Dechu Puliyanda

Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients.

Background. Sensitization to human leukocyte antigens (HLA) is a significant barrier to transplantation. Currently, no proven therapy exists to improve access to transplantation for highly sensitized patients. Here, we report a novel approach using intravenous immune globulin to modulate anti-HLA antibody and improve the chances for successful transplantation. Patients and methods. Forty-five highly HLA-sensitized patients presented as candidates for living-donor kidney transplantation (n=28), cadaveric kidney transplantation (n=15), or heart transplantation (n=2). All patients had a positive CDC crossmatch (CMX) with their donors. In living-donor recipients, intravenous immune globulin (IVIG) was added to the CMX evaluation to determine whether blocking antibodies present in IVIG could inhibit cytotoxicity. For those who showed in vitro inhibition with IVIG (n=26), IVIG was administered (usually as a single dose, 2 g/kg) and the CDC CMX was repeated against the prospective donor immediately after IVIG infusion. If negative, the patient underwent transplantation with their living-donor kidney within 24 to 72 hr. A similar but modified protocol was performed for cadaver donor candidates, all of whom were highly sensitized and had had CMX positivity with multiple donors, negating transplantation. Reductions in CMX positivity, posttransplantation serum creatinine level, number and severity of rejection episodes, and patient and graft survival rates were determined. Results. Forty-two patients underwent transplantation. IVIG treatment completely abrogated the donor-specific CMXs in 35 of 42 patients. In the remaining 7 patients, the CDC CMX was inhibited, but flow cytometry CMXs remained positive. A total of 13 (31%) of 42 recipients developed rejection episodes 3 to 49 days after transplantation. Three grafts (7%) were lost to rejection. Mean serum creatinine level at 24 months was 1.4±0.4 mg/dL. Patient and graft survival rates were 97.6% and 89.1%, respectively, at 24 months. Conclusions. The in vitro IVIG CMX technique predicts the ability of IVIG to reduce anti-HLA antibody levels in highly sensitized patients. Subsequent in vivo IVIG treatment of responders eliminates the positive CDC CMX and allows for successful transplantation. Thus a positive CMX result is not necessarily a contraindication for transplantation and allows access to transplantation for patients for whom it was previously contraindicated.

A Phase I/II Placebo-Controlled Trial of C1-Inhibitor for Prevention of Antibody-Mediated Rejection in HLA Sensitized Patients

Background Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR. Methods Twenty highly sensitized patients desensitized with IVIG + rituximab ± plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed. Results One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups. Conclusions The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted.

Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation: A Single-Center Experience

Intravenous Ig (IVIg) products are used in various medical conditions. Differences in excipients account for most adverse events (AE). Reports of complications including acute myocardial infarction (AMI) and acute renal failure (ARF) have emerged. Herein is described one institutions experience with IVIg-related complications. This study is a retrospective analysis of infusion-related AE that are associated with various IVIg products. Infusion-related AE were monitored during and after the administration of three IVIg products: Gamimune-N 10% (n = 76), Polygam (n = 105), and Carimune (n = 98). AE segregated to specific IVIg products. No patients who received Gamimune-N experienced AMI or ARF. Five (4.7%) patients (P < 0.01) in the Polygam group experienced AMI. Eight (8.2%) patients (P < 0.0001) in the Carimune group developed ARF. IVIg was safe to give on hemodialysis. IVIg products differ in osmolality, pH, and sugar and sodium content; this results in specific AE. Polygam resulted in no ARF but an increase in AMI. Carimune products at 9% concentration resulted in an increase in ARF. Gamimune-N 10% and other IVIg products were frequently associated with headaches. Administration of IVIg to patients who are on hemodialysis seems to be safe and effective.

Co-infection of polyomavirus-BK and cytomegalovirus in renal transplant recipients.

Background. Polyomavirus-BK (BK) is a significant cause of allograft dysfunction in renal transplant recipients. Cytomegalovirus (CMV) and BK infection are thought to be possible risk factors for one another, but no supporting data are yet available. Methods. The authors monitored BK and CMV infection by quantitative polymerase chain reaction (PCR) in 69 renal transplant recipients with serum creatinine elevation to determine the prevalence of co-infection. In addition, 150 adult renal transplant recipients were also retrospectively analyzed for both infections. Results. Of 69 recipients, 12 were plasma BK-PCR–positive. Eight of the 12 showed high BK levels (>103 copies) and BK nephropathy. Six of the 12 were also CMV-PCR–positive compared with only 3 of 57 plasma BK-negative patients (50% vs. 5.3%, P=0.001). Comparatively, the incidence of Epstein-Barr virus infection was similar in both groups (1 of 12 [8.3%] vs. 2 of 57 [3.5%], P =not significant). In addition, retrospective analysis of CMV-PCR–positivity in 150 adult renal transplant recipients showed similar results (5 of 6 in BK-PCR–positive [83%] vs. 8 of 144 in BK-PCR–negative [5.6%], P=0.00001). More plasma BK-PCR–positive patients had concomitant CMV infection than CMV-PCR–positive patients with BK infection (5 of 6 [83%] vs. 4 of 13 [31%], P=0.05). Conclusions. In conclusion, high plasma BK-positivity (>103) is significantly associated with BK nephropathy. Plasma BK-positivity is highly associated with co-infection of CMV, suggesting possible risk factors for one another. Therefore, detection of either infection strongly suggests the need to monitor for the other. This strategy may lead to the prevention of virus-induced complications by preemptive antiviral therapy in renal allografts.

A Phase I/II Trial of the Interleukin-6 Receptor-Specific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients.

Background Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti–IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy. Methods From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months. Results No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 ± 10.5 months but after TCZ was 8.1 ± 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor-specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 ± 25 mL/min. Conclusions Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy.

Assessment of Tocilizumab (Anti–Interleukin‐6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody‐Mediated Rejection and Transplant Glomerulopathy in HLA‐Sensitized Renal Allograft Recipients

Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor‐specific antibodies (DSAs) posttransplantation leads to chronic active antibody‐mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL‐6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti–IL‐6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long‐term outcomes. Tocilizumab‐treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long‐term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL‐6–IL‐6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.

Isolated heart and liver transplant recipients are at low risk for polyomavirus BKV nephropathy

Abstract:  Background:  BKV infection and nephropathy is a significant cause of allograft dysfunction in kidney transplantation. BKV viremia, rather than viruria, corresponds to BKV nephropathy. The prevalence of BKV viremia in non‐renal solid organ transplants has not been systematically evaluated.

Clinical significance of peripheral blood Epstein–Barr viral load monitoring using polymerase chain reaction in renal transplant recipients

Abstract:  PTLD is a complication of EBV infection. We examined the efficacy of EBV‐PCR monitoring to detect early replication in an attempt to prevent EBV‐associated PTLD. Blood EBV levels in 156 renal transplant recipients (58 children) from three institutions over nine yr were retrospectively analyzed. Patients who were asymptomatic and at high risk for PTLD were monitored for EBV infection by PCR or serology followed by PCR at the time of EBV seropositivity. More children than adults had positive EBV‐PCR (12/58 vs. 2/98, p < 0.001). Adults remained asymptomatic and viremia resolved post‐therapy. 3/12 EBV‐PCR positive children developed PTLD (3/12 children vs. 0/2 adults, p = NS). Two out of three with PTLD were initially monitored by serology, and later by PCR. PTLD resolved post‐therapy in all three patients. The remaining 9/12 EBV‐PCR positive children stayed asymptomatic. None of the children and adults with negative EBV‐PCR developed PTLD. EBV‐PCR monitoring in high‐risk renal transplant recipients, especially in children, may allow early diagnosis and intervention, and therefore may help in preventing EBV‐associated PTLD.

Induction Therapy in Pediatric Renal Transplant Recipients

Induction therapy to prevent the acute rejection of mismatched allografts with the ultimate aim of prolonging the life of the allograft has been the cornerstone of immunosuppression since the introduction of renal transplantation. Agents used for induction therapy have changed over time. Their role in transplantation is expanding to include corticosteroid avoidance and immunosuppression minimization.This review provides an overview of induction therapies for renal transplantation including historic therapies such as total lymphoid irradiation and Minnesota antilymphocyte globulin, and current therapies with polyclonal and monoclonal antibodies and chemical agents, with special emphasis on children. Data from adult studies, and pediatric studies whenever available, are summarized. A brief summary of experimental therapies with fingolimod and belatacept is provided. Historically, induction therapies were targeted at T cells. The role of induction therapies targeted at B cells is emerging in select groups of patients that include highly sensitized recipients and those receiving transplants from blood group incompatible donors.With the advent of newer maintenance immunosuppressive medications and with very low rates of acute rejection, induction protocols for renal transplantation need to be targeted so that excessive immunosuppression and infections are avoided. Several single-center and registry data analyses in children suggest that the addition of an interleukin (IL)-2 receptor antagonist may improve graft survival compared with no induction. The safety profile of IL-2 receptor antagonists is indistinguishable from that of placebo, with no apparent difference in the incidence of infection or post-transplant lymphoproliferative disease. IL-2 receptor antagonists and polyclonal lymphocyte-depleting antibodies offer equivalent efficacy in standard-risk populations. However, in high-risk patients, acute rejection rates and graft outcomes may be improved with the use of lymphocyte-depleting agents such as Thymoglobulin®. However, cytomegalovirus infection and other infections may be more common with this therapy. Therefore, in patients at high risk of graft loss, Thymoglobulin® may be the preferred choice for induction therapy, while for all other patients, IL-2 receptor antagonists should be considered the first-line choice for induction therapy. Newer lymphocyte-depleting agents such as alemtuzumab may be better utilized in minimization regimens involving one or two oral maintenance immunosuppressive agents.

Variables affecting estimated glomerular filtration rate after renal transplantation in children: A NAPRTCS data analysis

Moudgil A, Martz K, Stablein DM, Puliyanda DP. Variables affecting estimated glomerular filtration rate after renal transplantation in children: A NAPRTCS data analysis.
 Pediatr Transplantation 2010: 14:288–294.