Donor-derived cell-free DNA (dd-cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its ...pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd-cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor–specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd-cfDNA was higher among patients with antibody–mediated rejection (ABMR; median 1.35%; interquartile range IQR: 1.10%-1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%-1.10%; P < .001) and cell–mediated rejection (CMR; median: 0.27%, IQR: 0.19%-1.30%; P = .01). The dd-cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17-0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71-0.93) and a dd-cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd-cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.
Delayed graft function (DGF) is defined as need for dialysis early posttransplant. DGF is related to ischemia–reperfusion injury (IRI) that diminishes allograft function and may be complement ...dependent. Here, we investigate the ability of C1 esterase inhibitor (C1INH) to prevent IRI/DGF in kidney transplant recipients. Seventy patients receiving deceased donor kidney transplants at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours. The primary end point was need for hemodialysis during the first week posttransplant. Assessments of glomerular filtration rate and dialysis dependence were accomplished. Complications and safety of therapy were recorded. Similar characteristics with no significant differences in cold‐ischemia time or risk factors for DGF were seen. C1INH did not result in reduction of dialysis sessions at 1 week posttransplant, but significantly fewer dialysis sessions (P = .0232) were required 2 to 4 weeks posttransplant. Patients at highest risk for DGF (Kidney Donor Profile Index ≥85) benefited most from C1INH therapy. Significantly better renal function was seen at 1 year in C1INH patients (P = .006). No significant adverse events were noted with C1INH. Although the primary end point was not met, significant reductions in need for dialysis and improvements in long‐term allograft function were seen with C1INH treatment.
In a placebo‐controlled study for prevention of delayed graft function in kidney allografts, C1 esterase inhibitor demonstrates a significant benefit in improving renal function compared to placebo.
Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase ...inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial.
This is a
analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (
=35) or placebo (
=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model.
Three deaths occurred among C1 esterase inhibitor-treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor-treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor-treated recipients compared with placebo (
=0.03). Although no difference in eGFR slopes was observed between groups (
for group-time interaction =0.12), eGFR declined in placebo-treated recipients (-4 ml/min per 1.73 m
per year; 95% confidence interval, -8 to -0.1) but was stable in C1 esterase inhibitor-treated patients (eGFR slope: 0.5 ml/min per 1.73 m
per year; 95% confidence interval, -4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m
(95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m
(95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m
(95% confidence interval, 2 to 41 ml/min per 1.73 m
).
Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.
Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell‐directed anticancer therapies have illuminated the biologic relevance of B ...cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody‐mediated rejection (AMR) treatment by targeting CD20 found on B‐lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.
Emerging therapies aimed at modifying B cells, plasma cells, and alloantibodies will soon provide therapeutic benefits for transplant patients with antibody rejection.
•Tocilizumab in critically ill COVID-19 patients was associated with lower mortality.•Secondary infections were not more frequent among tocilizumab-treated patients.•Immunomodulation might benefit ...COVID-19 patients with advanced disease.
Elevated levels of pro-inflammatory cytokines are observed in severe COVID-19 infections, and cytokine storm is associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, is used to treat chimeric antigen receptor T cell-induced cytokine release syndrome and may attenuate the dysregulated immune response in COVID-19. We compared outcomes among tocilizumab-treated and non-tocilizumab-treated critically ill COVID-19 patients.
This was a retrospective observational study conducted at a tertiary referral center investigating all patients admitted to the intensive care unit for COVID-19 who had a disposition from the hospital because of death or hospital discharge between March 1 and May 18, 2020 (n = 96). The percentages of death and secondary infections were compared between patients treated with tocilizumab (n = 55) and those who were not (n = 41).
More tocilizumab-treated patients required mechanical ventilation (44/55, 80%) compared to non-treated patients (15/41, 37%; P < 0.001). Of 55 patients treated with tocilizumab, 32 (58%) were on mechanical ventilation at the time of administration, and 12 (22%) progressed to mechanical ventilation after treatment. Of patients treated with tocilizumab requiring mechanical ventilation, 30/44 (68%) were intubated within 1 day of administration. Fewer deaths were observed among tocilizumab-treated patients, both in the overall population (15% vs 37%; P = 0.02) and among the subgroup of patients requiring mechanical ventilation (14% vs 60%; P = 0.001). Secondary infections were not different between the 2 groups (tocilizumab: 31%, non-tocilizumab: 17%; P = 0.16) and were predominantly related to invasive devices, such as urinary and central venous catheters.
Tocilizumab treatment was associated with fewer deaths compared to non-treatment despite predominantly being used in patients with more advanced respiratory disease.
Posttransplant malignancy is a major cause of death in orthotopic heart transplant recipients. Our study objective is to identify whether pretransplant malignancy increases the risk for ...posttransplant malignancy.
Using the Organ Procurement and Transplantation Network/United Network for Organ Sharing database, adult (≥18 years old) recipients of a primary orthotopic heart transplant performed between 2000 and 2012 were included. The cohort was stratified according to the presence and type of pretransplant malignancy. Outcomes were posttransplant overall, skin, solid malignancies, and posttransplant lymphoproliferative disorder. Incidence of and time to first posttransplant malignancy, accounting for death as a competing event, were calculated. Fine and Gray competing risks regression was performed to examine risk factors associated with posttransplant malignancy.
Of 23,171 recipients, overall posttransplant malignancy was diagnosed in 2673 recipients (11.5%).The median time to overall, skin, solid posttransplant malignancies, and posttransplant lymphoproliferative disorder were 3.2 (1.6-5.7), 3.2 (1.7-5.6), 3.5 (1.7-5.9), and 2.5 years(0.8-5.2), respectively. Pretransplant malignancy increased the risk of posttransplant overall (subhazard ratio SHR, 1.51; 95% confidence interval 95% CI, 1.27-1.81), skin (SHR, 1.55, 95% CI, 1.23-1.93), and solid organ malignancies (SHR, 1.54; 95% CI, 1.13-2.11). Pretransplant skin malignancy increased the risk of posttransplant skin malignancy (SHR, 2.79; 95% CI, 1.82-4.28). Pretransplant solid malignancy also increased the risk of posttransplant skin malignancy (SHR, 1.55; 95% CI, 1.07-2.25) but not of posttransplant solid tumors (SHR, 1.23; 95% CI, 0.69-2.19). Older, male, and white were also risk factors for posttransplant malignancy.
A history of any pretransplant malignancy was associated with increased risks of skin and solid malignancies after transplantation. The specific type of posttransplant malignancy risk differed according to the type of pretransplant malignancy.
Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of ...their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.
Background Recent studies show a survival advantage with kidney transplant in elderly patients compared with those on dialysis therapy. Study Design In our present study, we examined and compared the ...association of expanded criteria donor (ECD) kidney and living kidney donation with the outcome of kidney transplant across different ages, including elderly recipients. Setting & Participants Using the Scientific Registry of Transplant Recipients, we identified 145,470 adult kidney transplant patients. Mortality and death-censored transplant failure risks were estimated by Cox proportional regression analyses during follow-up with a median of 3.9 years. Predictors ECD kidney and living kidney donation and age compared with others. Outcomes Mortality and death-censored transplant failure risk. Results Patients were aged 45 ± 16 years and included 40% women and 19% patients with diabetes. Compared with transplant recipients 55 to younger than 65 years, the fully adjusted death-censored transplant failure risk was higher in patients 75 years and older (HR, 1.30; 95% CI, 1.09-1.56), 35 to younger than 55 years (HR, 1.13; 95% CI, 1.08-1.17), and 18 to younger than 35 years (HR, 1.64; 95% CI, 1.57-1.71). Compared with non-ECD kidneys, ECD kidneys were significant predictors of mortality in nonelderly patients (18-<35 years: HR, 1.46 95% CI, 1.19-1.77; 35-<55 years: HR, 1.23 95% CI, 1.14-1.32; and 55-<65 years: HR, 1.26 95% CI, 1.15-1.38) and patients 65 to younger than 70 years (HR, 1.20; 95% CI, 1.05-1.36), but not in other groups of elderly patients (HRs of 1.12 95% CI, 0.93-1.36 for 70-<75 years and 1.04 95% CI, 0.74-1.47 for ≥75 years). Similar results were found for risk of transplant loss. Compared with deceased donor kidneys, a living donor kidney was associated with better survival in all age groups and lower transplant loss risk in patients younger than 70 years. Limitations Unmeasured confounders cannot be adjusted for. Conclusions For deceased donors, ECD kidneys are not associated with increased mortality or transplant failure in recipients older than 70 years. For all types of donors, the persistent association between living donor kidneys and lower all-cause mortality across all ages suggests that, if possible, elderly patients gain longevity from living donor kidney transplant.
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