Tom Cairns

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.

De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy.

Background The importance of human leukocyte antigen (HLA) matching in renal transplantation is well recognized, with HLA-DR compatibility having the greatest influence. De novo DQ donor-specific antibodies (DSAbs) are the predominant HLA class II DSAb after transplantation. The aim of this study was to establish the incidence and outcomes after the development of DQ DSAbs along with the impact of class II HLA mismatch on their development. Methods We retrospectively analyzed 505 patients who received a renal-alone transplant between 2005 and 2010. We excluded patients who received an ABO- and HLA-incompatible allograft, which we defined as those with a positive crossmatch or preformed DSAbs detected by single-antigen beads only. Results Of 505 patients, 92 (18.2%) developed DSAbs, with 50 (54.3%) of these 92 patients having DQ DSAbs. Patients who developed DQ DSAbs were at significant risk for antibody-mediated rejection, transplant glomerulopathy, and allograft loss (P<0.0001). Of 505 patients, 108 (21.4%) were matched at both the DR and DQ loci, 284 (56.2%) were mismatched at both loci, 38 (7.5%) were matched at DR alone, and 75 (14.9%) were matched at DQ alone. Patients mismatched at both DR and DQ were at risk for developing class II DSAbs when compared with those mismatched at either DR or DQ alone, P=0.001, and were at risk for antibody-mediated rejection, P=0.001. Conclusions DQ DSAbs are associated with inferior allograft outcomes. This study shows the importance of establishing the DQ match before transplantation to define immunologic risk.

C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome

BACKGROUND AND OBJECTIVES The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model. RESULTS Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD. CONCLUSIONS Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

Immediate destruction of xenogeneic islets in a primate model.

Transplantation of pancreatic islets from other species to man has the potential to cure diabetes, but whether such islet grafts will be subject to damage due to natural antibody-mediated hyperacute rejection is unknown. We have examined the fate of islet xenografts in a recipient with direct relevance to man, the cynomolgus monkey. Rabbit islets were prepared by an intraductal collagenase technique and incubated in neat rabbit, human, or cynomolgus serum, with and without heat inactivation, for up to 6 days. Islets were analyzed by flow cytometry for IGG and IGM binding, and scored for viability by supravital staining. For in vivo studies, isolated islets were prepared from 4 New Zealand White rabbits (15-34 x 10(3) islets 70-85% purity) and transplanted beneath the kidney capsule of normal cynomolgus monkeys after aggregation in either a rabbit or monkey blood clot. The tissue was retrieved at various times up to 4 days after transplantation and processed for light and electron microscopy. The results showed that rabbit islets bind heterophile antibody of both IGG and IGM subtypes. There was slow loss of islet viability in vitro over 3 days of culture in neat human or cynomolgus serum. Destruction of islets in vivo was more rapid with visible damage within 6 hr associated with neutrophil infiltration. Subsequently, there was heavy mononuclear cell infiltration leading to total destruction within 4 days. The results suggest that immediate mechanisms of graft rejection, possibly compliment and neutrophil mediated, represent a major barrier to islet xenotransplantation in humans.

Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCA-associated vasculitis

BACKGROUND Rituximab (RTX) has been shown to be effective as an induction agent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), but studies have been limited by short-term follow-up. We decided to investigate the long-term efficacy and safety of an RTX-based cyclophosphamide (CYP)-sparing regimen (CycLowVas) for renal AAV. METHODS Consecutive patients with renal AAV presenting de novo or with a major relapse, except those with serum creatinine >500 μmol/L, previous treatment with RTX and pulmonary haemorrhage or cerebral vasculitis, were treated with two pulses of RTX 2 weeks apart and six fortnightly doses of CYP, as well as a reducing protocol of daily oral steroids. Maintenance was with low-dose steroids and azathioprine. RESULTS Twenty-three patients were treated. Median follow-up was 39 months, with 17 patients reaching >2 years of follow-up. All patients achieved clinical remission within 6 weeks. Three major and two minor relapses occurred in five patients at a median of 30 months, which were treated by re-dosing with RTX for major relapses and steroid increase alone for minor relapses. Adverse events included one severe drug reaction, four non-serious and one serious infective episodes in the first 3 months, one skin malignancy at 21 months and one death at 19 months not related to treatment or disease. CONCLUSIONS A RTX-based low-dose CYP regimen is effective at inducing long-term disease-free remission and may be the platform on which to develop a steroid-minimizing regimen to further decrease adverse events in the future.

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.

Determinants of mycophenolic acid levels after renal transplantation.

There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.

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.