Efficacy and Safety of Ultra-Low-Dose Valganciclovir Chemoprophylaxis for Cytomegalovirus Infection in High-Risk Kidney Transplantation Patients

IntroductionValganciclovir (VGCV) prophylaxis of 900 mg twice daily for 6 months is recommended to prevent cytomegalovirus (CMV) infection, which is a major cause of decreased graft and patient survival in kidney transplant recipients. However, recent studies have shown the efficacy of 900 mg once daily for 3 to 6 months. Maintaining VGCV compliance is difficult because of high drug costs and side effects, such as thrombocytopenia and leukopenia. Therefore, we studied the efficacy of ultra-low dose, short-duration VGCV (450 mg every other day for 3 months) in preventing CMV infection in ABO-incompatible (ABOiKT) and deceased donor kidney transplant (DDKT) recipients.MethodsWe retrospectively reviewed the medical records of all kidney transplant patients > 18 years old treated at Bong Seng Memorial Hospital from June 2009 to July 2016 who received ultra-low-dose VGCV prophylaxis (450 mg every other day for 3 months). The review included 74 CMV seropositive donor/seropositive recipient (D+/R+) ABOiKT and 78 CMV D+/R+DDKT recipients. The primary outcome was occurrence of CMV infection. Secondary outcomes were graft and patient survival and hematologic side effects.ResultsMean prophylaxis and follow-up were 3 and 98 months, respectively. CMV disease occurrence was significantly higher in DDKT than in ABOiKT (12 cases, 8.1%, vs 1 case, .7%, P < .01). There were no significant differences in patient survival rate, graft survival rate, or hematologic side effects between the groups.ConclusionUltra-low-dose VGCV prophylaxis to prevent CMV infection is effective in ABOiKT, but other treatment protocols are needed for DDKT patients.     

Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics

BACKGROUND: Preformed HLA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong patient waiting time for kidney transplantation. We hypothesized that rituximab (RTX) could reduce PRA via B-cell depletion. This initial study reports the safety, pharmacokinetics, and pharmacodynamics of RTX in patients with end-stage renal failure. METHODS: The study was an investigator-initiated single-dose, dose-escalation phase I trial of RTX in chronic dialysis patients (PRA >50%). It was approved by the Institutional Review Board and the Food and Drug Administration. Nine subjects were treated with a single dose of RTX (n=3 per group) at 50, 150, or 375 mg/m. Peripheral lymphocyte cell surface markers and HLA Ab levels (%PRA and titers) were tested using flow cytometry. RESULTS: There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7 degrees C) during infusion. At 2 days after RTX therapy, there was depletion of CD19 cells (pre-RTX 181+/-137 vs. post-RTX 12+/-5.6, P =0.006). In 2 (22%) of 9 subjects, there was no appreciable change in PRA. Among the other seven patients, one had a decrease in PRA from 87% to 51% with a concurrent decrease in fluorescence intensity; five patients had changes in histogram architecture suggesting loss of antibody specificity; and one patient had a fourfold decrease in PRA titer from 1:64 to 1:16 at 6 months after treatment. In addition, one of the seven patients converted a donor-specific crossmatch to negative and underwent a successful living donor kidney transplantation. CONCLUSIONS: RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.     

Comparison of Thymoglobulin and Grafalon as Induction Agents in Renal Transplantation: A Prospective Study

BackgroundInduction immunosuppression is used to reduce the incidence of acute rejection and prevent delayed graft function. The 2 rabbit anti-thymocyte globulins- thymoglobulin and Grafalon (ATG Fresenius) have been commonly used for induction immunosuppression and treatment of acute rejection in solid organ transplantation. There are very few studies comparing the efficacy and side effects of both the anti-thymocyte globulins therefore this prospective study comparing the 2 types of anti-thymocyte globulins would be of clinical interest.Patients and MethodsThis prospective single center study was conducted at Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, India from April 2019 to June 2020. Sixty-two ABO-compatible renal transplant recipients were included in the study. They were divided in 2 groups of 31 patients each. One group received thymoglobulin (3 mg/kg) and the second group received Grafalon (6 mg/kg). All patients were followed up for 12 months and the 2 groups were compared for incidence of rejections, infections, graft function, patient survival, and graft survival.ResultsThere was no significant difference in the incidence of rejections, infective episodes, graft function, posttransplant diabetes mellitus, graft survival and patient survival in thymoglobulin or Grafalon groups. The hematological parameters were similar in both groups at 7 days, 1 month, and 6 months of follow-up. The absolute lymphocyte count was significantly lower in the thymoglobulin group at 12 months posttransplant.ConclusionsThymoglobulin and Grafalon were found to be equivalent in terms of safety and efficacy in short term, with no difference in rejections, infections, graft survival, or patient survival.     

Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome

Background

We report a 7-year-old boy with high-degree steroid-dependent idiopathic nephrotic syndrome (SDNS) who went into remission with rituximab (RTX) maintenance therapy.

Case-Diagnosis/Treatment

Four months after this patient received his first RTX infusion, there was a progressive and sustained decrease of immunoglobulin (Ig)G and IgM levels. Thirteen months after the initiation of RTX therapy he was in sustained remission without any steroid or oral immunosuppressive therapy; however, B cell depletion was still present. At this time he developed a fulminant myocarditis due to enterovirus. Despite aggressive treatment and the administration of intravenous polyvalent immunoglobulins there was no clinical improvement. He successfully underwent heart transplant surgery.

Conclusions

We conclude that B cell depletion with RTX is efficacious in the treatment of paediatric SDNS but that it may be associated with severe infectious complications. Therefore, we recommend a close monitoring of Ig levels in children who have received RTX therapy and a supplementation with intravenous Ig as soon as the Ig levels fall below the lower limit of the normal range     

Long-Term Outcome of Renal Transplantation in Patients With Familial Mediterranean Fever Amyloidosis: A Single-Center Experience

IntroductionFamilial Mediterranean fever (FMF) is an autosomal-recessive disorder, affecting multiple organs. The AA type of amyloidosis is most common and serious complication cause nephropathy and end-stage renal disease (ESRD). Renal transplantation (RTX) remains treatment of choice for ESRD. We aimed to investigate long-term results of RTX in patients with FMF amyloidosis.Patients and MethodsWe compared the outcomes of 18 patients (12 men and 6 women) with FMF amyloidosis among 601 (2.9%) transplants with 200 control patients. Demographic data and gene analysis were evaluated.ResultsIn our study the 1-year graft and patient survivals were 94.44% and 100%, respectively. At 5 years after RTX, they were 94.73% and 88.88%, respectively, in the FMF group without difference from controls. Mean creatinine level at 1 and 5 years were 1.43 ± 0.54 and 1.73 ± 0.89, respectively. The results of MEFV mutation analyses were: M694V/M694V homozygote in 1 patient, M694V/EQ148 in 3, M694V/V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2. Recurrence was noticed in 1 patient with M694V/M680I. One patient died because of graft loss and cardiac complications with M694V/M680I gene analysis. Colchicine was reduced in 4 patients owing to side effects.ConclusionLong-term outcomes of transplantation in patients with amyloidosis secondary to FMF is similar to that in the general transplant population and maintenance colchicine, even after decreasing its dose, effectively prevents recurrence of amyloidosis in the allograft.     

Bone-sparing effects of rituximab and body composition analysis in a cohort of postmenopausal women affected by rheumatoid arthritis – retrospective study

ObjectiveOsteoporosis is the most common bone tissue disease and it is characterized by a reduced bone mineral density (BMD). The main physiopathological mechanisms converge on the uncoupling between bone formation and resorption, thus leading to an enhanced risk of fractures. Several papers have documented the inverse relationships linking high inflammatory cytokines, anti-citrullinated protein antibodies, rheumatoid factor, and BMD in rheumatoid arthritis (RA). Rituximab (RTX) is a chimeric monoclonal antibody directed against the CD20 receptor of B cells. Since the Food and Drug Administration approved it for RA in 2006, there have been many clinical experiences regarding its use. Nevertheless, few studies evaluate the effect of rituximab on BMD. RA is a disease characterized by immune dysfunction with high levels of inflammatory cytokines, autoantibodies, and it is reasonable that a B cell depleting therapy could restore a physiological cytokine balance, thus exerting an osteoprotective effect on the bone tissue. The purpose of this paper is to highlight any difference in BMD and to assess differences in body composition over a retrospective 18-month follow-up period after RTX treatment with a B cell depleting therapy.Material and methodsWe analyzed by dual energy X-ray absorptiometry BMD expressed as g/cm² and body composition modifications over 18 months with RTX treatment of 20 postmenopausal RA patients.ResultsAfter eighteen months of therapy with RTX, a statistically significant increase in vertebral (L1–L4) BMD and the stability of femoral BMD were documented.ConclusionsRituximab is associated with an improvement of vertebral and preservation of femoral BMD, suggesting a bone-sparing effect due to B cell depletion. Furthermore, patients displayed a redistribution of fat masses toward the hip region.     

The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients

IntroductionRabbit Anti-Thymocyte Globulin (r-ATG) is a polyclonal antibody preparation, used to prevent and treat acute rejection episodes after organ transplantation. However, despite more than 40 years of clinical use, the optimal dose of r-ATG is still not defined. To find a better balance between efficacy and infectious complications, we embarked on a controlled study and monitored the effect of low and ultra-low dosages Thymoglobulin (Genzyme) on peripheral T, B, and NK cells.Patients and methodsKidney transplant recipients received either 0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg on the first 3 consecutive days post-transplantation. Thus, total doses were 1.5 mg/kg, 3.0 mg/kg and 6.0 mg/kg. A total of 40 patients were enrolled, including 11 controls. All patients were treated with Prednisolon, Advagraf (Astellas) and Mycophenolate Mofetil (Roche). T (CD3 +), B (CD19 +) and NK (CD3-CD16 + 56 +) cells were analyzed by flow cytometry. Baseline cell counts were compared to forty age and sex matched healthy persons. Post-transplantation cell counts of the 3 Thymoglobulin groups were compared to the 11 control patients, who received no induction therapy.ResultsAbsolute numbers of T, B, and NK cells were comparable in all patients pre-transplantation, but T and B cells were lower than in healthy persons (p = 0.007 and p = 0.0003, Mann Whitney test). In the first week, T cells and NK cells were significantly lower in all Thymoglobulin groups compared to controls. B cells were not affected. One month after Thymoglobulin NK cells had returned to control numbers in all groups, while T cells had already recovered to control counts in the 1.5 mg/kg group. During follow-up, T cells in the 3.0 mg/kg group also returned to control values, but at one year the patients in the 6.0 mg/kg group still had significantly lower T cells (p = 0.03). Patient and graft survival, rejection and infection incidence and renal function did not differ between groups.ConclusionPatients with end stage renal disease have significantly lower peripheral T and B cell counts than healthy persons. (Ultra-) low Thymoglobulin schedules deplete peripheral lymphocytes in a dose dependent way. Knowledge of the duration of this depletion contributes to finding the optimal immunosuppressive strategy for kidney transplant recipients.     

Intravesical Resiniferatoxin For Refractory Detrusor Hyperreflexia: A Multicenter,Blinded, Randomized,Placebo-Controlled Trial

Abstract

Objective: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH).

Methods: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 ml of placebo (n = 8 patients) or 0.005, 0.025, 0.05 , 0.10 , 0.2, 0.5, or 1.0 fLM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 1 2 posttreatment.

Results: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-j-μM and 1.0-j-μM RTX treatment groups, respectively. Patients in the 0.5-j-μM and 1.0-j-μM groups with MCC < 300 ml at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. There were no long-term complications.

Conclusion: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.     

A multicenter, open-label, comparative trial of two daclizumab dosing strategies vs. no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids for the prevention of acute rejection in simultaneous kidney-pancreas transplant recipients: interim analysis

INTRODUCTION: The safety and efficacy of daclizumab (1 mg/kg/dose every 14 d for five doses) has been established in kidney and heart transplant recipients. Alternative dosing regimens based on pharmacokinetic simulation and limited clinical trials are being investigated. The purpose of this ongoing multicenter study is to determine the safety and efficacy of two dosing regimens of daclizumab as an adjunctive immunosuppressive agent compared with no antibody induction in simultaneous kidney-pancreas transplant (SKPT) recipients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids as primary immunosuppression. METHODS: This is an interim report of a multicenter, prospective, open-label, randomized study with a target enrolment of 290 patients. Eligible SKPT patients were randomized to one of three groups: daclizumab 1 mg/kg/dose every 14 d for five doses (Group I), daclizumab 2 mg/kg/dose every 14 d for two doses (Group II), and no antibody induction (Group III). The primary endpoint of the study is a composite of the incidence of presumed or biopsy-proven kidney or pancreas rejection, graft loss, or death within the first 6 months post-transplantation. RESULTS: A total of 166 patients were randomized into the three groups [Group I (n = 70), Group II (n = 74), Group III (n = 22)]. Demographic and transplant characteristics were similar among the groups. At a minimum follow-up of 3 months, patient, kidney and pancreas graft survival rates were similar among the three groups. However, the rates of acute renal allograft rejection were 18% (Group I), 8% (Group II), and 36% (Group III), p < 0.05. The probabilities of either kidney or pancreas allograft rejection were 22% (Group I), 8% (Group II), and 38% (Group III). At 3 months, the actuarial event-free survival (no acute rejection, allograft loss, or death) rates were 67, 81 and 50% in Groups I, II, and III, respectively. There were no differences in the incidence of infectious complications among the groups and no serious adverse events associated with daclizumab were observed. CONCLUSIONS: The two-dose regimen (Group II) appears to be as effective as the five-dose regimen (Group I) in preventing acute rejection after SKPT and is associated with the lowest acute rejection rates and the highest rate of event-free survival (no rejection or graft loss). However, the benefits of daclizumab compared with no antibody induction await larger sample size accrual.     

Acute Anti-A/B Antibody-Mediated Rejection After ABO-Incompatible Kidney Transplantation Treated With Bortezomib and Plasmapheresis: A Case Report

BackgroundABO-incompatible kidney transplantation (KTP) is effective for avoiding transplantation-related issues. It is a viable alternative to ABO-compatible KTP, as both techniques have similar patient and graft survival rates. However, anti-A/B antibody-mediated rejection (AMR) can occur, resulting in poor long-term graft survival.CaseA 45-year-old man with end-stage renal disease presented with a serum creatinine level of 10.2 mg/dL. We decided to perform KTP with spousal donation. He had panel-reactive antibody class I and II and cross matching test negativity, a 3/6 mismatch on human leukocyte antigen typing, an ABO antibody titer of 1:256, and no donor-specific antibodies. The patient and donor blood types were O+ and A+, respectively. The anti-A/B antibody titer was reduced preoperatively with rituximab (200 mg/body), plasmapheresis, and intravenous immunoglobulin (0.2 mg/kg). Basiliximab and methylprednisolone were used for induction immunosuppression, and tacrolimus, mycophenolate mofetil, and prednisolone were used for maintenance immunosuppression. KTP was successful, and graft function was initially normal. On postoperative day (POD) 5, the serum creatinine level and anti-A/B antibody titer increased from 0.9 mg/dL to 1.9 mg/dL and 1:16 to 1:64, respectively. Graft biopsy revealed acute AMR and tubular injury. We started steroid pulse therapy, plasmapheresis, and subcutaneous bortezomib (2.6 mg, twice a day, every 3 days) with no side effects. The serum creatinine level decreased from 5.7 mg/dL to 1.5 mg/dL on POD 28. Graft biopsy showed no rejection, and normal function was maintained for 40 months.ConclusionsAcute, early anti-A/B AMR was successfully treated with plasmapheresis and bortezomib.     

A Novel,Blocking, Fc‐Silent Anti‐CD40 Monoclonal Antibody Prolongs Nonhuman Primate Renal Allograft Survival in the Absence of B Cell Depletion

CD40–CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti‐CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti‐CD40 antibody can still promote graft survival. The parent anti‐CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC‐mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc‐silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98–100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well‐tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc‐silent anti‐CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.     

The effect of additional propofol on intubation conditions

Study ObjectiveTo evaluate whether an additional dose of propofol prior to intubation improves intubation conditions.DesignProspective, randomized, double-blinded clinical study.SettingOperating room in university hospital.Patients102 ASA physical status I and II patients undergoing elective surgery with general anesthesia.InterventionsPatients received different doses of propofol (Groups A and B, 1.5 mg/kg; Group C, 2 mg/kg) preceded by fentanyl (1.5 μg/kg). In Group B, additional propofol (0.5 mg/kg) was administered 45 seconds after rocuronium. Intubation was performed 90 seconds after administration of rocuronium 0.6 mg/kg. Intubation conditions and hemodynamic variables were compared among the three groups.Measurements and Main ResultsIntubation conditions were acceptable in 61.8% of Group A patients, 58.8% of Group C patients, and 91.1% of Group B patients (P = 0.005). Mean arterial pressure (MAP) three minutes after intubation was significantly lower in Group C (P = 0.006 vs. Groups A and B), while MAP did not differ between Group A and Group B.ConclusionsAdministration of an additional dose of propofol (0.5 mg/kg) prior to intubation may significantly improve intubation conditions without increasing the frequency of hypotension.     

Reduced dose Thymoglobulin,tacrolimus, and mofetil mycophenolate results in excellent solitary pancreas transplantation outcomes

BACKGROUND: Graft survival following solitary pancreas transplantation has traditionally lagged behind that of simultaneous pancreas-kidney transplants. Thymoglobulin (TMG), a polyclonal rabbit-derived antilymphocyte antibody was originally introduced as treatment for acute rejection of renal allografts. However, data regarding the efficacy of TMG induction in solitary pancreas transplants is lacking. We present the 1-yr graft survival and acute rejection rate of 22 solitary pancreas transplants performed at the McGill University Health Centre using reduced dose TMG induction with lower dose tacrolimus and mophetil mycophenolate. PATIENTS AND METHODS: Eighteen pancreas after kidney and four pancreas transplants alone were performed between January 1998 and October 2000 at McGill University. Induction therapy with TMG at a starting dose of 1.5 mg/kg/d was started 12 h post-operatively. The daily dose of TMG was held if the total leukocyte count was <2,500/mm3 or if the lymphocyte count was <100/mm3. Maintenance therapy was initiated with steroids (tapered to 20 mg prednisone orally once a day) tacrolimus (2 mg twice a day), and mofetil mycophenolate (1 g daily). RESULTS: Patients received three to seven doses of TMG over the first seven post-operative days at a dose of 0.85 +/- 0.27 mg/kg/d (mean +/- SD). The mean follow-up was 1.28 +/- 0.14 yr. The 1-yr patient and graft survival was 100% (22 of 22) and 96% (21 of 22), respectively. The 1 yr acute rejection rate was 27.3% (six of 22). Five of the six rejections responded to steroid boluses. One was refractory to steroids and TMG resulting in graft loss. Presumed rejections were diagnosed on the basis of decreasing urine amylase and/or hyperglycemia. DISCUSSION: Monitoring the total leukocyte and lymphocyte count resulted in a 43% reduction in the amount of TMG used compared with the recommended dosing. Despite the reduced amounts, patient and graft survival were excellent with acute rejection rates comparing favorably to other published series.     

Anti-CD20 antibody suppresses anti-HLA antibody formation in a HLA-A2 transgenic mouse model of sensitization

BackgroundB cell depletion by anti-CD20 antibody is used in desensitization protocols and for treatment of antibody-mediated rejection (AMR). However, little is known about the efficacy and the mechanism(s) of action.MethodsA mouse model of HLA sensitization was used to study the effectiveness of anti-CD20 treatment on B cell depletion and anti-HLA antibody suppression.ResultsImmunization of C57BL/6 mice with skin grafts from a transgenic C57BL.Tg/HLA-A2.1 mouse resulted in robust production of anti-HLA IgM and IgG antibodies, and accelerated rejection of a secondary skin allograft (within 3 days) featured by intragraft IgG and C4d deposition. Both IgM and IgG alloantibodies are specific to HLA-A2 as well as to a panel of class I HLA, including A1, A3, A25, A26, A29, and A30. These alloantibodies were complement-dependently cytotoxic (CDC) against HLA-A2 expressing target cells. Administration of 2 doses of a mouse–anti-mouse CD20 monoclonal antibody significantly reduced the levels of anti-HLA IgG2a antibodies, suppressed serum CDC, and prolonged survival of the secondary skin allografts. Suppression of anti-HLA IgG antibodies was associated with significant depletion of B220⁺/CD5⁻ B cells from the blood, the spleen and the bone marrow of the treated animals.ConclusionAnti-CD20 treatment effectively depletes B220⁺/CD5⁻ B cells, resulting in potent suppression of anti-HLA IgG and prolongation of skin graft survival. The data are in support for the use of anti-CD20 antibodies in highly-HLA sensitized patients undergoing desensitization and for the treatment of AMR.     

Induction with ATG in DCD kidney transplantation; efficacy and relation of dose and cell markers on delayed graft function and renal function

AimWe aimed to analyse the efficacy of the Thymoglobulin dose used for induction in controlled DCD kidneys, and its initial impact on blood cell and CD3 count, as predictors of efficacy.Methods140 DCD patients who received ATG induction, were analysed. Intended dose was 1.25 mg/kg/day over 5 days, rounded to nearest 25 mg and not exceeding 125 mg/dose. Outcomes included the total dose in relation with rejection, DGF, graft survival, eGFR. The cell count response to ATG was assessed as predictors of outcome.ResultsGraft survival, was 96.2%, 92.4%, 85% at 1, 3 and 5 years. Rejection was 7% at 1 year and associated with eGFR at 3 (p = 0.003) and 5 years. ATG dose was not predictive of rejection but was associated with the day5 leucocyte and lymphocyte count (p < 0.001) and negatively with DGF (p = 0.05). In 31 patients day3 CD3 count was available and it was associated with rejection (p = 0.002), less DGF (p = 0.09), and 3 years eGFR (p = 0.01).ConclusionThymoglobulin provides excellent results in DCD kidneys that do not significantly differ with small dose variations. In higher doses it reduces DGF. Lymphocytes and CD3 count, may be useful surrogate markers of efficacy and outcome.     

Minimal effective dose of magnesium sulfate for attenuation of intubation response in hypertensive patients

Study ObjectiveTo study the minimal effective dose of magnesium sulfate to control blood pressure (BP) during intubation in hypertensive patients.DesignProspective, randomized, double-blind study.SettingOperating room of an academic medical center.Patients80 adult, ASA physical status 1 and 2, controlled hypertensive patients undergoing elective surgery under general anesthesia and requiring endotracheal intubation.InterventionsPatients were randomized to 4 groups. Patients in study groups received a magnesium sulfate infusion at a dose of 30 (Group I), 40 (Group II), or 50 mg/kg (Group III) before induction of anesthesia, while patients in control group (Group IV) received a 1.5 mg/kg lidocaine bolus 90 seconds before intubation. Anesthesia was induced and maintained with a propofol infusion. Laryngoscopy and intubation were performed 4 minutes after administration of vecuronium.MeasurementsHeart rate (HR) and BP were recorded before, during, and after endotracheal intubation for10 minutes. Measures to manage hemodynamic instability were recorded. Serum magnesium levels were also recorded.Main ResultsThe changes in HR were comparable among groups. Mean arterial pressure (MAP) was maintained within normal limits in Group I patients while Groups II and III patients showed a significant decrease in MAP (P = 0.01) compared with baseline. A total of 6 patients (30%) in Group II and 10 patients (50%) in Group III required interventions (P = 0.001). No patient in Group I and only one patient (5%) in Group IV required intervention.ConclusionsMagnesium 30 mg/kg is the optimum dose to control BP during intubation in hypertensive patients. A further increase in the dose of magnesium may cause significant hypotension.     

T and B lymphocyte dynamics after genetically-modified pig-to-baboon kidney xenotransplantation with an anti-CD40mAb-based immunosuppressive regimen

BackgroundThe aim was to monitor recovery of T/B lymphocytes in baboons after depletion by anti-thymocyte globulin (ATG) and anti-CD20mAb (Rituximab), followed by pig kidney transplantation and maintenance therapy with an anti-CD40mAb-based regimen.MethodsIn baboons (n = 14), induction was with ATG and anti-CD20mAb, and maintenance with (i) anti-CD40mAb, (ii) rapamycin, and (iii) methylprednisolone. Follow-up was for 6 months, or until rejection or other complication developed. Baboon blood was collected at intervals to measure T/B cells and subsets by flow cytometry. In a separate study in baboons receiving the same immunosuppressive regimen (n = 10), the populations of T/B lymphocytes in PBMCs, lymph nodes, and spleen were examined.ResultsAfter induction therapy, the total lymphocyte count and the absolute numbers of CD3⁺, CD4⁺, and CD8⁺T cells fell by >80%, and no CD22⁺B cells remained (all p < 0.001). T cell numbers began to recover early, but no CD22⁺B cells were present in the blood for 2 months. Recovery of both T and B cells remained at <30% of baseline (p < 0.001), even if rejection developed. At 6 months, effector memory CD8⁺T cells had increased more than other T cell subsets, but a greater percentage of B cells were naïve. In contrast to blood and spleen, T and B cells were not depleted in lymph nodes.ConclusionsATG and anti-CD20mAb effectively decreased T and B lymphocytes in the blood and, in the presence of anti-CD40mAb maintenance therapy, recovery of these cells was inhibited. The recovery of effector memory CD8⁺T cells may be detrimental to long-term graft survival.     

Modified distal anastomosis between colon and thoracic esophagus for hypopharynx reconstruction using free colon flap: A comparison study

BackgroundFree colon flap is the preferred method of hypopharynx reconstruction when the defect is substantial, or simultaneous voice reconstruction is planned. Most of the complications in free colon flaps are located at the anastomosis between colon and thoracic esophagus due to size mismatch of the lumen. We present our experience comparing a modified anastomosis technique and a conventional anastomosis technique at the distal end of interposed colonic segment.MethodsIn this retrospective review, 94 patients, divided into two groups, underwent hypopharynx reconstruction. Group A (18 patients), conventional anastomoses between colon and thoracic esophagus was performed, while in Group B (76 patients), underwent the modified method of anastomosis.ResultsThe average follow-up period was 46 months in group A and 54 months in group B. Fistula formation was found in 2 patients from Group A, and 1 patient from Group B. Strictures were observed in 4 patients from Group A, and 1 patient from Group B. Difference between both groups regarding complications of leakage and stricture formation was statistically significant (p < 0.05).ConclusionModified method for anastomosis between colon and thoracic esophagus was found to be effective in the reduction of complications associated with the use of a free colon flap for hypopharyngeal reconstruction. Further advances of this technique could gain momentum in the future.     

A strategy to achieve donor-specific hyporesponsiveness in cadaver renal allograft recipients by donor haematopoietic stem cell transplantation into the thymus and periphery.

INTRODUCTION: We designed a prospective, randomized clinical trial to evaluate the immune response to thymic and peripheral infusions of donor haematopoietic stem cells (HSCs) to create tolerance in recipients of cadaver renal allografts. METHOD: We divided 24 patients into two equal groups. For group A, 350 ml of unfractionated bone marrow (BM) was aspirated from the anterior iliac crests of donor cadavers. A 2 ml aliquot of concentrated marrow was infused into the thymus of the subject and 100 ml into the BM before surgery; the remaining 250 ml was infused peripherally post-transplantation. The mean nucleated cell count inoculated into the thymus was 3.3 x 10(4) cells/cm(3) and into the periphery 8.6 x 10(7) cells/kg body weight. Group B (controls) underwent renal transplantation directly. Recipients were lymphocytotoxicity cross-match negative in both groups. Group A received low dose prednisolone and cyclosporin; controls also received azathioprine. RESULTS: Over a mean follow-up of 703 days for both groups, group A had significantly better graft function with minimum acute rejection episodes or cytomegalovirus (CMV) infections, a mean serum creatinine (SCr) of 1.23 mg/dl and no graft or patient loss. Group B, with a mean SCr of 2.19 mg/dl had three patients with single acute rejection episodes, two of whom died following uncontrolled rejection-associated infections. The third patient maintained an SCr of 2.5 mg%. Actuarial graft survival was 87.5% in controls at the end of 2 years compared with group A with 100% graft survival at the end of 2 years. CONCLUSION: This novel approach of introducing unfractionated HSCs into the thymus and periphery to create tolerance is safe and efficacious and gives significantly better graft function, minimum acute rejection and no CMV disease with monotherapy.     

Factors Affecting Persistent Splenomegaly After Adult-to-Adult Living Donor Liver Transplantation Using a Left Lobe

BackgroundThe aim of the present study was to evaluate spleen volume (SV) and the factors influencing it after adult-to-adult living donor liver transplantation (A2LDLT) using a left lobe.MethodsPretransplant computed tomography (CT) and post-transplant CT 2 years after A2LDLT were examined by volumetric analysis in 24 patients. We divided the recipients into the following 2 groups according to the post-transplant SV: >500 mL (Group A) and ≤500 mL (Group B). The factors affecting the change in post-transplant SV were compared between the 2 groups.ResultsThe mean pretransplant SV decreased significantly after A2LDLT. Platelet counts after living donor liver transplantation increased significantly relative to the pretransplant values. Post-transplant SV was >500 mL in 9 patients (Group A) and ≤500 mL in 15 (Group B). Pretransplant SV, platelet count, anhepatic time, operative time, intraoperative blood loss, post-transplant portal vein pressure >20 mm Hg, and post-transplant portal vein flow >250 mL/min/100 g graft weight showed significant differences between the 2 groups. Actual graft volume (GV) and GV/standard liver volume ratio showed no intergroup differences. Multivariate analysis showed that the only significant factor related to a post-transplant SV of >500 mL was the pretransplant SV. Post-transplant platelet counts were significantly increased from the pretransplant values in both Group A and Group B.ConclusionsPretransplant SV is the only significant factor predicting a SV of >500 mL after A2LDLT. However, even in patients with a SV of >500 mL, the platelet count increased significantly from the pretransplant value.