The association of pro-resolving lipid mediators with pathogenesis of nephrotic syndrome

Nephrotic syndrome (NS) is characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) are common causes of primary NS in adults. In the pathogenesis of primary NS, immunological causes disrupt podocyte structure and functions. Resolvin-D1 (Rv-D1), protectin-D1 (P-D1), maresin-1 (Mar-1) and lipoxin A4 (LXA4), synthesized from omega-3 and omega-6 fatty acids, is a pro-resolving lipid mediator (PLM) with anti-inflammatory effect in the resolution phase of inflammation. In our study, we aimed to measure the serum and urine Rv-D1, LXA4, P-D1 and Mar-1 levels of NS patients by liquid chromatography tandem mass spectrometry (LC-MS/MS) method and to investigate their role in the pathogenesis of MN and FSGS. Our study, included 19 individuals in the control group and 26 individuals in the primary NS group. The NS group was divided into MN (n=18) and FSGS (n=8) subgroups. In LC-MS/MS analysis, compared to control group; in NS, MN and FSGS groups serum Rv-D1 levels were statistically significant lower (p<0,01, p<0,05 and p<0,05, respectively), urine Rv-D1/creatinine were higher (p<0,001, p<0,001 and p<0,05 respectively), in NS and MN groups urine Rv-D1 levels were also higher (p<0,001 and p<0,05 respectively). Compared to the control group in NS, MN and FSGS, while no significant difference was found between serum and urine LXA4 levels, urine LXA4/creatinine was found to be high in NS group (p<0,05). Since P-D1 and Mar-1 couldn't be detected by LC-MS/MS, Rv-D1, LXA4, P-D1 and Mar-1 levels were measured by ELISA method. Compared to the control group in NS; serum Rv-D1, LXA4, P-D1 and Mar-1 levels were lower (p<0,01, 0,01, 0,01 and 0,01 respectively), urine P-D1 and Mar-1 (p<0,001 and p<0,001 respectively) and urine Rv-D1/creatinine, LXA4/creatinine, P-D1/creatinine and Mar-1/creatinine levels were higher (p<0,001, p<0,001, p<0,001 and p<0,001, respectively). Compared to the control group in MN; serum Rv-D1, LXA4, P-D1 and Mar-1 levels are lower (p<0,05, 0,01, 0,05 and 0,01, respectively), urine Rv-D1, LXA4, P-D1 and Mar-1 (p<0,05, 0,05, 0,05 and 0,001, respectively) and urine Rv-D1/creatinine, LXA4/creatinine, P-D1/creatinine and Mar-1/creatinine levels were higher (p<0,001, p<0,001, p<0,001 and p<0,01 respectively). Compared to the control group in FSGS; serum Rv-D1, LXA4 and Mar-1 levels were lower (p<0,05, 0,01 and 0,05, respectively), urine Rv-D1, LXA4, P-D1 and Mar-1 levels (p<0,05, 0,05, 0,001 and 0,05, respectively) and Rv-D1/creatinine, LXA4/creatinine, P-D1/creatinine and Mar-1/creatinine were higher (p<0,001, p<0,001, p<0,001 and p<0,001, respectively). Low levels of PLMs in serum have been associated with dysregulation of the resolution phase of inflammation. GFB damage may cause PLMs to be excreted in the urine and decrease their levels in serum. In addition, high urine PLM levels suggest that they are excessively synthesized in the kidney to suppress local inflammation in NS. Correlation of PLMs with biochemical tests used in NS diagnosis and follow-up was determined. According to ROC analysis findings, these parameters may have biomarker values. It would be useful to repeat the research with larger study groups.