2021: Year of the Glomerulus

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Kenar D. Jhaveri, MD

Citation: Kidney News 13, 1

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The past decade has seen continual progress in the diagnosis and treatment of primary glomerular diseases. The discovery of disease-causing autoantibodies in membranous nephropathy (MN) and mutations in podocyte genes in focal segmental glomerulosclerosis (FSGS), together with the availability of modern immunosuppressive drugs, has provided new avenues for individualized therapy, and several important studies have been published in the past several years.

Whereas antibodies to the phospholipase A2 receptor (PLA2R) were discovered over 10 years ago and have entered mainstream practice, several novel antigens surfaced in the nephrology literature in 2020 (Figure 1). With the advent of novel autoantibodies like neural epidermal growth factor-like 1 (NELL-1) and exostosin 1 and 2 (EXT1 and EXT2), the science of MN is advancing (1, 2). In 2021, perhaps we will be better able to define the exact MN subtype and decide on appropriate workup (cancer screening/autoimmune workup) and individualized therapy.

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Various novel antigens associated with membranous nephropathy

Citation: Kidney News 13, 1

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While we are figuring out the type of autoantibodies, the treatment of MN is still in flux. The MENTOR trial (3) paved the road for rituximab to take the lead as a first-line therapy. However, the STARMEN trial, published in 2020 (4), is putting cyclophosphamide back in the spotlight. This trial compared the criterion standard used for decades (cyclophosphamide and alternating corticosteroids for 6 months) with tacrolimus as a bridge to rituximab. Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group. Anti-PLA2R titers showed a significant decrease in both groups, but the proportion of anti-PLA2R-positive patients who achieved immunologic response (depletion of anti-PLA2R antibodies) was significantly higher at 3 and 6 months in the cyclophosphamide-corticosteroid group (77% and 92%, respectively) in comparison with the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the cyclophosphamide-corticosteroid group and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups.

A critique of the STARMEN trial was the use of only one dose of rituximab with no monitoring of B cells. Another trial that is yet to be published is the RI-CYCLO trial (presented as a late-breaking poster at Kidney Week 2020), which also compared rituximab with cyclophosphamide and corticosteroids (5). The trial showed no difference in benefit or harm in the two arms, the cyclophosphamide-corticosteroid regimen induced remission earlier, and adverse events were equal in both arms. Will there ever be a superiority trial? That is less likely according to the authors because recruitment in such trials is usually slow. Will the older agent return as the top choice for nephrologists treating MN? Let’s await the publication of RI-CYCLO to see where the regimens will fall in the treatment choices for MN: rituximab, cyclophosphamide-glucocorticoids, or calcineurin inhibitors.

Novel therapies for lupus nephritis are emerging rapidly. The BLISS trial showed that patients with lupus nephritis who received belimumab (B cell activating factor inhibitor) plus standard therapy were significantly more likely to have a kidney response at 2 years than were those given placebo plus standard care (6). The kidney response was the primary endpoint: the ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate (GFR) that was no worse than 20% below the value before the kidney flare (preflare value) or ≥60 mL/ min per 1.73 m² of body surface area, and no use of rescue therapy. At week 104, 43% of patients assigned to the belimumab group had a primary efficacy kidney response compared with 32% of those in the placebo group. The majority of patients had class III or IV nephritis, most were Asian; only 14% were Black, and almost 90% were women. By week 24, more patients in the belimumab group had a primary efficacy kidney response, and by 1 year, 47% met this endpoint compared with 35% of the placebo group (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1 to 2.4; p = 0.02). This study is one of the first studies to bring in a new medication to treat lupus nephritis since the ALMS trial that made mycophenolate mofetil (MMF) common place (7).

For patients with lupus nephritis, kidney response improves when voclosporin, a novel calcineurin inhibitor, is added to MMF and low-dose corticosteroids, according to results from the yet-to-be-published phase 3 AURORA trial (presented at ASN Kidney Week 2020) (8). This international, double-blind, randomized, placebo-controlled trial compared the effectiveness and safety of twice-daily oral voclosporin 23.7 mg with placebo. All 357 study participants also received MMF 2 g daily and rapidly tapered low-dose oral corticosteroids. At 1 year, the kidney response rate was higher in the voclosporin group than in the placebo group (40.8% vs. 22.5%; OR, 2.65; p < 0.001). The median time to the achievement of a urine protein-to-creatinine ratio below 0.5 mg/mg was significantly and clinically better with voclosporin than with placebo (169 vs. 372 days; log rank p < 0.001). The year 2021 is going to see a paradigm change in the treatment of lupus nephritis.

Finally, in IgA nephropathy, we may have stumbled on a potential treatment with the use of dapagliflozin (DAPA) in patients with chronic kidney disease (CKD). Whereas the STOP-IgA (9) and TESTING (10) trials had patients using steroids for IgA nephropathy, 6% of patients in the DAPA-CKD study had IgA nephropathy and did well with treatment with sodium glucose cotransporter-2 (SGLT2) inhibitor (11). There were more patients in the DAPA-CKD study with IgA nephropathy (270) than in the STOP-IgA trial (162) and the TESTING trial (262). This may spark more use of SGLT2 inhibitors to decrease the progression of IgA nephropathy.

As I scratch the surface of novel markers and treatments and studies on the horizon for MN, IgA nephropathy, and lupus nephritis, several other glomerular diseases will see changes in management as 2021 arrives. Are we going to use less plasmapheresis in antineutrophil cytoplasmic antibody vasculitis (12), and when will oral complement inhibitors in trials (13) be the standard of care for vasculitis and C3 glomerulonephritis? That is yet to be seen.