Lupus Nephritis (LN) develops in ~ 40% of patients with systemic lupus erythematosus (SLE) [1]. Furthermore, 10–30% of patients with LN progress to end-stage renal disease (ESRD) becoming candidates for renal replacement therapy (RRT) [1, 2]. Achieving a complete clinical response (CR) is crucial to ensure long-term renal survival. Patients who achieve CR have a renal survival of 92% at 10 years, while this is 43% in those with partial response (PR) and only 13% in refractory disease [3].

Currently, the treatment of LN still shows suboptimal results. The renal survival rate has remained constant in the past two decades, suggesting the need to find new therapeutic strategies for those patients who are refractory to conventional treatment. Advances in the knowledge of the different immunopathogenic pathways involved in LN have allowed the development of multiple clinical trials in recent years, which have helped to obtain the approval of different drugs. Abatacept (ABT) is a biologic therapy approved to treat different inflammatory arthropathies [4]. ABT inhibits the activation of T lymphocytes through the blockade of the CD28-CD80/86 stimulation pathway. The utility of ABT in the field of LN has been tested in different studies without a clear benefit of its use despite the improvement observed in different parameters analyzed, such as proteinuria and immunological parameters [5]. We present two cases of refractory LN, where the addition of ABT allowed to achieve total remission of the disease.

A 49-year-old male under joint follow-up by Nephrology and Rheumatology consultation for SLE with WHO Class IV LN diagnosed by kidney biopsy in February 2005. The illness debuted with myocardial involvement, proteinuria (2.2 g/day measured by protein in urine-24 h excretion), microscopic hematuria and acute renal failure with serum creatinine (sCr) of 1.4 mg/dL. He showed serum antinuclear (ANA) positivity (1:1240), serum anti-dsDNA-, anti-Ro > 245 IU/mL and anti-RNP > 32 IU/mL. Initially, he received 3 pulses of 500 mg of 6-methylprednisolone (6-MP), 9 pulses (6 monthly pulses and 3 quarterly pulses) of intravenous (IV) cyclophosphamide (CYC) (1 g/m2), with double blockade of the renin-angiotensin system (RAS). Seven months after this treatment, he achieved a PR (proteinuria 0.68 g/day). However, during quarterly IV CYC pulses, the patient presented a relapse with nephrotic-range proteinuria (4.5 g/day), which was treated with 3 additional pulses of 6-MP followed by oral prednisone (PDN) (1 mg/kg) in tapering regimen and mycophenolate mofetil (MMF) 2 g/day, achieving a transient PR (0.7 g/g) in September 2006.

One year later (August 2007), due to a new renal flare (7.7 g/day), “off label” rituximab (RTX) was added to the background treatment (MMF 2 g/day and PDN 5 mg/day) in 4 weekly infusions at doses of 375 mg/m2. From 2007 to 2011 he received 4 more cycles of RTX (1000 mg every 14 days) achieving a transient PR (0.7 g/g) in July 2009.

Due to refractoriness to RTX, tacrolimus (TAC) was added during this time (January 2010). Six months after the start of multitarget therapy (RTX, TAC, MMF and PDN), proteinuria was stabilized at around 2–3 g/day. Nevertheless, in September 2011, proteinuria gradually increased again to nephrotic range and anti-dsDNA turned positive. Due to its persistence, it was decided to change RTX to Belimumab (BEL), as an off-label indication.

After 6 months of treatment with BEL (8 monthly infusions of 10 mg/kg) and multitarget therapy, nephrotic-range proteinuria (10 g/day) and immunological activity were still present. Due to the lack of responsiveness, it was decided to perform a new kidney biopsy. Anatomopathological findings showed persistence of LN class IV with an activity index of 10/24 and a chronicity index of 2/12, with glomerulosclerosis < 10%. Electron microscopy revealed diffuse podocyte fusion, which was related to the degree of proteinuria.

In the absence of other therapeutic alternatives, it was decided to abandon BEL and associate subcutaneous Tocilizumab (TCZ) (162 mg/week) to the multitarget therapy, as an off-label indication. The response was disappointing; the patient presented renal function deterioration for the first time (sCr 1.42 mg/dL) with persistent nephrotic-range proteinuria (12 g/day), active sediment (100–150 RBC/µL), hypoalbuminemia (2.5 g/dL) and complement consumption.

Given the refractoriness of the LN, in September 2014, off-label subcutaneous ABT (125 mg weekly) was added to his maintenance treatment (TAC, MMF, and PDN). Three months later, proteinuria decreased by half (6.5 g/day) with sediment normalization and renal function recovery (sCr 1.18 mg/day). Over the years proteinuria progressively decreased until achieving CR 6 years after ABT initiation: proteinuria 0.5 g/day, inactive sediment (10–20 RBC/µL), normal renal function and complement levels normalization and decrease of immunology activity (Fig. 1). Both TAC and MMF were gradually reduced until their complete withdrawal, while he has maintained treatment with low-dose oral prednisone (5 mg). The patient has remained clinically asymptomatic until this moment under ABT treatment with no infectious complications or hospital admissions derived from the disease and/or treatment.

Proteinuria evolution measured by 24 h-urine excretion (g/day)

A 52-year-old female with SLE diagnosed at the age of 26 (1996). She debuted with polyarthritis, oral aphthae, alopecia, malar erythema, and Raynaud’s phenomenon. At the beginning of her illness, she also presented nephrotic-range proteinuria, so a kidney biopsy was performed, which showed WHO class IV LN. The patient was treated at another center with IV CYC and 6-MP pulses followed by oral PDN. Azathioprine and chloroquine were not tolerated. So, MMF (1 g/day) was added to oral PDN and maintained from 2007 to 2010. One year later (2011), nephrotic-range proteinuria was detected, so off-label RTX was started. However, the treatment was withdrawn when she presented a serum sickness syndrome after the second RTX dose.

In 2012, she started follow-up in our hospital in the interdisciplinary consultation for Rheumatology and Nephrology. At that time, she was still receiving treatment with PDN 10 mg/day, and she had abandoned MMF for no clear reason. Laboratory findings showed normal renal function (sCr 0.75 mg/dL), proteinuria (1.5 g/g), consumption of complement (C3: 60 mg/dL and C4: 8 mg/dL) and positive anti-dsDNA (14 IU/mL). In 2016, due to a renal flare (proteinuria 4 g/day), MMF (2 g/day) was reintroduced, achieving PR (2 g/day).

In April 2018, after performing an update biopsy that confirmed WHO LN class IV (activity index 16/24, chronicity index 6/12), the patient was included in the phase III study, AURORA (AURinia Orelvo Renal Assessment, “A randomized, controlled, double-blind clinical trial comparing the efficacy and safety of Orelvo (Voclosporin 24.6 mg/12 h) versus placebo”. Throughout the trial, MMF, PDN (minimum dose 2.5 mg), and RAS blockers were continued.

In January 2020, the patient was withdrawn from the trial due to nephrotic syndrome (hypertension, edema, and proteinuria (UPCRs 3.9 g/g). It was decided to resume IV CYC in the Eurolupus-2 regimen (600 mg/14 days × 6 doses) and the PDN was increased to a dose of 1 mg/kg/day (50 mg/day). After the first CYC infusion, the patient referred gastrointestinal intolerance and she expressed her wish to stop the treatment, so she only received one single CYC dose.

In this clinical context, in February 2020, it was decided to add off-label subcutaneous ABT (125 mg weekly), maintaining MMF 3 g/day and PDN 5 mg/day. After 6 months, CR was reached (UPCRs 0.3 g/g) with eGFR (CKD-EPI) 61 ml/min, that has been stable to date (February 2023), with normalization of complement levels and reduction of anti-dsDNA concentrations (23 UI/mL). ABT effect allowed to gradually reduce MMF (1.5 g/day) and PDN (2.5 mg) doses. As the only adverse event, the patient presented Herpes Zoster in the right lower limb. Proteinuria evolution from the beginning of follow-up in our center is illustrated in Fig. 2.

Proteinuria evolution of case 2 measured by UPCR