Marien W. Fieren

Dialysate as food: combined amino acid and glucose dialysate improves protein anabolism in renal failure patients on automated peritoneal dialysis.

Protein-energy malnutrition as a result of anorexia frequently occurs in dialysis patients. In patients who are on peritoneal dialysis (PD), dialysate that contains amino acids (AA) improves protein anabolism when combined with a sufficient oral intake of calories. It was investigated whether protein anabolism can be obtained with a mixture of AA plus glucose (G) as a source of proteins and calories during nocturnal automated PD (APD). A random-order cross-over study was performed in eight APD patients to compare in two periods of 7 d each AA plus G dialysate obtained by cycler-assisted mixing of one bag of 2.5 L of AA (Nutrineal 1.1%, 27 g of AA) and four bags of 2.5 L of G (Physioneal 1.36 to 3.86%) versus G as control dialysate. Whole-body protein turnover was determined using a primed continuous infusion of L-[1-13C]leucine, and 24-h nitrogen balance studies were performed. During AA plus G dialysis, when compared with control, rates of protein synthesis were 1.20 +/- 0.4 and 1.10 +/- 0.2 micromol/kg per min leucine (mean +/- SD), respectively (NS), and protein breakdown rates were 1.60 +/- 0.5 and 1.72 +/- 0.3 micromol/kg per min (NS). Net protein balance (protein synthesis minus protein breakdown) increased on AA plus G in all patients (mean 0.21 +/- 0.12 micromol leucine/kg per min; P < 0.001). The 24-h nitrogen balance changed by 0.96 +/- 1.21 g/d, from -0.60 +/- 2.38 to 0.35 +/- 3.25 g/d (P = 0.061, NS), improving in six patients. In conclusion, APD with AA plus G dialysate improves protein kinetics. This dialysis procedure may improve the nutritional status in malnourished PD patients.

RISK FACTORS ASSOCIATED WITH ENCAPSULATING PERITONEAL SCLEROSIS IN DUTCH EPS STUDY

♦ Objective: Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with a multifactorial pathophysiology and possible increasing incidence. The aim of the present study was to evaluate the independent associations of PD duration, age, dialysis fluids, and kidney transplantation with EPS. ♦ Methods: A multicenter case–control study was performed in the Netherlands from 1 January 1996 until 1 July 2007. The population comprised 63 patients with EPS and 126 control patients. Control patients were selected from the national registry and were matched for date of PD start. Associations were analyzed using a log linear regression model. Primary outcome was appearance of EPS. ♦ Results: Compared with control patients, patients with EPS were younger at the start of PD (34.7 ± 15.4 years vs. 51.5 ± 14.7 years, p < 0.0001). The cumulative period on PD was longer in EPS patients than in control patients (78.7 ± 37.8 months vs. 32.8 ± 24 months, p < 0.0001), and the cumulative period on icodextrin was also longer in EPS patients (32.7 ± 23.3 months vs. 18.1 ± 15.7 months, p = 0.006). Compared with control patients, more EPS patients underwent kidney transplantation (47 vs. 59, p < 0.0001). With regard to the period after transplantation, the yearly probability of EPS increased in the year after transplantation to 7.5% from 1.75%. In multivariate regression analysis, cumulative PD duration, age at PD start, transplantation, time from last transplantation to EPS, calendar time, time on icodextrin, and ultrafiltration failure were independently associated with EPS. Transfer from PD to hemodialysis for reasons other than suspected EPS could not be identified as a risk factor for EPS. ♦ Conclusions: Duration of PD, age at PD start, kidney transplantation, time since last transplantation, ultrafiltration failure, and time on icodextrin were associated with a higher risk of EPS.

Tamoxifen is associated with lower mortality of encapsulating peritoneal sclerosis: results of the Dutch Multicentre EPS Study

BACKGROUND Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with an increasing incidence. There is no clear consensus on the treatment of EPS, but anecdotal reports indicate improvement in EPS patients treated with tamoxifen. At present, there is no evidence for the effect of tamoxifen treatment in EPS patients. This study investigates the effect of treatment with tamoxifen on survival in EPS patients. METHODS This study is a retrospective analysis of survival in EPS patients as part of the Dutch multicentre EPS study in the period January 1996 to July 2007. Sixty-three patients with severe EPS were followed up until August 2008. Demographic, patient and PD-related variables of EPS patients were investigated. Patients treated with tamoxifen were compared to patients not treated with tamoxifen. Survival was analysed with multivariate Cox regression analysis. RESULTS Twenty-four patients were treated with tamoxifen, and 39 were not treated with tamoxifen. The clinical and demographic characteristics were similar for the tamoxifen-treated and non-treated groups. The mortality rate was significantly lower in tamoxifen-treated patients compared to EPS patients not treated with tamoxifen (45.8% vs 74.4%, P=0.03). Survival in tamoxifen-treated patients, adjusted for calendar time, age, use of corticosteroids, presence of functioning transplantation, use of parental nutrition and centre influences was longer in comparison to not-treated patients (HR 0.39, P=0.056). CONCLUSIONS Tamoxifen treatment in EPS patients is associated with lower mortality and shows a trend to an increased multivariate-adjusted survival. This supports additional use of tamoxifen to treat patients with severe EPS.

Peritoneal Dialysis with Solutions Containing Amino Acids Plus Glucose Promotes Protein Synthesis during Oral Feeding

Inadequate food intake plays an important role in the development of malnutrition. Recently, an increased rate of protein anabolism was shown in fasting state in patients who were on automated peritoneal dialysis with combined amino acids (AA) and glucose (G) dialysate serving as a source of both proteins and calories. This study investigated the effects of such a dialysis procedure in the daytime in the fed state in patients who were on continuous ambulatory peritoneal dialysis (CAPD). A crossover study was performed in 12 CAPD patients to compare, at 7-d intervals, a mixture of AA (Nutrineal 1.1%) plus G (Physioneal l.36 to 3.86%) versus G only as control dialysate. Whole-body protein turnover was studied by primed constant intravenous infusion of (13)C-leucine during the 9-h dialysis. For meeting steady-state conditions during whole-body protein turnover, frequent exchanges with a mixture of AA plus G were done using an automated cycler. Fed-state conditions were created by identical liquid hourly meals. Using AA plus G dialysate, as compared with the control, rates of protein synthesis increased significantly (2.02 +/- 0.08 versus 1.94 +/- 0.07 mumol leucine/kg per min [mean +/- SEM]; P = 0.039). Rates of protein breakdown and net protein balance did not differ significantly between AA plus G and G. In conclusion, dialysate that contains AA plus G also improves protein synthesis in fed CAPD patients. The use of such a mixture may contribute to long-term improvement of the nutritional status in malnourished CAPD patients with deficient food intake.

A COLLABORATIVE APPROACH TO UNDERSTANDING EPS: THE EUROPEAN PERSPECTIVE

Manchester Royal Infirmary,1 Manchester, UK; University Medical Center Utrecht,2 Utrecht, Netherlands; Robert-Bosch-Hospital,3 Stuttgart, Germany; Erasmus Medical Center,4 Rotterdam, Netherlands; Hans Mak Institute,5 Naarden, Netherlands; University Hospital of North Staffordshire,6 Stoke-on-Trent, UK; Azienda Ospedaliera Universitaria Senese,7 Siena, Italy; Universite catholique de Louvain,8 Brussels, Belgium; Albert Schweitzer Hospital,9 Dordrecht, Netherlands; Karolinska Institutet,10 Stockholm, Sweden; Baxter Healthcare SA,11 Zurich, Switzerland; University of Amsterdam,12 Amsterdam, Netherlands; Leiden University Medical Center,13 Leiden, Netherlands; Rene Dubos Hospital,14 Pontoise, France; and University Medical Center Groningen,15 Groningen, Netherlands

Peritoneal protein losses and cytokine generation in automated peritoneal dialysis with combined amino acids and glucose solutions.

Objectives. Protein-energy malnutrition as a consequence of deficient protein intake frequently occurs in peritoneal dialysis (PD) patients. Previously, we showed that peritoneal dialysate containing a mixture of amino acids (AA) and glucose has anabolic effects. However AA-dialysate has been reported to increase intraperitoneal protein and AA losses and the release of proinflammatory cytokines (interleukine-6 (IL-6) and tumor necrosis factor alpha (TNFα)). We investigated the effect of AA plus glucose (AAG) solutions on peritoneal protein losses and cytokine generation. Methods. In 6 patients on standard automated peritoneal dialysis (APD) 12 APD sessions of 6 cycles each were performed during the night using dialysate containing 1.1% AA plus glucose or glucose alone as control. Protein losses and TNFα and IL-6 concentrations were measured in dialysates separately collected from nightly cycling and daytime dwell. Results. The 24 hour-protein losses with AAG (median 6.7 g, range 4.7–9.4 g) were similar to control dialysate (median 6.0 g, range 4.2–9.2 g). Daytime dialysate IL-6 levels were higher after nightly AAG dialysis than after control dialysis (142 pg/ml and 82 pg/ml, respectively, P<.05). TNFα concentrations were very low. Conclusion. Nightly APD with amino acids containing dialysate was associated with an increase in peritoneal IL-6 generation during the day. The addition of AA to standard glucose dialysis solutions did not induce a significant increase of peritoneal protein losses.

Activity of human peritoneal macrophages against a human tumor: role of tumor necrosis factor-α, PGE2 and nitrite, in vitro studies

Human peritoneal macrophages collected from renal patients on continuous ambulatory peritoneal dialysis (CAPD) during inflammation-free periods were induced to express antitumor activity in vitro when cultured in the presence of bacterial lipopolysaccharide (LPS) and even more activity when they were kept in the presence of LPS + IND (indomethacin). The antitumor activity was expressed against a human tumor-cell line, RC43, either in a cell-to-cell contact set-up between the macrophages and the RC43 target cells or when the tumor cells were exposed to supernatants of the cultured macrophages. The antitumor activity of macrophages was correlated to a marked increase in production of tumor necrosis factor-alpha (TNF alpha), not correlated to an increase in nitrite production and inversely correlated to the production of PGE2. The RC43 tumor cells were susceptible to recombinant human TNF alpha, recombinant human IL-1 beta, sodium nitrite and the leukotriene LTB4. The results obtained suggest that activated human macrophages might represent a useful tool for cancer immunotherapy.

Therapeutical effect of activated human macrophages on a human tumor line growing in nude mice

Human peritoneal macrophages were collected from dialysis bags of renal patients on Continuous Ambulatory Peritoneal Dialysis (CAPD), during an inflammation-free period. The macrophage suspension was cultured in presence of bacterial lipopolysaccharide (LPS) and phorbol myristate acetate (TPA). The cultured macrophages were tested for therapeutic effectiveness against a human tumor-cell fine, RC43, implanted subcutaneously in NMRI nude mice. The macrophages were injected around the tumor starting from the 14th day after inoculation, when the tumor growth was already detectable (mean tumor size 7 mm). Three injections of macrophages on days 14, 18 and 21 induced hemorrhagic patches at the tumor site and almost complete regression of the tumor. One injection of macrophages cultured either in presence of LPS + TPA or of LPS + TPA + PGE2 resulted in marked slow-down of the tumor growth. Injection of either TNF-alpha (4000 U/mouse) or of PGE2 (150 ng/mouse) given at the site of the palpable small tumor had no effect. Macrophages cultured in medium or in medium supplied with either TPA, LPS or TPA + LPS, were not effective in nude mice bearing large (16 to 19 mm) tumors. The results obtained suggest that activated human macrophages might be therapeutically effective at certain stages of human cancer.

Bioactive rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients

BACKGROUND Inadequate food intake plays an important role in the development of malnutrition in continuous ambulatory peritoneal dialysis (CAPD) patients. Aim of the study. The aim of the study was to investigate in CAPD patients whether circulating insulin-like growth factor-I (IGF-I) bioactivity may offer a more sensitive index to acute nutritional interventions than total IGF-I. METHODS An open-label, randomized, crossover study of 2 days-with a 1-week interval-was performed in 12 CAPD patients in the fed state to compare a mixture of amino acids (Nutrineal 1.1%) plus glucose (AA plus G) (Physioneal 1.36% to 3.86%) dialysate versus G only as control dialysate. Fed-state conditions were created by identical liquid hourly meals. IGF-I bioactivity was measured by the kinase receptor activation assay (IGF-I KIRA); total IGF-I was measured by immunoassay. RESULTS In the fed state, both after AA plus G as well as after G dialysis IGF-I bioactivity increased compared to baseline, while no changes in circulating total IGF-I levels were observed in both treatment arms. However, the increase in IGF-I bioactivity was only significant after AA plus G dialysis (P = 0.02). CONCLUSIONS Our results provide evidence that in CAPD patients changes in circulating IGF-I bioactivity are associated with nutrient intake and that IGF-I bioactivity rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients.

Inflammation amplifies the antitumor cytostasis by human peritoneal macrophages

The effect of an inflammatory environment on the antitumor cytostatic ability of human macrophages was examined. Peritoneal macrophages of patients on continuous ambulatory peritoneal dialysis (CAPD) were collected, when CAPD was without complication, during an intercurrent infectious inflammation and after recovery. Inhibition of3H-thymicline uptake served as a measure of cytostasis by macrophages co-cultured with target murine cells MOPC-315 plasmacytoma, WEHI-3B rnyelomonocytic leukemia and L929 transformed fibroblasts. Macrophages from inflammatory peritoneum expressed a markedly enhanced cytostasis, irrespective of the nature of the tumor cell. Endotoxin (LPS) challenge of inflammatory macrophages failed to further reinforce the cytostasis towards MOPC-315 plasmacytoma, but reinforced the cytostasis towards WEHI-3B leukemia (sensitive to inhibition by IL-1) and towards L929 (sensitive to TNFα). Cytostasis by supernatants of human peritoneal macrophages against L929 was markedly inhibited by anti-rHuTNFa and against WEHI-3B by anti-rHuIL-lβ. The results suggest a link between inflammatory function and antitumor cytostasis by macrophages. This link is constituted by mediators involved in the activation process of macrophages.