Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes

Mackay, Meggan; Dall’Era, Maria; Fishbein, Joanna; Kalunian, Kenneth C.; Lesser, Martin; Sánchez‐Guerrero, Jorge; Levy, Deborah M.; Silverman, Earl D.; Petri, Michelle; Arriens, Cristina; Lewis, Edmund J.; Korbet, Stephen M.; Conti, Fabrizio; Tesař, Vladimı́r; Hrušková, Zdenka; Borba, Eduardo F.; Bonfá, Eloísa; Chan, Tak Mao; Rathi, Manish; Gupta, Krishan Lal; Jha, Vivekanand; Hasni, Sarfaraz; West, Melissa; Solomons, Neil; Houssiau, Frédéric; Romero-Díaz, Juanita; Mejía-Vilet, Juan M.; Rovin, Brad H.

doi:10.1002/art.40724

Cited by 55 publications

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“…In terms of monitoring of LN, a number of posthoc analyses of major studies in LN suggested the value of an early proteinuria response, together with a normal serum creatinine, within 12 months, to predict a favourable long-term outcome of patients. 60 82– 85 By contrast, glomerular haematuria was consistently shown in the same studies to add no predictive value in these prognostic models. Although these findings may not necessarily impact routine clinical practice, where urine microscopy will continue to be part of patient monitoring, however, they may well carry implications regarding future design of optimal endpoints for clinical trials.…”

Section: Discussionmentioning

confidence: 93%

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

et al. 2020

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ObjectivesTo analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations.MethodsAccording to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012.ResultsWe identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500–700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b).ConclusionsThere is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.

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Section: Discussionmentioning

confidence: 93%

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

et al. 2020

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“…In monitoring renal response, reduction of UPr (to less than 0.8 g/day) following treatment is more important than residual haematuria 21. Patients with more severe proteinuria and longer-standing disease are less likely to respond or show more delayed responses 22 23…”

Section: Resultsmentioning

confidence: 99%

2019 update of the EULAR recommendations for the management of systemic lupus erythematosus

et al. 2019

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Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007–12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.

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“…Post hoc analyses from the MAINTAIN and Euro-Lupus Nephritis Trials suggest that proteinuria at 12 months represents the best single predictor for long-term renal outcome (ie, risk for end-stage kidney disease (ESKD) or doubling of serum creatine after 10 years). [23][24][25][26][27] Accordingly, therapy should aim for proteinuria <0.5-0.7 g/24 hours by 12 months (complete clinical response), although up to 50% of patients not reaching this milestone may still have stable longterm kidney function. 25 28 Evidence of improvement in proteinuria (with GFR normalisation/stabilisation) should be noted by 3 months, 29 30 and at least 50% reduction in proteinuria (partial clinical response) by 6 months.…”

Section: Treatment Of Adult Ln Goals Of Treatmentmentioning

confidence: 99%

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis

et al. 2020

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ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.ResultsThe changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

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Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes

Abstract: HITs, derived from short-term kidney responses to treatment correlate with long-term kidney outcomes, and now must be validated as surrogate endpoints for LN clinical trials. This article is protected by copyright. All rights reserved.

Cited by 55 publications

References 27 publications

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

2019 update of the EULAR recommendations for the management of systemic lupus erythematosus

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis

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