Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

Peritubular capillary basement membrane multilayering on electron microscopy: a useful marker of early chronic antibody-mediated damage.

BACKGROUND: Chronic antibody-mediated rejection is an important cause of late graft failure. Developing an early marker of the disease may allow diagnosis and treatment before irreversible graft damage has occurred. The aim of this study was to assess whether, on electron microscopy examination, peritubular capillary (PTC) basement membrane multilayering precedes and predicts the development of transplant glomerulopathy (TG). METHODS: We used a vintage matched case-control method. Sixteen case-control pairs were created among all renal transplant patients from October 2005. Cases were patients who developed TG, and controls were patients with a late (>36 months) posttransplant (indication or surveillance) biopsy without TG. Electron microscopy was carried out on a biopsy taken earlier in the posttransplantation period for both cases and controls. RESULTS: For every additional PTC of 25 examined with three or more layers in the early biopsy, the risk of having TG in the later biopsy was increased by 1.4-fold (95% confidence interval, 1.1-1.9; P=0.015). For every PTC of 25 with five or more layers, the risk was increased by 1.6-fold (95% confidence interval, 1.0-2.7; P=0.063). Thus, the risk of future TG increased substantially with every additional PTC of 25 showing multilayering in the early biopsy. CONCLUSIONS: Peritubular capillary basement membrane multilayering on electron microscopy is a useful marker of early chronic antibody-mediated damage, and information can be obtained by assessing PTC with three to four layers of basement membrane in addition to those with five or more layers. This finding must be validated in a prospective study.

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.

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.

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.

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.

Intracranial arterial calcification is highly prevalent in hemodialysis patients but does not associate with acute ischemic stroke.

Intracranial arterial calcification (IAC) is associated with ischemic stroke in the general population but this relationship has not been examined in hemodialysis patients. We examined the factors associated with IAC and its relationship with acute ischemic stroke in this population. We retrospectively studied 490 head computed tomographic scans from 2225 hemodialysis patients presenting with neurological symptoms at our center (October 2005-May 2009). Intracranial arterial calcification was graded using a validated scoring system. Multivariate regression was used to examine the factors associated with the presence of IAC, its severity, and its ability to predict acute ischemic stroke. Weibull's survival models analyzed the relationship between IAC severity and survival. Ninety-five percent of patients with ischemic stroke had IAC vs. 83% in the nonstroke group (P=0.02). Intracranial arterial calcification severity increased with age (P<0.001), hemodialysis vintage (P<0.001), serum phosphate (P<0.05), and major comorbidities. In patients with multiple computed tomographic scans during the study period, increased IAC severity at baseline was predictive of acute ischemic stroke (P=0.05) on logistic regression analysis. High-grade and not low-grade IAC was associated with worse survival (P=0.008). Intracranial arterial calcification is highly prevalent in hemodialysis patients, especially in those with acute ischemic stroke. Its severity is prognostically significant and associated with risk factors for vascular calcification and may confer a greater risk of acute ischemic stroke. The mechanisms underlying the high incidence of ischemic stroke in this patient group require further comprehensive study.

Renal transplants: what ultrasound can and cannot do.

Renal transplantation has emerged as the most cost-effective and patient-supportive way to treat chronic renal failure, with excellent graft survival rates thanks to improved surgical techniques and rejection management. Its success has placed a heavy burden on imaging, especially ultrasound, which is used in the selection of live donors and in monitoring each stage of the postoperative care of the recipient. Ultrasound is particularly useful for detecting vascular complications such as early occlusions and arterial stenosis. It can detect and monitor perinephric complications and transplant hydronephrosis, all clinically significant complications that affect management. Ultrasound can detect many of the late acquired diseases, especially intercurrent tumors that require surgery. It is the best method to guide interventions such as aspiration of collections and insertion of nephrostomy drains. It can also detect postbiopsy arteriovenous shunts and the end-stage kidney of chronic rejection. These, however, are of no great clinical significance, and the findings rarely affect clinical decisions. Ultrasound fails to discriminate between the important causes of early graft dysfunction, especially acute tubular necrosis, rejection, and drug toxicity: these important distinctions still rely on biopsy. There is hope that some of the newer ultrasound methods, especially the functional data from microbubble contrast agent dynamics, might supply useful information for their detection and differentiation.

Five years of steroid sparing in renal transplantation with tacrolimus and mycophenolate mofetil.

Steroid sparing with tacrolimus and mycophenolate mofetil (MMF) is associated with good short-term renal transplant outcomes. However, late allograft dysfunction and failure remain concerns. In this study, 101 consecutive patients underwent renal transplantation with tacrolimus, MMF, and 7 days of corticosteroids only. After a median follow-up of 51 months (range 36-62), overall patient survival is 97%, and overall survival with graft function is 91%. The acute rejection rate at 12 months was 19%. Late rejection was uncommon, with only three further episodes beyond 12 months. Graft function was stable during the study, with a mean creatinine of 140 micromol/L and mean estimated creatinine clearance of 57 ml/min at the end of follow-up. Six patients developed posttransplant diabetes mellitus (three cases beyond 12 months). This steroid avoidance regimen is associated with excellent medium-term patient and graft outcomes, and a low incidence of side effects.