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New solutions for peritoneal dialysis in adult and pediatric patients.

The standard PD solutions used today contain physiological electrolyte profiles similar to that of interstitial fluids and are supplemented with glucose as the osmotic agent. Improvements in solution composition during the last 20 years have been largely restricted to minor changes in buffer and electrolyte levels. Newer PD solutions, on the other hand, are designed to manage comorbidities associated with patients on maintenance dialysis, to tailor the ultrafiltration profile based upon dwell time, and to better preserve peritoneal membrane function and host defenses. The evidence to date indicates that, in malnourished PD patients (children and adults), IP amino acids improve protein nutritional status, particularly if low protein intakes are a cause of the malnutrition. The availability of glucose polymers allows the clinician to complement standard glucose-based formulations with one that can provide improved ultrafiltration in both CAPD and APD patients for long dwells, and in patients experiencing ultrafiltration loss owing to a large effective peritoneal surface area. Owing to the reduced calorie and carbohydrate load, glucose polymers may also offer long-term metabolic advantages. Although the control of acid-base balance can be well managed in the vast majority of patients with a 35-40 mmol/L lactate solution, the development and clinical evaluation of bicarbonate-based solutions is underway as a result of concern over the potentially bioincompatible nature of acidic lactate formulations. To date, in vitro, ex vivo, and limited clinical studies show that such formulations, and in particular bicarbonate/lactate combinations are efficacious and well tolerated, and show improved peritoneal cell function versus conventional solutions. In conclusion, ongoing research and development has produced a new generation of PD solutions that, to various degrees, meet different criteria established for an ideal PD solution for chronic adult and pediatric patients on PD. These criteria include good clearance and ultrafiltration, supply of nutrition, iso-osmolality, physiologic pH, bicarbonate buffer, and minimal absorption of the osmotic agent. Several of the new solutions have already demonstrated clinical utility in controlled clinical trials and are commercially available in Europe. Wider clinical use will further add to our understanding of the impact of these formulations on patient outcomes.

Adult↗

D-glucose increases the synthesis of tissue-type plasminogen activator (t-PA) in human peritoneal mesothelial cells.

Physical and chemical irritation of the peritoneum through glucose-based hyperosmolar dialysis solutions results in a nonbacterial serositis with fibrinous exudation. Thereby, human peritoneal mesothelial cells (HMC) play an important role in maintaining the balance between the peritoneal generation and degradation of fibrin by expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) as well as the specific plasminogen activator inhibitor-1 (PAI-1). In this study, we analyzed the effect of D-glucose and metabolically inert monosaccharides on the synthesis of t-PA and PAI-1 in cultured HMC. Incubation of HMC with D-glucose or the metabolically inert monosaccharides mannitol and L-glucose (5-90 mM) resulted in a time- and concentration-dependent increase in t-PA mRNA expression and antigen secretion without affecting PAI-1 synthesis. A similar effect was evident when HMC were first exposed sequentially to pooled spent peritoneal dialysis effluent for up to 4 hours, and subsequently incubated for 20 hours in control medium. The stimulating effect of high D-glucose on t-PA expression in HMC was prevented by treating the cells with different protein kinase C (PKC) inhibitors (Ro 31-8220, Gö 6976), but could not be mimicked by the PKC-activating phorbol ester PMA, indicating that this effect of high glucose is dependent on PKC activity, but not mediated through PKC activation. Also, using specific inhibitors (PD 98059, SB 203580) and activators (PMA, anisomycin, IL-1alpha) of the major routes of the mitogen-activated protein kinases (MAPKs) cascade, we found no evidence for a role of this cascade in regulating t-PA expression in HMC. We conclude that hyperosmolarity induces t-PA (but not PAI-1) in HMC via a regulatory mechanism that requires active PKC, but that does not involve a major pathway in the MAPK cascade.

Cells, Cultured↗

Peritoneal fluid kinetics: comparison between polyglucose solution and albumin solution.

Polyglucose (PG) solution has been shown to be capable of inducing peritoneal ultrafiltration despite its hypo-osmolality. However, the mechanism of osmosis by PG is not clear. In this study, we compared the fluid kinetics of albumin (ALB) solution (thought to be an ideal solution that should induce ultrafiltration through colloid osmosis) and PG solution. A 4-hour dwell study with frequent sampling was conducted in Sprague-Dawley rats (six rats in each group). The study used 25 mL of dialysate buffer, 10% ALB dialysis solution, 15% ALB dialysis solution, 20% ALB dialysis solution, or 7.5% PG solution, with 131I albumin as an intraperitoneal volume marker. All solutions were prepared by adding ALB or PG to a base dialysis solution (without osmotic agent). The initial osmolality values of the five solutions were 250 mOsm/kg, 284 mOsm/kg, 300 mOsm/kg, 320 mOsm/kg, and 280 mOsm/kg, and the dialysate drainage volumes at 4 hours were 17.0 +/- 0.8 mL, 22.4 +/- 0.8 mL, 25.4 +/- 0.6 mL, 27.3 +/- 0.9 mL, and 26.3 +/- 0.6 mL (buffer, 10% ALB, 15% ALB, 20% ALB, and 7.5% PG groups, respectively). The higher initial osmolality in the ALB groups was partially due to the sodium content in the ALB powder. The intraperitoneal volume was decreasing in the 10% ALB group, rather stable in the 15% ALB group, but slowly increasing in the 20% ALB group. In the PG group, intraperitoneal volume decreased initially and then started to increase after 2 hours. This pattern was closely related to the increase in the dialysate osmolality (to higher than plasma level). At 4 hours, the dialysate osmolality was significantly higher (and higher than plasma level) in the PG group as compared to all the ALB groups. No differences in peritoneal fluid absorption rate were observed among the four treatment groups. In the 15% ALB and 20% ALB groups, the transcapillary ultrafiltration rate (Qu) was lower in the later part of the dwell than in the initial part of the dwell; in the PG group, the opposite pattern was observed. Our results suggest that the osmosis of albumin dialysis solution is different from the osmosis of polyglucose solution. Polyglucose solution induces net ultrafiltration only when the dialysate osmolality increase to higher than plasma level, suggesting that degradation of polyglucose may be important for effective ultrafiltration.

Albumins↗

Management of high peritoneal transporters.

High transporters on chronic peritoneal dialysis are challenged by increased protein losses, high glucose absorption with associated metabolic abnormalities, and poor ultrafiltration. Furthermore, the relative risk of mortality and technique failure is higher in high transporters than in patients of other transport types. An approach for satisfactory management of such patients on peritoneal dialysis (PD) has not been clearly demonstrated.

Animals↗

Polyglucose dialysis solution influences serum iron parameters.

Owing to the lack of data dealing with the influence of polyglucose dialysis solution (PG-DS) on serum indicators of iron status, our study aimed at examining this problem in patients receiving PG-DS for the overnight exchange during treatment with continuous ambulatory peritoneal dialysis. We evaluated serum concentrations of iron, ferritin, and transferrin, total iron binding capacity (TIBC), and transferrin saturation (TSAT) at 1.6 +/- 0.8 months before introducing 7.5% PG-DS for an overnight 2 L exchange lasting about 10 hours (period I, n = 14), after 1.2 +/- 0.6 months of PG-DS administration (period II, n = 14), after 4.4 +/- 0.8 months of PG-DS administration (period III, n = 11), after 8.8 +/- 2.2 months of PG-DS administration (period IV, n = 9), and at 2.0 +/- 0.6 months after PG-DS discontinuation (period V, n = 11). Interference owing to PG-DS in laboratory determinations of serum iron parameters was excluded. Indices of nutritional status were also evaluated in all study periods. Significant differences in iron parameters were seen between periods I and III, or I and IV for transferrin (212 +/- 41 mg/dL vs 253 +/- 36 mg/dL), TIBC (304 +/- 40 micrograms/dL vs 338 +/- 31 micrograms/dL) and TSAT (34% +/- 15% vs 24% +/- 4%). After PG-DS withdrawal, these parameters all returned to pre-treatment values. Improvement in nutritional status was indicated by increases in total body mass (73.9 +/- 15.6 kg vs 77.4 +/- 13.8 kg), lean body mass (54.5 +/- 9.7 kg vs 56.9 +/- 8.5 kg), and serum total protein concentration (61.7 +/- 10.8 g/L vs 70.5 +/- 8.0 g/L). We conclude that serum transferrin concentration increases during PG-DS administration without enhanced iron binding to transferrin. An increase in transferrin level can be related to improved nutritional status.

Dialysis Solutions↗

Peritoneal dialysis solutions.

After several decades of experience of peritoneal dialysis therapy, we now understand the peritoneal membrane and the causes of its changes during long-term dialysis much better. Several new, more biocompatible solutions are available in clinic today, and the outcome of peritoneal dialysis therapy is expected to be further improved. However, limitations with the currently available peritoneal dialysis solutions still exist, and continual efforts are needed to develop solutions that are more efficient and more membrane-friendly. With the better understanding of the role of fluid balance in peritoneal dialysis, we believe that development of peritoneal dialysis fluid that protects the peritoneal surface layer (and thus the integrity of the peritoneum, thereby improving peritoneal fluid removal) may be an area of research in the near future.

Amino Acids↗

Stability of drug additives in peritoneal dialysis solutions in a new container.

OBJECTIVE: To evaluate the stability of gentamicin, tobramycin, netilmycin, vancomycin, cefazolin, unfractionated heparin, and low molecular weight heparin when added to four different peritoneal dialysis (PD) solutions [Extraneal (Baxter Healthcare, Castlebar, Ireland); Physioneal, Nutrineal, and Dianeal (Baxter Healthcare, Grosotto, Italy)] in new, non-PVC Clear-Flex containers. MEASUREMENTS: Gentamicin, tobramycin, netilmycin, vancomycin, cefazolin, unfractionated heparin, and low molecular weight heparin were injected into separate bags of PD solution. Samples were withdrawn at predefined sampling times and the concentration of each drug was analyzed using high-performance liquid chromatography (for gentamicin, tobramycin, vancomycin, and cefazolin), or bioassay (for netilmycin, gentamicin, and tobramycin in Nutrineal), or coagulation methods (heparins). RESULTS: Netilmycin, vancomycin, cefazolin, and heparin in Physioneal, Nutrineal, Extraneal, and Dianeal were stable for at least 24 hours at 25 degrees C and for an additional 4 hours at 37 degrees C. Gentamicin in Nutrineal, Extraneal, and Dianeal was stable for at least 24 hours at 25 degrees C and for an additional 4 hours at 37 degrees C; gentamicin in Physioneal was stable for less than 24 hours at 25 degrees C. Tobramycin in Nutrineal and Extraneal was stable for at least 24 hours at 25 degrees C and for an additional 4 hours at 37 degrees C; tobramycin in Physioneal and Dianeal was stable for less than 24 hours at 25 degrees C.

Amino Acids↗