Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation.

Renal transplant candidates with donor-specific alloantibody (DSA) have increased risk of antibody-mediated allograft injury. The goal of this study was to correlate the risk of antibody-mediated rejection (AMR), transplant glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of pretransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (-XM) transplants performed between April 2000 and July 2007. Using a combination of cell-based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and -XM groups. In +XM transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of -XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody-mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long-term allograft survival highlighting the need for improved therapy for these candidates.

Summary of the symposium establishing the safety of fat and macronutrient substitutes presented at the 33rd annual meeting of the Society of Toxicology, San Diego, California, March 13-17, 1994.

Macronutrient substitutes (MNS) are food ingredients designed to replace the organoleptic and/or functional properties of macronutrients such as fats or sugars in processed foods. Because they may be consumed in large quantities daily, traditional methods of safety evaluation are inappropriate. Conventional safety factors cannot be used in extrapolating animal data to humans due to the limitations of administering very large doses of MNS to animals. The proper evaluation of the safety of MNS involves appropriate studies in animals and humans including comparative biodispositional studies, genotoxicity and cytotoxicity studies, reproductive and developmental studies, mechanistic studies, digestive and fermentation studies, nutritional studies, and studies involving humans with special focus on gastrointestinal function. Guidelines for the proper conduct of human studies were presented and these include the use of competent investigators and IRB-approved protocols and the use of adequate numbers of healthy male and female volunteers. Postmarketing surveillance is the final step in the safety evaluation process for macronutrient substitutes. It was concluded that MNS should be evaluated on a case-by-case basis.

Apoptosis: molecular control point in toxicity.

Apoptosis is a controlled form of cell death that serves as a molecular point of regulation for biological processes. Cell selection by apoptosis occurs during normal physiological functions as well as toxicities and diseases. Apoptosis is the counterpart and counterbalance to mitosis in cell population determination. Complex patterns of cell signaling and specific gene expression are clearly involved in the control of cell fate. Exposure to an apogen, a trigger of apoptosis, can significantly increase apoptotic cell loss during homeostatic processes as well as acute or chronic toxicities. Alternately, suppression of apoptosis through, for example, interference in cell signaling can result in pathological accumulation of aberrant cells and diseases such as tumors. Investigations into the mechanisms underlying apoptosis have extended into many areas, driven by increasingly sophisticated instrumental and molecular biology techniques. This symposium summary explores related aspects of apoptosis, including control of cell population size and function, specific gene activity and regulation, chromatin condensation and scaffold detachment, oxidative stress-induced cell proliferation versus death by apoptosis or necrosis, and hepatotoxicant-induced apoptosis versus necrosis. Insights into the mechanisms governing apoptosis and increasing appreciation of the relevance of apoptotic cell death are redirecting research in toxicology and carcinogenesis and are yielding novel therapeutic approaches for the control of toxicity, disease, and ultimately perhaps senescence.

Disseminated superficial actinic porokeratosis with hyperkeratotic lesions.

A patient with disseminated superficial actinic porokeratosis (DSAP) presented with unusual exudative hyperkeratotic plaques in addition to lesions more typical of the disease. The plaques were unresponsive to various systemic antibiotics, but responded dramatically to systemic corticosteroid therapy.