PharmacologyTier 1Medical Sciences concept

Novel renoprotective drug targets in diabetic kidney disease (endothelin antagonists, finerenone, SGLT2i)

Core concept

Diabetic kidney disease is now treated with four independent, additive pillars, each hitting a different mechanism of glomerular injury

Pillar	Agent	Mechanism
1. RAS blockade	ACEi or ARB at maximum tolerated dose	Efferent arteriolar vasodilatation -> dec intraglomerular pressure
2. SGLT2 inhibition	Dapagliflozin, empagliflozin	inc distal NaCl -> tubuloglomerular feedback -> AFFERENT vasoconstriction; dec tubular O2 consumption
3. Non-steroidal MRA	Finerenone	Blocks MR-driven inflammation and fibrosis in kidney and heart
4. GLP-1 receptor agonist	Semaglutide (FLOW)	dec albuminuria, dec inflammation, weight and BP effects

The two arteriolar mechanisms are complementary - ACEi acts on the efferent vessel, SGLT2i on the afferent
Endothelin A receptor antagonists are the emerging fifth pathway - atrasentan, and zibotentan combined with dapagliflozin - potent antiproteinuric effect limited by fluid retention and heart failure

Finerenone
- Non-steroidal, selective, bulky - unlike spironolactone it does not bind androgen or progesterone receptors -> no gynaecomastia
- Tissue distribution is balanced between heart and kidney (steroidal MRAs concentrate in the kidney) -> less hyperkalaemia at equivalent effect
- FIDELIO-DKD and FIGARO-DKD: dec CKD progression and dec cardiovascular events in T2DM with CKD
- CONFIDENCE: finerenone + empagliflozin gives greater albuminuria reduction than either alone
- Start when eGFR >=25, potassium <=4.8-5.0 mmol/L, on a maximally tolerated RAS inhibitor with UACR >30 mg/g
- Recheck potassium at 4 weeks and after any dose change
Semaglutide (FLOW) - dec kidney disease progression and dec CV death in T2DM with CKD; benefit is additive to SGLT2i and MRA use
SGLT2 inhibitors - initiate down to eGFR ~20-25 and continue on dialysis initiation; the initial eGFR dip is expected
Sequencing - RAS inhibitor and SGLT2 inhibitor first, then add finerenone, then a GLP-1 RA if glycaemic or weight goals are unmet
- Do not delay one pillar to titrate another
Hyperkalaemia is the common limiting factor across pillars 1 and 3 - use potassium binders (patiromer, sodium zirconium cyclosilicate) rather than abandoning the drug

Albuminuria is both the target and the monitoring tool - a >30% fall in UACR predicts long-term kidney benefit
Screen annually in all type 2 (and type 1 from 5 years) with UACR and eGFR
A modest eGFR fall on starting any of these agents is haemodynamic and expected - accept up to ~30% and recheck at 2-4 weeks; a larger fall prompts a search for volume depletion or renal artery stenosis
Blood pressure target <130/80, and stop NSAIDs
Do not combine an ACE inhibitor with an ARB - more hyperkalaemia and AKI, no benefit (ONTARGET)
The pillars reduce cardiovascular events and heart failure as much as they reduce kidney outcomes - the patient with DKD dies of cardiovascular disease more often than of ESKD

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