Genetic Characterization of Kidney Failure of Unknown Etiology in Spain: Findings From the GENSEN Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) of unknown etiology (CKDUE) is one of the main global causes of kidney failure. While genetic studies may identify an etiology in these patients, few studies have implemented genetic testing of CKDUE in population-based series of patients which was the focus of the GENSEN. STUDY DESIGN: Case series. SETTINGS & PARTICIPANTS: 818 patients aged ≤45 years at 51 Spanish centers with CKDUE, and either an estimated GFR <15 mL/min/1.73 m2 or treatment with maintenance dialysis or transplantation. OBSERVATIONS: Genetic testing for 529 genes associated to inherited nephropathies using high-throughput sequencing (HTS). Pathogenic and/or likely pathogenic (P/LP) gene variants concordant with the inheritance pattern were detected in 203 (24.8%) patients. Variants in type IV collagen genes were the most frequent (COL4A5, COL4A4, COL4A3; 35% of total gene variants), followed by NPHP1, PAX2, UMOD, MUC1 and INF2 (7.3%, 5.9%, 2.5%, 2.5% and 2.5% respectively). Overall, 87 novel variants classified as P/LP were identified. The top 5 most common previously undiagnosed diseases were Alport syndrome spectrum (35% of total positive reports), genetic podocytopathies (19%), nephronophthisis (11%), autosomal dominant tubulointerstitial kidney disease (7%) and congenital anomalies of the kidney and urinary tract (CAKUT: 5%). Family history of kidney disease was reported by 191 (23.3 %) participants and by 65/203 (32.0%) patients with P/LP variants. LIMITATIONS: Missing data. Selection bias resulting from voluntary enrollment. CONCLUSIONS: Genomic testing with HTS identified a genetic cause of kidney disease in approximately one quarter of young patients with CKDUE and advanced kidney disease. These findings suggest that genetic studies are a potentially useful tool for the evaluation of people with CKDUE.

Cross-sectional study of quality of life in relation with vascular access in hemodialysis patients. Study in a hospital and a satellite center

Introduction: Vascular access for hemodialysis (HD) is essential for the patient. Even though Arteriovenous fistula (AVF) is the preferred access, in certain age groups, the central venous catheter (CVC) may provide advantages. This study aims to investigate the quality of life related to vascular access. Methods: Cross-sectional study including patients from a hospital, a home HD unit and a satellite hemodialysis center. Clinical data was collected from the patients, who went through a quality-of-life questionnaire SF12 and a Vascular Access Questionnaire (VAQ). Results: 91 patients participated, mostly male (70 %), with a mean age of 68.9 ± 16.2 years. AVF was the current vascular access in 60.4 %, the rest used a CVC. Home HD was performed in 12.1 % of patients and 76 % started it via CVC. Regarding patients who have had both AVF and CVC, 58 % prefer AVF and only 26.5 % of current CVC carriers would have a new AVF, mostly due to fear of pain (52 %). Most people (72.5 %) reported having received sufficient information, with no differences between both accesses. The SF12 results showed no differences between patients with AVF or CVC. Regarding the VAQ, patients with AVF were more satisfied with the social aspect (p = 0.036) and complications (p = 0.006). Conclusion: Patients with AVF had better outcomes than those using CVC regarding complications and social aspects. These differences are not attributable to a worse overall quality of life status of CVC patients. Most patients with CVCs refuse to go through a new AVF for fear of puncture pain.

Introducción: el acceso vascular para la hemodiálisis (HD) es esencial para el paciente. Aunque la fístula arteriovenosa (FAV) es el acceso preferido, en ciertos grupos de edad el catéter venoso central (CVC) puede aportar ventajas. Este estudio pretende investigar la calidad de vida relacionada con el acceso vascular. Métodos: el estudio transversal incluye pacientes del hospital, de una unidad de HD domiciliaria y de un centro de hemodiálisis periférico. Se recogieron datos clínicos de los pacientes que contestaron el cuestionario de calidad de vida SF12 y Cuestionario de Acceso Vascular (VAQ). Resultados: 91 pacientes, en su mayoría varones (70 %), con una edad media de 68,9 ± 16,2 años. La FAV era el acceso vascular actual en el 60,4 %. La HD domiciliaria se realizó en el 12,1 % de los pacientes y el 76 % la inició mediante CVC. En cuanto a los pacientes que han tenido tanto FAV como CVC, el 58 % prefiere la FAV y sólo el 26,5 % de los actuales portadores de CVC se sometería a una nueva FAV, sobre todo por miedo al dolor (52 %). La mayoría de las personas (72,5 %) declararon haber recibido suficiente información, sin diferencias entre ambos accesos. Los resultados del SF12 no mostraron diferencias según el acceso. En cuanto al VAQ, los pacientes con AVF estaban más satisfechos con el aspecto social y las complicaciones. Conclusión: los pacientes con FAV tuvieron mejores resultados en comparación con los que utilizaron CVC en cuanto a complicaciones y aspectos sociales, sin deberse a un peor estado general de la calidad de vida. La mayoría de los pacientes con CVC se niegan a someterse a una nueva FAV por miedo al dolor de la punción.

Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic hereditary renal disease, promoting end-stage renal disease (ESRD). Klinefelter syndrome (KS) is a consequence of an extra copy of the X chromosome in males. Main symptoms in KS include hypogonadism, tall stature, azoospermia, and a risk of cardiovascular diseases, among others. Gitelman syndrome (GS) is an autosomal recessive disorder caused by SLC12A3 variants, and is associated with hypokalemia, hypomagnesemia, hypocalciuria, normal or low blood pressure, and salt loss. The three disorders have distinct and well-delineated clinical, biochemical, and genetic findings. We here report a male patient with ADPKD who developed early chronic renal failure leading to ESRD, presenting with an intracranial aneurysm and infertility. NGS identified two de novo PKD1 variants, one known (likely pathogenic), and a previously unreported variant of uncertain significance, together with two SLC12A3 pathogenic variants. In addition, cytogenetic analysis showed a 47, XXY karyotype. We investigated the putative impact of this rare association by analyzing possible clinical, biochemical, and/or genetic interactions and by comparing the evolution of renal size and function in the proband with three age-matched ADPKD (by variants in PKD1) cohorts. We hypothesize that the coexistence of these three genetic disorders may act as modifiers with possible synergistic actions that could lead, in our patient, to a rapid ADPKD progression.

Incidencia y resultados de la COVID-19 en una unidad de diálisis domiciliaria en Madrid (España) durante el pico de la pandemia / COVID-19 incidence and outcomes in a home dialysis unit in Madrid (Spain) at the height of the pandemic

INTRODUCCIÓN: La enfermedad por coronavirus 2019 (COVID-19) es una infección viral causada por un nuevo coronavirus que está afectando a todo el mundo. Hay estudios previos de pacientes en hemodiálisis en centro, pero hay pocos datos sobre población en diálisis domiciliaria. Nuestro objetivo es estudiar la incidencia y evolución de la COVID-19 en una unidad de diálisis domiciliaria (UDD) durante el pico de la pandemia. MÉTODOS: Estudio observacional y retrospectivo que incluye todos los pacientes diagnosticados de COVID-19 de la UDD del Hospital Universitario La Paz (Madrid, España) entre el 10 de marzo y el 15 de mayo de 2020. Se recogieron los datos clínicos de la UDD (57 pacientes en diálisis peritoneal y 22 pacientes en hemodiálisis domiciliaria) y comparamos las características clínicas y la evolución de los pacientes con o sin infección por COVID-19. RESULTADOS: Doce pacientes fueron diagnosticados de COVID-19 (9 diálisis peritoneal, 3 hemodiálisis domiciliaria). No hubo diferencias estadísticamente significativas entre las características clínicas de los pacientes con COVID-19 y el resto de la unidad. La edad media fue 62 ± 18,5 años; la mayoría eran varones (75%). Todos los pacientes menos uno necesitaron hospitalización. Diez pacientes (83%) fueron dados de alta tras una media de 16,4 ± 9,7 días de hospitalización. Dos pacientes fueron diagnosticados durante su hospitalización por otro motivo y fueron los únicos que fallecieron. Los fallecidos eran de mayor edad que los supervivientes. CONCLUSIÓN: La incidencia de COVID-19 en nuestra UDD en Madrid durante el pico de la pandemia fue alto, especialmente en los pacientes en diálisis peritoneal, sin observarse un potencial beneficio para prevenir la infección en los pacientes en diálisis domiciliaria. La edad avanzada y la transmisión nosocomial fueron los principales factores relacionados con peor pronóstico

INTRODUCTION: The 2019 coronavirus (COVID-19) is a viral infection caused by a new coronavirus that is affecting the entire world. There have been studies of patients on in-center hemodialysis, but home dialysis population data are scarce. Our objective is to study the incidence and course of COVID-19 in a home dialysis unit (HDU) at the height of the pandemic. METHODS: An observational, retrospective study enrolling all patients diagnosed with COVID-19 from the HDU of Hospital Universitario La Paz (La Paz University Hospital) (Madrid, Spain) between March 10 and May 15, 2020. We collected clinical data from the HDU (57 patients on peritoneal dialysis and 22 patients on home hemodialysis) and compared the clinical characteristics and course of patients with and without COVID-19 infection. RESULTS: Twelve patients were diagnosed with COVID-19 (9 peritoneal dialysis; 3 home hemodialysis). There were no statistically significant differences in terms of clinical characteristics between patients with COVID-19 and the rest of the unit. The mean age was 62 ± 18.5 years; most were men (75%). All patients but one required hospitalization. Ten patients (83%) were discharged following a mean of 16.4 ± 9.7 days of hospitalization. Two patients were diagnosed while hospitalized for other conditions, and these were the only patients who died. Those who died were older than those who survived. CONCLUSION: The incidence of COVID-19 in our HDU in Madrid at the height of the pandemic was high, especially in patients on peritoneal dialysis. No potential benefit for preventing the infection in patients on home dialysis was observed. Advanced age and nosocomial transmission were the main factors linked to a worse prognosis

COVID-19 incidence and outcomes in a home dialysis unit in Madrid (Spain) at the height of the pandemic.

INTRODUCTION: The 2019 coronavirus (COVID-19) is a viral infection caused by a new coronavirus that is affecting the entire world. There have been studies of patients on in-center hemodialysis (HD), but home dialysis population data are scarce. Our objective is to study the incidence and course of COVID-19 in a home dialysis unit (HDU) at the height of the pandemic. METHODS: an observational, retrospective study enrolling all patients diagnosed with COVID-19 from the HDU of Hospital Universitario La Paz [La Paz University Hospital] (Madrid, Spain) between March 10 and May 15, 2020. We collected clinical data from the HDU (57 patients on peritoneal dialysis [PD] and 22 patients on home hemodialysis [HHD]) and compared the clinical characteristics and course of patients with and without COVID-19 infection. RESULTS: twelve patients were diagnosed with COVID-19 (9 PD; 3 HHD). There were no statistically significant differences in terms of clinical characteristics between patients with COVID-19 and the rest of the unit. The mean age was 62 ± 18.5 years; most were men (75%). All patients but one required hospitalization. Ten patients (83%) were discharged following a mean of 16.4 ± 9.7 days of hospitalization. Two patients were diagnosed while hospitalised for other conditions, and these were the only patients who died. Those who died were older than those who survived. CONCLUSION: The incidence of COVID-19 in our HDU in Madrid at the height of the pandemic was high, especially in patients on PD. No potential benefit for preventing the infection in patients on home dialysis was observed. Advanced age and nosocomial transmission were the main factors linked to a worse prognosis.

[COVID-19 incidence and outcomes in a home dialysis unit in Madrid (Spain) at the height of the pandemic]. / Incidencia y resultados de la COVID-19 en una unidad de diálisis domiciliaria en Madrid (España) durante el pico de la pandemia.

INTRODUCTION: The 2019 coronavirus (COVID-19) is a viral infection caused by a new coronavirus that is affecting the entire world. There have been studies of patients on in-center hemodialysis, but home dialysis population data are scarce. Our objective is to study the incidence and course of COVID-19 in a home dialysis unit (HDU) at the height of the pandemic. METHODS: An observational, retrospective study enrolling all patients diagnosed with COVID-19 from the HDU of Hospital Universitario La Paz (La Paz University Hospital) (Madrid, Spain) between March 10 and May 15, 2020. We collected clinical data from the HDU (57 patients on peritoneal dialysis and 22 patients on home hemodialysis) and compared the clinical characteristics and course of patients with and without COVID-19 infection. RESULTS: Twelve patients were diagnosed with COVID-19 (9 peritoneal dialysis; 3 home hemodialysis). There were no statistically significant differences in terms of clinical characteristics between patients with COVID-19 and the rest of the unit. The mean age was 62±18.5 years; most were men (75%). All patients but one required hospitalization. Ten patients (83%) were discharged following a mean of 16.4±9.7 days of hospitalization. Two patients were diagnosed while hospitalized for other conditions, and these were the only patients who died. Those who died were older than those who survived. CONCLUSION: The incidence of COVID-19 in our HDU in Madrid at the height of the pandemic was high, especially in patients on peritoneal dialysis. No potential benefit for preventing the infection in patients on home dialysis was observed. Advanced age and nosocomial transmission were the main factors linked to a worse prognosis.

Prominent Levels of the Profibrotic Chemokine CCL18 during Peritonitis: In Vitro Downregulation by Vitamin D Receptor Agonists.

Peritoneal dialysis (PD) is used as a renal replacement therapy, which can be limited by peritoneal membrane ultrafiltration failure (UFF) secondary to fibrotic processes. Peritonitis, a frequent complication of PD, is a major risk factor for peritoneal membrane fibrosis and UFF. Low peritoneal levels of the chemokine CCL18 are associated with preservation of peritoneal membrane function in PD. Given that CCL18 is involved in fibrotic processes and recurrent peritonitis, it is a risk factor for peritoneal membrane failure; thus, we evaluated CCL18 concentrations in peritoneal effluents from patients undergoing peritonitis episodes. Pharmacological interventions aimed at diminishing the production of CCL18 were also explored. Fivefold higher CCL18 peritoneal concentrations were found during acute bacterial peritonitis, in parallel with the increased infiltration of macrophages. Unexpectedly, CCL18 was also highly (50-fold) increased during sterile eosinophilic peritonitis, and peritoneal eosinophils were found to express CCL18. In vitro treatment of peritoneal macrophages with the vitamin D receptor agonist paricalcitol was able to reduce the secretion and the expression of CCL18 in isolated peritoneal macrophages. In conclusion, our study suggests that the chemokine CCL18 can be a mediator of peritoneal membrane failure associated with peritonitis episodes as well as providing a new potential therapeutic target.

Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis.

Peritoneal membrane failure (PMF) and, ultimately, encapsulating peritoneal sclerosis (EPS) are the most serious peritoneal dialysis (PD) complications. Combining clinical and peritoneal transport data with the measurement of molecular biomarkers, such as the chemokine CCL18, would improve the complex diagnosis and management of PMF. We measured CCL18 levels in 43 patients' effluent and serum at baseline and after 1, 2, and 3 years of PD treatment by retrospective longitudinal study, and evaluated their association with PMF/EPS development and peritoneal risk factors. To confirm the trends observed in the longitudinal study, a cross-sectional study was performed on 61 isolated samples from long-term (more than 3 years) patients treated with PD. We observed that the patients with no membrane dysfunction showed sustained low CCL18 levels in peritoneal effluent over time. An increase in CCL18 levels at any time was predictive of PMF development (final CCL18 increase over baseline, p = .014; and maximum CCL18 increase, p = .039). At year 3 of PD, CCL18 values in effluent under 3.15 ng/ml showed an 89.5% negative predictive value, and higher levels were associated with later PMF (odds ratio 4.3; 95% CI 0.90-20.89; p = .067). Moreover, CCL18 levels in effluent at year 3 of PD were independently associated with a risk of PMF development, adjusted for the classical (water and creatinine) peritoneal transport parameters. These trends were confirmed in a cross-sectional study of 61 long-term patients treated with PD. In conclusion, our study shows the diagnostic capacity of chemokine CCL18 levels in peritoneal effluent to predict PMF and suggests CCL18 as a new marker and mediator of this serious condition as well as a new potential therapeutic target.

Biocompatible Dialysis Solutions Preserve Peritoneal Mesothelial Cell and Vessel Wall Integrity. A Case-Control Study on Human Biopsies.

UNLABELLED: ♦ INTRODUCTION: Chronic exposure to conventional peritoneal dialysis (PD) solutions has been related to peritoneal function alterations in PD patients, and associated with mesothelial cell loss, submesothelial fibrosis, vasculopathy, and angiogenesis. In vitro and ex vivo analyses, as well as studies with animal models, have demonstrated that biocompatible PD solutions attenuate these morphological alterations. Our aim was to confirm the morphological benefits of biocompatible solutions in PD patients. ♦ METHODS: We analyzed biopsies from 23 patients treated with biocompatible solutions (study group, SG), and compared them with a control group (n = 23) treated with conventional solutions (CG), matched for time on PD. ♦ RESULTS: A total of 56.5% of SG patients showed total or partial preservation of mesothelial cells monolayer, in contrast with 26.1% of patients in CG (p = 0.036). Peritoneal fibrosis was not significantly less frequent in SG patients (47.8% SG vs 69.6% CG; p = 0.13). In patients without previous peritonitis, a significantly lower prevalence of fibrosis was present in SG patients (41.7% SG vs 77.8% CG; p = 0.04). Hyalinizing vasculopathy (HV) was significantly lower in SG (4.3% SG vs 30.4% CG; p = 0.02). Cytokeratin-positive fibroblast-like cells were detected in 10 patients (22%), but the prevalence was not significantly lower in SG. In the univariate regression analysis, the use of biocompatible solutions was associated with mesothelial monolayer integrity (p = 0.04) and an absence of vasculopathy (p = 0.04). ♦ CONCLUSION: The present study demonstrates in vivo in human biopsies that biocompatible solutions are better tolerated by the peritoneum in the medium and long term than conventional solutions.

Can EPS development be avoided with early interventions? The potential role of tamoxifen--a single-center study.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Identification of patients at high risk for EPS ("EPS-prone") and delivery of appropriate interventions might prevent its development. Our aim was to evaluate the clinical characteristics and outcomes of all EPS and EPS-prone patients diagnosed at our PD unit. METHODS: For a 30-year period representing our entire PD experience, we retrospectively identified all patients with EPS (diagnosed according to International Society for Peritoneal Dialysis criteria) and all patients defined as EPS-prone because they met at least 2 established criteria (severe peritonitis, PD vintage greater than 3 years, severe hemoperitoneum, overexposure to glucose, and acquired ultrafiltration failure). RESULTS: Of 679 PD patients, we identified 20 with EPS, for an overall prevalence of 2.9%. Mean age at diagnosis was 50.2 ± 16.4 years, with a median PD time of 77.96 months (range: 44.36 - 102.7 months) and a median follow-up of 30.91 months (range: 4.6 - 68.75 months). Of patients with EPS, 10 (50%) received tamoxifen, 10 (50%) received parenteral nutrition, and 2 (10%) underwent adhesiolysis, with 25% mortality related to EPS. Another 14 patients were identified as EPS-prone. Median follow-up was 54.05 months (range: 11.9 - 87.04 months). All received tamoxifen, and 5 (36%) received corticosteroids; none progressed to full EPS. We observed no differences in baseline data between the groups, but the group with EPS had been on PD longer (84 ± 53 months vs 39 ± 20 months, p = 0.002) and had a higher cumulative number of days of peritoneal inflammation from peritonitis (17.2 ± 11.1 days vs 9.8 ± 7.9 days, p = 0.015). Overall mortality was similar in the groups. The incidence of EPS declined during our three decades of experience (5.6%, 3.9%, and 0.3%). CONCLUSIONS: Being a serious, life-threatening complication of PD, EPS requires high suspicion to allow for prompt diagnosis and treatment. Early detection of EPS-prone states and delivery of appropriate intervention might prevent EPS development. Tamoxifen seems to be a key strategy in prevention, but caution should be used in interpreting our results. Additional randomized controlled studies are needed.

Pretransplant peritoneal dialysis relative to hemodialysis improves long-term survival of kidney transplant patients: a single-center observational study.

BACKGROUND: Kidney transplantation is the best option for the treatment of end-stage renal disease in terms of survival and quality of life. These results can be influenced by the pretransplant dialysis modality. The aim of this study was to evaluate whether the pretransplantation dialysis modality influences patient and allograft survival beyond 10 years and examine the potential risk factors associated with the outcomes. METHODS: We conducted an observational, retrospective, single-center clinical study that included 236 patients [118 undergoing peritoneal dialysis (PD) and 118 undergoing hemodialysis (HD)] who proceeded to transplantation during the period December 1990-2002. Donor and recipient data were collected from our hospital's clinical registries. The follow-up period extended to the patient's death, the loss of the allograft, or loss to follow-up. The end date of the study was set at March 2012. RESULTS: In the multivariate analysis, the long-term patient survival rate was higher for the PD group than for the HD group [HR = 2.62 (1.01-6.8); p = 0.04]; however, the allograft survival rate was not significantly different between the two groups [HR = 0.68 (0.41-1.10); p = 0.12]. CONCLUSION: Pretransplantation dialysis modality is associated with long-term patient survival, with outcomes favoring peritoneal dialysis over hemodialysis. However, the pretransplant dialysis modality does not influence long-term graft loss risk.

The influence of initial peritoneal transport characteristics, inflammation, and high glucose exposure on prognosis for peritoneal membrane function.

BACKGROUND: Fast transport status, acquired with time on peritoneal dialysis (PD), is a pathology induced by peritoneal exposure to bioincompatible solutions. Fast transport has important clinical consequences and should be prevented. OBJECTIVE: We analyzed the repercussions of initial peritoneal transport characteristics on the prognosis for peritoneal membrane function, and also whether the influence of peritonitis and high exposure to glucose are different according to the initial peritoneal transport characteristics or the moment when such events occur. METHODS: The study included 275 peritoneal dialysis patients with at least 2 peritoneal function studies (at baseline and 1 year). Peritoneal kinetic studies were performed at baseline and annually. Those studies consist of a 4-hour dwell with glucose (1.5% during 1981 - 1990, and 2.27% during 1991 - 2002) to calculate the peritoneal mass transfer coefficients of urea and creatinine (milliliters per minute) using a previously described mathematical model. RESULTS: Membrane prognosis and technique survival were independent of baseline transport characteristics. Fast transport and ultrafiltration (UF) failure are reversible conditions, provided that peritonitis and high glucose exposure are avoided during the early dialysis period. The first year on PD is a main determining factor for the membrane's future, and the mass transfer coefficient of creatinine at year 1 is the best functional predictor of future PD history. After 5 years on dialysis, permeability frequently increases, and UF decreases. Icodextrin is associated with peritoneal protection. CONCLUSIONS: Peritoneal membrane prognosis is independent of baseline transport characteristics. Intrinsic fast transport and low UF are reversible conditions when peritonitis and high glucose exposure are avoided during the early dialysis period. Icodextrin helps in glucose avoidance and is associated with peritoneal protection.

Influence of bicarbonate/low-GDP peritoneal dialysis fluid (BicaVera) on in vitro and ex vivo epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: Peritoneal membrane damage induced by peritoneal dialysis (PD) is largely associated with epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs), which is believed to be a result mainly of the glucose degradation products (GDPs) present in PD solutions. OBJECTIVES: This study investigated the impact of bicarbonate-buffered, low-GDP PD solution (BicaVera: Fresenius Medical Care, Bad Homburg, Germany) on EMT of MCs in vitro and ex vivo. IN VITRO STUDIES: Omentum-derived MCs were incubated with lactate-buffered standard PD fluid or BicaVera fluid diluted 1:1 with culture medium. Ex vivo studies: From 31 patients randomly distributed to either standard or BicaVera solution and followed for 24 months, effluents were collected every 6 months for determination of EMT markers in effluent MCs. RESULTS: Culturing of MCs with standard fluid in vitro resulted in morphology change to a non-epithelioid shape, with downregulation of E-cadherin (indicative of EMT) and strong induction of vascular endothelial growth factor (VEGF) expression. By contrast, in vitro exposure of MCs to bicarbonate/low-GDP solution had less impact on both EMT parameters. Ex vivo studies partially confirmed the foregoing results. The BicaVera group, with a higher prevalence of the non-epithelioid MC phenotype at baseline (for unknown reasons), showed a clear and significant trend to gain and maintain an epithelioid phenotype at medium- and longer-term and to show fewer fibrogenic characteristics. By contrast, the standard solution group demonstrated a progressive and significantly higher presence of the non-epithelioid phenotype. Compared with effluent MCs having an epithelioid phenotype, MCs with non-epithelioid morphology showed significantly lower levels of E-cadherin and greater levels of fibronectin and VEGF. In comparing the BicaVera and standard solution groups, MCs from the standard solution group showed significantly higher secretion of interleukin 8 and lower secretion of collagen I, but no differences in the levels of other EMT-associated molecules, including fibronectin, VEGF, E-cadherin, and transforming growth factor ß1. Peritonitis incidence was similar in both groups. Functionally, the use of BicaVera fluid was associated with higher transport of small molecules and lower ultrafiltration capacity. CONCLUSIONS: Effluent MCs grown ex vivo from patients treated with bicarbonate/low-GDP BicaVera fluid showed a trend to acquire an epithelial phenotype, with lower production of proinflammatory cytokines and chemokines (such as interleukin 8) than was seen with MCs from patients treated with a lactate-buffered standard PD solution.

Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis.

BACKGROUND: Depending on the cytokine microenvironment, macrophages (Mϕ) can adopt a proinflammatory (M1) or a profibrotic (M2) phenotype characterized by the expression of cell surface proteins such as CD206 and CD163 and soluble factors such as CC chemokine ligand 18 (CCL18). A key role for Mϕ in fibrosis has been observed in diverse organ settings. We studied the Mϕ population in a human model of peritoneal dialysis in which continuous stress due to dialysis fluids and recurrent peritonitis represent a risk for peritoneal membrane dysfunction reflected as ultrafiltration failure (UFF) and peritoneal fibrosis. METHODS: We used flow cytometry and quantitative reverse transcription-polymerase chain reaction to analyse the phenotype of peritoneal effluent Mϕ and tested their ability to stimulate the proliferation of human fibroblasts. Mϕ from non-infected patients were compared with those from patients with active peritonitis. Cytokine production was evaluated by enzyme-linked immunosorbent assay (ELISA) in spent dialysates and cell culture supernatants. RESULTS: CD206(+) and CD163(+) M2 were found within peritoneal effluents by flow cytometry analysis, with increased frequencies of CD163(+) cells during peritonitis (P = 0.003). TGFB1, MMP9 and CCL18 messenger RNA (mRNA) levels in peritoneal macrophages (pMϕ) were similar to those found in M2 cells differentiated in vitro. The ability of pMϕ to stimulate fibroblast proliferation correlated with CCL18 mRNA levels (r = 0.924, P = 0.016). CCL18 production by pMϕ was confirmed by immunostaining of cytospin samples and ELISA. Moreover, CCL18 effluent concentrations correlated with decreased peritoneal function, which was evaluated as dialysate to plasma ratio of creatinine (r = 0.724, P < 0.0001), and were significantly higher in patients with UFF (P = 0.0025) and in those who later developed sclerosing peritonitis (P = 0.024). CONCLUSIONS: M2 may participate in human peritoneal fibrosis through the stimulation of fibroblast cell growth and CCL18 production as high concentrations of CCL18 are associated with functional deficiency and fibrosis of the peritoneal membrane.

Peritoneal membrane phosphate transport status: a cornerstone in phosphate handling in peritoneal dialysis.

BACKGROUND AND OBJECTIVES: Phosphate control impacts dialysis outcomes. Our aim was to define peritoneal phosphate transport in peritoneal dialysis (PD) and to explore its association with hyperphosphatemia, phosphate clearance (PPhCl), and PD modality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Two hundred sixty-four patients (61% on continuous ambulatory PD [CAPD]) were evaluated at month 12. PPhCl was calculated from 24-hour peritoneal effluent. Phosphate (Ph) and creatinine (Cr) dialysate/plasma (D/P) were calculated at a 4-hour 3.86% peritoneal equilibration test. RESULTS: D/PPh correlated with D/PCr. PPhCl correlated better with D/PPh than with D/PCr. Prevalence of hyperphosphatemia (>5.5 mg/dl) was 30%. In a multiple regression analysis, only residual renal function was independently, negatively associated with hyperphosphatemia; in anuric patients, only D/PPh was an independent factor predicting hyperphosphatemia. D/PPh was 0.57 ± 0.10, and according to this, 16% of the patients were fast, 31% were fast-average, 35% were slow-average, and 17% were slow transporters. PPhCl was 37.5 ± 11.7 L/wk; it was lower in the slow transporter group (31 ± 14 L/wk). Among fast and fast-average transporters, PPhCl was comparable in both PD modalities. In comparison to automated PD, CAPD was associated with increased PPhCl among slow-average (36 ± 8 versus 32 ± 7 L/wk) and slow transporters (34 ± 15 versus 24 ± 9 L/wk). CONCLUSIONS: In hyperphosphatemic, particularly anuric, patients, optimal PD modality should consider peritoneal phosphate transport characteristics. Increasing dwell times and transfer to CAPD are effective strategies to improve phosphate handling in patients with inadequate phosphate control on automated PD.