Renal Physiology PDF

Renal physiology I structure & function, filtration and regulation Dr Mo Alabry [email protected] 25: Filtration and Micturition Learning objectives I. Structure and function: A. Adrenal gland...

Renal physiology I structure & function, filtration and regulation Dr Mo Alabry [email protected] 25: Filtration and Micturition Learning objectives I. Structure and function: A. Adrenal gland B. Gross structure of the urinary system C. Function D. Vasculature E. Glomerular network F. Tubule & nephron types Learning objectives II. Filtration: A. Starling forces B. Filtration barrier C. Glomerular filtration rate (GFR ) Learning objectives III. Auto regulation of renal blood flow : A. Myogenic response B. Tubuloglomerular feedback C. Paracrine control D. Central control I. Structure and function Metabolic wastes are passed from cells to the circulation and then on to the kidneys, where they are removed by filtration and excreted in urine. Excretion is only one of three essential kidney functions, however. The kidney is also an endocrine organ that controls red blood cell production by bone marrow. The kidney also has a vital homeostatic role in controlling blood pressure, tissue osmolality, electrolyte and water balance, and plasma pH. The kidney also efficiently employs osmotic gradients to recover filtered water, so that, despite the massive volume of fluid handled every day (~180 L), kidney energy use is only slightly greater than that of the heart (10% of total body energy consumption, compared with 7% for the heart). Overview of kidney function. A. Adrenal gland Anatomy of the adrenal gland. An adre Pathophysiology of renovascular hypertension in unilateral renal A. Gross Structure of the Urinary System The functional unit of the kidney is the nephron, comprising a blood filtration component (the glomerulus) and a filtrate recovery component (the renal tubule). Each kidney contains ~1,000,000 nephrons. Gross anatomy of the kidney. A. Gross Structure of the Urinary System The capsule is penetrated at the hilum by a ureter, a renal artery and renal vein, lymphatic vessels, and nerves. The outer band (cortex) lies beneath the capsule and is the site of blood filtration. The middle band (medulla) is a central region, divided into an outer medulla and an inner medulla. The outer medulla has an outer stripe and an inner stripe. It is divided into 8 to 18 conical renal pyramids The pyramids contain thousands of tiny ducts that each collect urine from multiple nephrons and guide it toward the ureter. The papilla is the innermost tip of the inner medulla and empties into pouches called minor and major calyces, which are extensions of the ureter. Minor calyces join to form major calyces, which drain into a common renal pelvis. The pelvis forms the head of a ureter, which propels urine to the urinary bladder for storage and voluntary release. B. Function Kidneys are composed largely of fluid, as are most tissues. Although the fluid within a kidney is compartmentalized (i.e., vascular, luminal, interstitial), and flow between the compartments is limited by cellular barriers, water is still able to move relatively freely between the three compartments, driven by osmotic pressure gradients. A survey of tissue osmolality in different regions of the kidney shows gross differences between the cortex and medulla. The cortex has an osmolality that approximates that of plasma, but the osmolality of the inner medulla is increased severalfold. This osmotic gradient is essential to normal kidney function because it is used to recover virtually all of the water that is filtered from the vasculature each day (average urinary water excretion is 1–2 L/d). The corticopapillary osmolality gradient. Osmolality values are in mOsmol/kg H 2O.  C. Vasculature The renal nephron functions by directing blood at high pressure through a network of leaky blood vessels. This pressure forces plasma out of the blood vessels through a filtration barrier during its passage. The plasma filtrate then moves into the renal tubule, which aims to recover essential solutes and more than 99% of the fluid, returning them to the blood vessels. This process involves a unique vascular arrangement for filtration and recovery. Fluid filtration occurs in the glomerular capillary network. The primary role of reabsorption belongs to the peritubular capillary network. The peritubular network is connected in series with the glomerulus, receiving blood directly from it. D. Glomerular network Blood enters the glomerulus at a high pressure (~50 mm Hg) from an interlobular artery through an afferent arteriole. It then flows through a tuft of specialised glomerular capillaries designed for filtration. These capillaries extensively branch and interconnect, maximising surface area for filtration. Mesangial cells, a type of myoepithelial (muscle and epithelial) cell, fill the spaces between capillaries. They contract and relax to modulate the glomerular capillary surface area and the rate of fluid filtration. Blood exits the glomerulus through an efferent arteriole, maintaining high pressure, instead of a venule. Both the afferent and efferent arterioles act as resistance vessels. They regulate glomerular blood flow and fluid filtration rates by either constricting or dilating. The glomerulus and its filtration barri er. E. Tubule & nephron types Learning objectives I. Structure and function: A. Adrenal gland B. Gross structure of the urinary system C. Function D. Vasculature E. Glomerular network F. Tubule & nephron types Learning objectives II. Filtration: A. Starling forces B. Filtration barrier C. Glomerular filtration rate (GFR ) A. Starling forces Glomerular Filtration Rate (GFR ): rate of filtration from plasma to Bowman’s space Governed by Starling Forces GFR = Kf [(PGC - PBS) - σ(GC - BS)] GFR is sensitive to changes in mean arterial blood pressure Concept check! Define the following Starling forces: Kf σ BS Kf: filtration coefficient σ: reflection coefficient BS: oncotic pressure of Bowman's Space  The barrier is composed of: Capillary endothelial cells B. Filtration barrier Thick glomerular basement membrane Filtration slit diaphragm 1st layer Glomerular capillary endothelial cells: It works as a three-step molecular filter. are dense with fenestrations, resembling a sieve. It produces a cell- and protein-free pores are ~70 nm in diameter, which allows free passage to water, solutes, and proteins. plasma ultrafiltrate. cells are too large to fit through the pores, so they remain trapped in the vasculature. 2nd layer Basement membrane: comprises three layers. An inner lamina rara interna is fused to the capillary endothelial cell layer. A middle layer, the lamina densa, is the thickest of the three. An outer lamina rara externa is fused to the podocytes. The basement membrane carries a net negative charge that repels proteins and reflects them back into the vasculature. 3rd layer Slit diaphragm: Glomerular capillaries are completely covered in foot processes that project from podocytes. Podocytes are specialised epithelial cells. The covering is not continuous. The foot processes end in “toes” that interdigitate, leaving narrow slits between them. The slits are bridged by a proteinaceous filtration slit diaphragm that prevents proteins and other large molecules from entering the Bowman space.  B. Filtration barrier 1st layer Glomerular capillary endothelial cells: are dense with fenestrations, resembling a sieve. Pores are ~70 nm in diameter, which allows free passage to water, solutes, and proteins. Cells are too large to fit through the pores, so they remain trapped in the vasculature. 2nd layer Basement membrane: comprises three layers. An inner lamina rara interna is fused to the capillary endothelial cell layer. A middle layer, the lamina densa, is the thickest of the three. An outer lamina rara externa is fused to the podocytes. The basement membrane carries a net negative charge that repels proteins and reflects them back into the vasculature. 3rd layer Slit diaphragm: Glomerular capillaries are completely covered in foot processes that project from podocytes. Podocytes are specialised epithelial cells. The covering is not continuous. The fluid that finally enters the tubule is plasma The foot processes end in “toes” that interdigitate, leaving narrow slits between them. ultrafiltrate containing electrolytes, glucose, and The slits are bridged by a proteinaceous filtration slit diaphragm that prevents proteins and other large other small organics, but anything larger than molecules from entering the Bowman space. ~5,000 Da is excluded Concept check! During the process of urine formation, the first step involves the filtration of blood through the glomerular capillaries. Which substance is primarily involved in this step and is not usually found in significant amounts in the filtrate due to being too large to pass through the filtration barrier? A) Glucose B) Sodium ions C) Urea D) Albumin E) Water C. Glomerular Filtration Rate (GFR ) In a healthy person, PBS, πBS, and πGC are all relatively unchanged. The main factor affecting GFR is hydrostatic pressure (PGC) (determined by aortic pressure and changes in afferent and efferent resistance). Because the afferent and efferent arterioles are resistance vessels controlling flow through the glomerulus their contraction state significantly impacts net renal blood flow (RBF)  Effects of changing afferent and efferent arteriolar resistance on GFR GFR increases with body size and decreases with age. A normal GFR range (adjusted to reflect body surface area) averages ~100 to 130 mL/min/1.73 m2. Learning objectives II. Filtration: A. Starling forces B. Filtration barrier C. Glomerular filtration rate (GFR ) Learning objectives III. Auto regulation of renal blood flow : A. Myogenic response B. Tubuloglomerular feedback C. Paracrine control D. Central control III. Auto regulation of renal blood flow RBF and GFR are governed by two overriding needs that are sometimes at odds with one another. Local vascular autoregulatory pathways maintain RBF at rates that optimize GFR. However, central control pathways may assume control and shunt blood away from the kidney when it is needed elsewhere. Central control is exerted hormonally and through the autonomic nervous system (ANS). Autoregulation stabilises RBF during changes in mean arterial pressure (MAP). All circulations in the body autoregulate to some degree, but the kidney’s autoregulation is well developed. RBF remains relatively stable over a MAP range of ~80 to 180 mm Hg. Autoregulation helps maintain a constant GFR over a similarly wide MAP pressure range. Autoregulation of renal blood flow A. Myogenic response Increased Arterial Blood Pressure Stretch of vascular smooth muscle cells of afferent arterioles Activates stretch-sensitive Ca2+-permeable channels Cytosolic Ca2+ rise triggers smooth muscle constriction Afferent arteriole vasoconstricts B. Tubuloglomerular feedback Renal autoregulation (internal): summary Maintains renal blood flow and GFR constant Two mechanisms: 1. Myogenic – afferent arteriole responds to changes in blood flow due to changes in pressure (stretch) 2. Tubuloglomerular feedback – afferent (and efferent) arteriole responds to changes in tubular flow Advantage: renal blood flow and GFR maintained constant despite changes in blood pressure Renal blood flow and GFR can be altered by overriding these mechanisms when appropriate by extrinsic mechanisms (e.g. sympathetic nerves) C. Paracrine control Adenosine is only one of several autoregulatory paracrines produced by the kidney. Prostaglandins (PGs) and nitric oxide both dilate glomerular arterioles and increase RBF and GFR. They may help offset intense Ang-II–mediated vasoconstriction during circulatory shock. PG-induced vasodilation becomes increasingly important for maintaining RBF during development of chronic kidney disease, that’s why inhibiting PG synthesis pharmacologically (NSAIDs) can precipitate acute renal failure. Endothelins are local vasoconstrictors released in response to Ang-II or when glomerular flow rates are very high. C. Central controls The kidney governs total body water and Na+ content, which, in turn, determines blood volume and MAP. The kidney also receives ~10% of cardiac output at rest. RBF is subject to control by the ANS, acting through neural and endocrine pathways. Neural: Endocrine: Glomerular arterioles are innervated by noradrenergic sympathetic terminals Hormonal regulation of RBF is mediated principally by that activate when MAP falls. adrenalin, atrial natriuretic peptide (ANP), and Ang-II. Sympathetic activation raises systemic vascular resistance by restricting ANP is released from cardiac atria when they are stressed by blood flow to all vascular beds, including the kidneys. high blood volumes. Mild sympathetic stimulation preferentially constricts the efferent arteriole, The ANP receptor has intrinsic guanylyl cyclase activity that which reduces RBF while simultaneously maintaining GFR at sufficiently dilates the afferent arteriole and increases RBF. high levels to ensure continued kidney function. It also relaxes mesangial cells to increase filtration barrier Intense sympathetic stimulation severely reduces blood flow through both glomerular arterioles, and urine formation ceases. surface area. In cases of severe haemorrhage, prolonged occlusion of arteriolar supply The net result is an increase in RBF and GFR and salt and vessels can cause renal ischemia, infarction, and failure. water excretion. Glomerular regulators Note: this is for your info. It will be discussed in depth in U10 Summary The functional unit of the kidney is the nephron, which comprises a blood filtration module (glomerulus) and a filtrate recovery module (renal tubule). The kidney contains two types of nephrons: superficial cortical nephrons and juxtamedullary nephrons. The latter are specialised for formation of concentrated urine. Blood is forced under pressure (~50 mm Hg) through a glomerular filtration barrier to separate plasma from cells and proteins. The kidney receives ~20% of cardiac output and filters ~20% of the plasma it receives for a total of ~180 L/day (glomerular filtration rate [GFR]). GFR is a function of renal blood flow (RBF). RBF is controlled by constriction and dilation of afferent and efferent glomerular arterioles. Afferent dilation and efferent constriction increase GFR. Afferent constriction and efferent dilation decrease GFR. The juxtaglomerular apparatus (JGA) is a functional complex comprising a section of the thick ascending limb (TAL) and the glomerular arterioles. The JGA is a sensory system that allows renal perfusion and filtration pressures to be modulated to stabilise tubule fluid flow. Flow is sensed by the macula densa, a specialised region of the tubule wall, via changes in luminal Na + and Cl− concentrations. If flow is too high, signals from the macula densa cause afferent arteriolar constriction and a decrease in GFR. If flow is too low, the afferent arteriole releases renin, which activates the renin–angiotensin–aldosterone system. Angiotensin II constricts the efferent arteriole and raises GFR. Learning objectives III. Auto regulation of renal blood flow : A. Myogenic response B. Tubuloglomerular feedback C. Paracrine control D. Central control