Anticoagulation use and the risk of stroke and major bleeding in patients on hemodialysis: From the VIVALDI, a population-based prospective cohort study.

BACKGROUND: Evidence supporting the use of anticoagulation for the prevention of stroke and thromboembolism in patients with kidney failure on hemodialysis (HD) and atrial fibrillation (AF) is limited. We prospectively assessed the incidences of stroke and major bleeding, as well as anticoagulation strategies in patients on HD with AF. METHODS: We recruited 625 prevalent HD patients into a population-based observational cohort study. The primary prospective outcomes were thromboembolic events (stroke, transient ischemic attack, systemic embolism) and major bleeding. Secondary outcomes included a composite of thromboembolic events, major bleeding, and cardiovascular death to determine net clinical harm. RESULTS: A total of 238 patients (38.1%) had AF, 165 (26.4%) already at baseline and 73 (15.9%) developed AF during a median follow up of 870 days. Forty (6.4%) thromboembolic events and 89 (14.2%) major bleedings occurred. Overall, 256 patients died (41.0%). In AF patients, use of vitamin K antagonists (VKAs) in 61 patients (25.6%) was not significantly associated with reduced risk of the primary thromboembolic outcome (subdistribution hazard ratio [SHR] 1.41 adjusted for age, sex, congestive heart failure, hypertension, stroke/transient ischemic attack/thromboembolism, vascular disease, and diabetes history score and antiplatelet co-medication (95% CI, 0.49-4.07), but with increased risk of major bleeding (SHR: 2.28; 95% CI, 1.09-4.79) compared with AF patients without anticoagulation (N = 139, 58.4%). Use of VKAs was associated with net clinical harm (adjusted SHR: 2.07; 95% CI, 1.25-3.42). CONCLUSIONS: Although the nonrandomized nature of the study is prone to bias, anticoagulation with VKAs was not associated with decreased thromboembolic risk, but rather with increased risk of major bleeding and may be net harmful to patients with AF on HD.

Antithrombotic agents for primary and secondary prevention of cardiovascular events in patients with end-stage renal disease on chronic hemodialysis.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is common in patients with end-stage renal disease (ESRD) on hemodialysis (HD). However, antithrombotic therapy to prevent CVD increases the risk of bleeding. We aimed to investigate the prevalence of CVD and the practice patterns of antithrombotic agents in patients with ESRD on HD. METHODS: In a cross-sectional population based cohort of chronic HD patients (n = 626) from Vienna, Austria, the medical histories of patients and use of antithrombotic treatment were recorded, and the distribution of antithrombotic therapies for primary (n = 260, 41.5%) or secondary (n = 366, 58.5%) prevention of CVD was analyzed. RESULTS: Single antiplatelet therapy (SAPT) was used in 234 patients (37.4%), dual antiplatelet (DAPT) in 50 (8.0%), combination of anticoagulation and antiplatelet in 59 (9.4%), anticoagulation monotherapy in 78 (12.5%), and no antithrombotics in 205 patients (32.7%). The prevalence of CVD was 58.5%. In primary CVD prevention, 23.5% (n = 61) of patients were treated with SAPT. For secondary prevention, SAPT was used in 173 (47.3%), DAPT in 49 (13.4%), and dual antithrombotic therapies in 50 patients (13.7%), while 55 (15.0%) patients received no antithrombotics. Age (odds ratio [OR] per 1 year increase 0.96, 95%CI 0.94-0.99, p = 0.004) and hereditary nephropathy (OR 4.13, 95%CI 1.08-15.78, p = 0.038) were independently associated with the absence of antithrombotic therapy in secondary CVD prevention. CONCLUSION: The majority of patients did not receive antithrombotic therapy for primary prevention. Only 15% did not receive antithrombotic agents in the secondary prevention setting. The net-clinical benefit of antithrombotic therapy in ESRD needs to be determined.

Venous thromboembolism and vascular access thrombosis in patients with end-stage renal disease on maintenance hemodialysis: Cross-sectional results of the Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemoDIalysis (VIVALDI).

BACKGROUND: Patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) are at risk for occurrence of vascular access thrombosis and venous thromboembolism (VTE). Understanding the extent of these complications and identifying risk factors can help improve management strategies. METHODS: Adult HD patients were cross-sectionally recruited into the Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemoDIalysis (VIVALDI). In this investigation, retrospective data on the incidence and risk of VTE and vascular access thrombosis was analyzed using logistic regression and negative binomial regression for counts of vascular access thrombosis episodes. RESULTS: The analysis includes 626 patients on HD, which constitutes 73% of the total HD population in Vienna, Austria. One-hundred-seventy-eight patients (28.4%) had 275 vascular access thrombosis events during 2463.1 patient-years on HD, corresponding to an incidence rate (IR) of 111.6 events per 1000 patient-years on HD. In the multivariable negative binomial regression model, we found that patients suffered from vascular access thrombosis 2.5 times more often (IR ratio 2.63, 95% confidence interval [CI] 1.48-4.68, p=0.001) if toxic nephropathy was their cause of ESRD (n=28, 4.5%) compared to patients with other causes of ESRD. Sixty-one patients (9.7%) had a history of VTE and the IR of VTE events during the time on HD was 10.9 per 1000 patient-years on HD (women: IR 15.1, men IR 8.6). Female sex (odds ratio [OR] 1.90, 95%CI 1.07-3.36, p=0.029) and atrial fibrillation (OR 2.00, 95%CI 1.10-3.64, p=0.023) were independently associated with VTE. CONCLUSIONS: Thromboembolic events including vascular access thrombosis and VTE are frequent complications in patients on HD. Risk evaluation for thromboembolism, including sex and clinical parameters, may identify high-risk patients and improve their clinical management.

Prevalence of Atrial Fibrillation and Antithrombotic Therapy in Hemodialysis Patients: Cross-Sectional Results of the Vienna InVestigation of AtriaL Fibrillation and Thromboembolism in Patients on HemoDIalysis (VIVALDI).

BACKGROUND: Atrial fibrillation (AF) adds significant risk of stroke and thromboembolism in patients on hemodialysis (HD). The aim of this study was to investigate the prevalence of AF in a population-based cohort of HD patients and practice patterns of antithrombotic therapy for stroke prevention in AF. METHODS: The Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemodialysis (VIVALDI), an ongoing prospective observational cohort study, investigates the prevalence of AF and the risk of thromboembolic events in HD patients in Vienna, Austria. We analyzed cross-sectional data of 626 patients (63.4% men, median age 66 years, approx. 73% of HD patients in Vienna), who provided informed consent. A structured interview with each patient was performed, recent and archived ECGs were viewed and medical histories were verified with electronic records. RESULTS: The overall prevalence of AF was 26.5% (166 patients, 71.1% men, median age 72 years) of which 57.8% had paroxysmal AF, 3.0% persistent AF, 32.5% permanent AF, and 6.6% of patients had newly diagnosed AF. The median CHA2DS2-VASc Score was 4 [25th-75th percentile 3-5]. In multivariable analysis, AF was independently associated with age (odds ratio: 1.05 per year increase, 95% confidence interval: 1.03-1.07), male sex (1.7, 1.1-2.6), history of venous thromboembolism (2.0, 1.1-3.6), congestive heart failure (1.7, 1.1-2.5), history of or active cancer (1.5, 1.0-2.4) and time on HD (1.08 per year on HD, 1.03-1.13). Antithrombotic treatment was applied in 84.4% of AF patients (anticoagulant agents in 29.5%, antiplatelet agents in 33.7%, and both in 21.1%). In AF patients, vitamin-K-antagonists were used more often than low-molecular-weight heparins (30.1% and 19.9%). CONCLUSIONS: The prevalence of AF is high amongst HD patients and is associated with age, sex, and distinct comorbidities. Practice patterns of antithrombotic treatment indicate a lack of consensus for stroke prevention in HD patients with AF.

A randomized trial of iron isomaltoside 1000 versus oral iron in non-dialysis-dependent chronic kidney disease patients with anaemia.

BACKGROUND: Iron deficiency anaemia is common in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and is often treated with oral or intravenous (IV) iron therapy. This trial compared the efficacy and safety of IV iron isomaltoside 1000 (Monofer®) and oral iron in NDD-CKD patients with renal-related anaemia. METHODS: The trial was a Phase III open-label, comparative, multicentre, non-inferiority trial conducted in 351 iron-deficient NDD-CKD patients, randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks (Group B). The patients in Group A were randomized into A1 (infusion of max. 1000 mg single doses over 15 min) and A2 (bolus injections of 500 mg over 2 min). A modified Ganzoni formula was used to calculate IV iron need. The primary end point was change in haemoglobin concentrations from baseline to Week 4. RESULTS: Iron isomaltoside 1000 was both non-inferior to oral iron at Week 4 (P < 0.001) and sustained a superior increase in haemoglobin from Week 3 until the end of the study at Week 8 (P = 0.009 at Week 3). The haemoglobin response was more pronounced with iron isomaltoside 1000 doses ≥1000 mg (P < 0.05). Serum-ferritin and transferrin saturation concentrations were also significantly increased with IV iron. Adverse drug reactions were observed in 10.5% in the iron isomaltoside 1000 group and 10.3% in the oral iron group. More patients treated with oral iron sulphate withdrew from the study due to adverse events (4.3 versus 0.9%, P = 0.2). CONCLUSIONS: Iron isomaltoside 1000 was more efficacious than oral iron for increase in haemoglobin and proved to be well tolerated at the tested dose levels in NDD-CKD patients.

Pre-implant biopsy predicts outcome of single-kidney transplantation independent of clinical donor variables.

BACKGROUND: Pre-implant biopsy findings account for the discard of many donor kidneys although their clinical value is not fully understood. We retrospectively investigated the predictive value of pre-implant histology, which in our center was obtained for protocol purposes, not for transplant decisions, on long-term allograft and recipient outcome after single-kidney transplantation. METHODS: This single-center study included 628 consecutive adult recipients of 174 Expanded Criteria Donor (ECD) and 454 Standard Criteria Donor kidneys. Chronic donor organ injury was assessed applying a chronic lesion score differentiating between mild, moderate, and severe histologic organ injury based on the integration of glomerular, vascular, tubular, and interstitial lesions. Recipients were followed over a median time of 7.8 years. RESULTS: Donor kidneys exhibiting mild or moderate chronic lesions yielded almost identical graft and recipient survival independent of ECD status or other clinical covariables (HR 1.20, 95% CI 0.83-1.74, P=0.326, and HR 1.27, 95% CI 0.83-1.95, P=0.274, respectively). However, if allograft injury was severe, occurring in 3% of transplanted kidneys, graft and recipient survival was significantly reduced (HR 3.13, 95% CI 1.61-6.07, P<0.001 and HR 2.42, 95% CI 1.16-5.04, P=0.005, respectively). CONCLUSION: The results suggest that donor kidneys displaying moderate chronic injury can safely be transplanted as single kidneys, while organs displaying severe injury should be discarded. Thus, pre-implant biopsy might offer an effective approach to increase the utilization of renal donor organs, especially from ECD and donors with cerebrovascular accident as cause of death, and to improve overall graft outcome.

Lisinopril pharmacokinetics and erythropoietin requirement in haemodialysis patients.

BACKGROUND: There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy. MATERIALS AND METHODS: We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6h thereafter; AUC1), and the seven post-dialysis lisinopril plasma levels were used for calculation of AUC2. RESULTS: The mean ESA index of all patients was 27·90±25·84 (IU/week/kg)/(g/dL). Average lisinopril AUC1 was 1212·48±1209·75 [mg*h/L], whereas AUC2 averaged 947·67±977·07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients. CONCLUSIONS: Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs.

Significance of peritubular capillary, glomerular, and arteriolar C4d staining patterns in paraffin sections of early kidney transplant biopsies.

BACKGROUND: Although diffuse linear C4d deposition in peritubular capillaries (PTCs) is a well-established criterion of alloantibody-mediated kidney transplant rejection, the actual relevance of focal or granular C4d deposits or staining outside PTC (glomeruli and arterioles) has yet to be established. METHODS: This study was designed to evaluate the diagnostic significance of such nontypical C4d staining patterns. A total of 539 early indication biopsies (329 kidney transplants) were analyzed by immunohistochemistry using a polyclonal anti-C4d antibody. RESULTS: We found a close interrelationship between diffuse or focal linear C4d deposition in PTC, linear endothelial deposition in glomeruli, and arteriolar C4d. These specific patterns were also related to transplant glomerulitis and recipient presensitization. No such associations, however, were observed for other patterns, such as granular C4d in PTC. Detection of diffuse but not focal linear C4d in PTC was found to be associated with adverse allograft survival (5-year death-censored graft survival: 48% vs. 82%, 89%, or 84% in patients with focal, minimal, or no C4d, respectively; P<0.0001). Univariate analysis also revealed inferior graft survival in recipients with linear C4d in glomeruli (P=0.02). Applying multivariate Cox regression analysis, however, only diffuse linear PTC staining was found to be predictive of graft loss (hazard ratio 3.95 [95% confidence interval 1.62-9.60]; P=0.002). CONCLUSION: There might be a relationship between humoral alloimmunity and distinct less established staining patterns, such as focal linear C4d in PTC, endothelial C4d in glomeruli, or arteriolar C4d. Nevertheless, our results reemphasize the prognostic value of diffuse linear PTC staining.

Acute infection with a single hepatitis C virus strain in dialysis patients: Analysis of adaptive immune response and viral variability.

BACKGROUND/AIMS: While the adaptive immune response is crucial for spontaneous resolution of acute hepatitis C virus (HCV) infection, it also constitutes the driving force for viral escape. For acutely HCV-infected dialysis patients, little is known about the host response and its impact on viral evolution. METHODS: Four haemodialysis patients accidentally infected with the same HCV strain were prospectively investigated with respect to the clinical course, CD4+ and CD8+ T-cell responses, neutralizing antibodies, viral kinetics and sequence variability. RESULTS: In one patient, a robust CD4+ T-cell response was associated with transient control of infection, while in the other patients, weak responses correlated with persistently high viremia. Despite the presence of CD8+ T-cell effectors in the first patient, no sequence differences were detected in targeted regions of the viral genome in any of the patients when viral persistence was established. Genetic stability in the envelope genes, including the hypervariable regions, correlated with low-level or absent neutralizing antibodies in all of the patients. CONCLUSIONS: The establishment of viral persistence in the special patient group of dialysis patients is due to a failure of the adaptive immune system, as shown by the absence of significant T-cell and antibody responses, as well as viral variability.

Predictors of new-onset decline in kidney function in a general middle-european population.

BACKGROUND: Limited epidemiological data are available on predictors of new-onset kidney disease. METHODS: In this longitudinal cohort study, 17 375 apparently healthy volunteers of the general Viennese population (46.4% women, age range 20-84 years, men 20-89 years) performed a baseline examination at some time within the study period (1990-2005) and completed a median of two follow-up examinations [interquartile range (IQR) 1 to 4]; the median follow-up period was 7 years (IQR 4 to 11). The outcome of interest was the development of kidney disease, defined as a decrease of the glomerular filtration rate (GFR) <60 ml/min/1.73 m(2) at the follow-up examinations [calculated by the abbreviated modification of diet in renal disease (MDRD) equation]. Logistic generalized estimating equations were used to analyse the relationship between the covariates and the outcome variable. RESULTS: The following parameters [odds ratios (OR) with 95% confidence intervals] predicted new-onset kidney disease: Age (increase by 5 years), OR = 1.36 (1.34-1.40); National Kidney Foundation-chronic kidney disease (NKF-CKD) stage 1 with proteinuria (+), OR = 1.39 (1.10-1.75); NKF-CKD stage 1 with proteinuria (>/=++), OR = 2.07 (1.11-3.87); NKF-CKD stage 2 with proteinuria (+), OR = 2.71 (2.10-3.51); NKF-CKD stage 2 with proteinuria (>/=++), OR = 3.80 (2.29-6.31); body mass index, OR = 1.04 (1.02-1.06); current-smoker, OR = 1.20 (1.01-1.43); performing no sports, OR = 1.57 (1.27-1.95); uric acid (increase by 2 mg/dl), OR = 1.69 (1.59-1.80); HDL-cholesterol (decrease by 10 mg/dl), OR = 1.12 (1.07-1.17); hypertension stage 1, OR = 1.35 (1.08-1.67); hypertension stage 2, OR = 2.01 (1.62-2.51); diabetes mellitus, OR = 1.44 (1.07-1.93). CONCLUSIONS: Cardiovascular risk factors as well as NKF-CKD stages 1 and 2 and proteinuria, the more the higher and an entirely novel finding, performing no sports, predicted new-onset kidney disease.

Rescue therapy with tacrolimus and mycophenolate mofetil does not prevent deterioration of graft function in C4d-positive chronic allograft nephropathy.

BACKGROUND: Humoral alloresponses may contribute to chronic allograft nephropathy (CAN) in a subset of kidney transplant recipients. For chronic humoral rejection, the efficacy of rescue therapy with tacrolimus and mycophenolate mofetil has been suggested. METHODS: Eleven recipients with C4d-positive CAN (index biopsy performed after a median of 3 years posttransplantation), who had been on cyclosporine A-based immunosuppression, were converted to tacrolimus, and if not part of basal therapy, to mycophenolate mofetil. We evaluated the effect of this tacrolimus/mycophenolate mofetil rescue therapy on clinical outcomes and on alloantibody formation detected with flow cytometric testing of panel-reactive antibody. RESULTS: Tacrolimus/mycophenolate mofetil rescue therapy (plus anti-rejection treatment in six recipients with additional signs of acute cellular rejection) failed to prevent progressive deterioration of graft function. Four patients returned to dialysis after 4 to 18 months. Serial post-transplant serology detected HLA class I and/or II reactivity in seven recipients. Tacrolimus/mycophenolate mofetil therapy did not affect the time course of alloantibody levels. One patient with C4d-positive transplant glomerulopathy, who did not respond to tacrolimus/mycophenolate mofetil rescue therapy, developed nephrotic-range proteinuria associated with a rapid decline of allograft function. Despite considerable reduction in alloantibody levels and nearly complete clearance of C4d deposits, immunoadsorption failed to prevent graft failure in this patient. CONCLUSION: Our data argue against the efficacy of tacrolimus/mycophenolate mofetil rescue therapy in established C4d-positive chronic allograft dysfunction. Prospective trials are needed to evaluate whether early initiation of this or other antihumoral strategies are capable of effectively preventing alloantibody-mediated chronic graft injury.

Peritransplant immunoadsorption: a strategy enabling transplantation in highly sensitized crossmatch-positive cadaveric kidney allograft recipients.

BACKGROUND: Kidney transplant recipients with a current positive complement-dependent cytotoxicity crossmatch (CDCXM) are at high risk for hyperacute rejection and graft loss. Immunoadsorption (IA) represents an efficient strategy to remove donor-specific alloantibodies. In this analysis, we evaluated effectiveness of peritransplant IA as an anti-humoral strategy to overcome a current positive CDCXM in presensitized renal allograft recipients. METHODS: Between 1999 and 2003, 40 high risk cadaveric kidney allograft recipients (median CDC panel reactive antibody [PRA] level, 77%; number of retransplants, n = 38) were subjected to peritransplant IA with protein A (one pretransplant IA session followed by a course of repeat posttransplant IA sessions) in addition to preemptive antilymphocyte antibody therapy. RESULTS: In nine of these patients, a current positive CDCXM was rendered negative by a single pretransplant IA session. Thirty-one recipients had a negative CDCXM already before pretransplant IA. No difference in graft survival was found between CDCXM-positive and CDCXM-negative recipients (3-year graft survival, 78% vs. 71%, P = 0.6). Comparable rates of immunological graft loss at 3 years were observed (11% vs. 13%, P = 0.8). Patient groups did not significantly differ with respect to median serum creatinine at 1 year (1.23 mg/dL [CDCXM-positive] vs. 1.57 mg/dl [CDCXM-negative], P = 0.07) and at the end of follow-up (median 32 months; 1.19 mg/dL vs. 1.63 mg/dL, P = 0.06). Moreover, patient groups showed similar rates of biopsy-proven cellular rejection (11% vs. 20%) or C4d-positive graft dysfunction (33% vs. 32%). CONCLUSION: Our results demonstrate that peritransplant IA enables successful cadaveric kidney transplantation in the context of a positive CDCXM.

Iron overload in kidney transplants: prospective analysis of biochemical and genetic markers.

BACKGROUND: The prevalence of iron overload and the influence of mutations in the HFE and TRF2 gene on biochemical markers of iron overload among renal transplant patients is unknown. METHODS: Serum iron, ferritin, transferrin saturation (TSAT), and liver function parameters were analyzed in a cohort of 438 renal transplants. In patients with iron overload, the time course of biochemical markers of iron status as well as the influence of iron loading mutations was investigated during a time period of 5 years. RESULTS: Of 438 renal transplant patients 41 (9.4%) presented with an iron loading phenotype (TSAT above 40% and/or ferritin above 800 ng/mL). Mutations in the HFE gene were present in 12 of 33 (36.3%) patients with iron overload. Among these one patient was homozygous for HFE C282Y, and two patients were compound heterozygous for HFE C282Y/H63D. No individual tested positive for nine other mutations in HFE as well as theTRF2 Y250X mutation. Over time we observed a decrease of mean iron and ferritin levels, and of mean TSAT in our study sample. In patients with mutations in HFE this decrease was less pronounced as compared to patients without mutations. We found an independent positive association between the presence of mutations in HFE and serum alanine-aminotransferase levels at follow-up (P= 0.003). CONCLUSION: Our study demonstrates that iron overload is frequently present in renal transplant patients and shows a continuous decrease over time. This decrease is possibly impaired by the HFE C282Y and HFE H63D mutations. Furthermore, mutations in HFE may influence liver function as reflected by increased alanine-aminotransferase concentrations.

Antibody maturation and viremia after primary cytomegalovirus infection, in immunocompetent patients and kidney-transplant patients.

To investigate antibody maturation and serum levels of cytomegalovirus (CMV) DNA after primary CMV infection, we studied 51 immunocompetent and 27 kidney-transplant patients. Compared with the immunocompetent patients, the transplant patients had significantly more-prolonged and -variable antibody maturation, clearly longer durations of viremia, and higher levels of CMV DNA; however, antibody maturation continued for >1 year even in immunocompetent patients. Long-term ganciclovir prophylaxis in the transplant patients was associated with either delayed immunoglobulin-G seroconversion, inhibition of antibody maturation (n=2), or immunoglobulin-class switching (n=1). In conclusion, antibody maturation continues in immunocompetent patients for a period longer than previously had been thought and is significantly delayed or even inhibited in kidney-transplant patients.

Risk factors for capillary C4d deposition in kidney allografts: evaluation of a large study cohort.

BACKGROUND: Capillary deposition of the complement split product C4d has turned out to be a valuable marker of antibody-mediated rejection. The impact of pre- and posttransplant variables including particular immunosuppressive regimens on the frequency of C4d deposition has not yet been systematically investigated in a large multivariate analysis. METHODS: In this retrospective study, the authors evaluated the incidence of C4d deposition in 388 kidney transplant recipients subjected to diagnostic biopsy within the first 6 months and analyzed the influence of potential confounders on the rate of C4d-positive graft dysfunction by applying multivariate logistic regression. RESULTS: Sixty-six recipients (17%) developed linear C4d deposits in at least a quarter of peritubular capillaries, a finding associated with inferior 1-year allograft survival (73% vs. 88% in C4d-negative patients, P=0.0003). A 50% reduction in the odds of C4d-positive graft dysfunction was found if calcineurin inhibitor or mycophenolate mofetil (MMF) therapy was started 2 to 4 hr before transplantation when compared with initiation after surgery (adjusted odds ratio [OR], 0.5; P=0.03). No differences with respect to C4d staining results were found for the use of tacrolimus, MMF, or sirolimus, or for cyclosporine C2 monitoring. Retransplantation (OR, 3.6; P<0.001) and presensitization (OR, 3.1; P=0.002) turned out to be strong independent risk factors for C4d deposition. CONCLUSIONS: The authors' results suggest a reduced risk of C4d-positive graft dysfunction for patients receiving immunosuppression before transplantation. Apart from first dose timing, no influence of particular immunosuppressive strategies on C4d staining results was found.

Dose-dependent effect of parenteral iron therapy on bleomycin-detectable iron in immune apheresis patients.

BACKGROUND: Iron deficiency and anemia are commonly encountered in patients with autoimmune diseases undergoing immune apheresis. This makes erythropoietin and iron substitution necessary in most patients. However, intravenous iron therapy may result in an increase of potentially toxic nontransferrin-bound iron. METHODS: We examined the effect of 50 mg or 100 mg of iron (III) sucrose on bleomycin-detectable iron (BDI) in immune apheresis patients. Six patients with autoimmune disorders and normal kidney function were enrolled. Before and after the injection of 50 mg or 100 mg of iron (III) sucrose, BDI was measured in serum samples at five different time points. RESULTS: There was no BDI traceable before injection of iron (III) sucrose. BDI was present in serum of all patients after the administration of 100 mg of iron (III) sucrose in concentrations up to 0.49 micromol/L. In contrast, only one patient showed BDI at a concentration of 0.16 micromol/L after the administration of 50 mg of iron (III) sucrose. CONCLUSION: We conclude that if parenteral iron is administered after apheresis treatment, despite the equal tolerability, use of 50 mg of iron (III) sucrose is superior to 100 mg of iron (III) sucrose in avoiding the formation of potentially toxic nontransferrin-bound iron.

Patient and graft survival in older kidney transplant recipients: does age matter?

An increasing gap between supply and demand of donor kidneys for transplantation exists. There is concern regarding the allocation of scarce organs to elderly patients, because the benefit obtained by the transplant may be less in elderly compared with younger recipients. It was the objective of this study to determine differences in patient and organ survival between organ recipients >65 yr and 50 to 64 yr of age at transplantation. A retrospective cohort of 627 patients >50 yr who received a kidney transplant between 1993 and 2000 was assembled. Detailed information on patient demographics, comorbidities, and immunological and donor characteristics was ascertained before transplantation. Five-year patient and graft survival were evaluated by Kaplan-Meier survival curves and multivariate Cox proportional-hazard models. Five-year patient mortality was similar between patients aged >65 and 60 to 64 at transplantation (relative risk [RR] = 1.07; 95% confidence interval [CI], 0.66 to 1.74). Patients aged 50 to 59 yr showed a clear trend toward lower 5-yr mortality (RR = 0.66; 95% CI, 0.43 to 1.03). Compared with patients >65 yr, 5-yr graft loss was not different in patients aged 60 to 64 (RR = 1.28; 95% CI, 0.82 to 2.02) or those aged 50 to 59 yr at transplantation (RR = 1.02; 95% CI, 0.68 to 1.53). After thorough control for confounding, 5-yr graft survival was not materially different by age group. Discrimination against older candidates for kidney transplantation on age-related grounds alone is not warranted.

Viral features of lamivudine resistant hepatitis B genotypes A and D.

Viral differences among lamivudine resistant hepatitis B (HBV) genotypes have not been yet investigated. Therefore, we analyzed the characteristics of these viral strains in vivo. Forty-one patients carrying lamivudine resistant HBV were enrolled. Twenty-six patients (63%) carried resistant HBV genotype A (group A) and 15 patients (37%) carried resistant HBV genotype D (group D). The rate of reverse transcriptase 204I mutants was significantly higher in group D (67%) compared with group A (19%), whereas rt204V mutants (81% in group A vs 33% in group D; P =.006) and rt180M mutants (81% in group A vs 40% in group D, P =.015) prevailed in group A. The median time of shift from rt204I to rt204V mutants was significantly shorter in group A (4 months in group A, >12 months in group D, P <.001). Additional resistance associated mutations were detected exclusively in group D (P =.004). In a multivariate analysis, HBV genotype (P =.039) and pretreatment serum HBV DNA (P =.001) were independently associated with emerging rt204I or rt204V mutants, respectively. Serum HBV copy numbers after emergence of resistance were higher in group A (mean log(10) 6.99 copies/ml; range 3-9) compared with group D (mean log(10) 6.1 copies/ml; range 3.3-8; P =.04). There was no difference between both groups regarding core promoter/precore mutations, viral turnover, and number of flares or disease progression during follow-up. In conclusion, the mutational pattern during selection of lamivudine resistant HBV strains differs between genotypes A and D. This may have consequences for a salvage regimen initiated for treatment of lamivudine resistant HBV.

Impairment of transendothelial leukocyte migration by iron complexes.

Although iron sucrose and iron gluconate are generally well tolerated in patients who are treated for renal anemia, recent clinical studies and cell culture experiments suggested significant toxicity and long-term side effects arising from the use of these iron complexes. Because of the possible role of iron in infection or cardiovascular disease, it was theorized that parenteral iron compounds influence endothelial and PMN interaction in vitro. A well-established double-chamber method was used to assess the effect of different concentrations of iron sucrose and iron gluconate (1, 25, 50, and 100 micro g/ml) on the transendothelial migration of PMN. Preincubation of PMN and endothelial cells as well as preincubation of PMN alone with 25, 50, or 100 micro g/ml iron resulted in a significant decrease in PMN migration. In contrast, after incubation of the endothelial cells alone with iron, no reduction in the transendothelial migration of PMN was observed. Preincubation of PMN and/or endothelial cells with 1 micro g/ml iron did not lead to any decrease in the rate of migrated PMN. The only significant change in experiments with 1 micro g/ml was an increase in PMN migration after preincubation of endothelial cells and PMN with iron gluconate. A four-way ANOVA showed a significant effect of the iron concentration (P < 0.000001), of type of iron complex (P < 0.005), of the preincubation of endothelial cell (P < 0.001), and of the preincubation of PMN with iron (P < 0.000001) on PMN diapedesis. It is concluded that iron sucrose and iron gluconate cause a significant inhibition of transendothelial migration of PMN.

TGF-beta1 impairs homocysteine metabolism in human renal cells: possible implications for transplantation.

We hypothesized that TGF-beta1 influences the metabolism of homocysteine (Hcy) and increases its cellular export, which may lead to hyperhomocysteinemia in patients with renal transplants. We exposed human renal proximal tubule epithelial cells (huRPTECs) to different concentrations of TGF-beta1, IL-1alpha, IL-10, or methionine and measured total Hcy (tHcy) in culture supernatants. We then examined the relationship between plasma levels of tHcy and TGF-beta1 in renal graft recipients. In multivariate analysis, the factors mediator (TGF-beta1, IL-1alpha, IL-10), mediator concentration, methionine concentration, and "mediator x concentration" interaction independently influenced tHcy concentrations in culture supernatants. A 31% increase in tHcy was observed after exposure of huRPTECs to TGF-beta1 compared to medium alone. However, TGF-beta1 plasma levels in kidney graft recipients showed no independent association with tHcy plasma concentrations. We demonstrated that the release of Hcy from huRPTECs is enhanced by TGF-beta1, but that TGF-beta1 plasma levels in renal graft recipients show no independent relationship with hyperhomocysteinemia.