An IL-10 homologue encoded by human cytomegalovirus is linked with the viral "footprint" in clinical samples.

Persistent infections with human cytomegalovirus (HCMV) affect the hosts' immune system and have been linked with chronic inflammation and cardiovascular disease. These effects may be influenced by a HCMV-encoded homologue of the anti-inflammatory cytokine, IL-10 (cmvIL-10). To assess this, we quantitated cmvIL-10 in plasma from renal transplant recipients (RTR) and healthy adults. Detectable levels of cmvIL-10 associated with seropositivity in RTR, but were found in some seronegative healthy adults. RTR with detectable cmvIL-10 had elevated interferon-γ T-cell responses to HCMV antigens, whilst cmvIL-10 in healthy adults associated with reduced populations of terminally-differentiated T-cells - a known "footprint" of HCMV. Plasma cmvIL-10 associated with lower VCAM-1 levels in healthy adults. The data suggest cmvIL-10 may suppress seroconversion and/or reduce the footprint of HCMV in healthy adults. This appears to be subverted in RTR by their high burden of HCMV and/or immune dysregulation associated with transplantation. A role for cmvIL-10 in protection of vascular health is discussed.

Utilising organs from hepatitis C virus PCR-positive donors in Western Australia.

We transplanted six solid organs from three hepatitis C virus (HCV) polymerase chain reaction (PCR)-positive donors during 2018-2023. Recipients were treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir for 4-12 weeks, with all six achieving sustained virological response without significant adverse events. As occurs in other jurisdictions, solid organ transplants from HCR PCR-positive donors can be safely utilised in Australia.

Markers of terminally differentiated T-cells as predictors of vascular health in renal transplant recipients and healthy adults.

Meta-analyses confirm a link between persistent human cytomegalovirus (HCMV) infections and cardiovascular disease, but the mechanisms are unclear. We assess whether proportions of T-cell populations are reliable predictors of subclinical atherosclerosis and/or reflect the burden of HCMV in healthy adults and renal transplant recipients (RTR). Samples were collected from healthy adults and RTR at baseline (T0) and after 32 (24-40) months (T1). Left carotid intima media thickness (cIMT) and proportions of T-cells expressing CD57, LIR-1 or the TEMRA phenotype increased in healthy adults and RTR. The T-cell populations correlated with levels of HCMV-reactive antibodies. Proportions of CD57+, LIR-1+ and TEMRA CD8+ T-cells correlated with left and right cIMT in healthy adults. Proportions of CD57+ and LIR-1+ CD8+ T-cells at T0 predicted left cIMT at T1 among healthy adults, but these associations disappeared after adjustment for covariates. We link LIR-1+ and CD57+CD8+ T-cells with the progression of cIMT in healthy adults.

A novel allocation strategy for the difficult-to-allocate donor: audit of deceased donor kidneys utilised for preemptive recipients within Western Australia.

Kidney donor allocation can occasionally be difficult in Australia given a small population spread over vast distances. Therefore, between 2017 and 2019 our service allowed transplantation from deceased donors into local (same-state) preemptive recipients, only if no well-matched dialysis-dependent transplant waitlist recipient was available. Transplantation using this novel allocation pathway was associated with good clinical and immunological outcomes.

Dietary habits in Australian, New Zealand and Malaysian patients with end stage kidney failure: A pre-specified cross-sectional study of the FAVOURED trial participants.

BACKGROUND: Dietary management plays an important role in patients with kidney failure. Current dietary habits of Australians and New Zealanders (ANZ) and Malaysians with chronic kidney disease (CKD Stage 4-5) have not been adequately investigated. We report the dietary habits of people with advanced CKD and their adherence to country-specific dietary guidelines. METHODS: Participants with CKD Stage 4-5, enrolled in the Omega-3 Fatty Acids (Fish oils) and Aspirin in Vascular access Outcomes in Renal Disease (FAVOURED) trial, completed a lifestyle questionnaire at baseline on their dietary intake. RESULTS: Of 567 participants, 538 (ANZ, n = 386; Malaysian, n = 152; mean ± SD age 54.8 ± 14.3 years, 64% male) completed the questionnaire. Dietary fruit and vegetable intakes were higher in ANZ participants; 49% (n = 189) consumed ≥2 serves day-1 of fruit and 61% (n = 235) ate ≥2 serves day-1 of vegetables compared to 24% (n = 36) and 34% (n = 52) of Malaysians, respectively (p < 0.0001). Only 4% (n = 15) of ANZ participants met Australian Dietary recommendations of two fruit and five vegetable serves day-1 . Fish consumption was higher in Malaysians with 83% (n = 126) consuming ≥2 serves week-1 compared to 21% (n = 81) of ANZ participants (p < 0.001). Red meat intake was higher in ANZ participants; however, chicken consumption was similar; 48% (n = 185) consumed >2 chicken serves week-1 and 65% (n = 251) ate >2 serves week-1 of red meat compared to 43% (n = 65) and 15% (n = 23) of Malaysians, respectively. CONCLUSIONS: Significant regional variation in dietary intake for fruit, vegetables and animal protein is described that likely reflects cultural and economic differences. Barriers to meeting recommended dietary intakes require further investigation.

Variants of HCMV UL18 Sequenced Directly from Clinical Specimens Associate with Antibody and T-Cell Responses to HCMV.

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host's burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2- γδ T-cells-populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden.

Sequencing of the Viral UL111a Gene Directly from Clinical Specimens Reveals Variants of HCMV-Encoded IL-10 That Are Associated with Altered Immune Responses to HCMV.

Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ~80% of adults worldwide. Acute infections are often asymptomatic in healthy individuals but generate diverse syndromes in neonates, renal transplant recipients (RTR), and people with HIV (PWH). The HCMV gene UL111a encodes a homolog of human interleukin-10 (IL-10) that interacts with the human IL-10 receptor. Deep sequencing technologies were used to sequence UL111a directly from 59 clinical samples from Indonesian PWH and Australian RTR, healthy adults, and neonates. Overall, 93% of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous variation. Carriage of these variants differed between neonates and adults, Australians and Indonesians, and between saliva and blood leukocytes. The variant alleles of N41D and S71Y occurred together in Australian RTR and were associated with higher T-cell responses to HCMV pp65. The variant P122S was associated with lower levels of antibodies reactive with a lysate of HCMV-infected fibroblasts. L174F was associated with increased levels of antibodies reactive with HCMV lysate, immediate-early 1 (IE-1), and glycoprotein B (gB) in Australian RTR and Indonesians PWH, suggesting a higher viral burden. We conclude that variants of UL111a are common in all populations and may influence systemic responses to HCMV.

Cytomegalovirus burden improves a predictive model identifying measures of vascular risk in renal transplant recipients and healthy adults.

Cytomegalovirus (CMV) has been implicated in vascular pathologies and may warrant inclusion in cardiovascular predictive algorithms. We addressed this in healthy older adults and renal transplant recipients (RTR) as they retain a high burden of CMV. RTR (n = 45) stable more than 2 years after transplantation and 58 age-matched healthy adults were assessed. Plasma inflammatory biomarkers (soluble isoform of the interferon-ß receptor [sIFNAR2], soluble tumour necrosis factorreceptor-1 [sTNFR1], soluble cluster of differentiation 14 [sCD14], C reactive protein, P-selectin, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1), and measures of CMV burden (antibodies, saliva CMV DNA, and interferon γ responses to CMV) were assessed in 2014 and evaluated in 2017 as predictors of vascular health-defined using flow-mediated dilatation (FMD), pulse wave velocity (PWV), and augmentation indices (Aix@ 75). Linear regression models adjusted for age, sex, and body mass index (BMI) were optimized to identify risk factors. In 2017, RTR had inferior vascular health marked by impaired FMD and PWV. Detectable CMV DNA (P = .02) was associated with impaired FMD, whilst CMV glycoprotein B (gB) antibody attenuated this effect (P = .03) (adjusted R2 = .42). In healthy adults, the optimal model for predicting FMD (R2 =.22) incorporated high P-selectin (P = .03) and low ICAM-1 (P = .03) levels with no significant impact of CMV. Elevated sIFNAR2 (P = .04) and gB antibody (P = .06) levels predicted increasing Aix@ 75 (poor vascular health) in healthy adults (R2 = .4), whilst optimal models for RTR (R2 = .37) linked low sIFNAR2 and CMV IE-1 antibody levels with lower Aix@ 75 (better vascular health). CMV IE-1 antibody was also protective in relation to PWV in healthy adults (R2 = .55). Overall, measures of active CMV replication were more predictive of impaired FMD in RTR than standard biomarkers, but increased CMV gB antibodies may be protective.

Identifying critically important vascular access outcomes for trials in haemodialysis: an international survey with patients, caregivers and health professionals.

BACKGROUND: Vascular access outcomes reported across haemodialysis (HD) trials are numerous, heterogeneous and not always relevant to patients and clinicians. This study aimed to identify critically important vascular access outcomes. METHOD: Outcomes derived from a systematic review, multi-disciplinary expert panel and patient input were included in a multilanguage online survey. Participants rated the absolute importance of outcomes using a 9-point Likert scale (7-9 being critically important). The relative importance was determined by a best-worst scale using multinomial logistic regression. Open text responses were analysed thematically. RESULTS: The survey was completed by 873 participants [224 (26%) patients/caregivers and 649 (74%) health professionals] from 58 countries. Vascular access function was considered the most important outcome (mean score 7.8 for patients and caregivers/8.5 for health professionals, with 85%/95% rating it critically important, and top ranked on best-worst scale), followed by infection (mean 7.4/8.2, 79%/92% rating it critically important, second rank on best-worst scale). Health professionals rated all outcomes of equal or higher importance than patients/caregivers, except for aneurysms. We identified six themes: necessity for HD, applicability across vascular access types, frequency and severity of debilitation, minimizing the risk of hospitalization and death, optimizing technical competence and adherence to best practice and direct impact on appearance and lifestyle. CONCLUSIONS: Vascular access function was the most critically important outcome among patients/caregivers and health professionals. Consistent reporting of this outcome across trials in HD will strengthen their value in supporting vascular access practice and shared decision making in patients requiring HD.

Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections.

Cytomegalovirus (CMV) infections may affect natural killer (NK) cells and are implicated in age-related disorders-notably poor vascular endothelial function. Changes may be greater in renal transplant recipients (RTR) as they have a high burden of CMV and may influence antibody-dependent cellular cytotoxicity (ADCC) responses to viral antigen. We obtained blood mononuclear cells from RTR stable after transplantation (n = 27) and age- and sex-matched controls (n = 28). Natural killer (NK) cells were assessed for expression of CD107a or TNF-α, after stimulation with autologous antibodies bound to CMV glycoprotein B (measuring ADCC) or anti-CD16 (measuring NK cell activation). Alleles of FCRG3A (encoding CD16; rs396991) were determined by the Taqman assay. The vascular endothelial function was assessed using flow-mediated dilatation (FMD) of the brachial artery. Proportions of NK cells expressing CD16 ex vivo were lower in RTR. Frequencies of NK cells expressing NKG2C or LIR-1 or lacking FcRγ were highest in CMV-seropositive RTR. ADCC was affected by rs396991 genotype and CMV gB antibody levels, but not by RTR status or detection of CMV DNA in plasma. Responses of FcRγ-NK cells to anti-CD16 were lower compared to FcRγ+ NK cells. Increased percentages of LIR-1 + and FcRγ- NK cells correlated with lower FMD. In summary, CMV evokes substantial and similar ADCC responses in CMV seropositive RTR and controls. The equivalence may reflect higher titers of CMV reactive antibody in RTR, as NK responses stimulated by ligation of CD16 were lower. NK cells that were LIR-1 + and/or FcRγ- were induced by CMV and correlated inversely with vascular endothelial function.

The Effects of OMEGA-3 Fatty Acid Supplementation Upon Interleukin-12 and Interleukin-18 in Chronic Kidney Disease Patients.

OBJECTIVE(S): Cardiovascular disease (CVD) remains a leading cause of mortality in chronic kidney disease (CKD) patients. Interventions targeting traditional risk factors have largely proven ineffective in CKD patients in part because of the increased role of nontraditional risk factors such as chronic inflammation. Omega-3 fatty acids (ω3FA) are inexpensive and safe natural agents, which target inflammation and have potential cardioprotective benefits. The aim of the study was to determine the effects of ω3FA supplementation upon serum interleukin (IL)-12, IL-18, and highly sensitive C-reactive protein (hsCRP) in patients with Stage 3-4 CKD. METHODS: We performed a post-hoc analysis of a randomized placebo-controlled trial in 73 nondiabetic CKD patients to determine the effects of ω3FA supplementation (4 g daily for 8 weeks) upon serum levels of IL-12, IL-18, and hsCRP. RESULTS: There were no preintervention differences in IL-12, IL-18, or hsCRP between treatment groups. Postintervention levels of IL-12, IL-18, and hsCRP were similar between the treatment groups. However, IL-12 and IL-18 increased in both treatment groups over the intervention period, whereas hsCRP remained unchanged. The magnitude of increase in serum IL-18 (ΔIL-18) was significantly less in participants in the ω3FA treatment group compared to placebo (P = .047). CONCLUSION(S): This study has shown that 4 g daily ω3FA supplementation may lower serum IL-18 levels in patients with moderate CKD. Although there were no apparent effects on several other markers of inflammation, this study provides evidence for a specific effect of ω3FA on inflammatory pathways.

The Detection of CMV in Saliva Can Mark a Systemic Infection with CMV in Renal Transplant Recipients.

Human cytomegalovirus (CMV) is often transmitted through saliva. The salivary gland is a site of CMV replication and saliva can be used to diagnose congenital CMV infections. CMV replication is monitored in whole blood or plasma in renal transplant recipients (RTR) and associates with clinical disease. However, these assays may not detect replication in the salivary gland and there is little data linking detection in saliva with systemic infection and clinical sequelae. RTR (n = 82) were recruited > 2 years after transplantation. An in-house quantitative PCR assay was used to detect CMV UL54 in saliva samples. CMV DNA was sought in plasma using a commercial assay. Vascular health was predicted using flow mediated dilatation (FMD) and plasma biomarkers. CMV-reactive antibodies were quantified by ELISA and circulating CMV-specific T-cells by an interferon-γ ELISpot assay. Vδ2- γδ T-cells were detected using multicolor flow cytometry reflecting population expansion after CMV infection. The presence of CMV DNA in saliva and plasma associated with plasma levels of antibodies reactive with CMV gB and with populations of circulating Vδ2- γδ T -cells (p < 0.01). T-cells reactive to CMV immediate early (IE)-1 protein were generally lower in patients with CMV DNA in saliva or plasma, but the level of significance varied (p = 0.02-0.16). Additionally, CMV DNA in saliva or plasma associated weakly with impaired FMD (p = 0.06-0.09). The data suggest that CMV detected in saliva reflects systemic infections in adult RTR.

CMV drives the expansion of highly functional memory T cells expressing NK-cell receptors in renal transplant recipients.

Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post-transplant. We describe how active and latent CMV affect T-cell subsets in RTRs who are stable on maintenance therapy. T-cell responses to CMV were assessed in RTRs (n = 54) >2 years post-transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8+ T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T-cell (TEM ), terminally differentiated T-cell (TEMRA ) and CD57+ TEMRA cell populations. Expression of NK-cell receptors, LIR-1 and KLRG1 on CD4+ and CD8+ CD57+ TEM and TEMRA cells correlated with elevated interferon-γ and cytotoxic responses to anti-CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8+ T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) -1 peptides. The data show that latent and active CMV infection can alter T-cell subsets in RTRs many years after transplantation, and up-regulate T-cell expression of NK-cell receptors. This may enhance effector responses of CD4+ and CD8+ T cells against CMV.

Omega-3 Polyunsaturated Fatty Acid Supplementation to Prevent Arteriovenous Fistula and Graft Failure: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Arteriovenous access failure frequently occurs in people on hemodialysis and is associated with morbidity, mortality and large healthcare expenditures. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) may improve access outcomes via pleiotropic effects on access maturation and function, but may cause bleeding complications. STUDY DESIGN: Systematic review with meta-analysis. SETTING & POPULATION: Adults requiring hemodialysis via arteriovenous fistula or graft. SELECTION CRITERIA: Trials evaluating omega-3 PUFA for arteriovenous access outcomes identified by searches in CENTRAL, MEDLINE, and Embase to 24 January 2017. INTERVENTION: Omega-3 PUFA. OUTCOMES: Primary patency loss, dialysis suitability failure, access abandonment, interventions to maintain patency or assist maturation, bleeding, gastrointestinal side-effects, all-cause and cardiovascular mortality, hospitalization, and treatment adherence. Treatment effects were summarized as relative risks (RR) and 95% confidence intervals (CI). Evidence was assessed using GRADE. RESULTS: Five eligible trials (833 participants) with a median follow-up of 12 months compared peri-operative omega-3 PUFA supplementation with placebo. One trial (n=567) evaluated treatment for fistulae and four (n=266) for grafts. Omega-3 PUFA supplementation prevented primary patency loss with moderate certainty (761 participants, RR 0.81, CI 0.68-0.98). Low quality evidence suggested, that omega-3 PUFA may have had little or no effect on dialysis suitability failure (536 participants, RR 0.95, CI 0.73-1.23), access abandonment (732 participants, RR 0.78, CI 0.59-1.03), need for interventions (732 participants, RR 0.82, CI 0.64-1.04), or all-cause mortality (799 participants, RR 0.99, CI 0.51-1.92). Bleeding risk (793 participants, RR 1.40, CI 0.78-2.49) or gastrointestinal side-effects (816 participants, RR 1.22, CI 0.64-2.34) from treatment were uncertain. There was no evidence of different treatment effects for grafts and fistulae. LIMITATIONS: Small number and methodological limitations of included trials. CONCLUSIONS: Omega-3 PUFA supplementation probably protects against primary loss of arteriovenous access patency, but may have little or no effect on dialysis suitability failure, access interventions or access abandonment. Potential treatment harms are uncertain.

Vascular Access Outcomes Reported in Maintenance Hemodialysis Trials: A Systematic Review.

BACKGROUND: Many randomized controlled trials have been performed with the goal of improving outcomes related to hemodialysis vascular access. If the reported outcomes are relevant and measured consistently to allow comparison of interventions across trials, such trials can inform decision making. This study aimed to assess the scope and consistency of vascular access outcomes reported in contemporary hemodialysis trials. STUDY DESIGN: Systematic review. SETTING & POPULATION: Adults requiring maintenance hemodialysis. SELECTION CRITERIA: All randomized controlled trials and trial protocols reporting vascular access outcomes identified from ClinicalTrials.gov, Embase, MEDLINE, and the Cochrane Kidney and Transplant Specialized Register from January 2011 to June 2016. INTERVENTIONS: Any hemodialysis-related intervention. OUTCOMES: The frequency and characteristics of vascular access outcome measures were analyzed and classified. RESULTS: From 168 relevant trials, 1,426 access-related outcome measures were extracted and classified into 23 different outcomes. The 3 most common outcomes were function (136 [81%] trials), infection (63 [38%]), and maturation (31 [18%]). Function was measured in 489 different ways, but most frequently reported as "mean access blood flow (mL/min)" (37 [27%] trials) and "number of thromboses" (30 [22%]). Infection was assessed in 136 different ways, with "number of access-related infections" being the most common measure. Maturation was assessed in 44 different ways at 15 different time points and most commonly characterized by vein diameter and blood flow. Patient-reported outcomes, including pain (19 [11%]) and quality of life (5 [3%]), were reported infrequently. Only a minority of trials used previously standardized outcome definitions. LIMITATIONS: Restricted sampling frame for feasibility and focus on contemporary trials. CONCLUSIONS: The reporting of access outcomes in hemodialysis trials is very heterogeneous, with limited patient-reported outcomes and infrequent use of standardized outcome measures. Efforts to standardize outcome reporting for vascular access are critical to optimizing the comparability, reliability, and value of trial evidence to improve outcomes for patients requiring hemodialysis.

The effect of n-3 fatty acids and coenzyme Q10 supplementation on neutrophil leukotrienes, mediators of inflammation resolution and myeloperoxidase in chronic kidney disease.

BACKGROUND: Neutrophils release leukotriene (LT)B4 and myeloperoxidase (MPO) that may be important mediators of chronic inflammation in chronic kidney disease (CKD). The n-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have the potential to attenuate inflammation through production of LTB5 and the Specialized Proresolving Lipid Mediators (SPM) that promote the resolution of inflammation. In animal models, coenzyme Q10 (CoQ) also attenuates inflammation by reducing MPO and LTB4. OBJECTIVE: This study evaluated the independent and combined effects of n-3 FA and CoQ supplementation on neutrophil leukotrienes, the pro-inflammatory eicosanoid 5-hydroxyeicosatetraenoic acid (5-HETE), SPM, and plasma MPO, in patients with CKD. DESIGN: In a double-blind, placebo-controlled intervention of factorial design, 85 patients with CKD were randomized to either n-3 FA (4 g), CoQ (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. Plasma MPO and calcium ionophore-stimulated neutrophil release of LTs, 5-HETE and SPM were measured at baseline and after 8 weeks. RESULTS: Seventy four patients completed the intervention. n-3 FA, but not CoQ, significantly increased neutrophil LTB5 (P < 0.0001) and the SPM 18-hydroxyeicosapentaenoic acid (18-HEPE), resolvin E1 (RvE1), resolvin E2 (RvE2) and resolvin E3 (RvE3) that derive from EPA, as well as 17-hydroxydocosahexaenoic acid (17-HDHA) and resolvin D5 (RvD5) that derive from DHA (all P < 0.01). Neutrophil LTB4 and its metabolites, and 5-HETE were not significantly altered by n-3 FA or CoQ. Plasma MPO was significantly reduced with n-3 FA alone (P = 0.013) but not when given in combination with CoQ. CONCLUSION: n-3 FA supplementation in patients with CKD leads to increased neutrophil release of LTB5 and several SPM, as well as a reduction in plasma MPO that may have important implications for limiting chronic inflammation.

The pathogenesis of hemodialysis vascular access failure and systemic therapies for its prevention: Optimism unfulfilled.

In patients receiving hemodialysis, the provision of safe and effective vascular access using an arteriovenous fistula or graft is regarded as a critical priority by patients and health professionals. Vascular access failure is associated with morbidity and mortality, such that strategies to prevent these outcomes are essential. Inadequate vascular remodeling and neointimal hyperplasia resulting in stenosis and frequently thrombosis are critical to the pathogenesis of access failure. Systemic medical therapies with pleiotropic effects including antiplatelet agents, omega-3 polyunsaturated fatty acids (fish oils), statins, and inhibitors of the renin-angiotensin-aldosterone system (RAAS) may reduce vascular access failure by promoting vascular access maturation and reducing stenosis and thrombosis through antiproliferative, antiaggregatory, anti-inflammatory and vasodilatory effects. Despite such promise, the results of retrospective analyses and randomized controlled trials of these agents on arteriovenous fistula and graft outcomes have been mixed. This review describes the current understanding of the pathogenesis of arteriovenous fistula and graft failure, the biological effects of antiplatelet agents, fish oil supplementation, RAAS blockers and statins that may be beneficial in improving vascular access survival, results from clinical trials that have investigated the effect of these agents on arteriovenous fistula and graft outcomes, and it explores future therapeutic approaches combining these agents with novel treatment strategies.

Changing survival of people with myeloma and end stage kidney disease: A cohort study using Australian and New Zealand dialysis and transplant registry 1963-2013.

BACKGROUND: It is unclear whether recent advances in myeloma therapy have improved survival for all those with myeloma and end stage kidney disease (ESKD). METHODS: Population-based registry cohort study using Australia and New Zealand Dialysis and Transplant Registry data 1963-2013. We measured survival of people with myeloma and other plasma cell dyscrasias and ESKD over time, and investigated prognostic factors for improved survival using survival analysis (results expressed as hazard ratios (HR) with 95% confidence intervals). RESULTS: We included 65 940 people (207 595 person-years); 1067 people (1.6%) with myeloma and 572 (0.9%) with other plasma cell dyscrasia. Myeloma ESKD rose from 0.8% before 1994 to 2.2% in 2004 and remained stable. People with myeloma were older, and age increased over time, from 62.5 before 1994 to 70.1 years from 2010, but the non-myeloma group age increased more steeply (52.0 before 1994; 62.2 from 2010). In myeloma patients, survival improved (P < 0.001) with recent predicted 5 year survival of 27.5% aged <55, 32.2% aged 55-64, 16.3% for 65-74 and 12.7% aged ≥75 years. Survival did not improve for plasma cell dyscrasia patients (P = 0.70). Myeloma patients on peritoneal dialysis had improved survival compared with those on haemodialysis (HR 0.7, CI 0.6-0.9), but those aged ≥65 had poorer survival (65-74 years HR 1.5, CI1.2-1.9; ≥75 HR 1.7, CI1.3-2.1), as did diabetics (HR 1.3, CI1.1-1.6). CONCLUSIONS: The proportion of people with myeloma and ESKD remains stable, but their survival has progressively improved in Australia and New Zealand. On starting ESKD treatment with myeloma, a 59 year old without diabetes on peritoneal dialysis can expect a 45% 5 year survival, where a 75-year-old diabetic on haemodialysis has 9% 5 year survival.

Asymptomatic CMV infections in long-term renal transplant recipients are associated with the loss of FcRγ from LIR-1+ NK cells.

While it is established that cytomegalovirus (CMV) disease affects NK-cell profiles, the functional consequences of asymptomatic CMV replication are unclear. Here, we characterize NK cells in clinically stable renal transplant recipients (RTRs; n = 48) >2 years after transplantation. RTRs and age-matched controls (n = 32) were stratified by their CMV serostatus and the presence of measurable CMV DNA. CMV antibody or CMV DNA influenced expression of NKG2C, LIR-1, NKp30, NKp46, and FcRγ, a signaling adaptor molecule, on CD56dim NK cells. Phenotypic changes ascribed to CMV were clearer in RTRs than in control subjects and affected NK-cell function as assessed by TNF-α and CD107a expression. The most active NK cells were FcRγ- LIR-1+ NKG2C- and displayed high antibody-dependent cell cytotoxicity responses in the presence of immobilized CMV glycoprotein B reactive antibody. However, perforin levels in supernatants from RTRs with active CMV replication were low. Overall we demonstrate that CMV can be reactivated in symptom-free renal transplant recipients, affecting the phenotypic, and functional profiles of NK cells. Continuous exposure to CMV may maintain and expand NK cells that lack FcRγ but express LIR-1.