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Physiology of the kidney Last updated: July 15, 2022

Summary

Urine production

Hormone synthesis

Physiology of the tubular system

Renal blood flow

Renal blood supply

Renal arteries (from the aorta) → segmental arteries → interlobar renal arteries → arcuate arteries →
intralobular renal arteries → afferent arterioles → glomeruli → efferent arterioles → vasa recta
(kidneys) and peritubular capillaries → renal veins (merge into the inferior vena cava)

Renal blood flow

Renal blood flow (RBF): the blood volume that flows through the kidney per unit of time

Normal: ∼ 20% of cardiac output, i.e., 1.2 L/min; kept at a constant rate by the renal autoregulatory
mechanism

RBF = RPF/(1 - Hct)

Renal plasma flow (RPF): the volume of plasma that flows through the kidney per unit of time

Para-aminohippuric acid (PAH): nearly 100% of PAH that enters the kidney is also excreted
(completely filtrated and secreted), thus clearance rate is used to estimate RPF

Effective renal plasma flow (eRPF)

eRPF = urine concentration of PAH × (urine flow rate/plasma concentration of PAH)

eRPF calculated with PAH slightly underestimates true RPF (see “Para-aminohippuric acid” below)

Regulation of renal blood flow [1]

The kidney has multiple mechanisms to regulate its own blood flow. This allows for changing the rate of
glomerular filtration if fluctuations in systemic blood pressure occur.

Myogenic autoregulation (Bayliss effect)

Mechanism

Blood flow in the renal arteries remains constant with varying arterial blood pressure (between 80–
180 mmHg).

Afferent arterioles contract if blood pressure increases; to maintain a normal pressure within the
glomeruli: ↑ arterial pressure → stretching of smooth muscle cells in the afferent arteriole wall →
contraction of vascular smooth muscles → vasoconstriction → ↓ RBF

If blood pressure drops, afferent arterioles dilate, to increase the pressure within the glomeruli

Prostaglandins

Mechanism: renal hypoperfusion (particularly renal medulla) → stimulation of prostaglandin synthesis

→ vasodilation of renal vessels → increased renal perfusion

Tubuloglomerular feedback

Description: feedback system between the tubules and glomeruli that adjusts the GFR according to the
resorption capacity of the tubules

Mechanism: macula densa (of the juxtaglomerular apparatus) senses alterations in the NaCl
concentration in the DCT

Hypotonic urine (↓ intraluminal Cl- concentration) → vasodilation of afferent arterioles → ↑ GFR

→ ↑ Cl- intraluminal concentration → ↑ RBF

Hypertonic urine (↑ intraluminal Cl- concentration) → adenosine secretion; → vasoconstriction

of afferent arterioles → ↓ capillary pressure → ↓ GFR → ↓ intraluminal Cl- concentration → ↓
RBF

Renin-angiotensin-aldosterone system (RAAS) [2]

Description: hormonal system that regulates arterial blood pressure and sodium concentration

Mechanism

Baroreceptors in the afferent arteriole detect the following

Renal hypoperfusion (e.g., caused by hypotension or hypovolemia)

Hyponatremia (registered by the macula densa when sodium concentration in the

distal convoluted tubule decreases)

Increased sympathetic tone (via activation of renal β1-receptors)

These changes cause a release of renin by juxtaglomerular cells → conversion of angiotensinogen

(produced in the liver) to angiotensin I → conversion of angiotensin I to angiotensin II via
angiotensin-converting enzyme (mostly produced in the lungs)

Angiotensin II

Acts as a strong vasoconstrictor

Desensitizes baroreceptors to hypertension preventing reflex bradycardia

Stimulates thirst in the hypothalamus

Increases ADH secretion from the posterior pituitary

Induces the secretion of aldosterone by the adrenal cortex

Aldosterone increases renal reabsorption of sodium and water; and augments the excretion of
potassium and protons → ↑ extracellular fluid, ↑ blood pressure, ↓ K+, ↑ pH

Effects

Systemic: ↑ arterial blood pressure and ↑ blood volume

Renal: maintenance of renal function and volume status in low volume states

↑ Vasoconstriction of the efferent arteriole causes ↑ effective filtration pressure and ↑

filtration fraction which helps maintain GFR (i.e., renal function) during renal hypoperfusion (i.e.,
decreased renal plasma flow)

Maintenance of GFR (i.e., renal function) during renal hypoperfusion (i.e., decreased
renal plasma flow) which is achieved by ↑ vasoconstriction of the efferent arteriole causing ↑
effective filtration pressure and ↑ filtration fraction

Compensatory increase in Na+ reabsorption in the proximal convoluted tubule (PCT) and
distal convoluted tubule (DCT) prevents net volume loss

ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II. ARBs inhibit the
effect of angiotensin II. Both drug classes are used to treat arterial hypertension.

Besides their inhibitory effects on the heart (e.g., ↓ heart rate), β-blockers decrease blood
pressure by inhibiting β1-receptors of the juxtaglomerular apparatus (JGA), which leads to
decreased renin release.

Hormonal effects on the kidney

Natriuretic peptides

Atrial natriuretic peptide (ANP): volume overload → dilation of atria → secretion of ANP by
myocytes

Brain natriuretic peptide (BNP): volume overload → dilation of ventricles → secretion of BNP by
myocytes

Effects

Inhibit epithelial Na+ transporter in the collecting duct → increased Na+ and water secretion →
decrease in the central venous pressure

Dilates renal afferent arterioles (via ↑ cGMP in vascular smooth muscle) → ↑ GFR (without
compensatory Na+ reabsorption; ) and ↑ natriuresis

Inhibits secretion of aldosterone, renin, ADH, and ACTH

Antidiuretic hormone (ADH)

Increases contraction of smooth muscle in blood vessels via V1 receptor → increased blood pressure
→ increased kidney perfusion

Increases free water reabsorption in the collecting duct; (stimulation of adenylate cyclase → ↑
cAMP → incorporation of aquaporins in the luminal membrane of collecting ducts)

Increases urea resorption (↑ incorporation of urea transporters in the collecting duct) → increased
corticomedullary osmotic gradient → facilitated concentration of urine

Angiotensin II and aldosterone: see “Renin-angiotensin-aldosterone system“ section above

Parathyroid hormone (PTH)

Secretion is induced by ↓ Ca2+, ↓ 1,25-(OH)2 vitamin D3, and ↑ PO43- in the plasma

Effects on the proximal convoluted tubule (PCT): ↑ Ca2+ reabsorption, ↑ 1,25-(OH)2 vitamin D3
synthesis, and ↓ PO43- reabsorption

Autonomic regulation

Mechanism

Noradrenaline → binds to α1 receptors → vasoconstriction of arterioles → ↑ resistance → ↓

renal blood flow

Dopamine → binds to D1 receptors → vasodilatation of arterioles → ↓ resistance → ↑

renal blood flow

Hypovolemic shock with severe hypotension activates the sympathetic nervous system.
Subsequently, the hypovolemia and noradrenaline-induced vasoconstriction result in low
renal blood flow → low GFR → low urine production → acute renal injury

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Measurement of renal function

This section focuses on fluid compartments, the basics of glomerular filtration, and tubular secretion. For
more information on kidney function tests, see “Diagnostic evaluation of the kidney and urinary tract.”
Fluid compartments

60% of body mass is composed of water.

Two-thirds of the total body water (i.e., 40% of body mass) is intracellular fluid (ICF), which is mainly
composed of potassium, magnesium, and organic phosphates.

One-third of the total body water (i.e., 20% of body mass) is extracellular fluid (ECF), which is mainly
composed of sodium, chloride, bicarbonate, and albumin.

75% of ECF is interstitial fluid.

25% of ECF is plasma.

A small amount (∼ 500 mL) of ECF is transcellular fluid (e.g., gastrointestinal secretions, sweat,
pleural fluid, pericardial fluid, urine, synovial fluid, intraocular fluid, CSF).

ECF volume can be measured with crystalloid tracers such as inulin or mannitol, which distribute
throughout the ECF but do not enter cells.

ICF and ECF are separated by capillary walls and cellular membranes.

H2O can move between fluid compartments by osmosis or in response to pressure differences.

Total blood volume (TBV) is ∼ 6 L. Blood is composed of:

∼ 45% cellular components (99% of which are red blood cells), which is equivalent to hematocrit (Hct
)

∼ 55% plasma ∼ 55% plasma

Plasma volume can be calculated with VPlasma = TBV x (1 - Hct)

Serum osmolality (or plasma osmolality): 285–295 mOsm/kg H2O

The 60–40–20 rule refers to total body water (60% of body mass), ICF (40% of body mass),
and ECF (20% of body mass).

Think of HIKIN to help you remember the main intracellular ion: HIgh K+ INtracellularly.

Renal clearance

Description: : the volume of plasma that is cleared of a certain substance per unit of time

Mechanism

Cx = Ux x V/Px

Px = Plasma concentration of substance X (mg/mL)

V = Urine flow rate (mL/min)

Ux = Urine concentration of substance X (mg/mL)

Cx = Clearance of substance X (mL/min)

If the clearance of substance X is:

> GFR: net tubular secretion of substance X

< GFR: net tubular reabsorption or substance X is not freely filtered in the glomerulus

= GFR: no net tubular secretion of reabsorption

Glomerular filtration rate [3]

Description: : the rate at which fluid is filtered by the kidneys

Mechanism

Normal GFR
2
♂ 95–145 mL/min/1.73 m
2
♀ 75–125 mL/min/1.73 m
The GFR physiologically declines with age.

GFR depends on the effective filtration pressure and is driven by the difference between hydrostatic
and osmotic pressure

EFP = (PGC – PBS) – (πGC – πBS)]

GC = glomerular capillary

BS = Bowman space

P = hydrostatic pressure

π = osmotic pressure

πBS normally equals 0

Normal effective filtration pressure is 13 mm Hg.

GFR can be described by the Starling equation for the glomerulus: Jv = Kf × [(PGC - PBS) - σ(πGC -
πBS)]

Jv = net fluid flow

Kf = filtration constant

σ = Staverman reflection coefficient sigma

In clinical settings, the two most commonly used equations for calculation of estimated GFR are the
“Modification of Diet in Renal Disease (MDRD) Study equation” and the “Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation” (see “Creatinine clearance“ below.

The GFR is used to estimate kidney function and to stage chronic kidney disease.

Relative solute concentrations along proximal convoluted tubules

Mechanism

Water is absorbed along the PCT along with other solutes (e.g., creatinine, electrolytes, glucose)

At the beginning of the PCT, the concentration of all solutes within the glomerularly filtered tubular
fluid (TF) is equivalent to the plasma concentration (P).

Compared to water, solutes can be reabsorbed along the PCT:

At the same rate →; no change in tubular fluid concentration compared to plasma concentration
(TF/P = 1)

At a lower rate →; increased tubular fluid concentration compared to plasma concentration (TF/P
> 1)

At a higher rate →; decreased tubular fluid concentration compared to plasma concentration (TF/P
< 1)

Specific solutes

Sodium (Na+): reabsorbed at the same rate as water throughout the PCT → (TF/P)Sodium = 1

Inulin

Not reabsorbed, nor secreted along the PCT → (TF/P)Inulin > 1

Inulin is unique in that its amount does not change along the PCT but its tubular concentration is
determined solely by water reabsorption.

PAH and creatinine: net tubular secretion along the PCT → (TF/P)PAH/Creat./Creat. > (TF/P)Inulin
>1

Chloride (Cl-): (TF/P)Chloride > 1 throughout the PCT

Initially reabsorbed at a slower rate than water and sodium → (TF/P)Chloride > 1 and rising

More distally in the PCT, reabsorbed at the same rate as water and sodium → still (TF/P)
Chloride > 1 but no longer increasing (plateaued)

Glucose: reabsorbed at a higher rate than water → (TF/P)Glucose < 1

The increase in inulin concentration along the PCT is the result of a constant amount of
inulin within the tubular fluid (no reabsorption or secretion) and the reabsorption of water.
The increase in inulin concentration along the PCT is the result of water reabsorption and
a constant amount of inulin within the tubular fluid (without tubular inulin secretion).

Water is reabsorbed along the PCT while the amount of inulin within the tubular fluid
stays the same (no reabsorption or secretion of inulin). This leads to an increasing
concentration of inulin along the PCT.

Inulin clearance

Description: used to assess the GFR

Mechanism

Inulin is freely filtered and neither reabsorbed nor secreted in the tubular system, i.e., the amount of
inulin in the urine reflects the amount that is filtered by the kidneys.

Inulin clearance can be used to calculate GFR: GFR = Uinulin x V/Pinulin = Cinulin

Uinulin = urine concentration of inulin

V = urine flow rate

Pinulin = plasma concentration of inulin

Cinulin = clearance of inulin

Creatinine clearance

Description: the rate of renal clearance of creatinine

Mechanism

Used in clinical settings to calculate GFR

Creatinine clearance = U x V / P

U = daily urine concentration of creatinine

V = rate of urine flow in mL/min

P = plasma concentration of creatinine

Direct calculation of creatinine clearance is time-consuming and becomes inaccurate if daily urine is
collected inappropriately.

Cockroft–Gault equation allows to estimate creatinine clearance

Creatinine clearance = ((140 - age) x weight (kg) x constant)/serum creatinine (mmol/L)

Constant = 1.23 for males and 1.04 for females

There are several prediction equations used in clinical practice to calculate estimated GFR (eGFR)
from serum creatinine concentration and demographic data:

Modification of Diet in Renal Disease (MDRD) Study equation

Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

All of the equations typically overestimate actual GFR slightly because small amounts of creatinine
are secreted by the renal tubules; in clinical practice, this overestimation can be neglected.

Para-aminohippuric acid (PAH) [2]

Description: used to estimate effective renal plasma flow

Mechanism

PAH is freely filtered in the glomerulus; and secreted into the tubular lumen, but not reabsorbed.
Hence, almost 100% of the PAH that enters the kidney is excreted.

Effective renal plasma flow (eRPF)

See “Renal blood flow” section above

eRPF = UPAH x V/PPAH = CPAH

CPAH = clearance of PAH

PPAH = plasma concentration of PAH

V = urine flow rate

UPAH = urine concentration of PAH

Clearance depends on the plasma concentration of PAH (∼ 650 mL/min)

If the plasma concentration of PAH is low, it gets completely excreted from the plasma through
filtration and secretion.

Secretion is dependent on an organic anion transporter that is located on the basolateral

membrane of the proximal convoluted tubule.

If concentration of PAH surpasses the transport capacity of the anion transporters (or if there is
damage to the PCT ), secretion is impaired, which reduces the total excreted amount of PAH.
This leads to slight underestimation of renal plasma flow.

Glucose clearance

Description: used to assess for glucosuria

Mechanism

In normoglycemic states (blood glucose: 60–120 mg/dL), glucose is completely filtered and
completely reabsorbed in the proximal convoluted tubule (PCT) through
sodium-glucose cotransporters (SGLT2). Glucose is not secreted, therefore, its clearance is normally
0 mL/min.

Glucose threshold

Defined as the plasma glucose concentration at which glucose is no longer reabsorbed but instead
excreted in urine

It equals to 180 mg/dL

Splay phenomenon

When the glucose threshold is met, the tubular sodium-glucose cotransporters in some nephrons
are fully saturated, causing glucose to be excreted into the urine.

At the same time, the maximum glucose reabsorption rate in other nephrons is only reached with
higher glucose concentrations (heterogeneity of nephrons).

Therefore, after exceeding the glucose threshold, the overall glucose reabsorption rate initially
increases further with rising glucose concentrations until all glucose transporters in all nephrons
are saturated.

At a tubular glucose transport rate ; of 380 mg/min, all glucose transporters (SGLT2) are saturated
and glucose reabsorption cannot increase further.

Above the glucose filtration rate of 380 mg/min the glucose clearance is proportional to the plasma
concentration.

Pregnancy: ↑ GFR → ↑ filtration of all solutes (including glucose) → glucosuria with normal plasma
glucose levels

SGLT2 inhibitors: inhibition of sodium-glucose cotransporters → decrease of glucose threshold →

glucosuria with plasma glucose levels below 180 mg/dL

SGLT1 is located in the 1ntestine.

SGLT2 is located in the proximal 2bule.

Renal filtration

Filtration fraction (FF)

Description: the fraction of the renal plasma flow (RPF) that is filtered from the capillaries into the
Bowman space

Mechanism

FF = GFR/RPF (i.e., FF = CInulin/CPAH)

CInulin = inulin clearance

CPAH = PAH clearance

Normal: 20%

Regulated via:

Prostaglandins → dilation of afferent arterioles → ↑ GFR and ↑ RPF (FF unchanged)

Angiotensin II → constriction of efferent arterioles → ↑ GFR and ↓ RPF → ↑ FF

PDA - Prostaglandins Dilate Afferent arterioles

ACE - Angiotensin II Constricts Efferent arterioles

Filtered load

Description: the amount of a substance X that is filtered by the glomerulus per unit of time

Mechanism: filtered load (mg/min) = GFR (mL/min) x plasma concentration of substance X (mg/mL)

Changes in glomerular dynamics

Renal plasma Filtration Possible cause

flow fraction

↓ ↓ Unchanged Afferent arteriole constriction (e.g., due to ↓ prostaglandins from

NSAID use)
GFR
Renal artery stenosis

Unchanged ↓ Increased plasma protein concentration (e.g., due to

multiple myeloma)

Unchanged ↓ Obstructive nephropathy

↓ ↑ Severe dehydration (e.g., due to diarrhea, vomiting)

↓ Unchanged Glomerulonephritis

↑ ↓ ↑ Efferent arteriole constriction (e.g., due to ↑ angiotensin II due to

RAAS activation)
GFR

Unchanged ↑ Decreased plasma protein concentration (e.g., due to cirrhosis,

malnutrition)

Renal excretion

Excretion rate

Description: the amount of substance X that is excreted into the urine per unit of time

Mechanism: excretion rate (mg/min) = urine flow rate (mL/min) x urine concentration of substance X
(mg/mL)

Fractional excretion

Description: the proportion of the glomerular filtered substance X that is excreted in the urine

Mechanism

Fractional excretion = excreted load (urinary flow rate x urinary concentration of X)/filtered load (
GFR × plasma concentration of X)

FE < 1: a large proportion of the filtered substance is reabsorbed in the tubules (e.g., water,
glucose, amino acids, sodium chloride)

FE > 1: a small proportion of the filtered substance is reabsorbed or additional tubular secretion
occurs (e.g., PAH, atropine)

Fractional excretion of sodium (FeNa): percentage of the glomerular filtered sodium that is excreted
in the urine

Used to establish the cause of acute kidney injury

FeNa = (UNa x SCr/SNa x UCr) x 100

UNa = urine concentration of Na

SNa = serum concentration of Na

UCr = urine concentration of creatinine

SCr = serum concentration of creatinine

Reabsorption rate = filtered load (GFR × plasma concentration of X) - excreted load (urine flow rate x
urine concentration of X)

Secretion rate = excreted load - filtered load

Renal metabolism

The kidneys and heart are the organs with the highest resting metabolic rates and mitochondrial content.

Catabolism: The kidneys have a high demand for nutrients and oxygen for ATP production. The energy
is needed to excrete waste products, reabsorb nutrients, and regulate blood pressure, electrolytes,
serum osmolality, and acid-base balance.

Substrate utilization by individual nephron segments is determined by the following factors:

Availability of oxygen and pO2: decreases gradually from the renal cortex, which relies on
beta-oxidation and oxidative phosphorylation, to the renal medulla, which is more dependent on
anaerobic glycolysis to fulfill energy demands

Density of pumps and channels utilizing ATP (primarily Na+/K+-ATPase):

The more intensive the transtubular transport, the higher the energy demand and the more
intensive the substrate utilization.

The proximal tubules reabsorb 80% of filtrate, including ions, glucose, and nutrients, and
therefore require more ATP for active transport than other segments.

Main substrates

Proximal tubule: fatty acids

Thick ascending limb of the loop of Henle: glucose

Distal convoluted tubule and the collecting duct: glucose

[6]
Anabolism: Cortical renal cells are capable of gluconeogenesis in fasting states.

The limited oxygen supply to the medulla makes it highly susceptible to hypoxic injury
(especially the S3 segment of the proximal tubule and the medullary thick ascending limb
of the loop of Henle).

References

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