A Trial of Extending Hemodialysis Hours and Quality of Life.

The relationship between increased hemodialysis hours and patient outcomes remains unclear. We randomized (1:1) 200 adult recipients of standard maintenance hemodialysis from in-center and home-based hemodialysis programs to extended weekly (≥24 hours) or standard (target 12-15 hours, maximum 18 hours) hemodialysis hours for 12 months. The primary outcome was change in quality of life from baseline assessed by the EuroQol 5 dimension instrument (3 level) (EQ-5D). Secondary outcomes included medication usage, clinical laboratory values, vascular access events, and change in left ventricular mass index. At 12 months, median weekly hemodialysis hours were 24.0 (interquartile range, 23.6-24.0) and 12.0 (interquartile range, 12.0-16.0) in the extended and standard groups, respectively. Change in EQ-5D score at study end did not differ between groups (mean difference, 0.04 [95% confidence interval, -0.03 to 0.11]; P=0.29). Extended hours were associated with lower phosphate and potassium levels and higher hemoglobin levels. Blood pressure (BP) did not differ between groups at study end. Extended hours were associated with fewer BP-lowering agents and phosphate-binding medications, but were not associated with erythropoietin dosing. In a substudy with 95 patients, we detected no difference between groups in left ventricular mass index (mean difference, -6.0 [95% confidence interval, -14.8 to 2.7] g/m2; P=0.18). Five deaths occurred in the extended group and two in the standard group (P=0.44); two participants in each group withdrew consent. Similar numbers of patients experienced vascular access events in the two groups. Thus, extending weekly hemodialysis hours did not alter overall EQ-5D quality of life score, but was associated with improvement in some laboratory parameters and reductions in medication burden. (Clinicaltrials.gov identifier: NCT00649298).

Comparison of intermittent and continuous extracorporeal treatments for the enhanced elimination of dabigatran.

CONTEXT: Severe bleeding associated with dabigatran frequently requires intensive care management. An antidote is currently unavailable and data reporting the effect of dialysis on elimination of dabigatran are encouraging, but limited. Objective. To report the effect of intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) at enhancing elimination of dabigatran. MATERIALS AND METHODS: Patients were identified by existing collaborative networks. Pre-filter dabigatran plasma concentrations were measured in all patients, and in dialysate of three patients. RESULTS: Seven patients received dialysis, five with active bleeding and two requiring emergent surgery. Five received IHD and two received CRRT. The plasma elimination half-life of dabigatran was 1.5-4.9 h during IHD, and 14.0-27.5 h during CRRT. Mean dabigatran plasma clearance during IHD was 85-169 mL/min in three patients. Time to obtain a subtherapeutic dabigatran concentration depended on the initial concentration, being 8-18 h for IHD in three patients while 4 h was insufficient in a supratherapeutic case. A 38% rebound in dabigatran levels occurred after one case during IHD, and thrombin time increased after IHD in another, but not after 144 h CRRT or 17 h IHD in two others; data were incomplete in three cases. The amount removed during IHD was proportional to the pre-IHD concentration and clearance, but was consistently low at 3.3-17.4 mg in three patients where this was determined. Moderate bleeding occurred while obtaining vascular access in one patient. Two patients died from intracerebral bleeding, and the influence of treatments could not be determined in these cases. DISCUSSION AND CONCLUSIONS: IHD enhanced elimination of dabigatran more efficiently than CRRT, but their net effect remains poorly defined. Dialysis decisions, including modality and duration, must be individualized based on a risk-benefit assessment.

A role for everolimus in post-transplant encapsulating peritoneal sclerosis: first case report.

Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that carries a high morbidity and mortality. The 'two hit theory' suggests that long term deterioration of the peritoneum combined with intraperitoneal inflammation is needed in the pathogenesis of EPS. For unclear reasons, post transplantation EPS is being increasingly reported in patients previously on PD. To date, there is no proven effective therapy with an absence of randomised controlled trials. Individual case reports and small case series have reported on the use of tamoxifen and corticosteroids for medical management of EPS. The use of everolimus has been reported in a single case, and never in the setting of renal transplantation. Here, we present the first case of post-transplant encapsulating peritoneal sclerosis treated successfully with a combination of everolimus, tamoxifen, low dose corticosteroid and surgery.

Sirolimus reduces vasculopathy but exacerbates proteinuria in association with inhibition of VEGF and VEGFR in a rat kidney model of chronic allograft dysfunction.

BACKGROUND: Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology. METHODS: Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed. RESULTS: Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells. CONCLUSIONS: Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.

Photopheresis therapy for problematic renal allograft rejection.

BACKGROUND: Photopheresis is an immunomodulatory therapy for the treatment of T cell-mediated disorders. It has been used for rejection prophylaxis in cardiac transplantation, adjuvant treatment of bronchiolitis obliterans in lung transplantation, treatment of graft verse host disease, and in a small number of cases, for treatment of acute rejection in renal transplantation. Little is known of long-term outcomes following the use of photopheresis in solid organ transplantation. METHODS: We report prospective follow-up of our consecutive experience of the use of photopheresis as adjuvant/salvage therapy for problematic rejection in patients undergoing renal transplantation. Transplant graft survival, infective and malignant outcomes were reported. RESULTS: A cohort of 10 renal transplants recipients received photopheresis therapy for therapy-resistant rejection. Conventional therapy included an average of 6.2 g pulse methyl-prednisolone and 17.1 days antilymphocyte therapy. The cohort received additional photopheresis therapy when the unresponsive nature of their rejections raised concerns of graft loss. Median follow-up censored for patient loss was 66.7 months following photopheresis commencement. Rejection resolved in association with photopheresis use in all 10 patients. Six patients continued to have stable graft function (median serum creatinine: 191.5 micromol/L) at a median follow-up of 71.0 months. There has been one patient death from sepsis and two from malignancy with functioning grafts while one graft has been lost to disease recurrence. CONCLUSION: Photopheresis may have a role as an adjuvant or salvage antirejection therapy in solid organ transplantation. Furthermore, evaluation in randomized controlled clinical trials is required to evaluate its potential.

Dentritic cell derived IL-18 production is inhibited by rapamycin and sanglifehrin A, but not cyclosporine A.

Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis.

TLR4 activation mediates kidney ischemia/reperfusion injury.

Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4(-/-) and MyD88(-/-) mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4(-/-) and MyD88(-/-) TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4(-/-) mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4(-/-) BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage.

Expression of growth arrest-specific gene 6 and its receptors in dysfunctional human renal allografts.

Growth arrest-specific gene 6 (Gas6) and its receptors Rse, Axl and Mer have recently been found to be involved in a rat model of chronic allograft nephropathy (CAN). Thus, in this study we investigated the function of Gas6 and its receptors in human renal allograft dysfunction. Expression of Gas6 and its receptors was detected by immunohistochemical staining. Gas6 and its receptors were widely expressed in glomeruli, tubules and vessels of renal allografts. Gas6 expression was detected in normal-functioning allografts and was increased in acute rejection ( P<0.05), acute tubular necrosis ( P<0.05) and CAN ( P<0.01). Gas6 receptors were not upregulated in any of the allograft groups, except for the Axl receptor, which increased only in acute tubular necrosis ( P<0.01). Gas6 expression was also found to correspond with the expression of alpha-smooth muscle actin, a general marker of CAN ( r(2)=0.21, P<0.01). These findings suggest that Gas6, acting as a growth factor, is increased in the process of kidney allograft dysfunction and in CAN.

Graft loss following renal transplantation in Australia: is there a centre effect?

BACKGROUND: Assessment of centre variation in renal transplantation outcome provides an opportunity to examine differences in quality of care between centres. However, differences in outcome may represent differences in patient factors between centres and be biased by sampling variability and inadequate data ascertainment. METHODS: Differences in 12-month graft survival in 1986 primary renal transplant adult recipients from 16 centres in Australia between 1993 and 1998 were examined. Fifteen recipient and donor factors known prior to transplantation were examined to determine factors independently predictive of graft survival. Differences between centres in these factors were examined. Unadjusted and multivariable adjusted outcomes for each centre were compared to the average for all centres. Multivariable hierarchical modelling was employed to account for potential bias due to sampling variability. RESULTS: Factors predictive of reduced 12-month graft survival on multivariable analysis that were significantly different between centres were time on dialysis prior to transplantation, donor age, organ source, and number of human lymphocyte antigen mismatches. Unadjusted 12-month graft survival for all centres was 91.7% and ranged from 83.1 to 96.4%. Although two centres performed significantly lower than average, this poorer outcome was accounted for in one of these two centres after adjusting for factors shown to be independently predictive of outcome. However, multivariable hierarchical modelling failed to identify any centre as performing significantly different to average, with 12-month graft survival ranging from 89.2 to 92.2%. Outcome in patients excluded from the study due to inadequate data ascertainment was significantly worse than patients who were included. CONCLUSIONS: There was no evidence of centre variation after accounting for variation in risk factors predictive of poor outcome between centres, as well as potential bias due to sampling variability. Exclusion of patients due to inadequate data remains an important source of bias in estimating accurate outcomes. Appropriate analytical strategies and consideration of sources of bias are important for the valid identification of centres with poorer outcomes.

Expression of growth arrest-specific gene 6 and its receptors in a rat model of chronic renal transplant rejection.

BACKGROUND: Growth arrest-specific gene 6 (Gas6) is involved in a number of cell functions that include proliferation of vascular smooth muscle cells and mesangial cells. The proliferation of these cells is a feature of chronic rejection (CR) after kidney transplantation. Therefore, we examined the gene expression of Gas6 and its receptors Rse, Axl, and Mer in a rat model of CR. METHODS: The rat model of CR was established in Lewis rat recipients of Fisher kidney transplants. The level of mRNA was measured by real-time quantitative reverse transcription-polymerase chain reaction. The proteins were detected by immunohistochemical staining and Western blot analysis. RESULTS: Gas6 mRNA was extensively expressed in kidney tissue of both allografts and isografts. There was significant increase in expression of Gas6 mRNA in allografts at 4 weeks posttransplantation. Immunohistochemical study showed that Gas6 and its receptor Rse proteins were highly expressed in kidney tissue. Western blot analysis has also confirmed that Gas6 and Rse proteins are expressed in kidney tissue. CONCLUSIONS: These findings suggest that Gas6 and its receptors have an as yet undefined role in kidney function and/or development and may be involved in the pathogenesis of CR. The action of Gas6 in rat kidney is mainly mediated through the Rse receptors rather than the Axl and Mer receptors.