The current study analysed 214 LN patients from a single referral center in Northeastern Brazil followed for 11 years on average, 22.3% of whom progressed to CKD and 24.8% to ESRD. This study demonstrated that achievement of a 24PTU value > 0.9 g/day at month 12 is a good predictor of a bad long-term renal outcome (CKD or ESRD), and that a sCr > 0.9 mg/dL and > 1.3 mg/dL at month 12 is also good predictor of CKD and ESRD, respectively.

Several clinical studies have evaluated the ability of short-term prognostic factors to predict long-term renal outcome in LN patients, such as elevated sCr, hypertension, proteinuria, haematuria, elevated anti-dsDNA, diffuse proliferative glomerulonephritis, chronic parenchymal injury and tubulointerstitial abnormality [5,6,7,8,9,10, 15,16,17,18]. However, PTU has recently gained prominence as the best predictor of long-term renal outcome in LN [6,7,8,9,10]. The best cut-off of 24PTU at 12 months has varied from 0.6 to 0.8 g/day across studies [7,8,9,10]. The renal outcomes of patients with LN vary in different ethnic groups, with the best renal prognosis in Caucasian patients, the worst in African patients and the medium in Asia and Hispanic patients [5, 18,19,20,21,22,23]. Most studies conducted to evaluate the ability of short-term prognostic factors to predict long-term renal outcome in LN patients were in white populations. A Brazilian study carried out in the Southeast of Brazil had 40.4% non-white patients [9], while in our study carried out in the Northeast of Brazil, the population of non-whites was the vast majority (78.7%). There are some racial, ethnic and geographical differences between the regions of Brazil, justifying the need for more studies to generalize the findings.

Studies with objectives similar to ours found 24PTU sensitivity and specificity values ranging from 58 to 90% and from 75 to 83%, respectively, with cut-off points from 0.6 to 0.8 g/day [7,8,9,10]. Two of these used data from European clinical trials (MAINTAIN and Euro-Lupus) [7, 8] while the other two were retrospective analyses [9, 10]. Clinical trials are designed for specific treatments and adherence to intervention protocols tends to be much higher than in observational studies; thus, outcomes are likely to be better than in real-life settings. In their cohort of predominantly Caucasian patients, Tamirou et al. defined good long-term outcome as sCr ≤ 1.0 mg/dL at least 7 years after entry into the trial and observed that 24PTU < 0.7 g/day at 12 months was the best predictor of good outcome, with 71% sensitivity and 75% specificity [7]. Dall’Era et al. concluded that 24PTU < 0.8 g/day at 12 months maximized sensitivity (81%) and specificity (78%) for good renal outcome [8]. In our study we considered two clinical bad outcomes (CKD and ESRD) and found similar sensitivity and specificity values, but a slightly higher cut-off for 24PTU (0.9 g/day). Both trial found that the inclusion of microscopic haematuria at 12 months in the set of outcome criteria significantly decreased sensitivity. The Brazilian retrospective cohort study found a similar cut-off (0.8 g/day) with a better sensitivity of 90%, and also showed that the haematuria is not a good predictor of renal outcome [9]. This can be explained by the lack of standardization in the analysis of the urine sediment, delays in sample examination, the use of automated techniques instead of microscopic reading, and by the many other reasons for haematuria in a population of mainly young women. Fung et al. found a conspicuously lower cut-off (0.6 g/day), though at the expense of much lower sensitivity (58%) and area under the curve [10]. The authors pointed out that their cohort had lower baseline 24PTU values than the cohorts of other studies and, in fact, baseline PTU levels were higher in the European studies (Euro-Lupus: 3.0 ± 2.3; MAINTAIN: 3.4 ± 2.9) [8, 10], in the Brazilian study (5.4 ± 4.5) [9], and in the present investigation (2.9 ± 3.0) than in the Canadian study (2.3 ± 2.3) [10]. Baseline sCr values were also high in the study by Ugolini-Lopes et al. (1.73 mg/dL) [9], and in our study (1.45 mg/dL) compared to the values reported in the MAINTAIN study (0.95 mg/dL) [7], the Euro-Lupus study (1.15 mg/dL) [8] and the Canadian study (0.72 mg/dL) [10], indicating more severe LN in Brazilian studies.

In a cohort of 1814 Chinese patients with biopsy-proven LN followed for 7.7 ± 5 years, the time-average proteinuria (TA-Pro) during the follow-up was an independent risk factor for ESRD, with better predictive value than baseline PTU. The patients with TA-Pro 0.5–1.0 g/24 h and TA-Pro > 1 g/24 h were associated with a 12.5-fold and 237.6-fold higher risk for ESRD than those with TA-Pro < 0.5 g/24 h, respectively [5]. Although the methodology of this study is different from the studies already mentioned, it reinforces the importance of controlling PTU during the follow-up of patients with NL. The PTU levels should be controlled at least to < 1.0 g/day, and optimally to < 0.5 g/day.

Although the 24PTU at 12 months has been proved to be the single best predictor of long-term renal outcome [6, 7, 9], we believe that other biomarkers are needed to impact therapeutic decision making in individual patients in the clinical, and also are needed to be used in controlled clinical trials of LN. The sCr at 12 months was a good predictor for long-term renal outcome in our cohort. The Canadian study suggests that while 24PTU may be more appropriate as a biomarker due its sensitivity to short-term change, there may be value in combining it with sCr [10]. Mackay et al. developed risk models to predict future adverse kidney outcomes based on clinical data acquired during the first year of therapy after diagnosis of LN. All these CKD, ESRD and severe kidney injury predictive models included PTU and sCr at 12 months [23]. The sCr values of patients developing CKD in our study were significantly higher from baseline and at 3, 6, 12 months, and during all follow-up than sCr values of patients who did not progress to CKD, suggesting that from baseline onwards sCr is a good predictor of renal outcome. In patients progressing to CKD and ESRD, sCr values decrease between baseline and 6 months after treatment, after which they rise again, possibly because the effective treatment of the first months is followed by a decline in immunosuppressants and corticosteroids. In short, the presence of elevated creatinine levels at the beginning of treatment suggests an increased risk of ESRD and the need to optimize immunosuppressive treatment.

An important point to note is about the high negative predictive value of 24PTU and sCr for ESRD. The probability that a patient with 24PTU < 0.9 g/day at 12 months not progressing to ESRD is 93.2%. Likewise, the probability that a LN patient with sCr < 1.3 mg/dL at 12 months not progressing to ESRD is 82%. Since predictive values depend on the prevalence of the outcome in the population being studied, these values tend to be higher in referral centers where severe patients are treated.

Our study may have been limited by the retrospective design and by the real-life setting since LN treatment heterogeneity may have influenced PTU response and outcome. Besides this, only 57% of the patients were submitted to renal biopsy. To avoid misdiagnosis of NL we strictly followed the clinical diagnostic criteria that include the presence of two consecutive 24PTU readings > 500 mg and an additional feature supporting active lupus such as positive serologies (hypocomplementemia and/or elevated anti-dsDNA antibodies) and/or active urinary sediment, in the absence of other causes [12]. On the other hand, compared to most other studies, our sample was large and follow-up was long, with focus on 24PTU and sCr as predictors of long-term renal outcome. In addition, our patients came from a single referral center in Northeastern Brazil.

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