{"doi":"10.1002/cld.960","title":"Frailty as an Immune‐Mediated Condition That Leads to an Increased Risk of Acute Cellular Rejection in Liver Transplant Recipients","abstract":"Watch a video presentation of this article Answer questions and earn CME Frailty, a biological syndrome of increased vulnerability to stressors and decreased physiological reserve, has been shown to be a critical determinant of health outcomes in many populations.1 Originally defined in the field of geriatrics, frailty has been linked to dysregulation of multiple physiological systems in older adults, including the immune system, with frail patients exhibiting an inflammatory phenotype.2-5 Translational studies have found that inflammatory biomarkers, such as soluble tumor necrosis factor receptor (sTNF-RII), interleukin-6, and C-reactive protein, are associated with frailty in older adults.6 Perhaps related to this immune dysregulation, frailty has also been associated with pharmacokinetic changes among the community-dwelling geriatric population that lead to increased rates of medication intolerance.7, 8 Frailty has increasingly been understood to be a critical predictor of adverse health outcomes in liver transplant patients.9-14 Patients with cirrhosis are particularly vulnerable to development of frailty due to chronic inflammation, malnutrition, and muscle wasting secondary to underlying liver disease and hepatic synthetic dysfunction. Up to 17% of patients with cirrhosis meet criteria to be classified as frail.13, 15 Studies have demonstrated that frailty status, by capturing the extrahepatic complications of cirrhosis that are not captured by the Model for End-Stage Liver Disease sodium score alone, can be used as a tool to improve mortality risk prediction in patients with cirrhosis.11-13 These pathophysiological underpinnings raise an intriguing possibility that frailty could play a role in our clinical algorithms as a signal of vulnerability to immune-related health outcomes in transplant patients. Early studies in kidney transplant recipients have supported this possibility. For example, in a single-center study of 525 kidney transplant recipients, frail patients were 1.3 times more likely to experience mycophenolate dose reduction than their nonfrail counterparts due to medication intolerance, which, in turn, was associated with a 5-fold increased risk for graft loss in frail versus nonfrail kidney transplant recipients.16 This study suggests that frail patients may be at higher risk for graft loss, a risk that is potentially mediated by immunosuppressive medication intolerance and mycophenolate dose reduction. We hypothesized that these findings would similarly apply to liver transplant recipients (Fig. 1). Among 241 liver transplant recipients, 19% of whom met criteria for “frail” by the Liver Frailty Index (≥4.5), frailty was associated with more than three times higher odds of acute cellular rejection within 3 months of liver transplantation. Importantly, we did not observe a difference between frail and nonfrail patients in rates of mycophenolate dose reduction either at the time of discharge after liver transplant or at 3 months of follow-up.17 In addition, frail and nonfrail patients had similar median tacrolimus trough levels within 3 months after liver transplant. Together, these data provide evidence in support of frailty as an immune-mediated condition with effects that linger into the early posttransplant period.5, 10 These data have important implications for the management of frail patients undergoing liver transplantation. Anecdotally, providers may perceive frail patients to have less robust immune systems and, therefore, lower need for high dose or aggressive immunosuppression. Frail patients may also be perceived to have a lower tolerance for immunosuppressive medications. These data demonstrate that they, in fact, may experience higher rates of acute cellular rejection related to frailty as an immune-mediated condition. Although larger, multicenter, prospective studies are needed to confirm these findings in liver transplant recipients, these early studies suggest that the frail phenotype may pl","journal":"Clinical Liver Disease","year":2020,"id":108639,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":257558,"name":"Jennifer C. Lai","orcid":"0000-0003-2092-6380","position":1,"is_corresponding":false},{"id":520361,"name":"Laila Fozouni","orcid":"0000-0002-1512-9996","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:12:46.854423Z","pmid":"32617158","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}