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Background: In end-stage renal disease patients treated with peritoneal dialysis (PD), the osmotic conductance to glucose (OCG) represents the intrinsic ability of the membrane to transport water in response to a crystalloid osmotic gradient. A progressive loss of OCG in long-term PD patients indicates the development of fibrosis in the peritoneal interstitium, and helps identify patients at risk for encapsulating peritoneal sclerosis. The double mini-peritoneal equilibration test (PET) has been proposed as a simple method to assess OCG using the difference in initial ultrafiltration rates generated by 2 successive dwells using 1.36% and 3.86% glucose-based, 1-h PET. However, the presence of a large peritoneal residual volume (RV) may potentially interfere with the correct evaluation of drained volumes, limiting the reliability of OCG assessed by the double mini-PET., Methods: We retrospectively reviewed data from 53 peritoneal function tests in 35 consecutive PD patients starting PD at our center between March 2013 and March 2017. The test consisted of a uni-PET (double mini-PET combined with a 3.86%, 4-h PET) performed at PD start, then yearly. In addition to peritoneal solute transport rate and net ultrafiltration, the tests provided information about osmotic water transport (OCG, sodium sieving, and free-water transport) as well as the RV estimated from albumin dilution., Results: Contrary to sodium sieving, net ultrafiltration, and free-water transport, OCG did not correlate with any of the other parameters of osmotic water transport. In multivariate regression analyses, the RV was identified as the only determinant of OCG, while it did not alter the robust association between sodium sieving/free-water transport and their respective determinants. Considering only baseline tests or the whole series of tests, the presence of a large intraperitoneal RV was associated with discrepant values between OCG and sodium sieving, and with an artificial increase in OCG., Conclusions: A large RV leads to significant overestimation of OCG using the double mini-PET, potentially reducing the ability of OCG to identify patients with progressive fibrosis in the peritoneal interstitium. On the other hand, sieving of the dialysate sodium, a biochemical surrogate for OCG, is independent of the RV and may therefore be more reliable. A call for caution is warranted in patients with a large RV to avoid misinterpretation of OCG values derived from the double mini-PET., (Copyright © 2018 International Society for Peritoneal Dialysis.)

Background Osmosis drives transcapillary ultrafiltration and water removal in patients treated with peritoneal dialysis. Crystalloid osmosis, typically induced by glucose, relies on dialysate tonicity and occurs through endothelial aquaporin-1 water channels and interendothelial clefts. In contrast, the mechanisms mediating water flow driven by colloidal agents, such as icodextrin, and combinations of osmotic agents have not been evaluated. Methods We used experimental models of peritoneal dialysis in mouse and biophysical studies combined with mathematical modeling to evaluate the mechanisms of colloid versus crystalloid osmosis across the peritoneal membrane and to investigate the pathways mediating water flow generated by the glucose polymer icodextrin. Results In silico modeling and in vivo studies showed that deletion of aquaporin-1 did not influence osmotic water transport induced by icodextrin but did affect that induced by crystalloid agents. Water flow induced by icodextrin was dependent upon the presence of large, colloidal fractions, with a reflection coefficient close to unity, a low diffusion capacity, and a minimal effect on dialysate osmolality. Combining crystalloid and colloid osmotic agents in the same dialysis solution strikingly enhanced water and sodium transport across the peritoneal membrane, improving ultrafiltration efficiency over that obtained with either type of agent alone. Conclusions These data cast light on the molecular mechanisms involved in colloid versus crystalloid osmosis and characterize novel osmotic agents. Dialysis solutions combining crystalloid and colloid particles may help restore fluid balance in patients treated with peritoneal dialysis., (Copyright © 2018 by the American Society of Nephrology.)

Background: The evaluation of the peritoneal transport characteristics is mandatory in peritoneal dialysis (PD) patients. This is usually performed in routine clinical practice with a peritoneal equilibration test (PET) using conventional dialysates, with low pH and high glucose degradation product (GDP) concentrations. An increasing proportion of patients are now treated with biocompatible dialysates, i.e. with physiological pH and lower GDP concentrations. This questions the appropriateness to perform a PET with conventional solutions in those patients. The aim of our study is to compare the results of the PET using biocompatible and conventional dialysates, respectively., Methods: Nineteen stable PD patients (13 males, 6 females; mean age: 67.95±2.36 years, mean body surface area: 1.83±0.04 m2, dialysis vintage: 2.95±0.19 years) were included, among which 10 were usually treated with biocompatible and 9 with conventional solutions. Two PETs were performed, within a 2-week interval, in each patient. PET sequence (conventional solution first or biocompatible solution first) was randomized in order to avoid 'time bias'. Small (urea, creatinine and glucose), middle (beta-2-microglobulin) and large molecules' (albumin and alpha-2-macroglobulin) dialysate/plasma (D/P) concentration ratios and clearances were measured during each PET. Ultrafiltration (UF) and sodium filtration were also recorded. Results of both tests were compared by the Wilcoxon paired test., Results: No statistical difference was found between both dialysates for small molecule transport rates or for sodium filtration and UF. However, a few patients were not similarly classified for small-solute transport characteristics within the PET categories. Beta-2-microglobulin and albumin D/P ratios at different time points of the PET were significantly higher with the biocompatible, when compared with the conventional, solutions: 0.10±0.03 versus 0.08±0.02 (P<0.01) and 0.008±0.003 versus 0.007±0.003 (P=0.01), respectively. A similar difference was also observed for beta-2-microglobulin that was higher with biocompatible dialysates (1.04±0.32 versus 0.93±0.32 mL/min, respectively)., Conclusion: Peritoneal transport of water and small solutes is independent of the type of dialysate which is used. This is not the case for the transport of beta-2-microglobulin and albumin that is higher under biocompatible dialysates. Vascular tonus modification could potentially explain such differences. The PET should therefore always be carried out with the same dialysate to make longitudinal comparisons possible.

Unlabelled: Background. Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) characterized by the development of an extensive fibrosis of the visceral peritoneum that may eventually lead to intestinal constriction. Its cause remains elusive. Nephrogenic systemic fibrosis (NSF), a disabling disease that can follow gadolinium-based contrast injection during magnetic resonance imaging, is characterized by systemic fibrosis of the skin, joints, liver, heart and vessels. Affected tissues are infiltrated by CD34+ and CD68+ fibroblasts. In the present study, we tested the hypothesis that EPS could have been triggered by a previous gadolinium injection. Methods. We performed histopathological analysis of the peritoneal membrane of two EPS and two control patients all exposed to long-term PD, including immunostaining with CD34 and CD68. The presence of gadolinium and other metals was also assessed by conventional and energy-filtered transmission electron microscopy., Results: Numerous CD34+ and CD68+ cells were found in both the EPS and control patients within the vascular endothelium and in macrophages, respectively, but not in interstitial fibrocytes, as it could be expected in NSF. No trace of gadolinium deposits could be found in the four peritoneal samples; dispersed tiny iron inclusions were evidenced in the connective tissue of both EPS patients., Conclusions: These findings argue against the implication of gadolinium in the development of EPS in long-term PD patients.

Peritoneal dialysis is now utilized as a renal replacement therapy modality in a substantial percentage of patients with end-stage renal disease, with excellent short-term patient and technique survival rates. However, the potential complications associated with longer-term therapy, such as ultrafiltration failure or encapsulating peritoneal sclerosis, have led to raise some concern about peritoneal dialysis as an adequate mode of treatment of end-stage renal disease in the long term. In the last decade, a substantial amount of information has been gathered on the characteristics of the peritoneal membrane at the onset of peritoneal dialysis, and on the anatomical and pathophysiologic changes that occur with long-term peritoneal dialysis. I will review this subject with a special focus on the various strategies that can help protect the peritoneal membrane during peritoneal dialysis so as to allow peritoneal dialysis to succeed as a long-term dialysis modality.

Background: The clinical determinants of baseline peritoneal membrane (PM) transport characteristics, as evaluated by a hypertonic peritoneal equilibration test (PET), remain ill-defined. Likewise, the longitudinal evolution of PM transport properties in peritoneal dialysis (PD) patients given automated PD (APD) and icodextrin still needs to be determined precisely. The aims of the present study were (1) to determine the clinical and biological factors affecting PM transport characteristics at PD onset and (2) to assess the longitudinal evolution of these markers., Methods: Seventy-two consecutive patients performed a baseline 3.86% glucose dialysate PET and were enrolled. Subgroups of 35 and 18 patients underwent another PET 1 and 2 year(s) later, respectively, and were included in the longitudinal part. For each patient, clinical and biological data were reviewed and PM transport markers calculated., Results: At onset of PD, angiotensin-converting enzyme (ACE) inhibitor intake (r = 0.31, P = 0.01), presence of a diabetes (r = 0.26, P = 0.03) and body surface area (BSA) (r = 0.26, P = 0.03) independently affected the mass transfer area coefficient (MTAC) of creatinine. Serum albumin (r = -0.46, P<0.001) and net ultrafiltration (r = -0.33, P = 0.009) inversely correlated with MTAC creatinine. Sodium sieving was inversely correlated with BSA (r = -0.33, P = 0.01). Serum albumin also inversely correlated with albumin clearance (r = -0.39, P = 0.02). Finally, the independent covariates that affected alpha2-macroglobulin clearance were age (P = 0.03), diabetes (P = 0.01) and the level of residual renal function (P<0.01). Serum albumin decreased with time on PD (P = 0.02). A rise in small solute transport and a decrease in net ultrafiltration, but no change in protein clearances, were also observed after 2 years of PD., Conclusions: Transport properties across the PM, as evaluated by MTAC creatinine and sodium sieving determinations, are correlated with anthropometric characteristics (BSA) and by comorbid conditions (witnessed by the presence of diabetes, a low serum albumin concentration and the prescription of an ACE inhibitor). The short-term evolution (2 years) of the PM transport properties of patients on APD and icodextrin is still characterized by a progressive increase in small solute transport and a loss of ultrafiltration capacity, as documented in ancient studies, but not with a modification in protein clearances. This conclusion merits, however, to be further evaluated in a larger cohort of PD patients after a longer follow-up.

Background: Patients starting peritoneal dialysis (PD) show a significant variability in small solute transport across the peritoneal membrane (PM). The latter parameter determines dialysis prescription and survival. Clinical factors probably influence solute transport across the PM, but the putative role of genetic variants is unknown., Methods: We have investigated the influence of functional polymorphisms of VEGF, ENOS, and IL-6, together with clinical and biological factors, on baseline peritoneal equilibration test (PET) parameters in a homogeneous population of 152 unrelated Caucasian PD patients from Belgium and the North of France., Results: The distribution of the 21 alleles (7 polymorphisms) and linkage disequilibrium parameters were similar in PD patients and healthy subjects. Univariate and multivariate analyses identified comorbidity, serum albumin, and the -174G/C polymorphism of IL-6 as independent predictors of small solute transport. The -174G/C polymorphism of IL-6 was associated with significantly higher IL-6 mRNA levels in the PM and higher plasma and dialysate IL-6 concentrations, suggesting a dominant effect of the C allele. Patients harboring the CC and GC genotypes (N= 92) were characterized by significantly higher permeability parameters and inflammatory markers than patients harboring the GG genotype (N= 60). In contrast with IL-6, VEGF and ENOS polymorphisms had no influence on baseline peritoneal permeability., Conclusion: These data (1) show that, together with clinical parameters, the functionally relevant -174G/C polymorphism of IL-6 contributes to the interpatient variability in small solute transport rate at the start of PD; and (2) substantiate the critical role played by IL-6 in the PM.

Background: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy linked to the exposure to aristolochic acid (AA) and characterized by extensive fibrosis and urothelial atypia. Although the fibrotic process has been documented in extrarenal tissues, the involvement of the peritoneum, as well as the efficacy of peritoneal dialysis in AAN patients, remain uncertain., Methods: The structure of the peritoneal membrane and the expression of basic fibroblast growth factor (bFGF), collagen type III, endothelial nitric oxide synthase (eNOS), and aquaporin-1 (AQP1) were investigated in peritoneal biopsies from an index AAN patient, four other AAN patients, four regular peritoneal dialysis patients, and two controls. Similar methods were used to investigate a rabbit model of AAN after intraperitoneal exposure to high-dose AA. AA-DNA adducts were screened by 32P-postlabeling analysis., Results: The AAN patients had renal failure, renal fibrosis, and urothelial atypia. The peritoneum of AAN patients had a normal structure, lacked cellular atypia, and, in comparison with regular peritoneal dialysis patients and controls, did not show abnormal regulation of fibrotic and endothelial markers. Furthermore, specific AA-DNA adducts were not identified in the peritoneum of AAN patients. In contrast, AA-DNA adducts were detected in peritoneal and kidney tissues of all exposed rabbits, and one of them developed a malignant mesothelioma., Conclusion: These data demonstrate the lack of fibrotic and vascular alterations and the absence of cellular atypia in the peritoneum from AAN patients. Thus, peritoneal dialysis should not be discouraged in these patients. Nevertheless, studies in a rabbit model of high-dose AA exposure may suggest a potential risk of peritoneal malignancy.

Long-term peritoneal dialysis (PD) is associated with alterations in peritoneal permeability and loss of ultrafiltration. These changes originate from increased peritoneal surface area, but the morphologic and molecular mechanisms involved remain unknown. The hypothesis that modifications of activity and/or expression of nitric oxide synthase (NOS) isozymes might play a role in these modifications, via enhanced local production of nitric oxide, was tested in this study. NOS activities were measured by the L-citrulline assay in peritoneal biopsies from seven control subjects, eight uremic patients immediately before the onset of PD, and 13 uremic patients on short-term (<18 mo, n = 6) or long-term(>18 mo, n = 7) PD. Peritoneal NOS activity is increased fivefold in long-term PD patients compared with control subjects. In uremic patients, NOS activity is positively correlated with the duration of PD. Increased NOS activity is mediated solely by Ca(2+)-dependent NOS and, as shown by immunoblotting, an upregulation of endothelial NOS. The biologic relevance of increased NOS in long-term PD was demonstrated by enhanced nitrotyrosine immunoreactivity and a significant increase in vascular density and endothelial area in the peritoneum. Immunoblotting and immunostaining studies demonstrated an upregulation of vascular endothelial growth factor (VEGF) mostly along the endothelium lining peritoneal blood vessels in long-term PD patients. In the latter, VEGF colocalized with the advanced glycation end product pentosidine deposits. These data provide a morphologic (angiogenesis and increased endothelial area) and molecular (enhanced NOS activity and endothelial NOS upregulation) basis for explaining the permeability changes observed in long-term PD. They also support the implication of local advanced glycation end product deposits and liberation of VEGF in that process.

Unlabelled: A specific method for measurement of nitric oxide synthase enzymatic activity in peritoneal biopsies., Background: Nitric oxide (NO) is synthesized by NO synthase (NOS) isoforms that are expressed in the peritoneum. Thus far, NOS activity in the peritoneum has been assessed by nonspecific methods. We describe the application of a specific method for determination of NOS activity in rat and human peritoneal biopsies., Methods: The L-citrulline assay is based on the stoechiometric production of NO and L-[3H]-citrulline from L-[3H]-arginine by NOS. The assay is technically difficult when applied on small samples with relatively low levels of NOS activity, which required specific procedures for extraction and samples processing. Reaction parameters ensuring assay linearity in the peritoneum were defined. Peritoneum lysates were also used for immunoblot analysis to identify the NOS isoforms involved., Results: A significant NOS activity is detected in the normal peritoneum because of both Ca2+-dependent and Ca2+-independent NOS. The specificity of NOS activity has been demonstrated by various controls, including the NOS inhibitor L-NMMA. Competition experiments with L-valine and amino acid analyses have reasonably excluded the interference of endogenous arginase and L-arginine, which both might underestimate NOS activity. The procedure is sensitive; it detects a high range of NOS activities as well as the appropriate NOS isoforms in various tissues and conditions, as shown by correlations with immunoblot studies., Conclusions: We have adapted and characterized the L-citrulline assay to measure specific NOS activities within the peritoneum. The peritoneum lysate assayed for NOS activity can also be used for characterizing NOS isoform expression by immunoblot analysis.

Aquaporin-1 (AQP1) has been claimed to be the molecular counterpart of the transcellular pathway for free-water movement across the peritoneum during peritoneal dialysis. We report the case of a 67-year-old man, on peritoneal dialysis for 11 years, in whom ultrafiltration failure due to an abolition of the transcellular water transfer (documented by a loss of sodium sieving) was associated with an apparently normal expression of AQP1. We suggest that an alteration of AQP1 structure, rather than of its expression, accounts for this observation.