ABSTRACT
AIM: The current study evaluated the feasibility and preliminary efficacy of a psychosocial intervention, the Kidney Optimal Health Program, in reducing symptoms of depression and anxiety in individuals with advanced chronic kidney disease. METHODS: Patients with stage 4 or 5 chronic kidney disease were randomized to either a nine-session psychosocial intervention programme or usual care. Feasibility was assessed through recruitment and retention rates and programme acceptability. Participants completed assessments of depression, anxiety and psychosocial health at baseline and at 3-, 6- and 12-month follow-up. A repeated-measures analysis of variance was used to compare groups on outcomes over time. RESULTS: One hundred and twenty-eight patients were screened for eligibility; 84 consented to participant and were randomized to receive the intervention (N = 42) or usual care (N = 42). 27 (32.1%) participants withdrew prior to baseline assessment. Of those who completed the baseline assessment (N = 57), trial retention was high (75.4% at 3-month, 80.7% at 6-month and 70.2% at 12-month follow-up). Participants reported high levels of programme acceptability. The patients who completed the intervention (N = 17) demonstrated significantly decreased depression at 12-month follow-up compared to the usual care group (N = 13). CONCLUSION: The results support the feasibility of the Kidney Optimal Health Program intervention in recruitment, retention and programme acceptability with an improved screening protocol. Preliminary support is provided for improvement in depressive symptoms in patients with advanced chronic kidney disease. Further investigation through a fully powered randomized controlled trial is warranted.
Subject(s)
Anxiety/etiology , Anxiety/therapy , Depression/etiology , Depression/therapy , Psychosocial Intervention , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/psychology , Aged , Feasibility Studies , Female , Humans , Male , Middle Aged , Severity of Illness IndexABSTRACT
Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality, and adverse outcomes in transplantation. Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. This regulated necrosis (RN) takes several forms, with necroptosis and ferroptosis being the best described. The precise mechanisms and relationships between the RN pathways in renal IRI are currently the subject of active research. The common endpoint of RN is cell membrane rupture, resulting in the release of cytosolic components with subsequent inflammation and activation of the immune system. We review the evidence and mechanisms of RN in the kidney following renal IRI, and discuss the use of small molecule inhibitors and genetically modified mice to better understand this process and guide potentially novel therapeutic interventions.
Subject(s)
Acute Kidney Injury/pathology , Kidney Transplantation/adverse effects , Kidney Tubules/pathology , Microvessels/pathology , Reperfusion Injury/pathology , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Animals , Apoptosis/drug effects , Apoptosis/genetics , Clinical Trials, Phase II as Topic , Disease Models, Animal , Epithelial Cells/pathology , Ferroptosis/drug effects , Ferroptosis/genetics , Humans , Kidney Failure, Chronic/surgery , Kidney Tubules/cytology , Mice , Mice, Transgenic , Microvessels/drug effects , Necroptosis/drug effects , Necroptosis/genetics , Necrosis/etiology , Necrosis/pathology , Oxazepines/pharmacology , Oxazepines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinases/genetics , Protein Kinases/metabolism , Randomized Controlled Trials as Topic , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Regional Blood Flow/drug effects , Regional Blood Flow/genetics , Reperfusion Injury/drug therapy , Reperfusion Injury/etiology , Signal Transduction/drug effects , Signal Transduction/genetics , Treatment Outcome , Triazoles/pharmacology , Triazoles/therapeutic useABSTRACT
We have previously reported that ICOS-Ig expressed locally by a PIEC xenograft induces a perigraft cellular accumulation of CD4+ CD25+ Foxp3+ T cells and specific xenograft prolongation. In the present study we isolated and purified CD4+ CD25+ T cells from ICOS-Ig secreting PIEC grafts to examine their phenotype and mechanism of xenograft survival using knockout and mutant mice. CD4+ CD25+ T cells isolated from xenografts secreting ICOS-Ig were analysed by flow cytometry and gene expression by real-time PCR. Regulatory function was examined by suppression of xenogeneic or allogeneic primed CD4 T cells in vivo. Graft prolongation was shown to be dependent on a pre-existing Foxp3+ Treg, IL-10, perforin and granzyme B. CD4+ CD25+ Foxp3+ T cells isolated from xenografts secreting ICOS-Ig demonstrated a phenotype consistent with nTreg but with a higher expression of CD275 (ICOSL), expression of CD278 (ICOS) and MHC II and loss of CD73. Moreover, these cells were functional and specifically suppressed xenogeinic but not allogeneic primed T cells in vivo.
Subject(s)
CD4-Positive T-Lymphocytes/cytology , Graft Survival , Heterografts/immunology , Inducible T-Cell Co-Stimulator Protein/metabolism , Animals , Apoptosis , Cell Line , Forkhead Transcription Factors/metabolism , Granzymes/metabolism , Interleukin-10/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Perforin/metabolism , Phenotype , Real-Time Polymerase Chain Reaction , Time FactorsABSTRACT
Living kidney donors (LKD) for paediatric kidney transplant recipients (KTR) have a heightened motivation to donate for emotional reasons and the clear health benefits to the KTR. We hypothesized that the cohort of LKD for paediatric KTR (LKD-P) includes motivated young parents with a higher lifetime end-stage kidney disease (ESKD) risk compared to adult KTR (LKD-A). Data from the Australia and New Zealand Dialysis and Transplant LKD Registry (2004-2015) was analysed to compare baseline characteristics and predonation ESKD risk in LKD-P (n = 315) versus LKD-A (n = 3448). LKD-P were younger (median age 42 vs. 50 years; P < 0.001) and had a marginally higher lifetime ESKD risk (median 0.44% vs. 0.40%; P < 0.01), with a similar proportion of LKD exceeding 1% risk threshold (5.4% vs. 5.6%; P = NS). Compared to grandparents as LKD-P, parents (median age 41 vs. 59 years; P < 0.001) had a higher lifetime ESKD (0.44% vs. 0.25%; P < 0.001). Although unique benefits to paediatric KTR justify the minor increase in lifetime ESKD risk in young parents, carefully selected grandparents are an alternative LKD-P option, allowing parents to donate for subsequent transplants.
Subject(s)
Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , Adult , Algorithms , Australia , Female , Humans , Living Donors , Male , Middle Aged , Motivation , New Zealand , Pediatrics , Registries , Retrospective Studies , Risk , Transplant RecipientsABSTRACT
AIM: Levels of plasma markers of myocardial fibrosis (galectin-3), stretch (B-type natriuretic peptide (BNP)) and injury (high-sensitivity troponin T (hs-TnT)) are affected by haemodialysis, residual renal function (RRF) and cardiac pathology. We aimed to determine the association of RRF, urine output and haemodialysis itself on cardiac biomarkers in haemodialysis patients. METHODS: Adult haemodialysis patients underwent venesection pre- and post-haemodialysis then echocardiography and inter-dialytic urine collection to calculate RRF (mL/min per 1.73m2 ) and urine output (mL/day). Galectin-3, BNP-32, NT-ProBNP and hs-TnT levels were compared across tertiles of echocardiographic parameters, RRF and urine output using the non-parametric test for trend across ordered groups. RESULTS: Twenty-three patients (17 male) with mean age 67.7±13.8 years and median (interquartile range) dialysis duration 13.6 (9.8-19.1) months participated. Galectin-3 was substantially lower following haemodialysis: 55 ng/mL (47-70) versus 23 ng/mL (19-27, P < 0.001), but other biomarkers changed little. By increasing RRF tertile, post-dialysis galectin-3 was 32.6 ng/mL (23.7-36.6), 21.9 ng/mL (19.0-23.2) and 19.0 ng/mL (16.9-21.0, P = 0.001); NT-ProBNP was 10 192 ng/L (2303-21 504), 2037 ng/L (1224-10 795) and 1481 ng/L (172-2890, P = 0.016). Results were similar for daily urine volume, but measured echocardiographic parameters were not associated with biomarker concentrations. CONCLUSION: Plasma concentration of galectin-3 is reduced by the haemodialysis procedure. Lower RRF and urine volume are strongly associated with higher levels of galectin-3 and NT-Pro-BNP. These associations are important to the clinical interpretation of these biomarker levels in haemodialysis patients.
Subject(s)
Galectin 3/blood , Heart Diseases/blood , Kidney Diseases/therapy , Kidney/physiopathology , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Renal Dialysis , Troponin T/blood , Aged , Aged, 80 and over , Biomarkers/blood , Blood Proteins , Echocardiography , Female , Galectins , Heart Diseases/diagnostic imaging , Heart Diseases/physiopathology , Humans , Kidney/metabolism , Kidney Diseases/blood , Kidney Diseases/diagnosis , Kidney Diseases/physiopathology , Male , Middle Aged , Predictive Value of Tests , Treatment Outcome , Urination , Urodynamics , Ventricular Function, LeftABSTRACT
BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.
Subject(s)
Carbazoles/therapeutic use , Heart Diseases/diagnosis , Propanolamines/therapeutic use , Renal Insufficiency, Chronic/complications , Adrenergic beta-Antagonists/therapeutic use , Adult , Aged , Biomarkers/blood , Carbazoles/pharmacology , Carvedilol , Female , Heart Diseases/etiology , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Natriuretic Peptide, Brain/drug effects , Peptide Fragments/blood , Peptide Fragments/drug effects , Propanolamines/pharmacology , Troponin T/blood , Troponin T/drug effectsABSTRACT
BACKGROUND: ß-Blocking agents reduce cardiovascular mortality in patients with heart disease, but their potential benefit in dialysis patients is unclear. We aimed to determine the feasibility of a randomized controlled trial (RCT). STUDY DESIGN: Pilot RCT. SETTING & PARTICIPANTS: Patients who received dialysis for 3 or more months and were 50 years or older (or ≥18 years with diabetes or cardiovascular disease) were recruited from 11 sites in Australia and New Zealand. We aimed to recruit 150 participants. INTERVENTION: After a 6-week run-in with the ß-blocker carvedilol, we randomly assigned participants to treatment with carvedilol or placebo for 12 months. OUTCOMES & MEASUREMENTS: The prespecified primary outcome was the proportion of participants who tolerated carvedilol, 6.25mg, twice daily during the run-in period. After randomization, we report participant withdrawal and the incidence of intradialytic hypotension (IDH). RESULTS: Of 1,443 patients screened, 354 were eligible, 91 consented, and 72 entered the run-in stage. 49 of 72 run-in participants (68%; 95% CI, 57%-79%) achieved the primary outcome. 5 of the 23 withdrawals from run-in were attributable to bradycardia or hypotension. After randomization, 10 of 26 allocated to carvedilol and 4 of 23 allocated to placebo withdrew. 4 participants randomly assigned to carvedilol withdrew because of bradycardia or hypotension. Overall, there were 4 IDH events per 100 hemodialysis sessions; in participants allocated to carvedilol versus placebo, respectively, there were 7 versus 2 IDH events per 100 hemodialysis sessions (P=0.1) in the 2 weeks immediately following a dose increase and 4 versus 3 IDH events per 100 hemodialysis sessions after no dose increase (P=0.7). LIMITATIONS: Unable to recruit planned sample size. CONCLUSIONS: Recruiting patients receiving dialysis to an RCT of ß-blocker versus placebo will prove challenging. Possible solutions include international collaboration and exploring novel trial designs such as a registry-based RCT.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Carbazoles/therapeutic use , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Propanolamines/therapeutic use , Renal Dialysis , Aged , Carvedilol , Double-Blind Method , Feasibility Studies , Female , Humans , Male , Middle AgedABSTRACT
Donor-recipient HLA mismatch remains a leading cause for sensitization and graft loss in kidney transplantation. HLA compatibility at an epitope level is emerging as an improved method of matching compared with current HLA antigen allocation. A novel epitope-based allocation approach to prospectively exclude donors with high-level mismatches was implemented for pediatric KTRs on the DD waiting list. Nineteen consecutive transplants were followed for 12 months, including eight DD KTRs listed with eplet exclusions, as well as three DD KTRs and eight LD KTRs without exclusions. KTRs with eplet exclusions had estimated GFR of 78.5 mL/min/1.73 m2 , no episodes of rejection, and time to transplant 6.55 months. HLA-A, HLA-B, HLA-DR antigen mismatches were similar between all groups. KTRs with exclusions had significantly lower class II eplet mismatches (20.4) than the contemporary DD KTRs without exclusions (63.7) and DD KTRs transplanted in the preceding decade (46.9). dnDSAs were identified in two of eight DD KTRs with exclusions, two of three DD KTRs without exclusions and five of eight LD KTRs. Epitope-based allocation achieved timely access to transplantation, low class II eplet mismatches, and low rates of dnDSAs in the first year. This strategy requires longer follow-up and larger numbers, but has the potential to reduce anti-HLA sensitization and improve both graft survival and opportunities for future retransplantation.
Subject(s)
Antibodies/immunology , Epitopes/immunology , HLA Antigens/immunology , Kidney Transplantation , Renal Insufficiency/surgery , Tissue and Organ Procurement/methods , Adolescent , Adult , Child , Female , Glomerular Filtration Rate , Graft Survival , Humans , Male , Middle Aged , Prospective Studies , Renal Insufficiency/immunology , Reoperation , Time Factors , Tissue Donors , Treatment Outcome , Young AdultABSTRACT
AIMS: The Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study aims to determine the feasibility of a large-scale randomized controlled trial with clinical endpoints comparing the beta-blocking agent carvedilol with placebo in patients receiving dialysis. METHODS: The BLOCADE Feasibility Study is a randomized, double-blind, placebo-controlled, parallel group feasibility study comparing the beta-blocking agent carvedilol with placebo. Patients receiving dialysis for ≥3 months and who are aged ≥50 years, or who are ≥18 years and have diabetes or cardiovascular disease, were eligible. The primary outcome was the proportion of participants who complete a 6-week run-in phase in which all participants received carvedilol titrated from 3.125 mg twice daily to 6.25 mg twice daily. Other measures included how many patients are screened, the proportion recruited, the overall recruitment rate, the proportion of participants who remain on study drug for 12 months and the incidence of intra-dialytic hypotension while on randomized treatment. RESULTS: The BLOCADE Feasibility Study commenced recruiting in May 2011 and involves 11 sites in Australia and New Zealand. CONCLUSIONS: The BLOCADE Feasibility Study will inform the design of a larger clinical endpoint study to determine whether beta-blocking agents provide benefit to patients receiving dialysis, and define whether such a study is feasible.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Carbazoles/therapeutic use , Cardiovascular Diseases/prevention & control , Kidney Failure, Chronic/therapy , Peritoneal Dialysis , Propanolamines/therapeutic use , Renal Dialysis , Research Design , Adrenergic beta-Antagonists/adverse effects , Australia , Carbazoles/adverse effects , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Carvedilol , Clinical Protocols , Double-Blind Method , Feasibility Studies , Female , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/diagnosis , Male , Medication Adherence , Middle Aged , New Zealand , Patient Selection , Peritoneal Dialysis/adverse effects , Propanolamines/adverse effects , Renal Dialysis/adverse effects , Sample Size , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of the renin-angiotensin system that counteracts the adverse effects of angiotensin II. In heart failure patients, elevated plasma ACE2 activity predicted adverse events and greater myocardial dysfunction. We aimed to describe plasma ACE2 activity and its clinical associations in patients with kidney disease. METHODS: Patients recruited from a single centre comprised of chronic kidney disease Stage III/IV (CKD), haemodialysis patients and kidney transplant recipients (KTRs). Plasma ACE2 enzyme activity was measured using a fluorescent substrate assay in plasma, collected at baseline and stored at -80°C. Linear regression was performed in both males and females separately to determine the covariates associated with log-transformed ACE2. RESULTS: The median (interquartile range) plasma ACE2 activity in pmol/mL/min was 15.9 (8.4-26.1) in CKD (n = 59), 9.2 (3.9-18.2) in haemodialysis (n = 100) and 13.1 (5.7-21.9) in KTR (n = 80; P < 0.01). In male haemodialysis patients, ACE2 activity was 12.1 (6.8-19.6) compared with 4.4 (2.5-10.3) in females (P < 0.01). Log-transformed ACE2 plasma activity was associated with post-haemodialysis systolic blood pressure in females [ß-coefficient 0.04, 95% confidence interval (95% CI) 0.01-0.06, P = 0.006]. In males, log-transformed ACE2 plasma activity was associated with B-type natriuretic peptide (ß-coefficient 0.39, 95% CI 0.19-0.60, P < 0.001). Plasma ACE2 activity was not associated with mortality. CONCLUSIONS: Plasma ACE2 activity is reduced in haemodialysis patients compared with CKD patients, and in female haemodialysis patients compared with male. The different associations of plasma ACE2 activity between male and female haemodialysis patients indicate that the role of ACE2 in cardiovascular disease may differ by gender.
Subject(s)
Kidney Transplantation , Peptidyl-Dipeptidase A/blood , Renal Dialysis , Renal Insufficiency, Chronic/enzymology , Aged , Angiotensin-Converting Enzyme 2 , Biomarkers/metabolism , Cohort Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/pathologyABSTRACT
Necroptosis, a pathway of regulated necrosis, involves recruitment and activation of RIPK1, RIPK3 and MLKL, leading to cell membrane rupture, cell death and release of intracellular contents causing further injury and inflammation. Necroptosis is believed to play an important role in the pathogenesis of kidney ischemia-reperfusion injury (IRI). However, the dynamics of necroptosis in kidney IRI is poorly understood, in part due to difficulties in detecting phosphorylated MLKL (pMLKL), the executioner of the necroptosis pathway. Here, we investigated the temporal and spatial activation of necroptosis in a mouse model of unilateral warm kidney IRI, using a robust method to stain pMLKL. We identified the period 3-12 hrs after reperfusion as a critical phase for the activation of necroptosis in proximal tubular cells. After 12 hrs, the predominant pattern of pMLKL staining shifted from cytoplasmic to membrane, indicating progression to the terminal phase of necroptotic cell death. Mlkl-ko mice exhibited reduced kidney inflammation at 12 hrs and lower serum creatinine and tubular injury at 24 hrs compared to wild-type littermates. Interestingly, we observed increased apoptosis in the injured kidneys of Mlkl-ko mice, suggesting a relationship between necroptosis and apoptosis in kidney IRI. Together, our findings confirm the role of necroptosis and necroinflammation in kidney IRI, and identify the first 3 hrs following reperfusion as a potential window for targeted treatments.
Subject(s)
Necroptosis , Reperfusion Injury , Animals , Mice , Kidney/pathology , Necrosis/pathology , Inflammation/metabolism , Reperfusion Injury/metabolismABSTRACT
The association between blood pressure and cardiovascular outcomes in patients undergoing hemodialysis remains controversial. This may relate in part to the technique and device used and the timing of the blood pressure measurement in relation to the hemodialysis procedure. Emerging evidence indicates that standardized hemodialysis unit blood pressure measurements or measurements obtained at home, either by the patient or using an ambulatory blood pressure monitor, may offer advantages over routine hemodialysis unit blood pressure measurements for determining cardiovascular risk and treatment. This review discusses the available evidence and implications for clinicians and clinical trials.
Subject(s)
Blood Pressure Determination/methods , Hypertension/prevention & control , Kidney Failure, Chronic/therapy , Renal Dialysis/adverse effects , Blood Pressure Monitoring, Ambulatory/methods , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Female , Follow-Up Studies , Humans , Hypertension/etiology , Kidney Failure, Chronic/diagnosis , Long-Term Care , Male , Monitoring, Physiologic/methods , Randomized Controlled Trials as Topic , Renal Dialysis/methods , Reproducibility of Results , Risk AssessmentABSTRACT
AIM: Immunophenotype peripheral blood T cells from renal transplant recipients (RTR) using cellular markers of regulatory T cells (Tregs) and flow cytometry, including Foxp3, and correlate these findings with clinical parameters. METHODS: Expression of phenotypic markers of Tregs was assessed by flow cytometric analysis of peripheral blood lymphocytes (PBL) from (i) RTR (n = 95); (ii) patients with end-stage renal failure (ESRF) awaiting transplantation (n = 17); and (iii) normal healthy controls (n = 18). RESULTS: The percentage of CD4(+) CD25(+) Foxp3(+) cells within the CD4(+) cell population did not significantly alter at different time points post-transplant. However, the percentage of CD4(+) CD25(+) Foxp3(+) cells within the CD4(+) population was significantly lower in RTR compared with patients with ESRF. In contrast, RTR and ESRF had a similar percentage of CD4(+) CD25(+) cells expressing Foxp3. Multivariate analysis of PBL and clinical parameters demonstrated (i) a positive linear relationship between the percentage CD4(+) CD25(+) cells expressing Foxp3 and estimated glomerular filtration rate and (ii) a higher percentage of CD4(+) CD25(+) cells in the CD4(+) cell population in patients with malignancy (the majority were skin cancers). Malignancy also correlated strongly with time post-transplant and age of the RTR. CONCLUSION: Immune monitoring of the PBL phenotype in RTR using CD4, CD25 and Foxp3 may stratify RTR and predict graft outcome and function, and risk of complications from immunosuppression. Longitudinal and functional studies of Tregs are essential to extend the findings of the present study.
Subject(s)
Forkhead Transcription Factors/blood , Kidney Failure, Chronic/surgery , Kidney Transplantation/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Aged , Biomarkers/blood , Female , Flow Cytometry , Glomerular Filtration Rate , Graft Rejection/immunology , Graft Rejection/prevention & control , Graft Survival , Humans , Immunophenotyping/methods , Immunosuppressive Agents/therapeutic use , Interleukin-2 Receptor alpha Subunit/blood , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/immunology , Linear Models , Male , Middle Aged , Monitoring, Immunologic , Multivariate Analysis , Neoplasms/immunology , Risk Assessment , Risk Factors , T-Lymphocytes, Regulatory/drug effects , Time Factors , Treatment Outcome , Victoria , Waiting ListsABSTRACT
BACKGROUND AND AIMS: Endothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD. METHODS: In a single centre prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR). RESULTS: Flicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR <90 mL/min/1.73 m2, compared to those with normal renal function (eGFR ≥90 mL/min/1.73 m2) (1.0 [0.4-2.1]% vs. 2.0 [0.8-3.6]%; p < 0.01). In patients with normal renal function, subjects with the lowest FI-RAD responses exhibited the greatest annual decline in eGFR. In uni- and multivariable analysis, among subjects with normal renal function, a 1% decrease in FI-RAD was associated with an accelerated decline in eGFR of 0.10 (0.01, 0.15; p = 0.03) and 0.07 mL/min/1.73 m2 per year (0.00, 0.14; p = 0.06), respectively. FI-RAD was not predictive of CKD progression in subjects with baseline eGFR <90 mL/min/1.73 m2. CONCLUSIONS: Retinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD, and serves as an indicator of long-term CKD progression in those with normal renal function.
Subject(s)
Cardiovascular Diseases , Renal Insufficiency, Chronic , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Disease Progression , Glomerular Filtration Rate , Heart Disease Risk Factors , Humans , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Risk FactorsABSTRACT
BACKGROUND: Cardiovascular mortality rates in the general population have decreased over time. We hypothesized that cardiovascular mortality rates in dialysis patients, which are higher than in the general population, have not decreased as much as those in the general population. STUDY DESIGN: Comparison of registry data with population data. SETTING & PARTICIPANTS: Data for prevalent Australian patients for whom dialysis was the first renal replacement therapy were obtained from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry for 1992-2005. Data for a comparable Australian general population were obtained from the Australian Bureau of Statistics. OUTCOME: Cardiovascular mortality rates per 100 person-years were calculated from ANZDATA Registry data, and age-specific relative risks were calculated relative to cardiovascular mortality rates in the general population. RESULTS: Included in this cohort were 34,741 dialysis patients with 93,112 person-years of follow-up and 7,267 cardiovascular deaths. Cardiovascular mortality rates decreased over time in the general population and in dialysis patients older than 55 years. In patients aged 55-64 years, cardiovascular mortality rates were 9.0 (95% CI, 7.8-10.3) per 100 person-years in 1992-1994 and 6.4 (95% CI, 5.5-7.3) in 2004-2005; corresponding relative risks were 32.4 (95% CI, 28.2-37.2) and 52.0 (95% CI, 45.2-59.9), respectively. The corresponding cardiovascular mortality rates for dialysis patients aged 65-74 years were 11.6 (95% CI, 10.4-13.0) and 8.3 (95% CI, 7.4-9.3); relative risks were 12.9 (95% CI, 11.6-14.5) and 20.8 (95% CI, 18.7-23.2). Using negative binomial regression, the relative risk associated with dialysis compared with the general population increased over time (P for interaction = 0.001). LIMITATIONS: Causes of death used to define cardiovascular mortality were not coded using identical systems in the ANZDATA Registry and the Australian population. CONCLUSIONS: Despite decreasing cardiovascular mortality rates in some dialysis patients, the excess cardiovascular risk compared with the general population is increasing.
Subject(s)
Cardiovascular Diseases/mortality , Kidney Failure, Chronic/therapy , Registries , Renal Dialysis/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Australia/epidemiology , Female , Humans , Male , Middle Aged , Regression Analysis , Risk , Young AdultABSTRACT
A novel strategy in the management of cardiovascular disease in patients with end-stage kidney disease is the use of biochemical markers to facilitate the detection of cardiovascular abnormalities in the hope that this will allow effective therapy to be instituted earlier. The cardiac troponins and B-type natriuretic peptide are among the best studied of these biochemical markers of cardiovascular disease. However, controversy remains regarding the interpretation of such results and the subsequent clinical application of these biomarkers, particularly when abnormal in patients with end-stage kidney disease. This review addresses some of the important issues to consider with the interpretation of abnormal cardiac troponin and B-type natriuretic peptide results in patients undergoing dialysis.
Subject(s)
Cardiovascular Diseases/blood , Kidney Failure, Chronic/therapy , Natriuretic Peptide, Brain/blood , Troponin/blood , Biomarkers/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Predictive Value of Tests , Prognosis , Renal Dialysis , Up-RegulationABSTRACT
Dendritic cells (DCs) and CTLA4Ig are important in regulating T-cell responses and therefore represent potential therapeutic tools in transplantation. In this study, CTLA4Ig was expressed in a C57BL/6 murine DC line (JAWS II) by lentiviral transduction and these cells were used to examine T-cell immunomodulatory effects in vitro and in vivo. A lower stimulation index to C57BL/6 was observed with splenocytes from BALB/c mice primed with JAWS II-CTLA4Ig compared with control JAWS II-green fluorescent protein (JAWS II-GFP). Mice primed with JAWS II-CTLA4Ig cells had significantly prolonged antigen-specific C57BL/6 skin graft survival compared with either JAWS II-GFP-primed or naïve mice (median 13, 11 and 11 days, respectively, P=0.0001). Furthermore, JAWS II-CTLA4Ig-primed mice that had been previously transplanted with skin grafts were re-transplanted with skin grafts 6 months later without immune manipulation. These mice demonstrated specific prolongation of second-set rejection responses, indicating systemic immune modulation induced by genetically modified DC. The mechanism was not due to expression of indoleamine 2,3-dioxygenase or induction of circulating regulatory T cells as assessed by flow cytometry of the peripheral blood lymphocytes. This potent effect demonstrated with skin grafts and second-set responses highlights the potential use of this strategy for transplantation more generally.
Subject(s)
Dendritic Cells/metabolism , Graft Survival , Immunoconjugates/metabolism , Skin Transplantation , T-Lymphocytes/metabolism , Abatacept , Animals , Cell Growth Processes/genetics , Cell Growth Processes/immunology , Cell Line , Dendritic Cells/immunology , Dendritic Cells/pathology , Graft Survival/genetics , Immunoconjugates/genetics , Immunoconjugates/immunology , Immunologic Memory/genetics , Lymphocyte Activation/genetics , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transgenes/geneticsABSTRACT
BACKGROUND: Renal impairment is a major risk factor for cardiovascular disease. This study addressed clinical predictors of outcome following cardiac surgery, focusing on pre-operative renal dysfunction. METHODS: All patients undergoing cardiac surgery at Austin Health from June 1, 2001 to June 30, 2006, were included in the analysis. Logistic regression models were used to evaluate clinical factors predicting "operative mortality" and common post-operative complications. RESULTS: The operative mortality was 1.36% for coronary artery bypass grafting (CABG) alone (n=1027), 5.07% for valve surgery alone (n=217), 4.43% for combined CABG and valve surgery (n=158) and 11.11% for other cardiac surgical procedures (n=270). Amongst CABG alone patients, pre-operative renal impairment was a strong predictor of operative mortality, with a 35-43% increased risk of death (p=0.005) for every 10 ml/min/1.73 m(2) that the glomerular filtration rate was lower. Peripheral vascular disease, recent myocardial infarction and congestive cardiac failure also predicted operative mortality. Pre-operative renal impairment also increased the rate of various post-operative complications, as well as duration of admission. CONCLUSION: Renal dysfunction is significantly associated with increased mortality and morbidity following cardiac surgery and necessitates careful consideration in risk benefit analysis when considering cardiac surgery.
Subject(s)
Coronary Artery Bypass/adverse effects , Heart Valve Prosthesis/adverse effects , Kidney Failure, Chronic/complications , Aged , Confidence Intervals , Coronary Artery Bypass/mortality , Databases, Factual , Female , Heart Failure , Heart Valve Prosthesis/statistics & numerical data , Humans , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction , Odds Ratio , Peripheral Vascular Diseases , Prognosis , Renal Replacement Therapy , Retrospective Studies , Treatment Outcome , VictoriaABSTRACT
A 64-year-old gentleman initially presented with nephrotic syndrome and membranous nephropathy with positive staining for C1q, which was suspicious for lupus membranous nephritis. Investigation led to the simultaneous diagnosis of colorectal cancer (CRC). The CRC was surgically excised and the patient's nephrotic syndrome resolved. The patient subsequently presented with classic systemic lupus erythematosus (SLE) including positive serological markers, mouth-ulcers and a photosensitive maculopapular rash. Two months later the patient represented with an SLE flare encompassing the full-hand of renal-pulmonary syndrome and vasculitic-neuropathy, importantly at this presentation occult recurrence of CRC was proven with tissue biopsy. Major histocompatibility class II haplotyping demonstrated HLA-DRB1*03, a known predisposition for SLE. This case depicts the scenario of tumour transformation triggering SLE development in a predisposed individual after an initial paraneoplastic manifestation in the form of membranous nephropathy (plus C1q). This supports the potential role of tumourgenesis in the development of SLE in a primed individual.
ABSTRACT
BACKGROUND: Vascular-access patency is critical for effective and uninterrupted haemodialysis. Limited literature exists evaluating if a surgical or repeated radiological approach is superior for reocclusion following failure of radiological recanalization. Few consistent early predictors of failure have been identified after radiological intervention for thrombosed vascular access. METHODS: 138 patients with thrombosed arteriovenous fistulas or prosthetic grafts treated by radiological intervention, over 10 years, were retrospectively investigated. Reocclusion was treated by either repeated thrombolysis or surgery. Radiological patency rates, after first and second episodes of access thrombosis at 12 months after intervention were analysed. Surgical and radiological patency rates for second access thrombosis were compared. The Cox and logistic regression models were used to identify potential factors associated with reocclusion. RESULTS: In patients who experienced reocclusion within 1 month after radiological intervention, the 3-month repeated radiological patency rate (n = 13) was 38.5%, compared to a 60% surgical patency rate (n = 10), but this did not reach statistical significance. Radiological patency rates after first access thrombosis at 3 and 12 months were 56.6 and 39.5%, respectively. In contrast, radiological patency rates after a second access thrombosis were 51.1 and 24.4%, respectively; a statistical difference in success was not achieved. Native arteriovenous fistulas were 3.23 times as likely to remain patent over 12 months following a first radiological intervention (p < 0.02) and less likely to experience a second reocclusion event (p < 0.01). Anticoagulation was associated with a lower risk of second reocclusion, whilst a history of venous thrombosis was associated with a greater risk (p < 0.02). CONCLUSION: Surgery achieves superior patency rates compared to repeated radiological interventions and should be considered if reocclusion occurs within a month following radiological thrombolysis.