Renal function

I. Introduction.

A. Kidneys - filter fluid from bloodstream into tubules, materials not needed stay in the tubules to be excreted; needed materials (ions, water) are reabsorbed to the blood; some material is actively pumped into the tubules for excretion.

- filtrate formed, as it passes through tubule its volume is reduced and composition altered -- wastes are eliminated, water and essential electrolytes and metabolites are conserved.

- the composition of urine can thus be highly varied -- homeostatic mechanisms minimize/prevent changes in ECF composition by changing amount of water and solutes in urine.

- regulate blood volume, chemical makeup of the blood; water and electrolyte balance, acid-base balance.

B. Ureters.

C. Urinary bladder.

D. Ureters.

II. Kidney functional anatomy.

A. Internal anatomy.

- renal capsule: fibrous connective tissue.

- cortex: light and granular.

- medulla - darker (reddish brown).

- medullary pyramids: cone shaped tissue, separated by cortex projections, renal columns.

- apex of medullary pyramids terminate in papillae.

B. Blood supply - kidneys receives 25% cardiac output per minute (1200 ml).

C. Nephrons: microscopic anatomy of kidney.

- structural and functional units of the kidney, responsible for urinary formation.

1. Glomerulus: tuft of capillaries.

- associated with the renal tubule.

- blind end of the renal tubule is cup-shaped, surrounds glomerulus -- Bowman's capsule.

- glomerulus and Bowman's capsule form renal corpuscle.

- glomerular capillaries are highly fenestrated.

- outer layer of Bowman's capsule -- parietal layer, simple squamous epithelium, no filtration function.

- inner layer of Bowman's capsule -- visceral layer, clings to glomerulus; formed by branching epithelial cells, podocytes; podocytes have numerous foot processes, pedicels, that form filtration slits.

- thus the glomerular caps and enveloping podocytes form a very porous filtration membrane -- solute rich filtrate thus enters Bowman's capsule; between the capillary endothelium and podocytes is a basement membrane.

2. Proximal convoluted tubule (PCT).

- reabsorbs substances from the filtrate.

- secretes substances into the filtrate.

3. Loop of Henle.

- hairpin loop, descending and ascending limbs.

- descending limb: freely permeable to water.

- ascending limb: freely permeable to NaCl.

4. Distal convoluted tubule (DCT).

- hormonally regulated reabsorption of H₂O

- secretion.

5. Collecting duct (CD) - several DCTs empty into it.

- hormonally regulated reabsorption of H₂O and NaCl.

D. Types of nephrons.

- some nephrons almost entirely in the cortex; very short loop of Henle -- cortical nephrons.

- other nephrons have a long loop of Henle which extends deep into the medulla -- juxtamedullary nephrons (15%).

F. Capillary beds in nephrons.

1. Cortical nephrons.

a. Glomerulus originates from afferent arteriole, empties into efferent arteriole; high blood pressure in the glomerulus, a specialization for filtration.

b. Peritubular capillaries arise from efferent arteriole; surround PCT, DCT, some of LH; empty into nearby venules; low pressure caps, very porous -- adaptations for reabsorption and secretion.

2. Juxtamedullary nephrons.

a. Glomerulus - as in cortical nephrons.

b. Peritubular capillaries - as in cortical nephrons.

c. Vasa recta: are thin walled looping vessels that parallel the Loop of Henle; they extend deep into the medulla and empty into nearby venules.

G. Vascular resistance along nephron circulation.

- blood pressure in glomerular caps about 55 mm Hg, however doesn't drop much across the capillary bed itself; pressure in peritubular caps is 8 mm Hg

- blood pressure decreases along nephron circulation from afferent arteriole to peritubular caps to vasa recta.

F. Juxtaglomerular apparatus.

- there is a close spatial relationship between PCT / DCT and afferent / efferent arteriole of glomerulus; where the DCT curves back between the afferent and efferent arterioles a group of cells are found predominantly in the walls of the afferent arteriole, JG cells; these cells sense blood pressure at the afferent arteriole, produce hormone renin.

- in the same location the walls of the DCT tubule contains specialized tubular cells, the macula densa, chemoreceptors and osmoreceptors -- monitor contents of DCT.

III. Renal physiology.

A. Introduction.

- 1000-1200 ml blood passes through the glomerulus per minute.

- thus, 650 ml/min plasma passes through the glomerulus per minute; 120-125 ml/min of plasma forced into tubules -- therefore you filter the equivalent of your plasma volume about 60 times a day, of your ECF volume 15 times per day, of your total body water 4 times per day.

- note that filtrate, however, very different from urine; filtrate is plasma minus its proteins; by the time the filtrate reaches the CD its volume has been reduced and its composition drastically altered.

- what remains in CD is urine -- metabolic wastes, unneeded substances.

- filter 180L/day -- urine volume only 1.5 L /day -- thus over 99% of filtrate is reabsorbed.

- thus renal function involves three basic processes, glomerular filtration, tubular reabsorption, and tubular secretion.

B. Glomerular filtration

- fluids/solutes moved across a membrane by hydrostatic pressure.

- filtration membrane very leaky and glomerular blood pressure high compared to other caps.

1. Characteristics of glomerular capillaries: glomerulus is a very efficient filter, glomerular caps form 100X more filtrate than other caps.

a. Filtration membrane or barrier -- neutral substances with effective molecular diameters of less than 4 nm are freely filtered, filtration of neutral substances with diameters of more than 8 nm approaches zero -- between these values filtration is inversely proportional to diameter

i. fenestrated capillary endothelium

ii. visceral membrane of Bowman's capsule -- podocytes with pedicels, filtration slits.

iii. intervening basement membrane -- size exclusion and charge exclusion of plasma proteins.

- filtration coefficient (K_f) for glomerular capillaries is much greater than that found in other capillary beds; K_f is a function of total capillary surface area as well as the permeability per unit surface area.

b. Glomerular net filtration pressure high compared to other caps -- 10 -15 mm Hg throughout capillary bed

- diameter of efferent arteriole smaller that that of afferent arteriole.

- forces involved in regulation of filtration, Starling forces

i. filtration pressures: blood hydrostatic pressure (55 mm Hg) and Bowman's capsule osmotic pressure (negligible).

ii. reabsorption pressures: blood osmotic pressure (30 mm Hg close to afferent arteriole) and Bowman's capsule hydrostatic pressure (15 mm Hg).

- thus  net filtration pressure is 10 mm Hg 

2. Glomerular filtration rate (GFR)

- total amount of filtrate formed by the kidney per minute, 125 ml/min; measured by calculating clearance for inulin or creatinine.

- depends on the surface area available for filtration, permeability of the filtration membrane, and net filtration pressure (GFR directly proportional to it).

- however, when BP in range of 80-180 mm Hg, GFR constant!!!

- this is important because changes in GFR can dramatically influence the amount and composition of urine produced and thus the volume and composition of blood -- thus very important to keep GFR constant within a wide range of BP.

a. Regulation of GFR - renal autoregulation.

- an intrinsic property of the kidneys.

i. Myogenic mechanism

- increased BP at afferent arteriole causes afferent arteriole constriction, decrease blood flow (BF) to glomerulus, decrease in glomerular BP, maintaining GFR stable.

ii. Tubuloglomerular feedback

- carried out by macula densa cells of JG apparatus.

- an increase in BP leads to momentary increased GFR -- this will lead to increased filtration, increased filtrate flow, decreased reabsorption, and NaCl concentration in tubule increases; changes in NaCl concentration detected by MD cells which in turn release a vasoconstrictor substance that acts on the afferent arteriole -- decreased BF to afferent arteriole, decreased glomerular BP, GFR stabilized.

- a decrease in BP has opposite effects.

b. Regulation of GFR - sympathetic innervation to afferent arteriole.

i.  if blood pressure drops -- hemorrhage or severe dehydration, for example:

• baroreceptors activated -- vasomotor center stimulated
• increased vasomotor tone to arterioles throughout body
  • including afferent arteriole (much more than efferent)
  • drop GFR --> drop urine ouput --> conservation of fluids --> enhance plasma volume
• increased sympathetic discharge to JG cells -- renin production

ii.  if blood pressure dramatically raised  -- converse is true

c.  Regulation of GFR -- renin-angiotensin-aldosterone system

- JG cells of juxtaglomerular apparatus release renin when blood pressure at afferent arteriole drops below 80 mm Hg -- sense stretch of walls of afferent arteriole; macula densa cells also detect slow filtrate flow, decreased levels of NaCl in tubule, also stimulate JG cells to release renin.

- renin stimulates conversion of angiotensinogen to angiotensin I (AI); AI converted to AII by converting enzyme; AII is potent vasoconstrictor; AII also stimulates adrenal cortex cells to release aldosterone; aldosterone acts on cells of kidney distal tubule and collecting duct to increase Na+ reabsorption -- WHERE SODIUM GOES THE WATER GOES -- water follows, blood volume increased, blood pressure stabilized.

C. Tubular reabsorption.

- recall 125 ml/min filtrate produced, 180 L/day; however, only 1.5 L/day urine excreted -- tubular reabsorption is one of the means by which the volume and composition of filtrate is drastically changed.

- reabsorption is movement of material (fluids/solutes) from renal tubule back to circulation.

- it is a transepithelial process that begins as soon as filtrate enters PCT -- here 60-70% of filtered solute is reabsorbed; 60-70% of filtered H₂O reabsorbed.

- transported substances move through three membrane barriers -- the luminal and basolateral membranes of the tubule cells (abut filtrate and ISF, respectively), and the endothelium of peritubular capillaries -- to reach the blood.

- most nutrients such as glucose and amino acids are usually totally reabsorbed; rate of reabsorption of water and many ions is more regulated and depends on hormonal signals.

- depending on substance reabsorbed, process may be active (primary or secondary active transport) or passive (none of membrane transport steps require ATP).

1. Active tubular reabsorption.

a. Primary active transport -- Na⁺ reabsorption.

- Na⁺ is the most abundant cation in the filtrate, the bulk of energy of active transport is devoted to its reabsorption -- this is important since Na⁺ reabsorption by active transport provides the energy and means for reabsorbing most other substances (both through secondary active transport and passive reabsorption).

- Na⁺ reabsorption is always active:

- Na⁺ enters the luminal membrane of tubule cells via channel

- inside the tubule cell, Na⁺ diffuses to the basolateral membrane where it is actively pumped to the ISF by a Na⁺-K⁺ pump; from there it diffuses into a peritubular capillary.

- note that the active pumping of Na⁺ from the tubule cell at the basolateral membrane results in a strong electrochemical gradient that sets up the passive entry of Na⁺ into the cell at the luminal border:

• the pump maintains intracellular Na⁺ low --sets up chemical gradient for Na⁺ diffusion into the cell.
• since K⁺ pumped into cell quickly leaks out into ISF via leakage channels, both the cell interior and the tubule lumen have a negative charge relative to the ISF -- an electrical gradient for Na⁺ diffusion into the cell.

b. Secondary active transport coupled to Na⁺ (in other words Na⁺ transport is always coupled to the transport of another solute; which solute depends on where along the tubule the Na⁺ transport is occurring)

i. - this is the manner in which glucose, amino acids, lactate, vitamins, and most cations (K⁺, Mg⁺⁺, Ca⁺⁺, etc.) are reabsorbed.

- the driving force for reabsorption of these substances comes from the gradient created by the Na⁺-K⁺ pump in the basolateral membrane of tubule cells (see above).

- a carrier protein (transporter) moves Na⁺ and down its concentration gradient at the luminal membrane together with the cotransported molecule; cotransported molecule moves across basolateral membrane and peritubular capillaries by diffusion.

ii. Transport maximum

- the transporters mentioned above are specific for one molecule, and there are different numbers of transporters for different molecules: there are large numbers of carriers for substances that are important to body, and fewer numbers of carriers for substances that are of minor use to the body (and thus don't need to be completely reabsorbed).

- there is a point at which all the transporters for a specific molecule could be in use -- in other words, the carriers for that molecule are saturated and at this point that molecule is being reabsorbed at the maximum possible rate. Therefore, for each molecule being reabsorbed there is a transport maximum (T_m), the maximum rate at which a molecule can possibly be reabsorbed (mg/min). If the concentration of a molecule in the renal tubules is great enough to saturate all the transporters for the molecule, the T_m for that molecule is exceeded and that molecule will spill into the urine (is excreted) -- example of glucose in diabetes mellitus.

2. Passive tubular reabsorption: diffusion, facilitated diffusion, osmosis.

- substances move along their electrochemical gradients without the use of ATP.

- however, even the majority of passive tubular reabsorptive processes are still dependent on the active reabsorption of Na⁺ .

a. Anion reabsorption.

- in the renal tubules as Na⁺ moves through renal tubule cells into peritubular capillaries -- sets up an electrical gradient that favors passive reabsorption of anions ( via own specific channels or between cells, NO PIGGYBACK with Na⁺ so not secondary active transport).

b. Obligatory water reabsorption: where Na⁺ goes the water follows.

- Na⁺ movement as described above sets up a strong osmotic gradient -- water moves by osmosis into peritubular capillaries (via membrane pores or between cells, NO PIGGYBACK).

c. Solvent drag.

- as water leaves the tubule the relative concentration of substances left in the tubule increases dramatically -- substances begin to follow their concentration gradients into tubule cells, peritubular capillaries.

- urea, other lipid-soluble substances reabsorbed in this fashion.

 D. Tubular secretion.

- movement of substances from blood of peritubular capillaries through tubule cell into the tubule lumen -- thus the excreted urine is composed of filtered and secreted substances.

- tubular secretion takes place mostly in the late DT and early CD and is usually and active process.

- major functions of tubular secretion:

1. Disposing of materials not filtered earlier -- disposing of penicillin, phenobarbital, ammonia.

2. Disposing of materials that were filtered and earlier reabsorbed -- urea, K⁺.

- an important way to eliminate K⁺ : virtually all K⁺ present in the filtrate is reabsorbed in the PCT and proximal LH; thus the only way to get rid of K⁺ is through secretion in the CD (hormonally regulated by aldosterone).

3. Regulation of blood pH.

- if blood pH drops renal tubule cells (DT) actively secrete H⁺ and retain more HCO₃^- and K⁺ ions.

- if blood pH rises H⁺ secretion halts, Cl^- rather than HCO₃^- is reabsorbed and HCO₃^- is allowed to leave the body in the urine.

E. Overall summary of nephron function.

Tubule segment	Reabsorption	Secretion
proximal convoluted tubule	all glucose/amino acids acids 65% Na+/65% H2O 90% HCO3- 50% Cl-, K+	some drugs ammonia
Loop of Henle, thin descending	H20 ( not coupled to Na+)	----
Loop of Henle, thick ascending	25% Na+ Cl- 40% K+ 15% H20	----
distal tubule	Na+ Cl- HC03- H20	H+ K+ NH4+
collecting duct	K+ (only if K+ plasma drops) Na+ Cl- HCO3- urea	----

F. Control of urine formation.

1. The creation of a cortex-medullary osmotic gradient.

2. The maintenance of the cortex-medullary osmotic gradient.

3. Formation of dilute or concentrated urine.

G. Ureters

- convey urine from kidneys to bladder; enter bladder inferiorly and obliquely so that bladder filling compresses opening of ureters preventing backflow of urine.

- trilayered wall: mucosa is transitional epithelium, muscularis is double layer of smooth muscle, adventitia is fibrous connective tissue.

- play active role in transporting urine to bladder: distension of ureter by incoming urine stimulates muscularis to contract, propelling urine.

H. Urinary bladder

- collapsible muscular sac that stores urine temporarily.

- trilayered wall: mucosa containing transitional epithelium, a thick muscular layer (detrusor muscle), fibrous adventitia.

- very distensible organ; in empty state walls have many folds, rugae; as urine accumulates, becomes distended, rugae disappear; moderately full bladder holds about 500 ml.

I. Urethra

- thin walled muscular tube that drains urine from the bladder and conveys it out of the body.

- involuntary internal urethral sphincter -- smooth muscle, at bladder-urethral junction.

- voluntary external urethral sphincter -- skeletal muscle, at urogenital diaphragm.

J. Micturition

- urination, voiding.

- about 200-300 ml urine accumulated, distention of bladder walls, stretch receptors activated, afferent impulses transmitted to spinal cord (and to brain -- feel urge to urinate); efferent impulses stimulate contraction of detrusor muscle and relaxation of internal sphincter; external sphincter can be voluntarily controlled.