Precision Medicine in Lups Nephritis: A Multicenter Proof-of-concept Study for Histopathological Biomarkers Analysis in Renal Biopsy
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- complete renal response
研究概览
简要总结
Lupus nephritis (LN) may affect approximately half of patients with Systemic Lupus Erythematosus (SLE). LN is a major cause of morbidity and the most important predictor of mortality in patients with SLE. Some 5-20% of patients with LN may develop end-stage renal disease within 10 years of follow-up from the time of diagnosis. Other studies have described progression to end-stage renal disease in 10-30% of patients with LN.
The European League Against Rheumatism, the European Renal Association and the European Dialysis and Transplant Association have recently updated their recommendations for the management of LN. These recommend the use of intravenous (IV) methylprednisolone boluses followed by lower doses of oral glucocorticoids (GC) and place mycophenolate mofetil (MMF) and the European regimen of cyclophosphamide (CYC) as the immunosuppressive drugs of first choice, with the IV CYC regimen for certain more aggressive cases. They also consider the use of "multitarget therapy" based on the combination of tacrolimus (TAC) and MMF and GC in patients with proteinuria in the nephrotic range who have not responded to the first line of treatment. For refractory active renal disease, they recommend as an alternative the use of rituximab (RTX) 1000 mg IV repeated after 15 days.
Belimumab has been shown to be significantly more effective than placebo in the treatment of patients with active LN. This finding will lead to positioning belimumab in the therapeutic algorithm for LN.
However, in clinical practice these immunosuppressive drugs are not always effective in the treatment of LN, and even one in 3 patients with an initial favorable response may experience renal recurrence.
The choice of the appropriate treatment for LN and its early initiation are key to improve the prognosis of these patients and to avoid progression to chronic renal failure.
The identification of biomarkers capable of predicting the response (or lack thereof) to one or another therapy at the time of LN diagnosis would allow to implement precision medicine, thus constituting a revolution in the treatment of patients with LN. Allows more targeted treatments with greater specificity to be established.
The objective of this project is to analyze histopathological biomarkers in the renal biopsy to predict the renal response to the different drugs used in the treatment of LN. This would contribute to a more specific and cost-effective therapeutic strategy.
详细描述
Sample size For this proof-of-concept study, our objective is to analyze around 60 renal biopsy samples (expandable according to the results obtained).
Methods:
The following general variables will be collected:
- demographic data: age, sex, ethnicity.
- clinical data on SLE:
- diagnosis and chronological data: time of SLE diagnosis, time of LN diagnosis, time form SLE diagnosis to LN.
- 1997 ACR SLE classification criteria,
- activity: involvement of different organs and systems by SELENA-SLEDAI at the time of LN diagnosis and at the time of the last evaluation of the patient (or death, if applicable).
- damage: by item and by domain according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at the time of LN diagnosis and at the time of the last evaluation of the patient (or death, if applicable).
- comorbidity: arterial hypertension, diabetes, dyslipemia, smoking habit, severe infections, neoplasms, etc. at the time of LN diagnosis and at the time of the last evaluation of the patient (or death, if applicable).
- laboratory data at the time of LN diagnosis and at the time of the last evaluation of the patient (or death, if applicable):
- blood (general tests): acute phase reactants (erythrocyte sedimentation rate and C-reactive protein), full blood count, creatinin, glomerular filtration rate, blood urea nitrogen, liver function tests, lipid profile.
- blood (serological tests): complement (C3 and C4), levels of anti-dsDNA antibodies, antiphospholipid antibodies: anticardiolipin (Ig M and Ig G), anti-beta2GP-1 (Ig M and Ig G), lupus anticoagulant.
- urine: hematuria, piuria, proteinuria, casts.
- histopathological markers of renal biopsy:
- histological class according to the 2003 ISN/RPS classification.
- National Institutes of Health (NIH) activity index: score (maximum 24) and by item (endocapillary hypercellularity, neutrophils/karyiorrhexis, hyaline deposits/wire loops, fibrinoid necrosis, cellular o fibrocellular crescents, interstitial inflammation).
- National Institutes of Health (NIH) chronicity index: score (maximum 12) and by item (global glomerulosclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis).
- markers related to B lymphocytes which may include but is not limited to: CD19, CD20 and CD138.
- markers related to BLyS (B lymphocyte stimulator) and its functional consequences which may include but is not limited to expression of BLyS and its receptors: BAFF-R, BCMA and TACI.
- markers related to other cell lineages which may include but is not limited to: CD3 for T cells and CD68 for macrophages.
- markers whose determination in urine has proved useful in the diagnosis and follow-up of LN which may include but is not limited to the proinflammatory cytokine Monocyte Chemoattractant Protein-1 (MCP-1) and the Neutrophil Gelatinase Associated Lipocalin (NGAL).
- SLE therapeutical data (including duration of the treatment):
- treatments for SLE prior to the diagnosis of LN: antimalarials, glucocorticoids (maximum dose), immunosuppressants: azathioprine (AZA), mophetil mycophenolate (MMF), cyclophosphamide (CYC); biological therapies: belimumab, rituximab.
- treatment of LN: glucocorticoids (maximum dose), immunosuppressants: AZA, MMF, CYC; biological therapies: belimumab, rituximab.
- therapeutical data of comorbidities (including duration of the treatment): antihypertensive agents, oral antidiabetics, insulin, hypolipidemic drugs.
- Evolution/prognosis of SLE: accumulated damage by using SDI (by item and by domain), comorbidities accrual, severe infections, organ failure, death.
Variables will be collected to establish different patterns of response to treatment and evolution of LN:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with a diagnosis of SLE according to the 1997 American College of Rheumatology (ACR) criteria.
- •Diagnosis of lupus nephritis type 3,4,5 or mixed forms of the above according to the International Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification of LN.
- •Date of performance of the renal biopsy: year 2000 or later. The reason for this time frame is the theoretical homogenization in the therapeutic management of LN with the introduction of MMF into the therapeutic armamentarium of LN and the extension of the use of the European intravenous cyclophosphamide guideline.
- •Availability of the patient's first renal biopsy specimen preserved for re-evaluation.
- •Availability of essential clinical data to carry out the study.
- •Signature of the informed consent by the patient.
排除标准
- •Refusal by the patient to sign the informed consent.
结局指标
主要结局
complete renal response
时间窗: 5 years after renal biopsy
proteinuria \<0.5 g/24 hours and (near) normal estimated GFR
次要结局
- partial renal response(5 years after renal biopsy)
- proteinuria levels at 12 months of treatment,(12 months after renal biopsy)