Physiology - Renal & Acid Base Flashcards
Describe the cell types in the glomerulus and their function
- **capillary endothelium ** fenestrated with pores 70-90nm diameter, surrounded by glomerular BM and podocytes
- podocytes with numerous pseudopodia that form filtration slits 25nm wide
- mesanglial cells = stellate shaped between basal lamina and capillary endothelium, regulate GFR, Control secretion of substances and immune complexes
Describe the juxtaglomerular apparatus
- area where the first part of the DCT nestles between the afferent and efferent arterioles, important in electrolyte and fluid balance
- made up of 3 cells types: macula densa (sense Na+), granular cells (secrete renin), extraglomerular mesangiall cells
What properties of substances in the blood prevent free passage across the glomerular membrane
- negatively charged substances are less permeable due to presence of negatively charged sialoproteins in wall
- large diameter > 8nm
Draw a nephron and describe the function of each part
- glomerulus = filtration
- afferent arteriole = brings blood to glomerulus
- efferent arteriole = carries blood away from glomerulus to vasa recta
- PCT = reabsorption of most solute and water
- descending LOH = water reabsorption
- ascending LOH = solute reabsorption
- DCT = solute reabsorption and secretion
- collecting duct p cells = reabsorb Na+ and secrete K+ i cells = excrete H+
- juxtaglomerular apparatus
- macular densa = senses Na+ in DCT to control GFR
- Lacis cell = extra-glomerular mesanglial cells
- Granular cells = secretes renin
What is the normal renal blood flow and how is it measured?
renal blood flow: 1.2-1.3L/min (25% of cardiac output)
measurement: used Fick’s principle with PAH (filtered, not reabsorbed or secreted)
- calculated renal plasma flow as an estimate of renal blood flow -
effective renal plasma flow = urine concentration x flow / plasma concentration
-renal blood flow = renal plasma flow / (1-haematocrit)
What factors determine renal blood flow
- perfusion pressure = systemic MAP
- renal arterial effects = constriction or dilation of afferent/efferent arterioles by local factors
(ATII constricts efferent > afferent arterioles, GFR stable or increase; dopamine causes renal vasodilation, increasing GFR; prostaglandins cause increased blood flow in renal cortex and reduced blood flow in renal medulla)
- neuro = NA constricts renal vessels (reduces renal bf), ACh dilates renal vessels (increases renal bf)
- autoregulation = contractile response of afferent arteriole to stretch, NO/angiotensin II constrict efferent arterioles
- regional differences = cortical blood flow is high, medullary blood flow is low
How does blood flow and oxygen extraction differ in different parts of the kidney
Cortex: high blood flow, low oxygen extraction
Medulla: low blood flow, high oxygen extraction, more vulnerable to hypoxia if flow is reduced
What are the consequences of sustained reduction in renal blood flow
- renal blood flow normally maintained at a MAP 70-210mmHg
- medulla is most vulnerable to hypoxia
- ATN
- uraemia
How do kidneys regulate the composition of urine
filtration, reabsorption and secretion
What is the definition of the glomerular filtration rate and what is the normal value
amount of fluid (plasma filtrate) filtered by the glomerulus per unit time, normally 125ml/min, 10% lower in women
What factors affect the GFR
1) capillary size, regulated by mesangial cells in glomerulus
- mesangial cell relaxation causes increased filtration: ANP, D, cAMP, PGE2
- mesangial cell contraction causes decreased filtration: ADH (vasopressin), H, NA, ATII, TXA2
2) capillary permeability -renal capillaries 50x more permeable than skeletal capillaries
3) hydrostatic and oncotic pressure gradient
- constriction of afferent arterioles reduces GFR
- dilation of afferent arterioles increases GFR
- constriction of efferent arterioles increases GFR
- clinical factors: systemic BP, ureteric obstruction, plasma protein concentration
4) number of functioning renal corpuscles
What are mesanglial cells?
- contractile cells that help regulate GFR located between the basal lamina and the endothelium of the glomerulus
- also secrete extracellular matrix and take up immune complexes
Describe a method used to measure GFR
- measure excretion of a substance that is freely filtered through the glomeruli and neither secreted or reabsorbed
- must be non-toxic and not metabolised
- example: insulin (creatinine sometimes used but some creatinine is secreted by the tubules)
- GFR = concentration of substance in urine x urine flow / concentration in plasma
What general mechanisms are involved in renal tubular reabsorption and secretion?
Active or passive transport mechanisms
Active:
- primary active transport: ion channels, pumps
- co-transport/symport, exchanger/antiport
- endocytosis
Passive:
- filtration
- simple diffusion
- facilitated diffusion
What factors influence clearance of substances by the kidney?
Renal factors:
- GFR
- tubular secretion
- tubular reabsorption
Non-renal factors:
- CO
- plasma protein binding
- pH & ionisation
- influence of hormones
- pathological conditions (AKI, GN, obstruction)
How does the ascending and descending limb of the LOH differ in function
thin descending limb of LOH: permeable to water (aquaporins), tubular fluid becomes hypertonic
thin ascending limb of LOH: Na+ and Cl- channels
thick ascending limb of LOH: Na+/2Cl-/K+ pump, Na+/H+ exchanger, many mitochondria, fluid becomes hypotonic
Outline the structure and function of the LOH
structure:
- thin descending limb starts at the end of the PCT
- thin ascending becomes thick ascending limb and terminates at the DCT where the macula densa is located
- cortical nephrons (85%) have a short LOH, juxtamedullary nephrons (15%) have a long LOH
function: countercurrent multiplier
Describe the process of tubuloglomerular feedback
- signals from renal tubules feed back to affect filtration of the glomerulus
- as rate of flow at ascending LOH and DCT increases, glomerular filtration decreases
- ↑intracellular Na+ at macular densa→↑ATPase activity→↑adenosine→afferent vasoconstriction→↓GFR
How does the kidney handle glucose
- freely filtered in the glomerulus
- reabsorbed in PCT by secondary active transport (Na+ dependant co-transport) via SGLT
- all glucose is reabsorbed until the threshold is achieved (180 mg/dL)
What are the consequences of glycosuria
osmotic diuresis leading to dehydration and electrolyte loss
Where does Na+ reabsorption occur in the nephron and how is it transported from the cell into the interstitium
reabsorption on apical membrane: PCT (60%) = Na+/H+ counter-transport, Na+/glucose co-transport -thick ascending LOH (30%) = Na+/2Cl-/K+ co-transporter -DCT (7%) = Na+/Cl- co-transporter -collecting duct (3%) = ENaC, Na+/H+ counter-transporter
reabsorption on basolateral membrane: 3Na+/2K+ ATPase (3 Na+ out of cell for 2 K+ into cell)
In the PCT, what other transport proteins are involved in the movement of Na+ across the apical membrane
Na+/glucose co-transport, Na+/phosphate co-transport, Na+/aa co-transport, Na+/H+ exchanger
What are the mechanisms that effect Na+ reabsorption?
Tubuloglomerular feedback mechanism: ↑Na+ at macular densa @ DCT → ↑adenosine → afferent vasoconstriction → ↓GFR → ↓Na+ excretion
Glomerulotubular balance: more filtered = more reabsorbed
Humeral: aldosterone increases ENaC, ANP reduces ENaC, endothelin cause natriuresis
What mechanisms cause reduction in Na+ excretion
- reduced GFR
- increased tubular reabsorption: aldosterone, reduced ANP, angiotensin II
Following high Na+ intake, what mechanisms act to enhance Na+ excretion?
Slight increase in ECF volume triggers the activation of stretch receptors in RA and pulmonary veins (veno-atrial stretch receptors):
- inhibit sympathetic outflow to kidney, decreasing Na+ reabsorption
- increase in arterial pressure leads to pressure natriuresis
- release of ANP, suppressing RAAS, reduced ATII and therefore reduced aldosterone
- hypothalamus decreases the production of vasopressin
How does aldosterone influence renal sodium handling
- overall increases tubular reabsorption of Na+ with secretion of K+ and H+
- latency period of 10-30 minutes for effect
- acts on distal tubule and collecting ducts to up-regulate basolateral 3Na+/2K+ pumps
- acts on collecting duct to up-regulate epithelial Na+ channels (ENaC) and Na+/H+ counter-transporters
How do the kidneys deal with K+
- freely filtered in the glomerulus
- actively re-absorbed in the PCT (with Na+ and H2O) and in thick ascending LOH (via Na+/2Cl-/K+ co-transporter)
- secreted in DCT and collecting duct under influence of aldosterone and electrically coupled to Na+ reabsorption
- total K+ excretion is approximately equal to intake to maintain K+ balance
What influences K+ handling in the kidney (how do other ions affect potassium transport)
-rate of secretion of K+ is proportional to the rate of flow of tubular fluid through the distal nephron -3Na+/2K+ATPase across most of basolateral membrane -Na+/2Cl-/K+ co-transporter on apical membrane of ascending thick LOH -secretion in the DCT and collecting duct is electrically coupled to Na+ reabsorption in the distal nephron, K+ and H+ compete for secretion in association with reabsorption of Na+ increased delivery of Na+ to the collecting ducts promotes increased secretion of K+ (thiazide diuretics) in acidosis where H+ excretion is increased, K+ secretion is decreased aldosterone increases the reabsorption of Na+ in the collecting ducts, thus promotes K+ secretion
Explain K+ transport in the collecting duct
-BL membrane: 3Na+/2K+ATPase (3 Na+ into interstitial fluid for 2 K+ into cell) -apical membrane: H+/K+ATPase (K+ reabsorbed in exchange for H+), K+ secretion channels (aldosterone)
What other major ions are involved in potassium transport in the nephron
Na+, H+
How does hydrogen ions influence potassium transport in the nephron (how does K+ handling change with pH)
- there is a H+/K+ pump in the collecting duct, in which K+ is reabsorbed and H+ is excreted
- acidosis decreases K+ excretion, alkalosis increases K+ excretion
How does aldosterone increased K+ secretion
- stimulates Na+/K+ATPase pump in BL membrane (2 K+ enter principal cell in exchange for 3 Na+ out)
- causes K+ channels to form in apical membrane of principal cells, with K+ moving into tubular lumen
- causes Na+ channels to form in apical membrane of principal cells, with Na+ entering cells from tubular lumen
Describe how water is reabsorbed in different part of the nephron
- PCT (70%): via aquaporin-1 channels
- Thin descending limb of LOH (15%): via aquaporin-1 channels
- Distal tubule (5%)
- Collecting duct (10%): via aquaporin-2 channels, dependant on the presence of vasopressin
Vasopressin causes increased expression and translocation of aquaporin-2 channels. Aquaporin-2 is normally stored in vesicles in principle cells of the collecting ducts. Water moves out of the hypotonic tubular fluid into the interstitium of the cortex, leaving the tubular fluid isotonic.
What is osmotic diuresis
- occurs when large quantities of unreabsorbed solutes in the renal tubules causes an increase in urine volume
- can be produced by administering compounds like mannitol that are filtered but not re-absorbed
- increased urine flow is due to reduced water re-absorption in the proximal tubules and LOH
- produced naturally in diabetes when glucose levels exceed the TMG
How does the countercurrent mechanism enable the kidneys to concentrate urine?
Concentrating mechanism depends on maintaining a gradient of increasing osmolality along medullary pyramids.
Gradient is produced by countercurrent multipliers in the LOH and maintained by vasa recta acting as countercurrent exchangers.
1) water moves out of thin descending limb
2) active transport of Na and Cl out of thick ascending limb of LOH
Thin descending limb is passively permeable to water and salt. Thick ascending limb is permeable to salt (via active transport) but not to water.
Vasa recta (in continuation with efferent arteriole, accompanies the LOH but flow in the opposite direction) acts as countercurrent exchangers (passive diffusions) in the kidney in which NaCl & urea diffuse into the descending limb and out of the ascending limb of the vessel, while water diffuses out of the descending limb and into the ascending limb of the vascular loop. As a result, the solute remains in the medulla pyramid and maintain the interstitial concentration.
What is the role of urea in the countercurrent mechanism
- urea freely filtered at glomerulus, transported by 4 different urea receptors in the kidney, 50% reabsorption in PCT
- urea helps establish the osmotic gradient in the medullary pyramid by increasing the osmolarity of the interstitium
- urea reabsorbed from collecting duct tubular fluid via transporters (increased by vasopressin) into the interstitium
- this causes raised osmolarity in interstitium, helps drive water reabsorption and concentrating capacity of nephron
- urea transporters are also present in thin ascending limb, allowing urea to move into tublar fluid
- continued cycling in this path allows for high concentrations of urea both in urine and interstitium
Describe the neurological pathways involved in normal micturition
- micturition is a sacral spinal reflex mediated by S2, S3, S4 nerve roots, subject to voluntary control
- first urge to void is at 150ml, void reflex initiated at 300-400ml
- void reflex: solely parasympathetic; stretch receptors in bladder wall carried to spinal cord by afferent fibres, efferent fibres mediate contraction of detrusor muscle and relaxation of internal sphincter
- pudendal nerve controls voluntary contraction of perineal muscles and external urethral sphincter
- only role of sympathetic nerves: prevention of micturition via contracting internal urethral sphincter
List factors that stimulate and inhibit micturition
stimulate: stretch, higher center input, parasympathetic, alpha blockers, voluntary abdominal contraction
inhibit: parasympathetic inhibitors (atropine), higher centers, sympathomimetics
Describe the muscles involved in micturition
- bladder: smooth muscle arranged in spiral, longitudinal and circular bundles
- detrusor muscle: circular muscle of the bladder responsible for bladder contraction and involuntary emptying
- internal urethral sphincter: smc, not encirculating, involuntary, no role in micturition, prevents semen reflux
- external urethral sphincter: skeletal muscle, encirculating, voluntary, pudendal innervation, relax during micturition
- perineal muscles: relaxes during micturition -bulbocavernosus muscle in males aids in expulsion of urine
What prevents vesico-ureteric reflux
the oblique passage of ureters through the bladder wall keeps the ureters closed except during peristalsis
Describe the process by which extracellular fluid tonicity is regulated
-osmoreceptors in the anterior hypothalamus lie outside the BBB and detect plasma tonicity -increased plasma osmotic pressure stimulate osmoreceptors to increase thirst and vasopressin -thirst increases water intake, diluting the ECF -vasopressin causes increased aquaporin channels in collective duct, reducing water excretion and diluting ECF
What is thirst and what causes it
- thirst is an appetite under hypothalamic control, also increased by learned or habit response when eating
- increased plasma osmolality stimulates osmoreceptors in the anterior hypothalamus, causing increased thirst
- psychogenic thirst is caused by psychiatric conditions
What are the actions of vasopressin
V2 activation: increases number of aquaporin-2 channels in collecting duct
V1activation: vasoconstriction leaading increased peripheral vascular resistance, increased BP
V1 activation: increased secretion of ACTH from anterior pituitary
How does vasopressin act on the kidney
- binds to V2 g-receptor in the collecting duct p cells, activating adenylate cyclase and increasing cAMP
- causes increased translocation of aquaporin-2 channels
What factors influence vasopressin secretion
stimulate: increased osmotic pressure, reduced ECF volume, pain, nausea/vomiting, angiotensin II
inhibit: decreased osmotic pressure, increased ECF volume, alcohol
What factors influence angiotensin II production
-angiotensin II is the effector protein in the RAAS converted from angiotensin I by ACE (secreted from the lungs) -anything that influences renin or ACE increases angiotensin II production increased production: increased sympathetic activity, increased circulating catecholamines, prostaglandin decreased production: increased Na+ and Cl- reabsorption across the macula densa, vasopressin
What are the physiological effects of angiotensin II
-tubular Na+ and Cl- reabsorption -adrenal gland secretion of aldosterone -arteriolar vasoconstriction -pituitary gland secretion of ADH -contraction of mesanglial cells causing decreased GFR
Explain how hypotension activates the RAAS and how it restores blood volume (renal response to dehydration)
- hypotension leads to reduced perfusion pressure of the afferent glomerular arteriole (via intrarenal baroreceptors)
- this stimulates secretion of renin by the juxtaglomerular cells
- renin converts angiotensinogen to angiotensin I, which is then converted to angiotensin II by ACE from the lungs
- actions of angiotensin II: vasoconstriction to increase SVR and increase BP, increases aldosterone secretion from adrenal gland, and stimulates the release of ADH from posterior pituitary
- aldosterone up-regulates Na+/K+ pumps and Na+ channels in collecting duct to increase sodium and water reabsorption
- ADH upregulates water channels in collecting duct to increase water reabsorption and also causes vasoconstriction
What is the role of vasopressin (ADH) in dehydration
-promotes water reabsorption in collecting duct via aquaporin insertion and vasoconstriction
What factors affect renin secretion
stimulate: low Na+, diuretics, hypotension, bleeding, upright posture, dehydration, beta-1 agonist
inhibit: vasopressin, angiotensin II, high Na+ in macula densa
What hormone systems are involved in the maintenance of extracellular fluid volume
-renin-angiotensin-aldosterone system, vasopressin
What are the effects of atrial naturetic peptide in response to fluid overload
-secreted by the heart in response to increased ECF volume causing the atria to stretch -cause dilation of afferent arterioles and relaxation of mesanglial cells, causing increased GFR -act directly on renal tubules to reduce Na+ reabsorption
Describe the effects of rapid IV infusion of 1000ml of normal saline and what is an alternative physiological fluid
- increased Cl-, acidosis, increased baroreceptor firing, decreased HR, increased BP, increased UO
- decreased renin/angiotensin, improved capillary return
alternative fluid: hartmann’s, plasmalyte
What hormonal changes occur after drinking a large volume of water
-begins about 15 minutes after ingestion, maximum effect in 45 minutes, resulting in diuresis -the act of drinking produces a small decrease in vasopressin secretion via a decrease in plasma osmolality
Where does acidification of the urine occur and how is H+ secreted
- acidification of the urine occurs in the PCT, DCT and collecting duct
- PCT:
1) Na+/H+ exchange transporter on the apical membrane pumps H+ into the tubular fluid (secondary active transport)
2) Na+/HCO3- co-transporter on the basolateral membrane pumps HCO3- into the interstitium
3) for each H+ secreted, one Na+ and one HCO3- enters the interstitial fluid - DCT and collecting duct:
4) H+ secretion is driven by ATPase pump, facilitated by aldosterone
5) 3 reactions tie up H+ in urine = bicarbonate, phosphate, ammonia
What is the limiting pH of urine and where is it reached
-the maximum gradient against which the mechanism to secrete H+ can operated corresponds to pH 4.5 -this is reached in the collecting duct
How does the kidney respond to metabolic acidosis and describe the role of buffers
- aim to return the serum pH to normal by increasing H+ excretion
1) kidney reabsorbed HCO3- by actively secreting H+
2) renal tubule contains carbonic anhydrase to catalyse conversion of CO2, H2CO3 and HCO3-
3) in PCT, H+ secreted by Na+/H+ exchanger, in DCT and collecting duct by H+ ATPase
4) tubular fluid is then buffered by: 1) bicarbonate (HCO3-) forms H2O and CO2, 2) phosphate (HPO4-2) forms H2PO4-, 3) ammonia (NH3) forms ammonium (NH4+, trapped)
What factors increase renal acid secretion/urine acidification?
high PCO2 high PaCO2 high aldosterone low K+ high CA
How can the body compensate for metabolic acidosis apart from renal
respiratory system responds by hyperventilation
What happens to glutamine synthesis in the liver in chronic metabolic acidosis
- glutamine synthesis is increased, allowing for more breakdown into glutamate + NH3
- this provides more NH3 to the kidney
What are the principle buffering systems in the body
-blood = bicarbonate, protein, haemoglobin -interstitium = bicarbonate -intracellular = protein, phosphate -urine = bicarbonate, phosphate, ammonia
What are the major physiological features and urine findings of acute intrinsic renal failure?
Features:
- loss of concentrating ability due to loss of countercurrent mechanism, causes polyuria and nocturia
- uraemia when breakdown products of protein metabolism are in blood, cause lethargy, anorexia, N/V, confusion
- acidosis due to failure of kidneys to excrete H+
- abnormal handling of Na+ causing oedema
Urinalysis: proteinuria, leucocytes, red cells, casts
What are urinary casts
-proteinaceous material precipitated in tubules washed into the bladder
List the H2CO3:HCO3 ratios for the following pH - 6.0, 7.1, 7.3, 7.4
pKa H2CO3 is 6.1
6.0 = 0.8
7.1 = 10
7.3 = 16
7.4 = 20
