RENAL CLEARANCE

Definition: 

• It is the volume of blood from which the drug is totally removed in unit time through renal excretion.  
• Expressed as CLR 
  
• It has units : mL/min 
• Major Organ for Excretion of Drugs is the Kidney.  
• Functional Units are 
• Nephron 
• Bowman‘s Capsule 
• Proximal Tubule 
• Loop of Henle 
• Distal Tubule 
• Collecting Duct 

EQUATION:

• CLR = Rate of urinary excretion / Plasma drug concentration 
• Physiologically,  
• CLR = Rate of Filtration + Rate of Secretion - Rate of Reabsorption 
•                                   Plasma drug concentration (C) 

Normal values of: 

• Renal blood flow (RBF) = 1200 ml/min  
• Glomerular filtration rate (GFR) = 125 ml/min  
• Urine flow = 1.5 ml/min. 

GFR is measured by exogeneous /endogenous markers like Inulin/Creatine. Inulin clearance is accurate measurement of GFR but tedious method while creatinine clearance widely used clinically for assessment of renal function. 

Creatinine clearance: 

• CLcr = Rate of creatinine excretion in urine 
•              Serum creatinine in mg% 

In Males: 

• CLcr = (140 – Age)*W 
•                   72 * Scr 

For Females: 

• CLcr = (140 – Age)*W = 0.9*Clcr of males
•                     85 * Scr
• Where,  
• CLcr   = creatinine clearance in ml/min
• Scr   = serum creatinine in mg%
• W    = weight in kgs. 
• Age = in terms of years. 
• Normal creatinine clearance values: 120-130 ml/min
• Value of 20-50 ml/min : moderate renal failure
• Value of < 10 ml/min : severe renal impairment 

Inulin Clearance:

This is for inulin, and yields the glomerular filtration rate. 

• Value for normal males:  124.5 ± 9.7 ml/min 
• Value for normal females:  108.8 ± 13.5 ml/min  

Factors affecting renal clearance: 

1. Physiological properties of drug: 

A.  Molecular size: 

MOLECULAR SIZE	EXCRETION BY KIDNEY
< 300 daltons, water soluble	Readily excreted
300-500 daltons	Excreted
> 500 daltons	Lesser extent

B. Pka:  

• Pka and ionized drug are poorly absorbed passively and excreted rapidly. 

C. Lipid Solubility: 

• Urinary excretion of unchanged drug is inversely proportional to the lipophilicity. 

2. Distribution & Binding Characteristics of drug: 

• Drug extensilvely bound to proteins have long half life because renal clearance is small and urine flow rate is just 1-2ml/min. 
• Example: 
• ClR of oxytetracycline (66% unbound) is 99ml/min. 
• ClR of doxycycline (7% unbound) is 16 ml/min. 
• 
  

3. Plasma Concentration of Drugs:

• Glomerular filtration and reabsorption are directly affected by plasma drug concentration as both are passive processes. 
• Drug not bound to plasma proteins and excreted by filtration only, shows a linear relationship between rate of excretion and plasma drug concentration. 

4. Blood Flow to Kidneys: 

• It is important for the drugs excreted by the glomerular filtration and those that are actively secreted. 
• For actively secreted drugs, increased perfusion increases the contact of drug with secretory sites and enhances their elimination. 
• Renal Clearance in such cases is called as perfusion rate limited. 

5. Biological Factors: 

• Renal clearance is approx. 10% lower in females than in males. 
• In new borns renal function is 30-40% less than the adults and attains maturity between 2.5 – 5 months age. 
• In old age, GFR decreases and tubular function is altered thus prolongs the half life of the administered drug. 

6. Drug Interactions: 

• Any drug interaction that results in alteration of binding characteristics, renal blood flow, active secretion, urine pH and intrinsic clearance and forced diuresis would alter the renal clearance of drug. 
• Example: Gentamycin induced nephrotoxicity by Furosemide.  Furosemide displaces Gentamycin from the binding sites. The free concentration of Gentamycin increases and accelerates its clearance. 

7. Disease States: Renal Impairment 

• Renal dysfunction & uremia impairs elimination of drugs that are primarily excreted  by the kidneys & ultimately leads to increase in the half life of the drugs.  

8. Dose Adjustment in Renal Failure: 

• No need to alter dose if fraction of unchanged drug excreted (fu) ≤ 0.3 and renal function (R.F.) is ≥0.7 of the normal.  But if not then dose required = normal dose * renal failure. 

9. Effect of Exercise: 

• Exhaustive exercise reduced RBF (Renal Blood Flow)  by 53.4% compared to the  pre-exercise values, and returned to 82.5% and 78.9% of the pre-exercise values at 30 and 60 min into the recovery period, respectively. As RBF decreases, CLR decreases. 

Renal Extraction Ratio: 

• The fraction of a drug that is excreted when it passes through the kidneys is called the extraction ratio (ER) of the drug. By definition, a drug that is not excreted at all has an ER of 0 and a drug that is completely removed after a single passage has an ER of 1. 
• The table below shows the extraction ratios for a number of drugs that are excreted in the urine (> 30% by this route):
• Extraction ratio: 

Low (< 0.2)	Intermediate	High
Acetazolamide	Procainamide	Glucuronides
Chlorporpamide	Quaternary ammonia compounds	Penicillins
Diazoxide		Sulfates
Digoxin		Glycine conjugates
Furosemide
Gentamicin
Kanamycin
Phenobarbital
Sulfasoxazole
Tetracycline