Is PEN Mightier?

Are all peritoneal dialysis (PD) fluids created equally? A prospective, randomized, controlled, open-label study published in the American Journal of Kidney Diseases attempts to answer this question by looking at peritoneal transport and inflammatory markers. Corresponding author Dr. Tak Mao Chan (TMC), from the University of Hong Kong, discusses this recent study with Dr. Sean Kalloo (eAJKD), eAJKD Contributor.

eAJKD: Can you summarize the study?

TMC: Conventional peritoneal dialysates induce inflammation and fibrosis of the peritoneal membrane with their high glucose content, presence of glucose degradation products, and acidic pH. This leads to impairment of transport functions and adverse clinical outcomes in patients on long-term PD. This prospective randomized study investigated a PD regimen that utilized three types of dialysate (Physioneal, Nutrineal, and Extraneal – abbreviated as the PEN regimen) with improved “biocompatibility” and low glucose content. The results showed that treatment with the PEN regimen for 12 months resulted in comparable residual kidney function when compared to conventional PD with Dianeal. In addition, patients treated with the PEN regimen showed better urine output, peritoneal membrane solute transport function, and biomarkers of peritoneal integrity and inflammation (dialysate CA-125, IL-6 and adiponectin, and serum adiponectin).

eAJKD: What are the main differences between biocompatible PD fluids and conventional PD fluids?

TMC: Conventional PD fluids have a high glucose content, high levels of glucose degradation products, excess lactate, and an acidic pH. In contrast, the more “biocompatible” PD fluids have reduced glucose content and glucose degradation products, and a more physiologic pH. Instead of relying on glucose to provide the osmotic drive (as in conventional dialysate), alternative osmotic agents in the novel PD fluids include amino acids or icodextrin.

eAJKD: One of your main findings was that patients using conventional PD fluids had a significant decrease in daily urine volume, while daily urine volume of the biocompatible-PD-fluid group did not change significantly. How can we interpret these results, and what role could this have in disease management?

TMC: Fluid overload affects many patients on PD, and contributes to the excessive cardiovascular mortality. Maintaining residual kidney function and urine volume has been linked to a better survival in PD patients. Our results showed that while urine volume decreased significantly in controls on conventional dialysate (mean value decreased from 1067 to 798 mL/d after 12 months), the urine volume was better maintained in patients treated with biocompatible fluids (from 1087 to 959 mL/d). It is intriguing that the difference in urine volume over time in the two groups was not accompanied by similar observations with residual kidney function. Indeed, kidney function showed similar rates of decline in both groups. The apparent “uncoupling” of residual kidney function and urine volume could suggest differences in renal tubular free water clearance, which warrants further studies.

eAJKD: The concept of spent dialysate CA-125 levels as a marker of mesothelial cell mass and integrity is addressed in your study. Can you explain your findings with regards to this marker, and discuss the possible long-term consequences of biocompatible PD fluid with respect to this marker?

TMC: A monolayer of mesothelial cells line the peritoneal cavity and act as the first line of defense against infective and chemical insults. CA-125 is a high molecular weight glycoprotein constitutively secreted by mesothelial cells. The level of CA-125 in effluent peritoneal dialysate has been demonstrated to correlate with mesothelial cell mass, and data from longitudinal studies showed a progressive decrease of dialysate CA-125 level with increasing duration of PD. The main reason for the reduction in mesothelial cell mass is the exposure to high glucose concentration, which induces denudation of the mesothelium. This allows seeping of the dialysate into the submesothelium, which induces the deposition of extracellular matrix and fibrous tissue as well as vasculopathy. This is accompanied by progressive deterioration of transport functions. Therefore, the level of CA-125 in peritoneal dialysate is considered a marker of peritoneal integrity. Our finding that treatment with the PEN regimen led to an increase in dialysate CA-125, in contrast to a decrease over time in control patients treated with Dianeal dialysate, has clinical significance. Not only does this provide an explanation for the better preservation of transport function (as shown by the dialysate-to-plasma creatinine ratio) in the PEN group, both results are evidence that the PEN regimen is associated with preservation of peritoneal membrane integrity.

eAJKD: Can you discuss the profiles of the systemic and local inflammatory markers with respect to the type of PD fluid used?

TMC: Although the circulating IL-6 levels were lower in the PEN group, the difference between the two groups was not significant. Dialysate IL-6 levels were significantly higher in the PEN group throughout the study. This could be due to increased local (intra-peritoneal) production or somehow the peritoneal membrane was more effective in removing IL-6 from the circulation to the dialysate. The role of dialysate IL-6 is controversial. It has been perceived as a marker for peritoneal inflammation, but acidic conventional peritoneal dialysate inhibits the secretion of IL-6 by mesothelial cells, and IL-6 also possesses anti-inflammatory and regenerative properties. Furthermore, a positive association between dialysate IL-6 and CA-125 levels has been reported by other investigators as well. It would be hard to conceive that the relatively lower dialysate IL-6 levels in the control group signified a lower inflammatory state.

Adiponectin is an adipokine that possesses anti-inflammatory and anti-atherogenic properties. Both circulating and dialysate adiponectin levels were higher in the PEN group compared to controls. Although we did not measure the percentage of body fat, the body weight and BMI were comparable in the two groups. The results suggest a direct effect of biocompatible PD fluids used in the PEN regimen on adiponectin levels.

eAJKD: What are the main points that one can take away from your paper with regards to clinical practice? 

TMC:

1. The PEN PD regimen with biocompatible peritoneal dialysate is associated with better preservation of urine output, which would be helpful in ameliorating chronic fluid overload.

2. The dialysate biomarker profiles suggest that the PEN PD regimen results in better preservation of peritoneal membrane integrity.

3. PD using the PEN regimen leads to higher adiponectin levels. Since adiponectin has anti-inflammatory effects, the clinical impact of this finding warrants further investigations.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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