Increased serum nitrate concentration in cardiac transplant patients. A marker for acute allograft cellular rejection

The purpose of the present study was to investigate whether nitrate serum level, reflecting total body production of nitric oxide in vivo, could serve as a noninvasive marker for acute human cardiac rejection. Serum nitrate concentration was determined by an enzymatic method. During routine right ventricular endomyocardial biopsies in 59 recipients, 145 tissue samples were obtained. Two groups of biopsy specimen were considered on the basis of posttransplant delay: group 1, < or = 90 days (n=47; 12-90 days); and group 2, >90 days (n=98; 3-81 months). All patients had normal ventricular systolic function on the day of biopsy and none had evidence of infection. Rejection grade correlated closely with serum nitrate concentration (P<0.001). In both groups, nitrate serum concentrations differed significantly (P<0.001) among cases without rejection, those with mild ongoing rejection (grade 1A/1B), and those with focal or diffuse aggressive infiltrates (grade 2 or higher). A cutoff value of 20 micromol/L, was determined that was positively predictive for grade 2 or higher rejection in 62% cases of early episodes of rejection and in 68% cases of late rejection. Conversely, a serum nitrate level below 20 micromol/L was negatively predictive in 97% and 94% of early and late cases, respectively. We conclude that the acute rejection process of the human transplanted heart is accompanied by a significant increase in serum nitrate level, reflecting increased nitric oxide production during the immune response. Because of its high negative predictive value, irrespective of the posttransplantation delay, nitrate serum determination may have clinical utility in the noninvasive monitoring of the cardiac transplant patient and could also add important information to endomyocardial biopsy analysis for treatment decision making.