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Background: Long-term exposure of conventional peritoneal dialysis (PD) fluid is associated with structural membrane alterations and technique failure. Previously, it has been shown that infiltrating IL-17-secreting CD4+T cells and pro-fibrotic M2 macrophages play a critical role in the PD-induced pathogenesis. Although more biocompatible PD solutions are recognized to better preserve the peritoneal membrane integrity, the impact of these fluids on the composition of the peritoneal cell infiltrate is unknown., Materials and Methods: In a uremic PD mouse model, we compared the effects of daily instillation of standard lactate (LS) or bicarbonate/lactate-buffered solutions (BLS) and respective controls on peritoneal fibrosis, vascularisation, and inflammation., Results: Daily exposure of LS fluid during a period of 8 weeks resulted in a peritoneal increase of αSMA and collagen accompanied with new vessel formation compared to the BLS group. Effluent from LS-treated mouse showed a higher percentage of CD4 + IL-17 + cell population while BLS exposure resulted in an increased macrophage population. Significantly enhanced inflammatory cytokines such as TGFβ1, TNFα, INFγ, and MIP-1β were detected in the effluent of BLS-exposed mice when compared to other groups. Further, immunohistochemistry of macrophage subset infiltrates in the BLS group confirmed a higher ratio of pro-inflammatory M1 macrophages over the pro-fibrotic M2 subset compared to LS., Conclusion: Development of the peritoneal fibrosis and angiogenesis was prevented in the BLS-exposed mice, which may underlie its improved biocompatibility. Peritoneal recruitment of M1 macrophages and lower number of CD4 + IL-17 + cells might explain the peritoneal integrity preservation observed in BLS-exposed mouse.

Purpose of the Study: Little information have been provided till now regarding the effect of high volume HDF (hv-OL-HDF) in respect to standard bicarbonate dialysis (BHD) in medium-long term protein-bound toxins removal., Procedures: A randomised cross-over multicentre study (REDERT study) was designed to compare the effects of hv-OL-HDF and low-flux BHD on uremic toxins serum levels in 36 chronic dialysis patients followed for 13 months. Group 1 patients were treated with BHD (Treatment A) for 6 months, and afterwards, they were transferred to hv-OL-HDF for a further 6 months (Treatment B). Group 2 patients were treated with Treatment B for 6 months, and afterwards, they were transferred to Treatment A for a further 6 months. Total and free pre-dialysis indoxyl-sulfate (IS) and p-cresyl-sulfate (pCS) were determined starting a midweek dialysis session at baseline and after six months of hv-OL-HDF or BHD. IS and pCS, were simultaneously measured, by liquid chromatography/electrospray ionization-tandem mass spectrometry, Kt/v and pre and post-dialysis b-2microglobulin (b2MG) levels were measured every three months., Results: Kt/V was significantly increased in hv-OL-HDF (from 1.47 ± 0.24 to 1.49 ± 0.16; p < 0.01) and was reduced in BHD (from 1.51 ± 0.2 to 1.36 ± 0.21; p < 0.001). The mean infusion volume in HDF was 20.9 ± 2.1 L with a mean total convective volume of 23.8 ± 2.3 L and a significant removal of b2MG was obtained in hv-OL-HDF at month 3 and month 6. Both free and total levels of IS and pCS were significantly reduced in hv-OL-HDF at month 6 in respect to BHD., Conclusions: In the present study we confirm the assumption that post-HDF is an effective technique in small and protein-bound uremic toxins removal.

Acetate in standard acetate-containing bicarbonate (AC) dialysis fluid could induce peripheral vasodilatation, suppression of myocardial function, and inflammatory cytokine production, resulting in intradialytic hypotension in conventional hemodialysis (HD) patients. Online hemodiafiltration (HDF) provides superior hemodynamic stability over HD. The potentially additive hemodynamic benefits of the novel acetate-free bicarbonate (AF) dialysis fluid in online HDF have never been explored before. The present randomized, double-blind, crossover study was conducted in 22 online HDF patients to investigate the impact of AF dialysis fluid on hemodynamic and cytokine changes compared with AC dialysis fluid in online HDF. The results demonstrated the comparable changes of arterial pressure between AF and AC online HDF. During the study periods, the incidences of composite intradialytic hypotension and other adverse events were not different. The baseline and hourly changes of cardiac index, cardiac output, and peripheral vascular resistance during dialysis were comparable (P=0.534, 0.199, and 0.641, respectively). The percent reductions of NT-proBNP and cTnT were not significantly different (72.6 ± 12.3 vs. 72.6 ± 12.8%, P=0.99 and 35.2 ± 12.8 vs. 36.7 ± 12.0%, P=0.51). The changes of all pro-inflammatory cytokines (IL-2β, IL-6, IL-8, and TNF-α) and anti-inflammatory cytokine (IL-10) during dialysis were comparable between both groups. In conclusion, AF dialysis solution does not offer additional hemodynamic benefit for stable online HDF patients. The hemodynamic stability provided by online HDF might protect the adverse effects of acetate., (© 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.)

Purpose: Hyperleptinemia and metabolic acidosis (MA) are frequently observed in patients on hemodialysis (HD). While the role of leptin in patients on HD is not completely understood, HD only partially corrects MA. Both leptin and acidosis have effect on bone disease. The goal of the present study was to evaluate the effects of MA correction on chronic kidney disease-mineral and bone disorder laboratory parameters and leptin levels., Methods: Forty-eight patients on HD, aged 43±19 years, were prospectively studied. Individual adjustments in the bicarbonate dialysate concentration were made to maintain pre-dialysis concentration≥22 mEq/l. Blood gas analysis was done monthly for 4 months (M1-M4)., Results: From M0 to M4, serum albumin increased (from 3.5 ±0.3 to 4.0±0.3 g/l, p<0.0001) while β2 microglobulin decreased (from 27.6±8.3 to 25.8±6.8 µg/ml, p=0.025). Serum leptin decreased in all but three patients, as well as leptin/adiponectin ratio (p<0.0001). There was a decrease in ionized serum calcium (from 5.0±0.5 to 4.7±0.5 mg/dl, p =0.002) and an increase in parathyroid hormone (PTH) [from 191 (85, 459) to 446 pg/ml (212, 983), p<0.0001] and in serum phosphate (from 5.4±1.4 to 5.8±1.1 mg/dl, p=0.048)., Conclusion: MA correction in HD patients can decrease leptin, an atherogenic marker. The impact of such treatment extends to uremic bone disease, as decrease in serum calcium and increase in PTH. However, this could be an undesirable effect because it may aggravate a secondary hyperparathyroidism. Whether the reduction in leptin levels has impact on outcomes in patients on hemodialysis deserves further investigation.

Bicarbonate dialysis is the treatment modality of choice for correction of metabolic acidosis in chronic renal failure. However, improper selection of dialysate concentrate can result in life-threatening human errors. We report a case of iatrogenic severe hypernatremia (sodium 207 mEq/L) and severe metabolic acidosis (pH 6.65) that resulted due to accidental use of inappropriate bicarbonate concentrate for hemodialysis treatment. There was successful recovery in this patient with no neurological sequelae. To the best of our knowledge, this is the first case report in adults of severe hypernatremia along with severe metabolic acidosis due to error in the preparation of dialysis fluid.

Background/aims: Ultrafiltration that occurs during hemodialysis (HD) promotes profound alterations in a relatively short period of time. The dialysate content of bicarbonate (DBic) and potassium (DK) may have impact over intradialytic hemodynamics, which goes beyond ultrafiltration, and its impact was evaluated in a prospective cohort., Methods: 30 patients under HD were submitted to hemodynamic assessment (HA) at the beginning and at the end of HD sessions, through a non-invasive method. Serum minus dialysate potassium concentration was expressed as K-Gap. Cardiac index (CI) and peripheral arterial resistance (PAR) variation (post-HD minus pre-HD) were expressed as ΔCI and ΔPAR. Dialysate content of sodium and calcium were expressed as DNa and DCa, respectively., Results: Mean DNa, DK and DBic were, respectively, 136.4 ± 1.1, 2.1 ± 0.6 and 38.2 ± 2.1 mEq/L. In 15 patients, DCa was >1.5 mmol/L and in the other 15 patients ≤ 1.5 mmol/L. The K-Gap ranged from 1.4 to 5.1 mEq/l (median 3.0 mEq/L). There was a reduction in post-HD CI and systolic blood pressure (ΔCI = -0.72l/min/m(2) and -11.3±15.1mmHg, respectively, p<0.001 for both). Conversely, PAR increased (ΔPAR = 272dyn.s/cm(5), p<0.001). Lower post-HD CI was was associated to higher DBic (p=0.0013) and lower K-Gap (p=0.026). In multivariate analysis, ΔCI was dependent on DBic and K-Gap, whereas ΔPAR was dependent on dialysate calcium during HD., Conclusion: We confirmed that Na and Ca dialysate content exerts and important role on hemodynamic during HD. In addition, our findings pointed out that higher dialysate concentrations of bicarbonate and potassium promote lower cardiac performance at the end of hemodialysis session., (© 2014 S. Karger AG, Basel.)

Background and Objectives: Double-chamber peritoneal dialysis fluids exert less toxicity by their neutral pH and reduced glucose degradation product content. The role of the buffer compound (lactate and bicarbonate) has not been defined in humans., Design, Setting, Participants, & Measurements: A multicenter randomized controlled trial in 37 children on automated peritoneal dialysis was performed. After a 2-month run-in period with conventional peritoneal dialysis fluids, patients were randomized to neutral-pH, low-glucose degradation product peritoneal dialysis fluids with 35 mM lactate or 34 mM bicarbonate content. Clinical and biochemical monitoring was performed monthly, and peritoneal equilibration tests and 24-hour clearance studies were performed at 0, 3, 6, and 10 months., Results: No statistically significant difference in capillary blood pH, serum bicarbonate, or oral buffer supplementation emerged during the study. At baseline, peritoneal solute equilibration and clearance rates were similar. During the study, 4-hour dialysis to plasma ratio of creatinine tended to increase, and 24-hour dialytic creatinine and phosphate clearance increased with lactate peritoneal dialysis fluid but not with bicarbonate peritoneal dialysis fluid. Daily net ultrafiltration, which was similar at baseline (lactate fluid=5.4±2.6 ml/g glucose exposure, bicarbonate fluid=4.9±1.9 ml/g glucose exposure), decreased to 4.6±1.0 ml/g glucose exposure in the lactate peritoneal dialysis fluid group, whereas it increased to 5.1±1.7 ml/g glucose exposure in the bicarbonate content peritoneal dialysis fluid group (P=0.006 for interaction)., Conclusions: When using biocompatible peritoneal dialysis fluids, equally good acidosis control is achieved with lactate and bicarbonate buffers. Improved long-term preservation of peritoneal membrane function may, however, be achieved with bicarbonate-based peritoneal dialysis fluids.

Background: In bicarbonate-based hemodialysis, dialysate total calcium (tCa) concentration may have effects on mineral metabolism., Study Design: Randomized crossover trial of 3 dialysate tCa concentrations (2.5, 2.75, and 3.0 mEq/L)., Setting & Participants: 22 stable anuric uremic patients underwent three 4-hour bicarbonate hemodialysis sessions with the 3 different dialysate tCa concentrations using a single-pass batch dialysis system., Outcomes: Hourly measurements of plasma water ionized calcium (iCa) and plasma parathyroid hormone (PTH) concentrations. tCa mass balances were measured from the dialysate side., Results: Hourly plasma water iCa concentrations were higher with a dialysate tCa concentration of 3.0 compared with 2.75 and 2.5 mEq/L (P < 0.05), as were iCa concentrations at the end of dialysis sessions (2.66 ± 0.1, 2.56 ± 0.12, and 2.4 ± 0.08 mEq/L, respectively; P < 0.001). Mean tCa mass balance values (diffusion gradient from the dialysate to the patient) were positive with all dialysate tCa concentrations and increased progressively with dialysate tCa concentration (75 ± 122, 182 ± 125, and 293 ± 228 mg, respectively; P < 0.001). Plasma PTH levels increased during dialysis using dialysate tCa concentration of 2.5 mEq/L (mean increase, 225 ± 312 pg/mL) and decreased with dialysate tCa concentrations of 2.75 and 3.0 mEq/L (mean decreases, 68 ± 325 and 99 ± 432 pg/mL, respectively)., Limitations: Small sample size and lack of measurement of total-body calcium mass balances., Conclusions: A dialysate tCa concentration of 2.75 mEq/L might be preferable to 2.5 or 3.0 mEq/L because it is associated with mildly positive tCa mass balance values, plasma water iCa levels in the reference range, and stable PTH levels during dialysis., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Electrolyte disorders may constitute a life-threatening emergency. Sometimes they can be treated with medical therapy but there are cases where emergency dialysis will be necessary. An important role is played by the dialysate (including different concentrations of electrolytes), which removes uremic toxins and balances the electrolyte disorders in patients with end-stage renal disease. The choice of dialysate is also important for control of the patient's vital functions during the dialysis session and in the period between sessions. Sodium is strongly related to weight gain between dialysis sessions and its concentration causes fluid overload or, on the contrary, hypotension. The choice of the buffer takes into account any possible bicarbonate- or acetate-related systemic effects. Potassium is very important for heart contraction and its fast removal could be associated with cardiac arrhythmias. The role of magnesium is still controversial. Calcium is related to hemodynamic stability, mineral bone disease and also cardiac arrhythmias. A correctly balanced dialysate is important to prevent and reduce intradialytic and interdialytic complications. The dialysate should be tailored to the needs of the individual patient.

Objective: Accumulation of advanced glycation end products (AGEs) may be involved in the pathogenesis of peritoneal membrane dysfunction. As glycoxidation may play an important role in AGE formation, peritoneal dialysis fluids with low levels of glucose degradation products (GDPs) might result in a reduction in AGE concentration in the peritoneal effluent. The aim of this study was to compare the effects of conventional glucose-containing dialysis solutions and low GDP level fluids on the concentration of the AGEs N(ε)-(carboxymethyl)lysine (CML) and N(ε)-(carboxyethyl)lysine (CEL) in peritoneal effluent., Design: Prospective randomized control study., Methods: 23 patients were treated with either conventional glucose-containing fluid (n = 11, group A) or low level GDP fluid (n = 12, group B) during a period of 12 weeks. Before and after this period, CML and CEL were measured in peritoneal effluent., Results: In groups A and B there were changes in CML concentrations [respectively 13.7 ± 17.0 and -16.0 ± 46.0 nmol/L (NS)] and CEL concentrations (respectively 20.3 ± 26.6 and -8.8 ± 18.9 nmol/L, p = 0.015). Residual renal function (RRF) in groups A and B was, respectively, 6.8 and 6.1 mL/min (NS). CML, but not CEL, in the peritoneal effluent was inversely related to RRF (r = -0.67, p < 0.05)., Conclusion: CEL, but not CML, in the peritoneal effluent appears to be influenced by the prescription of low GDP level fluid, probably due to the highly reduced concentration of methylglyoxal, which is needed for formation of CEL. CML is primarily influenced by RRF.

Introduction: Evidence that bicarbonate haemofiltration and dialysate fluids are superior to lactate in patients with acute kidney injury treated by continuous renal replacement therapy (CRRT) remains controversial., Methods: We prospectively audited acid-base during the first 48 h of CRRT in 62 patients, using bicarbonate and lactate fluids., Results: Baseline lactate was greater in the bicarbonate group (4.76 ± 0.77 vs. 2.92 ± 0.5 mmol/l, p < 0.01), but pH, bicarbonate, chloride and base excess were similar. Lactate fell significantly in the bicarbonate group to 2.88 ± 0.3 mmol/l at 24 h and 2.39 ± 0.2 mmol/l at 48 h, but not in the lactate group. Base excess improved more with bicarbonate, median increase in the first 24 h was 51.6% (29.1-96.9) versus 18.5% (-5 to 55) with lactate and 74.2% (38.5-123) versus 36.1% (-3.6 to 68), p < 0.05 at 48 h. However, there were no significant differences in bicarbonate, chloride, pH, blood pressure and vasopressor requirements. 13.3% of patients were switched from lactate to bicarbonate fluids due to failure to correct acidosis. Subgroup analysis of 19 patients with liver failure showed similar results., Conclusion: Bicarbonate fluids led to a more rapid fall in lactate and greater improvement in base excess during CRRT, but not overall control of acidosis., (Copyright © 2011 S. Karger AG, Basel.)

In the present study, we investigated the effect of hemodialysis (HD) with high-performance membrane filter (HPM-HD) using acetate-free bicarbonate dialysis (AFD) fluid on bioincompatibility as represented by inflammatory markers in patients undergoing maintenance HD therapy and compared it with conventional acetate-containing bicarbonate dialysis (ACD) fluid. A total of 36 maintenance HD patients were registered for study during the 4-month study period (22 males and 14 females, aged 63.5 ± 10.2 years, mean duration of dialysis 12.2 ± 8.6 years, chronic glomerular nephritis in 27 patients, diabetic nephropathy in 6 patients, and nephrosclerosis in 3 patients). These patients were subjected to ACD for the first 2 months followed by AFD fluid for the latter 2 months. Predialysis blood pH and bicarbonate were examined after each of the first and latter 2-month period. Blood variables of C-reactive protein (CRP) and interleukin-6 (IL-6) or fetuin-A were also determined. The filters (membrane surface area, raw material), the conditions of HD (blood flow rate, dialysate flow rate, dialysis time, dry weight) and drug regimen including erythrocyte-simulating agent (drug type, dosage) were unchanged throughout the study. There appeared to be significantly higher levels of predialysis blood pH and bicarbonate in the AFD phase than in the ACD phase. Blood CRP and IL-6 levels were significantly decreased in the AFD group as compared with those seen in the ACD group. From these results, it can be suggested that HPM-HD using AFD fluid contributes to correcting metabolic acidosis and alleviating microinflammation in HD patients., (Copyright © 2011 S. Karger AG, Basel.)

The beneficial effects of novel peritoneal dialysis solutions low in glucose degradation products regarding peritoneal cell apoptosis and necrosis are well established in vitro, however in vivo data is lacking. Cell-free DNA quantification is a possible method to determine cell damage through apoptosis and necrosis in vivo. We performed a prospective, cross-over study on 26 stable continuous ambulatory peritoneal dialysis (CAPD) patients, treating each patient for 3 months in a randomized order with a conventional, lactate-buffered, acidic solution (solution D) and a novel, bicarbonate/lactate-buffered neutral solution (solution P). The timed overnight peritoneal effluent was sampled for cell-free DNA quantification using a fluorometric assay. The effluent samples of eighteen patients were finally available for DNA quantification. The concentration range of cell-free DNA in the peritoneal effluents was 1.8-9.5 microg/L. The coefficient of intrapatient variation in overnight effluent cell-free DNA appearance was 15.6 +/- 12.4%. Cell-free DNA peritoneal appearance using solutions D and P was 14.9 +/- 6.8 microg and 11.8 +/- 3.4 microg, respectively (P = 0.02), with the average difference of 3.1 microg (95% CI, 0.7-5.6 microg). Our results show that cell-free DNA is present in the overnight peritoneal effluent of stable CAPD patients. A significant decrease in the cell-free DNA appearance with solution P was found; however, before accepting this as an indicator of a more biocompatible profile causing less peritoneal membrane cell necrosis and apoptosis, confirmatory data on larger patient samples are needed. Our results indicate the potential future role of cell-free DNA in the diagnosis and prognosis of therapy-related peritoneal membrane degeneration.

Background: The importance to maintain the peritoneal membrane integrity for peritoneal dialysis (PD) patients by using biocompatible solutions (with low or no glucose as osmotic factor and low in glucose degradation products-GDPs, without lactate as a buffer and with normal pH) becomes progressively more evident. The aim of the present study was to investigate the clinical effects of a novel bicarbonate-based biocompatible PD fluid, evaluating the alteration in the concentrations of dialysate marker CA125, a glucoprotein indicator of mesothelial cell mass. PATIENTS AND METHODS; This is a single-center, prospective cohort study of 12 stable CAPD patients (4 women, 8 men), mean age 71.3 +/- of 6.01 years, mean PD duration 31.9 +/- 21.33 months, treated with the usual conventional PD solutions (with increased GDPs, low pH, and lactate as a buffer system). After a six-month period, the patients changed for the next six-month period into bicarbonate PD solutions (BicaVera, Fresenius), after which they returned into their previous schema of conventional solutions for another six months. The dialysate marker of CA125 was repeatedly estimated at the beginning of the study (T0), after six months phase with the bicarbonate solutions (T6), and at the end of study (T12), after the second six-month use of the conventional PD solutions. All the samples were taken at the end of a four-hour dwell of an exchange with PD solution 2.5% glucose., Results: The dialysate mean value of CA125 at the beginning of the study (Td0-with conventional PD solutions) was 15.07 +/- 5.72U/mL. After six months with bicarbonate PD solutions, the mean CA125 value increased to 111.97 +/- 66.21U/mL, while the mean values dropped again to 22.72 +/- 16.06 U/mL at the end of the study, after the patients' return for another six months to the conventional solutions use. There was a statistically significant difference between the mean CA125 levels at the beginning (Td0) and the middle of the study (Td6; p = 0.00079) as well as between the mean levels of CA125 in the middle (Td6) and at the end of the study (Td12; p = 0.0014). In contrast, comparing the mean dialysate values of CA125 at the beginning (Td0) and at the end of the study (Td12), no statistically significant difference was revealed (p = 0.13)., Conclusions: For the use of the bicarbonate-based PD, more biocompatible solutions for six months produced a statistically significant increase in the dialysate concentration of the mesothelial cell mass indicator CA125. The decrease at the end of the study of CA125 mean value at a level similar with that observed at the beginning, after the six-month period of the conventional PD solutions, indicates that the clinical use of the new bicarbonate-based PD solutions may have an advantageous role in the preservation of peritoneal cell mass, maintaining also the integrity and longevity of the peritoneal membrane.

Peritonitis remains a major cause of morbidity among patients on peritoneal dialysis (PD), yet there is little information about the effect of new biocompatible dialysis solutions on peritonitis rates and treatment. In our unit, information on each peritonitis episode is prospectively collected. Since 2003, bicarbonate/lactate dialysate has been gradually introduced for new patients and for patients experiencing abdominal pain with conventional lactate solutions. From 2002 to 2005, data from 121 episodes of peritonitis (71 automated PD and 50 continuous ambulatory PD) were analyzed; 107 episodes occurred in patients using standard lactate dialysate and 14 episodes in patients using bicarbonate/lactate solution. Patients using bicarbonate/lactate had a significantly lower peritonitis rate of 1 per 52.5 patient-months compared to those using standard lactate dialysate (1 per 26.9 patient-months) (P=0.0179). Response to treatment, however, was not affected by the type of dialysate; cure rates (71.4 and 69.1%, respectively) and recurrence rates (21.4 and 15.8%, respectively) were not significantly different. Catheter removal was required in three (21.4%) patients using bicarbonate/lactate and 23 (22.4%) patients using lactate solution. Use of biocompatible dialysate appears to reduce the peritonitis rate by 50%, although this has to be confirmed in a randomized study. The type of dialysate, on the other hand, does not affect response to treatment.

Aim: To determine the incidence of intradialytic hypertension (IDH) during hemodialysis (HD) in end-stage renal disease (ESRD) patients using acetate dialysate compared to those using bicarbonate dialysate., Methods: This study was a double-blind cross-over randomized clinical trial. The effect of acetate and bicarbonate dialysate on blood pressure was analyzed in two consecutive HD sessions. The selected subjects were 41 stable ESRD patients scheduled for dialysis 2 times/week/from the HD unit of Dr.Soetom Hospital Surabaya, aged between 21-65 years old, with a hemoglobin level > or = 7 g/dL, serum albumin > or = 3 mg/dL and interdialytic weight gain < 4 Kg, and an average Qb 150-250 ml/minute. The dialysate sodium level was 138 mEq/L/ The study subjects were divided into tow groups: 21 patients in the group who received Acetate on the first session and Bicarbonate on the next (AB) and 20 patients in the group receiving Bicarbonate first (BA). Comparison of IDH during use of each dialysate was analyzed by Chi-Square and Mc Nemar Chi-Square test., Results: No characteristic differences were found in both groups: HD duration (for AB) was 28.83 +/- 13.89 vs. 34.95 +/- 24.80 months (for BA) (p = 0.333); Age (for AB) was 47.61 +/- 9.49 vs. 47.75 +/- 11.80 years (for BA) (p = 0.969); Hemoglobin (Hb) level (for AB) 8.19 +/- 0.84 vs. 7.94 +/- 0.41 mg/dL (for BA) (p = 0.238); serum Albumin (for AB) was 3.79 +/- 0.26 vs. 3.82 +/- 0.30 g/dl (for BA) (p = 0.652). The number of patients with IDH during acetate dialysate with IDH during bicarbonate dialysate was 1 (2.4%). Overall, there were 11 patients with Diabetic Kidney Disease (26.8%). Six out of them (54.5%) had IDH during acetate dialysate and only and 1 patient (9.1%) had IDH during acetate and bicarbonate., Conclusion: The incidence of IDH in hemodialysis using acetate is significantly greater than that when bicarbonate is used (p = 0.000).

Unlabelled: The in vitro biocompatibility performance of a 25 mmol/L bicarbonate/10 mmol/L lactate-buffered peritoneal dialysis fluid., Background: The biocompatibility profile of a new peritoneal dialysis (PD) solution (Physioneal 35) was determined using a selection of in vitro assay systems. Physioneal 35 is buffered by a combination of 25 mmol/L bicarbonate and 10 mmol/L lactate, thereby providing a solution with a total of 35 mmol/L of alkali to complement the currently available 25 mmol/L bicarbonate and 15 mmol/L lactate combination solution, Physioneal 40. In addition, the new solution contains a calcium concentration of 1.75 mmol/L rather than 1.25 mmol/L present in Physioneal 40. Physioneal 35 and 40 are manufactured in double chamber bag systems that permit separation of glucose from the buffer during sterilization. When the two chambers are mixed just before patient use, the resulting solution has a neutral pH and reduced glucose degradation content. Physioneal 35 was evaluated for its cytotoxicity potential using a murine fibroblast assay, its acute effect on human neutrophil and human peritoneal mesothelial cell function, and its in vitro potential to form advanced glycation end products (AGE). The biocompatibility characteristics of this new formulation were compared with that of a conventional, lactate-based solution and to that of its parent formulation, Physioneal 40., Methods: Proliferation of murine fibroblasts was determined after exposure to dialysis fluids for 72 hours. Cell viability was assayed by the ability to take up neutral red dye. Human neutrophils were exposed for 15 minutes to dialysis fluids, and their ATP content and phorbol 12-myristate 13-acetate (PMA) stimulated chemiluminescence response was determined as a measure of viability and respiratory burst activity, respectively. Cellular interleukin (IL)-1beta-driven IL-8 synthesis by human mesothelial cells following acute exposure to dialysis fluids was also assessed. Advanced glycation end product formation in the dialysis fluids was measured after 5 and 20 days of incubation with human serum albumin (HSA) as the model protein., Results: In all assays employed, the biocompatibility profile of Physioneal 35 was similar to that of the Physioneal 40 parent formulation. Physioneal 35 showed a significant improvement in biocompatibility performance compared to a pH neutralized conventional lactate-buffered peritoneal dialysis solution in the murine fibroblast assay. In the acute exposure assays, human neutrophil viability and respiratory burst were significantly improved compared with the acidic, conventional solution; however, no statistically significant improvement were seen in mesothelial cells. AGE formation, which is thought to be an important mechanism by which glucose and glucose degradation products cause structural and functional changes of the peritoneal membrane, was significantly lower in Physioneal 35 compared with the conventional dialysis solution., Conclusion: The biocompatibility profile of Physioneal 35 was similar to that of the original Physioneal 40 bicarbonate/ lactate-buffered dialysis solution, confirming that differences in both buffer content and calcium concentration do not affect biocompatibility performance. Both bicarbonate/lactate formulations (Physioneal 35 and Physioneal 40) were more biocompatible than a conventional lactate-buffered dialysis solution in this in vitro biocompatibility assessment.

In vitro biocompatibility performance of Physioneal. toneal dialysis (PD) has been a successful and effective form of chronic renal replacement therapy since its introduction over 20 years ago. Despite its overall success, there is a growing body of evidence that suggests shortcomings in the preservation of membrane integrity. This has led to the development of several second-generation PD solutions that demonstrate improved biocompatibility. Physioneal, a neutral pH, bicarbonate/lactate-buffered solution, was one of the first of these new PD solutions to become commercially available. This review will focus on one of the first preclinical stages in the development of Physioneal: studies on in vitro biocompatibility testing. Studies in leukocyte, mesothelial cell, and fibroblast populations demonstrated significantly improved biocompatibility of neutral pH, bicarbonate/lactate-based solutions compared to conventional solutions. The solutions contributed to improved leukocyte viability and response to bacterial infection (e.g., phagocytosis, superoxide radical generation, and endotoxin-stimulated cytokine release). Studies on peritoneal mesothelial cells demonstrate improved cell viability, proliferation, and response to proinflammatory stimuli, and a reduced potential for angiogenesis and peritoneal fibrosis, all suggesting a better preservation of membrane structure and function. The bicarbonate/lactate-based solutions demonstrated decreased cytotoxicity and preserved cell growth in fibroblast cultures as well. In vitro biocompatibility testing has clearly demonstrated that neutral pH, bicarbonate/lactate-buffered Physioneal solutions are superior to conventional solutions in preserving cell viability and function in cell populations that contribute to peritoneal homeostasis. This positive assessment now provides a foundation and rationale for moving forward with the next stages in preclinical testing: in vivo animal models and human ex vivo studies.

Unlabelled: Clinical experience with two physiologic bicarbonate/lactate peritoneal dialysis solutions in automated peritoneal dialysis., Background: Patients on automated peritoneal dialysis (APD) usually receive larger volumes of dialysis solution and more frequent, shorter exchanges than patients on continuous ambulatory peritoneal dialysis (CAPD), and therefore are likely to derive greater benefit from more physiologic solutions., Methods: Peritoneal dialysis solutions containing 25 mmol/L bicarbonate and either 10 or 15 mmol/L lactate were compared with standard lactate solutions (35 or 40 mmol/L) in two prospective, open-label studies of patients on APD. Each study included a 2-week baseline period (lactate solution), a 6-week treatment period (bicarbonate/lactate solution), and a 2-week follow-up period (same lactate solution as baseline). Biochemical analyses and assessments of vital signs and safety parameters were conducted at baseline, every 2 weeks during treatment, and at the end of the follow-up period. A product use questionnaire was administered in one study at the end of treatment., Results: A statistically significant rise in plasma bicarbonate (approximately 2 mmol/L) occurred when patients switched from a lactate solution to the bicarbonate/lactate solution with equimolar buffer concentration (P < 0.001 for each solution). Plasma bicarbonate decreased by 1.16 mmol/L after a switch from lactate 40 mmol/L to bicarbonate/lactate 35 mmol/L (P < 0.001). When patients switched to bicarbonate/lactate 35, the majority of individual venous plasma bicarbonate values were in the normal range. A switch from a lower calcium (1.25 mmol/ L) lactate solution to a higher calcium (1.75 mmol/L) lactate/bicarbonate solution resulted in a statistically significant rise in serum calcium (0.06 mmol/L, P < 0.018). The product use questionnaire revealed improvements in symptoms, including reduced pain on infusion., Conclusion: Bicarbonate/lactate solutions may be used safely and effectively in patients on APD. The availability of 2 formulations with different buffer and calcium content provides flexibility for the control of acidosis as well as calcium balance.

The application of animal models to study the biocompatibility of bicarbonate-buffered peritoneal dialysis solutions. Patients treated with peritoneal dialysis (PD) are at risk for development of ultrafiltration failure and peritonitis. These two significant complications can result in the termination of PD treatment. The relative unphysiologic composition of the currently used standard peritoneal dialysis fluids (PDF) is considered to be a major cause for the development of morphologic changes of the peritoneal membrane, ultimately resulting in ultrafiltration failure and probably contributing to changes in local defense mechanisms with the associated increased risk of peritonitis. In recent years, a major research focus has become the development of new and improved PD solutions. This has resulted in the development of an amino-acid-based PDF, a glucose polymer-based PDF, and several bicarbonate-buffered PDF. Typically, the first phase of biocompatibility testing of new PD solutions involves in vitro testing, employing isolated cells such as peritoneal macrophages or cell culture systems using human peritoneal mesothelial cells. The results of such evaluations are useful in providing insights into the biocompatibility performance of any given formulation, but suffer from several disadvantages, which can be better addressed using animal models. In vivo studies using animals permit the analysis of biocompatibility under conditions that allow for cell-to-cell interactions and dynamic changes in solution composition that more closely mimic the clinical situation. In this paper, we will review the use of animal models for the study of PDF biocompatibility and their application to the assessment of bicarbonate-buffered PDF.

Acid-base balance and peritoneal membrane longevity are of utmost relevance for pediatric patients undergoing peritoneal dialysis (PD). PD fluids with neutral pH and reduced glucose degradation product contents are considered more biocompatible, because they preserve peritoneal cell functions in vitro. To investigate the clinical effects of a novel PD fluid buffered with 34 mM pure bicarbonate at neutral pH, a randomized, prospective, crossover comparison with conventional, acidic, 35 mM lactate PD fluid was performed for two consecutive 12-wk periods with 28 children (age, 6 mo to 15 yr) undergoing automated PD (APD). Blood bicarbonate levels and arterial pH were significantly higher after 3 mo of bicarbonate PD (24.6 +/- 2.3 mM and 7.43 +/- 0.06, respectively), compared with lactate PD (22.8 +/- 3.9 mM and 7.38 +/- 0.05, respectively; P < 0.05). This effect was reversible among patients who returned from bicarbonate to lactate fluid. Low initial pH and young patient age independently predicted increased blood pH during bicarbonate APD. Peritoneal equilibration tests revealed subtle changes in solute transport, with a less steep creatinine equilibration curve during bicarbonate dialysis, suggesting reduced peritoneal vasodilation. The peritoneal release of carcinogen antigen-125 increased twofold during bicarbonate APD (29 +/- 15 versus 15 +/- 8 U/ml per 4 h, P < 0.01), which is consistent with recovery of the mesothelial cell layer. This effect was fully reversed when the patients returned to lactate fluid. Effluent carcinogen antigen-125 levels were inversely correlated with peritoneal glucose exposure during lactate but not bicarbonate APD, indicating improved in vivo mesothelial cell tolerance of high-dose glucose with the neutral-pH PD fluid with reduced glucose degradation product content. Among children undergoing APD, neutral-pH, bicarbonate-buffered PD fluid provides more effective correction of metabolic acidosis and better preservation of peritoneal cell mass than do conventional, acidic, lactate-based fluids.

Objective: Physiological bicarbonate/lactate-based solutions may correct acidosis in a better way than standard lactate-based solutions. In this study, a new 25 mmol/L bicarbonate/10 mmol/L lactate peritoneal dialysis (PD) solution was compared with a standard 35 mmolL lactate solution., Design: This was a prospective open label study. All patients had a 2-week baseline period using the standard lactate solution, followed by 8 weeks on the bicarbonate/ lactate solution and 2 weeks on the lactate-based solution., Setting: Four Danish and four Spanish nephrology centers., Patients: 40 well-dialyzed (creatinine clearance > 55 L/week/1.73 m2 body surface area) patients on continuous ambulatory PD., Interventions: Blood samples were taken for biochemistry (including venous blood gases) at week -2, day 1, weeks 2, 4, and 8, and at follow-up. A physical examination, a peritoneal equilibration test (PET), and quality of life (K/DQOL), ultrafiltration, and adequacy assessments were performed at baseline and at week 8. Vital signs and other safety parameters were followed at each visit. Extraneal (Baxter Healthcare, Castlebar, Ireland) was used by all patients for the long dwell., Main Outcome Measure: Effect on the venous plasma bicarbonate level., Results: Venous plasma bicarbonate levels rose from 24.4 mmol/L when patients were on the pure lactate to 26.1 mmol/L when using the bicarbonate/lactate solution (p < 0.001). When patients were using the bicarbonate/ lactate solution, 66% of values were maintained within the venous normal range of 24-30 mmol/L, versus 46.2% when patients were on the pure lactate solution (p < 0.001). There were no adverse findings with respect to clinical symptoms, vital signs, or physical examination. The PET and adequacy, ultrafiltration, and K/DQOL assessment results were unchanged., Conclusions: The new 25 mmol/L bicarbonate/ 10 mmol/L lactate solution provided better correction of acidosis than an equivalent 35 mmol/L standard lactate solution, without any safety issues.

To circumvent the potentially negative consequences of long-term exposure to unphysiologic acidic lactate-buffered peritoneal dialysis fluids (PDF), neutral pH solutions buffered with bicarbonate/lactate have recently been introduced in phase 2 and 3 clinical trials. This study examines the longitudinal changes in peritoneal macrophage (PMØ) function in patients dialyzed continuously with either lactate (LPD; 40 mM lactate, pH 5.2)-buffered or bicarbonate/lactate (TBL; 25 mM/15 mM bicarbonate/lactate, pH 7.3)-buffered PDF. Before the study, during the run in period of a phase 3 clinical trial, all patients had been taking LPD for at least the previous 18 wk. At the beginning of the study (day 0), both constitutive and serum-treated zymosan (STZ) stimulated tumor necrosis factor alpha (TNF-alpha) synthesis were assessed in PMØ isolated from 12-h dwell effluent (with 1.36% glucose) in all patients. The patients were subsequently randomized to either continuous TBL or LPD therapy and PMØ function was assessed after further 3- and 6-mo periods in all patients. At all time points measured STZ induced a dose-dependent increase in PMØ TNF-alpha secretion (P = 0.043 versus control for doses greater than 100 microg/ml). In patients continuously dialyzed with LPD, constitutive PMØ TNF-alpha synthesis levels (mean +/- SEM, pg/10(6) PMØ per18 h, n = 5 patients) were 154 +/- 65, 261 +/- 60, and 101 +/- 99 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1340 +/- 519, 1046 +/- 586, and 758 +/- 250 at 0, 3, and 6 mo, respectively. In patients dialyzed with TBL, constitutive PMØ TNF-alpha synthesis levels (pg/10(6) PMØ per 18 h, n = 5 patients) were 300 +/- 136, 106 +/- 35, and 213 +/- 62 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1969 +/- 751, 1541 +/- 330, and 2670 +/- 671 at 0, 3, and 6 mo, respectively. At 6 mo, STZ-stimulated PMØ TNF-alpha synthesis was significantly higher in patients treated with TBL compared with those treated with LPD (P = 0.0035). These data suggest that in patients continuously dialyzed with a neutral pH solution, there is a long-term improvement in PMØ function compared with patients on conventional therapy. Better PMØ function suggests improved host defense status and may affect the peritoneum's susceptibility to infection and potentially reduce the negative consequences of repeated intraperitoneal inflammation on long-term membrane function.

The long-term effects of a standard lactate-buffered dialysis fluid and a new, two-chamber, bicarbonate/lactate-buffered dialysis fluid (with fewer glucose degradation products and a neutral pH) were compared in an in vivo peritoneal exposure model. Rats were given daily injections, via an access port, of 10 ml of standard solution or bicarbonate/lactate-buffered solution for 9 to 10 wk. The omentum, peritoneum, and mesothelial cell layer were screened for morphologic changes. In addition, the bacterial clearing capacity of the peritoneal cells was studied. Significantly more milky spots and blood vessels were observed in the omenta of animals treated with standard solution (P < 0.03 for both parameters). Electron-microscopic analysis demonstrated dramatic changes in the appearance of the vascular endothelial cells of the milky spots and a severely damaged or even absent mesothelium on the peritoneal membrane of the standard solution-treated animals. In contrast, the mesothelium was still present in the bicarbonate/lactate-buffered solution group, although the cells lost microvilli. Both peritoneal dialysis fluids significantly increased the density of mesothelial cells (per square millimeter) on the surface of the liver and the thickness of the submesothelial extracellular matrix of the peritoneum (both P < 0.04 for both fluids versus control). A significantly better ex vivo bacterial clearing capacity was observed with peritoneal cells from the bicarbonate/lactate-buffered solution group, compared with the standard solution group (P < 0.05 in both experiments). These results demonstrate that instillation of bicarbonate/lactate-buffered solution into rats for 9 to 10 wk preserves both morphologic and immune parameters much more effectively, compared with standard solution. These findings may be of considerable clinical importance.

Background: In a randomized, controlled trial comparing a pH neutral, bicarbonate/lactate (B/L)-buffered PD solution to conventional acidic, lactate-buffered solution (C), the overnight dialysate levels of markers of inflammation/wound healing [hyaluronic acid (HA)], mesothelial cell mass/membrane integrity [cancer antigen 125 (CA125)], and fibrosis [transforming growth factor-beta1 (TGF-beta1) and procollagen I peptides (PICP)] were assessed over a six-month treatment period., Methods: One hundred six patients were randomized (2:1) to either the B/L group or C group. Overnight effluents were collected at entry into the study (time = 0 all patients on control solution) and then at three and six months after randomization. Aliquots were filtered, stored frozen, and assayed for HA, CA125, TGF-beta1, and PICP. Differences between groups were assessed by repeated-measures analysis of variance for unbalanced data using the SAS procedure MIXED., Results: In patients treated with B/L, there was a significant (P = 0.03) increase in CA125 after six months compared with time = 0 (19.76 +/- 11.8 vs. 24.4 +/- 13.8 U/mL; mean +/- SD; N = 51). In the same group of patients, HA levels were significantly decreased at both three and six months in the B/L-treated group (time = 0, 336.0 +/- 195.2; time = 3 months, 250.6 +/- 167.6; and time = 6 months, 290.5 +/- 224.6 ng/mL; mean +/- SD; P = 0.006, N = 47 and P = 0.003, N = 48, respectively). No significant changes in CA125 or HA levels were observed in the control group. There were no significant changes observed in the levels of PICP or TGF-beta1 in the B/L or C group over the six-month treatment period., Conclusions: These results suggest that continuous therapy with the B/L solutions modulates the levels of putative markers of peritoneal membrane integrity and inflammation. In the long term, this may positively impact the peritoneal membrane, increasing its life as a dialyzing organ.

Metabolic alkalosis (MA), defined as a primary increment in plasma bicarbonate concentration, is a common complication in hospitalized patients and is associated with high morbidity and mortality in severe cases. One of the major routes of compensation for MA (ie, the secretion of an alkaline urine) is lost in renal failure patients. We report three cases involving four episodes of extreme MA with an arterial pH value greater than 7.60, serum bicarbonate concentration greater than 55 mmol/L, and stupor or seizure. Profound vomiting or massive gastric drainage combined with concurrent oliguric renal failure was the underlying mechanism for severe MA. Hydration and normal central venous pressure failed to improve the MA. The extreme MA was reversed quickly and safely by conventional hemodialysis with normal bicarbonate dialysate of 25 to 28 mmol/L. To our knowledge, this is the first reported successful use of normal bicarbonate dialysate in the treatment of severe MA. We also found that either H(2) blockers or proton-pump inhibitors have a prophylactic effect on the formation of MA.

Arterial compliance (AC) is an important determinant of vascular structure, and abnormalities of AC can greatly affect the cardiovascular system. Given the vasoconstrictive properties of increased levels of serum ionized calcium (iCa), we investigated the way that dialysate calcium level can influence AC in the hemodialysis (HD) population. In a crossover randomized design, 19 dialysis patients undergoing regular bicarbonate HD (three times weekly) underwent two cycles of four successive HD sessions each with a low (LdCa; 1.25 mmol/L) and high dialysate calcium concentration (HdCa; 1.75 mmol/L). At the fourth session of each cycle, iCa level and hemodynamic parameters (systolic blood pressure [SBP], diastolic blood pressure, mean arterial pressure [MAP], pulse pressure [PP], heart rate, and AC) were measured pre-HD and post-HD. AC was measured noninvasively at the brachial artery by arterial pulse waveform analysis. The dialysate calcium level was a significant determinant of both pre-HD (r = 0.335; P < 0.05) and post-HD iCa level (r = 0.767; P < 0.001). Pre-HD AC increased significantly (P < 0.05) by 0.01+/- 0.02 mL/mm Hg (7% +/- 19%) on switching from HdCa to LdCa treatment. Multiple regression analysis showed that both pre-HD PP and iCa level were major inverse determinants of pre-HD AC in both the LdCa (R(2) = 0.65; P < 0.001) and HdCa (R(2) = 0.51; P < 0.01) treatment groups. AC increased by 32% (P < 0.01) and 37% (P < 0.05) during LdCa and HdCa dialysis, respectively. Intradialytic changes in AC were inversely correlated with changes in SBP and PP. In the HdCa group, changes in iCa level related significantly to MAP (r = 0.464; P < 0.05). The results show that changes in AC during HD are mainly mediated through concurrent changes of systemic hemodynamics, which are largely affected by dialysate calcium level through parallel changes in iCa level. Interdialytically, a significant, blood pressure-independent, inverse relationship between AC and iCa level exists. Therefore, HD with LdCa, by reducing the incidence of HD-induced hypercalcemia, may have a beneficial role in preventing the ongoing reduction of AC in HD patients and thus improving cardiovascular prognosis.

The impact on peritoneal macrophage (PMO) function of acidic lactate-buffered (Lac-PDF [PD4]; 40 mmol/L of lactate; pH 5.2) and neutral-pH, bicarbonate-buffered (TB; 38 mmol/L of bicarbonate; pH 7. 3) and bicarbonate/lactate-buffered (TBL; 25 mmol/L of bicarbonate/15 mmol/L of lactate; pH 7.3) peritoneal dialysis fluids (PDFs) was compared during a study of continuous therapy with PD4, TB, or TBL. During a run-in phase of 6 weeks when all patients (n = 15) were treated with their regular dialysis regimen with Lac-PDF, median PMO tumor necrosis factor alpha (TNFalpha) release values were 203.6, 89.9, and 115.5 pg TNFalpha/10(6) PMO in the patients subsequently randomized to the PD4, TB, and TBL treatment groups, respectively. Median stimulated TNFalpha values (serum-treated zymosan [STZ], 10 microgram/mL) were 1,894.6, 567.3, and 554.5 pg TNFalpha/10(6) PMO in the same groups, respectively. During the trial phase of 12 weeks, when the three groups of patients (n = 5 per group) were randomized to continuous treatment with PD4, TB, or TBL, median constitutive TNFalpha release values were 204.7, 131.4, and 155.4 pg TNFalpha/10(6) PMO, respectively. Stimulated TNFalpha values (STZ, 10 microgram/mL) were 1,911, 1,832, and 1,378 pg TNFalpha/10(6) PMO in the same groups, respectively. Repeated-measures analysis of variance comparing the run-in phase with the trial phase showed that PMO TNFalpha release was significantly elevated in patients treated with both TB (P = 0.040) and TBL (P = 0.014) but not in patients treated with Lac-PDF (P = 0. 795). These data suggest that patients continuously exposed to bicarbonate- and bicarbonate/lactate-buffered PDFs might have better preserved PMO function and thus improved host defense status.

A 38-year old man presented with drowsiness 14 hours after ingesting about 1200 mls (40 ounces) of antifreeze in a suicide attempt. He was successfully treated with an ethanol enriched, bicarbonate based-dialysate. With a concomitant peripheral intravenous infusion of ethanol, this enrichment of the dialysate helped maintain the intradialytic ethanol concentration between 97-135 mg/dl over an 8 hour dialysis session. The patient developed acute tubular necrosis and required further dialysis. He made a complete recovery after three weeks and was discharged with a serum creatinine of 1.4 mg/dl.

Background: Automated peritoneal dialysis (APD) has the possibility of increasing the dialysis efficacy by using higher fill volumes, frequent dialysate exchanges, and tidal techniques. It is then possible to treat patients adequately without residual renal function. The drawbacks of the required high amounts of dialysis solution of up to 30 litres per session are the high costs of lactate-based dialysate bags and difficulties for the patients in handling these bags. So far, bicarbonate-based peritoneal dialysate, which may be more biocompatible, is only available for CAPD in double-chamber bags. In APD this could be overcome by 'on-line' preparation of bicarbonate-buffered dialysate using advanced technologies originally designed for on-line preparation of substitution fluid for haemofiltration., Methods: Four patients without residual renal function were treated with APD five times weekly in a crossover study design. Patients received standard lactate-based (35 mmol/l) treatment (25 litres per session each) in weeks 1 and 3. In week 2 on-line-produced bicarbonate-buffered (37 mmol/l) dialysate was used. This dialysate was prepared by an AK 100 Ultra haemodialysis machine. The machine was modified for adding glucose from a 50% concentrate to the desired concentration of 1.7%. Electrolytes, pH, pCO2, and dialysis efficacy parameters were measured. Microbiological testing was carefully performed., Results: Creatinine clearances, Kt/V, and pCO2 did not vary between the different treatment phases, whereas the pH showed a distinct increase during the bicarbonate phase. Repeated determinations of endotoxins and culturing showed no contamination of the dialysate. The composition of the produced dialysate was reproducible with respect to pH, pCO2, sodium, calcium and bicarbonate, whereas the glucose concentration varied by +/- 20%., Conclusions: On-line preparation of PD fluid with the AK 100 Ultra is easy and safe to handle. APD with dialysate containing 37 mmol/l bicarbonate provides improved acid base balance and possibly improved biocompatibility, and may lead to a significant cost reduction. Further development in order to provide smaller machines and more precise ways of achieving a desired dialysate glucose concentration is necessary.

Background: Conventional peritoneal dialysis fluids (PDF) have been shown to compromise the function of both leukocytes and human peritoneal mesothelial cells (HPMC). Various in vitro studies have identified the low initial pH in combination with high lactate content, as well as the hyperosmolality and high glucose concentration present in currently used solutions as the primary determinants of their bioincompatibility. Bicarbonate buffered PDF (at neutral pH) display improved in vitro biocompatibility as compared to conventional, lactate buffered PDF. However, little information is currently available regarding the potential impact of PDF on the function of human peritoneal fibroblasts (HPFB), the major cell population present in peritoneal interstitium., Methods: The current study compares the effect of bicarbonate and lactate buffered PDF in a model system of resting peritoneal mesothelial cells and fibroblasts cultured from human omentum. Interleukin-1 beta-stimulated IL-6 release from HPMC and HPFB was used as the cell functional parameter., Results: While short (30 min) pre-exposure to lactate buffered PDF significantly reduced the IL-1 beta-stimulated IL-6 release from HPMC during a subsequent recovery period (24 hr), a significant decrease in HPMC IL-6 secretion with bicarbonate buffered PDF was only observed after prolonged (> or = 60 min) exposure. In contrast, no significant IL-6 inhibition was detected with HPFB pre-exposed to PDF for up to 90 minutes. A significant suppression of HPFB IL-6 secretion was only observed in coincubation experiments (24 hr) with dilutions of both types of PDF., Conclusions: These results indicate that (i) bicarbonate buffered PDF are less inhibitory to peritoneal cell function as compared to conventional, lactate buffered PDF; and (ii) HPFB may be more resistant than HPMC to bioincompatible PDF.

Background: The combination of a low pH and a high concentration of lactate which is present in most dialysis fluids is found to be cytotoxic in vitro. For these reasons it would seem logical to use a bicarbonate-containing solution and thus automatically provide a solution with a neutral pH., Methods: A parallel, randomized, open-label, prospective 2-month trial with an optional 4 month extension was undertaken to compare two novel bicarbonate-based solutions; one containing 38 mmol/l of bicarbonate (B), and one containing a mixture of 25 mmol/l bicarbonate and 15 mmol/l of lactate (B/L), with a control solution (C) containing 40 mmol/l lactate., Results: Three groups of 19 (C), 20 (B), and 20 (B/L) patients were recruited and data from approximately 55 patient months were accumulated in each group. The data show that both bicarbonate-based solutions maintain acid-base levels within the normal range, that there were no changes in any of the other blood biochemistry parameters measured in the peritoneal equilibration test or with regard to adequacy of dialysis, and that furthermore, both solutions were well tolerated., Conclusions: This study showed that either the bicarbonate or bicarbonate/lactate solutions could be utilized efficaciously in patients undergoing CAPD.

A randomized, double-blind, cross-over study was undertaken to determine the effects of novel bicarbonate (38 mM) and bicarbonate (25 mM)/lactate (15 mM) containing peritoneal dialysis (PD) solutions on infusion pain in patients who experienced inflow pain with conventional lactate (40 mM) solution. Pain was assessed using a verbal rating scale and the validated McGill Pain Questionnaire (MPQ). Eighteen patients were recruited to the study. Both novel solutions resulted in highly statistically significant reductions in inflow pain compared to the control lactate solution, as assessed with both the verbal rating scale and the MPQ. For all pain variables assessed, the bicarbonate/lactate solution was more effective than the bicarbonate solution in alleviating pain. In conclusion, both solutions reduced the infusion pain experienced with control solution, but the bicarbonate/lactate solution appears to be the most effective. In contrast to the most widespread current treatment, which is the manual injection of sodium bicarbonate, the bicarbonate/lactate solution does not have the associated increased risk of peritonitis.

Background: Metabolic acidosis adversely affects both protein and bone metabolism in patients with chronic renal failure, and could also affect morbidity and mortality. This trial aimed to investigate the effects of different dialysate bicarbonate concentrations on control of acid base balance, and nutritional status., Methods: Forty-six stable haemodialysis patients were dialysed using LowBic. (30 mmol/l) or HighBic. (40 mmol/l) bicarbonate dialysate in a single blind double crossover trial, of two consecutive six-month periods. Blood gas analysis, anthropometric indices and dialysis dose were measured, in addition to biochemical indices., Results: Predialysis 'arterial' plasma pH values were significantly higher when using the HighBic. dialysate (LowBic. 7.38 +/- 0.05, HighBic. 7.43 +/- 0.04, P < 0.001), as was predialysis serum total CO2 at all times during the study (P < 0.01). Kt/V, (LowBic. 1.27 +/- 0.19, HighBic. 1.27 +/- 0.25), urea generation rates (UGR) (LowBic. 1.99 +/- 0.77, HighBic. 1.92 +/- 0.77 mmol/min), and normalized protein catabolic rate (NPCR) (LowBic. 1.04 +/- 0.26, HighBic. 0.99 +/- 0.28 g/kg/day) did not differ, and values of parathroid hormone (PTH) were comparable. Triceps skinfold thickness (TSF) showed a significant change (LowBic. 14.8 +/- 6.9-11.8 +/- 5.5, HighBic. 14.9 +/- 6.3-15.8 +/- 6.4 mm, P < 0.05) which was reversed following dialysate change (HighBic. 11.8 +/- 5.5-13.3 +/- 7.2, LowBic. 15.8 +/- 6.4-13.8 +/- 6.7 mm, P < 0.05). No differences in mid upper arm circumference were found., Conclusions: Bicarbonate dialysate concentrations of 40 mmol/l were safe, well tolerated, and produced better control of acidosis, with an increase in TSF, compared to a bicarbonate concentration of 30 mmol/l.

Objective: Using the erythrocyte as a model for other kinds of cells not directly exposed to peritoneal dialysis (PD) solutions, we investigated the tolerance of the cell metabolism to lactate and bicarbonate buffers., Design: We studied, in vivo (in two groups of 5 PD patients each) and in vitro, the Embden-Meyerhof pathway (EMP) because it represents a potential target for the unphysiological effects of lactate or bicarbonate buffers. The EMP is the main glucose-utilizing route in the red blood cell (RBC), producing energy and reducing power., Methods: The enzymatic activities of the key steps in the glycolytic pathway and the energy charge (EC), determined by the levels of phosphorylated adenine nucleotides, were investigated spectrophotometrically and by high performance liquid chromatography (HPLC) in two groups of patients undergoing lactate (L-group) and bicarbonate (B-group) PD, respectively. The in vitro effects of both bicarbonate and lactate buffers on some EMP enzyme activities and energy production were determined. Cellular pH (pHi) was also investigated., Results: The B-group showed an EC value near the control levels, while in the L-group a significantly lower EC value was observed (t-test: p < 0.05 vs both B-group and controls). The key enzymes in the EMP, and in particular hexokinase, were higher in the L-versus B-group (p < 0.03 for the comparison of the Hk mean values). As demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, the bound form of glyceraldehyde-3-phosphate dehydrogenase (G-3-PD), an inactive form of this EMP enzyme, was significantly higher in the L-group with respect to the B-group (p < 0.004). In the in vitro experiments, high lactate concentrations acutely inhibited the key enzymatic steps of glycolysis, producing a significant decrease in glucose consumption and adenosine triphosphate production. These effects were not observed when bicarbonate was used in the incubations. Both in vivo and in vitro lactate, but not bicarbonate, induce a significant drop in pHi (p < 0.05). Decreased levels of pHi like those observed in the lactate-incubated RBC were demonstrated to be able to inhibit G-3-PD activity (25 +/- 2%) here used as an indicator of the actual decrease in pH., Conclusion: This study provides evidence for a damaging action of lactate with respect to bicarbonate buffer on the RBC metabolism. This condition was demonstrated observing a cell energy depletion, which coincides in vitro with an acute EMP impairment; the lactate accumulation together with the consequent lowering of pHi seem to be responsible for this effect, which was not observed when bicarbonate was used instead of lactate.

Lactate (L)-containing dialysate has a low pH, responsible for its poor biocompatibility. Dial-ysate-containing bicarbonate (B) with a physiological pH is available. We compare the peritoneal functional effects of these two solutions. Eight patients were studied two weeks apart using two consecutive peritoneal kinetic tests to determine convective and diffusive mass transfer coefficient (MTC) capacities for different solutes. Both L and B solutions were identical, except for pH and buffer content. Peritoneal equilibration values at four-hour dwell time were similar for all solutes, except for urea (B: 0.91 +/- 0.05 vs L: 0.87 +/- 0.06, p < 0.05). Peritoneal MTC (B vs L) values for urea (19.6 +/- 6.6 vs 18.2 +/- 4.5), creatinine (8.8 +/- 4.8 vs 7.8 +/- 3.5), phosphate (7.7 +/- 4.6 vs 6.0 +/- 2.2), and potassium (13.3 +/- 5.6 vs 11.7 +/- 5.0) were slightly higher for B (NS). Glucose-MTC was slightly lower for B (6.2 +/- 3.3 vs 7.5 +/- 3.2, NS). Ultrafiltration (UF) was lower for B (drained volume: 2120 +/- 204 vs 2443 +/- 285 mL after 4 hr, p < 0.05). Higher transperitoneal calcium [11 +/- 22 L vs -3.1 +/- 11.0 (positive balance) mg, p < 0.05] and sodium (48 +/- 30 L vs 13 +/- 20 mEq) removal were evident. With L, the loss of 43.0 +/- 6.3 mEq of bicarbonate appeared. The linear regression analysis of MTC values showed higher r coefficients for the bicarbonate solution. These results suggest that bicarbonate dial-ysate improves the diffusion capacity of the peritoneum with respect to lactate.

Our objective is to investigate transperitoneal buffer fluxes with solution containing lactate and bicarbonate, and to compare the final effect on body base balance of the two solutions. One hundred and four exchanges, using different dwell times, were performed in 52 stable continuous ambulatory peritoneal dialysis (CAPD) patients. Dialysate effluent lactate and bicarbonate and volumes were measured. Net dialytic base gain was calculated. Patients' acid-base status and plasma lactate were determined. In lactate-buffer CAPD solution, lactate concentration in dialysate effluent inversely correlated with length of dwell time, but did not correlate with plasma lactate concentration and net ultrafiltration. Bicarbonate concentration in dialysate effluent correlated with plasma bicarbonate and dwell time but not with ultrafiltration. The arithmetic sum of the lactate gain and bicarbonate loss yielded the net dialytic base gain. Ultrafiltration was the most important factor affecting net dialytic base gain. A previous study demonstrated that in patients using a bicarbonate-buffered solution the net bicarbonate gain is a function of dwell time, ultrafiltration, and plasma bicarbonate. By combining the predicted data of the dialytic base gain with the calculated metabolic acid production, an approximate body base balance could be obtained with both lactate- and bicarbonate-buffered CAPD solutions. The body base balance in CAPD patients is self-regulated by the feedback between plasma bicarbonate concentration and dialytic base gain. The level of plasma bicarbonate is determined by the dialytic base gain and the metabolic acid production. This can explain the large interpatient variability in acid-base correction. Bicarbonate-buffered CAPD solution is equal to lactate solution in correcting acid-base disorders of CAPD patients.

Commercially available solutions for continuous ambulatory peritoneal dialysis (CAPD) affect the viability and function of the cells in the peritoneal cavity. The low biocompatibility of the solutions may be caused by a low pH, hyperosmolality, high glucose content, and lack of potassium, glutamine, and other components essential for normal cellular functions. The nature of the buffer employed is also important for the cytotoxicity of the solutions. Lactate, the most frequently used buffer, has been shown to inhibit cellular functions important for the peritoneal defense system including phagocytosis, bacterial killing, and secretion of cytokines. It is generally believed that the cytotoxicity of lactate is caused by lowering of intracellular pH and impairment of metabolism due to changed redox potentials. However, the cytotoxicity of lactate is highly dependent upon the pH of the solutions, indicating that passive or active diffusion across the cell membrane is determining the effects of lactate. Bicarbonate has been heavily advocated as an alternative buffer because it is the most important naturally occurring buffer in plasma and it enables a pH of approximately 7.4 in the solutions. However, due to sedimentation of calcium carbonate (CaCO3) and production of toxic glucose metabolites it is difficult to prepare and store bicarbonate-based solutions. Moreover, investigations have revealed that even bicarbonate-based solutions are not optimal regarding biocompatibility, presumably due to a paradoxical intracellular acidification caused by influx of carbon dioxide (CO2). More recently, the effect of other buffers such as pyruvate and histidine have been examined. Especially pyruvate is a promising new buffer candidate.

For a long time bicarbonate, the physiological buffer of the body, was suggested to be the best buffer for peritoneal dialysis. However, since the production of bicarbonate-containing solutions is associated with technical problems, lactate was favored. To avoid the well-known disadvantages of lactate solution concerning biocompatibility and possible metabolic side effects, different attempts have been made to use bicarbonate as a buffer in peritoneal dialysis. One of the major approaches was the total replacement of lactate by bicarbonate combined with storage of the fluid in a specially designed double-chamber bag. Further solutions of the above-mentioned problem were the on-line preparation of bicarbonate fluids for intermittent peritoneal dialysis, the addition of bicarbonate just before use, the combination of bicarbonate with organic acids, or its combination with the dipeptide glycylglycine as a stabilizing agent. By now, the beneficial effect of the neutral bicarbonate fluid, for example, on cell viability and cell functions, has been demonstrated in many different in vitro and animal studies. However, only few reports on clinical experience have been published. These investigations demonstrated independently that bicarbonate fluids diminish inflow pain, are well tolerated by the patients, and may correct metabolic acidosis of uremic patients. A controlled randomized multicenter trial using 34 mmol/L bicarbonate for at least three months confirmed that bicarbonate is as efficacious as lactate in equimolar concentrations. Concomitant investigations on energy metabolism and redox state of red blood cells and phospholipid secretion of mesothelial cells additionally demonstrated the improvement of cell function with bicarbonate solutions. For some patients with severe metabolic acidosis the bicarbonate concentration used in the multicenter trial seemed to be too low. Thus, a fluid containing a higher bicarbonate concentration was tested in a pilot study resulting in the expected significant increase of arterial bicarbonate levels. In summary, bicarbonate-containing peritoneal dialysis solutions are a promising alternative to lactate, especially if bicarbonate concentrations are adjusted individually to the patient's need.

Objective: To evaluate bicarbonate fluxes across the peritoneal membrane and bicarbonate gain in patients treated with continuous ambulatory peritoneal dialysis (CAPD) using dialysis solutions with different bicarbonate concentrations., Patients and Design: Ninety-seven exchanges, using different dwell times and glucose and bicarbonate concentrations were performed in 43 stable CAPD patients. Dialysate effluent bicarbonate concentration and volumes were measured at different dwell times. Net dialytic bicarbonate gain was calculated. Patients' acid-base status was determined at the middle of the dwell., Results: In prolonged dwells (6-12 hours) the dialysate effluent bicarbonate concentration correlated with arterial plasma bicarbonate concentration (F = 129, p < 0.0001), but not with ultrafiltration rate or dialysis solution bicarbonate concentration. In 4-hour dwells, effluent bicarbonate concentration correlated with both plasma bicarbonate concentration and ultrafiltration rate (F = 32.52, p < 0.0001 and F = 4.4, p < 0.05, respectively). The effluent bicarbonate concentration may be predicted from the patient's plasma bicarbonate concentration and net ultrafiltration rate for either a 4-hour or prolonged (6-12 hours) dwell time. Net bicarbonate gain by the patient correlated with ultrafiltration rate, plasma bicarbonate, and dialysis solution bicarbonate concentration (F = 100.56, p < 0.0001 at 4 hours and F = 108.08, p < 0.0001 at 6-12 hours), with the ultrafiltration rate being the predominant parameter., Conclusions: The effluent bicarbonate concentration is related to plasma bicarbonate concentration, with ultrafiltration playing a marginal role only during short dwells. However, the ultrafiltration rate has a profound effect on net patient bicarbonate gain. Multiple linear regression analysis allows the prediction of the effect of acid-base status, ultrafiltration, dwell time, and dialysis solution bicarbonate content on net patient bicarbonate gain. It seems that bicarbonate content in the CAPD dialysis solution should be progressively increased with increasing solution osmolality.

In this prospective controlled study the purpose was to assess the long-term safety of calcium-free dialysate (O Ca) for hemodialysis and to determine the optimum calcium replacement. With this technique there is no calcium in the dialysate and calcium is infused into the drip chamber distal to the dialyzer. We compared the use of a standard bicarbonate dialysate with a calcium free dialysate in two groups of patients. One group (study 1) received 10 mmol/hour Ca replacement, the other (study 2) received 13.3 mmol/hour Ca during dialysis. Each O Ca period lasted six months. This experimental period was compared with the six months preceding and following in the same patient and as well, with a concurrent control group who received standard bicarbonate dialysis either with 1.5 mmol/l calcium in the dialysate in study 1 or 1.75 mmol/l in study 2. Each group had nine to eleven subjects. No adverse effects were seen in either of the studies. With 10 mmol/hour calcium replacement there was a small but not significant rise in the pre-dialysis intact parathyroid hormone level (PTH) whereas in all the other groups it remained the same or fell. There was significantly less rise in the post-dialysis calcium in the same group and this was associated with a small but not significant fall in both pre-dialysis total and ionized calcium. It was concluded that the O Ca technique can be used for long periods and that 13.3 mmol/hour is a satisfactory replacement using Discap 140 dialyzers or their equivalent.

Objective: The aim of the study was to investigate net ultrafiltration (NUF) with a new bicarbonate glycylglycine (BiGG) peritoneal dialysis solution compared to the standard lactate (La) solution., Design: In six groups of 12 normal rabbits each we measured NUF after a 2-, 4-, and 6-hour peritoneal dialysis with a BiGG solution (pH 7.35) and a standard La solution (pH 5.5) of similar glucose, electrolyte, and osmolality formulation. Furthermore, we studied the phosphatidylcholine concentration in the effluent of the two solutions., Results: NUF volume was significantly greater with the BiGG rather than with the La solution by approximately 15% (p < 0.05), 30% (p < 0.01), and 40% (p < 0.005) at 2, 4, and 6 hours, respectively. The glucose absorption rate was greater with the La solution than with the BiGG solution, but the difference was significant only at 2 hours (p < 0.05). pH was increased in the La solution from its initial value of 5.5 to 7.18, 7.32, and 7.40 at 2, 4 and 6 hours, respectively, while it remained almost unchanged in the BiGG solution. Phosphatidylcholine (PC) in the peritoneal effluent was significantly higher in the BiGG solution in all instances (p < 0.0001)., Conclusion: It is concluded that the BiGG solution, which has a stable pH, 7.35, due to the potent buffering capacity of bicarbonate and glycylglycine, enhances peritoneal NUF by maintaining a higher osmotic gradient and retarding lymphatic absorption through an increase in PC concentration in the peritoneal cavity.

Objective: The evaluation of the efficacy, adequacy, clinical tolerance, and safety of a new bicarbonate continuous ambulatory peritoneal dialysis (CAPD) solution., Design and Patients: A 6-week cross-over clinical study in 6 stable CAPD patients was performed. After a control period (2 weeks) with a standard CAPD solution (lactate, 35 mmol/L), a two-chamber bag containing 34 mmol/L of bicarbonate was used for 4 weeks. A breakable valve divided the two chambers, one containing bicarbonate and the other calcium. The two solutions were mixed just before use, thus avoiding the calcium and magnesium carbonate precipitation., Results: No differences between control and study periods were found for blood urea nitrogen, creatinine, total proteins, albumin, total and ionized calcium, phosphate, sodium, potassium, chlorine, and hemoglobin. Blood bicarbonate significantly increased from 21.25 +/- 2.02 to 23.36 +/- 1.15 (p < 0.05) during the study. The peritoneal equilibration tests for urea nitrogen, creatinine, proteins, sodium, potassium, and glucose were slightly reduced during bicarbonate dialysate, but this effect was compensated for by a slight increase of ultrafiltration, thus keeping peritoneal clearances constant. Residual renal function did not change during the study. No side effects occurred during the bicarbonate period., Conclusion: A CAPD bicarbonate solution is effective in uremic acidosis correction, does not affect dialysis adequacy, is safe, and well tolerated.