The Effect Of Osteoprotection On Immune Reconstitution Post Bone Marrow Transplant

Specialized microenvironments have been known to strongly influence stem cell fate in hematopoiesis. The interplay between osteolineage cells, specifically the mature osteoblast, and the hematopoietic stem cell (HSC) niche have been of particular note. Recently, preliminary unpublished data obtained in the Scadden laboratory suggests the critical role of the osteoblast in regulating T cells. The goal of this project was to initially determine whether stimulating the osteoblast in the HSC niche leads to increased immune reconstitution after hematopoietic stem cell transplant (HSCT). These results indicated that while bone manipulation pre-transplant may have a positive effect on T and B lymphocyte cell recovery, bone manipulation post-transplant seems to have a suppressing effect. Additionally, stimulation of the osteoblast may have an inhibitory effect on the regeneration of GR1+ myeloid cells. Based on these results, we then sought to determine how osteoprotection pre-HSCT modifies the kinetics of graft-versus-host disease (GVHD) and impacts the regeneration of immune cells. The data from this phase of my experiment suggests a possible immediate benefit in stimulation of the osteoblast in response to GVHD prior to HSCT. The overall results from my thesis project demonstrate a promising relationship between pre-HSCT stimulation of the osteoblast and lymphocyte recovery post-HSCT. ¿

Histiocytic sarcoma; case report of a rare disease in a kidney transplant recipient

BACKGROUND: Histiocytic sarcoma (HS) is a rare hematologic neoplasm with a few hundred cases having been described to date.

Evaluation of the vaccination status in pediatric renal transplant recipients

To assess the immunization status of pediatric renal transplant patients followed at a single center in Brazil, vaccination charts of all patients aged between one and 18 yr were analyzed both pre- and post-transplantation. Appropriate immunization was defined according to the National Immunization Program (routine vaccines) - for all Brazilian children - and the Special Immunobiological Agents Program that also includes special vaccines for immunodeficient or other high-risk children. A total of 46 patients was evaluated (mean age 13.7 yr; range 4-17 yr). Vaccination charts were found to be up to date in only two patients (4.3%) pretransplant and in two (4.3%) post-transplant. Although 36 patients (62.2%) in the pretransplant phase and 24 (52.1%) in the post-transplant phase had been vaccinated according to the National Immunization Program, they had not received the special vaccines indicated for their immunocompromised condition. Therefore, despite being followed at a referral center, almost all patients presented an incomplete immunization status pre- and post-transplant. This probably reflects missed opportunities and medical/parental apprehension related to vaccination of patients with chronic renal insufficiency, dialysis or kidney transplantation. Efforts should be made to ensure adequate vaccination in children with kidney diseases, especially before kidney transplantation.

Tuberculosis in renal transplant patients

Tuberculosis (TB) was diagnosed in 25 of 466 patients who underwent renal transplant over a period of 15 years. TB developed from 1 month to 9 years post-transplant. In 56% of the cases the onset was within the first post-transplant year. TB affected several isolated or combined organs. Pulmonary involvement was present in 76% of cases, either as isolated pleuro-pulmonary (56%) or associated with other sites (20%). The non-pulmonary sites were: skin, joints, tests, urinary tract, central nervous system and lymphonodules. The diagnosis was confirmed by biopsy in 64% of the cases, by identification of tubercle bacilli in 24% and only at necropsy in 12% Biopsy specimens could be classified in three histological forms: exudative, that occurred in early onset and more severe cases granulomatous in late onset and benign cases; and mixed in intermediate cases. Azathioprine dosages were similar along post-transplant time periods in TB patients and in the control groups; and in TB patients who were cured and who died. The number of steroid treated rejection crises was greater in TB than in the control group. Prednisone doses were higher and the number of rejection crises was greater in TB patients who died than in those who were cured. Fifteen patients were cured and ten died, two of them of causes unrelated to TB. Six of the eight TB-related deaths occurred in the first 6 post-transplant months. The outcome was poor in patients in whom TB arose early in post-transplant period and where the exudative or mixed forms were present; whereas the prognosis was good in patients with late onset and granulomatous form of TB. In one patient TB was transmitted by the allograft.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients.

Patients with a solid organ transplant have increased in numbers and in individual survival in Switzerland over the last decades. As a consequence of long-term immunosuppression, skin cancer in solid organ recipients (SOTRs) has been recognized as an important problem. Screening and education of potential SOTRs about prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, SOTRs should be seen by a dermatologist yearly for repeat education as well as early diagnosis, prevention and treatment of skin cancer. Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in the setting of long-term immunosuppression. Sun protection by behaviour, clothing and daily sun screen application is the most effective prevention. Cumulative sun damage results in field cancerisation with numerous in-situ SCC such as actinic keratosis and Bowen's disease which should be treated proactively. Invasive SCC is cured by complete surgical excision. Early removal is the best precaution against potential metastases of SCC. Reduction of immunosuppression and switch to mTOR inhibitors and potentially, mycophenolate, may reduce the incidence of further SCC. Chemoprevention with the retinoid acitretin reduces the recurrence rate of SCC. The dermatological follow-up of SOTRs should be integrated into the comprehensive post-transplant care.

Oral valganciclovir prophylaxis in kidney transplant recipients

Background: Immunosuppressive and antivira[ prophy[ actic drugs are needed to prevent acute rejection and infection after organ transplantation. We assessed the effectiveness of a new combined regimen introduced at our transplantation center. Methods: We reviewed at[ consecutive patients who underwent kidney transplantation at our institution over a 5.5-year period, with a follow-up of at [east 6 months. Patients transplanted from 1/2000 to 3/2003 (Period 1) were compared to patients transplanted from 4/2003 to 7/2005 (Period 2). In period 1, patients were treated with Basi[iximab, Cic[osporin, steroids and Mycophenotate or Azathioprine. Prophylaxis with Va[acic[ ovir was prescribed in CMV D+/R- patients; otherwise, a preemptive antivira[ approach was used. In period 2, immunosuppressive drugs were Basi[- iximab, Tacro[imus, steroids and Mycopheno[ate. A 3-month CMV prophylaxis with Va[gancic[ovir was used, except in D-/R- patients. Results: Sixty-three patients were transplanted in period 1 and 70 patients in period 2. Baseline characteristics of both groups were comparable; in particular 17% of patients were CMV D+/R- in period 1 compared to 23% in period 2 (p=0.67). Acute rejection was more frequent in period 1 than in period 2 (40% of patients vs 7%, respectively p<0.001). Nineteen patients (30%) in period 1 were diagnosed with CMV infection/disease that required treatment, compared with 8 patients (11.4%) in period 2 (p = 0.003). Of these 8 patients, at[ had CMV infection/disease after discontinuation of Va[gancic[ovir prophylaxis, 6 were D+/R- (75%), and at[ were treated with oral Va[gancic[ovir. There was no difference between periods in terms of incidence of BK nephropathy, post-transplant [ymphopro[ iferative disease, graft toss, and mortality. Conclusions: These results indicate that a 3-month course of oral Va[gancic[ovir is very effective to prevent CMV infection/disease in kidney transplantation. Late-onset CMV disease is a residual problem in D+/R- patients receiving VGC prophylaxis.

Lymphomatoid granulomatosis in a renal transplant patient.

Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive pulmonary angiitis considered as a variant of the lymphoproliferative disorder group. Patients with organ transplantation are at an increased risk for post-transplant lymphoproliferative disorders secondary to their immunosuppression. However, lymphomatoid granulomatosis has rarely been described in patients with renal transplantation. It often presents with severe pulmonary signs. We describe a case whose initial presentation was an isolated VIth nerve palsy. We review the radiological and pathological findings and discuss the etiopathogenesis and therapeutic options of this particular lymphoproliferative disorder. With careful and stepwise reduction in her immunosuppression, our patient showed a complete disappearance of her lymphomatoid granulomatosis, and she is clinically well more than 3 years after the diagnosis, with good kidney function.

Late pulmonary metastases of renal cell carcinoma immediatelyafter post-transplantation immunosuppressive treatment: a case report

INTRODUCTION We report a case of pulmonary metastatic recurrence of renal adenocarcinoma soon after radical nephrectomy that was followed by renal transplant and immunosuppressive medication. Increased risk of metastatic recurrence of renal cell carcinoma should be considered in the immediate post-transplant period when immunosuppressive medication is administered, even if nephrectomy had been performed many years earlier. CASE PRESENTATION In 1986 the patient demonstrated renal insufficiency secondary to mesangial glomerulonephritis. In 1992 he underwent left side radical nephrectomy with histopathological diagnosis of clear cell adenocarcinoma. Mesangial glomerulonephritis in the remaining right kidney progressed to end-stage renal failure. In October 2000 he received a kidney transplant from a cadaver and commenced immunosuppressive medication. Two months later, several nodules were found in his lungs, which were identified as metastases from the primary renal tumor that had been removed with the diseased kidney 8 years earlier. CONCLUSION Recurrence of renal cell carcinoma metastases points to tumor dormancy and reflects a misbalance between effective tumor immune surveillance and immune escape. This case demonstrates that a state of tumor dormancy can be interrupted soon after administration of immunosuppressant medication.

Epidemiology of fungal infections in liver transplant recipients: a six-year study of a large Brazilian liver transplantation centre

Liver transplant seems to be an effective option to prolong survival in patients with end-stage liver disease, although it still can be followed by serious complications. Invasive fungal infections (ifi) are related to high rates of morbidity and mortality. The epidemiology of fungal infections in Brazilian liver transplant recipients is unknown. The aim of this observational and retrospective study was to determine the incidence and epidemiology of fungal infections in all patients who underwent liver transplantation at Albert Einstein Israeli Hospital between 2002-2007. A total of 596 liver transplants were performed in 540 patients. Overall, 77 fungal infections occurred in 68 (13%) patients. Among the 77 fungal infections, there were 40 IFI that occurred in 37 patients (7%). Candida and Aspergillus species were the most common etiologic agents. Candida species accounted for 82% of all fungal infections and for 67% of all IFI, while Aspergillus species accounted for 9% of all fungal infections and for 17% of all IFI. Non-albicans Candida species were the predominant Candida isolates. Invasive aspergillosis tended to occur earlier in the post-transplant period. These findings can contribute to improve antifungal prophylaxis and therapy practices in Brazilian centres.

Prevalence of Staphylococcus aureus colonization in renal transplant patients

Objective to evaluate the prevalence of Staphylococcus aureus nasal colonization in renal transplant patients and to identify the related risk factors. Method Swabs were used to collect nasal samples from 160 patients who had undergone a transplant within the previous year at the Kidney and Hypertension Hospital. The ‘National Committee for Clinical Laboratory Standards’ norms were followed for the collection, isolation, identification and sensitivity measurements. Results There was a 9.4% (15) prevalence of Staphylococcus aureus nasal colonization, of which one (6.7%) was resistant to oxacillin. It was possible to identify as an associated risk factor a wait of more than one year for accessing dialysis prior to the transplant (p=0.029). Conclusion Given the high morbidity and mortality rates that this microorganism causes in the target population, other studies should be carried out, and pre- and post-transplant screening should occur in order to develop strategies that improve the prevention and control of the spread of Staphylococcus aureus.

Infectious Disease Burden after Solid Organ Transplantation (SOT) in the Swiss Transplant Cohort Study (STCS).

Infectious diseases (ID) are a major cause of morbidity and mortality after SOT. Since May 2008, the STCS has registered 95% of all SOT recipients in Switzerland. The extensive data set includes pre- and post-transplant variables that are prospectively collected at transplantation, 6 months post-transplant, and yearly thereafter. All ID events are recorded using internationally validated defi nitions. We obtained data from 1101 patients (79 heart, 685 kidney, 29 kidney-pancreas, 212 liver, and 96 lung transplants). So far the median observation times were 0.8 (IQR 0.3-1.4; heart); 1.1 (0.6-1.8, kidney); 1.1 (0.6-1.9, kidney-pancreas); 1.0 (0.5-1.7, liver); and 0.9 years (0.5-1.5, lung). The highest rates of proven or probable ID events were seen in lung (76%), followed by liver (64%), heart (62%), kidney-pancreas (62%), kidney (58%). During the observation period, ID was the cause of death in 19 patients (1.7%). Rates of infections per person-years according to pathogen and type of transplantation are shown in Figure 1. The data indicate that virus infections are only second after bacteria whereas fungi occur at relatively low rates. This prospective and standardized long-term collection of all ID events will allow a comprehensive assessment of the burden of ID across all SOT types in Switzerland. Regular analysis will identify new trends, serve as a quality control and help design anti-infectious interventions aiming at increasing safety and improving overall transplantation outcome.

Pharmacokinetic and pharmacodynamic evaluation of valganciclovir in solid organ transplant patients

Goal: To validate oral vatgancictovir (VGC) in the prophylaxis of CMV infection in Lung (Lu) and Liver (L) recipients and in the treatment of CMV infection/disease in solid organ transplant recipients, using pharmacokinetic and pharmacodynamic studies in comparison with i/v gancicLovir (GCV). Methods: patients undergoing organ transpLantation donor or recipient CMV-seropositive receiving VGC prophylaxis for a period of 3 months (D+/R- Lung recipients, 6 months) were enroLLed. Heart (H), Lu, and L recipients received 900mg VGC q.d., adjusted to kidney (K) function. No K recipients received more than 450mg of VGC q.d. GCV trough (Ctrough) and peak (Cpeak = 3 hours after drug administration) LeveLs, and CMV DNA were measured at 7, 30, and 60 days post-transpLant (prophyLactic study). Patients who developed CMV infection/disease after stopping prophylaxis were treated with VGC (1800mg per day adjusted to K function and GCV blood LeveLs). GCV trough and peak LeveLs, and CMV DNA were measured weekly for the first 3 weeks and biweekly thereafter, until therapy cessation (therapeutic study). PLasma concentration of GCV is measured by HPLC. Results: In the first 8 prophyLaxed patients (6 K, and 1 L and 1 H transplant recipient) of 450mg VGC q.d., the average GCV concentration was 0.5±0.3 mg/t at trough, and 3.9±l.0mg/t 3 hours after administration. Inter-patient variability was substantiaL, especiaLLy for Ctrough (63% of total variance), which correlated with the patient's estimated gtomerutar filtration rate (r square = 42%). No CMV DNA was detected during VGC prophy- Laxis. Two patients (1 H and 1 L) were treated for Late CMV disease. Average GCV Cpeak were 8.9±2.3 mg/L and 4.6±0.5 rag/L, and GCV Ctrough were 2.0±0.9 mg/t and 1.6±0.2 mg/t respectively in each patient during induction phase. VGC treatment afforded a decrease in CMV DNA from 5.2 and 4.4 Log copies/10E6 cettutes at week 0, to 3.9 and 3.0 at week 1, and 3.3 and 2.1 at week 3, respectively.

No detectable indirect effects of late-onset Cytomegalovirus disease after valganciclovir (VGC) prophylaxis in kidney transplant recipients

Background: Cytomegalovirus (CMV) disease remains an important cause of morbidity after kidney transplantation and has been associated with acute rejection, graft loss and other indirect effects. A 3-month course of VGC prophylaxis reduces the incidence of CMV disease. However, little is known about the indirect effects of lateonset CMV disease after VGC prophylaxis. Objective: To evaluate the impact and indirect consequences of late-onset CMV disease after VGC prophylaxis in kidney transplant recipients. Methods: Retrospective analysis of 61 consecutive adult kidney transplant recipient with positive CMV serology (donor or recipient) who received VGC prophylaxis for 3 months and completed a follow-up of at least 2 years post-transplantation. Patients who developed CMV disease within 1 year after transplantation were compared to CMV disease-free patients for renal function (plasma creatinine values) at 1, 6, 12 and 24 months and for the incidence of graft loss, acute rejection, diabetes, cancer and opportunistic infections. Results: 8/61 (13%) patients developed CMV disease at a median of 131 days after transplantation (range: 98-220). The CMV incidence in D+/R- high risk patients was 6/18 (33%), while it was 2/43 (5%) in intermediate-risk patients (p < 0.01). All 8 patients were treated by oral valganciclovir (median 39 days; range: 19-119) with a complete resolution of CMV disease. As shown in the figure, there was no difference in creatinine values between the two groups at any time during follow-up. There was no graft loss, and the incidence of acute rejection, cancer and opportunistic infections did not differ between the two groups. The incidence of post-transplant diabetes was higher (38% vs 15%) in patients with CMV disease, but this difference was not significant (p = 0.4). Conclusions: An incidence of 13% of late-onset CMV disease was observed despite 3 months VGC prophylaxis. However, no indirect consequences were found. Moreover, therapy of CMV disease by oral VGC was effective and safe. Larger trials are needed to study whether late-onset CMV disease is associated with indirect consequences, as described with early-onset CMV.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.