5.3 Acute Kidney Injury & Chronic Kidney Disease Staging

KDIGO Definition & Staging of Acute Kidney Injury

Acute Kidney Injury (AKI) is characterized by a rapid, reversible decline in renal excretory function, leading to the retention of nitrogenous waste products (urea, creatinine) and disruption of extracellular fluid and electrolyte homeostasis. The Kidney Disease: Improving Global Outcomes (KDIGO) consensus criteria define AKI by the presence of any one of the following:

• Increase in serum creatinine by >= 26.5 umol/L (>= 0.3 mg/dL) within 48 hours; OR
• Increase in serum creatinine to >= 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; OR
• Urine volume < 0.5 mL/kg/hour for 6 consecutive hours.

KDIGO Clinical Severity Staging

1. Stage 1:
   • Serum creatinine 1.5 to 1.9 times baseline, OR an absolute increase >= 26.5 umol/L (0.3 mg/dL)
   • Urine output < 0.5 mL/kg/hour for 6 to 12 hours
2. Stage 2:
   • Serum creatinine 2.0 to 2.9 times baseline
   • Urine output < 0.5 mL/kg/hour for >= 12 hours
3. Stage 3:
   • Serum creatinine >= 3.0 times baseline, OR serum creatinine >= 353.6 umol/L (>= 4.0 mg/dL), OR initiation of renal replacement therapy (RRT), OR in patients < 18 years, a decrease in eGFR to < 35 mL/min/1.73m2
   • Urine output < 0.3 mL/kg/hour for >= 24 hours, OR anuria for >= 12 hours

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Etiological Spectrum: Pre-Renal, Intrinsic & Post-Renal

1. Pre-Renal Azotemia (Functional Renal Hypoperfusion)

• Intact tubular and glomerular architecture responding physiologically to decreased renal blood flow.
• Absolute Hypovolemia: Hemorrhage, gastrointestinal fluid losses (diarrhea, vomiting), renal losses (excessive diuretics, osmotic diuresis), dermal losses (burns).
• Decreased Effective Circulating Arterial Volume: Congestive heart failure (cardiorenal syndrome), decompensated cirrhosis with ascites (hepatorenal syndrome), nephrotic syndrome, severe systemic vasodilation in sepsis.
• Hemodynamic Autoregulatory Impairment:
  • NSAIDs: Inhibit renal cyclooxygenase, blocking prostaglandin synthesis and preventing compensatory afferent arteriolar vasodilation.
  • ACE Inhibitors / ARBs: Inhibit angiotensin II, preventing compensatory efferent arteriolar vasoconstriction. In bilateral renal artery stenosis or severe hypovolemia, this abolishes intraglomerular hydrostatic pressure, precipitating acute pre-renal AKI.

2. Intrinsic Renal AKI (Parenchymal Damage)

• Acute Tubular Necrosis (ATN): Accounts for > 80% of intrinsic AKI cases:
  • Ischemic ATN: Prolonged, untreated pre-renal hypoperfusion, septic shock, major vascular surgery, prolonged hypotension.
  • Nephrotoxic ATN: Exogenous toxins include aminoglycosides (gentamicin, amikacin causing proximal tubular necrosis), iodinated intravenous radiocontrast, amphotericin B, cisplatin, and vancomycin. Endogenous toxins include myoglobin (rhabdomyolysis from crush injury, sickle cell crisis, prolonged immobilization, or statins), hemoglobin (massive intravascular hemolysis), and monoclonal light chains (multiple myeloma cast nephropathy).
• Acute Interstitial Nephritis (AIN): Drug-induced allergic/hypersensitivity reaction (75% of cases; penicillins, cephalosporins, sulfonamides, PPIs, NSAIDs, ciprofloxacin). Classically associated with sterile pyuria, white blood cell casts, and occasionally urinary eosinophils. Systemic triad of fever, maculopapular rash, and peripheral eosinophilia is present in < 10% of cases.
• Acute Glomerulonephritis (AGN): Post-infectious glomerulonephritis, lupus nephritis, ANCA-associated vasculitis, anti-GBM (Goodpasture) disease. Characterized by hematuria, dysmorphic red blood cells (acanthocytes), red blood cell casts, and variable proteinuria.
• Renal Atheroembolism (Cholesterol Crystal Embolization): Typically develops days to weeks following vascular catheterization, aortic surgery, or aggressive anticoagulation in elderly vasculopaths. Manifests with livedo reticularis on the lower extremities, "blue toe" syndrome, transient eosinophilia, and hypocomplementemia.

3. Post-Renal AKI (Obstructive Uropathy)

• Obstruction of the urinary collecting system from the renal calyces down to the external urethral meatus. To cause significant AKI in patients with two functioning kidneys, obstruction must be bilateral (or unilateral in a solitary functional kidney).
• Causes: Benign Prostatic Hyperplasia (BPH), prostate adenocarcinoma, cervical or pelvic malignancies (very common in Caribbean regional hospital admissions), retroperitoneal fibrosis, bilateral nephrolithiasis, blocked indwelling urinary catheter.
• Diagnostic Modality: Urgent renal ultrasonography to identify bilateral hydronephrosis and assess renal cortical thickness. (Note: Hydronephrosis may be absent in early acute obstruction [< 24-48 hours], retroperitoneal fibrosis, or severe volume depletion).

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Diagnostic Matrix: Pre-Renal Azotemia vs. Acute Tubular Necrosis

Differentiating pre-renal azotemia from intrinsic ATN is among the most vital diagnostic tasks in internal medicine: pre-renal azotemia responds dramatically to volume resuscitation, whereas indiscriminate fluid loading in established ATN causes lethal pulmonary edema.

Fractional Excretion of Sodium (FeNa) & Urea (FeUrea)

• Fractional Excretion of Sodium: Measures the percentage of filtered sodium excreted in the final urine:
  • FeNa Formula: FeNa (%) = [(Urine Na × Serum Cr) / (Serum Na × Urine Cr)] × 100
  • FeNa < 1%: Indicates intact tubular avidity for sodium reabsorption, characteristic of pre-renal azotemia.
  • FeNa > 2%: Supports impaired tubular sodium reabsorption and ATN in the appropriate clinical context; it is not diagnostic alone.
  • Caveat: FeNa is falsely elevated in patients actively receiving loop or thiazide diuretics. In patients on diuretics, calculate the Fractional Excretion of Urea (FeUrea):
    • FeUrea Formula: FeUrea (%) = [(Urine Urea × Serum Cr) / (Serum Urea × Urine Cr)] × 100
    • FeUrea < 35% supports pre-renal azotemia; it may help when diuretics confound FeNa, but must be interpreted with volume status, microscopy and clinical response.
    • FeUrea > 50% supports intrinsic tubular dysfunction; neither fractional-excretion index alone establishes the diagnosis.

Diagnostic Comparison Table

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Emergency Indications for Renal Replacement Therapy

When conservative medical management fails to correct life-threatening metabolic, electrolyte, or volumetric derangements in AKI, emergency renal replacement therapy (hemodialysis or continuous renal replacement therapy [CRRT]) must be initiated immediately. These are remembered via the AEIOU mnemonic:

• A — Acidosis: Severe refractory metabolic acidosis with arterial pH < 7.15 to 7.20, unresponsive to medical therapy (or where sodium bicarbonate administration is precluded by severe volume overload).
• E — Electrolytes: Severe refractory hyperkalemia (serum potassium > 6.5 mmol/L), or rapidly rising levels despite medical shifting maneuvers, or hyperkalemia accompanied by life-threatening ECG conduction delays (QRS widening, sine wave).
• I — Ingestions / Intoxications: Poisoning with dialyzable toxins with severe toxicity (SLIME mnemonic: Salicylates, Lithium, Isopropanol, Methanol, Ethylene glycol).
• O — Overload: Acute, refractory pulmonary edema and volume overload unresponsive to intravenous loop diuretics.
• U — Uremia: Manifestations of severe end-organ uremic toxicity: uremic pericarditis (pericardial friction rub, risk of hemorrhagic tamponade; note: anticoagulation is contraindicated), uremic encephalopathy (asterixis, myoclonus, seizures, coma), or uremic bleeding diathesis secondary to platelet dysfunction.

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Chronic Kidney Disease (CKD): Staging & Pathophysiology

Chronic Kidney Disease is defined as abnormalities of kidney structure or function present for greater than 3 months, with health implications. In the Caribbean, the overwhelming burden of CKD is driven by diabetic kidney disease and hypertensive nephrosclerosis, exacerbated by regional genetic risks and sickle cell nephropathy.

KDIGO Staging Framework (G and A Categories)

CKD staging requires dual classification by both Estimated Glomerular Filtration Rate (G-stage) and Albuminuria (A-stage):

• G-Stages (by eGFR in mL/min/1.73m2):
  • G1: Normal or high (eGFR >= 90) with structural or urinalysis markers of damage
  • G2: Mildly decreased (eGFR 60 to 89) with markers of damage
  • G3a: Mild-to-moderately decreased (eGFR 45 to 59)
  • G3b: Moderately-to-severely decreased (eGFR 30 to 44)
  • G4: Severely decreased (eGFR 15 to 29)
  • G5: Kidney Failure / End-Stage Kidney Disease (eGFR < 15, or dialysis-dependent)
• A-Stages (by Urine Albumin-to-Creatinine Ratio, uACR):
  • A1: Normal to mildly increased (uACR < 30 mg/g or < 3 mg/mmol)
  • A2: Moderately increased (uACR 30 to 300 mg/g or 3-30 mg/mmol; formerly "microalbuminuria")
  • A3: Severely increased (uACR > 300 mg/g or > 30 mg/mmol; includes nephrotic range proteinuria > 2200 mg/g)

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Systemic Complications & Management of CKD

1. CKD-Mineral and Bone Disorder (CKD-MBD)

• Pathophysiology: As functional nephron mass declines below 60 mL/min/1.73m2, renal phosphate clearance decreases, causing hyperphosphatemia. Elevated phosphate triggers secretion of Fibroblast Growth Factor 23 (FGF-23) from osteocytes. Concurrently, loss of renal 1-alpha-hydroxylase impairs the conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D (calcitriol), leading to reduced intestinal calcium absorption and hypocalcemia.
• Hypocalcemia, hyperphosphatemia, and low calcitriol stimulate excessive, uninhibited secretion of Parathyroid Hormone (PTH), driving secondary hyperparathyroidism.
• Consequences include high-turnover bone disease (osteitis fibrosa cystica), vascular and medial arterial calcification, and accelerated cardiovascular mortality.
• Management:
  • Dietary phosphate restriction (< 800-1000 mg/day).
  • Phosphate Binders: Non-calcium-based binders (e.g., Sevelamer carbonate) are preferred over calcium-based binders (calcium acetate, calcium carbonate) to avoid accelerating metastatic vascular calcification.
  • Vitamin D: Correct nutritional vitamin D deficiency first. In non-dialysis CKD, reserve calcitriol/paricalcitol for severe, progressive hyperparathyroidism in G4–G5 after addressing modifiable factors.
  • Calcimimetics: In dialysis patients needing PTH-lowering treatment, cinacalcet activates the parathyroid calcium-sensing receptor and lowers PTH; monitor calcium for hypocalcemia.

2. Anemia of Chronic Kidney Disease

• Pathophysiology: Caused primarily by deficient production of erythropoietin (EPO) by damaged peritubular interstitial renal fibroblasts, compounded by elevated hepcidin levels (which block intestinal iron absorption and trap iron inside reticuloendothelial macrophages).
• Management:
  • Correct iron deficiency before ESA. KDIGO iron-start criteria: hemodialysis, ferritin <=500 mcg/L and TSAT <=30%; non-HD, ferritin <100 with TSAT <40%, or ferritin 100–<300 with TSAT <25%. Withhold routine iron if ferritin >700 or TSAT >=40%.
  • Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa or darbepoetin alfa.
  • Hemoglobin Target: Maintain target hemoglobin strictly between 100 and 115 g/L (10.0-11.5 g/dL). Landmark randomized trials (CHOIR, CREATE, TREAT) demonstrated that targeting normal hemoglobin concentrations (> 130 g/L) significantly increases strokes, arteriovenous fistula thrombosis, and cardiovascular mortality.

3. Nephroprotective Therapy & Slowing Progression

• Renin-Angiotensin-Aldosterone System (RAAS) Blockade: ACE inhibitors or ARBs are first-line agents in hypertensive patients with albuminuria (uACR >= 30 mg/g). They selectively dilate the efferent arteriole, reducing intraglomerular hypertension and preserving glomerular structure. A serum creatinine rise up to 30% after initiation is hemodynamically acceptable.
• SGLT2 Inhibitors (Dapagliflozin, Empagliflozin): Block sodium-glucose cotransporter-2 in the proximal tubule, restoring tubuloglomerular feedback (afferent arteriolar constriction), lowering intraglomerular pressure, and dramatically reducing CKD progression and heart failure hospitalizations across diabetic and non-diabetic CKD.
• Non-Steroidal Mineralocorticoid Receptor Antagonists (Finerenone): Significantly reduces albuminuria and cardiorenal events in diabetic kidney disease when added to standard therapy.