Predicting Risk in Peritoneal Dialysis: Is Membrane Biology Destiny?

• peritoneal dialysis
• peritoneum
• risk
• peritoneal membrane
• epidemiology and outcomes
• survival
• chronic infmalation

The flux of solute and fluid across a dialyzer in hemodialysis is influenced by the flow rate of blood and dialysis fluid combined with the imposition of hydraulic pressure across the artificial membrane. The flux parameters are predictable given that the filters are mass produced and tightly regulated with respect to quality control. In contrast, patients on peritoneal dialysis (PD) use their own peritoneal membrane as a dialyzer. Similar to other biologic systems, the characteristics in one person can differ from another person; furthermore, the membrane characteristics can change over time.

To measure the transport capability in a given patient on PD, tests have been devised to determine transmembrane transport of small solutes and water. In North America, the standard peritoneal equilibration test (PET) has been used for decades to measure the rate of small solute movement and ultrafiltration across the peritoneal membrane (1). A 2-L bag of 2.5% dextrose solution is instilled in the peritoneal cavity and allowed to dwell for 4 hours. During this dwell, creatinine will diffuse from the blood into the dialysis fluid, and glucose will diffuse in the opposite direction, both along their respective concentration gradients. The volume of dialysate drained at the end of the dwell indicates how much fluid was ultrafiltered during this time. The concentration of creatinine in the dialysis fluid (D) at 4 hours is divided by the plasma creatinine (P), generating the D/P creatinine. Another way to examine membrane transport is to measure how rapidly glucose leaves the dialysate and enters the bloodstream. However, D/P glucose is not a measure of this reverse flux, because the glucose entering the blood will be metabolized in real time. One way to deal with this is to measure the glucose remaining in the dialysis fluid at the end of the dwell and compare it with the amount of glucose present in the fluid at the beginning. This measure generates the D4/D0 glucose. In patients with rapid transmembrane solute flux, the D/P creatinine will be high, and the D4/D0 will be low. In those with slower rates of solute movement, the D/P creatinine will be lower, and the D4/D0 will be higher. Typically, rapid transporters have faster dissipation of the glucose–generated osmotic gradient for ultrafiltration and therefore, less fluid removal compared with slower transporters.

The original intent of the PET was to aid in designing a PD prescription tailored to the membrane characteristics of the patient. A rapid transporter has faster dissipation of the glucose–generated osmotic gradient and could encounter problems with ultrafiltration, particularly during long dialysis dwells. In that case, shorter rather than longer dwells would serve the patient better. The slow or low transporter was postulated to have more successful dialysis by using longer dwells to allow sufficient time for solute flux.

Interestingly, in one of the substudies of the Canada-USA (CANUSA) Study of dose of PD, the PET itself was found to correlate with outcome. In this analysis of a cohort mostly on continuous ambulatory PD, higher transport status was associated with an increased risk for both technique failure and death (2). In the same year, another study by Wang et al. (3) showed that patient survival was significantly lower in high transporters.

Several theories have been postulated to explain the increased mortality and technique failure associated with rapid transport status: reduced ultrafiltration leading to extracellular fluid (ECF) volume overload, increased glucose absorption resulting in exaggerated glucose loading with consequent new–onset hyperglycemia or worsening of diabetic control, and suppression of appetite (4) and exaggeration of the atherogenic lipid disorders already seen more often in patients on PD compared with those on hemodialysis (3,5,6). In addition, rapid transporters were more likely to have decreased plasma albumin concentration, presumed to be the result of albumin loss into the PD fluid and perhaps, ECF volume overload; lower serum albumin is also strongly associated with suboptimal outcome in many studies (4,7).

Subsequent studies, however, particularly those done in patients on automated cycler peritoneal dialysis (APD), have been unable to show that rapid transport status confers an increased risk of mortality (8,9). Of note, the meta-analysis by Brimble et al. (10) in 2006 showed that higher transport status was associated with greater mortality risk, but this risk was found to be abrogated in patients on APD. It was postulated that, rather than having anything to do with solute clearance per se, it could be volume status that influences patient outcome, and this was better managed with shorter dwells on APD in rapid transporters (10,11).

However, patients with significant comorbidity and evidence of systemic inflammation are often rapid transporters at the outset of PD, and the worse outcome may be the result of the systemic inflammatory state itself rather than what is or is not traversing the peritoneal membrane (12). Indeed, in the study by Margetts et al. (13), the serum albumin measured before the PD catheter was even inserted was lower in those who ultimately proved to be rapid transporters after they were on PD. This observation suggests that at least some part of the hypoalbuminemia in rapid transporters is the result of factors other than transmembrane flux; the rapid transport state is a reflection of systemic inflammation and consequent vasodilatation of the vascular beds perfusing the peritoneum.

In this issue of the Clinical Journal of the American Society of Nephrology, Mehrotra et al. (14) examined a large cohort of patients who had baseline PET. The three parameters that were compared for their predictive values were the D/P creatinine, D4/D0 glucose, and the volume ultrafiltered during the 4-hour dwell with 2.5% dialysate. Given the mounting evidence that solute removal, as measured by Kt/V urea or creatinine clearance, does not influence outcome (11,15–17), it may be that membrane properties more closely related to ultrafiltration and ultimate attainment of euvolemia are more important for outcomes of both the technique and the patient. Hence, the diffusion rate of glucose out of the peritoneal cavity, which will determine the osmotic pressure gradient over the time of the dwell and the volume of fluid ultrafiltered over the 4-hour PET, may be more relevant if volume status is a stronger predictor of survival than small solute kinetics. Nonetheless, the study showed that peritoneal D/P creatinine was consistently associated with mortality and hospitalization rates, despite adjustment for comorbidities and the use of APD (14). Ultrafiltration volume from the PET was not associated with mortality but did show a strong association with hospitalization rates. Neither of the parameters was associated with technique failure.

Interestingly and reminiscent of the studies discussed above, those with higher D/P creatinine who were treated with continuous ambulatory PD had a greater risk of death and hospitalization than patients treated at any time with APD (14).

Do the results of this study mean that, in fact, small solute removal as determined by the PET is the most important parameter of transmembrane transport and trumps, both biologically and statistically, ultrafiltration volume and attainment of euvolemia? Should we return to the old days of obsessing over each 0.1 unit Kt/V urea as the sine qua non of successful dialysis?

The answer is that this study does not contradict the importance of ECF volume. Although the PET parameters of ultrfiltration volume and D4/D0 indirectly address the ease of ultrafiltration, they do not take into account other important determinants of volume status, including dietary salt and water intake, the strength and type of dialysis fluids being used by the patient, and most importantly, the residual kidney function. Reanalysis of the CANUSA Study showed that, for every 250 ml daily urine volume, there was a 36% reduction in mortality (11). This important factor was not analyzed in this study and likely had a very strong influence in determining volume status (14).

For patients on PD who depend on a biologic dialyzing membrane, transmembrane solute and water flux, as measured by the PET, may portend destiny in terms of attainment of normal volume status. The outcome, however, is confounded by the association of rapid transport status with systemic inflammation and the overarching contribution of residual renal salt and water excretion.

• Copyright © 2015 by the American Society of Nephrology