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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., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

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.

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., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

Background: Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown., Methods: In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly., Results: Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy., Conclusions: Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD.

Although in Western Europe and North America the prevalence of chronic hepatitis B virus (HBV) infection has declined in patients awaiting renal transplantation, it remains a relevant clinical problem, mainly in patients with a long history of renal replacement therapy (RRT) who may have been infected many years ago. At the same time, a significant proportion of renal transplant recipients (RTR) is at risk for HBV infection in areas with endemic HBV. HBV infection may increase morbidity and mortality in RTR. The majority of long-term studies reported reduced patient survival compared with hepatitis B surface antigen (HBsAg)-negative RTR. The risk for morbidity and mortality of HBsAg-positive RTR transplantation is probably related to the extent of pretransplant liver disease. A thorough evaluation, including liver biopsy in many patients, is required to assess the individual HBsAg-positive patient's risk-benefit ratio. The influence of immunosuppressive therapy on HBV replication and HBV-associated complications is not well established and for clinical practice individually tailored immunosuppression is recommended in HBsAg-positive RTR. Careful screening for HBV reactivation in HBsAg-positive RTR and a regular clinical follow-up after renal transplantation (RTX) including liver sonography is required for early detection of HBV-associated complications. With the availability of new antiviral drugs, new options for pre- and posttransplant therapy might improve the prognosis of RTR with chronic HBV infection., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background: The effect of mycophenolate mofetil (MMF) on homocysteine (Hcy) metabolism is unknown., Methods: This in vitro study examined whether mycophenolic acid or tacrolimus influences the formation of Hcy as determined by measuring the total Hcy (tHcy) concentrations in supernatants of human renal proximal tubule epithelial cells. Cells were incubated with and without vitamins (folate, vitamin B6 and B12) in the presence of low or high methionine concentrations at different mycophenolic acid (0, or 5, or 20 microg/mL) or tacrolimus (0, or 10, or 25 ng/mL) concentrations for 24, 48 or 72 hours. The concentration of tHcy in culture supernatants was measured by a fluorescence polarization immunoassay. The effect of MMF on tHcy plasma levels was also examined in 454 kidney graft recipients., Results: Comparisons of tHcy levels in culture supernatants over time by four way ANOVA showed that methionine concentration (P < 0.00001), time (P < 0.00001), vitamins (P = 0.002728), and mycophenolic acid concentration (P = 0.000095) were all significant predictors of tHcy concentrations. This was due to significantly lower tHcy levels with using mycophenolic acid at a high concentration versus control at the 48- and 72-hour time points. By contrast, tacrolimus showed no effect in vitro. Among the kidney graft recipients, male patients on MMF therapy showed lower plasma tHcy concentrations as compared to those on azathioprine (P = 0.03)., Conclusion: Our study suggests a tHcy lowering effect of MMF in male transplant recipients, which improves the cardiovascular disease risk profile, whereas tacrolimus showed no effect.

Capillary deposition of the complement split product C4d has been discussed as a marker for antibody-mediated kidney allograft rejection. The relationship between C4d staining and posttransplant alloantibody detection remains to be thoroughly investigated, however. In this study, C4d staining in peritubular capillaries (PTC) and the incidence of alloantibody formation, as detected with sensitive techniques, were evaluated among a cohort of transplant recipients who had undergone biopsies and had not been selected for a specific histologic diagnosis. One hundred thirteen biopsies, obtained from 58 cadaveric kidney transplant recipients, were tested. Serum samples obtained at the time of biopsy were evaluated by flow cytometric crossmatch (FCXM) testing and FlowPRA (One Lambda, Inc., Canoga Park, CA) analysis of anti-HLA panel reactivity. Most biopsies with C4d deposits in PTC (C4d(PTC)(+), n = 21 of 24) were associated with positive posttransplant FCXM results (T and/or B cell FCXM) and/or > or =5% FlowPRA (anti-HLA class I and/or II) reactivity. Approximately 50% of the C4d(PTC)(-) biopsies were observed to be associated with donor-specific alloantibodies. Accordingly, high specificity (93%) but low sensitivity (31%) were calculated for capillary C4d staining (with FCXM testing as the standard method). For clinical evaluation, three patient groups were defined, i.e., a group of recipients with positive C4d staining in at least one allograft biopsy (C4d(PTC)(+), n = 16) and two C4d(PTC)(-) groups, which were discriminated on the basis of posttransplant FCXM results as C4d(PTC)(-)/FCXM(+) (n = 22) and C4d(PTC)(-)/FCXM(-) (n = 20) groups. Univariate analyses revealed significant differences between these groups with respect to serum creatinine levels at 12 mo [median, 2.83 mg/dl (interquartile range, 1.93 to 4.2 mg/dl) versus 1.78 mg/dl (1.47 to 2.24 mg/dl) versus 1.59 mg/dl (1.2 to 1.71 mg/dl), P < 0.001]. Of the five immunologic graft losses, four occurred in the C4d(PTC)(+) group and one occurred in the C4d(PTC)(-)/FCXM(+) group. In a multivariate analysis, C4d positivity was observed to have an independent predictive value for inferior 12-mo graft function (P = 0.02), whereas the observed moderate difference between C4d(PTC)(-)/FCXM(+) and C4d(PTC)(-)/FCXM(-) recipients did not achieve significance. In conclusion, these data demonstrate that positive C4d staining, which is an independent predictor of kidney graft dysfunction, represents a reliable specific marker for antibody-dependent graft injury.

Osteoprotegerin (OPG) has a profound inhibitory effect on osteoclast differentiation and bone resorption. Because high-turnover renal osteodystrophy (ROD) is characterized by increased osteoclast activity, serum OPG concentrations might be used to distinguish between forms of ROD. Twenty-six patients on maintenance hemodialysis therapy underwent a transiliac crest biopsy for evaluation of histopathologic characteristics and histomorphometric studies. ROD was diagnosed as type II (normal or low turnover) or type III (high turnover plus osteoidosis) disease. Bone mineralization density distribution (BMDD) was characterized by measuring the mean trabecular calcium concentration in the biopsy specimen with quantitative backscattered electron imaging. Patients underwent additional dual-energy x-ray absorptiometry (DEXA) of the spine and hip and measurement of such biochemical markers of bone turnover as OPG, intact parathyroid hormone (iPTH), osteocalcin, calcitonin, bone alkaline phosphatase, and cross-laps. OPG levels were significantly reduced in patients with ROD III compared with ROD II (118 +/- 38 versus 204 +/- 130 pg/mL; P < 0.05) and correlated with BMDD (r = 0.43; P < 0.05). Patients with ROD III showed significantly lower BMDD compared with healthy controls (21.42% +/- 0.12% versus 22.17% +/- 0.81% weight; P < 0.01). Besides iPTH, which showed significantly greater levels in patients with ROD III than ROD II (382 +/- 322 versus 136 +/- 156 pg/mL; P < 0.05), none of the serological markers or DEXA was useful in separation of the groups. Discriminant function analysis showed that a combination of OPG and iPTH correctly classifies ROD II in 72% and ROD III in 88% of patients. We conclude that OPG in combination with iPTH can be used as a marker for noninvasive diagnosis of ROD in hemodialysis patients. Furthermore, OPG serum levels might be used to estimate trabecular bone mineralization in these subjects., (Copyright 2002 by the National Kidney Foundation, Inc.)

Iron deficiency anemia after renal transplantation has not been systematically investigated. The prevalence of anemia and the indicators of iron deficiency among 438 renal transplant recipients were examined. Anemia was present in 39.7% of the patients. The prevalence of iron deficiencies, as indicated by a percentage of hypochromic red blood cells (HRBC) of >or=2.5%, was 20.1%. The majority of severely anemic patients exhibited HRBC values in the upper quartile. Positive associations of hemoglobin levels with creatinine clearance, serum transferrin levels, male gender, transferrin saturation (TSAT), polycystic kidney disease, and age were observed. Negative associations with erythropoietin therapy, use of azathioprine, serum ferritin levels, and body mass index were observed. The risk for anemia was closely related to the highest quartile of HRBC percentages (odds ratio, 2.35; 95% confidence interval, 1.48 to 3.75; P = 0.00029), whereas ferritin levels and TSAT conferred no risk for anemia. Therefore, assessment of the HRBC proportion is superior to decreased ferritin and decreased TSAT measurements for the diagnosis of iron deficiencies among renal transplant recipients.

The prevalence of the methionine synthase (MTR) 2756A-->G polymorphism among individuals with severely elevated total homocysteine (tHcy) plasma levels is unknown. Therefore, 1,716 subjects, including 415 hemodialysis patients, 179 peritoneal dialysis patients, 733 kidney graft recipients, and 389 healthy subjects, were investigated. The distribution of MTR 2756A-->G, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T/1298A-->C, genotypes among study participants with extremely high tHcy plasma levels (>90th percentile) was compared with the genotype distribution of subjects with very low tHcy plasma levels (<10th percentile). The prevalence of MTR 2756AG and GG genotypes alone did not differ between individuals with extremely high or extremely low tHcy levels (P = 0.7402; odds ratio [OR], 1.076; 95% confidence interval [CI], 0.697 to 1.662). Conversely, combined MTR and MTHFR genotypes (MTR 2756AG and 2756GG and MTHFR 677TT/1298AA and 677CT/1298AC) were found more often in the highest (n = 34) compared with the lowest plasma tHcy decile (n = 19; P = 0.0252; OR, 1.983; 95% CI, 1.079 to 3.643). The number of patients with the wild-type MTR and MTHFR genotype was three times greater in the lowest compared with the highest decile (17 versus 6 patients, respectively; P = 0.0155; OR, 0.330; 95% CI, 0.126 to 0.861). In summary, our study shows that the 2756A-->G transition of MTR in combination with MTHFR 677TT/1298AA and 677CT/1298AC can be associated with extremely high tHcy plasma levels.

There is increasing evidence for an important pathogenetic role of alloantibodies in acute renal allograft rejection. Acute humoral rejection (AHR) has been reported to be associated with a poor transplant survival. Although treatment modalities for cellular rejection are fairly well established, the optimal treatment for AHR remains undefined. Ten of 352 kidney allograft recipients transplanted at the authors' institution between November 1998 and September 2000 were diagnosed as having AHR, supported by severe graft dysfunction, C4d deposits in peritubular capillaries (PTC), and accumulation of granulocytes in PTC. AHR was diagnosed 18.9 +/- 17.5 d posttransplantation. All patients were subjected to immunoadsorption (IA) with protein A (median number of treatment sessions, 9; range, 3 to 17). Seven recipients with additional signs of cellular rejection (according to the Banff classification) received also antithymocyte globulin. In nine of ten patients, AHR was associated with an increase in panel reactive antibody reactivity. A pathogenetic role of alloantibodies was further supported by a positive posttransplant cytotoxic crossmatch in all tested recipients (n = 4). In nine of ten recipients, renal function recovered after initiation of anti-humoral therapy. One patient lost his graft shortly after initiation of specific therapy. Another recipient with partial reversal of AHR returned to dialysis 8 mo after transplantation. Mean serum creatinine in functioning grafts was 2.2 +/- 1.2 mg/dl after the last IA session (n = 9) and 1.5 +/- 0.5 mg/dl after a follow-up of 14.2 +/- 7.1 mo (n = 8). In conclusion, this study suggests that AHR, characterized by severe graft dysfunction, C4d staining, and peritubular granulocytes, can be effectively treated by timely IA. In the majority of patients, IA treatment can restore excellent graft function over a prolonged time period.

The effect of the combined 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C genotype on total homocysteine (tHcy), folate, and vitamin B(12) plasma levels was investigated in 983 subjects, including 415 hemodialysis patients, 179 peritoneal dialysis patients, and 389 healthy individuals. Mean tHcy plasma concentrations were 27.2 +/- 15.8 micromol/L in hemodialysis patients, 25.4 +/- 19.1 micromol/L in peritoneal dialysis patients, and 8.9 +/- 3.5 micromol/L in healthy individuals. Hyperhomocysteinemia (tHcy > 15 micromol/L) was detected in 81.6% of patients and 2.6% of controls. Multiple stepwise regression analysis showed that the MTHFR 677C-->T/1298A-->C genotype (CC/AA, CC/AC, CC/CC, CT/AA, CT/AC, TT/AA), vitamin use, age, folate and vitamin B(12) plasma level were significant predictors of tHcy plasma levels. Analysis of variance showed that this effect of MTHFR genotypes on tHcy level was caused by significantly greater tHcy levels in 677TT/1298AA hemodialysis and peritoneal dialysis patients versus other genotypes. Compound heterozygous controls (677CT/1298AC genotype) had significantly greater tHcy levels compared with 677CC/1298AA controls. There was no major effect of MTHFR polymorphisms on folate and vitamin B(12) plasma concentrations. This study shows that the MTHFR 677TT/1298AA genotype, but not the 677CT/1298AC genotype, is a significant predictor of tHcy plasma levels in dialysis patients.

A line probe assay (INNO-LiPA HBV DR) detecting drug-resistant hepatitis B virus (HBV) strains was evaluated. Results concordant with sequence analysis were obtained with 48 of 56 serum samples from HBV-infected patients undergoing lamivudine therapy. In eight cases, additional minor subpopulations could be identified by the line probe assay.

The clinical management of cytomegalovirus infection and disease in renal transplant recipients has recently been significantly improved with the availability of data on prophylaxis with oral ganciclovir and valacyclovir. In addition, significant progress in early diagnosis and the quantitation of viral load has been achieved. The influence of novel immunosuppressants on the clinical course of cytomegalovirus infection has been clarified to some extent by recent clinical data. The identification of risk factors for cytomegalovirus disease beyond seroconstellation and immunosuppression is an ongoing process that might lead to a more targeted use of antiviral agents, given the risk of ganciclovir resistance. The understanding of the effects of cytomegalovirus on long-term graft outcome still needs to be deepened in order to design cytomegalovirus-specific interventions to improve graft survival.

Background: Immunosuppressive therapy may influence homocysteine metabolism in allograft recipients. We examined whether cyclosporine A influences the in vitro formation of homocysteine as determined by the measurement of total homocysteine (tHcy) concentrations in supernatants of human renal proximal tubule epithelial cells (hRPTEC), an important site of homocysteine metabolism., Methods: Cells were incubated with and without vitamins in the presence of low or high methionine concentrations at different cyclosporine A concentrations for 24, 48 and 72 hours (N = 7 for each experiment). The concentration of tHcy in culture supernatants was measured by a fluorescence polarization immunoassay. Data were analyzed by four-way ANOVA, three-way ANOVA and t tests., Results: The Hcy export from hRPTEC (tHcy in the culture supernatant) was 2.69 micromol/L during standard cell culture conditions at time point 24 hours and increased by 28.3% at 48 hours and by 44.6% at 72 hours. Comparisons of tHcy levels in culture supernatants over time by four way ANOVA showed that cyclosporine A at 200 or 800 ng/mL had no influence on tHcy export from hRPTEC (P = 0.67991). In contrast, the presence of vitamins in the medium (P = 0.000001), in vitro methionine loading (P < 0.000001), and prolonged incubation time (P < 0.000001) were associated with an increase of tHcy export from hRPTEC. Significant interactions in this analysis were "vitamins x methionine" (P = 0.001804), "vitamins x time" (P = 0.001478), "methionine x time" (P < 0.000001), and "vitamins x methionine x time" (P = 0.018128), pointing to a combined effect of vitamins in the presence of high methionine concentrations at the later time points., Conclusion: Our study shows that hRPTEC export Hcy into the cell culture medium, an effect that is enhanced by in vitro methionine loading and modulated by the presence of vitamins. Cyclosporine A had no major influence on Hcy export from tubule cells. Therefore, our findings do not support the assumption that cyclosporine A elevates total homocysteine plasma levels in organ transplant patients.

Background: Chronic hepatitis B virus (HBV) infection increases morbidity and mortality in renal transplant recipients (RTR). Lamivudine has shown promising results in patients with chronic hepatitis B, but experience with its use in RTR is limited., Methods: In a prospective, open labeled, uncontrolled trial, 19 HBsAg(+) RTR were treated with lamivudine for 12 months. HBV-serologic analysis, HBV-DNA quantitation, and HBV genome sequence analysis were performed every 3 months., Results: At baseline 16 patients were HBV DNA(+), 12 patients were HBeAg(+)/Ab (-). After 3 months HBV DNA was negative in 80% of patients. In the 3 patients with elevated liver enzymes, normal values were achieved within 12 weeks. At 12 months 4 of 8 HBeAg(+)/Ab(-) patients on treatment showed HBeAb, two of them with loss of HBeAg. Three patients developed mutations of the HBV polymerase gene associated with lamivudine resistance., Conclusions: Lamivudine is safe and effective in HB-sAg(+) RTR, the rate of HBe-seroconversion and of lamivudine-resistance is comparable to that of nonimmunosuppressed patients.