Nikos Emmanouilidis

Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study

BACKGROUND Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors (CNI) in liver-transplant recipients. We undertook a randomised study to assess the safety and efficacy of CNI withdrawal and replacement by mycophenolate mofetil. METHODS 28 people who had had renal dysfunction attributable to suspected CNI toxicity after liver transplantation participated in the study. We replaced CNI with mycophenolate mofetil in a stepwise pattern in half the group (study patients); the other half (controls) stayed on CNI immunosuppression. Renal function, blood pressure, uric acid, and blood lipids were measured before and 6 months after study entry. Side-effects of medication and graft function were recorded throughout the study. FINDINGS At the end of the study, mean (SD) serum creatinine had fallen by 44.4 (48.7) micromol/L in study patients compared with 3.1 (14.3) micromol/L in controls; a mean difference of 41.3 micromol/L (95% CI 12.4-70.2). Moreover, systolic and diastolic blood pressure, and serum uric acid decreased significantly in the study group but not in the control group (mean [95% CI] between group differences 10.8 mm Hg [3.0-18.6], 5.0 mm Hg [0.9-9.2], and 83.1 micromol/L [12.7-153.6], respectively). There were no changes in cholesterol or triglyceride concentrations in either group. Side-effects were reported by eight of the study patients. Three reversible episodes of acute graft rejection occurred in study patients during mycophenolate mofetil monotherapy, whereas none occurred in the control group. INTERPRETATION Substitution of CNI by mycophenolate mofetil can improve renal function, blood pressure, and uric acid concentration of liver-transplant patients, but there is an increased rejection risk with mycophenolate mofetil monotherapy.

Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil.

BACKGROUND Renal dysfunction caused by treatment with the calcineurin inhibitors (CNI) is a major problem in the long-term course after liver transplantation. PATIENTS In 22 liver graft recipients with renal dysfunction and stable graft function between 3 weeks and 12 years after transplantation, CNI were substituted by MMF at a final dose of 1.5-3 g/day between October 1996 and October 1998. METHODS In a prospective non-randomized study, the development of renal function, the side effects of MMF medication, and the stability of liver function were analyzed for a mean follow-up of 15 months. Results. (1) MMF was withdrawn in four patients for major side effects between 1 and 7 months after study entry; eight patients had minor side effects. (2) Six months after study entry, renal function had improved in 17 of the 22 study patients; mean serum creatinine +/-SD (micromol/L) was 201+/-77 at entry and 153+/-65 after 3 months (P<0.001). (3) Improvement occurred in 11 of 15 patients with creatinine elevation > or =12 months and in 6 of 6 patients with creatinine elevation < or =6 months. (4) One patient developed transient liver dysfunction and a second required retransplantation for progressive cholestasis but without signs of rejection. CONCLUSIONS In patients who undergo liver transplantation, substitution of CNI by MMF leads to improvement of acute as well as chronic renal dysfunction in most cases. Side effects of MMF may be limiting in some patients, and the immunological consequences remain to be studied.

Living donor liver transplantation: effect of the type of liver graft donation on donor mortality and morbidity

To investigate the influence of the type of liver graft donation on donor mortality and morbidity. The clinical course of 87 living liver donors operated on at our center between 2002 and 2009 was retrospectively analysed and data pertaining to all complications were retrieved. No donor mortality was observed and no donor suffered any life‐threatening complication. Four donors (4.6%) developed biliary leakage, nine (10.3%) had to be readmitted to hospital and six (6.9%) required some or other type of reoperation related to the previous liver donation. Reoperations included incisional or diaphragmatic hernia repair (n = 4), biliary leakage repair (n = 1) and segmental colon resection combined with diaphragmatic hernia repair (n = 1). There was a statistically significant difference in hospital stay (P < 0.001), autologous blood transfusions (P < 0.001) and operating time (P < 0.005) when right lobe donations (Segments V–VIII) were compared with left lobe (Segments II–IV) and left lateral lobe (Segments II–III) donations, whereas no difference was found between these groups regarding hospital readmission, operative revisions and the incidence or severity of complications. Right lobe donation was associated with prolonged hospital stay, increased blood transfusions and prolonged operating time when compared with left and left lateral lobe donation, whereas donor mortality and morbidity did not differ between these groups.

Surgery and radioablation therapy combined: introducing a 1-week-condensed procedure bonding total thyroidectomy and radioablation therapy with recombinant human TSH

OBJECTIVE The objective of this study was to determine whether the use of recombinant human TSH (rhTSH) to stimulate radioiodine uptake after thyroidectomy is as efficacious as a period of withholding thyroid hormones, while at the same time avoiding hypothyroidism, reducing sick leave time and shortening the hospital stay. DESIGN Our aim was to compare the standard procedure of differentiated thyroid cancer treatment, which consists of thyroidectomy followed by 4 weeks of hypothyroidism and a conclusive ablative activity of (131)iodine, with a new shortened treatment in which l-thyroxine (T(4)) medication is initiated a day after thyroidectomy, followed by application of rhTSH stimulation and subsequent ablation a few days after surgery. We presumed our treatment to represent the most sophisticated strategy for the reduction in sick leave days overall without any reduction in safety or the efficacy of ablative therapy. METHODS Patients (n=25) were randomized either for surgery and rhTSH stimulation or surgery and l-T(4) abstinence before the first application of radioiodine. Ablation success was determined by neck ultrasound and serum thyroglobulin during follow-up. RhTSH receivers were monitored for an average of 635 days (s.d.+/-289) and patients in l-T(4) abstinence for an average of 624 days (s.d.+/-205). Both groups were statistically compared for significant differences in treatment efficacy, safety and overall time of sick leave. RESULTS AND CONCLUSIONS Our shortened treatment proved to be equally efficacious and safe in comparison with the conventional therapy regimen. At the same time, it showed economic advantages through the reduction in average sick leave time from approximately 29 days (l-T(4) abstinence) down to approximately 6 days (rhTSH stimulation) as well as sustaining the patients quality of life by the complete avoidance of hypothyroidism.

Immunosuppressive and trafficking properties of donor splenic and bone marrow dendritic cells.

Background. Infusion of donor dendritic cells (DC) has been shown to prolong allograft survival in a number of models. However, many regimens that utilize donor DC do not consistently produced tolerance or long-term allograft survival. We hypothesized that one factor limiting the therapeutic effect of donor DC is their relative inability to traffic to recipient peripheral lymph nodes and inhibit the function of resident alloreactive T cells. Methods. Donor strain DC isolated from the spleens or bone marrow of Flt3L-treated mice were transferred intravenously into recipients at the time of skin grafting. Where indicated, recipients were treated with an anti-CD40L antibody and CTLA4-Ig. Results. Infusion of donor DC together with costimulatory blockade promoted donor-specific prolongation of skin allograft survival in mice. Perhaps due to their more immature phenotype, bone marrow DC trafficked more effectively to the spleen, bone marrow, and thymus and were associated with significantly longer allograft survival than were splenic DC. Neither population of DC trafficked well to peripheral lymph nodes. Consistent with our hypothesis, splenic but not lymph node T cells from DC-treated recipients displayed donor-specific hyporesponsiveness in vitro. Conclusion. These data suggest that one factor contributing to rejection following treatment with donor DC plus costimulation blockade is the persistence of donor-reactive T cells within the recipient’s secondary lymphoid structures. Strategies to improve DC trafficking to these structures may enhance their therapeutic effect.

Effect of incomplete parathyroidectomy preserving entire parathyroid glands on renal graft function.

HYPOTHESIS Parathyroidectomy (PT) corrects tertiary hyperparathyroidism in patients who have received renal grafts but can result in deterioration of renal function. OBJECTIVE To compare different surgical procedures for their effect on renal function and efficacy to cure tertiary hyperparathyroidism. DESIGN A retrospective cohort study. SETTING University clinic. PATIENTS Eighty-three patients with functioning renal grafts receiving PT for the first time. INTERVENTIONS Group 1 received an incomplete PT, with at least 1 entire parathyroid gland (PG) remaining in situ (n = 12). Group 2 received an incomplete PT, with the most morphologically conserved PG partially resected (n = 22). Group 3 received a complete PT, with autotransplantation of PG tissue (n = 49). MAIN OUTCOMES MEASURES The primary end point was the postoperative change in glomerular filtration rate. Secondary end points were rates of redialysis, hypercalcemia, and hyperparathyroidism within 5 years. RESULTS A decrease in glomerular filtration rate occurred postoperatively in 75 patients (90%) and correlated significantly with the extent of PG resection. Recovery of renal function at month 6 was observed in group 1, but not in groups 2 and 3 (P < .001). Seven patients (8%) needed permanent dialysis (1 in group 2 and 6 in group 3). Hypercalcemia was abrogated in 78 patients (94%), without significant differences among the groups. Assessment of parathyroid hormone levels in accordance with target ranges from the Kidney Disease Outcomes Quality Initiative guidelines did not reveal significant differences in the rates of recurrent hyperparathyroidism. CONCLUSION Incomplete PT preserving at least 1 entire PG does not cause deterioration of renal graft function and provides long-term correction of hypercalcemia and tertiary hyperparathyroidism.

Induction of chimerism and tolerance using freshly purified or cultured hematopoietic stem cells in nonmyeloablated mice.

The development of protocols to induce a state of durable mixed allogeneic hematopoietic chimerism to confer robust donor-specific transplant tolerance has been a major focus of the transplant community for the past decade. High levels of mixed allogeneic hematopoietic chimerism across a full major histocompatibility complex (MHC) barrier can be achieved by total myeloablation and transfusion of host and donor bone-marrow cells or, as shown more recently, can be achieved with nonmyeloablative preconditioning regimes in combination with donor bone-marrow transfusions (2-4) or transfusion of purified hematopoietic stem cells (HSC) (5-7). Here we illustrate useful experimental techniques for the study of hematopoietic chimerism in rodents by describing a system in which chimerism can be induced using nonmyeloablative conditioning, short-term costimulation blockade, and transplantation of purified or cultured hematopoietic stem cells.

Liver Transplantation for Hepatocellular Carcinoma: A Single Center Resume Overlooking Four Decades of Experience.

Background. This is a single center oncological resume overlooking four decades of experience with liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods. All 319 LT for HCC that were performed between 1975 and 2011 were included. Predictors for HCC recurrence (HCCR) and survival were identified by Cox regression, Kaplan-Meier analysis, Log Rank, and χ 2-tests where appropriate. Results. HCCR was the single strongest hazard for survival (exp⁡(B) = 10.156). Hazards for HCCR were tumor staging beyond the histologic MILAN (exp⁡(B) = 3.645), bilateral tumor spreading (exp⁡(B) = 14.505), tumor grading beyond G2 (exp⁡(B) = 8.668), and vascular infiltration of small or large vessels (exp⁡(B) = 11.612, exp⁡(B) = 18.324, resp.). Grading beyond G2 (exp⁡(B) = 10.498) as well as small and large vascular infiltrations (exp⁡(B) = 13.337, exp⁡(B) = 16.737, resp.) was associated with higher hazard ratios for long-term survival as compared to liver transplantation beyond histological MILAN (exp⁡(B) = 4.533). Tumor dedifferentiation significantly correlated with vascular infiltration (χ 2 p = 0.006) and intrahepatic tumor spreading (χ 2 p = 0.016). Conclusion. LT enables survival from HCC. HCC dedifferentiation is associated with vascular infiltration and intrahepatic tumor spreading and is a strong hazard for HCCR and survival. Pretransplant tumor staging should include grading by biopsy, because grading is a reliable and easily accessible predictor of HCCR and survival. Detection of dedifferentiation should speed up the allocation process.

Post-Operative Hemorrhage After Liver Transplantation: Risk Factors and Long-Term Outcome

BACKGROUND Increasing scarcity of donated liver grafts clearly demonstrates the desperate need for ongoing outcome analysis to improve patient and graft survival after liver transplantation. Coagulation is often severely deteriorated in patients suffering from liver disease, thus leading to bleeding complications after liver transplantation. MATERIAL AND METHODS We included 770 liver transplantations in this single-center retrospective analysis to identify independent risk factors for post-operative hemorrhage. The relevance of bleeding complications was assessed with special regards to coagulation-related variables. Multivariate regression analyses allowed weighing of different risk factors. RESULTS Post-operative hemorrhage leading to revision surgery was observed in 19.9% (n=153 cases) of cases and was revealed as an independent risk factor for mortality (p=0.014; HR: 1.457; 95%-CI: 1.081-1.964). Risk-adjusted multivariate regression analysis compiling all pre- and intra-operative donor and recipient variables revealed that only the number of transfused packed red blood cells (p<0.001; OR: 1.072; 95%-CI: 1.036-1.110), hepatitis B virus-related liver disease (p=0.019; OR: 0.082; 95%-CI: 0.010-0.666), model of end-stage liver disease-era (p=0.020; OR: 1.016; 95%-CI: 1.002-1.029), partial thromboplastin time at transplantation (p=0.021; OR: 1.016; 95%-CI: 1.002-1.029), and donor intensive care unit stay in days (p=0.009; OR: 1.009; 95%-CI: 1.002-1.016) were significantly associated with the occurrence of post-operative hemorrhage. CONCLUSIONS Post-operative hemorrhage relevantly contributed post-transplant mortality. Avoidance of excessive packed red blood cell use during transplantation and short donor-intensive care unit stay lead to a decreased rate of bleeding complications. Coagulations state at transplantation is also relevant for favorable outcome.

Presence of small parathyroid glands in renal transplant patients supports less-than-total parathyroidectomy to treat hypercalcemic hyperparathyroidism.

BACKGROUND Parathyroid glands (PG) are rarely analyzed in renal transplant (RTX) patients. This study analyzes comparatively PG of RTX and end-stage renal disease (ESRD) patients. The clinical part of the study evaluates if total parathyroidectomy with autotransplantation (TPT+AT) treats appropriately hypercalcemic hyperparathyroidism in RTX patients. METHODS TPT+AT was performed in 15 of 23 RTX and 21 of 27 ESRD patients. Remaining patients underwent less-than-total PT. Volume and stage of hyperplasia were determined from 86 PG of RTX and 109 PG of ESRD patients. Patients were categorized according to the presence of small PG (volume < 100 mm(3)). Calcium homeostasis and hyperparathyroidism were evaluated 2 years after PT in RTX patients. RESULTS PG of RTX patients were significantly smaller, but similar hyperplastic in comparison to PG of ESRD patients. Small PG were more frequent in RTX than in ESRD patients (19% vs 6%) and mainly graded normal or diffuse hyperplastic (94%). Forty-seven percent of RTX, but only 14% of ESRD, patients receiving a total PT possessed ≥1 small PG (P < .05). Overall, PT treated successfully hypercalcemic hyperparathyroidism. However, TPT+AT caused permanent hypocalcemia in 50% of RTX patients without small PG and even in 83% of RTX patients with small PG. All RTX patients receiving less-than-total PT were normocalcemic at 2-year follow-up. Logistic regression revealed a 10.7 times greater risk of permanent hypocalcemia in RTX patients with small PG receiving TPT+AT compared with RTX patients without small PG receiving TPT+AT or RTX patients undergoing less-than-total PT. CONCLUSION Surgeons performing PT should be aware of the high frequency of small and less diseased PG in RTX patients. In this context, TPT+AT might overtreat hypercalcemic hyperparathyroidism in RTX patients, especially when small PG are present.