This study was conducted to assess the differences in serum PCSK9 levels and lipids in different pathological types of PNS. The results demonstrated no significant differences in serum levels of these variables between the investigated PNS types.

Hypercholesterolemia and/or hypertriglyceridemia are common complications of nephrotic syndrome [2, 3]. Previously, it was believed that the mechanism of dyslipidemia is the increased synthesis of lipoproteins by hepatocytes in response to hypoproteinemia [2]. But later, studies suggested that the main cause of hypercholesterolemia is decreased expression of LDL-R in hepatocytes due to elevated plasma levels of PCSK9, with subsequently decreased uptake of LDL-C from the circulation [17, 18].

The present study showed a significant difference in serum PCSK9 levels between PNS patients and healthy individuals. This result is consistent with earlier reports [20]. Induction of nephrotic syndrome in a mice model led to increased plasma PCSK9 7- to 24-fold, which appeared to be due to increased hepatic secretion and decreased removal of PCSK9 [21].

We did not find significant differences in serum levels of TC, LDL-C, HDL-C, VLDL-C, TG, and PCSK9 between pathological types of PNS. Other investigators [20] reported similar findings when comparing serum PCSK9 levels in Chinese patients with MCD and MN. From this result, we can speculate that the investigated types of PNS had a similar stimulatory and inhibitory effect on hepatic synthesis and clearance of PCSK9, respectively.

Significant positive correlations between serum PCSK9 levels and TC and LDL-C were observed in our study, and these results are in line with earlier reports [17, 20,21,22]. Kwakernaak et al. demonstrated that changes in TC, LDL-C, and non-HDL-C in response to antiproteinuric treatment correlated with changes in serum PCSK9 levels [23]. Haas et al. studied a cohort of nephrotic syndrome patients during active disease and remission. During active disease, serum PCSK9 correlated significantly with serum levels of TC, LDL-C, and HDL-C, and after remission, hyperlipidemia resolved, and in parallel, serum PCSK9 levels decreased significantly, and the changes in serum PCSK9 correlated with the changes in TC, LDL-C, and HDL-C [21]. Jatem et al. [24] reported a series of 12 patients with refractory nephrotic syndrome and hypercholesterolemia who were treated with PCSK9 inhibitors. A significant correlation between serum PCSK9 and LDL-C was found before treatment, and after treatment, the significant reduction of LDL-C was associated with a significant reduction in serum PCSK9 levels. The significant correlation between serum levels of PCSK9 and cholesterol can be explained by the fact that high serum PCSK9 levels cause more degradation of LDL-R with subsequently decreased clearance of LDL-C from the circulation and finally high serum levels of TC and LDL-C [17].

A significant positive correlation was found between serum PCSK9 and TG in univariate analysis. But significance disappeared in multivariable analysis after adjustment for other variables. Consistent with our results, a significant correlation between serum PCSK9 and TG was noticed in a cohort of proteinuric patients before and after antiproteinuric treatment [23]. On the other side, other investigators did not find a significant correlation between TG and serum PCSK9 [20] or the changes in these variables after remission of nephrotic syndrome [21]. An inconsistent correlation between TG and serum PCSK9 indicates that there are other players involved in the development of hypertriglyceridemia in nephrotic patients [4, 25, 26].

Another important finding in this study is the positive correlation between daily protein excretion and serum PCSK9 levels which remained in model 1 of multivariable analysis. In line with this result, other researchers reported similar correlation results between plasma PCSK9 and urine protein-to-creatinine ratio before and after maximal antiproteinuric treatment for proteinuric patients [23]. Similarly, results of another study [21] showed a significant reduction in serum PCSK9 levels after remission of nephrotic syndrome. In the same study, induction of nephrotic syndrome in mice was associated with a significant increase in serum PCSK9 levels.

The male sex correlated significantly with serum PCSK9 levels (p = 0.014), and serum levels of PCSK9 were higher in males compared with females (347.80 ± 82.59 vs 292.43 ± 58.933, p = 0.008). The relation between serum PCSK9 and sex is variable as another study [27] reported higher serum levels of PCSK9 in females compared with males. The explanation for sex difference is unknown. It is largely not related to estrogen status as the levels were not different in postmenopausal females who received estrogen and those who were not treated with estrogen [27]. The contradictory results from different reports are mostly due to differences in patients’ characteristics, e.g., patients in the previously mentioned study were not nephrotic.

This study has some limitations. The sample size was small, and the number of patients in the different pathological types of PNS was not equal; thus, it may be claimed that these are the causes of the lack of difference in serum PCSK9 levels noticed in our study. The biochemical tests done for PNS patients were not performed for the control group except for serum PCSK9 which was measured to compare levels with nephrotic patients. This study included only 3 types of PNS, and despite these being the main types, the results cannot be generalized.

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