Severe lupus nephritis: the predictive value of a 50% reduction in proteinuria at 6 months

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1 Nephrol Dial Transplant (2013) 28: doi: /ndt/gft201 Advance Access publication 19 June 2013 Severe lupus nephritis: the predictive value of a 50% reduction in proteinuria at 6 months Stephen M. Korbet and Edmund J. Lewis for the Collaborative Study Group Correspondence and offprint requests to: Stephen M. Korbet; skorbet@aol.com See the Appendix for a list of additional members of the study group Section of Nephrology, Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA Keywords: proteinuria, remission, severe lupus nephritis ABSTRACT Background. A complete remission (CR) in severe lupus nephritis (SLN) is associated with a favorable long-term outcome. Initial therapy may be up to 6 months, but many patients do not achieve a CR until after 12 months. We assess the value of a 50% reduction in proteinuria (UPro) at 6 months in predicting the outcome in SLN patients. Methods. We evaluated the 86 adult patients in the prospective, controlled trial of plasmapheresis (PP) in SLN (NEJM 1992). Patients with a CR (n = 12), end-stage renal disease (ESRD) or death (n = 13) at 6 months were excluded. The remaining 61 patients were categorized into two groups based on having attained a 50% reduction in UPro at 6 months: (yes) 34 patients and (no) 27 patients. The long-term outcomes were compared. A CR was defined by a serum creatinine (SCr) of 1.4 mg/dl and UPro of 0.33 g/day. Results. Baseline features were similar, but the UPro was higher (7.1 ± 3.6 versus 4.6 ± 3.2, P 0.002) in the group with a 50% reduction in UPro at 6 months. At follow-up, a CR was attained in 56% of patients with a 50% reduction in UPro at 6 months compared with 22% (P = 0.009) in the group without. The 15- year renal survival (71 versus 25%, P = 0.005) and patient survival without ESRD (66 versus 18%, P = 0.004) was greatest in the patients with a 50% reduction in UPro at 6 months. Conclusion. A 50% reduction in UPro at 6 months predicts a favorable outcome in SLN. INTRODUCTION In severe lupus nephritis (SLN), attainment of a complete remission (CR) with treatment is associated with a significantly improved outcome [1 8]. While the initial course of therapy in SLN can be up to 6 months, <20% of patients will have attained a CR by that point [4, 5, 9 11]. The average time to CR ranges from 10 to 16 months with almost 50% of patients not attaining a CR until after 12 months [4, 6, 7, 11, 12]. Nonetheless, in patients not attaining a CR, a relative decrease in proteinuria by 6 months of treatment may still predict a long-term clinical outcome. The purpose of this study was to determine the long-term prognosis of patients who had achieved a 50% reduction in proteinuria from baseline by 6 months but had not attained a CR. MATERIALS AND METHODS Patients The study group is composed of the 86 adult patients who originally participated in the prospective, controlled trial of plasmapheresis (PP) in SLN [13]. In this study, with extended follow-up (121 ± 64 months overall, 113 ± 63 months in patients on standard therapy and 131 ± 64 months in the PP patients, P = NS), the patient data were pooled because there were no significant differences between the two treatment groups during the therapeutic trial [13]. The entry criteria, therapeutic and medical management protocols, and the results of the initial study have been previously described [13, 14]. In brief, patients were eligible when they were 16 years of age, had systemic erythematosus as defined by the American Rheumatism Association [15] and had biopsy-proven SLN. Patients with a serum creatinine of >6 mg/dl, previous PP or pregnancy were excluded from the study. The entry criteria required the histologic diagnosis of SLN using a modification of the 1982 World Health Organization ORIGINAL ARTICLE The Author Published by Oxford University Press on Downloaded from behalf of ERA-EDTA. All rights reserved. 2313

2 ORIGINAL ARTICLE (WHO) classification of lupus nephritis [16 18]. An adequate biopsy contained >10 non-sclerotic glomeruli, and the diagnosis of SLN was based on the presence of proliferation and/or necrosis in 50% of the glomeruli with or without concomitant membranous glomerulonephritis [13]. This pathologic rubric comprises three morphologically discrete forms of lupus glomerulonephritis: (i) segmental glomerulonephritis with active and/or necrotizing lesions in 50% of glomeruli (Category III 50%; 24 patients), (ii) diffuse glomerulonephritis (Category IV; 35 patients) and (iii) membranous glomerulonephritis with superimposed severe segmental ( 50% glomerular involvement, Category Vc: 50%; 19 patients) or diffuse proliferative glomerulonephritis (Category Vd; 6 patients). Because we have previously shown that the prognosis of these lesions is defined by the distribution of their proliferative component (segmental versus global inflammation) irrespective of the presence of membranous glomerulonephritis, we have grouped them accordingly into Category III 50% ± V (44 patients) and Category IV ± V (41 patients) [19]. Based on the International Society of Nephrology/Renal Pathology Society classification [20, 21], all patients had class IV-S or G ± V. One patient was not classifiable. Clinical, biochemical and serological information were obtained on patients at baseline and at specified follow-up times during the study (weekly for 8 weeks, then Weeks 12, 18, 24 and every 8 weeks thereafter for 2 5 years). The level of proteinuria was determined based on 24-h urine collections. Information at last follow-up on the clinical status of the patients with respect to death, end-stage renal disease (ESRD) and biochemical results for serum creatinine and urine protein levels were collected. Treatment protocol The details of the treatment protocols for this study have been published previously [13, 14]. All patients initially received standard therapy with prednisone 60 mg/day orally and cyclophosphamide 2 mg/kg/day orally. Forty patients were randomly assigned to receive standard therapy plus PP three times weekly for 4 weeks in addition to this treatment. After the initial 4 weeks of treatment, patients who improved clinically received cyclophosphamide at 1 mg/kg/day for an additional month, after which it was discontinued. The dosage of prednisone was gradually tapered over a 22-week period to 20 mg on alternate days. Patients whose renal symptoms had worsened at 4 weeks were continued on the initial high-dose prednisone and cyclophosphamide for an additional 4 weeks, and patients in the PP arm of the study also received an additional 12 treatments. Thereafter, renal and extrarenal flares were treated on the basis of other standardized protocols of the intensive drug therapy as previously described [14]. Study patients The purpose of this study was to determine the long-term prognosis for patients who had a 50% reduction in proteinuria (UPro) at 6 months but had not attained a CR (see definitions below). Patients who had attained CR (n = 12, 14%), died or reached ESRD (n = 13, 15%) at 6 months were excluded from the study. The 61 patients remaining are the focus of this study and they were divided into two groups based on whether they had attained a 50% reduction in UPro by 6 months: (yes) 34 patients (40%, overall) and (no) 27 patients (31%, overall) having either a <50% reduction, no reduction or an increase in UPro at 6 months. Outcome variables The outcomes were defined as follows: (i) CR: serum creatinine of 1.4 mg/dl and proteinuria of 0.33 g/day within 5 years of entering the study; (ii) ESRD: a serum creatinine of 6 mg/dl, or the initiation of renal replacement therapy and (iii) death. Statistical analyses Comparison of the clinical, laboratory and pathologic characteristics used Fisher s exact test for categorical data and the Mann Whitney test for continuous data. For the analysis of the length of time from entry to ESRD (renal survival), product-limit life-table distributions were compared with the log-rank test statistic. Results are reported as mean ± SD, and P < 0.05 was considered significant. RESULTS Baseline clinical characteristics The clinical characteristics of the 34 patients who demonstrated a 50% reduction in UPro at 6 months are compared with the 27 patients who did not are shown in Table 1. The only significant difference in baseline demographic or clinical features between the two groups of patients was the level of proteinuria being significantly higher in patients in the 50% UPro reduction group (7.1 ± 3.6 versus 4.6 ± 3.2 g/day, P = 0.002). The UPro at 6 months decreased to 1.7 ± 1.3 g/day in the 50% UPro reduction group, while it increased to 5.2 ± 4.2 g/day (P < ) in the group of patients without a 50% UPro reduction. The average reduction in UPro at 6 months was 76 ± 12% in the group of patients with a 50% UPro reduction compared with a 27 ± 71% increase in the other group. The treatment of SLN was similar between the two groups. Histologic features The proportion of patients with WHO class IV ± V lesions was greater (19 versus 8) and the proportion of patients with WHO class III 50% ± V lesions was less (15 versus 18) in patients in the 50% UPro reduction group (Table 2), but this did not reach statistical significance (P = 0.07). The proportion of patients with membranous lesions was similar between patients with a 50% reduction in UPro at 6 months and those without [24% (n = 8) versus 33% (n = 9), P = 0.56]. While the activity index was similar between patients with or without a 50% UPro reduction at 6 months, the chronicity index and the proportion of patients with a chronicity index of 4 were significantly less in the group of patients with a 50% reduction in UPro at 6 months Downloaded from S.M. Korbet et al.

3 Table 1. Baseline clinical characteristics Table 2. Histologic Features 50% UPro reduction at 6 months n 34 (40%) 27 (31%) Age (years) 31 ± ± Female 26 (76%) 23 (85%) 0.52 Race White 17 (63%) 23 (68%) 0.78 Black/other Serum creatinine 1.8 ± ± (mg/dl) >1.5 mg/dl 17 (50%) 14 (52%) 1.0 Proteinuria (g/day) Baseline 4.6 ± ± months 1.7 ± ± 4.2 < Treatment Standard PP % UPro reduction at 6 months N WHO III>50% ± V 15 (44%) 18 (67%) 0.07 WHO IV ± V 19 (56%) 8 (30%) Unclassified 1 Activity index 13 ± 5 12 ± (56%) 16 (59%) 1.0 Chronicity index 2.9 ± ± (35%) 19 (70%) Table 3. Follow-up 50% UPro reduction at 6 months N Follow-up (months) 133 ± ± CR 19 (56%) 6 (22%) Time to CR 21 ± ± Status at last follow-up: ESRD 6 (18%) 12 (44%) ESRD/death 3 (9%) 5 (19%) 0.44 Death 3 (9%) 2 (7%) 1.0 Stable renal function 22 (65%) 8 (30%) ESRD versus death/stable P = At last follow-up (Table 3), a significantly greater proportion of patients in the 50% UPro reduction group had stable renal function (65%) compared with 30% in the group of patients who did not have a 50% UPro reduction (P = 0.009), and fewer patients in the 50% UPro reduction group progressed to ESRD (27 versus 63%, P = 0.008). The overall renal survival (Table 4 and Figure 1) and patient survival without ESRD (Table 4 and Figure 2) were significantly greater in the group of patients with a 50% UPro reduction at 6 months compared with patients in the group not attaining a 50% UPro reduction. The 15-year renal survival (Table 4) was 71% in the 50% UPro reduction group compared with 25% in the group of patients who had not attained a 50% UPro reduction at 6 months. The 15-year patient survival without ESRD (Table 4) was also better at 66% in the 50% UPro reduction group compared with 18%. The renal survival and patient survival without ESRD for the patients in the 50% UPro reduction group were similar to that of the original 12 of 86 patients who had attained a CR by 6 months (data not shown). In the 12 patients with a CR by 6 months, the 15-year renal survival was 82% and the 15-year patient survival without ESRD was 82%. ORIGINAL ARTICLE Follow-up The length of follow-up was similar between the two groups (Table 3). A CR was attained in 56% of patients in the 50% UPro reduction group compared with 22% (P = 0.009) in those patients in the group without a 50% UPro reduction. The time to a CR was similar between the two groups at 21 ± 15 and 23 ± 13 months (P = 0.43). The group of patients who attained a 50% UPro reduction at 6 months was over four times as likely (odds ratio, 4.4; 95% confidence interval, ) to attain a CR compared with those patients who did not. DISCUSSION We find that in patients with SLN, a 50% reduction in UPro at 6 months is predictive of a favorable long-term prognosis. Patients with a 50% reduction in UPro at 6 months are four times as likely to go on to enter a CR and have an excellent long-term prognosis compared with patients who did not have a 50% reduction in UPro by 6 months. Thus, a 50% reduction in UPro at 6 months is predictive of response to treatment in patients with SLN Downloaded from Severe lupus nephritis

4 ORIGINAL ARTICLE Table 4. Renal survival and patient survival without ESRD 50% UPro reduction at 6 months N Renal survival year 100% (34) 93% (26) years 85% (27) 59% (16) years 74% (21) 50% (13) years 71% (11) 25% (1) Patient survival without ESRD 1 year 97% (34) 93% (26) years 79% (27) 55% (16) years 70% (21) 47% (13) years 66% (11) 18% (1) Numbers in parentheses () represents the number of patients at risk at each time point. FIGURE 1. Renal survival (censuring for death) in patients with SLN based on 50% UPro reduction at 6-month status. P = In SLN, the long-term prognosis is significantly improved in those patients who attain a CR with treatment [1 8]. Patients with a CR have a significantly reduced rate of loss in renal function [22] and a renal survival at 10 years of >90% compared with 30 50% for non-responsive patients [2, 5]. CR rates can vary considerably among studies of patients with proliferative or SLN ranging from 10 to 85% [4, 6, 7, 9, 10, 12, 23 25]. This marked variability is likely the result of differences in the definition of a CR, therapeutic protocols, patient mix, and most importantly, the length of follow-up. While the level of proteinuria to be achieved in order to define a CR has varied substantially [4, 26, 27], recent studies have required normalization of proteinuria to < g/day [5, 9, 10, 13, 24, 25]. Recently it has been recommended by The American College of Rheumatology [28] and in a European consensus FIGURE 2. Patient survival without ESRD in patients with SLN based on 50% UPro reduction at 6-month status. P = statement [29] that the criterion for a complete response or remission in proteinuria be defined by a urine protein/creatinine ratio of <0.2 g/g. The requirement for normalization in proteinuria results in fewer patients attaining the endpoint in studies assessing treatment response at 6 months or in those studies with limited follow-up. The timing from initiating treatment to attaining a CR has commonly been more than 6 months and ranges from 10 to 16 months on average [4, 6, 7, 11, 12]. In a study of 85 patients with proliferative lupus nephritis with long-term follow-up, Ioannidis et al. [12] found the median time to remission, defined by proteinuria of <1 g/day, to be 10 months. The proportion of patients entering a remission in that study was 33% at 6 months, 58% at 12 months and 78% at 24 months. Using a more strict criteria for defining a CR of proteinuria of <0.3 g/ day, Chan et al. [6] observed a CR in 82% of patients with diffuse proliferative lupus nephritis by 15 ± 13 months. The remission was reached within 12 months in 61% of patients with 39% of patients attaining a remission after 12 months from initiating treatment. This is similar to our experience with SLN [4] where a CR, defined by proteinuria of <0.3 g/day, is attained by 16 ± 14 months on average and the time to CR was 12 months in 49% of patients. In the current study, we find that by 6 months only 14% of patients had attained a remission. It is, therefore, understandable why studies on lupus nephritis with only 6 months of follow-up, such as those by Ginzler et al. [10] and Appel et al. [9], would report CR rates of only 14 and 8.5%, respectively. In these short-term studies, while the rate of CR is low, the proportion of patients with a 50% reduction in proteinuria at 6 months has been shown to be quite high at 50 and 55%, respectively [9, 10]. Unfortunately, little is known regarding the long-term prognosis of patients with this apparent early response to treatment with a 50% reduction in proteinuria at 6 months. Houssiau et al. [30], reporting the long-term follow-up in 90 patients with proliferative lupus nephritis, found that an early response to treatment was the best predictor of a favorable long-term outcome. They found that 88% of patients who had a 50% reduction in proteinuria at 6 months had a good outcome, defined by normal renal function, after long-term follow-up of 6 years. Furthermore, significantly more patients with a good outcome had a 50% reduction in proteinuria by 2316 Downloaded from S.M. Korbet et al.

5 6 months compared with patients with a poor outcome, defined by a combination of impaired renal function, doubling of serum creatinine or ESRD (75% versus 40%, P = 0.01). The positive predictive value for a good long-term renal outcome was as high as 90% in patients who have a reduction in proteinuria of 50 75% by 6 months. After 10 years of follow-up, Houssiau et al.[31] continued to find that an early response to treatment was predictive of a good renal outcome. Our observations in patients treated with SLN are consistent with that of Houssiau et al.[30 32]. As a result of this experience, it has recently been recommended that patients with proliferative lupus nephritis who do not have a 50% reduction in proteinuria by 6 months of treatment may perhaps require more intensive therapy or be switched to another form of treatment [31 33]. Further studies should be designed to determine whether a change in therapy at 6 months is truly warranted. In conclusion, we find that in patients with SLN, an early response to treatment with a 50% reduction of proteinuria by 6 months is useful in predicting a long-term renal outcome. Failure to have an early response has prognostic and possible therapeutic implications. CONFLICT OF INTEREST STATEMENT The results presented in this paper have not been published previously in whole or part, except in abstract format. APPENDIX The Lupus Nephritis Collaborative Study Group included the following: Rush-Presbyterian-St Luke s Medical Center, Chicago E.J. Lewis, J.L. Roberts (deceased), M.M. Schwartz, R.A. Rodby and H.L. Corwin; George Washington University, Washington, D.C. J.M. Lachin, S-P. Lan, P. Cleary; William Beaumont Hospital, Royal Oak Mich. J. Bernstein (deceased), H. Shapiro and B.F. Rosenberg; Cleveland Clinic, Cleveland M.A. Pohl, J. Clough, and G. Gephardt; University of Colorado, Denver T. Berl; Henry Ford Hospital, Detroit N. Levin; University of Iowa, Iowa City - L.G. Hunsicker, S. Bonsib; Evanston Hospital, Evanston, Ill. N. Simon and H. Friederici; Northwestern University, Chicago F. del Greco and F.A. Carone (deceased); Ohio State University, Columbus L. Hebert and H.M. Sharma; University of Pennsylvania, Philadelphia E. Nielson and J. Tomazewski; Tufts New England Medical Center, Boston A. Levey and A. Ucci; Medical College of Wisconsin, Milwaukee J. Lemann (deceased), S.S. Blumenthal and J. Garancis; New York Medical College, Valhalla K. Shapiro and P. Chander; West Virginia University, Morgantown F. Whittier, J.W. Graves, J. Bathon and R. Riley. Pathology Committee: M.M. Schwartz (Chairman) Rush- Presbyterian-St. Luke s Medical Center, Chicago, IL; J. Bernstein (deceased), William Beaumont Hospital, Royal Oak, MI; G.H. Hill (deceased), Francis Scott Key Medical Institution, a Johns Hopkins Medical Institution, Baltimore, MD; K. Holley, Mayo Clinic, Rochester, MI. REFERENCES 1. Appel GB, Cohen DJ, Pirani CL et al. 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