Shared alloimmune responses against blood and transplant donors result in adverse clinical outcomes following blood transfusion post-renal transplantation.

De novo HLA donor-specific antibodies (DSA) following transplantation are associated with alloimmune injury and allograft failure. Blood transfusions are allogeneic, and when given posttransplant (PTBT) they may independently increase the risk of HLA antibody development. This study aims to analyze the development of HLA transfusion-specific antibodies (TSA) to blood donors of transfusions given posttransplant and examine the impact on clinical outcomes. A total of 244 blood donors of transfusions received by 86 transplant patients (46 who developed a DSA post transfusion and 40 who remained DSA negative) were HLA typed. De novo TSA developed against 150/244 (61.5%) blood donors. In 70/150 (46.7%) cases the TSA was of shared HLA antibody specificity with a DSA response in the recipient (DSA+ = TSA+). This occurred when there was a greater overall HLA match between the blood and transplant donor. DSA+ = TSA+ patients had increased risk of allograft failure (P = .0025) and AMR (P = .02) compared with the DSA+ ≠ TSA+ patients. To conclude, PTBT may elicit de novo HLA antibodies. Enhanced HLA matching between the blood and transplant donor is more likely to result in a DSA and TSA of shared antibody specificities. Transfusion avoidance or the use of HLA matched or selected blood may reduce this risk and improve outcomes.

Allosensitization after transplant failure: the role of graft nephrectomy and immunosuppression - a retrospective study.

There are conflicting data about the role of transplant nephrectomy and immunosuppression withdrawal on the development of allosensitization and the impact on re-transplantation. We divided 109 first graft recipients into two groups according to whether they underwent nephrectomy (NX+, n = 61) or their graft was left in situ (NX-, n = 48). Sera were assessed for HLA-A/B/Cw/DR/DQ antibodies at the time of NX/transplant failure and after 3, 6, 12, 24 months. The NX+ group showed a higher rate of donor specific antibody (DSA) and non-DSA human leukocyte antigen (HLA) antibody production at all the time points. Multivariable analysis showed that nephrectomy was a strong, independent risk factor for the development of DSAs after 12 and 24 months (P = 0.005 and 0.008). In the NX- group, low tacrolimus levels correlated with DSA formation (AUC 0.817, P = 0.002; best cut-off level 2.9 ng/ml). Analysis with a standardized pool of UK donors showed a more difficult grade of HLA matchability following nephrectomy compared with the NX- group. Nephrectomy is followed by the long-term production of DSA and non-DSA HLA antibodies and negatively impacts on the chances of finding a HLA-compatible kidney. Tacrolimus levels ≥3 ng/ml are protective against the development of allosensitization and could facilitate re-transplantation in the NX- group.

Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab.

BACKGROUND: Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial. METHODS: The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS. RESULTS: 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group. CONCLUSIONS: In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.

Neurological complications of renal dialysis and transplantation.

Neurological complications from renal replacement therapy contribute significantly to morbidity and mortality in patients with renal failure. Such complications can affect either the central or peripheral nervous systems. Most neurological disturbances associated with the uraemic state do not respond fully to renal replacement therapy. There are also complications specifically associated with dialysis and transplantation. A multidisciplinary approach, involving both nephrologists and neurologists, is critical for the diagnosis and effective management of these disorders.

Alemtuzumab dose adjusted for body weight is associated with earlier lymphocyte repletion and less infective episodes in the first year post renal transplantation - a retrospective study.

The optimal dose of alemtuzumab for renal transplant induction is not known, and the doses reported in the literature vary. This study compares two separate dosing regimens of alemtuzumab in renal transplantation. The first is a standard fixed dose of 30 mg (SD), and the second is a dose adjusted for body weight at 0.4 mg/kg (AD). In this first year post-transplant, there was no difference in patient [HR 0.64 (0.22-1.86), P = 0.39] or allograft survival [HR 1.18 (0.48-2.90), P = 0.72] between the two groups. There was also no difference in overall rejection-free survival [HR 1.12 (0.79-1.58), P = 0.53]. However, absolute lymphocyte count was significantly higher at all measured time points in the first year in the AD group. There were also less episodes of urosepsis [HR 1.38 (1.03-1.85), P = 0.037] and fungal infection [HR 5.15 (2.00-13.28), P = 0.015] in the AD group compared with the SD group. This study shows that AD alemtuzumab is associated with earlier lymphocyte repletion and less infective episodes in the first year postrenal transplant, without increasing the risk of rejection. This work highlights the need for studies into the optimal dosing of monoclonal antibodies used in transplantation.

Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies.

The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy-free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor-specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation.

B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection.

We explored how B-lymphocytes influence in vitro T-cell alloresponses in patients with antibody-mediated rejection (AMR), testing whether B-cells would be preferentially involved in this group of patients. Peripheral blood mononuclear cells were collected from 65 patients having biopsy: 14 patients with AMR and 5 with no pathology on protocol; 38 with AMR and 8 with nonimmunologic damage on 'for cause'. Using enzyme-linked immunosorbent spot assays, we found interferon-γ production by indirect allorecognition in 45 of 119 total samples from the 65 patients. B-cells preferentially processed and presented donor alloantigens in samples from AMR patients. In a further 25 samples, B-cell-dependent allo-specific reactivity was shown by depletion of CD25(+) cells and these individuals had higher percentages of CD4CD25hi cells. In 21 samples, reactivity was shown by depletion of CD19(+) cells, associated with polarized cytokine production toward IL-10 after polyclonal activation by IgG/IgM. Overall, this shows a significant contribution by B-cells to indirect donor-specific T-cell reactivity in vitro in patients with AMR. Active suppression by distinct phenotypes of T- or B-cells in approximately half of the patients indicates that chronic AMR is not characterized by a universal loss of immune regulation. Thus, stratified approaches that accommodate the heterogeneity of cell-mediated immunity might be beneficial to treat graft dysfunction.

Incidence, risk factors, and outcomes of stroke post-transplantation in patients receiving a steroid sparing immunosuppression protocol.

Corticosteroid use after transplantation is associated with an increased incidence of cardiovascular events and death. Cerebrovascular disease is a common cause of morbidity and mortality post-renal transplantation; however, a dedicated analysis of cerebrovascular disease in recipients of a steroid sparing protocol has not been reported. The aim of this study was to examine the incidence, risk factors, and outcomes of CVA in transplant recipients receiving a steroid sparing protocol. We retrospectively analyzed 1237 patients who received a kidney alone or a simultaneous pancreas and kidney (SPK) transplant. Fifty-six of 1237 (4.53%) patients had a CVA post-transplant. All-cause mortality was significantly higher in the CVA group compared with the non-CVA group, OR: 3.4 (1.7-7.0), p < 0.001. Factors found to be associated with increased risk of CVA by multivariate analysis were older age, HR: 1.07 (1.04-1.09), p < 0.001; diabetes at the time of transplantation, HR: 2.83 (1.42-5.64), p = 0.003; corticosteroid use pre-transplant, HR: 3.27 (1.29-8.27), p = 0.013 and recipients of a SPK, HR: 4.03 (1.85-8.79), p < 0.001. This study has identified subgroups of patients who are at increased risk of CVA post-transplant in patients otherwise receiving a steroid sparing immunosuppression protocol.

Targeted Gene Deletion or Antagonism of the Prostaglandin E2 EP3 Receptor Protects Against Cardiac Injury Postmyocardial Infarction.

BACKGROUND: Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI. METHODS: To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI. RESULTS: CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice. CONCLUSIONS: Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure.

Prostaglandin E2 affects mitochondrial function in adult mouse cardiomyocytes and hearts.

Prostaglandin E2 (PGE2) signals differently through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic/pathologic effects. We previously reported that PGE2 via its EP3 receptor reduces cardiac contractility and male mice with cardiomyocyte-specific deletion of the EP4 receptor (EP4 KO) develop dilated cardiomyopathy. The aim of this study was to identify pathways responsible for this phenotype. We performed ingenuity pathway analysis (IPA) and found that genes differentiating WT mice and EP4 KO mice were significantly overrepresented in mitochondrial (adj. p value = 6.28 × 10-26) and oxidative phosphorylation (adj. p value = 1.58 × 10-27) pathways. Electron microscopy from the EP4 KO hearts show substantial mitochondrial disarray and disordered cristae. Not surprisingly, isolated adult mouse cardiomyocytes (AVM) from these mice have reduced ATP levels compared to their WT littermates and reduced expression of key genes involved in the electron transport chain (ETC) in older mice. Moreover, treatment of AVM from C57Bl/6 mice with PGE2 or the EP3 agonist sulprostone resulted in changes of various genes involved in the ETC, measured by the Mitochondrial Energy Metabolism RT2-profiler assay. Lastly, the EP4 KO mice have reduced expression of superoxide dismuatse-2 (SOD2), whereas treatment of AVM with PGE2 or sulprostone increase superoxide production, suggesting increased oxidative stress levels in these EP4 KO mice. Altogether the current study supports the premise that PGE2 acting via its EP4 receptor is protective, while signaling through its other receptors, likely EP3, is deleterious.

Renal impairment reduces the efficacy of thrombolytic therapy in acute ischemic stroke.

BACKGROUND: Renal impairment is a potent risk factor for stroke, which remains a leading cause of death and disability. Thrombolysis for acute ischemic stroke has transformed patient outcomes, although the safety and efficacy of this approach remain poorly characterized in patients with renal dysfunction, who manifest a higher risk of bleeding due to uremia. We therefore examined the impact of renal impairment on clinical outcomes with thrombolysis within the current 4.5-hour therapeutic window. METHODS: This retrospective multicenter cohort study (2009-2011) examined 229 stroke patients receiving thrombolysis with alteplase (0.9 mg/kg; mean age 70 ± 13 years; 59% male, 24% diabetic). Sixty-five patients had an estimated glomerular filtration rate (eGFR) <60 ml/min. The primary outcome was the improvement in National Institutes of Health Stroke Scale (NIHSS) score at 24 h. Secondary outcomes included the NIHSS score at 7 days, the incidence of symptomatic and asymptomatic intracranial hemorrhage (ICH), extracranial bleeding and death during the index hospitalization. Univariate and multivariate regression analyses were performed to determine the association between demographic characteristics and comorbid factors of interest and outcomes. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: There was no significant difference in mean time to thrombolysis between the groups (221 ± 66 vs. 220 ± 70 min from symptom onset; p = 0.9). An eGFR <60 ml/min was independently associated with a statistically significant reduction of the therapeutic effect of alteplase at 24 h on multivariate regression [coefficient -2.3, 95% confidence interval (CI) -3.7 to -0.9; p = 0.002], and this persisted at 7 days (coefficient -3.5, 95% CI -5.3 to -1.7; p < 0.001). On modeling eGFR as a continuous variable, every 10 ml/min decline in eGFR was associated with a 0.40 diminution in NIHSS score improvement with alteplase (95% CI 0.07-0.74; p = 0.02). Older age and a higher presenting NIHSS score were associated with a greater therapeutic effect (p = 0.04 and p < 0.001, respectively). In-patient mortality was 5%, with no significant differences between groups. Renal impairment was not associated with a higher rate of ICH (6.2 vs. 6.7%; p = 0.9). Greater NIHSS score at presentation was the only factor associated with a greater risk of death (odds ratio 1.24, 95% CI 1.10-1.40; p < 0.001) and ICH (odds ratio 1.12, 95% CI 1.03-1.23; p = 0.004). CONCLUSIONS: Our results suggest that renal impairment is associated with reduced efficacy of thrombolysis in acute ischemic stroke without any excess hemorrhagic complications. This may relate to diminished fibrinolysis in the uremic milieu or differences in infarct anatomy. Longer-term prospective studies are required to characterize and improve functional outcomes following stroke in a manifestly high-risk group.

A case of chronic antibody-mediated rejection in the making.

A kidney transplant recipient developed chronic antibody-mediated rejection (ABMR) with clinically significant transplant glomerulopathy while under careful clinical monitoring. The patient developed a de novo donor-specific antibody (DSA) posttransplantation, and a protocol renal biopsy showed C4d deposition with no histological evidence of rejection. Subsequently he developed peritubular capillary basement membrane multilayering, with negative C4d and DSA. Finally, he developed proteinuria and transplant glomerulopathy, with reappearance of DSA and C4d. Despite having a de novo antibody and progressive antibody-mediated damage, this patient under close histological and serological surveillance did not fulfill Banff criteria for acute or chronic ABMR until his disease was advanced. This case illustrates the limitations of current Banff criteria in this setting, due to the fluctuating nature of DSA and C4d staining.

Deleterious effects of cardiomyocyte-specific prostaglandin E2 EP3 receptor overexpression on cardiac function after myocardial infarction.

AIMS: Prostaglandin E2 (PGE2) is a lipid hormone that signals through 4 different G-protein coupled receptor subtypes which act to regulate key physiological processes. Our laboratory has previously reported that PGE2 through its EP3 receptor reduces cardiac contractility at the level of isolated cardiomyocytes and in the isolated working heart preparation. We therefore hypothesized that cardiomyocyte specific overexpression of the PGE2 EP3 receptor further decreases cardiac function in a mouse model of heart failure produced by myocardial infarction. MAIN METHODS: Our study tested this hypothesis using EP3 transgenic mice (EP3 TG), which overexpress the porcine analogue of human EP3 in the cardiomyocytes, and their wildtype (WT) littermates. Mice were analyzed 2 wks after myocardial infarction (MI) or sham operation by echocardiography, RT-PCR, immunohistochemistry, and histology. KEY FINDINGS: We found that the EP3 TG sham controls had a reduced ejection fraction, reduced fractional shortening, and an increased left ventricular dimension at systole and diastole compared to the WT sham controls. Moreover, there was a further reduction in the EP3 TG mice after myocardial infarction. Additionally, single-cell analysis of cardiomyocytes isolated from EP3 TG mice showed reduced contractility under basal conditions. Overexpression of EP3 significantly increased cardiac hypertrophy, interstitial collagen fraction, macrophage, and T-cell infiltration in the sham operated group. Interestingly, after MI, there were no changes in hypertrophy but there were changes in collagen fraction, and inflammatory cell infiltration. SIGNIFICANCE: Overexpression of EP3 reduces cardiac function under basal conditions and this is exacerbated after myocardial infarction.

Appraising stroke risk in maintenance hemodialysis patients: a large single-center cohort study.

BACKGROUND: Stroke incidence in hemodialysis patients is up to 10 times greater than in the general population and is associated with a worse prognosis. Factors influencing stroke risk by subtype and subsequent prognosis are poorly described in the literature. STUDY DESIGN: Retrospective single-center cohort study. SETTING & PARTICIPANTS: 2,384 established maintenance hemodialysis patients at a single center from January 1, 2002, to June 1, 2009. PREDICTOR: Patient demographics, comorbid conditions. OUTCOMES: Incidence of acute stroke (International Classification of Diseases, 9th Revision codes 430, 431, 432.9, 433.1, and 434.1 with evidence of compatible neuroimaging), patient survival. MEASUREMENTS: Cumulative patient survival, incidence of acute fatal and nonfatal stroke. RESULTS: 127 strokes occurred during 9,541 total patient-years of follow-up. First (incident) stroke occurred at a rate of 14.9/1,000 patient years (95% CI, 12.2-17.9) with a predominance of ischemic compared with hemorrhagic subtypes (11.2 vs 3.7/1,000 patient-years). 54% of hemorrhagic strokes occurred in patients of South Asian ethnicity compared with ischemic strokes, which occurred predominantly in white patients (45% of events). Diabetes mellitus (HR, 1.92; 95% CI, 1.29-2.85; P = 0.001) and prior cerebrovascular disease (HR, 4.54; 95% CI, 3.07-6.72; P < 0.001) were independently associated with incident cerebrovascular accident on multivariate analysis. Acute stroke was associated with worse patient survival (HR, 3.26; 95% CI, 2.47-4.30; P < 0.001) and overall 1-year mortality of 24%, which was significantly worse in patients with hemorrhagic events (39% vs 19% mortality for ischemic subtypes). Serum albumin level >3.5 g/L (HR, 0.38; 95% CI, 0.19-0.76; P = 0.007) and C-reactive protein level >3.0 mg/l (HR, 1.36; 95% CI, 1.12-1.64; P = 0.002) influenced survival after stroke on multivariate analysis. LIMITATIONS: Retrospective analysis of data cannot prove causality. CONCLUSIONS: The high incidence of stroke in hemodialysis patients is associated with high mortality, especially hemorrhagic subtypes. Strict management of hypertension, better appreciation of hemodialysis anticoagulation, and large-scale interventional studies are urgently required to direct prevention and treatment of this significant disease.

Long-term renal function and survival of renal transplant recipients admitted to the intensive care unit.

INTRODUCTION: We determined the long-term mortality and renal allograft function of renal transplant recipients admitted to the intensive care unit (ICU). METHODS: A single institution retrospective observational cohort study of all renal transplant patients admitted to the ICU was performed. Serum creatinine was recorded up to one yr after hospital discharge and survival data were collected for three yr. RESULTS: Chest sepsis was the commonest reason for ICU admission. ICU and hospital mortality were 32% and 19% respectively. Predictors of hospital mortality included the presence of sepsis and duration of mechanical ventilation (MV). Of the patients who were discharged from ICU, three-yr mortality was 50%. Renal function at one yr was worse than that at hospital discharge and at baseline, though not statistically significant. Death-censored allograft loss was 11% over the three-yr follow up period. CONCLUSIONS: Sepsis and requirement for MV are independent predictors of mortality in renal transplant recipients admitted to ICU. Renal transplant recipients with chest sepsis may warrant earlier ICU admission. Any loss of renal allograft function during an episode of critical illness appears to have a lasting effect, and longterm patient and allograft survival is poor.

Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization.

Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.

Malignancies confined to disused arteriovenous fistulae in renal transplant patients: an important differential diagnosis.

BACKGROUND: Swelling in an arteriovenous fistula (AVF) is commonly caused by thrombosis, aneurysm and infection. However, due to the increased risk of malignancy after transplantation, this should also be considered. PATIENTS: We discuss 4 patients with malignancy confined to an AVF after renal transplantation presenting in a 2-year period. Angiosarcoma was diagnosed in 3 patients and the other had post-transplant lymphoproliferative disorder (PTLD). Angiosarcoma behaves aggressively and 2 of our patients died within 6 months of diagnosis. There are 6 previous cases and 5 died within 16 months of diagnosis. PTLD at AVFs has not been documented previously. CONCLUSION: Malignancy at an AVF is a rare but important differential that can impact significantly on patient morbidity and mortality. Predilection for malignancy at an AVF is not understood. We review the literature and discuss possible aetiologies.

Renal artery stenosis: comparative assessment by unenhanced renal artery MRA versus contrast-enhanced MRA.

OBJECTIVES: To evaluate steady-state free precession (SSFP) non-contrast-enhanced MR angiography (Unenhanced-MRA) versus conventional contrast-enhanced MR angiography (CE-MRA) in the detection of renal artery stenosis (RAS). METHODS: Retrospective analysis of 70 consecutive patients referred for suspected RAS, examined by SSFP Unenhanced-MRA and CE-MRA. Image quality, quality of visible renal arterial segments, presence and grade of RAS were evaluated. The Unenhanced-MRA were compared against reference standard CE-MRA results. RESULTS: 149 renal arteries were assessed with 21 haemodynamically significant stenoses (≥ 50% stenosis) demonstrated by CE-MRA. Combined sensitivity and specificity for RAS detection by Unenhanced-MRA was 72.8% and 97.8% respectively. There is substantial correlation for RAS detection between Unenhanced-MRA and CE-MRA with kappa values of between 0.64 and 0.74. There was excellent inter-observer correlation for RAS on Unenhanced-MRA (kappa values 0.82-1.0). CONCLUSIONS: Our study has shown Unenhanced-MRA to be a viable alternative to CE-MRA, yielding images equal in quality without the requirement for gadolinium contrast agents. The sensitivity and specificity for the detection of haemodynamically significant stenoses are comparable to CE-MRA. Potentially, Unenhanced-MRA could be used as an initial investigation to avoid performing CE-MRA in patients with normal renal arteries, however we suggest that its real value will lie in being complementary to CE-MRA.

Long-term Tesio catheter access for hemodialysis can deliver high dialysis adequacy with low complication rates.

PURPOSE: The use of central venous catheters for long-term hemodialysis has been associated with increased mortality and high prevalence of infection and venous stenosis. However, because central venous catheters still constitute a significant proportion of vascular access in prevalent populations, even in the Fistula-First era, the authors examined the long-term patient outcomes and performance of this vascular access type to inform current clinical practice. MATERIALS AND METHODS: The authors conducted a retrospective cohort study of 433 patients on maintenance hemodialysis in a dialysis program from January 1999 through April 2008 all using twin-catheter Tesio Caths (TCs) (MedCOMP, Harleysville, Pennsylvania). Written and electronic records were examined with respect to laboratory indices as well as mortality, access-related infection, need for thrombolytic infusion, access revision and dialysis adequacy. RESULTS: A total of 759 TCs were inserted with 552,035 catheter days follow-up. Thirty-six percent of insertions were in patients incident to dialysis (< 90 days). Mean single-pool Kt/V was 1.6 ± 0.3. Cumulative cohort survival rates were 85%, 72%, and 48% at 1, 2, and 5 years, respectively. No patients died as a result of lack of vascular access. Cumulative assisted primary access site patencies were 76%, 62%, and 42% at 1, 2, and 5 years, respectively. The prevalence of symptomatic central venous stenosis was 5%. Catheter-related bacteremia occurred at a rate of 0.34 per 1,000 catheter days. CONCLUSIONS: Appropriate use of TCs with protocolized care can deliver effective long-term hemodialysis with good adequacy and rates of access-related infection approaching those seen with arteriovenous grafts.

Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin.

Expression of hepcidin, the key hormone governing iron transport, is reduced by anemia in a manner which appears dependent on increased bone marrow activity. The temporal associations between plasma hepcidin and other iron parameters were examined in healthy humans after erythropoietin administration and venesection. Profound hepcidin suppression appeared abruptly 24 hours after subcutaneous erythropoietin (P=0.003), and was near maximal at onset, with peak (mid-afternoon) levels reduced by 73.2%, gradually recovering over the following two weeks. Minor changes in circulating iron, soluble transferrin receptor and growth differentiation factor-15 were observed after the reduction in hepcidin. Similar but more gradual changes in these parameters were observed after reducing hematocrit by removal of 250 mL blood. These human studies confirm the importance of a rapidly responsive marrow-hepcidin axis in regulating iron supply in vivo, and suggest that this axis is regulated by factors other than circulating iron, soluble transferrin receptor or growth differentiation factor-15.