Makoto Tsujita

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.

De Novo Anti-HLA DSA Characteristics and Subclinical Antibody-Mediated Kidney Allograft Injury.

Background It is unclear whether all donor-specific antibodies (DSA) can cause chronic antibody-mediated rejection (AMR). Subclinical stage before manifestation of renal dysfunction may be a critical period for reversing AMR. The aim of our study was to identify factors related to the development of subclinical AMR and to clarify the characteristics of de novo DSA. Methods Eight hundred ninety-nine renal transplants were screened for HLA antibody. De novo DSA were detected in 95 patients. Forty-three patients without renal dysfunction who underwent renal biopsies were enrolled in this study. Eighteen patients (41.9%) were diagnosed with biopsy-proven subclinical AMR and treated with plasmapheresis and rituximab-based therapy, whereas 25 showed no findings of AMR. Results Significant subclinical AMR-related factors were younger recipients, history of acute T cell–mediated rejection and DSA class II, especially DR-associated DSA. Mean fluorescence intensity (MFI) values of DR-DSA were significantly higher, whereas DQ-DSA was not different between subclinical AMR and no AMR. The &Dgr;MFI (>50%), DSA-MFI values greater than 3000, and C1q binding DSA were also significant subclinical AMR-related factors (P < 0.05). Among 18 patients treated for subclinical AMR, 8 patients (44.4%) obtained over 50% reduction of DSA-MFI and/or improvement or no deterioration of pathological findings. In contrast, 25 patients without subclinical AMR did not show renal dysfunction clinically. Moreover, all of the 8 patients with rebiopsy after 2 years continued to demonstrate no AMR. Conclusions About 40% of patients with de novo DSA demonstrated biopsy-proven subclinical AMR, leading to progressive graft injury. To validate the intervention and treatment for de novo DSA-positive patients without renal dysfunction, further study is necessary.

Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis

BackgroundCirculating factor(s) has been thought to be the underlying cause of focal segmental glomerulosclerosis (FSGS), and recent studies foster this idea by demonstrating increased soluble urokinase receptor (suPAR) levels in the serum of FSGS patients.MethodsTo explore the possible contribution of suPAR in FSGS pathogenesis, we analyzed serum suPAR levels in 17 patients with FSGS and compared them with those in patients with steroid-sensitive nephrotic syndrome, chronic glomerulonephritis, or non-glomerular kidney diseases.ResultsSerum suPAR levels in patients with FSGS were higher than those in patients with steroid-sensitive nephrotic syndrome or chronic glomerulonephritis, but not higher than those in patients with non-glomerular kidney diseases. suPAR levels negatively correlate with estimated glomerular filtration rate and were decreased after renal transplantation in patients with FSGS as well as in those with non-glomerular kidney diseases. Furthermore, 6 FSGS patients with post-transplant recurrence demonstrated that suPAR levels were not high during the recurrence.ConclusionsBased on our results, elevated suPAR levels in FSGS patients were attributed mainly to decreased glomerular filtration. These data warrant further analysis for involvement of possible circulating factor(s) in FSGS pathogenesis.

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 1u2003cm, and the mean diameter was 18.7u2003mm (range 14.9–24.1u2003mm). 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.

A case report of recurrence of mixed cryoglobulinemic glomerulonephritis in a renal transplant recipient.

Takeda A, Ootsuka Y, Suzuki T, Yamauchi Y, Tsujita M, Kawaguchi T, Horike K, Oikawa T, Goto N, Nagasaka T, Watarai Y, Uchida K, Morozumi K. A case report of recurrence of mixed cryoglobulinemic glomerulonephritis in a renal transplant recipient.u2028Clin Transplant 2010: 24 (Suppl. 22): 44–47.

Association of Dialysis Duration with Outcomes after Transplantation in a Japanese Cohort

BACKGROUND AND OBJECTIVESnEvidence regarding the differences in clinical outcomes after preemptive kidney transplantation (PKT) and non-PKT in Japan is lacking.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnWe conducted a retrospective cohort study at a single center in Japan. Consecutive patients ages >18 years old who had received a kidney transplant from a living donor between November of 2001 and December of 2013 at our institution (n=786) were enrolled. The primary study outcome was the occurrence of clinical events before the end of 2014. Clinical events were defined as any of the following: death with functioning graft (DWFG), graft loss, or post-transplant cardiovascular disease (CVD).nnnRESULTSnThe median follow-up period was 61.0 (35.3-94.0) months. PKT was performed in 239 patients (30.4%). Clinical events occurred in 78 (9.9%). In the Cox proportional hazard model for univariate analysis, factors found to be associated with higher risk of clinical events included older age, men, ABO incompatibility, longer dialysis duration, diabetes, pretransplant CVD, and large ventricular mass index. PKT was associated with lower risk. Clinical event rate in patients who received a PKT was 3.3% compared with 10.8%, 11.1%, 10.4%, 10.2%, 16.7%, and 16.2% among patients who were on dialysis for <1, 1 to <2, 2 to <3, 3 to <4, 4 to <5, and ≥5 years before transplant, respectively (P=0.002). The multivariate analysis showed that ABO incompatibility (hazard ratio [HR], 2.98; 95% confidence interval [95% CI], 1.89 to 4.71), duration of dialysis per year (HR, 1.07; 95% CI, 1.03 to 1.11), and diabetes (HR, 3.54; 95% CI, 2.05 to 6.12) were only three independent risk factors for the incidence of clinical events.nnnCONCLUSIONSnEven in Japan, where the long-term outcomes of patients on hemodialysis are excellent, PKT could be beneficial to reduce DWFG, graft loss, and post-transplant CVD.

How to estimate kidney function in kidney transplant recipients with mild to moderate kidney impairment: comparison of estimated glomerular filtration (eGFR) values between creatinine-based GFR equations and cystatin C-based GFR equations for Japanese population.

BackgroundWith the recent increase in renal transplantations in Japan, accurate assessment of renal function is required.MethodsThis study included 73 patients who had undergone renal transplantation at Nagoya Daini Red Cross Hospital at least 6xa0months previously and had stable renal function for >3xa0months. Glomerular filtration rates (GFRs) were measured by inulin clearance (mGFR) and compared with estimated cystatin C-based GFRs (eGFRcys), estimated creatinine-based GFRs (eGFRcre) and their average values (eGFRave).ResultsmGFR was 43.3xa0±xa014.1xa0mL/min/1.73xa0m2, eGFRcre was 39.6xa0±xa011.7, eGFRcys was 56.0xa0±xa017.1, and eGFRave was 47.8xa0±xa013.7xa0mL/min/1.73xa0m2. Serum cystatin C was 1.39xa0±xa00.37xa0mg/L and serum creatinine was 1.58xa0±xa00.51xa0mg/dL. The correlation coefficients between mGFR and eGFRcre, eGFRcys, and eGFRave were 0.768, 0.831, and 0.841, respectively (Pxa0<xa00.001, for all).The intraclass correlation coefficients were 0.754, 0.816, and 0.840, respectively (Pxa0<xa00.001, for all).The mean differences between measured and estimated GFR values were 3.74xa0mL/min/1.73xa0m2 with a root-mean square error (RMSE) of 9.06 for eGFRcre, +12.64 with RMSE of 9.48 for eGFRcys, and +4.45 with RMSE of 7.86 for eGFRave. Bland–Altman plots showed that eGFRcys overestimated GFR values compared with mGFR values in most cases and that eGFRave overestimated GFR values in 53 of 73 cases, whereas eGFRcre underestimated the values in 53 of 73 cases.ConclusioneGFRave may be the best marker to estimate kidney function in Japanese renal transplant recipients with mildly reduced or normal kidney function.

Stable renal engraftment in a patient following successful tandem autologous/reduced-intensity conditioning allogeneic transplantation for treatment of multiple myeloma with del(17p) that developed as a post-transplantation lymphoproliferative disease following renal transplantation

Multiple myeloma (MM) developing after renal transplantation is rare. From January 1972 to December 2011, a total of 1,485 patients underwent renal transplantation in Nagoya Daini Red Cross Hospital; 14 (0.9xa0%) of these recipients developed post-transplantation lymphoproliferative disorders (PTLDs) including two plasma cell neoplasms. Here, we report the clinical course of a 35-year-old male with immunoglobulin G k-type MM of recipient origin that developed 5xa0years after renal transplantation from a human leukocyte antigen (HLA)-haploidentical female sibling donor, which was performed to address dialysis-dependent chronic glomerulonephritis. Cytogenetic analysis revealed significant del(17p) abnormalities in myeloma cells. After non-response to bortezomib treatment, the patient achieved partial response with a thalidomide-containing salvage regimen and underwent successful tandem autologous/reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated male donor matched for seven of eight HLAs. At the 8-month follow-up time point, the patient’s performance status remained good, and the transplanted kidney remains functional without rejection. To the best of our knowledge, this is the first report of a successful use of allogeneic HSCT for a patient who developed MM as a PTLD after renal transplantation. This patient has a transplanted kidney and transplanted hematopoietic cells that currently coexist without rejection.