Discussion
The long-term prognosis of patients with LN presented with poor renal functions was unknown, as they were mostly excluded from most clinical trials.6–11 On the other hand, these patients were considered with high risks of progression into ESRD, thus proper management strategies are needed.4 5 Data are lacking in guiding risk stratifications among these specific group of patients with LN. We retrospectively reviewed 107 consecutive patients with LN with impaired renal function (eGFR 15–59 mL/min/1.73 m2). Totally, 14.0% of them progressed to ESRD after a median follow-up of 60 months. This is slightly higher than the 5-year ESRD risk estimates (11%, 95% CI 10% to 12%) provided by a previous meta-analysis.2 Considering renal histological classes, 5-year ESRD risks have been estimated to be highest in patients with class IV LN (19%, 95% CI 12 to 29%).2 The general progression risk in our cohort could be partly explained by the popularity of class IV renal histology (class IV 64.5%, class IV+V 21.4%, table 1).
The two models we constructed for ESRD prediction underscored the importance of baseline renal function and treatment response at 6 months. The formal one has been traditionally introduced as a critical prediction component in multiple studies.4 5 In this specific cohort, the optimal cut-off for eGFR was 33 mL/min/1.73 m2 in the nomogram. When applied to patients with milder renal function impairment, proper adjustment of this cut-off is needed. Many recent studies have shown that treatment response (combination of eGFR and proteinuria) at 12 month predicts the long-term renal prognosis and renal flares.14 19 20 The treatment goal derived from the 2019 EULAR/ERA-EDTA is a notable decrease in proteinuria (with GFR normalisation/stabilisation) by 3 months, at least 50% reduction in proteinuria by 6 months, and ultimately proteinuria <0.5–0.7 g/24 hours by 12 months since the start of treatment.16 In our study, we did not observe a significant difference among the proportions of NR at 6, 12 and 24 months (43.0% vs 34.0% vs 35.9%, Kendall’s W test, p=0.459), thus NR at 6 months was chosen for early prediction (online supplemental figure S8). Also, we found that treatment response at 6 months was a better predictor than most baseline features. As shown in the nomogram (figure 2) and Kaplan-Meier curves (online supplemental figure S4), the impact of NR at 6 months was larger than eGFR ≤33 mL/min/1.73 m2 and fibrous crescent.
During follow-up, 40.2% of patients with LN ended up with reduced renal function despite standard induction therapy. Among these patients, 84.6% presented NR at 6 months (online supplemental table S2). Patients with CKD were at higher risk of progression to ESRD during a longer follow-up, and further observations were needed for these patients.
Specifically, proteinuria after 12 months of treatment has been recognised as a better predictor than the baseline proteinuria in multiple studies of patients with LN.21–24 In our study, the medium proteinuria levels at baseline and 6 months were significantly higher in the ESRD group (table 1). However, proteinuria level at 6 months was not selected by the LASSO regression model, which was also validated by receiver operating characteristic (ROC) curves. As shown in online supplemental figure S9, the area under curve of proteinuria at 6 months was 0.754 and the optimal cut-off value was 2.5 g/24 hours, with a sensitivity of 73.3% and a specificity of 75%. The discrepancy between our analysis and the literature might arouse from the differences in patients’ characteristics. For example, analyses of two important LN trials, the MAINTAIN Nephritis Trial and the Euro-Lupus Nephritis Trial, proposed proteinuria <0.7–0.8 g/24 hours at 12 months after induction therapy was the single best predictor of long-term renal prognosis.21 22 However, the baseline serum creatinine and proteinuria of patients with LN in this trial was lower than those of our patients.
The use of hydroxychloroquine (HCQ) was not found to be a protective factor for ESRD in our study (HR 0.971, 95% CI 0.327 to 2.883, p=0.957). Although HCQ is an important background therapy among patients with SLE, as recommended by the EULAR/ERA-EDTA.16 However, most supporting data originated from retrospective observational studies, and the benefit of HCQ in patients with LN was relatively controversial. A recent large retrospective population-based cohort study showed that HCQ use in patient with SLE is neutral in reducing subsequent risk of CKD.25 Moreover, the serum concentrations of HCQ and adherence of HCQ usage may also affect its therapeutic efficacy.26–28 The renal protective role of HCQ in patients with LN still needs to be further investigated.
Further analysis revealed that clinical indicators of SLE duration and hypertension, as well as the pathology variable of CI, were independent risk factors for NR at 6 months, in keeping with previous studies.14 19 Notably, the proportion of hypertension and renal CI scores were higher in our patients compared with those in other studies.4 8
We proposed two sets of nomograms, with or without renal pathology features, as convenient tools for prognosis prediction in real-world practice. This was based on the practical notion that not all patients with LN were appropriate for renal biopsy, especially for those with contraindications. Renal pathology features, especially chronic indicators, significantly improved the C-indexes of these models, for both ESRD prediction and NR prediction. CI score was an independent risk for predicting treatment response and renal outcome. Fibrous crescent was strongly associated with CI (r=0.532, p<0.001) and has been validated as an independent risk factor for ESRD in other studies.29–31 The renal vascular pathology was not evaluated in our text because previous studies indicated that it was not associated with renal outcomes and lacked the good assessment parameters.32 33
In terms of AEs, 4 patients from a total of 111 receiving induction therapy died, and the leading causes of death were pulmonary infections and cardiovascular events, in keeping with previous data.34 35 Since the majority of AEs were observed at the start of treatment and for comparison with published randomized controlled trial (RCT) studies, we summarised the AEs during the 6-month induction treatment period. Notably, 23.4% of patients experienced CMV infections and 3.6% with invasive fungal infections, which were rarely mentioned in RCT studies. A retrospective study of a Chinese population showed that 5.3% of hospitalised patients with LN had CMV infection, which may mimic lupus flares leading to difficulties in diagnosis and subsequent treatment management.36 37 Our analysis found that CMV was not a predictor of treatment response or ESRD, although it was more common in responders. It suggested that we need to be vigilant about CMV infection and that its effect on lupus needs to be verified in a larger sample of studies.
There were some limitations in our study. First, this was a single-centre retrospective study and the sample size was relatively limited. Second, due to the limitations of the retrospective study itself, detailed data on therapy adjustment after NR were not available in the context, resulting in a lack of in-depth interpretation of the treatment of patients with NR, as well as lack of data related to maintenance regimens, the renal flares and withdrawal of immunosuppressive therapy. Third, our model is based on patients with renal biopsy and needs further validation if it can be fully replicated to patients without renal biopsy. Further prospective studies with multiple centres and more therapeutic information are needed.