Foto del docente

Paola Todeschini

Assistant professor

Department of Experimental, Diagnostic and Specialty Medicine - DIMES

Academic discipline: MED/14 Nephrology

Research

Keywords: cardiovascular complication in Ktx recipients kidney transplantation chronic allograft nephropaty immunosuppressive therapy pregnancy and transplant

 

1) BK virus nephropathy in kidney tranplant.

2) Evaluation of bioptic score on kidney tranplant to evaluated the allocation for single or double kidney tranplant.

3) Role of anti-HLA specific antibody on developement of chronic rejection. Eveluation of early markers of immunological activation.

4) Pregnancy after organ tranplantation: follow up of new born and mother.

5) Predictive factors on chronic allograft nephropathy

6) VDR expression of on endothelial progenitor cells in dialysis patients

7) New immunosuppression strategy in kidney trasplant patient

8) Evaluation of NGAL (Neutrophil Gelatinase-Associatel Lipocalin) as a mediator of biological and pathological states.

9) Vascular complications after kidney transplant (Atrial Fibrillation, Deep Venous Thrombosis)

10) Genetic cardiovascular risk factors after renal transplantation: role of cytokine polymorphisms

11) De novo malignancies after organ transplantation: epidemiology and focus on viral infection

12) Reduction of oxidative damage and kidney transplantation outcome

13)  New insight in artificial renal replacement treatments: automatic adaptive system dialysis for hemodialysis-associated hypotension and disequilibrium symptoms

14)  Restless-leg sindrome in uremia

15) pregnancy after solid organ transplant: outcome and immunosuppressive therapy

 

 

 



Early diagnosis of polyomavirus type BK infection in tailoring immunosuppression for kidney transplant patients: screening with urine qualitative polymerase chain reaction assay

Polyomavirus type BK (BKV) nephropathy is increasingly a significant cause of graft dysfunction and even failure. Early diagnosis followed by reduction of immunosuppression has been associated with an improved prognosis. The aim of the study is  to  screen  patients with the urine qualitative polymerase chain reaction (PCR) for BKV DNA. We followed with blood BKV PCR if the urine screen was positive and then reduced immunosuppression in viremic patients. An early diagnosis of BKV infection with reduction of immunosuppression may reverse viremia and retard progression of BKV nephropathy. BKV screening by PCR assays should be considered in kidney transplant recipients, especially those with impaired graft function.

Evaluation of bioptic score on kidney tranplant to evaluated the allocation for single or double kidney tranplant.

Marginal organs not suitable for single kidney transplantation are considered for double kidney transplantation (DKT). Double-kidney transplantation is performed using organs from marginal donors with a histological score not suitable for single kidney transplantation. The number of patients on the waiting list for renal transplantation has progressively increased in the last decade, while the number of potential donors have remained the same. The expansion of the donor pool using marginal donors may represent a possible, although partial solution to this problem. Dual transplant of marginal kidneys otherwise not considered for single transplant may give access to an expanded pool of cadaveric organs without exposing recipients to the drawbacks of a limited nephron mass supply The aim of the study is to verify the results obtained with double-kidney transplantation in terms of graft and patient survival and complications in comparation with patients that received a kidney transpant with bipoptic score suitrable for single transplant. Moreover the score used in this study is useful to determine whether a kidney should be refused or suitable for single or dual-kidney transplantation.

Impact of early humoral alloreactivity  after transplantation on the long-term survival of renal allografts.

She is active involved in a multicentric study in collaboration with the Departiment of Transplant Immunology of General Hospidal of Padua about the role of antibody immunoresponse in developement of acute and cronic rejection. The primary end point of the study is the detection of early immunological markers involved in the umoral response against renal transplantation in the aim of  developement of immunomodulation strathegic protocol . The study involved the evaluation of several blood samples  to decected serum antibody against kidney transplant. A kidney biopsy will be done in the patient who developed antibody, associated with plasmepheresis and increase of immunosuppression therapy.The study is divided in an obsevational phase and in a interventistic phase. in the observational phase we analyze blood sample of transplant patient to dectect early specific antibody involved in humoral rejection; in interventistic phase we perform plasmapheresis on patien who develop specific antibody.

 Outcome of pregnancy after organ transplantation: a retrospective survey in Italy.

We are strictly involved in a multicenter retrospective study describes pregnancies after kidney transplantation and is the first such survey in Italy.The number of women who decide to have a child after organ transplantation has increased. We determined the outcomes of over 100  pregnancies of women who had undergone kidney, liver or heart transplantation. All recipients had been maintained on immunosuppressive therapy before and during pregnancyIn the last few years advances in surgical techniques and immunosuppression have improved not only survival, but also quality of life in organ transplanted patients. Hence, the number of women of child-bearing age who decide to have a child--which means resuming a normal life--has increased. 

The study analize the outcomes of pregnancies in kidney transplant recipients from data collected in questionnaires, hospital records, and phone interviews. All recipients were maintained on cyclosporine (CsA), azathioprine (AZA), corticosteroids or tacrolimus (FK506) before and during pregnancy Preliminare data showed that in kidney transplant recipients who became pregnant the incidence of spontaneous abortion and preterm delivery was increased. Newborns delivered to these patients had low birth weight, but no congenital defects were noted and their development was normal.

 Immunosuppressive therapy and chronic allograft nephropathy

In the kidney graft field  she focused her studies on CAN. Chronic allograft nephropathy (CAN) is an anatomical and clinical alteration, characterized by proteinuria, hypertension and a progressive decline of kidney function, that begins at variable times (months, years) and that can lead to the loss of  the transplanted organ. The pathogenesis of CAN  involves both immunological (early acute rejection, hyperimmunization, HLA-mismatches between donor and recipient, suboptimal immunosuppression, etc) and non-immunological factors (ischemia/reperfusion injury, reduced nephron mass, age differences between donor and recipient, dialysis time, hypertension, dislipidemia, proteinuria, etc.). The possible strategies for prevention of CAN consist of procedures aimed at the reduction of some potential risk factors like optimization of the conditions for organ explantation, diminution of ischemia/reperfusion injury etc. Moreover, some categories of immunosuppressive drugs, such as calcineurin inhibitors, can have a nephrotoxic effect, often regardless of therapeutic dosage.

The introduction in clinical practice of novel immunosuppressive drugs with no nephrotoxicity, like mycophenolate mofetil and rapamycin, makes therapeutical strategies able to decrease of the incidence of CAN feasable .

 

New trend in the field of immunosuppressive therapy in renal transplant

The prevention of allograft rejection a foremost challenge for the clinicians involved in transplant. Among the regimens aimed to suppress transplant recipient immune response against the graft, tacrolimus represents a milestone of immunosuppressive therapy. The formulation of Prograf capsules requires twice-a-day administration. Advagraf is a recently developed slow-release once-a-day oral formulation of tacrolimus, with similar efficacy and safety profile of 12-hour formulation (Prograf). It been shown that poor compliance is one relevant factor associated with graft loss: once-daily dosing can contribute to improved patient adherence. Few data are currently available on Advagraf use in clinical practice, especially as early immunosuppressive therapy in transplants. We therefore evaluated the efficacy and pharmacokinetics of single-dose formulation compared to the traditional Prograf twice-daily dosing in de novo renal transplants.The groups did not differ significantly in terms of patient characteristics and drug efficacy. Drug blood levels tended to be lower in the first weeks post-transplant, particularly in Advagraf-treated patients who required higher drug doses The groups did not differ significantly in terms of patient characteristics and drug efficacy. Drug blood levels tended to be lower in the first weeks post-transplant, particularly in Advagraf-treated patients who required higher drug doses . This study suggests that in de novo kidney transplant, single-dose formulation of tacrolimus has a similar short-term efficacy compared with twice-a-day administration. The data also highlight the necessity to increase Advagraf dosage in the first week post-transplant to achieve effective therapeutic levels (11-15 ng/ml). .An emerging finding is the reduction of lipids with a considerable importance for cardiovascular risk.

Genetic cardiovascular risk factors after renal transplantation: role of cytokine polymorphisms

Cardiovascular disease (CVD) represents the main cause of morbidity and mortality after renal transplantation. A pathogenetic link between inflammation, atherosclerosis and CVD have been demonstrated. For this reason, genetic factors regulating cytokine production and the balance between pro- and anti- inflammatory molecules could have a deep influence on CVD risk. In the view of the modern paradigm of atherosclerosis as an inflammatory disease, the present study was undertaken to investigate the impact of inflammatory cytokine polymorphisms on post-renal transplant CVD. To evaluate the association between cytokine polymorphisms and CVD, a case-control study was carried out on 798 renal allograft recipients transplanted between 1997 and 2008, 196 of them with CVD (CVD group) and 602 controls free of cardiovascular complications (no-CVD group). TNF-α/G-308A, TGF-β1/L10P, TGF-β1/R25P, IL-10/G-1082A, IL-10/C-819T, IL-10/C-592A, IL-6/G-174C, IFN-γ/T+874A, IL-8/T-251A and VEGF/C+936T polymorphisms were genotyped using PCR-SSP and RFLP. The patients in CVD and no-CVD group differed significantly in IL-10 and TNF-α genotype frequencies. Using multivariate analyses to test the association with CVD, the high producer genotype of the pro-inflammatory cytokine TNF-α was significantly associated with a 4.41-fold increased cardiovascular risk. Conversely, the carriage of high producer genotype of the anti-inflammatory cytokine IL-10 resulted protective against post-transplant CVD, with an adjusted OR of 0.2 (0.02-0.29). This work seems to indicate that gene polymorphisms involved in inflammatory response might represent cardiovascular risk markers in renal allograft recipients and suggests a prognostic value of TNF-α and IL-10 genotypes. Further studies are necessary to evaluate if patients with a CVD "predisposing" genotype should be treated more aggressively.

Incidence of late deep venous thrombosis  in renal transplant patients 

Kidney transplant recipients (KTR) manifest a hypercoagulable state that contributes to increase the incidence of deep vein thrombosis (DVT), also occurring late in stable patients..It has been proven an imbalance of hemostatic mechanisms in KTR, with a multifactorial rise in procoagulant factors, partly related to traditional risk factors (diabetes, pregnancy, obesity, preexisting thrombophilic states), partly transplant-related (surgery per se, immunosuppressive therapy, primary nephropathy disease, pretransplant dialysis mode, post-transplant erythrocytosis, post-transplant infections).We observed a group of patients with an episode of DVT at least 4 months after transplant. who developed DVT (lower limbs, lower limbs complicated by pulmonary embolism, retinal) at least 4 months after transplantation. Primary nephropathy, immunosuppressive regimen, post-transplant infections and erythrocytosis were recorded All patients received low dose subcutaneous low molecular weight heparin (LMWH) as trombophylactic treatment for the first week after transplantation and then with oral anticoagulants.  DVT was diagnosed by color duplex ultrasonography . Significant increased incidence of DVT was observed in patients receiving cyclosporine or cyclosporine+mTOR inhibitors, in those with polycystic kidney diseases, systemic lupus erythematosus, nephrotic syndrome (especially if steroid-sensitive) and in those with rapid and excessive correction of hematocrit values after transplant. DVT was not significantly related to acute infection (CMV) or  dialysis modality. Hypercoagulability in KTR is a multifactorial condition representing a severe complication in stable transplants. The prevention may consist either in an accurate pre-transplant thrombophilia screening or in identification of patients at higher DVT risk requiring long-term antiplatelet therapy. A longer observation period is needed to assess the optimal duration and type of anticoagulant therapy in these patients.

Influence of the immunogenetic KIR and HLA systems on long-term renal transplant outcome.

Numerous studies have established the importance of innate immunity, particularly natural killer (NK) cells, in transplantation tolerance. NK cells express killer cell immunoglobulin-like receptors (KIRs) on their surface. By recognizing and binding major histocompatibility complex class I antigens, KIRs prevent autologous cell killing and promote lysis of non-self antigen-presenting cells. This study investigated the role of 16 KIR genes and donor-recipient KIR/HLA combinations on 5-year outcomes in a population of deceased donor kidney transplant recipients.We genotyped 126 renal transplant patients and their donors for HLA A, B, C, DR, and KIR genes. Patients underwent standardized transplantation and immunosuppressive protocols and were followed-up for 5 years. Graft function was evaluated by serum creatinine level and glomerular filtration rate calculated using the 4-variable modification of diet in renal disease (MDRD) equation. The presence of KIR2DS3 in the recipients was associated with better graft function indexes over time (p<0.05), but Conversely, the presence KIR2DS3 in the recipients combined with the presence of its HLA ligand in the donor had a detrimental effect on the trends of serum creatinine levels and eGFR trends, also confirmed by multivariate analysis. Kidney transplant recipients negative for the KIR2DL1 gene displayed higher creatinine levels after 5 years. The present study demonstrates an important role of the KIR immunogenetic system in the long-term immune response to kidney transplantation

De novo malignancies after organ transplantation: focus on viral infections.

Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end stage organ diseases with 107,000 transplants performed worldwide in 2010. Newly developed anti-rejection drugs greatly helped to prolong long-term survival of both the individual and the transplanted organ, and they facilitate the diffusion of organ transplantation. Presently, 5-year patient survival rates are around 90% after kidney transplant and 70% after liver transplant. However, the prolonged chronic use of immunosuppressive drugs is well known to increase the risks of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly 2-fold elevated risk for all types of de-novo cancers, persistent infections with oncogenic viruses - such as Kaposi sarcoma herpes virus, high-risk human papillomaviruses, and Epstein-Barr virus - are associated with up to 100-fold increased cancer risks. This review, focusing on kidney and liver transplants, highlights updated evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses and cancer risk. The implicit capacity of oncogenic viruses to immortalise infected cells by disrupting the cell-cycle control can lead, in a setting of induced lowered immune surveillance, to tumorigenesis and this ability is thought to closely correlate with cumulative exposure to immunosuppressive drugs. Mechanisms underlying the relationship between viral infections, immunosuppressive drugs and the risk of skin cancers, post-transplant lymphoproliferative disorders, Kaposi sarcoma, cervical and other ano-genital cancers are reviewed in details.

 


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