IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and approximately 30-40% of IgAN patients may lose their kidney function gradually and progress to end-stage renal disease (ESRD) within 20 years from the time of diagnosis. Patients are miserable and bear a huge financial burden due to the high recurrence rates and poor renal prognosis of IgAN (1). Therefore, it is particularly important to identify high-risk patients and take corresponding measures. Accumulating evidence has illustrated that IgAN is an immune system disease, where inflammation is closely related to the severity and prognosis of the disease (2).

Platelet-related parameters, including platelet (PLT), platelet-to-albumin ratio (PAR), and platelet-to-lymphocyte ratio (PLR) are easy to obtain clinically and have been proved to be novel prognostic indicators for several inflammatory diseases (3–5). In addition to hemostasis, platelets may also be able to trigger and aggravate inflammation by interacting with immune cells and secreting proinflammatory cytokines (6). Moreover, the results of multiple studies consistently report that PAR and PLR are associated with inflammation and have been described as emerging inflammation indexes (3–5). Nevertheless, few studies have demonstrated the precise relationship between platelet-related parameters and IgAN. Accordingly, we examined the data of 966 patients with IgAN to determine whether platelet-related parameters are risk factors for ESRD in patients with IgAN.

IgAN is a prevalent disease in which multiple factors are involved in its development and progression (13). Although the definite pathogenesis of IgAN is still unclear, most scholars agree that autoimmunity and inflammation play important roles in it (2, 13). In recent research, platelet-related parameters have been found to be related to chronic kidney disease (CKD), diabetic nephropathy, sclerosing nephropathy, and some other renal diseases (14, 15). Accordingly, it is supposed that platelets might be associated with IgAN.

Without considering the effect of covariates, the K-M curve found that PLT, PLR, and PAR were strongly correlated with the renal outcomes of IgAN ( Figure 2 ), suggesting that all of them might serve as potential predictors. ROC curves ( Figure 1 ) further demonstrated that PAR and PLR had better predictive power than PLT, where the predictive values of PAR and PLR were similar. Multivariate Cox regression adjusting for demographic data, pathological findings, treatment, and laboratory results indicated that compared with PLR, albumin, and PLT, PAR seemed to be a better marker of adverse renal outcome ( Tables 1 , 2 ), implying PAR was the only platelet-related parameter that could be used as an independent risk factor. Although there was no report on the relationship between PAR and IgAN, PAR was proven to be closely related to the severity and prognosis of many inflammatory diseases. Yukai Wang et al. reported that PAR was positively correlated with the disease activity of axial spondyloarthritis (16). PAR was also illustrated to predict the mortality of patients suffering from severe fever with thrombocytopenia syndrome (17). PAR plays a similar role in predicting outcomes of patients with peritoneal dialysis (18). Hence, the consistent results of multiple articles suggested that the PAR might become a novel prognostic indicator in the future (4, 5, 16–18).

To more accurately evaluate the predictive power of the PAR, we analyzed the predictive effect of the PAR on patients with different clinicopathological characteristics through subgroup analysis. Grouped by Oxford classification, PAR tended to have great predictive power in patients with M1, E0, S0, S1, T0, T1-2, and C1-2, while it might lose its ability in patients with M0, E1, and C0. It should be noted that the majority of the enrolled patients had no pathological damage, such as mesangial hypercelluarity and endocapillary hypercellularity. In other words, the sample size of M0 and E1 patients was small, which might be an important reason for the negative conclusion. Undoubtedly, these statistical results need to be confirmed by further large-sample clinical cohorts. PAR could not predict the prognosis of C0 patients well because PAR might interact with the crescent; that is, patients with high PAR might have a higher risk of developing crescent. The interaction between the two was an important reason for the negative results. Similarly, grouped by the clinical manifestations, PAR was more suitable for the prediction of proteinuria≥1.0 g/d, CKD 3-4, normal blood pressure, hypertension, Alb>30 g/L, and anemia. Our results also indicate that patients with high PAR usually had adverse renal survival when they did not receive any immunosuppressive therapy. These results seemed to show that PAR might better predict the prognosis and outcome of patients who were already very severe, which might be because patients with mild renal impairment progressed to ESRD relatively slowly, while patients with severe renal impairment developed into the end -point relatively quickly (19).

At present, it is not completely clear why the PAR can predict the prognosis of IgAN. We initially thought that high PAR patients seemed to have severer clinical manifestations and pathological lesions since high-grade proteinuria, endocapillary proliferation, and crescents were more frequent in the high PAR group, which might explain the relationship between PAR and prognosis. Interestingly, after eliminating the influence of different baselines on outcome variables, PAR could still predict the poor prognosis of IgAN. Therefore, the previous explanation did not seem to fully explain this phenomenon. Emerging studies have revealed that the platelet count is positively related to some chronic inflammatory markers (20, 21). In addition to reflecting the nutritional status of the body, ALB is considered to be associated with inflammation (22, 23). It is proposed that a new indicator PAR that combines the above two might be able to better reflect the body’s inflammatory state (24). Chronic inflammation undoubtedly participated in the pathogenesis and development of IgAN, and inflammatory mediators might damage the structure and function of the kidney tissue (25). Hence, a high level of PAR, meaning a hyperinflammatory state and/or poor nutrition, definitely predicts the adverse renal outcomes of IgAN.

PAR, the PLT divided by the ALB, is easy to obtain in the clinic through peripheral white blood cell (WBC) count and liver/kidney function tests, and is much cheaper than other inflammatory indicators. In addition, PAR is a combination marker that seems to be more accurate in prediction than other platelet-related parameters. It has been reported that PAR might be more stable and less likely to be affected by dynamic physiological conditions than other platelet parameters and/or inflammatory markers (17, 18, 26, 27). As PAR seemed to be related to the inflammatory responses, it would be crucial to show whether PAR was correlated with one of the most used inflammatory serum markers such as the C-reactive protein (CRP). Clinically, at least in our medical center, CRP and IL-6 are not routine examination items for patients with IgA nephropathy, and there is no guideline recommending routine examination of CRP and IL-6 in IgAN patients. It should be noted that only 251 patients had CRP tests. There is a large amount of missing data, so there is a certain bias in the statistical analysis. Nevertheless, we performed Spearman correlation analysis and found that PAR and CRP were significantly positively correlated (r=0.612, P<0.001), implying that PAR is suggestive of inflammatory responses in IgAN. Besides, several studies have reported that PAR was indeed an inflammatory index, so it was believed that PAR might be a preferred one since it was cheap and easy to calculate in the clinic. Hence, PAR, a novel inflammation marker, might be used in clinical practice.

Previous studies have suggested proteinuria was a well-established risk factor for kidney function decline in IgAN. However, the proteinuria was not shown to be an independent risk factor for the renal outcomes. The following reasons may explain this phenomenon. Our study found that patients in the high PAR group usually presented with higher levels of proteinuria. At the same time, the correlation analysis suggested that there was a positive correlation between PAR and proteinuria (r=0.33, P<0.001). When these two indicators were put into the model at the same time, the predictive effect of these indicators might be masked, which might explain why the proteinuria was not shown to be an independent risk factor for the renal outcomes. Notably, PAR could still serve a good marker for prognosis, implying it was strongly correlated with the prognosis of IgAN. To demonstrate this, we excluded platelet-related indicators from this COX model and found that proteinuria indeed remained an independent risk factor for IgAN (HR 1.123, 95%CI 1.02, 1.230, P=0.013), which was consistent with our speculation. This seems to suggest that inflammation state might be better predictors of IgAN prognosis than proteinuria. But this speculation needs further verification.

Limitations should be noted in this study. First, this was a single-center study with a relatively short follow-up period. Second, the optimal cut-off value was based on this cohort, which means it might not be suitable for other populations and races. Third, since this was a retrospective study, there were no detailed data for regular follow-up in each subject, so dynamic analysis of PAR could not be performed. Fourth, retrospective analyses are prone to residual confounding effects of comorbidity, lift style, and medications that affect blood cell counts and selection bias. Therefore, high-quality prospective studies with large samples are required.

PAR is an ideal inflammatory parameter to identify the renal outcomes of IgAN patients with severe clinicopathological manifestations and could be used as an independent risk factor for IgAN progression.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The study was approved by the Ethical Committee of West China Hospital of Sichuan University (2019-33). The patients/participants provided their written informed consent to participate in this study.

Study design: WQ, YT, and TJX. Data acquisition: WQ, JT, SW, ZJ, LD, GS, XL, and AQ. Data analysis: JT and GS. Supervision: WQ and YT. Each author accepted accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.

This study was partly supported by the National Key R&D Program of China (2020YFC2006503) and grants from the project of the National Natural Science Foundation of China (No. 81970612).

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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