Koji Nanmoku

Neither pre-transplant rituximab nor splenectomy affects de novo HLA antibody production after renal transplantation

The long-term effect of rituximab and splenectomy on de novo HLA antibody production and chronic antibody-mediated rejection after renal transplantation is uncertain. In order to gain insight on this, we studied 92 ABO-incompatible and 228 ABO-identical/compatible consecutive renal transplant patients and determined their de novo HLA antibody production and graft outcome. Patients with pretransplant donor-specific antibodies had been excluded. ABO-incompatible transplants included 30 recipients treated with rituximab, 51 by splenectomy, or 11 with neither, due to low anti-A or -B antibody titer. Graft survival in ABO-identical/compatible patients (97.7% at 5 years) was significantly higher than in ABO-incompatible (87.0% at 5 years), rituximab (96.7% at 3 years), or splenectomy (85.7% at 5 years) patients. Only four patients had clinical chronic antibody-mediated rejection (two each identical/compatible and incompatible). There was no significant difference in prevalence of de novo HLA antibody, including donor-specific and nondonor-specific antibodies among ABO-identical/compatible patients (13.9%), patients receiving rituximab (14.3%) or splenectomy (13.2%), or among those receiving cyclosporine, tacrolimus, mycophenolate mofetil, mizoribine, and everolimus. Renal function remained stable in most recipients with de novo HLA antibody. Thus, neither pretransplant splenectomy nor rituximab treatment has an inhibitory effect on de novo HLA antibody production during medium-term follow-up. Further study on long-term effects is needed.

Tertiary Hyperparathyroidism Resistant to Cinacalcet Treatment

Cinacalcet hydrochloride (cinacalcet) has been reported to be efficacious for patients with tertiary hyperparathyroidism (THPT). We experienced five patients with THPT requiring parathyroidectomy (PTx) because of resistance to cinacalcet treatment and investigated their clinical characteristics and clinical course. The maximum diameter of the parathyroid gland estimated by ultrasonography before renal transplantation was evaluated. Serum total calcium, phosphorus, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and creatinine (Cr) levels were investigated every three months after the administration of cinacalcet and at PTx. After surgery, the Cr levels were followed. In all five patients, at least one parathyroid gland had a largest diameter of more than 1 cm, and the mean diameter was 18.7 mm (range 14.9–24.1 mm). Intact PTH and ALP levels gradually increased after the initiation of cinacalcet and the Cr levels transiently increased after PTx. These findings suggest that the existence of a severely enlarged nodular hyperplastic gland is a main factor involved in resistance to cinacalcet.

Kidney volume changes in patients with autosomal dominant polycystic kidney disease after renal transplantation.

Background. Few studies have investigated whether the volume of native kidney and liver (when combined with polycystic disease) in patients with autosomal dominant polycystic kidney disease (ADPKD) decreases after renal transplantation. Methods. Changes in the volume of native kidney (bilateral: n=28; unilateral: n=5) and liver (concomitant polycystic disease: n=18) were analyzed in 33 patients with ADPKD, who underwent renal transplantation. Volumetry was retrospectively conducted using simple computed tomography scan data 6 months before transplantation, at the time of transplantation, and 1, 3, and 5 years after transplantation. Volume change was calculated on the basis of the value at the time of transplantation. Results. Mean±standard deviation values of bilateral native kidney volume were 3100±1417 (range: 756 to 6525; median: 2499) cm3 at the time of transplantation. Kidney volumes were significantly reduced in all but one patient after renal transplantation, decreasing by 37.7% and 40.6% at 1 and 3 years, respectively. The major proportion of the decrease was observed within the first year posttransplantation. In contrast, 16 of 18 patients showed significant increase of liver volumes after renal transplantation. The mean rates of increase were 8.6% and 21.4% at 1 and 3 years, respectively. Conclusions. As the volume of native polycystic kidneys could be reduced after renal transplantation, resection would be unnecessary if the space for kidney graft is available in the absence of infection, bleeding, or malignancy. When ADPKD is combined with polycystic liver disease, the possibility of intolerable symptoms caused by growing liver cysts should also be taken into account.

Frequent development of subclinical chronic antibody-mediated rejection within 1 year after renal transplantation with pre-transplant positive donor-specific antibodies and negative CDC crossmatches ☆

Although short-term graft survival has been improved by recent desensitization protocols including B cell depletion therapy, little is known about risk factors of chronic antibody-mediated rejection (CAMR) in HLA-incompatible (HLA-I) renal transplantation (RTx). Twenty-six HLA-I RTx with positive donor-specific antibodies (DSA) and negative T cell cytotoxic crossmatches were compared with 88 ABO-incompatible (ABO-I) and 207 ABO-identical/compatible (ABO-Id/C) RTx. The desensitization therapy consisted of mycophenolate mofetil, rituximab and double-filtration plasmapheresis. Protocol biopsies within 1 year revealed subclinical CAMR in 36% of HLA-I, 5% of ABO-I and 3% of ABO-Id/C, although clinical acute AMR was observed in 8%, 3% and 1%, respectively. The incidence of CAMR was not different between class I and class II DSA. Most of class I DSA (94%) changed to negative 1 year after RTx, whereas 77% of class II DSA remained positive. In addition, the remaining DRB ± DQB DSA caused CAMR in 80% of patients, while DQB DSA alone did not. The progress of subclinical CAMR within 1 year could not be circumvented by rituximab. Sustained class II (DRB ± DQB) DSA detection after RTx may pose a potential risk for developing CAMR, but negative change in class I DSA could also elicit CAMR.

Potent Immunosuppression for ABO-Incompatible Renal Transplantation May Not Be a Risk Factor for Malignancy

ABO-incompatible (ABOi) renal transplantation has been increasing, but malignant tumor is a troubling complication of kidney transplantation due to potent immunosuppression. Few previous studies, however, have demonstrated that potent immunosuppression for ABOi living-donor renal transplantation (LDRT) is a risk factor for malignancy. In the present research, data on 252 LDRT patients ftom 2003 to 2008 were retrospectively analyzed to clarify whether ABOi LDRT was associated with malignancy. A potent immunosuppressive regimen for ABOiLDRT consisted of splenectomy, cyclophosphamide, and double-filtration plasmapheresis to minimize the risk of antibody-mediated rejection, in addition to conventional immunosuppresssants including calcineurin inhibitor, prednisolone, and anti-CD25 monoclonal antibody. A total of 11 incidences of malignancy were observed during a median follow-up of 48 months. The incidence rates in ABO-compatible (ABOc; n = 189) and ABOi (n = 63) LDRT groups were 4.2 % (8/189) and 4.8 % (3/63), respectively. Kaplan-Meier survival analysis showed no statistical difference in event-free survival for malignancy between ABOc and ABOiLDRT groups (log-rank P = .73). Multivariable Cox regression analyses identified no associations of malignancy with ABOi LDRT or any immunosuppressant use. In conclusion, our investigation suggested that potent immunosuppression with splenectomy and cyclophosphamide for ABOi LDRT may not be a risk factor for malignancy.

Significance of C4d deposition in antibody‐mediated rejection

The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody‐mediated rejection (ABMR) in Banff classification since 2003. However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d‐negative ABMR has been more focused in renal allograft pathology. The aim of this study was to make certain of C4d staining for ABMR that was diagnosed by clinical and morphological findings. C4d staining was employed by immunofluorescence. This study included 14 patients with acute ABMR and 16 with chronic active ABMR. Eight of acute ABMR were ABO‐blood‐type‐incompatible renal transplantation (ABOinRTx) pre‐treated by DFPP and splenectomy or rituximub. In acute ABMR after ABOinRTx, C4d staining along peritubular capillary (PTC) was positive in five of them (62.5%). Only one graft biopsy of five acute ABMR with donor‐specific antibody (DSA) showed C4d positive. We assembled 16 graft biopsies showing typical transplant glomerulopathy and thickened PTC basement membrane with peritubular capillaritis as a suspicious pathological chronic active ABMR. Four of eight DSA‐positive patients were C4d negative in PTC; however, three of four DSA‐positive and C4d‐negative patients in PTC chronic active ABMR were C4d positive in only glomerular capillaries. C4d positivity could not come to a specific marker of ABMR diagnosing based on clinically and ordinary morphological findings.

Clinical Characteristics and Outcomes of Renal Transplantation in Elderly Recipients

BACKGROUND Elderly renal transplant candidates constitute one the fastest-growing populations among end-stage renal disease patients. Since the impacts of advanced recipient age have not yet been fully defined, we evaluated the clinical characteristics and outcomes of elderly renal transplant recipients. METHODS Among 564 adult renal transplant recipients, at our center between 2000 and 2009, 64 were at least 60 years of age (Elderly group), and 500 were younger than 60 years (Young group) at the time of the procedure. We compared their clinical features and surgical management. RESULTS There were significant differences in mean donor age (55.6 years vs. 53.2 years, P = .030) and gender mismatch (77.0% vs. 63.4%, P = .035). However, there were no significant differences between the two groups in patient and graft survivals (P = .177 and P = .365, respectively). Malignancy after transplantation was a significant risk factor upon univariate evaluation but only ABO incompatibility upon multivariate analysis of patient and graft survival. The main cause of graft loss among the Elderly group was death with a functioning graft due to heart failure. CONCLUSIONS Renal transplantation is a feasible, safe option for the elderly and should be actively implemented. However, screening for cancer and heart disease should be mandatory to improve outcomes.

Clinical characteristics and outcomes of adenovirus infection of the urinary tract after renal transplantation

Urinary tract infection caused by human adenovirus (HAdV) after renal transplantation (RT) results in graft loss because of concomitant nephropathy and acute rejection and may result in death because of systemic dissemination.

Impact of Renal Transplantation and Nephrectomy on Urinary Soluble Klotho Protein.

BACKGROUND Klotho is a single-pass transmembrane protein predominantly expressed in the kidneys. The soluble form of klotho has been shown to participate in various pathophysiological activities. However, information regarding the kinetics of soluble klotho remains limited. We herein assessed serial changes in the amounts of 24-hour urinary excreted soluble klotho among renal transplant recipients and concomitant living donors before and after transplantation. METHODS A total of 15 recipients and donors were included in the current study, and the amounts of urinary soluble klotho were quantified using a sandwich enzyme-linked immunosorbent assay. RESULTS Urine samples were available in 6 of the 15 recipients prior to the procedure. The amounts of urinary klotho in these 6 recipients and overall living donors at the baseline were 58.6 ng/day (IR: 29.3-142) and 698.8 ng/day (IR: 62.3-1619.5), respectively. Those in the recipients on postoperative day 2 (median 522.3 ng/day; IR 337.1-1168.5, P < .05) and day 5 (median 723.2 ng/day; IR 254.7-1238.6, P < .05) were significantly higher than the baseline values. Among the living donors, only a transient increase was observed in the amounts of urinary klotho on postoperative day 2. CONCLUSION The current data regarding the urinary soluble klotho in recipients support the hypothesis that the kidney is a major source of urinary soluble klotho among the numerous components of the urinary tract. In living donors, the complex nature of events associated with acute reductions in the renal mass may modulate the release of soluble klotho from the kidneys into the urine.

Virus-Associated Hemophagocytic Syndrome in Renal Transplant Recipients: Report of 2 Cases from a Single Center

Virus-associated hemophagocytic syndrome (HPS) is a potentially fatal complication of immunosuppression for transplantation. However, it presents with heterogeneous clinical symptoms (fever, disturbed consciousness, and hepatosplenomegaly) and laboratory findings (pancytopenia, elevated hepatic enzyme levels, abnormal coagulation, and hyperferritinemia), impeding diagnosis. Case 1: A 39-year-old female developed fever 4 years after ABO-incompatible living-related renal transplantation. Laboratory findings revealed thrombocytopenia, elevated hepatic enzymes, Epstein-Barr virus (EBV) DNA seropositivity, and hyperferritinemia. EBV-associated HPS was confirmed by bone marrow aspiration. Steroid pulse therapy and etoposide were ineffective. Disseminated intravascular coagulation resulted in multiple organ failure, and the patient died 32 days after disease onset. Case 2: A 67-year-old male was admitted with rotavirus enteritis a month after living-unrelated renal transplantation. He developed sudden-onset high fever, disturbance of consciousness, and tachypnea 8 days after admission. Laboratory findings revealed elevated hepatic enzyme levels, hyperkalemia, and hyperferritinemia. Emergency continuous hemodiafiltration ameliorated the fever, and steroid pulse therapy improved abnormal laboratory values. Varicella-zoster virus meningitis was confirmed by spinal tap. Acyclovir improved consciousness, and he was discharged 87 days after admission. Fatal virus-associated HPS may develop in organ transplant patients receiving immunosuppressive therapy. Pathognomonic hyperferritinemia is useful for differential diagnosis.