Initial evidence demonstrating the association between the vascular status in surgically resected renal parenchymal pathology and sexual function

Abstract

Our goal is to evaluate the association between histopathology of glomerulosclerosis (GS) and atherosclerosis (AS) in the nephrectomized normal parenchyma together with patients’ background, and erectile dysfunction (ED) of patients treated with radical nephrectomy (RN) for renal cell carcinoma (RCC). ED was assessed with the International Index of Erectile Function in 65 patients who were less than age 70 years at the time of questionnaire. Glomeruli status was assessed by the extent of global GS. AS was graded based on lumen occlusion and frequency of involvement. Patients’ backgrounds included any comorbidities, post-RN renal insufficiency, tumor pathology, demographics and social status. The presence of diabetes mellitus and lack of a spouse were independent predictors for severe ED, whereas G0/1 AS was an independent predictor for mild/no ED. The extent of global GS was significantly lower in patients with mild/no ED than in other patients. Our study represents the first report identifying healthy arterial status in the renal parenchyma as a significant indicator of favorable erectile function and that the evaluation of AS severity is not a superior indicator of severe ED in the presence of comorbidities or social status among patients treated with RN.

Introduction

Erectile dysfunction (ED) is a form of endothelial dysfunction^{1, 2} that is also prevalent in patients with chronic kidney disease (CKD).³ Approximately 70% of men with CKD have concurrent ED,⁴ which may improve after renal transplantation or restoration of glomerular filtration rate (GFR).⁵ Because CKD is associated with a significant increase in cardiovascular events,⁶ the concerns for patients with renal cell carcinoma (RCC) after radical nephrectomy (RN) involve not only oncological outcome but also CKD progression. On the other hand, cardiovascular disease (CVD) and ED are two deeply intertwined disease processes.^{7, 8} As stated above, ED, CKD and CVD are closely related to each other. Therefore, the investigation of ED in RCC patients treated with RN may be useful for the further study and elucidation of these relationships. Moreover, the investigation of glomerular and vascular status in a surgically resected parenchymatous organ is suggested for explaining the relationships between ED, CKD and CVD, as such statuses may serve as biomarkers that may predict CKD progression and CVD occurrence. To elucidate the pathophysiological relationships between CKD and ED and between CVD and ED, we investigated the association between the histopathology, focused on glomerulosclerosis (GS) and atherosclerosis (AS) in the nephrectomized normal parenchyma together with patients’ background, and sexual function of patients who have undergone RN for RCC.

Materials and methods

Patient, demographics and ED evaluation

A total of 134 male RCC patients underwent RN at our institution between 2000 and 2012. Our study selected cases to be included in the present study based on the following criteria: (1) under 70 years of age at the time of the questionnaire for ED evaluation; (2) written consent; and (3) the absence of end-stage kidney disease. The study was approved by an appropriately constituted ethics committee at our institution. A total of 65 patients were eligible for this study. Patients’ backgrounds included pre-operative comorbidities, post-RN renal functional deterioration, tumor pathology and social status at the time of the questionnaire. The pre-operative comorbidities analyzed were diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HL), CKD and history of CVD. CKD was defined as the patient’s estimated GFR <60 ml min⁻¹ per 1.73 m². The post-RN renal functional deterioration was assessed by percent decrease in eGFR, which was defined as (pre-RN eGFR−6 months to 1 year post-RN eGFR)/pre-RN eGFR × 100. The eGFR was calculated using the following equation: eGFR=194 × serum creatinin^−1.094 × age^−0.287.⁹ This formula is currently recommended by the Japanese Society of Nephrology. The social status variables analyzed were the patient’s spouse (presence or absence) and residential area (urban or rural). Sexual function was assessed by the International Index of Erectile Function (IIEF) questionnaire.

Histopathological analysis

Non-neoplastic parenchymal tissue samples, which were the most distant portions from the tumors, were obtained from the surgically resected kidneys after obtaining informed consent from the patients. The two specific histopathological features evaluated were global GS and AS. The global GS extent was calculated by the number of globally sclerotic glomeruli divided by the total number of available glomeruli. At least 100 glomeruli were assessed in most specimens. In the AS evaluation, the inter-lobar or arcuate arteries were graded. AS grading was performed according to a previously described procedure:¹⁰ G0—no AS; G1—subintimal AS without significant occlusion of the arterial lumen (<10%), involving occasional vessels; G2—subintimal AS with involvement of most vessels, with occlusion of <50% of lumen; and G3—severe AS with irregular and prominent occlusion of lumens (>50%), typically involving the majority of vessels. Pathology specimens were reviewed under the supervision of a co-author (YU) who is the chairman of the pathology department at our institute.

Statistical analysis

The continuous variables were compared with the Mann–Whitney U test or the Student’s t-test. Nominal variables were compared with the chi-square test. The associations between variables in the univariate analysis P<0.05 and ED severity were analyzed using a multivariate logistic regression model.

Results

Evaluation of the IIEF questionnaire

Fifteen domains of the IIEF questionnaire were fully completed in all cases. To focus on the evaluation of erectile function, the severity of ED was graded as no (26–30), mild (22–25), mild to moderate (17–21), moderate (11–16) or severe (6–10) using the IIEF-erectile function domain data according to a previous study.¹¹ Five (7.7%), ten (15.4%), eleven (16.9%), nine (13.8%) and thirty (46.2%) patients were categorized as no, mild, mild to moderate, moderate and severe ED, respectively.

Patient cohort background

The median (range) duration from RN until time of the IIEF questionnaire was 45.8 (7.2–146.2) months. The median (range) age at RN and time of the IIEF questionnaire was 60 (39–68) years and 64 (44–69) years, respectively. Patient demographics including oncological, renal functional, social backgrounds and pre-operative comorbidities are summarized in Table 1. Sixty-three patients had no evidence of relapse; however, two patients were receiving sunitinib therapy for metastatic relapse. The mean (s.d.) value of post-RN percent eGFR decrease was 28.5 (14.2). Forty (61.5%) patients had at least one of the comorbidities: DM, HTN, HL, CKD or history of CVD pre-operatively.

Table 1 Patient’s backgrounds in 65 RCC cases treated with RN

Some comorbidities were related to each other. The most characteristic results were the linked relationships between DM and CKD as well as that between HTN and CKD. In the 11 CKD patients, 6 had HTN and DM, 2 had DM and 2 had HTN. It is suggested that DM or HTN or both caused CKD in our patient cohort. The social status variables showed that 41 (63.1%) patients lived in an urban district, and 52 (80%) patients had a spouse at the time of IIEF questionnaire.

The management of comorbidity before RN

All of the DM patients were controlled by oral medicine or insulin injection, and no patient showed hyperglycemia that created the surgical risk. HTN in 20 of the 24 HTN patients was controlled by oral medicine, and no patient showed severe HTN, which indicated systolic pressure >180 mm Hg or diastolic pressure >110 mm Hg. HL in five of the nine HL patients was controlled by oral medicine. None of the 11 CKD patients had their conditions controlled by oral medicine such as small spherical activated charcoal products for the prevention of end-stage renal disease. In the ten patients who had a history of CVD, two, one and one patients were controlled by oral medicine for HTN, HTN and HL and HTN and DM, respectively.

The association between age, renal insufficiency from RN and comorbidities, and histopathological features

The comparisons of age, renal insufficiency from RN and comorbidities between the two types of AS were evaluated (Table 2). Age at the time of the IIEF questionnaire was significantly higher in the G2-3 AS group than in the G0-1 AS group. The case distributions were significantly shifted to G2-3 AS in the DM and history of CVD groups. Similarly, the comparison of age, renal insufficiency from RN and the comorbidities between the low and high global GS extent was evaluated (Table 3). The cutoff value between the low and high global GS groups was the mean global GS extent. The age at RN and the percent eGFR decrease from RN were significantly higher in the high global GS extent group than in the low global GS extent group. The case distributions were significantly shifted to the high global GS extent in the HTN and CKD groups.

Table 2 The comparison of age, renal insufficiency from RN and comorbidities between two types of AS

Table 3 The comparison of age, renal insufficiency from RN and comorbidities between low and high global GS extent

Association between the patient’s background and ED severity

Because of the small number of patients categorized as no ED, no and mild ED patients were grouped together into one category (no/mild ED). Twenty-five (38.5%) patients had no comorbidity of any of the five diseases analyzed in the study. The lack of comorbidities was significantly associated with no/mild ED patients compared with other patients (P=0.0105). Age at the time of the IIEF questionnaire (P=0.009) and percent eGFR decrease (P=0.0489) were significantly lower in the no/mild ED patients than in the other patients. On the other hand, DM (P=0.0264), history of CVD (P=0.0196) and lack of a spouse at the time of the IIEF questionnaire (P=0.0126) were significantly associated with the severe ED patients, compared with other patients. There was no difference in the continuous variables between severe ED patients and the other patients.

Association between the histopathological evaluation and ED severity

The mean (s.d.) global GS extent in the patient cohort was 11.6 (5.9) %. The global GS extent was significantly lower in the no/mild ED patients than in the other patients (Figure 1). Three (4.6%), twenty-one (32.3%), twenty-two (33.8%) and nineteen (29.2%) patients were categorized, in G0, 1, 2 and 3 AS, respectively. Because of the small number of the patient cohort, G0 and 1 were included together in one category (G0/1 AS), and G2 and 3 were included together as another category (G2/3 AS). G0/1 AS was significantly associated with no/mild ED patients compared with the other patients (P=0.0009). There was no significant difference in global GS extent and AS severity between severe ED patients and other patients. The typical microphotographs of global GS and G1, 2 and 3 AS are shown in Figure 2.

Figure 1

The comparison of global glomerulosclerosis (GS) extent between no/mild erectile dysfunction (ED) and other patients.

Figure 2

Arrows indicate typical structures of global glomerulosclerosis (GS) (a), G1 atherosclerosis (AS) (b), G2 AS (c) and G3 AS (d). Original magnifications of all microphotographs are × 200.

Multivariate analysis of the significant factors predicting ED severity

The previously mentioned significant patient background and histopathological factors were included in the multivariate logistic regression analysis. The presence of pre-operative DM, and the lack of a spouse at the time of the IIEF questionnaire were independent predictors of severe ED, whereas G0/1 AS was an independent predictor of no/mild ED (Table 4).

Table 4 Multivariate logistic regression analysis predicting severe ED or no/mild ED

Discussion

The pathophysiology of the interaction between renal functional impairment and ED is complex and multifactorial. CKD and its final consequence of chronic renal failure cause endothelial dysfunction,^{12, 13} decreased levels of free and total testosterone¹⁴ and molecular alterations in both the nitric oxide synthase pathway and insulin growth factor-1 system,¹⁵ all of which lead to ED. Autonomic dysfunction, dysfunction of the muscles of the cavernous bodies and psychiatric problems also are involved in the pathogenesis of ED in patients with CKD. Although empirical studies have proven the strong relationship between CKD and ED, the pathogenesis of renal functional impairment in CKD in such studies has not focused on a surgical cause but rather on medical causes, which in a sense is systemic disease. The current question under debate is whether medical CKD and post-RN CKD should be considered the same entity. Despite the significant increase in CKD mortality due to medical causes,⁶ surgically induced CKD did not necessarily correlate with increased mortality in a recent large study.¹⁶ If the issue is limited to the relationship between surgical CKD and ED, then there are few studies available in which a comparative evaluation between RN and partial nephrectomy,¹⁷ and ED prevalence in a donor nephrectomy cohort¹⁸ are discussed. Because surgical CKD is a recent unique entity, its clinical manifestations are not entirely known. However, a few studies have demonstrated the utility of global GS in the histopathological evaluation of nephrectomized normal kidney parenchyma as a predictive marker for progression of renal functional impairment after RN.^{19, 20} Our study is the first attempt to evaluate whether global GS is a useful biomarker for the prediction of ED. Because low levels of global GS extent and post-RN percent eGFR decrease were associated with no/mild ED in the univariate analysis, normal renal function preservation may be a minimum requirement for normal erectile function.

ED is an early marker of a more generalized vascular systemic disorder, such as coronary artery disease.²¹ Arteriosclerosis is the leading cause of such a vascular disorder and consequently leads to the onset of CVD. Despite the linked evidence between ED and CVD onset, the exact mechanism of how arteriosclerosis influences ED remains unclear. Ponholzer et al.²² demonstrated the direct comparison of AS between systemic and penile arteries by autopsy study, and suggested the linked factor of DM. However, multiple linked factors are involved between systemic arteriosclerosis and ED onset. The kidney is one of the surgically targeted parenchymatous organs and may be the best material for evaluating arterial status because of ease in obtaining large amounts of parenchymatous tissue by the major surgery of RN. The evaluation of arterial and glomerular statuses in surgically resected normal renal parenchyma has been suggested as a useful method for predicting vascular disorders and kidney disease related to systemic medical disease.^{10, 23} Our study demonstrated that the case distributions were significantly shifted to G2-3 AS in the DM and history of CVD groups and significantly shifted to the high global GS extent in the HTN and CKD groups. Older age was significantly related to G2-3 AS and the high global GS extent. Apart from ED, it is suggested that renal parenchymal histopathology indicates signs that are precisely influenced by systemic disease. Our study is the first report demonstrating the relationship between the status of the renal parenchymatous arteries and ED severity. Therefore, the status of the arteries in renal parenchyma is suggested as a key relay point that connects ED and systemic medical disease.

Our study demonstrated that DM and lack of a spouse are independent predictors of severe ED. The reason why severe ED could not be predicted by only two histopathological aspects of global GS extent and AS in the renal arteries is that multiple interactive factors appear to be necessary for the onset of ED. Because psychiatric problems are often entwined with multiple physical disorders, it is difficult to describe a simple pathogenesis of ED. Conversely, our study demonstrated that the healthy status of the renal parenchymatous arteries was a useful marker for favorable erectile function. Considering the results: that low levels of global GS extent, percent decrease in eGFR, and lack of comorbidities had significant relationships with favorable erectile function in the univariate analysis, our study implies that preservation of renal function and prophylaxis of DM, HTN, HL and CVD, all of which are closely linked to arteriosclerosis, are crucial for comprehensive management of ED. Moreover, with regard to comprehensive management of post-RN patients, it is also suggested that nephrectomized tumor and normal renal parenchymal pathology provides valuable information that can help assess a patient outcome comprehensively from the aspect of quality of life as well as addition to prognostic life expectancy.

Our study has certain limitations. First, the duration between RN and the administration of the IIEF questionnaire was not fixed. It is possible that some new disease onset after RN may have influenced sexual function, particularly in the case of a long interval. However, our study confirmed that none of patients suffered from any new problematic disease onset after RN during the interview at the same time of the IIEF questionnaire. Second, metastatic relapse and molecular targeted therapy in two cases may have influenced sexual function. Other limitations include the retrospective nature of the study and small sample size. External validation of our findings and further exploration of the impact of parenchymatous histopathological evaluation on sexual function will help to further characterize ED.

Conclusions

Our research suggests that the healthy status of the renal parenchymatous arteries is a significant indicator of favorable erectile function and that the evaluation of AS severity is not a superior indicator of severe ED in the presence of comorbidities or social status among patients with RCC after RN. The preservation of renal function and prophylaxis of DM, HTN, HL and CVD all of which are closely linked to arteriosclerosis are crucial for comprehensive management of ED.