A case of recurrent type 1 diabetes mellitus with insulitis of transplanted pancreas in simultaneous pancreas-kidney transplantation from cardiac death donor.

AIMS/HYPOTHESIS: A 41-year-old woman undergoing simultaneous pancreas-kidney transplantation from an HLA-mismatched cardiac death donor abruptly developed overt hyperglycaemia under standard immunosuppressive therapy at 48 months after transplantation. Unexpectedly, we found insulitis in the transplanted pancreas and characterised the insulitis. METHODS: Pancreas graft biopsies were performed 3 years before and after the development of hyperglycaemia and the specimens were examined histologically. RESULTS: Insulitis was absent in the first biopsy, although oxidative DNA changes revealed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining were diffusely present both in islet cells and exocrine cells. No Ki67-positive proliferating cells were seen in the islets. Anti-glutamic acid decarboxylase antibody was undetectable 6 months earlier but increased to 6.3 U/l at the development of hyperglycaemia. The level of anti-insulinoma-associated protein 2 antibody was 18.5 U/l. Insulin secretion was severely suppressed and insulin therapy was resumed. In the second biopsy, although acute allograft rejection was minimal, insulin-positive beta cells were markedly reduced, and glucagon-positive alpha cells predominated. CD3-positive T lymphocytes, CD8-positive cytotoxic T lymphocytes and CD68-positive macrophages infiltrated around and into islets. The infiltrating cells expressed Fas ligand as well as granzyme B. More than 80% of islets were affected by insulitis. 8-OHdG-positive cells were also present in islets and exocrine tissue. The percentage of Ki67-positive cells in total islet cells was 1.5%. There were no TUNEL-positive apoptotic cells in the islet cells. CONCLUSIONS/INTERPRETATION: The histological features of insulitis in transplanted pancreas were consistent with common type 1 diabetes mellitus, but the clinical course of the recurrence appeared to be more rapid.

Living donor kidney transplantation preceding pancreas transplantation reduces mortality in type 1 diabetics with end-stage renal disease.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) is a definitive treatment for type 1 diabetics with end-stage renal disease (ESRD). Because of the shortage of deceased donors in Japan, the mortality rate during the waiting period is high. We evaluated mortality risk in patients with type 1 diabetes waiting for SPK, and the benefit of living-donor kidney transplantation (LDK) preceding pancreas transplantation, which may reduce mortality in patients awaiting SPK. METHODS: This retrospective study included 71 patients with type 1 diabetes. Twenty-six patients underwent SPK, 15 underwent LDK, and 30 were waiting for SPK. Their cumulative patient and graft survival rates were retrospectively evaluated. Risk factors contributing to mortality in patients with type 1 diabetes awaiting SPK were evaluated with the use of a Cox proportional hazards model. RESULTS: The 5-year cumulative patient survival rates in the SPK and LDK groups were 100% and 93.3%, respectively (P = .19), and 5-year kidney graft survival rates were 95.7% and 100% (P = .46), respectively. The cumulative survival rate in patients awaiting SPK was 77.7% at 5 years after registration. Duration of dialysis was the only factor significantly associated with patient and graft survivals according to both univariate and multivariate analyses. CONCLUSIONS: Patient and graft survival rates were similar in the SPK and LDK groups, but the survival rate of patients awaiting SPK decreased over time. Duration of dialysis was an independent risk factor for patient and graft survival. LDK preceding pancreas transplantation may be an effective therapeutic option for patients with type 1 diabetes and ESRD.

Outcome of renal transplantation in patients with type 2 diabetic nephropathy: a single-center experience.

BACKGROUND: Renal transplantation has been established as a treatment for end-stage renal disease (ESRD) due to diabetic nephropathy. However, few studies have focused on the outcome after renal transplantation in patients with ESRD and type 2 diabetic nephropathy. To investigate the effect of renal transplantation on ESRD with type 2 diabetic nephropathy, we retrospectively analyzed patients who received renal transplantation at our facility. This study aimed to compare the outcome of renal transplantation for type 2 diabetic nephropathy with that for nondiabetic nephropathy. METHODS: We studied 290 adult patients, including 65 with type 2 diabetic nephropathy (DM group) and 225 with nondiabetic nephropathy (NDM group), who underwent living-donor renal transplantation at our facility from February 2008 to March 2013. We compared the 2 groups retrospectively. RESULTS: In the DM and NDM groups, the 5-year patient survival rates were 96.6% and 98.7%, and the 5-year graft survival rates were 96.8% and 98.0%, respectively, with no significant differences between the groups. There were no significant differences in the rates of surgical complications, rejection, and infection. The cumulative incidence of postoperative cardiovascular events was higher in the DM group than in the NDM group (8.5% vs 0.49% at 5 years; P = .002). CONCLUSIONS: Patient and graft survival rates after renal transplantation for type 2 diabetic nephropathy are not inferior to those for recipients without diabetic nephropathy. Considering the poor prognosis of patients with diabetic nephropathy on dialysis, renal transplantation can provide significant benefits for these patients.

Effect of FR167653 on pancreatic ischemia-reperfusion injury in dogs.

BACKGROUND: The role of inflammatory cytokines is still unclear in ischemia-reperfusion injury of the pancreas. We investigated the effect of FR167653 (FR), a newly developed compound that is a potent suppressor of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha on ischemia-reperfusion injury of the isolated pancreatic tail in dogs. METHODS: The tail of the pancreas was subjected to ischemia for 90 minutes. During occlusion of the vascular inflow, the head of the pancreas was removed. A control group (n = 14) and an FR treatment group (n = 11) were evaluated for survival rate, tissue blood flow, arterial oxygen pressure (Pao(2)), serum amylase and lipase levels, glucose and insulin, liver enzymes, creatinine, IL-1beta mRNA in the peripheral blood, and histopathology. RESULTS: Six of the 14 control animals and 2 of the 11 FR-treated animals died. The FR treatment group showed lower amylase (P=.037) and lipase (P =.030) levels, lower IL-1beta mRNA expression (P =.033), and less pancreatic tissue damage (P =.041) than did the control group, but there was no remarkable change in endocrine function (P =.422). Pao(2) during the acute phase in the FR treatment group was maintained (P=.009), but pulmonary tissue was damaged. Results of biochemical and histologic examinations of the liver and kidneys were unremarkable. CONCLUSIONS: FR ameliorates ischemia-reperfusion injury of the pancreas and reduces the production of inflammatory cytokines that may contribute to secondary damage to distant organs.

Development of acquired cystic disease and adenocarcinoma of the kidney in glomerulonephritic chronic hemodialysis patients.

The fate of the contracted kidney in long-term hemodialysis patients was examined. Total kidney volume was measured by computer assisted tomography in 96 chronically hemodialyzed patients with chronic renal failure due to chronic glomerulonephritis. The presence of cysts and/or tumor in the renal parenchyma was evaluated. Kidney volume decreased progressively up to 3 years after the start of dialysis. However, after 4 years of dialysis, it then increased in a number of cases. Multiple cysts were found in 43.5% of patients on dialysis for less than 3 years and in 79.3% of patients who had been on dialysis for more than 3 years. They were found in 100% of those whose total kidney volume exceeded 50 ml despite more than 3 years dialysis. Bilateral nephrectomy was performed in 4 cases who had been dialyzed for more than 5 years and all showed acquired cystic disease of the kidney. Three out of 4 resected cases had adenocarcinoma and multiple adenomas in addition to acquired cystic disease of the kidneys. The other had intracystic epithelial hyperplasia. These results suggest that long-term hemodialysis is associated with a very high incidence of acquired cystic disease of the kidney. There is frequent enlargement of the contracted kidney, and a high incidence of renal adenocarcinoma in patients with glomerulonephritis leading to treatment with hemodialysis.

Three-phase bone scintigraphy and viability of vascularized bone grafts for mandibular reconstruction.

Three-phase bone scintigraphy was undertaken to check the anastomotic patency and monitor the viability of vascularized bone grafts. Ten consecutive patients who underwent vascularized bone grafting of the mandible were reviewed. A successful clinical outcome was achieved in 8 patients. The graft failed in 2 patients. In this series, 3-phase bone scintigraphy of radiolabeled (99m)Tc-methylene-diphosphonate was performed at 7 days, and at 1, 3, 6, and 12 months after reconstruction. Assessments made using 3-phase bone images were compared with the clinical findings. The clinical outcome of the cases presented in our series correlated extremely well with 3-phase bone images. Three-phase bone scintigraphy is a useful method for the assessment of patency and viability of vascularized bone grafts. The use of this method can be very helpful in assessing the anastomotic patency and viability of a graft which for clinical reasons is suspected of being non-viable.

Inhibitory effects of N,N'-diphenyl-p-phenylenediamine on the early stage of the enhanced hepatocarcinogenesis caused by coadministration of ethionine and a choline-deficient L-amino acid-defined diet in rats.

Effects of N,N'-diphenyl-p-phenylenediamine (DPPD), an antioxidant, on liver carcinogenesis caused by a choline-deficient L-amino acid-defined (CDAA) diet containing ethionine were studied in Fischer 344 rats. Male animals, 6 weeks old, were fed a CDAA diet, a choline-supplemented L-amino acid-defined (CSAA) diet or a CDAA diet containing 0.05% ethionine with or without 0.2% DPPD. Histological changes and lesions positive for gamma-glutamyltransferase (GGT) were analyzed 12 weeks after the beginning of the experiment. The levels of 8-hydroxyguanine (8-OHGua) in DNA and 2-thiobarbituric acid-reacting substances (TBARS) were measured as the parameters for cellular oxidative damage after 4 and 11 days of treatment. Expression of c-myc and c-Ha-ras was also investigated in relation to cell proliferation after 2, 4, 8 and 11 days. Histologically, development of diffuse fatty liver observed in rats fed a CDAA diet was inhibited, while massive oval cell proliferation and cholangiofibrosis resulted from the addition of ethionine with/without DPPD. The sizes but not numbers of GGT-positive lesions seen in the liver of rats fed a CDAA diet were increased and the levels of 8-OHGua formation and TBARS generation were also increased by the ethionine supplement. Both numbers and sizes of GGT-positive lesions were decreased and the level of TBARS, but not 8-OHGua, was decreased by adding DPPD. The increased expression of c-myc and c-Ha-ras detected in the liver of rats fed a CDAA diet was further increased by addition of ethionine and again reduced by DPPD. These results indicate that an antioxidant DPPD can inhibit the early stage of enhanced hepatocarcinogenesis caused by coadministration of ethionine and a CDAA diet, by blocking cellular oxidative damage as well as c-myc and c-Ha-ras expression.

[Possible bronchospasm after administration of vecuronium].

A 62 year-old female developed bronchospasm after intravenous vecuronium administration. Vecuronium is reported to have major advantages over pancuronium due to the lack of significant histamine-releasing activity and cardiovascular side effects. However, macular rash, systemic collapse and bronchospasm have been reported before. The patient received cholecystectomy under general anesthesia. She had a history of urticaria when she had had a intravenous pyelography and showed positive skin test to antibiotic, ceftizoxime. During induction with thiopental plus vecuronium and on addition of vecuronium, bronchospasm was induced within five minutes in each time. Both episodes of bronchospasms were relieved with intravenous aminophylline and methylprednisolone. During the operation arterial blood gas samples were taken twice and showed no abnormal findings. Further blood samples were taken for complement C3, C4, plasma IgE and white blood cell counts. Skin test to vecuronium was also performed. In spite of these data, the mechanism of bronchospasm remained obscure. Careful attention should be paid to the use of vecuronium, especially for the patient who showed allergic response to some drugs.

[Intra-arterial infusion chemotherapy for advanced uterine cancer before surgical treatment].

Three cases of advanced uterine cancer were treated by CDDP intra-arterial infusion chemotherapy before curative operation. In Case I (stage IVb, G2), chemotherapy was done by BOAI method before radical hysterectomy and by implantable reservoir system after operation. In Case II (IIIa, G1), modified radical hysterectomy could be performed after chemotherapy using an implantable reservoir system, though inoperable at first. In Case III (IVa, G1), the patient was given intra-uterine arterial infusion chemotherapy twice with BOAI method before radical hysterectomy. The results suggested that this treatment is effective for advanced uterine cancer, and further study of prognosis was considered necessary.

[A case of histological complete remission by preoperative intraarterial infusion chemotherapy].

We experienced a case of histological complete remission by preoperative intraarterial infusion chemotherapy in the treatment of histologically diagnosed endometrial cancer of well differentiated type. MRI demonstrated invasion of the myometrium to a depth of more than 1/2 and left partial parametrium. This patient was given intra-uterine arterial infusion chemotherapy twice (CDDP & ADM ia, CPA iv). Radical hysterectomy was done 3 weeks after intraarterial infusion chemotherapy. The extirpated uterus was histologically complete remission. Thus, in this case shows that intraarterial infusion chemotherapy is effective for neo-adjuvant chemotherapy of endometrial cancer.

[A case of stage IVb ovarian carcinoma successfully treated with intra-arterial infusion chemotherapy using implantable reservoir system].

A patient with liver metastasis from ovarian cancer was treated by intra-arterial infusion chemotherapy (well differentiated adenocarcinoma--CDDP 50 mg/body, ADR 30 mg/body, CPA 500 mg/body (iv)). After the chemotherapy, the metastatic tumor appeared remarkably smaller and could be resected successfully at the second reduction surgery. This patient is active 30 months after the first appearance and enjoying a favorable quality of life.

[Intra-arterial infusion chemotherapy for advanced endometrial cancer before surgical treatment].

Nine cases of advanced uterine body cancer (stage III: 8, stage IVa: 1) were treated by intra-arterial infusion chemotherapy before curative operation. This treatment produced primary tumors smaller than half sizes in eight cases. Necrotic changes were found in over two-thirds of the lesions in six cases. This chemotherapy enabled us to operate curatively in seven cases. After the operations, we performed various types of treatment including intra-arterial infusion chemotherapy. No evidences of disease have been found in four cases, but there is no significant difference between the groups receiving and not receiving the intra-arterial infusion chemotherapy (n = 16) in terms of survival rate of stage III. Further study of the prognosis is necessary.

Protocol biopsy findings in living donor kidney transplant patients treated with once-daily or twice-daily tacrolimus formulation.

BACKGROUND: Once-daily extended-release tacrolimus (Tac-QD) has been shown to have equivalent efficacy and safety to the twice-daily formulation (Tac-BID) in kidney transplant patients. However, detailed comparison of allograft pathology found on a protocol biopsy (PB) in Tac-QD- versus Tac-BID-based regimens has not been described. METHODS: We retrospectively investigated 119 de novo living donor kidney transplant patients treated with Tac-QD (n = 90) or Tac-BID (n = 29) and their 3- and 12-month PB results. Other immunosuppressive drugs administered included basiliximab, mycophenolate mofetil, and methylprednisolone. We evaluated daily doses and trough levels of Tac and serum creatinine levels, and compared pathologic findings. RESULTS: Daily doses were higher in the Tac-QD group, but trough levels and serum creatinine levels were comparable. On 3- and 12-month PB, the frequency of subclinical rejection was similar between the groups, whereas interstitial fibrosis and tubular atrophy (IF/TA) were less common in the Tac-QD group at 12 months (42.2% vs 20.6%, P = .04). Univariate and multivariate logistic regression analyses revealed that allograft rejection (borderline changes or higher) was associated with IF/TA (odds ratio 4.09, 95% confidence interval 1.76-10.10, P = .001). The Tac-QD-based regimen showed a trend toward the absence of IF/TA but it did not reach statistical significance. Tubular vacuolization and arteriolar hyaline changes were also comparable in the two groups. CONCLUSIONS: We found a trend toward milder IF/TA, but no significant differences in kidney allograft pathology in patients who were administered Tac-QD- versus Tac-BID-based regimens at 12 months. The effects of Tac-QD on chronic allograft injury must be studied by longer observation.

Early disappearance of urinary decoy cells in successfully treated polyomavirus BK nephropathy.

BACKGROUND: Polyomavirus BK nephropathy (BKVN) is an important infectious complication in kidney transplant patients. Regular screening using polymerase chain reaction for BK virus DNA in plasma and urinary cytology is effective for early diagnosis of BKVN. However, methods of follow-up and therapeutic targets are not well described. METHODS: Ten patients with BKVN who received biweekly urinary cytology and repeat biopsies after diagnosis were retrospectively studied. Histological remission of BKVN was determined when biopsy revealed negative SV40 large T-antigen (TAg) staining. Results of urinary cytology and repeat biopsy findings were compared. RESULTS: Urinary decoy cells disappeared in 8 of 10 patients 55 ± 25 (range 13-79) days after index biopsies. In those cases, allograft function was preserved and the final serum creatinine level was 2.14 ± 1.19 (0.80-4.55) mg/dL after 962 ± 393 (325-1563) days of follow-up. Two cases with persistent urinary decoy cells shedding lost their graft 195 and 362 days later. Amongst 29 repeat biopsies, there were 13 TAg-positive and 16 negative biopsies. In 12 of 13 TAg-positive biopsies (92%), urinary decoy cells were still positive, whereas at the same time in 15 TAg-negative biopsies, decoy cells had already disappeared (94%). CONCLUSIONS: Cytology testing is advantageous because of its cost effectiveness. Clearance of decoy cells from urine was closely related to histological remission of BKVN, and may possibly be a therapeutic target in BKVN.

Effect of cell permeable peptide of c-Jun NH2-terminal kinase inhibitor on the attenuation of renal ischemia-reperfusion injury in pigs.

The outcomes of organ transplantation have improved due to better immunosuppressive drugs, surgical techniques, and management of complications. However, ischemia-reperfusion injury remains a challenge affecting graft survival. In this study, we employed injection of a protein transduction domain (PTD) to inhibit the c-Jun NH2-terminal kinase (JNK) pathway thereby attenuating ischemia-reperfusion injury in a porcine model. The PTD-JNK inhibitor (JNKI) was administered into the renal artery, allowing it to be taken into various elements including vascular endothelial cells by endocytosis via the PTD. Serum creatinine and blood urea nitrogen concentrations were lower among PTD-JNKI than controls. In addition, renal tissue blood flow was maintained in the PTD-JNKI group, resulting in less tissue injury and fewer apoptotic cells. These results suggested that the PTD technique improved renal transplantation outcomes.

Impact of flow cytometry crossmatch B-cell positivity on living renal transplantation.

BACKGROUND: Various studies have reported poorer graft survival among individuals displaying T-cell-positive flow cytometry crossmatches (FCXM). Good outcomes have been observed in immunologically high-risk patients with the use of rituximab, plasmapheresis, and γ-globulin. Because the relevance of FCXM B-cell-positivity (BCXM (+)) alone remains controversial, we examined its impact on living donor renal transplantations. PATIENTS AND METHODS: We retrospectively studied 146 adult renal transplantation recipients from April 2007 to June 2012, dividing the patients into BCXM (+) (n = 31) versus BCXM (-) recipients (n = 115). We examined patient and graft survivals as well as rejection rates at 0 to 3, 3 to 12, and 12 to 24 months. We also determined the incidence of infectious diseases. We performed stepwise multivariate regression to identify risk factors contributing rejection episodes. RESULTS: One-year patient and graft survivals were 100% in both groups. The BCXM (-) group have a 16.8% rejection probability whereas the BCXM (+) group, 33.2% (P = .201). There were no significantly differences in the incidence of infectious diseases. Only the rate of a sensitizing history was an independent risk factor for a rejection episode. CONCLUSION: BCXM (+) showed only a tendency but not a significant impact on rejection episodes compared with BCXM (-); short-term graft survivals were similar.

Effect of milrinone on ischemia-reperfusion injury in the rat kidney.

BACKGROUND: Milrinone (MIL), a phosphodiesterase (PDE) 3 inhibitor, exhibits cardiotonic and angioectatic effects. Various PDE inhibitors have been shown to suppress inflammatory cytokines. In this study, we evaluated the angioectatic and anti-inflammatory cytokine effects of MIL on renal function after warm ischemia in a rat ischemia-reperfusion (I-R) injury model. MATERIALS AND METHODS: MIL or control solution was perfused from the left renal artery to the right kidney, and the left kidney was excised. The right renal artery, vein, and ureter were clamped and then released after 50 minutes to produce warm ischemia. We evaluated control (n = 7), MIL (n = 7), and sham operation (n = 7) groups for serum creatinine, blood urea nitrogen (BUN), blood flow, expression of tumor necrosis factor (TNF)-α mRNA, apoptosis index, and histological evidence of acute tubular necrosis. RESULTS: Serum creatinine and BUN concentrations peaked at 24 hours after reperfusion. MIL treatment significantly reduced serum creatinine (control group 1.27 ± 0.45 mg/dL vs MIL group 0.77 ± 0.19 mg/dL, P < .05; sham 0.35 ± 0.2 mg/dL) and BUN (control 67.6 ± 13.6 mg/dL vs MIL 51.0 ± 8.8 mg/dL, P < .05; sham 23.0 ± 4.2 mg/dL) levels at 24 hours. Thereafter, serum creatinine and BUN concentrations in the MIL group remained significantly lower compared with the control group for 120 hours (P < .05). MIL group exhibited significantly higher tissue blood flow, less acute tubular necrosis, lower expression of TNF-α mRNA in renal tissue, and lower apoptotic index (P < .05). CONCLUSIONS: MIL maintained renal tissue blood flow by its vasodilatory effect, suppressed expression of TNF-α mRNA by increasing intracellular cyclic adenosine monophosphate, and ultimately decreased tubular cell apoptosis, thus protecting renal function after warm I-R injury.

Living donor renal transplantation using grafts with multiple arteries procured by laparoscopic nephrectomy.

OBJECTIVE: Kidney grafts with multiple renal arteries (MRAs) are not uncommon, but they do make transplantation more difficult. Laparoscopic graft nephrectomy has become the standard; however, the safety and reliability must be maintained for both a donor and a recipient even in case of MRAs. This study evaluated the short-term outcomes of living donor renal transplant using grafts with MRAs procured by laparoscopic nephrectomy. PATIENTS AND METHODS: This study reviewed all living donor kidney transplantations performed from January 2008 to June 2009, which were divided into 3 groups according to the number of renal graft arteries. The serum creatinine level, warm ischemic time (WIT), rewarming time, total ischemic time (TIT), operative time, acute rejection episodes, and complications in each group were evaluated. RESULTS: The serum creatinine level showed no difference among the groups. Longer TIT was observed in the MRAs group, but WIT and rewarming time did not differ. The acute rejection rate was not different. There were no vessel complications in any donors and recipients. CONCLUSION: Harvesting kidney grafts with MRAs by laparoscopic nephrectomy requires a longer TIT; however, transplantation can be performed safely and reliably for both donors and recipients.

Histologic studies of islets of Langerhans in transplanted pancreata from marginal donors in Japan.

The serious shortage of brain-dead donors leads to the use of pancreata from marginal donors, including cardiac death in Japan. We studied the islet histology of pancreas graft biopsies to investigate the adequacy of using pancreata from marginal donors. Pancreas allograft biopsy was performed originally to diagnose acute rejection (Drachenberg grade I-III) at a mean of 6 months after transplantation. The percentage of beta cells showing oxidative DNA changes, replication, and apoptosis was investigated in 7 recipients of simultaneous pancreas-kidney transplantations with good graft function from marginal donors. Their causes of death were cerebrovascular with donor ages >44 years (n = 3), cardiac (n = 2), and cerebrovascular (n = 2). The percentage of beta cells per islet in the transplanted pancreas (71.9 +/- 3.3%) did not correlate with glycemic control or insulin secretion, but did correlated inversely with donor age (r = -0.81; P < .05). Oxidative DNA changes as revealed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining were diffusely present in islet cells as well as in the exocrine cells of the transplanted pancreas. The percentage of 8-OHdG-positive cells per pancreas (71.8 +/- 4.5%) did not correlate with glycemic levels, insulin secretion, donor age, or ischemic time. There were no Ki67-positive replicating cells or terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive apoptotic islet cells. Transplanted pancreata from marginal donors showed preserved beta cells and function despite diffuse oxidative changes.