Renal Physiology Notes

Function of the Kidney

Filtration, Excretion, Electrolyte balance, Acid-base balance (long term), Endocrine functions - blood pressure (via renin secretion) and stimulating production of red blood cells (via erythropoietin)

Anatomy of the Kidney

The kidneys lie against the posterior abdominal wall at the level of T12 to L3 Right kidney is slightly lower because of the liver Rib 12 cross the approximate middle of the left kidney Retroperitoneal, along with ureters, urinary bladder, renal artery and vein, and the adrenal glands

Renal artery and vein come off the abdominal aorta and the inferior vena cava respectively Blood flow through kidney Aorta Renal a. Segmental a. Interlobar a. Arcuate a. Interlobular a. Afferent arteriole Glomerulus Efferent arteriole Peritubular capillaries Interlobular v. Arcuate v. Interlobar v. Renal v. Inferior vena cava Note: Juxtamedullary nephrons have their blood flow through the vasa recta, rather than the peritubular capillaries

The Nephron

Each nephron is composed of two principle parts renal corpuscle (which filters the blood plasma) and the renal tubulue (which converts filtrate to urine) Renal corpuscle Consists of the glomerulus and the two layered Bowman capsule that encloses it. Outer layer of Bowmans capsule = simple squamous epitherlium Inner layer of Bowmans capsule = consists of podocytes which wrap around the capillaries of the glomerulus The two layers are separated by the collecting capsular space Vascular poles of renal corpuscle afferent arteriole enters Urinary poles of renal corpuscle proximal convoluted tubule leaves Renal tubule Four Regions:

1. Proximal convoluted tubule (PCT) simple cuboidal or columnar epithelium, prominent microvilli, most absorption occurs here 2. Loop of Henle thin descending limb, thin ascending limb, thick ascending limb, urinary concentration, mostly in medulla of kidney 3. Distal convoluted tubule (DCT) begins shortly after ascending limb of Loop of Henle re-enters the Cortex, shorter and less coiled than PCT, cuboidal epithelium nearly totally devoid of microvilli, end of nephron 4. Collecting duct fine regulation, cortical and medullary its in both, receives fluid from the DCTs of several nephron, numerous collecting ducts then converge toward tip of medullary pyramid, merge into cortical and medullary its in both, receives fluid from the DCTs of several nephron, numerous collecting ducts then converge toward tip of medullary pyramid, merge into papillary duct Flow of Urine from Glomerular capsule Glomerular capsule proximal convoluted tubule Loop of Henle distal convoluted tubule Collecting duct Papillary duct Minor calyx Major calyx Renal pelvis Ureter Urinary bladder Urethra

Renal innervation

Wrapped around each renal artery is a renal plexus of nerves and ganglia Renal plexuses carry sympathetic innervations from the abdominal aortic plexus and parasympathetic innervations from the vagus nerves, as well as afferent pain fibres from the kidneys enroute to the spinal cord Stimulation of sympathetic fibres of renal plexuses tends to reduce Glomerular blood flow and therefore the rate of urine production (although these rates are influenced by other factors as well) Sympathetic fibres also respond to falling blood pressure by stimulating kidneys to secrete renin, which is an enzyme which activates hormonal mechanisms for restoring BP

The Glomerulus

The filtration apparatus of the kidney The Glomerular Filtration Barrier is composed of 3 different types of cells: Endothelial cells fenestrae in cell cytoplasm, Glomerular capillaries are 100x more permeable to water than muscle capillaries Mesangial cells negative charge, along with mesangial matrix form the Glomerular mesangium, which constitutes the central core of the glomerulus to which capillaries are attached, elongated cytoplasmic processes Podocytes aka Glomerular epithelial cell, incapable of mitosis, located on outside of capillaries, consists of: cell body, major cytoplasmic processes, foot processes, filtration slits between foot processes, filtration slit diaphragms,

Urine production is dependent on glomerular filtration, tubular re-absorption and tubular secretion and water conservation
Glomerular Filtration
Movement of fluid and solutes from the glomerular capillaries into Bowmans space Produces glomerular filtrate similar to blood plasma except that is has almost no protein Almost any molecule smaller than 3nm can pass freely through the glomerular filtration membrane water, electrolytes, glucose, fatty acids, amino acids, nitrogenous wastes and vitamins (these substances have about the same concentration in glomerular filtrate as in blood plasma) Some substances, e.g. Iron, calcium and thyroid hormones, are retained as they are bound to plasma proteins (the tiny amount of unbound versions of these substances pass through freely) Glomerular Filtration pressure Net filtration pressure = Blood hydrostatic pressure of 60mmHg Colloid osmotic pressure of 32mmHg Capsular pressure of 18mmHg = 10mmHg The high blood pressure of the glomeruli makes the kidneys especially vulnerable to Hypertension Glomerular Filtration Rate The amount of filtrate formed per minute by the two kidneys combined For every 1mmHg of net filtration pressure, the kidneys produce 12.5mL of filtrate per minute = Filtration coefficient Kf Kf is dependent on the permeability and surface area of filtration barrier, Kf is about 10% lower in women than in men

Glomerular filtration rate (GFR) = Net filtration pressure (NFP) x Filtration Coefficient (K f)
Reference man: GFR = 10 x 12.5 = 125mL/min = 180L/day Reference woman: GFR = 105mL/min = 150L/day

Approximately 60x the amount of blood in the body An average adult reabsorbs 99% of the filtrate and excretes 1 to 2L of urine per day Regulation of GFR Must be precisely controlled too high and urine output rises and creates threat of dehydration and electrolyte depletion too low and wastes reabsorbed that should be in urine, azotemia (high levels of nitrogen) may occur Only way to change GFR from moment to moment change Glomerular blood pressure Glomerular blood pressure can be changed by three homeostatic mechanisms: renal autoregulation, sympathetic control and hormonal control Renal autoregulation Ability of nephrons to adjust their own blood flow and GFR without external (nervous or hormonal) control Allows GFR to remain relatively stable despite changes in arterial blood pressure (If there was no renal autoregulation and BP rose from 100 to 125mmHg, then urine output would increase from 1-2L per day to 45L/day) Dynamic equilibrium cant completely prevent changes in GFR, cannot compensate for extreme blood pressure variations Two mechanisms of Autoregulation: 1. Myogenic Mechanism based on tendency of smooth muscle to contract when stretched When blood pressure rises, afferent arteriole stretches and subsequently constricts When blood pressure falls, afferent arterioles relax and allow blood to flow more easily into glomerulus 2. Tubuloglomerular Feedback Glomerulus receives feedback on the status of downstream tubular fluid and adjusts filtration to regulate the composition of the fluid, stabilise its own performance and compensate for fluctuations in blood pressure Juxtaglomerular apparatus located at very end of Loop of Henle, just as it has re-entered the Cortex 3 Special cell types: Macula densa closely spaced epithelial cells at end of Loop of Henle facing the arterioles Juxtaglomerular (JG) cells enlarged smooth muscle cells in the afferent arterioles (and to some extent in the efferent ones) directly across from macula densa When stimulated by macula densa dilate or constrict arterioles Also contain granules of renin, which they secrete in response to a drop in BP Mesangial cells in the cleft between afferent and efferent arterioles and among capillaries of the glomerulus, connected to macula densa and JG cells by gap junctions and communicate with them via paracrine secretions Build a supportive matrix for the glomerulus (as said above) Constrict or relax its capillaries to regulate blood flow and GFR Phagocytise tissue debris Sympathetic control Sympathetic fibres richly innervate renal blood vessels In strenuous exercise or acute conditions such as circulatory shock, they (along with adrenaline) constrict afferent arterioles This reduces GFR and urine production, while redirecting blood from kidneys to heart, muscles and brain Hormonal control When BP drops because of blood loss or other causes, the sympathetic renal nerves stimulate the juxtaglomerular cells to secrete the enzyme renin Renin acts on angiotensinogen, causing it to split off Angiotensin-I In the lungs and kidneys, ACE (angiotensin converting enzyme) removes two more amino acids, converting it to Angiotensin-II which: - Is a potent vasoconstrictor widespread vasoconstriction raises MAP throughout body - In kidneys, constricts efferent arterioles and, to a lesser degree, afferent arterioles. By constricting glomerular output more than inlet, it raises glomerular BP and GFR. Or, at least, prevents a drastic reduction in GFR - Constriction of efferent arterioles lowers BP in the peritubular capillaries. Since capillary BP normally opposes fluid reabsorption, this reduction in BP strongly enhances the reabsorption of NaCl and water from the nephron. More water is return to the bloodstream - Stimulates adrenal cortex to secrete aldosterone promotes sodium and water reabsorption in the distal convoluted tubule and collecting duct - Directly stimulates sodium and water reabsorption in the proximal convoluted tubule - Stimulates posterior pituitary gland to secrete ADH (antidiuretic hormone which is the same as vasopressin), which promotes water reabsorption by the collecting duct

- Stimulates sense of thirst and encourages water intake Tubular re-absorption Movement of materials from the filtrate in the tubules into the peritubular capillaries Taking fluid back into the body Tubular secretion Movement of solutes from peritubular capillaries into the tubules Removing fluid from the body

Proximal Convoluted Tubule

Reabsorbs about 65% of glomerular filtrate, also secretes some substances from blood into the tubule Abundant mitochondria for ATP for active transport Approximately 6% of ones resting ATP and calorie consumption Solutes are reabsorbed isotonically Two routes of reabsorption: 1. Transcellular route substances pass through the cytoplasm and out of the base of the epithelial cells 2. Paracellular route substances pass between cells, the tight junctions between the tubular epithelial cells are quite leaky and allow significant amounts of water to pass through, solvent drag water drags through lots of dissolved solutes via the paracellular route Sodium Chloride Sodium reabsorption Two types of transport proteins in the apical cell surface are responsible from sodium uptake 1. Symports simulatenous binding of Na+ and another solute such as glucose, amino acids, or lactate 2. Na+ - H+ antiport pulls Na+ into cell while pumping H+ out of cell into the tubular fluid, means not only is sodium reabsorbed, but acid is also eliminated from body fluid, Angiotensin II activates the Na+ - H+ antioport and therefore exerts a strong influence on sodium reabsorption, sodium is then pumped by the Na+ - K+ pump in the basal surface of the epithelial cell out into the ECF, where it is then picked up by the blood stream in the peritubular capillaries Chloride reabsorption Follows sodium by electrical attraction, as it is negatively charged Various antiports that absorb Cl- in exchange for other anions that are ejected into the tubular fluid Chloride and potassium ions are driven out through the basal cell surface by the K+ - Cl- symport Also diffused out via the paracellular route Other electrolytes Potassium, Magnesium and phosphate ions diffuse through the paracellular route Phosphate is also co-transported into epithelial cells with Na+ Some calcium is reabsorbed through the paracellular route in the PCT, but most Calcium is reabsorbed later in the nephron Glucose Co-transported with Na+ by symports called sodium-glucose transport proteins (SGLTs). Then removed from basolateral surface of the cell by facilitated diffusion. Normally all glucose in the tubular fluid is reabsorbed and there is none in the urine. Nitrogenous Waste Urea diffuses through the tubule epithelium with water. 40 60% of urea is reabsorbed in the nephron, urine has a substantially higher urea concentration due to the fact that 99% of the water is reabsorbed. Kidney keeps urea at a safe level in the blood but doesnt completely clear it PCT reabsorbs almost all uric acid, but later parts of the nephron secrete it back in the tubular fluid Creatinine is not reabsorbed at all, stays in tubule and is passed in the urine Water Two thirds of water is reabsorbed by the PCT Reabsorption of salt and organic solutes makes tubule cells and tissue fluid hypertonic to tubular fluid water follows the solutes via osmosis through both paracellular and transcellular (aquaporins) route In the PCT, water is reabsorbed at a constant rate obligatory water reabsorption Uptake by the Peritubular capillaries Three factors promote osmosis and solvent drag: 1. High interstitial fluid pressure due to accumulation of reabsorbed fluids physically drivs water into the capillaries

2. Narrowness of efferent arteriole lowers blood hydrostatic pressure (BHP) from 60mmHg to about 8mmHg less resistance to reabsorption than in most systemic capillaries 3. Water is filtered out of blood in the glomerulus but a lot of the protein remains, therefore the blood has a higher COP (colloid osmotic pressure). High COP plus low BHP in capillaries and high hydrostatic pressure in the tissue fluid, balance of forces strongly favours reabsorption Angiotensin II further accentuates reabsorption tendency. Constricts both afferent and efferent arterioles , reducing blood pressure in the peritubular capillaries and therefore reducing resistance to fluid reabsorption Tubular secretion Two purposes in Loop of Henle and PCT: Waste removal and acid-base balance

Loop of Henle

Generates salinity gradient that enables collecting duct to concentrate the urine and conserve water Reabsorbs about 25% of Na+, K+ and Cl- and 15% of water in the glomerular filtrate

Distal Convoluted Tubule and Collecting Duct

Fluid arriving here still contains about 20% water and 7% salts from the glomerular filtrate Reabsorb variable amounts of water and salts Regulated by several hormones aldosterone, atrial natriuretic peptide, antidiuretic hormone and parathyroid hormone Two kinds of cells in DCT and Collecting Duct - Principal cells: more abundant, have receptors for foregoing hormones and are involved in salt and water balance - Intercalated cells: fewer in number, high density of mitochondria, reabsorb K+, secrete H+ into tubule lumen, and are mainly involved in acid-base balance Aldosterone Salt retaining hormone Steroid secreted by adrenal cortex when blood Na+ concentration falls or its K+ concentration rises. Fall in blood pressure also induces aldosterone secretion indirectly stimulates kidney to secrete renin, which leads to a production of Angiotensin II, which stimulates aldosterone secretion Acts on thick segment of ascending limb of Loop of Henle, on the DCT and on the cortical portion of the collecting duct Stimulates these regions to absorb more Na+ and secrete more K+. Water and Clfollow the Na+, so the net effect is that the body retains NaCl and water. Urine volume is reduced and high as higher concentration of K+ Retention of salt and water helps to maintain blood volume and pressure Natriuretic peptides ANP is secreted by the atrial myocardium in response to high blood pressure Four actions that result in excretion of more salt and water in the urine, reducing BP and volume - Dilates afferent arterioles and constrict efferent arterioles increasing glomerular filtration rate - Antagonises the renin-angiotensin-aldosterone mechanism by inhibiting renin and aldosterone secretion - Inhibits ADH secretion and action of ADH on kidney - Inhibits NaCl reabsorption by the collecting duct Brain natriuretic peptide (BNP) which is secreted by the heart despite its name, had similar effects but is secreted in much smaller amounts Antidiuretic Hormone Secreted by posterior lobe of pituitary gland in response to dehydration and rising blood osmolarity Makes collecting duct more permeable to water, so water in tubular fluid reenters the tissue fluid and bloodstream rather than being lost in the urine Parathyroid Hormone Calcium deficiency (hypocalcaemia) stimulates the parathyroids to secrete PTH Acts in several ways to restore calcium homeostasis In Kidney, acts on PCT to increase phosphate excretion and acts on thick segment of ascending Loop of Henle and on the DCT to increase calcium reabsorption Increases the phosphate content and lowers the calcium content of the urine Because phosphate is not retained along with the calcium, the calcium ions stay in circulation rather than precipitating into the bone tissue. Calcitriol and Calcitonin have similar but weaker effects on the DCT PTH also stimulates calcitriol synthesis by the epithelial cells of the PCT

Regulation of ECF Composition & Volume

Antidiuretic hormone (vasopressin) and thirst defence of tonicity Osmotically active solute amount in ECF defence of volume - The amount of Na+ in the ECF is the most important determinant of ECF volume

Regulation of Na+ secretion

Na+ is actively transported out of all portions of the tubule except the descending thin limb of the Loop of Henle. Many regulatory mechanisms, amount excreted is adjusted to equal the amount ingested over a wide range of dietary intakes. Urinary output ranges from less than 1mEq/d on a low salt diet to 400mEq/d or more when dietary sodium intake is high. Decrease in sodium excretion when ECF volume reduced Factors affecting Na+ reabsorption include circulating level of aldosterone, circulating level of ANP and other natriuretic hormones, and the rate of tubular secretion of H+ and K+

Renin-Angiotensin System