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Mechanistic Deep Dive
SGLT2i Renal Mechanism
- Inhibit SGLT2 in PCT â â Na + glucose reabsorption
- â Distal Na delivery â tubuloglomerular feedback â â glomerular hyperfiltration
- Reduces intraglomerular pressure
- Anti-inflammatory + anti-fibrotic
- Lower renal O2 consumption
- Independent of glucose lowering
Finerenone vs Spironolactone
- Finerenone: non-steroidal, selective for MR
- Less hyperkalemia
- Less anti-androgen effect (gynecomastia, menstrual irregularity)
- Eplerenone: between (selective steroidal)
GLP-1 RA Renal Mechanism
- â Glomerular hyperfiltration
- Anti-inflammatory + anti-fibrotic
- Weight loss â reduces hyperfiltration further
- CV benefit may also benefit kidney
HIF Pathway
- HIF-α subunits stabilized in hypoxia
- HIF-PHIs inhibit prolyl hydroxylases â HIF stable
- â EPO transcription
- â Hepcidin â improved iron utilization
- Side effects: thrombotic events, malignancy concerns (long-term unclear)
Recent Trials & Updates
FLOW (2024)
- Semaglutide for T2DM + CKD
- 24% â composite renal endpoint
- Extends GLP-1 RA indication
DAPA-CKD (2020) + EMPA-KIDNEY (2022)
- Extended SGLT2i to non-DM CKD
- Foundation for broader use
ASCEND-D + ASCEND-ND (2021)
- Daprodustat in dialysis + non-dialysis
- FDA approval 2023
- Non-inferior to ESAs
PYRAMID, PROTECT (2024)
- Sparsentan for IgA + FSGS
- Endothelin antagonist combined ARB
AMPLITUDE (Ongoing)
- Inaxaplin for APOL1 nephropathy
EMPATHY (Ongoing)
- Empagliflozin in earlier CKD
High-Yield Specialist Points
Starting + Continuing SGLT2i
- Start at any eGFR ⥠20-25 (drug-specific)
- Initial 30% Cr â acceptable, indicates working
- Continue down to dialysis (real-world)
- Hold during acute illness, surgery (euglycemic DKA risk)
Starting Finerenone
- eGFR ⥠25
- K †4.8 to initiate
- Monitor K within 4 weeks
- Titrate from 10 to 20 mg
Combining 4 Pillars
- Multidisciplinary management
- Stepwise initiation (not all at once if multiple high-risk)
- Monitor: BP, K, Cr, weight
- Adjust as needed
GLP-1 RA Practical
- Subcutaneous injection (most)
- Oral semaglutide (Rybelsus) available
- Once weekly preferred (semaglutide, dulaglutide)
- GI side effects (nausea); tirzepatide has more
- Pancreatitis caution
Iron Repletion Strategies
- Oral: ferrous sulfate 325 mg BID-TID
- IV iron: faster repletion, common in HD
- Hepcidin â blunted oral absorption in CKD
ESAs Practical
- Subcutaneous monthly (darbepoetin) or weekly (epoetin)
- HD: post-dialysis
- Target Hgb 10-11.5 (donât normalize)
- Watch for CV events at higher Hgb (CHOIR, TREAT)
HIF-PHI Selection
- Oral advantage (vs injection)
- Effective at lower hemoglobin levels
- Side effects: thrombotic, BP, possible CV
- Long-term data evolving
Vascular Calcification Management
- Phosphate control
- Avoid excess Ca
- Vitamin K (controversial)
- Tenapanor (Na-H exchanger inhibitor in gut) â for hyperphosphatemia
Aminoglycoside Avoidance
- Especially in CKD
- Alternative antibiotics
- Risk of acute decline
Polypharmacy Management
- Many CKD patients on 10+ medications
- Regular medication review
- Pharmacist involvement
- Deprescribing when appropriate
CKD + Pregnancy
- Pre-conception counseling
- Higher risk (preeclampsia, IUGR, prematurity)
- Avoid ACE/ARB/MRA in pregnancy
- LMWH for clotting
- Multidisciplinary team
Patient + Family Education
- CKD as chronic condition
- Lifestyle modification
- Drug interactions
- Vaccinations (flu, pneumococcal, COVID, RSV ⥠60)
- Mental health
- Treatment options for ESKD
Conservative Management Option
- For elderly, multimorbid, dialysis-refusing
- Kidney supportive care
- Symptom management
- Quality of life focus
Pearls
- 4 pillars CKD treatment: ACE/ARB + SGLT2i + finerenone + GLP-1 RA
- HIF-PHI new for renal anemia
- Non-Ca phosphate binders preferred (vascular calcification)
- Patiromer + SZC for chronic hyperkalemia
- Sodium bicarbonate for acidosis (target HCO3 22-26)
- Statin in albuminuric CKD + age + ASCVD risk
- Emerging: sparsentan, iptacopan, inaxaplin
- Conservative care option for select advanced