Attieh, Rose Mary

Introduction Clonal hematopoiesis (CH) in solid organ transplant (SOT) recipients can lead to impaired tolerance to immunosuppressive therapy, increased risk for complications, and potentially compromise graft and patient outcomes. The impact of mutational profile in CH on risk for hematological transformation and patient/graft outcomes for kidney transplant (KT) recipients is largely unknown. Our aim was to assess the prevalence of CH and progression of CH in KT, evaluate the impact of CH on allograft function, assess patient outcomes and determine Clonal Hematopoietic Risk Score status. Methods We retrospectively reviewed the CH profile of patients 18+ years of age who received a kidney transplant at Mayo Clinic Enterprise between 01/01/1994-12-31/2022 and underwent bone marrow biopsy with aspirate pre- and/or post-transplant. Bone marrow biopsies were primarily performed post-transplant in the workup for cytopenias. Transplant database was used to collect our variables of interest including post-transplant malignancy and outcomes. CH was ascertained through next-generation sequencing (NGS) on bone marrow samples. A 47-gene panel was utilized in our study. CH was defined by presence of somatic mutation with a variant allele frequency of > 2.0%. CH in absence of cytopenias was classified as CHIP while CH in individuals with one or more cytopenias was classified as clonal cytopenias of undetermined significant (CCUS). The Clonal Hematopoiesis Risk Score (CHRS) was utilized for CHIP and CCUS risk stratification We excluded the patients who had a prior hematologic malignancy. Results 305 kidney transplant recipients met our study criteria. The median time to follow up, defined as time from transplant until first bone marrow biopsy with evidence of CH, was 46.1 months. The frequency of CH in kidney recipients was 27/305 (9.0%), of these 14/27 (52%) patients were found to have CCUS and 10/27 (37%) were found to have evidence of post-transplant myeloid malignancy. Of these cases, 5/10 (50%) developed acute myeloid leukemia while 5/10 (50%) developed myelodysplastic syndrome. Both CCUS and myeloid neoplasms were more common in female patients, accounting for 8/14 (57%) and 7/13 (54%) of each cohort, respectively. Amongst CCUS, the most frequent mutations were seen in ASXL1, DNMT3A and TET2. More than half of patients with CH, 14/27 (52%), exhibited mutations in 2 or more genes. Meanwhile, in cases of myeloid malignancy, the commonly mutated genes were ASXL1 and TP53, seen in 3/10 and 3/10 cases, respectively. The CCUS risk status was intermediate, with median score of 11.8 (range 9.5-14). One CCUS patient transformed to myelodysplastic syndrome. The time to progression from CCUS to myelodysplastic syndrome was 14.3 months and their respective CHRS status was determined to be high-risk. Infectious complications, including viral and opportunistic infections, were seen in 12/27 (44%) recipients with CH, with CMV viremia being the most common, followed by BK viremia. In this cohort, post-transplant cardiovascular events and venous thromboembolic events occurred in 2/27 (7.0%) and 7/27 (26%) patients, respectively. Allograft failure was seen in 17/27 (63%) recipients at a median of 93.4 months post-transplant. After a median of 122 months, there were 14/27 (52%) deaths at a median duration of 93.4 months post-transplant. Causes of mortality included myeloid malignancy, infection, cardiovascular complications, end-stage renal disease or were unknown. Conclusions Renal transplant recipients carry mutations in epigenetic regulators resulting in adverse outcomes. Similar to the general population, DNMT3A, TET2 and ASXL1 mutations were the most common mutations in post-transplant CCUS. Infections, cardiovascular events, and allograft failure were frequent. Prospective studies in a larger cohort are needed to evaluate the impact of CCUS in survival and myeloid malignancy transformation risk.

The number of kidney after liver transplants (KALT) increased after the implementation of the United Network of Organ Sharing (UNOS) safety net policy, but the effects of the policy on KALT outcomes remain unknown. Using the UNOS database, we identified KALT between 60 and 365 days from liver transplant from January 1, 2010, to December 31, 2020. The main outcome was 1- and 3-year patient, liver, and kidney graft survival. Secondary outcomes included 6-month and 1-year acute rejection (AR) of liver and kidney, and 1-year kidney allograft function. Of the 256 KALT, 90 were pre-policy and 166 post-policy. Compared to pre-policy, post-policy 1- and 3-year liver graft survival was higher (54% and 54% vs. 86% and 81%, respectively, p <0.001), while 1- and 3-year kidney graft survival (99% and 75% vs. 92% and 79%, respectively, p =0.19), and 1- and 3-year patient survival (99% and 99% vs. 95% and 89%, respectively, p =0.11) were not significantly different. Subgroup analysis revealed similar trends in patients with and without renal failure at liver transplant. Liver AR at 6 months was lower post-policy (6.3% vs. 18.3%, p =0.006) but was similar (10.5% vs. 13%, p =0.63) at 1 year. Kidney AR was unchanged post-policy at 6 months and 1 year. Creatinine at 1 year did not differ post-policy versus pre-policy (1.4 vs. 1.3 mg/dL, p =0.07) despite a higher proportion of deceased donors, higher Kidney Donor Profile Index, and longer kidney cold ischemia time post-policy ( p <0.05 for all). This 3-year follow-up after the 2017 UNOS policy revision demonstrated that the safety net implementation has resulted in improved liver outcomes for patients who underwent KALT with no increased AR of the liver or the kidney allografts.

Acute kidney injury (AKI) is common in cirrhotic patients affecting almost 20% of these patients. While multiple etiologies can lead to AKI, pre-renal azotemia seems to be the most common cause of AKI. Irrespective of the cause, AKI is associated with worse survival with the poorest outcomes observed in those with hepatorenal syndrome (HRS) and acute tubular necrosis (ATN). In recent years, new definitions, and classifications of AKI in cirrhosis have emerged. More knowledge has also become available regarding the benefits and drawbacks of albumin and terlipressin use in these patients. Diagnostic tools such as urinary biomarkers and point-of-care ultrasound (POCUS) became available and they will be used in the near future to differentiate between different causes of AKI and direct management of AKI in these patients. In this update, we will review these new classifications, treatment recommendations, and diagnostic tools for AKI in cirrhotic patients.

Abstract Background and Aims Individuals who are most susceptible to developing PTLD are those who are EBV-negative and receive organs from EBV-positive donors (EBV R-/D+). The evidence regarding the connection between ATG induction therapy and PTLD is inconsistent. No studies have specifically examined the relationship between ATG use and PTLD in subgroups of EBV-negative transplant recipients (EBV R-). Using the UNOS database, we studied the association between the use of induction agents and PTLD in EBV R- patients. Method We analyzed data from 2007 to 2022 of EBV R- patients who underwent their first kidney-only transplant and excluded those who received induction agents other than ATG, basiliximab, or alemtuzumab. We used logistic regression to evaluate the association between induction agents and PTLD. Results Of 20,531 recipients, 50.7% received ATG, 19.13% received basiliximab, 13.42% received alemtuzumab, and 16.75% received no induction. The overall PTLD incidence was 2.14%. ATG recipients had higher rates of deceased donor transplants, higher degree of HLA mismatch, longer dialysis vintage, and were less likely to be white, compared to non-ATG recipients. Multivariate analysis showed ATG recipients had a higher risk of PTLD compared to non-ATG (odds ratio = 1.47, p&lt;0.001). After excluding recipients who did not receive induction, ATG remained a significant independent risk factor for PTLD when compared to recipients who received either basiliximab or alemtuzumab (odds ratio = 1.35, p = 0.007). There was no statistically significant difference in PTLD risk among patients treated with basiliximab, alemtuzumab, or no induction (refer to Table 1). Conclusion The use of ATG induction in EBV-negative kidney transplant recipients is associated with a higher risk of PTLD compared to basiliximab, alemtuzumab, and no induction. The risk of PTLD should be considered when choosing induction therapy for this patient population.