Biopsy-proven Acute Rejection Rates Research Articles

Immunosuppressive Induction Therapy Using the Antithymocyteglobulin Grafalon: A Single-Center Non-Interventional Study.

Background: Induction therapy with depleting antibodies in the setting of liver transplantation (LT) is discussed controversially to this day. The rabbit antithymocyteglobulin (ATG) Thymoglobulin (rATG) was introduced as early as 1984 and was frequently used as a standard regime for induction therapy after LT. There are no public reports characterizing Grafalon (ATG-F), a novel ATG, as an induction agent after LT. Objectives: The aim of this observational non-interventional study was to investigate the safety and efficacy of Grafalon induction therapy and characterize its clinical effects in the setting of LT. Methods: A cohort of 80 patients undergoing deceased donor LT at the Medical University of Vienna and receiving Grafalon as part of the clinical standard immunosuppressive regimen was prospectively included between March 2021 and November 2022. Patients were monitored closely for leukocytopenia and thrombocytopenia during the first postoperative week and followed up for incidence and severity of biopsy-proven acute rejection (BPAR), overall survival, and bacterial infections in the first year after LT. Results: The incidences of thrombocytopenia and leukocytopenia following Grafalon treatment peaked on postoperative day four, with 64% and 31%, respectively. However, there were no cases of severe leukocytopenia after the first postoperative week. Induction therapy with Grafalon resulted in a rate of localized bacterial infections and bacteremia of 28% and 21%, respectively. The rate of BPAR was 12.5% in the first year after LT; the one-year survival rate in this cohort was 90%. Conclusions: Overall, this study provides evidence of the safety and efficacy of Grafalon as an induction agent. Further studies investigating the potential long-term effects of Grafalon, as well as comparison studies with different immunosuppressive regimens, are needed in order to draw further conclusions.

Evaluation of Tacrolimus Concentrations and Clinical Outcomes Between Extended and Immediate Release Formulations in Kidney Transplant

Objectives: Tacrolimus remains the mainstay of immunosuppression in kidney transplantation. Understanding the relationship between therapeutic tacrolimus levels and outcomes of acute rejection, patient/graft survival, and tolerability are important. The relationship between time to therapeutic tacrolimus levels and outcomes has not been well established, specifically with the use of extended release tacrolimus formulation (LCP-Tac). This study investigated time to therapeutic tacrolimus levels of 2 tacrolimus formulations, LCP-Tac and immediate release tacrolimus (IR-Tac), as a predictor of clinical outcomes. Methods: This was a single-center, retrospective, cohort study of kidney transplant recipients at Duke Hospital between 2013-2021. The primary objective evaluated the difference in time to therapeutic tacrolimus levels with LCP-Tac vs IR-Tac regimens. Secondary endpoints included time within therapeutic range during the first 3 months post-transplant, incidence of biopsy-proven rejection, development of de novo donor specific antibodies, and patient and allograft survival at 12 months post-transplant. Results: 128 patients were included (63 in LCP-Tac group and 65 in IR-Tac group). The time to therapeutic tacrolimus level was similar between formulations (7.2 days with LCP-Tac compared to 6.7 days with IR-Tac, P = .63). The time within therapeutic range during the first 3 months post-transplant, via modified Rosendaal, was similar with LCP-Tac and IR-Tac (56.1% vs 64.8%, respectively). Rates of biopsy-proven acute rejection at 12 months were similar (7/63 (11.1%) compared to 4/65 (6.2%)). There was no difference in patient/graft survival between groups. Conclusions: The time to therapeutic tacrolimus levels did not differ based on tacrolimus formulation and was not correlated with clinical outcomes.

Renal Transplantation in Patients With Tuberculosis: A Single-center Experience From an Endemic Region.

Despite being a common infection in end-stage kidney disease patients, there are no evidence-based guidelines to suggest the ideal time of transplantation in patients on antitubercular therapy (ATT). This study aimed to examine the outcome of transplantation in patients while on ATT compared with those without tuberculosis (TB). This was a retrospective study. Renal transplant recipients transplanted while on ATT were compared with a 1:1 matched group (for age, sex, diabetic status, and type of induction agent) of patients without TB at the time of transplant. Patient outcomes included relapse of TB and graft and patient survival. There were 71 patients in each group. The mean duration for which ATT was given pretransplant was 3.8 ± 2.47 mo. The average total duration of ATT received was 12.27 ± 1.25 mo. Mortality in both the groups was similar (8.4% in the TB group versus 4.5% in the non-TB group; P = 0.49). None of the surviving patients had recurrence of TB during the follow-up. Death-censored graft survival (98.5% in the TB group versus 97% in the non-TB group; P = 1) and biopsy-proven acute rejection rates (9.86% in the TB group versus 8.45% in the non-TB group; P = 1) were also similar in both the groups. Successful transplantation in patients with end-stage kidney disease on ATT is possible without any deleterious effect on patient and graft survival and no risk of disease recurrence. Multicentric prospective studies are needed.

Evaluating anti-thymocyte globulin induction doses for better allograft and patient survival in Asian kidney transplant recipients

Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the optimal dose of ATG induction regimen in Asian kidney recipients is unclear. Using the Korean Organ Transplantation Registry, we performed a retrospective cohort study of 4579 adult patients who received renal transplantation in South Korea and divided them into three groups according to the induction regimen: basiliximab group (n = 3655), low-dose ATG group (≤ 4.5 mg/kg; n = 467), and high-dose ATG group (> 4.5 mg/kg; n = 457). We applied the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) package to generate high-quality propensity score weights for intergroup comparisons. During four-year follow-ups, the high-dose ATG group had the highest biopsy-proven acute rejection rate (basiliximab 20.8% vs. low-dose ATG 22.4% vs. high-dose ATG 25.6%; P < 0.001). However, the rates of overall graft failure (4.0% vs. 5.0% vs. 2.6%; P < 0.001) and mortality (1.7% vs. 2.8% vs. 1.0%; P < 0.001) were the lowest in the high-dose ATG group. Our results show that high-dose ATG induction (> 4.5 mg/kg) was superior to basiliximab and low-dose ATG induction in terms of graft and patient survival in Asian patients undergoing kidney transplant.

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P=.041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

Very Low Dose Anti-Thymocyte Globulins Versus Basiliximab in Non-Immunized Kidney Transplant Recipients.

The choice between Basiliximab (BSX) or Anti-Thymocyte Globulin (ATG) as induction therapy in non-immunized kidney transplant recipients remains uncertain. Whilst ATG may allow steroid withdrawal and a decrease in tacrolimus, it also increases infectious complications. We investigated outcomes in non-immunized patients receiving a very low dosage of ATG versus BSX as induction. Study outcomes were patient/graft survival, cumulative probabilities of biopsy proven acute rejection (BPAR), infectious episode including CMV and post-transplant diabetes (PTD). Cox, logistic or linear statistical models were used depending on the studied outcome and models were weighted on propensity scores. 100 patients received ATG (mean total dose of 2.0mg/kg) and 83 received BSX. Maintenance therapy was comparable. Patient and graft survival did not differ between groups, nor did infectious complications. There was a trend for a higher occurrence of a first BPAR in the BSX group (HR at 1.92; 95%CI: [0.77; 4.78]; p = 0.15) with a significantly higher BPAR episodes (17% vs 7.3%, p = 0.01). PTD occurrence was significantly higher in the BSX group (HR at 2.44; 95%CI: [1.09; 5.46]; p = 0.03). Induction with a very low dose of ATG in non-immunized recipients was safe and associated with a lower rate of BPAR and PTD without increasing infectious complications.

Treatment of De Novo Renal Transplant Recipients With Calcineurin Inhibitor-free, Belatacept Plus Everolimus-based Immunosuppression.

Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients: A Multicenter Cohort

Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. Prospective cohort. 862 deceased donors for 1,137 kidney recipients at 13 centers. We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. Multivariable Fine-Gray models with death as a competing risk. Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. BPAR was ascertained through for-cause biopsies, not surveillance biopsies. In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.

P16.37: Outcomes of COVID-19 Vaccination Among Kidney Transplant Recipients Admitted for COVID-19 at the National Kidney And Transplant Institute: A Retrospective Study

Background: Kidney transplant recipients are immunocompromised hosts of COVID-19 with a higher risk of infection and severe disease due to underlying CKD and long-term immunosuppression, thus vaccination against COVID is strongly recommended. However, studies indicate that transplant recipients mount lower antibody responses following vaccination compared with healthy individuals. Due to limited information on the outcomes of COVID-19 vaccination on transplant recipients, this study will examine the efficacy of vaccination in preventing severe to critical COVID in this immunocompromised population. Objective: To determine the outcomes of kidney transplant recipients admitted for COVID-19 at the National Kidney and Transplant Institute and the impact of COVID-19 vaccination status on their survival. Methods and Materials: A retrospective study of 131 kidney transplant recipients admitted for COVID-19 from March 2020 to December 2021. Descriptive statistics were used to summarize the clinical characteristics and outcomes of the participants. Results: The median age was 51 years old with a male gender distribution of 54.5%. Chronic glomerulonephritis was the most common primary renal disease. Diabetes, hypertension, and cardiovascular disease were the most common co-morbidities. Patients belonging to the critical COVID group were observed to have older kidney allografts with a median age of 120 months. Among 131 kidney transplant recipients, 24.8% were fully vaccinated and 74.2% were either unvaccinated or partially vaccinated. Of the 32 patients in the vaccinated group, 3 were vaccinated with Astra Zeneca, 5 received Janssen, 7 from Moderna, 10 from Pfizer, 1 received Sputnik and 12 received Coronavac (Sinovac). Among the vaccinated group, those who received Moderna and Pfizer vaccines were observed to have moderate COVID-19 disease progression only with 57.1% from the Moderna group and 40% from the Pfizer group. Among patients who progressed to critical COVID-19, it was observed that a significant number of them came from the Coronavac group. The need for oxygenation was observed in 64% of patients, of which 65.5% were unvaccinated. Acute kidney injury was reported in 43.5% of the overall population, 63.2% of which were observed in the unvaccinated group. Of the 16% who had graft loss during COVID-19 admission, 57.1% were unvaccinated. The incidence of death was lower among fully vaccinated than those in the partial and unvaccinated groups. Likewise, the probability of survival is highest among fully vaccinated than those partially vaccinated and unvaccinated. Renal graft biopsy on patients with COVID-19 has not been practiced at NKTI thus rendering rates of biopsy-proven acute rejection a limitation of the study. Conclusion: Our experience shows that lack of COVID-19 vaccination among kidney transplant recipients demonstrates a higher rate of mortality associated with COVID-19. Key words: COVID-19, renal transplantation, survival, Philippines.

Outcomes of 6 Human Leukocyte Antigen-Mismatched Living Donor Kidney Transplant: A Study With Biopsy Amendment.

In this study, we examined the graft and patient survival outcomes in patients with end-stage kidney disease who received 6 HLA-mismatched incompatible living donor kidney transplant. Patients who underwent living donor kidney transplant between January 2010 and March 2020 were evaluated retrospectively. Group A included kidney transplant recipients with 6 HLA mismatches, and group B included kidney transplant recipients with 0 to 5 HLA mismatches. Patients with <1 year of follow-up were excluded. All rejection episodes were diagnosed via Tru-Cut biopsy and histopathological evaluation. There were 15 patients in group A and 176 patients in group B. The mean follow-up was 54.1 ± 30 months. The number of patients who underwent pretransplant immune desensitization and received tacrolimus-based triple maintenance immunosuppression therapy was significantly higher in group A. In group A, there were 13 acute rejections seen in 9 patients (81<); in group B, there were 67 acute rejections seen in 51 patients (28.9<; P = .019). No differences were observed between the groups in terms of baseline glomerular filtration rate (60 ± 16 vs 61.6 ± 20 mL/min/1.72 m2; P = .76), final control glomerular filtration rate (60.7 ± 15 vs 58 ± 19 mL/ min/1.72 m2; P = .59), graft loss (0< vs 4<; P = .94), and mortality (6.6< vs 3<; P = .39). The presence of 6 HLA mismatches was associated with higher rates of biopsy-proven acute rejection. However, 6 HLA-mismatched incompatible living donor kidney transplant can be safely performed in centers where posttransplant followup is supported by indication and protocol biopsies and where there is a pathological infrastructure with extensive knowledge and experience.

Comparing safety of proton‐pump inhibitors versus H2‐receptor antagonists in kidney transplant recipients: A systematic review and meta‐analysis

Multiple studies have been conducted to compare the safety of proton-pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) as acid-suppressive treatment in kidney transplant recipients with conflicting results. This systematic review and meta-analysis aimed to evaluate the risk of adverse effects in kidney transplant patients receiving PPIs compared to those treated with H2RAs. A systematic search was performed on the databases from inception to June 2021. The treatment effects were expressed as odds ratio (OR), weighted mean differences (WMD) and their 95% confidence intervals (CI) and pooled by a random-effects model. Eight studies, consisting 4,844 patients, were included. Patients were followed for a mean duration of 23.57months after transplantation. Compared with H2RAs, PPIs exposure was associated with similar rate of biopsy-proven acute rejection (BPAR) (OR= 1.05, 95% CI 0.83-1.34, p=0.67), mortality (OR=1.31, 95% CI 0.56-3.07, p=0.533), graft loss (OR=1.06, 95% CI 0.59-1.93, p=0.842), Clostridioides difficile infection (OR=1.37, 95% CI 0.49-3.85, p=0.545) and pneumonia (OR=1.83, 95% CI 0.95-3.52, p=0.072). The estimated glomerular filtration rate (eGFR) at 12months was lower in patients who received PPIs than those treated with H2RAs (WMD=-1.01, 95% CI -1.89 to -0.12ml/min/1.73m2 , p=0.02). The PPI-treated kidney transplant patients experienced higher rate of antibody-mediated rejection (AMR) (OR=1.87, 95% CI 1.03-3.04, p=0.039) and hypomagnesemia (OR=2.16, 95% CI 1.46-3.20, p˂0.001). Compared with H2RAs, PPIs were not associated with higher risks of BPAR, mortality, graft loss or infection-related outcomes. However, taking PPIs was associated with higher rates of AMR and hypomagnesemia, and lower eGFR at one year after transplantation. Further well-controlled studies are needed to assess the impact of acid-suppressive strategy on long-term outcomes in KTRs.

Efficacy and Safety of Iguratimod Supplement to the Standard Immunosuppressive Regimen in Highly Mismatched Renal Transplant Recipients: A Pilot Study.

Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings.

Patient and Graft Survival Outcomes During 2 Eras of Immunosuppression Protocols in Kidney Transplantation: Indiana University Retrospective Cohort Experience

Since 1964 when Indiana University performed its first kidney transplant, immunosuppression protocol was steroid-based until 2004 when steroid-free immunosuppression protocol was adopted. We describe clinical outcomes on our patients administered early steroid withdrawal (ESW) protocol (5 days) compared with our historical cohort (HC), who were on chronic steroid-based immunosuppression. We performed a retrospective study evaluating kidney transplant recipients between 1993 and 2003 (HC, n=1689) and between 2005 and 2016 (ESW cohort, n=2097) at the Indiana University program, with a median follow-up of 10.5 years and 6.1 years, respectively. Primary outcomes were patient and death-censored graft survival at 1, 3, and 5 years in both study cohorts. Secondary outcomes were 1-year rates of biopsy-proven acute rejection; graft function at 1, 3, and 5 years; and risk of post-transplant infection (BK virus and cytomegalovirus) in the ESW cohort. Cox proportional model and Kaplan-Meier estimates were used to estimate survival probabilities. Fisher exact tests were used to compare episodes of acute rejection in the ESW cohort. No difference was observed in patient survival between the ESW and HC cohorts (P=.13). Compared with the ESW cohort, death-censored graft survival was significantly worse in the HC (5 year: 86.4% vs 90.6%, log-rank P < .001). One-year acute rejection reported in the ESW cohort alone was 15.7% and significantly worse in Black patients and younger patients (P < .05). In this sizeable single-center cohort study with significant ethnic diversity, ESW is a viable alternative to steroid-based immunosuppression protocol in kidney transplant recipients.

Impact of recipient and donor smoking in living‐donor kidney transplantation: a prospective multicenter cohort study

The smoking status of kidney transplant recipients and living donors has not been explored concurrently in a prospective study, and the synergistic adverse impact on outcomes remains uncertain. The self-reported smoking status and frequency were obtained from recipients and donors at the time of kidney transplantation in a prospective multicenter longitudinal cohort study (NCT02042963). Smoking status was categorized as "ever smoker" (current and former smokers collectively) or "never smoker." Among 858 eligible kidney transplant recipients and the 858 living donors, 389 (45.3%) and 241 (28.1%) recipients were considered ever smokers at the time of transplant. During the median follow-up period of 6years, the rate of death-censored graft failure was significantly higher in ever-smoker recipients than in never-smoker recipients (adjusted HR, 2.82; 95% CI 1.01-7.87; P=0.048). A smoking history of >20 pack-years was associated with a significantly higher rate of death-censored graft failure than a history of ≤20 pack-years (adjusted HR, 2.83; 95% CI 1.19-6.78; P=0.019). No donor smoking effect was found in terms of graft survival. The smoking status of the recipients and donors or both did not affect the rate of biopsy-proven acute rejection, major adverse cardiac events, all-cause mortality, or post-transplant diabetes mellitus. Taken together, the recipient's smoking status before kidney transplantation is dose-dependently associated with impaired survival.

ABO-Incompatible Kidney Transplantation in India: A Single-Center Experience of First Hundred Cases.

Aim:ABO-incompatible (ABOi) kidney transplantation overcomes immunological barrier of blood group incompatibility. There have been very few published experiences of ABOi kidney transplantation from India. We present our single-center experience of the first hundred ABOi kidney transplants.Material and Methods:This is a single-center retrospective study of consecutive first hundred ABOi kidney transplant with at least 6 months of follow-up.Results:During the study period (2011–2020), a total of 121 ABOi kidney transplants were performed. Of these, first hundred patients were analyzed. Median follow-up duration was 33 (10–101) months. Mean recipient and donor age were 41.5 ± 13 and 47.68 ± 11.25 years, respectively. Mean HLA mismatch was 4 ± 1.5. Median baseline anti-blood group antibody titer was 128 (2–1024). Most common recipient blood group was O. Patient and death censored graft survival was 93% and 94%, respectively, at median follow-up of 33 months. Biopsy-proven acute rejection (BPAR) rate was 17% with acute antibody-mediated rejection being 3%. Rate of infection was 37%, most common being urinary tract infection.Conclusion:ABOi kidney transplant patients had acceptable patient and graft survival as well as BPAR rates. With current preconditioning protocol, infection rate was high.

Is There a Place for Induction Therapy With Polyclonal Antibodies to Improve Renal Function After Liver Transplantation?

Is There a Place for Induction Therapy With Polyclonal Antibodies to Improve Renal Function After Liver Transplantation?

Induction Immunosuppressive Therapy for Kidney Transplant in Elderly Recipients: A Single-Center Experience.

The number of elderly kidney transplant recipients is increasing, and age-tailored induction immunosuppression regimens are needed. We compared safety and efficacy of basiliximab versus thymoglobulin at various dosages. Of 590 kidney transplants at our center from 2012 to 2019, 119 (20.1%) were for recipients over 65 years of age; 118 patients received deceased donor kidneys, and 1 received a related living donor kidney. We retrospectively reviewed medical records for demographics, baseline characteristics, donor characteristics, induction regimens, infectious complications, graft function, and patient survival. Patients were subdivided into the following 4 induction immunosuppression groups: basiliximab (n = 15, 12.6%), 3 mg/kg thymoglobulin (n = 8, 6.7%), 4.5 mg/kg thymoglobulin (n = 67, 56.3%), and 6 mg/kg thymoglobulin (n = 29, 24.4%). All patients received pulse doses of methylprednisolone followed by a prednisone taper. Other maintenance immunosuppression agents included tacrolimus and mycophenolic acid. Recipients in the basiliximab and 3 mg/kg thymoglobulin groups were older (median age ⟩70 years; P ⟨ .001). The 4.5 and 6 mg/kg thymoglobulin groups had higher proportions of African American patients and patients with calculated panel reactive antibody over 20%. There were significantly fewer infectious complications in the basiliximab and 3 mg/kg thymoglobulin groups. Despite differences in biopsy-proven acute rejection rates, estimated glomerular filtration rate and graft and patient survival rates at 1 year were similar across groups. All patients with biopsy-proven acute rejection were African American patients. Kidney transplant in patients ≥65 years is safe and feasible. Changes in this unique population's immune system warrant age-tailored regimens. We found that patients at low immunologic risk would benefit from basiliximab orthymoglobulin at 3 mg/kg. Regardless of calculated panel reactive antibodies, African American patients should be considered as high immunologic risk group forrejection, and higher thymoglobulin dosing should be considered.

Rapid Steroid Withdrawal after Renal Transplantation Reduces Mortality: Five Year Follow-Up of a Randomized Controlled Trial (Harmony Study) Confirms Long Term Efficacy and Safety

Background: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled one year “Harmony” trial, in which 587 predominantly deceased-donor kidney transplant recipients were randomized either to basiliximab or rabbit ATG induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. Methods: Following the end of the original one-year study period, patients were asked to participate in the observational follow-up (FU) study examining most of the end points of the original study. Hereby, de novo incidences between year one and three as well as year three and five were assessed at the three-/five-year visits, respectively. Findings: Biopsy-proven acute rejection and death-censored graft survival rates remained low and independent of RSWD. RSWD was an independent positive factor for patient survival (adjusted hazard ratio 0·554, 95% confidence interval 0·314 to 0·976; p=0·041). Survival rate was increased with 89·4 % or 90·4 % in RSWD patients (basiliximab or rabbit ATG) compared to 84·7 % in control patients (p = 0·064). The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original one-year study period was not compensated by later incidences during FU. Also, incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during FU period. Unexpectedly, patient incidences of bacterial infections requiring hospitalization was reduced in the rabbit ATG group. Interpretation: The Harmony FU trial confirms excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy. This is the first randomized study demonstrating increased patient survival in RSWD patients. The results shown here support that RSWD should become the new gold standard approach in an immunologically low-risk, elderly, and severely diseased population of Caucasian kidney transplant recipients. Trial Registration: Follow-up study DRK5786; Original trial NCT 00724022). Funding: The FU trial was designed and run by the first and last author who received financial support from Astellas Pharma GmbH and Sanofi (Investigator Initiated Trial (NCT 00724022, follow up study DRK5786). Neither of the funders had any role in data collection, data analysis, data interpretation, or writing of the manuscript. An independent contract research organization (Coordination Center for Clinical Studies of the Technical University of Dresden, Dresden, Germany) was responsible for data collection, monitoring and statistical analyses. Declaration of Interest: CH received grant support, consulting fees, and lecture fees from Astellas, Sanofi, Genzyme, Roche Pharma, Novartis, and Wyeth/Pfizer. CK received consulting fees and lecture fees from Astellas, Chiesi, Novartis, Sanofi-Genzyme. JWM received grant support, consulting fees, and lecture fees from Vifor, GSK, Novartis, Astra-Zeneca and Boehringer Ingelheim. OW has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Kohler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. BB received grant support, consulting fees and lecture fees from Astellas, Bayer, Chiesi and Novartis. All other authors declare no competing interests. Ethical Approval: The study was approved by the institutional review boards of all sites participating in the follow-up period.

Early tacrolimus exposure does not impact long-term outcomes after liver transplantation.

BACKGROUNDTacrolimus trough levels (TTL) during the first weeks after liver transplantation (LT) have been related with long-term renal function and hepatocellular carcinoma recurrence. Nevertheless, the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debateAIMTo evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODSOne hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied. Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 (n = 98) and > 10 ng/mL (n = 57). Multivariate analyses were performed to assess risk factors for patient mortality.RESULTSMean levels within the first month post-transplant were 7.4 ± 1.7 and 12.6 ± 2.2 ng/mL in the ≤ 10 and > 10 groups, respectively. Donor age was higher in the high TTL group 62.9 ± 16.8 years vs 45.7 ± 17.5 years (P = 0.002) whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7% vs 15.8% (P = 0.02). Recipient features were generally similar across groups. After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in: Mean estimated glomerular filtration rate (P = 0.69), hepatocellular carcinoma recurrence (P = 0.44), de novo tumors (P = 0.77), new-onset diabetes (P = 0.13), or biopsy-proven acute rejection rate (12.2% and 8.8%, respectively; P = 0.50). Eighteen patients died during the follow-up and were evenly distributed across groups (P = 0.83). Five-year patient survival was 90.5% and 84.9%, respectively (P = 0.44), while 5-year graft survival was 88.2% and 80.8%, respectively (P = 0.42). Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSIONDifferences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.

Impact of kidney and recipient weight incompatibility on the allograft outcomes in kidney transplant recipients with pre-transplant diabetes mellitus: a single center retrospective cohort study

Background: The aim of this study was to analyze the impact on the adverse allograft outcome of transplanting relatively small kidneys in patients with pre-transplant diabetes mellitus (DM). Methods: From January 2010 to December 2018, 1,290 kidney transplants (KTs) were performed in Seoul St. Mary’s Hospital. Of these, 793 cases of non-sensitized living donor KT recipients were enrolled. They were divided into four groups (non-DM large kidney, non-DM small kidney, DM large kidney, and DM small kidney) according to the median kidney weight and recipient weight ratio (2.9 g/kg) and presence or absence of pre-transplant DM. The primary outcome of this study was death censored graft loss (DCGL) rate. Results: There was no significant difference in the biopsy-proven acute rejection rate among the four groups. DM small kidney group showed the highest DCGL rate (18/131 [13.7%], P=0.004) and was to be the independent risk factor for DCGL (adjusted haz ard ratio, 2.829; P=0.003). Moreover, renal function after 4 years of transplantation worsened faster in the DM small kidney group compared to other groups, and allograft survival decreased after 1 year of transplantation. Conclusions: Our results suggest that transplanting large kidneys rather than small kidneys is considered to have an advantage in terms of allograft outcome in pre-transplant DM patients, and this should be considered in donor selection.