Outcomes of short-duration antiviral prophylaxis for hepatitis C positive donor kidney transplants.

Trials describing 4- to 12-week courses of direct-acting antiviral drugs (DAAs) to treat hepatitis C virus (HCV) transmission from infected donors to uninfected kidney transplant recipients (D+/R- transplants) may be limited in "real-world" application by costs and delayed access to DAAs. We previously reported HCV transmission of 13% among D+/R- transplants with 2- to 4-day pangenotypic sofosbuvir/velpatasvir (SOF/VEL) perioperative prophylaxis, where one patient with HCV transmission was a nonresponder to first-line full-course DAA. Here, we report new data with a 7-day prophylaxis protocol (N = 50), as well as cumulative treatment and outcome data on all HCV D+/R- transplants (N = 102). Overall, nine patients (9/102; 9%; 95% CI: 5%-16%) developed HCV transmission, with a significant decline noted in the 7-day group (2/50; 4%; 95% CI: 0%-13%) compared with 2- to 4-day prophylaxis (7/52; 13%; 95% CI: 5%-25%). All patients with HCV transmission achieved sustained virologic response post full-course therapy (including one nonresponder from initial trial). A 1:1 matched analysis (N = 102) with contemporary HCV D-/R- transplants (controls) showed that although the pretransplant wait time was significantly shorter for D+/R- compared with D-/R- (mean: 1.8 vs. 4.4 years; p < .001), there were no differences in infections, rejection, development of de novo donor-specific antibody, or transplant outcomes up to 6 months of transplant.

Letermovir prophylaxis in solid organ transplant-Assessing CMV breakthrough and tacrolimus drug interaction.

BACKGROUND: Valganciclovir is the preferred drug for cytomegalovirus (CMV) prophylaxis in solid organ transplantation. A limitation to its use is profound myelosuppression. Letermovir is a new agent approved for CMV prophylaxis in hematopoietic stem cell transplantation and is associated with less toxicity. This study aims to assess the effectiveness and safety of letermovir in solid organ transplantation. METHODS: A single-center, matched cohort study was performed on 31 transplant recipients who were converted from valganciclovir to letermovir from November 2017 to June 2020. The primary outcome was the rate of CMV breakthrough infections while on prophylaxis. Secondary outcomes included rate of leukopenia, doses of immunosuppression, rejection, non-CMV infection, and renal function. Statistical analyses of continuous variables included the student's t-test, ANOVA test, and Wilcoxon Signed Rank test. Categorical data were analyzed with chi-square test and Fisher's Exact test. RESULTS: There was no difference in the rate of CMV breakthrough between patients on letermovir (8.7%) and valganciclovir (13.5%), (P = .7097). After conversion to letermovir, patients required lower tacrolimus doses at -3.34 mg (SD-1.3, P = .0273), between conversion and day 7. Transplant Infectious Disease The median difference in tacrolimus trough concentrations from conversion to day seven was 9.1 ng/ml [4.9, 16.95] (P = .0002). Leukopenia improved by 1.8 109/L [1.08, 4.85] (P < .0001). CONCLUSIONS: Patients converted from valganciclovir to letermovir did not show an increased rate of CMV breakthrough compared to a historical, matched cohort of patients remaining on valganciclovir. A significant drug interaction was noted with tacrolimus, leading to a recommendation to reduce the dose by 40-50% upon initiation of letermovir.

High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury.

The clinical importance of subclinical, early T cell-mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor-derived cell-free DNA (dd-cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd-cfDNA. Forty-two patients had elevated dd-cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd-cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] -16.22% to -1.39%) (-3.50 mL/min/1.73 m2 IQR -8.00 to -1.00) vs 0% (-4.92%, 4.76%) in low dd-cfDNA patients (P = .004), de novo donor-specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd-cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy.

Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.

We conducted an adaptive design single-center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra-short-term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)-nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R-). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12-week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first-line DAA therapy; and two after retreatment with second-line DAA). At a median follow-up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%-20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R - transplants.

Diagnostic Accuracy of Noninvasive Tests to Detect Advanced Hepatic Fibrosis in Patients With Hepatitis C and End-Stage Renal Disease.

BACKGROUND & AIMS: For patients with liver disease from hepatitis C virus (HCV) infection complicated by end-stage renal disease (ESRD), it is important to assess liver fibrosis before kidney transplantation. We evaluated the accuracy of non-invasive tests to identify advanced hepatic fibrosis in patients with HCV and ESRD. METHODS: In a retrospective study, we collected data on ratio of aspartate aminotransferase:alanine aminotransferase (AST:ALT), AST platelet ratio index (APRI), FIB-4 score, fibrosis index score, and King's score from 139 patients with ESRD and HCV infection (mean age, 52.8 y; 76.3% male; 86.4% African American; 45.3% with increased level of ALT). Results were compared with findings from histologic analyses of biopsies (reference standard). The primary outcome was detection of advanced fibrosis, defined as either bridging fibrosis or cirrhosis. Area under the receiver operating characteristic (AUROC) curves were constructed and optimal cutoff values were determined for each test. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated. We repeated the analysis with stratification for normal levels of ALT (≤ 35 U/L for men and ≤ 25 u/L for women) and increased levels of ALT. RESULTS: FIB-4 scores identified patients with advanced fibrosis with an AUROC of 0.71 (95% CI, 0.61-0.80), the King's score with an AUROC of 0.69 (95% CI, 0.58-0.80), and the APRI with and AUROC of 0.68 (95% CI, 0.59-0.79). The accuracy of these tests increased when they were used to analyze patients with increased levels of ALT. All tests produced inaccurate results when they were used to assess patients with normal levels of AST and ALT. CONCLUSIONS: In patients with ESRD and HCV infection, FIB-4 scores, King's scores, and the APRI identify those with advanced fibrosis with AUROC values ranging from 0.68-0.71. Accuracy increased modestly when patients with increased levels of ALT were tested, but the tests produced inaccurate results for patients with a normal level of ALT.

Impact of belatacept conversion on kidney transplant function, histology, and gene expression - a single-center study.

Prior studies on belatacept conversion from calcineurin inhibitor (CNI) have been limited by an absence of postconversion surveillance biopsies that could underestimate subclinical rejection, or a case-controlled design. A total of 53 adult patients with allograft dysfunction underwent belatacept conversion (median: 6 months) post-transplant. At a median follow-up = 2.5 years, patient survival was 94% with a death-censored graft survival of 85%. Seven (13%) patients had acute rejection (including 3 subclinical) at median 6 months postconversion. Overall, eGFR improved (P = <0.001) from baseline = 31±15 to 40.2 ± 17.6 ml/min/1.73m2 by 6 months postconversion, but then stayed stable. This improvement was also observed (P < 0.001) in comparison with a propensity matched control cohort on CNI, where eGFR stayed stable (mean ~ 32ml/min/1.72m2 ) over 2-year follow-up. Patients converted < 6 months post-transplant were more likely to have a long-term improvement in kidney function. Paired gene expression analysis of 30 (of 53) consecutive pre- and postconversion surveillance biopsies did not reveal changes in inflammation/acute injury; although atrophy-fibrosis score worsened (mean = 0.28 to 0.44; P = 0.005). Thus, improvement in renal function with belatacept conversion occurred early and then sustained in comparison with controls where renal function remained unchanged overtime. We were unable to show molecular signals that could be related to CNI administration and regressed after withdrawal.

Successful kidney transplantation in a patient with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome).

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) may not be recognized until organ failure related to the microvascular thrombosis occurs. Kidney failure may be the initial presenting clinical feature. Kidney transplantation has been contraindicated because of the assumption that the continuing microvascular thrombosis will cause inevitable graft failure. CASE REPORT: We report a 48-year-old nulliparous woman who presented with end-stage kidney disease that was attributed to hypertension. Her past history included a thromboembolic stroke at age 32, for which she was placed on permanent anticoagulation. Immediately after living unrelated-donor kidney transplant, she developed severe hemolysis and acute decline in urine output for which she received red blood cell and platelet transfusions and an infusion of eculizumab (1200 mg). She promptly responded and was discharged on her fifth postoperative day with a serum creatinine level of 1.0 mg/dL. Two weeks later, thrombocytopenia and hemolysis recurred. By this time, undetectable ADAMTS13 activity (<5%) with no demonstrable inhibitor had been reported. She responded rapidly to plasma infusions. Genetic analysis confirmed the diagnosis of congenital TTP, documenting known pathogenic mutations in each of the ADAMTS13 genes. She continued to receive twice-monthly infusions for 4 months. Surveillance kidney biopsies at 6 and 12 months posttransplant demonstrated no evidence of thrombotic microangiopathy or graft rejection. After 2 years of follow-up her creatinine remains stable at 1.0 mg/dL (estimated glomerular filtration rate, 65 mL/min/1.73 m2 ). CONCLUSION: Our experience suggests that kidney transplantation may be an appropriate management for carefully selected patients with congenital TTP who develop end-stage renal disease.

Long-term outcomes and transmission rates in hepatitis C virus-positive donor to hepatitis C virus-negative kidney transplant recipients: Analysis of United States national data.

The use of kidneys from hepatitis C virus (HCV)-positive (D+) deceased donors for HCV-negative recipients (R-) might increase the donor pool. We analyzed the national Organ Procurement and Transplant Network (OPTN) registry from 1994 to 2014 to compare the outcomes of HCV D+/R- (n = 421) to propensity-matched HCV-negative donor (D-)/R- kidney transplants, as well as with waitlisted patients who never received a transplant, in a 1:5 ratio (n = 2105, per matched group). Both 5-year graft survival (44% vs 66%; P < .001) and patient survival (57% vs 79%; P < .001) were inferior for D+/R- group compared to D-/R-. Nevertheless, 5-year patient survival from the time of wait listing was superior for D+/R- when compared to waitlisted controls (68% vs 43%; P < .001). Of the 126 D+/R- with available post-transplant HCV testing, HCV seroconversion was confirmed in 62 (49%), likely donor-derived. Five-year outcomes were similar between D+/R- that seroconverted vs D+/R- that did not (n = 64). Our analysis shows inferior outcomes for D+/R- patients although detailed data on pretransplant risk factors was not available. Limited data suggest that HCV transmission occurred in half of HCV D+/R- patients, although this might not have been the primary factor contributing to the poor observed outcomes.

Outcomes of kidney transplants and risk of infection transmission from increased infectious risk donors.

Concern over transmission of viral infections has been reported to result in higher discard rates of high infectious risk kidneys (HIR) although data on actual viral transmission rates are lacking. At our center, we performed 89 HIR and 533 non-HIR kidney transplants (KTs) between 2004 and 2011. Follow-up screening labs in recipients of HIR kidneys tested for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus did not reveal any cases of viral transmission over median follow-up of 4.3 years. Patient and graft outcomes were similar at 5 years between HIR and non-HIR KTs. An updated analysis of the Organ Procurement and Transplant Network (OPTN) registry of deceased-donor kidney transplants between 2008 and 2012 included 57 526 transplants was performed. Retrospective calculation of KDRI (kidney donor risk index) differed (P<.001) between all groups with median KDRI of 0.99 for HIR kidneys, 1.07 for non-HIR standard criteria donor kidneys, and 1.81 for non-HIR expanded criteria donor (ECD) kidneys. This was reflected in the significantly improved 5-year graft survival for HIR KTs when compared with non-HIR ECD KTs (84% vs 78%; P<.001). Our data can guide counseling of KT candidates about the safety and benefits of HIR kidneys.

Pre-transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post-kidney transplantation.

Previous studies that have assessed the association of pre-transplant antiphospholipase A2 receptor autoantibody (PLA2R-Ab) concentration with a recurrence of membranous nephropathy (rMN) post-kidney transplant have yielded variable results. We tested 16 consecutive transplant patients with a history of iMN for pre-transplant PLA2R-Ab. Enzyme-linked immunosorbent assay titers (Euroimmun, NJ, USA) >14 RU/mL were considered positive. A receiver operating characteristic (ROC) analysis was performed after combining data from Quintana et al. (n = 21; Transplantation February 2015) to determine a PLA2R-Ab concentration which could predict rMN. Six of 16 (37%) patients had biopsy-proven rMN at a median of 3.2 yr post-transplant. Of these, five of six (83%) had a positive PLA2R-Ab pre-transplant with a median of 82 RU/mL (range = 31-1500). The only patient who had rMN with negative PLA2R-Ab was later diagnosed with B-cell lymphoma. One hundred percent (n = 10) of patients with no evidence of rMN (median follow-up = five yr) had negative pre-transplant PLA2R-Ab. In a combined ROC analysis (n = 37), a pre-transplant PLA2R-Ab > 29 RU/mL predicted rMN with a sensitivity of 85% and a specificity of 92%. Pre-transplant PLA2R-Ab could be a useful tool for the prediction of rMN. Patients with rMN in the absence of PLA2R-Ab should be screened for occult malignancy and/or alternate antigens.

Perioperative Desensitization Improves Outcomes Among Crossmatch Positive Recipients of Deceased Donor Renal Transplants.

CONTEXT: Graft failure due to chronic rejection is greater among renal transplant patients with donor-specific antibody (DSA) than among DSA-free patients. For patients dependent on deceased donor transplantation, preoperative desensitization to eliminate DSAs may be impractical. We speculated that perioperative desensitization might eliminate preexisting DSAs and prevent de novo DSAs and improve graft outcomes. We report that brief perioperative desensitization using either intravenous immunoglobulin (IVIG) or plasmapheresis/IVIG (PP/IVIG) treatment improves clinical outcomes among patients with positive crossmatches. DESIGN: Immediately following deceased donor transplantation, 235 renal recipients were assigned points for PRA and flow crossmatches (FCXM): delayed graft function (DGF) ≤ 1 point received standard therapy; 2 points received high-dose IVIG; and ≥3 points received PP/IVIG. The DSAs were serially monitored by single antigen bead luminex for 1 year. Five-year clinical outcomes were determined from the chart review. RESULTS: All desensitized patients had preoperatively positive FCXM with DSA. Rejection was more common (P < .05) among desensitized than nonsensitized groups. However, overall graft survivals were similar between the groups (P = not significant) and superior to historic untreated patients (P < .05). Treatment with PP/IVIG more effectively eliminated preexisting DSAs (67% vs 33%, P < 0.05) than IVIG, but neither regimen prevented de novo formation of DSA (20%, P = not significant). Graft survival was >90% in all desensitizated patients with DSA elimination as well as PP/IVIG patients with residual DSA. In contrast, IVIG patients with persistent DSA had poorer graft survival (45%, P < .05). CONCLUSION: Preemptive perioperative desensitization improved overall graft survival of sensitized patients compared to historic untreated patients. Plasmapheresis/IVIG had greater impact on DSA eradication and graft survival than IVIG alone.

Management and Outcomes of Kidney Transplant Candidates With Severe Pulmonary Hypertension: A Single-center Strategy and Experience.

Background: Severe pulmonary hypertension (PH) is associated with high mortality posttransplant and thus is considered a contraindication to kidney transplantation. In this study, we describe the pretransplant management and posttransplant outcomes in patients with severe PH using a multidisciplinary approach. Methods: Between 11 of 2013 and 8 of 2022, we identified all patients with severe PH on initial pretransplant workup who underwent ultrafiltration (UF) or medical therapy for PH before transplant. Posttransplant we evaluated the perioperative course, renal function, graft, and patient survival. We compared survival to those who remained waitlisted or were delisted. Results: Three-two patients (mean age = 55.03 ± 10.22 y) diagnosed with severe PH on pretransplant screening echocardiogram. Thirty patients (94%) were subjected to a median of 4 (range, 3-8) UF sessions with an average weight loss of 4.33 ± 2.6 kg. Repeat assessment of PH revealed a decline in mean pulmonary artery systolic pressure from 67 ± 12 mm Hg to 43 ± 13 mm Hg (P < 0.0001). Seventeen patients (53%) received a kidney transplant. The mean estimated Glomerular Filtration Rate at 3, 6, 9, and 12 mo was 72 ± 27, 72 ± 28, 75 ± 29, and 75 ± 29 mL/min/1.73 m2. Among, those who underwent transplantation both graft and patient survival was 100% at 1-y posttransplant. Overall, since the UF intervention, at a median follow-up of 88 ± 12 mo those transplanted had a patient survival of 88% while those who remained on dialysis had a survival of 53% (P = 0.0003). Conclusion: In this single-center study, we report postcapillary PH can be a significant contributor to elevations in pulmonary artery systolic pressure. Using a multidisciplinary approach, PH can improve with volume removal and phosphodiesterase 5 inhibitors therapy leading to a successful posttransplant outcome.

Cell-free DNA for the detection of kidney allograft rejection.

Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .

Right versus left fully robotic live donor nephrectomy and open kidney transplantation: Does the laterality of the donor kidney really matter?

Objective: Robotic-assisted live donor nephrectomy (LDN) is being gradually adopted across transplant centers. The left donor kidney is preferred over right due to anatomical factors and ease of procurement. We aimed to study donor and recipient outcomes after robotic procurement and subsequent open implantation of right and left kidneys. Methods: All fully robotic LDNs and their corresponding open kidney transplants performed at our center between February 2016 and December 2021 were retrospectively analyzed. Results: Out of 196 robotic LDN (49 [right] vs. 147 [left]), 10 (5.1%) donors had intra-operative events (6.1% [right] vs. 4.8% [left], p=0.71). None of the LDN required conversion to open surgery. The operative times were comparable for the two groups. Nausea (13.3%) was the most common post-operative complication. There was no mortality in either LDN group. Herein, we report our outcomes on 156 recipients (39 right and 117 left allografts) excluding robotic implants, exports, and pediatric recipients. There were no significant differences between right and left kidney recipients with respect to 1-year post-transplant patient survival (100.0% vs. 98.1%, p=0.45) or graft survival (93.9% vs. 97.1%, p=0.11), or delayed graft function (7.7% vs. 5.1%, p=0.55). Conclusion: Non-hand-assisted robotic live donor nephrectomies can be safely performed with excellent outcomes. Right LDN was not associated with higher incidence of complications compared to left LDN. Open implantation of robotically procured right renal allografts was not associated with higher risk of recipient complications.

Correlation of Donor-derived Cell-free DNA With Histology and Molecular Diagnoses of Kidney Transplant Biopsies.

BACKGROUND: Circulating donor-derived cell-free DNA (cfDNA), a minimally invasive diagnostic tool for kidney transplant rejection, was validated using traditional histology. The molecular microscope diagnostic system (MMDx) tissue gene expression platform may provide increased precision to traditional histology. METHODS: In this single-center prospective study of 208 biopsies (median = 5.8 mo) posttransplant, we report on the calibration of cfDNA with simultaneous biopsy assessments using MMDx and histology by area under the curve (AUC) analyses for optimal criterion, as well as for, previously published cfDNA cutoffs ≤ 0.21% to "rule-out" rejection and ≥1% to "rule-in" rejection. RESULTS: There were significant discrepancies between histology and MMDx, with MMDx identifying more antibody-mediated rejection (65; 31%) than histology (43; 21%); the opposite was true for T cell-mediated rejection [TCMR; histology: 27 (13%) versus MMDx: 13 (6%)]. Most of the TCMR discrepancies were seen for histologic borderline/1A TCMR. AUC for cfDNA and prediction of rejection were slightly better with MMDx (AUC = 0.80; 95% CI: 0.74-0.86) versus histology (AUC = 0.75; 95% CI: 0.69-0.81). A cfDNA ≤ 0.21% had similar sensitivity (~91%) to "rule-out" rejection by histology and MMDx. Specificity was slightly higher with MMDx (92%) compared with histology (85%) to "rule-in" rejection using cfDNA criterion ≥1%. Strong positive quantitative correlations were observed between cfDNA scores and molecular acute kidney injury for both "rejection" and "nonrejection" biopsies. CONCLUSIONS: Molecular diagnostics using tissue gene expression and blood-based donor-derived cell-free DNA may add precision to some cases of traditional histology. The positive correlation of cfDNA with molecular acute kidney injury suggests a dose-dependent association with tissue injury irrespective of rejection characteristics.

Donor-derived Cell-free DNA in Solid-organ Transplant Diagnostics: Indications, Limitations, and Future Directions.

The last few years have seen an explosion in clinical research focusing on the use of donor-derived cell-free DNA (dd-cfDNA) in solid-organ transplants (SOT). Although most of the literature published so far focuses on kidney transplants, there are several recent as well as ongoing research studies on heart, lung, pancreas, and liver transplants. Though initially studied as a noninvasive means of identifying subclinical or acute rejection in SOT, it is rapidly becoming clear that instead of being a specific marker for allograft rejection, dd-cfDNA is more appropriately described as a marker of severe injury, although the most common cause of this injury is allograft rejection. Multiple studies in kidney transplants have shown that although sensitivity for the diagnosis of antibody-mediated rejection is excellent, it is less so for T-cell-mediated rejection. It is possible that combining dd-cfDNA with other novel urine- or blood-based biomarkers may increase the sensitivity for the diagnosis of rejection. Irrespective of the cause, though, elevated dd-cfDNA seems to portend adverse allograft prognosis and formation of de novo donor-specific antibody. Although current data do not lend themselves to a clear conclusion, ongoing studies may reveal the utility of serial surveillance for the management of SOT as following levels of dd-cfDNA over time may provide windows of opportunity to intervene early and before irreversible allograft injury. Finally, cost-effectiveness studies will be needed to guide the ideal incorporation of dd-cfDNA into routine clinical practice.