Updates from recent publications

IgAN/IgAV

Barratt et al (2019) KI Reports in press, Barbour et al (2019) JAMA Intern Med. 179:942

The PROTECT study is a phase III trial, aimed at 280 patients with IgAN, to compare combined AngII-RA and ET-A inhibitor with single blocking of AngII-R. The paper of Barratt describes how this study will implement surrogate efficacy endpoints. To facilitate risk stratification, 2 full prediction models, combining clinical and biopsy to predict disease progression have been described. This study of Barbour and colleagues made use of 3927 patients from different large multi-ethnic cohorts. This can be an important contribution to future clinical trial design.

Chen et al (2019) CJASN in press, Suzuki et al (2019) KI reports in press

In a large study of 1200 patients with biopsy-proven IgAN, it was shown that plasma levels of gal-deficient IgA1 (gdIgA1)/C3 was associated with the development of CKD (Chen et al). In a smaller study (10 IgAN, 20 IgAV), increased levels of both gdIgA1 as well as IgG autoantibodies against gdIgA1 were observed (Suzuki et al). Interestingly, these altered levels of autoantibodies were also observed in B cell cultures from these patients, and were not observed in patients with IgA-vasculitis without renal involvement.

Liu et al (2019) AJKD 74:15

A double blind phase II study has been performed with 60 patients with IgAN (proteinuria 0,75-3 g/d; EGFR >30ml) randomized for oral hydrocloroquine or placebo. Patients in the treatment arm showed a significant reduction in proteinuria. With the notion that reduction in proteinuria seems to become an accepted surrogate end point, this opens the way for further exploration of this antimalarial drug in IgAN, for which a lot experience already excist in the treatment of SLE.

Jarrick et al (2019) JASN 30:866

In Sweden a nation-wide population based study was performed concerning the mortality in IgAN. It was found that patients with IgAN had a 1.5 fold increased risk for death, both compared to the general population as compared to siblings and spouses. There was no increased mortality preceding the ESRD.

SLE

Aringer et al (2019) Arthritis & Rheumatol 71:1400

Recently the 2019 EULAR/ACR classification criteria for SLE have been published. This includes positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains. These weighted criteria will help in a better classification of patients.

Arazi et al (2019) Nat Immunol 20:902, Der et al (2019) Nat Immunol 20:915

To increase mechanistic insights into the pathogenesis of lupus nephritis, two separate studies have focussed on single cell sequencing of renal biopsies of patients with LN. Arazi et al concentrated on the immune landscape and isolated and sequenced infiltrating immune cells from 24 biopsies. They identified 21 subsets of immune cells, signs of local B cell activation and a clear IFN-signature in most of these cells. In parallel they looked at the urine sediment and observed a strong correlation in gene expression in these cells.

Within the same consortium, Der et al performed scSeq on renal cells of 21 biopsies of patients with LN. They identified an IFN signature in tubular cells. In parallel they investigated 17 skin biopsies form the same patients, performed scSeq and observed that also keratinocytes showed such an IFN-signature. Both studies open the way to new monitoring tools in addition to the renal biopsy.

Membranous Nephropathy (MN)

Fervenza et al (2019) NEJM 381:36; Seitz-Polski et al (2019) CJASN 14:1173

In the MENTOR trial, 130 patients with Membranous Nephropathy underwent randomization for either rituximab or cyclosporin. At 12 months, it was shown that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. Treatment with rituximab showed a faster and greater magnitude of decline in autoantibodies to anti-PLA2R.

Since different protocols of rituximab treatment have been used, xx et al compared different regimens of rituximab. Participants of the NICE cohort (infusions of 1-g rituximab at 2-week intervals) were compared with participants from the GEMRITUX study (two infusions of 375 mg/m2 at 1-week interval). At month 6, before any treatment modifications, more remission was found in the NICE cohort, which was accompanied by higher levels of circulating rituximab. It is suggested that the higher dose rituximab protocol is more effective in depleting B-cells and thereby prevent epitope spreading which is associated with remission of MN.

Sethi et al (2019) JASN 30:1123

While anti-PLA2R is an established marker of primary membranous nephropathy (MN), there have up to now been no reports of autoantibodies in secondary forms of MN. Using microdissection and mass spectrometry Sethi and co-works were able to identify Exotosin 1 and 2 as antigens in a substantial subset of secondary MN, especially patients with class 5 lupus nephritis, but also some cases with primary MN associated with autoimmune features. Exotosin 1/2 immune complexes were never found in patients with PLA2R antibodies, and the IgG subclass distribution of the autoantibodies differed. No circulating antibodies where detected.

Nephrotic Syndrome

Colucci et al (2019) Kidney Int 96:971

Colucci and co-workers had made the serendipitous finding that some children with nephrotic syndrome had increased amounts of IgM on the surface of their T cell. When studying this in detail they made a series of interesting observations. Increased T cell IgM was found only on patients with steroid sensitive nephrotic syndrome, and not in those with established genetic causes or forms steroid resistant cases. When following steroid sensitive cases over time they found the amount of T cell IgM to be predictive of relapse. However, Increased T cell IgM was not correlated to total IgM levels or markers of acute inflammation such CRP. Rituximab treatment was associated with a reduction of T cell IgM, while relapse after such treatment was associated with reappearance of IgM on the cells. Biochemical analysis suggests that glycosylation differences might explain the binding of IgM to T cells.