High levels of oxidized LDL in circulating immune complexes are associated with increased odds of developing abnormal albuminuria in Type 1 diabetes

Abstract

Background: Modified low-density lipoprotein (LDL) immune complexes (IC) have proinflammatory properties and play a role in albuminuria development.

Methods: We measured oxidized LDL (oxLDL) and advanced glycation end-product (AGE)-LDL in IC isolated from sera of Type 1 diabetic subjects followed for 14-20 years and studied their association with abnormal albuminuria. Patients with albumin excretion rates (AER)<40 mg/24 h at baseline and follow-up (n=302) were deemed resistant to developing abnormal albuminuria. Patients with AER<40 mg/24 h at baseline whose AER levels progressed to >40 mg/24 h were considered prone to abnormal albuminuria (n=185), those who progress to AER>299 mg/24 h were considered as having macroalbuminuria (n=57). The odds of developing abnormal albuminuria were estimated by logistic regression based on natural log-transformed levels of oxLDL and AGE-LDL in IC and stratified by baseline AER decile.

Results: OxLDL and AGE-LDL were significantly higher in IC isolated from patients progressing to abnormal albuminuria. In unadjusted conditional logistic analysis, an increase of 1 SD in oxLDL and AGE-LDL levels in IC significantly increased the odds ratio (OR) for development of macroalbuminuria, respectively, by a factor of 2.5 and 1.8 (P<0.001, P=0.008). The increased odds of developing macroalbuminuria remained significant when adjusted for treatment group, diabetes duration, retinopathy, baseline hemoglobin A1c and LDL (OR=2.5 and 1.8, respectively, P<0.01).

Conclusion: Higher levels of oxLDL and AGE-LDL in circulating IC were associated with increased odds to develop abnormal albuminuria.

Fig. 1.

Recruitment flow chart. 1441 subjects were recruited into the study at DCCT baseline. 905 of the subjects had longitudinal follow-up and blood collection for the MUSC Program Project during the EDIC phase of the study. A total of 518 of those subjects had sufficient samples (≥800 mL of serum) to perform the measurement of oxLDL and AGE–LDL in isolated IC. Of those 518 subjects, 28 had elevated AER at baseline (>40 mg/24 h) and were excluded from the analysis. Additionally, three more subjects were removed due to a lack of EDIC AER data. The remaining 487 were then assessed for albuminuria status. 302 subjects had no AER values >40 mg/24 h for the duration of DCCT and EDIC and were considered resistant to the development of abnormal albuminuria. One hundred and eighty-five subjects had one or more AER measurements ≥40 mg/24 h and were considered as having abnormal albuminuria. Additionally, 57 of the 185 subjects developed macroalbuminuria during follow-up (AER ≥ 300 mg/24 h).