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 âoptimizedâ ie the maximum tolerated dose had to be at least 50% of max (đ) and BP < 150/100
Note biopsy timing doesnât 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 IrbesartanâŚ.?
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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 letâs 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
@hswapnil the other question is that (hopefully) we will need to pick therapies from an embarrassment of riches - so many agents being tested in IgAN - complement inhibitors, APRIL inhibitors, budesonide all immunomodulating - then non immune therapies too. Which treatment for whom and when? A really interesting space to watch over the next few years
Agreed. ERAs need to be combined with diuretics (Flozins, others, perhaps MRAs) - @ChristosArgyrop sez we should be doing this automatically (aka Cards combining ARNi with Valsartan)
Also:
- if Flozin/RASi/ERAs become standard baseline therapy, there will be less people remaining with 1 g proteinuria to qualify for the immunosuppression strategies. Is that wrong, as Sean Barbour pushed back on the podcast? https://podcasts.apple.com/ca/podcast/freely-filtered-a-nephjc-podcast/id1461664501?i=1000574598538
@ChristosArgyrop @hswapnil maybe we need to tailor immune therapies based on histology (or some other biomarker) independent of proteinuria? Now with EMPA-K and DAPA-CKD, I think almost all patients will get SGLT2i regardless of MEST-C score
Christos Argyropoulos MD, PhD@hswapnil @Bneuen let me push back on the idea that 1gm of protein in the urine is an absolute standard for anything in the era of 3 or 4 drugs with antiproteinuric effect. Residual relative risk of (spitballing here) 300mg/g vs <30 mg/g in the new era may be equal to the residual relative risk of 1gm/gm vs <30mg/g in the ancient pre 2017 times
@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 âcureâ like outcome?