Dapsone-Induced Artifactual A1c Reduction in Islet Transplant Recipients

Abstract

The success of any treatment for type 1 diabetes mellitus, from insulin therapy to islet transplantation, is measured by improved glycemic control with or without insulin independence (1). The most well established measure of this is glycated hemoglobin (A1c), which results from exposure of hemoglobin A to plasma glucose over the lifespan of the red blood cell (RBC). An alternative measure is fructosamine, glycated albumin, which is unaffected by RBC lifespan (2). Chronic immunosuppression is required for recipients of allografts, including islets. Consequently, chronic prophylaxis against Pneumocystis jiroveci pneumonia (PCP/PJP) is also required. Trimethoprim/sulfamethoxazole is the agent of choice due to efficacy and ease of administration, however when not tolerated, dapsone (4,4′-diaminodiphenyl sulfone) is typically the preferred alternative. Dapsone, the parent of the sulfones, was introduced for leprosy treatment more than 60 years ago and has proven therapeutic efficacy in several conditions, more recently PCP/PJP prophylaxis in immunocompromised patients. Effective use of dapsone may be limited by dose-dependent adverse hematological reactions including hemolysis and methemoglobinemia (3, 4), less well described is the reduction in A1c caused by this agent (5–8). Three islet transplant recipients at our center received dapsone for PCP/PJP prophylaxis because of sulfa allergy (n=2) and chronic posttransplant leucopenia (n=1). Duration of treatment was 516±456 days (range 163–1,031 days). All subjects demonstrated a significant decrease in A1c during dapsone therapy (6.3±0.3 vs. 4.5±0.6%, P<0.001, n=18–40) with a return to pre-dapsone levels after cessation of therapy (6.3±0.3 vs. 6.6±0.8%, P=0.15, n=18–40). There was no significant change in fructosamine levels over the same time period (pre 267.3±16.7, during 262.4±25.7, and post 277.6±25.4 uMol/L; P=0.14, n=14–22; Fig. 1). During dapsone treatment, fingerstick glucose (FSG) levels were higher than predicted from A1c levels with negative correlation between A1c and mean FSG (r=−0.29, n=108) and a concomitantly positive correlation between fructosamine and FSG values (r=0.28, n=442). The high-performance liquid chromatography for A1c analysis was unremarkable in these patients.FIGURE 1.: Alteration of A1c and fructosamine (FA) in a single subject (A) and mean levels of A1c (B) and fructosamine (C) in all three subjects before, during and after dapsone treatment.The reason for the observed false reduction in A1c is unknown. A reduction in RBC lifespan and/or hemolysis could cause this. Two of the three subjects demonstrated mild intermittent anemia without reticulocytosis during dapsone therapy; however, this was considered secondary to bone marrow suppression and protocol blood draws rather than hemolysis, although specific testing for hemolysis was not performed. This level of anemia was similar to that seen in the majority of our transplant recipients (1, 9). Alternatively, the oxidative effect of dapsone could affect the rate of hemoglobin glycation through altered reactivity of the amino terminus, with which the glucose molecule interacts, or the rate of Amadori rearrangement of the β-chain after glucose molecule attachment, through altered steric factors (10). Inaccuracy in A1c results in erroneous estimation of mean glucose concentrations. For both subject care and for evaluation of outcomes of beta-cell replacement therapies, an accurate measure of glycemic control is essential. A1c is possibly the most well recognized and most common measure of glycemic control, consequently recognition and/or avoidance of the interaction between dapsone and A1c should be attempted whenever possible. ACKNOWLEDGMENTS We express gratitude to the staff of the Clinical Islet Transplant Program, the Islet Cell Processing Center, the General Clinical Research Center, and the Informatics Core for their continuous support. Tatiana Froud Diabetes Research Institute Department of Surgery University of Miami Miller School of Medicine Miami, FL Raquel N. Faradji Lisa Gorn Diabetes Research Institute Department of Medicine University of Miami Miller School of Medicine Miami, FL Kathy Monroy Charlotte Paz David A. Baidal Gaston Ponte Pablo Cure Raffaella Poggioli Diabetes Research Institute University of Miami Miller School of Medicine Miami, FL Antonello Pileggi Camillo Ricordi Diabetes Research Institute Department of Surgery University of Miami Miller School of Medicine Miami, FL Rodolfo Alejandro Diabetes Research Institute Department of Medicine University of Miami Miller School of Medicine Miami, FL