Free pentosidine and neopterin as markers of progression rate in diabetic nephropathy

Background. Patients with diabetic nephropathy experience a progressive and usually inexorable decline in renal function. The presence of the structurally defined advanced glycation end product (AGE) pentosidine on tissue and circulating proteins has been correlated with the severity of diabetic complications. Methods. To delineate a role for this AGE in the progression of diabetic nephropathy, glycohemoglobin and free and protein- bound pentosidine were measured in baseline stored serum and urine from a subgroup of patients with diabetes mellitus and proteinuria originally followed by the Collaborative Study Group Trial. To delineate a potential role for an immune-activation response to AGEs, the inflammatory markers, interleukin-6 (IL-6), C-reactive protein (CRP), and the monocyte activation marker neopterin were also measured at baseline. The patients chosen represented 67 subjects whose creatinine levels had 'doubled' over the course of the study whether or not they later were treated with captopril, and 67 paired 'non-doublers.' Results. Baseline disease activity, as manifested by glycohemoglobin, serum creatinine and degree of proteinuria was equal in the two groups, as was protein-bound pentosidine and the immune-markers IL-6 and CRP. At baseline the 'doublers' as compared to the 'non-doublers' had elevated serum levels of free pentosidine and neopterin. Baseline increases in these two parameters were also associated with an increased rate of 'doubling' of serum creatinine by the proportional hazards method. Conclusion. Differences in individual responsiveness to AGEs, as manifested by either the production of free pentosidine or its release from a protein- bound form, and by evidence of monocyte/macrophage activation, are associated with progression of diabetic nephropathy.