Case 10: Yong Mon Park

Kidneys in Drug Metabolism

Phase 1 and 2 reaction in tubules (mostly PCT)

Drug Metabolism: Phase 1 Reaction

Oxidation, reduction, hydrolysis by cytochrome P450 convert drug to polar + water-soluble metabolite for excretion

Drug Metabolism: Phase 2 Reaction

Conjugation by UDP-glucoronosyltransferase

• Glucoronidation and glycation

Convert drugs to very polar + water-soluble metabolites for excretion

Drugs Metabolized by Kidneys

Most in liver

Probenecid (inhibit uric acid reabsorption) 

• Treat: Gout

Nalidixic acid (Fluoroquinilone)

• Treat: UTI, GI infection

Sulfonamides (Sulfa Drugs)

• Drugs with sulfonamid group

  • Antibiotics (sulfadiazine, sulfamethoxazole, dapsone)

  • Diuretics (thiazides, furosemide)

• Commonly cause drug-induced hypersensitivity

Kidneys in Drug Excretion

Filtration

Secretion

Reabsorption

Excretion: Glomerular Filtration

Most drugs

Unbound drug filtered from blood

Excretion: Tubular Secretion

Mostly in PCT

Organic transporters move charged drugs into lumen

Excretion: Tubular Reabsorption

Lipophilic/unionized drugs

Passive diffusion

Increase Excretion: Decrease reabsorption = Change urine pH = Drug in ionized (water-soluble) form

Tubular Damage Affecting Tubuloglomerular Feedback

Impaired NaCl Sensing

• Tubular damage + inflammation = Decreased detection and signalling at macula densa = Downregulate tubuloglomerular feedback = Abnormal GFR

Leaky Tubules

• Damaged tubules = Filtrate backleak = Decreased excretion with normal filtration = Decreased net filtration (GFR)

*Decreased RBF

• Inflammation + fibrosis from damage = Decrerase RBF and O2 delivery (ischemia) = Decreased GFR

Medication Allergy: Immune Response

1. Drugs bind endogenous proteins = Immunogenic complexes

2. APCs present complexes to T-cells = Type 1 OR 4 Reaction

3. Increase inflammatory cells, crystals, and proteins in renal tubules = Acute interstitial nephritis = AKI

Medication Allergy: Type 1 Reaction

Immediate

• Antibodies

1. Helper T-cells activate B-cells to produce IgE antibodies against drug

2. IgE attach to Fc receptors on mast cells and basophils

3. Drug re-exposure cause IgE complexes on mast cells and basophils to cross-link = Degranulation + histamine release

4. Increase inflammatory cells in renal tubules = Acute interstitial nephritis = AKI

Medication Allergy: Type 2

Delayed

• Sensitized T-cells

1. T-cells recognize drug-modified peptides presented by APCs = T-cells differentiate + produce cytokines + recruit immune cells

Medication Allergy: Sulfanomides

Common: Antibiotics

• Inhibit folic acid synthesis (bacteriostatic)

• Ex: Sulfamethoazole/trimethoprim (SMZ/TMP)

Less Common: Nonantibiotic

• Furosemide (loop diuretic)

Sulfanomide Alternatives

Antbiotics:

• Fluoquinolone

  • Inhibit DNA replication (bactericidal)

  • Ex: Ciprofloxacin

• Nitrofuran

  • Inhibit protein synthesis (bactericidal)

  • Ex: Nitroflurantoin

• Beta-lactams

  • Inhibit cell wall synthesis (bactericidal)

  • Ex: Penicillin, cephalosporin

Nonantibiotic:

• Nonsulfanomide diuretic (spironolactone)

UTI Treatment: First-Line

SMZ/TMP

Nitrofuran

UTI Treatment: Second-Line

Beta-lactams

• Cephalosporins

• Amoxicillin/clavulanate