Associations of impaired grip strength and gait function with the severity of erectile dysfunction in men undergoing dialysis: a cross-sectional study

Abstract Objective To investigate the associations of impaired muscle strength and gait function with the severity of erectile dysfunction (ED) in men undergoing dialysis. Methods This cross-sectional study included 63 men undergoing dialysis. ED was assessed with the Sexual Health Inventory for Men (SHIM). Patients were divided into the mild/moderate (SHIM score ≥8) and severe ED groups (SHIM score ≤7). Correlations between variables were analyzed using Spearman’s rank correlation coefficient. Multivariable logistic regression analyses were performed to evaluate the impact of impaired grip strength and gait function on the severity of ED. Results The median age of the study participants was 62 years; all had ED, with 67% having severe ED. Spearman’s rank correlation test demonstrated significant negative and positive correlations between gait function and SHIM score (ρ = −0.257, p = 0.042) and between grip strength and SHIM score (ρ = 0.305, p = 0.015), respectively. In the multivariable analyses, impaired grip strength was significantly associated with severe ED (odds ratio [OR]: 4.965, p = 0.017), whereas gait function was not (OR: 3.147, p = 0.064). Conclusion Impaired muscle strength was significantly associated with severe ED, whereas impaired gait function had a marginal effect on this erectile condition.


Introduction
Erectile dysfunction (ED) is a common feature in men with end-stage renal disease (ESRD), with a reported prevalence of 80%-90% [1-3]. ED negatively affects the quality of life (QOL) in men with ESRD and in healthy men [4]. In addition, men undergoing hemodialysis (HD) with severe ED reportedly have poorer QOL than those with mild/moderate ED [5]. Although it is well-known that the pathogenesis of ED in men undergoing dialysis is multifactorial [6][7][8][9][10], factors that contribute to the severity of ED remain unclear.
Impaired muscle strength and gait function are frequently observed in men undergoing dialysis [11,12]. These conditions share the same risk factors with ED, such as age, endothelial dysfunction, peripheral neuropathy, diabetes mellitus (DM), and hormonal disturbances [13][14][15][16][17]. Therefore, we hypothesized that impaired muscle strength and gait function might contribute to the severity of ED in men undergoing dialysis. This study aimed to investigate the associations of impaired muscle strength and gait function with the severity of ED in men undergoing peritoneal dialysis (PD) and/or HD.

Ethics statement
This study was conducted in accordance with the ethical standards of the Declaration of Helsinki and was approved by the ethics review board of Mutsu General Hospital (authorization number: H29-2). All participants provided written informed consent.

Patient selection
This cross-sectional study assessed 186 men undergoing PD and/or HD between July 2016 and May 2018 at Mutsu General Hospital. Among these 186 men, 123 were excluded based on the following exclusion criteria: (1) aged �75 years; (2) cognitive deficiency, blindness, and/or inability to communicate and/or walk; (3) insufficient baseline information; and (4) refusal to participate in the study. Finally, 63 men undergoing PD and/or HD were included in the analysis (Figure 1).

Evaluation of variables
The following variables were analyzed: age, body mass index, hypertension, dyslipidemia, DM, cardiovascular disease, adequacy of HD (Kt/V), depression, laboratory values, education level, marital status, smoking status, current habitual drinking, and medications (i.e. b-blockers, calcium [Ca]-blockers, thiazide diuretics, spironolactone, methyldopa, clonidine, and antidepressants). The following laboratory values were measured as part of the routine clinical examination: serum hemoglobin, creatinine, albumin, C-reactive protein, Ca, inorganic phosphorus, intact parathyroid hormone, total cholesterol, low-density lipoprotein, and triglycerides. Serum total testosterone and free testosterone were measured for research purposes. Hypogonadism was defined serum total testosterone level �300 ng/ dL. Blood sampling was performed in the morning. Blood was drawn after 12 h of fasting and serum was separated by centrifugation with 3000 rpm for 5 min.
Laboratory values except for total testosterone and free testosterone were measured using an enzymatic assay with an automatic analyzer (BioMajesty 6070 G; Nihon denshi, Tokyo, Japan). Serum total testosterone and free testosterone were measured using chemiluminescent immunoassay and radioimmunoassay, respectively. Adjusted Ca levels were calculated using Payne's formula [18]. The adequacy of HD was calculated from the Kt/V method as follows: Kt/V ¼ À ln (R À 0.008 � t) þ (4 À 3.5 � R) 0.55 � UF/V; where R is pre-dialysis blood urea nitrogen (BUN)/post-dialysis BUN, t is the duration of the session in hours, À ln is the natural logarithm negative, UF is the weight loss in kilograms, and V is the volume of urea distribution in liters [19]. Kt/V was calculated in men undergoing HD. Self-reported depression was assessed using the vitality questionnaire of the Short Form 36 Health Survey. Patients with certain responses to the questionnaire (i.e. "all of the time" or "most of the time") and/or who were taking antidepressants were considered as having depression [20]. Smoking status was quantified using the Brinkman index.

Assessment of muscle strength and gait function
Grip strength was measured by a hand dynamometer in a standing position. The averages of right and left grip strength were used for analyses. Gait function was evaluated using the Timed Get Up and Go (TGUG) test. Patients were instructed to stand up from a chair, walk 3 m, turn without taking hold, walk back to the chair, and sit down again ( Figure S1) [23].

Statistical analysis
Statistical analyses were performed using the BellCurve for Excel 3.20 (Social Survey Research Information Co., Ltd., Tokyo, Japan), SPSS version 24.0 (SPSS, Inc., Chicago, IL, USA), GraphPad Prism 5.03 (GraphPad Software, San Diego, CA, USA), and R 4.0.2 (The R Foundation for Statistical Computing, Vienna, Austria). Quantitative variables were expressed as their median with interquartile range. Categorical variables were compared using the Fisher exact test or chisquared test, while quantitative variables were compared using the Mann-Whitney U test. Correlations between variables were analyzed using Spearman's rank correlation coefficient. The optimal cutoff values of age, the TGUG test, and grip strength for severe ED were calculated with the receiver operating characteristic (ROC) curve. Uni-and multivariable logistic regression analyses were performed to evaluate the impact of impaired grip strength and gait function on the severity of ED. Since the TGUG test and grip strength are similar indices for evaluating the physical function, we included these in multivariable regression models separately. Thus, two types of multivariable regression analyses were performed. The predictive accuracies of age, gait function, and grip strength for severe ED were evaluated using the area under the ROC curve (AUC) and compared using the DeLong test. Statistical significance was set at p < 0.05.
The median SHIM score was 4.0. All men (100%) had any level of ED. Of those, 21 (33%) and 42 (67%) patients reported mild/moderate (mild/moderate ED group) and severe ED (severe ED group), respectively (Figure 1). No patient was receiving any type of treatment for ED at the time of the investigation. No significant differences in the patient background were observed between both groups except for age, duration of dialysis, and grip strength (Table 1). No patients were taking spironolactone, methyldopa, or clonidine in both groups.

Correlations of the TGUG test and grip strength with SHIM score
Spearman's rank correlation test demonstrated a significant negative correlation between the TGUG test and SHIM score (Figure 2(A); q ¼ À 0.257, p ¼ 0.042). In contrast, a significant positive correlation was observed between grip strength and SHIM score (Figure 2

Association between gait function and the severity of ED
The median TGUG test in all men was 10.3 s ( Table 1). The severe ED group had a longer TGUG test than the mild/moderate ED group, but this was not statistically significant (Table 1 and Figure 3(A); 10.7 vs. 9.7 s, respectively, p ¼ 0.052). The optimal cutoff value of the TGUG test for severe ED was 9.9 s ( Figure S2(A)). Patients with TGUG test �9.9 s had a significantly higher prevalence of severe ED than those with TGUG test <9.9 s (78% vs. 52%, respectively, p ¼ 0.031).

Association between grip strength and the severity of ED
The median grip strength in all men was 29 kg (Table  1). The severe ED group had significantly weaker grip strength than the mild/moderate ED group (Table 1 and Figure 3(B); 27 vs. 35 kg, respectively, p ¼ 0.007). The optimal cutoff value of grip strength for severe ED was 34 kg (Figure S2(B)). Patients with grip strength �34 kg had a significantly higher prevalence of severe ED than those with grip strength >34 kg (80% vs. 41%, respectively, p ¼ 0.001).

Uni-and multivariable analyses for severe ED
The optimal cutoff value of age for severe ED was 63 years (Figure S2(C)). The univariable analyses revealed that age, hypogonadism, TGUG test, and grip strength were significantly associated with severe ED (Table 2). In the multivariable analysis (Model 1; including the TGUG test), the TGUG test was not

Predictive accuracies of gait function and grip strength for severe ED
The predictive accuracy of TGUG test �9.9 s plus age �63 years for severe ED was superior to that of age �63 years alone, but this was not statistically significant ( Figure S3 Similarly, the predictive accuracy of grip strength �34 kg plus age �63 years for severe ED was superior to that of age �63 years alone, but this was not statistically significant ( Figure S3(B); AUC: 0.755 vs. 0.679, respectively, 95% CI: À 0.007-0.148, p ¼ 0.073).

Discussion
Although impaired muscle strength and gait function are frequently observed in men undergoing dialysis [11,12] and share the same risk factors with ED [13][14][15][16], no study has evaluated the impact of impaired muscle strength and gait function on the severity of ED in men undergoing dialysis. To the best of our knowledge, this is the first study to investigate the associations of impaired muscle strength and gait function with the severity of ED in men undergoing dialysis. Our results revealed that impaired grip strength was significantly associated with severe ED and impaired gait function had a marginal effect on this erectile condition.
In this study, impaired grip strength was significantly associated with severe ED (Table 3), and this result was consistent with a previous study conducted in community-dwelling older men [24]. One possible mechanism that might explain this association is the pelvic floor muscles; their muscle strength reportedly has a positive correlation with grip strength [25]. Moreover, pelvic floor muscles play an important role in maintaining erectile rigidity [26]. Their efficient contractions prevent venous outflow from the penis, subsequently enhancing penile rigidity [27]. The other possible mechanism is endothelial dysfunction, a well-known risk factor of ED [28]. Yoo et al. have investigated the association between peripheral endothelial function and grip strength in community-dwelling elderly women and revealed that endothelial dysfunction was significantly associated with the risk of impaired grip strength on multivariable analysis [29]. Moreover, the endothelium is recognized as a key regulator of blood flow in the micro-and macrovascular circulation [30]. Rasmussen et al. have examined the effects of hyperinsulinemia on muscle protein metabolism in healthy subjects using  stable isotope tracer techniques and demonstrated a strong positive correlation between insulin-induced changes in blood flow and changes in muscle protein synthesis [31]. Thus, endothelial dysfunction might contribute to muscle atrophy in line with decreased muscle protein synthesis. In addition, Wang et al. have identified endothelial cells as the major apoptotic cells in the atrophic muscle using an aging mouse model [32].
These studies indicate a close relationship between endothelial dysfunction and impaired muscle strength. However, the direct biological mechanism of the association between impaired muscle strength and the severity of ED remains unclear, and further studies are needed to address this issue. Although a significant association between impaired grip strength and severe ED was observed, the association between impaired gait function and this erectile condition was marginal in the present study. In contrast, Okamoto et al. have reported that, in communitydwelling men, more severe ED was significantly associated with impaired gait function, but not with grip strength [33]. The reason behind this discrepancy is unclear. Although gait function is well correlated with grip strength [34], the TGUG test evaluates not only muscle strength but also dynamic balance and functional mobility [35,36]. Considering this in the interpretation of our results, impaired muscle strength affects the severity of ED to a greater extent than impaired dynamic balance and functional mobility in men undergoing dialysis. However, several limitations prevent us from making a definitive conclusion. Our future studies with a sufficient sample size will address this issue.
This study has several limitations. First, its cross-sectional study design does not allow the determination of cause-and-effect associations. Second, we did not evaluate zinc deficiency, hyperprolactinemia, and the imbalance in the hypothalamic-pituitary-gonadal axis, which might increase the prevalence of ED in patients undergoing dialysis [37,38]. Third, a relatively small number of patients were enrolled, and the number of patients undergoing PD was also small. Lastly, we could not compare muscle strength and gait function between men with and without ED because all men had ED. However, despite these limitations, the present study was still able to demonstrate the negative impact of impaired muscle strength and gait function on the severity of ED in men undergoing dialysis.

Conclusions
Impaired muscle strength was significantly associated with severe ED, whereas impaired gait function had a marginal effect on this erectile condition.