Transplant Recipients Research Articles

Early acute kidney injury after tacrolimus administration in heart transplant recipients receiving basiliximab induction therapy.

In this study, we aimed to analyze the association among the timing of tacrolimus initiation, time required to reach the target blood concentration, and early acute kidney injury (AKI) after tacrolimus administration in heart transplant recipients who received basiliximab induction therapy. 88 patients treated with tacrolimus-based immunosuppressive therapy were retrospectively reviewed. Induction therapy was administered to 52 patients. AKI was evaluated within 7 days of tacrolimus administration. The rate of increase in tacrolimus trough concentration to the target trough concentration of 10 µg/mL early after its administration was set to be similar in the basiliximab induction and non-induction group; 8 and 2 patients developed AKI in the induction and non-induction group, respectively. In the induction group, there was no significant difference in the timing of tacrolimus initiation and the time required to reach the target concentration between patients who developed and did not develop AKI. In contrast, the cumulative incidence of AKI was significantly different between patients with an estimated glomerular filtration rate below and those with an estimated glomerular filtration rate above 43 mL/min/1.73m2 at the start of tacrolimus administration (37.5% and 11.4%, respectively; p=0.045). In patients receiving basiliximab induction therapy, the timing of tacrolimus initiation and the time to reach the target concentration are unlikely to be associated with early AKI after tacrolimus administration. However, the recovery of sufficient renal function after heart transplantation is important for determining the start time of tacrolimus.

Heterologous Versus Homologous COVID-19 Boosters: Immune Response Outcomes in Renal Transplant Recipients.

We aimed to investigate the immune responses to homologous and heterologous COVID-19 booster vaccinations in renal transplant recipients (RTRs) and to identify factors affecting these responses. In this prospective multicenter observational study, we measured the antibody kinetics of 90 RTRs using the chemiluminescent microparticle immunoassay method. The mean age of participants was 45.2 ± 11.4 years, with 35.6% being female. On the 42nd day after the first vaccine dose, the median antibody level was 16.7 (IQR 2.5-249.5) AU/mL, and the seropositivity rate was 60% (n = 36). Mycophenolic acid (MFA) (OR: 0.087, 95% CI: 0.024-0.311) and ACE inhibitor use (OR: 0.203, 95% CI: 0.052-0.794) were identified as independent factors affecting seropositivity. Patients who received the Pfizer/BioNTech booster had significantly higher antibody levels compared to those who received the CoronaVac/Sinovac booster (p = 0.021). Additionally, a significantly higher rate of COVID-19 positivity was observed among patients who received the CoronaVac/Sinovac booster (p = 0.031). Heterologous COVID-19 booster vaccination is significantly more effective than homologous inactivated booster vaccination in enhancing immune responses and preventing new infections in RTRs. MFA and ACE inhibitor usage were independent factors affecting seropositivity. Additional COVID-19 vaccine doses are needed in this patient group.

Risk Factors of Post-Traumatic Stress in Pediatric Solid Organ Transplant Recipients.

Life with end-stage organ failure is accompanied by an accumulation of traumatic medical or surgical experiences. Despite recovery after solid organ transplantation (SOT), many children and adolescents develop post-traumatic stress symptoms (PTSS). PTSS remain underappreciated as a major comorbidity in SOT programs, despite their association with decreased quality of life. We conducted a retrospective, cross-sectional study of 86 pediatric SOT recipients (17 heart, 44 kidney, and 25 liver) to evaluate potential determinants of PTSS. Trauma symptoms were measured by the Child Trauma Screening Questionnaire (CTSQ). Demographic, baseline, and contemporaneous factors were tested for independent association with CTSQ scores. The median post-transplant CTSQ score was 2 (IQR 1-4), and 22% were identified as high risk (score ≥5) for PTSD. Higher CTSQ scores were independently associated with the number of ICU days within the previous 12 months, the number of medications (complexity), and involvement with foster care in the primary model (R2 [adj.] = 0.26). The addition of the Family Impact Module improved the overall model (R2 [adj.] = 0.33), wherein higher family functioning was independently associated with lower CTSQ scores. An exploratory analysis of pre-transplant patients (n = 34) found a median pre-transplant CTSQ of 2 (IQR 1-6), suggesting that PTSS are onset before transplant and persist afterward. PTSS are highly prevalent in the SOT population. Risk factors include recent adverse medical experiences and complexity, whereas family stability may be protective. Additional research is needed to improve early ascertainment and support for patients at high risk of developing PTSS throughout their transplant journey.

Immunosuppressive Therapy, Puberty and Growth Outcomes in Pediatric Kidney Transplant Recipients: A Pragmatic Review.

Kidney transplantation in children with end-stage kidney disease significantly enhances survival and quality of life but poses unique challenges related to chronic immunosuppressive therapy. In fact, despite being essential for preventing organ rejection, immunosuppressive therapy can have significant side effects specific to pediatric patients, such as adverse impacts on physiological growth, puberty, and fertility. The resulting short stature and delayed or incomplete pubertal development can profoundly affect young patients' psychological and social well-being, impacting self-esteem and overall quality of life, and may significantly hamper compliance and therapeutic adherence. Most studies on immunosuppression in pediatric kidney transplant recipients focus on general side effects and outcomes like long-term graft survival or acute complications. On the other side, there is limited evidence in the current literature on the specific issues of growth, puberty, and fertility in this patient population. In this pragmatic review, we aimed to summarize the most relevant information available on these critical aspects of post-transplant management in pediatric patients, also providing some practical indications on management strategies for minimizing these often neglected but still important complications.

Dosing strategy of tacrolimus when co-administered with Wuzhi tablet in renal transplant recipients.

Tacrolimus (TAC) is a first-line immunosuppressant to prevent allograft rejection. Wuzhi tablet is widely used as a TAC-sparing agent in China that could significantly elevate TAC exposure. However, insufficient data support the dose recommendation of TAC when co-administered with Wuzhi. A total of 305 adult renal transplant patients with 2,541 TAC trough concentrations (C0) were enrolled for population pharmacokinetic (PPK) modeling. CYP3A5 polymorphism was genotyped, and corresponding clinical factors were recorded. Nonlinear mixed-effects modeling and Monte Carlo simulation were used for dose recommendation. PK parameters were calculated based on one-compartment model with first-order absorption and elimination. The estimated total clearance (CL/F) and volume of distribution (Vd/F) of TAC were 23.84 L/h and 1,075.96 L, respectively. Wuzhi, CYP3A5 genotype, hematocrit (HCT), and weight were found to have a significant influence on CL/F. CL/F was significantly lower in the individuals who were CYP3A5 non-expressers and received TAC together with Wuzhi. CYP3A5 genotype (expressers or non-expressers), body weight (40-80 kg), and hematocrit (20 - 40%) were selected as the specific clinical scenarios, and the starting dose of TAC ranged from 1.5 to 4.5 mg when co-administered with Wuzhi. We establish a TAC PPK model comprising Wuzhi as a covariate in renal transplant recipients and recommend an initial dose of TAC when co-administered with Wuzhi, which could provide reference for the individualized regimens of TAC.

Skin cancer incidence in Mexican renal transplant recipients: a cohort over 56 years.

Skin cancer is a primary health concern in renal transplant recipients (RTRs). Existing research mainly stems from North America, Europe, and Australia, with limited data from Latin America. This 56-year (1967-2023) retrospective cohort study explores skin cancer incidence in Mexican RTRs. Our objective was to assess the long-term incidence of malignant cutaneous neoplasms in Mexican RTRs. Over 56 years, 1642 RTRs (58% male) were studied. Median follow-up was 8.4 years; median age at transplantation was 32.6 years. Skin cancer incidence was 6.6% (95% CI: 5.5-7.9), with an incidence density rate of 6.5 (95% CI: 5.4-7.9) per 1000 person-years and a median latency of 9.8 years. Incidence increased with longer transplantation-related immunosuppression (TRI), with a relative risk for >30 years of TRI of 4.8 (95% CI: 2.6-9.1) for any skin cancer and 7.5 (95% CI: 3.8-14.6) for squamous cell carcinoma (SCC). SCC was the most common malignancy (76.1%), followed by basal cell carcinomas (BCC), with a 3.6:1 ratio. Metastatic SCC occurred in 6.5% of skin cancer patients, with a skin cancer-related mortality rate of 2.7%. Limitations of the study include its single-center and retrospective design and unassessed factors such as human papillomavirus infection and sun exposure. Our study provides unique insights into the epidemiology of skin cancer among Mexican RTRs. It constitutes the largest cohort of skin cancer cases among RTRs in Mexico and, to our knowledge, in Latin America. Despite the lack of recognition of a high skin cancer incidence in non-White RTRs, our 6.6% incidence underscores the need to enhance surveillance programs.

Cardiovascular Risk in Pediatric Renal Transplant Recipients.

The survival of pediatric chronic kidney disease (CKD) patients has improved in recent decades due to advances in dialysis and transplantation. However, cardiovascular disease (CVD) emerges as the main cause of mortality in patients with CKD. To estimate cardiovascular risk in children with CKD at least 1 year after kidney transplantation. In addition, the possible association of cardiovascular risk with classic biochemical markers and potential new markers of this outcome was investigated. An observational ambidirectional (retrospective capture of risk factors and prospective study of outcomes) research including 75 patients who underwent renal transplant between 2003 and 2013 with postoperative follow-up of at least 1 year was conducted. The outcome variables adopted were the LV mass Z-score and the presence of coronary calcification on computed tomography using calcium Agatston score. Only one patient had an elevated calcium score, and three children (4%) had an LV mass Z-score ≥ 2.0. After multivariable analysis, only gender, serum triglyceride, and serum renalase concentration remained significantly associated with LV mass. The low incidence of cardiovascular changes in the population studied confirms the benefit of transplantation for the cardiovascular health of children. Nevertheless, long-term follow-up of these patients is recommended, given the limited duration of kidney function provided by transplantation and the high likelihood of further dialysis and kidney transplants being required in these children.

Investigation of Nosocomial Urinary Tract Infections Post Transplantation, Main Pathogens, and Sensitivity Tests

Background: Regarding end-stage organ disease, transplantation is recommended as the best therapeutic management. After organ transplantation, the incidence of nosocomial urinary tract infections (NUTIs) due to multidrug-resistant Gram-negative bacilli increases. Aim: The study aimed to investigate NUTIs post-transplantation, the main pathogens involved, and sensitivity tests conducted in a tertiary hospital in Isfahan, Iran. Methods: A retrospective survey on patients admitted to a tertiary hospital in Isfahan (Alzahra), Iran, was performed between 27 March, 2017, and 9 February, 2022. The information recorded included the date of infection, date of hospitalization, gender, age, type of pathogens, and resistance or sensitivity to antibiotics. Results: 73 kidney transplant recipients (61% females) with a mean age of 43. 2 ± 15.1 years were included. Within this population involving both genders, the main pathogens involved in NUTIs were as follows: Escherichia coli (30%), Klebsiella pneumonia (19%), Candida albicans and non-albicans (14%), Enterococcus faecalis (12%), Enterobacteriaceae (8%), Pseudomonas aeruginosa (6%), Staphylococcus spp. (6%), Acinetobacter baumannii (4%), and Streptococcus spp. (4%). Antibiotic susceptibility testing showed the most sensitivity of isolates against amikacin (n=29; 66%), meropenem (n= 28; 64%), piperacillin/tazobactam (n=26; 54%), cefepime (n= 25; 40%), ceftazidime (n= 27; 30%), ciprofloxacin (n= 40; 18%), and co-trimoxazole (n= 29; 10%). Conclusion: Escherichia coli, Klebsiella pneumonia, and Candida spp. were the major causes of NUTIs within the studied organ-transplanted recipients. Amikacin, meropenem, and piperacillin/ tazobactam have shown more than 50% sensitivity against isolates. Further evidence-based pharmacotherapy investigations associated with the different spectrum antibiotics and overall antimicrobial success rate is recommended to be advantageous.

Cilgavimab and tixagevimab as pre-exposure prophylaxis in vaccine non-responder kidney transplant recipients during a period of prevalent SARS-CoV-2 BA.2 and BA.4/5 variants—a prospective cohort study (RESCUE-TX)

The response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination is severely impaired in patients on maintenance immunosuppression after kidney transplantation. We conducted a prospective cohort study of 194 kidney transplant recipients (KTR) who exhibited no response to SARS-CoV-2 vaccinations (i.e., SARS-CoV-2 spike protein antibodies ≤264 U/mL) and had no prior documented infection. Patients received 300mg of cilgavimab/tixagevimab as SARS-CoV-2 pre-exposure prophylaxis (PrEP) between March 4, 2022, and May 3, 2022 and were contrasted to a matched cohort of 186 KTRs also without immunization again defined as SARS-CoV-2 spike protein antibodies ≤264 U/mL and no documented prior infection. The primary outcome was the serum kinetics of cilgavimab/tixagevimab, the secondary endpoints were time to SARS-CoV-2 breakthrough infection, severity of disease and variant specific live viral invitro neutralization tests of patient sera. Longitudinal serum level monitoring showed a half-life of 91 days for both antibodies (95% CI 86-95 days for cilgavimab and 85-96 days for tixagevimab) in KTRs. Invitro neutralization tests showed effectiveness against the BA.2 omicron subvariant but not BA.5. The cumulative incidence of SARS-CoV-2 infections until May 15, 2022, (BA.2 dominance) was 15/194 vs 36/186 in the PrEP and control group respectively (OR=0.35, 95% CI 0.18-0.66) but was not different thereafter (BA.4/5 dominance). The number of severe infections during the BA.2 period was lower in the prophylaxis than in the control group (OR=0.37, 95% CI 0.17-0.79). This study showed that SARS-CoV-2 PrEP with cilgavimab/tixagevimab demonstrated clinical effectiveness against variants that are neutralised (BA.2) but not against BA.4/5. This study was funded by the Medical University of Vienna and an unrestricted grant from AstraZeneca (ESR-21-21585).

Establishing normal global longitudinal strain values in heart transplant patients: a novel approach to enhancing detection of rejection and cardiac allograft vasculopathy

Abstract In the realm of heart transplantation, accurate cardiac monitoring is pivotal for patient outcomes. This study pioneers in filling a critical void by delineating the normative values of Global Longitudinal Strain (GLS), specifically tailored for heart transplant recipients, distinguishing them from the general population. We conducted a retrospective analysis on a cohort of 110 patients who underwent heart transplantation, meticulously compiling echocardiographic data over the first 18 months post-operation. Our research focused on two primary indicators of cardiac function: Ejection Fraction (EF) and Global Longitudinal Strain (GLS). The data indicated that EF values remained within the normal range and relatively stable throughout the monitoring period. In contrast, GLS values exhibited a gradual increase over time, suggesting a post-transplant myocardial adaptation process. However, these GLS values did not reach the established reference ranges for non-transplanted, healthy hearts, highlighting the distinctive physiological landscape of transplant recipients. Our study elucidates the superior sensitivity of GLS in detecting subtle myocardial changes that might precede clinically apparent dysfunction, advocating its utility as a crucial surveillance tool for this demographic. By pinpointing the modified GLS benchmarks applicable to post-heart transplant patients, our findings advocate for a recalibrated echocardiographic assessment protocol. Such a protocol can significantly enhance the surveillance for post-transplant complications, most notably graft rejection and the onset of cardiac allograft vasculopathy (CAV). The study posits that incorporating these refined GLS thresholds into routine post-transplant evaluations could facilitate early intervention, potentially mitigating adverse outcomes and improving the long-term prognosis for heart transplant recipients. Thus, our research underscores the need for updated clinical guidelines that integrate these novel echocardiographic insights, paving the way for improved patient-centric cardiac care in the transplant setting.

OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients

Abstract Background Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Purpose Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30% of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95% CI: 0.76-0.90), 74.3% and 87.1%, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6%]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95% CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

Treatment with mTOR Inhibitors as primary immunosuppression after combined heart and kidney transplantation

Abstract Background It has been hypothesized that combined heart and kidney transplantation (HKT) may lead to immune modulation and attenuation of cardiac allograft vasculopathy (CAV) progression. Sirolimus (SRL) has been shown to mitigate the progression of CAV and confer renal protection. With the increasing use of SRL as primary immunosuppression in heart transplant (HT) recipients, the effect of HKT on CAV progression compared to HT-only remains undetermined. Purpose We sought to investigate the patterns of conversion from calcineurin inhibitors (CNI) to SRL, and its impact on CAV progression and outcomes in HKT compared to HT-only in a cohort with frequent use of SRL as primary immunosuppression. Methods A cohort of 302 patients who underwent either HT only (n=262) or combined HKT (n=40) was analyzed. CAV progression was assessed by measuring the delta (Δ) annual change in plaque volume (PV) normalized to vessel length (PV/VL in mm3/mm) and plaque index (PI) (%) (calculated as the PV to VV ratio) between baseline and last follow-up coronary intravenous ultrasound (IVUS). Clinical adverse outcomes included all-cause death and CAV-associated events. Secondary outcomes included differences in renal function and incidence of SRL-associated proteinuria (defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL) between HT-only and HKT recipients. Results Overall, 217 (72%) patients were converted from CNI to SRL as primary immunosuppression. HT recipients were more likely to be converted to SRL than combined HKT recipients (74% vs. 55%, P=0.01). HKT was associated with significantly higher ΔPV/VL (P=0.01) and a trend toward a higher ΔPI (P=0.06) than HT-only, but this association was markedly attenuated after adjustment to SRL conversion. HKT was associated with similar risk of death (adjusted hazard ratio [HR] 0.69, 95%CI: 0.28-1.71, P=0.43) and CAV-related events (adjusted HR 0.83, 95% CI: 0.30-2.31, P=0.72). Conversion to SRL was significantly associated with decreased risk of death and CAV-related events in the overall cohort. This association was not modified by the type of organ transplantation (Pinteraction=NS), and without a significant effect on estimated glomerular filtration rate (eGFR) or proteinuria. Conclusions HKT recipients compared to HT-only were less likely to be converted from CNI to SRL-based immunosuppression and had a greater CAV progression but without significant differences in all-cause mortality or CAV-related events. The clinical benefit and safety of conversion to SRL appeared similar in the HKT and isolated HT cohorts.

Cardiovascular risk factors and kidney transplantation: a retrospective analysis

Abstract Introduction Cardiovascular disease (CVD) poses a significant risk to end-stage kidney disease (ESKD) patients and remains the leading cause of morbidity and mortality among kidney transplant (KT) recipients. With a global rise in ESKD patients dependent on dialysis, transplant programs face growing pressure to consider candidates with a greater burden of CVD for KT despite potential long-term risks. Enhancing pre-KT cardiac risk assessment is crucial to prevent cardiovascular complications post-transplant and meet the demand for KT globally. Purpose High-quality studies evaluating pre-KT cardiovascular risk factors in patients with ESKD are lacking. Our study aims to evaluate the association between pre-KT cardiovascular risk factors and the development of major adverse cardiac events (MACE) post-KT. Methods This retrospective cohort study of ESKD patients at a tertiary center consisted of consecutive patients referred for cardiovascular assessment prior to KT between January 2013 and January 2023. Clinical and demographic data prior to KT and outcomes 1-year post-KT were extracted. Patients who underwent multi-organ transplantation were excluded. The primary endpoint was MACE, defined as all-cause death, myocardial infarction (MI), ischemic stroke, coronary revascularization, heart failure requiring hospitalization, and cardiac resuscitation. Results A total of n=233 patients were referred for cardiac evaluation prior to KT. Of these, n=145 (62%) patients had a KT, n=69 (30%) patients died pre-KT, and n=19 (8%) patients were removed from the transplant program. Of the n=143 KT recipients that met our inclusion criteria, 122 (85%) were free of MACE, while 21 (15%) met the primary endpoint in the year following KT. Patients with MACE were significantly older (mean age = 65 vs. mean age = 59, p < 0.001), and more likely to have coronary artery disease (85.7% vs. 50.8%, p = 0.01), cardiomyopathy (42.9% vs. 17.2%, p = 0.04), smoking history (71.4% vs. 46.7%, p = 0.04), and diabetes (85.7% vs. 49.2%, p = 0.02). Furthermore, deceased donor KT was associated with a greater likelihood of MACE (85.0% vs. 57.5%, p = 0.02) compared to living donor recipients. There were no significant differences with respect to left ventricular ejection fraction, diagnosis of heart failure, or prior MI between MACE and non-MACE groups (p > 0.17 for all). Conclusion Among pre-KT patients with CVD, there is a high mortality rate (30%) prior to KT. Following a successful KT, 15% of patients experienced MACE within 1-year. Our findings underscore the urgency of developing strategies to facilitate timely kidney transplantation, particularly in light of the anticipated rise in demand for kidney transplants. The elevated incidence of major adverse events in the year following a successful KT emphasizes the necessity of collaborative care by cardiologists and nephrologists for these patients, and the need for further studies to improve long-term outcomes.

Clinical outcomes in patients with unintended pregnancy after liver transplantation: A multicenter registry cohort study.

The consequences of unintended pregnancy in liver transplant (LT) recipients, a growing part of the high-risk obstetric population, remain unknown. To fill this gap, we conducted a retrospective registry cohort study to describe the risk factors, obstetric and neonatal morbidity, and graft outcomes associated with unintended pregnancy after LT. This study utilized the Transplant Pregnancy Registry International (TPRI) and included 565 pregnancies of LT recipients between 1967 and 2019 from 289 hospitals, primarily in North America. The primary outcome of acute cellular rejection (ACR) and secondary outcomes of graft loss, severe maternal morbidity, and neonatal composite morbidity were compared by pregnancy intention. The study population included 60.9% with intended pregnancies and 39.1% unintended pregnancies. Recipients with unintended pregnancy were more likely to self-report as Black race, to be younger, nulliparous, and have exposure to teratogenic immunosuppression. ACR was more common with unintended pregnancy (3.7% vs 1.2%, p=0.047). Unintended pregnancies had lower median birth weight (2806.6 vs 2948.4 grams, p=0.033). Unintended pregnancy was not associated with increased neonatal morbidity or severe maternal morbidity. These findings underscore the importance of family planning counseling, access to safe and effective contraceptive options, as well as multidisciplinary prenatal care in the growing population of reproductive-aged LT recipients.

Altered clot formation and fibrinolysis in heart transplant recipients

Abstract Background Long-term survival after heart transplantation (HTx) is limited by cardiac allograft vasculopathy (CAV), a frequent accelerated form of coronary artery disease. The pathogenesis remains incompletely understood, but thrombosis may be involved. We aimed to investigate clot formation and fibrinolysis in HTx patients and relate the findings to prognosis. Methods This prospective cohort study included 69 patients (median 8.4 years after HTx) with angiographically documented CAV 0 (not significant, n=36), CAV 1 (mild, n=19), and CAV 2-3 (moderate to severe, n=14). Healthy individuals (n=69) served as age- and gender-matched controls. Using a plasma-based fibrin clot formation and lysis assay, we assessed the following clot properties off-aspirin: 1) clot formation reflected by peak absorbance, 2) fibrinolysis measured by clot lysis time, and 3) a combined measure of clot formation and lysis reflected by area under the curve (AUC). Major adverse cardiac events (MACE) included heart failure hospitalization, cardiovascular death, and significant CAV progression. Results Median follow-up time was 5.1 (2.1-5.9) years. Five CAV 2-3 patients were excluded as it was not considered safe to interrupt aspirin therapy. Five patients had missing values due to either lysis resistance or severely decreased fibrin formation, and four of these underwent MACE with CAV progression and/or heart failure during follow up. Peak absorbance was significantly higher in HTx patients compared with healthy controls (0.72 vs. 0.50 aggregation units (AU), p<0.0001). Further, a stepwise increment above reference range through CAV groups was seen; CAV 2-3 patients (0.85 ± 0.12 AU) versus CAV 1 patients (0.72 ± 0.17 AU, p<0.05) and CAV 0 patients (0.68 ± 0.27 AU, p=0.06). Clot lysis time was significantly longer in HTx patients compared with healthy controls (1275 vs. 733 seconds, p<0.0001). AUC was significantly increased compared with healthy controls (1399 vs. 547 AU x seconds, p<0.0001). Overall, clot formation and fibrinolysis was not related to MACE. Conclusion HTx-patients have increased clot formation and prolonged fibrinolysis compared with healthy controls. Further, HTx-patients have an increased combined measure of these parameters compared with healthy controls, suggesting imbalance between fibrin clot formation and fibrinolysis. None of the measured parameters were related to prognosis.Clot formation and fibrinolysis

Stratification risk computation of primary graft gysfunction in heart transplant recipients on a smartphone application

Abstract Introduction There are no standardized guidelines for helping graft allocation in heart transplant (HTx) and accepting transplants from marginal donors and donors after circulatory arrest make decision making even more complex and time consuming than ever. The organ allocation process should include a risk analysis for primary graft dysfunction (PGD) that represents the most dreadful complication of HTx. There are 3 score systems validated to predict PGD but none has clear superior predictive capability compared to the others and the complexity of score computation potentially discourage their clinical use. A score integrating all the variables presented in a user-friendly format should improve efficacy and safeness of the organ allocation process. Methods Severe PGD defined as need for temporary mechanical circulatory support (ECMO) in the first 24 hours following HTx was considered the end-point for risk stratification computation. As a derivation cohort we used meta-analytic approach for identifying variables that are independently associated to severe PGD. The overall prevalence of each variable was determined to define the absolute risk increase value in presence of each factor. We then created a scoring system applying multivariate logistic regression model. As a validation cohort we studied the performance of the score in a retospective series of HTx performed at our institution from 2013 to 2022. We used C statistic equivalent to the area under a receiver-operating characteristic curve for dichotomous outcomes. Values above 0.7 were considered acceptable. We eventually developed an application for smartphone for risk computation. Results On 64 papers screened, 5 studies were considered eligible for the derivation cohort definition. Cumulative number of patients considered was 10’175 with an incidence of severe PGD of 7.1% (CI 5.3 - 10.4) and a 30-day mortality of 41%. 13 variables were identified (table 1). The ROC curve predicted the use of ECMO with the specificity and the sensitivity of 0,81 and 0,92 respectively. We have included in the validation cohort 128 out of 150 transplanted patients, excluding pediatric and double organs transplants. The mean donor age was 45 +/- 12,4 years, 72 (54%) were men. The mean recipient age was 57 +/- 9,3; 92 were men; 32 recipients (25%) needed ECMO support within 24 hours post-transplant; 75% of the donors in the ECMO group were > 40 y.o.; 30 days mortality was 3.1% and 6,2% in the non-ECMO and ECMO group respectively. We validated the model on our cohort defying a binary outcome (ECMO yes/no). Conclusion Clinicians fill donor, recipient and surgical parameters in user-friendly smartphone application identifying patients that are most likely to need ECMO support post HTx. The decision-making process during organ allocation evolves from what was once little more than personal experience and intuition to a reliable evidence-based method based on personalized risk prediction.Table 1

Visual coronary artery calcium assessment on routine chest CT can readily and cheaply identify liver transplant recipients with a low cardiac risk

Abstract Background Peri- and postoperative cardiac complications play an important role in survival of patients after liver transplantation (LT). However, the optimal approach for cardiac risk prediction in these patients has been debated on. LT recipients routinely receive non-gated computed tomography (CT) of the abdomen and chest to follow-up on their liver diseases. This study analyzed whether performance of coronary artery calcium (CAC) assessment on freely available scans can enhance cardiac risk stratification of LT recipients. Methods Consecutive LT recipients from 2008-2023 were included and analyzed retrospectively. CAC was scored visually on non-gated CT on a semi-quantitative ordinal scale and stratified in two groups according to CAC severity. Peri-operative (≤90 days) and post-operative all-cause mortality and cardiac events were analyzed. Furthermore, all-cause mortality and cardiac events were analyzed and compared between the groups with a Kaplan Meier curve and Cox proportional hazard regression. Results A total of 149 patients were included with a median age of 58 years. The median follow-up time was 5 years. The majority (74%) of patients had no or mild CAC. None of these patients died perioperatively due to cardiac causes, or experienced peri-operative cardiac events. The post-operative 10-year survival of LT recipients with no or mild calcifications was significantly better (p<0.01) than patients with severe CAC. The 10-year cardiac event-free survival was significantly better in patients with no or mild CAC (p<0.01) and the incidence increased >4-fold from only 4% in patients with no-mild CAC to 18% in patients with severe CAC. Of interest, severe CAC was a significant predictor of cardiac events (HR 4.6, p=0.02), while classical cardiovascular risk factors e.g. diabetes were not. Conclusion CAC assessment on routinely available non-gated CT can readily enhance peri- and postoperative cardiac risk stratification of LT recipients, as it identifies a selection of low-risk individuals for having peri- and post-operative cardiac events and all-cause mortality. Thereby, reducing test burden for the patients and saving healthcare expenses.

Endomyocardial biopsy in the diagnosis of cardiac sarcoidosis

Abstract Background Definite diagnosis of cardiac sarcoidosis (CS) requires proof of sarcoid granulomas in the heart. Endomyocardial biopsy (EMB) is considered a risky procedure with poor sensitivity (<25%) in CS (1), although comprehensive studies on its diagnostic performance are not available. Purpose We investigated the sensitivity, complications, and prognostic significance of EMB in a large cohort of patients with CS to help to choose diagnostic strategy when the disease is suspected. Methods We analysed the data of 260 consecutive patients diagnosed with CS in 1988-2022 at our institution. All met the diagnostic criteria of the Heart Rhythm Society (1). The use, findings, and complications of EMB were retrospectively noted in addition to patients’ demographics, presenting phenotype, diagnostic examinations, and future serious cardiac events. The data were retrieved from hospital records and an ongoing CS registry (2). Advanced imaging studies (cardiac magnetic resonance, positron emission tomography) were re-analysed and the follow-up information was updated until June 2023. EMB’s performance was assessed also in 30 cardiac transplant recipients having CS at the histopathologic study of the explanted heart. Results Of the 260 patients (mean age 49, 60% females), 216 (83%) underwent diagnostic EMB, 48 with repeat procedures. The sensitivity of EMB was 38%, rising to 49% after repeats. The predictors of positive EMB (Table 1) included the presenting phenotype and characteristics of the activity, extent, and location of myocardial involvement. Presentation with ventricular tachyarrhythmia, left ventricular (LV) ejection fraction ≤45%, elevation of cardiac troponins, and presence of middle or apical LV septal late gadolinium enhancement on magnetic resonance imaging were independent predictors (p<0.05) of positive biopsy. The sensitivity of EMB was directly related to the count of the predictors present (Figure 1). The rate of procedural complications was 9.7% overall and 0.7% for major events. One pericardial effusion needed drainage, but no deaths or long-term sequels followed the biopsies. Minor complications included 10 paroxysms of ventricular tachycardia and 6 small pericardial effusions. The 10-year rate (95% CI) of the composite of cardiac death, end-stage heart failure, or ventricular tachyarrhythmia was 55% (44-67%) with positive EMB vs 29% (17-44%) with negative EMB (p<0.001). When adjusted for the presenting phenotype and LV ejection fraction, EMB did not predict outcome events. In the 30 patients with CS in explanted hearts, the sensitivity of EMB, including the repeats, was 60%. Conclusion The sensitivity of EMB is better than usually presented in CS and the higher the more extensive myocardial involvement is. Risk of serious complications is <1%. In patients with suspect CS, the pre-test likelihood and value of positive EMB should be weighed against the procedural risks in shared decision-making when choosing the diagnostic pathway.

Challenging endomyocardial biopsies' gold standard status in rejection screening: a prospective blinded study on cardiovascular magnetic resonance in heart transplant patients

Abstract Background The detection of rejection is crucial for graft survival after heart transplantation. Endomyocardial biopsies (EMBs) serve as the gold standard for rejection surveillance despite its limitations, while cardiac magnetic resonance (CMR), in conjunction with donor-derived cell-free DNA (dd-cfDNA) analysis, holds promise as a non-invasive approach. Purpose In this prospective blinded study, our aim was to evaluate feasibility of CMR for rejection screening, validating it against EMB, dd-cfDNA, and clinical status. Methods We blindly analyzed 250 studies involving CMR, EMB, dd-cfDNA, and clinical data in 58 heart transplant recipients (17 children and 41 adults). Of these 250 studies, 239 (96%) were assessed within 1 to 28 months after transplantation, and 11 studies (4%) 3-14 years post-transplant. In CMR T1- and T2-mapping analyses, acute rejection was defined by T1 or T2 times exceeding the specified thresholds (T1 ≥ 1060 ms, T2 ≥ 55 ms) in at least 2/16 heart segments. EMB findings were graded according to the ISHLT criteria (2005 and 2013), and acute cellular rejection (ACR) grade ≥ 2 or antibody-mediated rejection (AMR) grade ≥ 1 were considered significant. The cutoff for abnormal dd-cfDNA was set at 0.2%. Solely clinical rejection included patients with absent or normal EMB (ACR grade 0-1 and AMR grade 0), but with symptoms or ECG/echocardiographic findings indicative of acute rejection. Results Our study revealed 22 acute rejections, with 15 confirmed through EMB and 7 diagnosed solely based on clinical indicators. Among the EMB-confirmed cases, 3/15 exhibited AMR grade 1, 10/15 demonstrated ACR grade 2 and 2/15 ACR grade 3. CMR identified rejection in 77% (17/22) of cases. Specifically, it successfully identified rejection in 67% (10/15) of EMB-confirmed cases and 100% (7/7) of solely clinically diagnosed cases. Examining the concordance between CMR findings and dd-cfDNA levels, 35% (6/17) of the CMR-identified rejection cases exhibited abnormal dd-cfDNA, while 30% (5/17) showed normal levels. Notably, in one case, despite normal CMR results, both EMB and dd-cfDNA indicated rejection. Conversely, in four instances where EMB indicated acute rejection, both CMR and dd-cfDNA levels were normal. These findings highlight a potential discrepancy in the diagnostic accuracy of EMB, suggesting its tendency to both over- and underdiagnose acute heart transplant rejection. The integration of CMR and dd-cfDNA in the diagnostic process may provide a more comprehensive and reliable assessment of rejection episodes, offering valuable insights for clinical decision-making in heart transplant recipients. Conclusions EMB presents challenges in both under- and overdiagnosing rejection in heart transplant surveillance. A strategy based on CMR, combined with dd-cfDNA analyses, shows promise as a new gold standard for rejection screening.Flowchart

Much ado about nothing: the impact of coronary angiography on kidney function in individuals with chronic kidney disease

Abstract Background and Objectives Chronic kidney disease (CKD) is associated with premature coronary artery disease and an increased risk of cardiovascular morbidity and mortality (1). Historically, there has been a tendency to delay or even avoid coronary angiography (CA) in those with CKD due to an increased risk of contrast-induced nephropathy or concern over precipitating the need for chronic dialysis. Such "renal nihilism" may account for the poorer outcomes observed in CKD patients who present with acute coronary syndromes (2). The role of this retrospective analysis was to evaluate the impact of CA on the temporal trend in kidney function in individuals with CKD over a 24-month period. Methods The clinical details of 120 individuals under long-term local follow-up by various Nephrology clinics (CKD clinic, low creatine clearance, polycystic kidney disease, transplant and immunosuppression clinics) was collected. All underwent CA locally. Kidney function was observed at set intervals of 12-, 9-, 6- and 3-months prior to CA, immediately post-CA, and at 3-, 6-, 9- and 12-months post-CA. Only results obtained after the desired time point but within 28 days were included. All CAs regardless of either their indication (elective or urgent) or whether percutaneous intervention (PCI) was performed, were included. Patients already on dialysis at the time of the CA were excluded. Statistical analysis was performed via one-way ANOVA. Results Patient characteristics are summarised in table 1. The average age of patients was 67, with a male preponderance (72%). 22% had CKD 3, 24% had CKD 4 and 12% had CKD 5. 9% were kidney transplant recipients. 37% underwent urgent CA whilst a total of 22% had PCI. 27% progressed to requiring renal replacement therapy (RRT). The mean length to RRT was 2.8 years. The rate of decline in kidney function in the last 12 months prior to CA was 7.7% and 6.3% in the year after CA (figure 1). There was no statistically significant difference in kidney function after CA (p = 0.395). This was replicated in analyses focussing on CKD classes 3, 4 and 5 individually, within stable kidney transplant recipients, and within analysis comparing PCI vs non-intervention CAs. Conclusion The results demonstrate CA does not accelerate the decline in kidney function in those with known CKD over a 12-month period, and suggests where appropriate, an invasive treatment strategy should be consider and utilised more often in this population.Table 1:Patient characteristicsFigure 1:Trend in eGFR relative to CA