For-cause Biopsies Research Articles

Urinary Exosomal Cystatin C and Lipopolysaccharide Binding Protein as Biomarkers for Antibody-Mediated Rejection after Kidney Transplantation.

We aimed to discover and validate urinary exosomal proteins as biomarkers for antibody−mediated rejection (ABMR) after kidney transplantation. Urine and for-cause biopsy samples from kidney transplant recipients were collected and categorized into the discovery cohort (n = 36) and a validation cohort (n = 65). Exosomes were isolated by stepwise ultra-centrifugation for proteomic analysis to discover biomarker candidates for ABMR (n = 12). Of 1820 exosomal proteins in the discovery cohort, four proteins were specifically associated with ABMR: cystatin C (CST3), serum paraoxonase/arylesterase 1, retinol-binding protein 4, and lipopolysaccharide−binding protein (LBP). In the validation cohort, the level of urinary exosomal LBP was significantly higher in the ABMR group (n = 25) compared with the T-cell-mediated rejection (TCMR) group and the no major abnormality (NOMOA) group. Urinary exosomal CST3 level was significantly higher in the ABMR group compared with the control and NOMOA groups. Immunohistochemical staining showed that LBP and CST3 in the glomerulus were more abundant in the ABMR group compared with other groups. The combined prediction probability of urinary exosomal LBP and CST3 was significantly correlated with summed LBP and CST3 intensity scores in the glomerulus and peritubular capillary as well as Banff g + ptc scores. Urinary exosomal CST3 and LBP could be potent biomarkers for ABMR after kidney transplantation.

216.3: Enhanced Histological Yield and Actionable Findings When Biopsy Is Guided by Donor-derived Cell-free DNA (dd-cfDNA)

Introduction: Implementation of molecular biomarkers in kidney transplantation has expanded the amount of information available to clinicians before deciding topursue biopsy. We evaluated how use of donor-derived cell-free DNA testing (dd-cfDNA) impacts histologic biopsy yield. Methods: 1663 kidney transplant (KTx) recipients enrolled in the Kidney allograft Outcomes AlloSure Registry (KOAR, NCT03326076) were followed with dd-cfDNA post-transplant; testing was obtained either as part of a surveillance strategy or for-cause; indications for biopsy and histologic diagnoses were captured. This analysis included only for-cause biopsies. Results: 65 biopsies (from 59 pts) driven by elevated dd-cfDNA levels were compared to 540 biopsies (392 pts) obtained for causes other than elevated dd-cfDNA. Patient age (55 vs 56 years), percent deceased donor (84.75% vs 78.83%), and biopsy timing post-transplant (123 vs 105.5 days) did not differ betweengroups (Table 1). Among dd-cfDNA-guided biopsies, yield was enriched for rejection (48% vs 29%) and included fewer cases of ATI/ATN (12% vs 22%)compared to biopsies obtained for other causes (p<0.05) (Figure 1). Among dd-cfDNA-guided biopsies with rejection (ABMR, TCMR, or Mixed), median dd-cfDNA was 1.46% (IQR: 1.15 - 2.87). Among biopsies not performed due to elevated dd-cfDNA but with paired results available (n = 267), median dd-cfDNA was0.24%. Within this group, patients with rejection had median dd-cfDNA of 0.82% and demonstrated an increase of 133% from the preceding result. Conclusions: Dd-cfDNA surveillance enhances the histologic yield for actionable results in for-cause allograft biopsies. A low dd-cfDNA result can obviate the need for biopsy even in the presence of other clinical factors that are routinely used to guide the biopsy decision.

401.3: Microvascular Inflammation in Renal Transplant Recipients Without Antibody Mediated Rejection

Purpose: Microvascular inflammation (MVI) defined by glomerulitis (g) and peritubular capillaritis (ptc) is a hallmark of ABMR in renal transplantation. The prevalence and significance of MVI in patients without ABMR is less understood. Methods: Here, we analyzed MVI in the 1st post-transplant year, its relationship to DSA, and its clinical significance in a large cohort of patients without ABMR. Along with any for-cause biopsy (fcBx), patients underwent 2 protocol biopsies (pBx, 3 & 12mos). Bx were categorized as early (0-4mos) or late (5-12mos). Serum was screened for DSA at 0, 1, 3, 6, 9 & 12mos post-transplant. Results: MVI Prevalence: 956/1187 patients transplanted between 2013-18 underwent 1950 Bx (67% protocol, 33% for-cause). Of these Bx, 64 had either ABMR or GN and were excluded. MVI was noted in 23% (g+ptc score 1-1.5 in 13% & ≥2 in 10%) of the remaining 1887 Bx with greater prevalence in fcBx (fcBx 14% vs. pBx 7%) and late Bx (late Bx 29% vs. early Bx 17%). Of note, the MVI prevalence and its severity increased with increasing grades of tubulointerstitial inflammation (TII) (Fig 1A). Of note, 65% of patients with allograft infections (pyelonephritis & BKVN) had MVI. MVI & DSA: DSA was detected concurrently in 12% of all the 1887 Bx without ABMR. Although, MVI was associated with concurrent DSA detection in these Bx (OR 1.8, 95% CI 1.3-2.5, p<0.,001), ~60% of the biopsies never had DSA (concurrent/historic or future). Furthermore, in biopsies stratified by the grade of TCMR, there was no significant difference in concurrent DSA detection between patients with and without MVI (Fig.1B). Outcomes: MVI in patients without ABMR was associated with decreased 7yr-graft survival (Fig 1C, p<0.001). Importantly, the combination of MVI and TII was associated with worse graft survival when compared to either no inflammation or TII alone (Fig1C, p<0.001). Further, in a select sub-group of patients with allograft infection, MVI was associated with a trend towards decreased graft survival compared to no MVI (76% vs. 88%). Finally, MVI was associated with poor graft survival independent of potential confounders including DSA (HR 2.5, 95% CI 1.6-3.4, p<0.001). Conclusion: MVI is common even in the absence of ABMR or DSA and is a marker for the severity of allograft inflammation and subsequent poor clinical outcomes.

242.2: Is There Any Role of Combined Use of Gene Expression Profiling and Donor Derived Cell Free DNA in Worsening Renal Allograft Function

Introduction: There are multiple noninvasive tests available to assess risk of renal allograft rejection. Donor-derived cell-free DNA (dd cf DNA) test is used to assess rejection in the settings of worsening renal allograft function while Gene profiling is used to assess the subclinical rejection in the settings of stable graft function. OmniGraf™ is a combination of Gene profiling and dd cf DNA tests and used for diagnosing possible subclinical rejection in the settings of stable renal allograft function. But not much has been observed in the settings of worsening renal allograft function. Here we are presenting our study aiming to correlate OmniGraf™ result with the biopsy outcomes. Methods: We selected 40 patients who had a biopsy either for cause or for protocol along with OmniGraf™ and serum creatinine checked around the same time of the biopsy. Patients were divided into 2 major groups, 1.protocol, and 2. For-cause biopsy, later subdivided into 4 groups depending on the OmniGraf™ result combinations. TX is considered No Rejection, Non-TX is considered increased risk of subclinical rejection.TRAC is the dd cf DNA test, High TRAC more than 0.7% is considered increased risk of rejection. Result: In the protocol biopsy group 12 out of 19 patients who had TX with normal TRAC had rejction on the biopsy.The normal result of OmniGraf™ TX with normal TRAC was supposed to predict no rejection, so if biopsy was not performed it might have missed 57% of rejection.This suggest that the normal result does not predict absence of rejection. The subgroup NonTX with Normal TRAC had 66% patients showing rejection,showed 100% rejection. This suggests that Non TX, irrespective of TRAC level is good in predicting possible rejection, irrespective of the type of rejection.In the for-cause biopsy group, the subgroup 2 of 2 patients with TX and normal TRAC had rejection on biopsy. Normal result of OmniGraf™ is not reliable to rule out rejection. The subgroup TX with high TRAC is good in capturing rejection for 6 out of 6 patients. This suggest that Tx may not be useful in this group in predicting rejection as dd cf DNA test, alone might have been able to predict the rejection. The subgroup Non TX with normal TRAC is showing 37.5 % patients, positive for rejection on biopsy while NON TX with high TRAC group has 60% of patients with rejection. This suggest that Non-TX part is good in predicting increasing risk of rejection in both groups irrespective of the High TRAC. Conclusion: Checking a single OmniGraf™ test to evaluate the risk without doing biopsy will miss subclinical rejection.It is probably more useful in serial monitoring of OmniGraf™ than one single value to capture subclinical rejection. Our data are limited to suggest clinical or statistical relevance, It would be useful to evaluate these results on a larger scale to understand the usefulness of this test in kidney transplant recipients with worsening renal allograft function.

216.9: Urinary Extracellular Vesicle DNA Cargo Reflects Kidney Allograft Injury

Introduction: Following allograft injury, donor-derived cell-free DNA (dd-cfDNA) levels increase. Numerous research studies have demonstrated increased dd-cfDNA levels in blood and urine as biomarkers of kidney allograft injury in patients with transplanted kidney. Extracellular vesicles (EVs) are nanosized particles released by almost all cells. Because of the anatomical proximity of kidney EV-producing cells and urine, (dd)DNA containing urinary EVs (uEVs) are potentially relevant biomarkers of allograft injury. The aim of our study was to explore uEVs and their DNA cargo, to reveal their association with allograft injury and finally to compare their biomarker potential with (dd)cfDNA found directly in the urine of patients with transplanted kidney. Method: We collected a second morning urine sample from 40 patients before surveillance or for-cause biopsy. We also collected blood and biopsy samples for donor-recipient genotyping. Considering histological analysis, we divided patients into normal histology, rejection injury (combination of antibody- (ABMR) and T-cell mediated rejection (TCMR)), and non-rejection injury group. First, we isolated uEVs (using protocol based on size-exclusion chromatography), their DNA cargo (uEV-DNA), and cfDNA from urine. We used nanoparticle tracking analysis to determine the concentration and size of uEVs. For DNA parameter analysis, including yield, copy number, integrity index, and donor-derived fraction, we used fluorometry and digital droplet PCR. We applied DNase assay and electron microscopy (TEM) immunogold labelling technique to investigate whether DNA was present inside or outside the uEVs. Results: The median uEV concentration was 8.47x1010/ mmol U-creatinine. The concentration was similar in all patient groups, whereas the size parameter differed significantly, as patients with rejection and non-rejection injury had significantly larger uEVs compared with patients with normal histology (177.5 nm and 174.1 nm vs. 160.7 nm, respectively; P=0.045). DNA co-isolated with uEVs and in several parameters correlated with urinary cfDNA. uEV-DNA and cfDNA yields (Figure 1A) and DNA copy number (Figure 1B) were significantly higher in both allograft injury groups. For uEV-DNA, the copy number of donor-derived DNA was significantly higher in patients with ABMR than in patients with TCMR (3044.3 vs. 680.9 copies, respectively; P=0.036). Regarding the long/short gene amplicon ratio, uEV-DNA (green) was less fragmented compared with cfDNA (yellow; Figure 1C). The TEM DNA labelling showed that the DNA was bound to the EV surface. uEV-DNA characteristics correlated with interstitial inflammation, inflammation in areas of fibrosis, and combination of glomerulitis and peritubular capillaritis Banff scores. Conclusion: In kidney transplant recipients, DNA bound to the surface of uEVs reflects allograft injury, particularly allograft rejection and is therefore a suitable potential biomarker for kidney allograft injury.Slovenian Research Agency Grants P3-0323, P1-0170, P4-0165, P4-0407.

216.2: Acute Tubular Injury and Necrosis Do Not Lead to Meaningful Elevations in Donor-Derived Cell-free DNA (dd-cfDNA)

KOAR registry. Introduction: Associations between non-rejection histologic diagnoses and dd-cfDNA have not been extensively characterized. We explored these associations inkidney transplant recipients enrolled in the Kidney allograft Outcomes AlloSure Registry (KOAR, NCT03326076). Methods: For-cause and surveillance biopsies with NR (no rejection or other abnormalities, except IF/TA) or acute tubular injury/necrosis (ATI/ATN), and paireddd-cfDNA within 30 days were included. The incidence of a composite outcome (eGFR decline > 25%, rejection, and de novo donor-specific antibody detection) at 12 months after biopsy was also assessed. Results: 166 biopsies (141 patients) with NR and 70 biopsies (64 patients) with ATI/ATN were included; compared to patients with ATI/ATN, patients with NRhad lower KDPI (49% vs 64%, p <0.05) and shorter cold ischemia time (13 vs 18 hours, p<0.01). ATI/ATN biopsies were more likely to be for-cause (91.4% vs59.6%, p<0.001), earlier post-transplant (83.0 vs 116.5 days, p<0.001), and occur at lower eGFRs (43 vs 32 mL/min, p<0.001) (Table 1). There was no significant difference in median dd-cfDNA between NR (0.23%, IQR: 0.11 - 0.53) and ATI/ATN (0.21%, IQR: 0.13 - 0.55) biopsies (p = 0.993) (Figure 1). When patients were stratified by dd-cfDNA at the time of their first biopsy (< 0.5% vs ≥ 0.5%), there was a non-significant trend towards a higher incidence of the 12-month clinical composite among those with dd-cfDNA ≥ 0.5% (27.5% vs 12.9%, p=0.53), with eGFR decline being most common (78.5% of events). Conclusions: Our findings suggest that acute tubular injury/necrosis is not associated with substantial elevations in dd-cfDNA. The use of dd-cfDNA to identify patients with non-actionable histologic findings (including ATI/ATN) may allow more nuanced clinical decision-making and reduce the number of unnecessary biopsies.

216.7: The Immunohistochemical Expression of Endothelial Activation Biomarkers Is a Potential Tool to Predict Kidney Allograft Outcomes

Background and Objective: Few reports assessed biomarkers of endothelial activation in kidney allograft biopsies using immunohistochemistry (IHC). This study aimed to analyze the IHC expression of Caveolin-1 (Cav), Von Willebrand Factor (Vwf), and T-Cadherin (Cad) in for-cause allograft biopsies diagnosed as Interstitial Fibrosis and Tubular Atrophy (IF/TA) of unknown etiology and evaluate its association with graft loss. Methods: This was a retrospective single-center cohort study including kidney biopsies performed in a single center between January 2013 and December 2017, whose histological, laboratory and clinical analysis concluded for IF/TA of unknown etiology. Samples with antibody-mediated changes were excluded. Patients were followed for three years after the biopsy or until graft loss/death. Results: Seventy-one (71) samples from 66 patients were included. Eighteen (25.4%) patients lost their grafts, mainly due to chronic rejection (33.3%). Cav and Cad were not associated with graft loss. Vwf had good accuracy to predict graft failure (AUC 0.637, 95%CI 0.486-0.788, p = 0.101). The presence of more than 10% of Vwf positivity in the microvasculature (Vwf > 10%) was associated with reduced death-censored graft survival (58.2% versus 85.4%, p = 0.006). The multivariate analysis showed that Vwf > 10% was an independent risk factor for graft loss (HR = 2.88, 95%CI 1.03-8.02, p = 0.043). Conclusion: Vwf might be an additional tool to predict allograft outcomes in kidney transplant recipients with IF/TA of unknown etiology, probably reflecting immune endothelial activation.

344.2: Delta Changes in Donor-Derived Cell-Free DNA (dd-cfDNA) Complement the Donor Fraction in Kidney Transplant Surveillance

Introduction: Delta changes in dd-cfDNA levels over time may identify patients with evolving alloimmune injury, providing complementary information to thedonor fraction. We explored the dd-cfDNA trajectories preceding biopsy-proven rejection (BPAR) events among kidney transplant recipients enrolled in theKidney allograft Outcomes AlloSure Registry (KOAR, NCT03326076) and undergoing longitudinal surveillance with dd-cfDNA. Methods: In the primary analysis, we compared the change in dd-cfDNA from baseline to the time of BPAR (for-cause or surveillance biopsies). We identifiedpatients with first-time rejection events and at least 3 prior dd-cfDNA results; the index result was obtained ≤30 days before BPAR; we then selected the lowestof two preceding results as the patient-specific baseline and compared this with the index result. We then analyzed patients with rejection (first or subsequent, atleast 90 days apart) and ≥2 dd-cfDNA results, including one within 30 days of the index biopsy. The reference change value (RCV) was calculated using areference population of patients with stable allograft function, at least 3 dd-cfDNA measurements, and no significant clinical events. Results: A total of 28 patients with BPAR met criteria for the primary analysis; among these, median baseline dd-cfDNA was 0.22% (IQR: 0.19 - 0.35) and mediandd-cfDNA at the time of rejection was 1.35% (IQR: 0.75 - 2.75), representing a 491% (IQR: 177 - 1133) increase between these results, obtained 71.5 (IQR: 46 -113) days apart (Table 1A).51 events met criteria for the second analysis where a median increase of 253% (IQR: 72 - 821%) between sequential dd-cfDNAvalues obtained 69 days (IQR: 45 - 108) apart preceded biopsy-proven rejection events (Table 1B). The calculated RCV for the stable reference population withinKOAR was 56.3%. 39 of these 51 events (76%) demonstrated increases greater than this RCV. Conclusions: Longitudinal surveillance with dd-cfDNA allows the integration of delta changes and trajectories over time, allowing earlier identification ofevolving allograft injury. Significant changes from an established baseline and between sequential values ahead of biopsy-proven rejection highlight how longitudinal surveillance may improve diagnostic performance.

Donor-directed immunologic safety of COVID-19 vaccination in renal transplant recipients

Infection risk and COVID-19 outcomes make SARS-CoV-2 vaccination essential forsolid-organ transplant recipients. Reports of immune activation after vaccination causing graft failure raise concerns, but data are limited. Here, we document graft function, donor-derived-cell-free-DNA(dd-cfDNA), and donor-specific antibodies (DSA) in solid-organ renal transplant recipients after vaccination.Retrospective demographics, graft function, and immunologic parameters were collected in 96 renal transplant patients one month after their second vaccine dose. For-cause biopsies were performed based on clinician judgment.Similar proportions of subjects experienced increases (39.6 %) and decreases (44.8 %) in serum creatinine in the post-vaccination period, p = 0.56. Similar proportions of subjects experienced increases (23 %) and decreases (25 %) in serum ddcfDNA in the post-vaccination period, p = 0.87. Post-vaccination changes in serum creatinine and ddcfDNA (r(95) = −0.04, p = 0.71), serum creatinine and cumulative DSA MFI (r(95) = 0.07, p = 0.56), and ddcfDNA and cumulative DSA MFI(r(95) = 0.13, p = 0.21) were not significantly correlated. Five subjects had increased cumulativeDSA MFI, but there were no de novo cases. Biopsies on three subjects confirmed pre-existing diagnoses.Our study found minimal evidence ofdonor-directed immunologic activity post-vaccination, and all immunologic changesdid not correlate to graft dysfunction. We believe these findings do not amount to evidence ofpost-vaccination deleterious donor-directed activation. SARS-CoV-2 vaccination is immunologically safe and should continue for renal transplant recipients.

Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients.

BackgroundClotrimazole troches are used as prophylaxis against oropharyngeal candidiasis post‐transplant and have limited systemic absorption. Following several occurrences of tacrolimus concentration fluctuations after clotrimazole discontinuation, its use as prophylaxis was discontinued post‐kidney transplant.MethodsWe conducted a retrospective cohort study to evaluate the effect of clotrimazole prophylaxis on tacrolimus trough concentrations post‐kidney transplant. The study included adult patients who received a kidney transplant at Cleveland Clinic Main Campus from August 1, 2019 to July 1, 2020 and were maintained on per‐protocol, standard‐dose tacrolimus through 90 days post‐transplant. Patients were excluded if they received cyclosporine, systemic antifungals, strong CYP3A4 inhibitors or inducers, or a simultaneous multiorgan transplant. The primary objective was to compare tacrolimus trough concentrations before and after completion of clotrimazole prophylaxis. Secondary objectives were to compare the time to first post‐transplant goal tacrolimus trough concentration, the rate of for‐cause allograft biopsies within 90 days after transplant, and the incidence and type of candidiasis within 30 days after transplant, pre‐ and post‐protocol change.ResultsFollowing clotrimazole discontinuation, the median tacrolimus trough concentration decreased from 10.5 ng/ml (IQR 8.4–12.2) to 6.6 ng/ml (IQR 5–8.7, p < 0.0001). No statistically significant differences in the rate of for‐cause allograft biopsies (4.9% vs. 9.7%, p = 0.264) or incidence of candidiasis (1.2% vs. 5.4%, p = 0.217) were observed between those who received clotrimazole and those who did not receive clotrimazole.ConclusionsOur study provides further evidence of a significant drug–drug interaction between tacrolimus and clotrimazole among kidney transplant recipients that can potentially lead to negative allograft outcomes.

MP54-04 A PHASE II STUDY OF CHECK POINT INHIBITOR, DURVALUMAB (MEDI4736) FOR BACILLUS CALMETTE-GUERIN UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER

You have accessJournal of UrologyCME1 May 2022MP54-04 A PHASE II STUDY OF CHECK POINT INHIBITOR, DURVALUMAB (MEDI4736) FOR BACILLUS CALMETTE-GUERIN UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER Roger Li, Kyle Rose, Michael Poch, Philippe Spiess, Scott Gilbert, Wade Sexton, and Jingsong Zhang Roger LiRoger Li More articles by this author , Kyle RoseKyle Rose More articles by this author , Michael PochMichael Poch More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Scott GilbertScott Gilbert More articles by this author , Wade SextonWade Sexton More articles by this author , and Jingsong ZhangJingsong Zhang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) represents a difficult clinical scenario, for which radical cystectomy (RC) is standard of care. Many patients are either unfit or unwilling to undergo RC, and bladder preserving treatment options are limited. We aimed to investigate the efficacy of durvalumab, a PD-L1 inhibitor, in the treatment of BCG-unresponsive carcinoma in situ (CIS) containing NMIBC. METHODS: This was a single center, open-label, phase II study of patients with BCG-unresponsive CIS of the bladder. After enrollment, patients received IV Durvalumab 1500mg IV, every 4 weeks for a total of 12 months. Cystoscopy with for-cause biopsy was performed every 3 months during the 12-month administration period, then every 4 months for a second 12 month surveillance period. Patients were taken off study if disease persistence or progression to invasive disease occurred. The primary endpoint was complete response (CR) by mapping biopsy at 6 months. Secondary outcomes were the duration of complete response and recurrence free survival (RFS). Pre- and post-treatment PD-L1 status was determined by the SP263 assay. Adverse events were captured using CTCAE v4.03. RESULTS: Seventeen patients were enrolled and began durvalumab for BCG-unresponsive CIS-containing NMIBC. Median age was 77 years (IQR 69-79), 13 (76.5%) patients had CIS alone, and the median number of prior BCG instillations was 12 (IQR 12-12). Four patients came off of study after 3 month bladder biopsy demonstrating persistent high grade NMIBC. Among the 13 patients who underwent 6-month mapping biopsy, 3 (18%) patients had a 6-month CR with a median duration of response of 14 months. Three (18%) patients progressed to muscle invasive or metastatic disease and 9 (53%) underwent RC. No correlation was observed between PD-L1 expression and clinical response to durvalumab. Grade 1-2 treatment-related adverse events occurred in 11 patients; most frequently fatigue (35%), diarrhea (18%), pancreatic enzyme elevation (12%), rash (6%), and hypothyroidism (6%). CONCLUSIONS: Immune checkpoint inhibition with durvalumab in BCG-unresponsive CIS-containing NMIBC demonstrated a favorable safety profile, but a modest CR rate. Additional research is needed in a larger cohort to determine generalizable efficacy with immune checkpoint inhibitors, and to better understand the safety profile in NMIBC. Source of Funding: AstraZeneca © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e927 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Roger Li More articles by this author Kyle Rose More articles by this author Michael Poch More articles by this author Philippe Spiess More articles by this author Scott Gilbert More articles by this author Wade Sexton More articles by this author Jingsong Zhang More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP54-06 LONGITUDINAL HEALTH-RELATED QUALITY OF LIFE OUTCOMES IN ADULTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER RECEIVING A CHEMOABLATIVE GEL AS A PRIMARY TREATMENT (OPTIMA II: PHASE 2B, SINGLE ARM, OPEN-LABEL TRIAL)

You have accessJournal of UrologyCME1 May 2022MP54-06 LONGITUDINAL HEALTH-RELATED QUALITY OF LIFE OUTCOMES IN ADULTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER RECEIVING A CHEMOABLATIVE GEL AS A PRIMARY TREATMENT (OPTIMA II: PHASE 2B, SINGLE ARM, OPEN-LABEL TRIAL) Angela Smith, Ramsankar Basak, Dana Mueller, Robert Lipman, Randall Teal, Alison Hilton, Kara Giannone, Myra Waheed, and Angela Stover Angela SmithAngela Smith More articles by this author , Ramsankar BasakRamsankar Basak More articles by this author , Dana MuellerDana Mueller More articles by this author , Robert LipmanRobert Lipman More articles by this author , Randall TealRandall Teal More articles by this author , Alison HiltonAlison Hilton More articles by this author , Kara GiannoneKara Giannone More articles by this author , Myra WaheedMyra Waheed More articles by this author , and Angela StoverAngela Stover More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Low-grade non-muscle-invasive bladder cancer (LG NMIBC) is treated with transurethral resection of the bladder tumor (TURBT), which can worsen health-related quality of life (HRQOL). The trial “OPTimized Instillation of Mitomycin for Bladder Cancer Treatment” (Optima II, clinicaltrials.gov: NCT03558503) is a Phase 2b, open label, multicenter trial evaluating a nonsurgical alternative as a primary treatment. Patients receive six weekly instillations of UGN-102, a mitomycin-containing reverse thermal gel. We report on HRQOL changes at the primary endpoint of 3 months. METHODS: Of 63 patients enrolled in the Optima II trial, 44 were in the HRQOL cohort and completed quarterly questionnaires (61% men, 57% age 65+, and 89% non-Hispanic White). Longitudinal changes were evaluated using the Sign test and correlations with demographic and clinical characteristics with regression. Ten patients (23%) were interviewed and transcripts were double-coded using standard methods. RESULTS: The chemoablative reverse thermal gel did not cause decrements in patient-reported urinary symptoms, bloating/flatulence, or malaise (Figure). Sexual function mildly worsened. Demographic and clinical characteristics were not correlated with HRQOL changes. By 3 months, 31/44 (70%) LG NMIBC patients achieved a complete response (negative endoscopic examination, cytology, and for-cause biopsy). In interviews, patients appreciated a nonsurgical alternative, would recommend the gel to other patients, and would choose the gel over TURBT. CONCLUSIONS: Adults with LG NMIBC receiving a nonsurgical, chemoablative gel as a primary treatment maintained their HRQOL through 3 months, and interviewed patients would recommend the gel to other patients. A Phase 3 trial is warranted. Source of Funding: Bladder Cancer Advocacy Network Patient Survey Network Award, supported by Urogen Pharma © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e928 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Angela Smith More articles by this author Ramsankar Basak More articles by this author Dana Mueller More articles by this author Robert Lipman More articles by this author Randall Teal More articles by this author Alison Hilton More articles by this author Kara Giannone More articles by this author Myra Waheed More articles by this author Angela Stover More articles by this author Expand All Advertisement PDF DownloadLoading ...

PD26-07 SEQUENTIAL ENDOLUMINAL CABAZITAXEL AND GEMCITABINE WITH PEMBROLIZUMAB FOR DOCETAXEL-UNRESPONSIVE NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF THE UPPER AND LOWER URINARY TRACTS

You have accessJournal of UrologyCME1 May 2022PD26-07 SEQUENTIAL ENDOLUMINAL CABAZITAXEL AND GEMCITABINE WITH PEMBROLIZUMAB FOR DOCETAXEL-UNRESPONSIVE NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF THE UPPER AND LOWER URINARY TRACTS Vignesh T. Packiam, Ian McElree, Ryan L. Steinberg, Adam Prescott, Rohan Garje, Yousef Zakharia, and Michael A. O'Donnell Vignesh T. PackiamVignesh T. Packiam More articles by this author , Ian McElreeIan McElree More articles by this author , Ryan L. SteinbergRyan L. Steinberg More articles by this author , Adam PrescottAdam Prescott More articles by this author , Rohan GarjeRohan Garje More articles by this author , Yousef ZakhariaYousef Zakharia More articles by this author , and Michael A. O'DonnellMichael A. O'Donnell More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002574.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Sequential intravesical Gemcitabine and Docetaxel (Gem/Doce) has shown over 50% 2-year high-grade (HG) recurrence free survival in patients with BCG-unresponsive non-muscle invasive bladder cancer. Subsequent recurrences may be due to overexpression of p-glycoprotein drug efflux pumps induced by prolonged Doce exposure. Cabazitaxel (Cabaz) has reduced efflux pump affinity and retains efficacy following Doce resistance in prostate cancer. We report outcomes of patients treated with sequential endoluminal Gem/Cabaz and intravenous Pembrolizumab (GCP) for patients with high-risk Doce-unresponsive NMIUC who refused or were poor candidates for cystectomy. METHODS: This is a retrospective analysis of 14 patients (18 treated units; 14 lower tract, 4 upper tract) who were treated with GCP from September 2020 to July 2021 with at least 3-month evaluation. Patients received 6 weekly endoluminal 50 cc instillations of sequential 1g Gem (90 minutes) and 5mg Doce (90 minutes) with concomitant intravenous Pembro (200/400mg q3/6weeks respectively). Maintenance treatment was administered every 2-4 weeks until disease progression or unacceptable toxicities. The primary outcome was complete response (CR) at 3 month evaluation, defined as no disease on cystoscopy, bladder/upper tract wash cytology or for-cause biopsies. We also evaluated tolerability and adverse events. RESULTS: Median follow-up was 6 months. Prior treatments included BCG in 93%, Gem/Doce in 100%, and additional Doce containing regimens in 79% of patients. Considering treated units, 79% presented with positive cytology or biopsy proven CIS, 7% with HG Ta and 14% with HG T1 disease. One patient did not start Pembro due to fatigue. At first evaluation, 12/14 (86%) patients and 16/18 (89%) treated units had CR. In those with at least 6 months of post-treatment evaluation, 7/10 (70%) patients and 9/12 (75%) treated units remained disease-free. Two patients recurred with positive cytology or CIS at 5 and 6 months, respectively. One patient was found to have muscle invasive bladder cancer at 3-months and underwent cystectomy (pTisN2). Three patients developed cystitis requiring dose modification of endoluminal agents and 2 patients stopped Pembro due to hepatitis and arthralgias. CONCLUSIONS: GCP shows promising early efficacy in heavily pretreated patients with high-risk NMIUC. The ∼33% of patients requiring dosing adjustments may reflect determination of optimal dosing. Prospective evaluation of this regimen is underway. Source of Funding: This work was supported by the John & Carol Walter Family Foundation and the Carver College of Medicine © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e489 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Vignesh T. Packiam More articles by this author Ian McElree More articles by this author Ryan L. Steinberg More articles by this author Adam Prescott More articles by this author Rohan Garje More articles by this author Yousef Zakharia More articles by this author Michael A. O'Donnell More articles by this author Expand All Advertisement PDF DownloadLoading ...

Incidence of acute rejection and patient survival in combined heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p<0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p=0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p=0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5years (CHLT 82.1% vs. HA 80.9% [p=0.73]; CHLT 82.1% vs. HA 80.9% [p=0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.

US payer budget impact of a microarray assay with machine learning to evaluate kidney transplant rejection in for-cause biopsies

Aim This study evaluates the economic impact to US commercial payers of MMDx-Kidney used in conjunction with histologic evaluation of for-cause kidney transplant biopsies. Materials and methods An Excel-based model was developed to assess the cost impact of histology plus MMDx-Kidney versus histology alone for the evaluation of potential rejection in kidney transplant patients who receive a for-cause biopsy. Different model time periods were assessed, ranging from 1 to 5 years post-biopsy. A targeted literature review was used to identify parameter estimates, validated by two external clinicians with expertise in managing kidney transplant rejection. A sensitivity analysis was conducted to evaluate the relative impact of key clinical and cost parameters. In particular, the model identified the magnitude of MMDx-Kidney’s impact on graft failure from rejection that would be required for MMDx-Kidney to be cost-neutral. Results By more accurately characterizing rejection, MMDx-Kidney is estimated to increase antirejection treatment costs by $1,126 per test. Nevertheless, a break-even analysis shows that the costs of MMDx-Kidney and anti-rejection medication, as well as the costs associated with an increase in the number of patients with functioning transplants, may be offset by reductions in costs associated with graft failure (i.e. costs of hospitalizations, dialysis, and repeat transplants) over 5 years, assuming MMDx-Kidney reduces annual graft failure from rejection by at least 5%. For the base case, with a 25% relative reduction in annual rate of graft failures from rejection, MMDx-Kidney increases overall costs incurred in the first year of the model but starts generating savings by the second year of the model. Conclusions Compared with histologic evaluation of for-cause kidney transplant biopsies alone, the use of MMDx-Kidney in conjunction with histologic evaluation improves the diagnoses of graft dysfunction and may have the potential to generate overall savings from reductions in rejection-related graft failure.

A Novel High-throughput Droplet Digital PCR-based Indel Quantification Method for the Detection of Circulating Donor-derived Cell-free DNA After Kidney Transplantation.

Donor-derived cell-free DNA (ddcfDNA) is a promising minimally invasive biomarker for acute rejection (AR) in kidney transplant recipients. To assess the diagnostic value of ddcfDNA as a marker for AR, ddcfDNA was quantified at multiple time points after kidney transplantation with a novel high-throughput droplet digital PCR indel method that allowed for the absolute quantification of ddcfDNA. In this study, ddcfDNA in plasma samples from 223 consecutive kidney transplant recipients was analyzed pretransplantation; at 3, 7, and 180 d after transplantation; and at time of for-cause biopsies obtained within the first 180 d after transplantation. Median (interquartile range) ddcfDNA concentration was significantly higher on day 3 (58.3 [17.7-258.3] copies/mL) and day 7 (25.0 [10.4-70.8] copies/mL) than on day 180 after transplantation (4.2 [0.0-8.3] copies/mL; P < 0.001 and P < 0.001, respectively). At time of biopsy-proven AR (BPAR), between day 11 and day 180 after transplantation, ddcfDNA concentration was significantly higher (50.0 [25.0-108.3] copies/mL) than those when biopsies showed non-AR (0.0 [0.0-15.6] copies/mL; P < 0.05). ddcfDNA concentration within the first 10 d after transplantation showed no significant difference between recipients with BPAR and those with non-AR in their biopsy or between recipients with BPAR and ddcfDNA measured at day 3 and day 7. Unfortunately, ddcfDNA concentration is not a good biomarker to detect AR within the first 10 d after transplantation; however, BPAR occurring after 10 d after transplantation can be detected in kidney transplant recipients by ddcfDNA using a novel and unique high-throughput droplet digital PCR indel method.

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gamma-glutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Monitoring intracellular tacrolimus concentrations and its relationship with rejection in the early phase after renal transplantation

IntroductionAfter kidney transplantation, rejection and drug-related toxicity occur despite tacrolimus whole-blood pre-dose concentrations ([Tac]blood) being within the target range. The tacrolimus concentration within peripheral blood mononuclear cells ([Tac]cells) might correlate better with clinical outcomes. The aim of this study was to investigate the correlation between [Tac]blood and [Tac]cells, the evolution of [Tac]cells and the [Tac]cells/[Tac]blood ratio, and to assess the relationship between tacrolimus concentrations and the occurrence of rejection. MethodsIn this prospective study, samples for the measurement of [Tac]blood and [Tac]cells were collected on days 3 and 10 after kidney transplantation, and on the morning of a for-cause kidney transplant biopsy. Biopsies were reviewed according to the Banff 2019 update. ResultsEighty-three [Tac]cells samples were measured of 44 kidney transplant recipients. The correlation between [Tac]cells and [Tac]blood was poor (Pearson’s r = 0.56 (day 3); r = 0.20 (day 10)). Both the dose-corrected [Tac]cells and the [Tac]cells/[Tac]blood ratio were not significantly different between days 3 and 10, and the median inter-occasion variability of the dose-corrected [Tac]cells and the [Tac]cells/[Tac]blood ratio were 19.4% and 23.4%, respectively (n = 24). Neither [Tac]cells, [Tac]blood, nor the [Tac]cells/[Tac]blood ratio were significantly different between patients with biopsy-proven acute rejection (n = 4) and patients with acute tubular necrosis (n = 4) or a cancelled biopsy (n = 9; p > 0.05). ConclusionTacrolimus exposure and distribution appeared stable in the early phase after transplantation. [Tac]cells was not significantly associated with the occurrence of rejection. A possible explanation for these results might be related to the low number of patients included in this study and also due to the fact that PBMCs are not a specific enough matrix to monitor tacrolimus concentrations.

Correlation of Glomerular Size With Donor-Recipient Factors and With Response to Injury.

Glomerular size in renal allografts is impacted by donor-recipient factors and response to injury. In serial biopsies of patients with well-functioning grafts, increased glomerular size correlates with better survival. However, no previous study has addressed the association of glomerular size at the time of a for-cause biopsy and clinical/histopathologic markers of injury, or effect on long-term graft outcome. Two cohorts of kidney transplant recipients enrolled in the Deterioration of Kidney Allograft Function study were evaluated. The prospective cohort (PC, n = 581): patients undergoing first for-cause kidney biopsy 1.7 ± 1.4 (mean ± SD) y posttransplant; and the cross-sectional cohort (CSC, n = 446): patients developing new-onset renal function deterioration 7.7 ± 5.6 y posttransplant. Glomerular planar surface area and diameter were measured on all glomeruli containing a vascular pole. Kidney biopsy was read centrally in a blinded fashion according to the Banff criteria. Glomerular area was significantly higher in the CSC than the PC; time from transplant to indication biopsy was associated with glomerular area in both cohorts (P values ≤ 0.001). Glomerular area was associated with indices of microvascular inflammation (glomerulitis, peritubular capillary infiltrates; P values ≤ 0.001) and segmental glomerulosclerosis (P value < 0.0001). In the CSC, higher glomerular area was associated with higher estimated glomerular filtration rate (P value ≤ 0.001) and increased graft survival after accounting for microvascular inflammation (adjusted hazard ratio = 0.967; 95% confidence interval: 0.948-0.986; hazard ratio in biopsies without evidence of diabetes or antibody mediated rejection = 0.919, 95% confidence interval: 0.856-0.987). Glomerular size is associated with histopathologic features present at the time of indication biopsy and with increased graft survival in the CSC.