Renal Transplantation Improves Erectile Function in Patients with End-Stage Renal Disease: A Systematic Review and Meta-Analysis

You have accessJournal of UrologyReview Article1 Apr 2021Renal Transplantation Improves Erectile Function in Patients with End-Stage Renal Disease: A Systematic Review and Meta-Analysis Nikolaos Pyrgidis, Ioannis Mykoniatis, Ioannis Sokolakis, Ioanna Minopoulou, Meletios P. Nigdelis, Petros Sountoulides, Paolo Verze, Georgios Hatzichristodoulou, and Dimitrios Hatzichristou Nikolaos PyrgidisNikolaos Pyrgidis *Correspondence: Alois 16, Pilaia, Thessaloniki, Greece telephone: 0030 6982 14 2006; E-mail Address: [email protected] First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece , Ioannis MykoniatisIoannis Mykoniatis First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece , Ioannis SokolakisIoannis Sokolakis Department of Urology, 'Martha-Maria' Hospital Nuremberg, Nuremberg, Germany , Ioanna MinopoulouIoanna Minopoulou School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece , Meletios P. NigdelisMeletios P. Nigdelis School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece , Petros SountoulidesPetros Sountoulides First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece , Paolo VerzePaolo Verze Department of Medicine, Surgery, Dentistry "Scuola Medica Salernitana", Urology Unit—University of Salerno, Salerno, Italy , Georgios HatzichristodoulouGeorgios Hatzichristodoulou Department of Urology, 'Martha-Maria' Hospital Nuremberg, Nuremberg, Germany , and Dimitrios HatzichristouDimitrios Hatzichristou First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece View All Author Informationhttps://doi.org/10.1097/JU.0000000000001577AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: Erectile dysfunction has a lower prevalence in renal transplant recipients compared to dialysis patients. Despite this observation, the effect of renal transplantation on erectile function remains unknown. We aimed to assess the role of renal transplantation on erectile function and to determine potential factors improving or deteriorating erectile dysfunction. Materials and Methods: We conducted a systematic review and random effects meta-analysis of observational studies comparing erectile function preoperatively and postoperatively in renal transplant recipients (PROSPERO ID: CRD42020189580). Records reporting relevant outcomes were identified through search of PubMed®, Embase®, Cochrane Library and Scopus® databases from inception to September 2020. Judgment of the strength of evidence was performed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We included 20 studies with 1,695 renal transplant recipients. At postoperative evaluation the number of patients with erectile dysfunction was reduced (RR 1.21, 95% CI 1.02–1.45, I2=88%). Renal transplant recipients reported an improvement in erectile function (RR 2.53, 95% CI 1.44–4.44, I2=90%) and the mean International Index of Erectile Function score increased by 3.04 points (95% CI 0.63–5.45, I2=96%) after renal transplantation. These effects were not demonstrated in the sensitivity analysis. In individuals reporting severe erectile dysfunction, no favorable effect of renal transplantation was observed (RR 1.51, 95% CI 0.85–2.68, I2=33%). For all outcomes the strength of evidence was considered low or very low due to methodological concerns and high heterogeneity among the included studies. Conclusions: Renal transplantation improves erectile function and the risk of erectile dysfunction reduces postoperatively compared to preoperatively. However, evidence on the matter is mostly based on low quality data. More studies with standardized outcomes are needed to validate and strengthen our findings. Abbreviations and Acronyms ED erectile dysfunction EF erectile function HD hemodialysis IIEF International Index of Erectile Function MMF mycophenolate mofetil PDE5i phosphodiesterase type 5 inhibitors RR risk ratio RT renal transplantation RTR renal transplant recipient Renal transplantation is considered the optimal renal replacement therapy in patients with end-stage renal disease.1 The number of renal transplant recipients is increasing worldwide with more than 90,000 RTs performed every year.2 In the United States alone, about 220,000 individuals live with a functioning kidney transplant.3 Among RTRs, erectile dysfunction has an estimated prevalence of about 59%4 and is considered a major burden that affects quality of life and may lead to anxiety, depression and loss of self-esteem.5 In dialysis patients, the prevalence of ED is even higher and may exceed 75%.4,6 The lower prevalence of ED among RTRs compared to dialysis patients has been attributed to the recovery of renal function, the restoration of important metabolic and endocrine parameters such as urea or testosterone levels as well as to the general improvement of quality of life.7 On the contrary, various factors such as immunosuppressant medications, multiple RTs and perioperative complications may deteriorate erectile function among RTRs.8 Still, the lower prevalence of ED among RTRs may be explained by the fact that individuals undergoing RT are generally younger, in better physical and mental health state and they present fewer comorbidities compared to dialysis patients.9 Epidemiological data and relevant non-systematic, qualitative reviews do not comprehensively address this matter and render the effect of RT on EF controversial.10,11 Within this framework, we systematically synthesized the available evidence and generated a meta-analysis, aiming to assess the effect of renal transplantation on erectile function and to determine potential factors improving or deteriorating erectile dysfunction. Materials and Methods Search Strategy We predefined and documented the aims and methods of this systematic review and meta-analysis in a protocol registered at PROSPERO (ID: CRD42020189580). We performed our study in compliance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement (supplementary data 1, https://www.jurology.com).12 Two authors (NP, IM) systematically searched PubMed, Embase, Cochrane Library and Scopus databases from inception to September 2020 for studies exploring the effects of renal transplantation on EF. We conducted a targeted search of the grey literature, including conference abstracts published in major nephrology, urology, transplantation and sexual medicine journals as well as websites providing information on dissertations. EudraCT and Clinicaltrials.gov were also perused for additional ongoing trials. The reference lists of all eligible studies, relevant reviews and major transplantation guidelines were hand-searched to identify further trials. Our detailed search strategy is presented in supplementary data 2 (https://www.jurology.com). Selection Criteria We included prospective or retrospective cohort studies assessing self-reported EF with validated tools at the pretransplantation and posttransplantation state. We considered single-arm, multi-arm or comparative studies without language restrictions in patients older than 18 years of age. In contrast, we excluded studies assessing only sexual function or studies evaluating EF with nonvalidated tools or in a dichotomous (yes/no) way. Similarly, we did not encompass cross-sectional studies measuring EF only preoperatively or postoperatively. Narrative reviews, editorials and letters to the editor were also excluded. When multiple records with potential overlapping populations were identified, only the most recent study was included. Data Extraction and Quality Assessment Two authors (NP, IM) independently screened all identified records for eligibility. Any disagreements were resolved by consensus. Data from all included records were extracted in a predefined Microsoft® Excel® spreadsheet. From each study, we retrieved information about study and patient characteristics, RT details and EF outcomes. Established methods, recommended by the Cochrane Collaboration, were applied to calculate data from full-text articles, summary tables and figures.13 When the standard deviation for the mean change from baseline of the EF domain of the International Index of Erectile Function-15 or IIEF-5 was not reported, it was obtained from the standard error, confidence interval or p value provided from each study. When none of the latter was reported, SD was estimated based on the correlation coefficient reported from other included trials.13 In trials evaluating EF at multiple timepoints preoperatively or postoperatively, only the data most proximate to RT assessment were retrieved. Between the reviewers, a pilot test of the data extraction process was performed to guarantee coherence. In case of data unavailability, we directly contacted study authors for further information.14 We evaluated the quality of each included study with a modified version of the Newcastle-Ottawa Scale for cohort studies. Based on the Newcastle-Ottawa Scale, each study is judged upon 8 items, grouped into 3 categories that include selection of participants, comparability of results as well as outcomes (supplementary data 3, https://www.jurology.com).15 Two investigators (IS, MPN) assessed the quality of records independently and any discrepancies were resolved by consensus. Accordingly, the risk of bias across studies (publication bias) was estimated via visual assessment of funnel plot asymmetry and the Egger's statistical test.16 Grading of Evidence, Data Synthesis and Statistical Analysis We determined the overall strength of evidence for all outcomes applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.17 Three authors (NP, IM, IS) assessed the risk of bias, inconsistency, indirectness, imprecision and publication bias among included trials. We performed an inverse variance, random effects meta-analysis for the following outcomes: 1) the ratio of patients experiencing some level of ED preoperatively versus postoperatively; 2) the ratio of patients with improved EF at postoperative assessment versus the ratio of patients with deteriorated EF at postoperative assessment, and 3) the mean IIEF-15 or IIEF-5 change from baseline in RTRs. In particular, the authors of the included studies, reported the absolute number of patients presenting with ED before and after RT in a binary way. Similarly, included studies reported, in a binary way, the absolute number of patients presenting with any improvement or deterioration of EF at postoperative evaluation compared to the preoperative evaluation. Therefore, for outcomes 1 and 2 we performed a meta-analysis of risk ratios. On the other hand, regarding outcome 3, we performed a single-arm meta-analysis of raw mean differences to estimate the effect of RT on IIEF-15 or IIEF-5. Regarding RRs, the denominator of the total number of patients evaluated preoperatively and the denominator of patients evaluated postoperatively consisted of the same patients. Therefore, the number of RTRs with ED before RT versus after RT was directly compared to estimate the relevant ratio. Similarly, the denominator of patients with improved EF and the denominator of patients with deteriorated EF at postoperative assessment consisted also of the same patients. Therefore, the number of patients with improved versus deteriorated EF at the postoperative assessment was also directly compared to estimate the relevant ratio. Further information on RR synthesis methods can be found in supplementary data 4, (https://www.jurology.com). We conducted a sensitivity analysis for all outcomes with studies of good methodological quality and a subgroup analysis for the number of RTRs with severe ED at preoperative vs postoperative evaluation. Moreover, we assessed heterogeneity with the I2. For all measures, p values lower than 0.05 were considered statistically significant. All analyses were performed using the R statistical software (version 3.6.3). Results Study Results and Quality Assessment The systematic search yielded 2,051 articles, resulting in 85 eligible study records after screening all titles and abstracts. Ultimately, 20 studies were included in the qualitative and quantitative synthesis of the effects of RT on EF.18–37 All identified records were prospective or retrospective cohort studies. The selection process is illustrated in figure 1 and supplementary data 5 (https://www.jurology.com). Figure 1. Flow diagram of study selection process Employing the modified Newcastle-Ottawa Scale, 7 studies were considered of good, 1 of moderate and 12 of poor quality. The low methodological quality of most studies was mainly attributed to the nonrepresentative sample size, the variety in measure of patient-reported outcomes and the diversity of mean followup among studies. The detailed quality assessment is presented in supplementary data 6 (https://www.jurology.com). Study Characteristics A total of 1,695 RTRs with a mean age of 41.8±10.5 years were included in our systematic review and meta-analysis. Dialysis duration before RT was 26.2 months (range 4 to 93.8). Among studies providing relevant data, an end-to-end anastomosis of the graft to the internal iliac artery or an end-to-side anastomosis to the external iliac artery was selected in most cases. Common concomitant comorbidities included hypertension in 80% of the cases, smoking in 32%, diabetes in 24% and previous RT in 3.1%. Among 4 included studies reporting the change in testosterone levels, in 2 studies testosterone levels significantly increased, in 1 remained stable and in 1 testosterone levels significantly decreased after RT. Eight studies evaluated the differences in EF before and after RT with the EF domain of the IIEF-15 and 10 with its abridged version (IIEF-5). On the other hand, in 2 studies a questionnaire developed by the authors was employed. Overall, 8 studies assessed all participants postoperatively at 3, 6 or 12 months and 6 at a mean followup time of 71.7±52.4 months, while another 6 studies did not report the exact timepoint of postoperative EF evaluation. The detailed characteristics of all included studies are presented in tables 1 and 2. Table 1. Characteristics of all included studies Reference Country Population Tool for EF Assessment No. Participants No. Living Donor RTRs Immunosuppresants after RT No. Previous RT Type of Renal Transplant Anastomosis Ahmad 200918 Pakistan Adult males on HD undergoing RT IIEF-5 30 NA NA NA NA Bujdak 200319 Slovakia Adult males on HD undergoing RT IIEF-5 58 NA NA NA NA El-Bahnasawy 200420 Egypt Adult males undergoing RT EF domain of IIEF-15 400 400 Cyclosporine based treatment in 215 patients 14 End-to-end internal iliac artery: 369; End-to-side external iliac artery: 21; End-to-side common iliac artery: 10 Gontero 201221 Italy Adult males on HD undergoing RT EF domain of IIEF-15 22 NA Tacrolimus, prednisolone, MMF: 17; Tacrolimus, prednisolone: 2; Tacrolimus, prednisolone, sirolimus: 2; Cyclosporine, prednisolone, MMF: 1; Sirolimus, prednisolone, MMF: 1; Prednisolone, MMF: 1 NA End-to-side external iliac artery Guo 201022 China Married males receiving living-donor kidney transplant (including Hepatitis B virus+patients) IIEF-5 87 87 Corticosteroids, tacrolimus + MMF as supplementary treatment NA Internal iliac artery: 84; External iliac artery: 3 Jabali 202023 Kurdistan Adult males undergoing RT IIEF-5 59 NA Cyclosporine, MMF + tacrolimus: 32; Prednisolone, MMF + tacrolimus: 26; Everolimus, MMF + tacrolimus: 1 NA NA Jürgensen 200824 Germany Adult males undergoing simultaneous pancreas kidney transplantation EF domain of IIEF-15 101 NA NA NA NA Mirone 200925 Italy Adult males on HD undergoing RT EF domain of IIEF-15 78 0 Azathioprine: 8; MMF: 18; Ly antigen: 3; Methylprednisolone: 30; Prednisone: 31; Everolimus: 5; Rapamycin: 2; Sirolimus: 5; Tacrolimus: 10; Cyclosporin: 57 variously combined 5 End-to-side internal iliac artery Nanjappa 201226 India Adult males undergoing RT IIEF-5 127 NA NA NA Internal or external iliac artery anastomosis Nassir 200927 Saudi Arabia Adult males with sexual partners on HD or peritoneal dialysis EF domain of IIEF-15 16 NA NA NA NA Park 2013 28 Korea Adult males undergoing RT EF domain of IIEF-15 25 NA NA NA NA Peşkircioǧlu 199829 Turkey Adult males undergoing RT Questionnaire developed by Peşkircioǧlu et al. 65 NA NA 4 NA Pourmand 2007 30 Iran Adult males on HD undergoing RT IIEF-5 64 64 Prednisone, cyclosporine + MMF 0 Internal iliac artery: 45; External iliac artery: 11; Common iliac artery: 8 Qiao 200931 China Adult males receiving deceased-donor kidney transplant IIEF-5 48 0 NA NA NA Russo 200432 Italy Adult males undergoing RT EF domain of IIEF-15 113 NA NA NA NA Shamsa 200533 Iran Males receiving living-donor kidney transplant IIEF-5 15 15 Cyclosporine, azathioprine, MMF or prednisolone 0 Internal iliac artery Soliman 201734 Egypt Hepatitis C virus+adult males on dialysis undergoing RT IIEF-5 30 NA NA NA NA Teng 201135 China Adult males on dialysis undergoing RT IIEF-5 24 6 Cyclosporine: 7; Tacrolimus, MMF, prednisone: 17 0 NA Tian 200736 China Married males undergoing RT EF domain of IIEF-15 212 NA NA NA NA Tsujimura 2002 37 Japan Adult males undergoing RT Questionnaire developed by Tsujimura et al. 121 93 Cyclosporine, prednisone: 85; Azathioprine, prednisone: 23; Tacrolimus, prednisone: 13 1 Internal iliac artery NA, not available. Table 2. Baseline characteristics of included participants Reference Age±SD Mos. Dialysis before RT±SD Mos. EF assessment after RT No. Smoking No. Hypertension No. Diabetes Testosterone prior to RT (ng/dl) Testosterone after RT, ng/dl Ahmad 200918 39±7.4 NA All participants were assessed at 6 mos postop NA 14 13 633 NA Bujdak 200319 46.4±10 NA NA NA 48 6 NA NA El-Bahnasawy 200420 37±10 17.2±16.9 66.2±55.6 86 300 53 NA NA Gontero 2012 21 50.6±12.1 75±35.5 All participants were assessed at 3 mos postop 13 19 1 410±182 419±129 Guo 201022 NA 11.1±5.5 All participants were assessed at 6 mos postop 48 83 5 NA NA Jabali 202023 49.4±7.1 5.3±7.2 NA NA 10 21 NA NA Jürgensen 200824 NA NA NA NA NA 101 NA NA Mirone 200925 45.5±8.7 53.9±4 All participants were assessed at 12 mos postop 16 69 7 NA NA Nanjappa 201226 NA NA All participants were assessed at 3 mos postop NA NA NA 805±170 943±216 Nassir 200927 49.2±11.4 NA NA NA NA NA NA NA Park 201328 53.5±12.3 22±18.8 124±69.2 NA NA NA NA 516±243 Peşkircioǧlu 199829 42.5±9.3 NA 72±41.5 NA NA NA NA NA Pourmand 200730 42.3±10.4 16.8±18.7 All participants were assessed at 6 mos postop NA NA NA NA NA Qiao 200931 35.2±8.2 18.1±9.6 41.8±31.9 31 37 NA NA NA Russo 200432 43.5±10.2 43.6±34.1 53.6±49.2 NA NA NA NA NA Shamsa 200533 35.3±12 51.7±93.8 NA 11 6 NA 633 387 Soliman 201734 NA NA All participants were assessed at 12 mos postop NA NA NA NA NA Teng 201135 40.8±7.1 12.8±20.5 All participants were assessed at 6 mos postop NA NA 0 307±94 654±314 Tian 200736 NA NA NA NA NA NA NA NA Tsujimura 200237 44.7±0.8 42.3±4 107.9±6 NA NA NA NA 391±17 NA, not available. Patients with ED before and after RT Comparative data on the number of individuals with ED before and after RT were provided for 921 individuals from 14 studies.18,21–23,25–29,31–33,35,36 Before RT, 589 (64%) participants reported some degree of ED, compared to 492 (53.4%) after RT. RT was associated with a reduced risk of experiencing some level of ED (RR 1.21, 95% CI 1.02–1.45, I2=88%; fig. 2). However, in the sensitivity analysis of the 6 studies with good methodological quality, no significant difference in the number of patients with ED before and after RT was demonstrated (RR 1.13, 95% CI 0.88–1.44, I2=92%; supplementary data 7.1, https://www.jurology.com). In the subgroup analysis of 8 trials with 331 individuals reporting severe ED, no favorable effect of RT on ED was observed (RR 1.51, 95% CI 0.85–2.68, I2=33%; supplementary data 8, https://www.jurology.com). Moreover, the inspection of funnel plot asymmetry and the Egger's test did not indicate any important publication bias among the trials included in our quantitative synthesis (p=0.16; supplementary data 9, https://www.jurology.com). Figure 2. Forest plot of risk ratio of patient-reported ED at preoperative evaluation compared to postoperative evaluation. IV, inverse variance. Patients with Improved EF vs Deteriorated EF at Postoperative Assessment Overall, 14 studies with 1,322 participants provided comparative data on the effect of RT on postoperative EF.18–20,24,25,27–30,32,33,35–37 At postoperative evaluation, 515 (39%) individuals reported some improvement in EF, whereas 211 (16%) reported a deterioration. RTRs were at a higher likelihood of experiencing an improvement in EF after RT (RR 2.53, 95% CI 1.44 to 4.44, I2=90%; fig. 3). Additionally, 596 (45%) participants maintained the same EF levels at postoperative assessment. In the sensitivity analysis, we included 3 studies with good methodological quality. No significant effect was observed (RR 4.89, 95% CI 0.15–154.68, I2=92%; supplementary data 7.2, https://www.jurology.com). Figure 3. Forest plot of risk ratio of patients with improved EF at postoperative evaluation compared to patients with deteriorated EF. IV, inverse variance. Mean Change of the IIEF-15 and IIEF-5 Score Seven of the 18 studies which assessed EF with the IIEF-15 or IIEF-5 provided the preoperative and postoperative overall score.21,25–27,30,34,35 Five studies reported an improvement of the EF after RT, while 2 a deterioration. Overall, we included 361 RTRs in the analysis and their EF significantly improved by a mean of 3.04 points on the IIEF (95% CI 0.63–5.45, I2=96%; fig. 4). Furthermore, assessing the IIEF change from baseline of the 5 studies with good methodological quality, no significant difference was estimated (mean difference 1.72, 95% CI 0.89–4.33, I2=97%; supplementary data 7.3, https://www.jurology.com). Figure 4. Forest plot of mean difference in IIEF-15 or IIEF-5 before and after RT. MD, mean difference; IV, inverse variance. Grading of Evidence Although the significance of all outcomes was deemed important among the reviewers, the certainty of available evidence was considered low or very low. The observational design of included records, the low methodological quality of most studies and the high heterogeneity among study results downgraded the strength of evidence for all outcomes. Even though there is evidence that other factors may influence EF and affect the level of ED in RTRs, no study assessed the effects of potential confounders. The detailed grading of all outcomes is summarized in supplementary data 10 (https://www.jurology.com). Discussion This systematic review and meta-analysis suggests that RT leads to a significant improvement of EF. At postoperative evaluation, RT was associated with a reduced risk of experiencing some level of ED. Furthermore, RTRs were at a higher likelihood of experiencing an improvement in EF after RT and, accordingly, the mean IIEF-15 or IIEF-5 increased. Still, the robustness of our findings was considered low or very low due to the methodological concerns and high heterogeneity among the included studies. Additionally, it should be stressed that the favorable effects of RT on EF were not observed when undertaking a sensitivity analysis of studies with good quality and a subgroup analysis of patients with severe ED. Interestingly, almost all authors assessed EF with the IIEF-15 or IIEF-5, highlighting that IIEF constitutes the gold standard tool to evaluate ED in RTRs and individuals with end-stage renal disease. The underlying mechanisms of ED in end-stage renal disease patients are complex, including both organic and psychogenic factors.38 Concomitant cardiovascular comorbidities, dysfunction of the hypothalamic-pituitary-gonadal axis, neurovascular and endothelial alterations, metabolic disorders, long-term dialysis and psychosocial parameters may all deteriorate EF.39 RT reverts many of these factors by increasing renal clearance and hormonal secretion, by terminating dialysis dependence and by improving quality of life.40 On the other hand, after RT, other risk factors, such as perioperative and graft complications as well as endothelial dysfunction from immunosuppressant agents, may emerge.41 Overall, it seems that EF, in most cases, improves after RT.42 However, it remains unclear whether this improvement is clinically important. Additionally, in patients with severe vascular ED or penile abnormalities, RT does not exert favorable effects as it does not reverse the initial cause of ED.10 Phosphodiesterase type 5 inhibitors are considered the gold standard treatment modality among RTRs with persistent or de novo ED, as they present a safe and effective clinical profile.43 Of interest, PDE5i not only improve EF but they do not affect the concentrations of immunosuppressant agents such as cyclosporine or tacrolimus.44,45 Other recommended treatment modalities such as intracavernosal injections, topical or intraurethral alprostadil, vacuum erectile devices, testosterone replacement, low-intensity extracorporeal shockwave therapy and penile implants may also prove beneficial in nonresponders or in patients with contraindications to PDE5i.46–49 Last but not least, psychosexual therapy alone or in combination with another therapeutic approach should also be considered in patients with predominant psychogenic ED.50 Strengths and Limitations RT is a necessary, life-saving procedure that does not permit for randomized comparative trials between RTRs and dialysis patients. Therefore, the evidence about the effects of RT on EF is only based on scarce, observational data. In this context, we provided the first study to address this matter in a holistic approach, using data synthesis and meta-analytical techniques. Even though our outcomes do not provide high level of evidence, our study may raise clinical awareness about the potential benefit of RT on ED. Indeed, our findings displayed high heterogeneity and raised methodological concerns. In an attempt to overcome these biases, we performed a sensitivity and a subgroup analysis. However, the paucity of available data did not permit us to conduct further predefined subgroup and metaregression analyses. Therefore, our findings may be underpowered. Accordingly, the strength of existing evidence was graded low or very low for all outcomes. Another limitation that should be taken into consideration is the variety in the timepoint of postoperative EF evaluation. Assessing EF after a short postoperative followup may lead to falsely increased ED estimates due to graft malfunction and alterations in patients' body image. On the other hand, assessing EF after a long postoperative followup may also influence outcomes due to the effect of potential confounding factors. Future Perspectives In a field of research where randomized controlled trials are not possible, large, high-quality prospective cohort studies are needed to validate and strengthen our findings. Future studies should address the role of RT on EF by measuring sexual and erectile function with the IIEF. In an attempt to adjust for potential confounders, they should evaluate EF at multiple postoperative timepoints, report the preferred surgical procedure, the different immunosuppression regimens and all perioperative or graft complications. Moreover, these studies should provide data regarding previous or current treatments with PDE5i or with other therapeutic options both at the pretransplantation and at the posttransplantation state. Accordingly, future studies aiming to determine the effect of potential risk factors for ED in RTRs should report the type and duration of dialysis prior to RT as well as previous successful and unsuccessful RTs. They should also address the effect of psychosocial parameters by assessing the presence of depression or other psychogenic causes of ED. Ideally, a carefully designed, long-term, multicenter cohort study could evaluate the aforementioned factors in the same patients at the predialysis state and at multiple timepoints during dialysis and after RT in an attempt to further elucidate the pathophysiology of ED in patients with chronic kidney disease. It should be stressed that randomized controlled trials evaluating the treatment options in patients with persistent or de novo ED after RT as well as studies assessing the effect of combination therapy in nonresponders to PDE5i are also necessary. Moreover, further systematic reviews and meta-analyses summarizing the available body of literature and providing relevant recommendations are needed to formulate clinical guidelines about treatment modalities in RTRs. Well-conducted molecular and animal studies may help to better understand the pathophysiology of the observed improvement of EF after RT as well as to address whether immunosuppressant agents lead to a significant penile endothelial dysfunction. Additionally, other aspects of sexual and reproductive health in both male and female RTRs should also be considered in future studies in an attempt to improve quality of life in this subgroup of patients that is increasing worldwide. Conclusion This systematic review and meta-analysis suggests that renal transplantation improves erectile function and that the risk of experiencing some level of erectile dysfunction reduces postoperatively compared to preoperatively. Of note, the number of patients with severe erectile dysfunction did not improve after renal transplantation. Still, the strength of evidence for our findings was deemed low due to the methodological concerns of most of the included studies. Understanding the underlying mechanisms leading to improvement of erectile function in renal transplant recipients is important. Erectile dysfunction is highly prevalent in end-stage renal disease patients and warrants clinical attention as it affects quality of life. To date, evidence on the matter is mostly based on scarce, low quality data. Therefore, more studies with standardized outcomes are needed to validate our findings. 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Google Scholar All authors participated in the drafting, writing, and editing of the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 205Issue 4April 2021Page: 1009-1017Supplementary Materials Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.Keywordskidney failureerectile dysfunctionmeta-analysiskidney transplantationchronicMetricsAuthor Information Nikolaos Pyrgidis First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece *Correspondence: Alois 16, Pilaia, Thessaloniki, Greece telephone: 0030 6982 14 2006; E-mail Address: [email protected] More articles by this author Ioannis Mykoniatis First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece More articles by this author Ioannis Sokolakis Department of Urology, 'Martha-Maria' Hospital Nuremberg, Nuremberg, Germany More articles by this author Ioanna Minopoulou School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece More articles by this author Meletios P. Nigdelis School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece More articles by this author Petros Sountoulides First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece More articles by this author Paolo Verze Department of Medicine, Surgery, Dentistry "Scuola Medica Salernitana", Urology Unit—University of Salerno, Salerno, Italy More articles by this author Georgios Hatzichristodoulou Department of Urology, 'Martha-Maria' Hospital Nuremberg, Nuremberg, Germany More articles by this author Dimitrios Hatzichristou First Department of Urology, G. Gennimatas Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece More articles by this author Expand All All authors participated in the drafting, writing, and editing of the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. Advertisement Advertisement Loading ...