Causes of Ineligibility for Recipients in Living Kidney Transplantation.

BACKGROUND: Even if a living donor candidate exists, there are some cases that do not result in kidney transplantation (KTx) due to problems on the recipient side. The aim of this study was to clarify causes of ineligibility for KTx in these cases, so as to make RTx more applicable for patients. METHODS: We targeted 470 patients with end-stage renal disease who applied for the primary kidney KTx from 2010 to 2012. Then we selected those who were not applicable for KTx and investigated recipient causes of ineligibility for KTx or not receiving KTx. RESULTS: The average age of recipients was 47.6 ± 12.9 (7-82) years. A majority of the 470 patients were male (n = 305, 64.9%). Two hundred ninety-seven patients intended to receive a living donor KTx and the others hoped for a deceased donor KTx. Of the 297 patients, 207 (70.0%) underwent KTx and 9 (1.9%) were being prepared for KTx at the time of the survey. Eighty-three patients (27.9%) did not receive a living KTx, with 59 of these due to recipient-related problems and 30 due to donor-related problems. We further classified the reasons for these 59 recipients not undergoing KTx as follows: (1) unclear reasons (35.6%); (2) insufficient intention to receive transplant (13.6%); (3) heart disease (10.2%); (4) malignancy (8.5%); (5) immunologic risks (5.1%); (6) death during the waiting period (5.1%); (7) cerebrovascular events (5.1%); (8) cardiovascular problems (5.1%); (9) psychiatric disorders (3.4%); and (10) infections (3.4%). CONCLUSION: Nearly 50% of the reasons for ineligibility as a recipient were related to their intention to receive KTx, with 94.9% of the nontransplanted cases due to nonimmunologic reasons. Thanks to the recent advances in immunosuppressive therapy, there were only 3 patients who could not undergo KTx due to immunologic risks. Based on these results, transplant surgeons should not only emphasize physical evaluation but should also pay careful attention to the recipient's intention to receive KTx.

Influence of Long-term Dialysis on the Outcome of Kidney Transplantation: A Single-Center Study.

AIM: We investigated clinical outcomes of patients in Japan with a history of long-term dialysis treatment. METHODS: We conducted 1171 kidney transplantations between 2000 and 2015. Sixty of the patients had undergone dialysis therapy for >20 years before the transplantation. We compared graft and patient survivals between the recipients with >20 years of dialysis (long dialysis group [LGD]) and those with <20 years (control group [CG]) in a case-control study, in which sex and age of both donors and recipients, ABO compatibility, and calendar year of transplantation were matched. RESULTS: Average age of LDG was 52.8 ± 8.9 years, and that of CG was 54.2 ± 12.6 (P > .05). Durations of dialysis were 25.4 ± 1.57 vs 5.8 ± 5.8 years, respectively (P < .05). The graft survival rates were 91.6%, 89.9%, and 81.8% at 3, 5, and 10 years in LDG vs 90.71%, 84.8%, and 78.3% in CG, respectively (P > .05). The patient survival rates were 96.6%, 93.2%, and 88.6% in LDG vs 94.5%, 91.0%, and 83.9%, respectively (P > .05). There was no significant difference in mean estimated glomerular filtration rates for post-transplant 10 years between them. CONCLUSION: LDG showed satisfying clinical outcomes comparable to those of CG both in graft and patient survivals and renal function.

Development of novel treatment with a bioabsorbable esophageal patch for benign esophageal stricture.

Using a large animal model, we examined whether circumferential stricture after esophageal endoscopic submucosal dissection (ESD) can be treated by grafting a bioabsorbable esophageal patch. Circumferential ESD was performed on the thoracic esophagus in pigs (n = 6) to create a stricture, for which one of the following interventions was performed: (1) the stricture site was longitudinally incised, and an artificial esophageal wall (AEW) was grafted after placing a bioabsorbable stent (AEW patch group, n = 3); (2) endoscopic balloon dilation (EBD) was performed every other week after stricture development (EBD group, n = 3). In both groups, esophageal fluoroscopy was performed 8 weeks after the interventions, and the esophagus was excised for histological examination of the patched site. In the AEW patch group, esophageal fluoroscopy revealed favorable passage through the patched site. Histologically, the mucosal epithelium and lamina propria had regenerated as in the normal area. In the EBD group, the circumferential stricture site showed marked thickening, and there were hypertrophic scars associated with epithelial defects on the luminal surface. Histologically, defects of the mucosal epithelium and full-thickness proliferation of connective tissue were observed. AEW patch grafting was suggested to be a potentially novel treatment strategy for post-ESD esophageal circumferential stricture.

Negative impact of underlying non-insulin-dependent diabetes mellitus nephropathy on long-term allograft survival in kidney transplantation: a 10-year analysis from a single center.

INTRODUCTION: We analyzed the relationship between underlying nephropathy and long-term outcomes in kidney transplant recipients. METHODS: We retrospectively analyzed data from 678 patients who underwent kidney transplantation (KTx) between 1998 and 2011. Recipients with 13 major nephropathies were evaluated for graft and patient survival, and causes of graft loss. RESULTS: The best 10-year graft survival rates (100%) were in the patients with autosomal-dominant polycystic kidney disease, preeclampsia, Alport syndrome, and purpura nephritis. The worst rate (50.8%) was in patients with non-insulin-dependent diabetes mellitus nephropathy (NIDDMN; P = .039). Causes of graft-loss in the NIDDM patients included chronic rejection (6 cases), acute rejection (3 cases), infection (2 cases), and cardiovascular event (2 cases). Significant risk factors for graft loss were donor age (P < .01) and NIDDMN (P < .01). CONCLUSION: Underlying NIDDMN before KTx was a significant risk factor for long-term graft function. Immunologic factors and nonimmunologic factors influenced the long-term outcomes in patients with underlying NIDDMN.

Long-term impact of hypertension on renal allografts.

OBJECTIVE: We assessed the impact of hypertension on renal transplant function and survival in the past decade after introduction of mycophenolate mofetil and rituximab. METHODS: We examined the 184 patients who underwent renal transplantation from March 1982 to September 1999 and presented at our outpatient clinic from 2001 to 2011. They were divided into group 1 with mean systolic blood pressure (mSBP) >130 mm Hg and Group 2 with mSBP <130 mm Hg. We compared mean serum creatinine (sCr) levels for 9 years and 12-year actuarial graft survival rates. Risk factors for graft survival were assessed by Cox regression analysis. RESULTS: There were 75 group 1 and 109 group 2 recipients. The mean sCr level of group 1 was 1.59 ± 0.12 mg/dL and that of group 2 1.54 ± 0.10 mg/dL (P < .0001). Of note was that mean sCr levels of group 1 started to increase about 3 years after transplantation. Although 5-year graft survival rates of both groups were 100%, 9- and 12-year rates among group 1 were 97.3% and 90.5%, respectively, whereas among group 2 they were 99.1% and 98.1%, respectively (P = .0195). Cox univariate and multivariate analyses showed mean SBP to be the only significant risk factor for graft survival (P < .05). CONCLUSIONS: We concluded that the hypertensive group showed deteriorating renal function from around 3 years after transplantation that lowered graft survival afterward, resulting in a clear distinction from the nonhypertensive group at around 10 years after transplantation. Mean SBP was a significant risk factor for graft survival. Hypertension may be a surrogate for a poor renal graft prognosis in the long run.

Renal transplantation in patients with human T-cell lymphotropic virus type 1.

BACKGROUND: Renal transplantation (RTx) in carriers of human T-cell lymphotropic virus type 1 (HTLV-1) has a risk of developing overt leukemia upon immunosuppression. Although there have been a few reports of such cases, it is unclear HTLV-1 carrier if patients on the modern immunosuppressants would develop HTLV-1-associated myelopathy or adult T-cell leukemia lymphoma. METHODS: We retrospectively reviewed the clinical outcomes of RTx in nine HTLV-1 carriers to assess a risk of developing leukemia from 2002 to 2011 using immunosuppression with a calcineurin inhibitor, mycophenolate mofetil (MMF), and steroid. The anti-CD25 monoclonal antibody basiliximab was used for induction. In two cases of ABO-incompatible RTx, the rituximab was also administered before RTx. RESULTS: The ratio of male to female subjects was 2 to 7 with an overall mean recipient age of 54.3 ± 8.1 years. We prescribed cyclosporine (n = 5) or tacrolimus (n = 4). There was only one graft loss due to the death caused by aspiration pneumonia with a functioning graft. No one developed overt leukemia with combined treatment with MMF, basiliximab and rituximab. CONCLUSION: We concluded that RTx in HTLV-1 carriers could be performed using a modern immunosuppressive regimen, without the risk of developing leukemia.

Overcoming memory T-cell responses for induction of delayed tolerance in nonhuman primates.

The presence of alloreactive memory T cells is a major barrier for induction of tolerance in primates. In theory, delaying conditioning for tolerance induction until after organ transplantation could further decrease the efficacy of the regimen, since preexisting alloreactive memory T cells might be stimulated by the transplanted organ. Here, we show that such "delayed tolerance" can be induced in nonhuman primates through the mixed chimerism approach, if specific modifications to overcome/avoid donor-specific memory T-cell responses are provided. These modifications include adequate depletion of CD8+ memory T cells and timing of donor bone marrow administration to minimize levels of proinflammatory cytokines. Using this modified approach, mixed chimerism was induced successfully in 11 of 13 recipients of previously placed renal allografts and long-term survival without immunosuppression could be achieved in at least 6 of these 11 animals.

Hand-assisted laparoscopic splenectomy in ABO-incompatible kidney transplant recipients.

OBJECTIVE: We perform living-related ABO-incompatible kidney transplantations to alleviate the organ shortage in our country. Splenectomy has been performed routinely in these recipients, although its clinical significance remains controversial. In this study, we have reported our experience with a hand-assisted laparoscopic splenectomy (HALS) technique. METHODS: Between April 2000 and December 2006, 50 patients (23 males) underwent ABO-incompatible kidney transplantation with HALS. The mean age and weight of the recipients were 44 +/- 13 years and 56 +/- 12 kg, respectively. All patients underwent preoperative plasmapheresis to reduce isoagglutinin (A and/or B antibody). In 6/50 patients, a hand-assisted device was placed through a peritoneal window in the right lower abdominal skin incision for kidney engraftment. In the remaining 44 patients, a 6-cm upper midline or periumbilical midline incision was made for the hand-assisted device in the lateral position. RESULTS: An ABO-incompatible procedure was completed successfully in all cases. The average HALS time was 118 +/- 42 minutes, with an average pneumoperitoneum time of 79 +/- 40 minutes and average blood loss of 48 +/- 81 g. There were two conversions to open splenectomy because of intraoperative bleeding and suspected pneumothorax. Two other cases required relaparotomy because of hematoma and perforation of the ileum. Successfully operations were achieved through the previous periumbilical incision. CONCLUSIONS: Although meticulous, rigorous surgical technique is essential, HALS is safe and feasible for recipients of ABO-incompatible grafts with tissue weakness and a bleeding tendency because of renal failure and preoperative plasmapheresis.

Depletion of CD8 memory T cells for induction of tolerance of a previously transplanted kidney allograft.

Heterologous immunologic memory has been considered a potent barrier to tolerance induction in primates. Induction of such tolerance for a previously transplanted organ may be more difficult, because specific memory cells can be induced and activated by a transplanted organ. In the current study, we attempted to induce tolerance to a previously transplanted kidney allograft in nonhuman primates. The conditioning regimen consisted of low dose total body irradiation, thymic irradiation, antithymocyte globulin, and anti-CD154 antibody followed by a brief course of a calcineurin inhibitor. This regimen had been shown to induce mixed chimerism and allograft tolerance when kidney transplantation (KTx) and donor bone marrow transplantation (DBMT) were simultaneously performed. However, the same regimen failed to induce mixed chimerism when delayed DBMT was performed after KTx. We found that significant levels of memory T cells remained after conditioning, despite effective depletion of naïve T cells. By adding humanized anti-CD8 monoclonal antibody (cM-T807), CD8 memory T cells were effectively depleted and these recipients successfully achieved mixed chimerism and tolerance. The current studies provide 'proof of principle' that the mixed chimerism approach can induce renal allograft tolerance, even late after organ transplantation if memory T-cell function is adequately controlled.

Improved outcomes of renal transplantation from cardiac death donors: a 30-year single center experience.

Outcomes of renal transplantation from donation after cardiac death (DCD) donors over 30 years were analyzed. Between 1975 and 2004, 256 renal transplantations from DCD donors were performed. The recipients were divided into four groups according to a time period as follows: 1975-1979 (Group 1; n = 18), 1980-1989 (Group 2; n = 81), 1990-1999 (Group 3; n = 84) and 2000-2004 (Group 4; n = 73). Of the 256 transplanted kidneys from DCD donors, 38 (15%) functioned immediately after transplantation. The incidence of delayed graft function (DGF) was 72%. Warm ischemic time and total ischemic time were 7.4 +/- 9.4 min and 11.9 +/- 5.6 h, respectively. The overall graft survival rates at 1, 5 and 10 years were 80%, 72% and 53%, respectively. Graft survival rates in each group have continually improved over time (5-year graft survival; 23% vs. 64% vs. 74% vs. 91%, respectively). However, there was no significant difference in graft survival rates between the groups of patients who survived with a functioning graft for more than 1 year. A multivariate Cox regression analysis showed acute rejection and donor age to be independently associated with graft outcome. DCD donors are a valuable source of kidneys for transplantation with promising long-term outcomes.

Effect of mechanical stress imposition on co-culture of hepatic parenchymal and nonparenchymal cells: possibility of stimulating production of regenerating factor.

The effect of mechanical stress generated within a three-dimensional bioreactor on the co-culture of hepatic parenchymal cells (PC) and hepatic nonparenchymal cells (NPC) was assessed to develop a bioartificial liver that can produce factors accelerating liver regeneration. A rotating radial flow bioreactor was used to provide mechanical stress to a co-culture of PC and NPC that were isolated from rats. They were co-cultured in the reactor under static or dynamic conditions. Albumin, interleukin-6 (IL-6), hepatocyte growth factor (HGF), and lactate dehydrogenase (LDH) were measured at intervals. Electron microscopy was also performed. LDH was not significantly different between the static and mechanical stress-loaded cultures, while albumin and interleukin-6 levels were higher in the latter at all sampling times. Only the co-cultures loaded with mechanical stress produced HGF in the early stage of culture (hours 3 and 6). Histologically, the cells retained their structure when cultured under dynamic conditions. These results suggested that an appropriate level of mechanical stress enabled co-cultures of PC and NPC to produce IL-6, HGF, and other factors that accelerate liver regeneration.

Comparative study of clinical outcome in kidney transplantation between early steroid withdrawal protocol using basiliximab, calcineurin inhibitor, and mycophenolate mofetil and triple regimen consisting of calcineurin inhibitor, mycophenolate mofetil, and steroid.

AIMS: Effect of early steroid withdrawal protocol using basiliximab in kidney transplantation (KTx) on the clinical outcomes was investigated as compared with triple regimen. METHODS: Kidney transplant patients in group 1 (n = 62) were treated with 8 mg/kg of cyclosporine (CsA), 2000 mg of MMF, two bolus IV injections of 20 mg of basiliximab and 500 mg of methylprednisolone (MP) rapidly tapered and withdrawn at 14 postoperative days (POD). Group 2 (n = 56) was treated with same dose of CsA and MMF, and 250 mg of MP tapered and continued. Acute rejection (AR) episodes were treated with MP pulse therapy followed by muromonab CD3 (OKT3) in case of steroid-resistant rejection. RESULTS: In 46 of 62 cases (74.2%) in group 1, steroid was successfully withdrawn at 13.7 +/- 1.7 POD. Graft survival at 3, 6, and 12 months in group 1 was 100%, 100%, and 98.4% (one death with functioning graft), and 100%, 98.2%, and 96.4% in group 2, respectively. The incidence of AR was 12.9% for group 1 and 42.9% for group 2, among which 21 cases in group 2 were treated with ALG or OKT3; no patient needed ALG or OKT3 in group 1. Fifteen cases in group 1 and 13 cases in group 2 developed CMV antigenemia, among which febrile episode was exhibited in 3 cases (4.8%) in group 1 and 5 cases (8.9%) in group 2. CONCLUSIONS: Early steroid withdrawal protocol using basiliximab is promising for reducing the incidence of AR (especially steroid-resistant rejection), CMV diseases, and steroid-related complications.

Cyclosporine-sparing effect of basiliximab in renal transplant recipients with mycophenolate mofetil.

UNLABELLED: Basiliximab added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early steroid withdrawal in renal transplantation. Furthermore, the cyclosporine-sparing effects between groups with and without basiliximab induction therapy were compared. PATIENTS: Between September 2001 and June 2003, 90 patients underwent renal transplants with cyclosporine-based immunosuppression, namely, cyclosporine, mycophenolate mofetil, and methylprednisolone, (group 1; n = 25). During the latter half of the study basiliximab was administered during the induction phase (group 2; n = 65). In group 2, steroids were completely withdrawn on postoperative day 14 in 57 patients. RESULTS: The incidence of acute rejection was significantly higher among group 1 patients (P = .005). The incidence of steroid-resistant rejection in group 1 patients was significantly higher (P = .025). At each time point cyclosporine levels in group 1 patients were significantly higher (P < .01). The incidence of infection was comparable between the groups. Patient and graft survival rates in group 1 were 100% and 100%; in group 2, they were 99% and 99%, respectively. In group 2, steroids were discontinued in 57 patients with permanent withdrawal achieved in 32 patients (56%). CONCLUSION: The use of basiliximab, together with mycophenolate mofetil allowed for a significant reduction in the cyclosporine dose without increasing the risk of acute rejection. Although further follow-up is necessary to confirm the effect, this regimen may attenuate cyclosporine nephrotoxicity thereby affecting the long-term outcomes of renal transplantation.

Effect of continuous application of shear stress on liver tissue: continuous application of appropriate shear stress has advantage in protection of liver tissue.

Rapid blood flow changes occur in the liver following a massive resection or in the grafted liver following transplantation, under which shear stress (SS) change induced by the flow change may determine the postoperative results. We observed changes in liver tissue structure and liver-specific function, and consequently assessed SS effect. The cultured liver tissue exposed to continuous application of moderate SS was shown to express and maintain a long-term liver-specific function. There was also evidence showing that destruction of the liver structure was inhibited. However, the cultured liver tissue not exposed to SS or exposed to high SS was shown to lose liver-specific function soon after expression. The liver structure was destroyed in the early stage of incubation. These results suggested that continuous application of appropriate SS has advantages over other types of stresses to protect liver tissue.

Atypical alkaline phosphatase isozymes in serum and urine of patients with renal failure.

BACKGROUND: Alkaline phosphatases (ALPs) originating from different organs are frequently detected in the serum and urine of patients with renal failure. METHODS: We investigated the characteristics of ALPs in the serum and urine of 108 patients with chronic renal failure (CRF) and of 106 healthy control subjects. RESULTS: In polyacrylamide gel electrophoresis, three atypical ALP bands in serum of patients were designated as atypical-s1, -s2 and -s3, respectively. In contrast, five atypical bands (u1, u2, u3, u4 and u5) were detected in the urine of patients. The atypical ALPs were electrophoretically isolated and assayed to determine their biochemical properties, i.e., neuraminidase sensitivity, heat stability, reactivity to anti-intestinal or anti-tissue nonspecific ALP antibodies, molecular sizes and sugar chain heterogeneities. From these results, we found that atypical-s1 and -s2 were the intestinal-type ALP, while s3 was the tissue-unspecific type ALP. Atypical-u1, -u2 and -u3 were high-molecular type ALPs, which we suggested as the ones that originated from the intestine. Atypical-u4, a tissue-unspecific type ALP, was detected with considerable frequency in the urine of patients. In patients with CRF, the appearance of these atypical ALPs was accompanied by a deterioration of the creatinine clearance. CONCLUSIONS: The appearance of atypical ALPs in the serum and urine of patients with CRF may be a useful marker for renal disease.

Expression of pyrimidine 5'-nucleotidase subclass I during erythrocyte maturation in rats.

The subclass I enzyme of rat pyrimidine 5'-nucleotidase (P5N-I), which preferentially hydrolyzes (deoxy)CMP and UMP, is distributed specifically in red blood cells (RBCs), and its activity increases approximately six-fold as compared to the control value after erythropoietic induction by phenylhydrazine administration. In this study, we detected rat P5N-I protein by using antibodies against the chicken P5N-I enzyme. The molecular mass of rat P5N-I was approximately 37 kDa, as estimated by gel filtration chromatography and Western blot analysis. The pI value of the enzyme was approximately 5.7. This protein band was detected only in RBC lysate extract, i.e., not in cytosol from the erythropoietic spleen. Protein mass of the P5N-I enzyme, estimated by immunoblot analysis, was increased in proportion to the enzyme activity after erythropoietic induction in rats. No phosphorylation of the enzyme protein was detected by immunoblot analysis with anti-phosphoserine or anti-phosphotyrosine antibody. In conclusion, these findings indicate that the rat P5N-I enzyme is expressed specifically in reticulocytes and may therefore be essential in the maturation process of rat erythrocytes.