No abstract

Background Mast cell activation syndrome (MCAS), a recently recognized non-neoplastic mast cell (MC) disease driving chronic multisystem inflammation ± allergy, appears prevalent and thus important. We report the first systematic characterization of a large MCAS population. Method Demographics, comorbidities, symptoms, family histories, and physical exam and laboratory findings were reviewed in 298 retrospective and 115 prospective MCAS patients. Blood samples from prospective subjects were examined by flow cytometry for clonal MC disease and tested for cytokines potentially driving the monocytosis frequent in MCAS. Results Demographically, white females dominated. Median ages at symptom onset/diagnosis were 9/49 years (ranges 0–88/16–92); median time from symptom onset to diagnosis was 30 years (range 1–85). Median numbers of comorbidities/symptoms/family medical issues were 11/20/4 (ranges 1–66/2–84/0–33). Gastroesophageal reflux, fatigue, and dermatographism were the most common comorbidity, symptom, and exam finding. Abnormalities in routine labs were common and diverse but typically modest. The most useful diagnostic markers were heparin, prostaglandin D2, histamine, and chromogranin A. Flow cytometric and cytokine assessments were unhelpful. Conclusions Our study highlights MCAS’s morbidity burden and challenging heterogeneity. Recognition is important given good survival and treatment prospects.

Acute antibody-mediated rejection (AMR) in heart transplantation is often associated with hemodynamic compromise, and is associated with increased mortality and development of accelerated transplant coronary artery disease (TCAD). The diagnosis of AMR has historically been controversial and outcomes with aggressive immunosuppressive therapy including plasmapheresis and cyclophosphamide are poor. Advances in diagnostic techniques like the demonstration of immunopathologic evidence for antibodymediated rejection by deposition of the complement split product C4d in tissue and detection of anti-HLA antibodies by flow cytometry will assist in further characterizing AMR. Immunosuppression targeting B-lymphocytes and use of m-TOR inhibitors to alter the predilection to develop TCAD and improve survival in AMR remains to be proven.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease. Overproduction of nitric oxide (NO) has been implicated in its pathogenesis. Several retrospective studies have indicated a correlation between serum nitrate and nitrite (NOx) and disease activity. This measure of NO production can be falsely elevated by exogenous dietary and medication sources of NOx and variably reduced by serum thiols. These variables can make NOx a less reliable tool for studying the role of NO in SLE. Peroxynitrite, a by-product of NO and superoxide, nitrates tyrosine moieties. The resulting 3-nitrotyrosine (3NT) serves as a long-term indicator of NO-mediated protein modifications that is not affected by exogenous sources of NOx or serum thiols. We hypothesized that for these reasons serum 3NT levels would correlate with lupus disease activity more significantly than serum NOx. To address this hypothesis, we prospectively evaluated lupus disease activity, serum protein 3NT levels, and NOx levels in a cohort of lupus patients at 3-month intervals. Serum 3NT correlated with disease activity among African-Americans, while NOx correlated with disease activity among Caucasians. Subjects with active lupus nephritis had higher levels of serum 3NT than those without renal disease. Immunohistochemical analysis of renal biopsies from subjects with active proliferative lupus nephritis revealed renal expression of inducible NO synthase. The results of this study suggest that overproduction of NO may play a pathogenic role in SLE and lupus nephritis. Serum 3NT may be a useful, new tool for studying the contributions of NO to the pathogenesis of SLE.

Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriate investigated and resolved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Reactive oxygen species (ROS) are increasingly believed to be important intracellular signaling molecules in mitogenic pathways involved in the pathogenesis of glomerulonephritis (GN). We explored the effects of the antioxidants alpha-lipoic acid and N-acetyl-l-cysteine on ERK activation in cultured mesangial cells and the role of ERK activation in the severity of glomerular injury in a rat model of anti-Thy 1 GN. In cultured mesangial cells, growth factors stimulated ERK phosphorylation by 150-450%. Antioxidants reduced this increase by 50-60%. Induction of anti-Thy 1 nephritis in rats led to a 210% increase in glomerular ERK phosphorylation. This increase in phosphorylated ERK was reduced by 50% in animals treated with alpha-lipoic acid. Treatment with alpha-lipoic acid resulted in significant improvement of glomerular injury. Cellular proliferation was reduced by 100%, and the number of proliferating cell nuclear antigen-positive cells was reduced by 64%. The increased expression of glomerular transforming growth factor-beta1 protein and mRNA in rats with anti-Thy 1 nephritis was significantly attenuated and mesangial cell transformation into myofibroblasts was completely prevented by treatment with alpha-lipoic acid. The effects of alpha-lipoic acid were at least partially due to inhibition of oxidative stress. In rats with anti-Thy 1 nephritis, ROS production was increased 400-500%, and this increase was inhibited by 55% by treatment with alpha-lipoic acid. We suggest that ROS may mediate glomerular injury by inducing ERK phosphorylation. alpha-Lipoic acid should be considered a potential therapeutic agent in certain types of human GN.

We have identified a list of protein spots that can be used to develop a clinical assay to predict ISN/RPS class and chronicity for patients with lupus nephritis. An assay based on antibodies against these spots could eliminate the need for renal biopsy, allow frequent evaluation of disease status, and begin specific therapy for patients with lupus nephritis.

BackgroundProteasome inhibitors are a relatively new class of chemotherapeutic agents. Bortezomib is the first agent of this class and is currently being used for the treatment of multiple myeloma. However, recent reports have linked exposure to bortezomib with the development of thrombotic microangiopathy. A new agent in this class, carfilzomib, has been recently introduced as alternative therapy for relapsing and refractory multiple myeloma. We report a case of renal thrombotic microangiopathy associated with the use of carfilzomib in a patient with refractory multiple myeloma.Case presentationA 62 year-old Caucasian man with hypertension and a 4-year history of multiple myeloma, had been previously treated with lenalidomide, bortezomib and two autologous hematopoietic stem cell transplants. After the second hematopoietic stem cell transplant, he developed acute kidney injury secondary to septic shock and required dialysis for 4 weeks. Subsequently, his serum creatinine stabilized at 2.1 mg/dL (185.64 μmol/L). Seventeen months after the second hematopoietic stem cell transplant, he was initiated on carfilzomib for relapse of multiple myeloma. Six weeks later, he developed abrupt worsening of lower extremity edema and hypertension, and new onset proteinuria. His kidney function remained stable. Kidney biopsy findings were consistent with thrombotic microangiopathy. Eight weeks after discontinuation of carfilzomib, proteinuria and hypertension improved. Due to progression of multiple myeloma, he died a few months later.ConclusionIn view of the previously reported association of bortezomib with thrombotic microangiopathy, the temporal association of the clinical picture with the initiation of carfilzomib, and the partial resolution of symptoms after discontinuation of the drug, we conclude that carfilzomib may have precipitated a case of clinically evident renal thrombotic microangiopathy in our patient.