Peritoneal Protein Loss With Time in Peritoneal Dialysis.

Longitudinal evolution of peritoneal protein loss (PPL), a reflection of hydrostatic pressure-driven leak of plasma proteins through the large-pore pathway, is not clear. Time on PD causes loss of mesothelial cells, vasculopathy, and increased thickness of the submesothelial fibrous layer. Are these structural changes associated with progressive increase of PPL, in a parallel with the rise in the D/P creatinine? The aim of the present study was to identify longitudinal changes of PPL over time. This single-center, longitudinal study included 52 peritoneal dialysis (PD) patients with a median follow-up of 26.5 months, evaluated at two different time points with a minimum interval of 6 months. Repeated measures analysis was performed using paired sample t-test or the nonparametric Wilcoxon signed-rank test, depending on the distribution. After a median interval of 15.5 months, lower levels of residual renal function and urine volume, lower Kt/V, and creatinine clearance were found. D/P creatinine and PPL were stable, but a decrease in ultrafiltration was present. Systemic inflammation, nutrition, and volume overload showed no significant change with time on PD. Analysis of a subpopulation with over 48 months between initial and subsequential assessment (n = 11) showed again no difference in inflammation, nutritional and hydration parameters from baseline, but importantly PPL decreased after more than 4 years on PD (mean difference 1.2 g/24, p = 0.033). D/P creatinine and dip of sodium remained unchanged. The absence of deleterious effects of time on PD is reassuring, pointing to the benefit of updated PD prescription, including the standard use of more biocompatible solutions towards membrane preservation and adjusted prescription avoiding overhydration and inflammation while maintaining nutritional status. After controlling for confounders, PPL may act as a biomarker of acquired venous vasculopathy, even if small pore fluid transport rates and free water transport are preserved.

Glucose-induced pseudohypoxia and advanced glycosylation end products explain peritoneal damage in long-term peritoneal dialysis.

Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is the most important functional change, and peritoneal fibrosis is the major morphological alteration. Both are caused by the continuous exposure to dialysis solutions that are different from plasma water with regard to the buffer substance and the extremely high-glucose concentrations. Glucose has been incriminated as the major cause of long-term peritoneal membrane changes, but the precise mechanism has not been identified. We argue that glucose causes the membrane alterations by peritoneal pseudohypoxia and by the formation of advanced glycosylation end products (AGEs). After a summary of UF kinetics including the role of glucose transporters (GLUT), and a discussion on morphologic alterations, relationships between function and morphology and a survey of the pathogenesis of UF failure (UFF), it will be argued that impaired UF is partly caused by a reduction in small pore fluid transport as a consequence of AGE-related vasculopathy and - more importantly - in diminished free water transport due to pseudohypoxia, caused by increased peritoneal cellular expression of GLUT-1. The metabolism of intracellular glucose will be reviewed. This occurs in the glycolysis and in the polyol/sorbitol pathway, the latter is activated in case of a large supply. In both pathways the ratio between the reduced and oxidised form of nicotinamide dinucleotide (NADH/NAD+ ratio) will increase, especially because normal compensatory mechanisms may be impaired, and activate expression of hypoxia-inducible factor-1 (HIF-1). The latter gene activates various profibrotic factors and GLUT-1. Besides replacement of glucose as an osmotic agent, medical treatment/prevention is currently limited to tamoxifen and possibly Renin/angiotensis/aldosteron (RAA) inhibitors.

Low immunoglobulin G concentrations are not associated with an increased risk of peritoneal dialysis-related peritonitis.

BACKGROUND: Peritonitis is a common and severe complication of peritoneal dialysis (PD) and is associated with high morbidity and sometimes also with mortality. Identification of risk factors, as well as protective mechanisms for peritonitis, is important to reduce peritonitis-induced morbidity. According to the current literature, IgG concentrations might be associated with peritonitis in PD-treated patients. In this study, we aimed to investigate possible associations between dialysate or serum IgG concentration and peritonitis risk in a longitudinal cohort of PD-treated patients. MATERIALS AND METHODS: We analyzed prospectively collected data obtained during the first standard peritoneal permeability analysis (SPA), performed in incident PD patients, aged > 18 years who started PD treatment in our tertiary-care university hospital from January 1, 1994 until December 31, 2008. Patients were divided in groups according to dialysate or serum IgG concentrations and according to peritonitis incidence. A possible association between low dialysate or serum IgG concentrations and time to the first peritonitis episode was investigated using cox proportional hazard models. RESULTS: 120 patients were included in our analyses with a median follow-up time of 36 (16 - 92) months. No significant association between dialysate, nor serum IgG and time to peritonitis was found (HR 0.27 (95% CI 0.65 - 1.62), p = 0.911 and HR 0.87 (95% CI 0.70 - 1.68), p = 0.708, respectively). Moreover, IgG concentrations were not associated with peritonitis incidence, nor with the recurrence of peritonitis. Finally, we found no significant difference in dialysate or serum IgG concentrations between patients who remained peritonitis-free (58.0 ± 35.6 mg/L in dialysate, 11.1 ± 4.4 g/L in serum), and those who experienced a peritonitis episode during follow-up (59.5 ± 41.9 mg/L in dialysate, 10.3 ± 4.3 g/L in serum), respectively. CONCLUSION: Dialysate or serum IgG are not major determinants of local peritoneal defense against peritonitis.

Corrigendum: Aging of the Peritoneal Dialysis Membrane.

[This corrects the article DOI: 10.3389/fphys.2022.885802.].

Aging of the Peritoneal Dialysis Membrane.

Long-term peritoneal dialysis as currently performed, causes structural and functional alterations of the peritoneal dialysis membrane. This decay is brought about by the continuous exposure to commercially available glucose-based dialysis solutions. This review summarizes our knowledge on the peritoneum in the initial phase of PD, during the first 2 years and the alterations in function and morphology in long-term PD patients. The pseudohypoxia hypothesis is discussed and how this glucose-induced condition can be used to explain all peritoneal alterations in long-term PD patients. Special attention is paid to the upregulation of hypoxia inducing factor-1 and the subsequent stimulation of the genes coding for glucose transporter-1 (GLUT-1) and the growth factors transforming growth factor-ß (TGFß), vascular endothelial growth factor (VEGF), plasminogen growth factor activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF). It is argued that increased pseudohypoxia-induced expression of GLUT-1 in interstitial fibroblasts is the key factor in a vicious circle that augments ultrafiltration failure. The practical use of the protein transcripts of the upregulated growth factors in peritoneal dialysis effluent is considered. The available and developing options for prevention and treatment are examined. It is concluded that low glucose degradation products/neutral pH, bicarbonate buffered solutions with a combination of various osmotic agents all in low concentration, are currently the best achievable options, while other accompanying measures like the use of RAAS inhibitors and tamoxifen may be valuable. Emerging developments include the addition of alanyl glutamine to the dialysis solution and perhaps the use of nicotinamide mononucleotide, available as nutritional supplement.

Assessment of the size selectivity of peritoneal permeability by the restriction coefficient to protein transport.

Transport of serum proteins from the circulation to peritoneal dialysate in peritoneal dialysis patients mainly focused on total protein. Individual proteins have hardly been studied. We determined serum and effluent concentrations of four individual proteins with a wide molecular weight range routinely in the standardised peritoneal permeability analysis performed yearly in all participating patients. These include ß2-microglobulin, albumin, immunoglobulin G and α2-macroglobulin. The dependency of transport of these proteins on their molecular weight and diffusion coefficient led to the development of the peritoneal protein restriction coefficient (PPRC), which is the slope of the relation between the peritoneal clearances of these proteins and their free diffusion coefficients in water, when plotted on a double logarithmic scale. The higher the PPRC, the more size restriction to transport. In this review, we discuss the results obtained on the PPRC under various conditions, such as effects of various osmotic agents, vasoactive drugs, peritonitis and the hydrostatic pressure gradient. Long-term follow-up of patients shows an increase of the PPRC, the possible causes of which are discussed. Venous vasculopathy of the peritoneal microcirculation is the most likely explanation.

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.

Do low GDP neutral pH solutions prevent or retard peritoneal membrane alterations in long-term peritoneal dialysis?

Several studies have been published in the last decade on the effects of low glucose degradation product (GDP) neutral pH (L-GDP/N-pH) dialysis solutions on peritoneal morphology and function during the long-term PD treatment. Compared to conventional solutions, the impact of these solutions on the morphological and functional alterations of the peritoneal membrane is discussed, including those of effluent proteins that reflect the status of peritoneal tissues. Long-term PD with conventional solutions is associated with the loss of mesothelium, submesothelial and interstitial fibrosis, vasculopathy, and deposition of advanced glycosylation end products (AGEs). L-GDP/N-pH solutions mitigate these alterations, although vasculopathy and AGE deposition are still present. Increased vascular density was found in some studies. Small solute transport increases with PD duration on conventional solutions. Initially, higher values are present on L-GDP/N-pH treatment, but these may be reversible and remain stable with PD duration. Consequently, ultrafiltration (UF) is lower initially but remains stable thereafter. At 5 years, UF and small pore fluid transport are higher, while free water transport decreased only slightly during follow-up. Cancer antigen 125 was initially higher on L-GDP/N-pH solutions, suggesting better mesothelial preservation but decreased during follow-up. Therefore, L-GDP/N-pH solutions may not prevent but reduce and retard the peritoneal alterations induced by continuous exposure to glucose-based dialysis fluids.

AQP1 Promoter Variant, Water Transport, and Outcomes in Peritoneal Dialysis.

BACKGROUND: Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability. METHODS: We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies. RESULTS: The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P = 0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P = 0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P = 0.001), as well as a higher risk of death from any cause (24% vs. 15%, P = 0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant. CONCLUSIONS: A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis. (Funded by the Swiss National Science Foundation and others.).

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, and 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.

Overhydration May Be the Missing Link between Peritoneal Protein Clearance and Mortality.

INTRODUCTION: Peritoneal protein loss (PPL) has been associated with mortality. Inflammation was assumed a putative cause with malnutrition as a consequence. Hydrostatic convection is a major drive for microvascular protein transport, but most studies in peritoneal dialysis (PD) patients overlooked this mechanism. An association between peritoneal protein clearance (PPCl) and venous congestion has been reported recently. The aim of this study was to explore the importance of fluid overload in PPCl in PD. METHODS: Sixty-seven prevalent PD patients were assessed with peritoneal equilibration test and multifrequency bioelectrical impedance assessment (BIA). PPL and PPCl were calculated from simultaneously obtained 24-h peritoneal effluent. RESULTS: PPL averaged 5.2 g/24 h. It was higher in patients on continuous treatment than in those without a long dwell. Significant associations between PPCl and BIA parameters of overhydration were found in both univariable and multivariable analyses. Lean mass index, partly dependent on hydration status, was associated with PPCl in univariable but not in multivariable analysis. A multiple linear model identified extracellular water excess and higher D/P creatinine as predictors of higher PPCl, independent of PD duration, type of PD, age, gender, albumin, cardiovascular disease, C-reactive protein, or lean mass index. CONCLUSIONS: The uni- and multivariable strong associations between fluid overload and PPCl support the importance of hydrostatic pressure-induced convection for PPCl. Also, peritoneal small solute transport was associated with PPCl. Both are amenable by adjusted dialysis prescription, especially focused on fluid status and avoidance of overhydration. The assumption of an association with inflammation and malnutrition was not confirmed.

Peritoneal dialysis induces alterations in the transcriptome of peritoneal cells before detectible peritoneal functional changes.

Long-term peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane. Inflammation may be the key moment, and, consequently, fibrosis may be the end result of chronic inflammatory reaction. The objective of the present study was to identify genes involved in peritoneal alterations during PD by comparing the transcriptome of peritoneal cells in patients with short- and long-term PD. Peritoneal effluent of the long dwell of patients with stable PD was centrifuged to obtain peritoneal cells. The gene expression profiles of peritoneal cells using microarray between patients with short- and long-term PD were compared. Based on microarray analysis, 31 genes for quantitative RT-PCR validation were chosen. A 4-h peritoneal equilibration test was performed on the day after the long dwell. Transport parameters and protein appearance rates were assessed. Genes involved in the immune system process, immune response, cell activation, and leukocyte and lymphocyte activation were found to be substantially upregulated in the long-term group. Quantitative RT-PCR validation showed higher expression of CD24, lymphocyte antigen 9 (LY9), TNF factor receptor superfamily member 4 (TNFRSF4), Ig associated-α (CD79A), chemokine (C-C motif) receptor 7 (CCR7), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and IL-2 receptor-α (IL2RA) in patients with long-term PD, with CD24 having the best discrimination ability between short- and long-term treatment. A relationship between CD24 expression and genes for collagen and matrix formation was shown. Activation of CD24 provoked by pseudohypoxia due to extremely high glucose concentrations in dialysis solutions might play the key role in the development of peritoneal membrane alterations.

Relationships Between Peritoneal Protein Clearance and Parameters of Fluid Status Agree with Clinical Observations in Other Diseases that Venous Congestion Increases Microvascular Protein Escape.

BACKGROUND: Peritoneal effluent from peritoneal dialysis (PD) patients contains proteins, mainly transported from the circulation through large pores in the venular part of the peritoneal microvessels. Hydrostatic convection is the major driver for peritoneal protein transport, although in PD there is additional diffusion. Consequently, venous pressure may have a role in peritoneal protein transport. The aim of the study was to investigate the importance of venous congestion on the magnitude of peritoneal protein clearance in incident PD patients using non-invasive measurements. METHODS: A total of 316 adult PD patients, on PD for 8 - 12 weeks and collecting 24-hour urine and dialysate for total protein determination, underwent standard peritoneal equilibration testing (PET) along with measurement of N terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), multifrequency bioimpedance analysis, and a transthoracic echocardiogram. RESULTS: Statistically significant univariate relationships for peritoneal protein clearance with a Spearman correlation coefficient > 0.25 were present for 4-hour dialysate/plasma (D/P) creatinine, NT-proBNP, extracellular/total body water, extracellular water excess, left ventricular mass, and right atrial area. Negative correlations were found with serum total protein and residual renal function. On multivariate analysis, logNTproBNP (ß 0.11, p = 0.007) and right atrial area (ß 0.01, p = 0.03) were significant independent predictors of peritoneal protein clearance. CONCLUSION: Indicators of venous congestion showed the most important relationships with peritoneal protein clearance. These indicators have not been assessed in previous studies on the presence or absence of relationships between peritoneal protein clearance and mortality.

Development and Validation of Residual Kidney Function Estimating Equations in Dialysis Patients.

RATIONALE & OBJECTIVE: Measurement of residual kidney function is recommended for the adjustment of the dialysis prescription, but timed urine collections are difficult and prone to errors. Equations to calculate residual kidney function from serum concentrations of endogenous filtration markers and demographic parameters would simplify monitoring of residual kidney function. However, few equations to estimate residual kidney function using serum concentrations of small solutes and low-molecular-weight proteins have been developed and externally validated. STUDY DESIGN: Study of diagnostic test accuracy. SETTING & PARTICIPANTS: 823 Chinese peritoneal dialysis (PD) patients (development cohort) and 826 PD and hemodialysis patients from the Netherlands NECOSAD study (validation cohort). TESTS COMPARED: Equations to estimate residual kidney function (estimated clearance [eCl]) using serum creatinine, urea nitrogen, cystatin C, ß2-microglobulin (B2M), ß-trace protein (BTP), and combinations, as well as demographic variables (age, sex, height, and weight). Equations were developed using multivariable linear regression analysis in the development cohort and then tested in the validation cohort. Equations were compared with published validated equations. OUTCOMES: Residual kidney function measured as urinary clearance (mCl) of urea nitrogen (mClUN) and average of creatinine and urea nitrogen clearance (mClUN-cr). RESULTS: In external validation, bias (difference between mCl and eCl) was within ± 1.0 unit for all equations. Accuracy (percent of differences within ± 2.0 units) was significantly better for eClBTP, eClB2M, and eClBTP-B2M than eClUN-cr for both mClUN (78%, 80%, and 81% vs 72%; P < 0.05 for all) and mClUN-cr (72%, 78%, and 79% vs 68%; P < 0.05 for all). The area under the curve for predicting mClUN > 2.0 mL/min was highest for eClB2M (0.853) and eClBTP-B2M (0.848). Results were similar for other validated equations. LIMITATIONS: Development cohort only consisted of PD patients, no gold-standard method for residual kidney function measurement. CONCLUSIONS: These results confirm the validity and extend the generalizability of residual kidney function estimating equations from serum concentrations of low-molecular-weight proteins without urine collection.

Early Detection of Imminent Encapsulating Peritoneal Sclerosis: Free Water Transport, Selected Effluent Proteins, or Both?

BACKGROUND: No diagnostic tool or methodology is currently available for early detection of imminent encapsulating peritoneal sclerosis (EPS). The objective of this study was to investigate the predictive value of free water transport (FWT) and construct a panel of peritoneal effluent proteins for EPS alone or in combination with FWT. These parameters could be incorporated in the follow-up of peritoneal dialysis (PD) patients. METHODS: A case-control study, nested in a longitudinal PD patient cohort, was conducted. Time-specific areas under the receiver operating characteristic (ROC) curve were calculated for FWT and effluent biomarkers at a lag time up to 3 years before EPS diagnosis. Free water transport was combined with appearance rates (AR) of biomarkers to assess their clinical validity. RESULTS: Free water transport volume and AR of effluent biomarkers were investigated in 11 EPS patients and 34 long-term PD patients. Diagnostic performance was best for FWT (area under the curve [AUC] 0.94) followed by plasminogen activator inhibitor (PAI-1) AR. Throughout, diagnostic panels of FWT and AR of cancer antigen 125 (CA125), interleukin-6 (IL-6), or (PAI-1) yielded specificity estimates above 84%. The combination of FWT and PAI-1 AR identified the largest proportion of EPS patients at 1 year prior to diagnosis (sensitivity 100%, specificity 94%). CONCLUSION: Measurement of FWT is simple and has the highest predictive value for imminent EPS. The addition of effluent biomarkers provides an all-round insight into the state of the peritoneum. Our data indicate that combining FWT with either PAI-1, CA125, or IL-6 has the highest specificity. This is required to avoid unnecessary discontinuation of PD treatment.

Peritoneal vasculopathy in the pathophysiology of long-term ultrafiltration failure: A hypothesis based on clinical observations
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Ultrafiltration failure in long-term peritoneal dialysis patients is a well-known and important, but poorly-explained complication of the treatment. Transcapillary ultrafiltration consists mainly of small-pore fluid transport and partly of free-water transport. The former is to a large extent dependent on the hydrostatic pressure gradient and on the number of perfused peritoneal microvessels. Free-water transport depends mainly on the crystalloid osmotic gradient. A longitudinal analysis of peritoneal transport has shown a dramatic decrease of net ultrafiltration and small-pore fluid transport after 4 years of peritoneal dialysis. It will be argued that in contrast to common belief, a decrease of osmotically induced water transport cannot be the major contributor to long-term ultrafiltration failure. By exclusion of potential alternatives, the presence of vasculopathy in the peritoneal microcirculation is the most likely explanation. The resulting narrowing of vascular lumina will decrease the hydrostatic pressure gradient and thereby small-pore fluid transport and net ultrafiltration. Deposition of advanced glycosylation end products in peritoneal vessels may be important in the development of vasculopathy. This hypothesis is supported by morphological and functional results of dialysis with "biocompatible" solutions.
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Ultrafiltration Failure Is a Reflection of Peritoneal Alterations in Patients Treated With Peritoneal Dialysis.

Ultrafiltration (UF) failure is a common and important complication of peritoneal dialysis (PD), especially in long-term patients without residual urine production, because it often causes overhydration, which is an important cause of death in this population. The current review provides an overview of the pathways of peritoneal fluid transport, followed by the mechanisms and causes of UF failure. The egression of circulating fluid to the tissue compartment and its subsequent re-uptake by the colloid osmotic pressure are markedly influenced by PD, because the dialysis solutions contain glucose as a low molecular weight agent causing removal of fluid from the circulation by crystalloid osmosis. Pores involved in transcapillary UF consist of inter-endothelial small pores and the intra-endothelial water channel aquaporin-1. The former allows transport of plasma fluid with dissolved low molecular weight solutes and accounts for 60% of the filtered volume, the latter transports 40% as pure water. This free water transport (FWT) is driven by the crystalloid pressure gradient, while small pore fluid transport (SPFT) is dependent on both hydrostatic and crystalloid osmotic pressure. The number of perfused peritoneal microvessels as assessed by small solute transport parameters, is differently associated with UF: a positive relationship is present with SPFT, but a negative one with FWT, because the effect of more vessels is counteracted by a faster disappearance rate of glucose. Ultrafiltration failure can be present shortly after the start of PD, for instance due to mesothelial-to-mesenchymal transition. Late UF failure develops in 21% of long-term patients. Both FWT and SPFT can be affected. Patients with encapsulating peritoneal sclerosis have severely impaired FWT, probably due to interference of interstitial collagen-1 with the crystalloid osmotic gradient. This mechanism may also apply to other patients with reduced FWT. Those with mainly impaired SPFT likely have a reduced hydrostatic filtration pressure due to vasculopathy. Deposition of advanced glycosylation end products is probably important in the development of this vasculopathy. It can be concluded that long-term UF failure may affect both SPFT and FWT. Vasculopathy is important in the former, interstitial fibrosis in the latter. Measurements of peritoneal transport function should include separate assessments of small pore-and FWT.

Prediction models for the mortality risk in chronic dialysis patients: a systematic review and independent external validation study.

OBJECTIVE: In medicine, many more prediction models have been developed than are implemented or used in clinical practice. These models cannot be recommended for clinical use before external validity is established. Though various models to predict mortality in dialysis patients have been published, very few have been validated and none are used in routine clinical practice. The aim of the current study was to identify existing models for predicting mortality in dialysis patients through a review and subsequently to externally validate these models in the same large independent patient cohort, in order to assess and compare their predictive capacities. METHODS: A systematic review was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. To account for missing data, multiple imputation was performed. The original prediction formulae were extracted from selected studies. The probability of death per model was calculated for each individual within the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD). The predictive performance of the models was assessed based on their discrimination and calibration. RESULTS: In total, 16 articles were included in the systematic review. External validation was performed in 1,943 dialysis patients from NECOSAD for a total of seven models. The models performed moderately to well in terms of discrimination, with C-statistics ranging from 0.710 (interquartile range 0.708-0.711) to 0.752 (interquartile range 0.750-0.753) for a time frame of 1 year. According to the calibration, most models overestimated the probability of death. CONCLUSION: Overall, the performance of the models was poorer in the external validation than in the original population, affirming the importance of external validation. Floege et al's models showed the highest predictive performance. The present study is a step forward in the use of a prediction model as a useful tool for nephrologists, using evidence-based medicine that combines individual clinical expertise, patients' choices, and the best available external evidence.

Effect of glomerular filtration rate at dialysis initiation on survival in patients with advanced chronic kidney disease: what is the effect of lead-time bias?

PURPOSE: Current clinical guidelines recommend to initiate dialysis in the presence of symptoms or signs attributable to kidney failure, often with a glomerular filtration rate (GFR) of 5-10 mL/min/1.73 m2. Little evidence exists about the optimal kidney function to start dialysis. Thus far, most observational studies have been limited by lead-time bias. Only a few studies have accounted for lead-time bias, and showed contradictory results. We examined the effect of GFR at dialysis initiation on survival in chronic kidney disease patients, and the role of lead-time bias therein. We used both kidney function based on 24-hour urine collection (measured GFR [mGFR]) and estimated GFR (eGFR). MATERIALS AND METHODS: A total of 1,143 patients with eGFR data at dialysis initiation and 852 patients with mGFR data were included from the NECOSAD cohort. Cox regression was used to adjust for potential confounders. To examine the effect of lead-time bias, survival was counted from the time of dialysis initiation or from a common starting point (GFR 20 mL/min/1.73 m2), using linear interpolation models. RESULTS: Without lead-time correction, no difference between early and late starters was present based on eGFR (hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.81-1.3). However, after lead-time correction, early initiation showed a survival disadvantage (HR between 1.1 [95% CI 0.82-1.48] and 1.33 [95% CI 1.05-1.68]). Based on mGFR, the potential survival benefit for early starters without lead-time correction (HR 0.8, 95% CI 0.62-1.03) completely disappeared after lead-time correction (HR between 0.94 [95% CI 0.65-1.34] and 1.21 [95% CI 0.95-1.56]). Dialysis start time differed about a year between early and late initiation. CONCLUSION: Lead-time bias is not only a methodological problem but also has clinical impact when assessing the optimal kidney function to start dialysis. Therefore, lead-time bias is extremely important to correct for. Taking account of lead-time bias, this controlled study showed that early dialysis initiation (eGFR >7.9, mGFR >6.6 mL/min/1.73 m2) was not associated with an improvement in survival. Based on kidney function, this study suggests that in some patients, dialysis could be started even later than an eGFR <5.7 and mGFR <4.3 mL/min/1.73 m2.