Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials.

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.

Krüppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation.

Pathologic glomerular epithelial cell (GEC) hyperplasia is characteristic of both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Although initial podocyte injury resulting in activation of STAT3 signals GEC proliferation in both diseases, mechanisms regulating this are unknown. Here, we show that the loss of Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, enhances GEC proliferation in both RPGN and FSGS due to dysregulated STAT3 signaling. We observed that podocyte-specific knockdown of Klf4 (C57BL/6J) increased STAT3 signaling and exacerbated crescent formation after nephrotoxic serum treatment. Interestingly, podocyte-specific knockdown of Klf4 in the FVB/N background alone was sufficient to activate STAT3 signaling, resulting in FSGS with extracapillary proliferation, as well as renal failure and reduced survival. In cultured podocytes, loss of KLF4 resulted in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. This triggered IL-6 release into the supernatant, which activated STAT3 signaling in parietal epithelial cells. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. Finally, human kidney biopsy specimens with RPGN exhibited reduced KLF4 expression with a concomitant increase in phospho-STAT3 expression as compared with controls. Collectively, these results suggest the essential role of KLF4/STAT3 signaling in podocyte injury and its regulation of aberrant GEC proliferation.

Telenephrology: Providing Healthcare to Remotely Located Patients with Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) patients who live far (>30 miles) from their nephrologist experience lower rates of clinic visit adherence, limited access to treatment, and higher rates of hospitalization and mortality than patients who live in close proximity to their nephrologist. Strategies to minimize disparities between urban and remotely located CKD patients are needed. The purpose of this study was to determine whether adherence to clinic visits and clinical outcomes in the remote management of CKD via telenephrology is comparable to in-person conventional care. METHODS: Renal clinic adherence and composite outcomes of death, end-stage renal disease (ESRD), or doubling of serum creatinine (Cr) were measured in geographically remote Hudson Valley VA Medical Center (HVVAMC) CKD patients enrolled in telenephrology (n = 112) and CKD patients enrolled in the Bronx VAMC renal clinic (n = 116). RESULTS: Prior to implementing the telenephrology service, 53.1% of scheduled visits of rural HVVAMC patients to the Bronx VAMC renal clinic were either cancelled or were "no-shows." This was reduced by nearly half (28.5%) after instituting telenephrology (p < 0.001). Moreover, the frequency of attending appointments was greater in the telenephrology (71.9%) vs. in-person Bronx VA cohort (61.0%). The incidence of the composite outcome of death, ESRD, or doubling of Cr was similar between both groups (p = 0.96) over 2 years of follow-up. CONCLUSIONS: Remote CKD care delivered through telenephrology improves renal clinic visit adherence while delivering comparable renal outcomes. Application of this technology is a promising method to provide access to care to rural CKD patients and to minimize the disparity between urban/rural patients.

Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers.

Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.

A Retrospective Study in Adults with Metabolic Syndrome: Diabetic Risk Factor Response to Daily Consumption of Agaricus bisporus (White Button Mushrooms).

Adults with metabolic syndrome from different race/ethnicities are often predisposed to developing type 2 diabetes (T2D); however, growing evidence suggests that healthy diets and lifestyle choices can significantly slow or prevent progression to T2D. This poorly understood relationship to healthy dietary patterns and prevention of T2D motivated us to conduct a retrospective analysis to determine the potential impact of a minor dietary lifestyle change (daily mushroom consumption) on known T2D risk factors in racially diverse adults with confirmed features of the metabolic syndrome. Retrospectively, we studied 37 subjects who had participated in a dietary intervention focused on vitamin D bioavailability from white button mushrooms (WBM). All 37 had previously completed a 16-week study where they consumed 100 g of WBM daily and were then followed-up for one month during which no mushrooms were consumed. We analyzed differences in serum risk factors from baseline to 16-week, and from baseline to one-month follow-up. Measurement of serum diabetic risk factors included inflammatory and oxidative stress markers and the antioxidant component naturally rich in mushrooms, ergothioneine. Significant beneficial health effects were observed at 16-week with the doubling of ergothioneine from baseline, increases in the antioxidant marker ORAC (oxygen radical absorption capacity) and anti-inflammatory hormone, adiponectin and significant decreases in serum oxidative stress inducing factors, carboxymethyllysine (CML) and methylglyoxal (MG), but no change in the lipid oxidative stress marker 8-isoprostane, leptin or measures of insulin resistance or glucose metabolism. We conclude that WBM contain a variety of compounds with potential anti-inflammatory and antioxidant health benefits that can occur with frequent consumption over time in adults predisposed to T2D. Well-controlled studies are needed to confirm these findings and identify the specific mushroom components beneficial to health.

"Out of Sight, Out of Mind": The Failed Renal Allograft as a Cause of ESA Resistance.

Approximately 10% of patients treated with erythropoiesis-stimulating agents (ESAs) for the anemia of chronic kidney disease are unresponsive or relatively resistant to therapy. The etiology of this is usually linked to iron deficiency or an independent underlying illness. We describe a hemodialysis patient with a failed renal transplant 1.5 years earlier, who developed progressive erythropoietin resistance and anemia without an apparent cause. He simultaneously developed nonspecific malaise and fatigue. By exclusion, the only possible cause of these signs and symptoms was inflammation from acute and chronic rejection in the retained failed renal allograft. Following pulse steroids and transplant nephrectomy, the patient's symptoms resolved and both his hemoglobin improved and his erythropoietin requirements decreased significantly. The patient never required a blood transfusion and was successfully relisted for a deceased donor renal transplant. Hence, inflammation from a retained transplant allograft may be an under-recognized cause of erythropoietin resistance in dialysis patients. Although transplant nephrectomy remains a controversial practice due to concerns of alloantibody production, it may be considered in patients with failed renal allografts and anemia refractory to treatment with ESAs.

Nutritional vitamin D supplementation and health-related outcomes in hemodialysis patients: a protocol for a systematic review and meta-analysis.

BACKGROUND: The prevalence of vitamin D deficiency in hemodialysis patients is high. While most hemodialysis patients are treated with activated vitamin D (1,25[OH]2D) to prevent renal osteodystrophy, clinical practices of the screening and treatment of 25(OH)2D deficiency are highly variable. It is unclear if nutritional vitamin D supplementation with D2 or D3 provides an additional clinical benefit beyond that provided by activated vitamin D treatment in this population. METHODS/DESIGN: We will conduct a systematic review of nutritional vitamin D (D2/D3) supplementation and health-related outcomes in hemodialysis patients according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary objective is to assess the impact of nutritional vitamin D supplementation on clinical outcomes relevant in hemodialysis patients, such as mortality, cardiovascular events, infections, and fractures. Secondary outcomes will include anemia, hyperparathyroidism, medication use (erythrocyte-stimulating agents, activated vitamin D), and quality of life. We will search MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov for randomized, controlled trials of nutritional vitamin D supplementation (ergocalciferol/D2 or cholecalciferol/D3) in chronic hemodialysis patients. The Cochrane Risk Assessment Tool will be used to assess the quality of eligible studies. We will perform meta-analyses using standard techniques for the outcomes listed above if pooling is deemed appropriate/sufficient. The results of this systematic review may highlight gaps in our knowledge of the relevance of nutritional vitamin D in end-stage renal disease, allowing for the informed design of clinical trials assessing the impact of nutritional vitamin D therapy in the hemodialysis population in the future. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014013931.

Lung Cancer Prognosis in Elderly Solid Organ Transplant Recipients.

BACKGROUND: Treatment-related immunosuppression in organ transplant recipients has been linked to increased incidence and risk of progression for several malignancies. Using a population-based cancer cohort, we evaluated whether organ transplantation was associated with worse prognosis in elderly patients with non-small cell lung cancer (NSCLC). METHODS: Using the Surveillance, Epidemiology, and End Results Registry linked to Medicare claims, we identified 597 patients aged 65 years or older with NSCLC who had received organ transplants (kidney, liver, heart, or lung) before cancer diagnosis. These cases were compared to 114,410 untransplanted NSCLC patients. We compared overall survival (OS) by transplant status using Kaplan-Meier methods and Cox regression. To account for an increased risk of non-lung cancer death (competing risks) in transplant recipients, we used conditional probability function (CPF) analyses. Multiple CPF regression was used to evaluate lung cancer prognosis in organ transplant recipients while adjusting for confounders. RESULTS: Transplant recipients presented with earlier stage lung cancer (P = 0.002) and were more likely to have squamous cell carcinoma (P = 0.02). Cox regression analyses showed that having received a non-lung organ transplant was associated with poorer OS (P < 0.05), whereas lung transplantation was associated with no difference in prognosis. After accounting for competing risks of death using CPF regression, no differences in cancer-specific survival were noted between non-lung transplant recipients and nontransplant patients. CONCLUSIONS: Non-lung solid organ transplant recipients who developed NSCLC had worse OS than nontransplant recipients due to competing risks of death. Lung cancer-specific survival analyses suggest that NSCLC tumor behavior may be similar in these 2 groups.

Assessment and management of hypertension in transplant patients.

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.

Monitoring T cell alloreactivity.

Currently, immunosuppressive therapy in kidney transplant recipients is center-specific, protocol-driven, and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. The individualization of immunosuppression requires the development of assays able to reliably quantify and/or predict the magnitude of the recipient's immune response toward the allograft. As alloreactive T cells are central mediators of allograft rejection, monitoring T cell alloreactivity has become a priority for the transplant community. Among available assays, flow cytometry based phenotyping, T cell proliferation, T cell cytokine secretion, and ATP release (ImmuKnow), have been the most thoroughly tested. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Future studies are required to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice.

Effect of cholecalciferol supplementation on inflammation and cellular alloimmunity in hemodialysis patients: data from a randomized controlled pilot trial.

BACKGROUND: Memory T-cells are mediators of transplant injury, and no therapy is known to prevent the development of cross-reactive memory alloimmunity. Activated vitamin D is immunomodulatory, and vitamin D deficiency, common in hemodialysis patients awaiting transplantation, is associated with a heightened alloimmune response. Thus, we tested the hypothesis that vitamin D3 supplementation would prevent alloreactive T-cell memory formation in vitamin D-deficient hemodialysis patients. METHODS AND FINDINGS: We performed a 12-month single-center pilot randomized, controlled trial of 50,000 IU/week of cholecalciferol (D3) versus no supplementation in 96 hemodialysis patients with serum 25(OH)D<25 ng/mL, measuring effects on serum 25(OH)D and phenotypic and functional properties of T-cells. Participants were randomized 2:1 to active treatment versus control. D3 supplementation increased serum 25(OH)D at 6 weeks (13.5 [11.2] ng/mL to 42.5 [18.5] ng/mL, p<0.001) and for the duration of the study. No episodes of sustained hypercalcemia occurred in either group. Results of IFNγ ELISPOT-based panel of reactive T-cell assays (PRT), quantifying alloreactive memory, demonstrated greater increases in the controls over 1 year compared to the treatment group (delta PRT in treatment 104.8+/-330.8 vs 252.9+/-431.3 in control), but these changes in PRT between groups did not reach statistical significance (p = 0.25). CONCLUSIONS: D3 supplements are safe, effective at treating vitamin D deficiency, and may prevent time-dependent increases in T-cell alloimmunity in hemodialysis patients, but their effects on alloimmunity need to be confirmed in larger studies. These findings support the routine supplementation of vitamin D-deficient transplant candidates on hemodialysis and highlight the need for large-scale prospective studies of vitamin D supplementation in transplant candidates and recipients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01175798.

Low Dietary Intake of Vitamin D and Vitamin D Deficiency in Hemodialysis Patients.

BACKGROUND: The purpose of this study was to test the hypothesis that decreased dietary intake of Vitamin D contributes to Vitamin D deficiency in end-stage renal disease (ESRD) patients on hemodialysis (HD). METHODS: We performed a cross-sectional study of 58 hemodialysis outpatients from two Mount Sinai Medical Center (MSMC)-affiliated outpatient HD units in New York City and 648 outpatients at MSMC with CKD stages I-IV. Serum 25(OH)D concentrations were measured from August 2010 to July of 2011 in recruited hemodialysis patients (n=58) and linked with results of dietary and lifestyle surveys. The Mount Sinai Data Warehouse (electronic medical record) was used to capture 25(OH) Vitamin D levels for outpatients with CKD stages I-IV who had Vitamin D testing during the same time period. RESULTS: The prevalence of Vitamin D insufficiency/deficiency in the HD cohort was 96.6%. Mean (SD) and median (IQR) 25(OH)D concentrations were 15.65 (6.82) and 13.55 (10.15) ng/mL, respectively. Dietary surveys showed a median weekly Vitamin D intake of 1044 IU (IQR=808, vs. a recommended weekly allowance of 4200 IU) and specific avoidance of foods containing both Vitamin D and phosphorus. In contrast, mean and median 25(OH)D concentrations in patients with CKD stages I-IV were 25.66 (13.44) and 23.60 (15.48) ng/mL (p<0.001 vs. HD patients). CONCLUSIONS: Vitamin D deficiency is more prevalent in HD patients than in pre-dialysis patients with CKD and is associated with decreased dietary intake of Vitamin D. Dialysis restrictions imposed to reduce dietary phosphorus intake likely contributes to the development of hypovitaminosis D in ESRD patients.

Diabetic nephropathy in a nonobese mouse model of type 2 diabetes mellitus.

A large body of research has contributed to our understanding of the pathophysiology of diabetic nephropathy. Yet, many questions remain regarding the progression of a disease that accounts for nearly half the patients entering dialysis yearly. Several murine models of diabetic nephropathy secondary to Type 2 diabetes mellitus (T2DM) do exist, and some are more representative than others, but all have limitations. In this study, we aimed to identify a new mouse model of diabetic nephropathy secondary to T2DM in a previously described T2DM model, the MKR (MCK-KR-hIGF-IR) mouse. In this mouse model, T2DM develops as a result of functional inactivation of insulin-like growth factor-1 receptor (IGF-1R) in the skeletal muscle. These mice are lean, with marked insulin resistance, hyperinsulinemia, hyperglycemia, and dyslipidemia and thus are representative of nonobese human T2DM. We show that the MKR mice, when under stress (high-fat diet or unilateral nephrectomy), develop progressive diabetic nephropathy with marked albuminuria and meet the histopathological criteria as defined by the Animal Models of Diabetic Complications Consortium. Finally, these MKR mice are fertile and are on a common background strain, making it a novel model to study the progression of diabetic nephropathy.

Immunosuppressive effects of erythropoietin on human alloreactive T cells.

Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence, predominantly from animal models, indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4(+) and CD8(+) T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions, EPO induced a dose-dependent decrease in allogeneic CD4(+) T-cell proliferation (EPO 1000 U/ml: 44.6%±22.9% of vehicle, P<0.05; 2000 U/ml: 11.1%±4% of vehicle, P<0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells, resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling, inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4(+) T cells after adoptive transfer into NOD scid γc(null) mouse recipients, verifying the effects in vivo. Although activated T cells expressed CD131, an alternative EPO receptor, addition of a specific CD131 agonist peptide, ARA290, did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity, providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients.

The association of IL28B polymorphism and graft survival in patients with hepatitis C undergoing liver transplantation.

Hepatitis C virus (HCV) infection is the leading cause of liver transplantation (LT) in Western countries. Polymorphism in the IL28B gene region has a major impact on the natural history and response to antiviral treatment in HCV. We investigated whether IL28B polymorphism was associated with graft survival in patients with or without HCV undergoing LT. 1,060 adult patients (age >18 years) underwent LT between years 2000 and 2008. Patients with previous LT, living donor LT and patients dying or requiring retransplants within 30 days of LT were excluded. DNA samples of 620 (84%) recipients and 377 (51%) donors were available for genotyping of IL28B rs12979860C>T. Donor IL28B genotypes had no significant differences in graft survival irrespective of HCV status. There was no difference in graft outcome in the non-HCV cohort (n = 293) based on recipient IL28B genotype. In the HCV group (n = 327), recipients with CC or CT genotype had better graft survival compared to TT genotype (62% vs. 48%, p = 0.02). HCV recipients with CC or CT genotype had delayed time to clinically relevant HCV recurrence compared to TT (10.4 vs. 6.7 months, p = 0.002). The beneficial effect of the CC/CT genotype on HCV recurrence and graft survival was independent of antiviral treatment. In conclusion, our study demonstrated that in contrast to donor IL28B genotype recipient IL28B was associated with graft survival and clinically relevant HCV recurrence in HCV infected recipients. No effect of IL28B genotype was manifest in non-HCV LT recipients.

Incidence and consequences of acute kidney injury in kidney transplant recipients.

BACKGROUND: In the nontransplant setting, acute kidney injury (AKI) may lead to chronic kidney disease (CKD) and end-stage renal disease, but the epidemiology of AKI in transplant recipients has not been characterized. The purpose of this study was to determine the incidence and consequences of AKI in kidney transplant recipients outside the peritransplant period and unrelated to acute rejection. STUDY DESIGN: Retrospective longitudinal cohort study. SETTING & PARTICIPANTS: 27,232 adult Medicare-insured transplant recipients with transplant survival of 6 months or longer in the US Renal Data System in 1995-2000. PREDICTORS: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) hospital discharge diagnostic codes were used to identify AKI during the first 3 posttransplant years. OUTCOMES: Transplant loss from any cause, mortality (death with a functioning transplant), and death-censored transplant loss. MEASUREMENTS: Estimated glomerular filtration rate calculated by the MDRD (Modification of Diet in Renal Disease) Study equation 6 months posttransplant. RESULTS: 3,066 (11.3%) patients had 4,181 hospitalizations with AKI, of which 14.8% required dialysis therapy. The incidence of AKI more than doubled during the study, and AKI was more frequent in patients with lower levels of transplant function. AKI was associated independently with increased risk of transplant loss from any cause (HR, 2.74; 95% CI, 2.56-2.92), death with a functioning transplant (HR, 2.36; 95% CI, 2.14-2.60), and death-censored transplant loss (HR, 3.17; 95% CI, 2.91-3.46). However, AKI-associated risks paradoxically were higher in patients with earlier CKD stage. LIMITATIONS: Because of the limited sensitivity of ICD-9-CM codes for non-dialysis-requiring AKI events, the overall incidence of AKI likely is underestimated in this study. CONCLUSIONS: We conclude that AKI is increasingly common and associated with transplant failure and death. Later CKD stage increases the risk of AKI, but AKI-associated risks of transplant failure were greater in those with higher levels of kidney function (earlier CKD stage).

Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients.

Chronic allograft vasculopathy (CAV) contributes to heart transplant failure, yet its pathogenesis is incompletely understood. Although cellular and humoral alloimmunity are accepted pathogenic mediators, animal models suggest that T cells and Abs reactive to graft-expressed autoantigens, including cardiac myosin (CM), could participate. To test the relationship between CAV and anti-CM autoimmunity in humans, we performed a cross-sectional study of 72 heart transplant recipients: 40 with CAV and 32 without. Sera from 65% of patients with CAV contained anti-CM Abs, whereas <10% contained Abs to other autoantigens (p < 0.05), and only 18% contained anti-HLA Abs (p < 0.05 versus anti-CM). In contrast, 13% of sera from patients without CAV contained anti-CM Abs (p < 0.05; odds ratio [OR], associating CAV with anti-CM Ab = 13, 95% confidence interval [CI] 3.79-44.6). Multivariable analysis confirmed the association to be independent of time posttransplant and the presence of anti-HLA Abs (OR = 28, 95% CI 5.77-133.56). PBMCs from patients with CAV responded more frequently to, and to a broader array of, CM-derived peptides than those without CAV (p = 0.01). Detection of either CM-peptide-reactive T cells or anti-CM Abs was highly and independently indicative of CAV (OR = 45, 95% CI 4.04-500.69). Our data suggest detection of anti-CM immunity could be used as a biomarker for outcome in heart transplantation recipients and support the need for further studies to assess whether anti-CM immunity is a pathogenic mediator of CAV.