;PDOPPS Korea and Arbor Research InvestigatorsIntroduction
Patients with end-stage kidney disease suffer from various cutaneous disorders including xerosis, pruritus, and hyperpigmentation [1,2]. The pathophysiology of these skin disorders remains unclear, but histopathological findings of their skin are notable for microangiopathy, fragmented elastin-like fibers, and hyperkeratosis [3]. These complications significantly impair the quality of life and prognosis of patients. Particularly in peritoneal dialysis (PD) patients, higher levels of pruritus may contribute to technique failure or mortality [4].
Patients undergoing PD are at increased risk of infection, including catheter-related infection, due to the insertion of a silicone rubber catheter through the anterior abdominal wall [5]. Catheter-related infections manifest as exit-site infections (ESIs) and tunnel infections (TIs). ESIs are typically recognized as purulent discharge at the skin surface where the catheter exits the body. TIs are characterized by inflammation of the tunnel that passes through the anterior abdominal wall [6,7]. These infections are critical risk factors for peritonitis, a major complication in PD that impacts catheter removal, transfer to hemodialysis, hospital admissions, and patient mortality [8,9]. Globally, the incidence of ESIs is estimated to be between 0.06 and 0.42 episodes per patient-year [7].
Preventing PD-related infections is crucial for maintaining the therapy, and significant research has focused on peritonitis. In contrast, research into catheter-related infections remains insufficient [6,10,11]. We hypothesized that impaired skin barrier function in PD patients might be a significant risk factor for catheter-related infections. This study aimed to investigate these relationships and identify key prevention strategies for catheter-related infections in PD patients.
Methods
Cohort study design
This research was conducted as a multicenter prospective cohort study using data from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) in Korea. Initiated in 2014, the PDOPPS is an international prospective cohort study aimed at enhancing the knowledge of managing PD patients worldwide. The details of the PDOPPS study have been previously described [12].
The current analysis utilized Korea PDOPPS data (626 PD patients, 20 facilities) from phase 2 (2019–2021) [13]. The PDOPPS received approval from both a central institutional review board (IRB) in the USA and the IRB at Soonchunhyang University Cheonan Hospital in Korea (No. 2019-07-045). Eligible patients provided informed consent to participate in the study until the enrollment target was attained, in accordance with the Declaration of Helsinki of the World Medical Association. Patients lacking self-reported data on skin xerosis or those with follow-up periods shorter than 120 days were excluded to ensure a focus on sufficiently observed cases (Fig. 1). All patients were aged 18 years or older at the time of study enrollment.
Skin microbiota analysis
We analyzed the skin microbiota database of dialysis patients (hemodialysis, 40 and PD, 36) at Soonchunhyang University Cheonan Hospital from our previous research [14]. Nineteen overlapping patients were concurrently enrolled in both the PDOPPS and the microbiota study. This study investigated the association between chronic kidney disease (CKD)-associated pruritus and skin microbiota. Skin microbiome samples were collected from three sites: the back (sebaceous area), antecubital fossa (moist area), and shin (dry area). The skin sites were swabbed using the NBgene-SKIN (NBG-S22S) skin sampling kit (Noble Bio). Following collection, the samples were transported to the Probiotics Microbiome Convergence Center of Soonchunhyang University (Asan, Korea) for DNA extraction. The study obtained approval from the IRB at Soonchunhyang University Cheonan Hospital in Korea (No. 2021-12-020).
Variables of cohort study
Study coordinators at each participating site abstracted data from medical records for each enrolled patient. Abstracted data included demographics, comorbidities, dialysis status, and clinical outcomes. The initial values of body mass index (BMI), type of PD therapy (either continuous ambulatory PD or automated PD), and laboratory parameters during the phase 2 period were utilized. Furthermore, the catheter-related infection rate was calculated per patient annually. Upon reviewing the prevalence of catheter-related infections, the causative agents were identified. Enteric bacteria included Escherichia coli, Pseudomonas aeruginosa, Serratia marcenscens, etc. Additional details, such as the type of PD therapy during the infection, instances of relapsed infection, recurrent infection, and repeated infection, along with other relevant information, were listed.
The definitions of relapsed infection, recurrent infection, and repeated infection of the PDOPPS study followed the International Society for Peritoneal Dialysis (ISPD) guidelines [6,11]. Relapsed infection refers to an infection episode that occurred within 4 weeks after completing therapy for a prior episode, involving the same organism or a sterile (culture-negative) episode. This classification includes cases where a specific organism recurs, a culture-negative episode precedes an infection with a specific organism, or an infection with a specific organism is followed by a culture-negative episode. Recurrent infection is defined as an infection episode that occurred within 4 weeks after the completion of treatment for a previous episode but is caused by a different pathogen. Repeat infection describes an infection episode that occurred more than 4 weeks after the completion of treatment for a previous infection, involving the same pathogen.
Evaluation of the degree of xerosis and pruritus
In the original data of the PDOPPS study, PD patients reported their severity of skin xerosis or skin pruritus on a 5-point scale: not at all (1), somewhat (2), moderately (3), very much (4), and extremely (5). These scales were grouped into three categories: none (1), low-grade (2–3), and high-grade (4–5).
In the skin microbiota study, pruritus severity was determined with the self-reported questionnaire: the Worst Itch Numeric Rating Scale (WI-NRS). It indicated the degree on a scale from 0 to 10, where 0 represents no pruritus and 10 is the most severe pruritus [15]. Our previous study additionally utilized two multidimensional questionnaires: the 5D Itch Scale and UP-Dial, to validate the reliability of WI-NRS. Yet, we solely relied on WI-NRS results as a criterion for categorizing pruritus severity as used in our previous studies (low-grade pruritus, 0–3; high-grade pruritus, 4–10) [14]. The relative abundance of Staphylococcus aureus was specifically examined at three skin sites.
Statistical analysis
Statistical analyses were conducted using IBM SPSS version 25.0 (IBM Corp.). Categorical variables such as male sex, hypertension, xerosis, and pruritus were expressed as counts (percentages). Continuous variables such as age, BMI, and duration of dialysis were presented as either mean ± standard deviation or median (interquartile range), as appropriate. For group comparisons, the chi-square test or Fisher exact test was employed for categorical variables. One-way analysis of variance and the Kruskal-Wallis test were used in continuous variables, except for the microbial analysis. The Wilcoxon rank-sum test was used to compare the relative abundance of skin microorganisms.
For further examination, Cox regression analysis assessed the relation between variables and time-to-event outcomes, providing hazard ratios (HRs) and 95% confidence intervals (CIs). The starting point was the initiation date for follow-up for each patient during phase 2 of PDOPPS. Endpoints were defined as the censoring date derived from the database; date of death for patients who died, the minimum of 7 days after the date of last dialysis, and end of facility follow-up for other patients. Multivariate models were employed for the analysis. Kaplan-Meier plots were generated to examine the impact of skin dryness and skin pruritus on catheter-related infections and S. aureus-associated catheter-related infections, with comparisons made using log-rank tests. Moreover, logistic regression analysis was conducted to analyze the risk factors of xerosis and pruritus, and the results were presented as odds ratios (OR) and 95% CI. Missing values were excluded from the analysis without imputation (Supplementary Table 1, available online).
Results
Patients with xerosis have a higher frequency of catheter-related infection
The characteristics of the patients are detailed in Table 1 and Supplementary Table 2 (available online). Patients with high-grade xerosis tend to have concurrent high-grade pruritus (68.0%), in contrast to those with low-grade (8.1%) or no (0.8%) xerosis (p < 0.001). The evaluation of laboratory parameters revealed that higher serum creatinine (p < 0.001), total calcium (p < 0.05), phosphorus (p < 0.001), and calcium-phosphorus (Ca-P) product levels (p < 0.001) are notable in patients with high-grade xerosis. Additionally, the proportion of patients who own pets was higher in the high-grade xerosis group (19.4%) compared to the low-grade (15.4%) or no (8.4%) xerosis group (p < 0.05). When comparing the incidence rate per patient-year of catheter-related infection as average ± standard deviation on an individual basis during the observation period, patients with high-grade xerosis had a higher incidence rate (0.13 ± 0.36 infections/patient-year) than low-grade (0.08 ± 0.33 infections/patient-year) or no (0.03 ± 0.15 infections/patient-year) xerosis (p < 0.01).
Xerosis and pruritus are risk factors for catheter-related infection
The association between poor skin conditions and the first event of catheter-related infections was assessed by Kaplan-Meier and Cox regression analyses. The median follow-up duration was 706 days (interquartile range [IQR], 365–855 days) in overall patients, with no significant differences between groups according to their degree of self-reported xerosis (no xerosis: 577 days [IQR, 332–854 days], low-grade xerosis: 832 days [IQR, 365–855 days], and high-grade xerosis: 837 days [IQR, 397–855 days]; p > 0.05). During the follow-up period, a total of 64 catheter-related infection events were observed. The Kaplan-Meier curves showed that the first event of catheter-related infections is more likely to occur in patients with high-grade xerosis (p = 0.006) (Fig. 2A) and high-grade pruritus (p = 0.001) (Fig. 2B), compared to low-grade or no xerosis and pruritus.
Table 2 depicts the univariate and multivariate Cox regression analysis for the risk factors of a first catheter-related infection episode. In the multivariate Cox proportional hazards model, patients with high-grade xerosis had a 2.71 times higher risk for the infection compared to those with no xerosis (95% CI, 1.19–6.18; p = 0.02) (Table 2), and patients with high-grade pruritus had 2.57 times higher risk of infection compared to those with no pruritus (95% CI, 1.27–5.22; p = 0.009) (Table 2).
Xerosis and pruritus are associated with a higher risk of Staphylococcus aureus-associated catheter-related infection
The detailed aspects of catheter-related infection are listed in Supplementary Table 3 (available online). Among the total of 97 cases of catheter-related infection, most of the cases were ESIs only (93%). While looking at the etiologic organisms of the infections, interestingly, gram-positive strains are more cultured in patients with high-grade xerosis (60.5%), compared to patients with low-grade (34.0%) or no xerosis (33.2%). Furthermore, S. aureus-associated catheter-related infections accounted for 34.9% of cases in patients with high-grade xerosis (15 out of 43), which was higher than the cases occurring in patients with low-grade (14.9%, 7 out of 47) or no (16.7%, 1 out of 6) xerosis.
To investigate whether high-grade xerosis increases susceptibility to catheter-related infections caused by S. aureus, the Kaplan-Meier curves and Cox regression analysis were utilized. According to the Kaplan-Meier curves, patients with high-grade xerosis exhibited a significantly higher probability of experiencing a first event of S. aureus-associated catheter-related infection, compared to patients with low-grade or no xerosis (p < 0.001) (Fig. 2C). This tendency was also apparent when comparing the degree of pruritus (p < 0.001) (Fig. 2D). In the multivariate Cox proportional hazards model, patients with high-grade xerosis had 5.66 times higher risk for S. aureus-associated infection (95% CI, 1.97–16.30; p = 0.001) (Table 3) than those with low-grade or no xerosis, while patients with high-grade pruritus had a 5.93 times higher risk (95% CI, 2.18–16.15; p < 0.001) (Table 3) compared to those with low-grade or no pruritus.
Staphylococcus aureus is more abundant in the skin of patients with high-grade pruritus
The microbial analysis aimed to find out whether the abundance of S. aureus varies with skin conditions in dialysis patients. The result revealed that in the antecubital fossa, a moist area similar to the abdomen, the relative abundance of S. aureus was significantly higher in the high-pruritus group, compared to the low-pruritus group (p < 0.05) (Fig. 3) [16]. Additionally, the amount of S. aureus in the back and shin, the sebaceous area, and the dry area, respectively, was also higher in patients with high pruritus, though not significantly (p > 0.05) (Fig. 3).
Pet ownership, high serum creatinine levels, and high calcium-phosphorus products may be the risk factors for xerosis
Risk factors for xerosis and pruritus in PD patients were assessed by multiple logistic regression analysis (Table 4). After adjustment, having any pets (OR, 1.63; 95% CI, 1.00–2.65, p = 0.05), serum creatinine levels (OR, 1.06; 95% CI, 1.00–1.13, p = 0.04), and Ca-P product levels (OR, 1.02; 95% CI, 1.00–1.04, p = 0.03) remain significantly associated with xerosis. Risk factors for pruritus included diabetes mellitus (OR, 1.54; 95% CI, 1.03–2.31, p = 0.04) and Ca-P product level (OR, 1.03; 95% CI, 1.01–1.04, p = 0.003).
Discussion
The recently updated ISPD catheter-related infection guidelines emphasize preventive measures to reduce the incidence of catheter-related infections [6]. These preventive measures include prophylactic antibiotics and proper catheter care, not to mention that improving the skin condition itself can prevent catheter-related infections.
In our study, we confirmed strong associations between skin conditions and catheter-related infections. It is indeed no surprise that poor skin condition increases the risk of catheter-related infections, as the skin barrier is essential for protecting our body from pathogens [17]. When the skin barrier is compromised, pathogens more easily penetrate the skin at vulnerable catheter insertion sites. Dry or itchy skin, both symptoms of disrupted skin barrier function, were associated with an increased risk of infection in our findings [18].
Impaired barrier function may alter the strains and frequency of causative pathogens for infections by modifying the skin microbiota composition [14,19]. Our previous study explored the relationship between CKD-associated pruritus and the skin microbiome in dialysis patients. This study selected three body regions for analyzing skin microbiota composition: the back as a sebaceous area, the antecubital fossa as a moist area, and the shin as a dry area. Results revealed significant differences between groups categorized by the pruritus severity, with Cutibacterium being significantly lower and Escherichia higher in the sebaceous back region of the high-pruritus group compared to the group with low pruritus.
Remarkably, this study revealed that patients with xerosis or pruritus are at a high risk of S. aureus-associated infection. In addition, based on the data from the previous research, S. aureus was found to be significantly higher in the group with severe pruritus, particularly notably in the antecubital fossa. This finding is particularly noteworthy, considering that the antecubital fossa shares a moist environment similar to the abdomen, where PD patients insert their catheters [16]. These findings suggest that the compromised skin barrier in these patients provides an environment conducive to the proliferation of S. aureus, increasing their susceptibility to infection. S. aureus is known to be one of the most common organisms cultured in infected areas, challenging to treat due to multiple antibiotic resistance [20,21]. Therefore, these findings highlight the importance of skin care for PD patients.
The relationship between S. aureus and xerosis has been extensively studied in other dermatological conditions such as atopic dermatitis [22]. It has been widely recognized that the severity of atopic dermatitis is associated with colonization of S. aureus. Research has revealed that in individuals with low natural moisturizing factor, there was an increased expression of corneodesmosin in corneocytes, making invasion by S. aureus easier [23,24]. Moreover, the disruption of the skin barrier increases pH level, providing an environment favorable for the colonization of S. aureus [25]. While further research is needed to determine whether these kinds of skin conditions are also present in the skin of PD patients, proper skin care may be important for PD patients to inhibit S. aureus growth on their abdomen.
Furthermore, a recent study on the skin microbiota of hemodialysis patients with tunneled cuffed catheters revealed an increased proliferation of Staphylococcus and a reduction of Cutibacterium in the pericatheter region [26]. These results align with the characteristics of compromised skin in dialysis patients observed in our previous research, manifesting as xerosis or pruritus [14]. Skin damage may arise from catheter insertion, and PD patients are likely to suffer similar impairments, particularly those with preexisting severe xerosis [27]. These findings explain why S. aureus is a common pathogen causing catheter-related infections in PD patients, and why the infection risk is especially elevated in those with severe xerosis and pruritus.
While demonstrating that compromised skin conditions increase the risk of catheter-related infections, this study also investigated factors that deteriorate skin barrier function. Among the identified factors, high serum creatinine levels and indicators such as the Ca-P product are well-known factors that can worsen skin conditions in dialysis patients based on previous research [1,28,29]. Additionally, pet ownership emerged as a newly discovered factor in this study. With the increase in single-person households in modern society, the number of households raising pets is also on the rise. PD patients are no exception to this tendency; therefore, this finding is noteworthy.
Companion animals for PD patients may be beneficial, promoting the enhancement of overall life satisfaction and improving their mental health [30,31]. However, foreign substances such as saliva, fur, and dander derived from pets may act as allergens on the skin of PD patients [32–34]. Individuals with pet ownership may be significantly affected by these substances, leading to the occurrence of xerosis. The wide range of CIs for the OR of pet ownership suggests that their impact on xerosis may vary depending on the individual’s sensitivity to allergens. Therefore, it is recommended that PD patients who are sensitive to allergens from pets should frequently clean their residences and avoid close contact with pets.
This study has some limitations. One of them is that skin conditions such as xerosis and pruritus were assessed using subjective scales. While pruritus is inherently difficult to measure as an objective and quantifiable indicator, the degree of xerosis may be quantified by using experimental methods such as transepidermal water loss measurement. However, in this study, as the database from PDOPPS was used directly, measurements using experimental devices were not conducted.
Nevertheless, this study provides fundamental knowledge for exploring preventive measures against catheter-related infections, which are currently not addressed in existing guidelines. Based on the results of this study, moisturizers or lotions can be attempted to maintain or improve skin barrier function in PD patients. In addition, using humidifiers in their living space, avoiding irritants including pet-derived substances, chemicals, and cold or dry air, and applying sunscreens outdoors may be effective strategies to prevent xerosis. Furthermore, prebiotic or probiotic therapies may be applied to prevent catheter-related infections by modifying the composition of resident microbiota on the abdominal skin. While current prophylactic antibiotic therapy may be effective for prevention, its limitations such as the development of resistant strains and disruption of the microbial ecosystem should be considered. Instead of using antibiotics, altering the skin environment on the abdominal skin could be an effective method of infection prevention.
This study is significant in identifying skin conditions as a new risk factor for catheter-related infections and proposing upcoming management guidelines. Further research is needed to investigate whether the incidence of catheter-related infections is reduced when the skin condition is improved.
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