Immunoglobulin A (IgA) nephropathy (IgAN), characterized by diffusely deposited IgA in the kidneys, is the most prevalent primary glomerulonephritis and a leading cause of end-stage renal disease (ESRD), in which 20–40% of IgAN patients reach ESRD 10–20 years after the initial diagnosis (1). Recognizing risk factors of ESRD would be beneficial for to slowing the progression of IgAN.

Abnormal lipoprotein metabolism, which could lead to impaired renal function and accelerated atherosclerosis (2), is often characterized by the presence of high TG and low HDL-C in chronic kidney disease (CKD) (3). It is well known TG usually increases in the early stages of CKD and is associated with delayed catabolism. However, TG levels fluctuate substantially based on feeding status, thus limiting its utility as a predictive biomarker (4). The single HDL-C, despite the functions of anti-inflammatory and antithrombotic, remains controversial in predicting cardiovascular disease (CVD) or mortality (5). The combination of TG and HDL-C, which is the TG/HDL-C ratio, could therefore overcome the problem and has been proposed as a more practical atherogenic and insulin resistance marker (6, 7). It has attracted increasing attention for the better predictive value for CVD (6, 8) and disease prognosis such as peritoneal dialysis (7), coronavirus disease 2019 (9), type 2 diabetes (10), and CKD (11). However, whether the TG/HDL-C ratio could be another predictor of IgAN progression remains unknown. To clarify these issues, we conducted this study.

Dyslipidemia is common in China, with a prevalence of 41.9 %, and is commonly characterized by the presence of high TG and low HDL-C in CKD (16). Recently, the combination of TG and HDL-C, the TG/HDL-C ratio, has attracted increasing attention for its better predictive power for cardiovascular events and insulin resistance than the lonely combination (17, 18). Noticeably, several studies have shown a positively relationship between the TG/HDL-C ratio and renal function decline in CKD patients (16, 18–20). However, whether TG/HDL-C has a role in IgAN progression remains unknown.

In this study, 78 (6.8%) patients developed ESRD in our 1146 biopsy-proven IgAN patients. A higher TG/HDL-C ratio in patients with IgAN was associated with more severe clinical features and pathologic lesions. Our further analysis revealed a higher serum TG/HDL-C level was an independent risk factor for the progression to ESRD (HR 1.775, 95% CI 1.056-2.798, P=0.029).

Previous studies have reported that the reduction in renal function in patients is related to high TG/HDL-C levels (11, 16), but no study has focused on IgAN patients. To our knowledge, this is the first study assessing the correlation between the TG/HDL-C ratio and ESRD in IgAN patients. Moreover, the TG/HDL-C ratio has a greater influence in advanced IgAN patients (eGFR< 60 mL/min/1.73 m²) or these with 24-hour urine protein of ≥1 g/day in our study. This might be due to the slow progression of mild renal disease, especially within a limited follow-up period (12).

Here, higher SBP, DBP and BMI levels were shown in the high TG/HDL-C group. Further analysis showed TG/HDL was positively correlated with BMI (r=0.380, P < 0.001). In our multivariate Cox regression analyses, BMI was not independent risk factor for renal progression. It is well known obesity often result in excessive accumulation of energy, accompanied by abnormalities in lipid parameter levels. Some studies showed it was associated with the early development of hypertension and CKD progression (21). However, emerging epidemiologic evidence indicated that obesity was not a direct and independent risk factor for IgAN (22). It was possible that high BMI indirectly accelerated the progression of IgAN by inducing metabolic syndrome on patients, in which TG/HDL-C is strongly associated with it (23). Additionally, we would like to stress that high TG/HDL-C patients tend to have hypertension and more severe renal pathologic lesions of segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis. Considering that abnormalities in lipid parameter levels could accelerated atherosclerosis is plausible to believe that pathology of IgAN patients with a high TG/HDL-C level.

Abnormalities in lipid parameter levels could lead to impaired renal function and accelerated atherosclerosis (2). TG usually increases in the early stages of CKD and is associated with delayed catabolism and decreased activity of hepatic TG lipase and peripheral lipoprotein lipase. However, based on feeding status, TG levels could fluctuate substantially, thus limiting its utility as a predictive biomarker (4). HDL-C, inversely associated with outcomes, decreases in patients with CKD (11). The combination of these two markers could therefore overcome this problem and lead to a far more consistent, stable, fasting measurement of dyslipidaemia, which has indeed attracted much more attention in disease prognosis, including cardiovascular disease (6), diabetes (10), and peritoneal dialysis (7). Here, the potential mechanisms by which the TG/HDL-C ratio serves as a prognostic biomarker in IgAN patients may be as follows. TG/HDL-C is a reliable indicator of insulin resistance, which induces oxidative stress. Oxidative stress impairs the activation of nuclear factor erythroid-2-related factor-2, which protects against kidney tissue injury (16). The filtered proteins, such as fatty acids, phospholipids, and cholesterol contained in the filtered proteins (albumin and lipoproteins), could include direct toxic effects of lipids on glomerular cells and promote matrix production (3, 24). Moreover, these materials act as damage-associated molecular patterns (DAMPs) and are recognized by Toll-like receptors (TLR2 and TLR4), which can activate inflammatory responses, causing tubulointerstitial fibrosis and injury in the reabsorption process (25, 26). Additionally, further tissue injury is contributed owing to impaired HDL-mediated reverse cholesterol transport by limiting the unloading of the excess cellular cholesterol and phospholipid burden (25). Thus, in the future, recognizing the TG/HDL-C ratio as a potentially modifiable risk factor for patients may allow the utilization of preventative strategies to optimize both treatment and survival outcomes.

Some limitations warrant consideration. First, this was a retrospective study based on a single-center database. Second, the median follow-up time of 54 months was relatively short. Further multicenter validation in different ethnic populations with longer follow-ups was needed.

The TG/HDL-C ratio may be considered as a prognostic biomarker in IgAN patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the ethical committees of West China Hospital of Sichuan University (2019-33). The patients/participants provided their written informed consent to participate in this study.

GP, AQ, SW, LD, XL, and DY collected and analysed the data. GP and AQ wrote the main manuscript text. YT, XZ and JT reviewed and edited the manuscript. WQ supervised all the work and revised the manuscript. All authors contributed to the article and approved the submitted version.

This study is partly supported by the National Key R&D Program of China (2020YFC2006503) &(2020YFC2006500).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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