High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis

Background:The EULAR/ERA-EDTA recommendations for lupus nephritis (LN) state that renal response should be achieved within 12 months following induction therapy. However, there is an unmet need for early predictors of renal outcome in order to adjust the immunosuppression regimen and optimize the renal outcome.Objectives:To identify predictors of poor renal outcome at baseline, 3 months and 6 months after starting induction therapy.Methods:Retrospective cohort study over 36 months including patients with Systemic lupus erythematosus (SLE) fulfilling the ACR’97 and/or the SLICC’12 classification criteria and with biopsy-proven proliferative LN (class III/IV), enrolled in the CHUC Lupus Cohort from 1999 to 2018. Poor renal outcome was defined as longer time to complete renal response (CRR), characterized by proteinuria <0.5g/day and normal renal function, according to EULAR/ERA-EDTA criteria. Clinical-analytical characteristics at baseline, 3 months and 6 months after starting induction treatment were compared using survival analysis for time-to-CRR. Variables with p<0.25 on univariate analysis using Log-Rank tests were further evaluated as predictors applying multivariate Cox proportional hazards regression models (Backward Stepwise method, Wald-based) with estimation of hazard ratios (HR) and 95% confidence intervals (95%CI).Results:56 patients were included (76.8% female, age at LN diagnosis 30.0 ± 13.2 years). Over the follow-up, 51 patients (91.1%) achieved CRR, within a median time of 6.0 months. In multivariate analysis, predictors of poor renal outcome were proteinuria >2g/day at baseline (HR 1.98; 95%CI 1.04-3.77; p=0.037) and induction therapy with pulse cyclophosphamide (CYC), as compared to mycophenolate mofetil (MMF) (HR=2.05; 95%CI 1.07-3.94; p=0.030) (Figure 1). Diabetes mellitus (HR=6.0; 95%CI 1.24-29.07; p=0.026) and negative anti-RNP antibody (HR 3.17; 95%CI 1.27-7.93; p=0.013) at baseline predicted poor renal outcome at 3 months. At this timepoint, level of proteinuria and clearance rate were not predictive of renal response. At 6 months, no predictors of LN outcome were found for those patients that did not achieve CRR up to this timepoint. Use of glucocorticoid pulses and/or antihypertensive drugs did not predict LN outcome.Figure 1.Conclusion:In this SLE cohort, most patients with proliferative LN achieved CRR. Proteinuria above 2 g/day at baseline and diabetes mellitus were predictors of poor renal outcome, while positive anti-RNP was protective. Induction treatment with CYC was associated with poorer outcome as compared with MMF. Given the retrospective non-randomized nature of this study, caution is needed when drawing conclusions regarding both treatments efficacy.Disclosure of Interests:Mariana Luis: None declared, Ana Rita Prata: None declared, Helena Assunção: None declared, José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Luís Inês: None declared

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Lupus Nephritis: Induction Therapy

Lupus ◽

10.1191/0961203305lu2114oa ◽

2005 ◽

Vol 14 (3_suppl) ◽

pp. 27-32 ◽

Cited By ~ 3

Author(s):

TM Chan

Keyword(s):

Mycophenolate Mofetil ◽

Lupus Nephritis ◽

Adverse Effects ◽

Induction Therapy ◽

Chinese Patients ◽

Renal Outcome ◽

Induction Treatment ◽

Renal Survival ◽

Proliferative Lupus Nephritis

Effective induction therapy is of pivotal importance in minimizing renal parenchymal damage by the active immune-mediated inflammatory processes in severe proliferative lupus nephritis. Preservation of nephron mass is prerequisite to long-term renal survival. Data from US-based studies have shown improved efficacy with induction treatment comprising corticosteroid and cyclophosphamide, compared with corticosteroid treatment alone. Data from European studies have shown similar efficacy with a modified treatment regimen, in which smaller doses of cyclophosphamide were given at weekly or fortnightly intervals over a shortened treatment duration, and the treatment related adverse effects appeared less frequent with the reduced-dose regimen. We have also reported that sequential immunosuppression with prednisolone and oral cyclophosphamide as induction followed by azathioprine maintenance was associated with a high incidence of remission and relatively favourable long-term renal outcome in Chinese patients. However, cyclophosphamide treatment is associated with considerable adverse effects, which could be potentially fatal. Mycophenolate mofetil selectively inhibits lymphocyte proliferation, and thus targets an instrumental step in the pathogenesis of systemic lupus erythematosus. There is accumulating evidence that the combined use of mycophenolate mofetil and corticosteroid presents an effective treatment for severe proliferative lupus nephritis in different ethnic groups, and is associated with much fewer adverse effects compared with cyclophosphamide-based regimens. Recent data from our group also demonstrate the long-term efficacy of mycophenolate mofetil in preserving renal survival, when used continuously as both induction and maintenance therapy.

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SAT0211 RENAL INJURY IN SYSTEMIC LUPUS ERYTHEMATOSUS CHARACTERIZED BY THROMBOTIC MICROANGIOPATHY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1198 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1048.1-1048

Author(s):

W. Hu

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Renal Biopsy ◽

Lupus Erythematosus ◽

Thrombotic Microangiopathy ◽

Renal Injury ◽

Renal Outcome ◽

Pathological Examination ◽

Systemic Lupus ◽

Tubulointerstitial Lesions

Background:Classical lupus nephritis (LN) is characterized by glomerular immune complex(IC) deposition with glomerular proliferation, basement membrane destruction and cell infiltration. Non-IC mediated renal injury with thrombotic microangiopathy (TMA) was also reported in patients with systemic lupus erythematosus (SLE-renal TMA), but most studies were reported in patients with both LN and renal TMA.Objectives:In this study, clinical features and outcomes of SLE-renal TMA in absence of obvious IC in SLE patients were analyzed.Methods:Patients with glomerular TMA and/or vascular TMA in the absence of obvious subendothelial or epithelial immune deposits were screened out from 2332 biopsied in SLE patients who underwent first renal biopsy from January 2005 to August 2016. Their clinical, histological features and outcomes were retrospectively analyzed.Results:In 2332 renal biopsies obtained from SLE patients, 257 (11.0%) showed renal TMA, of which 237 showed both renal TMA and LN, and 20 biopsies had only renal TMA (SLE-renal TMA). There were 2 males and 18 females with an average age of (25 ± 10) years. The median course of SLE and LN were 3.0(1.0, 6.0) and 0.8(0.5, 1.9) months. All 20 patients deserved acute kidney injury, of which 11 (55%) needed renal replacement therapy (RRT) and 12 (60%) were nephrotic syndrome. Blood system involvement was found in all cases, including 13 cases (65.0%) with TMA triad (microvascular hemolytic anemia, thrombocytopenia and elevated lactate dehydrogenase).Pathological examination showed that 17 cases (85.0%) had both glomerular TMA and vascular TMA. Immunofluorescence and electron microscopy showed that 8 cases (40%) had no IC deposition in glomerulus and 12 cases (60%) had only IC deposition in mesangium. Acute tubulointerstitial lesions in patients requiring RRT were more serious than those no needing for RRT((43.6±24.9) %vs(21.7±20.1) %,P=0.047). The fusion range of foot process was positively correlated with proteinuria (r2= 0.347,P=0.006).All patients received high-dose methylprednisolone pulse therapy. Four patients received plasma exchange and three patients received gamma globulin, respectively. Eleven patients requiring RRT all stop RRT in a median time of 16.0 (9.0, 30.0) days. During a median follow-up of 58.0 (36.0, 92.3) months, complete remission (CR) was obtained in 15 cases, partial remission in 4 cases and no remission in 1 case. Six cases (30%) relapsed. No case died or progressed to end stage renal disease.Conclusion:Renal injury characterized by TMA is not uncommon in SLE renal biopsy cases. The clinical manifestation is special and the renal injury is serious. The renal outcome is good by intensive immunosuppressive therapy. It should be considered as a unique type of renal injury in SLE.References:[1]Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002. 347(8): 589-600.[2]Anders HJ, Weening JJ. Kidney disease in lupus is not always ‘lupus nephritis’. Arthritis Res Ther. 2013. 15(2): 108.[3]Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther. 2013. 15(1): R12.[4]Hu WX, Liu ZZ, Chen HP, Zhang HT, Li LS, Liu ZH. Clinical characteristics and prognosis of diffuse proliferative lupus nephritis with thrombotic microangiopathy. Lupus. 2010. 19(14): 1591-8.[5]Tomov S, Lazarchick J, Self SE, Bruner ET, Budisavljevic MN. Kidney-limited thrombotic microangiopathy in patients with SLE treated with romiplostim. Lupus. 2013. 22(5): 504-9.[6]Li C, Yap D, Chan G, et al. Clinical Outcomes and Clinico-pathological Correlations in Lupus Nephritis with Kidney Biopsy Showing Thrombotic Microangiopathy. J Rheumatol. 2019 .[7]Chen MH, Chen MH, Chen WS, et al. Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan. Rheumatology (Oxford). 2011. 50(4): 768-75.[8]Park MH, AUID- Oho, Caselman N, Ulmer S, Weitz IC, AUID- Oho. Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Adv. 2018. 2(16): 2090-2094.Disclosure of Interests:None declared

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Association of coexisting anti-ribosomal P and anti-dsDNA antibodies with histology and renal prognosis in lupus nephritis patients

Lupus ◽

10.1177/0961203320983906 ◽

2021 ◽

pp. 096120332098390

Author(s):

Ayako Wakamatsu ◽

Hiroe Sato ◽

Yoshikatsu Kaneko ◽

Takamasa Cho ◽

Yumi Ito ◽

...

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Renal Outcome ◽

Class V ◽

Double Stranded Dna ◽

Number Of Patients ◽

Renal Histology ◽

Renal Prognosis ◽

Incidence Of Ckd ◽

Ribosomal P

Objectives Anti-ribosomal P protein autoantibodies (anti-P) specifically develop in patients with systemic lupus erythematosus. Associations of anti-P with lupus nephritis (LN) histological subclass and renal outcome remain inconclusive. We sought to determine the association of anti-P and anti-double-stranded DNA antibody (anti-dsDNA) with renal histology and prognosis in LN patients. Methods Thirty-four patients with LN, having undergone kidney biopsy, were included. The 2018 revised ISN/RPS classification system was used for pathophysiological evaluation. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for > 3 months. Results Six patients (17.6%) were positive for anti-P and 26 (76.5%) for anti-dsDNA. Among the six patients with anti-P, one did not have anti-dsDNA, but did have anti-Sm antibody, and showed a histological subtype of class V. This patient maintained good renal function for over 14 years. The remaining five patients, who had both anti-P and anti-dsDNA, exhibited proliferative nephritis and were associated with prolonged hypocomplementemia, and the incidence of CKD did not differ from patients without anti-P. Conclusion Although this study included a small number of patients, the results indicated that histology class and renal prognosis associated with anti-P depend on the coexistence of anti-dsDNA. Further studies with a large number of patients are required to confirm this conclusion.

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OP0165 LONG-TERM OUTCOME OF A RANDOMIZED CONTROLLED TRIAL COMPARING TACROLIMUS WITH MYCOPHENOLATE MOFETIL AS INDUCTION THERAPY OF SEVERE LUPUS NEPHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2568 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 104.1-104

Author(s):

C. C. Mok ◽

L. Y. Ho ◽

C. H. To ◽

K. Y. S. Ying

Keyword(s):

Lupus Nephritis ◽

Induction Therapy ◽

Roc Analysis ◽

Controlled Trial ◽

Renal Flare ◽

Stage 4 ◽

Ckd Stage ◽

Renal Prognosis ◽

The Mean

Background:Objectives:To report the 10-year outcome of a cohort of patients with lupus nephritis (LN) treated with combined glucocorticoids with either mycophenolate mofetil (MMF) or tacrolimus (TAC) as induction in a randomized controlled trial (RCT).Methods:150 patients with active lupus nephritis were randomized to receive either MMF (2-3g/day) (N=76) or TAC (0.1-0.06mg/kg/day) (N=74) in combination with high-dose prednisolone (0.6mg/kg/day for 6-8 weeks and tapered) as induction therapy between 2005 and 2012. Complete renal (CR) or good partial renal responders were switched to azathioprine (AZA) (2mg/kg/day) for maintenance. We hereby report the 10-year outcomes of the patients in terms of renal flares (proteinuric/nephritic), renal function decline (drop in eGFR by ≥30% from baseline), development of chronic kidney disease (CKD) stage 4/5 (eGFR<30ml/min) and mortality. Factors affecting renal prognosis were studied by Cox regression analysis. Renal parameters (urine P/Cr ratio [uPCr], eGFR) at different time points from 6 to 24 months were studied for their predictive value of a poor renal prognosis by ROC analysis.Results:150 patients (92% women) with active LN were studied (ISN/RPS class III±V 36%; IVG/S±V 46%; pure V 19%). The mean age was 35.5±12.8 years and SLE duration was 50.2±62 months. The mean histological activity and chronicity score was 8.2±3.4 and 2.6±1.6, respectively. At baseline, 59(39%) patients were hypertensive, 62(41%) had active urinary casts, 112(75%) had microscopic hematuria and 67% patients had eGFR<90ml/min. As reported previously, the rate of complete renal response (CR) was 59% in the MMF and 62% in the TAC group (p=0.71). Maintenance therapy with AZA was given to 79% patients. After a follow-up of 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of patients treated initially with MMF and 53% and 30% in those treated with TAC, respectively. There was a total of 77 renal flares in 43 (57%) patients treated with MMF (0.11/patient-year) and 92 renal flares in 46 (62%) of patients treated with TAC (0.12/patient-year; p=0.44). The cumulative risk of having a renal flare of patients treated with MMF/AZA was 28% at 3 years, 42% at 5 years and 58% at 10 years, whereas the corresponding figures for patients treated with TAC/AZA was 32% at 3 years, 53% in 5 years and 66% in 10 years (p=0.43). For those who achieved CR after induction therapy, the mean time to first renal flare was 70.4±47.1 months in the MMF group and 65.2 ±50 months in the TAC group (p=0.61). The cumulative incidence of a composite outcome of decline of eGFR by ≥30%, development of CKD stage 4/5 or death at 5 and 10 years was 24% and 33%, respectively, in patients treated with MMF, and 17% and 33%, respectively, in those treated with TAC (p=0.90). Factors significantly associated with this outcome were first time lupus nephritis (HR 0.26[0.11-0.59]; p=0.001), uPCR at 6 months (HR 1.33[1.02-1.76]; p=0.04) and eGFR at 6 months (HR 0.98[0.97-0.997]; p=0.02). Exploratory ROC analysis demonstrated that an eGFR cut-off of 80ml/min (AUC 0.70; sensitivity 0.64, specificity 0.66) and uPCR cut-off of 0.75 (AUC 0.73; sensitivity 0.69, specificity 0.74) at month 18 best predicted CKD stage 4/5 or decline of eGFR by ≥30%.Conclusion:Long-term data of our RCT showed that TAC remained non-inferior to MMF as induction therapy of LN in terms of renal flares, renal function decline and mortality. Relapsed renal disease, lower eGFR and more proteinuria post-induction therapy were associated with a poorer outcome. An uPCR ≤0.75 and eGFR of >80ml/min at 18 months best predicted a better outcome at 10 years, and should be considered as a target for induction/consolidation therapy.Acknowledgments:NILDisclosure of Interests:None declared

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Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-206897 ◽

2015 ◽

Vol 75 (3) ◽

pp. 526-531 ◽

Cited By ~ 68

Author(s):

Farah Tamirou ◽

David D'Cruz ◽

Shirish Sangle ◽

Philippe Remy ◽

Carlos Vasconcelos ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Lupus Nephritis ◽

Positive Predictive Value ◽

Maintenance Therapy ◽

Early Response ◽

Renal Outcome ◽

Proliferative Lupus Nephritis ◽

Long Term Follow Up

ObjectiveTo report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.MethodsIn 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up.ResultsDeath (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker.ConclusionsThe long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome.Trial registration numberNCT00204022.

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