Minireviews
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. Jul 6, 2015; 4(3): 379-387
Published online Jul 6, 2015. doi: 10.5527/wjn.v4.i3.379
Erectile dysfunction in chronic kidney disease: From pathophysiology to management
Eirini Papadopoulou, Anna Varouktsi, Antonios Lazaridis, Chrysoula Boutari, Michael Doumas
Eirini Papadopoulou, Anna Varouktsi, Antonios Lazaridis, Chrysoula Boutari, Michael Doumas, 2nd Propaedeutic Department of Internal Medicine, Aristotle University, 54643 Thessaloniki, Greece
Author contributions: Papadopoulou E and Doumas M conceived the idea of the manuscript; Papadopoulou E, Varouktsi A, Lazaridis A, and Boutari C performed the systematic search of the literature and drafted different parts of the manuscript; Doumas M overviewed the final draft; all authors approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Michael Doumas, Associate Professor, 2nd Propaedeutic Department of Internal Medicine, Aristotle University, 49 Konstantinoupoleos street, 54643 Thessaloniki, Greece. michalisdoumas@yahoo.co.uk
Telephone: +30-2310-992836 Fax: +30-2310-992834
Received: November 20, 2014
Peer-review started: November 22, 2014
First decision: December 12, 2014
Revised: April 3, 2015
Accepted: May 27, 2015
Article in press: May 28, 2015
Published online: July 6, 2015

Abstract

Chronic kidney disease (CKD) is encountered in millions of people worldwide, with continuously rising incidence during the past decades, affecting their quality of life despite the increase of life expectancy in these patients. Disturbance of sexual function is common among men with CKD, as both conditions share common pathophysiological causes, such as vascular or hormonal abnormalities and are both affected by similar coexisting comorbid conditions such as cardiovascular disease, hypertension and diabetes mellitus. The estimated prevalence of erectile dysfunction reaches 70% in end stage renal disease patients. Nevertheless, sexual dysfunction remains under-recognized and under-treated in a high proportion of these patients, a fact which should raise awareness among clinicians. A multifactorial approach in management and treatment is undoubtedly required in order to improve patients’ quality of life and cardiovascular outcomes.

Key Words: Chronic kidney disease, Erectile dysfunction, Management, Quality of life, Hypertension, Diabetes mellitus, Phosphodiesterase-5 inhibitors

Core tip: Erectile dysfunction is highly prevalent among patients with chronic kidney disease in rates that reach even 70%, especially in those suffering from end stage renal disease. The rates of patients suffering from sexual dysfunction tend to be higher when additional risk factors, such as coronary artery disease, diabetes mellitus, hypertension or prescription of antihypertensive drugs, coexist. Integrated management of these patients through lifestyle measures, hormonal replacement, and use of drugs such as phosphodiesterase-5 inhibitors, is essential in order to improve sexual function among these patients, thereby maintaining a satisfactory quality of life.



INTRODUCTION

Sexual dysfunction is highly prevalent in patients with chronic kidney disease (CKD) especially those receiving dialysis. Almost 70% of men with CKD report erectile dysfunction (ED) and these estimates are higher than in the general population[1]. The cause is generally multifactorial with psychological, neurological, endocrinological, vascular and iatrogenic factors acting in concert to increase the likelihood of ED[2]. A number of recent studies suggest an association between endothelial dysfunction and ED[3].

This review aims to analyze the pathophysiology of ED in patients with CKD, to present its prevalence rates in various stages of CKD, to highlight comorbid conditions and common risk factors, which both diseases share and, eventually, to discuss possible therapeutic options, which might improve sexual function of CKD patients.

We performed a systemic search of the literature using the PubMed, OVID, EMBASE and Cochrane Central Register databases from their inception to July 2014. The studies addressing the association between ED and CKD were identified by using the following terms in various combinations: CKD, erectile dysfunction, impotence, renal failure, end stage renal disease, kidney transplantation, phosphodiesterase (PDE)-5 inhibitors. In addition, we reviewed the reference lists of the identified original papers, the studies citing identified papers and review papers relevant to this topic.

Data were extracted by four independent members of our team (Papadopoulou E, Varouktsi A, Lazaridis A, Boutari C) and were discussed with the senior author of our paper (Doumas M). The following criteria were required for a study to be included in our review: observational studies with at least 20 participants, detailed description of a proper estimation of renal function and erectile function.

PATHOPHYSIOLOGY

Erectile dysfunction is defined as the persistent inability to attain and/or maintain penile erection sufficient for sexual intercourse[4]. The erectile process is a complex neurovascular event. In response to sexual stimulation, cavernous nerve terminals and endothelial cells release nitric oxide (NO) which is believed to be the main vasoactive mediator of penile erection. NO promotes penile vasodilation and blood flow, by activating soluble guanyl cyclase to produce 3, 5-cyclic guanosine monophosphate resulting in an enzymatic cascade that reduces intracellular calcium and induces relaxation of cavernosal smooth muscle[5].

Appropriate hormonal environment permits a successful erection with testosterone playing a primary role[6]. Disturbances in neurovascular control, abnormal hormone levels or psychological factors are responsible for the vast majority of ED that is broadly classified as psychogenic (generalized, situational), organic (vasculogenic, neurogenic, anatomic, endocrinologic) or mixed[7].

Psychological factors include primary lack of sexual arousal, chronic disorder of sexual intimacy, depression and performance anxiety. Physiological factors are a more common aetiology and neurological disorders such as Parkinson’s disease, stroke, tumour, multiple sclerosis and spinal cord injury are noted to be associated with ED. In addition hormonal disorders such as hypogonadism, hyperprolactinemia and both hyperthyroid and hypothyroid states are known to result in ED. Arterial insufficiency associated with diabetes, hypertension, dyslipidemia, cigarette smoking, blunt perineal or pelvic trauma and pelvic irradiation, tend to be the most common cause of ED[8].

In men with chronic renal disease a combination of testicular failure and secondary disturbances in the pituitary-gonadal axis can be detected in the early stages of CKD and progressively worsen as the renal disease progresses[9]. Some authors have reported that successful kidney transplantation may improve sexual function with reference to the previous situation of haemodialysis[10]. Impaired spermatogenesis and testicular damage with decreased volume of ejaculate, either low or complete azoospermia, low percentage of motility and infertility were reported[11].

Histological changes in the testes revealed decreased spermatogenic activity especially in the later stages of spermatogenesis which are hormonally dependent[12]. Testicular biopsy is often performed to demonstrate reduced spermatogenesis[13]. Leydig and Sertoli cells show absence of hypertrophy or hyperplasia and the reduced levels of total and free testosterone presented in CKD, suggest a Leydig cell dysfunction[14].

Hypogonadism (low testosterone) defined as total testosterone below 300 ng/mL is a prevalent condition in men with CKD especially in those undergoing dialysis and can contribute to decreased libido, ED, oligospermia infertility and anaemia[15]. On the other hand total plasma estrogen concentration is often elevated. The plasma concentration of the pituitary gonadotropin luteinizing hormone (LH) is elevated probably as a result of the decreased release of testosterone from the Leydig cells and the consequent loss of normal negative feedback. In addition the metabolic clearance rate of LH is reduced and it is not corrected by dialysis[16].

In uremic subjects disturbances in LH secretion has been observed but it is not known whether this is the result of a change in GnRH release from the hypothalamus or a change in the responsiveness of the pituitary. However kidney transplantation seems to restore the secretory pattern of LH. Follicle-stimulating hormone (FSH) secretion is also elevated in men with CKD. A peptide called inhibin produced by the Sertoli cells has a negative feedback on the release of FSH. Uremic patients with severe damage in seminiferous tubules and Sertoli cells tend to have higher plasma FSH concentrations as less inhibin is secreted[9].

Prolactin levels also appear substantially elevated in men with CKD, with a prevalence of hyperprolactinemia from 30%-65%, as a consequence of both reduced renal clearance and increased production. Again these abnormalities seem to resolve after kidney transplantation. Evidence indicates that hyperprolactinemia is associated with infertility, loss of libido, testosterone deficiency and increased risk of cardiovascular events and mortality in CKD. Bromocriptine treatment reduces prolactin levels with no significant side effects[14].

According to the “artery size hypothesis” atherosclerosis is more likely to develop first in the smaller arteries than in the larger ones. Since penile arteries are significantly smaller (1-2 mm diameter) than coronary arteries (3-4 mm), symptoms of ED occur several years before coronary artery disease (CAD) symptoms. ED is also found to be a stronger predictor of CAD than any of the traditional risk factors such as family history, hypertension, dyslipidemia and can be considered as a marker of ischemic heart disease in both CKD and non CKD patients[17,18].

NO is the primary neurotransmitter of penile erection. In chronic renal failure NO bioavailability is reduced. The expression of NO-synthase (NOS) has been shown to be alterned thus leading to a disturbance in sexual function[12]. Possible causes of NO deficiency are substrate limitation (L-arginine), as a result of disturbances in the renal biosynthesis of this amino acid and increased levels of circulating endogenous inhibitors of NOS especially asymmetric dimethylarginine (ADMA). Elevated levels of ADMA has emerged as an independent risk factor in end stage renal disease and reducing ADMA concentration might be a therapeutic goal[19].

Uremic polyneuropathy is an important contributor of ED. Patients undergoing haemodialysis are reported to have an abnormal response to Valsalva manoeuvre, impaired nocturnal penile tumescence and bulbocavernous reflex as evidence of autonomic and peripheral neuropathy, all correlated to sexual dysfunction[20].

CKD is associated with higher anxiety, higher distress, high depression and especially dialysis patients report interpersonal difficulties, lower employment, reduced social activity and low quality of life (QoL)[21]. Changes in body shape and image (catheter, fistula) also contribute to lack of desire and sexual dysfunction. The presence of higher depressive symptoms which are highly prevalent in patients undergoing haemodialysis are independently associated with sexual dysfunction and probably common factors are responsible for both[22].

Treatment of hypertension has also been associated with sexual dysfunction. Β-blockers could cause ED by decreasing testosterone levels and potentiating α1-adrenergic activity in the penis. Patients taking thiazide diuretics report difficulty in gaining and maintaining an erection and difficulty with ejaculation. Spironolactone can cause gynecomastia, decreased libido and ED while drugs such as calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, are associated with lower incidence of these side effects. Other drugs commonly involved in the development of ED are cimetidine, tricyclic antidepressants and metoclopramide[9,23,24].

Available data point towards a detrimental effect of CKD on spermatogenesis[9]. Moreover, zinc deficiency caused by reduced dietary intake, malabsorption and possible loss during haemodialysis, has been implicated in the pathophysiology of reduced sperm motility in CKD patients[9,23,25].

PREVALENCE

Sexual dysfunction is a common feature in patients with CKD despite the fact that is often underestimated by clinicians. Existing comorbidities such as diabetes mellitus, hypertension, atherosclerosis, and certain medications (medications e.g., antidepressants diuretics, beta-blockers and other antihypertensive drugs) as well as pathophysiological conditions such as peripheral vascular disease, peripheral neuropathy and uremia are associated with a decrease in erectile function of male patients[26].

Since 1997, Rosen et al[27] have developed the International Index of Erectile Dysfunction (IIEF), a questionnaire which includes all aspects of male sexual functions (erectile function, orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction) and can evaluate as objectively as possible sexual function in male patients. Variable prevalence rates have been reported, mainly due to the study populations’ diversity and the variety of sexual dysfunction assessment instruments. Bellinghieri et al[11] reported a direct correlation between IIEF and GFR, an inverse correlation between testosterone and cholesterol and an increased number of diabetic patients with ED in stage 3 of chronic renal failure.

The prevalence of erectile dysfunction is strongly age-dependent. The prevalence rises sharply with age. In particular, in the Massachusetts Male Aging Study (MMAS), erectile dysfunction is found in 8% in patients aged in their 40 s and rises up to 80% in patients over 70 years of age[28]. Messina et al[29] reported that men under 50 years old with CKD have a higher prevalence of ED than men over age 50 years, while in the MMAS the level of impotence and the prevalence of erectile dysfunction was positively associated with the subjects’ age[30].

During the last decades the prevalence of end stage renal disease has significantly increased worldwide and due to the progress in renal replacement therapy. People with end stage renal disease (ESRD) appear to have a reduction in the QoL, which is associated with several factors such as age, therapy complications, psychological factors, and co-existing diseases[31]. Mesquita et al[32] reported that the prevalence of ED was 76.5%, with 72.3% in stage 3 CKD, 81.5% in stage 4 and 87.5% in stage 5 CKD.

A study of 174 male HD patients (controls: 1133 healthy males) revealed that the prevalence of ED in men older than 40 years was higher than 80%, significantly higher than that described in control groups of the same age[33]. Espinoza et al[34] reported an ED prevalence of 48.9% in kidney transplant recipients in a study conducted among men with kidney transplantations. Rosas et al[26] reported that the prevalence of ED was 82% for all HD patients in a cross sectional study of 302 subjects treated with haemodialysis. ED was present in 90% of older HD patients (> 50 years) whereas its prevalence in younger subjects (< 50 years) was 63%[26].

A large systematic review and meta-analysis of observational studies (50 studies, 8343 patients) reported that the prevalence of any level of erectile dysfunction is approximately 70% (21 studies, 4389 patients) with no difference in prevalence rates among hemodialysis and peritoneal dialysis patients. However, in kidney transplant recipients the prevalence was lower (59% vs 75%)[35].

EFFECT OF COMORBIDITIES

Erectile and kidney dysfunction share common risk factors and are associated with diseases involving endothelial impairment such as diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, smoking and obesity[32].

Cigarette smoking is an established modifiable risk factor of arteriosclerosis. As a result of the MMAS, Feldman et al[28] reported that current smokers presented an adjusted odds ratio of 1.97 for incident ED compared to non-smokers (P = 0.03). Other studies also report a higher prevalence of ED in the groups of smokers compared to non-smokers and a higher percentage of smoking in men with severe/complete ED but these results did not appear to be significant in multivariate analysis[36].

As far as obesity is concerned, the nine-year follow-up prospective study from the MMAS revealed that it had an independent effect on ED, as a BMI ≥ 28 kg/m2 predicted incident ED (OR: 1.96, P = 0.01). Similar results were observed in the Rancho-Bernando Study, where the age-adjusted BMI appeared to be significantly higher in men with severe ED or men who were sexually inactive (P < 0.05)[28,37].

Dyslipidemia is associated with an increased risk of erectile dysfunction due to its effect on endothelium and smooth muscle cells of the corpus cavernosum. The prospective study of MMAS failed to indicate a link between serum lipids and prediction of ED[28]. On the other hand, in the Rancho-Bernando Study elevated serum cholesterol levels and triglyceride levels were associated with more severe ED, as men without ED had lower cholesterol levels compared to men with moderate ED (P < 0.05), and men with no sexual activity or severe/complete ED had higher triglyceride levels than men without ED (P < 0.05)[37]. In a prospective study among 2869 men, Ponholzer et al[38] reported that hyperlipidemia was independently and significantly correlated to the presence of erectile dysfunction with an OR of 2.29 (P = 0.04). Hyperlipidemia is common among men with ED at rates that may reach 40%[39]. There have been reports that lipid-lowering therapy and use of statins may have a negative impact on erectile function; nevertheless statins are not generally accepted as a cause of ED and through their pleiotropic effects, statins may increase vascular NO activity and improve endothelial function[40].

Diabetes mellitus is considered to be a risk factor for ED due to vasculopathy and autonomic neuropathy and, additionally, one of the most frequent causes of CKD. Several studies have shown that it is highly prevalent and independently associated with erectile dysfunction in general population. Giuliano et al[41] reported a prevalence of ED of 71% among patients with DM and noted a trend of association between decreased mean IIEF-5 score and an increased duration of type 1-diabetes, lack of glycemic control and existence of complications. In a study of arterial risk factors (diabetes, hypertension, hyperlipidemia and smoking) among 440 impotent men, diabetes was the only risk factor that in isolation significantly reduced the penile blood-pressure index[42]. In another large prospective study including 2869 men diabetes was associated with a three times higher risk for ED[38]. Diabetic nephropathy is one of the most common causes of CKD and highly prevalent among end stage renal disease patients. Diabetes mellitus is significantly associated and considered to be an independent risk factor for erectile dysfunction in these patients[29,33,43]. No association between ED and cause of CKD has been proven. Nevertheless, in a study including 119 men with CRF in hemodialysis program, the highest prevalence of ED was among men whose kidney disease was due to diabetes[36]. Rosas et al[26] found that men with diabetes had twice the odds of suffering from erectile dysfunction compared to non-diabetic men in a cohort study among 302 subjects in hemodialysis, whereas Mesquita et al[32] reported that among 81 patients with CKD, diabetic patients were 4 times more likely to have impaired erectile function compared to non-diabetic subjects (P = 0.048).

In the general population, hypertension is considered to be a risk factor for erectile dysfunction due to its contribution in the atherosclerotic process and the endothelial dysfunction in penile vessels. In a multicenter prospective study conducted in Spain among 2130 men with primary hypertension, erectile dysfunction was reported in 45.8% of them[44]. In a smaller study, which included 634 Greek patients with essential hypertension, erectile dysfunction was prevalent in 35.2% of them compared to a rate of 14.1% found in the normotensives subjects (P < 0.01) and was associated with the severity of hypertension[23]. Despite the fact that a strong association between hypertension and the emerge of erectile dysfunction has been well established in several other studies[38,41,45], data occasionally remain uncertain if hypertension is an independent risk factor for[28,42]. Although the frequency of hypertension is high among patients with CKD in rates reaching even 70%-95%, its association with sexual dysfunction among these patients is not always statistically significant[29,32,36,43]. Erectile dysfunction observed in hypertensive patients may be associated with the disease itself or it may be caused by the antihypertensive therapy being administered to these patients. In CKD patients, the drug therapy prescribed is often multifactorial including many types of old-antihypertensive drugs such as central acting antihypertensive drugs, diuretics (e.g., thiazide diuretics and spironolactone), and beta-blockers, especially nonselective ones, which have shown a major influence on erectile function. New-generation agents, which include calcium-channel blockers, nebivolol and renin-angiotensin system inhibitors seem to have less deteriorating effects in sexual activity[6,46]. Indeed, Giuliano et al[41] reported greater IIEF-5 scores in patients receiving ACE inhibitors or angiotensin II receptor blockers compared to other antihypertensive treatment, while Rosas et al[26] revealed a significant association between ACE inhibitors and a decreased prevalence of erectile dysfunction in hemodialysis patients (OR: 0.42). As far as CKD patients are concerned, other widely used drugs, which are traditionally associated with increased rates of erectile dysfunction such as antidepressants, H2 antagonists and benzodiazepines, should be taken into account as their use may impair sexual function[46].

Atherosclerosis and vascular calcification are very common in the CKD population, thus contributing to higher rates of cardiovascular disease and mortality among these patients. These findings tend to be present even among young adults undergoing hemodialysis compared to healthy subjects of the same age[47]. In the uremic subjects with ESRD, cardiovascular disease (CVD) is responsible for 40%-50% of all deaths and CVD mortality rates in those patients are approximately 15 times higher than the general population[21]. In addition to typical cardiovascular disease risk factors, end stage renal disease patients have impaired calcium and phosphorus homeostasis, deficiency of calcification inhibitors and receive high doses of vitamin D treatment, factors which have shown to promote the vascular calcification process[48]. In the general population, it has been reported that erectile dysfunction is associated with silent coronary disease as patients experiencing sexual dysfunction symptoms tend to have higher coronary artery calcification scores even in the absence of angina symptoms[49,50], a finding which is additionally observed among hemodialysis patients with severe ED, who also tend to present greater coronary artery calcium scores[3]. In a retrospective cohort study of 12825 ED patients, it was reported that there was a two-fold increase in the risk of acute myocardial infarction among men with ED[51]. Due to the apparent link between erectile dysfunction and other vascular abnormalities, CKD patients suffering from erectile dysfunction are in high risk of CVD. Therefore, clinicians should perform a careful evaluation in order to assess coexisting comorbid conditions and modify possible risk factors.

Cardiovascular risk and its association with sexual activity should be evaluated in all men with indications or confirmed cardiovascular disease. According to the Second Princeton Consensus Conference algorithm, patients are classified as low, intermediate or high cardiac risk depending on their sexual activity and their management depends on which category they are integrated. Although the Princeton-II algorithm is based on acknowledged cardiovascular risk factors such as hypertension, diabetes mellitus or history of myocardial infarction or angina symptoms, CKD is not included as a condition increasing the cardiovascular risk in men with erectile dysfunction. Considering the increased risk of cardiovascular disease among patients suffering from renal failure and sexual dysfunction, it becomes obvious that these patients should be likewise evaluated and managed[52].

MANAGEMENT OF ED

The improvement of sexual function in CKD patients through a multifactorial approach is associated with an increase in patients’ QoL and improved cardiovascular outcomes.

Lifestyle and general measures

Treatment of erectile dysfunction should start with an assessment of general status, evaluation of possible covariates and adoption of lifestyle measures, such as quit smoking, decrease of alcohol consumption and regular physical activity. As far as dialysis patients are concerned, clinicians should focus on optimization of dialysis delivery and adequate nutritional intake of these patients. The medication profile of each patient should be reviewed, considering that many drugs such as diuretics, beta-blockers, antidepressants, and H2-antagonists are related to erectile dysfunction. Moreover, drugs inducing hyperprolactinaemia such as metoclopramide, haloperidol, phenothiazine, chlorpromazine, and methyldopa should be taken into account[53].

“Curable” causes of erectile dysfunction

Psychogenic ED: Psychotherapy and psychoeducational interventions such as rational, emotive therapy, sex group therapy and sexual counseling should be recommended when depression and other psychogenic causes of erectile dysfunction are suspected or in cases, in which it is indicated[53].

Hormonal-endocrine approach: Therapy with recombinant human Erythropoietin (rHuEPO) has shown to improve many aspects of functional health, such as exercise tolerance, sexual function, and QoL of patients with CKD[54]. This improvement is likely to be associated with the correction of anemia, induced by the introduction of rHuEPO. In addition, some studies have shown that rHuEPO therapy is associated with alterations on endocrine function, affecting the pituitary-gonadal feedback mechanism. There is evidence supporting that it is associated with reduced prolactin, FSH and LH levels and increased plasma testosterone levels[55,56], although some small studies support that the prolactin levels suppression remains controversial among rHuEPO recipients[57]. Testosterone deficiency is a recognizable contributing factor in the development of anemia in CKD patients. Testosterone replacement therapy may increase blood count, QOL and sexual function[56].

Testosterone replacement therapy has been associated with multiple benefits in men with late onset hypogonadism. However, its effectiveness in men with CKD remains controversial considering that the improvement noted in libido, sexual desire, mood and energy is more profound than in erectile dysfunction individually[58]. Testosterone treatment may be also beneficial in increasing muscle mass and strength and in enhancing erythropoiesis[56]. Derivatives of testosterone can be delivered as injectable, oral, buccal, transdermal and subdermal preparations. Potential side effects such as cardiovascular adverse events, prostate cancer or exacerbation of sleep apnea should be identified and carefully assessed by clinicians[56].

An additional potential therapeutic option affecting endocrine disorders in CKD patients is dopaminergic agonists such as bromocryptine, which normalize prolactin levels, elevate plasma testosterone levels and improve libido and potency[59]. It has been reported that oral zinc supplements improve testosterone levels but its effect on sexual function remains conflicting. Subsidiary administration of oral vitamin E has shown that it may decrease prolactin and plasma testosterone levels[56].

First line therapy-oral pharmacotherapy

Since their introduction in 1998, phosphodiesterase-5 inhibitors are considered first-line agents for erectile dysfunction treatment in the general population. Sildenafil which is the agent most widely used is metabolized mainly in the liver and excreted approximately 80% in the feces and 13% in the urine; therefore, its pharmacokinetics are not significantly different in mild to moderate renal disease compared to healthy men, although its bioavailability may be increased in patients with creatinine clearance < 30 mL/min[60]. In several RCTs for treatment of sexual dysfunction in patients with CKD, treatment with sildenafil and vardenafil is associated with improvement in the overall score of IIEF-5, an increase of the score of all individual IIEF-5 tool domains (erection frequency, erection quality, penetration ability, maintenance frequency of penetration, maintenance of erection after penetration and erection confidence) compared to placebo and an increase of the overall satisfaction score of the IIEF-15 sexual assessment tool. For the use of other agents such as tadalafil or mirodenafil in CKD patients data is limited[61]. Sildenafil citrate is also considered an important first-line therapeutic option among kidney transplant recipients with sexual dysfunction as it has no effect on renal function or immunosuppressive drug levels[62]. The frequency of adverse events in CKD patients is similar to the general population, with headaches, flushing, dyspepsia, myalgia, and back pain, nasal congestion being most commonly reported, while more serious adverse events such nonarteritic anterior ischemic optic neuropathy or cardiovascular events are extremely rare. Due to the possible emerge of hypotension these agents are contraindicated in patients receiving nitrates. In addition, PDE-5 inhibitors should not be administered with PDE-3 inhibitors, such as cilostazol which is used for the management of peripheral artery disease.

Other therapeutic options beyond PDE-5 inhibitors

Vacuum constriction devices are an alternative therapeutic option. They provide negative pressure to the penis, resulting in increased blood flow and thus, causing erection. However, the satisfaction rates among patients remain variable.

Intraurethral or intracavernosal delivery of alprostadil (prostaglandin E1) individually or in combination with other drugs such as papaverine or phentolamine can be used as a second-line therapy in case of non-response to oral drugs. A penile prosthesis is another therapeutic option in case of previous therapeutic failure and is preferred by some patients as it provides more permanent results. Nevertheless, it is recommended to be delayed after renal transplantation, as a percentage of ESRD patients may improve their sexual function afterwards[53].

Erectile dysfunction in post-transplant patients

Kidney transplantation is considered to be the most effective therapeutic option for patients suffering from CKD. The majority of kidney transplantations are carried out in middle age, where sexual function and fertility remain important[62]. Several studies suggest that erectile dysfunction remains highly prevalent, reaching 50% after kidney transplantation[34,63]. Sexual function post-operatively may be limited by graft malfunction, preexisting comorbid conditions of diabetes mellitus, hypertension, smoking and dyslipidemia, duration of dialysis before transplantation, effects of immunosuppressive or hypertension therapy and is associated with the original cause of kidney insufficiency[10,64]. The influence of haemodialysis duration before kidney transplantation observed by Rebollo et al[10] may be owing to the longer duration of peripheral vascular disease, and thus, prolonged vascular damage and hormonal changes in dialysis patients. With regard to immunosuppressive treatment, Malavaud et al[63] reported no statistically significant association between cyclosporine therapy and erectile dysfunction, while the study of Rebollo et al[10] showed no association between ED and use of tacrolimus as immunosuppressant. The combination of cyclosporine and prednisone may have a more beneficial effect than azathioprine in gonadal function after kidney transplantation[65]. Renal transplantation usually results in normalization of hormonal profiles of kidney transplant recipients, reducing high levels of prolactin and LH and elevating plasma testosterone[65-68]. Despite these alterations, recovery of sexual function is not present in all patients, as erectile dysfunction may be affected by various factors and thus, can be highly prevalent in patients with renal insufficiency even after kidney transplantation.

CONCLUSION

Sexual dysfunction and chronic renal failure share common pathophysiological pathways and are affected by similar comorbid conditions. Erectile dysfunction tends to be more frequent in patients with CKD. Its incidence is strongly associated with age and stage of renal failure. Despite the advances in therapeutic options, especially the emerge of PDE-5 inhibitors, and the potential relief they may offer, erectile dysfunction still remains highly prevalent and further studies are needed.

Footnotes

P- Reviewer: Azadzoi K, Barzilay JI, Kadoglu A S- Editor: Gong XM L- Editor: A E- Editor: Yan JL

References
1.  Vecchio M, Palmer SC, Tonelli M, Johnson DW, Strippoli GF. Depression and sexual dysfunction in chronic kidney disease: a narrative review of the evidence in areas of significant unmet need. Nephrol Dial Transplant. 2012;27:3420-3428.  [PubMed]  [DOI]
2.  Bortolotti A, Parazzini F, Colli E, Landoni M. The epidemiology of erectile dysfunction and its risk factors. Int J Androl. 1997;20:323-334.  [PubMed]  [DOI]
3.  Inci K, Hazirolan T, Aki FT, Oruc O, Tombul T, Tasar C, Erkan I, Bakkaloglu M, Turgan C, Ergen A. Coronary artery calcifications in hemodialysis patients and their correlation with the prevalence of erectile dysfunction. Transplant Proc. 2008;40:77-80.  [PubMed]  [DOI]
4.  NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA. 1993;270:83-90.  [PubMed]  [DOI]
5.  Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich). 2006;8:53-62.  [PubMed]  [DOI]
6.  Manolis A, Doumas M. Hypertension and sexual dysfunction. Arch Med Sci. 2009;5:S337-S350.  [PubMed]  [DOI]
7.  Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am. 2005;32:379-395, v.  [PubMed]  [DOI]
8.  Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart. 2003;89:251-253.  [PubMed]  [DOI]
9.  Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol. 1999;10:1381-1388.  [PubMed]  [DOI]
10.  Rebollo P, Ortega F, Valdés C, Fernández-Vega F, Ortega T, García-Mendoza M, Gómez E. Factors associated with erectile dysfunction in male kidney transplant recipients. Int J Impot Res. 2003;15:433-438.  [PubMed]  [DOI]
11.  Bellinghieri G, Santoro D, Mallamace A, Savica V. Sexual dysfunction in chronic renal failure. J Nephrol. 2008;21 Suppl 13:S113-S117.  [PubMed]  [DOI]
12.  Palmer BF. Outcomes associated with hypogonadism in men with chronic kidney disease. Adv Chronic Kidney Dis. 2004;11:342-347.  [PubMed]  [DOI]
13.  Dohle GR, Elzanaty S, van Casteren NJ. Testicular biopsy: clinical practice and interpretation. Asian J Androl. 2012;14:88-93.  [PubMed]  [DOI]
14.  de Vries CP, Gooren LJ, Oe PL. Haemodialysis and testicular function. Int J Androl. 1984;7:97-103.  [PubMed]  [DOI]
15.  Carrero JJ, Bárány P, Yilmaz MI, Qureshi AR, Sonmez A, Heimbürger O, Ozgurtas T, Yenicesu M, Lindholm B, Stenvinkel P. Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease. Nephrol Dial Transplant. 2012;27:709-715.  [PubMed]  [DOI]
16.  Prem AR, Punekar SV, Kalpana M, Kelkar AR, Acharya VN. Male reproductive function in uraemia: efficacy of haemodialysis and renal transplantation. Br J Urol. 1996;78:635-638.  [PubMed]  [DOI]
17.  Manolis A, Doumas M. Sexual dysfunction: the ‘prima ballerina’ of hypertension-related quality-of-life complications. J Hypertens. 2008;26:2074-2084.  [PubMed]  [DOI]
18.  Steele TE, Wuerth D, Finkelstein S, Juergensen D, Juergensen P, Kliger AS, Finkelstein FO. Sexual experience of the chronic peritoneal dialysis patient. J Am Soc Nephrol. 1996;7:1165-1168.  [PubMed]  [DOI]
19.  Baylis C. Arginine, arginine analogs and nitric oxide production in chronic kidney disease. Nat Clin Pract Nephrol. 2006;2:209-220.  [PubMed]  [DOI]
20.  Kersh ES, Kronfield SJ, Unger A, Popper RW, Cantor S, Cohn K. Autonomic insufficiency in uremia as a cause of hemodialysis-induced hypotension. N Engl J Med. 1974;290:650-653.  [PubMed]  [DOI]
21.  National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.  [PubMed]  [DOI]
22.  Peng YS, Chiang CK, Hung KY, Chiang SS, Lu CS, Yang CS, Wu KD, Yang CC, Lin RP, Chang CJ. The association of higher depressive symptoms and sexual dysfunction in male haemodialysis patients. Nephrol Dial Transplant. 2007;22:857-861.  [PubMed]  [DOI]
23.  Doumas M, Tsakiris A, Douma S, Grigorakis A, Papadopoulos A, Hounta A, Tsiodras S, Dimitriou D, Giamarellou H. Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects. J Androl. 2006;27:469-477.  [PubMed]  [DOI]
24.  Chang SW, Fine R, Siegel D, Chesney M, Black D, Hulley SB. The impact of diuretic therapy on reported sexual function. Arch Intern Med. 1991;151:2402-2408.  [PubMed]  [DOI]
25.  Chia SE, Ong CN, Chua LH, Ho LM, Tay SK. Comparison of zinc concentrations in blood and seminal plasma and the various sperm parameters between fertile and infertile men. J Androl. 2000;21:53-57.  [PubMed]  [DOI]
26.  Rosas SE, Joffe M, Franklin E, Strom BL, Kotzker W, Brensinger C, Grossman E, Glasser D, Feldman HI. Prevalence and determinants of erectile dysfunction in hemodialysis patients. Kidney Int. 2001;59:2259-2266.  [PubMed]  [DOI]
27.  Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49:822-830.  [PubMed]  [DOI]
28.  Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, McKinlay JB. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med. 2000;30:328-338.  [PubMed]  [DOI]
29.  Messina LE, Claro JA, Nardozza A, Andrade E, Ortiz V, Srougi M. Erectile dysfunction in patients with chronic renal failure. Int Braz J Urol. 2007;33:673-678.  [PubMed]  [DOI]
30.  Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Construction of a surrogate variable for impotence in the Massachusetts Male Aging Study. J Clin Epidemiol. 1994;47:457-467.  [PubMed]  [DOI]
31.  Türk S, Guney I, Altintepe L, Tonbul Z, Yildiz A, Yeksan M. Quality of life in male hemodialysis patients. Role of erectile dysfunction. Nephron Clin Pract. 2004;96:c21-c27.  [PubMed]  [DOI]
32.  Mesquita JF, Ramos TF, Mesquita FP, Bastos Netto JM, Bastos MG, Figueiredo AA. Prevalence of erectile dysfunction in chronic renal disease patients on conservative treatment. Clinics (Sao Paulo). 2012;67:181-183.  [PubMed]  [DOI]
33.  Naya Y, Soh J, Ochiai A, Mizutani Y, Ushijima S, Kamoi K, Ukimura O, Kawauchi A, Fujito A, Ono T. Significant decrease of the International Index of Erectile Function in male renal failure patients treated with hemodialysis. Int J Impot Res. 2002;14:172-177.  [PubMed]  [DOI]
34.  Espinoza R, Gracida C, Cancino J, Ibarra A. Prevalence of erectile dysfunction in kidney transplant recipients. Transplant Proc. 2006;38:916-917.  [PubMed]  [DOI]
35.  Navaneethan SD, Vecchio M, Johnson DW, Saglimbene V, Graziano G, Pellegrini F, Lucisano G, Craig JC, Ruospo M, Gentile G. Prevalence and correlates of self-reported sexual dysfunction in CKD: a meta-analysis of observational studies. Am J Kidney Dis. 2010;56:670-685.  [PubMed]  [DOI]
36.  Cerqueira J, Moraes M, Glina S. Erectile dysfunction: prevalence and associated variables in patients with chronic renal failure. Int J Impot Res. 2002;14:65-71.  [PubMed]  [DOI]
37.  Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol. 2004;43:1405-1411.  [PubMed]  [DOI]
38.  Ponholzer A, Temml C, Mock K, Marszalek M, Obermayr R, Madersbacher S. Prevalence and risk factors for erectile dysfunction in 2869 men using a validated questionnaire. Eur Urol. 2005;47:80-85; discussion 85-86.  [PubMed]  [DOI]
39.  Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol. 2004;171:2341-2345.  [PubMed]  [DOI]
40.  Vrentzos GE, Paraskevas KI, Mikhailidis DP. Dyslipidemia as a risk factor for erectile dysfunction. Curr Med Chem. 2007;14:1765-1770.  [PubMed]  [DOI]
41.  Giuliano FA, Leriche A, Jaudinot EO, de Gendre AS. Prevalence of erectile dysfunction among 7689 patients with diabetes or hypertension, or both. Urology. 2004;64:1196-1201.  [PubMed]  [DOI]
42.  Virag R, Bouilly P, Frydman D. Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet. 1985;1:181-184.  [PubMed]  [DOI]
43.  Neto AF, de Freitas Rodrigues MA, Saraiva Fittipaldi JA, Moreira ED. The epidemiology of erectile dysfunction and its correlates in men with chronic renal failure on hemodialysis in Londrina, southern Brazil. Int J Impot Res. 2002;14 Suppl 2:S19-S26.  [PubMed]  [DOI]
44.  Aranda P, Ruilope LM, Calvo C, Luque M, Coca A, Gil de Miguel A. Erectile dysfunction in essential arterial hypertension and effects of sildenafil: results of a Spanish national study. Am J Hypertens. 2004;17:139-145.  [PubMed]  [DOI]
45.  Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol. 2000;163:460-463.  [PubMed]  [DOI]
46.  Derby CA, Barbour MM, Hume AL, McKinlay JB. Drug therapy and prevalence of erectile dysfunction in the Massachusetts Male Aging Study cohort. Pharmacotherapy. 2001;21:676-683.  [PubMed]  [DOI]
47.  Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-1483.  [PubMed]  [DOI]
48.  Vo TM, Disthabanchong S. Are there ways to attenuate arterial calcification and improve cardiovascular outcomes in chronic kidney disease? World J Cardiol. 2014;6:216-226.  [PubMed]  [DOI]
49.  Jackson G, Padley S. Erectile dysfunction and silent coronary artery disease: abnormal computed tomography coronary angiogram in the presence of normal exercise ECGs. Int J Clin Pract. 2008;62:973-976.  [PubMed]  [DOI]
50.  Chiurlia E, D’Amico R, Ratti C, Granata AR, Romagnoli R, Modena MG. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol. 2005;46:1503-1506.  [PubMed]  [DOI]
51.  Blumentals WA, Gomez-Caminero A, Joo S, Vannappagari V. Should erectile dysfunction be considered as a marker for acute myocardial infarction? Results from a retrospective cohort study. Int J Impot Res. 2004;16:350-353.  [PubMed]  [DOI]
52.  Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F, Vardi Y, Wespes E. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57:804-814.  [PubMed]  [DOI]
53.  Ayub W, Fletcher S. End-stage renal disease and erectile dysfunction. Is there any hope? Nephrol Dial Transplant. 2000;15:1525-1528.  [PubMed]  [DOI]
54.  Beusterien KM, Nissenson AR, Port FK, Kelly M, Steinwald B, Ware JE. The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients. J Am Soc Nephrol. 1996;7:763-773.  [PubMed]  [DOI]
55.  Kokot F, Wiecek A, Schmidt-Gayk H, Marcinkowski W, Gilge U, Heidland A, Rudka R, Trembecki J. Function of endocrine organs in hemodialyzed patients of long-term erythropoietin therapy. Artif Organs. 1995;19:428-435.  [PubMed]  [DOI]
56.  Iglesias P, Carrero JJ, Díez JJ. Gonadal dysfunction in men with chronic kidney disease: clinical features, prognostic implications and therapeutic options. J Nephrol. 2012;25:31-42.  [PubMed]  [DOI]
57.  Lawrence IG, Price DE, Howlett TA, Harris KP, Feehally J, Walls J. Erythropoietin and sexual dysfunction. Nephrol Dial Transplant. 1997;12:741-747.  [PubMed]  [DOI]
58.  Anantharaman P, Schmidt RJ. Sexual function in chronic kidney disease. Adv Chronic Kidney Dis. 2007;14:119-125.  [PubMed]  [DOI]
59.  Vircburger MI, Prelević GM, Perić LA, Knezević J, Djukanović L. Testosterone levels after bromocriptine treatment in patients undergoing long-term hemodialysis. J Androl. 1985;6:113-116.  [PubMed]  [DOI]
60.  Grossman EB, Swan SK, Muirhead GJ, Gaffney M, Chung M, DeRiesthal H, Chow D, Raij L. The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis patients. Kidney Int. 2004;66:367-374.  [PubMed]  [DOI]
61.  Vecchio M, Navaneethan SD, Johnson DW, Lucisano G, Graziano G, Querques M, Saglimbene V, Ruospo M, Bonifati C, Jannini EA. Treatment options for sexual dysfunction in patients with chronic kidney disease: a systematic review of randomized controlled trials. Clin J Am Soc Nephrol. 2010;5:985-995.  [PubMed]  [DOI]
62.  Lasaponara F, Paradiso M, Milan MG, Morabito F, Sedigh O, Graziano ME, Abbona A, Piccoli GB, Rossetti M, Mezza E. Erectile dysfunction after kidney transplantation: our 22 years of experience. Transplant Proc. 2004;36:502-504.  [PubMed]  [DOI]
63.  Malavaud B, Rostaing L, Rischmann P, Sarramon JP, Durand D. High prevalence of erectile dysfunction after renal transplantation. Transplantation. 2000;69:2121-2124.  [PubMed]  [DOI]
64.  Barroso LV, Miranda EP, Cruz NI, Medeiros MA, Araújo AC, Mota Filho FH, Medeiros FC. Analysis of sexual function in kidney transplanted men. Transplant Proc. 2008;40:3489-3491.  [PubMed]  [DOI]
65.  Burgos FJ, Pascual J, Gomez V, Orofino L, Liaño F, Ortuño J. Effect of kidney transplantation and cyclosporine treatment on male sexual performance and hormonal profile: a prospective study. Transplant Proc. 1997;29:227-228.  [PubMed]  [DOI]
66.  Chu SH, Tay SK, Chiang YJ, Chuang CK, Chen HW, Chen CS, Chou CC, Huang CC. Male sexual performance and hormonal studies in uremic patients and renal transplant recipients. Transplant Proc. 1998;30:3062-3063.  [PubMed]  [DOI]
67.  Akbari F, Alavi M, Esteghamati A, Mehrsai A, Djaladat H, Zohrevand R, Pourmand G. Effect of renal transplantation on sperm quality and sex hormone levels. BJU Int. 2003;92:281-283.  [PubMed]  [DOI]
68.  Tsujimura A, Matsumiya K, Tsuboniwa N, Yamanaka M, Miura H, Kitamura M, Kishikawa H, Nishimura K, Ichikawa Y, Nagano S. Effect of renal transplantation on sexual function. Arch Androl. 2002;48:467-474.  [PubMed]  [DOI]