Transport Status: Classification and Implications
Classifying Peritoneal Membrane Transport Status
In 1987, Twardowski et al. proposed the first method to classify membrane function by measuring the rate at which solutes equilibrate between the dialysate and body plasma (1). This dialysate-to-plasma ratio, called the D/P ratio, measures the combined effect of diffusion and ultrafiltration (1,2). A low solute D/P means that transport across the peritoneal membrane for a given solute occurs slowly, and equilibrium between the dialysate and plasma is reached gradually. In contrast, a high solute D/P means that transport of a solute across the membrane occurs quickly, and equilibrium is reached sooner (1-3) (Figure 1). D/P ratios are typically assessed for various solutes including urea, creatinine, and sodium.
Another important concept is the D/D0 glucose, which is defined as the dialysate glucose at 4 hours versus the dialysate glucose at time zero (2). Glucose is a common osmotic agent in peritoneal dialysis (PD) solutions, but is limited by absorption from the dialysate into systemic circulation. As absorption occurs, the osmotic gradient dissipates and ultrafiltration is lost. A high D/D0 glucose indicates slow glucose absorption and sustained ultrafiltration, whereas a low D/D0 glucose indicates quick absorption and a rapid loss of ultrafiltration (2) (Figure 1).
Using the D/P ratio of creatinine and D/D0 glucose, patients can be classified into one of four transport categories: High (fast), high average, low average, and low (slow) (1-3) (Figure 1).
Figure 1 – Twardowski Curves: Transport Status Based on the Peritoneal Equilibration Test (PET)
Fast transporters generally have a D/P creatinine greater than 0.80 (1,3). These patients achieve rapid and complete equilibration of small solutes due to a larger functional membrane surface area and higher membrane permeability (1,4,5). However, fast transporters quickly lose their osmotic gradient and achieve poor ultrafiltration because dialysate glucose is rapidly absorbed into the blood (Table 1). Thus, fast transporters have the greatest D/P ratios for creatinine and urea, but the lowest D/D0 glucose.
Unlike fast transporters, slow transporters have the lowest D/P ratios for creatinine and urea, where the D/P creatinine is typically less than 0.55 (1,3). These patients achieve a slower and less complete equilibration for small solutes. On the other hand, slow transporters have the greatest D/D0 glucose due to slower glucose transport across the peritoneal membrane. As a result, they can sustain their osmotic gradient for longer periods and therefore achieve better ultrafiltration (2) (see Table 1). Patients who are high-average or low-average transporters have moderately high or moderately low diffusion and ultrafiltration characteristics (2). Typically, the D/P creatinine for high-average transporters will range from 0.65 to 0.80, while low-average transporters will have a D/P creatinine ranging from 0.55 to 0.64 (3) (See Table 1). However, it is important to remember that such cut-offs may vary based on the geographical area, time on PD, and other factors related to the testing process or population studied (3).
Other testing methods can be further used to classify patients by: The time required for solutes to achieve 50% equilibration between the dialysate and plasma (called the Pt50) (9); the mass transfer area coefficient (MTAC) of small solutes (10); the amount of proteins lost through large membrane pores (11,12); and a patient’s 24-hour solute clearance (13). More specific information on peritoneal membrane testing methods can be found in the Understanding Testing Methods section of the Peritoneal Dialysis article.
Clinical Implications of Peritoneal Transport Status
Using Transport Status to Choose the Best PD Regimen (APD versus CAPD)
Once membrane function has been determined, clinicians can better predict the most appropriate PD regimen for a given patient (3,14,15). As shown in Table 1, slow transporters generally have reduced solute clearance and sustained ultrafiltration, and can therefore be well maintained on modalities allowing for longer dwell times, such as continuous ambulatory peritoneal dialysis (CAPD) (3,14,15). The use of CAPD provides a longer time-period to equilibrate small solutes and allow adequate fluid removal.
In contrast, fast transporters, are in general good candidates for automated PD (APD) regimens that use shorter dwell times. Examples of APD regimens include nightly intermittent peritoneal dialysis (NIPD) or continuous cyclic peritoneal dialysis (CCPD) (3,14-16). The short dwell time allows patients to maximize small solute clearance while still retaining enough dialysate glucose to permit adequate ultrafiltration (5,14-16). Such recommendations for fast transporters have been endorsed by the International Society for Peritoneal Dialysis (ISPD) (17), UK Renal Association (UKRA) (18), and European Best Practice Guidelines (EBPG) (19). However, it should be noted that while small solute clearance is improved with shorter cycles, middle-molecule clearance might be worsened, as these molecules diffuse poorly across the peritoneal membrane and require more time to equilibrate (20).
The purported benefit of prescribing APD in fast transporters is largely based on observational studies, many of which have reported poor survival with fast transporters using CAPD. Table 2, summarizes several studies that have evaluated the impact of transport status and PD modality.
However, there is little direct evidence comparing the use of APD to CAPD in fast transporters. Of the studies that have been conducted, most tend to be underpowered or provide limited information on the PD regimen used. Despite the notion that fast transporters might be better suited for APD, drawing conclusions on the impact of modality on patient outcome has several inherent limitations. For one, patients using APD usually receive a greater number of exchanges per day and tend to use higher dialysate volumes. As such, these patients often receive a higher dialysate dose. Independent from dialysis modality and dose, data also suggests that fast transporters tend to have more peritoneal inflammation (23,24), poorer nutritional status (25, 26-29), and other comorbidities which may lead to worse outcomes (30).
Using Transport Status to Further Optimize Dwell Time
As stated above, fast transporters benefit from APD because the shorter dwell time helps maintain the osmotic gradient necessary for ultrafiltration. One method to obtain an approximate measure for the optimal dwell time for an individual patient is the determination of the accelerated peritoneal examination (APEX) point. As shown in Figure 2, this point describes the peritoneal permeability for both glucose and urea using equilibration curves obtained from a standard PET. The time at which the two curves cross is termed the APEX point, and indicates the optimal dwell time needed to maximize ultrafiltration (6-8,31). The shorter the APEX time, the higher the peritoneal permeability, and vice-versa. However, it should be noted that the APEX point has been best studied in children, and few studies have validated it in adults.
Figure 2 – Accelerated Peritoneal Examination (APEX) Point
In addition to influencing the PD regimen, knowledge of a patient’s transporter status may also help determine the most appropriate osmotic agent. Specifically, using high glucose concentrations or icodextrin for longer PD dwells has been shown to induce a greater ultrafiltration response in fast transporters (32-35).
The transport characteristics of the peritoneal membrane play an important role in solute clearance and ultrafiltration. Thus, the ability to determine and classify these characteristics has become an important means of predicting the most effective PD modality (36). In general, patients with a high (fast) peritoneal transport status will benefit from APD modalities that use shorter dwell times, whereas patients with a low (slow) transport status will benefit from longer dwell modalities such as CAPD. However, in practice, patient lifestyle and other non-medical issues may influence the peritoneal prescription more than transport status alone.
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