Medication adherence and rejection rates in older vs younger adult liver transplant recipients

A growing number of older adults are undergoing liver transplantation (LT) in the United States. In some settings, it is thought that adherence declines with age. This retrospective study examined adherence and clinical outcomes in older vs younger adult LT recipients. Medical records of adult LT recipients from 2009 to 2012 from a single urban center were reviewed. The medication level variability index (MLVI) was the predefined primary outcome, with nonadherence defined as MLVI >2.5. The secondary outcome was incidence of rejection. Outcomes were evaluated starting 1 year post‐LT until 2015. A total of 42 of 248 patients were ≥65 at transplant. Older adults had significantly better adherence than younger ones (65%≥65 were adherent vs 42% younger adults; chi‐square two‐tailed P=.02). Survival analyses of rejection between age groups censored by time since transplant showed no difference among the four age groups (χ²=0.84, P=.84). Older age was not found to be a risk factor for reduced adherence or graft rejection in patients surviving at least 1 year post‐LT.     

The impact of reduced immunosuppression on graft outcomes in elderly renal transplant recipients

Abstract: Optimal immunosuppression (IS) for elderly kidney transplant recipients is unknown. We conducted a retrospective cohort study of recipients aged 60 yr or older to examine the impact of reduced IS on graft outcomes. Group 1 patients (n = 101) were initiated on mycophenolate mofetil 2 g/d and tacrolimus, target level 10–12 ng/mL; Group 2 patients (n = 88) with 1 g/d and 8–10 ng/mL, respectively. Dose adjustments were made as required. The groups were comparable except for diabetes, end‐stage renal disease duration, and induction. Mycophenolate mofetil dose was reduced in 62% and 38% of the patients, respectively (p < 0.01). Patients were followed for 23.8 ± 14.2 and 21.3 ± 11.8 months post‐transplant (p = 0.2). Twenty‐seven cases in Group 1 (26.7%) and eight in Group 2 (9.1%) lost their grafts (p = 0.01); 19 (18.8%) and 7 (8.0%) cases in each group because of death, respectively (p = 0.09). Sixteen patients in Group 1 (15.8%) and 18 in Group 2 (20.5%) experienced acute rejection (p = 0.36). Patients in Group 2 had a lower risk of graft loss compared with those in Group 1 [adjusted hazard ratio (HR): 0.27, p = 0.006, 95% CI: 0.11–0.69]. There were no significant differences between the groups regarding graft function, BK virus nephropathy, and CMV infection. Our results suggest that reduction in overall IS in this group was associated with improved graft and patient survival.     

Risk of malignancy with long-term immunosuppression in renal transplant recipients

BACKGROUND: Improvements in immunosuppressive regimens have significantly enhanced patient and graft survival in renal transplant recipients. However, susceptibility to neoplastic disorders is increased as a consequence of prolonged immunosuppression. Available data pertaining to cancer risks in renal transplant recipients have been inconsistent, and much of it is derived from international studies, which may not be truly representative of the United States population. METHODS: We studied a total of 1979 transplants performed in 1739 patients from a single center in the United States with a mean follow-up of 6.1 years, and a total of 9852 person-years' follow-up. RESULTS: The mean age at the time of diagnosis of cancer was 50 years, and the mean interval between transplant and diagnosis of cancer was 95 months. Older patients receiving a transplant had a significantly higher risk for developing cancer as opposed to younger patients (RR 6.2 for >60 years compared with <40 years). When compared with the general population using data from the Surveillance, Epidemiology and End Results (SEER) registry, the overall risk for nonskin malignancies was modestly increased in our transplant recipients, with a standardized incidence ratio (SIR) of 1.4 (P= 0.01). When stratified by age groups, younger age at transplant (<40 years) had the highest SIR, at 2.3 (P < 0.001). Similarly, duration post-transplant >10 years had an SIR of 2.4 (P < 0.001). CONCLUSION: We believe that this study is representative of the United States' renal transplant population, and highlights the need for reduced immunosuppression in the long-term and increased vigilance for cancers in younger patients receiving renal transplantation.     

Acute cellular rejection in liver transplant recipients under cyclosporine immunosuppression: predictive factors of response to antirejection therapy

BACKGROUND: Predictive factors of response to antirejection therapy in acute cellular rejection (ACR) in liver transplantation are not well established. METHODS: To investigate the possible existence of these factors, we reviewed 111 consecutive episodes of ACR fulfilling the following criteria: histologically confirmed ACR; cyclosporine-based immunosuppression; initial antirejection treatment with high-dose steroid boluses; minimum follow-up of 2 weeks after treatment; and no other graft complication interfering with evaluation of therapeutic response. ACR episodes not responding to initial steroid therapy were given additional treatment (OKT3 and/or repeated steroid boluses). We analyzed the association of the response to the antirejection treatment with different clinical, laboratory, histological, and donor-recipient compatibility variables at two times: after the initial antirejection therapy, and after all the antirejection therapy administered. RESULTS: Eighty episodes of ACR (72%) resolved after the initial therapy with high-dose steroid boluses, and another 18 (16%), initially steroid-resistant, resolved with additional antirejection treatment. Thirteen episodes (12%) were refractory to all antirejection treatment administered. Variables with independent predictive value of nonresponse to initial therapy with steroid boluses were late-onset ACR (>2 months after transplantation), high serum bilirubin and alanine aminotransferase, low blood cyclosporine concentration in the week before antirejection treatment, and severe histological endothelialitis. Late-onset ACR and high serum bilirubin were also independent predictors of refractoriness to all the treatment administered. CONCLUSIONS: Response to antirejection treatment in ACR in liver transplantation can be predicted by several clinical and laboratory data. ACR episodes with factors predictive of therapeutic unresponsiveness could benefit from more aggressive antirejection treatment.     

Weaning of immunosuppression in living donor liver transplant recipients

BACKGROUND: Some reported studies have indicated the possibility of immunosuppression withdrawal in cadaveric liver transplantation. The aim of this study was to evaluate the possibility and feasibility of weaning living donor liver transplant recipients from immunosuppression. METHODS: From June of 1990 to October of 1999, 63 patients were considered to be weaned from immunosuppression. They consisted of 26 electively weaned patients and 37 either forcibly or incidentally weaned patients (nonelective weaning) due to various causes but mainly due to infection. Regarding elective weaning, we gradually reduced the frequency of tacrolimus administration for patients who survived more than 2 years after transplantation, maintained a good graft function, and had no rejection episodes in the preceding 12 months. The frequency of administration was reduced from the conventional b.i.d. until the start of weaning to q.d., 4 times a week, 3 times a week, twice a week, once a week, twice a month, once a month, and finally, the patients were completely weaned off with each weaning period lasting from 3 to 6 months. The reduction method of nonelective weaning depended on the clinical course of each individual case. When the patients were clinically diagnosed to develop rejection during weaning, then such patients were treated by a reintroduction of tacrolimus or an additional steroid bolus when indicated. RESULTS: Twenty-four patients (38.1%) achieved a complete withdrawal of tacrolimus with a median drug-free period of 23.5 months (range, 3-69 months). Twenty-three patients (36.5%) are still being weaned at various stages. Sixteen patients (25.4%) encountered rejection while weaning at median period of 9.5 months (range, 1-63 months) from the start of weaning. All 16 were easily treated with the reintroduction of tacrolimus or additional steroid bolus therapy. CONCLUSIONS: We were able to achieve a complete withdrawal of immunosuppression in some selected patients. Although the mechanism of graft acceptance in these patients has yet to be elucidated, we believe that a majority of long-term patients undergoing living donor liver transplantation may, thus, be potential candidates to be successfully weaned from immunosuppression.     

Tolerability of everolimus-based immunosuppression in maintenance liver transplant recipients

Vallin M, Guillaud O, Morard I, Gagnieu M‐C, Mentha G, Adham M, Morelon E, Boillot O, Giostra E, Dumortier J. Tolerability of everolimus‐based immunosuppression in maintenance liver transplant recipients.
Clin Transplant 2011: 25: 660–669. © 2010 John Wiley & Sons A/S. Abstract: Background: The aim of this study was to evaluate the tolerability of the conversion from calcineurin inhibitor (CNI) to everolimus (ERL) in maintenance liver transplant (LT) recipients. Methods: From January 2005 to March 2008, ERL was introduced after LT as maintenance immunosuppressive therapy because of (i) de novo or recurrent cancer after LT, (ii) pre‐existing liver carcinoma on the liver explant or (iii) CNI toxicity. CNI dosage was progressively reduced until discontinuation. Results: The study population included 94 patients, of mean age 57 ± 10. The mean delay between LT and ERL introduction was 5 ± 5 yr. After a mean follow‐up of 12 ± 7 months, 70% of the patients did present at least one side effect. The mean trough level of ERL was 6 μg/L at the end of follow‐up. Main side effects included hyperlipidemia (37%), dermatitis (19%), mucositis (15%), and proteinuria (18%). Biopsy‐proven acute rejection occurred in 9% of patients. Global ERL discontinuation rate was 21% (16% because of side effects). Conclusions: The results of our experience indicate that conversion to ERL is associated with adverse effects in 70% of patients leading to drug discontinuation in 16% (and amenable to dose reduction in the remainders). Longer follow‐up periods are necessary to capture the impact of ERL fully on renal function and survival in cancer patients.     

Acute rejection risk in kidney transplant recipients on steroid-avoidance immunosuppression receiving induction with either antithymocyte globulin or basiliximab

Immunosuppression with rapid discontinuation of corticosteroids, usually with induction therapy, is safe in kidney transplant recipients. In 89 patients, we induced immunosuppression with basiliximab or rabbit antithymocyte globulin (17 and 72 patients, respectively). Selection criteria for basiliximab were age (>or=65 years), history (malignancy; chronic infection), and type 1 diabetes mellitus (eligible for pancreas transplant). Steroids were administered through posttransplantation day 4 (five doses); maintenance immunosuppression was with tacrolimus and mycophenolate mofetil. At last follow-up (average, 286 days), most patients were steroid-free (antithymocyte globulin, 90%; basiliximab, 88%). Protocol biopsies were performed at 1, 4, and 12 months posttransplantation. The overall risk of biopsy-proven acute rejection was 12%. At 6 months posttransplantation, acute rejection-free survival was 93% for antithymocyte globulin, 65% for basiliximab (P<.001). Median time to biopsy-proven acute rejection was 27 and 71 days, respectively. The low incidence of biopsy-proven acute rejection with steroid-avoidance immunosuppression may be further reduced with antithymocyte globulin.     

Renal transplantation outcomes: a comparative analysis between elderly and younger recipients

Renal transplantation is presently the best treatment for end-stage renal disease, although considered contraindicated for elderly patients. However, more investigation is needed due to higher life expectancy rates of the general population and the increasing number of over 60-yr-old patients with chronic renal failure dependent upon dialysis. This study aims to determine graft and patient survival rates of renal transplant patients 60 yr and older compared to a younger group (50-59 yr old). Relevant pre- and post-transplant clinical data related to graft and patient survival in both groups were also investigated. Three-hundred and twenty consecutive renal transplant patients were enrolled in this study and grouped based on age at the time of the transplantation: one-hundred and ten patients at or over 60 yr old (elderly group) and 210 patients ranging from 50 to 59 yr old (younger group). There were no statistical differences in either group regarding clinical characteristics and immunological risk factors. The incidence of acute rejection was higher in the younger group (37.6%) than in the elderly (22.7%) (p = 0.01). Censored to death graft survivals at five yr were respectively 86.7% for patients > or = 60 yr and 82.1% for patients 50-59 yr old (p = 0.49). Patient survival rates at five yr were respectively 76.2% for patients > or = 60 yr and 81.6% for patients 50-59 yr old (p = 0.33). Our data show that renal transplantation for elderly patients has similar results to those found in younger individuals, which does not make age, in and of itself, a contraindication for transplantation.     

Hepatitis E virus infection and rejection in kidney transplant recipients

BackgroundHepatitis E virus (HEV) infection has been associated with immune-mediated kidney diseases in developing countries. However, its relationship with kidney transplant outcomes has never been studied. We investigated the association between HEV infection and kidney graft rejection among kidney transplant recipients (KTRs).MethodsWe conducted a matched cohort and longitudinal study utilizing banked sera following kidney transplantation during 1988–2012. Studies with evidence of post-transplantation HEV infection were identified by positive ELISA tests (anti-HEV IgM or anti-HEV IgG seroconversion) or positive HEV PCR and matched to KTR controls with negative HEV ELISA and PCR tests in a 1:5 ratio by age, sex, crossmatch status, immunosuppression era, and time of HEV testing. Outcome data collected included time to first kidney graft rejection, transaminases, and glomerular filtration rates. Log-ranked test was used to analyze survival.ResultsOf 271 KTRs, 9 (3%) had evidence of post-transplantation HEV infection and were compared to 45 negative, matched controls. Median age at transplantation was 46 years. Kidney graft rejection was reported in 8 (89%) of cases and 21 (47%) of controls. Median time to first episode of kidney graft rejection was 17.4 months in cases and 30.8 months in controls (p = 0.029), with a higher hazard of developing kidney graft rejection in cases (HR = 3.23, 95% CI: 1.19–8.79). Lower mean glomerular filtration rates over time were observed in cases (35 mL/min/1.73m²) versus controls (42.4 mL/min/1.73m²) but did not reach significance (p = 0.24).ConclusionSubjects with evidence of post-transplantation HEV infection demonstrated earlier kidney graft rejection compared to controls.     

The elderly have similar outcomes compared to younger patients after ORIF with locking plate for comminuted proximal humerus fracture

Objective

The aim of this study was to compare clinical and radiological outcomes of elder and younger patients with comminuted proximal humerus fracture treated with osteosynthesis with locking plate.

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case–control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17–83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03–1.36), and therapy with renin–angiotensin–aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47–34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.     

Infusion of donor spleen cells and rejection in liver transplant recipients

Intact or inactivated donor lymphoid cells have been found to downregulate the alloimmune response in a number of experimental models. We conducted a randomized, prospective, double blind, and placebo-controlled trial to determine whether heat-treated donor spleen cells would affect early rejection after liver transplantation. Donor spleen was obtained during organ procurement for 40 patients undergoing liver transplantation. All patients were treated with cyclosporine, azathioprine and steroids. The patients were randomized after surgery to receive either heat-treated (45 degrees C for 1 h) spleen cells or placebo. Patients underwent protocol biopsies at 1 wk, 4 and 12 months, or as needed. Biopsies were reviewed in a blind fashion and scored according to the Banff consensus criteria. Randomization resulted in 19 patients in the spleen cell group and 21 in the placebo group. One-yr graft survival was 94 and 100%, respectively. Early rejection was more frequent in the spleen cell group (61 vs. 35%, p, not significant). The histopathological rejection activity index at 7 d was also higher for the patients in the spleen cell group: 39% of spleen cell treated patients had a score of 4 or higher as opposed to 5% in the placebo group (p < 0.01). The mean score was 2.9 +/- 2.8 for the spleen cell group versus 1.3 + 1.7 for the placebo group (p = 0.034). It is concluded that heat-treated donor spleen cells given within 24 h after liver transplantation were not clinically beneficial and increased the intensity of rejection in 7-d protocol liver biopsies.     

Use of immune function test in monitoring immunosuppression in liver transplant recipients

Immune function test (Immuknow^?) is a measure of cell‐mediated immunity based on peripheral CD4⁺ T cell adenosine triphosphate activity (desired range, 225–525 ng/mL). We evaluated the role of immune function test (IFT) in monitoring and adjustment of immunosuppression in orthotopic liver transplant (OLT) recipients. A total of 289 IFTs were obtained from 171 patients from March 2007 to June 2008. Graft/patient status was classified as stable, serious infection, or malignancy. IFT levels were analyzed with duration of follow‐up after OLT, graft/patient status, and the presence of hepatitis C (HCV) infection. The mean age was 54 ± 14 yr, with 62% men. The median follow‐up was 65 (2–249) months. Mean IFT levels were significantly lower in patients who were <24 months than in those ≥24 months post‐OLT (220 ± 19.5 vs. 257 ± 11.3 ng/mL, p = 0.03). Clinically stable patients had higher IFT levels than those with serious infection or malignancy (254 ± 11.1 vs. 162.5 ± 23.9, p < 0.001). HCV‐infected patients had lower IFT levels than uninfected patients (206.7 ± 15.7 vs. 273 ± 12.0 ng/mL, p < 0.001). Immunosuppression was reduced in 58 patients with IFT levels <225 ng/mL, and 90% maintained stable graft function after a median follow‐up of 22 (1–39) months. IFT may be a useful tool in monitoring and lowering of immunosuppression in long‐term OLT recipients.     

Cytokine gene polymorphism and early graft rejection in liver transplant recipients

Cytokines, which play important roles in allograft rejection, show variable production among individuals. These variations may be related to genetic polymorphisms within the regulatory regions of the cytokine genes. We investigated the association between the role tumor necrosis factor alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interferon gamma (IFN-gamma), interleukin (IL)-10 and IL-6 gene polymorphisms and early graft rejection among liver transplant recipients. Forty-three liver transplant recipients enrolled in this study were divided into 2 groups based on events in the first 2 months posttransplantations, namely, those experiencing at least 1 rejection episode (n = 26) or those without any episode (n = 17). The allele or genotype frequencies of cytokine gene polymorphisms showed no difference between liver recipients with or without nonrejection. In conclusion, there was no significant correlation between early graft rejection and cytokine gene polymorphism of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma in liver transplant recipients.