Charlotte Strandhave

No significant effect of angiotensin II receptor blockade on intermediate cardiovascular end points in hemodialysis patients

Agents blocking the renin-angiotensin-aldosterone system are frequently used in patients with end-stage renal disease, but whether they exert beneficial cardiovascular effects is unclear. Here the long-term effects of the angiotensin II receptor blocker, irbesartan, were studied in hemodialysis patients in a double-blind randomized placebo-controlled 1-year intervention trial using a predefined systolic blood pressure target of 140 mm Hg (SAFIR study). Each group of 41 patients did not differ in terms of age, blood pressure, comorbidity, antihypertensive treatment, dialysis parameters, and residual renal function. Brachial blood pressure decreased significantly in both groups, but there was no significant difference between placebo and irbesartan. Use of additional antihypertensive medication, ultrafiltration volume, and dialysis dosage were not different. Intermediate cardiovascular end points such as central aortic blood pressure, carotid-femoral pulse wave velocity, left ventricular mass index, N-terminal brain natriuretic prohormone, heart rate variability, and plasma catecholamines were not significantly affected by irbesartan treatment. Changes in systolic blood pressure during the study period significantly correlated with changes in both left ventricular mass and arterial stiffness. Thus, significant effects of irbesartan on intermediate cardiovascular end points beyond blood pressure reduction were absent in hemodialysis patients.

Marine n-3 fatty acids, atrial fibrillation and QT interval in haemodialysis patients.

Patients treated with haemodialysis are at high risk of sudden cardiac death (SCD) often caused by arrhythmias. Atrial fibrillation (AF) is frequent among haemodialysis patients and is associated with increased mortality. Prolonged QTc is a risk marker of ventricular arrhythmia and is thereby associated with SCD. Studies have suggested that n-3 PUFA may have an antiarrhythmic effect, but the exact mechanism is not clear. The aim of this study was to examine whether AF was associated with n-3 PUFA in plasma phospholipids and whether supplementation with n-3 PUFA would shorten the QTc interval in haemodialysis patients compared to placebo. In a double-blinded randomised, placebo-controlled intervention trial 206 haemodialysis patients with CVD were treated with 1·7 g n-3 PUFA or placebo (olive oil) daily for 3 months. Blood samples and electrocardiogram evaluations were carried out at baseline and after 3 months. The QT interval, PQ interval and heart rate were measured in all patients with sinus rhythm (SR). At baseline 13 % of patients had AF. The content of the n-3 PUFA, DHA, was significantly lower (P < 0·05) in serum of patients with AF compared with patients with SR. Thus, the DHA content was independently negatively associated with AF. Supplementation with n-3 PUFA did not shorten the QT interval significantly compared to the placebo group (P = 0·42), although subgroup analysis within the n-3 PUFA group revealed a shortening effects on QTc (P = 0·01). In conclusion, an inverse association was found between the presence of AF and the plasma DHA in haemodialysis patients. Intervention with n-3 PUFA did not shorten the QTc interval compared to placebo.

Post-Transplant Lymphoproliferative Disorder Following Kidney Transplantation: A Population-Based Cohort Study

Post‐transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long‐term post‐transplantation follow‐up. A retrospective population‐based cohort study including all kidney transplant recipients at two Danish centres (1990–2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient‐years (95% CI: 4.0–7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9–5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post‐transplant patient survival was inferior in patients with PTLD, while death‐censored graft survival was not. Using registry data together with extensive pathological review and long follow‐up, a rather high incidence of PTLD was found.

Haptoglobin Genotype and Risk Markers of Cardiovascular Disease in Patients with Chronic Kidney Disease

Sudden cardiac death and atherosclerosis have a major impact on cardiovascular mortality in chronic kidney disease (CKD). Inflammation with elevated high-sensitive C-reactive protein (hs-CRP) is involved in both sudden cardiac death and atherosclerosis, and decreased heart rate variability (HRV) is a predictor of both sudden cardiac death and atherosclerosis. Haptoglobin (Hp) is characterised by three genotypes (1-1, 2-1, and 2-2) with different antioxidant abilities. The aim was to examine whether HRV and hs-CRP were associated with Hp genotype in CKD patients. Fifty-six patients with CKD stage 2–5 were included. Hp genotype was determined by high-performance liquid chromatography. HRV was analysed from the 24 h Holter recordings. Hs-CRP was measured using an immunoturbidimetric assay. The results show that the HRV indices SDNN and SDANN were significantly lower in the Hp 2-2 patients (P = 0.02 and 0.04, resp.). In an adjusted linear regression model, Hp 2-2 was associated with both SDNN (P = 0.005) and SDANN (P = 0.01). Hs-CRP was higher in the Hp 2-2 patients (P = 0.002). In an adjusted linear regression model, the association between Hp 2-2 and hs-CRP remained significant (P = 0.003). In conclusion, a negative association was observed between Hp 2-2 and HRV, and Hp 2-2 was positively associated with hs-CRP in CKD patients.

Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study)

Background and Aim Little is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan. Design Randomized, double-blind, placebo-controlled, one-year intervention trial. Setting and Participants Eighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year. Intervention Irbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients. Outcomes and Measurements Cardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension. Results At baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on baseline parameters. Conclusion Use of the ARB irbesartan as an add-on to other antihypertensive therapy did not significantly affect intradialytic hemodynamics, neither in short nor long-term, and no significant increase in hypotensive episodes was seen. Trial registration Clinicaltrials.gov NCT00791830

Marine n-3 polyunsaturated fatty acids affect the blood pressure control in patients with newly diagnosed hypertension – a 1-year follow-up study

Marine long-chained n-3 polyunsaturated fatty acids (PUFA) are recognized for their cardio-protective effects, including potential lowering of blood pressure. We hypothesized that higher habitual fish intake and n-3 PUFA plasma levels were associated with lower blood pressure and being less likely to receive antihypertensive medication after one-year follow-up. In this prospective study of 115 patients, we assessed 24 h ambulatory and central blood pressure, plasma phospholipid fatty acid composition using gas chromatography and participants completed a food frequency questionnaire, including fish-eating habits. All measurements were repeated at one-year follow-up. At baseline, patients consuming fish ≥2 times per month for dinner had significantly higher plasma levels of total marine n-3 PUFA, docosahexaenoic acid and eicosapentaenoic acid as well as significantly lower central blood pressure and a trend towards lower peripheral blood pressure. At follow-up, 21 patients (18%) without antihypertensive medication had significantly higher plasma levels of n-3 PUFA, docosahexaenoic acid and eicosapentaenoic acid as well as a higher, but still acceptable 24 h ambulatory blood pressure (137/85 mmHg) compared to subjects receiving antihypertensive medication. The untreated group was more prone to take fish oil capsules and increased their plasma levels of n-3 PUFA compared to baseline. In patients with newly diagnosed, untreated hypertension, regular fish consumption was accompanied by lower blood pressure. After one year, patients without antihypertensive medication were characterized by a significant increase and higher plasma levels of n-3 PUFA. This supports a blood pressure-lowering effect and suggests an increase in marine n-3 PUFA intake as part of non-pharmacological treatment of hypertension.

HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based Cohort

Background Posttransplant lymphoproliferative disorder (PTLD) is a feared complication to organ transplantation, associated with substantial morbidity and inferior survival. Risk factors for PTLD include T cell–depleting induction therapy and primary infection or reactivation of Epstein-Barr virus. Possible associations between certain HLA types and the risk of developing PTLD have been reported by other investigators; however, results are conflicting. Methods We conducted a retrospective, population-based study on 4295 Danish solid organ transplant patients from the Scandiatransplant database. Having identified 93 PTLD patients in the cohort, we investigated the association of HLA types with PTLD, Epstein-Barr virus status and time to PTLD onset. The outcomes survival and PTLD were evaluated using Cox regression; mismatching, and the PTLD-specific mortality were evaluated in a competing risk analysis. Results Risk of PTLD was associated with male sex (odds ratio, 1.70; 95% confidence interval, 1.07-2.71), and, in women, HLA-DR13 conferred an increased risk (odds ratio, 3.22; 95% confidence interval, 1.41-7.31). In multivariate analysis, HLA-B45 and HLA-DR13 remained independent predictive factors of PTLD. Mismatching in the B locus was associated with a reduced risk of PTLD (P < 0.001). Overall survival was poor after a PTLD diagnosis and was significantly worse than that in the remaining transplant cohort (P < 0.001). Conclusions Our data indicate risk-modifying HLA associations, which can be clinically useful after transplantation in personalized monitoring schemes. Given the strong linkage disequilibrium in the HLA region, the associations must be interpreted carefully. The large size, virtually complete ascertainment of cases and no loss to follow-up remain important strengths of the study.

Haptoglobin Genotype Is Not Associated With Graft Loss, Cardiovascular or All-Cause Mortality in Renal Transplant Recipients.: Abstract# C1774

C1774 Haptoglobin Genotype Is Not Associated With Graft Loss, Cardiovascular or All-Cause Mortality in Renal Transplant Recipients. M. Svensson,1 H. Krarup,2 D. Dahle,3 I. Eide,3 J. Christensen,4 C. Strandhave,4 T. Leivestad,3 A. Hartmann.3 1Department of Nephrology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 3Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; 4Department of Nephrology, Aalborg University Hospital, Aalborg, Denmark. Purpose Haptoglobin (Hp) is an innate antioxidant and scavenges haemoglobin. In humans, Hp is present in three major genotypes: Hp 1-1, 2-1, and 2-2. The antioxidant ability of Hp is genotype-dependent. Hp 2-2 has previously been associated with a progressive decline in renal function and enhanced risk of cardiovascular disease and mortality. In renal transplant recipients no previous data exist regarding the infl uence of Hp genotype. The aim of this study was to examine the relation between Hp genotype, graft loss, cardiovascular and all-cause mortality in renal transplant recipients. Methods In a cohort of 1989 Norwegian renal transplant recipients Hp genotype was determined using high-performance liquid chromatography. Follow-up data on graft loss, cardiovascular and all-cause mortality were registered in a validated database (Norwegian renal registry). Data were analyzed using a multivariate Cox proportional hazard model. Results Median follow-up was 5.1 years with 432 (21.7%) events. When divided in three groups according to Hp genotype no difference was seen between groups regarding graft-loss, cardiovascular or all-cause mortality. In a multivariate analysis, adjustment for the following variables: age, gender, estimated glomerular fi ltration rate, body mass index, diabetes, cardiovascular disease, time on dialysis, transplant number, donor age, living donor, HLA-DR mismatches, cholesterol and number of anti-hypertensives, did not alter the results. Multivariate analysis for graft loss or death: Hp 2-2 (ref), Hp 2-1 (HR 1.13 (0.92-1.39), p 0.25) and Hp1-1 (HR 0.97 (0.71-1.3), p 0.82). Conclusion In a large cohort of renal transplant recipients with long-term follow-up, Hp genotype did not infl uence graft loss, cardiovascular or all-cause mortality. Abstract# C1775 Endothelial Progenitor Cells in Kidney Transplant Patients. F. Damiano,1 G. Ligabue,1 S. De Biasi,2 M. Granito,1 A. Cossarizza,2 G. Cappelli.1 1Dept of Surgery, Medicine, Dentistry and Morphological Scienses, University Hospital of Modena, Nephrology Unit, Modena, Italy; 2Dept of Surgery, Medicine, Dentistry and Morphological Scienses, University of Modena & Reggio Emilia,, Modena, Italy. Background: Circulating bone-marrow derived endothelial progenitor cells (EPCs) promote vascular repair. Lower concentrations of EPCs correlate with cardiovascular risk. In uremic patients, the number of functionally active EPCs is reduced. Kidney transplantation (KTx) improves both survival and endothelial function in patients with advanced renal failure. The aim of this study was to determine the impact of KTx and immunosuppressive therapy on the number of EPCs. Methods: EPCs were measured by fl ow cytometry analysis in 51 renal transplant patients (52±13,92 years; mean eGFR 52,61±19,90 ml/min) and 25 healthy subjects (49±15 years; mean eGFR 94±23 ml/min). We examined the associations between counts of EPCs and traditional cardiovascular risk factors, uremia related risk factors, kidney function and immunosuppressive agents. Results: EPCs numbers were similar in Kidney transplant recipients and controls. We found signifi cant (p<0.05) independent inverse associations between counts of EPCs and age, sistolic and diastolic blood pressure and C-Reactive Protein (CRP). Renal transplant recipients with reduced graft function (mean eGFR <30 ml/min) had lower EPCs counts compared with healthy volunteers(1,05-05 ± 1,17-05 vs.3,9504 ± 8,35-04 as % on 5x106 PBMc; p=0,0105). Patients receiving regimen therapy including corticosteroids showed signifi cantly lower EPCs number (1,77-02± 1,24-02 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p<0,0001). The use of Cyclosporine and Everolimus induced a further decrease in EPCs number compared to Cyclosporine and Mycophenolate (7,70-05 ± 1,65-04 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p=0,0044). Conclusions: EPCs numbers in KTx are comparable to those found in healthy subjects. In addition, this study suggests negative associations in KTx between EPC counts and age, blood pressure, CRP, graft function and use of some immunosuppressive drugs combination. These fi ndings indicate an improved potential for endothelial repair after KTx, suggest a different effect from different anti-rejection drugs and emphasize the role of EPCs as marker of endothelial health and predictors of cardiovascular outcomes. C1775 Endothelial Progenitor Cells in Kidney Transplant Patients. F. Damiano,1 G. Ligabue,1 S. De Biasi,2 M. Granito,1 A. Cossarizza,2 G. Cappelli.1 1Dept of Surgery, Medicine, Dentistry and Morphological Scienses, University Hospital of Modena, Nephrology Unit, Modena, Italy; 2Dept of Surgery, Medicine, Dentistry and Morphological Scienses, University of Modena & Reggio Emilia,, Modena, Italy. Background: Circulating bone-marrow derived endothelial progenitor cells (EPCs) promote vascular repair. Lower concentrations of EPCs correlate with cardiovascular risk. In uremic patients, the number of functionally active EPCs is reduced. Kidney transplantation (KTx) improves both survival and endothelial function in patients with advanced renal failure. The aim of this study was to determine the impact of KTx and immunosuppressive therapy on the number of EPCs. Methods: EPCs were measured by fl ow cytometry analysis in 51 renal transplant patients (52±13,92 years; mean eGFR 52,61±19,90 ml/min) and 25 healthy subjects (49±15 years; mean eGFR 94±23 ml/min). We examined the associations between counts of EPCs and traditional cardiovascular risk factors, uremia related risk factors, kidney function and immunosuppressive agents. Results: EPCs numbers were similar in Kidney transplant recipients and controls. We found signifi cant (p<0.05) independent inverse associations between counts of EPCs and age, sistolic and diastolic blood pressure and C-Reactive Protein (CRP). Renal transplant recipients with reduced graft function (mean eGFR <30 ml/min) had lower EPCs counts compared with healthy volunteers(1,05-05 ± 1,17-05 vs.3,9504 ± 8,35-04 as % on 5x106 PBMc; p=0,0105). Patients receiving regimen therapy including corticosteroids showed signifi cantly lower EPCs number (1,77-02± 1,24-02 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p<0,0001). The use of Cyclosporine and Everolimus induced a further decrease in EPCs number compared to Cyclosporine and Mycophenolate (7,70-05 ± 1,65-04 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p=0,0044). Conclusions: EPCs numbers in KTx are comparable to those found in healthy subjects. In addition, this study suggests negative associations in KTx between EPC counts and age, blood pressure, CRP, graft function and use of some immunosuppressive drugs combination. These fi ndings indicate an improved potential for endothelial repair after KTx, suggest a different effect from different anti-rejection drugs and emphasize the role of EPCs as marker of endothelial health and predictors of cardiovascular outcomes. Abstract# C1776 Osteoporosis and Fractures After Solid Organ Transplantation: A Nationwide Population-Based Case-Control Study. T. Yu,1,2 C. Kao.2 1Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Clinical Medicine, China Medical University, Taichung, Taiwan. Objectives: Metabolic bone disease after solid organ transplantation (SOT) is becoming an important complication to consider in chronic transplant patients. However, few population studies have described long-term outcomes of osteoporosis and related fractures after SOT. Therefore, we devoted to investigate the prevalence of bone disorders after SOT and to compare the risk of different SOT in a nationwide population-based study. Methods: We used Taiwan’s National Health Insurance Research Database to identify 9,535 solid organ transplant recipients and 38,140 gender and age matched-control subjects to compare the incidence and risk of bone disorders in both groups. Results: Patients with SOT had a signifi cantly higher incidence rate of osteoporosis and related fractures as compared to the non-SOT group. The overall hazard ratio of osteoporosis after transplantation for SOT patients was 5.36 (95% CI= 3.298.72) as well as HR of related fractures was 6.07(95% CI =4.039.16) after adjustment. The highest sexand age-specifi c HR were observed in the male patients (HR=7.79, 95% CI=3.46-17.5) and those with an age ≤50 years (HR=7.46, 95% CI=2.50-22.3). In addition, SOT patients without any comorbidity had an 8.96-fold higher risk of developing osteoporosis than non-SOT subjects (HR=8.96, 95% CI=5.25-15.3). To compare the risk of osteoporosis and related fractures among different SOT patients, the highest risk of osteoporosis as well as fractures was noted among patients receiving lung transplantation followed by other types of SOT. Conclusion: In the study, we report unacceptably high rates of metabolic bone disorders after SOT in chronic transplant patients over a long follow-up period. Pre-transplant bone disorders and immunosuppressant agents are supposed to be involved with metabolic disorders after transplantation. C1776 Osteoporosis and Fractures After Solid Organ Transplantation: A Nationwide Population-Based Case-Control Study. T. Yu,1,2 C. Kao.2 1Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Clinical Medicine, China Medical University, Taichung, Taiwan. Objectives: Metabolic bone disease after solid organ transplantation (SOT) is becoming an important complication to