James E. Cooper

Selective revascularization of hepatic artery thromboses after liver transplantation improves patient and graft survival.

BACKGROUND Hepatic artery thrombosis (HAT) can be a devastating complication of orthotopic liver transplantation (OLT), but early diagnosis may allow successful revascularization and graft salvage. METHODS We reviewed data on 1,026 liver transplants at our institution. For patients in whom HAT was diagnosed within 30 days after OLT, we recorded indications for ultrasonography and liver function tests at diagnosis, management of HAT, and graft and patient survival. RESULTS Thirty-two patients (3.1%) developed HAT at 6.8+/-6.6 days (range, 1-29 days) after OLT. Twelve patients (37.5%) were asymptomatic at diagnosis. In 11 of these 12, HAT was diagnosed on routine duplex at 2.0+/-1.55 days after OLT; in the 12th patient, HAT was noted during re-exploration for unrelated bleeding on postoperative day 3. Eleven of 12 patients (91.6%) were revascularized; one patient (8.4%) received no treatment with no sequelae. Of the 11 who were revascularized, 9 (81.8%) had graft salvage and 2 (18.2%) received a second transplant, with one death. Twenty patients (62.5%) were symptomatic. In these 20, HAT was diagnosed at 9.85+/-6.93 days after OLT. Symptoms were: elevated liver function test results (serum glutamic oxaloacetic transaminase: 722+/-1792 U/ml, serum glutamic pyruvic transaminase: 678+/-963 U/ml, and bilirubin: 10.2+/-6.2 mg/dl) in 13 patients (65%); bile leak in 4 patients (20%), and sepsis in 3 (15%). Five of the 20 patients (25%) were revascularized; of these 5, 2 (40%) had graft salvage, 2 (40%) received a second transplant with 1 death, and 1 (20%) died of a liver abscess. Twelve symptomatic patients (60%) had immediate re-OLT; 10/12 are alive, 1 died of sepsis, and 1 died late of unrelated causes. Three symptomatic patients had no treatment; two died of biliary sepsis and one survived. Overall graft salvage was 83.3% in asymptomatic patients and 15% in patients with symptoms (P<0.001). Graft salvage in asymptomatic patients undergoing revascularization was 81.8%, versus 40% in symptomatic patients (P=NS). One-year patient survival was 91.7% in asymptomatic patients and 65% in symptomatic patients (with one late death excluded) (P=NS). CONCLUSIONS Routine postoperative duplex ultrasonography should be performed early after liver transplantation. We believe that emergent revascularization of hepatic artery thrombosis in asymptomatic patients and retransplantation in symptomatic patients lead to improved graft salvage and patient survival with a relatively low incidence of late biliary complications.

Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes.

Background. Donor-specific antibodies (DSAs) after kidney transplantation have been associated with poor graft outcomes in multiple studies. However, these studies have generally used stored sera or a single cross sectional screening test to identify patients with DSA. We evaluated the effectiveness of a prospective DSA screening protocol in identifying kidney and kidney/pancreas recipients at risk for poor graft outcomes. Methods. From September 2007 through September 2009, 244 consecutively transplanted kidney and kidney/pancreas recipients without pretransplant DSA were screened for de novo DSA at 1, 6, 12, and 24 months and when clinically indicated. Results. DSA was detected in 27% of all patients by protocol or indication screening. Patients with DSA (DSA+) were significantly more likely to have experienced acute rejection (AR) compared with no DSA (DSA−) (29% vs. 9.5%, P<0.001), and lower estimated 2-year graft survival (83% vs. 98%, P<0.001). Only 3 of 19 DSA (+) patients with AR had DSA detected before the AR episode. When excluding patients with AR, 2-year graft survival was similar between DSA (+) and DSA (−) patients (100% vs. 99%) as was estimated glomerular filtration rate. Patients with DSA detected by protocol screening had similar outcomes compared with DSA (−), whereas those with DSA detected by indication experienced significantly worse outcomes. Conclusions. Patients with de novo DSA experience worse graft outcomes due to previous/concurrent episodes of AR. A prospective DSA screening protocol failed to identify patients at risk for AR or poor short-term graft outcomes.

Assessment and Management of Hypertension in Transplant Patients

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.

Acute kidney injury in kidney transplantation.

Purpose of reviewAcute kidney injury (AKI) in transplant recipients is a prevalent condition with a broad list of potential inciting causes. This review highlights recent data describing the epidemiology and long-term consequences of transplant AKI, novel interventions in the management of delayed graft function (DGF), and noninvasive diagnostic strategies. Recent findingsThe incidence and outcomes of nontransplant AKI are well documented, and similar data are emerging in the transplant setting with recent reports suggesting a high incidence rate and significant impact on long-term graft outcomes. DGF represents a ‘pure’ form of transplant AKI, and many interventional trials aiming to limit ischemia–reperfusion-induced injury have recently been reported or are currently ongoing. The search for accurate noninvasive predictors of DGF and acute rejection is ongoing and recent literature describes novel plasma and urine-based biomarkers as well as transcriptional profiling methods with high potential for clinical applicability. SummaryAKI in transplant recipients is a frequent occurrence with significant potential for poor long-term graft outcomes. Recent efforts to limit ischemia–reperfusion injury and diagnose transplant AKI via noninvasive methods may help to minimize the impact of AKI on future graft function.

Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients.

Background. Despite the prevalent use of rabbit antithymocyte globulin (rATG) as an induction agent in kidney transplantation, the appropriate dose for preventing acute rejection in high-risk patients is not known. Few studies have examined total exposure of rATG less than 6 mg/kg, with fewer studies examining lower dose rATG in patients with increased risk factors for acute rejection. Methods. We retrospectively analyzed outcomes of 83 kidney transplant recipients at increased risk for acute rejection (repeat transplant, African American race, and panel reactive antibody ≥20%) from July 2004 to July 2007 who were treated with rATG 1.5 mg/kg per day for 3 (n=39) or 4 (n=44) doses for induction to determine the impact of reduced-exposure rATG in the prevention of acute rejection. rATG was initiated intraoperatively and continued on consecutive days. All patients received triple maintenance immunosuppression including prednisone and calcineurin inhibitor. Patients requiring dialysis within 48 hr after transplant were excluded from analysis. Results. One-year acute rejection rates were 10% and 11% in the 3- and 4-dose cohorts, respectively, with 100% patient and graft survival at 1 year in both groups. Patients in the 3-dose cohort were discharged from the hospital sooner than the 4-dose cohort (median length of hospital stay, 3 vs. 4 days; P=0.004). Conclusions. Our results suggest that a 3- or 4-dose course of rATG (1.5 mg/kg/dose) provides excellent protection against acute rejection even in patients at increased risk, with the potential for cost savings from a reduction in hospital stay and medication administration.

The risk of acute rejection and the influence of induction agents in lower‐risk African American kidney transplant recipients receiving modern immunosuppression

While kidney transplant recipients of African American (AA) descent are frequently considered at increased risk of acute rejection, the value of induction therapy is not defined in settings of lower immunologic risk and modern immunosuppression.

High dose intravenous immunoglobulin therapy for donor-specific antibodies in kidney transplant recipients with acute and chronic graft dysfunction.

Background Postkidney transplant donor-specific antibodies (DSA) have been identified as important contributors to graft loss. Few therapeutic options exist and have been met with limited success. We report outcomes in patients with de novo DSA and graft damage treated with a protocol of high-dose intravenous immunoglobulin (IVIG). Methods Retrospective analysis of 28 kidney transplant recipients with de novo DSA and graft damage in the form of either chronic graft dysfunction (group 1, n=20) or a recent previous acute antibody-mediated rejection (AMR) episode (group 2, n=8) prescribed a standard regimen of high-dose (5 g/kg) IVIG dosed over 6 months. Results Mean fluorescence intensity (MFI) of 70 total DSA decreased by 12%at the end of treatment (T1, P=0.14) and by 18%at last follow up (T2, P=0.035) compared with treatment initiation (T0) MFI. The most robust effect was seen in class I DSA (37% decrease at T2 versus T0, P=0.05) and in DSA from patients in group 2 (52% decrease at T2 versus T0, P=0.008). Graft function stabilized in patients in group 2 but continued to decline in those in group 1. Conclusion High-dose IVIG resulted in modest DSA MFI reductions in patients with previous graft damage, with a larger effect occurring in class I DSA in patients with a previous acute AMR. There was no clinical treatment benefit in patients with ongoing chronic graft damage, whereas high-dose IVIG may reduce the risk of chronic graft dysfunction in those with an acute AMR event.

Clinical Significance of Pre‐Transplant Donor Specific Antibodies in the Setting of Negative Cell‐Based Flow Cytometry Crossmatching in Kidney Transplant Recipients

Antibodies to donor‐specific HLA antigens (donor‐specific antibodies [DSA]) detected by single‐antigen bead (SAB) analysis prior to kidney transplant have been associated with inferior graft outcomes. However, studies of pretransplant DSA, specifically in the setting of a negative flow cytometry crossmatch (FCXM) without desensitization therapy, are limited. Six hundred and sixty kidney and kidney–pancreas recipients with a negative pretransplant FCXM from September 2007 to August 2012 without desensitization therapy were analyzed with a median follow‐up of 4.2 years. All patients underwent cell‐based FCXM and SAB analysis on current and historic sera prior to transplantation. One hundred and sixty‐two patients (24.5%) had DSA detected prior to transplant. One‐year acute rejection rates were similar in DSA‐positive versus DSA‐negative patients (15.4% vs. 11.4%, respectively; p = 0.18) and were higher in those with DSA mean fluorescence intensity (MFI) greater than or equal to 3000 in multivariable analysis (p = 0.046). The estimated glomerular filtration rate (eGFR) at 3 and 4 years was lower in the DSA(+) versus the DSA(−) group (p = 0.050 at 3 years) without an impact on 5‐year death‐censored graft survival (89.0% vs. 90.6%, respectively; p = 0.53). Timing (current or historic) of DSA detection did not alter these findings. In conclusion, pretransplant DSA in the setting of a negative FCXM confers minimal immunologic risk in the intermediate term, does not necessitate desensitization therapy and should not represent a barrier to renal transplant.

APOL1 Polymorphisms in a Deceased Donor and Early Presentation of Collapsing Glomerulopathy and Focal Segmental Glomerulosclerosis in Two Recipients

Two common polymorphisms in APOL1 (G1 and G2) are conserved in persons of African ancestry, and the presence of two polymorphisms (commonly referred to as risk variants) has been identified as a risk factor for chronic kidney disease and focal seg‐mental glomerulosclerosis. In kidney transplantation, deceased donors with two APOL1 risk variants carry an increased risk of renal allograft failure in the recipient. An emerging question is whether these data should influence deceased donor assessment or be used to refine prediction of allograft survival. We present the first detailed report of two cases of recipient glomerular disease in the first year following transplant from a deceased donor later defined as carrying two APOL1 risk variants. A possible “second hit” predisposing to renal disease in these recipients is discussed, one with active cytomegalovirus infection concurrent with collapsing glomerulopathy and renal failure and the other with chronic, slowly healing wound infection and focal segmental glomeru‐losclerosis but stable renal function. In retrospect, awareness of the donor APOL1 risk alleles would not have influenced donor selection and ultimately did not influence posttransplant management. These case reports inform further discussion of the value of APOL1 testing for deceased donors.