Renal Physiology PDF

**[Renal Physiology]** - The **renal corpuscle** of the nephron is composed of the glomerulus and the Bowman's capsule and is connected to convoluted tubules in the cortex and the loop of Henle which extends into the medulla. - Multiple nephrons empty into a single collecting duct befo...

**[Renal Physiology]** - The **renal corpuscle** of the nephron is composed of the glomerulus and the Bowman's capsule and is connected to convoluted tubules in the cortex and the loop of Henle which extends into the medulla. - Multiple nephrons empty into a single collecting duct before emptying into the ureters Bladder. - **There are two types of nephrons:** 1. **Cortical nephrons Majority (80%).** - Renal corpuscle is located in the outer portion of the cortex. - Loops of Henle are short Only extend into the outer region of the medulla. - Surrounded by peritubular capillaries. - The ascending limb of the loop of Henle **[does not]** have defined thick and thin regions. 2. **Juxtamedullary nephrons Minority (20%).** - Renal corpuscle is located in the deep cortex. - Loops of Henle are long Extend into the deep medulla. - The peritubular capillaries are called 'vasa recta' (but are the same as the cortical nephrons). - The ascending limb of the loop of Henle **[has]** defined thick and thin regions which enables the kidney to secrete a very dilute or very concentrated urine. - **The kidneys are high vascular and receive a large amount of the cardiac output (20-25% of CO at rest).** - 95% of this blood volume supplies the renal cortex (i.e., where the glomerulus is located). - **The vascular components of the nephrons include:** a. **Glomerulus** Ball-like tuft of the glomerular (fenestrated) capillaries; these filter blood plasma. - Blood flow through the glomerulus capillaries occurs in series. - Hydrostatic pressure is high (\~55 mm Hg) in these capillaries. b. **Afferent arteriole** Supplies the glomerulus (has a thick muscular wall). c. **Efferent arteriole** Drains the glomerulus and subdivides to form the peritubular capillaries (later join to form the venules and renal vein). d. **Peritubular capillaries** Subdivision of the efferent arteriole. - Blood flow through the peritubular capillaries occurs in series. - Hydrostatic pressure is low (\~13 mm Hg) Important is reabsorption / equilibrium. - The peritubular capillaries also interact with the Bowman's capsule at the juxtaglomerular region which senses the osmolarity of the filtrate to regulate GFR. - The **net filtration pressure (NFP)** is a balance between osmotic pressure and hydrostatic pressure. - **Starling's Law NFP = (CHP + IFOP) -- (PCOP + IFHP).** - **Pressures that promote filtration:** a. Capillary hydrostatic pressure (CHP). b. Interstitial fluid osmotic pressure (IFOP). - **Pressures that promote reabsorption:** a. Plasma colloid osmotic pressure (PCOP). b. Interstitial fluid hydrostatic pressure (IFHP). - **At the glomerular capillaries** CHP \> PCOP which drives filtration. - **At the peritubular capillaries** PCOP \> CHP which drives reabsorption. - This increase in PCOP is created by the filtration of most blood plasma products, aside for the large proteins (e.g., albumin). - Lower volume (≈ lower hydrostatic pressure) + higher \[protein\] Strong absorptive environment. - The process of filtration occurs from the glomerulus Bowman's (capsule) space in response to net glomerular hydrostatic pressure. - For the most part the glomerular filtrate is same (Isotonic = 300 mOsm/L) as the blood plasma, but **[does not]** contain cell / platelets, protein complexes, and large-to-medium sized (\>50 kDa) proteins. - The rate of filtration -- termed 'glomerular filtration rate (GFR)' -- is dependent on the permeability of the membrane, surface area of the membrane, and the filtration pressure. - **There are three physical barriers:** a. **Glomerular capillary wall** Pores between the endothelial cells. b. **Basement membrane** Mix of collagen (structural) and glycoproteins (repel plasma proteins). c. **Podocytes** Mobile cells that form filtrations slits via their foot processes. - **Factors that determine glomerular filterability**: a. **Molecular weight (major)** Size-exclusion. b. **Charge of the molecule (minor)** Negative charge of the basement membrane and podocytes repel anions. - The average GFR across both kidneys for a young healthy 70 kg adult is **125 mL/min or 180 L/day** (36x blood volume) of fluid. - **Homeostasis requires the kidneys to maintain a relatively constant GFR as:** a. Too high of a GFR will reduce reabsorption; while b. Too low GFR will result in excessive reabsorption and inadequate excretion of waste products which can cause renal hypoxia. - **[The GFR is directly related to net filtration pressure NFP = GBHP -- CHP - BCOP]** - **Glomerular blood hydrostatic pressure (GBHP**) The blood pressure of the glomerular capillaries force water and solutes through filtration slits. - GBHP = 55 mm Hg. - **Capsular hydrostatic pressure (CHP)** The hydrostatic pressure exerted against the filtration membrane by fluid already in the capsular space and represents "back pressure". - CHP = 15 mm Hg. - **Blood colloid osmotic pressure (BCOP)** Due to presence of proteins in the blood plasma and opposes filtration. - BCOP = 30 mm Hg - **Control of filtration pressure:** - **Renal arteriolar resistance can be modified to control the amount of renal blood flow:** - **Efferent arteriole constriction** Reduces renal blood flow but increases GFR. - **Afferent arteriole constriction** Reduces renal blood flow and GFR. - **There are three mechanism for regulating GRF:** a. **Renal autoregulation** - The kidneys can autoregulate to maintain a constant renal blood flow and GFR over a large range of arterial pressures (80 mm Hg to 180 mm Hg). - **If there was no autoregulation Extreme fluid and salt loss.** - At normal MAP (100 mm Hg), GFR is 125 mL/min or 180 L/day Result in 1.5 L/day of urine production. - If MAP was increased to 125 mm Hg GFR would increase to 225 L/day Increase urine output to 46.5 L/day (which is unmanageable for life). - Ultimately this is important as regular day-to-day activities result in a range of blood pressures. - **There are two mechanism:** 1. **Myogenic mechanism** - Stretch response mechanism Contraction of smooth muscle cells in the afferent arterioles Reduced GFR. a. Increased MAP automatically induces vasoconstriction of afferent arteriole Reduced RBF Reduced GFR to return MAP to normal. b. Decreased MAP induces afferent arteriole vasodilation Increased flow Increased GFR to return MAP to normal. 2. **Tubuloglomerular mechanism** - The macula densa provide feedback to the glomerulus based on filtrate osmolarity Inhibits NO release Afferent arteriole constriction Reduced GFR. a. Increased GFR Increased filtrate solute (NaCI) with reduced absorption time. b. Decreased GFR Reduced filtrate solute (NaCI) with increased reabsorption time. - **The juxtaglomerular apparatus contains a few cell types:** a. **Macula densa** Salt sensors (NaCI). - The macula densa are a collection of densely packed epithelial cells at the TAL/DCT junction. - Juxtaposed to its own glomerulus between the afferent and efferent arterioles which enables it to rapidly alter the glomerular resistance in response to changes in the flow rate through the distal nephron. - It does this by monitoring tubular fluid composition through the Na-K-2CI cotransporter (NKCC2). - **When GFR is low:** - Low \[NaCI\] is sensed by Na-K-2CI cotransporter Activates kinases that trigger the release of **NO (vasodilates afferent arteriole) and renin.** - **When GFR is high:** - High \[NaCI\] is sensed by Na-K-2CI cotransporter Switches off NO and renin release and triggers the **release of adenosine.** - Adenosine binds to **ADORA1** receptors Vasoconstriction of the afferent arteriole. b. Granular cells. c. Mesangial cell Fine-tuning. b. **Neural regulation** - The **sympathetic nerves (noradrenaline)** can modulate arteriole resistance. - At maximal effect, SNS innervation can drive significant afferent arteriole vasoconstriction Reduced GFR. - This type of effect is usually minimal (only fight-or-flight) but has a strong overriding effect (e.g., after haemorrhage Renal shut-down). - At moderate effect, SNS innervation can drive minor afferent and efferent arteriole constriction Reduced RBF / GFR Decreased urine production Increased blood volume and blood pressure (due to fluid retention). c. **Hormonal regulation** - **There are two major regulating hormones:** a. **Atrial natriuretic peptide (ANP)** Increases afferent blood flow but decreased efferent blood flow Increased GFR but no change in renal blood flow (i.e., same net blood flow but increased resistance due to backpressure). - ANP is an antagonist of angiotensin II. b. **Angiotensin II** Decreases afferent blood flow (minor) and efferent blood flow (major) Reduced renal blood flow with slightly reduced or no change in GFR. - This effect occurs as RBF is restricted by constriction of the afferent arteriole, but GFR is maintained as the constriction of the efferent arterioles is greater (i.e., blood comes into the glomerulus faster than it travels out). - Angiotensin II has a major effect on blood pressure due to the reduced RBF Increased perfusion pressure when the afferent arteriole is released. - **Angiotensin II is regulated by tubuloglomerular feedback:** 1. Reduced GFR Hypo-osmolar filtrate. 2. Macula densa detects reduced \[NaCI\]. 3. Renin is released by the juxtamedullary cells. 4. Renin Converts angiotensinogen to angiotensin I. 5. Angiotensin I is converted to angiotensin II at the lungs via angiotensin converting enzyme (ACE). 6. Angiotensin II Afferent and efferent arteriole constriction. 7. Reduced RBF but maintained GFR (or slightly increased). - **Fine tuning of filtration** is conducted by the **intraglomerular mesangial cells**. - These cells **regulate the intraglomerular capillary blood flow** by **contracting** in conjunction with the glomerular capillary endothelium basement membrane Decreased surface area Reduced GFR. - **These cells respond to:** - Angiotensin II, ANP, ADH, NO, and Capillary stretch. - Tubular reabsorption is **highly selective and reclaims all sugar and 99.5% of salts** that have been filtered. - Only excessive amounts of sugar and salts, and waste products (e.g., creatinine) are not reabsorbed - Reabsorption can occur through the **paracellular and transcellular pathways.** - Paracellular pathway is only located at the proximal convoluted tubule, and transcellular pathways mostly occurs at the distal end due to 'fine-tuning' and higher requirement for selectivity. - **Methods of transport:** 1. **Active transport** Na+, H+, K+, Ca2+, Mg2+ 2. **Secondary active transport** Glucose, AAs, H+, CI- (usually with Na+ as cotransporter molecule). - Active transport is saturable (t~max~) In diabetes mellitus, glucose can be detected in urine as there is a greater glucose load in the filtrate than normal. - Normal glucose load is \~125 mg/min with the max being 375 mg/min. 3. **Pinocytosis (active process / ATP required**) Filtered proteins (\