Clearance (medicine)

In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics. Clearance is a function of glomerular filtration, secretion from the peritubular capillaries to the nephron, and reabsorption from the nephron back to the peritubular capillaries.

1 Definition
2 Derivation of equation
3 Solution to the differential equation
- 3.1 Steady-state solution
4 Measurement of renal clearance
5 See also
6 References

Definition

When referring to the function of the kidney, clearance of a substance is the inverse of the time constant that describes its removal rate from the body divided by its volume of distribution (or total body water).

In steady-state, it is defined as the mass generation rate of a substance (which equals the mass removal rate) divided by its concentration in the blood.

It is considered to be the amount of liquid filtered out of the blood that gets processed by the kidneys or the amount of blood cleaned per time because it has the units of a volumetric flow rate [ volume / time ]. However, it does not refer to a real value; "[t]he kidney does not completely remove a substance from the total renal plasma flow."^[1] From a mass transfer perspective^[2] and physiologically, volumetric blood flow (to the dialysis machine and/or kidney) is only one of several factors that determine blood concentration and removal of a substance from the body. Other factors include the mass transfer coefficient, dialysate flow and dialysate recirculation flow for hemodialysis, and the glomerular filtration rate and the tubular reabsorption rate, for the kidney. A physiologic interpretation of clearance (at steady-state) is that clearance is a ratio of the mass generation and blood (or plasma) concentration.

Its definition follows from the differential equation that describes exponential decay and is used to model kidney function and hemodialysis machine function:

$V \frac{dC}{dt} = -K \cdot C + \dot{m} \qquad (1)$

Where:

$\dot{m}$ is the mass generation rate of the substance - assumed to be a constant, i.e. not a function of time (equal to zero for foreign substances/drugs) [mmol/min] or [mol/s]
t is dialysis time or time since injection of the substance/drug [min] or [s]
V is the volume of distribution or total body water [L] or [m³]
K is the clearance [mL/min] or [m³/s]
C is the concentration [mmol/L] or [mol/m³] (in the USA often [mg/mL])

From the above definitions it follows that $\frac{dC}{dt}$ is the first derivative of concentration with respect to time, i.e. the change in concentration with time.

It is derived from a mass balance.

Derivation of equation

Equation 1 is derived from a mass balance:

$\Delta m_{body}=(-\dot m_{out}+ \dot m_{in} +\dot m_{gen.})\Delta t \qquad (2)$

where:

$\Delta t$ is a period of time
$\Delta m_{body}$ the change in mass of the toxin in the body during $\Delta t$
$\dot m_{in}$ is the toxin intake rate
$\dot m_{out}$ is the toxin removal rate
$\dot m_{gen.}$ is the toxin generation rate

In words, the above equation states:

The change in the mass of a toxin within the body ( $\Delta m$ ) during some time $\Delta t$ is equal to the toxin intake plus the toxin generation minus the toxin removal.

Since

$m_{body} = C \cdot V \qquad (3)$

and

$\dot m_{out}=K \cdot C \qquad (4)$

Equation A1 can be re-written as:

$\Delta (C \cdot V)=(-K \cdot C+ \dot m_{in} +\dot m_{gen.})\Delta t \qquad (5)$

If one lumps the in and gen. terms together, i.e. $\dot m=\dot m_{in} +\dot m_{gen.}$ and divides by $\Delta t$ the result is a difference equation:

$\frac{\Delta (C \cdot V)}{\Delta t} = -K \cdot C + \dot{m} \qquad(6)$

If one applies the limit $\Delta t \rightarrow 0$ one obtains a differential equation:

$\frac{d(C \cdot V)}{dt}= -K \cdot C + \dot{m} \qquad(7)$

Using the chain rule this can be re-written as:

$C \frac{dV}{dt}+V \frac{dC}{dt} = -K \cdot C + \dot{m} \qquad(8)$

If one assumes that the volume change is not significant, i.e. $C \frac{dV}{dt}=0$ , the result is Equation 1:

$V \frac{dC}{dt} = -K \cdot C + \dot{m} \qquad(1)$

Solution to the differential equation

The general solution of the above differential equation (1) is:

$C = \frac{\dot{m}}{K} + (C_{o}-\frac{\dot{m}}{K}) e^{-\frac{K \cdot t}{V}} \qquad (9)$ ^[3]^[4]

Where:

C_o is the concentration at the beginning of dialysis or the initial concentration of the substance/drug (after it has distributed) [mmol/L] or [mol/m³]
e is the base of the natural logarithm

Steady-state solution

The solution to the above differential equation (9) at time infinity (steady state) is:

$C_{\infty} = \frac {\dot{m}}{K} \qquad (10a)$

The above equation (10a) can be re-written as:

$K = \frac {\dot{m}}{C_{\infty}} \qquad (10b)$

The above equation (10b) makes clear the relationship between mass removal and clearance. It states that (with a constant mass generation) the concentration and clearance vary inversely with one another. If applied to creatinine (i.e. creatinine clearance), it follows from the equation that if the serum creatinine doubles the clearance halves and that if the serum creatinine quadruples the clearance is quartered.

Measurement of renal clearance

Renal clearance can be measured with a timed collection of urine and an analysis of its composition with the aid of the following equation (which follows directly from the derivation of (10b)):

$K = \frac {C_U \cdot Q}{C_B} \qquad (11)$

Where:

K is the clearance [mL/min]
C_U is the urine concentration [mmol/L] (in the USA often [mg/mL])
Q is the urine flow (volume/time) [mL/min] (often [mL/24 hours])
C_B is the plasma concentration [mmol/L] (in the USA often [mg/mL])

Note - the above equation (11) is valid only for the steady-state condition. If the substance being cleared is not at a constant plasma concentration (i.e. not at steady-state) K must be obtained from the (full) solution of the differential equation (9).

References

↑ Seldin DW (2004). "The development of the clearance concept". J. Nephrol. 17 (1): 166–71. PMID 15151274. Available at: http://www.sin-italy.org/jnonline/Vol17n1/166.html. Accessed on: Sept 2, 2007.
↑ Babb AL, Popovich RP, Christopher TG, Scribner BH (1971). "The genesis of the square meter-hour hypothesis". Transactions - American Society for Artificial Internal Organs 17: 81–91. PMID 5158139.
↑ Gotch FA (1998). "The current place of urea kinetic modelling with respect to different dialysis modalities". Nephrol. Dial. Transplant. 13 Suppl 6: 10–4. doi:10.1093/ndt/13.suppl_6.10. PMID 9719197. Full Text
↑ Gotch FA, Sargent JA, Keen ML (2000). "Whither goest Kt/V?". Kidney Int. Suppl. 76: S3–18. doi:10.1046/j.1523-1755.2000.07602.x. PMID 10936795.

Urinary system, physiology: renal physiology and acid-base physiology

Filtration	Renal blood flow - Ultrafiltration - Countercurrent exchange

Hormones affecting filtration	Antidiuretic hormone (ADH) - Aldosterone - Atrial natriuretic peptide

Secretion/clearance	Pharmacokinetics - Clearance of medications

Reabsorption	Solvent drag - Na⁺ - Cl^- - urea - glucose - oligopeptides - protein

Endocrine	Renin - Erythropoietin (EPO) - Calcitriol (Active vitamin D) - Prostaglandins

Assessing Renal function/ Measures of dialysis	Glomerular filtration rate - Creatinine clearance - Renal clearance ratio - Urea reduction ratio - Kt/V - Standardized Kt/V - Hemodialysis product - PAH clearance (Effective renal plasma flow - Extraction ratio)

Acid-base physiology	Fluid balance - Darrow Yannet diagram - Body water - Interstitial fluid - Extracellular fluid - Intracellular fluid/Cytosol - Plasma - Transcellular fluid - Base excess - Davenport diagram - Anion gap - Arterial blood gas

Buffering/compensation	Bicarbonate buffering system - Respiratory compensation - Renal compensation

Other	Fractional sodium excretion

Medication > Pharmacology

Pharmacokinetics	ADME: Absorption · Distribution · Metabolism · Excretion (Clearance) Loading dose · Volume of distribution (Initial) · Rate of infusion Compartment · Bioequivalence · Bioavailability Biological half-life · Plasma protein binding Phase 1 reaction · Phase 2 reaction Therapeutic index (LD50/ED50)

Pharmacodynamics	Toxicity (Neurotoxicology) · Dose-response relationship (Efficacy, Potency)

Agonism and antagonism	Agonist: Inverse agonist · Physiological agonist · Partial agonist Antagonist: Competitive antagonist · Physiological antagonist

Other fields	pharmacogenetics · pharmacogenomics · Neuropsychopharmacology (Neuropharmacology, Psychopharmacology)

Clearance (medicine)

Contents

Definition

Derivation of equation

Solution to the differential equation

Steady-state solution

Measurement of renal clearance

See also

References