Per-protocol Repeat Kidney Biopsy in Incident Cases of Lupus Nephritis
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 206
- 试验地点
- 2
- 主要终点
- Complete Renal Response (CRR) at month 24 from baseline
研究概览
简要总结
Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE). Among people living with SLE, 35-60% will develop LN during the course of the disease. This complication is one of the factors that contribute to deterioration of the renal function.
Some centres perform kidney biopsies after completion of treatment for an episode of LN as a part of the treatment evaluation. The term "repeat biopsy" is often used to describe these biopsies. Several studies have reported that repeat kidney biopsies show activity at the level of tissue, even in patients with normal routine blood and urine markers. The investigators strongly believe that this information is important, and should be taken into consideration during decision of treatment. To provide evidence for this, the investigators have designed a collaborative project within the frame of the Lupus Nephritis Trials Network. With this research project, the investigators want to contribute to an increased proportion of patients with LN who achieve remission (inactivity) of LN, and a reduced proportion of patients who worsen in renal function in the long term.
Patients with SLE who develop a first episode of LN will be asked to participate in this project, and will receive treatment according to current guidelines. Half of the patients will undergo a repeat biopsy 12 months later, and half of the patients will not. The selection of patients who will undergo or not undergo repeat biopsy will be random. Patients with high disease activity at the level of kidney tissue will receive more intense immunosuppressive treatment. Patients who have not undergone repeat biopsy will continue to be treated according to standard routine.
The investigators will compare the results of treatment between the group of patients who underwent and the group of patients who did not undergo repeat biopsy, with regard to (i) complete disease inactivity at month 24 and (ii) renal function at month 60 from treatment initiation.
The investigators expect that significantly greater proportions of patients in the repeat biopsy group will have inactive disease at month 24 and adequate levels of renal function at month 60. This will provide support for performing repeat biopsies as a part of the treatment evaluation, in order to optimise the therapeutic management and improve the long-term prognosis of patients with LN.
详细描述
Study rationale
Lupus nephritis (LN) affects 35-60% of patients with systemic lupus erythematosus (SLE), and constitutes one of the most severe disease manifestations. Several factors contribute to renal function impairment in LN, including genetic cargo, nephron endowment, disease activity, drug-induced toxicity and renal flares. Five to 20% of the afflicted patients develop end-stage kidney disease (ESKD) within ten years from the first LN episode. Available therapies induce complete renal remission in only 20-30% of patients after six months of treatment, and even patients who respond to therapy may relapse in 35% of the cases.
To date, clinical and laboratory tests cannot reliably reflect histopathological findings, and kidney biopsy is indispensable for diagnosis, classification, and exclusion of mimickers. The role of control biopsies after induction therapy is debatable, despite accumulating evidence of discrepancies between clinical and histological responses. In the concrete, several elegant post-treatment biopsy studies have demonstrated persistent activity at the level of tissue despite adequate clinical response, suggesting that intensified immunosuppression may be required in these patients. However, studies investigating the role of repeat kidney biopsies in treatment evaluation and long-term renal outcome have to date included limited numbers of patients, and varying definitions regarding treatment response and renal outcome. Thus, the concept of a prospective multicentric per-protocol repeat biopsy study to generate evidence for future recommendations for the diagnostic and therapeutic management of LN gains increasing support.
Several studies have sought to identify predictors of long-term renal prognosis, including routine clinical and serological markers. Proteinuria levels < 0.7-0.8 g/day at month 12 after initiation of treatment have been validated in different cohorts as a readily available predictor of favourable long-term renal outcome. However, while the positive predictive value (PPV) of this target was high, the negative predictive value (NPV) was poor in two of three studies, since most patients not achieving the proteinuria target still had a good long-term outcome (Tamirou et al. 2015; Ugolini-Lopes et al. 2017). Associations between chronic tissue damage in repeat biopsies and long-term renal function impairment have been demonstrated in European and Hispanic LN populations (Piñeiro et al. 2016). It was recently demonstrated in a retrospective study that a high grade of residual activity in per-protocol repeat biopsies predicted subsequent renal relapse in patients with incident LN, and a high grade of chronic damage in repeat biopsies predicted long-term renal function impairment. More specifically, NIH activity index scores > 3 predicted subsequent renal flares, whereas NIH chronicity index scores > 3 were associated with renal function deterioration in the long term. It is worth noting that active lesions in glomeruli mostly accounted for the former association with relapses, whereas chronic damage in the tubulointerstitial compartment were found to be a more important contributor to the latter association with long-term renal function (Parodis et al. 2020).
Study objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Fulfilment of the EULAR/ACR classification criteria of SLE.
- •18 years of age or above.
- •Incident biopsy-proven proliferative or membranous LN, or combinations thereof (with UPCR ≥ 1 g/g), i.e. 2003 ISN/RPS class III (A or A/C) ± V, class IV (A or A/C) ± V, or class V.
- •Consent to the possibility of a repeat kidney biopsy at month 12 from baseline.
- •Initiation of the following treatment regimens:
- •intravenous pulses of methylprednisolone (total dose of 500-3000 mg);
- •oral prednisone or equivalent 0.3-0.5 mg/kg/day with tapering;
- •hydroxychloroquine unless contraindicated;
- •angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs);
- •either one of mycophenolate mofetil (MMF) equivalent dose 2-3 g/day, or IV cyclophosphamide (CYC) according to the Euro-Lupus regimen;
- •the NIH protocol for IV CYC (0.5-0.75 g/m2 monthly for six months) could be considered in severe cases;
- •add-on therapies (e.g. calcineurin inhibitors, biologics) to the above two regimens are optional.
排除标准
- •Antiphospholipid syndrome nephropathy (APSN).
- •Pregnancy at baseline (pregnancy during follow-up will not lead to exclusion).
- •Medical contraindications to kidney biopsy, e.g. thrombocytopenia < 50,000/μL, uncontrolled hypertension or end-stage kidney disease (ESKD).
- •Anticipated non-adherence to therapy.
- •Medical conditions interfering with outcome evaluations.
- •Inability to read and/or sign the informed consent form.
结局指标
主要结局
Complete Renal Response (CRR) at month 24 from baseline
时间窗: Month 24 from baseline
UPCR ≤ 0.5 g/g in two consecutive first-morning void urine specimens and no increase in serum creatinine by ≥ 25% from baseline.
次要结局
- Renal function impairment at month 60(Month 60 from baseline)
- Renal relapse (proteinuric flare)(Between month 12 and month 60 from baseline)
- Reabsorption of immune deposits in repeat kidney biopsies(Month 12 from baseline)
- End-stage kidney disease (ESKD)(Between month 12 and month 60 from baseline)
- Mortality rate(Between month 12 and month 60 from baseline)
研究者
Ioannis Parodis
Principle Investigator
Karolinska Institutet