Chapter 15 Glomerular disease

15.1 Proteinuria

Svenningsen et al. (2009): - activation of ENaC by proteolytic enzymes drives oedema in nephrotic syndrome.

15.2 IgAN

STOP-IgAN (2015): - supportive care only vs. immunosuppression (pred, CYC, aza) for 3 yrs in IgAN with PER > 0.75 g/day (n = 160). No significant difference in eGFR, uPCR, renal outcomes but more adverse events (infections, T2DM, weight gain) in immunosuppression group. German population.

TESTING 2017 (2017): - oral methylprednisolone vs. placebo in IgAN with PER > 1 g/day. Trial terminated prematurely due to excess of serious infections in the steroid group. (In this original protocol, a higher-dose prednisolone group recieved up to 60 mg/day equivalent prednisolone dose.)

TESTING 2022 (2022): - oral methylprednsiolone vs. placebo in IgAN with PER > 1 g/day (n = 503). Trial extended with revised protocol to use a uniformly lower dose of methylprednisolone and to give PJP prophylaxsis. The doses given equated to prednisolone 0.5 mg/kg/day (capped at 40 mg) for 2 months, tapering by 5 mg per month for total 6 – 9 months. 50% RRR in composite end-point (40% decline in eGFR, ESKD, renal death). Serious adverse events higher in steroid group (10% vs. 2%) - mainly in higher steroid dose group. Predominantly Chinese cohort; pre-SGLT2i era.

NEFIGAN (2017): - targeted-released budesonide vs. placebo in IgAN with PER > 0.75 g/day (n = 149 over 9 months). Reduction in uPCR (25%) without safety signal. Theoretically attractive as should exert few systemic steroid effects (high first-pass metabolism of budesonide).

NEFIGARD (2022): - ongoing phase 3 trial of targeted-release budesonide in IgAN and PER > 1g/day (n = 360). 25% reduction in uPCR and 7% higher eGFR at 9 months. Not yet reported in full. Surrogate outcomes; short follow-up; pre-SGLT2i era. See also the preliminary report.

DAPA-CKD subgroup (2021): - a pre-specified analysis of DAPA-CKD (dapagliflozin vs. placebo in CKD with albuminuria); n = 270. Benefits in this subgroup broadly similar to whole DAPA-CKD cohort. 70% RRR in composite endpoint (50% eGFR decline, ESKD, death). This effect magnitude is greater than in any other IgAN trial.

Pillebout et al. (2010): - very small RCT of pred + cyclophosphamide vs. pred alone in severe adult HSP with renal and gut disease. No additional benefit from CYC.

15.3 Membranous

Beck et al (2009): - description of PLA2R autoantibodies in membranous nephropathy.

MRC Membranous (2013): - prednisolone & chlorambucil vs. CsA vs. supportive care in primary membranous nephropathy. Rate of renal decline was slower in the prednisolone & chlorambucil group.

MENTOR (2019): - rituximab vs. oral CsA in iMN with CrCl > 40 ml/min and PER > 5g/day. Primary outcome of complete or partial remission of proteinuria by 24 months was acheived in 60% of RTX group and 20% of CsA group.

15.4 Minimal change

MinTAC (2020): - tacrolimus vs prednisolone monotherapy in adult MCD. Tacrolimus non-inferior wrt primary outcome of inducing complete remission by 8 weeks. ~90% in either group entered remission by 6 months; ~70% in each group relapsed.

15.5 FSGS

Savin et al. (1996): - patients with recurrent FSGS after transplant have a circulating factor that could increase glomerular permeablity in an in vitro assay.

15.6 APOL1 nephropathy

Parsa et al. (2013): - APOL1 risk variants were associated with accelerated progression of CKD in the AASK and CRIC study cohorts.

15.7 aHUS

Legendre et al. (2013): - recovery of renal function and freedom from TMA events observed in eculizumab-treated aHUS.