 0.10 to indicate significant heterogeneity All statistical analyses were performed using Review Manager Version 5.2 (The Cochrane Collaboration 2012).

We conducted sensitivity analyses to explore the influence of the following factors on effect size: repeating the analysis excluding unpublished studies; repeating the analysis taking account of risk of bias; repeating the analysis excluding any very long or large studies to establish how much they dominate the results; repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, and country. A funnel plot was visually inspected. For all the analyses, a two-tailed p-value < 0.05 indicated statistical significance. We conducted the analyses in Review Manager (RevMan) Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Possible source of heterogeneity was explored based on the type of anastomosis (end-to-side to external iliac artery, end-to-end to internal iliac artery or end-to-side to common iliac artery), risk of bias, type of transplantation and year of publication.

Results

The literature search using the specified databases retrieved 1703 articles. After removing duplicates, 943 articles were screened by title and abstract and 43 articles were read in full-text. We then removed articles where the inclusion criteria were not met, articles that included meta-analyses and articles where the study population was not the same before and after renal transplantation. Finally, a total of 28 articles were included in the present meta-analysis, comprising a total of 2252 participants (Fig. 1).

Fig. 1
figure 1

Flow diagram of study selection process

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The articles included in this meta-analysis were observational conducted worldwide. The follow-up period varied between three and 282 months. 17 studies reported the type of renal replacement therapy before renal transplantation. The majority of patients underwent haemodialysis, while out of the same 17 studies, a total of 35 patients were on peritoneal dialysis and 34 patients had a pre-emptive transplantation. Dialysis time before RT was between 6 months to 7 years. 11 studies reported the type of donor involved in the process of RT. The follow-up between studies varied between three months to 72 months. The majority of studies used the IIEF-5 questionnaire as the main method to assess sexual function, while 5 studies used questionnaires developed by the authors. The characteristics of all included studies are included in Table 1.

Table 1 Characteristics of all included studies
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Regarding the baseline characteristics of all included participants, few studies reported life-style risk factors such as smoking and alcohol [14, 17,18,19, 29,30,31,32,33] or the weight of included participants [17, 18, 30, 33]. Four studies [10, 13, 29, 34] excluded patients with diabetes mellitus. 12 studies reported data on immunosuppressive therapy, while five studies reported other chronic medications. 10 studies also reported the hormone panel before and after renal transplantation. The complete baseline characteristics of all included participants are summarized in Table 2.

Table 2 Baseline characteristics of all included studies
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Presence or absence of erectile dysfunction after renal transplantation

28 studies included (2252 patients) compared the rate of sexual dysfunction before and after renal transplantation. In dichotomic analysis with a comparison before and after renal transplantation, we found an improvement of 13% regarding sexual dysfunction after renal transplantation. (RR 0.87) (95% CI 0.76–1.00) (Fig. 2).

Fig. 2
figure 2

Forest plot of the risk-ratio of patients with ED pretransplant compared to postoperative evaluation

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Improvement versus worsening of erectile dysfunction

We evaluated the impact of renal transplantation on sexual function in an analysis that included 19 studies comprising a total of 1613 participants. Our results show that post-renal transplantation, there was an improvement in erectile dysfunction with 234% (RR 2.3) (95% CI 1.36, 4.01) (Fig. 3).

Fig. 3
figure 3

Forest plot of the risk ratio of patients improved sexual function compared to patients with worsening sexual function at postoperative evaluation

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Impact of renal transplantation on IEEF score

Data reported in six studies show an improvement of mean IEEF score with 3.92 points after KT: (MD 3.92) (CI 95% 3.26 to 4.58) (Fig. 4).

Fig. 4
figure 4

Forest plot of mean difference in IEEF-15 or IEEF-5 score pre and postoperative evaluation

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Subdomain analysis was not performed due to insufficient data. Three studies reported other components, such as erectile function, orgasmic function, intercourse satisfaction and overall satisfaction. However, there was not enough data to perform an analysis on these components, but the results generally suggest an improvement in sexual function after renal transplantation.

Type of anastomosis and impact on erectile function

14 studies included the type of anastomosis used during renal transplantation. Gontero et al. reported worsening erectile function with end-to side external iliac artery anastomosis and five studies reported good results using end-to-end or end-to-side internal iliac artery anastomosis. However, there was not enough data to perform an analysis.

Type of immunosuppression used after renal transplantation

13 Studies reported the current regimen of immunosuppression and five studies reported concurrent medications for comorbidities, but there was insufficient data, so that we could not perform a formal analysis based on these components.

Second transplantation and erectile function

Few studies in our analysis reported the number of included patients that had a second transplant. A total of 49 patients underwent a second kidney transplant, but there was insufficient data to perform an analysis.

Risk of bias

We explored the publication bias and found an equal distribution of the included trials (Fig. 5).

Fig. 5
figure 5

Funnel-plot assessing publication bias

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The quality of the included studies was assessed using the Newcastle–Ottawa scale (NOS). Starts were awarded for each quality item investigated. Overall, the quality of studies was adequate, with only a few studies that had an average quality score under 7 points. The full assessment of the studies included and overall quality score of each study can be seen in Table 3.

Table 3 Newcastle- Ottawa scale for assessment of quality of included studies (each asterisk represents if individual criterion within the subsection was fulfilled)
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Discussion

Sexual dysfunction is prevalent among individuals with chronic kidney disease. A meta-analysis of 50 studies comprising 8343 participants with CKD, both males and females, reported a high summary estimate of erectile dysfunction in men with CKD—70% [6]. The cause of erectile dysfunction in CKD could be related to the underlying disease (diabetes, arterial hypertension), but it can also be related to the uremic effects on the nervous system and the changes in the hormone panel, such as diminished testosterone production [35].

Our meta-analysis shows that renal transplantation improves erectile function in participants with end-stage renal disease. The majority of the participants included in our study were on renal replacement therapy (especially haemodialysis) before renal transplantation and only 34 had a pre-emptive transplant. Compared to pre-transplant evaluation, our study shows a 13% improvement in erectile dysfunction after renal transplantation. This improvement is also reflected in an analysis of six studies that shows a mean rise of 3.92 points in the IIEF score post-transplant.

Payne et al. [36] conducted a literature review regarding the prevalence and treatment of erectile dysfunction in male solid organ transplant recipients and indicated that the prevalence of erectile dysfunction in male renal transplant recipients was between 54 and 66%. However, it did not evaluate the population pre-transplantation.

Our findings are in line with other meta-analyses that researched sexual function after renal transplantation in CKD patients or patients on renal replacement therapy. One meta-analysis published in 2020 by Kang et al. [37] that included 9 observational studies indicated that renal transplantation may improve erectile function in patients with end-stage kidney disease. They also showed improvement in the mean IIEF 5 and IIEF-15 scores. Compared to our meta-analysis, Kang et al. did not include the same study population before and after renal transplantation and the overall sample size was significantly smaller compared to our analysis. Another meta-analysis conducted by Pyrgidis et al. [38] included a total of 10,320 males with end-stage kidney disease and showed a high prevalence of erectile dysfunction in patients with chronic kidney disease: 79% in patients on haemodialysis, 71% in patients with peritoneal dialysis, 82% in patients starting dialysis. The lowest prevalence of erectile dysfunction was 59% in participants with renal transplantation. However, although Pyrgidis et al. showed that in renal transplantation there is a lower prevalence of erectile dysfunction, they did not evaluate the effect of renal transplantation on erectile function.

Our meta-analysis has a few strong points. First, it has a large population of males (2252 participants) with end-stage kidney disease that underwent renal transplantation. Another advantage is that we only included studies using the same study population before and after renal transplantation. This way, we could evaluate directly the impact of renal transplantation on erectile function. Additionally, the majority of the studies in our meta-analysis used the standardized IIEF to assess sexual function.

However, our study has some limitations, one of which being the observational nature of the studies included and the lack of RCTs conducted on this subject. Another limitation is that we cannot completely rule out overlapping study populations. For example, two of the articles included: El-Bahnasawy et al. A and El-Bahnasawy et al. B had an overlap of 50 patients. Other limitations include the inability to perform analyses regarding the effect of the type of anastomosis used and the effect on erectile function. We could not perform analyses on other factors that could affect erectile function, such as concurrent immunosuppressive regimens used after renal transplantation.

Abnormalities in the serum levels of testosterone, LH, FSH and prolactin have been reported in patients with ESKD. Specifically, testosterone levels tend to be suboptimal in patients on haemodialysis. Some of the studies included in this meta-analysis reported the hormone levels before and after renal transplantation. For example, Akbari et al. and Teng et al. showed that the level of testosterone increased after renal transplantation, while levels of LH, FSH and prolactin decrease. Increase in testosterone levels seem to be consistent among the studies that reported hormone levels, but an analysis could not be performed on these components due to insufficient data.

The underlying pathological mechanisms involving ED and CKD are not completely understood, but various treatments are available, including phosphodiesterase type 5 inhibitors or testosterone therapy in patients with low levels of testosterone. It is important to study the effect of renal transplantation on erectile dysfunction, since erectile dysfunction further affects quality of life and could accentuate certain neuropsychiatric disorders, such as depression and anxiety.

Conclusions

In conclusion, the findings from our meta-analysis show improvement in erectile dysfunction after renal transplantation when compared to pre-transplant evaluation. Additionally, there is also improvement in mean IIEF score. However, further studies with a larger number of patients are needed to investigate the impact of renal transplantation on erectile dysfunction. Moreover, studies are needed to determine whether the type of anastomosis used has an effect on post-transplant sexual function.