Swapnil Hiremath 
MDHeadline result from the #Sparsentan PROTECT trial in #IgANephropathy in #Lancet https://authors.elsevier.com/c/1grIl_3CjG8WAP
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Big proteinuria reduction:
This is the methods section of interest - RASi āoptimizedā ie the maximum tolerated dose had to be at least 50% of max (š) and BP < 150/100
Note biopsy timing doesnāt matter
Note exclusion for heart failure (Endothelin antagonist specific issue!)
This is the interim result for FDA approval (obtained) of 36 week follow up, final follow up is 114 weeks, plus an observational period
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This is the other way of looking at proteinuria reduction - again pretty impressive
You may think - perhaps this is related to BP reduction with 400 mg Sparsentan vs 300 mg Irbesartanā¦.?
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But you would be wrong
Hardly any difference in BP!
Hmm - maybe Endothelin blockade does something specific hemodynamically?
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Adverse effects of interest - as expected more sodium retention and even more AKI (!) with #Sparsentan
The clinical kidney outcomes were less with Sparsentan (7 vs 13) but this is where I would like to see longer term effects of that sodium retention with Sparsentan. So letās wait and see for final results I say
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Remiss in not showing table 1 - here it is
~ 40 years old
~ 70% men
~ 30% Asian
Just over a gram of proteinuria
GFR just under ~ 60
About 6+ years from biopsy - so mostly burnt out IgA like the Flozin trials?
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On the topic of flozins - no flozins allowed during double blind phase
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My 2 cents: I am not using #Sparsentan - clearly flozins cheaper, with CV benefit. Sparsentan might reduce proteinuria but in long term cause CV harm.
Should we use them in combo? Maybe
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Brendon Neuen@hswapnil knew I should head to Mastadon for the discussion! IMO RASi and SGLT2i now the foundation upon which other therapies added. Given the fluid retention issue I see ERAS as an adjunct to SGLT2i in ppl who remain at very high risk; the MoA seems probably disease agnostic - being tested in lots of CKD aetiologies (AFFINITY, ALIGN, ZENITH etc.). How we mitigate the fluid retention issue will be key, given long time frames over which ppl with CKD are treated
Christos Argyropoulos MD, PhD@Bneuen @hswapnil We mitigate the risk by hitting the books : it is either a residual ETRB effect (less likely) or a pressure natriuresis effect (much more likely). Regardless, pressure natriuresis works by sodium resorption along the nephron, so hit it with a proximal (sglt2i), a distal (MRA or even amiloride) and possibly a pendrin inhibitor (probenecid being one of them). No matter what one chooses initially, one should eval the pt within 3-4wk and adjust the regimen accordingly.
@ChristosArgyrop @Bneuen the point Sean Barbour was making is that there is something immunologically going on in these patients (like those included in TESTING) that a course of steroids fixes - these patients (and mostly within months of biopsy) May deserve steroids and a ācureā like outcome?