Several clinical studies have evaluated the ability of short-term prognostic histological factors to predict long-term renal outcome in LN patients, such as elevated sCr at the beginning of LN, hypertension, proteinuria, diffuse proliferative glomerulonephritis, chronic parenchymal injury and tubulointerstitial abnormality.5,13-16 However, PTU has recently gained prominence as the best predictor of long-term renal outcome in LN.8,9,10,17
The current study analyzed 214 LN patients from a single center followed for 11 years on average, 47.2% of whom progressed to CKD and 25.6% to ESRD. Proteinuria >0.9 g/day at 12 months was found to be the best individual predictor of poor long-term renal outcome (ESRD). (sensitivity 83%, specificity 65%, PPV 40%, NPV 93%). Four studies with objectives similar to ours found sensitivity values ranging from 83% to 90%, with cut-off points from 0.6 to 0.8 g/day (Table 2).8-10,13 Two of these used data from European clinical trials (MAINTAIN and Euro-Lupus), 8,10 while the other two were retrospective analyses.9,18 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. observed that PTU <0.7 g/day at 12 months was the best predictor of good outcome at 7 years, with 71% sensitivity and 75% specificity,8 matching the results of the Euro-Lupus trial.10 Likewise, Dall’Era et al. concluded that PTU <0.8 g/day at 12 months maximized sensitivity (81%) and specificity (78%) for good renal outcome.10 Both studies found that the inclusion of microscopic hematuria at 12 months in the set of outcome criteria significantly decreased sensitivity, whereas the addition of sCr did not improve performance. The Brazilian retrospective cohort study (n=94) mentioned above found a similar cut-off (0.8 g/day) as the best predictor of long-term renal outcome,9 while the Canadian study found a conspicuously lower cut-off (0.6 g/day), though at the expense of much lower sensitivity (58%) and area under the curve (AUC: 0.65).17 The authors of the Canadian study 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).17 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),8 the Euro-Lupus study (1.15 mg/dL)10 and the Canadian study (0.72 mg/dL),17 indicating more severe nephritis.
An important point to note is that the outcome assessed in our study was end-stage renal disease, defined as the need for permanent hemodialysis or peritoneal dialysis. The studies reviewed above assessed good long-term renal outcome, defined as sCr <1 mg/dL or <1.5 mg/dL. Our findings should, therefore, be interpretated differently; i.e., after 12 months of treatment, PTU >0.9 g/day was predictive of poor renal outcome (ESRD), with 83% sensitivity and 65% specificity. On the other hand, in the MAINTAIN study, for example, PTU <0.7 g/day at 12 months was the best predictor of good renal outcome (sCr ≤1 mg/dL). Thus, a PPV of 40% means that 40% of the patients with PTU >0.9 g/day at 12 months will develop ESRD during the 11-year follow-up period. This is important because it means that 60% of the patients may still experience a good course despite PTU values >0.9 g/day after 1 year of treatment. Patients with PTU <0.9 g/day at 12 months are not likely to develop ESRD because of the high negative predictive value in our study (93%). Since predictive values depend on the prevalence of the outcome in the population being studied, positive predictive values tend to be higher in referral centers where severe patients are treated.
The sCr values of patients developing CKD were significantly higher at 3, 6, and 12 months and at 5 years and/or the last evaluation than at baseline, suggesting that from baseline onwards serum creatinine is a good predictor of renal outcome. Some studies have shown that the addition to PTU of the variable sCr at 12 months increases specificity, but without improving performance.8-10,17 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.
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. On the other hand, compared to most other studies, our sample was large and follow-up was long, with focus on PTU as a predictor of long-term renal outcome. In addition, our patients came from a single referral center in Northeastern Brazil, with a unique ethnic profile.
Overall, we demonstrated that, in a Brazilian real-life setting, PTU <0.9 g/day at 12 months was the best predictor of long-term renal outcome.