Section 4.7: Clinical Pharmacology: Renal & Urological Disorders

Clinical Pharmacology: Renal & Urological Disorders

Acute Kidney Injury (AKI)

AKI is a rapid decline in kidney function characterized by a rise in serum creatinine (SCr) and/or a decline in urine output.

• KDIGO Staging:
  • Stage 1: SCr increase of $\ge 0.3 \text{ mg/dL}$ within 48 hours or $1.5\text{–}1.9 \times$ baseline.
  • Stage 2: SCr increase of $2.0\text{–}2.9 \times$ baseline.
  • Stage 3: SCr increase of $\ge 3.0 \times$ baseline, SCr $\ge 4.0 \text{ mg/dL}$, or initiation of renal replacement therapy.
• Classifications and Drug-Induced Causes:
  • Prerenal AKI: Caused by renal hypoperfusion. Drug causes include NSAIDs (block prostaglandin-mediated afferent arteriole vasodilation) and ACEIs/ARBs (block angiotensin II-mediated efferent arteriole vasoconstriction).
  • Intrinsic AKI (Acute Tubular Necrosis - ATN): Direct damage to tubular cells. Drug causes include Aminoglycosides, Amphotericin B, Cisplatin, and Radiocontrast dye.
  • Intrinsic AKI (Acute Interstitial Nephritis - AIN): Immune-mediated hypersensitivity. Drug causes include Beta-lactams, PPIs, and NSAIDs.
  • Postrenal AKI: Obstruction of urine flow (e.g., anticholinergic drugs causing urinary retention, or acyclovir/sulfonamides crystallizing in tubules).

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Chronic Kidney Disease (CKD) Dosing and Complications

CKD is defined as kidney damage or GFR $< 60 \text{ mL/min/1.73 m}^2$ for $\ge 3$ months. Dosing adjustments are required for renally cleared drugs (e.g., gabapentin, enoxaparin, fluoroquinolones, metformin) to prevent accumulation and toxicity.

• Anemia of CKD: Caused by decreased erythropoietin production by the kidneys.
  • Treatment: Erythropoietin-Stimulating Agents (ESAs) like epoetin alfa or darbepoetin alfa.
  • Clinical Safety: Initiate ESAs only when $\text{Hb} < 10 \text{ g/dL}$ and target a range of $10\text{–}11 \text{ g/dL}$. Do not exceed $11 \text{ g/dL}$ due to increased risks of stroke, cardiovascular events, and death. Ensure iron stores are adequate (ferritin $> 500 \text{ ng/mL}$, TSAT $> 30%$) prior to starting ESAs.
• CKD Mineral and Bone Disorder (CKD-MBD): Hyperphosphatemia develops due to decreased renal phosphorus excretion. High phosphorus stimulates parathyroid hormone (PTH) release, causing secondary hyperparathyroidism and osteodystrophy.
  • Phosphate Binders: Must be taken with meals to bind dietary phosphate: calcium-based binders (Calcium Acetate, Calcium Carbonate) carry a risk of hypercalcemia and vascular calcification, while non-calcium-based binders (Sevelamer Carbonate, Lanthanum Carbonate) are preferred in patients with hypercalcemia or arterial calcification.
  • Vitamin D Analogs: Active vitamin D (Calcitriol) or analogs (paricalcitol) suppress PTH but can increase calcium and phosphate absorption.
  • Calcimimetics: Cinacalcet increases the sensitivity of calcium-sensing receptors on the parathyroid gland, reducing PTH secretion without raising calcium levels.

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Renal Replacement Therapy (RRT) & Drug Dialyzability

In patients on hemodialysis (HD), drug clearance during a session depends on:

• Molecular Weight: Smaller molecules ($< 500 \text{ Daltons}$) are easily cleared; large molecules (like vancomycin, $\sim 1450 \text{ Daltons}$) are poorly cleared by traditional dialyzers.
• Volume of Distribution ($V_d$): Drugs with small $V_d$ ($< 1 \text{ L/kg}$) remain in the blood and are dialyzable. Drugs with large $V_d$ ($> 2\text{–}5 \text{ L/kg}$) reside in tissues and are not removed.
• Protein Binding: Only unbound (free) drug is filtered. Highly protein-bound drugs ($> 80%$) are not dialyzable.
• Water Solubility: Highly water-soluble drugs are more readily cleared than lipid-soluble ones.
• Dialyzer Membrane: High-flux membranes have larger pore sizes and clear more drugs.

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Urinary Tract Infections (UTIs)

• Uncomplicated Cystitis: Occurs in healthy, non-pregnant, premenopausal females. First-line therapies:
  • Nitrofurantoin Monohydrate/Macrocrystals 100 mg BID for 5 days. Note: Contraindicated if $\text{CrCl} < 30 \text{ mL/min}$ due to lack of efficacy (insufficient concentration in urine).
  • Trimethoprim/Sulfamethoxazole (TMP/SMX) 160/800 mg (DS) BID for 3 days.
  • Fosfomycin 3 g orally as a single dose.
• Complicated Cystitis / Pyelonephritis: Treated with fluoroquinolones (Ciprofloxacin or Levofloxacin) or IV beta-lactams (e.g., Ceftriaxone) for 7–14 days.

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Benign Prostatic Hyperplasia (BPH)

BPH management targets static (enlarged prostate) and dynamic (smooth muscle tone) obstruction of the bladder neck.

• Alpha-1 Adrenergic Antagonists: Relax smooth muscle in the bladder neck and prostate.
  • Selective $\alpha_{1A}$ Blockers (Tamsulosin, Silodosin): Minimal systemic blood pressure effects. Side effects include retrograde ejaculation and floppy iris syndrome (avoid starting before cataract surgery).
  • Non-selective $\alpha_1$ Blockers (Terazosin, Doxazosin): Cause vasodilation. Side effects include orthostatic hypotension, dizziness, and syncope. Dose must be titrated slowly and administered at bedtime.
  • Onset: Rapid symptom relief (within days).
• 5-Alpha Reductase Inhibitors (5-ARIs): Block conversion of testosterone to dihydrotestosterone (DHT), shrinking the prostate gland.
  • Agents: Finasteride, Dutasteride.
  • Onset: Slow (takes 3 to 6 months to see benefit).
  • Clinical Safety: Teratogenic. Pregnant women or women of childbearing potential should not touch or handle crushed/broken tablets due to risk of absorption and feminization of a male fetus.