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Physiologic Functions of Kidneys

Regulation of water and electrolyte balances
Regulation of body fluid osmolality
Regulation of acid-base balance (H+ concentration)
Regulation of arterial blood pressure
Elimination of metabolic wastes & foreign chemicals
Production of hormones: erythropoietin, vitamin D, renin
Degradation of peptide hormones
Synthesis of ammonia, prostaglandins, kinins, glucose


Production of ultrafiltrate of blood plasma

Ultrafiltrate is modified in uriniferous tubule (tubular parenchyma of kidney)
End product is urine: moved through ureters by peristalsis, stored in bladder, emptied via urethra



EPO, a glycoprotein hormone

Synthesized and secreted by endothelial cells of the peritubular capillaries in cortex
Acts on erythrocyte progenitor cells in the bone marrow
Regulates red blood cell formation in response to decreased blood oxygen concentration



an acid protease
Synthesized and secreted by juxtaglomerular cells
Cleaves circulating angiotensinogen to make angiotensin I
Controls blood pressure and volume


Vitamin D3

A precursor form of Vitamin D3 is hydroxylated in the proximal tubules of the kidney
The active form created via hydroxylation is called calcitriol


Waste Products Eliminated by the Kidneys

Urea (metabolism of amino acids) -- (Azotemia= high nitrogen products in the blood)
Creatinine (from muscle creatine)
Uric acid (from nucleic acids)
End products of Hb breakdown (bilirubin)
Metabolites of various hormones
Drug metabolites (anions and cations)


Two parts of the nephron

1. Renal corpuscle
- Bowman’s capsule (double-layered epithelial cup)
- Glomerulus (10-20 capillary loops)

2. Tubule system
- Proximal convoluted and straight tubule
- Thin descending and ascending limbs of the loop of Henle
- Distal straight (thick ascending limb) tubule
- Distal convoluted tubule


Types of Nephrons

1. Cortical
- Short loops of Henle
- Surrounded by peritubular

2. Juxtamedullary
- Long loops of Henle
- Long efferent arterioles are divided into specialized peritubular capillaries (vasa recta)
** Function is to concentrate urine


Body water distribution for a 70 kg individual

.6 x body weight is total body water = 42 L

.2 x body weight is ECF (14 L)
.4x body weight is ICF (28 L)

Interstitial fluid is 3/4 of ECF (10.5 L)
Plasma is the other 1/4 (3.5 L)
Of the plasma, venous is 80%, Arterial is 20%.

Arterial = Effective Circulating Volume


Third space

Transcellular fluid is also included in the ECF. It normally contains only a small amount of water (1-2 L) such as epithelial secretions, synovial, peritoneal, pericardial, intraocular, CSF.
It is said to occupy a “third space”- i.e., “3”
ECF fluid compartments.


Donnan Effect

more Na+ in the plasma than in the interstitial fluid

the greater amount of (-) proteins pulls more cations into the plasma.


Movement of Water

The capillary cell membrane (barrier between ECF compartments) is highly permeable to both water * and small ions

Fluid distribution is due to balance between hydrostatic pressure and colloid osmotic pressure (Starling Forces)

The cell membrane (barrier between ECF and ICF) is highly water-permeable
Not permeable to most electrolytes

Fluid distribution between two compartments is dependent on osmotic effects (Na+, Cl-, K+, HCO3-)


Fluid Shifts - Osmotic Equilibration

Maintenance of body fluid balance is regulated by two factors:
ECF Volume
ECF Osmolarity – this controls ICF volume since water enters/leaves ECF rapidly to balance the osmolarity between ECF and ICF compartments

“Osmotic Equilibration”
Movement of water across cell membranes from higher to lower concentration as a result of an osmotic pressure difference (difference in number of solute particles in solution) across the membrane
Osmotic pressure exerted across a membrane by a solute is due to the membrane being impermeable to that solute


What happens when you withdraw 3 liters pure HxO from ECF?

osmotic gradient is created

H2O rapidly diffuses from ICF to ECF to re-establish osmotic equilibrium. Note that there are proportional changes in each compartment’s volume.



Palpable swelling produced by expansion of interstitial fluid volume. Caused by:

1. Alteration in capillary hemodynamics (altered Starling forces with increased net filtration pressure) - fluid moves from vascular space into the interstitium
2. Renal retention of dietary Na+ & H2O, expansion of ECF volume
3. Lymph blockage



located in the anterior hypothalamus
Increase discharge rate in response to a 1% rise in CSF osmolarity and send signals to the “thirst” center
Results in sensation of thirst and release of anti-diuretic hormone (ADH)


Volume receptors

located in the right atrium
Increase discharge rate in response to increased blood volume and send signals via the vagus nerve to the medulla
These afferent signals inhibit the pressor area of the vasomotor center, thereby suppressing sympathetic discharge
These afferents also reach the hypothalamus to inhibit thirst and ADH secretion
During volume decrease, this pathway may stimulate thirst and ADH, but volume must drop >10% (less sensitive than osmoreceptors)


Antidiuretic hormone (ADH/AVP)

Secreted by the hypothalamus and released by the posterior pituitary
Stimulated by input from osmoreceptors and volume receptors
Promotes water reabsorption from distal convoluted tubule and collecting ducts



Secretion is stimulated by circulating Angiotensin II (as a result of sympathetic activation), rise in plasma K+, fall in plasma Na+
Promotes reabsorption of Na+ from DCT and secretion of K+


Atrial natriuretic peptide

Released by cells in the atria in response to increased volume (stretch) to promote sodium excretion in the kidney



The most prompt and effective mechanism in place for correcting an increase in osmolarity
Thirst center is located in hypothalamus
Stimulated by osmoreceptors and Ang II, inhibited by impulses from volume receptors


Salt craving

Evoked by a drop in plasma Na+ concentration, likely sensed in the amygdala


Sympathetic discharge

Hypovolemia leads to decreased discharge of atrial receptors, resulting in less excretion of Na+ and H2O; may stimulate ADH and thirst as well if volume drops significantly


Renal Blood Flow (RBF)

At rest, kidneys receive ~20% of cardiac output (called the renal fraction).

*** High pressure in glomerular capillaries (≈ 60 mmHg) causes filtration of blood.
1100-1300 ml filtered/min which produces 125-130 ml of fluid (glomerular filtrate).

*** Low pressure in the peritubular capillaries (≈ 13 mmHg) permits fluid reabsorption.
Pressure in both capillary beds can be regulated by resistance changes in afferent and efferent arterioles.


Renal vascular supply (name the vessels)

aorta--> renal artery--> segmental arteries--> interlobar arteries--> arcuate arteries--> interlobular arteries--> afferent arterioles--> glomerulus-> efferent arteriols--> vasa recta or peritubular capillaries--> (interlobular veins, if from peritubular capillaries)--> arcuate veins--> interlobar veins--> segmental veins--> renal veins-> inferior vena cava


Organize the following by filtration/ reabsorption:

- Creatinine
- Na, Cl
- Amino acids, glucose
- organic acids and bases

Filtration only: creatinine
filtration and partial reabsorption: Na, Cl
Filtration and complete reabsorption: amino acids and glucose
Filtration and secretion: organic acids and bases


Forces Affecting GFR

GFR is remarkably high (c. 125 ml/min, 180 l/day)

GFR is the product of 3 physical factors:
Hydraulic conductivity (Lp) of glomerular membrane (permeability or porosity of capillary wall)
Surface area available for filtration (c. 2 m2)
Capillary ultrafiltration pressure (PUF)

Note: Product of 1 and 2 is ultrafiltration coefficient Kf

GFR = Kf · PUF


Ultrafiltration Pressure: Driving Force for Glomerular Filtration

PUF is determined by hydrostatic and colloid osmotic pressures in the glomerular capillaries and in Bowman’s capsule:
PUF = (PGC + piBC) - (PBC + piGC)
piBC ~ 0, so

PUF = PGC - (PBC + piGC)


Mechanisms for Altering GFR: Altered Kf

things that change surface area or conductivity

Contraction of mesangial cells (by renal sympathetic nerve activation, Ang II) shortens capillary loops, lowers Kf and, thus lowers GFR.
Some disease states can cause this as well


Mechanisms for Altering GFR: Altered PUF

things that change PGC

Renal arterial blood pressure
Afferent arteriolar resistance
Efferent arteriolar resistance
With slight increases in resistance, GFR will increase.
With significant increases in resistance, GFR will decrease.



1. In normal individuals, GFR is primarily regulated by alterations in PGC

2. PGC is determined by changes systemic arterial pressure (PA), afferent arteriolar resistance (RA), efferent arteriolar resistance (RE)


Control of GFR by adjusting resistance of afferent and efferent arterioles

Afferent arteriolar constriction:
Greater pressure drop upstream of glomerular capillaries
PGC falls, which lowers GFR
Renal blood flow falls due to increased resistance

Efferent arteriolar constriction:
Pooling of blood in glomerular capillaries
Increased PGC increases GFR


Myogenic autoregulatory mechanisms at the kidney

Mechanism to maintain constant RBF and GFR
Resistance of blood vessels to stretch when exposed to high arterial pressure
Vascular smooth muscle cells contract in response to stretch via movement of Ca2+ from ECF into cells
Occurs within seconds
May be most important in protecting the kidney from hypertension-induced damage


Tubuloglomerular feedback autoregulatory mechanisms

Macula densa cells in the distal tubule detect changes in NaCl (volume is inferred) delivery

Macula densa cells communicate with juxtaglomerular cells in the afferent arteriole to affect resistance

A drop in delivery of NaCl (and therefore volume) to macula densa leads to
- Decreased resistance to blood flow in the afferent arteriole
- Increased renin release from the juxtaglomerular cells
- -- Ang II constricts the efferent arteriole >>afferent arteriole
Ensures constant delivery of NaCl to distal tubule and prevents changes in renal excretion


Juxtaglomerular apparatus

Includes the macula densa, juxtaglomerular cells, and the extraglomerular mesangial cells
Adjacent to afferent/efferent arterioles at the vascular pole of the renal corpuscle
Regulates the body’s salt and water balance by monitoring NaCl levels (distal tubule), blood pressure (afferent arteriole)
Renin is released when levels are low


TGF response to decreased GFR

If our drop in GFR was caused by a severe decrease in volume, the SNS would be activated, leading to afferent arteriolar constriction to conserve Na+ and H2O.


TGF response to increased GFR

This results in constriction of afferent arteriole and decreased renin release, with a fall in GFR.

Collecting ducts have limited reabsorptive capacity – this prevents those resources from being overwhelmed.


Effects of Sympathetic Stimulation

Sympathetic nervous system activation
- Diverts the renal fraction to vital organs
- Seems to be most important in reducing GFR during severe, acute disturbances (defense reaction, stress, brain ischemia, hypovolemia, hemorrhage, etc.)

SNS activation causes ↑ renin secretion by granular cells
- Angiotensin II thus produced restores blood pressure (systemic vasoconstriction)
- Angiotensin II promotes arteriolar constriction (efferent > afferent): raises blood pressure, may stabilize GFR (moderate Ang II)

SNS activation ↑ Na+ reabsorption in PCT, thick ascending limb of LOH, DCT, collecting duct


Sympathetic Innervation at the kidney

In afferent arterioles, sympathetic neurons synapse on:

Smooth muscle causing arteriolar constriction
Protective during increased BP
Granular cells causing renin secretion


Effects of Angiotensin II

Ang II is a circulating hormone and autacoid. Receptors are present in all blood vessels of kidney.
*** Half-life is less than 1 min

Afferent arterioles appear to be “protected” from the effects of Ang II, while efferent arterioles are highly sensitive to it, although both constrict in response to AngII
Aids in maintaining GFR in instances of pressure or volume depletion, helps to increase Na+ and H2O reabsorption
↑ Na+ reabsorption via ↑ activity of NHE in proximal tubule
Stimulates aldosterone secretion from adrenal cortex
Stimulates the thirst center
Stimulates ADH secretion from posterior pituitary



Aldosterone is secreted by the zona glomerulosa of the adrenal cortex
Aldosterone diffuses into principal cells; induces synthesis of mRNA for proteins involved with Na+ transport
Stimulates Na+ reabsorption (ENaC)
This leads to a lumen-negative potential difference
This is balanced by passive Cl- reabsorption & K+/H+ secretion
Stimulates K+ secretion (and is inhibited by low plasma K+)
Stimulates H+ secretion via ↑ H+ATPase activity in intercalated cells of CCD


Antidiuretic Hormone (ADH) Actions

(also known as vasopressin or AVP)
increases permeability of late distal tubule and collecting duct to water (via the insertion of aquaporins)
Increases the activity of Na+-K+-2Cl- cotransporter (NKCC)
Increases urea permeability in the inner medullary collecting ducts


Two major stimuli for AVP/ADH release:

hyperosmolalityvolume depletion

Hypothalamic osmoreceptors are more important than hepatic osmoreceptors


Atrial Natriuretic Peptide (ANP) response to increased ECF volume

ANP increases GFR by dilating the afferent arteriole (it causes systemic vasodilation)
ANP inhibits Na+ reabsorption in medullary collecting duct
ANP suppresses renin, AVP/ADH, and aldosterone secretion


Glomerular Filtration Rate (GFR)

Glomerular filtration rate (GFR): volume of plasma filtered into the combined nephrons of both kidneys per unit time (e.g. ml/min)
GFR is an index of functioning renal mass
GRF is determined by Starling forces in the glomerulus and glomerular capillary permeability
Reductions in GFR in disease states are most often due to a decrease in net permeability resulting from a loss of filtration surface area induced by glomerular injury
In normal subjects, GFR is primarily regulated by alterations in glomerular hydrostatic pressure that are mediated by changes in arteriolar resistance


Calculating filtration rate

Filtration rate of any freely filtered substance = GFR x plasma concentration of substance
GFR = 125 ml/min
Plasma glucose concentraiton = 1 mg/ml
Rate of glucose filtration = 125 mg/min


Renal Clearance

Measurement of GFR relies on the concept of clearance.
Clearance: the volume of plasma from which a substance is completely removed (cleared) by the kidneys in a given time period
Units are volume/time, e.g. ml/min, l/hr, etc.

Describes how effectively the kidneys remove a substance from the bloodstream and excrete it in the urine; different substances have different clearances.


Clearance formula

UxV/ P

urine concentration of x X urine flow rate / plasma concentration of x


Creatinine Clearance ~ GFR

Inulin is the gold standard for measuring GFR. However, it must be infused i.v.
We need another method for estimating GFR that’s not so cumbersome…
Substance must be freely filtered, and not reabsorbed, secreted, synthesized, or metabolized by the kidney.

Creatinine is produced endogenously from metabolism of creatine by skeletal muscle.
Not perfect: creatinine secretion in proximal tubule overestimates Ucreatinine; substances in blood cause overestimation of Pcreatinine


Important Clinical Limitations to using creatinine as measure of GFR

Strenuous exercise is a physiologic mechanism causing increased plasma creatinine
Significant disease progression can occur with little or no elevation in plasma creatinine, especially in patients with GFR > 60 mL/min
- In glomerular disease (drop in glomerular permeability due to decreased surface area available for filtration), a drop in GFR is counteracted by tubuloglomerular feedback to maintain GFR at near-normal levels
- Nephron loss may be compensated for by remaining nephrons (25-30% loss can still appear normal)
- Once GFR does fall, the rise in plasma creatinine will be minimized by increased creatinine secretion in proximal tubule


Estimating RPF via PAH Clearance

Para-aminohippuric acid (PAH)
Exogenously introduced, freely filtered, avidly secreted in proximal tubule
PAH: completely cleared from plasma of peritubular capillaries when plasma PAH concentration is low
This method underestimates RPF by about 10%


Filtration Fraction (FF)

Filtration fraction is the part of the renal plasma flow (RPF) that is filtered into the tubules
- Normally about 20% (GFR/RPF)

FF changes with ultrafiltration pressure
- With an increased FF, the oncotic pressure of the efferent arterioles increases, aiding reabsorption of tubular fluid


Basic Processes of Urine Formation

Glomerular filtration: Filtration of plasma from glomerular capillaries into Bowman’s capsule
Tubular reabsorption: Transferral of substances from tubular lumen to peritubular capillaries
Tubular secretion: Transferral of substances from peritubular capillaries to tubular lumen
Excretion: Voiding of substances in the urine


Proximal Tubular Transport

Proximal tubule reabsorbs 60-80% of the filtrate
- Most of filtered H2O, Na+, K+, Cl-, bicarbonate, Ca2+, phosphate, lactate, citrate
Na+/H+ exchanger is the countertransporter that drives HCO3- reabsorption
- Normally, all the filtered glucose, amino acids
Secondary active transport (bicarbonate, too)
- This equates to roughly 130 of the 180 L that is filtered daily!

Several organic anions and cations (drug metabolites, creatinine, urate) are secreted in proximal tubule
It is the most abundant component of the tubule system


Late proximal tubule

The fluid entering the late proximal convoluted tubule has a higher concentration of Cl- due to preferential reabsorption of HCO3- earlier.
The late proximal tubule reabsorbs NaCl.
The diffusion of Cl- results in a lumen-positive potential difference.


Loop of Henle Solute and Water Transport

Thin descending, thin and thick ascending segments
Descending limb is highly permeable to H2O, moderately permeable to solutes
Rougly 20% of filtered water is absorbed here

Ascending limb is highly permeable to solutes, but impermeable to water
Roughly 25% of filtered Na+, Cl-, K+ are reabsorbed (thick)
Ca2+, HCO3-, Mg2+ are also absorbed here (electrogenic transport due to lumen-positive potential difference)


Loop diuretics

Furosemide, Ethacrynic acid, and bumetanide work against the Na+, 2Cl-, K+ cotransporter


Loop of Henle

Found in the medulla
Establishes a hypertonic medullary interstitium
Thin descending limb is highly permeable to water, and less permeable to solutes
Thin ascending limb is highly permeable to NaCl and impermeable to water


Distal Tubule Solute and Water Transport

First portion of the tubule is formed by the macula densa

Next part is highly convoluted and permeable to most ions, but is impermeable to urea and water (diluting segment)
- 5% filtered load of NaCl is reabsorbed in the early distal tubule via Na-Cl cotransporter


2 types of cells in the late distal tubule and collecting duct

Principle cells (light cells)
- Na+ reabsorption (3%) and K+ secretion
K+ diffuses out of cell and into the tubular fluid, Na+ is transported by epithelial Na+ channels
- Site of potassium-sparing diuretics
--- They inhibit the stimulatory effect of aldosterone at this site
--- Can also directly block sodium channels on the luminal membranes, decreasing the effectiveness of the Na-K pump
- Pale-staining; single primary cilium and relatively few short microvilli; small, spherical mitochondria; many ADH-regulated water channels (aquaporin-2)

Intercalated cells (dark cells)
- Secrete H+ ions via H-ATPase transporter (active transport!)
- Considerably fewer in number; many mitochondria; dense cytoplasm with numerous vesicles present
- α-intercalated cells secrete H+, whereas β-intercalated cells secrete HCO3-


Purpose of the late distal tubule and collecting duct

The “fine tuner” of the filtrate

Impermeable to urea; reabsorbs Na+ and secretes K+, under hormonal influence; secretes H+ against a large concentration gradient; permeability to water is controlled by ADH


Medullary Collecting Duct

Although the medullary collecting duct reabsorbs less than 10% of the filtered water and Na+, it’s the final site for processing urine
Permeability to water is controlled by ADH
Permeable to urea
Can secrete H+ ions against their concentration gradient


5 factors affect K+ secretion in collecting duct

Extracellular K+ concentration
Na+ reabsorption: negative luminal voltage ‘attracts’ K+
Luminal fluid flow rate: dilution of secreted K+
Extracellular pH: K+ and H+ exchange across cell membranes
Aldosterone: Stimulates K+ secretion in collecting duct


Situations that alter K+ handling

Most classes of diuretics increase Na+ and volume delivery to late distal tubule and collecting duct, which increases K+ secretion

Low-sodium diet: less Na+ delivery to late distal tubule, collecting duct --> less K+ secretion, excretion --> may cause hyperkalemia

Clinical Application: Hyperkalemia may be treated by increasing downstream delivery of Na+ to the distal tubules/collecting ducts. Results in increased Na+ reabsorption and K+ secretion.


Ca2+ handling by the nephron

67% in proximal tubule
25% in thick ascending limb
8% in distal tubule

Thiazide duretics lower intracellular Na+ over time (by increasing excretion), which promotes activity of the Na+/Ca2+ antiporter and therefore Ca2+ reabsorption.


Phosphate handling by the nephron

80% in proximal tubule
(PTH inhiits this, leading to phosphate excretion, AKA phosphaturia)

10% Distal tubule


Mg2+ handling by nephron

The bulk of the filtered Mg2+ is reabsorbed in the thick ascending limb of Henle’s loop by paracellular movement


Normal arterial acid-base values

pH 7.4
[H+] 40 mmol/L
PCO2 40 mmHg
[HCO3-] 24 mEq/L


4 Lines of Defense Against pH Changes

1. Intracellular buffers
2. Chemical buffers
3. Respiration
4. Kidneys

Six factors control renal H+ secretion:
Intracellular pH
Plasma PCO2
Carbonic anhydrase
Na+ reabsorption
Extracellular K+


Respiratory Acid-Base Disturbances and the renal responses

Respiratory acidosis: increased arterial PCO2

Renal response: increased H+ secretion restores extracellular pH, increases HCO3- further

Respiratory alkalosis: decreased arterial PCO2

Renal response: less H+ secretion, more HCO3-excretion in urine


What happens to Ca2+ levels during acidemia and alkalemia?

Acidemia: H+ binds to plasma proteins that Ca2+ normally binds = hypercalcemia
Alkalemia: bound Ca2+ leads to hypocalcemia (common in respiratory alkalosis)


Metabolic Acid-Base Disturbances and respiratory/ renal response

Metabolic Acidosis: low plasma pH due to gain of fixed acid in body fluids or loss of HCO3- ; [HCO3-] decreases
Respiratory compensation: ↑ ventilation
Renal response: ↑ H+ secretion; production of new HCO3-

Metabolic Alkalosis: abnormally high plasma pH due to excessive gain of strong base or HCO3-, excessive loss of fixed acid; [HCO3-] increases
Respiratory compensation: ↓ ventilation
Renal response: incomplete reabsorption of filtered HCO3-, and intercalated cells secrete HCO3-


Anion Gap (A.G.)

Used in differential diagnosis of metabolic acidosis

A.G. = measured cation (Na+) - measured anions (Cl-, HCO3-)
Normal range: 8-11 mEq/l ; A.G. is either normal or increased, depending on cause of metabolic acidosis

Hyperchloremic acidosis:: A.G. is unchanged (loss of HCO3- is matched by gain of Cl-)
HCl + HCO3- --> Cl- + H2O + CO2

High anion gap acidosis: HCO3- is replaced by an unmeasured anion (lactate, ketoacidosis, poisoning) and A.G. increases
HA + HCO3- --> A- + H2O + CO2


Blood Urea Nitrogen (BUN)

The liver produces urea in the urea cycle as a waste product of the digestion of protein.
The kidney freely filters urea at the glomerulus, then it both reabsorbs and secretes it.
-- Roughly 50% is excreted.



Increased blood levels blood urea nitrogen (BUN) and creatinine (Cr) that occur as a result of decreased kidney function. The greater the increase in blood BUN and creatinine, the greater the decrease in function.


Prerenal Azotemia and BUN/Cr

, BUN/Cr > 20 (normal ~15)
Decreases blood flow to the kidneys; no inherent kidney disease
Decreased filtration of BUN and Cr but enhanced BUN reabsorption and Cr secretion in the proximal tubule
Examples: hemorrhage, shock, volume depletion, congestive heart failure, adrenal insufficiency, narrowing of the renal artery, etc.


Primary renal Azotemia and BUN/Cr

(acute renal failure), BUN/Cr less than 15

An intrinsic disease of the kidney, generally the result of renal parenchymal damage
Decreased filtration of BUN and Cr; decreased reabsorption of BUN, decreased secretion of creatinine due to tubule damage (which causes Cr to build up more than BUN)
Examples: glomerulonephritis, acute tubular necrosis, and other renal diseases


Postrenal Azotemia and BUN/Cr

BUN/Cr is initially > 15, but it will drop over time
Blockage of urine flow in an area below the kidneys; no inherent kidney disease
Increased resistance to urine flow can cause back up into the kidneys and increased nephron tubular pressure. This pressure causes increased reabsorption of BUN. Over time, the increased pressure will cause tubule epithelial damage and the BUN/Cr will drop.
Examples: congenital abnormalities such as vesicoureteral reflux, blockage of the ureters by kidney stones, pregnancy, compression of the ureters by cancer, prostatic hyperplasia, etc.