Dynamics of necroptosis in kidney ischemia-reperfusion injury.

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.

Correctional health care and Australian prisoners as recipients of kidney transplants: Legal and ethical issues.

AIM: This research aims to examine the legal and ethical issues surrounding Australia prisoners as potential kidney transplant recipients. METHODS: Examination of relevant statutory and common law including human rights law, state and territory corrections legislation and negligence law. Ethical principles considered, particularly in regards to practical and logistical considerations including adequate delivery of transplantation medical care and implications on the broader organ donation program. Approaches in the United States of America and United Kingdom are compared with the Australian approach. RESULTS: Prisoners are more likely than non-incarcerated individuals to have chronic medical conditions. For most people with kidney failure, kidney transplantation improves both quality of life and life expectancy compared with dialysis therapy. Prisoners have a right to access reasonable medical care under state-based corrections legislation, which is underpinned by human rights law and ethical principles, primarily beneficence, transparency and justice. The right of prisoners to receive reasonable medical care likely extends to ensuring prisoners with kidney failure are considered for kidney transplantation and waitlisted if medically appropriate. Social factors and logistical factors can be relevant when considering eligibility for transplantation as they can relate to a person's ability to comply with medical therapy. Additionally, organ allocation decisions can be emotive, and a decision to offer a kidney transplant to a prisoner may generate significant negative publicity. CONCLUSION: Prisoners with kidney failure should be considered for kidney transplantation. Logistical barriers, such as guard availability, should be addressed by state departments responsible for prisoner health.

Challenges of Glycemic Control in People With Diabetes and Advanced Kidney Disease and the Potential of Automated Insulin Delivery.

Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease in the world. It is known that maintaining optimal glycemic control can slow the progression of CKD. However, the failing kidney impacts glucose and insulin metabolism and contributes to increased glucose variability. Conventional methods of insulin delivery are not well equipped to adapt to this increased glycemic lability. Automated insulin delivery (AID) has been established as an effective treatment in patients with type 1 diabetes mellitus, and there is emerging evidence for their use in type 2 diabetes mellitus. However, few studies have examined their role in diabetes with concurrent advanced CKD. We discuss the potential benefits and challenges of AID use in patients with diabetes and advanced CKD, including those on dialysis.

Impact of chronic kidney disease on illness perceptions, coping, self-efficacy, psychological distress and quality of life.

Chronic kidney disease (CKD) negatively impacts psychological well-being and quality of life (QoL). Underpinned by the Common Sense Model (CSM), this study evaluated the potential mediating role of self-efficacy, coping styles and psychological distress on the relationship between illness perceptions and QoL in patients living with CKD. Participants were 147 people with stage 3-5 kidney disease. Measures included eGFR, illness perceptions, coping styles, psychological distress, self-efficacy and QoL. Correlational analyses were performed, followed by regression modelling. Poorer QoL was associated with greater distress, engagement in maladaptive coping, poorer illness perceptions and lower self-efficacy. Regression analysis revealed that illness perceptions predicted QoL, with psychological distress acting as a mediator. The proportion of variance explained was 63.8%. These findings suggest that psychological interventions are likely to enhance QoL in CKD, if they target the mediating psychological processes associated with illness perceptions and psychological distress.

Inducible Co-Stimulator (ICOS) in transplantation: A review.

Prevention of T cell activation is one of the goals of successful organ and tissue transplantation. Blockade of T cell co-stimulation, particularly of the CD28:B7 interaction, has been shown to prolong graft survival. Inducible Co-Stimulator (ICOS) is the third member of the B7 family and here we review the literature on ICOS, its receptor (B7RP-1), and blockade of this pathway in transplant models. ICOS:B7RP-1 are a single receptor:ligand pair with a loss of function of either being implicated in some autoimmune diseases. ICOS has multiple functions, related to its constitutive expression on B cells and activated T cells. In in vitro transplant models, ICOS:B7RP-1 blockade has produced mixed results as to its ability to modulate lymphocyte proliferation. Several in vivo transplant models demonstrate varying degrees of success in prolonging graft survival. Timing and dose of treatment appear important, and combination with other immunosuppressive treatments may also be of benefit. As ICOS has multiple functions, it may be that the observed variable results are due to inadvertent inactivation of graft protective functions. If these barriers can be overcome, ICOS:B7RP-1 blockade could provide an important target for future immunosuppression regimens.

Retinal microvascular function predicts chronic kidney disease in patients with cardiovascular risk factors.

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.

A psychosocial intervention for individuals with advanced chronic kidney disease: A feasibility randomized controlled trial.

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.

Clinical Outcomes and Risk Factors for Tunneled Hemodialysis Catheter-Related Bloodstream Infections.

Diabetes and left internal jugular vein insertion site were significantly associated with increased risk of a catheter-related bloodstream infection from a tunneled hemodialysis catheter. Ex-smoker status was significantly associated with reduced risk.

Cocaine-associated atypical haemolytic uraemic syndrome in a genetically susceptible individual.

Atypical haemolytic uraemic syndrome (aHUS) is a severe, life-threatening condition that requires early recognition and urgent treatment. In aHUS rare genetic variants in CFH, CFI, CD46, C3 and CFB predispose to complement over activation. This case describes a case of aHUS in which there was a strong temporal association between disease onset and the use of smoked cocaine. The patient was found to have a rare genetic variant in the CFI gene which may have been unmasked by first-time exposure to cocaine. The patient stabilized and improved with early administration of eculizumab, supporting the notion of an underlying immunological pathogenesis and the importance of early intervention.

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention.

The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for consensus on practical aspects of mycophenolate target concentration intervention in contemporary tacrolimus-containing regimens and future research to define maintenance phase exposure targets. However, given ongoing consequences of both overimmunosuppression and underimmunosuppression in kidney transplantation, impacting short- and long-term outcomes, these should be a priority. The imprecise "one-dose-fits-all" approach should be replaced by the clinically proven MPA target concentration strategy.

Eculizumab therapy in gemcitabine-induced thrombotic microangiopathy in a renal transplant recipient.

A renal transplant recipient 7 years post-transplantation, diagnosed with locally advanced pancreatic adenocarcinoma developed thrombotic microangiopathy (TMA) after treatment with gemcitabine and nab-paclitaxel. Gemcitabine was the most likely cause for TMA and was ceased. He received methylprednisolone and plasma exchange with fresh frozen plasma and albumin. Despite plasma exchange, his renal allograft function worsened, and he had persistent haematological evidence of haemolysis. Eculizumab was commenced with resolution-significant improvement in his renal and haematological markers. This case highlights an unusual occurrence of progressive gemcitabine-induced TMA in a renal allograft that had an excellent response to eculizumab. The clinical response also demonstrates involvement of complement dysregulation in gemcitabine-induced TNA.

Antigen-specific CD4+ CD25+ T cells induced by locally expressed ICOS-Ig: the role of Foxp3, Perforin, Granzyme B and IL-10 - an experimental study.

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.

Regulated necrosis in kidney ischemia-reperfusion injury.

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.

Paraneoplastic systemic lupus erythematosus associated with colorectal cancer.

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.

Lifetime risk of end-stage kidney disease in living donors for paediatric kidney transplant recipients in Australia and New Zealand - a retrospective study.

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.

Perioperative risk assessment for successful kidney transplant in leigh syndrome: a case report.

BACKGROUND: Leigh syndrome (LS) is a rare neurodegenerative mitochondrial disorder which typically presents in childhood but has a varied clinical course. Renal involvement such as proximal tubulopathy in patients with mitochondrial disorders has been described. However, end stage renal disease (ESRD) is uncommon and literature regarding patients undergoing kidney transplantation is limited. Successful deceased donor renal transplant has not been previously described in a patient with Leigh Syndrome. CASE PRESENTATION: We report a 21-year-old Han Chinese man who presented with limb weakness and unsteady gait, which progressed rapidly over a period of months until he was wheelchair-bound. He subsequently developed ESRD and was commenced on hemodialysis. Investigations revealed a m.13513G > A mutation with clinical and radiological features consistent with LS. His mitochondrial disease stabilised and he underwent a multidisciplinary assessment for deceased donor kidney transplantation to identify and minimise the LS-associated perioperative risks and potential negative effects of immunosuppressants on his LS. Successful kidney transplantation followed with excellent graft function three and a half years post-transplant and improvement in the patient's physical function. CONCLUSION: This case highlights the importance of careful pre-transplant perioperative risk assessment and post-transplant care in a rare and heterogeneous neurological disease to achieve an ultimately excellent clinical outcome. To our knowledge, this is the first report of successful deceased donor kidney transplant in a patient with known LS.

Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy.

BACKGROUND AND OBJECTIVES: Alport syndrome is an inherited disease characterized by renal failure, hearing loss, and ocular abnormalities, including temporal retinal thinning. This study compared retinal thinning in Alport syndrome and other renal diseases. METHODS: Alport syndrome was diagnosed on renal biopsy and genetic testing. Subjects underwent optical coherence tomography (OCT) (Spectralis OCT, Heidelberg Instruments). Retinal thinning was determined from horizontal macular OCT scans through the foveal center using the formula: Temporal thickness index (TTI) = (nasal - temporal thickness) ÷ nasal thickness × 100%, and compared with the normal range for each age group. Statistical analysis was performed using Student's t test, Mann-Whitney U test, and ROC analysis (SPPS, IBM). RESULTS: The mean temporal retinal thickness index was 12.4 ± 5.2% in men (n = 19) and 7.4 ± 1.4% in women (n = 28) with X-linked Alport syndrome; 13.1 ± 4.5% (n = 4) in recessive disease; 6.4 ± 2.2% (n = 5) in Thin basement membrane nephropathy; and 6.3 ± 3.3% (n = 14) in other renal diseases. Thinning was worse in men than women with X-linked disease (p < 0.01), and worse in men who developed early onset renal failure (R2 = 0.75). Temporal retinal thinning was 84% sensitive for men with X-linked Alport syndrome and 67% specific (AUC = 0.83) compared with other renal diseases. CONCLUSIONS: Retinal temporal thinning is diagnostic for X-linked Alport syndrome in men and distinguishes them this condition from Thin basement membrane nephropathy, but only in men (p = 0.002). Temporal retinal thinning may also identify men and women with the rarer autosomal recessive disease.

Effect of haemodialysis and residual renal function on serum levels of galectin-3, B-type natriuretic peptides and cardiac troponin T.

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.

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

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.