Urinary apoAl: Novel marker of renal disease?

Dear Editor,

We wholeheartedly agree with Jacobs Cacha and Lopez Hellin that further studies of the structure and composition of urinary apolipoprotein Al (apoAl) are warranted to ascertain its role as a marker or pathophysiologic mechanism of FSGS. While both groups found high molecular weight forms (HMW) of apoAl in urine of renal transplant patients with recurrent FSGS [1, 2] and in FSGS in native kidneys [3], it is not clear if these are the same or different forms of apoAl. Further, our study found increased urinary apoAl levels and HMW apoAl in other glomerulopathies and tubulopathies suggesting relevance beyond FSGS.

These are important considerations since lipoproteins, including apoAl, are readily modified by various reactive oxygen/nitrogen species or resulting reactive carbonyls including myeloperoxidase, malondialdehyde, acrolein, and isolevuglandins (IsoLG). Such modifications lead to structural, morphological and functional changes in the lipoproteins and are considered central in the pathogenesis of many different diseases. Modification by IsoLG are particularly interesting because of their very rapid reaction with lysine residues of proteins and proclivity to crosslink and alter protein function. Recently, IsoLG was shown to cross-link apoAl to generate larger size apoAl-containing HDL particles with potentially harmful properties, e.g., impaired capacity to elicit cholesterol efflux and weakened anti-inflammatory functions [4]. Interestingly, specific aldehyde scavengers blocked the adverse consequences of IsoLG modification of apoA, highlighting the potential therapeutic application of lessening lipoprotein IsoLG adducts. We measured IsoLG adducts in the urine samples of our pediatric cohort and found a significant correlation between urinary apoAl and urinary IsoLG adducts (unpublished studies). Critically, the immunoprecipitated apoAl fraction from the urine samples was found to be markedly enriched in IsoLG adducts compared to IsoLG adducts in urinary fraction containing all proteins. This finding suggests that among urinary proteins, apoAl is particularly vulnerable to IsoLG adduction. In companion in vitro cell culture studies, we found that IsoLG-modified apoAl was more avidly taken up by tubular cells than normal unmodified apoAl, findings that parallel the well-established understanding that lipid oxidation upregulates cellular uptake. The IsoLG-modified apoAl also stimulated tubular epithelial cell production of cytokines and VEGF-C. Whether modified apoAl also potentiates podocyte injury in FSGS is not known.

Together, these observations support the concept that renal disease that disrupts glomerular filtration barrier and/or reabsorptive capacity permits increased urinary appearance of apoAl. Some apoAl may be modified. The modifications may be by different oxidants and may produce different forms of apoAl. It will be important to determine whether different renal diseases, including FSGS, cause different lipoprotein modifications that in turn are manifested by different structural, compositional or morphological differences in the urinary apoAl.