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.).

Adverse pregnancy outcomes in pregnant women with chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of adverse pregnancy outcomes, but the risk at different stages of CKD (defined by estimated glomerular filtration rate, eGFR) compared with women without CKD has not been quantified in large cohorts. OBJECTIVES: To quantify the association between CKD and adverse pregnancy outcomes according to CKD definition, CKD stage and presence or absence of diabetes. SEARCH STRATEGY: A systematic search of EMBASE and MEDLINE from inception to 5 January 2023. SELECTION CRITERIA: English-language randomised controlled trials as well as cohort and case-control studies investigating adverse pregnancy outcomes in pregnant women with CKD. DATA COLLECTION AND ANALYSIS: Two reviewers conducted independent data extractions. A random-effects model was used to estimate risk. MAIN RESULTS: We included 19 studies with 3 251 902 women. Defining CKD using eGFR or serum creatinine produced results with greater effect size but wider confidence intervals. Compared with CKD stages 1-2, women with CKD stages 3-5 have a greater risk, but also greater imprecision in the risk estimate, of the following outcomes: pre-eclampsia (OR 55.18, 95% CI 2.63-1157.68, vs OR 24.74, 95% CI 1.75-348.70), preterm birth (OR 20.24, 95% CI 2.85-143.75, vs OR 8.18, 95% CI 1.54-43.46) and neonatal intensive care unit admission (OR 19.32, 95% CI 3.07-121.68, vs OR 9.77, 95% CI 2.49-38.39). Women with diabetic kidney disease, compared with women without diabetic kidney disease, have higher risks of maternal mortality, small-for-gestational-age neonates, pre-eclampsia and gestational hypertension. CONCLUSIONS: There is heterogeneity in the definition of CKD in pregnancy. Future studies should consider ways to standardise its definition and measurement in pregnancy.

Management of adults with diabetes on dialysis: Summary of recommendations of the Joint British Diabetes Societies guidelines 2022.

Diabetes is the commonest cause of end-stage kidney disease in many parts of the world, and many people on dialysis programmes live with diabetes. Such people are vulnerable to complications from their diabetes, and their care may be fragmented due to the many specialists involved. This updated guidance from the Joint British Diabetes Societies aims to review and update the 2016 guidance, with particular emphasis on glycaemic monitoring in the light of recent advances in this area. In addition, the guidance covers clinical issues related to the management of diabetes in people on peritoneal dialysis, along with acute complications such as hypoglycaemia and ketoacidosis, and chronic complications such as foot and eye disease.

Interleukin-6 signaling drives fibrosis in unresolved inflammation.

Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.

Estimating the association between systemic Interleukin-6 and mortality in the dialysis population. Re-analysis of the global fluid study, systematic review and meta-analysis.

BACKGROUND: Systemic inflammation, measured as circulating Interleukin-6 (IL-6) levels, is associated with cardiovascular and all-cause mortality in chronic kidney disease. However, this has not been convincingly demonstrated in a systematic review or a meta-analysis in the dialysis population. We provide such evidence, including a re-analysis of the GLOBAL Fluid Study. METHODS: Mortality in the GLOBAL fluid study was re-analysed using Cox proportional hazards regression with IL-6 levels as a covariate using a continuous non-logarithmic scale. Literature searches of the association of IL-6 levels with mortality were conducted on MEDLINE, EMBASE, PyschINFO and CENTRAL. All studies were assessed for risk of bias using the QUIPS tool. To calculate a pooled effect size, studies were grouped by use of IL-6 scale and included in the meta-analysis if IL-6 was analysed as a continuous linear covariate, either per unit or per 10 pg/ml, in both unadjusted or adjusted for other patient characteristics (e.g. age, comorbidity) models. Funnel plot was used to identify potential publication bias. RESULTS: Of 1886 citations identified from the electronic search, 60 were included in the qualitative analyses, and 12 had sufficient information to proceed to meta-analysis after full paper screening. Random effects meta-analysis of 11 articles yielded a pooled hazard ratio (HR) per pg/ml of 1.03, (95% CI 1.01, 1.03), [Formula: see text]= 81%. When the analysis was confined to seven articles reporting a non-adjusted HR the result was similar: 1.03, per pg/ml (95% CI: 1.03, 1.06), [Formula: see text]=92%. Most of the heterogeneity could be attributed to three of the included studies. Publication bias could not be determined due to the limited number of studies. CONCLUSION: This systematic review confirms the adverse association between systemic IL-6 levels and survival in people treated with dialysis. The heterogeneity that we observed may reflect differences in study case mix. SYSTEMATIC REVIEW REGISTRATION: PROSPERO - CRD42020214198.

A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

Trends in Peritoneal Dialysis Technique Survival, Death, and Transfer to Hemodialysis: A Decade of Data from the RDPLF.

INTRODUCTION: There is limited information on the trends of peritoneal dialysis (PD) technique survival over time. This study aimed to estimate the effect of calendar time on technique survival, transfer to hemodialysis (HD) (and the individual causes of transfer), and patient survival. METHODS: This retrospective, multicenter study, based on data from the French Language Peritoneal Dialysis Registry, analyzed 14,673 patients who initiated PD in France between January 1, 2005, and December 31, 2016. Adjusted Cox regressions with robust variance were used to examine the probability of a composite end point of either death or transfer to HD, death, and transfer to HD, accounting for the nonlinear impact of PD start time. RESULTS: There were 10,201 (69.5%) cases of PD cessation over the study period: 5,495 (37.4%) deaths and 4,706 (32.1%) transfers to HD. The rate of PD cessation due to death or transfer to HD decreased over time (PR 0.96, 95% CI: 0.95-0.97). Compared to 2009-2010, starting PD between 2005 and 2008 or 2011 and 2016 was strongly associated with a lower rate of transfer to HD (PR 0.88, 95% CI: 0.81-0.96, and PR 0.91, 95% CI: 0.84-0.99, respectively), mostly due to a decline in the rate of infection-related transfers to HD (PR 0.96, 95% CI: 0.94-0.98). CONCLUSIONS: Rates of the composite end point of either death or transfer to HD, death, and transfer to HD have decreased in recent decades. The decline in transfers to HD rates, observed since 2011, is mainly the result of a significant decline in infection-related transfers.

Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.

Impact of the implementation of an assisted peritoneal dialysis service on peritoneal dialysis initiation.

BACKGROUND: There is limited information available on the impact that provision of an assisted peritoneal dialysis (PD) service has on the initiation of PD. The aim of this study was to assess this impact in a centre following initiation of assisted PD in 2011. METHODS: This retrospective, single-centre study analysed 1576 patients incident to renal replacement therapies (RRTs) between January 2002 and 2017. Adjusted Cox regression with a time-varying explanatory variable and a Fine and Gray model were used to examine the effect of assisted PD use on the rates and cumulative incidence of PD initiation, accounting for the non-linear impact of RRT starting time and the competing risks (transplant and death). RESULTS: Patients starting PD with assistance were older than those starting unassisted: median (interquartile range): 70.0 (61.5-78.3) versus 58.7 (43.8-69.2) years old, respectively. In the adjusted analysis assisted PD service availability was associated with an increased rate of PD initiation [cause-specific hazard ratio (cs-HR) 1.78, 95% confidence interval 1.21-2.61]. During the study period, the rate of starting PD fell before flattening out. Transplantation and death rates increased over time but this did not affect the fall in PD initiation [for each year in the study cs-HR of starting PD 0.95 (0.93-0.98), sub-distribution HR 0.95 (0.94-0.97)]. CONCLUSIONS: In a single-centre study, introducing an assisted PD service significantly increased the rate of PD initiation, benefitting older patients most. This offsets a fall in PD usage over time, which was not explained by changes in transplantation or death.

Estimating risk of encapsulating peritoneal sclerosis accounting for the competing risk of death.

BACKGROUND: Risk of encapsulating peritoneal sclerosis (EPS) is strongly associated with the duration of peritoneal dialysis (PD), such that patients who have been on PD for some time may consider elective transfer to haemodialysis to mitigate the risk of EPS. There is a need to determine this risk to better inform clinical decision making, but previous studies have not allowed for the competing risk of death. METHODS: This study included new adult PD patients in Australia and New Zealand (ANZ; 1990-2010) or Scotland (2000-08) followed until 2012. Age, time on PD, primary renal disease, gender, data set and diabetic status were evaluated as predictors at the start of PD, then at 3 and 5 years after starting PD using flexible parametric competing risks models. RESULTS: In 17 396 patients (16 162 ANZ, 1234 Scotland), EPS was observed in 99 (0.57%) patients, less frequently in ANZ patients (n = 65; 0.4%) than in Scottish patients (n = 34; 2.8%). The estimated risk of EPS was much lower when the competing risk of death was taken into account (1 Kaplan-Meier = 0.0126, cumulative incidence function = 0.0054). Strong predictors of EPS included age, primary renal disease and time on PD. The risk of EPS was reasonably discriminated at the start of PD (C-statistic = 0.74-0.79) and this improved at 3 and 5 years after starting PD (C-statistic = 0.81-0.92). CONCLUSIONS: EPS risk estimates are lower when calculated using competing risk of death analyses. A patient's estimated risk of EPS is country-specific and can be predicted using age, primary renal disease and duration of PD.

How unmeasured confounding in a competing risks setting can affect treatment effect estimates in observational studies.

BACKGROUND: Analysis of competing risks is commonly achieved through a cause specific or a subdistribution framework using Cox or Fine & Gray models, respectively. The estimation of treatment effects in observational data is prone to unmeasured confounding which causes bias. There has been limited research into such biases in a competing risks framework. METHODS: We designed simulations to examine bias in the estimated treatment effect under Cox and Fine & Gray models with unmeasured confounding present. We varied the strength of the unmeasured confounding (i.e. the unmeasured variable's effect on the probability of treatment and both outcome events) in different scenarios. RESULTS: In both the Cox and Fine & Gray models, correlation between the unmeasured confounder and the probability of treatment created biases in the same direction (upward/downward) as the effect of the unmeasured confounder on the event-of-interest. The association between correlation and bias is reversed if the unmeasured confounder affects the competing event. These effects are reversed for the bias on the treatment effect of the competing event and are amplified when there are uneven treatment arms. CONCLUSION: The effect of unmeasured confounding on an event-of-interest or a competing event should not be overlooked in observational studies as strong correlations can lead to bias in treatment effect estimates and therefore cause inaccurate results to lead to false conclusions. This is true for cause specific perspective, but moreso for a subdistribution perspective. This can have ramifications if real-world treatment decisions rely on conclusions from these biased results. Graphical visualisation to aid in understanding the systems involved and potential confounders/events leading to sensitivity analyses that assumes unmeasured confounders exists should be performed to assess the robustness of results.

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis.

Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-ß1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.

A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent.

Encapsulating peritoneal sclerosis (EPS) is a potentially devastating complication of peritoneal dialysis (PD). Diagnosis is often delayed due to the lack of effective and accurate diagnostic tools. We therefore examined peritoneal effluent for potential biomarkers that could predict or confirm the diagnosis of EPS and would be valuable in stratifying at-risk patients and driving appropriate interventions. Using prospectively collected samples from the Global Fluid Study and a cohort of Greek PD patients, we utilized 2D SDSPAGE/ MS and iTRAQ to identify changes in the peritoneal effluent proteome from patients diagnosed with EPS and controls matched for treatment exposure. We employed a combinatorial peptide ligand library to compress the dynamic range of protein concentrations to aid identification of low-abundance proteins. In patients with stable membrane function, fibrinogen γ-chain and heparan sulphate proteoglycan core protein progressively increased over time on PD. In patients who developed EPS, collagen-α1(I), γ-actin and Complement factors B and I were elevated up to five years prior to diagnosis. Orosomucoid-1 and a2-HS-glycoprotein chain-B were elevated about one year before diagnosis, while apolipoprotein A-IV and α1-antitrypsin were decreased compared to controls. Dynamic range compression resulted in an increased number of proteins detected with improved resolution of protein spots, compared to the full fluid proteome. Intelectin-1, dermatopontin, gelsolin, and retinol binding protein-4 were elevated in proteome-mined samples from patients with EPS compared to patients that had just commenced peritoneal dialysis. Thus, prospective analysis of peritoneal effluent uncovered proteins indicative of inflammatory and pro-fibrotic injury worthy of further evaluation as diagnostic/prognostic markers.

Peritoneal inflammation precedes encapsulating peritoneal sclerosis: results from the GLOBAL Fluid Study.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an uncommon condition, strongly associated with a long duration of peritoneal dialysis (PD), which is itself associated with increased fibrosis in the peritoneal membrane. The peritoneal membrane is inflamed during PD and inflammation is often associated with fibrosis. We hypothesized that patients who subsequently develop EPS might have a more inflamed peritoneal membrane during PD. METHODS: We performed a nested, case-control study identifying all EPS cases in the UK arm of the GLOBAL Fluid Study and matching them by centre and duration of PD with two to three controls. Dialysate and plasma samples were taken during repeated peritoneal equilibration tests prior to cessation of PD from cases and controls. Samples were assayed by electrochemiluminescence immunoassay for interleukin-1ß (IL-1ß), tumour necrosis factor α (TNF-α), interferon-γ (IFN-γ) and IL-6. Results were analysed by linear mixed models adjusted for age and time on PD. RESULTS: Eleven EPS cases were matched with 26 controls. Dialysate TNF-α {0.64 [95% confidence interval (CI) 0.23, 1.05]} and IL-6 [0.79 (95% CI 0.03, 1.56)] were significantly higher in EPS cases, while IL-1ß [1.06 (95% CI -0.11, 2.23)] and IFN-γ [0.62 (95% CI -0.06, 1.29)] showed a similar trend. Only IL-6 was significantly higher in the plasma [0.42 (95% CI 0.07, 0.78)]. Solute transport was not significantly different between cases and controls but did increase in both groups with the duration of PD. CONCLUSIONS: The peritoneal cavity has higher levels of inflammatory cytokines during PD in patients who subsequently develop EPS, but neither inflammatory cytokines nor peritoneal solute transport clearly discriminates EPS cases. Increased systemic inflammation is also evident and is probably driven by increased peritoneal inflammation.

Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival.

Systemic inflammation, as evidenced by elevated inflammatory cytokines, is a feature of advanced renal failure and predicts worse survival. Dialysate IL-6 concentrations associate with variability in peritoneal small solute transport rate (PSTR), which has also been linked to patient survival. Here, we determined the link between systemic and intraperitoneal inflammation with regards to peritoneal membrane function and patient survival as part of the Global Fluid Study, a multinational, multicenter, prospective, combined incident and prevalent cohort study (n=959 patients) with up to 8 years of follow-up. Data collected included patient demographic characteristics, comorbidity, modality, dialysis prescription, and peritoneal membrane function. Dialysate and plasma cytokines were measured by electrochemiluminescence. A total of 426 survival endpoints occurred in 559 incident and 358 prevalent patients from 10 centers in Korea, Canada, and the United Kingdom. On patient entry to the study, systemic and intraperitoneal cytokine networks were dissociated, with evidence of local cytokine production within the peritoneum. After adjustment for multiple covariates, systemic inflammation was associated with age and comorbidity and independently predicted patient survival in both incident and prevalent cohorts. In contrast, intraperitoneal inflammation was the most important determinant of PSTR but did not affect survival. In prevalent patients, the relationship between local inflammation and membrane function persisted but did not account for an increased mortality associated with faster PSTR. These data suggest that systemic and local intraperitoneal inflammation reflect distinct processes and consequences in patients treated with peritoneal dialysis, so their prevention may require different therapeutic approaches; the significance of intraperitoneal inflammation requires further elucidation.

Centre variation in home dialysis uptake: A survey of kidney centre practice in relation to home dialysis organisation and delivery in England.

BACKGROUND: Disparities in home dialysis uptake across England suggest inequity and unexplained variation in access. We surveyed staff at all English kidney centres to identify patterns in service organisation/delivery and explore correlations with home therapy uptake, as part of a larger study ('Inter-CEPt'), which aims to identify potentially modifiable factors to address observed variations. METHODS: Between June and September 2022, staff working at English kidney centres were surveyed and individual responses combined into one centre-level response per question using predetermined data aggregation rules. Descriptive analysis described centre practices and their correlation with home dialysis uptake (proportion of new home dialysis starters) using 2019 UK Renal Registry 12-month home dialysis incidence data. RESULTS: In total, 180 responses were received (50/51 centres, 98.0%). Despite varied organisation of home dialysis services, most components of service delivery and practice had minimal or weak correlations with home dialysis uptake apart from offering assisted peritoneal dialysis and 'promoting flexible decision-making about dialysis modality'. Moderate to strong correlations were identified between home dialysis uptake and centres reporting supportive clinical leadership (correlation 0.32, 95% Confidence Interval (CI): 0.05-0.55), an organisational culture that values trying new initiatives (0.57, 95% CI: 0.34-0.73); support for reflective practice (0.38, 95% CI: 0.11-0.60), facilitating research engagement (0.39, 95% CI: 0.13-0.61) and promoting continuous quality improvement (0.29, 95% CI: 0.01-0.53). CONCLUSIONS: Uptake of home dialysis is likely to be driven by organisational culture, leadership and staff attitudes, which provide a supportive clinical environment within which specific components of service organisation and delivery can be effective.

International variations in serum PTH and calcium levels and their mortality associations in peritoneal dialysis patients: Results from PDOPPS.

BACKGROUND: Mineral bone disorder (MBD) in chronic kidney disease (CKD) is associated with high symptom burden, fractures, vascular calcification, cardiovascular disease and increased morbidity and mortality. CKD-MBD studies have been limited in peritoneal dialysis (PD) patients. Here, we describe calcium and parathyroid hormone (PTH) control, related treatments and mortality associations in PD patients. METHODS: We used data from eight countries (Australia and New Zealand (A/NZ), Canada, Japan, Thailand, South Korea, United Kingdom, United States (US)) participating in the prospective cohort Peritoneal Dialysis Outcomes and Practice Patterns Study (2014-2022) among patients receiving PD for >3 months. We analysed the association of baseline PTH and albumin-adjusted calcium (calciumAlb) with all-cause mortality using Cox regression, adjusted for potential confounders, including serum phosphorus and alkaline phosphatase. RESULTS: Mean age ranged from 54.6 years in South Korea to 63.5 years in Japan. PTH and serum calciumAlb were measured at baseline in 12,642 and 14,244 patients, respectively. Median PTH ranged from 161 (Japan) to 363 pg/mL (US); mean calciumAlb ranged from 9.1 (South Korea, US) to 9.8 mg/dL (A/NZ). The PTH/mortality relationship was U-shaped, with the lowest risk at PTH 300-599 pg/mL. Mortality was nearly 20% higher at serum calciumAlb 9.6+ mg/dL versus 8.4-<9.6 mg/dL. MBD therapy prescriptions varied substantially across countries. CONCLUSIONS: A large proportion of PD patients in this multi-national study have calcium and/or PTH levels in ranges associated with substantially higher mortality. These observations point to the need to substantially improve MBD management in PD to optimise patient outcomes. LAY SUMMARY: Chronic kidney disease-mineral bone disorder (MBD) is a systemic condition, common in dialysis patients, that results in abnormalities in parathyroid hormone (PTH), calcium, phosphorus and vitamin D metabolism. A large proportion of peritoneal dialysis (PD) patients in this current multi-national study had calcium and/or PTH levels in ranges associated with substantially higher risks of death. Our observational study design limits our ability to determine whether these abnormal calcium and PTH levels cause more death due to possible confounding that was not accounted for in our analysis. However, our findings, along with other recent work showing 48-75% higher risk of death for the one-third of PD patients having high phosphorus levels (>5.5 mg/dL), should raise strong concerns for a greater focus on improving MBD management in PD patients.

An update on absolute and relative indications for dialysis treatment modalities.

Background: Choosing a dialysis modality is an important decision for people to make as their kidney failure progresses. In doing so, their options should be informed by any absolute or relative indications that may favour one modality over another. Methods: In creating this update, we reviewed literature using a framework that considered first, high-level outcomes (survival and modality transition) from large registry data and cohort studies when considering optimal patient pathways; second, factors at a dialysis provider level that might affect relative indications; and third, specific patient-level factors. Both main types of dialysis modality, peritoneal (PD) and haemodialysis (HD), and their subtypes were considered. Results: For most people starting dialysis, survival is independent of modality, including those with diabetes. Better survival is seen in those with less comorbidity starting with PD or home HD, reflecting continued improvements over recent decades that have been greater than improvements seen for centre HD. There are provider-level differences in the perceived relative indications for home dialysis that appear to reflect variability in experience, prejudice, enthusiasm, and support for patients and carers. Absolute contraindications are uncommon and, in most cases, where modality prejudice exists, e.g. obesity, Adult Polycystic Kidney Disease, and social factors, this is not supported by reported outcomes. Conclusion: Absolute contraindications to a particular dialysis modality are rare. Relative indications for or against particular modalities should be considered but are rarely more important than patient preferences.

The Peritoneal Membrane and its Role in Peritoneal Dialysis.

A healthy and functional peritoneal membrane is key to achieve sufficient ultrafiltration and to restore fluid balance, a major component of high-quality prescription in patients treated with peritoneal dialysis (PD). Variability in membrane function at the start of PD or changes over time on treatment influence dialysis prescription and outcomes, and dysfunction of the peritoneal membrane contributes to fluid overload and associated complications. In this review, we summarize the current knowledge about the structure, function and pathophysiology of the peritoneal membrane with a focus on clinical implications for patient-centered care. We also discuss the molecular and genetic mechanisms of solute and water transport across the peritoneal membrane, including the role of aquaporin water channels in crystalloid vs. colloid osmosis; why and how to assess membrane function using peritoneal equilibration tests; the etiologies of membrane dysfunction and their specific management; and the impact of genetic variation on membrane function and outcomes in patients treated with PD. This review also identifies the gaps in current knowledge and perspectives for future research to improve our understanding of the peritoneal membrane and, ultimately, to improve the care of patients treated with PD.

Narrative Review of Glycemic Management in People With Diabetes on Peritoneal Dialysis.

There is an increasing number of people with diabetes on peritoneal dialysis (PD) worldwide. However, there is a lack of guidelines and clinical recommendations for managing glucose control in people with diabetes on PD. The aim of this review is to provide a summary of the relevant literature and highlight key clinical considerations with practical aspects in the management of diabetes in people undergoing PD. A formal systematic review was not conducted because of the lack of sufficient and suitable clinical studies. A literature search was performed using PubMed, MEDLINE, Central, Google Scholar and ClinicalTrials.gov., from 1980 through February 2022. The search was limited to publications in English. This narrative review and related guidance have been developed jointly by diabetologists and nephrologists, who reviewed all available current global evidence regarding the management of diabetes in people on PD.We focus on the importance of individualized care for people with diabetes on PD, the burden of hypoglycemia, glycemic variability in the context of PD and treatment choices for optimizing glucose control. In this review, we have summarized the clinical considerations to guide and inform clinicians providing care for people with diabetes on PD.