Clinical Kidney Journal, 2022 , v o l. 15, no. 1, 109 –118 doi: 10.1093/ckj/sfab133 Advance Access Publication Date: 10 July 2021 Original Article Clinical Kidney Journal ORIGINAL ARTICLE Frailty among chronic kidney disease patients on the kidney transplant waiting list: the sex–frailty paradox Marı́a José Pérez-Sáez1, Carlos E. Arias-Cabrales1, Vanesa Dávalos-Yerovi2, Dolores Redondo1, Anna Faura1, Marı́a Vera1, Anna Bach1, Guillermo Pedreira1, Ernestina Junyent1, Marta Crespo1, Ester Marco2, Leocadio Rodrı́guez-Man ~ as3 and Julio Pascual1, for the FRAIL-MAR Study Group 1 Nephrology Department, Hospital del Mar, Barcelona, Spain, 2Physical Medicine and Rehabilitation Department, Parc de Salut Mar (Hospital del Mar-Hospital de l’Esperança), Rehabilitation Research Group, Hospital del Mar Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain and 3Geriatrics Department, Hospital Universitario de Getafe, Madrid, Spain Correspondence to: Julio Pascual; E-mail: julpascual@gmail.com ABSTRACT Background. Frailty is defined as decreased physiologic reserve and resistance to stressors that predisposes patients towards poor health results. Its prevalence in chronic kidney disease (CKD) patients who are kidney transplant (KT) candidates is high. Frailty is associated with a higher rate of complications and mortality after transplant. It is unknown whether frailty phenotype differs depending on sex in this population. Methods. This was a prospective longitudinal study of 455 KT candidates evaluated for frailty by physical frailty phenotype at the time of inclusion on the KT waiting list. Pre-frailty was defined as the presence of two criteria and frailty as three or more criteria. Univariate and multivariate analyses searched for associations of frailty status, frailty components and gender differences. Results. Thirty percent of the total cohort resulted to be pre-frail (20%) or frail (10.3%), but disparities were observed between sexes, with 22.5% of men and 47.2% of women falling into one of these categories. Among frailty criteria, women presented with a higher percentage of exhaustion (39.6% versus 17%) and slowness (22.2% versus 9.6%) compared with men. Comorbidity burden was higher among frail men, whereas social factors were poorer between frail women. Disability was common among those patients who were frail, both men and women. Conclusions. Frailty is twice as frequent in advanced CKD women as men. Frailty criteria distribution and phenotype seem to differ among sexes, which might have implications in terms of specific and individualized interventions to improve their status before transplantation. Received: 8.2.2021; Editorial decision: 14.6.2021 C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 109 110 | M.J. Pérez-Sáez et al. GRAPHICAL ABSTRACT Keywords: frailty, gender, kidney transplantation, risk factor, sex INTRODUCTION In recent years, many medical disciplines have shown in- creasing awareness of how diseases manifest differently be- Frailty is characterized by decreased physiologic resistance to tween men and women. CKD is no exception, and, despite more stressors and was first studied in the community-dwelling aged women than men suffering advanced CKD, a higher population [1]. It is a frequent condition among chronic kidney percentage of men initiate dialysis or undergo transplantation disease (CKD) patients, representing between 15% and 21% of [19–21]. This discrepancy may be attributed to biological (sex) those in whom advanced CKD is present [2]. In the setting of differences, such as the CKD progression rates [20, 22], or to haemodialysis, up to 70% of patients have been reported to sociocultural (gender) differences, including access to care or have some degree of frailty [3, 4] and this is related to poorer attitudes towards disease [20, 23]. outcomes, including poor cognitive function, falls, hospitaliza- Mortality is also different among women and men with CKD: tions and mortality [5–8]. Access to the kidney transplantation while men present higher rates within non-dialysis CKD stages, (KT) waiting list may also be diminished in frail CKD patients, they become equal among sexes once renal replacement ther- and even when they reach the KT waiting list, the probability of apy (RRT) is started [20, 22]. getting a transplant is lower [9, 10]. In the end, around 20% of Frailty studies of community-dwelling populations have KT recipients are frail [11], and these patients present with a found that females have higher frailty prevalence than males higher rate of complications and mortality after KT [11–16]. [24]. However, the so-called male–female health-survival para- In Spain, <25% of dialysis patients have access to trans- dox shows a higher survival rate in women than in men, result- plantation [17], and despite the well-known weight of frailty in ing in longer times with disability and poor health status in KT outcomes, clinicians often struggle with frailty measure- women compared with men [24–26]. In contrast, among liver ment at the outpatient clinic. However, identifying patients at transplant candidates, women have higher frailty scores but risk for poor results is of crucial importance to assess progno- also higher mortality while listed [27]. In the CKD setting, frailty sis, establish prevention strategies and implement therapeutic seems also to be more frequent in women [4, 5, 28–31], but their approaches like prehabilitation. A complete frail profile mortality rates on the KT waiting list are lower than that ob- characterization, added to information about both social and served in men [30, 31]. On the other hand, not only prevalence medical variables, might help to mitigate or reverse some of but also frailty components and characteristics between male them, and, therefore, improve frailty in candidates for trans- and female frail patients may differ [27, 28, 32]. This may be of plantation [18]. importance to identify frailty sex-specific factors to take into Sex differences in frailty among KT candidates | 111 consideration and intervene on if possible before KT. Assessing and pulmonary diseases, type of RRT, etc.). In addition, we sex differences in frailty among CKD patients waiting for KT assessed self-reported pharmacological treatment adherence by may improve risk stratification before transplant and help tar- four-item Morisky–Green–Levine Medication Adherence Scale get specific interventions. Furthermore, it will allow future re- [38], considering the patient adherent if none of the items search about the sex-related impact of frailty on outcomes and were present, basic activities of daily living by Barthel scale (dis- mortality both in patients on dialysis and after transplant. ability if score 90) [39, 40], and instrumental activities of daily The aim of this study was to analyse the frailty phenotype in living by Lawton–Brody scale (disability if <8 in women and <5 in a cohort of CKD transplant candidates from a sex-perspective men) [41]. Nutritional evaluation included bioimpedance spec- point of view. troscopy (BIS) by Body Composition Monitor (Fresenius Medical Care, Bad Homburg, Germany) at the time of inclusion; Simplified Nutritional Appetite Questionnaire (SNAQ) questionnaire for risk MATERIALS AND METHODS of malnutrition, positive if 14 [42]; and albumin levels at the Study design time of inclusion. Unfortunately, BIS was assessed at the time the patient attended to the transplantation clinic, regardless of hae- This is a prospective longitudinal clinical cohort study analy- modialysis session, so we could not adjust for this variable. For sing baseline frailty status in advanced CKD patients who were inflammation information, we also collected C-reactive protein being studied for transplantation at Hospital del Mar, Barcelona, (CRP) levels at the time of inclusion. To evaluate access to trans- Spain. Clinical and epidemiological information were collected plantation, pre-dialysis waitlisting and time to transplantation from our local database. The Institutional Review Board of were analysed. Hospital del Mar approved this study and all enrolled partici- pants provided written informed consent. The study was under- taken following the principles of the declaration of Helsinki, Statistics only relying on the official centre database. Continuous variables are expressed as mean 6 standard devia- tion (SD) or median and interquartile range (IQR) according to Patient cohort and frailty measurement their normal distribution. Categorical data are expressed as per- Between June 2016 and June 2020, 455 KT candidates were centages. Comparisons of baseline characteristics between two prospectively evaluated for frailty at the time of inclusion on groups were made using Chi-square or Fisher’s exact tests to the KT waiting list. Physical frailty phenotype defined by Fried analyse categorical variables, Student’s t-test for continuous et al. [1] was used. The frailty phenotype has been validated variables with normal distribution and Mann–Whitney test for before in CKD patients [5, 7–9, 33] and comprises five compo- non-parametric variables. Logistic regression was used to esti- nents: shrinking (self-report of unintentional weight loss of mate the odds ratio (OR) for frailty status. All variables with ob- 4.5 kg during the past year), weakness [grip strength below an served differences between groups (P < 0.10) were included in established cut-off on the basis of sex and body mass index the analysis for adjustment except for SNAQ test as it may have (BMI)], exhaustion (self-report), low activity (kilocalories per collinearity with one of the Fried criteria for frailty (shrinking). week below an established cut-off) and slowed walking speed Statistical analysis was performed using SPSS version 21 soft- (walking time of 4.5 m below an established cut-off by sex and ware (IBM, Armonk, NY, USA). P-values <0.05 were considered height) [1]. Frailty assessment was performed at the trans- statistically significant. plantation outpatient clinic. Supplementary data, Table S1 shows the specifics regarding methods for Fried criteria assessment. RESULTS Each of the five components was scored as 0 or 1, represent- Characteristics of frail and robust patients ing the absence or presence of that component. The aggregate frailty score was calculated as the sum of the component scores During the study period, 455 KT candidates were evaluated for (range 0–5). Robust patients were defined as a score 0–1, pre- frailty phenotype at the time of KT waiting list inclusion. Of frail as those who ranked 2 and frail patients were defined by a them, 317 (69.7%) resulted to be robust, 91 (20%) pre-frail and 47 score 3 as previously described by other groups [9, 11, 34, 35]. (10.3%) were frail patients. Frailty phenotype total score and cri- The cut points for robust and pre-frail patients differed from the teria distribution are presented in Figure 1. For frail patients standard Fried physical frailty phenotype classification because (score 3), the majority scored 3, eight patients scored 4 and there are too few adults with advanced CKD who had none of one patient scored 5 (Figure 1A). Regarding criteria distribution, the frailty components. To increase the power of the study, pre- weakness was the most prevalent frailty criterion among candi- frail and frail categories (score 2) were joined for the analysis dates, present in 50% of candidates (Figure 1B). [36, 37]; we refer to this group as frail throughout the rest of this Merging pre-frail and frail patients in a unique category of frail article. patients (score 2), the comparison between robust and frail patients is summarized in Table 1. Frail patients had a similar age to robust ones. Among women, the percentage of patients Study variables with a frail phenotype was much higher than among men (47.2% Study variables were retrieved from our local database. We in- versus 22.5%, P < 0.001). Similarly, among frail patients, the per- cluded demographics (age, sex, ethnicity); social (education de- centage of women was much higher than the percentage of men fined by four categories: no, primary education, secondary (49.3% versus 24.0%, P < 0.001). Frail patients had lower self- education and tertiary education; family or social support, reported pharmacological adherence, poorer family support and defined by its presence or absence; economic incomes, lower economic incomes. They had also higher comorbidity bur- defined by three categories: non-regular incomes, retired with den and disability rates and presented with less lean mass and pension and active worker with salary) and clinical data (comor- more fat mass in their body composition. The multivariate analy- bidities such as hypertension, diabetes mellitus, chronic cardiac sis for frailty status demonstrated that women were more likely 112 | M.J. Pérez-Sáez et al. 81 A B Score 60 Percentage of patients 38 53.1% 0 50 138 1 91 40 2 30 24.7% 3 20 16.2% 13.9% 4 187 10 5.8% 5 0 ng s n ity d es tio ee tiv ki kn us rin sp ac ea ha Sh ng w W Ex Lo ki al w ed ow Sl FIGURE 1: Frailty phenotype prevalence and criteria distribution among 455 kidney transplant candidates. A: Number of patients who scored positive 0 to 5 criteria. B: Percentage of patients who presented each different criteria. Table 1. Baseline characteristics of 455 KT candidates stratified by frailty status (two categories) All Robust Frail (Fried 2) n ¼ 455 n ¼ 317 n ¼ 138 P-valuea Sociodemographics Age, years (mean 6 SD) 60.6 6 12.4 60.5 6 12.6 61.2 6 11.3 0.380 Sex, female, n (%) 144 (31.6) 76 (24.0) 68 (49.3) <0.001 Caucasian, n (%) 412 (95.8) 284 (95.9) 128 (95.5) 0.922 Medical treatment adherenceb, n (%) 333 (82.4) 238 (85.6) 95 (75.4) 0.010 Education, no/primary, n (%) 273 (62.4) 184 (58.0) 89 (64.5) 0.363 Deficient family support, n (%) 64 (14.4) 35 (11.3) 29 (21.0) 0.017 Socioeconomic status, no incomes, n (%) 41 (9.4) 23 (7.3) 18 (13.0) 0.047 Comorbidities Hypertension, n (%) 438 (96.5) 305 (96.5) 133 (96.4) 0.940 DM, n (%) 168 (37.0) 110 (34.8) 58 (42.0) 0.143 Heart failure, n (%) 26 (5.7) 13 (4.1) 13 (9.4) 0.025 Ischaemic coronary disease, n (%) 75 (16.5) 52 (16.4) 23 (16.7) 0.945 LV ejection fraction, %, median (IQR) 63.0 (59.0–67.0) 63.0 (58.5–66.2) 64.0 (59.0–69.0) 0.103 Peripheral vasculopathy, n (%) 43 (9.5) 26 (8.2) 17 (12.3) 0.168 Cerebral vasculopathy, n (%) 35 (7.7) 15 (4.7) 20 (14.5) <0.001 COPD, n (%) 35 (7.7) 26 (8.2) 9 (6.5) 0.536 RRT modality, n (%) Haemodialysis 257 (59.4) 171 (57.2) 86 (64.2) 0.194 Peritoneal dialysis 93 (21.5) 64 (21.4) 29 (21.6) Disability status Disability for activities of daily livingc, n (%) 91 (20.0) 52 (16.4) 39 (28.3) <0.001 Disability for instrumental activities of daily livingd, n (%) 136 (29.9) 75 (23.6) 64 (46.4) <0.001 Nutrition and inflammation status BMI, kg/m2 (mean 6 SD) 27.8 6 12.4 27.7 6 5.4 28.1 6 5.7 0.538 Risk for malnutritione, n (%) 111 (24.4) 64.0 (23.1) 47.0 (37.3) 0.003 Lean mass, kg/m2, median (IQR) 13.9 (11.6–16.5) 14.5 (12.5–16.9) 12.2 (10.8–14.8) <0.001 Fat mass, kg/m2, median (IQR) 12.7 (9.1–16.5) 11.9 (8.5–16.4) 13.6 (11.0–18.2) 0.031 Overhydration, L, median (IQR) 1.0 (0.1–2.1) 1.0 (0.0–2.0) 1.1 (0.2–2.5) 0.486 Albumin, g/dL, mean 6 SD 4.2 6 0.5 4.2 6 0.5 4.1 6 0.6 0.123 CRP, mg/dL, median (IQR) 0.3 (0.1–0.8) 0.3 (0.1–0.7) 0.3 (0.1–0.9) 0.932 Access to transplantation Pre-dialysis waitlisted, n (%) 83 (19.2) 64 (21.4) 19 (14.2) 0.087 Time to transplantation, months, median (IQR) 22.2 (10.5–32.1) 19.7 (9.3–30.2) 23.0 (12.5–34.2) 0.125 a Comparisons were made among robust and frail patients. b Morisky–Green ¼ 0. c Barthel 90. d Lawton–Brody <8 if women and <5 if men. e SNAQ 14. DM, diabetes mellitus; LV, left ventricular; COPD, chronic obstructive pulmonary disease. Sex differences in frailty among KT candidates | 113 to be frail [OR 1.91; 95% confidence interval (CI) 1.00–3.60] (Table Sex differences in frailty phenotypes 2). Other factors associated with frailty were deficient family sup- Considering the higher risk for women to be frail, we aimed to port (OR 2.57; 95% CI 1.28–5.13), comorbidities such as heart fail- analyse male (n ¼ 70, 22.5%) and female (n ¼ 68, 47.2%) frailty ure (OR 2.97; 95% CI 1.03–8.54) or cerebrovascular disease (OR 3.95; phenotypes separately (Table 3). Frail women had poorer results 95% CI 1.35–11.6) and disability for activities of daily living, both in social variables like level of education (72.1% with low level basic (OR 2.67; 95% CI 1.05–6.81) and instrumental (OR 2.55; 95% CI of education versus 57.1% of men) or economic incomes 1.34–4.85) (Table 2). (20.6% with no incomes versus 5.7% of men). On the other hand, frail men had a stronger presence of comorbidities like ischaemic coronary disease, peripheral and cerebral vasculop- Table 2. Multivariate analysis for factors associated with frailty in athy, or pulmonary disease (Table 3). In terms of disability, the whole cohort both frail women and men presented similar rates of disability OR (95% CI) P-value for activities of daily living (29.4% versus 27.2%, respectively), but frail women had more difficulties with instrumental Female sex 1.91 (1.00–3.60) 0.047 activities than frail men, with 64.7% of them presenting with Deficient family support 2.57 (1.28–5.13) 0.008 disability (Table 3). Heart failure 2.97 (1.03–8.54) 0.043 Table 4 shows all differences between robust and frail male Cerebral vasculopathy 3.96 (1.35–11.6) 0.012 KT candidates, showing a higher percentage of comorbidities Daily living activities disability 2.67 (1.05–6.81) 0.039 (peripheral and cerebral vasculopathy) and disability among Instrumental daily living 2.55 (1.34–4.85) 0.003 those who were frail. In addition, more male frail patients were activities disability on haemodialysis as RRT modality compared with robust Medical treatment adherence (yes) 1.46 (0.75–2.86) 0.266 Socioeconomic status (no incomes) 1.48 (0.60–3.69) 0.391 patients (73.5% versus 52.8%, respectively). Factors associated Lean mass (kg/m2) 0.93 (0.85–1.02) 0.116 with frailty in male patients included deficient family support Fat mass (kg/m2) 1.001 (0.96–1.04) 0.966 (OR 3.35; 95% CI 1.37–8.23), cerebral vasculopathy (OR 3.28; 95% CI 1.01–10.62), haemodialysis as RRT modality (OR 2.51; 95% CI Table 3. Comparison between male and female frail (Fried 2) KT candidates Female Male n ¼ 68 n ¼ 70 P-value Sociodemographics Age, years, mean 6 SD 62.7 6 11.3 60.1 6 11.6 0.208 Caucasian, n (%) 65 (95.6) 67 (95.7) 0.999 Medical treatment adherencea, n (%) 42 (61.7) 53 (75.7) 0.066 Education, no/primary, n (%) 49 (72.1) 40 (57.1) 0.008 Deficient family support, n (%) 14 (20.6) 15 (21.4) 0.800 Socioeconomic status, no incomes, n (%) 14 (20.6) 4 (5.7) 0.018 Comorbidities Hypertension, n (%) 64 (94.1) 69 (98.6) 0.162 DM, n (%) 27 (39.7) 31 (44.3) 0.586 Heart failure, n (%) 5 (7.3) 8 (11.4) 0.413 Ischaemic coronary disease, n (%) 5 (7.3) 18 (25.7) 0.004 LV ejection fraction, %, median (IQR) 64.0 (58.0–69.5) 63.0 (59.0–67.7) 0.959 Peripheral vasculopathy, n (%) 3 (4.4) 14 (20.0) 0.005 Cerebral vasculopathy, n (%) 5 (7.3) 15 (21.4) 0.019 COPD, n (%) 1 (1.5) 8 (11.4) 0.018 Haemodialysis as RRT modality, n (%) 36 (52.9) 50 (71.4) 0.022 Dependency status Disability for activities of daily livingb, n (%) 20 (29.4) 19 (27.1) 0.487 Disability for instrumental activities of daily livingc, n (%) 44 (64.7) 20 (28.6) <0.001 Nutrition and inflammation status BMI, kg/m2, median (IQR) 27.8 (23.7–32.6) 27.6 (25.0–31.4) 0.858 Risk for malnutritiond, n (%) 30 (44.1) 17 (24.3) 0.055 Lean mass, kg/m2, median (IQR) 11.4 (10.3–12.3) 14.6 (11.3–16.8) <0.001 Fat mass, kg/m2, median (IQR) 15.2 (11.9–20.5) 13 (9.5–16.2) 0.012 Overhydration, L, median (IQR) 0.5 (0.1–1.9) 1.5 (0.3–3.2) 0.025 Albumin, g/dL, mean 6 SD 4.1 6 0.63 4.12 6 0.49 0.583 CRP, mg/dL, median (IQR) 0.4 (0.2–1.1) 0.3 (0.2–0.8) 0.925 Access to transplantation Pre-dialysis waitlisted, n (%) 16 (23.5) 3 (4.3) 0.001 Time to transplantation, months, median (IQR) 29.1 (15.0–40.2) 19.5 (10.3–27.2) 0.125 a Morisky–Green ¼ 0. b Barthel 90. c Lawton–Brody <8 if women and <5 if men. d SNAQ 14. DM, diabetes mellitus; LV, left ventricular; COPD, chronic obstructive pulmonary disease. 114 | M.J. Pérez-Sáez et al. Table 4. Baseline characteristics of 311 KT male candidates stratified by frailty status (two categories) Robust Frail (fried 2) n ¼ 241 n ¼ 70 P-value Sociodemographics Age, years, mean 6 SD 60.2 6 13.5 60.4 6 12.4 0.986 Caucasian, n (%) 213 (95.9) 65 (95.6) 0.934 Medical treatment adherencea, n (%) 179 (85.6) 53 (84.1) 0.189 Education, no/primary, n (%) 132 (54.8) 40 (57.1) 0.725 Deficient family support, n (%) 24 (10.1) 15 (21.4) 0.078 Socioeconomic status, no incomes, n (%) 12 (5.0) 4 (5.7) 0.806 Comorbidities Hypertension, n (%) 231 (96.3) 69 (98.6) 0.333 DM, n (%) 87 (36.3) 31 (44.3) 0.223 Heart failure, n (%) 11 (4.6) 8 (11.4) 0.035 Ischaemic coronary disease, n (%) 43 (17.8) 18 (25.7) 0.144 LV ejection fraction, %, median (IQR) 62.0 (57.0–65.0) 63.0 (59.0–68.0) 0.611 Peripheral vasculopathy, n (%) 22 (9.1) 14 (20.0) 0.012 Cerebral vasculopathy, n (%) 11 (4.6) 15 (21.4) <0.001 COPD, n (%) 22 (9.1) 8 (11.4) 0.566 Haemodialysis as RRT modality, n (%) 121 (52.8) 50 (73.5) 0.003 Dependency status Disability for activities of daily livingb, n (%) 44 (18.2) 19 (27.1) 0.007 Disability for instrumental activities of daily livingc, n (%) 45 (18.6) 20 (28.5) <0.001 Nutrition and inflammation status BMI, kg/m2, median (IQR) 27.4 (24.1–31.6) 28.2 (25.3–31.4) 0.949 Risk for malnutritiond, n (%) 37 (15.3) 17 (24.3) 0.095 Lean mass, kg/m2, median (IQR) 15.2 (13.5–17.5) 14.6 (11.4–16.7) 0.121 Fat mass, kg/m2, median (IQR) 11.7 (8.2–15.4) 13.0 (9.5–16.1) 0.728 Overhydration, L, median (IQR) 1.3 (0.1–2.1) 1.5 (0.3–2.9) 0.356 Albumin, g/dL, mean 6 SD 4.3 6 0.5 4.2 6 0.5 0.289 CRP, mg/dL, median (IQR) 0.3 (0.1–0.7) 0.3 (0.2–0.8) 0.898 Access to transplantation Pre-dialysis waitlisted, n (%) 56 (24.5) 3 (4.4) <0.001 Time to transplantation, months, median (IQR) 20.2 (9.0–33.1) 19.4 (10.2–27.1) 0.785 a Morisky–Green ¼ 0. b Barthel 90. c Lawton–Brody <8 if women and <5 if men. d SNAQ 14. DM, diabetes mellitus; LV, left ventricular; COPD, chronic obstructive pulmonary disease. Table 5. Multivariate analysis for factors associated with frailty in respectively) and slowness in walking speed (22.2% versus 9.2%) male patients were the two of them more differently distributed among sexes (Figure 2). OR (95% CI) P-value Deficient family support 3.35 (1.37–8.23) 0.008 DISCUSSION Instrumental activities disability 5.32 (1.86–15.15) 0.002 Haemodialysis as RRT (yes) 2.51 (1.13–5.57) 0.024 This prospective study describes the frail profile characteriza- Cerebral vasculopathy 3.28 (1.01–10.62) 0.047 tion in a Spanish cohort of advanced CKD patients waiting for Heart failure 3.35 (0.95–11.92) 0.061 KT. Pre-frailty (score 2, 20%) and frailty (score 3, 10.3%) were Peripheral vasculopathy 1.72 (0.58–5.02) 0.324 common, but were much more frequent in women (47.2%). Sex- Basic activities disability 1.35 (0.38–4.77) 0.641 related differences in frailty phenotype are relevant: first, in terms of frailty criteria, with women experiencing more exhaus- tion and slowness than men; and secondly, regarding frailty 1.13–5.57) and disability for instrumental activities of daily liv- characteristics, with more burden of disease associated with ing (OR 5.32; 95% CI 1.82–15.15) (Table 5). In contrast to men, frail men and more social factors associated with women. women did not present a higher comorbidity burden, but they Frailty is a common condition among CKD patients. It ranges had more disability and less lean mass in their body composi- from 15% to 21% [2] of CKD non-dialysis patients to >70% of tion (11.4 versus 12.0 kg/m2, Table 6). The multivariate analysis haemodialysis patients [3]. In Spain, only two studies with re- showed that women were more frequently non-adherent to duced sample sizes have analysed frailty in haemodialysis pharmacological treatment (OR 2.75; 95% CI 1.1–7.47) and patients, reporting disparities from 6% to >40% of patients [29, showed an increased disability in basic (not instrumental, like 43] presenting three or more Fried criteria [1]. Regarding KT can- in men) activities (Table 7). didates, studies have reported lower incidence of frailty— Although all frailty criteria were more frequent in women around 14%—but this percentage increases up to 18–20% when than in men, self-reported exhaustion (39.6 versus 17.0%, KT recipients are considered [11, 35]. We report a 30% Sex differences in frailty among KT candidates | 115 Table 6. Baseline characteristics of 144 KT female candidates stratified by frailty status (two categories) Robust Frail (fried 2) n ¼ 70 n ¼ 68 P-value Sociodemographics Age, years, mean 6 SD 61.3 6 12.1 63.2 6 11.3 0.318 Caucasian, n (%) 71 (95.9) 63 (95.5) 0.994 Medical treatment adherencea, n (%) 59 (85.5) 42 (66.7) 0.031 Education, no/primary, n (%) 52 (68.4) 49 (72.1) 0.634 Deficient family support, n (%) 11 (15.1) 14 (20.6) 0.432 Socioeconomic status, no incomes, n (%) 11 (15.1) 14 (20.6) 0.334 Comorbidities Hypertension, n (%) 74 (97.4) 64 (94.1) 0.330 DM, n (%) 23 (30.3) 27 (39.7) 0.235 Heart failure, n (%) 2 (2.6) 5 (7.4) 0.188 Ischaemic coronary disease, n (%) 9 (11.8) 5 (7.4) 0.364 LV ejection fraction, %, median (IQR) 65.0 (60.0–68.0) 64.0 (58.0–69.0) 0.398 Peripheral vasculopathy, n (%) 4 (5.3) 3 (4.4) 0.813 Cerebral vasculopathy, n (%) 4 (5.3) 5 (7.4) 0.605 COPD, n (%) 4 (5.3) 1 (1.5) 0.215 Haemodialysis as RRT modality, n (%) 50 (71.4) 36 (54.5) 0.041 Dependency status Disability for activities of daily livingb, n (%) 2 (2.8) 20 (29.4) <0.001 Disability for instrumental activities of daily livingc, n (%) 24 (34.3) 24 (64.7) <0.001 Nutrition and inflammation status BMI, kg/m2, median (IQR) 26.2 (22.2–31.4) 28.1 (24.3–33.1) 0.216 Risk for malnutritiond, n (%) 27 (35.5) 30 (44.1) 0.354 Lean mass, kg/m2, median (IQR) 12.0 (10.0–13.0) 11.4 (10.3–12.0) 0.046 Fat mass, kg/m2, median (IQR) 14.5 (10.0–19.2) 15.2 (11.9–20.5) 0.115 Over hidratation, L, median (IQR) 0.6 (0.5 to 1.3) 0.6 (0.1–2.0) 0.118 Albumin, g/dL, mean 6 SD 4.2 6 0.4 4.1 6 0.6 0.558 CRP, mg/dL, median (IQR) 0.4 (0.1–0.8) 0.4 (0.2–1.1) 0.833 Access to transplantation Pre-dialysis waitlisted, n (%) 8 (11.4) 16 (24.2) 0.050 Time to transplantation, months, median (IQR) 17.2 (9.1–25.0) 29.2 (15.1–40.0) 0.017 a Morisky–Green ¼ 0. b Barthel 90. c Lawton–Brody <8 if women and <5 if men. d SNAQ 14. DM, diabetes mellitus; LV, left ventricular; COPD, chronic obstructive pulmonary disease. Table 7. Multivariate analysis for factors associated with frailty in establishes that comorbidity burden is associated with frailty female patients status only in men, while social factors were present in both sexes. OR (95% CI) P-value Female sex was associated with frailty in our cohort, women Medical treatment adherence (no) 2.75 (1.1–7.47) 0.046 being 2-fold more inclined to be frail than men. This difference Basic activities disability 8.80 (1.00–77.21) 0.050 has been analysed in the general population [24]. In a system- Haemodialysis as RRT (yes) 2.22 (0.91–5.42) 0.079 atic review, Gordon et al. [24] found that females presented with Instrumental activities disability 1.91 (0.82–4.46) 0.132 higher frailty index scores [47] than males at all ages. The spe- Lean mass (kg/m2) 0.86 (0.7–1.06) 0.166 cific role of sex in frailty status has also been explored in the setting of some clusters of chronic disease patients, such as the human immunodeficiency virus (HIV) population [32] or liver prevalence of frailty among KT candidates, although not only transplant candidates [27], with a higher percentage of women patients with 3 Fried criteria [1], but also patients with 2 cri- among frail patients in both settings. Therefore, the logic se- teria were considered. This consideration has been previously quence is likely to be as follows: women have higher rates of reported in other studies [36, 37], where outcomes have been frailty, frailty is associated with poorer health results and found similar if two or three of frailty criteria were present. This women have higher mortality rates than men. However, the frailty status has been related to comorbidity burden and dis- concept of the male–female health-survival paradox refers to ability [44], and its presence implies poorer outcomes after the marked discrepancy between the health and survival of the transplantation [11–16]. Our data show that frail patients had a sexes: females have greater levels of disability, more comorbid- greater number of comorbidities such as heart failure or cere- ities and poorer self-rated health, but longer life expectancy [25, bral vasculopathy, and higher disability for activities of daily liv- 48]. Narrowing down to the point, the sex–frailty paradox also ing. Other social aspects like family support or economic arises from the higher rate of frailty among women, but the incomes were worse among frail patients, as has been previ- lower mortality that they present compared with men in the ously described [45, 46]. However, the multivariate analysis general population [24, 26]. In a similar setting to CKD, Lai et al. 116 | M.J. Pérez-Sáez et al. 70 describes frailty criteria distribution between sexes and frail 61.8% Men patients’ characteristics depending on sex. CKD women expe- 60 Women rienced a higher percentage of exhaustion and slowness than men. These two criteria can be the result of the lower lean Percentage of patients 50.2% 50 mass that women had compared with men and might trans- 39.6% late a higher level of sarcopenia among women [52]. In addi- 40 tion, comorbidities were more related to frail men, whereas social factors were more related to frail women. Again, 30 24.3% whether this difference in frailty criteria distribution between 22.2% sexes has an impact on CKD and transplant outcomes 20 17.0% 13.5% requires further investigation. 9.7% 9.6% This study has the inherent limitations of a descriptive one- 10 3.9% centre study, so external validation may not be assumed. In ad- 0 dition, the study was designed based on previous reports from ng s n ity d other groups, assuming similarity among US and European pop- es tio ee tiv ki kn us rin sp ac ulations, and classifying as robust patients those with 0–1 frailty ea ha Sh ng w W Ex Lo criterion. We also merged pre-frail (2 criteria) and frail patients ki al w (3 criteria) due to the low number of patients with 3 criteria ed (only 10.3%), which might have an impact on the results. ow Sl However, to our knowledge, this is the first study to disaggre- FIGURE 2: Frailty phenotype prevalence and criteria distribution differences be- gate frailty data between men and women in a cohort of KT tween male and female kidney transplant candidates. candidates. This may have implications for the detection of patients at risk, and for specific and targeted interventional approaches to improve frailty before transplantation. [27] evaluated 1405 candidates for liver transplantation and Frailty is very frequent among CKD patients on the KT found higher frailty scores in women than men. However, in waiting list. Prevalence, criteria distribution and associated this case, waitlisted mortality was also higher among women factors are different between men and women. Further studies and frailty could explain part of that excess of mortality [27]. In are needed to elucidate if this frailty has similar impact on CKD patients, frailty has been reported to be more frequent in outcomes between different sexes. women [4, 5, 28–31], but this issue has not been precisely addressed and requires further investigation. Some sex differences have been well established in CKD epidemiology SUPPLEMENTARY DATA and evolution. Women present with advanced stages of CKD Supplementary data are available at ckj online. more frequently than men, perhaps due to the longer life expec- tancy they have and possibly because glomerular filtration rate equations tend to overdiagnose CKD in female patients FUNDING [19, 20, 49]. In addition, kidney function declines faster in men The Frail-MAR project is currently supported by a FIS-FEDER and they more often need RRT. The potential protective effects grant PI19/00037 (ISCIII) and a ‘Proyecto Estrella de Mejora of estrogens or the damaging effects of testosterone may also de la Calidad’, Parc de Salut Mar, Barcelona, Spain. M.J.P.-S. play a role [20, 22]. has support from a Spanish Society of Transplant scholar- In terms of transplantation, women have reduced access to ship. V.D.-Y. is supported by a Jordi Gras contract from the the KT waiting list compared with men and fewer chances to Institut Mar for Medical Research (IMIM). receive a transplant from a deceased donor [20, 21, 50, 51]. This might be partly explained by sex itself and the biological effect of pregnancy sensitization, but also by gender and therefore so- CONFLICT OF INTEREST STATEMENT cial factors, such as lower probability of having a KT discussion The authors of this study declare no conflict of interest. with their nephrologist [23]. More importantly, mortality is higher among men at all levels of advanced CKD, whereas mor- tality among individuals on dialysis or after transplant is similar DATA AVAILABILITY STATEMENT in both sexes [20, 22]. In the setting of frailty, two studies have The datasets generated during and/or analyzed during the cur- shown that CKD women who were KT candidates had longer rent study are available from the corresponding author on rea- hospitalizations than men while listed. Hospitalization was a sonable request. marker of reduced survival on dialysis, decreased likelihood of transplantation, readmissions after transplant and diminished patient survival. However, although readmissions after trans- APPENDIX plant were more frequent between women, they did not experi- FRAIL-MAR Study Group members ence higher rates of graft loss or mortality [30, 31]. So far, the consequences of sex disparities in frailty prevalence among Marı́a José Pérez-Sáez, Carlos E. Arias-Cabrales, Dolores CKD patients remain uncertain. Redondo, Francesc Barbosa, Higini Cao, Silvia Collado, Maria Regarding frailty criteria distribution, women have shown Dolores Arenas, Anna Buxeda, Carla Burballa, Marta Crespo, a different frailty phenotype than men among HIV patients Julio Pascual, Anna Faura, Marı́a Vera, Anna Bach, Guillermo [32], liver transplant candidates [27] and KT candidates [28, Pedreira, Ernestina Junyent, Montserrat Folgueiras, Yolanda 50], with poorer results also in the Short Physical Castillo, Aida Martı́nez, Marisol Fernández, Eva Barbero, Rosa Performance Battery test in the latter study. Our study Causadı́as (Department of Nephrology, Hospital del Mar), Alicia Sex differences in frailty among KT candidates | 117 Calvo (Department of Cardiology, Hospital del Mar), Jesús 11. McAdams-DeMarco MA, Ying H, Olorundare I et al. Carazo (Department of Anesthesiology, Hospital del Mar), Albert Individual frailty components and mortality in Frances, Lluis Cecchini (Department of Urology, Hospital del kidney transplant recipients. Transplantation 2017; 101: Mar), Vanesa Dávalos, Ester Marco, Delky Meza de Valderrama, 2126–2132 Andrea Morgado, Elena Mun ~ oz (Department of Rehabilitation 12. Goldfarb DA. Re: Frailty and early hospital readmission after and Physical Medicine, Hospital del Mar), Xavier Nogués kidney transplantation. J Urol 2014; 191: 1366–1367 (Department of Internal Medicine, Hospital del Mar), Leocadio 13. McAdams-Demarco MA, Law A, King E et al. Frailty and mor- Rodrı́guez-Man~ as (Department of Geriatrics, Hospital tality in kidney transplant recipients. Am J Transplant 2015; Universitario de Getafe, Madrid), Olga Vázquez (Department of 15: 149–154 Geriatrics, Hospital del Mar), Marı́a Dolores Muns (Dietary Unit, 14. McAdams-Demarco MA, King EA, Luo X et al. Frailty, length Department of Endocrinology and Nutrition, Hospital del Mar), of stay, and mortality in kidney transplant recipients. Ann Miguel Gárriz, Marı́a Polo Gómez (Psychology Department, Surg 2017; 266: 1084–1090 Neuropsychiatric Institute, Hospital del Mar), Sara Hurtado, 15. McAdams-DeMarco MA, Chu NM, Segev DL. Frailty and long- Maite López (Diagonal Hemodialysis Center, Fresenius Medical term post-kidney transplant outcomes. Curr Transplant Rep Care), Laura Ribera, Margarita Guino (Glories Hemodialysis 2019; 6: 45–51 Center, Fresenius Medical Care), Ramón Roca, Jordi Calls, Alicia 16. Garonzik-Wang JM, Govindan P, Grinnan JW et al. Frailty and Rovira (Department of Nephrology, Hospital de Mollet), Josep delayed graft function in kidney transplant recipients. Arch Mora, Omar Ibrik, Florentina Liria (Granollers Hemodialysis Surg 2012; 147: 190–193 Center, Fresenius Medical Care), Thaı̈s López, Jaume Almirall, 17. ONT. Actividad de Donación y Trasplante Renal. Espan ~ a. Vol Carmen Moya (Department of Nephrology, Hospital Parc Taulı́), XII, 2018 Fátima Moreno, Manel Ramı́rez de Arellano, Sandra Rubio 18. Puts MTE, Toubasi S, Andrew MK et al. Interventions to pre- (Department of Nephrology, Consorci Sanitari de Terrassa), vent or reduce the level of frailty in community-dwelling Ignacio Cidraque, Carlota Pájaro (Cetirsa Terrassa Hemodialysis older adults: A scoping review of the literature and interna- Center, Fresenius Medical Care), Núria Garra, Josep Galcerán, tional policies. Age Ageing 2017; 46: 383–392 Marina Fenollar (Department of Nephrology, Hospital de 19. Murphy D, McCulloch CE, Lin F et al.; Centers for Disease Manresa), Sara Outón, Fabiola Dapena, Josep Jara (Department Control and Prevention Chronic Kidney Disease Surveillance of Nephrology, Consorci Sanitari del Garraf), Rosa Garcı́a, Team. Trends in prevalence of chronic kidney disease in the Mónica Manresa (Department of Nephrology, Hospital de United States. 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