Immunosuppressant drug monitor: A non-invasive device to measure tacrolimus level in the saliva of transplanted patients.

Solid organ and vascularized composite allograft transplantation are pivotal in enhancing both life expectancy and quality of life. However, the significant risk of donor tissue rejection requires lifelong immunosuppressive therapy. Tacrolimus, a common component of immunosuppressive regimens, offers effectiveness in preventing organ rejection but poses challenges due to its narrow therapeutic window and toxicity, making it essential to carefully monitor its concentration. Tacrolimus trough levels are currently measured in blood, requiring frequent blood draws from patients, and results are available after 3 to 6 h. To address the need for a fast, minimally-invasive, and simple method to monitor tacrolimus concentrations, we have assessed a new device for at-home analysis, the Immunosuppressant Drug Monitor (IDM) that can extract, identify and quantify tacrolimus in saliva within 15 min. We included males and females hospitalized at Massachusetts General Hospital Transplant Unit, between the ages of 21 and 65 years, and treated with Tacrolimus. Informed consent, demographic and treatment data were collected. Each subject was asked to provide a 5 mL saliva sample that was de-identified and processed by the IDM, while a 5 mL blood sample was drawn and supplied to the MGH clinical lab for analysis by the current standard, immunoassays. The predicted tacrolimus concentration found in saliva was compared to the blood trough level results. 62 samples from 31 different patients were obtained. The male to female ratio and ethnicity distribution were well balanced. The majority of patients were within 30 days of initiating tacrolimus treatment. After IDM calibration and exclusion, 21 samples were measured by the IDM. Using an exponential function fit, the IDM showed a correlation of R2 = 0.39 between the saliva Test Line absorption and the measured tacrolimus concentration in blood, with an average absolute error of 1.8 ng/mL. Our results demonstrate a clear correlation between blood and saliva measurements. The IDM provided promising results to monitor immunosuppressant drug concentrations in patients after transplantation. Future larger studies will further develop the correlation, and the IDM's potential impact on patient outcomes.

Impact of the New Glomerular Filtration Rate Formulas on Kidney Function Assessment in Living Kidney Donors and Candidates.

New estimated glomerular filtration rate (GFR) equations that do not include a race coefficient have been created to better estimate kidney function, reduce inequities in kidney disease care, and improve the historically limited access to transplantation in African Americans. The impact of these new equations on estimated GFR (eGFR) in living donors pre- and postdonation is not known. Methods: To address this, we conducted a single-center retrospective cohort study of 150 kidney donors and donor candidates. We calculated pre- and postdonation eGFR using the old and new equations and compared them with measured GFR by 2.8 mCi Tc-99m diethylene triamine penta-acetic acid clearance (mGFRDTPA) and 24-h creatinine clearance (mGFRCrCl). We evaluated the impact of the new equations on donation eligibility and postdonation eGFR. Results: We found that using the new eGFR equations resulted in higher predonation eGFR compared with the old equations but remained significantly lower than mGFRDTPA and mGFRCrCl. We also found that using the new eGFR equations would not exclude any potential donors based on our center's GFR criteria for donation. At 6 mo postdonation, the new equations resulted in higher eGFR values compared with the old equations. Conclusions: The new eGFR equations continue to underestimate GFR in healthy donor candidates but would not exclude any potential donors from donation and resulted in higher eGFR predonation and postdonation in a predominantly White population. eGFR equations designed specifically for potential kidney donors are still needed for better kidney function assessment.

Long-term Outcome Reporting in Older Kidney Transplant Recipients and the Limitations of Conventional Survival Metrics.

Introduction: The kidney transplant recipient population in the United States is aging rapidly, which may exacerbate some of the limitations of conventional outcome metrics. Methods: Using data from the Scientific Registry of Transplant Recipients (SRTR), age-stratified unadjusted Kaplan-Meier and competing risk survival analyses were performed on a cohort of 238,123 adult recipients of a first-time single kidney transplant between 2000 and 2017. These were compared with a multistate model incorporating 5 post-transplant states (alive with functioning graft, death with functioning graft, graft failed (alive), retransplanted, and death after graft failure). Results: Kaplan-Meier resulted in an age-dependent overestimation of the risks of graft failure and death with functioning graft, compared with competing risk or multistate models. In elderly (≥75 years old) recipients, the absolute overestimation of the risk of death with functioning graft was 4-fold higher than in those younger than 55 years. The multistate model demonstrated that for patients transplanted at age 55 years and older, the probability of being back on dialysis was never more than 4% at any point post-transplant. The underlying reasons were low graft failure rates and high mortality after resuming dialysis as follows: 2-year mortality after graft failure was 38%, 54%, and 67% in recipients aged from 55 to 64 years, from 65 to 74 years, and those aged 75 years and older, versus 20% in those younger than 55 years. Conclusion: Multistate models provide an accurate and comprehensive assessment of the life course of kidney transplant recipients. This may be particularly relevant in older recipients, who are more prone to event rate overestimation and for whom outcomes after graft failure are substantially worse than for younger recipients.

Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection.

BACKGROUND: To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS: We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS: The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS: Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

Navigating the unknown: the coronavirus disease 2019 pandemic and solid organ transplantation.

PURPOSE OF REVIEW: This review summarizes the impact of coronavirus disease 2019 (COVID-19) on solid organ transplantation and the most recent data pertinent to disease course and outcomes in this patient population. RECENT FINDINGS: The COVID-19 pandemic negatively impacted solid organ transplantation with decreased transplant rates in 2020 but improved in 2021, albeit not entirely to prepandemic levels. Mortality rates of COVID-19 in this patient population continued to be higher, although have improved with more available therapeutic options and vaccination. Immunosuppressed patients were found to require additional vaccine doses given blunted response and continue to be more vulnerable to the infection. Data on immunosuppression alteration when patients have COVID-19 are not available and is an area of ongoing research. Significant interaction with the metabolism of immunosuppression limits the use of some of the new antiviral therapies in patients with organ transplants. Finally, many logistical challenges continue to face the transplantation discipline, especially with pretransplant vaccine hesitancy, however acceptance of organs from donor who had COVID-19 recent infection or died from the infection is increasing. SUMMARY: Immunosuppressed solid organ transplant recipients continue to be vulnerable to COVID-19 infection with a blunted response to the available vaccines and will likely remain more susceptible to infection.

Willingness of Kidney and Liver Transplant Candidates to Receive HCV-Infected Organs.

INTRODUCTION: Transplantation of organs exposed to hepatitis C virus (HCV) into uninfected patients has yielded excellent outcomes and more widespread adoption may lead to fewer discarded organs and more transplants. Patient perceptions may shed light on acceptability and likely the uptake of HCV+/HCV- transplantation, gaps in understanding, and perceived benefits/risks. METHODS: We surveyed 435 uninfected kidney and liver transplant candidates at four centers about their attitude towards HCV-infected organs. RESULTS: The percentage of patients willing to accept HCV-infected organs increased from 58% at baseline, to 86% following education about HCV, direct-acting antiviral agents (DAAs), and HCV+/HCV- transplantation benefits/risks. More willingness to accept an organ from an intravenous drug user (P < 0.001), age >50 y old (P = 0.02), longer waiting time (P = 0.02), more trust in the transplant system (P = 0.03), and previous awareness of DAAs (P = 0.04) were associated with higher willingness to accept an HCV-infected organ. The most important reasons for accepting an HCV-infected organ were a decrease in waiting time (65%), lower mortality and morbidity risk while on the waiting list (63%), effectiveness of DAAs (54%), and a quicker return to higher functional status (51%). CONCLUSIONS: Presenting patients with information about HCV+/HCV- transplantation in small doses that are calibrated to account for varying levels of health and numerical literacy is recommended.

Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.

INTRODUCTION: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. METHODS: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. RESULTS: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61]. CONCLUSIONS: In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment.

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.

Overexpression of PD-1 on T cells promotes tolerance in cardiac transplantation via ICOS-dependent mechanisms.

The programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is a potent inhibitory pathway involved in immune regulation and is a potential therapeutic target in transplantation. In this study, we show that overexpression of PD-1 on T cells (PD-1 Tg) promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model when combined with costimulation blockade with CTLA-4-Ig. PD-1 overexpression on T cells also protected against chronic rejection in a single MHC II-mismatched cardiac transplant model, whereas the overexpression still allowed the generation of an effective immune response against an influenza A virus. Notably, Tregs from PD-1 Tg mice were required for tolerance induction and presented greater ICOS expression than those from WT mice. The survival benefit of PD-1 Tg recipients required ICOS signaling and donor PD-L1 expression. These results indicate that modulation of PD-1 expression, in combination with a costimulation blockade, is a promising therapeutic target to promote transplant tolerance.

COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: A comparative analysis from a multicenter study.

Lung transplant recipients (LTR) with coronavirus disease 2019 (COVID-19) may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with COVID-19 to compare mortality by 28 days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with COVID-19, 1,081 (66%) were hospitalized including 120/159 (75%) LTR and 961/1457 (66%) non-lung SOTR (p = .02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p = .032), and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p = .04). Among LTR, chronic lung allograft dysfunction (aOR 3.3, 95% CI 1.0-11.3, p = .05) was the only independent risk factor for mortality and age >65 years, heart failure and obesity were not independently associated with death. Among SOTR hospitalized for COVID-19, LTR had higher mortality than non-lung SOTR. In LTR, chronic allograft dysfunction was independently associated with mortality.

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection.

BACKGROUND: Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. METHODS: Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. RESULTS: An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. CONCLUSIONS: Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.

Acute kidney injury in renal transplant recipients undergoing cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is a key risk factor for chronic kidney disease in the general population, but has not been investigated in detail among renal transplant recipients (RTRs). We investigated the incidence, severity and risk factors for AKI following cardiac surgery among RTRs compared with non-RTRs with otherwise similar clinical characteristics. METHODS: We conducted a retrospective cohort study of RTRs (n = 83) and non-RTRs (n = 83) who underwent cardiac surgery at two major academic medical centers. Non-RTRs were matched 1:1 to RTRs by age, preoperative (preop) estimated glomerular filtration rate and type of cardiac surgery. We defined AKI according to Kidney Disease: Improving Global Outcomes criteria. RESULTS: RTRs had a higher rate of AKI following cardiac surgery compared with non-RTRs [46% versus 28%; adjusted odds ratio 2.77 (95% confidence interval 1.36-5.64)]. Among RTRs, deceased donor (DD) versus living donor (LD) status, as well as higher versus lower preop calcineurin inhibitor (CNI) trough levels, were associated with higher rates of AKI (57% versus 33% among DD-RTRs versus LD-RTRs; P = 0.047; 73% versus 36% among RTRs with higher versus lower CNI trough levels, P = 0.02). The combination of both risk factors (DD status and higher CNI trough level) had an additive effect (88% AKI incidence among patients with both risk factors versus 25% incidence among RTRs with neither risk factor, P = 0.004). CONCLUSIONS: RTRs have a higher risk of AKI following cardiac surgery compared with non-RTRs with otherwise similar characteristics. Among RTRs, DD-RTRs and those with higher preop CNI trough levels are at the highest risk.

Coronavirus Disease 2019 in Solid Organ Transplant: A Multicenter Cohort Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described. METHODS: We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS: Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 1.7-5.5, P < .001], congestive heart failure [aOR 3.2, 95% CI 1.4-7.0, P = .004], chronic lung disease [aOR 2.5, 95% CI 1.2-5.2, P = .018], obesity [aOR 1.9, 95% CI 1.0-3.4, P = .039]) and presenting findings (lymphopenia [aOR 1.9, 95% CI 1.1-3.5, P = .033], abnormal chest imaging [aOR 2.9, 95% CI 1.1-7.5, P = .027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.

Short Bowel Syndrome and Kidney Transplantation: Challenges, Outcomes, and the Use of Teduglutide.

Among patients with short bowel syndrome who commonly have kidney disease, kidney transplantation remains challenging. We describe the clinicopathologic course of a 59-year old man with short bowel syndrome secondary to Crohn's disease who underwent a deceased donor kidney transplant that was complicated by recurrent acute kidney allograft injury due to volume depletion from diarrhea, ultimately requiring the placement of permanent intravenous access for daily volume expansion at home resulting in the recovery of allograft function. Teduglutide treatment at 1.8 years post-transplant led to a dramatic decrease in diarrhea. A literature review of similar cases yielded 18 patients who underwent 19 kidney transplants. Despite high rates of complications, at the time of last follow-up (median 2.1 years [0.04-7]), 94% of the patients were still alive and 89% had functioning allografts, with a median eGFR of 37.5 [14-122] ml/min/1.73m2. In conclusion, despite high rates of complications, kidney transplantation in patients with short bowel syndrome is associated with acceptable short- and midterm outcomes. Further, we report for the first time the effects of the glucagon-like peptide-2 analogue teduglutide for short bowel syndrome in a kidney transplant recipient.

The COVID-19 pandemic: A community approach.

An unprecedented global pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has quickly overwhelmed the health care systems worldwide. While there is an absence of consensus among the community in how to manage solid organ transplant recipients and donors, a platform provided by the American Society of Transplantation online community "Outstanding Questions in Transplantation," hosted a collaborative multicenter, multinational discussions to share knowledge in a rapidly evolving global situation. Here, we present a summary of the discussion in addition to the latest published literature.