A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug‐induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin—7.5 g dL−1, platelet count—20 × 109/L, LDH—698 U L−1, creatinine—3.12 mg dL−1. No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348–E352, 2016. © 2016 Wiley Periodicals, Inc.

BackgroundAlthough graft loss is a primary endpoint in many studies in kidney transplantation and a broad spectrum of risk factors has been identified, the eventual causes of graft failure in individual cases remain ill studied. MethodsWe performed a single-center cohort study in 1000 renal allograft recipients, transplanted between March 2004 and February 2013. ResultsIn total, 365 (36.5%) graft losses were identified, of which 211 (57.8%) were due to recipient death with a functioning graft and 154 (42.2%) to graft failure defined as return to dialysis or retransplantation. The main causes of recipient death were malignancy, infections and cardiovascular disease. The main causes of graft failure were distinct for early failures, where structural issues and primary nonfunction prevailed, compared to later failures with a shift towards chronic injury. In contrast to the main focus of current research efforts, pure alloimmune causes accounted for only 17.5% of graft failures and only 7.4% of overall graft losses, although 72.7% of cases with chronic injury as presumed reason for graft failure had prior rejection episodes, potentially suggesting that allo-immune phenomena contributed to the chronic injury. ConclusionIn conclusion, this study provides better insight in the eventual causes of graft failure, and their relative contribution, highlighting the weight of nonimmune causes. Future efforts aimed to improve outcome after kidney transplantation should align with the relative weight and expected impact of targeting these causes.

Background: Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development. Methods: Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004–2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality. Results: A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4–9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age ( P <0.001), donor male sex ( P <0.001), donor tobacco consumption ( P =0.001), recipient dyslipidemia ( P =0.009), class II anti–human leukocyte antigen donor-specific antibodies ( P =0.004), and acute cellular rejection ≥2R ( P =0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality ( P <0.001). Conclusions: In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04117152.

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Background: After orthotopic heart transplantation (HTx), allografts undergo diffuse myocardial injury (DMI) that contributes to functional impairment, especially to increased passive myocardial stiffness, which is an important pathophysiological determinant of left ventricular (LV) diastolic dysfunction. Echocardiographic shear wave (SW) elastography is an emerging approach for measuring myocardial stiffness in vivo. Natural SWs occur after mechanical excitation of the myocardium, e.g. after mitral valve closure (MVC) and their propagation velocity is directly related to myocardial stiffness, thus providing an opportunity to assess myocardial stiffness at end-diastole.Objectives: To investigate if propagation velocities of naturally occurring SWs at MVC increase with the degree of DMI and with invasively determined LV filling pressures as a reflection of an increase in myocardial stiffness in HTx recipients.Methods: 52 HTx recipients that underwent right heart catheterization (all) and cardiac magnetic resonance (CMR, n=23) during their annual check-up were prospectively enrolled.Echocardiographic SW elastography was performed in parasternal long axis views of the LV using an experimental scanner at 1135 ± 270 frames per second. The degree of DMI was quantified with T1 mapping.Results: SW velocity at MVC correlated best with native myocardial T1 values (r=0.80, p<0.0001) and was the best non-invasive parameter to correlate with pulmonary capillary wedge pressures (PCWP; r=0.54, p<0.001). Standard echocardiographic parameters of LV diastolic function correlated poorly with both native T1 values and PCWP.Conclusions: End-diastolic shear wave propagation velocities, as measure of myocardial stiffness, showed a good correlation with CMR defined diffuse myocardial injury and with invasively determined left ventricular filling pressures in HTx patients. These findings thus suggest that shear wave elastography has the potential to become a valuable non-invasive method for the assessment of diastolic myocardial properties in heart transplant recipients.