PK in Renal Impairment

## Renal Impairment and Drug Therapy

Chronic kidney disease (CKD) affects approximately 15% of adults worldwide. Reduced renal function directly impairs excretion of renally cleared drugs and their metabolites, but also alters absorption, protein binding, distribution, and even hepatic metabolism through uremic toxins.

## Effects on Each PK Parameter

### Absorption

- Uremia raises gastric pH (urease-producing bacteria generate ammonia), reducing absorption of drugs requiring acid
- Edema of the GI tract may impair absorption
- Gastroparesis from diabetic nephropathy slows gastric emptying

### Distribution

- **Hypoalbuminemia** (nephrotic syndrome, advanced CKD) increases free drug fraction. Phenytoin free fraction may double, making total levels misleading — free phenytoin levels should be monitored.
- **Uremic toxins** displace drugs from albumin binding sites, further increasing free fractions
- Fluid overload increases Vd for hydrophilic drugs (vancomycin, aminoglycosides)

### Metabolism

CKD reduces hepatic CYP activity even in the absence of liver disease. Uremic toxins inhibit CYP3A4, CYP2C9, and CYP2D6. Non-renal clearance of drugs like erythromycin and codeine is reduced by 30-50% in severe CKD. This is often underappreciated.

### Excretion

The primary concern. As GFR declines:

| CKD Stage | eGFR (mL/min) | Clinical Action |
|-----------|--------------|-----------------|
| 1 | > 90 | Usually no adjustment needed |
| 2 | 60-89 | Monitor; adjust selected drugs |
| 3a/3b | 30-59 | Adjust most renally cleared drugs |
| 4 | 15-29 | Significant adjustments; avoid nephrotoxins |
| 5 | < 15 | Dialysis considerations; major adjustments |

## Dose Adjustment Methods

### Dose Reduction

Reduce each dose while maintaining the same dosing interval. This lowers Cmax and average Css while maintaining time-dependent activity. Preferred for concentration-dependent toxicity.

**Adjusted dose = Normal dose x (Patient CrCl / Normal CrCl)**

### Interval Extension

Keep the same dose but extend the interval between doses. This maintains Cmax for concentration-dependent drugs (aminoglycosides) while allowing more elimination time.

**Adjusted interval = Normal interval x (Normal CrCl / Patient CrCl)**

### Combination

Many drugs require both dose reduction and interval extension. Drug-specific guidelines from package inserts or renal dosing references should be followed.

## Dialysis Considerations

Hemodialysis removes drugs with:

- Low molecular weight (< 500 Da for conventional dialysis, < 20 kDa for high-flux)
- Low protein binding (free drug is dialyzable)
- Small Vd (drug is in the blood compartment)
- Water solubility

Post-dialysis supplemental doses are needed for aminoglycosides, vancomycin, and many beta-lactams. Drugs with large Vd (digoxin, amiodarone) are minimally affected by dialysis.

## Key Takeaways

- CKD affects all PK parameters, not just renal excretion
- Uremic toxins reduce hepatic CYP activity, affecting non-renal clearance
- Hypoalbuminemia increases free drug fractions — monitor free levels when applicable
- Choose dose reduction, interval extension, or both based on the drug's PK profile
- Dialyzability depends on molecular weight, protein binding, Vd, and water solubility