An Overview of Renal Physiology

stretched. As arterial pressure increases, the

a creatinine clearance tends to overestimate the

afferent arteriole is stretched and the smooth

true GFR by the amount that is secreted into the

muscle contracts, (2) tubuloglomerular feedback:

urine.

this mechanism involves a feedback loop in which

Given that creatinine clearance is only an esti-

the macula densa of the distal tubule cells senses

mate of GFR and in some cases creatinine secre-

some component of the distal tubule fluid (likely

tion by the tubules can be increased (such as

chloride concentration), which then affects GFR.

with chronic kidney disease), there is a need for

For example, when GFR increases, distal tubule

a more precise and more easily obtained mea-

flow rate increases sending a signal that causes

sure of GFR. Furthermore, collection of 24 h

RBF and GFR to return to normal levels. Other

urine is difficult and unreliable. Using data from

factors that alter renal blood flow and GFR

thousands of patients in the Modification of

include, (1) sympathetic control: sympathetic

Diet in Renal Disease (MDRD) trial where sensi-

neurons that release norepinephrine innervate

tive GFR was measured, a regression equation

both the afferent and efferent arterioles.

was developed that allows a serum creatinine

Norepinephrine produces vasoconstriction by

value to be converted into an estimated GFR

binding to alpha 1-adrenoceptors, thereby

with a high degree of correlation to a measured

decreasing renal blood flow and glomerular fil-

GFR. The equation requires only a measure-

tration rate; (2) hormones: there are various

ment of serum creatinine: GFR = 175 × serum

vasoconstrictor hormones including epineph-

creatinine – 1.154 × age – 0.203 × 1.212 [if black]

rine, norepinephrine, angiotensin II, thrombox-

× 0.742 [if female]. Use of this equation has

ane, and parathyroid hormone. Vasodilator hor-

gained widespread acceptance as a method for

mones include PGE2, PGI2, bradykinin, hista-

determining and following GFR.

mine, and atrial natriuretic peptide; (3) protein

intake: high protein intake increases both GFR

Body Fluid Compartments

and renal blood flow.

The GFR is equal to the sum of the filtration

rates of all the functioning nephrons and thus is

The amount of the body that is composed of

an important index of kidney function and it is

water is variable and dependent upon the

used clinically as a global marker of kidney

amount of fat. Thus, patients with higher body

function. A decreasing GFR is a sensitive and

fat percentages will have lower water content.

vitally important marker of worsening kidney

For this reason, women tend to have about 5%

function. While there are many methods for

less total body water than men. Total body water

determining the GFR, two are used most com-

constitutes approximately 60% of body weight

monly in the clinical setting: (1) creatinine clear-

(or 42 L for a 70 kg male). This is further divided

ance determination from a 24-h urine collection

into an intracellular compartment (40% of body

or (2) use of regression formulas to determine

weight) and an extracellular compartment (20%

GFR based upon serum creatinine measure-

of body weight). The extracellular compartment

ments. Creatinine clearance is determined by

is further divided into an intravascular (5% of

the collection of a 24-h urine specimen and a

body weight) and interstitial compartments

plasma sample, both of which are measured for

(15% of body weight).

creatinine concentration. Given that, in the

The major solute constituents are electrolytes

steady state, creatinine excretion is equal to the

with a smaller proportion of proteins, nutrients,

creatinine filtration rate, clearance can be deter-

and waste products. Sodium is by far the most

mined as the urine concentration of creatinine

abundant extracellular cation, while chloride

multiplied by the urine volume divided by the

and bicarbonate are the most abundant extra-

plasma concentration of creatinine. In should be

cellular anions. Potassium is the most abundant

noted that this relationship holds true only for

intracellular cation and organic phosphates and

an ideal molecule that only appears in the urine

proteins are the most abundant intracellular

via glomerular filtration and then is not secreted,

anions. In order to maintain the unequal distri-

metabolized, or absorbed by the tubules. While

bution of solutes across body compartments,

creatinine is freely filtered and does not undergo

several mechanisms are operative: (1) semiper-

either tubular reabsorption, it can undergo

meable cell membranes, and (2) the existence of

tubular secretion. Thus, a GFR calculated using

cellular channels and pumps (transporters) that

108

Practical Urology: EssEntial PrinciPlEs and PracticE

use energy to maintain a difference in solute

proximal sodium reabsorption also decreases

concentrations across the membranes.

by 25%. Thus the net effect of GT-balance is to

The osmolality of interstitial fluid is equal to

minimize the ability of changes in GFR to pro-

that of intracellular fluid, and changes in osmo-

duce large changes in sodium excretion.

lality between these compartments govern fluid

movement. For instance, if the osmolality of the

extracellularcompartmentwasacutelyincreased

Control of Body Osmolality and

(for instance, with mannitol) this would cause

Body Fluid Volume

water movement out of cells down the osmotic

gradient into the extracellular compartment.

The volume of the extracellular compartment

The osmolality of the extracellular fluid (ECF) is

is dependent upon the amount of body sodium

tightly regulated with variations of only 1–2% in

(since this is the major extracellular cation).

normal circumstances. This need for tight con-

Within the extracellular compartment, hydro-

trol is due to the important effect of osmolality

static and oncotic pressures (Starling forces)

on cellular volume. For example, if the osmolal-

determine the movement of fluid and volume

ity of the ECF falls, it creates a disequilibrium

between the plasma and interstitial spaces.

favoring movement of water into the intracellu-

lar compartment with resultant cellular swell-

Regulation of Sodium, Chloride,

ing. In the central nervous system, this can lead

to intracranial hypertension and mental status

and Water Reabsorption by the

changes that in the extreme can lead to cerebel-

Proximal Tubule

lar herniation and death. This contrasts with the

volume of the ECF fluid, which is not as tightly

regulated and can vary by a much larger per-

Important factors regulating the movement of

centage. Body osmolality is regulated by renal

solute and water from proximal tubule lumen

handling of water and is under the control of

into the peritubular capillaries are the Starling

arginine vasopressin (AVP, or antidiuretic hor-

forces which include capillary oncotic pressure

mone (ADH)). Body volume is regulated by

(pcap), the hydrostatic pressure in the intercellu-

renal handling of sodium and the major media-

lar space (Pis), the interstitial oncotic pressure

tors are the renin-angiotensin-aldosterone sys-

(pis), and the capillary hydrostatic

pressure

tem (RAAS) and the sympathetic nervous

(Pcap). Peritubular capillary pressure can be

system (SNS).

altered by the vascular tone of the efferent arte-

In response to water deprivation (or sodium

riole. An increase in efferent arteriole tone will

ingestion), plasma osmolality is increased. This

reduce peritubular capillary pressure (provid-

is sensed by osmoreceptors in the supraoptic

ing less hindrance to solute reabsorption). On

and paraventricular nuclei in the hypothalamus

the other hand, a decrease in efferent arteriole

and leads to the release of AVP. AVP is released

tone will increase peritubular capillary pressure

in response to either increased osmolality (less

and increase hindrance to solute reabsorption.

than 1% change) or decreased volume (greater

Furthermore, the peritubular oncotic pressure

than 10% change) of the ECF. Note that secre-

can be altered by the efferent arteriole as well.

tion of AVP in response to increased osmolality

Efferent arteriole constriction can increase

has a lower threshold and a higher sensitivity

the filtration fraction (FF = GFR/RPF), which

(slope) than the response to decreased ECF vol-

will increase peritubular oncotic

pressure.

ume. The hypothalamic receptors also increase

An increase in peritubular oncotic pressure

thirst. AVP then acts to increase the water per-

will increase solute and water reabsorption by

meability of the collecting duct in the distal

the proximal tubule. These forces are involved

tubuleresultinginfreewaterretention,decreased

in a phenomenon known as glomerulotubular

urine volume, and increased urine osmolality.

balance (G-T balance). The operation of G-T

The combination of thirst and increased free

balance enables a constant fraction of filtered

water reabsorption by the kidney restores

sodium and water to be reabsorbed by the prox-

plasma osmolality to normal.

imal tubule despite variations in GFR. For exam-

In contrast, in the setting of excess water

ple, when GFR decreases by 25% the rate of

ingestion, plasma osmolality is decreased and