**4. Discussion**

In this study, we found that NLR and PLR at the point of diagnosis of RPGN are associated with renal outcome. In particular, NLR was considered to be a useful prognostic indicator for the recovery from HD in patients with RPGN.

RPGN often causes a progressive decline in renal function that leads to ESRD at a high rate. In this study, we observed that around 16% of the cases resulted in ESRD. Several renal prognostic indicators of RPGN, such as the degree of decline in renal function on admission, histological classification, and the level of the anti-GBM antibody, have been suggested in previous reports [4,19]. However, it is difficult to accurately predict renal outcome without a renal biopsy or in patients who require HD. Therefore, it is important to establish a simple renal prognostic indicator other than renal function or histological assessment.

NLR and PLR are simple and cost-effective markers, that represent the ratio of the number of cells with two different hemocytes. Neu and Plt increase with inflammation [11,20], while Lym may decrease with inflammation in autoimmune diseases [21]. Since the majority of the patients included in this study had an etiology of autoimmune vasculitis, it was expected that the increase in Neu and Plt, and the decrease in Lym, would be proportionate to the degree of inflammation. Therefore, we considered that NLR and PLR could be more reliable than a single hemocyte number. Infection, cancers, ischemic heart disease and peripheral vascular disease affect NLR and PLR [22]. In addition, steroids increase Neu, while immunosuppressive agents may reduce Neu by myelosuppression. Thus, in this study, we excluded patients who had infectious diseases and who were already administered steroids or immunosuppressive drugs at diagnosis, and confirmed no patient had a history of malignancy, ischemic heart disease or peripheral vascular disease.

NLR and PLR have been reported to be associated with AAV disease activity; high NLR and PLR indicate a higher disease activity [11,12,20,22]. On the other hand, several studies have mentioned that the application of NLR and PLR is limited. It has been demonstrated that NLR is a good predictor of the relapse rate, but not of death in patients with AAV [22]. PLR is also able to predict the disease activity but cannot predict relapse in AAV patients [20]. In this study, both NLR and PLR at diagnosis were significantly higher in patients with preserved renal function than in patients with maintenance HD. We speculate that a higher NLR and PLR indicate acute disease and an active phase, sustaining the possibility of a positive response to immunosuppressive therapy, whereas a lower NLR and PLR may sugges<sup>t</sup> a chronic phase with irreversible renal injury. This was confirmed by the histological

analysis, which revealed significant di fferences in glomerular changes. The majority of the glomeruli in the maintenance HD group were globally sclerosing, indicating irreversible renal injury. Cellular crescent presence, suggesting a possibility of improvement, was highly observed in the temporary HD group. We demonstrated that an NLR < 4.0 or PLR < 137.7 at diagnosis were associated with negative renal outcomes, especially in patients requiring HD. An NLR < 5.0 at diagnosis could predict irreversible renal failure.

Since the patients in the pre-dialysis group showed variable renal function, and the multivariate analysis revealed that renal function was the strongest influencing factor, we investigated the predictive abilities of NLR and PLR in patients requiring HD. Among the 13 patients, NLR at diagnosis was significantly higher in the temporary HD group than in the maintenance HD group. Although PLR showed an increased presence in the temporary HD group, the di fference was not significant. The half-life of Neu and Plt could a ffect this result. Neu can survive for less than 24 h, while Plt survives for 10 days, and their lifespans are controlled by endogenous apoptosis [23,24]. Plt, which is increased by inflammation, circulates for a longer period than Neu. In predicting the course of patients requiring HD, it would be desirable to evaluate the acute phase of inflammation and disease activity. Therefore, NLR would be a better predictor than PLR for withdrawal of HD.

There are some limitations to our study. First, all the patients were treated based on the clinical guidelines for the ANCA-associated RPGN [25]; thus, the treatment strategy di ffered in each patient. Since all four patients with an anti-GBM disease required maintenance HD, this may a ffect the result of our study. However, we observed a significant di fference in NLR between the temporary and maintenance HD groups when these patients were eliminated. In addition to the variations in NLR and PLR, this study was a retrospective study, with a small number of subjects. Therefore, the results of the present study should be carefully interpreted, and a prospective study with a larger number of patients is required to confirm the suitability of NLR and PLR as predicative factors in renal outcomes.
