Abstract
Objective
This study characterized the impact of voclosporin on kidney histology in patients with lupus nephritis (LN) who had protocolized repeat kidney biopsies in the AURORA clinical trials.
Methods
Patients were randomized to voclosporin or placebo treatment for up to 3 years; all patients received mycophenolate mofetil and low‐dose glucocorticoids. Patients had baseline kidney biopsies within 6 months before study start and repeat biopsies after approximately 18 months of study treatment. The revised National Institutes of Health indices for LN activity and chronicity (CI) were calculated in addition to a semiquantitative assessment of vascular and tubular lesions.
Results
Sixteen patients in the voclosporin group and 10 patients in the control group had both baseline and repeat kidney biopsies. Patient clinical characteristics were similar at baseline. In the voclosporin group, most (n = 13) patients had pure class IV lesions (pure class V, n = 1; mixed, n = 2). In the control group, three patients had pure class IV (pure class III, n = 3; pure class V, n = 1; mixed, n = 3). Most of the voclosporin‐treated patients had no change in CI (n = 8) or a change no greater than 2 (n = 6); control‐treated patients also had no change in CI (n = 3) or a change no greater than 2 (n = 6). No trends in vascular lesions or tubular compartment changes were observed.
Conclusion
Outcomes from this small subgroup show that exposure to study treatment was not associated with nephrotoxicity based on histopathologic evaluation after 18 months. These data are reassuring and further contribute to the safety profile of voclosporin for the treatment of adults with active LN.
INTRODUCTION
Lupus nephritis (LN) can lead to loss of kidney function and is associated with a high risk of end‐stage kidney disease and death. 1 , 2 Response to treatment can be slow, and treatment regimens are associated with considerable toxicity. 3 LN is characterized by proteinuria, which is damaging to kidneys and is independently associated with cardiovascular morbidity, thrombosis, chronic kidney disease, and an increased mortality risk. 4 Decline in proteinuria is a marker of treatment response and overall prognosis. 5 , 6
Immunosuppressants, including calcineurin inhibitors (CNIs), are used in the treatment of LN, as recommended by recent treatment guidelines. 5 , 6 , 7 CNIs work through inhibition of T cell function, resulting in disease modification and inhibition of synaptopodin degradation, stabilizing the podocyte cytoskeleton. 8 Additionally, CNIs have a hemodynamic effect associated with reversible vasoconstriction of the afferent arterioles that can acutely decrease proteinuria. 9
A factor limiting chronic use of CNIs is the potential for nephrotoxicity. First‐generation CNIs cyclosporine A (CsA) and tacrolimus (Tac) have been implicated in the development of irreversible chronic lesions in the kidney, particularly when used at higher doses in the solid organ transplant setting. 10 , 11 , 12 , 13
Voclosporin, a second‐generation CNI, is indicated for the treatment of adults with active LN and has a distinct pharmacological and clinical profile compared with CsA and Tac. 14 In the AURORA clinical program, a voclosporin‐based triple therapy regimen with mycophenolate mofetil (MMF) and low‐dose glucocorticoids (GCs) resulted in rapid and sustained proteinuria reductions in patients with active LN with an acceptable long‐term safety profile. 15 , 16 Based on these results, recent American College of Rheumatology guidelines recommend voclosporin as part of a triple immunosuppressive regimen as a first‐line treatment option for all LN classes. 7
To assess the impact of voclosporin on kidney histopathology in patients with LN, the AURORA clinical program included a protocolized repeat kidney biopsy substudy. Results from patients enrolled in this substudy are reported here.
PATIENTS AND METHODS
Study design
The AURORA clinical program was composed of two phase 3 clinical trials: the pivotal 1‐year AURORA 1 study and the follow‐up 2‐year AURORA 2 study. The study designs of AURORA 1 and AURORA 2 have been reported. 15 , 16 Briefly, patients in AURORA 1 were randomized to receive double‐blind voclosporin (23.7 mg twice daily), or matching placebo, with MMF (target 2 g/day) and GCs. 14 Patients in AURORA 2 continued on the same double‐blind study drug (voclosporin or placebo), MMF, and GCs at the doses used at the end of AURORA 1 (Figure 1). 15 , 16 The AURORA 1 inclusion criteria required patients to have a locally read baseline kidney biopsy with evidence of active LN requiring treatment and International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of III, IV, and/or V disease. 17 AURORA 2 inclusion criteria required patients to complete study treatment in AURORA 1, and, in the opinion of the investigator, required continued immunosuppressive therapy.
Figure 1.
AURORA 1 and AURORA 2 study designs. AURORA 1 enrolled patients with active lupus nephritis, urine protein‐creatinine ratio greater than or equal to 1.5 g/g (≥2 g/g for class V) and estimated glomerular filtration rate greater than 45 mL/min/1.73 m2; patients were randomized to receive double‐blind voclosporin (23.7 mg twice daily) or matching placebo, with MMF (target 2 g/day) and low‐dose oral GCs. A protocol‐defined GC taper included intravenous methylprednisolone on days 1 and 2. Oral GC was initiated on day 3 with 20 to 25 mg/day prednisone or equivalent and tapered to a target dose of 2.5 mg/day by week 16. Patients in AURORA 2 continued on the same double‐blind study drug (voclosporin or placebo), MMF, and GCs at the doses used at the end of AURORA 1. GC, glucocorticoid; MMF, mycophenolate mofetil.
AURORA 2 patients had an opportunity for a kidney biopsy to be performed at approximately 6 months into AURORA 2 as part of an elective repeat kidney biopsy substudy. Additional inclusion criteria specific for the biopsy substudy required that the locally read kidney biopsy at baseline had been performed within 6 months of screening for AURORA 1 and investigator confirmation that biopsy sample requirements could be met, including staining of samples and transfer of slide images to a central laboratory, as well as substudy‐specific, patient‐signed, informed consent.
The protocol was approved by an institutional review board or independent ethics committee at each trial site; all participants provided informed consent in accordance with the Declaration of Helsinki and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice guideline. The aggregated data underlying this article, the study protocol, and statistical analysis plan will be shared with researchers on reasonable request to the corresponding author.
Kidney biopsy sample preparation
Baseline and repeat kidney biopsies were processed by local laboratories to prepare slides for the central reads using recuts of the original biopsy blocks. Slides were prepared for routine light microscopy and stained with hematoxylin and eosin, periodic acid‐Schiff (PAS), Masson's trichrome, and Jones’ methenamine silver‐PAS. Once processed, four whole‐slide scanned images, corresponding to each of these four stains, were captured and transferred electronically to a central United States–based College of American Pathologists–accredited laboratory (Arkana Laboratories, Arkansas, USA). Histopathologic grading and assessment were conducted by one reader from a panel of seven nephropathologists; the same reader reviewed both the baseline and repeat kidney biopsies obtained from the same patient. Nephropathologists were blinded to treatment arm, biopsy sequence (baseline or repeat), clinical parameters of patients, and initial biopsy reports from the local pathologists.
Histologic assessments
A total of 37 patients from the AURORA 2 study enrolled in the kidney biopsy substudy; 16 in the voclosporin group and 10 in the control group had sufficient kidney biopsy samples at both baseline and repeat to allow activity indices (AIs) and chronicity indices (CIs) to be assessed. Grading of baseline and repeat biopsies was based on the revised National Institutes of Health (NIH) indices for LN activity and chronicity, following the 2018 update to the ISN/RPS AI and CI scoring system. 18 , 19
Additional manifestations associated with CNI nephrotoxicity were assessed in vascular and tubular compartments. Vascular assessment included arterial sclerosis, thrombotic microangiopathy, and arteriolar hyalinosis. Tubular compartment assessment focused on the presence of isometric tubular vacuolization, a nonspecific morphologic finding often seen with CNI‐induced toxicity. 20
Clinical parameters
Assessed clinical outcomes included complete renal response (CRR, defined as a urine protein‐creatinine ratio [UPCR] ≤0.5 g/g; stable estimated glomerular filtration rate [eGFR]; low‐dose GCs [<10 mg prednisone per day for ≥3 consecutive days or for ≥7 days during the 8 weeks before assessment], and no rescue medication), partial renal response (PRR; defined as a reduction in UPCR of ≥50% from baseline), blood pressure, UPCR, laboratory assessments and adverse events (AEs). Kidney function was assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL/min/1.73 m2 and compared with the results of the overall AURORA population.
RESULTS
Baseline demographics and disease characteristics for biopsy substudy patients were generally like those of the overall AURORA 1 population. For instance, mean UPCR at baseline in the substudy was 4.59 g/g in the voclosporin group and 4.71 g/g in the control group compared with the overall AURORA 1 population that had 4.14 g/g in the voclosporin group and 3.87 g/g in the control group. 15 The biopsy substudy population represented seven countries with the largest number from Peru, and most patients were of Hispanic or Latino ethnicity (Table 1).
Table 1.
Baseline demographics and disease characteristics of patients in the voclosporin and control groups of the kidney biopsy substudy*
| Characteristics | Voclosporin (n = 16) | Control (n = 10) |
|---|---|---|
| Age, years | ||
| Median (IQR) | 27.0 (24–33) | 33.5 (27–43) |
| Sex, n (%) | ||
| Female | 15 (93.8) | 9 (90.0) |
| Race, a n (%) | ||
| Mestizo | 9 (56.3) | 4 (40.0) |
| White | 4 (25.0) | 3 (30.0) |
| Asian | 3 (18.8) | 3 (30.0) |
| Ethnicity, a n (%) | ||
| Hispanic or Latino | 9 (56.3) | 6 (60.0) |
| Non‐Hispanic or non‐Latino | 7 (43.8) | 4 (40.0) |
| Region, n (%) | ||
| North America | 0 (0.0) | 3 (30.0) |
| Latin America | 9 (56.3) | 4 (40.0) |
| Europe | 4 (25.0) | 2 (20.0) |
| Asia | 3 (18.8) | 1 (10.0) |
| Country, n (%) | ||
| Belarus | 1 (6.3) | 2 (20.0) |
| Mexico | 1 (6.3) | 2 (20.0) |
| Peru | 8 (50.0) | 2 (20.0) |
| Philippines | 3 (18.8) | 1 (10.0) |
| Russia | 2 (12.5) | 0 (0.0) |
| Ukraine | 1 (6.3) | 0 (0.0) |
| USA | 0 (0.0) | 3 (20.0) |
| Time since LN diagnosis, years | ||
| Median (IQR) | 3.5 (1.0–5.0) | 4.0 (1.0–10.0) |
| Time since SLE diagnosis, years | ||
| Median (IQR) | 3.5 (1.0–5.5) | 6.0 (1.0–14.0) |
| Biopsy class, n (%) | ||
| Pure class III | 0 (0.0) | 3 (30.0) |
| Pure class IV | 13 (81.3) | 3 (30.0) |
| Pure class V | 1 (6.3) | 1 (10.0) |
| Mixed class III/V or IV/V | 2 (12.6) | 3 (30.0) |
| eGFR, mL/min/1.73 m2 | ||
| Corrected, mean (SD) | 80.3 (16.4) | 82.6 (12.3) |
| UPCR, g/g | ||
| Mean (SD) | 4.59 (2.5) | 4.7 (2.6) |
| ≥2 g/g, n (%) | 13 (81.3) | 9 (90.0) |
| C3, mg/dL | ||
| Mean (SD) | 78.1 (37.36) | 90.9 (39.74) |
| Median (min, max) | 71.5 (29, 149) | 97.5 (39, 158) |
| Low, n (%) b | 10 (62.5) | 4 (40.0) |
| C4, mg/dL | ||
| Mean (SD) | 15.6 (8.93) | 17.1 (10.77) |
| Median (min, max) | 12.0 (8, 41) | 14.0 (6, 37) |
| Low, n (%) c | 10 (62.5) | 6 (60.0) |
| Anti‐dsDNA antibodies, IU/mL | ||
| Mean (SD) | 55.7 (70.2) | 86.2 (107.9) |
| Median (min, max) | 25.0 (2, 238) | 52.0 (2, 339) |
| High dsDNA, n (%) d | 7 (43.8) | 6 (60.0) |
| Missing | 1 (6.3) | 0 (0.0) |
| SLEDAI total score | ||
| Mean (SD) | 13.9 (5.68) | 10.9 (3.73) |
| Median (min, max) | 14.0 (4, 24) | 12.0 (6, 17) |
| SLEDAI nonrenal score | ||
| Mean (SD) | 6.4 (4.01) | 4.1 (2.33) |
| Median (min, max) | 6.0 (0, 12) | 4.0 (2, 8) |
| Prior use of ACEi/ARBs, n (%) | 13 (81.3) | 8 (80.0) |
Data from pretreatment baseline in AURORA 1 for 10 patients in the control group and 16 patients in the voclosporin group of the biopsy substudy. Kidney function assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL/min/1.73 m2. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; C3, complement 3; C4, complement 4; dsDNA, double‐stranded DNA; eGFR, estimated glomerular filtration rate; IQR, interquartile range; LN, lupus nephritis; max, maximum; min, minimum; SD, standard deviation; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; UPCR, urine protein‐creatinine ratio.
Race and ethnicity of patients in AURORA 1 were self‐reported using a fixed set of predefined categories.
Low C3 was defined as less than 90 mg/dL.
Low C4 was defined as less than 16 mg/dL.
High anti‐dsDNA was defined as greater than 25 IU/mL.
The median time between the baseline kidney biopsy and start of AURORA 1 was 0.99 months (range 0.3–4.8 months) for the voclosporin group and 1.49 months (range 0.3–1.7 months) for the control group of the biopsy substudy. The repeat kidney biopsy occurred after a median of 17.8 months (range 15.2–23.6 months) of study treatment for the voclosporin group and 16.5 months (range 13.6–21.4 months) for the control group. Of the patients in the biopsy substudy, all but three completed 36 months of study treatment; one patient in the voclosporin group and two in the control group discontinued study drug early because of AEs.
The median dose of study drug (voclosporin or placebo) in the biopsy substudy was 42.5 mg/day in the voclosporin group and 47.2 mg/day in the control group, consistent with the overall AURORA 1 population reporting 41.3 mg/day study drug in the voclosporin group and 45.5 mg/day in the control group. Exposure to GCs and MMF was also similar between substudy groups during the AURORA 1 and AURORA 2 studies. Before the baseline kidney biopsy in AURORA 1, several patients in the voclosporin group and in the control group reported GC and MMF use (Table S1).
Clinical findings
Higher rates of CRR and PRR were observed in the voclosporin group of the biopsy substudy. In biopsy substudy patients, the early mean reductions in UPCR observed in AURORA 1 were maintained out to 3 years in AURORA 2, with no increase in UPCR at the follow‐up visit taking place 4 weeks after study drug discontinuation, consistent with the results of the overall AURORA study population (Tables S2 and S3; Figure S1).
Over the 3‐year study period, corrected mean eGFR remained stable and within the normal range in both groups of the biopsy substudy, consistent with findings from the overall AURORA population (Table S2; Figures S2 and S3). 15 , 16 Mean blood pressure and levels of electrolytes, glucose, and serum creatinine were stable over time in the substudy, consistent with previous reports. 15 , 16
There were no unexpected AEs related to treatment; the safety profile and frequency of AEs in the substudy were similar to the overall AURORA 1 and AURORA 2 populations. 15 , 16 In the substudy patients treated with voclosporin, the AE of “glomerular filtration rate (GFR) decreased” by MedDRA preferred term was reported in six (37.5%) patients in year 1 and two (12.5%) patients in year 2, with no reports in year 3; no AEs of GFR decreased were reported in the control group. AEs led to permanent discontinuation of study treatment in two patients (renal impairment and disseminated tuberculosis both considered by the investigator as related to the study drug) in the control group and in one patient in the voclosporin group who experienced worsening systemic lupus erythematosus considered by the investigator as unrelated to voclosporin.
Activity and chronicity scoring
Median CI and AI were similar between treatment groups of the substudy at baseline and remained stable over time (Table 2; Table S4). Individual CIs over time were variable between patients, with increases, decreases, and no change in score observed in both groups. Most patients in the voclosporin group had no change in CI (n = 8) or a change of ≤2 (n = 6); one patient had a decrease from 7 to 4 and another had an increase from 6 to 10. The latter patient discontinued the study because of an AE of worsening systemic lupus erythematosus. In the control group, most patients had a score change ≤2 (n = 6); three patients had no change in CI, and one had a decrease from 5 to 1 (Figure S4).
Table 2.
Patient‐level histology data in the voclosporin group*
| Patient no. | AURORA 1 baseline | Biopsy scores, baseline/repeat b | Renal response at month 18 c | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Biopsy class a | sCr, mg/dL | UPCR, g/g | Time from biopsy to enrollment, days | AI | CI | AS | TMA | AH | ITV | ||
| Voclosporin | |||||||||||
| 1 | IV | 1.30 | 1.9 | 146 | 0/0 | 6/10 | NA/3 | 1/0 | 1/1 | 0/0 | PRR |
| 2 | IV | 1.26 | 3.5 | 10 | 0/0 | 10/9 | 1/1 | 0/0 | 0/0 | 0/0 | CRR |
| 3 | IV | 1.24 | 8.7 | 31 | 9/1 | 8/9 | 2/0 | 0/0 | 1/1 | 1/1 | PRR |
| 4 | IV | 0.37 | 5.7 | 36 | 0/4 | 10/8 | NA/0 | 0/0 | 0/0 | 0/0 | CRR |
| 5 | IV | 0.92 | 3.9 | 43 | 0/0 | 5/5 | NA/0 | 0/0 | 0/0 | 0/0 | PRR |
| 6 | IV | 0.48 | 2.0 | 37 | 4/0 | 4/5 | 3/3 | 0/0 | 1/1 | 1/0 | CRR |
| 7 | IV | 0.45 | 2.8 | 58 | 0/0 | 7/4 | 0/1 | 0/0 | 1/0 | 0/1 | CRR |
| 8 | IV | 0.80 | 6.5 | 7 | 0/0 | 3/3 | 0/0 | 0/0 | 1/1 | 0/0 | CRR |
| 9 | IV | 0.69 | 8.7 | 27 | 6/1 | 3/3 | NA/0 | 0/0 | 0/0 | 0/0 | PRR |
| 10 | III/V | 1.19 | 4.2 | 15 | 4/0 | 3/3 | 2/2 | 0/0 | 0/0 | 0/0 | CRR |
| 11 | IV | 0.77 | 7.1 | 83 | 6/0 | 2/2 | 0/2 | 0/0 | 0/0 | 0/0 | CRR |
| 12 | IV | 0.37 | 2.5 | 15 | 0/0 | 0/2 | 0/0 | 0/0 | 0/0 | 0/0 | PRR |
| 13 | IV | 0.69 | 1.5 | 7 | 0/0 | 0/2 | 0/1 | 0/0 | 0/1 | 0/0 | CRR |
| 14 | IV | 0.55 | 7.3 | 41 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | PRR |
| 15 | IV/V | 1.09 | 4.9 | 20 | 0/0 | 0/0 | NA/NA | 0/0 | 0/0 | 0/0 | CRR |
| 16 | V | 0.69 | 2.1 | 14 | 0/0 | 0/0 | 1/1 | 0/0 | 0/0 | 0/0 | No response |
| Control | |||||||||||
| 17 | III/V | 1.09 | 9.1 | 52 | 0/0 | 7/9 | 3/3 | 0/0 | 0/0 | 0/0 | PRR |
| 18 | IV | 0.60 | 7.0 | 9 | 1/0 | 4/4 | 3/3 | 0/0 | 0/1 | 0/0 | No response |
| 19 | IV/V | 0.99 | 5.4 | 47 | 10/1 | 4/4 | 0/1 | 0/0 | 1/1 | 0/0 | CRR |
| 20 | IV | 1.13 | 2.1 | 49 | 6/0 | 3/4 | 1/0 | 0/0 | 0/1 | 0/0 | CRR |
| 21 | III/V | 0.77 | 2.2 | 42 | 5/0 | 1/3 | 2/2 | 0/0 | 0/0 | 0/0 | CRR |
| 22 | V | 0.43 | 1.7 | 13 | 1/0 | 4/2 | 2/2 | 0/0 | 0/0 | 0/0 | No response |
| 23 | IV | 0.57 | 4.0 | 7 | 0/0 | 5/1 | 2/NA | 0/0 | 1/0 | 0/0 | PRR |
| 24 | III | 0.76 | 7.7 | 48 | 0/0 | 0/1 | 2/0 | 0/0 | 0/0 | 0/0 | No response |
| 25 | III | 0.77 | 3.3 | 51 | 4/3 | 1/0 | 3/3 | 0/0 | 0/1 | 0/0 | CRR |
| 26 | III | 0.67 | 4.5 | 30 | 3/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | CRR |
Analysis includes data from before treatment in AURORA 1 (baseline) to month 18 of AURORA 2 for 26 patients in the kidney biopsy substudy. AH, arteriolar hyalinosis; AI, activity index; AS, arterial sclerosis; CI, chronicity index; CRR, complete renal response; ITV, isometric tubular vacuolization; NA, no arteries available for assessment; PRR, partial renal response; sCr, serum creatinine; TMA, thrombotic microangiopathy; UPCR, urine protein‐creatinine ratio.
Biopsy class was assigned at baseline based on local pathology read according to the 2003 Nephrology/Renal Pathology Society classification. 17
Histopathologic grading based on the National Institutes of Health indices for lupus nephritis activity (scale 0–24) and chronicity (scale 0–12). 18
All patients who achieved CRR at month 18 also had PRR. Vascular assessment included AS (0 = absent, 1 = mild, 2 = moderate, and 3 = severe), TMA (0 = absent and 1 = present), AH (0 = absent and 1 = present), and ITV (0 = absent and 1 = present).
Baseline AI of 0 was reported for 69% of the patients in the voclosporin group and 30% of the control group of the substudy population; three patients with an AI of 0 had a component of class V LN. Of the 11 patients classified with only proliferative LN (class III or IV) and an AI of 0, 7 had chronic damage with CIs ranging from 3 to 10, and the remaining 4 patients had no chronic damage at baseline. All patients with baseline histologic activity had resolution at repeat biopsy with an AI of 0 or a large decline, apart from one patient in the control group that had an AI of 4 at baseline and 3 at the repeat biopsy (Table 2; Figure S4).
Vascular and tubular evaluation
Vascular and tubular examination and scoring was performed in both baseline and repeat kidney biopsies. No trends in vascular changes were observed. One patient in the voclosporin group and three patients in the control group had arteriolar hyalinosis on repeat biopsy that was not present on the baseline biopsy. Two patients in the voclosporin group and one patient in the control group had arterial sclerosis on repeat biopsy not apparent on the baseline biopsy (Table 2).
DISCUSSION
This is the first study to assess histologic changes in the kidneys of patients with active LN enrolled in a randomized, blinded clinical trial and treated with voclosporin or placebo in combination with MMF and low‐dose GCs. Exposure to voclosporin for a median of 18 months was not associated with onset or progression of nephrotoxicity based on evaluation of histologic compartments and vascular lesions.
CIs, histologic measurements of chronic kidney injury, remained stable at follow‐up in both treatment groups. 21 Given that injury patterns may not be comprehensively captured by the NIH AI and CI scoring system, we also evaluated the vascular and tubular compartments for arterial sclerosis, arteriolar hyalinosis, isometric tubular vacuolization, and thrombotic microangiopathy, lesions that are commonly associated with CNI nephrotoxicity. 11 , 12 Notably, our data did not indicate any significant trends or signals of CNI nephrotoxicity in either treatment group.
For most patients, AI, a histologic measure of kidney inflammation, decreased or remained unchanged between baseline and repeat biopsies. Of patients with an AI ≥1 at baseline, all but two patients in the control arm achieved a clinically important decline in AI at the repeat biopsy, consistent with their clinical outcome as complete or partial renal responders. However, two patients with significant residual activity on repeat biopsy, including a placebo‐treated patient with an AI of 3 and a voclosporin‐treated patient with an AI of 4, were also considered complete renal responders at repeat biopsy. This may represent the known discordance between clinical and histologic response seen in patients with LN. 22 , 23 , 24 , 25 , 26 Alvarado et al reported on 25 patients with LN with repeat biopsies and found that, despite achieving clinical CRR (n = 16), nine patients had an AI >0 and five had an AI ≥2. 26
Unexpectedly, and of potential concern, were the substudy patients enrolled into the AURORA 1 trial with an AI of 0. Eight of these 14 patients had moderate to severe chronic kidney damage based on CI scores that could contribute to the clinically relevant levels of proteinuria at trial entry. The remaining six patients demonstrating no activity or chronic damage at baseline had elevated proteinuria that decreased demonstrably with treatment. Two of the six patients had a class V component on biopsy that likely accounted for their proteinuria at baseline. Proteinuria in the remaining four patients is more difficult to explain. This may reflect the known discordance of proteinuria with histologic findings, variations in determining the AIs and CIs among nephropathologists, and limitations of these tools to capture all clinically relevant histologic lesions. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 Finally, study enrollment was based on the local investigator's judgment and local pathology readings without adjudication or verification by the study sponsor. From this experience, we propose that future studies in LN include protocolized central verification of LN activity to adjudicate results for all LN trials.
The AURORA clinical program provided a unique opportunity to evaluate repeat kidney biopsies following extended treatment with voclosporin compared with placebo. Clinical efficacy results in this substudy were consistent with outcomes reported in the larger studies demonstrating that voclosporin was effective at reducing or resolving proteinuria. 15 , 16 Given the toxicity of proteinuria to the kidney, the ability of voclosporin to lower proteinuria even in patients with chronic kidney damage, resulting from its impact on glomerular hemodynamics and podocyte structure, provides an additional tangible example of the benefit of voclosporin in LN.
Interpretation of this analysis is preliminary, limited by small sample size and selection bias of including AURORA 2 patients, who found treatment in AURORA 1 (either voclosporin or placebo) acceptable and who elected to continue the same blinded therapy in AURORA 2. The repeat biopsy substudy of AURORA 2 overlapped with the COVID‐19 pandemic; pandemic‐related restrictions likely limited the ability to participate. Additionally, although findings reported here after 18 months of treatment are reassuring, evaluating repeat kidney biopsies after longer exposure periods and in larger patient subgroups representative of the global LN population (eg, patients with impaired renal function or patients of African ancestry) is necessary to better understand the safety of voclosporin in a real‐world setting. Finally, the NIH indices used for histologic assessments in this study are established as a semiquantitative tool in LN and are used clinically and in research for both initial and repeat biopsy evaluation. In addition to the use of molecular diagnostics and noninvasive biomarkers, ongoing work promises to expand the clinical value of the NIH indices as classification and prognostic tools to optimize the evaluation and management of LN. 27 , 30
These data demonstrate that treatment with voclosporin for approximately 18 months, in combination with low‐dose MMF and GCs, is not associated with increased risk of kidney injury. The lack of histologic evidence of nephrotoxicity in this small subgroup, in addition to the positive clinical outcomes demonstrated, further our understanding of the safety and efficacy of long‐term voclosporin use in LN.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Birardi confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
ROLE OF THE STUDY SPONSOR
The study and manuscript were supported and funded by Aurinia Pharmaceuticals Inc. Aurinia was involved in the study design and in the analysis and interpretation of the data. Aurinia approved the manuscript for submission
Supporting information
Data S1 Supporting Information
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ACKNOWLEDGMENTS
Statistical support was provided by Matt Truman (Truman Statistical Services). Editorial support was provided by Kara McNair (MediComm Partners). The authors thank Krista Piper for significant contributions to the voclosporin clinical trial program.
Supported by Aurinia Pharmaceuticals Inc.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.43209).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/art.43209.
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