Hakan Sozen

Inducing tolerance to MHC-matched allogeneic islet grafts in diabetic NOD mice by simultaneous islet and bone marrow transplantation under nonirradiative and nonmyeloablative conditioning therapy.

Background. Human type 1 diabetes is associated with defects in the hematopoietic stem cells. Simultaneous donor islet and bone marrow transplantation may be an ideal therapeutic approach for inducing tolerance to islet allogeneic antigens and restoring self-tolerance to islet autoimmune antigens. Methods. Using a nonobese diabetic (NOD) mouse model of human type 1 diabetes, we investigated whether tolerance to MHC-matched allogeneic islet grafts from male nonobese diabetes-resistant (NOR) donors can be induced in female NOD recipients by simultaneous islet and bone marrow transplantation under fludarabine phosphate-based nonmyeloablative and irradiation-free conditioning therapy. Donor-specific chimerism in the peripheral blood of tolerant mice (n=7) was measured by semiquantitative polymerase chain reaction for a male-specific marker (SRY). Results. Donor-specific tolerance to NOR islet grafts was induced in all diabetic NOD mice after simultaneous islet and bone marrow transplantation and treated with fludarabine phosphate, cyclophosphamide, anti-mouse lymphocyte serum, and rapamycin. At 100 days and 200 days after transplantation, the average percentage of male NOR marker in DNA derived from the peripheral blood of NOD recipients that had long-term islet graft survival was over 10%. Conclusion. Our data suggest that this approach may induce donor-specific tolerance in clinical islet transplantation and living-related donor solid organ transplantation.

A substantial level of donor hematopoietic chimerism is required to protect donor-specific islet grafts in diabetic NOD mice.

Background. Mixed chimerism can induce tolerance to alloantigens and restore self-tolerance to autoantigens, thereby permitting islet transplantation. However, the minimal level of donor chimerism that is required to prevent islet allograft rejection and recurrence of autoimmune diabetes has not been established. Methods. We investigated whether allogeneic Balb/c donor chimerism can be induced in C57BL/6 mice, in prediabetic NOD mice, and in diabetic NOD mice after transplantation of a modest dose of bone marrow by using purine nucleoside analogue, fludarabine phosphate and cyclophosphamide conditioning therapy, followed by short-term anti-CD40 ligand monoclonal antibody and rapamycin posttransplant treatment. We also investigated whether the induced donor chimerism is sufficient to prevent the onset of diabetes in prediabetic NOD mice and protect donor islet grafts in diabetic NOD mice. Results. Allogeneic donor chimerism could be induced under the authors’ approach that is nonmyeloablative and radiation-free. Diabetes onset was prevented in chimeric prediabetic NOD mice. The induction of mixed chimerism protected donor-specific islet grafts in diabetic NOD mice. At 60 days after islet transplantation, all donor Balb/c islet grafts survived in diabetic NOD mice whose level of donor-derived lymphocytes was higher than 30% at the time of islet transplantation (n=8). In contrast, Balb/c islet grafts were rejected in five of seven diabetic NOD mice whose level was lower than 30%. Conclusions. Our data demonstrate that a donor lymphocyte chimerism (>30%) at the time of islet transplantation is required to protect donor-specific islet grafts, and indicate that a strictly non–irradiation-based protocol can be used to achieve this goal.

May-Thurner syndrome in renal transplantation.

renal insufficiency. Intraarticular corticosteroids may be considered in patients in whom other drugs may be dangerous and one or few joints are involved. Parenteral pulse corticosteroids may be considered otherwise. Correction of serum magnesium levels has been reported to associate with reduction of the number of pseudogout attacks (5, 6) and should be considered in patients with hypomagnesemia. Patients on tacrolimus therapy who present with acute arthritis should be investigated for serum magnesium levels, radiological chondrocalcinosis, and careful search of CPPD crystals in synovial fluid samples. Additionally, cultures of synovial fluid and also of blood and the site of any potential source of infection should not be neglected for cultures despite finding crystals in synovial fluid samples, as septic arthritis may also occasionally complicate crystalline arthritis. Prevention of factors that could lead to CPPD crystal deposition, such as hypomagnesemia, should be considered, and proper correction of magnesium deficiency can prevent further pseudogout attacks in magnesium-deficient patients (1, 6).

Protective Effect of Resveratrol, A Red Wine Constituent Polyphenol, on Rats Subjected to Portal Vein Thrombosis

This experimental study investigated the prophylactic effects of the antioxidant and antiaggregant compound resveratrol (R) on portal vein thrombosis (PVT) in rats. Thirty rats weighing 200- 250 g were distributed in 3 groups: Group A (n = 10) and underwent PVT+R, Group B (n = 10) PVT alone, and Group C (n = 10) were subjected to a sham operation. Group A rats received R (60 mg/d per naso-gastric tube) for 10 days before PVT. Concerning antioxidant status, statistically significant increases in both tissue and plasma levels of reduced glutathione (GSH) and decrease in malondialdehyde (MDA) levels were observed in the PVT+R group compared with the PVT group (P < .001 for all). Comparison of these parameters with those of the sham group revealed significantly higher tissue and plasma levels of GSH and low MDA levels among the sham-operated group when compared with to the PVT+R or PVT groups (P < .001 for all). Concerning the antiaggregant status, significant increases of c-AMP levels were detected in rats treated with R before experiencing PVT (P < .001). Cyclic AMP levels in the sham group were significantly higher than those of either the PVT or PVT+R groups (P < .001). One may advise patients undergoing liver transplantation and carrying certain cardiovascular disease risk factors to ingest foods containing R to minimize PVT.

An absent inferior vena cava in a pediatric renal transplant recipient

The patient, a 13-month-old female, was born with autosomal recessive polycystic kidney disease (ARPKD) and pulmonary hypoplasia. She had been on hemodialysis for the previous 6 months because of malignant hypertension. Subsequently, she required bilateral nephrectomies. In addition, she had already developed hepatic fibrosis with portal hypertension, esophageal varices, and persistent thrombocytopenia as expected in most patients with AR-PKD (1). She was evaluated for a combined cadaveric liver and kidney transplant. However, since her synthetic liver function was adequate and her portal hypertension stable, she was then considered for a living related kidney transplant. Her mother was found to be a suitable donor, having a 3-antigen HLA match. The patient underwent a living related kidney transplant on 17 September 1998. The operation proceeded normally until the distal aorta and proximal common iliac vessels were exposed; it then became evident that the inferior vena cava was absent (Figs. 1 and 2). After extensive dissection of the retroperitoneum, a small vessel (about 3 mm in diameter) was identified that appeared to be a branch of the left common iliac vein. With no other options for venous reconstruction, we used this small branch in an end-to-side anastomosis with the donor renal vein. The renal artery was then connected in an end-to-side fashion to the recipient’s aorta. The ureter was anastomosed to the bladder using the Leadbetter-Politano technique. Induction immunosuppression included methylprednisolone (2 mg/kg), Zenapax (daclizumab, the study drug for a research protocol; 1 mg/kg), and azathioprine (1.25 mg/kg), followed by cyclosporine on postoperative day 3. Postoperatively, her graft function progressively improved. Venous duplex studies confirmed the patency of the anastomosis. Her postoperative course was somewhat prolonged secondary to pulmonary care and nutritional requirements. She was discharged home on postoperative day 26 with a creatinine level of 0.2 mg/dL.

Resistance to the Induction of Mixed Chimerism in Spontaneously Diabetic NOD Mice Depends on the CD40/CD154 Pathway and Donor MHC Disparity

Abstract:  Blockade of CD40/CD154 pathway has proven effective in promoting the induction of allogeneic mixed chimerism. Using NOD mouse model of human type 1 diabetes, we investigated whether allogeneic mixed chimerism can be induced in prediabetic NOD mice and in spontaneously diabetic NOD mice under nonmyeloablative and irradiation‐free conditioning therapy and anti‐CD154 mAb as a short‐term posttransplant treatment. We found that spontaneously diabetic NOD mice are more resistant to the induction of allogeneic mixed chimerism than prediabetic NOD mice under our nonmyeloablative and irradiation‐free conditioning therapy. This alloresistance in spontaneously diabetic NOD mice is dependent on the CD40/CD154 pathway and donor MHC disparity.

OUTCOME OF RENAL TRANSPLANTATION IN CHILDREN WITH DIFFERENT ORIGINATED URINARY TRACT DYSFUNCTION: A SINGLE-CENTER EXPERIENCE: 657

Introduction: Renal transplantation in patients with urinary tract dysfunction (UTD) of various origins is a challenging issue in the field of pediatric transplantation. AIM: To evaluate patient and graft survivals as well as the risks of the surgery and immunosuppressive therapy pediatric patients of UTD at Gazi University, Transplantation Center. PATIENTS AND METHODS: Among 56 pediatric transplantation recipients since 1996, UTD was displayed in 7 (12,5%) pediatric recipients. Videourodynamic tests were performed to all patients preoperatively as well as postoperatively if required. The cause of urologic disorders were as follows; PUV (n=2), PUV+neurogenic bladder (n=2) meningiomyocele+neurogenic bladder (n=1), and right multicystic dysplastic kidney (MCDK)+PUV (n=2). Clean intermittent catheterization (CIC) was needed in three patients to empty the bladder. None of patients had pretransplantation augmentation. Only one patient whom has VUR+neurogenic bladder has augmentation operation during transplantation. Carrel Patch technique in cadaveric, standard technique in Living donors with continuous 6/0 7/0 Propylene suture (end to side RA/V to Ext IA/V, Abd aorta and IVC in small kids) were used for vascular anastomosis. Haberal’s corner saving suture technique were used with ureteral stenting for ureteroneocystostomy anastomosis. Three out of 7 patients received kidneys from cadaveric and 4 from living donors. All patients were received calcineurin-based triple immunosuppressive therapy. RESULTS: The mean age at transplantation was 10,7±3,8 years old ( 415 years old). The median follow-up after transplantation was 26 months (18 to 142 months). Three patients who have neurogenic urine bladder had recurrent symptomatic curable urinary tract infections. Three out of 7 recipients have BKVAN. One out of 3 grafts was lost due to BKAVA and other two have normal graft functions. None of the recipients had urine leak after transplantation. None of the grafts were lost due to UTD. Although, we lost one graft (nonUTD problem), remaining all 6 patients are doing well with mean creatinine 1,5 ±1,1 mg/dl (median 1,2 mg/dl). CONCLUSION: Renal transplantation is a safe and effective treatment option.. While surgery and follow-up is more complicated in such patients group, UTD and/or underlying urologic diseases should be followed up very closely than other transplantation patients.

EC-MPS MAY HAS LESS HEPATOTOXICITY AND GASTROINTESTINAL IN KIDNEY TRANSPLANT RECIPIENTS (SUMMARY OF THE SIDE EFFECTS AT POSTOPERATIVE FIRST 3 MONTHS); SINGLE CENTER EXPERIENCE: 652

Introduction: Mycophenolates (MPA) are the most frequently used immunosuppressive drugs in solid organ transplantation. Entericcoated mycophenolate sodium (EC-MPS) is a new formulation of mycophenolic acid that delivers the active moiety MPA, the same active moiety delivered by mycophenolate mofetil (MMF). Aim: Here we retrospectively analyzed data from patient charts at Gazi University Transplantation Center to assess and compare efficacy and adverse events of MMF and EC-MPS in first 3 months after transplantation. Material and Methods: Data collected from patients who received first kidney transplantation years between 2006-2009 in Gazi University Transplantation Center. Between these years, totally 83 kidney transplantations were performed. Twenty one out of 83 are pediatric, 62 out of 83 are adult recipient. Eighty out of 83 recipients enrolled for this study. There were 52 de novo MMF (group A), and 28 EC-MPS (group B) patients in each group. In group A, mean age was 32,4 ±14,6 years old. Twenty three of the recipients were female and 29 of were male. Transplantations were performed from deceased donor in 29 and from living donor in 23. In group B, mean age was 29,1 ±13,5 years old. Twelve of recipients were female and 16 were male. Transplantations were performed from deceased donor in 18 and from living donor in 10. Immunosuppressive protocol consists of calsineurin based triple regimen and Basiliximab induction (only for cadavers, second or more transplantation, high PRA). All recipients received preoperatively single dose of either MMF 1000 mg or ECMPS 720 mg in living transplantation. After transplantation, from DO, all patients received either MMF 1000 mg b.i.d. or EC-MPS 720 mg b.i.d. Results: In group A, we have not seen any side effect of MMF in 42% (n=22) recipients during postoperative first 3 months. Fifty six percent of recipients had following side effects; gastrointestinal 23%, bone marrow 23% and hepatotoxicity 11%. Majority of the GISE is diarrhea (n=10), and dyspepsia (n=2) follows. Majority of BMSE is leukopenia (n=9), and pansitopenia (n=2), anemia (n=1) follows. Side effects have ceased by stopping MMF in 11 patients, by reducing the drugs in 11 patients and by converting in 7 patients. In group B, we have not seen any side effect of EC-MPS in 50% (n=14) recipients postoperative first 3 months. Fifty percent of recipients had following side effects; bone marrow 25%, gastrointestinal 21,5% and hepatotoxicity 3,5%. Majority of the GISE is diarrhea (n=4) and dyspepsia (n=2), floating (n=1). Majority of BMSE is leukopenia (n=6), and pansitopenia (n=1) follows. Side effects have ceased by stopping EC-MPS in 4 patients, by reducing the dose in 7 patients and by converting in 5 patients. We have not seen any statistical differences between two groups concerning side effects (p> 0,5) within 3 months after transplantation. Conclusion: EC-MPS and MMF demonstrated therapeutic equivalence in de novo renal transplant patients. EC-MPS has significantly less hepatotoxicity, and better GI side effect.