Neill Duncan

Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements.

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.

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.

Bacteremia Associated with Tunneled Hemodialysis Catheters: Outcome after Attempted Salvage

BACKGROUND AND OBJECTIVES Treatment without catheter replacement (catheter salvage) has been described for bacteremia associated with tunneled venous catheters in hemodialysis patients, but few data are available on which to base an estimation of the likelihood of treatment success. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a prospective cohort study, all cases of catheter-associated bacteremia that occurred in a large dialysis center were identified during a 12-mo period. Catheter salvage was attempted according to a standard protocol in all cases in which a favorable early response to antibiotic therapy was seen, and patients were followed for at least 6 mo. Bacteremias, catheter changes, and all major clinical events were recorded. RESULTS During a period covering 252,986 catheter days, 208 episodes were identified involving 133 patients, 74% of which were selected for attempted salvage. Salvage was successful in 66.1% of incident bacteremias with a very low complication risk (0.9%). Some bacteremias, however, recurred as late as 6 mo after the initial infection; salvage was less likely to be successful in treating recurrences. CONCLUSIONS Appropriately used catheter salvage can be successful in approximately two thirds of cases; however, recurrences continue to occur up to 6 mo later and are unlikely to be cured without catheter replacement.

Cardiac Survival after Pre-emptive Coronary Angiography in Transplant Patients and Those Awaiting Transplantation

BACKGROUND AND OBJECTIVES Recent interest has focused on wait listing patients without pretreating coronary artery disease to expedite transplantation. Our practice is to offer coronary revascularization before transplantation if indicated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between 2006 and 2009, 657 patients (427 men, 230 women; ages, 56.5 ± 9.94 years) underwent pretransplant assessment with coronary angiography. 573 of 657 (87.2%) patients were wait listed; 247 of 573 (43.1%) patients were transplanted during the follow-up period, 30.09 ± 11.67 months. RESULTS Patient survival for those not wait listed was poor, 83.2% and 45.7% at 1 and 3 years, respectively. In wait-listed patients, survival was 98.9% and 95.3% at 1 and 3 years, respectively. 184 of 657 (28.0%) patients were offered revascularization. Survival in patients (n = 16) declining revascularization was poor: 75% survived 1 year and 37.1% survived 3 years. Patients undergoing revascularization followed by transplantation (n = 51) had a 98.0% and 88.4% cardiac event-free survival at 1 and 3 years, respectively. Cardiac event-free survival for patients revascularized and awaiting deceased donor transplantation was similar: 94.0% and 90.0% at 1 and 3 years, respectively. CONCLUSIONS Our data suggest pre-emptive coronary revascularization is not only associated with excellent survival rates in patients subsequently transplanted, but also in those patients waiting on dialysis for a deceased donor transplant.

Kidney Transplantation With Minimized Maintenance: Alemtuzumab Induction With Tacrolimus Monotherapy—an Open Label, Randomized Trial

Background. Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days. Methods. One hundred twenty-three live or deceased donor renal transplant recipients were randomized 2:1 to receive alemtuzumab/tacrolimus or daclizumab/tacrolimus/mycophenolate. The primary endpoint was survival with a functioning graft at 1 year. Results. Both regimens produced equivalent, excellent outcomes with the primary outcome measure of 97.6% in the alemtuzumab arm and 95.1% in the daclizumab arm at 1 year (95% confidence interval of difference 6.9% to −1.7%) and at 2 years 92.6% and 95.1%. Rejection was less frequent in the alemtuzumab arm with 1- and 2-year rejection-free survival of 91.2% and 89.9% compared with 82.3% and 82.3% in the daclizumab arm. There were no significant differences in terms of the occurrence of opportunistic infections. Conclusion. Alemtuzumab induction with tacrolimus maintenance monotherapy and short-course steroid use provides a simple, safe, and effective immunosuppressive regimen for renal transplantation.

Translumbar central venous catheters for long-term haemodialysis

BACKGROUND Vascular access for haemodialysis is achieved by tunnelled central venous catheter (CVC) in at least 23% of prevalent patients in the UK, Canada and the USA. Use of CVCs is associated with an increased incidence of venous stenosis that can progressively limit future vascular access routes. Lack of conventional venous access routes mandates the use of alternative strategies such as the translumbar approach. METHODS We retrospectively analysed patients at our centre requiring translumbar inferior vena caval CVCs (TesioCath) for haemodialysis in the period 1999-2008. Written and electronic records capturing dialysis adequacy and complications, hospital admissions and laboratory data were examined. RESULTS Thirty-nine pairs of translumbar CVCs were inserted in 26 patients with 15 864 catheter days follow-up, mean patient age 61.9 +/- 12.1 years, 31% diabetic, 15% with ischaemic heart disease. All insertions were successful. Insertion of one CVC was associated with a self-limiting retroperitoneal haematoma. No patients died of a catheter-related cause or through lack of vascular access. Cumulative assisted primary catheter site patency was 81% at 6 months and 73% at 1 year (median 18.5 months). Good dialysis adequacy was achieved throughout (mean single-pool Kt/V 1.5 +/- 0.4). The incidence of access-related infection was 2.84/1000 catheter days (exit site infection rate 2.02/1000 catheter days; catheter-related bacteraemia rate 0.82/1000 catheter days). Catheter dysfunction (need for thrombolytic infusion or catheter change) led to 0.88 admissions per 1000 catheter days. CONCLUSION Translumbar inferior vena caval CVCs can offer relatively safe and effective long-term haemodialysis access in patients with no other options.

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.

High but stable incidence of subdural haematoma in haemodialysis—a single-centre study

BACKGROUND The incidence of subdural haematoma (SDH) is high in haemodialysis (HD), with data suggesting an increasing incidence over time. The prognosis remains poor with 40% mortality at 30 days. The extent of this problem in non-US populations has not been described in the literature. METHODS We conducted a retrospective, single-centre UK study of non-traumatic SDH in patients established on maintenance HD between 1 January 2002 and 1 June 2009. RESULTS The prevalence of SDH was 0.4% at our centre with an overall annual incidence of 189 per 100 000 patients. SDH was associated with increased patient age (mean 71.3 +/- 8.5 years) but not associated with a higher prevalence of major comorbid conditions and antiplatelet or anticoagulant use. Mortality was high (46% at 30 days, 58% at 1 year). We did not observe a trend to increasing prevalence of this condition over time. Conclusions. SDH has a higher (>20 times) incidence in HD patients than in the general population and is associated with high mortality. Although the prevalence in this study was lower than in published US studies, the incidence rate is similar. Further studies to validate prognostic criteria that guide decisions regarding surgery are required.

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.