Chapter 7  ·  Module 7

Hypertension in Chronic Kidney Disease

Pathophysiology, renoprotective pharmacology, and the emerging triple strategy

The Chronic Kidney Disease-Hypertension Bidirectional Cycle

Self-Amplifying — Each Side Worsens the Other

How Chronic Kidney Disease Drives Hypertension

Nephron Loss

Reduced natriuretic capacity → sodium and water retention → volume-dependent hypertension

RAAS Activation

Ischemic nephrons release renin inappropriately → angiotensin II → vasoconstriction + aldosterone → more sodium retention

Sympathetic Activation

Renal afferent nerve signals from damaged kidney → increased sympathetic outflow → raises cardiac output and peripheral resistance

↓ All three mechanisms elevate systemic blood pressure ↓

Intraglomerular HTN

Elevated glomerular capillary pressure from hyperfiltration and efferent constriction

Proteinuria

Filtered proteins activate tubular inflammation and fibrosis — nephrotoxic

More Nephron Loss

Tubular injury → interstitial fibrosis → glomerulosclerosis → cycle repeats

RAAS Inhibitor Renoprotection & Monitoring

Mechanism Beyond Blood Pressure

Why RAAS Inhibitors Protect the Kidney

  • Angiotensin II constricts efferent arteriole → raises intraglomerular pressure; RAAS inhibitors dilate efferent arteriole → reduce intraglomerular pressure → less proteinuria and less glomerulosclerosis
  • Reduce glomerular filtration barrier permeability (independent of pressure effect)
  • Block angiotensin II-driven transforming growth factor beta production → less interstitial fibrosis
  • First-line for all CKD with albuminuria above 30 mg/g (KDIGO 2021 Category A)
  • Do NOT combine ACEi + ARB: VA NEPHRON-D — excess acute kidney injury, no renal benefit

Monitoring After Initiation

The Acceptable Creatinine Rise

  • Check creatinine, eGFR, potassium at 2–4 weeks
  • Rise up to 30%: expected and acceptable — reflects reduced intraglomerular pressure (the goal)
  • Rise 30–50%: check for volume depletion, NSAIDs, contrast; consider dose reduction
  • Rise above 50%: hold drug, reassess, restart at lower dose
  • Potassium above 5.5 mEq/L: dose reduction or discontinuation
  • Sick-day rule: hold RAAS inhibitor + diuretic during vomiting, diarrhea, or fever

Drug Selection Across Chronic Kidney Disease Stages

Key Transitions: Thiazide Efficacy Falls, Loop Diuretics Replace, Potassium Risk Rises

Stage-by-Stage Prescribing Guide

Stage / eGFR RAAS Inhibitor Diuretic Other Notes
Stage 1–2
eGFR ≥60		 ACEi or ARB if albuminuria above 30 mg/g; optional without albuminuria Thiazide or thiazide-like — full efficacy Standard four-class framework; target below 130/80
Stage 3
eGFR 30–59		 Continue if tolerated; first-line with albuminuria Chlorthalidone or indapamide preferred; transition to loop diuretic at eGFR 30–45 if volume control inadequate CCBs (amlodipine) highly effective — no dose adjustment; monitor potassium every 3 months
Stage 4
eGFR 15–29		 Continue if potassium below 5.0; fosinopril (ACEi) or telmisartan (ARB) preferred — dual or biliary elimination Loop diuretics first-line; torsemide preferred (better bioavailability) Spironolactone/eplerenone: extreme caution (hyperkalemia); bisoprolol preferred beta-blocker (dual elimination)
Stage 5 / ESRD
eGFR below 15		 Continue for cardiovascular protection if potassium manageable; telmisartan or candesartan preferred (not dialyzed) High-dose loop diuretics pre-dialysis; ultrafiltration on hemodialysis Volume control dominates; CCBs effective and safe at all stages

Emerging Triple Renoprotective Strategy — Type 2 Diabetic CKD

1

RAAS Inhibitor

ACEi or ARB
Dilates efferent arteriole → reduces intraglomerular pressure
Blocks angiotensin II fibrosis (TGF-beta)
Lewis 1993; RENAAL; IDNT; REIN

2

SGLT2 Inhibitor

Canagliflozin, Dapagliflozin, Empagliflozin
Restores tubuloglomerular feedback → afferent constriction → reduces intraglomerular pressure
CREDENCE (−40%); DAPA-CKD (−39%); EMPA-KIDNEY (−28%)

3

Finerenone

Non-steroidal MRA
Blocks aldosterone-mediated inflammation and fibrosis at mineralocorticoid receptor
Lower hyperkalemia risk than spironolactone; no sex hormone effects
FIDELIO-DKD: −18% renal composite

Why Three Drugs? Three Complementary Targets

Each agent targets a distinct driver of progressive nephron loss in type 2 diabetic CKD. RAAS inhibitors reduce efferent arteriolar tone and angiotensin II-driven fibrosis. SGLT2 inhibitors restore tubuloglomerular feedback, reducing afferent arteriolar pressure. Finerenone blocks aldosterone-mediated renal inflammation and fibrosis. Together they address all three major pathways — and their combination is supported by guideline recommendations from KDIGO and ADA.