Randomized, controlled trial of glucose-sparing peritoneal dialysis in diabetic patients.

Glucose-containing peritoneal dialysis solutions may exacerbate metabolic abnormalities and increase cardiovascular risk in diabetic patients. Here, we examined whether a low-glucose regimen improves metabolic control in diabetic patients undergoing peritoneal dialysis. Eligible patients were randomly assigned in a 1:1 manner to the control group (dextrose solutions only) or to the low-glucose intervention group (IMPENDIA trial: combination of dextrose-based solution, icodextrin and amino acids; EDEN trial: a different dextrose-based solution, icodextrin and amino acids) and followed for 6 months. Combining both studies, 251 patients were allocated to control (n=127) or intervention (n=124) across 11 countries. The primary endpoint was change in glycated hemoglobin from baseline. Mean glycated hemoglobin at baseline was similar in both groups. In the intention-to-treat population, the mean glycated hemoglobin profile improved in the intervention group but remained unchanged in the control group (0.5% difference between groups; 95% confidence interval, 0.1% to 0.8%; P=0.006). Serum triglyceride, very-low-density lipoprotein, and apolipoprotein B levels also improved in the intervention group. Deaths and serious adverse events, including several related to extracellular fluid volume expansion, increased in the intervention group, however. These data suggest that a low-glucose dialysis regimen improves metabolic indices in diabetic patients receiving peritoneal dialysis but may be associated with an increased risk of extracellular fluid volume expansion. Thus, use of glucose-sparing regimens in peritoneal dialysis patients should be accompanied by close monitoring of fluid volume status.

A rapid assay for icodextrin determination in plasma and dialysate.

Icodextrin is a glucose polymer osmotic agent used to achieve sustained ultrafiltration during long peritoneal dialysis dwells. Previous assays for icodextrin in plasma and dialysate samples involved laborious methods, such as gel permeation chromatography with post-column derivatization of the eluted glucose polymers. We developed and validated a simple and more rapid assay for icodextrin using amyloglucosidase to hydrolyze all glucose polymers to glucose. Glucose was determined pre- and post-hydrolysis using a glucose hexokinase assay, and icodextrin concentration was calculated as the difference between glucose levels before and after hydrolysis. The complete hydrolysis of icodextrin to glucose was confirmed using anion exchange chromatography. Recovery studies using icodextrin powder added to plasma or dialysate showed 100% +/- 15% recovery for plasma concentrations from 10 mg/dL to 800 mg/dL and for dialysate concentrations from 50 mg/dL to 800 mg/dL. The percent relative standard deviation (%RSD) based on multiple replicates was within 6%, except at plasma icodextrin concentrations of 10 mg/dL and below. This simple and reliable assay has been used routinely in our laboratory to analyze thousands of plasma and dialysate samples from patients using Extraneal peritoneal dialysis solution (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.).

Peritoneal dialysis in the 21st century: the potential of gene therapy.

One of the greatest biotechnologic advances of the last 25 yr is genetic engineering--the ability to identify and isolate individual genes and transfer genetic elements between cells. Genetic engineering forms the basis of a unique biotechnology platform called gene therapy: an approach to treating disease through genetic manipulation. It is becoming clear that during peritoneal dialysis, the peritoneal membrane undergoes various structural and functional changes that compromise the dialyzing efficiency of the membrane and eventually lead to membrane failure. A gene therapy strategy based on genetic modification of the peritoneal membrane could improve the practice of peritoneal dialysis through the production of proteins that would be of therapeutic value in preventing membrane damage and preserving its dialyzing capacity. The peritoneal membrane can be genetically modified by either ex vivo or in vivo gene transfer strategies with a variety of potentially therapeutic genes, including those for anti-inflammatory cytokines, fibrinolytic factors, and antifibrotic molecules. These genes could be administered either on an acute basis, such as in response to peritonitis, or on an intermittent basis to maintain physiologic homeostasis and perhaps to prevent the adverse changes in the membrane that occur over time. The anticipated effect of a gene therapy strategy could be measured in maintenance of desired transport characteristics and in patients being able to remain on the therapy for longer periods of time without the negative outcomes. In summary, the use of a gene therapy strategy to enhance peritoneal dialysis is an innovative and exciting concept with the potential to provide new treatment platforms for patients with end-stage renal disease.

Gene transfer of transforming growth factor-beta1 to the rat peritoneum: effects on membrane function.

Long-term peritoneal dialysis is limited by physiologic changes in the peritoneum that lead to ultrafiltration failure. To determine the role of profibrotic cytokines in the alteration of peritoneal transport, a rodent model of transforming growth factor-beta (TGF-beta)-mediated peritoneal fibrosis was established. An adenoviral vector driving the active form of TGF-beta1 (AdTGFbeta1) was administered intraperitoneally, and peritoneal structure and function were evaluated for 28 d after infection. Seven days after AdTGFbeta1 infection, thickening of the peritoneum, with cellular proliferation and increased vascularization, was noted. By day 28, there was persistent thickening and extensive collagen deposition. The mesenteric collagen content was significantly elevated, compared with control adenovirus-treated animals, 21 d after infection (2.9 versus 1.8 mg hydroxyproline/g tissue, P = 0.006). Blood vessel density, as measured using factor VIII immunohistochemical analyses, was significantly increased from day 4 to day 21 but decreased by day 28. Animals infected with AdTGFbeta1 demonstrated increased transport of solutes and decreased net ultrafiltration, which was maximal on day 7 and returned to baseline levels by day 28. It was demonstrated in vitro and in vivo that TGF-beta1 induced production of vascular endothelial growth factor. Overexpression of TGF-beta1 after adenovirus-mediated gene transfer causes peritoneal fibrosis, neoangiogenesis, and increased peritoneal membrane solute transport. This model should allow further delineation of the relative contributions of profibrotic and angiogenic cytokines to changes in peritoneal function and may lead to potential new interventions for peritoneal membrane failure.