Chronic Kidney Disease (CKD) - Full Clinical Notes

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1. DEFINITION

• Abnormal urine (proteinuria, hematuria)
• Abnormal blood tests (elevated creatinine)
• Abnormal imaging (small, scarred, or cystic kidneys)
• Abnormal GFR

Key point: Duration of at least 3 months is essential - it distinguishes CKD from Acute Kidney Injury (AKI).

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2. STAGING (KDIGO 2012 / 2024 - GFR + Albuminuria Based)

GFR Categories (G-staging)

Practical rule: Refer to nephrology when GFR < 30 mL/min/1.73 m². Initiate RRT preparation in G4.

Albuminuria Categories (A-staging)

Both GFR AND albuminuria categories together predict outcomes and guide management. CKD risk is described as a "heat map" - the combination of high A-category + low G-category = greatest risk.

Estimating GFR in Practice

• Cockcroft-Gault (older, useful for drug dosing): CrCl = (140 - Age) × Weight / (72 × SCr) × 0.85 if female
• MDRD: GFR = 1.86 × (SCr)^-1.154 × (Age)^-0.203 × 0.742 (if female)
• Cystatin-C based eGFR: preferred when muscle mass is abnormal (amputees, malnutrition, bodybuilders)

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3. CAUSES / ETIOLOGY

1. Diabetic nephropathy - leading cause in developed countries
2. Hypertensive nephrosclerosis - major cause in elderly
3. Glomerulonephritis - major cause in developing countries

• Polycystic kidney disease (PKD) - most common hereditary cause
• Obstructive uropathy (BPH, stones, retroperitoneal fibrosis)
• Reflux nephropathy (childhood VUR causing scarring)
• Tubulointerstitial nephritis (analgesic, NSAID, contrast nephropathy)
• Recurrent AKI (cumulative injury)
• HIV-associated nephropathy
• Lupus nephritis, Alport syndrome

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4. PATHOPHYSIOLOGY

Mechanisms of Progression

• Increased intraglomerular pressure → glomerular injury and sclerosis
• Angiotensin II plays a central role - causes efferent arteriolar vasoconstriction, raising intraglomerular pressure, and also promotes interstitial fibrosis directly
• Progressive loss of nephrons → further compensation by remaining nephrons → vicious cycle

Key pathologic drivers:

• Proteinuria - itself nephrotoxic (tubular uptake of filtered proteins triggers inflammatory and fibrotic cascades)
• Hypertension - accelerates glomerulosclerosis
• Metabolic acidosis - activates complement and promotes tubular injury
• Inflammation and fibrosis - ultimately leads to interstitial fibrosis and tubular atrophy (IFTA), the final common pathway

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5. CLINICAL FEATURES

Early CKD (G1-G3a) - Usually Asymptomatic

• Detected incidentally on routine lab work
• Hypertension (often the only finding)
• Proteinuria or hematuria on urinalysis

As CKD Progresses (G3b-G4):

• Fatigue, mild anemia
• Nocturia (early loss of concentrating ability)
• Edema (sodium retention)
• Bone pain, fractures (renal osteodystrophy)
• Pruritus (phosphate and uremic toxin accumulation)

Advanced CKD / Uremia (G5):

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6. WORKUP / INVESTIGATIONS

Initial Assessment

Key Imaging Pearls:

• Small kidneys (< 9 cm bilateral) = chronic process, CKD
• Normal or large kidneys with CKD = consider: diabetic nephropathy (early), amyloidosis, ADPKD, HIV nephropathy
• Duplex Doppler: assess for renal artery stenosis
• Renal biopsy indicated when cause is unclear and will change management (especially GFR > 30 and significant proteinuria)

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7. COMPLICATIONS & THEIR MANAGEMENT

7.1 Hypertension

• Strongly linked to CKD progression and cardiovascular death
• Target BP: < 120-130/80 mmHg (KDIGO 2024)
• First-line agents:
  • ACE inhibitors (e.g., ramipril, lisinopril) OR ARBs (e.g., losartan, telmisartan): reduce intraglomerular pressure and proteinuria; best evidence in diabetic and proteinuric CKD
  • Do NOT combine ACE inhibitor + ARB (increased harm - ONTARGET trial)
  • Loop diuretics (furosemide, torsemide) for fluid overload - higher doses needed in CKD due to diuretic resistance
  • Combination with metolazone for diuretic resistance

7.2 Anemia

• Normocytic normochromic anemia from decreased erythropoietin (EPO) production
• Also: iron deficiency (poor intake, dialysis losses), shortened RBC survival, marrow suppression
• Target Hb: 10 - 11.5 g/dL (avoid > 13 g/dL - increases cardiovascular events)
• Management:
  • Iron replacement first (oral or IV ferric carboxymaltose/iron sucrose - IV preferred in dialysis patients)
  • Erythropoiesis-stimulating agents (ESA) - epoetin alfa or darbepoetin - once iron replete; start when Hb < 10 g/dL

7.3 Metabolic Acidosis

• Impaired H+ excretion and reduced ammonia synthesis → anion gap or non-anion gap acidosis
• Acidosis worsens hyperkalemia, promotes bone dissolution, accelerates muscle wasting, speeds CKD progression
• Treatment:
  • Sodium bicarbonate (NaHCO3) supplementation - target serum HCO3 > 22 mEq/L
  • Dietary protein restriction helps (less acid load)
  • Veverimer (novel, binds HCl in GI tract) - emerging therapy

7.4 Hyperkalemia

• Risk from: decreased K+ excretion, metabolic acidosis (K+ shifts out of cells), dietary intake, RAAS blockers, potassium-sparing diuretics
• Management:
  • Dietary potassium restriction (limit bananas, oranges, tomatoes, potatoes)
  • Adjust or hold ACE inhibitor/ARB cautiously (weigh benefit vs. risk - do not reflexively stop)
  • Novel potassium binders: patiromer (Veltassa), sodium zirconium cyclosilicate (Lokelma) - allow continued use of RAAS blockers
  • Dialysis for severe/refractory hyperkalemia

7.5 CKD-Mineral Bone Disease (CKD-MBD)

• Osteitis fibrosa cystica (high-turnover bone disease from high PTH)
• Adynamic bone disease (low PTH, low turnover - often from over-suppression with calcium)
• Osteomalacia (rare today; was from aluminum toxicity in early dialysis era)
• Vascular calcification → increased cardiovascular mortality

1. Phosphate binders with meals to reduce GI phosphate absorption:
   • Calcium-based: calcium carbonate, calcium acetate (limit total elemental Ca to < 1500 mg/day)
   • Non-calcium-based (preferred in vascular calcification): sevelamer carbonate, lanthanum carbonate; ferric citrate and sucroferric oxyhydroxide (for dialysis patients)
2. Vitamin D repletion: If 25-OH vitamin D < 30 ng/mL, replete with ergocalciferol 50,000 IU weekly or cholecalciferol 2000-4000 IU daily
3. Active vitamin D (calcitriol or analogues): Calcitriol 0.25-1 µg/day, paricalcitol 1-5 µg/day - suppress PTH; monitor for hypercalcemia
4. Cinacalcet (calcimimetic): Acts on parathyroid Ca-sensing receptor to suppress PTH release; for dialysis patients only; risk of hypocalcemia

7.6 Cardiovascular Disease

• Leading cause of death in CKD patients (not ESRD itself)
• Risk starts rising from GFR < 60; dramatically elevated in G4/G5
• Mechanisms: hypertension, volume overload, LVH, accelerated atherosclerosis, uremic toxins, anemia, vascular calcification
• Management:
  • Statin therapy (cardiovascular benefit shown in SHARP trial even though no CKD progression benefit)
  • BP control (as above)
  • SGLT2 inhibitors (see Section 8 - Disease-Modifying Therapy)

7.7 Fluid Overload / Edema

• Due to sodium retention as GFR falls
• Management: dietary salt restriction (< 2 g Na/day), loop diuretics + metolazone for resistance
• "Sick day rules": instruct patients to hold diuretics during vomiting/diarrhea to avoid AKI from volume depletion

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8. DISEASE-MODIFYING / PROGRESSION-SLOWING THERAPY

8.1 RAAS Blockade (ACE inhibitors / ARBs)

• Mechanism: Dilate efferent arteriole → reduce intraglomerular hypertension; also reduce proteinuria directly
• Evidence: Strongly proven in diabetic nephropathy (IDNT, RENAAL, UKPDS trials); also beneficial in non-diabetic proteinuric CKD
• KDIGO 2024: Recommend for all patients with CKD + proteinuria (ACR > 300 mg/g) and/or hypertension, regardless of diabetes
• Monitor: Creatinine may rise up to 30% initially (acceptable - due to hemodynamic effect); hyperkalemia

8.2 SGLT2 Inhibitors (Gliflozins)

• Agents: Empagliflozin, dapagliflozin, canagliflozin
• Mechanism: Block glucose reabsorption in proximal tubule → tubuloglomerular feedback restoration → afferent arteriolar constriction → reduced intraglomerular pressure; also reduce inflammation and fibrosis
• Key trials:
  • CREDENCE (canagliflozin) - 30% reduction in renal composite endpoint
  • DAPA-CKD (dapagliflozin) - benefit in BOTH diabetic AND non-diabetic CKD
  • EMPA-KIDNEY (empagliflozin) - broad benefit across CKD spectrum
• KDIGO 2024 recommendation: All patients with CKD + T2DM, and most patients with CKD + eGFR ≥ 20, should receive an SGLT2 inhibitor
• Bonus benefits: Net neutral effect on potassium (counteracts hyperkalemia risk of RAAS blockers), weight loss, cardiovascular protection
• Caution: Genital mycotic infections; do not start if eGFR < 20; hold before surgery

8.3 Finerenone (Non-steroidal Mineralocorticoid Receptor Antagonist)

• Mechanism: Selective MRA - blocks aldosterone-mediated inflammation and fibrosis in kidney
• Evidence: FIDELIO-DKD and FIGARO-DKD trials - reduced CKD progression and cardiovascular events in T2DM + CKD with albuminuria, on top of RAAS blockade
• KDIGO 2024: Recommended for T2DM + CKD with ACR > 300 mg/g despite maximal RAAS blockade
• Advantage over spironolactone/eplerenone: lower hyperkalemia and gynecomastia risk

8.4 The "4-Pillar" Approach for Diabetic CKD (2024 Standard of Care)

1. RAAS blockade (ACE inhibitor or ARB)
2. SGLT2 inhibitor
3. Finerenone (if still progressing with albuminuria)
4. GLP-1 receptor agonist (e.g., semaglutide, dulaglutide) - additional CV and renal protection

8.5 Blood Pressure Control

• Target: < 120-130 mmHg systolic (KDIGO 2024, aligned with SPRINT trial)
• Reduces hyperfiltration-mediated injury

8.6 Protein Restriction

• Low-protein diet (0.6-0.8 g/kg/day) may slow progression by reducing hyperfiltration and acid load
• Very low protein diet (0.3-0.4 g/kg/day) + keto-acid supplements - used in severe CKD to delay dialysis
• Must avoid malnutrition - monitor albumin, body weight

8.7 Other

• Smoking cessation (direct nephrotoxic effect, worsens vascular disease)
• Weight loss (obesity drives hyperfiltration)
• Tolvaptan for ADPKD (vasopressin V2 receptor antagonist - slows cyst growth and CKD progression); requires LFT monitoring

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9. PREPARATION FOR RENAL REPLACEMENT THERAPY (RRT)

When to refer / prepare:

• Nephrology referral: GFR < 30 (Stage G4)
• Begin RRT education: Stage G4
• Vascular access creation: Stage G4 - protect non-dominant forearm (no IV lines, no blood pressure cuffs, no blood draws from that arm)

Indications to START dialysis (the classic "AEIOU"):

The GFR number alone is NOT an indication for dialysis. Start based on symptoms and metabolic derangements, not a specific GFR target (no mortality benefit to starting early).

Options for RRT:

1. Hemodialysis (HD) - 3-4 hours, 3x/week at dialysis center; home HD also available
2. Peritoneal Dialysis (PD) - uses peritoneal membrane as dialysis membrane; home-based; CAPD (continuous ambulatory) or APD (automated/overnight)
3. Kidney transplantation - best outcome; pre-emptive transplant (before dialysis) is ideal; living donor > deceased donor

Vaccinations in CKD:

• Hepatitis B vaccine: all patients with GFR < 30 (impaired response - need higher dose)
• Pneumococcal vaccine (PPSV23 + PCV20): all CKD patients regardless of stage
• Annual influenza vaccine
• COVID-19 vaccine

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10. MONITORING SCHEDULE (Practical)

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11. MEDICATIONS TO AVOID / USE WITH CAUTION IN CKD

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12. SPECIAL POPULATIONS

CKD in Diabetes

• Most common cause; RAAS + SGLT2 + finerenone is now standard of care
• Tight glycemic control slows progression (HbA1c target ~7%; avoid hypoglycemia)
• GLP-1 agonists (semaglutide) reduce albuminuria and provide CV protection

CKD in Pregnancy

• CKD worsens maternal and fetal outcomes: preterm delivery, pre-eclampsia, LBW
• Women with preconception GFR < 40 and proteinuria > 1 g/day have highest risk of permanent GFR decline
• Hold RAAS blockers (teratogenic - fetal renal dysgenesis); switch to methyldopa, labetalol, nifedipine for BP

CKD in Elderly

• eGFR declines physiologically with age (~1 mL/min/year after age 40)
• Distinguish physiologic aging from true CKD (absence of proteinuria or damage markers = likely physiologic)
• Conservative management (avoiding dialysis) may be appropriate in frail elderly - shared decision-making

CKD in Children

• Often from structural/congenital causes (CAKUT - congenital anomalies of kidney and urinary tract)
• Metabolic acidosis and growth failure are key management priorities
• Recombinant GH therapy for growth failure

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13. WHEN TO URGENTLY ESCALATE

• Rapidly declining GFR (> 5 mL/min/1.73m²/year or > 25% in 12 months)
• Nephrotic syndrome (proteinuria > 3.5 g/day + edema + hypoalbuminemia + hyperlipidemia)
• Active urinary sediment (RBC casts, WBC casts) - suggests active glomerulonephritis
• GFR < 30 - mandatory nephrology referral
• Refractory hyperkalemia, severe acidosis, uremic symptoms - possible urgent dialysis
• Unexplained bilateral small kidneys without prior diagnosis

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14. QUICK SUMMARY TABLE

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• CKD-EPI equation without race correction is now the standard
• SGLT2 inhibitors are now a first-line recommendation for CKD (not just for T2DM)
• The 4-pillar approach (RAAS + SGLT2 + finerenone + GLP-1 agonist) is the new paradigm for diabetic CKD
• Systolic BP target lowered to < 120 mmHg in many CKD patients
• Novel potassium binders (patiromer, SZC) enable sustained use of RAAS blockers

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1. Definition - The 3-month rule, what counts as kidney damage
2. Staging - Full KDIGO G1-G5 + A1-A3 dual staging system with clinical meaning for each stage
3. GFR Equations - CKD-EPI (current standard), MDRD, Cockcroft-Gault with practical guidance
4. Etiology - The "Big Three" causes plus all important others
5. Pathophysiology - Hyperfiltration → Angiotensin II → fibrosis cycle, role of proteinuria
6. Clinical Features - Stage-by-stage progression up to full uremia, with system-by-system breakdown
7. Workup - Complete investigation list with interpretation tips (e.g., small kidneys = CKD, normal/large = think specific causes)
8. Complications & Management - Hypertension, anemia, metabolic acidosis, hyperkalemia, CKD-MBD, cardiovascular disease - each with specific drug doses
9. Disease-Modifying Therapy - The 2024 "4-pillar" approach (RAAS + SGLT2 + Finerenone + GLP-1 agonist) - the biggest shift in CKD management in a decade
10. RRT Preparation - The AEIOU indications for dialysis, HD vs. PD vs. transplant
11. Drugs to Avoid - NSAIDs, contrast, metformin, aminoglycosides, etc.
12. Special Populations - Diabetes, pregnancy, elderly, pediatric
13. Monitoring Schedule - Stage-by-stage frequency
14. Red Flags - When to urgently escalate