Elevated Terminal C5b-9 Complement Complex 10 Weeks Post Kidney Transplantation Was Associated With Reduced Long-Term Patient and Kidney Graft Survival.

Background: The major reason for graft loss is chronic tissue damage, as interstitial fibrosis and tubular atrophy (IF/TA), where complement activation may serve as a mediator. The association of complement activation in a stable phase early after kidney transplantation with long-term outcomes is unexplored. Methods: We examined plasma terminal C5b-9 complement complex (TCC) 10 weeks posttransplant in 900 patients receiving a kidney between 2007 and 2012. Clinical outcomes were assessed after a median observation time of 9.3 years [interquartile range (IQR) 7.5-10.6]. Results: Elevated TCC plasma values (≥0.7 CAU/ml) were present in 138 patients (15.3%) and associated with a lower 10-year patient survival rate (65.7% vs. 75.5%, P < 0.003). Similarly, 10-year graft survival was lower with elevated TCC; 56.9% vs. 67.3% (P < 0.002). Graft survival was also lower when censored for death; 81.5% vs. 87.3% (P = 0.04). In multivariable Cox analyses, impaired patient survival was significantly associated with elevated TCC [hazard ratio (HR) 1.40 (1.02-1.91), P = 0.04] along with male sex, recipient and donor age, smoking, diabetes, and overall survival more than 1 year in renal replacement therapy prior to engraftment. Likewise, elevated TCC was independently associated with graft loss [HR 1.40 (1.06-1.85), P = 0.02] along with the same covariates. Finally, elevated TCC was in addition independently associated with death-censored graft loss [HR 1.69 (1.06-2.71), P = 0.03] as were also HLA-DR mismatches and higher immunological risk. Conclusions: Early complement activation, assessed by plasma TCC, was associated with impaired long-term patient and graft survival.

Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End-Stage Renal Disease.

Drug dosing is challenging in patients with end-stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P-glycoprotein (P-gp)/organic anion-transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (-3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P-gp/OATP activity.

Increased levels of inflammatory mediators and proinflammatory monocytes in patients with type I diabetes mellitus and nephropathy.

AIMS: To investigate and describe the relationship between diabetic nephropathy and systemic inflammation in patients with type 1 diabetes mellitus (T1DM). METHODS: Patients with T1DM, with or without reduced renal function due to diabetic nephropathy, were included. Differences in inflammatory mediators, adhesion molecules, markers of endothelial dysfunction and subsets of monocytes were studied in patients with mean disease duration of 31years. RESULTS: Patients with T1DM with and without renal failure were compared. Patients with nephropathy had increased plasma levels of proinflammatory monocytes, as well as circulatory PAI-1, syndecan-1, VEGF, IL-1ß, IL-1Ra and CCL4. Peripheral blood mononuclear cells from patients with nephropathy numerically increased soluble ICAM and PAI-1 in co-culture with primary endothelial cells compared to cells from patients without nephropathy. CONCLUSIONS: T1DM patients with kidney failure have higher levels of proinflammatory monocytes and circulatory inflammatory mediators compared to patients with T1DM alone. The results highlight the importance of inflammation and endothelial dysfunction in diabetic nephropathy with reduced GFR.

A heparin-coated dialysis filter (AN69 ST) does not reduce clotting during hemodialysis when compared to a conventional polysulfone filter (F×8).

BACKGROUND: We investigated whether the heparin-coated AN69 ST hemodialysis (HD) filter induced less hypercoagulability during HD than a conventional polysulfone filter (F×8). METHODS: In a crossover design, 11 patients were treated alternately with AN69 ST and F×8 filters (45 sessions). All filters were primed with unfractionated heparin (UFH) and unadsorbed UFH was removed by saline flushing. Half the conventional dalteparin dose was given as a bolus dose at the start of HD. Clotting was evaluated hourly in the venous air trap. Prothrombin fragments 1 and 2 (PF1 + 2), antithrombin (AT), ß-TG and anti-FXa activity were repeatedly measured. RESULTS: One patient treated with enalapril had two repeated adverse reactions to the AN69 ST filter and was excluded from the study. Use of the AN69 ST filter did not decrease the mean clot score or PF1 + 2, but decreased ß-TG compared to the F×8 filter. CONCLUSION: The heparin-coated AN69 ST filter did not induce less coagulation when compared to the F×8 filter.

Experience from an active preemptive kidney transplantation program--809 cases revisited.

BACKGROUND: Preemptive kidney transplantation (PKT) is increasingly acknowledged. We wanted to investigate the results of an active PKT policy in an unselected end-stage renal disease population with high prevalence of PKT. METHODS: From 1989 to 2007, 3400 first kidney transplantations were performed in which 809 were PKTs (24%). PKT patients were 7.4 years younger (P<0.001), had more live donors (LD; 64% vs. 35%, P<0.001), and fewer were panel reactive human leukocyte antigen antibody positive (2% vs. 6%, P<0.001). RESULTS: In the Cox regression analyses of patient mortality, uncensored and death-censored graft failures, all potential risk factors tested were statistically significant, except for recipient sex (i.e., recipient and donor age, PKT, deceased donor [DD], diabetes nephropathy, human leukocyte antigen-DR mismatch, and panel reactive antibody positivity). For patient mortality, PKT and DD had a hazard ratio (HR) of 0.75 (P=0.001) and 1.38 (P<0.001), respectively. The results were similar for uncensored and death-censored graft failures. Risk analyses were also performed separately for DD and LD cohorts. The results were comparable, except that PKT was not a significant risk factor in the LD cohort (HR=0.82, P=0.12 for mortality and HR=0.83, P=0.051 for uncensored graft failure). However, in DD recipients, patient mortality (HR=0.70, P=0.004) and uncensored graft failure (HR=0.68, P<0.001) were significantly reduced with PKT. CONCLUSION: PKT reduced the risk of patient mortality and uncensored graft failure in DD recipients. Our study confirms the advantages of PKT in an unselected end-stage renal disease population with a high prevalence of PKT.

Risk factors for mortality in diabetic nephropathy patients accepted for transplantation.

BACKGROUND: There is a high incidence of silent coronary artery disease (CAD) in patients with diabetes. We wanted to investigate risk factors for mortality, and especially CAD, in a well-defined cohort of diabetic nephropathy transplant candidates accepted for transplantation. METHODS: From 1999 through 2004, 155 patients underwent work up for living or deceased kidney (KA) or simultaneous pancreas-kidney (SPK) transplantation. The work up included coronary angiography for all patients and 136 were accepted. Mean (SD) age was 50 (12) years, 62% had type 1 diabetes, 73% were males, and 34% were on dialysis. Mean follow-up from time of acceptance for transplantation was 3.6 (1.9) years. RESULTS: Survival of KA transplanted patients was 97% at 1 year, 89% at 3 years, and 76% at 5 years, whereas in SPK patients 100%, 94%, and 90%, respectively (P=0.065). One- and 3- year survival was only 57% and 20% in those remaining wait-listed (P<0.001). In univariate analysis mortality was associated with KA transplantation (hazard ratio [HR]=0.30, P=0.011) and SPK transplantation (HR=0.10, P=0.001), and age (HR=1.04, P=0.014). In multivariable analysis, KA transplantation (HR=0.28, P=0.006), SPK transplantation (HR=0.09, P=0.001), age (HR=1.06, P=0.002), type 2 diabetes (HR=0.14, P=0.003), and duration of diabetes (HR=0.94, P=0.019) were parameters associated with mortality. CONCLUSIONS: The only modifiable risk factor was transplantation with risk reduction up to 90%. CAD was not a risk factor for mortality when medically treated and revascularized according to standard guidelines.