Post-transplant Evolution Research Articles

Resultados del trasplante hepático con donantes de más de 70 años

Organ shortage has forced transplant teams to progressively expand the acceptance of marginal donors. MethodsWe performed a comparative analysis of the post-transplant evolution depending on donor age (group I: less than 70 years old (n=474) vs. group II: 70 or more years old [n=105]) over a 10 year period (2002-2011). ResultsDonors over 70 years old were similar to donors less than 70 years old in terms of ICU stay, gender, weight, laboratory results, and use of vasoactive drugs. However, the younger donor group presented with cardiac arrest more often (GI: 14 vs. GII: 3%, P=.005). There were no differences in initial poor function (GI: 6% vs. GII: 7,7%; P=.71), ICU stay (GI: 2.7±2 vs. GII: 3.3±3.8, P=.46), hospital stay (GI: 13.5±10 vs. GII: 15.5±11, P=.1), or hospital mortality (GI: 5.3 vs. GII: 5.8%, P=.66) between receptors of more or less than 70 year old grafts. After a median follow up of 32 months, no differences were found in the incidence of biliary tract complications (GI: 17 vs. GII: 20%, P=.4) or vascular complications (GI: 11 vs. GII: 9%, P=.69). The actuarial 5 year survival was similar for both study groups (GI: 70 vs. GII: 76%, P=.54). ConclusionsIn our experience, the use of grafts from donors older than 70 years, when other risk factors are avoided (cold ischemia, steatosis, sodium levels), does not worsen the results of liver transplantation on the short or long term.

Risk Factors Associated With Decreasing Graft Function in Kidney Transplant Recipients.

After kidney transplantation, the majority of patients have a modest function, most of them corresponding to stage 3 CKD (Chronic Kidney Disease). The purpose of this study was to assess the post-transplant evolution of renal function and to identify the risk factors associated with worsening of kidney function. Methods: The study included 231 renal transplant patients registered inour center for routine follow-up during January 2011. The follow-up period was 30 mo. MDRD (Modification of Diet in Renal Disease) eGFR (Estimated Glomerular Filtration Rate) were determined every 6 mo.For each patient, eGFR slope was determined by applying linear regression to all 6 available eGFR from baseline to 30 mo. The patients were separated according to the eGFR slope values in tertiles: declined, no change and improved eGFR. Results: Patient's characteristics were: median age 36 years (34-38) at the moment of transplantation, most of them were on haemodialysis before transplantation (70%) and received a kidney from a living donor (59%), the mean age of the donor being 42 years. Median time since transplantation to enrolment was 28 mo (13-48). The immunosuppressive regimen was in most cases based on calcineurin inhibitor (95%), mainly on tacrolimus (77%) and mycophenolate mofetil (94%). The median eGFR registereda slight reduction from 53.7 ml/min/1.73 m2(50.9-56.4) at baseline to 51.7 (47.5-54.1) at the end of the study.73 pts. a decline of eGFR (<-0.94 ml/min), 80 (35%) had no change of eGFR (0.94-1.33 ml/min), 78 (34%) had improved eGFR (>1.33 ml/min). In a multivariable Cox regression analysis, the factors associated with the progression of graft dysfunctionwere younger recipient age (p=0.001), deceased donor (p=0.022), older donor age (p=0.003), higher BMI at baseline (p=0.045), appearance of de novo DSA (donor specific antibodies) (p=0.005). We didn't find any relationship between eGFR slope and recipient gender, primary kidney disease, donor eGFR, HLA mismatch, arterial hypertension, urologic complications, urinary tract infections, acute rejection, immunosuppressive therapy. Conclusions: Younger recipient age, deceased donor, older donor age, higher BMI at baseline, appearance of de novo DSA are independent factors associated with a negative eGFR slope in our study recipients.

A Planning Algorithm for Correction Therapies After Allogeneic Stem Cell Transplantation

In this paper we continue the investigation of a basic mathematical model describing the dynamics of three cell lines after allogeneic stem cell transplantation: normal host cells, leukemic host cells and donor cells, whose evolution ultimately lead either to the normal hematopoietic state achieved by the expansion of the donor cells and the elimination of the host cells, or to the leukemic hematopoietic state characterized by the proliferation of the cancer line and the suppression of the other cell lines. A theoretical basis for the control of post-transplant evolution is provided. We describe several scenarios of change of system parameters by which a bad post-transplant evolution can be corrected and turned into a good one and we propose therapy planning algorithms for guiding the correction treatment.

MATHEMATICAL MODELING OF CELL DYNAMICS AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION

In this paper a basic mathematical model is introduced to describe the dynamics of three cell lines after allogeneic stem cell transplantation: normal host cells, leukemic host cells and donor cells. Their evolution is one of competitive type and depends upon kinetic and cell–cell interaction parameters. Numerical simulations prove that the evolution can ultimately lead either to the normal hematopoietic state achieved by the expansion of the donor cells and the elimination of the host cells, or to the leukemic hematopoietic state characterized by the proliferation of the cancer line and the suppression of the other cell lines. One state or the other is reached depending on cell–cell interactions (anti-host, anti-leukemia and anti-graft effects) and initial cell concentrations at transplantation. The model also provides a theoretical basis for the control of post-transplant evolution aimed at the achievement of normal hematopoiesis.

An economic analysis of antiviral therapy in patients with advanced hepatitis C virus disease: still not there!

An economic analysis of antiviral therapy in patients with advanced hepatitis C virus disease: still not there!

Post-transplant lymphoproliferative disorders in renal transplantation: two decades of experience

Post-transplant lymphoproliferative disease (PTLD) represents a heterogeneous group of diseases characterised by a proliferation of lymphocytes occurring after solid organ transplantation. Most cases of PTLD are B-cell and their development has been closely associated with the Epstein-Barr virus (EBV), whose proliferation is encouraged by the inhibition of the cytotoxic function of T lymphocytes due to immunosuppressive drug treatment for transplant recipients. Several risk factors have been described for the development of this disorder, such as the seronegative state of the EBV receptor, the degree of overall net immunosuppression, especially with the use of monoclonal and polyclonal antibodies, acute rejection and cytomegalovirus (CMV) disease. We studied the incidence of PTLD and its relationship with EBV as well as its evolution and possible risk factors in 1176 adult recipients of cadaveric renal transplantation performed in our hospital between 1988 and 2009, with a follow-up of 1-255 months. The presence of EBV in the lymphoproliferative tissue was determined using in situ hybridisation. We analysed the incidence of PTLD over two time periods, 1988-1998 and 1999-2009 with 472 and 704 patients respectively. A total of 28 recipients (2.38%), 22 men and 6 women with a mean age of 46.5 (15.36) years (18-70 years) with a mean post-transplant evolution of 72.9 (56.3) months (1-180 months), developed PTLD. Thirteen (46.4%) did not show any of the classic risk factors described. The presence of EBV in lymphoproliferative tissue was detected in 18 out of 26 patients studied (69.2%). In terms of histology, 25 out of 28 were type B (89.2%). Ten out of 28 patients diagnosed (35.7%) received treatment with rituximab, six died during the follow-up, five as a direct result of their illness. The incidence for the two time periods was very similar for both groups, with 0.003922 cases/year-patient in the 1988-1998 period and 0.003995 cases/year-patient in the 1999-2009 period. Overall post-transplant survival for patients with PTLD was 73.6% at 5 years and 36.9% at 10 years, versus 87.8% and 75.9% for disease-free recipients (P<.0001). We calculated a graft survival of 62.6% at 5 years and 27.3% at 10 years versus 72.4% and 53.9% for grafts in disease-free recipients (P<.0001). In our study, patient survival one year after presenting the disease was 30.9% and 23.2% at year two. For the graft, survival was 15.5% and 7.7%, respectively. We conclude that PTLD is a disorder that is generally type B; it is significantly associated with EBV. Its incidence has not changed over time and half of all PTLD cases had no identifiable risk factors, which led to a poor prognosis despite the development of new treatments.

Functional Improvement Between Brain Death Declaration and Organ Harvesting

Introduction The quality of harvested organs is crucial for graft survival and for posttransplant evolution. This study sought to investigate the evolution of the functional status of brain death (BD) patients during the period between declaration and organ harvesting (BD duration). Materials and Methods The study included all BD patients who underwent organ harvesting between January 2006 and June 2009. We compared the functional status regarding hemodynamics, respiration, kidney and liver function, coagulation, water, electrolytes, and acid–base balance evaluated at the moment of BD declaration (P1) and just before organ harvesting (P2). The results of the comparison were expressed as improvement, stable, or aggravation. We calculated mean values of the functional parameters in P1 and P2 and the statistical significance of the differences. Results Twelve BD patients were included in the study. The time interval between P1 and P2 was 16.08 ± 8.54 hours (range, 6–32). The number of patients with vasopressor support was 9/12 at P1 and 0/12 at P2, oxygenation disturbances 1/12 in P1 and 0/12 in P2, renal dysfunction 9/12 in P1 and 2/12 in P2, liver dysfunction 7/12 in P1 and 1/12 in P2, coagulopathy 4/12 in P1 and 0/12 in P2, hypernatremia 8/12 in P1 and 3/12 in P2, and metabolic acidosis 9/12 in P1 and 1/12 in P2. The overall assessment showed improvement in all patients. The most statistically significant improvement was registered in the cardiovascular, respiratory, renal, liver, and acid–base status ( P < .05). Conclusion With early, aggressive, protocolized donor management, functional improvement may be achieved during BD duration.

Interaction between estradiol and tacrolimus in kidney-transplanted menopausal women

Sir, Hormone replacement therapy for symptoms caused by oestrogen deficiency is often used by menopausal women. Transdermal administration is regularly used by means of a dermal application gel. Its active principle, the synthesis 17β estradiol, is a well-known substance known as an inhibitor of the microsomial cytochrome P450 enzymatic system. We present the case of a kidney transplant woman who faced a brutal degradation of her graft function consequent to an increase of her tacrolimus plasma level. This 65-year-old patient had benefited from a kidney transplant as a consequence of renal insufficiency due to hyperuricaemia-induced interstitial nephropathy (uromoduline gene mutation). Her medical history also included hypertension, hysterectomy for fibroma and partial thyroidectomy. Her treatment included tacrolimus 9 mg/day, mycophenolic acid 540 mg/day, prednisolone 4 mg/day, lisinopril 20 mg/day, atorvastatin 10 mg/day, l-thyroxine 100 mg/day and alprazolam 0.5 mg/day. She had a normal post-transplant evolution with good renal function (creatinine 1.1 mg/dl, GFR estimated according to MDRD 53 ml/min/1.73 m2, plasma tacrolimus trough levels ranging between 5.0 and 7.5 ng/ml). Her renal function suddenly deteriorated 10 days after a gynaecological consultation, with a very high tacrolimus plasma level: creatinine increased to 1.6 and 2 mg/dl, GFR decreased to 28 ml/min/m2 and tacrolimus plasma trough levels reached 14.2 and 18.3 ng/ml. No other cause of graft-function loss was detected: an echography with Doppler was normal; no urinary infection was found. A thorough investigation of her medication revealed a new oestrogen gel-based treatment (Estreva 0.1%, Merck, France) requesting daily application of 0.5 mg/day (one-third of the recommended doses). Despite the small estradiol doses, plasma tacrolimus concentrations apparently significantly increased because of medical interaction between tacrolimus and the oestrogen preparation. A drastic reduction (60%) in the daily doses of tacrolimus was necessary to reach the therapeutical plasma concentrations again: the tacrolimus plasma trough level reached 6.4 ng/ml, serum creatinine 1.3 mg/dl and eGFR 44 ml/min/m2, 2 weeks after a progressive reduction in the tacrolimus dosage. Both tacrolimus and estradiol are metabolized through the CYP450 3A4 enzyme complex [1,2,5]. Tacrolimus is a well-known strong inhibitor of the 2-estradiol metabolization phases (hydroxylation and glucuronidation) [2,4], delaying its elimination. While estradiol inhibits hepatic as well as intestinal CYP450 3A4 [3], it induces a lowering in the tacrolimus metabolism. This inhibition shows an inter-individual variability [3]. The transdermic administration avoids the hepatic ‘1st passage’ phenomenon, which explains the fact that even small doses are sufficient to create a systemic effect. Co-administration of tacrolimus with oestrogen is possible, but a close monitoring of tacrolimus trough levels and renal function is necessary. Even small doses of estradiol can create severe interactions with tacrolimus; therefore, clinicians should be aware of this harmful drug interaction in order to avoid potential renal graft dysfunction. Conflict of interest statement. None declared.

Isolated Liver Transplantation in an Infant With Ultrashort Gut

Intestinal function in children with very short bowel syndrome and related intestinal failure may improve after isolated liver transplantation. An infant with an ultrashort gut, ileo-cecal valve, and whole colon received total parenteral nutrition from the first days of life. Enteral feeding failed because of the progressive dilatation of the jejunal portion and motility disorders. He developed early severe cholestatic liver disease (aspartate transferase 186, alanine transferase 103 U/L, serum bilirubin 8.4 mg/dL) and subsequent liver failure. At 8 months of age, he benefited from isolated liver transplantation (left segment graft from living donor). His early posttransplant evolution was characterized by recovery of oral alimentation, improvement of digestive and absorption functions, but he did not achieve TPN-independence. At 20 months, 50% to 60% of his energy needs were covered by parenteral nutrition and he has satisfactory growth indices (3rd percentile for weight and height), reduced stool volume, and frequency. Isolated liver transplantation allowed, in this particular case, time for further intestinal adaptation thereby avoiding the need for intestinal transplantation early in life.

Comparison Between Clinical and Histopathological Scoring in Cadaveric Kidney Transplantation and Its Correlation With Posttransplant Evolution

Introduction There are several scoring systems, both clinical (Deceased Donor Score [DDS]) and histopathological (Remuzzi [REM]), that attempt to determine acceptability criteria for deceased donor kidney transplant. A retrospective study was performed among a group of kidney transplant recipients to evaluate posttransplant evolution with clinical and histopathological scores. Materials and methods Among 107 first deceased donor kidney transplant patients, 95 had undergone a pretransplant biopsy. Donor age was 38.46 ± 16.9 years; recipient age: 49.2 ± 16.3 years; DDS was 15.58 ± 7.29. REM was 2.89 ± 1.7. Delayed graft function was 64.2%. Induction therapy was administered to 49.5%. Cold ischemia time (CIT) was 1364 ± 348 minute. Time on dialysis was 2275 ± 1501 days. Induction therapy, immunosuppressive regimens, CIT, and time on dialysis were not significantly different among the groups. One-year patient and graft survival were 94.5% and 86%, respectively and 2-year values, 92.6% and 81%, respectively. Conclusion DDS showed a significant correlation with serum creatinine values over 1 and 2 years. REM did not show a significant association with any events. The differences were sustained after adjusting for other variables. Graft survival maintained a strong correlation with DDS categories and no association with REM. The clinical characteristics of a deceased donor appeared to be of greater importance than the biopsy findings in terms of posttransplant events.

Second Neoplasm after Bone Marrow Transplant (BMT).

Introduction: the second neoplasm, are pathologies described during the post transplant evolution, often associated to immunosuppression. The post transplant lymphoproliferative syndromes, habitually associated to viruses are the most frequent. The BMT is a procedure clearly different from the rest of the transplants, and this difference would also be observed on the incidence and type of tumor in its evolution.The incidence of second malignancies after BMT is low, and is related to the use of chemotherapy, particulary alkylating. agents radiotheraphy and immunosuppression.Objective: To analyze the incidence and characteristics of second neoplasm of the patients undergoing BMT in our Institute.Results: Between 06/93 and 04/05 over a total of 416 transplants, 132 Allogenic and 284 Autologous, 6 cases of second tumor in variable intervals post procedure were stated.Table 1.The data reflects an incidence of second neoplasias of 1,4% (6/416). None of then received radiotherapy in conditioning. No lymphoproliferative syndrome was observed; 2 cases of acute leukemias; being the rest solid tumors with expected evolutions for each pathology.Table 1CaseDiseaseConditioningBMT2nd TumorTime betwen BMT-TumorEvolution1MML-PAMAUTOLung Cancer120 monthsDead2CMLBuCyALLOColon Cancer72 monthsDead3MDSBuCyALLOMerckel cells tumor60 monthsDead4NHLCBVAUTOAML65 monthsDead5NHLCBVAUTOBladder Cancer58 monthsAlive 26 months6NHLCBVAUTOAML4 monthsDead

Antibodies Against the Donor Antigen Glutathione S-Transferase T1 After Renal Transplantation

The aim of the present study was to determine whether a kidney graft expressing the glutathione S-transferase T1 enzyme (GSTT1) could cause an alloimmune response in a recipient with the null GSTT1 genotype that was similar to that observed in liver transplant. We have found anti-GSTT1 antibodies in the sera of a number of patients and confirmed that only one of the four possible genetic combinations—positive donor/null receptor—could lead to the production of these antibodies. Nevertheless, the main finding of this study is that in kidney transplantation, this mismatch was not sufficient to trigger an immune reaction. Longer follow-up of the posttransplant evolution of the patients is required in order to clarify the contribution of the factors involved in this process.

COMPARISON OF CYTOKINE GENE POLYMORPHISMS IN PATIENTS WITH SHORT- AND LONG-TERM RENAL TRANSPLANT SURVIVAL.

P19 Aim: Cytokines play an important role in the regulation of the immune response to alloantigens, conditioning both rejection and functional tolerance to the grafted tissue. There is strong evidence that cytokine production is under genetic control and that polymorphisms on their genes correlate with the amount of cytokine produced. Although, there is accumulating evidence that cytokine gene polymorphisms correlate with graft survival and post-transplant evolution, it is still controversial on the type of post-transplant events that are influenced by such polymorphisms and which of these polymorphisms exhibit the higher association. The aim of the present study was to compare the frequency of several cytokine alleles in patients with different post-transplant outcomes, this is, patients that lost their kidney graft during the first year post-transplant, due to acute rejection, compared to patients that have functional grafts, with no evidence of rejection, after more than 10 years post-transplantation. Patients and Methods: The group of patients with rejection during the first year (n=61) includes 5 with HLA-haploidentical living-related donor (LRD) and 56 with cadaveric donor (CD) (HLA-ABDR mismatches=4.0[tmsnew]177[/tmsnew]0.13), 52 of whom received cyclosporine in their immunosuppression protocols. The group of patients with no rejection (n=61) includes 36 with LRD (10 HLA identical and 26 HLA-haploidentical) and 25 with CD (HLA-ABDR mismatches=4.0[tmsnew]177[/tmsnew]0.23); 46 of them received cyclosporine. Cytokine genotyping was done by PCR-SSP (Polymerase chain reaction – Sequence Specific Primers) using the Cytokine Typing Tray Kit produced by the Collaborative Transplant Study (CTS) that includes IL-1α, IL-1β, IL-1R, IL-1Ra, IL-2, IL-4, IL-6, IL-10, TNFα, IFNγ and TGFβ. Results: With the number of patients genotyped, so far, it has been possible to demonstrate an increased frequency of GG/GG genotypes for IL-2(-330/+166) in the group of short-term compared to long-term survivors (p=0,0110). This difference was particularly higher for IL-2(-330) GG genotype that was present in 27% of short-term survivors compared to only 2% of the long-term survivors (p=0,0041). TNFα(-238) GG genotype was found in a higher frequency in short-term (91%) than in long-term (64%) survivors (p=0,0023). There were no significant differences for other cytokine polymorphisms. Conclussion: Although the number of short- and long-term survivors after kidney transplantation is still small, the results suggest that the genotypes of IL-2 and TNFα gene promoters influence graft survival. IL-2 is important in the regulation of T cell activation and clonal expansion, whereas TNFα is an important mediator during graft rejection, supporting that the genetic regulation of graft survival is the result of different steps of immune reaction elicited by allografts.

Spectral analysis of heart rate variation following simultaneous pancreas and kidney transplantation

Only marginally improved results have been observed in standard autonomic function tests (AFT) in follow-up studies after simultaneous pancreas and kidney transplantation (SPK). We therefore used power spectral analysis (PSA) of heart rate variability (HRV) to assess the effect of SPK on autonomic neuropathy in patients with type I diabetes mellitus (DM I). We evaluated 82 patients with DM I who were insulin and dialysis free following SPK. Both pre- and posttransplant (at [mean ± SD], 25 ± 15 months post-SPK) examinations were performed in 29 patients. Posttransplant evolution was examined in another 60 patients with two serial examinations at 20 ± 20 and 43 ± 27 months after SPK. Comparisons included 32 age-matched healthy controls and 13 patients with kidney transplant alone (KTA) matched for age and duration of DM I at a comparable time point posttransplant. Short-term time (modified Ewing battery) and frequency domain (PSA of HRV: LF-low, HF-high frequency, and TP-total spectral power) analysis was performed with a telemetric, on-line, computer-aided system.Significantly worse results in all standard AFT and PSA indexes were obtained for SPK patients compared with controls at all time points. No significant improvement was seen in SPK patients in the posttransplant period and no differences were found compared with KTA patients.Thus the results of a power spectral analysis of HRV failed to show improvement following SPK. This examination adds little positive information to that obtained from standard autonomic function tests.

Infectious complications associated with liver transplantation: analysis of 104 patients

Infectious complications are the main cause of morbidity and mortality during the first year after liver transplantation. The aim of the present study was to determine the incidence, microorganisms and factors associated with the development of infectious complications. Retrospective analysis of infectious episodes during the first year after transplantation in 104 patients undergoing transplantation between April 1995 and December 1996. The various clinical variables related to the pre-transplant disease, the surgical intervention and post-transplant evolution were evaluated with the aim of identifying predictive factors for the development of bacterial infectious complications. During the first year, 51 patients (49%) presented 111 infectious episodes. The most frequent infections were bacterial (66%); 21% were cytomegalovirus infections and 22% were fungal. The incidence of bacterial infections was highest during the first month (80% of all infectious episodes in this period). Two variables were independently associated with the development of bacterial infections in the first month following transplantation: prolonged ischemia of the graft (p = 0.002) and length of stay in the intensive care unit (p = 0.002). Infectious complications caused 8 of the 11 deaths that occurred during the 1-year follow-up. Mortality associated with invasive fungal infections was 100%. Although the overall incidence of infections and associated mortality has decreased, it remains the main cause of mortality and morbidity in the first year after transplantation.

The characteristics of Trypanosoma cruzi strains isolated from patients who have undergone a heart transplant

Three strains of Trypanosoma cruzi were isolated from Chagas' disease patients transplanted for heart failure, after cardiac transplantation, and were studied in an experimental model of Chagas' disease, in mice, with evaluation of parasitic load, mortality and extension of inflammatory infiltrates in the heart. These parameters were compared with the standard strain Y. The strains had differences in the studied parameters, but there was no clear relationship between those and post-transplant evolution of the patients. Probably the clinical response is multifactorial and derives only in part from biological characteristics of the infecting T. cruzi strain, as measured in our model.

Serum immunoglobulin levels following allogeneic bone marrow transplantation.

In order to study the posttransplant evolution of serum immunoglobulin levels, we measured serum IgG, IgA and IgM levels in 50 recipients of allogeneic bone marrow before transplantation and at different intervals thereafter (days 39, 120, 365 and 730). IgG and IgM levels were depressed for 1 year and IgA levels for 2 years posttransplant. Immunoglobulin deficiency was more severe and prolonged in patients with graft versus-host-disease. Hypogammaglobulinemia may contribute to the frequent infections observed in these patients, especially those with chronic graft-versus-host disease.

The “One Day at a Time” Syndrome in Post-Transplant Evolution: The Regressive Megalomanic Model versus the Progressive Hypomanic Model

After kidney transplantation patients experience an initial period of euphoria which is usually followed by a phase of disillusionment and depression. At this point the "one day at a time syndrome" appears as an attitude of adaptation and defense. It is proposed that there are two dynamically and prognostically different varieties of this syndrome: A first type represents a regressive megalomanic defense whereby depressive anxiety concerning the rejection of the part-self represented by the graft is conscious but depressive anxiety concerning the eventual death of the whole self is omnipotently denied. This variety of the syndrome is related to a more negative prognosis both psychologically and somatically. The second type of the "one day at a time syndrome" is a progressive hypomanic defense whereby depressive anxiety concerning the rejection of the part-self represented by the graft is present and conscious but relative and does not preclude the conscious depressive anxiety concerning the eventual death of the whole self, which once acknowledged can gradually be mastered, permitting the pursuit of as pleasurable a life as possible. This variety of the syndrome is prognostically more favourable both physically and psychologically.