Acquired Decline in Ultrafiltration in Peritoneal Dialysis: The Role of Glucose

Ultrafiltration is essential in peritoneal dialysis (PD) for maintenance of euvolemia, making ultrafiltration insufficiency preferably called ultrafiltration failure—an important complication. The mechanisms of ultrafiltration and ultrafiltration failure are more complex than generally assumed, especially after long-term treatment. Initially, ultrafiltration failure is mainly explained by a large number of perfused peritoneal microvessels, leading to a rapid decline of the crystalloid osmotic gradient, thereby decreasing aquaporin-mediated free water transport. The contribution of peritoneal interstitial tissue to ultrafiltration failure is limited during the first few years of PD, but becomes more important in long-term PD due to the development of interstitial fibrosis, which mainly consists of myofibroblasts. A dual hypothesis has been developed to explain why the continuous exposure of peritoneal tissues to the extremely high dialysate glucose concentrations causes progressive ultrafiltration decline. First, glucose absorption causes an increase of the intracellular NADH/NAD+ ratio, also called pseudohypoxia. Intracellular hypoxia stimulates myofibroblasts to produce profibrotic and angiogenetic factors, as well as the glucose transporter GLUT-1. Second, the increased GLUT-1 expression by myofibroblasts increases glucose uptake in these cells, leading to a reduction of the osmotic gradient for ultrafiltration. Reduction of peritoneal glucose exposure to prevent this vicious circle is essential for high-quality long-term PD.

New Insights into the Physiology of Peritoneal Fluid Transport

10.1177/089686080802803s27 ◽

2008 ◽

Vol 28 (3_suppl) ◽

pp. 144-149

Author(s):

Raymond T. Krediet ◽

Annemieke M. Coester ◽

Alena Parikova ◽

Watske Smit ◽

Dirk G. Struijk

Keyword(s):

Water Transport ◽

Fluid Transport ◽

Free Water ◽

Osmotic Gradient ◽

Ultrafiltration Failure ◽

Ultra Filtration ◽

Relationship Of ◽

The Relationship

A review is given on the mechanisms of free water transport, the various methodologies for its measurement, its dependency on the osmotic gradient, and the assessment of osmotic conductance in individual patients. The importance of impaired free water transport in long-term ultra-filtration failure is discussed, relative to peritoneal solute transport status. Furthermore, the relationship of free water transport with locally released potassium is considered, together with a potential role of impaired K+ channel function with peritoneal alterations. Finally, the role of impaired osmotic conductance to glucose and its effects on free water transport in long-term patients with ultrafiltration failure is reviewed.

Overnight Mesothelial Cell Exfoliation: A Magic Tool for Predicting Future Ultrafiltration Failure in Patients on Continuous Ambulatory Peritoneal Dialysis

10.1177/089686080802803s21 ◽

2008 ◽

Vol 28 (3_suppl) ◽

pp. 107-113

Author(s):

Talerngsak Kanjanabuch ◽

Monchai Siribamrungwong ◽

Rungrote Khunprakant ◽

Sirigul Kanjanabuch ◽

Piyathida Jeungsmarn ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Continuous Ambulatory Peritoneal Dialysis ◽

Mesothelial Cell ◽

Mesothelial Cells ◽

Nutrition Status ◽

Continuous Exposure ◽

Peritoneal Membrane ◽

Dialysis Solution ◽

⋄ Background Continuous exposure of the peritoneal membrane to dialysis solutions during long-term dialysis results in mesothelial cell loss, peritoneal membrane damage, and thereby, ultrafiltration (UF) failure, a major determinant of mortality in patients on continuous ambulatory peritoneal dialysis (CAPD). Unfortunately, none of tests available today can predict long-term UF decline. Here, we propose a new tool to predict such a change. ⋄ Mesothelial cells from 8-hour overnight effluents (1.36% glucose dialysis solution) were harvested, co-stained with cytokeratin (a mesothelial marker) and TUNEL (an apoptotic marker), and were counted using flow cytometry in 48 patients recently started on CAPD. Adequacy of dialysis, UF, nutrition status, dialysate cancer antigen 125 (CA125), and a peritoneal equilibration test (3.86% glucose peritoneal dialysis solution) were simultaneously assessed and were reevaluated 1 year later. ⋄ Results The numbers of total and apoptotic mesothelial cells were 0.19 ± 0.19 million and 0.08 ± 0.12 million cells per bag, respectively. Both numbers correlated well with the levels of end dialysate–to–initial dialysate (D/D0) glucose, dialysate-to-plasma (D/P) creatinine, and sodium dipping. Notably, the counts of cells of both types in patients with diabetes or with high or high-average transport were significantly greater than the equivalent counts in nondiabetic patients or those with low or low-average transport. A cutoff of 0.06 million total mesothelial cells per bag had sensitivity of 1 and a specificity of 0.75 in predicting a further decline in D/D0 glucose and a sensitivity of 0.86 and a specificity of 0.63 to predict a further decline in UF over a 1-year period. In contrast, dialysate CA125 and other measured parameters had low predictive values. ⋄ Conclusions The greater the loss of exfoliated cells, the worse the expected decline in UF. The ability of a count of mesothelial cells to predict a future decline in UF warrants further investigation in clinical practice.

Peritoneal Glucose Exposure and Changes in Membrane Solute Transport with Time on Peritoneal Dialysis

Journal of the American Society of Nephrology ◽

10.1681/asn.v1251046 ◽

2001 ◽

Vol 12 (5) ◽

pp. 1046-1051 ◽

Cited By ~ 4

Author(s):

SIMON J. DAVIES ◽

LOUISE PHILLIPS ◽

PATRICK F. NAISH ◽

GAVIN I. RUSSELL

Keyword(s):

Renal Function ◽

Peritoneal Dialysis ◽

Solute Transport ◽

Residual Renal Function ◽

Causative Role ◽

Continuous Exposure ◽

Hypertonic Glucose ◽

Ultrafiltration Failure ◽

Glucose Exposure

Abstract. Peritoneal solute transport increases with time on treatment in a proportion of peritoneal dialysis (PD) patients, contributing to ultrafiltration failure. Continuous exposure of the peritoneum to hypertonic glucose solutions results in morphologic damage that may have a causative role in changes in peritoneal function. The purpose of this analysis was to establish whether increased exposure to glucose preceded changes in solute transport in a selected group of long-term PD patients. Peritoneal solute transport, residual renal function, peritonitis rate, and peritoneal exposure to glucose were recorded prospectively in a cohort of 303 patients at a single dialysis center. A subgroup of individuals, treated continuously for 5 yr, were identified and defined retrospectively as having either stable or increasing transport status. Of the 22 patients who were treated continuously for 5 yr, 13 had stable solute transport (solute transport at start, 0.67 [±0.1]; at 5 yr, 0.67 [±0.1]), whereas 9 had a sustained increase (solute transport at start, 0.56 [±0.08]; at 5 yr, 0.77 [±0.09]). Compared with the stable patients, those with increasing transport had earlier loss in residual renal function and were exposed to significantly more hypertonic glucose during the first 2 yr of treatment that preceded the increase in solute transport. This was associated with greater achieved ultrafiltration compensating for the reduced urinary volumes in these patients. Further increases in glucose exposure were observed as solute transport continued to rise. Peritonitis, including severity of infection and causative organism, was similar in both groups. In this selected group of long-term survivors on PD, an increase in solute transport with time was preceded by increased peritoneal exposure to hypertonic glucose. This is supportive evidence that hypertonic glucose may play a causative role in alterations in peritoneal membrane function.

The Difference in Causes of Early and Late Ultrafiltration Failure in Peritoneal Dialysis

10.1177/089686080502503s10 ◽

2005 ◽

Vol 25 (3_suppl) ◽

pp. 41-45 ◽

Cited By ~ 17

Author(s):

Watske Smit ◽

Alena Parikova ◽

Dirk G. Struijk ◽

Raymond T. Krediet

Keyword(s):

Peritoneal Dialysis ◽

Solute Transport ◽

Major Complication ◽

Transport Parameters ◽

Short Term ◽

Lymphatic Absorption ◽

Equal Distribution ◽

Long Term Treatment ◽

♦ Objective Ultrafiltration failure (UFF) is a major complication of peritoneal dialysis. Although it seems associated with long-term treatment, it can also occur in recently started patients. To identify the causes of this complication in patients with early and late UFF we studied a group of 48 patients. Patients were classified as early if they had been treated for less than 2 years and as late if they had been treated for more than 4 years. ♦ Method The patients were studied using a standard peritoneal permeability analysis. They all had a net ultrafiltration of less than 400 mL after a 4-hour dwell with 3.86% glucose. As possible causes for UFF, the solute transport parameters dialysate-to-plasma ratio (D/P) and mass transfer area coefficient of creatinine were compared, as well as the effective lymphatic absorption rate (ELAR) and the maximum dip in D/P sodium as an assessment of osmotic conductance to glucose. ♦ Results 25 short-term patients were compared with 23 long-term patients. Both groups showed an equal distribution of high small solute transport rates as a cause of UFF. The chi-square test showed that a high ELAR was a more frequent cause in early UFF compared to late UFF. However, a decreased osmotic conductance to glucose was significantly more often observed in late UFF. Some patients showed more than one cause of the complication. ♦ Conclusion This study has shown that UFF in long-term patients is often caused by a decreased osmotic conductance to glucose, most likely caused by a dysfunction of peritoneal water channels in combination with increased peritoneal surface area. In short-term patients, aquaporin dysfunction is rare, but a high ELAR was a very important factor in the occurrence of UFF.

Analysis of the Prevalence and Causes of Ultrafiltration Failure during Long-Term Peritoneal Dialysis: A Cross-Sectional Study

10.1177/089686080402400616 ◽

2004 ◽

Vol 24 (6) ◽

pp. 562-570 ◽

Cited By ~ 74

Author(s):

Watske Smit ◽

Natalie Schouten ◽

Nicole van den Berg ◽

Monique J. Langedijk ◽

Dirk G. Struijk ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Water Transport ◽

Cell Mass ◽

Mesothelial Cell ◽

Glucose Absorption ◽

Lymphatic Absorption ◽

Vascular Surface ◽

Long Term Treatment ◽

Background Ultrafiltration failure (UFF) is a major complication of peritoneal dialysis (PD). It can occur at any stage of PD, but develops in time and is, therefore, especially important in long-term treatment. To investigate its prevalence and to identify possible causes, we performed a multicenter study in The Netherlands, where patients treated with PD for more than 4 years were studied using a peritoneal function test (standard peritoneal permeability analysis) with 3.86% glucose. UFF was defined as net UF < 400 mL after a 4-hour dwell. Results 55 patients unselected for the presence or absence of UFF were analyzed. Mean age was 48 years (range 18 – 74 years); duration of PD ranged from 48 to 144 months (median 61 months); UFF was present in 20 patients (36%). Patients with and without UFF did not differ in age or duration of PD. Median values for patients with normal UF compared to patients with UFF were, for net UF 659 mL versus 120 mL ( p < 0.01), transcapillary UF rate 3.8 versus 2.1 mL/minute ( p < 0.01), effective lymphatic absorption 1.0 versus 1.6 mL/min ( p < 0.05), mass transfer area coefficient (MTAC) for creatinine 9.0 versus 12.9 mL/min ( p < 0.01), dialysate-to-plasma ratio (D/P) for creatinine 0.71 versus 0.86 ( p < 0.01), glucose absorption 60% versus 73% ( p < 0.01), maximum dip in D/P sodium (as a measure of free water transport) 0.109 versus 0.032 ( p < 0.01), and osmotic conductance to glucose 3.0 versus 2.1 μL/min/mmHg ( p < 0.05). As causes for UFF, high MTAC creatinine, defined as > 12.5 mL/min, or a glucose absorption > 72%, both reflecting a large vascular surface, a lymphatic absorption rate (LAR) of > 2.14 mL/min, and a decreased dip in D/P sodium of < 0.046 were identified. Most patients had a combination of causes (12 patients), whereas there was only a decreased dip in D/P sodium in 3 patients, only high MTAC creatinine in 1 patient, and only high LAR in 2 patients. We could not identify a cause in 2 patients. Both groups had similar clearances of serum proteins and peritoneal restriction coefficients. However, dialysate cancer antigen 125 concentrations, reflecting mesothelial cell mass, were lower in the UFF patients (2.79 vs 5.38 U/L). Conclusion The prevalence of UFF is high in long-term PD. It is caused mainly by a large vascular surface area and by impaired channel-mediated water transport. In addition, these patients also had signs of a reduced mesothelial cell mass, indicating damage of the peritoneum on both vascular and mesothelial sites.

Ultrafiltration Failure and Impaired Sodium Sieving during Long-Term Peritoneal Dialysis: More than Aquaporin Dysfunction?

10.3747/pdi.2015.00188 ◽

2016 ◽

Vol 36 (2) ◽

pp. 227-231 ◽

Cited By ~ 5

Author(s):

Johann Morelle ◽

Amadou Sow ◽

Nicolas Hautem ◽

Olivier Devuyst ◽

Eric Goffin

Keyword(s):

Peritoneal Dialysis ◽

Water Transport ◽

Free Water ◽

Peritoneal Fibrosis ◽

Osmotic Water ◽

Ultrafiltration Failure ◽

Normal Expression ◽

Initial Hypothesis ◽

Sodium Sieving

Fifteen years ago, our group reported the case of a 67-year-old man on peritoneal dialysis for 11 years, in whom ultrafiltration failure and impaired sodium sieving were associated with an apparently normal expression of aquaporin-1 (AQP1) water channels in peritoneal capillaries. At that time, AQP1 dysfunction was suggested as the cause of impaired free-water transport. However, recent data from computer simulations, and structural and functional analysis of the peritoneal membrane of patients with encapsulating peritoneal sclerosis, demonstrated that changes in the peritoneal interstitium directly alter osmotic water transport. In light of these insights, we challenge the initial hypothesis and provide several lines of evidence supporting the diagnosis of encapsulating peritoneal sclerosis in this patient and suggesting that severe peritoneal fibrosis accounted for the loss of osmotic conductance developed during the course of peritoneal dialysis.

Monitoring of Long-Term Peritoneal Membrane Function

10.1177/089686080102100222 ◽

2001 ◽

Vol 21 (2) ◽

pp. 225-232 ◽

Cited By ~ 12

Author(s):

Simon J. Davies

Keyword(s):

Peritoneal Dialysis ◽

Solute Transport ◽

Water Transport ◽

Drop Out ◽

Published Data ◽

Peritoneal Membrane ◽

Membrane Function ◽

Technique Survival ◽

Objective Peritoneal membrane function influences dialysis prescription and clinical outcome and may change with time on treatment. Increasingly sophisticated tools, ranging from the peritoneal equilibration test (PET) to the standard permeability analysis (SPA) and personal dialysis capacity (PDC) test, are available to the clinician and clinical researcher. These tests allow assessment of a number of aspects of membrane function, including solute transport rates, ultrafiltration capacity, effective reabsorption, transcellular water transport, and permeability to macromolecules. In considering which tests are of greatest value in monitoring long-term membrane function, two criteria were set: those that result in clinically relevant interpatient differences in achieved ultrafiltration or solute clearances, and those that change with time in treatment. Study Selection Clinical validation studies of the PET, SPA, and PDC tests. Studies reporting membrane function using these methods in either long-term (5 years) peritoneal dialysis patients or longitudinal observations (> 2 years). Data Extraction Directly from published data. Additional, previously unpublished analysis of data from the Stoke PD Study. Results Solute transport is the most important parameter. In addition to predicting patient and technique survival at baseline, there is strong evidence that it can increase with time on treatment. Whereas patients with initially high solute transport drop out early from treatment, those with low transport remain longer on treatment, although, over 5 years, a proportion develop increasing transport rates. Ultrafiltration capacity, while being a composite measure of membrane function, is a useful guide for the clinician. Using the PET (2.27% glucose), a net ultrafiltration capacity of < 200 mL is associated with a 50% chance of achieving less than 1 L daily ultrafiltration at the expense of 1.8 hypertonic (3.86%) exchanges in anuric patients. Using a SPA (3.86% glucose), a net ultrafiltration capacity of < 400 mL indicates ultrafiltration failure. While there is circumstantial evidence that, with time on peritoneal dialysis, loss of transcellular water transport might contribute to ultrafiltration failure, none of the current tests is able to demonstrate this unequivocally. Of the other membrane parameters, evidence that interpatient differences are clinically relevant (permeability to macro-molecules), or that they change significantly with time on treatment (effective reabsorption), is lacking. Conclusion A strong case can be made for the regular assessment by clinicians of solute transport and ultrafiltration capacity, a task made simple to achieve using any of the three tools available.

Different Cellular Response of Human Mesothelial Cell MeT-5A to Short-Term and Long-Term Multiwalled Carbon Nanotubes Exposure

BioMed Research International ◽

10.1155/2017/2747215 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Li Ju ◽

Wei Wu ◽

Min Yu ◽

Jianlin Lou ◽

Hao Wu ◽

...

Keyword(s):

Carbon Nanotubes ◽

Cell Motility ◽

Multiwalled Carbon Nanotubes ◽

Mesothelial Cell ◽

Continuous Exposure ◽

Short Term ◽

Multiwalled Carbon ◽

Long Term Treatment ◽

Human Mesothelial Cell

Despite being a commercially important product, multiwalled carbon nanotubes (MWCNTs) continue to raise concerns over human health due to their structural similarity to asbestos. Indeed, exposure to MWCNT has been shown to induce lung cancer and even mesothelioma, but contradictory results also exist. To clarify the potentially carcinogenic effects of rigid and rod-like MWCNT and to elucidate the underlying mechanisms, the effects of MWCNT on human mesothelial cell MeT-5A were examined throughout 3 months of continuous exposure, including cytotoxicity, genotoxicity, and cell motility. It was found that MWCNT did not affect MeT-5A cell proliferation at 10 μg/cm2 within 72 h treatment, but under the same condition, MWCNT induced genotoxicity and perturbed cell motility. In addition, MeT-5A cells demonstrated different cellular responses to MWCNT after short-term and long-term exposure. Taken together, our results indicated a possible carcinogenic potential for MWCNT after long-term treatment, in which Annexin family proteins might be involved.

Ultrafiltration Failure in Peritoneal Dialysis: A Pathophysiologic Approach

Blood Purification ◽

10.1159/000368972 ◽

2015 ◽

Vol 39 (1-3) ◽

pp. 70-73 ◽

Cited By ~ 18

Author(s):

Isaac Teitelbaum

Keyword(s):

Peritoneal Dialysis ◽

Surface Area ◽

Free Water ◽

Fluid Loss ◽

Free Water Clearance ◽

Peritoneal Surface ◽

Ultrafiltration Failure ◽

Rapid Transport ◽

Technique Failure ◽

Sodium Sieving

Background: Ultrafiltration failure is a significant cause of technique failure for peritoneal dialysis and subsequent transfer to hemodialysis. Summary: Ultrafiltration failure is defined as failure to achieve at least 400 ml of net ultrafiltration during a 4 h dwell using 4.25% dextrose. Four major causes of ultrafiltration failure have been described. A highly effective peritoneal surface area is characterized by transition to a very rapid transport state with D/P creatinine >0.81. Low osmotic conductance to glucose is characterized by attenuation of sodium sieving and decreased peritoneal free water clearance to <26% of total ultrafiltration in the first hour of a dwell. Low effective peritoneal surface area manifests with decreases in the transport of both solute and water. A high total peritoneal fluid loss rate is the most difficult to diagnose clinically; failure to achieve ultrafiltration with an 8-10 h icodextrin dwell may provide a clue to diagnosis. Key Messages: Knowledge of the specific pathophysiology of the various causes of ultrafiltration failure will aid in the diagnosis thereof.

Volume Stress-Induced Peritoneal Endothelin-1 Release in Continuous Ambulatory Peritoneal Dialysis

Journal of the American Society of Nephrology ◽

10.1681/asn.v10122585 ◽

1999 ◽

Vol 10 (12) ◽

pp. 2585-2590

Author(s):

STANISLAO MORGERA ◽

SIMONE KUCHINKE ◽

KLEMENS BUDDE ◽

ANDREAS LUN ◽

BERTHOLD HOCHER ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Continuous Ambulatory Peritoneal Dialysis ◽

Peritoneal Membrane ◽

Endothelin 1 ◽

Target Values ◽

Ultrafiltration Failure ◽

Significant Difference ◽

The Impact ◽

Volume Stress

Abstract. In long-term peritoneal dialysis, functional deterioration of the peritoneal membrane is often associated with proliferative processes of the involved tissues leading to peritoneal fibrosis. In continuous ambulatory peritoneal dialysis (CAPD), failure to achieve target values for adequacy of dialysis is commonly corrected by increasing dwell volume; in case of ultrafiltration failure, osmolarity of the dialysate gets increased. In a prospective study, the impact of increasing dwell volume from 1500 ml to 2500 ml per dwell (volume trial) or changing the osmolarity of the dialysate from 1.36 to 3.86% glucose (hyperosmolarity trial) on the peritoneal endothelin-1 (ET-1) release was analyzed. ET-1 is known to exert significant proliferative activities on a variety of cell types leading to an accumulation of extracellular matrix. A highly significant difference in the cumulative peritoneal ET-1 synthesis was found between the low- and high-volume exchange, whereas differences in the hyperosmolarity setting were only moderate. Sixty minutes after initiating dialysis, the cumulative ET-1 synthesis was 2367 ± 1023 fmol for the 1500 ml versus 6062 ± 1419 fmol for the 2500 dwell (P < 0.0001) and 4572 ± 969 fmol versus 6124 ± 1473 fmol for the 1.36 and 3.86% glucose dwell (P < 0.05), respectively. In conclusion, increasing dwell volume leads to a strong activation of the peritoneal paracrine endothelin system. Because ET-1, apart from being a potent vasoactive peptide, contributes to fibrotic remodeling, this study indicates that volume stress-induced ET-1 release might contribute to structural alteration of the peritoneal membrane in long-term peritoneal dialysis.