Correcting anemia and native vitamin D supplementation in kidney transplant recipients: a multicenter, 2 × 2 factorial, open-label, randomized clinical trial.

Anemia and vitamin D deficiency are associated with allograft failure, and hence, are potential therapeutic targets among kidney transplant recipients (KTRs). We conducted a multicenter, two-by-two factorial, open-label, randomized clinical trial to examine the effects of anemia correction and vitamin D supplementation on 2-year change in eGFR among KTRs (CANDLE-KIT). We enrolled 153 patients with anemia and >1-year history of transplantation across 23 facilities in Japan, and randomly assigned them to either a high or low hemoglobin target (>12.5 vs. <10.5 g/dl) and to either cholecalciferol 1000 IU/day or control. This trial was terminated early based on the planned interim intention-to-treat analyses (α = 0.034). Among 125 patients who completed the study, 2-year decline in eGFR was smaller in the high vs. low hemoglobin group (i.e., -1.6 ± 4.5 vs. -4.0 ± 6.9 ml/min/1.73 m2 ; P = 0.021), but did not differ between the cholecalciferol and control groups. These findings were supported by the fully adjusted mixed effects model evaluating the rate of eGFR decline among all 153 participants. There were no significant between-group differences in all-cause death or the renal composite outcome in either arm. In conclusion, aggressive anemia correction showed a potential to preserve allograft kidney function.

Loss of antibodies to hepatitis E virus in organ transplant patients with hepatitis E.

AIM: Studies regarding changes in antibodies to hepatitis E virus (HEV) after HEV infection in organ transplant patients are limited. This study aimed to clarify HEV infection trends in organ transplant patients who contracted HEV using data from a previous Japanese nationwide survey. METHODS: This study was undertaken from 2012 to 2019. Among 4518 liver, heart, and kidney transplant patients, anti-HEV immunoglobulin G (IgG) antibodies were positive in 164; data were collected from 106 of these patients, who consented to participate in the study. In total, 32 liver transplant patients, seven heart transplant patients, and 67 kidney transplant patients from 16 institutions in Japan were examined for IgG, IgM, and IgM antibodies to HEV and the presence of HEV RNA in the serum. The χ2 -test was used to determine the relationship between the early and late postinfection groups in patients with anti-HEV IgG positive-to-negative conversion rates. The Mann-Whitney U-test was used to compare clinical factors. RESULTS: Anti-HEV IgG positive-to-negative conversion occurred in 25 (23.6%) of 106 organ transplant patients. Of eight patients with hepatitis E who tested positive for HEV RNA, one (14.0%) had anti-HEV IgG positive-to-negative conversion. Twenty-four (24.5%) of 98 patients negative for HEV RNA had anti-HEV IgG positive-to-negative conversion. CONCLUSIONS: This study revealed, for the first time, the changes in HEV antibodies in organ transplant patients. Loss of anti-HEV IgG could often occur unexpectedly in organ transplant patients with previous HEV infection.

Positivity rate of interferon-γ release assays for estimating the prevalence of latent tuberculosis infection in renal transplant recipients in Japan.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and developing active tuberculosis. QuantiFERON®-TB Gold Plus (QFT-Plus) has two TB-specific antigens tubes (TB1 and TB2). TB1 elicits CD4 T-cell response, and TB2 elicits both CD4 and CD8 T-cells responses, with expected increased sensitivity. The aim of this study was to estimate the prevalence of LTBI in renal transplant recipients in Japan. We conducted a cross-sectional study by using two interferon-γ release assays (IGRAs), QFT-Plus and T-SPOT®.TB (TSPOT). One hundred thirty-five recipients were prospectively enrolled. The median age was 49 years (range: 20 to 79). The positivity rates of QFT-Plus and TSPOT were 5.9% (95%CI 3.0-11.3) and 3.7% (95%CI 1.6-8.4), respectively, with no significant difference. The concordance rate was 95.5% (κ coefficient, 0.76). Age of 60 years and higher was related to the higher positivity rate in both QFT-Plus and TSPOT. The positivity rates of TB1 and TB2 were 5.1% (95%CI 2.5-10.2) and 5.9% (95%CI 3.0-11.2), respectively, with no significant difference. The concordance rate was 99.3% (κ coefficient, 0.93). TB2 did not show a higher positivity rate compared with TB1. The estimated prevalence of LTBI by using the both IGRAs was 3.7-5.9% in renal transplant recipients. These results were equivalent to the IGRAs positivity rate in the general Japanese population, even under the condition of immunosuppressive therapy. In consideration of the higher risk of developing active TB from LTBI, we can use both IGRAs as acceptable tools for LTBI diagnosis in renal transplant recipients.

Impact of primary diabetic nephropathy on arteriolar hyalinosis lesions in patients following kidney transplantation.

AIM: Arteriolar hyalinosis (AH) is a common lesion in allograft biopsies taken following kidney transplantation. Recent studies have shown that severe AH may predict transplant outcomes and provide information about previous exposure to certain drugs, such as calcineurin inhibitors (CNI). However, the incidence of AH as a direct result of diabetic nephropathy (DN) after kidney transplantation has not been fully evaluated. This study aimed to assess the impact of primary DN on the development of AH lesions in patients who underwent kidney transplantation. METHODS: Eighty-three patients who underwent living-donor kidney transplantation between April 2005 and June 2015 were enrolled in this study. A total of 33 patients had DN prior to transplantation. Allograft biopsies were scored according to the Banff classification, and the relationship between the individual histological lesions and clinical baseline data was assessed. RESULTS: At early biopsy (3-12 months), there were no differences in the rates of AH lesions between the DN group and the non-DN group (ah ≥ 1: 37% vs. 41.3%, P = 0.719; aah ≥ 1: 14.8% vs. 6.5%; P = 0.453). However, there were significant differences between the groups in biopsies taken more than 3 years after the transplant (ah ≥ 2: 83.3% vs. 36.8%, P = 0.013; aah ≥ 2: 66.7% vs. 21.1%, P = 0.011). Multivariable analysis showed that both the length of time after transplantation and the presence of DN were independent risk factors for ah ≥ 2 (odds ratio [OR]: 2.55, 95% confidence interval [CI]: 1.47-19.54, P = 0.011) and aah ≥ 2 (OR: 7.55, 95% CI: 1.49-38.33, P = 0.015). CONCLUSION: This is the first report showing that the presence of primary DN disease contributes to the development of severe AH late in the course after kidney allografts.

Comparison of interferon-γ release assays, QuantiFERON TB-GIT and T-Spot.TB, in renal transplantation.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and progressing to active tuberculosis (TB). This study was conducted in National hospital for tuberculosis and renal transplantation (RT) in Japan. The purpose is to compare two interferon-γ release assays (IGRAs), QuantiFERON®-TB Gold in Tube (QFT) and T-SPOT®.TB (TSPOT), in patients after renal transplantation for detecting latent TB infection (LTBI). Total 92 renal transplant recipients (median age 46 years, range 17-75) were prospectively enrolled, and QFT and TSPOT were concurrently examined. Total subjects were 92 patients (median age 46 years, range 17-75). The positive rate in QFT and TSPOT were 6.5% (95% confidence interval (CI) 3.0-13.5) and 2.2% (95% CI 1.0-7.6), respectively. There was a significant difference in IGRAs positivity (P < 0.05). The negative rate in QFT and TSPOT were 91.3% (95% CI 83.8-95.5) and 95.7% (95% CI 89.3-98.3), respectively. There was no significant difference in IGRAs negativity. No patients among either IGRAs negative patients developed active TB during median follow-up of 994 days. Neither QFT nor TSPOT reaches estimated TB infection rate in Japan, especially elderly recipients aged 60 year-old or more. Therefore, both IGRAs might underestimate LTBI owing to immune suppressive therapy and aging. Physicians for renal transplantation need to understand the characteristics of both IGRAs and pay attention to the possibility of developing active TB even in patients of negative IGRAs results.

Focal segmental glomerular sclerosis recurrence with massive proteinuria and anuria immediately after kidney transplantation.

Here, we report a case of focal segmental glomerular sclerosis (FSGS) recurrence immediately (47 minutes) after transplantation. A 1-hour biopsy specimen showed large periodic acid-Schiff-positive granules within the cells of the swollen proximal tubule, while electron microscopy revealed podocyte swelling and partial foot process effacement. These findings were worse on day 2 biopsy. Massive proteinuria and anuria were then observed. Two courses (2 × 2 times) of plasmapheresis and rituximab were administered, and the graft function gradually recovered. A day 22 biopsy specimen showed improvement in findings compared to those observed on day 2. One year after transplantation, no signs of FSGS recurrence are evident, and graft function remains good.

[Current status and future of clinical kidney transplantation in Japan].

Kidney transplantation has been established to be the therapy for an end-stage renal disease. In Japan, living donor kidney transplantation is frequently performed (> 80%) because of a shortage of the deceased donors. The graft survival has been improved to 93.4% (5-year graft survival in living donor kidney transplantation after 2001). ABO-incompatible cases are increasing and more than 20% are ABO-incompatible in Japan (30% in our institution). In our institution, 225 kidney transplantations (182: living donors, 43: deceased donors) have been performed from 2004.4 to 2010.6. Although the graft survival is excellent, posttransplant infections including cytomegalovirus, EB virus and BK virus are problems which should be solved. For the safety of the recipients, we should use kidney grafts from brain-dead donors.

A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis in Heart and Kidney Transplant Recipients in Japan.

BACKGROUND: Recently, chronic hepatitis E has been reported in solid organ transplant (SOT) recipients in European countries. Previously, we clarified the prevalence of hepatitis E virus (HEV) infection in Japanese liver transplant recipients and identified 2 chronic hepatitis E patients infected by blood transfusion. However, the rate of HEV infection in recipients of SOTs other than liver in Japan remains unclear, so we conducted a nationwide survey to clarify the prevalence of chronic HEV infection in Japanese heart and kidney transplant recipients. METHODS: A total of 99 heart and 2526 kidney transplant recipients in 17 hospitals in Japan were examined for the presence of the IgG class of anti-HEV antibodies as well as for serum HEV RNA. RESULTS: The prevalence of anti-HEV IgG among heart and kidney transplant recipients was 7.07% (7/99) and 4.08% (103/2526), respectively. One heart transplant patient (1.01%) and 11 kidney transplant patients (0.44%) were found to be positive for HEV RNA. The HEV isolates from all viremic patients were typed as genotype 3. Four patients developed chronic hepatitis E after transplantation. Three patients were treated with ribavirin; their liver enzymes normalized, and HEV RNA became negative immediately. Sustained virologic response was achieved in all cases. CONCLUSIONS: This is the first nationwide survey of HEV infection in Japanese heart and kidney transplant recipients. The prevalence of anti-HEV IgG and HEV RNA in heart and kidney transplant recipients in Japan was lower than that in European countries. Of note, 42% of viremic transplant patients developed chronic hepatitis.

Clinical islet transplantation in Japan.

INTRODUCTION: The results of clinical islet transplantation in Japan are, here in, reported and discussed its efficacy and problems. METHODS: Since the first islet transplantation was performed in 2004, 65 islet isolations and 34 islet transplantations to 18 type 1 diabetic patients have been performed in Japan. RESULTS: Following islet transplantation, patients experienced decreased insulin requirements and lower hemoglobin A1C levels, and positive serum C-peptide levels. All patients achieved stabilized blood glucose levels and the disappearance of hypoglycemic unawareness. Although three patients achieved insulin independency for a limited period, persistent islet graft function was difficult to maintain. Overall islet graft survival was 86.5% at 6 months, 78.7% at 1 year, and 62.9% at 2 years after the first islet transplantation. In our institution, we carried out 23 islet isolations and six islet transplantations to four patients. Although insulin independency was not achieved, all patients showed a disappearance of hypoglycemic unawareness. CONCLUSIONS: Using data from the Japanese Trial of Islet Transplantation, the effectiveness of islet transplantation was shown even when using the pancreata from non-heart-beating donors. Although there are a number of problems to be solved and further improvement is needed, we can state that the introduction of clinical islet transplantation offers hope for type 1 diabetic patients.

A Case of Epstein-Barr Virus-Associated Leiomyosarcoma Concurrently With Posttransplant Lymphoproliferative Disorders After Renal Transplantation.

Epstein-Barr virus (EBV) infection might induce not only posttransplantation lymphoproliferative disorder (PTLD) but also leiomyosarcoma. We report a case of EBV-associated leiomyosarcoma concurrently with PTLD after renal transplantation. The patient was a 30-year-old woman who underwent living donor kidney transplantation at 27 years of age. Preoperative EBV viral capsid antibody immunoglobulin M, immunoglobulin G (IgG), and EBV nuclear antigen IgG were negative. Multiple lung and liver tumors were detected 1.5 years after transplantation. She was diagnosed with PTLD after tumor biopsy. Her EBV DNA was 110 copies/mL detected by real-time polymerase chain reaction when PTLD was diagnosed. She received dose reduction of immunosuppressive therapy and several chemotherapies. Because her hepatic lesion was still progressive while pulmonary lesion was reduced, a liver tumor biopsy was performed, but the biopsy specimens were necrotic. A left lateral segmentectomy was performed as a third biopsy for treatment-resistant hepatic lesion 2.5 years after her first PTLD diagnosis. Pathologically, she was diagnosed with EBV-associated leiomyosarcoma. She was treated with sirolimus, but died 7 months after the operation. This is the first case of the coincidence of leiomyosarcoma associated with EBV and PTLD. This case was exceedingly rare; however, we must consider the coincidence of leiomyosarcoma associated with EBV and PTLD when encountering treatment-resistant PTLD.

Cryopreservation of human pancreatic islets from non-heart-beating donors using hydroxyethyl starch and dimethyl sulfoxide as cryoprotectants.

Although widely used, DMSO is toxic for pancreatic islets. We combined hydroxyethyl starch (HES) with DMSO to simplify the procedure of freezing and thawing, and to decrease the toxicity of DMSO. A preclinical study was performed using islets from beagle dogs. After storage for 4 weeks, the islets were thawed and examined. The islet structure was well maintained after thawing. Although the number of the islets decreased to 71.2 +/- 20.1%, the function of the islets was evaluated by static incubation after thawing and showed a 1.80 +/- 0.78 stimulation index. We have introduced this technique for the cryopreservation of human islets from non-heart-beating donors. Twelve cases of human islet cryopreservation were performed. The sample tube of each human cryopreservation was thawed to evaluate the morphology, contamination, and endocrine function. Although fragmentation was observed in five samples (41.6%), the other seven (58.4%) showed a normal structure when evaluated by microscopic and electron microscopic study. The stimulation index (SI) of static incubation deteriorated from 3.37 +/- 3.02 to 1.34 +/- 0.28 after thawing. We divided the thawed islets into two groups: group 1 (n=8), SI > 1.2; group 2 (n=4), SI < 1.2. The group 1 islets showed a higher rate of normal structure (87%) than did group 2 (25%). Moreover, the SI before cryopreservation was 4.01 +/- 3.57 in group 1, which was higher than the SI of 2.11 +/- 0.72 in group 2. Based on the good results from the preclinical study using a large-animal model, this method was introduced for clinical application. Even from the pancreata of non-heart-beating donors, a successful islet cryopreservation was achieved. However, the isolated islets with poor function should not be cryopreserved for transplantation.

[A case of complete response to combination therapy of S-1 and CDDP for Stage IV gastric cancer with Virchow's lymph node and para-aorta lymph node metastasis].

The patient was a 53-year-old male with Stage IV gastric cancer with Virchow's lymph node and para-aorta lymph node metastasis. The chemotherapy regimen was given S-1 orally at 80 mg/m(2) day on day 1 to 21 and CDDP intravenously at 60 mg/m(2) day on day 8, repeated for 35 days. After two courses and a reduced regimen with S-1 64 mg/m(2) day plus CDDP 35 mg/m(2) day, the tumor lesion became CR and the serum CEA 575 ng/mL level before therapy decreased to the normal level. The patient received six courses of oral S-1(64 mg/m(2) day)for 28 days followed by a 14- day rest as maintenance therapy. The serum CEA elevated 13 months after the treatment, and the patient received a reduced course and two-course S-1/CDDP therapy. The serum CEA decreased to normal level and the patient has now survived 1 year 5 months without recurrence.

Renal Autotransplantation and Extracorporeal Nephron-Sparing Surgery for De Novo Renal Cell Carcinoma in a Kidney Allograft.

De novo renal cell carcinoma (RCC) rarely occurs in kidney allografts; however, the risk of RCC in these patients is 100-fold that of the general healthy population. Although total nephrectomy has been the standard treatment for kidney allograft RCC, several authors have reported that early-stage RCC in kidney allografts was successfully treated with nephron-sparing surgery. We herein describe a new procedure involving renal autotransplantation and extracorporeal nephron-sparing surgery, which was performed to treat de novo RCC near the hilum of a transplanted kidney. In the 22 months since transplantation, the patient's renal function has been favorable, and no recurrence has been observed. In conclusion, renal autotransplantation is a feasible technique for the treatment of RCC in kidney allografts, especially RCC located near the hilum.

Sentinel lymph node mapping for gastric cancer using a dual procedure with dye- and gamma probe-guided techniques.

BACKGROUND: Increasing evidence supports the sentinel lymph node (SN) concept for melanoma and breast cancers. SN biopsy may replace routine lymph node dissection in the treatment of these cancers. But there are little data evaluating this concept in patients with gastric cancer. The objective of this study was to test the feasibility of SN mapping in gastric cancers by using the dual-mapping procedure with dye and radioactive colloid. STUDY DESIGN: Thirty-one consecutive patients preoperatively diagnosed as T1-2 and N0 underwent SN biopsy using the dual-mapping procedure. Distributions of SNs identified by the dye-guided technique (blue nodes; BNs) were compared with those identified by the gamma probe guided technique (hot nodes; HNs). RESULTS: Among the 31 patients, 7 were found to have lymph node metastases. All positive nodes were detected by SN biopsy using the dual method. So, an accuracy rate of 100% was achieved in predicting the status of regional lymph nodes. Both BNs and HNs were identified in 28 of 31 patients (90%), but significant discrepancy of distribution was noted between BNs and HNs. Among the 28 patients with identified BNs, there was one metastasis in a non-BN. So the accuracy rate was 96% for the dye-guided technique. In contrast, among the 28 patients with identified HNs, 2 patients had metastasis in non-HNs, making the accuracy rate 93% for the gamma probe-guided technique. CONCLUSIONS: SN mapping is feasible in gastric cancer, but the dye-guided and gamma probe-guided techniques are complementary. So we recommend the dual-mapping procedure.

[Treatment of colorectal cancer--hepatic metastases].

The aim of this study was to evaluate the effect of the local therapy for colorectal liver metastases on overall survival. Seventy-two patients who had resected liver metastases from colorectal cancer during the period from 1982 to 2001 were evaluated for survival. There was no significant difference in overall survival by either surgical method for colorectal liver metastases or postoperative arterial infusion chemotherapy. However, the 5-year survival rate of resected metachronous liver metastases with postoperative arterial infusion chemotherapy was 44.9%, and that for patients with no extra hepatic metastases was 57.4%. Patients who have metachronous liver metastases from colorectal cancer should therefore be considered for postoperative arterial infusion chemotherapy. It is necessary to improve the outcome for cases that have extra hepatic metastases.

A Review of Autologous Islet Transplantation.

Autologous islet transplantation after total or semitotal pancreatectomy aims to preserve insulin secretory function and prevent the onset of diabetes. The major indication for pancreatectomy is chronic pancreatitis with severe abdominal pain, a benign pancreatic tumor, and trauma. The metabolic outcome of autologous islet transplantation is better than that of allogeneic transplantation and depends on the number of transplanted islets. Achieving islet isolation from a fibrous or damaged pancreas is one of the biggest challenges of autologous islet transplantation; a major complication is portal vein thrombosis after crude islet infusion. However, the incidence of portal vein thrombosis has decreased as islet preparation techniques have improved over time.

Laparoscopic-assisted distal pancreatectomy and nephrectomy from a live donor.

BACKGROUND: The simultaneous transplantation of pancreas and kidney from live donors is performed in select countries. One of the reasons for this reduced applicability is the invasiveness of the donor operation. We propose the method of laparoscopic-assisted operation to be performed on live donors with minimal invasion. METHOD: The donor was placed in the right lateral decubitus position. A 7-cm upper midline incision was made, and a handport was installed in addition to two or three 12-mm ports. After the removal of the left kidney graft, the spleen and the distal part of the pancreas were completely mobilized. The splenic vein and artery were identified and mobilized. The donor was then rotated to a supine position. Dissection of the pancreatic parenchyma using ultrasound shears and ligation of the splenic vessels were performed through midline incision under direct vision. The distal part of the pancreas and the spleen were extracted. RESULTS: Since December 2007, 3 donors have undergone this operation. In all 3 cases, the postoperative course was uneventful, and both the renal and pancreatic grafts functioned well. CONCLUSION: This technique is minimally invasive and safe, and may become the standard method of live donor operation for simultaneous pancreas-kidney transplantation.

Living donor pancreas transplantation in Japan.

BACKGROUND/PURPOSE: Living-donor pancreas transplants (LDPs) were introduced at Chiba-East National Hospital in 2004, and 12 LDPs have been performed at this institution to date. Based on the outcome of these 12 LDPs, the efficacy and safety of LDPs are herein discussed. METHODS: Twelve diabetic patients underwent LDPs; ten had simultaneous pancreas and kidney transplants from living donors, one had pancreas transplant after a kidney transplant from a living donor, and one had a pancreas transplant alone from a living donor. The donors were parents or brothers and the ABO blood types were incompatible in three LDPs. The procedures for the donor and recipient operations were performed according to the technique established by the University of Minnesota. Bladder drainage was used in 11 recipients and enteric drainage was used in one patient. Tacrolimus, basiliximab, mycophenolate mofetil, and prednisone were used for induction and immunosuppressive treatment. A splenectomy, double-filtered plasmapheresis, and plasma exchange were added in the ABO-incompatible LDPs. RESULTS: No complications were observed in the donors during hospitalization. The 1-year survivals of the patients, kidney grafts, and pancreas grafts were 100, 100, and 100%, respectively. The 3-year survivals were 91.7, 90, and 91.7%, respectively. Three patients developed leakage of pancreatic juice and one patient required a surgical procedure. Cytomegalovirus antigenemia was detected in five patients (42%). CONCLUSIONS: Based on the excellent outcome of the LDPs at this institution, LDPs is therefore expected to become a promising option for the treatment of patients with severe diabetes.

Acute cellular rejection occurring on the first day after living-related renal transplantation: a case report.

The patient was a 52-year-old man who received an ABO-compatible but non-identical living-related renal graft from his wife. The graft started to function immediately and the urine output rate was over 100 mL/h. However, this was gradually decreased within 12 h after transplantation. On day 2 post-transplant, the urine output almost stopped. A biopsy specimen revealed lymphocyte dominant cellular infiltration in the interstitium with mild tubulitis (according to Banff's schema grade Ia) and no C4d deposition in peritubular capillaries. Immunohistochemistry disclosed T-cell infiltration. The patient responded to a course of steroid pulse therapy (five days of 500 mg of methylprednisolone). The urine output gradually increased and the level of serum creatinine gradually decreased to 1.0 mg/dL. These clinical and histological findings strongly suggested acute cellular rejection. Acute cellular rejection occurring within 24 h post-transplant is extremely rare. In the present case acute cellular rejection occurred within the first day after living-related renal transplantation and was strongly suspected from histopathological findings in the allograft biopsy specimen.