The Evolving Role of Calcineurin Inhibitors in Treating Lupus Nephritis

Rationale for Calcineurin Inhibition in Lupus Nephritis

SLE is the end result of a number of immune aberrations that involve defective clearance of autoantigens and immune complexes resulting in excessive activation of T helper cells and B cells, leading to autoantibody production and complement activation and eventually, tissue inflammation and end organ injury. Calcineurin inhibitors (cyclosporin and tacrolimus) block T cell activation via suppression of the calcium- and calmodulin-dependent phosphatase calcineurin. Calcineurin inhibition leads to decreased nuclear translocation of transcription factors (e.g., NF-AT) involved with IL-2 transcription (7). In addition to its immunomodulatory effects, the calcineurin inhibitors also are able to decrease proteinuria via direct podocyte stabilization and afferent arteriole vasoconstriction (Figure 1). This antiproteinuric effect occurs independent of immune modulation, such as has been shown in patients with nephrotic syndrome due to nonimmunologic mechanisms (8). Podocyte stabilization occurs in part via preventing synaptopodin 14-3-3 degradation by cathepsin L (9). Therefore, calcineurin inhibitors are an attractive option for management of lupus nephritis because of their dual ability to inhibit T cell activation and reduce proteinuria via nonimmune-mediated mechanisms.

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Figure 1.

Calcineurin inhibition results in both decreased T cell proliferation and in podocyte stabilization. (A) Cyclosporin (CsA) binds cyclophilin (CpN), and tacrolimus (FK506) binds FK binding protein (FKBP). The resulting complex (cyclosporin-cycophilin [CsA-CpN] or tacrolimus-FK binding protein [FK506-FKBP]) binds and competitively inhibits calcineurin (CaN) from dephosphorylating phosphorylated nuclear factor of activated T cells (NFAT-P) to nuclear factor of activated T cells (NFAT). When dephosphorylated, NFAT will activate translation and transcription of various cytokines (IL-2, TNF-α, and IFN-γ), which will promote T cell proliferation in part by IL-2 binding to the IL-2 receptor on the T cell. (B) Calcineurin inhibition on podocyte calcineurin activation is involved with podocyte actin cytoskeleton destabilization. Phosphorylated synaptopodin binds with 14-3-3, which in turn, stabilizes the actin cytoskeleton of the podocyte. When activated, calcineurin dephosphorylates synaptopodin, which in turn, marks it for destruction by cathepsin L, and this in turn results in podocyte cytoskeleton destabilization. Calcineurin inhibitors will, therefore, protect synaptopodin from destruction and promote actin cytoskeleton stabilization.

Experience Using Calcineurin Inhibitor Therapy in Lupus Nephritis

The Future Landscape of Calcineurin Inhibitors in Lupus Nephritis

Despite the success of multitarget regimens for lupus nephritis in the past, both tacrolimus and cyclosporin require regular drug monitoring (25). Voclosporin is similar to cyclosporin but has a modification of a functional group that allows for potent binding to calcineurin and faster elimination of metabolites, and drug-level monitoring is not required (26). The AURA-LV study (27) was a phase 2, multicenter, randomized, control trial comparing two doses of voclosporin (23.7 or 39.5 mg twice daily) with placebo in combination with MMF and rapidly tapered corticosteroids to induce remission in proliferative lupus nephritis over 48 weeks of treatment. Compared with the previous multitarget trials, the AURA-LV study was significantly more diverse, randomizing 265 subjects across 79 centers in 20 countries. Complete remission was attained in 49.4% of patients in the low-dose voclosporin group, 39.8% of patients in the high-dose voclosporin group, and 23.9% of patients in the placebo group. The patients in the voclosporin group achieved remission faster as well. The lack of a dose effect with voclosporin alongside increased rates of adverse events in the voclosporin group tempers excitement regarding the AURA-LV study. A phase 3 trial of voclosporin, however, is pending publication, which should be more revelatory in evaluating the efficacy and safety of this agent in treating lupus nephritis.

Safety Profile of Calcineurin Inhibitor Therapy in Lupus Nephritis

Calcineurin inhibitors are associated with hypertension (partly by stimulation of the sodium chloride cotransporter [28]) and a number of metabolic side effects, including glucose intolerance and dyslipidemia (25). Moreover, long-term calcineurin inhibitor use is associated with chronic nephrotoxicity (29). The available data give mixed results regarding calcineurin inhibitor safety in lupus nephritis. In Liu et al. (19), more patients in the multitarget group dropped out because of adverse events (5.5% versus 1.7%). Moreover, there was a higher rate of serious adverse events in the multitarget group (7.2% versus 2.8%), including more pneumonias (3.9% versus 0.6%). However, in the maintenance trial by Zhang et al. (21), which was an extension of the trial by Liu et al. (19), there was actually more adverse events in the azathioprine arm (44.4%) compared with the multitarget arm (16.4%). In the AURA-LV study (27), there were more serious adverse events in the low-dose voclosporin group (28.1%) compared with the high-dose voclosporin (25%) and placebo (15.9%) groups, with the most frequent adverse event being infection. There were also more deaths in the low-dose voclosporin group (ten deaths) versus the high-dose voclosporin group (two deaths) or the placebo group (one death); however, the majority of the deaths happened at two study sites where more patients were randomized to low-dose voclosporin. With respect to AKI risk while on calcineurin inhibitor during the above trials, there were often more transient increases in serum creatinine among the calcineurin inhibitor group compared with the competitor (most frequently in the trial by Mok et al. [14]); however, there was usually no difference in kidney function at the end of the trial (with the trial by Mok et al. [14] being an exception). Nevertheless, we must keep in mind that relatively few lupus nephritis trials followed long-term use of calcineurin inhibitors to comment on long-term nephrotoxicity, and few have long-term protocol biopsies. It is of note that not all of the trials published tacrolimus and cyclosporin drug levels, and it is necessary to correlate the drug level with the observed toxicities and to use the lowest level that allows efficacy without toxicity. With respect to adverse events reported in the meta-analyses, Hannah et al. (23) report that tacrolimus compared with competitor drug has lower incidence of leukopenia, gastrointestinal side effects, and menstrual disorders and trends toward a lower incidence of infection and a higher incidence of new-onset hypertension and hyperglycemia. Moreover, Palmer et al. (24) report more frequent major infection in the MMF group compared with the calcineurin inhibitor group (although neither drug had different odds of major infection when compared with intravenous cyclophosphamide), lower odds of ovarian failure in the calcineurin inhibitor group compared with oral cyclophosphamide, and lower odds of nausea in the calcineurin inhibitor group compared with intravenous cyclophosphamide. Table 2 summarizes the most common adverse events among trials evaluating calcineurin inhibitors in lupus nephritis.

Limitations of Published Data on Calcineurin Inhibitors in Lupus Nephritis

Many of the studies discussed above are from China, and because outcomes in lupus nephritis are heavily influenced by race and ethnicity, it is difficult to extend the positive results of Chinese studies to international populations. Moreover, remission is a heterogeneous outcome with variable definitions across lupus nephritis studies, and in the short term, it is essentially proteinuria based. Because calcineurin inhibitors lower proteinuria independent of their effect on immune function, their efficacy cannot be assessed solely by proteinuria reduction when on drug. Studies looking at 6-month remission rates are biased toward showing a calcineurin inhibitor effect, and a more appropriate assessment of these agents’ efficacy would be remission rates over a longer time horizon when the drugs have been tapered to gauge whether the remission achieved earlier is sustained. The duration of follow-up is relatively short among the induction trials included in this review, with the median follow-up time of 52 weeks and a range of 24–104 weeks. In fact, kidney flare after coming off calcineurin inhibitors is well described, and it was found in the 2016 study by Mok et al. (14), the study by Austin et al. (16), and the study by Yap et al. (17). A nonproteinuria-based outcome (e.g., progression to kidney failure, doubling of serum creatinine, or all-cause mortality) may be more appropriate for evaluating calcineurin inhibitor efficacy in lupus nephritis.

Another way to assess if the calcineurin inhibitor is having a true immunologic effect would be to follow complement and anti-dsDNA levels. It would be difficult to use this as a test of calcineurin inhibitor efficacy when multitarget therapy is used; however, some of the trials that compared calcineurin inhibitor as a single agent against one or more competitors did publish complement and dsDNA-level trends over time and found that they increased and decreased, respectively, by similar magnitudes in the calcineurin inhibitor group compared with the control group (10,13,14).

Given difficulty in using proteinuria to gauge short-term efficacy for calcineurin inhibitors, an even more robust outcome to evaluate induction-phase therapy may be repeat protocol biopsies. Early clinical and histologic outcomes can be discordant in proliferative lupus nephritis, and progression from active to chronic lesions on a biopsy remains the most consistent predictor of long-term risk for kidney failure (30). Repeat biopsies are not routinely performed in lupus nephritis trials but can be helpful in evaluating whether calcineurin inhibitors have had any effect beyond proteinuria reduction via nonimmunologic mechanisms. Although improvement in immunosuppressive regimens has led to reduced risk of reaching kidney failure among patients with lupus nephritis, there still remains a number of treatment failures with the KDIGO 2012–recommended first-line regimens. Calcineurin inhibitors along with azathioprine are among the small group of immunosuppressive agents that can be used in pregnancy and lactation. Multitarget therapy seems to offer higher rates of remission, albeit with the caveat that they have been predominately studied in a homogenous population (mostly in Asia). At this juncture, it seems that calcineurin inhibitors may have a role in lupus nephritis among younger refractory patients and patients with severe proteinuria. The increase in adverse events in some of the multitarget trials may temper excitement about calcineurin inhibitor use in lupus nephritis as does the lack of long-term nonproteinuria-based data given the known nonimmunologic effect of calcineurin inhibitors on proteinuria reduction. Publication of the phase 3 trial evaluating voclosporin will be helpful in better understanding the benefit of adding a calcineurin inhibitor to MMF in induction for lupus nephritis and in further evaluating the safety signal seen in the AURA-LV study. Larger calcineurin inhibitor studies with more diverse patient populations, longer time horizons, and protocol biopsies will help address whether the benefit of calcineurin inhibitor is largely nonimmunologic, whether race and/or ethnicity influence response to calcineurin inhibitors in lupus nephritis, and whether long-term calcineurin inhibitor exposure leads to worsening CKD in the lupus nephritis population. These trials should help further clarify the evolving role of calcineurin inhibitors in treating lupus nephritis.

Disclosures

Dr. Bomback, Dr. Peleg, and Dr. Radhakrishnan have nothing to disclose.