Glucose Exposure in Peritoneal Dialysis Is a Significant Factor Predicting Peritonitis.

INTRODUCTION: Loss of residual renal function (RRF) as well as high peritoneal glucose exposure are associated with increased peritonitis frequency in peritoneal dialysis (PD) patients. Our objective was to investigate the contribution of RRF and peritoneal glucose exposure to peritonitis in PD patients. METHODS: In this prospective longitudinal cohort study, 105 incident end-stage renal disease patients that started PD between January 2006 and 2015 were studied. Follow-up was 5 years with censoring at death or switch to another treatment modality. Cox regression models were used to calculate the association between glucose exposure, RRF, and peritonitis. Kaplan-Meier analysis was used to examine the difference in occurrence of peritonitis between patients with high and low glucose exposure and between those with and without residual diuresis. RESULTS: One hundred and five patients were followed for a mean of 23 months. Fifty-one patients developed a peritonitis. Cox regression models at 6 months showed that glucose exposure and not residual diuresis significantly predicted PD peritonitis. Kaplan-Meier analysis after 6 months of follow-up showed that time to first PD peritonitis was significantly longer in the low glucose exposure group. Similarly, patients with RRF had a significantly longer interval to first peritonitis compared to patients without RRF. CONCLUSION: A higher exposure to glucose rather than loss of RRF is associated with an increased risk of peritonitis. This confirms the detrimental effects of glycemic harm to the peritoneal host defense on invading microorganisms and argues for the use of the lowest PD glucose concentrations possible.

No increase in small-solute transport in peritoneal dialysis patients treated without hypertonic glucose for fifty-four months.

BACKGROUND: Glucose is widely used as an osmotic agent in peritoneal dialysis (PD), but exerts untoward effects on the peritoneum. The potential protective effect of a reduced exposure to hypertonic glucose has never been investigated. METHODS: The cohort of PD patients attending our center which tackled the challenge of a restricted use of hypertonic glucose solutions has been prospectively followed since 1992. Small-solute transport was assessed using an equivalent of the glucose peritoneal equilibration test after 6 months, and then every year. Study was stopped on July 1st, 2008, before use of biocompatible solutions. Repeated measures in patients treated with PD for 54 months were analyzed by using (1) the slopes of the linear regression for D4/D0 ratios over time computed for each individual, and (2) a linear mixed model. RESULTS: In the study period, 44 patients were treated for a total of 2376 months, 2058 without hypertonic glucose. There was one episode of peritoneal infection every 18 patient-months. The mean of slopes of the linear regression for D4/D0 ratios was found to be significantly positive (Student's test, p < .001) and the results of the mixed model reflected a similar significant increase for D4/D0 ratios over time. These results reflected a significant decrease of small-solute transport. CONCLUSION: In this large series, minimizing the use of hypertonic glucose solutions was associated in patients on long term PD with an overall decrease of small-solute transport within 54 months, despite a high rate of peritoneal infection.

Effects of incremental peritoneal dialysis with low glucose-degradation product neutral pH solution on clinical outcomes.

PURPOSE: Incremental peritoneal dialysis (IPD) could decrease unfavorable glucose exposure results and preserve (RKF). However, there is no standardization of dialysis prescriptions for patients undergoing IPD. We designed a prospective observational multi-center study with a standardized IPD prescription to evaluate the effect of IPD on RKF, metabolic alterations, blood pressure control, and adverse outcomes. METHODS: All patients used low GDP product (GDP) neutral pH solutions in both the incremental continuous ambulatory peritoneal dialysis (ICAPD) group and the retrospective standard PD (sPD) group. IPD patients started treatment with three daily exchanges five days a week. Control-group patients performed four changes per day, seven days a week. RESULTS: A total of 94 patients (47 IPD and 47 sPD) were included in this study. The small-solute clearance and mean blood pressures were similar between both groups during follow-up. The weekly mean glucose exposure was significantly higher in sPD group than IPD during the follow-up (p < 0.001). The patients with sPD required more phosphate-binding medications compared to the IPD group (p = 0.05). The rates of peritonitis, tunnel infection, and hospitalization frequencies were similar between groups. Patients in the sPD group experienced more episodes of hypervolemia compared to the IPD group (p = 0.007). The slope in RKF in the 6th month was significantly higher in the sPD group compared to the IPD group (65% vs. 95%, p = 0.001). CONCLUSION: IPD could be a rational dialysis method and provide non-inferior dialysis adequacy compared to full-dose PD. This regimen may contribute to preserving RKF for a longer period.

Dialysis Duration and Glucose Exposure Amount Do Not Increase Mortality Risk in Peritoneal Dialysis Patients: A Population-Based Cohort Study From 2004 to 2012.

Background: Although the bio-incompatibility of glucose-based peritoneal dialysis (PD) solution is well documented, it is used worldwide. How PD duration and the amount of dialyzate glucose exposure affect survival in patients with end-stage renal disease remain inconclusive due to improper study designs in the extant literature. Methods: All incident patients with PD from 2004 to 2007 who were older than 18 years in Taiwan were included. Patients were censored when they received a transplant or at the end of 2012. Glucose exposure through PD solution was calculated by the mean glucose contained per liter when receiving PD. For those who had already shifted to hemodialysis (HD) and survived longer than 2, 3, and 4 years (the index dates), the cause-specific Cox regression model was used to make the survival comparison by PD duration and mean glucose concentration in these three cohorts, respectively. The model was adjusted by demographics, case-mix, time cohort (2004-2005 vs. 2006-2007), peritonitis episode (none vs. ≥once), and mean PD solution glucose exposure (tertile). Results: A total of 3,226 patients were included, with a mean age of 53.4 ± 15.2 years, 44.6% being male, and 34.2% having diabetes mellitus. The 1, 2, 3, and 4-year survival rates were 94, 87, 80, and 74%, while technical survival rates were 86, 70, 56, and 45%, respectively. The overall transplant events were 309 (9.6%) only. There were 389, 495, and 553 incident patients with PD shifting to HD included in 2-, 3-, and 4-year cohort, respectively. The population with moderate glucose concentration exposure had the highest mortality, and the high glucose concentration exposure had non-significant lower mortality in each cohort. In various fixed time-window cohorts, the duration of PD treatment did not increase mortality risk after adjustments. In addition, glucose exposure did not affect the mortality rate. Conclusion: For incident PD patients with PD duration no longer than 4 years, neither PD duration nor glucose exposure amount increases the long-term mortality risk.

Relative Contributions of Pseudohypoxia and Inflammation to Peritoneal Alterations with Long-Term Peritoneal Dialysis Patients.

Long-term peritoneal dialysis is associated with alterations in peritoneal function, like the development of high small solute transfer rates and impaired ultrafiltration. Also, morphologic changes can develop, the most prominent being loss of mesothelium, vasculopathy, and interstitial fibrosis. Current research suggests peritoneal inflammation as the driving force for these alterations. In this review, the available evidence for inflammation is examined and a new hypothesis is put forward consisting of high glucose-induced pseudohypoxia. Hypoxia of cells is characterized by a high (oxidized-reduced nicotinamide dinucleotide ratio) NADH-NAD+ ratio in their cytosol. Pseudohypoxia is similar but occurs when excessive amounts of glucose are metabolized, as is the case for peritoneal interstitial cells in peritoneal dialysis. The glucose-induced high NADH-NAD+ ratio upregulates the hypoxia-inducible factor-1 gene, which stimulates not only the glucose transporter-1 gene but also many profibrotic genes like TGFß, vascular endothelial growth factor, plasminogen activator inhibitor-1, and connective tissue growth factor, all known to be involved in the development of peritoneal fibrosis. This review discusses the causes and consequences of pseudohypoxia in peritoneal dialysis and the available options for treatment and prevention. Reducing peritoneal exposure to the excessively high dialysate glucose load is the cornerstone to avoid the pseudohypoxia-induced alterations. This can partly be done by the use of icodextrin or by combinations of low molecular mass osmotic agents, all in a low dose. The addition of alanyl-glutamine to the dialysis solution needs further clinical investigation.

Clinical characteristics associated with the properties of gut microbiota in peritoneal dialysis patients.

BACKGROUND: Gut microbiota alters in patients with end-stage renal disease, which contributes to inflammation, atherosclerosis, and results in increased incidence of cardiovascular diseases. The present study investigated the potential clinical factors, which influence the gut microbial structure and function in patients undergoing peritoneal dialysis (PD). METHODS: This is a cross-sectional study performed in 81 prevalent PD patients. Gut microbiota was assessed by high throughput sequencing of 16S ribosomal ribonucleic acid gene in fecal samples. Gas chromatography was conducted to measure stool short-chain fat acid (SCFA) concentrations. Demographic parameters and clinical characteristics, including dialysis regimen, residual renal function, nutrition, and inflammation, were retrieved and related to the properties of gut microbiota. RESULTS: PD duration, peritoneal glucose exposure, and estimated glomerulus filtration rate (eGFR) were identified to be associated with microbial variations. Significant separation of microbial composition was shown between patients with short or long PD duration (p = 0.015) and marginal differences were found between patients grouped by different levels of peritoneal glucose exposure (p = 0.056) or residual renal function (p = 0.063). A couple of gut bacteria showed different abundance at amplicon sequencing variant level between these patient groups (p < 0.05). In addition, stool isobutyric and isovaleric acid concentrations were significantly reduced in patients with longer dialysis duration, higher peritoneal glucose exposure, or declined eGFR (p < 0.05). CONCLUSIONS: This pilot study demonstrated that long dialysis duration, high peritoneal glucose exposure, and loss of residual renal function were associated with gut microbiota alteration and reduced branched-chain SCFA production in PD patients.

High Glucose Concentrations Affect Band 3 Protein in Human Erythrocytes.

Hyperglycemia is considered a threat for cell homeostasis, as it is associated to oxidative stress (OS). As erythrocytes are continuously exposed to OS, this study was conceived to verify the impact of either diabetic conditions attested to by glycated hemoglobin (Hb) levels (>6.5% or higher) or treatment with high glucose (15-35 mM, for 24 h) on erythrocyte homeostasis. To this aim, anion exchange capability through the Band 3 protein (B3p) was monitored by the rate constant for SO42- uptake. Thiobarbituric acid reactive species (TBARS), membrane sulfhydryl groups mostly belonging to B3p, glutathione reduced (GSH) levels, and B3p expression levels were also evaluated. The rate constant for SO42- uptake (0.063 ± 0.001 min-1, 16 min in healthy volunteers) was accelerated in erythrocytes from diabetic volunteers (0.113 ± 0.001 min-1, 9 min) and after exposure to high glucose (0.129 ± 0.001in-1, 7 min), but only in diabetic volunteers was there an increase in TBARS levels and oxidation of membrane sulfhydryl groups, and a decrease in both GSH and B3p expression levels was observed. A combined effect due to the glycated Hb and OS may explain what was observed in diabetic erythrocytes, while in in vitro hyperglycemia, early OS could explain B3p anion exchange capability alterations as proven by the use of melatonin. Finally, measurement of B3p anion exchange capability is a suitable tool to monitor the impact of hyperglycemia on erythrocytes homeostasis, being the first line of high glucose impact before Hb glycation. Melatonin may be useful to counteract hyperglycemia-induced OS at the B3p level.

Association Between Peritoneal Glucose Exposure and Peritonitis in Peritoneal Dialysis Patients: The balANZ Trial.

BACKGROUND: Glucose is the primary osmotic medium used in most peritoneal dialysis (PD) solutions, and exposure to glucose has been shown to exert detrimental effects both locally, at the peritoneal membrane, and systemically. Moreover, high dialysate glucose exposure may predispose patients to an increased risk of peritonitis, perhaps as a result of impaired host defences, vascular disease, and damage to the peritoneal membrane. METHODS: In this post-hoc analysis of a multicenter, multinational, open-label randomized controlled trial of neutral pH, low-glucose degradation product (GDP) versus conventional PD solutions (balANZ trial), the relationship between peritonitis rates of low (< 123.1 g/day) versus high (≥ 123.1 g/day) dialysate glucose exposure was evaluated in 177 incident PD patients over a 2-year study period. RESULTS: Peritonitis rates were 0.44 episodes per patient-year in the low-glucose exposure group and 0.31 episodes per patient-year in the high-glucose exposure group, (incidence rate ratio [IRR] 0.69, p = 0.09). There was no significant association between dialysate glucose exposure and peritonitis-free survival on univariable analysis (high glucose exposure hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.40 - 1.08) or on multivariable analysis (adjusted HR 0.64, 95% CI 0.39 - 1.05). Moreover, there was no relationship between peritoneal glucose exposure and type of organism causing peritonitis. Physician-rated severity of first peritonitis episodes was similar between groups, as was rate and duration of hospital admission. CONCLUSIONS: Overall, this study did not identify an association between peritoneal dialysate glucose exposure and peritonitis occurrence, severity, hospitalization, or outcomes. A further large-scale, prospective, randomized controlled trial evaluating patient-level outcomes is merited.

Investigating physiological glucose excursions before, during, and after Ramadan in adults without diabetes mellitus.

AIM: The study aimed to investigate physiological effects of Ramadan fasting on continuously monitored glucose levels in relation to Ramadan in young non-diabetic adults. METHODS: Continuous glucose monitoring was employed to measure interstitial glucose for several days 1-2weeks before Ramadan, in the middle of Ramadan, and 4-6weeks after Ramadan to assess glucose exposure and glucose variability. RESULTS: A total of 34,182 accurate glucose sensor readings and 438 capillary blood glucose values [mean absolute difference median (interquartile range) 8.5 (6.9-11.1)%] were obtained from 18 non-diabetic adults [13 females; aged 24 (21-27) years; baseline body mass index 23.9 (20.6-28.9) kg/m2]. The continuous glucose monitoring profiles showed an increase in the hyperglycemic (above 140mg/dL) area under the curve after Ramadan compared to both before (P=0.004) and during Ramadan (P=0.003), along with an increased glucose variability after Ramadan (P=0.014). Both the area under the interstitial glucose concentration curve for the entire day and the average glucose were positively associated with body mass index during (P=0.004 and P=0.005, respectively) and after Ramadan (P=0.013 and P=0.01, respectively). Atypical continuous glucose patterns were recognized in 11% of subjects, distinguished by a prolonged increased glucose exposure, particularly in response to a meal. CONCLUSION: The time-point 4-6weeks after Ramadan was distinguished by greater glucose exposure and wider glucose variability that may reflect ongoing changes in insulin sensitivity in response to altering lifestyle patterns in non-diabetic young adults across the spectrum of body weight.

The Association Between Glucose Exposure and the Risk of Peritonitis in Peritoneal Dialysis Patients.

UNLABELLED: ♦ BACKGROUND AND OBJECTIVE: Little or no clinical evidence is available on the association between glucose exposure and peritoneal host defense in peritoneal dialysis (PD) patients. The objective of the present study was to quantify the exposure to glucose during the first year on PD and investigate the association with subsequent peritonitis. ♦ METHODS: We analyzed prospectively collected demographic and peritonitis data from incident adult PD patients between 1990 and 2010. For the present study, we conducted a review of both in- and outpatient medical records of all patients to obtain their day-to-day dialysis schemes during the first year on PD. From these data, the average exposure to glucose was quantified. The exposure was stratified into low- and high-glucose groups based on the median, analyzed per standard deviation and in quartiles. Cox proportional hazard models were used to calculate crude and adjusted hazard ratios (HRs) and 95% confidence intervals for the association between glucose exposure and peritonitis. Adjustments were made for age, sex, primary kidney disease, diabetes mellitus, Davies comorbidity score and the treatment period. ♦ RESULTS: In total, 230 patients were included in the study of whom 151 (66%) experienced a first peritonitis episode. The median follow-up time was 2.6 years (interquartile range [IQR]: 1.9 - 3.8) in the low-glucose group and 3.1 (IQR: 2.1 - 4.2) in the high-glucose group. After adjustment for confounding factors, no association between high glucose exposure and the risk of peritonitis was found (HR: 0.81; 0.55 - 1.17). No association was present when glucose exposure was analyzed per standard deviation (SD) (HR: 0.98; 0.79 - 1.21) or patient quartiles were applied. No association was identified between glucose exposure and severe peritonitis, Staphylococcus aureus peritonitis, or a peritonitis episode that lasted more than 14 days. ♦ CONCLUSIONS: Exposure to glucose is not associated with an increased risk of peritonitis. The equilibrium between glycemic harm to peritoneal host defense and detrimental effects of glucose on invading microorganisms may determine the susceptibility to peritoneal infection.

Postprandial and basal hyperglycaemia in type 2 diabetes: Contributions to overall glucose exposure and diabetic complications.

Both postprandial and fasting (basal) hyperglycaemia contribute to overall hyperglycaemia (ambient hyperglycaemia) in type 2 diabetes (T2D). Postprandial glucose is the main contributor in fairly well controlled individuals, whereas basal hyperglycaemia becomes the preponderant contributor in poorly controlled patients. A more generally acceptable description of the contribution of postprandial glucose is to simply say that the absolute impact of postprandial glucose to HbA1c remains constant at approximately 1% across the entire HbA1c spectrum of non-insulin-treated patients with T2D. While epidemiological and pathophysiological studies seem to indicate that excessive postprandial glucose excursions play a role in or are predictors of cardiovascular diseases, there is still currently a lack of clinical evidence that correcting post-meal hyperglycaemia can improve clinical outcomes. However, even in the absence of consensus, there are many reasons for thinking that excessive postprandial glucose might be an independent risk factor for diabetic complications as it contributes to both overall glucose exposure and glycaemic variability, especially in those who have HbA1c levels < 7.5-8%. Given that excessive glucose fluctuations from peaks to nadirs activate oxidative stress, it seems reasonable to consider that a key player in the pathogenesis of diabetic complications, according to the latest IDF guidelines, is post-meal glucose, thereby warranting its assessment and treatment when found at abnormally elevated levels. Nevertheless, healthcare professionals should bear in mind that targeting both post-meal and basal plasma glucose, giving equal consideration to both of them, is probably the best strategy for achieving optimal glycaemic control and thus preventing or reducing the risk of diabetic complications.

Effect of peritoneal dialysis on glycemic variability in patients with diabetes and its clinical implications / 中华临床营养杂志

Objective To compare glycemic profile between diabetic patients receiving peritoneal dialysis and diabetic patients with normal kidney function, and to investigate the impact of peritoneal dialysis on glycemic control through continuous glucose monitor system ( CGMS). Methods 19 diabetic patients with end-stage renal disease receiving regular peritoneal dialysis (DMPD group) and 8 patients with non-diabetic ne-phropathy receiving regular peritoneal dialysis ( PD group) were randomly selected and matched with 20 diabetic patients with normal kidney function (DM group) based on age, gender and 72 hours mean glucose. CGMS were applied on all patients for 72 hours. Glycemic variability parameters were compared among the three groups. Results Peritoneal transport function was positively correlated with mean glucose, glucose standard deviation and mean amplitude of glycemic excursion. Compared with PD group, multiple variation parameters, such as intraday glycemic standard deviation (P<0. 001), covariant efficiency (P=0. 009) and mean of daily difference (P=0. 043), were significantly lower in DMPD group. Though both DMPD and DM group exhibited profile as trough in wee hours and post-prandial hyperglycemia, DMPD had higher glycemic level in wee hours (P<0. 001). Conclusion Diabetic patients with end-stage renal disease receiving regular peritoneal dialysis have smaller glucose variability than diabetic patients with normal renal function.

The level of advanced oxidation protein products in serum is associated with dialysate glucose exposure dose in patients undergoing non-diabetic maintenance peritoneal dialysis / 实用医学杂志

Objective To investigate the association between the level of advanced oxidation protein products (AOPP) in serum and the dialysate glucose exposure dose in patients undergoing non-diabetic maintenance peritoneal dialysis (PD). Methods In this cross-sectional study, the levels of serum AOPP were measured in 192 non-diabetic PD patients. Based on the exposure dose of dialysate glucose , PD patients were assigned into the high-dose exposure and low-dose exposure groups. Serum C-reactive protein levels were also measured and the rates of cardio-vascular disease (CVD) were recorded in both groups. Results The levels of serum AOPP were higher in the high-dose exposure group, as compared with the low-dose exposure group [(78.7 ± 15.6) mmol/L vs. (71.7 ± 14.8) mmol/L, P = 0.003]. The serum C-reactive protein levels [4.6 (3.0-11.4) mg/L vs. 3.0 (2.2-5.3) mg/L, P < 0.001] and the rates of CVD (53.6% vs. 35.8%, P = 0.014) were also higher in the high-dose exposure group. After multivariate adjustment ,the level of serum AOPP was independently associated with dialysate glucose exposure dose (β = 0.157, P = 0.031) and duration of PD (β = 0.164, P =0.043). Conclusion The serum AOPP levels are associated with the dialysate glucose exposure doses in non-diabetic PD patients. Minimizing the glucose load might reduce the risk of developing CVD.