Multicentre registry analysis of incremental peritoneal dialysis incidence and associations with patient outcomes.

BACKGROUND: Incremental peritoneal dialysis (PD) is increasingly advocated to reduce treatment burden and costs, with potential to better preserve residual kidney function. Global prevalence of incremental PD use is unknown and use in Australia and New Zealand has not been reported. METHODS: Binational registry analysis including incident adult PD patients in Australia and New Zealand (2007-2017), examining incidence of and outcomes associated with incremental PD (first recorded PD exchange volume <42 L/week (incremental) vs. ≥42 L/week (standard)). RESULTS: Incremental PD use significantly increased from 2.7% of all incident PD in 2007 to 11.1% in 2017 (mean increase 0.84%/year). Duration of incremental PD use was 1 year or less in 67% of cases. Male sex, Aboriginal and Torres Strait Islander (ATSI) or Maori ethnicities, age 45-59 years, medical comorbidities or treatment at a centre with low use of automated PD or icodextrin was associated with lower incidence of incremental PD use. Low body mass index and higher estimated glomerular filtration rate was associated with higher incidence. After accounting for patient and centre variables, commencing PD with an incremental prescription was associated with reduced peritonitis risk (adjusted hazard ratio 0.73, 95% confidence interval (CI) 0.61-0.86).When kidney transplantation and death were considered as competing risks, the association between incremental PD and peritonitis was not significant (sub-hazard ratio [SHR] 0.91, 95%CI 0.71-1.17, p = 0.5), however cumulative incidence of 30-day transfer to haemodialysis was lower in those receiving incremental PD (SHR 0.73, 95%CI 0.56-0.94, p = 0.01). There was no association between incremental PD and death. CONCLUSIONS: Incremental PD use is increasing in Australia and New Zealand and is not associated with patient harm.

Incremental Versus Standard (Full-Dose) Peritoneal Dialysis.

Incremental peritoneal dialysis (PD), defined as less than "standard dose" PD prescription, has a number of possible benefits, including better preservation of residual kidney function (RKF), reduced risk of peritonitis, lower peritoneal glucose exposure, lesser environmental impact, and reduced costs. Patients commencing PD are often new to kidney replacement therapy and possess substantial RKF, which may allow safe delivery of an incremental prescription, often in the form of lower frequency or duration of PD. This has the potential to help improve quality of life (QOL) and life participation through reducing time requirements and burden of treatment. Alternatively, incremental PD could potentially contribute to reduced small solute clearance, fluid overload, or patient reluctance to increase dialysis prescription when later needed. This review discusses the definition, rationale, uptake, potential advantages and disadvantages, and clinical trial evidence pertaining to the use of incremental PD.

Incremental peritoneal dialysis is a safe and feasible prescription in incident patients with preserved residual kidney function.

BACKGROUND: Incremental peritoneal dialysis (PD) is recommended as a component of high-quality care by the international society for PD; however, its feasibility and clinical outcomes have not been widely reported. The aim of this study is to describe our experience with incremental PD. METHODS: This was a retrospective cohort study of incident PD patients at Eastern Health between 2015 and 2019. Patients who stopped PD within 30 days were excluded. Incremental PD was defined in CAPD as using <8 L/day of exchange volume and in automated PD as dialysing without a last fill. Dialysis modality accorded with patient and physician preferences. RESULTS: The 96 patients were included in this study; 54 with incremental PD. Compared to full-dose PD, incremental PD patients were more likely to be female, had less comorbid diabetes (28% vs. 52%) and higher residual kidney function (RKF) (Kt/V 2.0 ± 0.7 vs. 1.4 ± 0.7). Age, BMI and starting eGFR did not differ between groups. Incremental PD exposed patients to lower exchange volumes (4.4 ± 2.1 vs. 8.5 ± 1.1 L/day), glucose load (46 ± 41 g/day vs. 119 ± 46) and was associated with a longer peritonitis-free survival. PD technique survival, rates of peritonitis or hospitalization were comparable between groups. Predictors for longer incremental PD use included older age and higher starting eGFR. CONCLUSIONS: Incremental PD is a feasible, goal-directed initial prescription in patients with RKF with comparable peritonitis rates and technique survival. Validation of this prescription in prospective studies is warranted.

Calciprotein Particle Formation in Peritoneal Dialysis Effluent Is Dependent on Dialysate Calcium Concentration.

BACKGROUND: The accumulation of fetuin-A-containing calciprotein particles (CPP) in the serum of patients with renal disease and those with chronic inflammation may be involved in driving sterile inflammation and extraosseous mineral deposition. We previously showed that both fetuin-A and CPP were present in the peritoneal dialysis (PD) effluent of stable PD patients. It is unknown whether different PD fluids might affect the formation of CPP in vivo. METHOD: Peritoneal effluent from 12 patients was collected after a 6-hour dwell with 7 different commercial PD fluids. Calciprotein particles and inflammatory cytokines were measured by flow cytometry. RESULTS: High inter-subject variability in CPP concentration was observed. Peritoneal dialysis fluids containing 1.75 mmol/L calcium were associated with enhanced formation of CPP in vivo, compared with fluids containing 1.25 mmol/L calcium. Osmotic agent, fluid pH, and glucose concentration did not affect CPP formation. Peritoneal dialysis effluent CPP levels were not associated with changes in inflammatory cytokines. CONCLUSION: High calcium-containing PD fluids favor intraperitoneal CPP formation. This finding may have relevance for future PD fluid design.

Non-Touch Aseptic Technique Maintains Sterility of Antibiotic-Admixed Peritoneal Dialysis Fluid.

There is a paucity of data on the sterility of peritoneal dialysis fluid (PDF) after drug admixture. International Society for Peritoneal Dialysis (ISPD) guidelines suggest using sterile technique when admixing antibiotics; however, the degree of sterility remains unclear. This issue is most pertinent when preparing take-home PDF for outpatient treatment of peritonitis. This study compares the sterility of PDF admixed with antibiotics using a non-touch aseptic technique (NTAT) versus sterile technique.Groups of 8 PDF mixtures (1.5% Dianeal or Icodextrin [Baxter International Inc., Spring Grove, IL, USA]) were admixed with 1 g/L ceftazidime and vancomycin, or 20 mL saline, either by a pharmacist using sterile technique in a sterile suite, or a nurse in a clinical room using NTAT. Dianeal inoculated with 1 × 106 colony-forming units (CFU)/L of coagulase-negative Staphylococcus (CNS), with and without antibiotics, served as positive controls. Admixed PDFs were left at room temperature for 72 hours, then cultured using the BacT/ALERT system. A positive culture by day 5 constituted a contamination. Differences in proportion of contamination between groups were assessed using the Chi-squared test.Eighty PDF bags underwent microbiological testing. Sterility was maintained in all bags, independent of technique (NTAT versus sterile technique), type of PDF (Dianeal versus Icodextrin), or whether antibiotics were admixed. Of the positive controls, CNS-inoculated PDFs without antibiotics were all culture positive; however, when inoculated into antibiotic-admixed PDFs, only S. haemolyticus remained culture-positive (p < 0.0001).In conclusion, PDF sterility can be maintained using NTAT for up to 3 days at room temperature. Currently, there is insufficient evidence to adopt sterile technique in sterile suites when admixing take-home PDF.

A controlled study of the effects of ferric carboxymaltose on bone and haematinic biomarkers in chronic kidney disease and pregnancy.

Background: Intravenous (IV) iron can modulate fibroblast growth factor 23 (FGF23) concentrations and cause transient but significant hypophosphataemia. However, it is unknown what other markers might be involved, especially in different patient groups. This study aimed to determine changes in bone and haematinic biomarkers following IV ferric carboxymaltose (FCM) and to identify risk factors for hypophosphataemia in pregnant subjects and those with chronic kidney disease (CKD). Methods: Changes in bone [serum FGF23, fractional excretion of phosphate urinary fractional excretion of phosphate (FEPi), serum phosphate and serum vitamin D derivatives] and haematinic [plasma hepcidin, serum ferritin and transferrin saturation (TSAT)] biomarkers after 1 g of IV FCM were followed in iron-deficient pregnant and CKD patients and compared with controls (estimated glomerular filtration rate > 60 mL/min/1.73 m2). Data were collected at baseline and up to 42 days after infusion. Risk factors for post-FCM hypophosphataemia were also assessed. Results: Sixty-five subjects completed the study (control, n = 20; pregnant, n = 20; CKD, n = 25). A uniform but variable increase across groups was seen in intact FGF23 (peak Day 2), whereas c-terminal FGF23 varied markedly. Trough serum phosphate timed with the peak FEPi at Day 7, recovering by Day 21 in the pregnant group and Day 42 in other groups. Independent predictors of a low phosphate nadir included baseline phosphate, FEPi and weight-adjusted FCM dose. All groups showed an early and marked increase in plasma hepcidin (peak Day 2), serum ferritin and TSAT (peak Day 7 for both). Conclusions: Changes in bone and haematinic biomarkers differ between patient groups following IV FCM. For patients with lower serum phosphate concentrations, limiting the dose and measuring levels 7 days after administration may mitigate clinically significant hypophosphataemia.

Practice of Peritoneal Dialysis Catheter Flushing in Australia and New Zealand: Multi-Center Cross-Sectional Survey.

BACKGROUND: Evidence of effective interventions to prevent peritoneal dialysis (PD) catheter malfunction before first use is presently insufficient to guide clinical care. Regular flushing of the PD catheter (e.g. before PD commencement) has been adopted by some practitioners in the belief that it will prevent catheter obstruction and/or malfunction. The aim of this study was to characterize and evaluate PD catheter flushing practices across Australian and New Zealand PD units. METHODS: An on-line survey was distributed to all 62 PD units in Australia (12 August 2016; n = 51) and New Zealand (2 February 2017; n = 11), with questions relating to PD catheter flushing practices, audit, and outcomes. RESULTS: Forty-nine units of variable size (< 16 to > 100 patients) completed the survey (79% response rate). All centers flushed PD catheters at some stage after insertion as routine unit practice. Forty-one units (84%) routinely flushed during periods of PD rest at varying intervals ranging from alternate daily to monthly. The type and volume of solution used to flush varied between units. Units that practised routine flushing of PD catheters were almost twice as likely to audit their catheter-related outcomes (66% vs 38%, p = 0.23) and more likely to have reported blocked catheters in the preceding 12 months (84% vs 0%, p = 0.01) compared with those units that did not routinely flush PD catheters. Thirty units (61%) regularly audited and monitored catheter-related outcomes. CONCLUSIONS: This study identified a wide variation in center practices relating to PD catheter flushing. Drawing conclusions about any relationship between flushing practices and clinical outcomes was impeded by the relatively low uptake of regular auditing and monitoring of catheter-related outcomes across surveyed units. Evaluation of the benefits and harms of standardized PD catheter flushing practices on patient outcomes in a randomized trial is needed to guide practice.

Long-term graft survival in patients with chronic antibody-mediated rejection with persistent peritubular capillaritis treated with intravenous immunoglobulin and rituximab.

Chronic antibody-mediated rejection (cAMR) is the major cause of premature renal allograft loss and is resistant to therapy with 12-month graft failure of up to 50% reported. We examined the duration of graft survival and associates of graft failure in patients with donor-specific antibody-positive cAMR and treatment-resistant peritubular capillaritis between June 2007 and October 2010. Those with advanced interstitial fibrosis (n=5) were excluded. Included patients (n=24) received treatment with high-dose intravenous immunoglobulin and fixed-dose rituximab (500 mg). Compared with previous reports, the study group experienced prolonged graft survival (median 82.1 months). Graft loss was predicted by eGFR and degree of proteinuria at diagnosis but not by donor-specific HLA antibody class or intensity, nor individual or summed Banff scores. Allograft biopsies were further examined for infiltrating leukocyte subtypes and location with high numbers of glomerular leukocytes, particularly macrophages, independently associated with an increased risk of graft failure. This study suggests that patients with cAMR and persistent microcirculatory inflammation, excluding those with advanced histological damage, can expect prolonged graft survival when treated with IVIg and rituximab. Trial level evidence is required to validate this observation. Further examination of the role of macrophages in cAMR is warranted.

Effects of intravenous iron on fibroblast growth factor 23 (FGF23) in haemodialysis patients: a randomized controlled trial.

BACKGROUND: Intravenous iron affects serum levels of intact fibroblast growth factor-23 (iFGF23) and its cleavage product c-terminal FGF23 (cFGF23) in iron-deficient people with normal renal function. We hypothesized that intravenous iron modulates iFGF23 and cFGF23 in haemodialysis patients differently according to the type of iron used. METHODS: Prevalent, stable haemodialysis patients requiring protocol-based intravenous iron therapy were randomized to a single 200 mg dose of either ferric carboxymaltose (FCM) or iron sucrose (IS). The primary outcome was change in iFGF23 and cFGF23 from pre-infusion to Day 2 post-infusion. Serum hepcidin, ferritin and phosphate were also measured. Pair-wise comparisons utilised the Wilcoxon rank sum test; linear mixed models with an interaction term for treatment and time evaluated between-group effects. RESULTS: Forty-two participants completed the study. In those randomized to FCM (n = 22), median (interquartile range) values pre-infusion and Day 2, respectively, were 843 pg/mL (313-1922) and 576 pg/mL (356-1296, p = 0.05) for iFGF23, 704RU/mL (475-1204) and 813RU/mL (267-1156, p = 0.04) for cFGF23, and 1.53 mmol/L (1.14-1.71) and 1.37 (1.05-1.67, p = 0.03) for phosphate. These parameters did not change following IS. Both serum ferritin (p < 0.001) and hepcidin (p < 0.001) increased in both groups, and the increase in hepcidin was greater in the FCM group (p = 0.03 for between-group difference). CONCLUSIONS: Contrary to iron-deficient people with normal renal function, haemodialysis patients given protocol-driven intravenous FCM demonstrated a fall in iFGF23 and a rise in cFGF23, changes not evident with IS. This suggests a differential effect of intravenous iron treatment according to both formulation and renal function. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register ACTRN12614000548639 . Registered 22 May 2014 (retrospectively registered).

Multifaceted Assessment of Health Literacy in People Receiving Dialysis: Associations With Psychological Stress and Quality of Life.

Health literacy (HL) refers to a person's ability to engage effectively with health information and services. We aimed to describe the HL of people receiving dialysis and the factors associated with it. A cross-sectional design was used, with demographic and clinical data as predictors. Participants were people receiving dialysis at a metropolitan health service in Melbourne, Australia. Health consumers with conditions not requiring dialysis were included for comparison. The Health Literacy Questionnaire, Kidney Disease Quality of Life-36, and Depression Anxiety Stress Scales-21 were administered. Participants (M age = 68.2 ± 13.7 years; n = 57 males) were 76 people receiving hemodialysis within a dialysis unit, 16 people receiving home peritoneal dialysis, and 8 people receiving home hemodialysis. Participants scored higher on the HL domains social support for health and engagement with health care providers but lower on active management of health than the comparison group (n = 813). Hierarchical cluster analysis revealed 2 clusters within the dialysis sample representing higher (n = 43) and lower (n = 57) profiles of HL. The higher HL cluster reported better quality of life across 4 of 5 domains of the Kidney Disease Quality of Life-36, fewer symptoms of depression and anxiety, and higher serum albumin (mean difference = 2.06 g/L, p = .04) than the lower HL cluster. These results show that people receiving dialysis feel better supported and informed about their health than other health consumers but are less active in managing it. Higher HL is associated with better mental health and quality of life. Identifying HL characteristics may help direct specific interventions to improve patient education and support.

Myeloid mineralocorticoid receptor activation contributes to progressive kidney disease.

Clinical and experimental studies have shown that mineralocorticoid receptor (MR) antagonists substantially reduce kidney injury. However, the specific cellular targets and mechanisms by which MR antagonists protect against kidney injury must be identified. We used conditional gene deletion of MR signaling in myeloid cells (MR(flox/flox) LysM(Cre) mice; MyMRKO) or podocytes (MR(flox/flox) Pod(Cre) mice; PodMRKO) to establish the role of MR in these cell types in the development of mouse GN. Accelerated anti-glomerular basement membrane GN was examined in groups of mice: MyMRKO, PodMRKO, wild-type (WT) littermates, and WT mice receiving eplerenone (100 mg/kg twice a day; EPL-treated). At day 15 of disease, WT mice had glomerular crescents (37%±5%), severe proteinuria, and a 6-fold increase in serum cystatin-C. MyMRKO, PodMRKO, and EPL-treated mice with GN displayed proteinuria similar to that in these disease controls. However, MyMRKO and EPL-treated groups had a 35% reduction in serum cystatin-C levels and reduced crescent numbers compared with WT mice, whereas PodMRKO mice were not protected. The protection observed in MyMRKO mice appeared to result predominantly from reduced recruitment of macrophages and neutrophils into the inflamed kidney. Suppression of kidney leukocyte accumulation in MyMRKO mice correlated with reductions in gene expression of proinflammatory molecules (TNF-α, inducible nitric oxide synthase, chemokine (C-C motif) ligand 2, matrix metalloproteinase-12), tubular damage, and renal fibrosis and was similar in EPL-treated mice. In conclusion, MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN, and myeloid deficiency of MR provides protection similar to eplerenone in this disease.

Acute polyarthritis immediately after kidney transplantation: a medication-induced rheumatoid arthritis flare?

A patient with known steroid-dependent rheumatoid arthritis (RA) developed an acute symmetrical polyarthropathy of small and medium-sized joints associated with markedly elevated inflammatory markers suggestive of RA flare, on day 4 after deceased-donor renal transplantation. The patient received standard induction immunosuppression with methylprednisolone and basiliximab, and had commenced prednisolone, tacrolimus and mycophenolate mofetil. Serological investigations and joint aspirate to exclude infective causes and crystal arthropathy were unremarkable. High-dose prednisolone (50 mg daily) resulted in partial but unsustained symptomatic improvement. On suspicion of a medication-related adverse event, tacrolimus and mycophenolate mofetil were changed to cyclosporine A and azathioprine on day 16. This was followed by rapid improvement in symptoms and normalization of inflammatory markers. Unexpected sequelae in the early post-transplantation period create diagnostic and management challenges. Medication-related adverse events are not uncommon, and we speculate in this case on the potential for medication-induced immune system dysregulation stimulating disease activity in a chronic autoimmune condition after introduction of new immunosuppressants.

Slow and steady. Reducing thrombotic events in renal transplant recipients treated with IVIg for antibody-mediated rejection.

Intravenous immunoglobulin (IVIg) therapy for antibody-mediated rejection (AMR) is increasing and is associated with a small but significant incidence of thrombosis. We determined thrombosis rates in patients treated with high-dose IVIg for AMR before and after alteration of an infusion protocol. The newer protocol introduced routine administration of aspirin 300 mg, enoxaparin 1 mg/kg, intravenous hydration and a maximum infusion rate of 100 mg/kg per hour (previously 200 mg/kg per hour). Nine thromboses in 275 infusions occurred before the protocol alteration (event rate 3.3%). Two were arterial thromboses including an acute myocardial infarct and a renal transplant artery thrombosis, which resulted in infarction of 2/3 of the graft. Seven venous thromboses occurred, six in arteriovenous fistulae and one case with bilateral above knee deep venous thromboses. Significant associations with thromboses were seen with higher IVIg dose and male sex. In the 6 months since the introduction of the new infusion protocol, 74 infusions have been administered with no thrombotic events. There have been no significant bleeding or fluid overload side-effects. Infusion times, however, have been doubled. A slower rate of infusion combined with antiplatelet and anticoagulation has thus far eliminated the small but significant IVIg-related thrombosis rate previously observed in our patients treated for AMR without resulting in significant side-effects. Further study is now required to define which elements of this protocol are essential.

Review: membranes for haemodialysis.

Haemodialysis, by design, uses a semipermeable membrane to separate blood from dialysate. The qualities of this membrane determine the nature of the 'traffic' between the blood and dialysate. In this sense, the qualities of the membrane determine what size molecules move from one compartment to the other, the amount and rate at which they might move and the amount and rate of water movement across the membrane. In addition, the nature of the membrane influences the biological response of the patient both in terms of what is or is not removed by the dialysis process and by way of the reaction to the biocompatibility of the membrane. This brief review will explore aspects of dialysis membrane characteristics.

Lentiviral-mediated fetal gene therapy for monogenic disorders: development of an in vitro rabbit model.

OBJECTIVE: Fetal gene replacement is a novel, potential therapy for monogenic disorders which are diagnosed prenatally. The purpose of this study was to develop in vitro, respiratory-epithelium targeted, lentiviral (LV)-mediated gene transfer in fetal rabbit tracheas. METHODS: Via triple plasmid transfection, vesicular stomatitis virus-G (VSV-G)-pseudotyped LV vector containing green fluorescent protein (GFP) marker gene, under the control of a cytomegalovirus promoter was constructed. LV bioavailability in rabbit amniotic fluid (AF) was evaluated by infectivity assays of 293T cell monolayers in variable concentrations of AF. Fetal tracheas from time-mated rabbits (term gestation, G = 31 days) were collected on G 23-25 days, and placed in tissue culture (substrate-enriched DMEM, 37 degrees C, 5% CO(2)/room air). The tracheal cultures were transfected with 1 x 10(5) LV particles, and analyzed daily for: reporter gene by polymerase chain reaction, and reporter gene product (GFP) by whole-mount fluoroscopy and immunohistochemistry. RESULTS: 293T cell infectivity assays confirmed bioavailability of LV in rabbit AF. Following in vitro transfection, GFP DNA and GFP were detectable in fetal rabbit tracheas by 4 and 5 days, respectively. Immunocytochemistry localized GFP to the luminal aspect of tracheal epithelium. CONCLUSIONS: In vitro, LV-mediated GFP gene transfer to fetal rabbit tracheas occurs within 4 days, and gene expression is evident by 5 days post-transfection. This observation, and the bioavailability of LV through AF, suggests the appropriateness of this model for the future evaluation of in vivo, transamniotic gene delivery strategies.

Lentiviral vector-mediated, in vivo gene transfer to the tracheobronchial tree in fetal rabbits.

BACKGROUND/PURPOSE: Fetal gene replacement is a novel, potential therapy for antenatally diagnosed monogenic disorders. The purpose of this study was to evaluate in vivo techniques of lentiviral (LV) vector-mediated gene transfer to the tracheobronchial tree in a rabbit model of fetal gene therapy. METHODS: Via triple plasmid transfection, vesicular stomatitis virus-G-pseudotyped LV vector containing green fluorescent protein (GFP) reporter gene under the control of a cytomegalovirus promoter was constructed. In vivo gene transfer of 5 x 10(6) LV particles to fetuses of time-mated NZW rabbits (term = 31 days) was attempted using 2 techniques: (1) direct amniotic injection (gestation = 24-26 days) and (2) direct tracheal injection (gestation = 26 days). Injected fetuses and saline-injected littermate controls were delivered and killed on gestational day 30. Fetal and maternal tissues were analyzed. RESULTS: Both in vivo techniques produced gene transfer to fetal tissues (trachea, lung, liver, intestine), including those of some controls. In one prep, GFP DNA was identified in maternal lung. CONCLUSIONS: Lentiviral vector-mediated GFP gene transfer to fetal rabbit tracheobronchial epithelium occurs within 4 days of transfection by both amniotic injection or direct fetal tracheal injection. This in vivo model confirms bioavailability of vector through amniotic fluid with some cross-infection of adjacent fetuses. Vector access to fetal tissues appears to be by both luminal and hematogenous routes. Transplacental gene transfer from fetus to mother may occur in this model.