Renal Function and Renal Failure

RENAL FUNCTION AND RENAL FAILURE

Renal function can be determined by measuring the GFR. Both endogenous and exogenous substances have been used as markers to measure GFR. In order to be useful as a marker, the agent should entirely get excreted in unchanged form by glomerular filtration only and should be physiologically and pharmacologically inert. The rate at which these markers are excreted in urine reflects the GFR and changes in GFR reflects renal dysfunction. Inulin (the exogenous fructose polysaccharide) and serum creatinine level have been used successfully for such purposes.

Inulin clearance provides an accurate measure of GFR but has the disadvantage of being a tedious method. Clinically, creatinine clearance is widely used to assess renal function.

Creatinine is an endogenous amine produced as a result of muscle catabolism. It is excreted unchanged in the urine by glomerular filtration only. An advantage of this test is that it can be correlated to the steady-state concentration of creatinine in plasma and needs no collection of urine. The method involves determination of serum creatinine levels. Since creatinine production varies with age, weight and gender, different formulae are used to calculate creatinine clearance from the serum creatinine values.

For Children (between 1 to 20 years),

For Adults (above 20 years),

where, Cl_cr = creatinine clearance in ml/min,

S_cr = serum creatinine in mg%,

H = height in cms, and

W = weight in Kg.

Age is measured in years.

A direct method for determining creatinine clearance is determination of the amount of creatinine excreted in urine in 24 hours (to calculate the rate of creatinine excretion) and the mean of serum creatinine from blood samples taken just before and immediately after the urine collection period. Following formula is used:

Cl_R = Rate of excretion creatinine / in creatinine Serum mg %                    (6.18)

The normal creatinine clearance value is 120 to 130 ml/min. A value of 20 to 50 ml/min denotes moderate renal failure and values below 10 ml/min indicate severe renal impairment.

The renal function, RF is calculated by equation 6.19.

RF = Cl_cr of patient / Cl_cr of a person normal                   (6.18)

Dose Adjustment in Renal Failure

Generally speaking, drugs in patients with renal impairment have altered pharmacokinetic profile. Their renal clearance and elimination rate are reduced, the elimination half-life is increased and the apparent volume of distribution is altered. Thus, dose must be altered depending upon the renal function in such patients. However, except for drugs having low therapeutic indices, the therapeutic range of others is sufficiently large and dosage adjustment is not essential.

Dosage regimen need not be changed when

·           The fraction of drug excreted unchanged, fu is ≤ 0.3, and

·           The renal function RF is  ≥ 0.7 of normal.

The above generalization is based on the assumption that the metabolites are inactive and binding characteristics and drug availability are unaltered and so is the renal function in kidney failure conditions. When the f_u value approaches unity and RF approaches zero, elimination is extremely slowed down and dosing should be reduced drastically. The significance of nonrenal clearance increases in such conditions.

The required dose in patients with renal impairment can be calculated by the simple formula:

Drug dose in renal impairment  = Normal dose x RF  (6.20)

The dosing interval in hours can be computed from the following equation:

Dosing interval = Normal interval in hours / RF (6.21)

When the drug is eliminated both by renal and nonrenal mechanisms, the dose to be administered in patients with renal failure is obtained from equation 6.22.

Drug dose = Normal dose RF x Fraction excreted in urine + Fraction eliminated nonrenally

(6.22)

Dialysis and Haemoperfusion

In severe renal failure, the patients are put on dialysis to remove toxic waste products and drugs and their metabolites which accumulate in the body.

Dialysis is a process in which easily diffusible substances are separated from poorly diffusible ones by the use of semipermeable membrane.

There are two procedures for dialysis:

1. Peritoneal dialysis, and

2. Haemodialysis.

In the former, the semipermeable membrane is the natural membrane of the peritoneal cavity. The method involves introduction of the dialysate fluid into the abdomen by inserting the catheter and draining and discarding the same after a certain period of time. In haemodialysis, the semipermeable membrane is an artificial membrane. Since the system is outside the body, it is also called as extracorporeal dialysis. The equipment is referred to as artificial kidney or haemodialyser. Apart from the removal of toxic waste from the body, haemodialysis is also useful in the treatment of overdose or poisoning situations where rapid removal of drug becomes necessary to save the life of the patient. Patients of kidney failure require dialysis of blood every 2 days. Each treatment period lasts for 3 to 4 hours.

Factors that govern the removal of substances by haemodialysis are:

Water Solubility: Only water-soluble substances are dialyzed; lipid soluble drugs such as glutethimide cannot be removed by dialysis.

Molecular Weight: Molecules with size less than 500 Daltons are dialyzed easily, e.g. many unbound drugs; drugs having large molecular weight such as vancomycin cannot be dialyzed.

Protein Binding: Drugs bound to plasma proteins or blood cells cannot be dialyzed since dialysis is a passive diffusion process.

Volume of Distribution: Drugs with large volume of distribution are extensively distributed throughout the body and therefore less easily removed by dialysis, e.g. digoxin.

The Fig. 6.4 shows schematic representation of haemodialysis.

Fig. 6.4. Diagrammatic representation of a haemodialyser. The blood and the dialysate flow counter-currently.

The dialyzing fluid contains sodium, potassium, calcium, chloride and acetate ions, and dextrose and other constituents in the same concentration as that in plasma. The unwanted metabolites in the patient’s blood such as urea, uric acid, creatinine, etc. diffuse into the dialysate until equilibrium. Since the volume of dialysate is much greater than that of blood and since it is replenished with fresh fluid from time to time, almost complete removal of unwanted substances from the blood is possible. Drugs which can be removed by haemodialysis are barbiturates, aminoglycosides, chloral hydrate, lithium, etc.

The rate at which a drug is removed by the dialyser depends upon the flow rate of blood to the machine and its performance. The term dialysance, also called as dialysis clearance, is used to express the ability of machine to clear the drug from blood. It is defined in a manner similar to clearance by equation:

where, Cl_d = dialysance or dialysis clearance

Q = blood flow rate to dialyser

C_in = concentration of drug in blood entering the dialyser

C_out = concentration of drug in blood leaving the dialyser

In haemoperfusion, the blood is passed through a bed of adsorbent such as charcoal or resin; as a result, drugs and other unwanted molecules are adsorbed while plasma proteins are not. The method is also useful in treating severe drug intoxication. The limitation of haemoperfusion is that it also removes the blood platelets, white cells and endogenous steroids.