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Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications.

Introduction Owing to organ shortage, the number of kidney transplantation (KT) involving older adult living donors is increasing. We aimed to investigate the effects of living-donor age and donor-recipient age differences on KT outcomes. Methods This single-center, retrospective cohort study involved 853 adult LDKTs performed between January 2008 and December 2018. Recipients were stratified into the following 5 groups based on donor age and donor-recipient age difference: donor age, 30 to 49 years and age difference, −10 to 15 years; donor age, 50 to 69 years and age difference, −10 to 15 years; donor age, 50 to 69 years and age difference, 15 to 40 years; donor age, 70 to 89 years and age difference, −10 to 15 years; and donor age, 70 to 89 years and age difference, 15 to 40 years (groups 1, 2, 3, 4, and 5, respectively). As a primary outcome, the risk of graft loss was investigated. The secondary outcomes were postoperative estimated glomerular filtration rates (eGFRs) and mortality rates of recipients. Results Group 4, representing KT between older adult donors and older adult recipients, had the highest graft loss risk and mortality. The eGFRs of the recipients from donors aged 70 to 89 years (groups 4 and 5) were significantly lower than those from donors in the other groups. Although the differences in the eGFR between groups 4 and 5 were not significant, the eGFR of group 4 was lower than that of group 5 at 6 months post-KT. Conclusion LDKTs from older adult donors to older adult recipients resulted in the worst graft survival and mortality rates.

Aim Bacterial and fungal infections are serious, life-threatening conditions after kidney transplantation. The development of oral/oesophageal candidiasis after kidney transplantation is not a reported risk factor for subsequent severe infection. This study was performed to investigate the relationship between oral/oesophageal candidiasis after kidney transplantation and the development of subsequent infection requiring hospitalization. Methods This retrospective study included 522 consecutive patients who underwent kidney transplantation at Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 1 January 2010 to 1 February 2019. Ninety-five percentage of patients were living donor transplant recipients. Visual examination was performed to detect oral candidiasis, beginning immediately after kidney transplantation; upper gastrointestinal endoscopy was performed 8-10 months after kidney transplantation. Twenty-five patients developed candidiasis (Candida-onset group) and 497 did not (non-Candida-onset group). The follow-up periods were 67 (37-86) months in the Candida-onset group and 55 (34-89) months in the non-Candida-onset group. Severe infection was defined as bacterial or fungal infection requiring hospitalization; viral infections were excluded. Results Severe infection developed in 9/25 (36%) patients in the Candida-onset group and in 77/497 (15%) patients in the non-Candida-onset group (p = .006). Binomial logistic analysis revealed that Candida infection (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.06-6.06; p = .037) and use of rituximab (OR 1.81, 95% CI 1.12-2.93; p = .016) were significant predictors of subsequent severe infection. Conclusion Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation and suggests an over-immunosuppressive state, which should prompt evaluation of immunosuppression.

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single‐center randomized, double‐blind, placebo‐controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1‐month posttransplant. The primary endpoint was the change in eGFR from baseline to 12‐month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12‐month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m2 (95% CI; −0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m2 (95% CI, −0.02 to 3.7) in the placebo group, with no significant between‐group difference (−0.7 mL/min/1.73 m2 [95% CI; −3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR, A randomized, double‐blind, placebo‐controlled trial shows that vitamin D supplementation fails to protect renal transplants, as assessed by estimated glomerular filtration rate and allograft histology.

The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.

OBJECTIVES Our aim was to investigate effects of surgery on living donors' body composition and clarify factors related to it. MATERIALS AND METHODS We evaluated preoperative computed tomography images of 335 living kidney donors (127 men, 209 women) to calculate 3 body composition parameters and changes with aging by sex: (1) skeletal muscle mass, quantified by skeletal muscle index; (2) fat distribution, calculated by visceral adipose tissue/subcutaneous adipose tissue ratio; and (3) muscle quality, quantified by intramuscular adipose tissue content. Thereafter, with pre- and postoperative computed tomography images from 75 living kidney donors (25 men, 50 women) after hand-assisted laparoscopic donor nephrectomy, we compared pre- and postoperative body composition changes. RESULTS Annual change in intramuscular adipose tissue content with age was 0.0049 in men and 0.0091 in women. Of 75 patients, 49 had lower quality of muscle, intramuscular adipose tissue content was significantly higher after nephrectomy (P < .001), and median change in intramuscular adipose tissue content was 0.061 (range, 0.018-0.11) in men and 0.052 (range, 0.017-0.18) in women. Univariate analysis revealed that skeletal mass index and visceral adipose tissue/subcutaneous adipose tissue ratio changes were significantly different between the intramuscular adipose tissue content improvement and deterioration groups. Multivariate analysis revealed skeletal mass index change was an independent factor for intramuscular adipose tissue content change (P = .0019). Intramuscular adipose tissue content change was negatively correlated with skeletal mass index change (r = -0.40). CONCLUSIONS Although muscle quality deteriorates after nephrectomy, maintaining muscle mass is important to retaining muscle quality.

Summary While donor-specific human leukocyte antigen (HLA) antibodies are a frequent cause for chronic antibody-mediated rejection in organ transplantation, this is not the case for antibodies targeting blood group antigens, as ABO-incompatible (ABO-I) organ transplantation has been associated with a favorable graft outcome. Here, we explored the role of CD4 T cell-mediated alloresponses against endothelial HLA-D-related (DR) in the presence of anti-HLA class I or anti-A/B antibodies. CD4 T cells, notably CD45RA-memory CD4 T cells, undergo extensive proliferation in response to endothelial HLA-DR. The CD4 T cell proliferative response was enhanced in the presence of anti-HLA class I, but attenuated in the presence of anti-A/B antibodies. Microarray analysis and molecular profiling demonstrated that the expression of CD274 programmed cell death ligand 1 (PD-L1) increased in response to anti-A/B ligation-mediated extracellular signal-regulated kinase (ERK) inactivation in endothelial cells that were detected even in the presence of interferon-γ stimulation. Anti-PD-1 antibody enhanced CD4 T cell proliferation, and blocked the suppressive effect of the anti-A/B antibodies. Educated CD25+CD127− regulatory T cells (edu.Tregs) were more effective at preventing CD4 T cell alloresponses to endothelial cells compared with naive Treg; anti-A/B antibodies were not involved in the Treg-mediated events. Finally, amplified expression of transcript encoding PD-L1 was observed in biopsy samples from ABO-I renal transplants when compared with those from ABO-identical/compatible transplants. Taken together, our findings identified a possible factor that might prevent graft rejection and thus contribute to a favorable outcome in ABO-I renal transplantation.

Once-daily extended-release tacrolimus (TACER) is commonly administered following kidney transplantation (KTx); however, its optimal dosage remains unknown.In this multi-center, randomized controlled trial, 62 living donor KTx recipients were assigned to either standard-exposure (SE; n = 32) or low-exposure (LE; n = 30) TACER (Graceptor®, Astellas Pharm Inc.) groups. All patients received basiliximab and mycophenolate mofetil (MMF). The primary outcomes were acute rejection, graft/patient survival, and the secondary outcomes were incidence of cytomegalovirus infection, and de novo donor-specific antibodies (dnDSA) production.The tacrolimus trough level and estimated area under the blood concentration-time curve (eAUC) were significantly higher in SE than in LE (SE vs. LE; 1 year: 5.0 ± 0.9 ng/ml and 206.9 ± 26.8 ng h/ml vs. 3.4 ± 1.0 ng/ml and 153.9 ± 26.4 ng h/ml; 2 years: 4.8 ± 1.0 ng/ml and 204.9 ± 30.1 ng h/ml vs. 3.8 ± 0.9 ng/ml and 164.4 ± 27.0 ng h/ml). In contrast, the dosage and eAUC of MMF did not differ between groups. Two-year graft and patient survival rates were 100% in both groups, and acute rejection rates were 0% and 10% in the SE and LE, respectively (p = 0.11). The mean estimated glomerular filtration rates did not differ between the groups. Cytomegalovirus infection was slightly lower in the LE (SE: 12.5% and LE: 6.7%, p = 0.37). In the LE, four cases of dnDSA were noted within 2 years of transplantation; no case was observed in the SE (p = 0.034).Although the LE TACER regimen showed similar rates of acute rejection, as well as graft and patient survival compared with SE after KTx, LE was significantly more associated with dnDSA. Further investigation of its long-term effect on graft survival is warranted. (University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000033089).

Risk factors associated with subchondral insufficiency fracture (SIF) of the femoral head have not been established. The aim of the present study was to determine the incidence and risk factors for SIF of the femoral head following renal transplantation (RT).We analyzed the cases of 681 RT patients (mean age at surgery: 49.5 ± 13.6 years, 249 women, 432 men) to determine the incidence of SIF. Hip magnetic resonance imaging (MRI) was performed 6 months post-RT. The following potential predictors of SIF were evaluated: (1) patient's condition at RT: bone mineral density (BMD), pre-RT laboratory values including calcium (Ca), phosphorus (P), calcium-phosphorus product (Ca × P), and intact parathyroid hormone; the patient and donor's blood relationship; and mismatching number of human leukocyte antigens (HLAs), and (2) post-RT dosage(s) of steroid(s), the immunosuppressive regimen, and the incidence of acute rejection.SIF was observed in 15 hips (13 patients, 1.9%). We successfully matched 39 patients without SIF. A multivariate logistic regression analysis adjusted for cumulative dosages of steroids, revealed the following were risk factors for SIF: osteoporosis (OR: 11.4, p = 0.046), lumbar BMD (OR: 0.003, p = 0.038), pre-RT serum P (OR 2.68, p = 0.004), and pre-RT serum Ca × P (OR: 1.11, p = 0.005).Since osteoporosis, the lumbar BMD, serum P, and serum Ca × P were identified as risk factors for a post-RT SIF, these factors should be evaluated before RT for the prediction of the SIF risk.

Vitamin D deficiency, persistent hyperparathyroidism, and bone loss are common after kidney transplantation (KTx). However, limited evidence exists regarding the effects of cholecalciferol supplementation on parathyroid hormone (PTH) and bone loss after KTx. In this prespecified secondary endpoint analysis of a randomized controlled trial, we evaluated changes in PTH, bone metabolic markers, and bone mineral density (BMD). At 1 month post-transplant, we randomized 193 patients to an 11-month intervention with cholecalciferol (4000 IU/d) or placebo. The median baseline 25-hydroxyvitamin D (25[OH]D) level was 10 ng/mL and 44% of participants had osteopenia or osteoporosis. At the end of the study, the median 25(OH)D level was increased to 40 ng/mL in the cholecalciferol group and substantially unchanged in the placebo group. Compared with placebo, cholecalciferol significantly reduced whole PTH concentrations (between-group difference of -15%; 95% confidence interval [CI] -25 to -3), with greater treatment effects in subgroups with lower 25(OH)D, lower serum calcium, or higher estimated glomerular filtration rate (pint

Introduction: Recent reports have described an increased risk of renal disease in living kidney donors compared with the general population. However, these reports do not detail the outcomes of medically complex living donors (MCLDs) with preoperative comorbidities (PCs), such as hypertension, dyslipidemia, glucose intolerance, and obesity. Analysis of living donors with end-stage renal disease (ESRD) has shown that these PCs may contribute significantly to the development of ESRD. We aimed to evaluate the effect of PCs on postoperative renal function and mortality in MCLDs. Methods: Between January 2008 and December 2016, 807 living-donor kidney transplants were performed in our unit. Of these, 802 donors completed postoperative follow-up of >5 months. Donors were stratified into 4 groups based on the number of PCs present: healthy living donors (HLDs) with no PCs (n = 214) or MCLDs with 1 PC (n = 302), 2 PCs (n = 196), or 3 PCs (n = 90) (denoted MCLD [PC 1], MCLD [PC 2], or MCLD [PC 3], respectively). We compared pathology observation data from baseline biopsy, postoperative estimated glomerular filtration rate (eGFR), postoperative urinary protein concentration, and mortality between HLD and MCLD groups. Results: Interstitial fibrosis, tubular atrophy, glomerulosclerosis, and arteriolosclerosis were more frequent in MCLDs (PC 3) than in HLDs. No significant differences were identified between HLDs and MCLDs in terms of postoperative eGFR and short-term mortality. Overt proteinuria and ESRD were not observed. Conclusions: Appropriate postdonation management of MCLDs with PCs may result in similar outcomes as for HLDs. Keywords: baseline biopsy, estimated glomerular filtration rate, kidney transplantation, medically complex living donor, preoperative comorbidities, proteinuria

Atypical anti-glomerular basement membrane (GBM) nephritis is a rare variant of the classical anti-GBM antibody disease. Patients present with an undetectable anti-GBM antibody but show linear glomerular basement membrane staining for immunoglobulin. We present a 69-year-old man who underwent a living-donor kidney transplant. The aetiology of the renal failure was a focal segmental glomerulonephritis-like lesion resistant to immunosuppressive therapy. A renal graft biopsy revealed diffuse endocapillary hypercellularity, and mild mesangiolysis with linear GBM staining for IgG. The patient was diagnosed with atypical anti-GBM nephritis since the patient tested negative for circulating anti-GBM antibodies. Treatment involved intravenous methylprednisolone, plasma exchange, and rituximab administration. Protocol graft biopsy performed 1 year after the renal transplant showed a focal segmental glomerulonephritis-like lesion possibly progressing from endocapillary hypercellularity and mesangiolysis. These findings were similar to his native kidney biopsy findings. Although classical recurrent anti-GBM nephritis is rare when a renal transplant is performed after decreased disease activity, this case was considered as a case of recurrent atypical anti-GBM nephritis after renal transplant.

Introduction: Living kidney donation improves the lives of individuals with kidney failure; however, recent studies have suggested that living kidney donors may be at a relatively higher risk of reduced renal function than healthy non-donors. We therefore aimed to evaluate the clinical and pathological findings in living kidney donors who developed kidney disease. Methods: From January 1991 to May 2019, 1,625 live kidney donations were performed at our hospital. Among the donors, 7 developed kidney disease after donation and underwent open renal biopsy. We studied the clinical and pathological findings of these patients from their clinical records. Results: There were 3 patients with immunoglobulin A (IgA) nephropathy, 2 with membranous nephropathy, 1 with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, and 1 with secondary focal segmental glomerulosclerosis (FSGS). All patients with IgA nephropathy had latent IgA deposition on their baseline biopsy. One patient with membranous nephropathy demonstrated findings of membranous nephropathy on the baseline biopsy, despite being asymptomatic. All patients, except for those with ANCA-associated nephropathy and secondary FSGS, recovered from the nephritis or maintained an adequate renal function after treatment. Discussion/Conclusion: Baseline biopsy is necessary for assessing the renal condition of kidney donors, and these donors require long-term follow-up based on their baseline biopsy findings. If donors develop kidney disease, appropriate diagnosis and treatment are essential.

Purpose We evaluated de novo donor-specific antibody (DSA) production of everolimus (EVR)-based immunosuppression for primary kidney transplant recipients involved in the A1202 study at our institute. Methods From March 2008 to August 2009, 24 recipients were prospectively randomized into 2 groups. The EVR group received reduced cyclosporin A and EVR. The standard protocol (STD) group received standard cyclosporin A and mycophenolate mofetil. Both groups received basiliximab and steroids. De novo DSA was identified using LABScreen single antigen beads (One Lambda, Canoga Park, Calif., United States). Mean fluorescence intensity (MFI) values > 1000 were considered positive. P Results Graft survival was 100% in the EVR group and 90.9% in the STD group. All patients remained on the primary protocol in the EVR group, but 3 patients in the STD group (27.3%) were converted to tacrolimus due to DSA and non-adherence. Estimated glomerular filtration rate was similar in both groups. No EVR group recipients and 9.1% of STD group recipients were treated for T-cell-mediated rejection. No recipients of the EVR group exhibited peritubular capillaritis, while 9.1% in STD group developed chronic active antibody-mediated rejection. LABScreen revealed an accumulative class II DSA production rate of 15.4% in the EVR group and 18.3% in the STD group at 10 years. When the MFI cut-off level was set to 6000, anti-HLA antibody and de novo DSA-free survival was significantly better in the EVR group. Conclusions EVR-based immunosuppression provided equivalent or even better clinical outcomes. EVR suppressed de novo DSA production at 10 years follow-up; however, further follow-up is inevitable.

Background and Aims Although elderly living donors are recognized as a marginal donor for kidney transplantation, the number of elderly living donors are increasing because of insufficiency. We investigated the impact of donor age on living donor kidney transplantation. Method A total 858 adult living donor kidney transplantation (LDKT) between January 2008 and December 2018 was included in this study and followed up until September 2020. LDKTs were stratified into 3 groups according to the donor age; 157 LDKTs from donors aged 30 – 49, 592 LDKTs from donors aged 50 – 69, and 109 LDKTs from donors aged 70 – 89. To investigate the impact of donor age on living donors, postoperative estimated glomerular filtration rates (eGFR), mortality rate and incidence of end stage renal disease were compared between 3 donor age groups. To investigate the impact of donor age on recipients, postoperative eGFR was compared between 3 donor age groups and the risk factors of graft loss were analyzed using Cox regression hazard model. Results The eGFRs of donors demonstrated a decline with increased donor age and significant differences at all time points among 3 donor age groups. (Figure 1) Mortality rate and incidence of end stage renal disease of donors were similar among 3 donor age groups. (Figure 2) The eGFRs of recipients demonstrated a decline with increased donor age and significant differences at all time points among 3 donor age groups. (Figure 3) Multivariate analysis using Cox regression hazard model demonstrated donor aged 70 – 89 as a significant risk of graft loss (P = 0.024, hazard ratio 3.053, 95% confidence interval 1.160 – 8.040). Conclusion The prognosis of living donors after donation were not affected by the donor age except for the lower eGFR with increased donor age. The eGFRs of recipients and graft loss rates were the worst in the recipients transplanted from donors aged 70 – 89.

Background and Aims Thrombotic microangiopathy (TMA) is characterized by mechanical hemolytic anemia, thrombocytopenia, and renal impairment. TMA that occurs in kidney transplant recipients has multiple etiologies and may be de novo or recurrent. Main causes of TMA among recipients are atypical hemolytic uremic syndrome (aHUS), immunosuppressive drugs, ischemia-reperfusion injury (IRI), viral infections, and antibody-mediated rejection (ABMR). Pathological findings of TMA with thrombosis in glomeruli and arterioles are not rare in graft biopsies, but the clinical signs vary widely by etiologies, and incidence and risk factors for each are uncertain. The purpose of this study is to clarify the current status of TMA after kidney transplantation. Method The subjects were 1,336 patients (5,425 biopsy specimens) who underwent kidney transplantation (851 ABO-compatible and 485 ABO-incompatible) at Japanese Red Cross Nagoya Daini Hospital and Masuko Memorial Hospital from January 1, 2000 to June 30, 2018. We investigated patient characteristics and graft survival in 69 patients with pathological findings of TMA (12 with symptomatic TMA and 57 with asymptomatic TMA) and 1,207 patients without findings of TMA. Sixty patients were excluded because of incomplete data or biopsy specimens. TMA patients with acute kidney injury (AKI) were defined as symptomatic TMA in this study. Results The incidence of post-transplant TMA was 5.2% (symptomatic TMA : 0.9%, asymptomatic TMA : 4.3%) in our cohort. Multivariate analysis revealed significant risk factors for TMA were presence of donor specific antibodies (DSA) and use of cyclosporine (odds ratio [OR] 3.52; 95% confidence interval [CI] 1.58-7.88; p=0.002 and OR 3.70; 95% CI 1.68-8.11; p=0.001, respectively). Causes of symptomatic TMA were ABMR : 66.7% (5 patients with ABO-incompatibility, 3 with preformed DSA), aHUS : 16.7%, cytomegalovirus and adenovirus infection : 8.3%, and causes of asymptomatic TMA were drug-induced: 40.4% (21 patients with calcineurin inhibitor, 2 with everolimus), ABMR: 31.6% (10 with ABO-incompatibility, 8 with de novo DSA), IRI : 14.0 %. Onset of post-transplant TMA was significantly associated with lower graft survival (Figure A), with a stronger correlation in symptomatic TMA than in asymptomatic TMA (Figure B and C). Conclusion TMA with AKI that occurred after kidney transplantation had a poor graft prognosis. Therefore, avoiding transplantation, changing donors or using tacrolimus instead of cyclosporine should be considered for patients with DSA or ABO-incompatibility.

Background and Aims Chronic antibody mediated rejection caused by de novo donor specific antibody (dnDSA) is one of the biggest reasons for graft failure. At present, because it is difficult to treat CAMR, prevention of de novo DSA production is important. We investigated the risk factor for dnDSA production in living donor kidney transplantation. Method 807 patients underwent living donor kidney transplantation between January 2008 and December 2016. 159 recipients were excluded because of preformed DSA (58 recipients), pediatric transplantation (35 recipients), pancreas transplantation after kidney transplantation (4 recipients), and insufficient data on DSA after transplantation (62 recipients). 648 recipients were enrolled in this study. In 84 out of 648 recipients, dnDSA were detected until December 2018. With cox regression analysis, the risk factors for de novo DSA production were investigated between dn DSA positive and negative groups. The impact of donor characteristics including age and sex, and recipient characteristics including age, sex, hemodialysis vintage, cold ischemic time, past history of transfusion, pregnancy, and transplantation, HLA mismatch, pre-operative Flow PRA results, ABO incompatibility, rituximab induction, splenectomy, pre-operative plasmapheresis, transplantation from first-degree relatives, conversion of calcineurin inhibitor (CNI), conversion of mycophenolate mofetil, mizoribin, and everolimus, CNI used for induction, induction with mycophenolate mofetil, mizoribin, and everolimus, CNI withdrawal, withdrawal of mycophenolate mofetil, mizoribin, and everolimus, and rejection within 6 months after transplantation were investigated. Results In the univariate analysis, male recipient, male donor, and CNI withdrawal were the significant risk factors (P=0.020, HR 1.795, 95%CI 1.095-2.942; P=0.027, HR 0.568, 95%CI 0.344-0.938; P Conclusion Calcineurin inhibitor withdrawal was the significant risk factor for de novo DSA production in living donor kidney transplantation

Background and Aims In living donor kidney transplantation, the progress of immunosuppressants in recent decades has led to an average graft survival period more than 15 years. However, the rate of graft loss (GL) within 5 years is still about 5%. Since the incidence of early GL is low, clinical evidence of causes and risk factors are limited and it remains unclear whether early GL was predictable before transplantation. Our purposes were to characterize a patient population with GL, to identify risk factors associated with early ( Method The subjects were 1,779 patients who underwent living donor kidney transplantation at Japanese Red Cross Nagoya Daini hospital and Masuko Memorial Hospital from January 1, 1972 to December 31, 2018 (former group (1972-1999) : 503, latter group (2000-2018) : 1,276). We retrospectively examined patient characteristics, timing and causes of GL in 445 cases with GL by December 31, 2019 (GL cases in former group : 335, GL cases in latter group : 110). Results The 5- and 10-year graft survival rates were on an increasing trend, with 74.7% and 58.3% in former group and 95.2% and 88.7% in latter group, respectively. In latter group, T cell-mediated rejection and recurrence of primary diseases were significantly more frequent in GL cases within 5 years after transplantation than over 5 years (10% vs 0%, p=0.02 and 6% vs 0%, p=0.04). Although not significant, GL due to antibody-mediated rejection tended to more frequent in over 5 years after transplantation (22% vs 45%). Compared the causes of GL within 5 years after transplantation between GL cases in former group and latter group, rate of allograft rejection significantly reduced (88％ vs 44%, p Conclusion Our analysis suggests that management of infections, medication nonadherence and recurrence of primary diseases have become more important for living donor kidney transplant recipients in recent years with improved immunosuppressants.

There is a lack of evidence about the risk factors associated with osteonecrosis of the femoral head (ONFH). To determine the incidence and risk factors for ONFH following renal transplantation (RT). In total, data of 681 RT patients (mean age at surgery, 49.5 ± 13.6 years; 249 women and 432 men) were evaluated to determine the incidence of ONFH. Hip magnetic resonance imaging (MRI) was performed six months after RT. The following potential predictors of ONFH were evaluated: (1) patient’s condition at RT; laboratory test results including calcium (Ca), phosphorus (P), calcium-phosphorus product (Ca × P), and intact parathyroid hormone before RT; blood relationship between the patient and donor; and mismatching number of human leukocyte antigens (HLAs), especially HLA class I and class II and (2) dosages of steroids after RT, immunosuppressive regimen, and incidence of acute rejection. ONFH was observed in 30 hips (21 cases, 3.1%). We successfully matched 63 patients without ONFH. Multivariate logistic regression analysis, adjusted for cumulative dosages of steroids, revealed that mismatching number of HLA (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.10–2.36; p = 0.014), HLA class II (HR, 3.73; 95% CI, 1.46–9.56; p = 0.001), P before RT (HR, 1.62; 95% CI, 1.02–2.58; p = 0.041), and Ca × P before RT (HR, 1.06; 95% CI, 1.01–1.11; p = 0.024) were risk factors for ONFH. A greater number of HLA mismatches, HLA class II, serum P, and serum Ca × P were risk factors for ONFH after RT. Therefore, these factors should be evaluated in order to predict ONFH after RT.

Background De novo donor-specific HLA antibody (DSA) and antibody-mediated rejection (ABMR) are strongly associated with late allograft loss in renal transplant recipients. However, the impact of therapeutic intervention with the current treatment options for ABMR remains unclear. This study aimed to elucidate the efficacy of treatment for ABMR. Methods Sixty-seven patients who had de novo DSAs underwent diagnostic biopsy for ABMR, and these patients were classified into 3 groups: ABMR-free group (n = 40), clinical ABMR group (n = 15), and subclinical ABMR group (n = 12). The ABMR-positive groups were treated mainly with double-filtration plasmapheresis followed by rituximab and corticosteroid pulse. The patient characteristics and graft outcomes were compared between groups. Results The clinical and subclinical ABMR groups were younger and had a higher number and mean fluorescence intensity (MFI) of de novo DSAs than the ABMR-free group. The graft survival in the clinical ABMR group was significantly lower than that in the ABMR-free group, but the subclinical ABMR group had a surprisingly good graft survival rate compared to the ABMR-free group (43.3% vs 100% vs 94.2% 5 years after diagnostic biopsy in the clinical ABMR, subclinical ABMR, and ABMR-free groups, respectively, P Conclusions Our findings indicated that early therapeutic intervention for patients with de novo DSAs may improve graft survival.

To evaluate the surgical outcomes of parathyroidectomy (PTx) for secondary hyperparathyroidism (SHPT) resistant to calcimimetic treatment, we retrospectively studied 187 patients with SHPT who had no history of calcimimetic treatment (NCMT group) and 186 patients with SHPT who were resistant to calcimimetic treatment (RCMT group). Success rate and operative time of PTx were compared among the two groups. Operative time was significantly longer in the RCMT group than in the NCMT group (180 vs. 158 min, P < 0.001), but the difference was attenuated after multivariate adjustment including the weight of the largest parathyroid gland. No significant differences were observed in success rate of PTx (90.9% vs. 91.4%, P = 1.000) between the two groups. In patients with SHPT who are resistant to calcimimetic treatment, operative time could be elongated but success rate of PTx remains unchanged. This article is protected by copyright. All rights reserved.

Complete parathyroidectomy (PTx) is essential during total PTx for secondary hyperparathyroidism (SHPT) to prevent recurrent and persistent hyperparathyroidism. Pre-operative imaging evaluations, including computed tomography (CT), ultrasonography (US), and Tc-99m sestamibi (MIBI) scans, are commonly performed. Between June 2009 and January 2016, 291 patients underwent PTx for SHPT after pre-operative evaluations involving CT, US, and MIBI scans, and the diagnostic accuracies of these imaging modalities for identifying the parathyroid glands were evaluated in 177 patients whose intact parathyroid hormone (PTH) levels were 9 ng/mL after PTx, and the diagnostic validities of the imaging modalities for the remnant parathyroid glands were evaluated. A combination of CT, US, and MIBI scans achieved the highest diagnostic accuracy (75%) for locating bilateral upper and lower parathyroid glands before initial PTx. The accuracies of CT, US, and MIBI scans with respect to locating remnant parathyroid glands before additional PTx were 100%, 28.6%, and 100%, respectively. A combination of CT, US, and MIBI scans is useful for initial PTx for SHPT, and CT and MIBI scans are useful imaging modalities for additional PTx procedures.

Everolimus (EVR) is often administered with cyclosporine A (CsA), according to an established protocol. Although the administration protocol of EVR with tacrolimus (TAC) has not been established, it has been clinically demonstrated that a higher dose of EVR is necessary when used in combination with TAC than with CsA. In this study, we aimed to determine the optimal dose of EVR administered with TAC to maintain a similar EVR level in the blood to that observed when EVR is administered with CsA. Between June 2009 and January 2016, 22 patients who underwent living donor kidney transplantation were enrolled in this study. Among them, 12 patients were administered steroids, basiliximab, CsA, and EVR (CsA + EVR group) and 10 were administered steroids, basiliximab, TAC, and EVR (TAC + EVR group). Blood samples were collected at different time points from patients in both CsA + EVR and TAC + EVR groups, after drug administration. The trough EVR level in both groups was maintained within 3–8 ng/mL during the perioperative period. The optimal EVR doses for both groups were estimated by using a population pharmacokinetic analysis. Overall, the optimal dose of EVR for the TAC + EVR group was 3.59-fold higher than that for the CsA + EVR group to maintain a similar trough level to that of the latter group. Thus, administration of a higher EVR dose is recommended when provided in combination with TAC than with CsA to prevent adverse events caused by under immunosuppression, that could lead to acute kidney rejection.

Chronic antibody-mediated rejection, caused by de novo donor-specific antibody (dnDSA) production, results in poor graft survival. To prevent dnDSA production, optimal blood levels of immunosuppressive drugs in living donor kidney transplant recipients were determined. A total of 772 recipients underwent living donor kidney transplantation between January 2008 and December 2017. Graft survival and risk factors for dnDSA production were investigated in 647 recipients. Optimal blood levels of tacrolimus (TAC) and extended-release TAC (TACER) were measured in recipients receiving steroids and mycophenolate mofetil, combined with TAC (n = 53) or TACER (n = 135). Receiver operating characteristic (ROC) curve analysis and comparisons between dnDSA-negative and dnDSA-positive recipients were carried out. The Kaplan-Meier method revealed significantly poor graft survival in dnDSA-positive recipients (P 0.001). Cox regression models indicated calcineurin inhibitor withdrawal as a significant risk for dnDSA production (P 0.001; hazard ratio 6.637; 95% confidence interval 2.667-6.517). Average trough levels of TAC and TACER in dnDSA-negative recipients were significantly higher than those in dnDSA-positive recipients (4.88 vs 3.69 ng TAC/ml, P = 0.023, and 4.60 vs 3.85 ng TACER/ml, P = 0.001). ROC curve analysis indicated 4.325 and 3.990 ng/ml as the best trough levels under TAC- and TACER-based regimens, respectively, to prevent dnDSA production (areas under the curve: 0.788 and 0.813, respectively). Maintenance of the trough levels of TAC 4.325 ng/ml and TACER 3.990 ng/ml may prevent dnDSA production.

Aneurysm formation is a potential complication of granulomatosis with polyangiitis (GPA), previously known as Wegener’s granulomatosis. It is a very rare complication, but immediate diagnosis and therapy should be performed because an aneurysm can be life-threatening if it ruptures. An accessory left gastric artery (ALGA) is also a rare variant gastric artery that may obtain its blood supply from the left hepatic artery and left gastric artery. We herein describe a 57-year-old Japanese man who was diagnosed with GPA complicated by aneurysm rupture in an ALGA. Emergency surgery was performed after failure of arterial coil embolization to interrupt blood flow in the ALGA. The patient underwent partial resection of the lesser omentum, which contained all aneurysms. During partial resection of the lesser omentum, both the left gastric artery and ALGA were ligated because they were thought to be feeders of the aneurysms. Postoperative recovery was uneventful; no bleeding or recurrence of the aneurysms occurred. Immediate diagnosis and therapy should be performed for patients with GPA with symptoms of vascular ischemia or aortitis. Endovascular intervention is the first-choice therapy especially for hemodynamically stable patients with ruptured aneurysms or aneurysms located on variant arteries, which may have multiple blood supplies. In the present case, although endovascular treatment failed, the approach described herein was helpful during open surgery.

A73 -year-old man underwent a sigmoidectomy for sigmoid colon cancer with liver metastasis. After the operation, he received CapeOX combined with bevacizumab therapy. After 6 courses, the liver metastasis was undetectable on computed tomography scans. After 15 courses, computed tomography revealed ascites, and chemotherapy was discontinued. Two months later, computed tomography revealed portal vein thrombosis. Owing to the chronic nature of the thrombosis, thrombolytic therapy was not initiated. However, preservation therapy using antiplatelet drugs for 1 month resolved the ascites and the thrombosis. The risk of serious thrombosis must be considered when using bevacizumab.