Hayato Nishida

Cytomegalovirus infection following renal transplantation in patients administered low‐dose rituximab induction therapy

Anti‐CD20 antibody (rituximab) is recently being used as a B cell‐depleting agent in renal transplantation (RTx). However, the incidence of infectious complications associated with rituximab therapy remains uncertain. We evaluated the incidence of cytomegalovirus (CMV) infection associated with rituximab therapy in RTx. A total of 83 patients were enrolled. The immunosuppressive regimen consisted of tacrolimus or cyclosporin, mycophenolate mofetil, methylprednisolone and basiliximab. In 54 patients, only one dose of rituximab (200 or 500 mg/kg body weight) was given before RTx. A total of 25 of 43 (58.1%) recipients who were CMV seropositive prior to RTx and who received rituximab induction therapy developed CMV infection, compared to 18 of 24 (75%) CMV seropositive recipients who did not receive rituximab therapy (P = 0.1676). A total of 8 of 11 patients who were CMV seronegative prior to RTx and who received rituximab developed CMV infection. However, CMV seroconversion was seen in all 8 of these infected patients. Low‐dose rituximab induction therapy in renal transplant recipients appears to have no influence on the incidence of CMV infection and CMV seroconversion. However, we have to consider anti‐CMV prophylaxis therapy, because of high incidents of CMV infection, especially for CMV seronegative recipients who received rituximab.

Usefulness of splenectomy for chronic active antibody‐mediated rejection after renal transplantation

In this study, the usefulness of splenectomy performed for the treatment of chronic antibody-mediated rejection (C-AMR) was assessed. The subjects were three sensitized patients who had undergone living-donor kidney transplantation at our department. The pathological findings and anti-HLA antibody titers in the circulating blood, detected using Luminex Single Antigen Beads, before and after splenectomy were compared. After splenectomy, the pathological findings, including tubulitis, glomerulitis and severity of C4d deposition [1], improved in all the three patients. Donor-specific antibody (DSA) and/or nonDSA completely disappeared in two of the three patients. Neither DSA nor nonDSA antibodies disappeared entirely in the remaining patient, who was the most strongly sensitized on account of repeated sensitization by first and third grafts, but the anti-HLA antibody titers decreased. Splenectomy appears to be one of the choices that should be considered for the treatment of C-AMR. All three patients were immunologically high-risk recipients. In all three recipients, the immunosuppressive drugs used for induction [2] were tacrolimus (FK, Prograf , Astellas Fujisawa, Osaka, Japan)/mycophenolate mofetil (MMF, Cellcept ; Roche, Nutley, NJ, USA) methylprednisolone (MP, Medorol ; Pfizer, Tokyo, Japan), with the addition of 200 mg anti-CD20 antibody (rituximab, Rituxan ; Zenyaku, Tokyo, Japan) and antiCD25 antibody (basiliximab, Simulect , Novartis, Basel, Switzerland). Briefly, FK506 was started 7 days before transplantation, at 0.15 mg/kg/day, and adjusted to maintain a FK trough level in whole blood between 8 and 12 ng/ml for 1 or 2 months postoperatively, and between 7 and 9 ng/ml thereafter. MMF was also started 7 days before transplantation at a dose of 2000 mg/day and decreased to 1000–1500 mg/day 1 month postoperatively adjusted based on the number of the white blood cell counts. MP was also started 7 days before transplantation, at 125 mg/day. On the day of operation, the dose of MP was increased to 500 mg/day and then tapered to 6–8 mg/day within 1–2 months after transplantation. Two of the three patients experienced acute severe rejection within 1 week of transplantation and were treated with high-dose gamma-globulin therapy and a total of more than 10 sessions of plasmapheresis therapy. We succeeded in weaning both from hemodialysis over the course of 1 month by initiating anti-rejection therapy, but as expected, subsequent renal biopsies revealed serious residual C-AMR. Although one of the three patients did not have any serious rejection reaction clinically, that is, oliguria or fever, the serum creatinine level was high and renal biopsy revealed severe AMR, just as in the other two patients. We selected patients with AMR in the chronic stage, after 1 year had elapsed after the transplantation, as the subjects of this study, and assessed whether splenectomy might be effective in such patients who are at a high risk of graft loss. Although all three patients received anti-CD20 antibody [3,4], there were no changes in the anti-HLA antibody titers after the administration of this antibody in any of the patients (data, not shown). This finding implies that the CD20 cells eliminated by rituximab were probably different from the plasma cells that actually produced the antibodies. It is noteworthy that while the plasma cells were not suppressed by rituximab and there were no changes in the types or titers of the anti-HLA antibodies following its administration, the antibody titers decreased following splenectomy [5]. There was no doubt that the immune system was activated by the current kidney transplantation in all the three sensitized patients, and that the symptoms had been caused by clonal proliferation of some of the memory B cells present in the spleen or bone marrow, their conversion to plasma cells, and the promotion of antibody production by the plasma cells themselves (Fig. 1). Some of these cells of B-cell lineage that had proliferated in the spleen were sufficiently suppressed by rituximab alone, while others were not. The splenectomy performed in these patients may have suppressed the remaining activated B-cell lineage cells [5]. The interval between the splenectomy and the start of the actual decrease in the titers of the antibodies is of great interest. The changes in the titers of the anti-HLA antibodies measured using Luminex Single Antigen Beads are shown in Fig. 2. In all the three patients, nonDSA,

Renal transplantation after myeloablative and non-myeloablative hematopoietic cell transplantation from the same donor

Abstract:  Hematopoietic cell transplantation is a key treatment to prolong patient survival for many hematological disorders. Renal impairment is well recognized as a significant complication of hematopoietic cell transplantation, which can progress to end‐stage renal disease. Herein, we report our experience of two patients who underwent renal transplantation from the same donor who provided cells for the preceding hematopoietic cell transplantation. One patient had undergone peripheral blood stem cell transplantation with a non‐myeloablative conditioning regimen, whereas the other had received bone marrow transplantation with a myeloablative regimen. Chronic immunosuppressive therapy was not needed in either one to maintain the kidney graft function. Not only bone marrow transplantation with a myeloablative conditioning regimen, but also peripheral blood stem cell transplantation with a non‐myeloablative regimen can confer immunological tolerance.

Sequential molecularly targeted drug therapy including axitinib for a patient with end-stage renal failure and metastatic renal cell carcinoma

A 62‐year‐old male patient with end‐stage renal disease and metastatic renal cell carcinoma (RCC) was referred to our hospital. Sequential targeted therapy consisting of sorafenib, sunitinib, and everolimus was administered, but the patients disease gradually progressed. Axitinib was subsequently administered at a decreased dose of 6 mg/day for 2 weeks, after which the dose was escalated to 10 mg/day. Axitinib therapy was maintained for a total of 6 months without severe adverse effects. Sequential molecularly targeted drug therapy including axitinib, with careful monitoring, is one possible treatment option for patients with metastatic RCC with renal impairment.

MP88-18 ERK5 IS A PROMISING THERAPEUTIC TARGET FOR CLEAR CELL RENAL CELL CARCINOMA

RASAL2 methylation or c-FOS mRNA or VEGFA mRNA in RCC tissues. Overexpression of RASAL2 in 786-O cells could inhibit the recruitment and tube formation of HUVECs, while RASAL2 knockdown (KD) in ACHN cells enhanced the recruitment and tube formation of HUVECs in vitro. Also, overexpression of RASAL2 could inhibit tumorigenecity of xenografts. Mechanistically, RASAL2 KD could enhance the phosphorylation of GSK3 and upregulate the expression of c-FOS and VEGFA. Furthermore, RASAL2 was inversely correlated with VEGFA and CD31 in tissues from human RCC specimens and xenografts. CONCLUSIONS: RASAL2 was downregulated in RCC tissues, which could lead to tumor angiogenesis via p-GSK3/c-FOS/VEGFA signaling pathway. Therefore, RASAL2 could be a potential target to prevent patients with RCC from resistance to anti-vascular therapy.

Pazopanib-induced crystal deposition in intestinal mucosa in a patient with retroperitoneal liposarcoma

Pazopanib was administered to a 44‐year‐old man with local recurrence of retroperitoneal liposarcoma. Computed tomography showed an intestinal edema, which gradually progressed 15 months after pazopanib administration although he had no clinical symptoms. Upper gastrointestinal endoscopy implicated marked edematous hypertrophy of the Kerklings fold. Pathological findings showed crystal deposition and fat accumulation, without a malignant component. All these abnormal findings resolved after pazopanib discontinuation.

Levels of 4EBP1/eIF4E Activation in Renal Cell Carcinoma Could Differentially Predict Its Early and Late Recurrence

Micro‐Abstract A subset of patients who undergo curative surgery for localized clear cell renal cell carcinoma (ccRCC) will experience early or late recurrence. Tumor viability depends on protein synthesis via the eukaryotic initiation factor (eIF)4E‐binding protein 1 (4EBP1/eIF4E) axis. Activation levels of the axis in ccRCC tissues could differentially affect tumor recurrence and the timing of recurrence after curative nephrectomy. Background The objective was to explore the predictive markers of late recurrence (LR) > 5 years after curative nephrectomy for renal cell carcinoma (RCC). Patients and Methods We retrospectively examined the data from 303 patients with localized clear cell RCC treated surgically at our institution from 1993 to 2011. Activation of the eukaryotic initiation factor (eIF)4E‐binding protein 1 (4EBP1)/eIF4E axis at the mammalian target of rapamycin complex 1 (mTORC1) was evaluated in the tumor specimens. Weak, intermediate, and strong immunohistochemistry staining grades were defined for 4EBP1, phosphorylated 4EBP1, and eIF4E. The effects of clinicopathologic factors and activation level grades on tumor recurrence were analyzed using multivariate Cox regression models. To validate the present findings, we investigated clinical data from The Cancer Genome Atlas and protein/phosphoprotein data from corresponding patients from The Cancer Proteome Atlas. Results Of the 303 patients, 31 and 16 patients developed early recurrence (ER, ≤ 5 years) and LR, respectively. The activation levels were comparable among the subcategories of pathologic TN stage, Fuhrman grade, and microvascular and capsular invasion. Pathologic stage ≥ T1b, Fuhrman grade 3/4, and an intermediate or strong activation level correlated significantly with overall recurrence and ER. Strong activation of the axis and pathologic stage ≥ T1b were identified as independent predictors of LR. Only 2 patients with weak activation experienced recurrence (1 each with ER and LR). Similar results were confirmed by the analyses of The Cancer Genome Atlas and The Cancer Proteome Atlas data. Conclusion The activation level of the axis in RCC tissues could independently predict for recurrence and differentially affect the timing of recurrence.

Renoprotective Procedures with a Cold Ischemia Time of

Introduction: We evaluated whether nephron sparing surgery (NSS) combined with meticulous suturing of the cut stump under clamping with cooling is beneficial for oncological outcomes and also assessed the relationship between cold ischemia time and deterioration of renal function. Methods: One hundred and six patients with renal cell carcinoma (RCC) were subjected to this procedure. Oncological outcomes and renal function according to the estimated glomerular filtration rate (eGFR) and the tubular excretion rate on renoscintigraphy before and at 12 months after surgery were evaluated. Results: Cancer recurrences were observed in 2 patients with past history of RCC; however, no patient died of cancer. Renal function was evaluated depending on 4 different ischemia times. All groups did not show a remarkable decrease of renal function in terms of eGFR. Renoscintigraphy revealed the deterioration of the affected kidney in patients with >60 min ischemia. Conclusion: The renoprotective procedure of NSS provided maximum preservation of renal function until 60 min of cold ischemia time.

CEREBRAL VENOUS SINUS THROMBOSIS IN PATIENTS WITH METASTATIC TESTICULAR CANCER DURING CHEMOTHERAPY: REPORTS OF TWO CASES

Cerebral venous sinus thrombosis (CVT) is rare but sometimes develops in association with malignant neoplasm. We report two cases of CVT that occurred during cisplatin-based chemotherapy for testicular cancer. A 46-year-old man with stage IIA non-seminomatous germ cell tumour was treated with conventional doses of etoposide and cisplatin (EP). On day 11 of the third treatment course, he developed a systemic seizure. Brain computed tomography (CT) and magnetic resonance (MR) imaging could not detect the cause. Enhanced chest-pelvic CT revealed pelvic thrombosis. Administration of phenytoin for epilepsy of unknown cause and heparin for thrombosis was started. He had completed 4 courses of EP therapy without seizure recurrence. After re-evaluating the brain CT images retrospectively, we found high density of superior sagittal sinus (SSS) and strongly suspected CVT. Another patient was a 47-year-old man with stage IIIB seminomatous germ cell tumour treated with bleomycin, etoposide, and cisplatin (BEP) therapy. On day 11 of the second treatment course, he developed a systemic seizure. Brain CT revealed subarachnoid haemorrhage localised in the right parietal lobe. CT venography revealed a filling defect in the superior sagittal sinus (SSS). MR venography revealed a SSS stenosis. We diagnosed the cause of the seizure as CVT and started administration of anticoagulant therapy. After the thrombus had diminished, chemotherapy was restarted and another 2 courses of BEP therapy was completed.

Rise in ambient temperature predisposes aging, male Japanese patients to renal colic episodes due to upper urolithiasis

Abstract Objective: Urolithiasis is a common urological problem, and its incidence has been increasing worldwide, including in Japan. Relationships between stone etiology and rise in ambient temperature have been reported, but it remains unclear how age and gender affect these relationships. Materials and methods: A retrospective examination was conducted of the medical archives of 1005 patients (aged ≥15 years) with acute renal colic diagnosed with urolithiasis upon image examination who consecutively visited emergency departments in three hospitals. The patients were categorized into six groups according to age: younger than 30, 30–39, 40–49, 50–59, 60–69, and 70 years and older. The net difference and fold increase in the number of patients in summer (July to September) versus in winter (December to February) were calculated. Results: Overall, the actual number of the patients varied according to the temperature rise throughout the year and among the age groups. Net increases in the number of patients were observed in all age groups for both genders, apart from 30–39-year-old women. The age group of 50–59 years considerably outnumbered all other groups. A significant statistical correlation was detected between the fold increase and male aging using Spearman’s rank correlation analysis (ρ = 0.94, p = 0.017), but not in females (ρ = –0.03, p = 1). Conclusions: These results support a positive association between ambient temperature rise and increase in the incidence of renal colic due to urolithiasis in Japan, and indicate that aging and gender affect the association differently.