Actions of the Japanese Pancreas and Islet Transplantation Association regarding transplanted human islets isolated using Liberase HI

Purpose

The potential for introducing transmissible spongiform encephalopathy (TSE) into islet cells was indicated by recognizing that Liberase HI is isolated from Clostridium histolyticum grown in media containing brain–heart infusion broth. A national team within the Japanese Pancreas and Islet Transplantation Association implemented an islet transplantation program in Japan using Liberase HI. The program comprised 65 islet isolations from non–heart-beating donors and 34 transplants into 18 patients. Herein, we have summarized how the Association followed these recipients over the long term.

Procedures

We established an ad hoc committee to follow recipients transplanted with islets isolated using Liberase HI after becoming informed of the associated dangers of using this enzyme. We also stopped islet transplantations using Liberase. The committee addressed the major concerns of the risk of the collagenase being contaminated with TSE and of the recipient follow-up. All recipients were examined by diffusion MRI and EEG and then scheduled for evaluation and follow-up by specialists in Creutzfeldt-Jakob disease (CJD). Bioassays of bovine spongiform encephalopathy prions in the enzyme proceeded using knock-in mice expressing bovine prion protein. These assays could detect contaminating prions at a dilution of 1 × 10⁴. After inactivating its collagenase activity, Liberase HI was injected into the abdominal cavities of knock-in mice. Four months later, prion infectivity in Liberase HI was evaluated by immunohistochemical staining and Western blotting of spleen homogenates using anti-prion protein antibodies.

Main findings

Western blotting and immunohistochemical staining did not detect prions in Liberase HI. Diffusion MRI and EEG evaluations performed by CJD specialists confirmed that none of the transplanted recipients had CJD.

Conclusions

Three years of follow-up revealed that none of the Japanese recipients of islet transplants developed CJD. Prion bioassays showed that the Liberase HI used to isolate islets for transplantation was free of infectious TSE prions.     

Early steroid withdrawal protocol with basiliximab, cyclosporine and mycophenolate mofetil in renal-transplant recipients

OBJECTIVE: Adverse effects of steroids have led to efforts to minimize their use in recipients of organ transplants. This study evaluated an early steroid withdrawal protocol including basiliximab, cyclosporine (CsA) and mycophenolate mofetil (MMF) in renal-transplant recipients. METHODS: Between January 2001 and April 2005, our early steroid withdrawal protocol was used in 130 patients who underwent renal transplantation. Immunosuppression consisted of CsA (6-8 mg/kg), MMF (2 g/kg) and methylprednisolone (MP); basiliximab was given as induction therapy (steroid withdrawal group). MP was administered in a dose of 500 mg or 250 mg at renal transplantation; thereafter, the dose was rapidly tapered and MP was withdrawn on day 14 post-transplant. RESULTS: The incidence of acute rejection in the steroid withdrawal group was similar to that in the conventional steroid treatment group (without basiliximab) (18% vs. 21%). The severity of rejection episodes was similar in the two groups. Patient and graft survivals were 100% and 97% in the steroid withdrawal group. In 80 of the 130 patients (62%) in the steroid withdrawal group, MP was successfully withdrawn, with good allograft function during follow-up. In the other 50 patients (38%), MP was reinitiated because of acute rejection or other reasons. The success rate of steroid withdrawal 12 months after transplantation in recipients of ABO-compatible grafts was significantly higher than that in recipients of ABO-incompatible grafts (66% vs. 44%). The dose of MMF during the 12 months after renal transplantation was significantly lower in steroid reinitiated group than in the successful withdrawn group (p<0.05). Patients in the successful withdrawn group showed metabolic benefits such as lower cholesterol levels as compared with the steroid reinitiated group. CONCLUSION: Although further follow-up is necessary to confirm our results, our protocol successfully permitted the early withdrawal of steroids in 62% of renal-transplant recipients, with no resumption of steroid treatment during 3 years of follow-up.     

Prediction of postoperative visual outcome based on hole configuration by optical coherence tomography in eyes with idiopathic macular holes

Purpose

To evaluate whether an index based on hole configuration can be used to predict visual outcome in eyes with idiopathic macular holes.

Design

Prospective interventional case series.

Methods

Thirty-five eyes of 32 patients with idiopathic stage 2 or 3 macular hole were enrolled in this study. The best-corrected visual acuity (BCVA), cross-sectional image of the macular hole by optical coherence tomography (OCT), and retinal thickness in the central (<1000 μm), inner (1000 to 2220 μm), and outer ring areas (2220 to 3450 μm) as defined by the OCT retinal mapping program were evaluated preoperatively and at 1, 3, 6, and 12 months postoperatively. The change in retinal thickness of the inner ring area at the 6-month postoperative period was used to evaluate the degree of preoperative retinal deformation. The macular hole index (MHI) (ratio of hole height to base diameter of hole) was calculated and correlated with minimum diameter of hole, base diameter of hole, the postoperative decrease in macular thickness, and the postoperative BCVA. The postoperative BCVA was further evaluated in two patient-matched groups.

Results

Retinal thickness values in the inner ring area were decreased at the 1-month postoperative period. MHI significantly correlated with the postoperative decrease in macular thickness in the inner ring area at 6 months (correlation coefficient = −0.632, P = .030, Spearman analysis) and with the postoperative BCVA (P = .013, multiple regression analysis). Postoperative BCVA in the MHI ≥0.5 group was better than that in the MHI <0.5 group (P = .032, Mann-Whitney test).

Conclusions

The MHI is a ratio easily calculated from OCT transverse images of the macular area. The MHI represents the preoperative configuration of a macular hole and is a prognostic factor for visual outcome.     

Preconditioning regimen consisting of anti-CD20 monoclonal antibody infusions, splenectomy and DFPP-enabled non-responders to undergo ABO-incompatible kidney transplantation

Patients undergoing ABO-incompatible kidney transplantation must have their anti-donor blood-type antibody titer (ADBT) reduced to below 1:16 by using either plasma-exchange (PEX) or double filtration plasma exchange (DFPP) before they can safely undergo a transplantation. The ADBT can be reduced to under 1:16 in most cases; however, some cases (non-responders) do not respond to PEX or DFPP treatment. To enable kidney transplantations to be performed in non-responders, we developed a new preconditioning regimen consisting of anti-CD20 monoclonal antibody (rituximab) infusions, a splenectomy, and DFPP. Four non-responders were infused with rituximab at a dose of 375 mg/m(2) weekly for 3-4 wk and splenectomized 1 or 2 wk before transplantation. Four to five DFPP-sessions were then performed after the splenectomy. Using this preconditioning regimen, the ADBT was reduced to below 1:16, enabling kidney transplantations to be successfully performed in all patients. After the kidney transplantation, no episodes of humoral rejection were observed, and only one episode of cellular rejection was encountered. The cellular rejection was associated with a reduction in immunosuppressant administration because of CMV infection that occurred 80 d after the kidney transplantation. The renal allografts were functioning well in all patients after a mean follow-up period of 390 d. No serious complications or side effects were encountered. We have developed a new preconditioning regimen that enables PEX and DFPP non-responders to undergo ABO-incompatible kidney transplantations.     

Immunization by blood-type antigen in human immunoglobulin products before ABO-incompatible kidney transplantation

A 29-year-old man wanted to receive an ABO-incompatible kidney transplant. His blood type was O, and the donor, his father, was A1. After endoscopic splenectomy performed before kidney transplantation, the recipient developed a high fever and leukocytosis, and he was treated with antibiotics and 5 g of human immunoglobulin products by intravenous infusion for 3 d. Soon after the infusions, his anti-blood type A antibody titer (anti-A titer) rose, and several sessions of plasma-exchange (PEX) and double-filtration plasmapheresis (DFPP) failed to lower it. Three courses of anti-CD20 monoclonal antibody were administered to suppress the antibody production more specifically, and the rituximab infusions and repeated PEX and DFPP session lowered the anti-A titer and enabled kidney transplantation. Mild humoral rejection was observed 16 d after transplantation, but the recipient's serum creatinine was 1.5 mg/dL when discharged from the hospital. The increased anti-A titer may have been due to immunization by blood-type A antigen, with the human immunoglobulin products given to the patient being the source of the antigen. Administration of human immunoglobulin products to recipients of ABO-incompatible kidney transplants should be avoided, because it may cause an unexpected increase in anti-blood-type antibody titer.     

A case of POEMS syndrome with cystoid macular edema

PURPOSE: To introduce a case of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome with bilateral cystoid macular edema (CME). DESIGN: Interventional case report. METHODS: Temporal changes of serum vascular endothelial growth factor (VEGF) levels and macular thickness were evaluated. RESULTS: A 53-year-old woman with POEMS syndrome was referred complaining of long-standing impaired vision. Typical CME demonstrating petal-like dye pooling was observed in both eyes. After subtenon administrations of triamcinolone acetonide (TA), pars plana vitrectomy, and intraocular TA injection in the right eye, macular thickness decreased. Intraocular VEGF levels were <31 pg/ml at the vitrectomy and intraocular TA injection, whereas serum the VEGF level was >2000 pg/ml throughout the follow-up periods. In the untreated left eye, macular thickness altered related to serum VEGF level. CONCLUSIONS: Based on the low intraocular VEGF level and serum VEGF-related change of macular thickness, elevated serum VEGF might be a cause of CME in POEMS syndrome.