Chapter 6 Renal Physiology
I. Overview
A. General functions of the kidneys
1. The kidneys are an extraordinarily effective recycling facility into which the body’s extracellular fluid compartment is cycled many times a day.
2. Substances that are not needed, such as excess water, electrolytes, and potentially toxic end products of metabolism, are discarded into the urine.
3. Substances that are needed, such as most of the filtered sodium, water, glucose, and bicarbonate, are reclaimed and returned to the circulation.
4. The kidneys have particularly strong control over homeostasis of water, sodium, potassium, calcium, phosphate, bicarbonate, and the nonvolatile acids.
B. Functional anatomy of the kidney (Fig. 6-1)
1. To achieve their recycling functions, the kidneys receive a substantial fraction (20% to 25%) of the cardiac output despite comprising less than 2% of body weight.
3. The basic functional unit of the kidney is the nephron, where blood is filtered; there are approximately 1 million nephrons per kidney.
4. Fluid and compounds that are not recycled (urine) drain from the nephron into the calyceal system.
C. Structure of the filtration unit: the nephron (Fig. 6-2)
2. Each glomerulus is an expansion of an afferent arteriole into a diffuse capillary bed, the glomerular capillaries, which have an extensive surface area for filtration; these capillaries are surrounded by an expansion of the renal tubular system (Fig. 6-3).
6-3 Anatomy of the glomerulus.
(From Bargmann W: Histologie und Mikronscopische Anatomie des Menschen. Stuttgart, Germany, Georg Thieme, 1977, p 86.)
3. The ultrafiltrate of plasma created in the glomerulus flows into the tubular system, where selective reabsorption and secretion of solutes and water occurs along the various segments of the nephron.
• For substances in the lumen of the glomerular capillaries to be filtered into the renal tubular system, they must traverse the three component layers of the glomerular filtration barrier (Fig. 6-4).
1. Function of the filtration barrier
• Effectively prevents the passage of cells and large-molecular-weight proteins into the glomerular ultrafiltrate, thereby preventing their loss into the urine
6-4 Layers of the glomerular filtration barrier. GBM, Glomerular basement membrane.
(From Mount DB, Pollak MR: Molecular and Genetic Basis of Renal Disease. Philadelphia, Saunders, 2008, Fig. 21-2B.)
2. Layers of the filtration barrier
• Each of these layers is highly specialized for filtration.
c. Visceral epithelial cells (podocytes)
• The overlying visceral epithelial cells, or podocytes, project foot processes that overlie the glomerular basement membrane.
II. Regulation of Glomerular Function
A. Filtration forces at the glomerulus (Fig. 6-5)
1. The forces that drive fluid across the glomerular membrane and into Bowman space are the same as the Starling forces that cause fluid movements in systemic capillaries.
2. Forces that promote filtration are the hydrostatic pressure in the glomerular capillaries (PGC) and the oncotic pressure in Bowman space (ΠBS); however, because most proteins are not readily filtered into Bowman space, the latter is typically negligible.
3. Forces that oppose fluid movement across the glomerular membrane are the hydrostatic pressure in Bowman space (PBS) and the oncotic pressure in the glomerular capillaries (ΠGC).
4. Summation of these forces yields the net filtration pressure (NFP), which is the pressure gradient driving filtration across the glomerulus.
B. Glomerular filtration rate (GFR)
1. Overview
• The GFR is dependent on the filtration forces acting at the glomerulus and the unit permeability (Lp) and available surface area (S) of the glomerular capillaries.
• In the healthy kidney, the product of these two factors (LpS) is equal to approximately 12.5 mL/minute per mm Hg filtration pressure.
• Typical values for GFR in healthy adults are approximately 90 mL/minute in women and 120 mL/minute in men.
2. Calculation of GFR
3. Filtration fraction
• The percentage of renal plasma flow (RPF) that is filtered across the renal glomerular capillaries
4. Regulation of GFR
• Overview
a. Although alteration of any of the determinants of NFP at the glomerulus can alter GFR, the primary mechanism through which GFR is normally regulated is through regulation of the glomerular hydrostatic pressure.
b. The glomerular hydrostatic pressure depends on the systemic arterial pressure and afferent and efferent arteriolar resistances, respectively.
• Systemic arterial pressure
a. As systemic arterial pressure increases, the increased renal perfusion tends to increase glomerular hydrostatic pressure and GFR.
b. However, the changes in glomerular hydrostatic pressure are relatively small compared with the often substantial fluctuations in systemic arterial pressure.
c. This attenuation is due to intrinsic autoregulatory mechanisms in the kidneys, which maintain relatively constant renal perfusion despite fluctuations in systemic arterial pressure (see later discussion and Fig. 6-7).
d. Consequently, the contribution of systemic arterial pressure is typically minor, and the primary determinants of glomerular hydrostatic pressure are afferent and efferent arteriolar resistance.
• Afferent arteriolar resistance (Fig. 6-6; Table 6-1)
a. Dilation of the afferent arteriole through prostaglandins such as prostaglandin E2 increases renal blood flow, glomerular hydrostatic pressure, and, hence, GFR.
• Efferent arteriolar resistance
a. Mild to moderate vasoconstriction of the efferent arteriole (angiotensin II) increases glomerular hydrostatic pressure, resulting in increased filtration across the glomerulus.
b. However, this increased GFR comes at the expense of reducing overall renal blood flow and increasing the filtration fraction at the glomerulus, which in turn increases the glomerular oncotic pressure that opposes filtration.
c. Therefore, with marked vasoconstriction of the efferent arteriole, GFR typically decreases, because the reduced renal blood flow and increased glomerular oncotic pressure overcome the effects of the increased glomerular hydrostatic pressure on GFR (see Fig. 6-6).
TABLE 6-1 Effect of Changes in Starling Forces on Renal Plasma Flow, Glomerular Filtration Rate, and the Filtration Fraction
5. Renal Blood Flow
• Overview
c. Vasodilatory prostaglandins maintain afferent arteriolar dilatation, whereas the sympathetic nervous system and angiotensin II promote vasoconstriction with preferential vasoconstriction of the efferent arteriole (Fig. 6-7).
Clinical note: Narrowing of the renal arteries (renal artery stenosis) most commonly occurs as a result of atherosclerosis or fibromuscular hyperplasia. In unilateral renal artery stenosis, hypertension may occur because decreased perfusion of the affected kidney is incorrectly “interpreted” as intravascular volume depletion, which triggers a neurohormonal cascade response (the renin-angiotensin-aldosterone system and antidiuretic hormone [ADH]; see Chapter 3), causing fluid retention and vasoconstriction resulting in hypertension. When both renal arteries are affected (bilateral renal artery stenosis), renal blood flow may become so compromised that the kidneys are unable to perform their normal recycling functions, resulting in the toxic accumulation of metabolic byproducts.
• Autoregulation of renal blood flow
a. Process in which intrinsic renal mechanisms act to maintain fairly constant renal perfusion, GFR, and distal flow in the nephron in the face of widely varying systemic arterial pressures
c. At very high or very low arterial blood pressures, autoregulatory mechanisms fail, and renal blood flow parallels changes in systemic arterial pressure (Fig. 6-8); this is why at the extremes of blood pressure, hypotension and malignant hypertension, acute kidney injury may occur as a result of renal ischemia or damage from pathologically elevated glomerular hydrostatic pressures, respectively.
d. Autoregulation occurs through the myogenic mechanism and tubuloglomerular feedback, as discussed below.
• Myogenic mechanism
a. Response to increased arteriolar pressure
• As in other arterioles, an increase in pressure in the afferent arteriole stimulates reflexive vasoconstriction by stimulating smooth muscle cell contraction.
• This minimizes the increase in glomerular hydrostatic pressure and GFR that would otherwise occur.
• Tubuloglomerular feedback
a. In this mechanism, the rate of NaCl delivery to the distal nephron significantly influences the glomerular blood flow and therefore the GFR.
b. This mechanism is dependent on the presence of a specialized structure termed the macula densa, which is located at the end of the thick ascending limb and abuts the glomerulus adjacent to the afferent arteriole (Fig. 6-9; see Figs. 6-2 and 6-3).
c. The macula densa and the specialized cells within the glomerulus and the walls of the afferent arteriole are referred to as the juxtaglomerular apparatus.
e. When filtration increases, through an unclear mechanism the increased NaCl delivery to the macula densa triggers vasoconstriction of the afferent arteriole (see Fig. 6-9).
f. When filtration decreases, decreased NaCl delivery to the macula densa triggers vasodilation of the afferent arteriole, which increases GFR and increases delivery of NaCl to the macula densa.
III. Measuring Renal Function
A. Overview
1. The term renal function is used to refer to the rate at which the kidneys remove toxins from the circulation.
2. The main mechanism of toxin removal is filtration of toxin-laden plasma through the glomerulus, leaving the toxins behind in the tubule and reabsorbing 99% of the filtrate.
B. Clearance
1. Clearance is the volume of plasma from which a substance has been completely cleared by the kidneys per unit of time.
2. If a substance is freely filtered across the glomerulus and then neither reabsorbed nor secreted into the tubule (e.g., inulin), its rate of clearance is equivalent to GFR.
C. Calculating clearance
1. If a substance is present in the blood at a concentration of 1 mg per 100 mL, the clearance of the substance from 100 mL of blood per minute will result in 1 mg of this substance being excreted into the urine each minute.
2. If the amount of the substance excreted in the urine is divided by its plasma concentration (Px, in milligrams per milliliter), the quotient reflects the volume of plasma that has been cleared of that substance in 1 minute, called its clearance (Cx):
3. This can be expressed in terms of urinary flow rate (V, in mL/minute) and urinary concentration (Ux, in mg/mL):
4. Example: Given a typical excretion rate of urea into the urine of 15 mg/minute and a typical plasma concentration of urea of 0.2 mg/mL, the clearance of urea can be calculated as follows:
5. Note that the Curea is less than the typical GFR, which is approximately 90 to 120 mL/minute, consistent with net reabsorption of urea along the nephron.
D. Measuring the GFR
1. Creatinine clearance (Fig. 6-10)
• Creatinine is formed continually as a breakdown product in skeletal muscle and released into the bloodstream.
• Creatinine is freely filtered across the glomeruli and neither reabsorbed nor secreted to a significant extent (in actuality it is slightly secreted but we will ignore this fact for purposes of the current discussion).
• The amount that enters the urine is therefore approximately equal to the amount that is filtered across the glomeruli.
• Thus, the plasma concentration of creatinine is a good approximation of renal function.
• The amount of creatinine that enters the urine in 1 minute is equal to the product of the urinary flow rate (V) and the urinary creatinine concentration (V × Ucr).
• The amount of creatinine that filters across the glomeruli is equal to the product of the plasma creatinine concentration and the GFR (Pcr × GFR).
• Because these two expressions define the same quantity, they can be equated and solved for the GFR, as follows:
so that
• This is the same equation as the equation for creatinine clearance (Ccr = V × Ucr/Pcr); therefore, creatinine clearance is approximately the same as the GFR.
• Creatinine clearance is used clinically as an estimate of GFR; however, because there is in fact a mild degree of tubular secretion of creatinine (~ 10%), it is actually a slight overestimate of GFR.
E. Clearance and reabsorption/secretion
2. Renal clearance for a given substance approximates GFR if that substance is freely filtered and does not undergo net reabsorption or secretion along the nephron (e.g., inulin).
6-11 Filtration, reabsorption, and secretion along the nephron.
(From Boron W, Boulpaep E: Medical Physiology, 2nd ed. Philadelphia, Saunders, 2009, Fig. 33-8.)
3. If a substance undergoes net reabsorption along the nephron, its clearance is less than GFR because some of it is returned to the plasma from which it was initially “cleared” (e.g., urea).
F. Using clearance values to estimate effective renal plasma flow
1. If a substance were filtered and secreted so efficiently that it was completely eliminated from plasma by the time blood leaves the kidney (i.e., concentration in renal vein = 0), its clearance would give a very good approximation of RPF, because the amount of plasma cleared of the substance would represent all the plasma that initially entered the kidney, including the filtered fraction at the glomerulus and the unfiltered fraction in the peritubular capillaries.
2. An example of such a substance is para-aminohippuric acid (PAH), an organic acid that is not metabolized and needs to be administered intravenously.
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TABLE 6-2 Summary of Important Clearance Values
| Substance | Approximate Clearance Rate (as % of GFR) |
|---|---|
| Urea | 50 |
| Inulin | 100 |
| Creatinine | 100 |
| Para-aminohippuric acid | >>100 |
| Sodium | 1 |
| Potassium | 10 |
| Glucose | 0 |
| Amino acids | 0 |
GFR, Glomerular filtration rate.
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