Assessing Mechanical Catheter Dysfunction in Peritoneal Dialysis Patients: A Case Control, Proof- of-Concept Study

Krystell Oviedo Flores Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna Lukas Kaltenegger Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna Fabian Eibensteiner Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna Markus Unterwurzacher Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Medical University of Vienna Klaus Kratochwill Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Medical University of Vienna Christoph Aufricht Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna Franz König Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna Andreas Vychytil (  andreas.vychytil@meduniwien.ac.at ) Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna


Introduction
Successful treatment and technique survival on peritoneal dialysis (PD) depend on a long-term peritoneal access that provides effective peritoneal drainage of dialysis uid for maintenance of an adequate uid and salt homeostasis [1]. PD catheter tip migration is a major complication that usually requires catheter reposition or replacement and may eventually lead to technique failure [2]. Catheter dislocation may be associated with slow and incomplete drainage of dialysis uid from the peritoneal cavity. It is important to note that while drain volume can be larger than ll volume even with malpositioned catheters [3], drainage may be incomplete, leading to increased abdominal pressure and a higher risk of hernias and dialysate leaks [4].
Low ultra ltration (UF) capacity may be misleading in patients with PD catheter dysfunction as incomplete peritoneal drainage of dialysate can result in insu cient ultra ltration and uid overload. Therefore, the recent ISPD guidelines recommend that low UF capacity should be evaluated by considering mechanical drainage problems rst, before suspecting membrane dysfunction [5]. Previous publications have suggested the association of slow drainage of PD uid, poor net UF or constant alarms during cycler treatment with catheter dysfunction [6,7]. However, until now no standard procedure has been systematically evaluated on the usability to assess mechanical drainage problems in PD patients.
In contrast to isolated measurements of ultra ltration capacity, for example during the peritoneal equilibration test (PET), automated peritoneal dialysis (APD) cycler readouts allow meticulous daily analysis of important treatment parameters. The aim of this proof-of-concept study was to analyze the usability of cycler parameters routinely used in our center for identifying APD patients with catheter malfunction.

Results
Out of 117 APD patients treated between 2015 and 2021, 14 patients with veri ed catheter dysfunction (12%) and 19 controls (16%) could be identi ed. There were no signi cant differences in demographic data (Table 1)  For these four selected parameters the cut-off values for predicting catheter dislocation based on ROC curves were > 7 alarms/week (sensitivity: 85%, speci city: 79%), > 22 min drain time at end of the cycler session (sensitivity: 79%, speci city: 89%), <150 mL mean net UF of last ll (sensitivity: 93%, speci city: 66%), and >2 days per week with negative UF of last ll (sensitivity: 71%, speci city: 78%) ( Figure 1, Supplementary Table S3)   Table 2 summarizes the simple and stepwise logistic regression of the parameters for predicting catheter dislocation. Each additional alarm per week increased the odds of catheter dislocation by a factor of 1.3 (95% CI 1.062; 1.586, p=0.011) leading to an increase by 40.6 for 14 alarms (mean difference between cases and controls). Each additional minute of mean drain time increased the odds of catheter dislocation by a factor of 1.1 (95% CI 1.015; 1.247, p=0.025). A 1 milliliter (ml) decrease of mean UF of last ll increased the odds for catheter dislocation by a factor of 1.006 (95% CI 0.989; 0.999, p=0.013).
The mean difference between cases and controls was approximately 200 mL leading to an increase of the odds by 3.33 for a catheter dislocation. Furthermore, an increase of days with negative UF of last ll tended to be associated with catheter dislocation (p=0.063). In the stepwise logistic regression analysis (including only the four parameters) the total number of alarms improved the t of the model for the prediction of catheter dislocation compared to the null model (AUC p<0.001).
After adding the SD-Res of net UF in the last ll as well as the SD-Res of the gcUF to the existing four covariates into the stepwise regression model and using BIC as criterion for selection all covariates except total alarms were eliminated, indicating that SD-Res does not improve the prediction model.

Discussion
We demonstrated that a protocol assessing several cycler readout parameters might be a feasible, easyto-perform tool to adequately screen APD patients for catheter dysfunction.
Patients with a malfunctioning catheter may clinically present with slow drainage of PD uid, prolonged drain times, poor net UF [6,7] or constant alarms during cycler treatment [10], resulting in impairment of quality of life. Early diagnosis prevents the possibility of volume overload and complications associated with increased intraperitoneal volume that subsequently may lead to technique failure [11].
Recent ISPD guidelines recommend that mechanical problems should be excluded prior to membrane function testing in patients with insu cient UF capacity. However, there exists no standard protocol on how to diagnose catheter dysfunction [5].
One of the requirements for good catheter performance is an adequate position of the PD catheter tip. The ISPD guidelines on PD access recommend using the upper border of the pubic symphysis as a reference point for the ideal location of the catheter tip deep in the pelvic area [7]. During or after catheter implantation, the position of the catheter tip might be con rmed with a plain abdominal radiological examination, but this is not routinely performed [17].
Single diagnostic tests performed in yearly intervals (e.g. ultra ltration capacity during the PET) may not be suitable for diagnosing mechanical problems. Net ultra ltration is more variable than peritoneal small solute transport. Availability of daily treatment data extracted from the APD cycler card software allows a better clinical evaluation of mechanical drainage problems in routine practice.
In this proof-of-concept study, we con rmed the clinically observed impression that the parameters under investigation serve as predictors for diagnosis of catheter dysfunction. This is the rst controlled analysis evaluating parameters obtained from the APD cycler software for the diagnosis of catheter dysfunction in two well-de ned patient groups. The selected cases and controls represent typical APD patients with radiological con rmation of PD catheter position and clinical assessment of catheter performance.
In the stepwise logistic regression analysis, only number of alarms/week was a statistically signi cant predictor of catheter dislocation. As the Pearson and Spearman correlation coe cients between number of total alarms and the other metric variables revealed values above 0.5 (indicating moderate to strong correlations), none of the other variables could contribute anything in addition. However, considering the limited patient number this analysis does not refute the importance of other parameters for diagnosing mechanical drainage problems.
A combination of at least two of three parameters which had signi cant ROC curves and an AUC of > 0.75 (number of alarms, drain time, net ultra ltration of last ll) could identify a similar number of patients with catheter dislocation compared to using the number of alarms alone (85.7%). However, when using a combination of parameters, the percentage of false positive control decreased (Table 3a).
The results of this study are strengthened by the accordance of the cut-off values derived from the ROC curves with conclusions of other authors in the recent literature. We determined that a cut-off value of > 7 alarms/week is a good predictor of catheter dysfunction. According to Neri et al [9], the use of tidal PD optimized catheter ow function, resulting in the presence of < 1 alarm per day (corresponding to < 7 alarms per week). Accordingly, other authors suggest that out ow failure prompts alarms in APD patients treated with HomeChoicePro™ [10]. Moreover, the cut-off value for mean drain time of > 22 minutes for predicting catheter dysfunction found in our study is similar to the conclusion of other authors who suggested that a drainage time of less than 20 minutes is a marker of good catheter performance [3,18]. A sub-optimal catheter position results in poor hydraulic function that may cause out ow failure and can prolong drain time at the end of the cycler session [17,19]. We demonstrated that low or negative UF of last ll during the daytime dwell was evident in patients with catheter dislocation. Our selected cut-off value of UF for predicting catheter dysfunction of 150 mL is consistent with data reported by Plum et al [20] who found an ultra ltration volume of last ll of 278 ± 43 mL/day in APD patients treated with icodextrin during the long dwell.
Our study has certain limitations. We acknowledge that we are reporting a retrospective, single-center study of patients on APD, which may limit statistical power and generalizability of our results. For example, albeit not statistically signi cant, assessing the number of treatment days with negative UF of last ll may be more practicable than analyzing cut-off values of ultra ltration with icodextrin. Although we included all APD patients treated in our center between 2015 and 2021 who were suitable for inclusion in either groups, the sample size is still small and may have limited the validity of the multiple logistic regression analysis and the representativeness of the results. Larger, prospective studies are required to con rm our clinical observations.
In conclusion, a timely intervention in patients with catheter dysfunction may prevent adverse events with potential negative impact on technique survival [11]. In this context, the use of total number of alarms/week as well as a combination of parameters derived from the APD cycler card management software with the selected cut-off values are good predictors for assessing catheter function. Our ndings may be especially interesting because these parameters are also available in new APD cyclers with devices connected to remote monitoring platforms, which are rapidly gaining importance and availability [11,12].

Study Design
This retrospective case-control, proof of concept study included patients with end-stage chronic kidney disease treated with HomeChoicePro™ APD system (Baxter International Inc., Illinois, United States) at the Division of Nephrology and Dialysis, Medical University of Vienna.
To validate parameters related to mechanical drainage problems we studied two well-characterized patient groups using data retrieved from the APD cycler card management software PD Link (Baxter International Inc., Illinois, United States). Two investigators retrospectively analyzed the PD catheter position based on posteroanterior and/or lateral abdomen X-ray, if available, as described below.
Clinical records or a retrospective bio databank were reviewed by both investigators to assess catheter drainage function and patients' demographic data. This study was performed in line with the principles of the Declaration of Helsinki and involves retrospectively collected data. Informed consents were collected from all our patients to include them in our biobank (study protocol EK 2035/2015) and approval was granted by the Local Ethics Committee of the Medical University of Vienna.

Patient Selection
Patients included in this study received regular APD between January 2015 and March 2021 at the Medical University of Vienna. In our center since the 1990´s, all patients use a coiled single-cuff PD catheter and perform tidal peritoneal dialysis. Patients with incomplete data (no abdominal X-ray or data on catheter performance) were withdrawn. Patients with a history of large open abdominal or pelvic surgery, ascites, malignant pelvic neoplasia or death within 15 days after APD start, were excluded (Fig.   2).

Cases
All patients with clinical evidence of drainage problems that required a diagnostic and/or therapeutic intervention (repeated abdominal X-ray to verify catheter position, use of laxatives, catheter repositioning or replacement) with con rmed catheter dislocation in an abdominal X-ray (verifying catheter tip dislocation outside the deep pelvic area) were selected as cases.

Controls
Patients with an uncomplicated course of treatment without clinical evidence of mechanical problems and a recent X-ray con rming position of the PD catheter tip in the recto-vesical/ recto-uterine space were selected as controls. Patients with a computed tomography (CT) peritoneography or an explorative laparoscopy/adhesiolysis after start of PD were excluded from the control group since requirement of these diagnostic or therapeutic measures do not represent an uncomplicated course of treatment.

Parameters
Based on previous publications [8 -12] and on our own clinical expertise, daily cycler readout parameters are routinely used at our center to detect mechanical drainage problems early during routine follow-up. Number of alarms, drain time at the end of cycler session, net UF from last ll, number of days with negative UF of last ll and net UF from cycler treatment (net UF and glucose-corrected UF [gcUF]) were analyzed in the present study.
The observation period for both groups consisted of seven days of continuous APD treatment. Among cases, these parameters were analyzed in the week immediately before the diagnostic imaging studies con rming catheter tip migration. The time-period selected for the analysis of the control group was seven days selected randomly depending on data availability, within a pre-de ned time window between 1 and 3 months after the start of PD. This time window was chosen considering the appearance of changes of peritoneal membrane function parameters early after PD start that may in uence ultra ltration [5].
Furthermore, daily glucose load was calculated as total grams of glucose in the fresh PD uid infused each day. Daily glucose corrected ultra ltration (gcUF) was calculated as UF in mL divided by glucose load in grams. APD prescription was not modi ed during the observation period.

Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics (IBM Corp., Armonk, NY, USA), R (GNU General Public License [13]) and GraphPad Software (California, USA). Results were expressed as relative frequencies for categorical variables, mean with standard deviation (SD) for continuous variables, and median with interquartile range (IQR) for skewed distributions. Comparison of categorical variables was performed with Fisher's exact test. Continuous variables were analyzed with Mann-Whitney U-test (MWU). The receiver-operating curves (ROC) for each parameter were computed from the observed proportion utilizing Clopper method [14], without correction for multiple comparisons of area calculation. Selected cut-off values for the parameters were identi ed via means of the highest sensitivity and speci city.
Stepwise logistic regression (catheter dislocation versus control as dependent variable) was performed to evaluate the contribution of several covariates to anticipation of catheter dislocation using "stepwise" in the R-package "RcmdrMisc" [15] with BIC (Bayesian Information Criterion) as criterion for selection.   SupplementaryMaterial.docx