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Kidney Function Overview

• Primary function of the kidneys is to maintain a stable internal environment.
• Mechanisms of action include balancing solute and water transport, excreting waste, conserving nutrients, and regulating acid-base balance.
• Kidneys have an endocrine function, secreting hormones like renin, erythropoietin, and 1.25-dihydroxy-vitamin D3.
• Hormones secreted regulate blood pressure, erythrocyte production, and calcium metabolism.
• Kidneys synthesize glucose from amino acids through gluconeogenesis.
• Kidneys form urine through glomerular filtration, tubular reabsorption, and secretion.
• Urine travels through the ureters to the bladder for storage, and is expelled through the urethra.

Kidney Anatomy

• Kidneys are paired organs located in the posterior abdominal cavity, behind the peritoneum.
• They lie on either side of the vertebral column, approximately from the 12th thoracic to the 3rd lumbar vertebrae.
• The right kidney is slightly lower than the left due to displacement by the liver.
• Each kidney measures approximately 11cm long, 5-6 cm wide, and 3-4 cm thick.
• The renal capsule surrounds each kidney and is embedded in a mass of fat, attaching it to the posterior abdominal wall.
• The position and fatty cushion protect the kidneys from trauma.
• The hilum, a medial indentation, is the entry and exit point for renal blood vessels, nerves, lymphatic vessels, and the ureter.

Kidney Structures

• The cortex is the outer layer containing glomeruli, most proximal tubules, and some distal tubule segments.
• The medulla is the inner part consisting of regions called pyramids.
• Renal columns are extensions of the cortex lying between the pyramids, extending to the renal pelvis.
• The apexes of the pyramids project into minor calyces, which unite to form major calyces.
• Minor calyces are cup-shaped cavities receiving urine from collecting ducts through the renal papilla.
• Major calyces join with minor calyces to form the renal pelvis, which connects to the proximal end of the ureter.
• Walls of calyces, pelvis, and ureter are lined with epithelial cells and contain smooth muscle for moving urine to the bladder.
• A lobe, the structural unit of the kidney, consists of a pyramid and the overlying cortex.
• Each kidney has an average of 14 lobes.

Nephron

• Each kidney contains approximately 1.2 million nephrons.
• Nephrons are the functional units of the kidney.
• Tubular structure with subunits that contribute to the formation of urine.
• Subunits include the renal corpuscle, proximal convoluted tubule, Loop of Henle, distal convoluted tubule, and collecting duct.
• Different epithelial cells lining various segments of the tubule facilitate reabsorption and secretion.
• Cells of the proximal convoluted tubule permit reabsorption of 60% of the glomerular filtrate.
• Intercalated cells secrete H+ and reabsorb HCO3- or secrete HCO3- and reabsorb K+.
• Principle cells reabsorb Na+ and water and secrete K+.

Types of Nephrons

• Superficial cortical nephrons, 85% of all nephrons, extend partially into the medulla.
• Midcortical nephrons have short and long loops.
• Juxtamedullary nephrons lie close to and extend deep into the medulla, important for concentration of urine.

Renal Corpuscle

• The glomerulus is a tuft of capillaries looping into the Bowman capsule, supplied by the afferent arteriole and drained by the efferent arteriole.
• Juxtaglomerular cells, or renin-releasing cells, are located around the afferent arteriole.
• Macula densa cells, Na+ sensing cells of the distal convoluted tubule, lie between the afferent and efferent arterioles.
• The juxtaglomerular apparatus (JGA), consisting of the juxtaglomerular cells and macula densa cells, controls blood flow, glomerular filtration, and renin secretion.
• The Bowman capsule is composed of a visceral epithelium (visceral layer) forming podocytes.
• The visceral epithelium reflects back at the vascular pole, becoming the outer parietal epithelium (parietal layer).
• Mesangial cells (shaped like smooth muscle cells) and mesangial matrix (type of connective tissue) lie between and support the glomerular capillaries.
• Mesangial cells contract to regulate glomerular capillary blood flow.
• Mesangial cells have phagocytic properties, releasing inflammatory cytokines and growth factors.

Glomerular Filtration Membrane

• The glomerular filtration membrane separates the blood of all glomerular capillaries from the fluid in Bowman space, allowing filtration of blood components except blood cells and plasma proteins with a molecular weight > 70,000.
• Glomerular filtrate passes through three layers to form primary urine.
• The inner capillary endothelium is composed of cells in continuous contact with the basement membrane, synthesizing nitric oxide and endothelin-1 to regulate glomerular blood flow.
• It contains pores maintained by vascular epithelial growth factor (VEGF).
• The middle glomerular basement membrane is composed of a selectively permeable network of proteoglycans (type IV collagen).
• The outer visceral epithelium is composed of specialized cells (podocytes) with pedicles that adhere to the basement membrane.
• Filtration slits or slit membranes are formed by interlocking pedicles of adjacent podocytes.
• Nephrin, podocin, CD2-associated protein, and other transcellular protein molecules ensure proper function of the filtration slits.
• Alterations of the filtration slits results in glomerular disease.

Bowman Space

• Bowman space (urinary space) is the space between the visceral and parietal epithelia, continuous with the lumen of the renal tubules.
• Endothelium, basement membrane, and podocytes are covered with protein molecules bearing negative (anionic) charges that retard the filtration of anionic proteins, preventing proteinuria.

Proximal Convoluted Tubule

• The proximal convoluted tubule continues from the Bowman capsule.
• Consists of segments: initial convoluted segment (pars convolute) and straight segment (pars recta).
• Descends toward the medulla.
• The wall of tubule is one layer of cuboidal epithelial cells with a surface layer of microvilli which is the only surface inside the nephron with microvilli-covered cells, increasing reabsorptive surface area.

Distal Tubule

• Contains straight and convoluted segments.
• Extends from the macula densa to the collecting duct.
• The collecting duct descends down the cortex to the renal pyramids of the inner and outer medullae.
• Drains urine into the minor calyx.
• Is composed of two epithelial cell types including principal cells and intercalated cells.
• Principal cells secrete K+ and reabsorb Na+ and water.
• Intercalated cells secrete Hydrogen and reabsorb K+.

Loop Of Henle

• The proximal convoluted tubule joins the “hairpin-shaped” Loop of Henle.
• Composed of the thin descending segment, thin ascending segment, and thick ascending segment.
• The thin descending segment is permeable to water.
• The thin ascending segment is permeable to ions but not water.
• The thick ascending segment actively transports ions to the interstitium and passes urine into the distal convoluted tubule.
• Major structural difference between the two nephrons = length of the Loop of Henle
• Cortical nephrons are more numerous; glomeruli close to the surface of the cortex or in midcortex and the loop is short and may not extend into medulla.
• Juxtamedullary nephrons which are important for concentration and dilution of urine: glomeruli located deep in cortex close to medulla may extend the whole length of medulla (approx. 40mm) and represent 12% of the total # of nephrons.

Renal Blood Flow

• The kidneys receive about 20% to 25% of the cardiac output, equivalent to 1000 to 1200mL of blood per minute in adults.
• Interlobular artery → afferent arteriole → glomerulus → efferent arteriole → peritubular capillaries (around the tubules) → venules → interlobular vein.
• Renal arteries arise as the fifth branches of the abdominal aorta, divide into anterior and posterior branches at the renal hilum, and then subdivide into lobar arteries supplying blood to the lower, middle, and upper thirds of the kidney.
• Interlobar artery subdivisions travel down renal columns and between pyramids and form afferent glomerular arteries.
• Arcuate arteries consist of branches of interlobar arteries at the cortical-medullary junction; they arch over the base of the pyramids and run parallel to the surface.
• Glomerular capillaries consist of four to eight vessels and are arranged in a fist-like structure; they arise from the afferent arteriole and empty into the efferent arteriole, which carries blood to the peritubular capillaries. They are the major resistance vessels for regulating intrarenal blood flow.
• Peritubular capillaries surround convoluted portions of the proximal and distal tubules and the loop of Henle; they are adapted for cortical and juxtamedullary nephrons.
• Vasa recta is a network of capillaries that forms loops and closely follow the loops of Henle; it is the only blood supply to the medulla (important for formation of concentrated urine).
• Renal veins follow the arterial path in reverse direction and have the same names as the corresponding arteries; they eventually empty into the inferior vena cava.
• Normal hematocrit is 45% results in about 600 to 700 mL of plasma that flows through the kidney per minute.
• 20% (approximately 120 to 140 mL/min) of plasma is filtered at the glomerulus and passing into the Bowman capsule.
• 80% (about 480 mL/min) of plasma flows through the efferent arterioles to the peritubular capillaries.
• Normally all but 1 to 2 mL per minute of the glomerular filtrate is reabsorbed into the peritubular capillaries, returning to the circulation.
• Glomerular filtration rate (GFR; filtration of plasma per unit of time) is directly related to perfusion pressure in the glomerular capillaries.
• GFR is directly related to renal blood flow (RBF).
• GFR is regulated by intrinsic autoregulatory mechanisms, neural regulation, and hormonal regulation.
• Mean arterial pressure decreases OR vascular resistance increases which results in RBF declines and urinary output decreases.
• Normal urinary output is 30 mL/hour minimum in adults or 0.5 to 1.0 mL/kg/hour.

Regulation of Glomerular Filtration Rate

• Autoregulation is a local mechanism that keeps rates of glomerular perfusion (GFR) constant ranging from arterial pressures between 80 and 180 mmHg.
• Changes in afferent arteriolar pressure and resistance occur in same direction.
• Intrarenal blood flow + GFR remains relatively constant independent of renal perfusion pressure.
• This relationship is maintained by an intrinsic autoregulatory myogenic mechanism of contraction.
• The purpose of autoregulation to keep RBF and GFR constant when there are increases or decreases in systemic blood pressure.
• Purpose of autoregulation: solute and water excretion (blood volume) is regulated despite arterial pressure changes.
• Prevents barotrauma if there is high systemic BP.
• Kidney blood vessels are innervated by sympathetic nerve fibers that are located primarily on afferent arterioles
• Reduced systemic arterial pressure = increased renal sympathetic nerve activity.
• Sympathetic nerves release catecholamines.
• Stimulates afferent renal arteriolar vasoconstriction and decreases RBF and GFR
• Increases renal tubular sodium and water reabsorption and increases blood pressure.
• Decreased afferent renal sympathetic nerve activity produces the opposite effects
• Response that regulates water and sodium balance.
• Renalase hormone released by the kidney and heart promotes metabolism of catecholamines and participates in blood pressure regulation
• Sympathetic nervous system participates in hormonal regulation of renal blood flow with NO SIGNIFICANT parasympathetic innervation.
• Innervation of the kidney arises primarily from the celiac ganglion and greater splanchnic nerve.

RAAS System

• The RAAS System is a major hormonal regulator of renal blood flow (RBF), which can increase systemic arterial pressure, reabsorption of sodium and water, and RBF.
• Renin release is triggered by decreased blood pressure in the afferent arterioles, decreased sodium chloride concentrations in the distal convoluted tubule, sympathetic nerve stimulation of β-adrenergic receptors on the juxtaglomerular cells and release of prostaglandin.
• When a person experiences hypotension, RENIN is released and starts a cascade of events that leads to the release of the angiotensin.
• When renin is released, splits α-globulin (angiotensinogen produced by liver hepatocytes) in the plasma and forms angiotensin I.
• Angiotensin I can be converted to angiotensin II by the presence of angiotensin converting enzyme (ACE – produced from the pulmonary / renal endothelium.
• Stabilize systemic blood pressure and preserve extracellular fluid volume during hypotension or hypovolemia is regulated by physiologic effects of the RAAS system: sodium reabsorption, potassium excretion, systemic vasoconstriction, sympathetic nerve stimulation and thirst stimulation with increased drinking
• Natriuretic peptides (group of peptide hormones) or natural antagonists to the renin-angiotensin aldosterone system.
• Atrial natriuretic peptide (ANP) is secreted from myocardial cells in the atria.
• Brain natriuretic peptide (BNP) is secreted from myocardial cells in the cardiac ventricles.
• C-type natriuretic peptide is secreted from vascular endothelium and in the nephron and causes vasodilation.
• Urodilatin a renal natriuretic peptide secreted by the distal convoluted tubules and collecting duct causes vasodilation, increased renal blood flow, and diuretic effects.
• Vitamin D3 is a potent negative endocrine regulator of renin gene expression.
• ACE inhibitors inhibit formation of angiotensin II and aldosterone.

Hormonal Effects on Renal Blood Flow

• Adenosine causes vasoconstriction of afferent arteriole and decreases RBF and GFR.
• Angiotensin II constricts afferent and efferent arterioles, decreasing RBF and GFR.
• Atrial and brain natriuretic peptides cause vasodilation of afferent arteriole and vasoconstriction of efferent arteriole, with modest increase in GFR and little change in RBF.
• Bradykinin causes vasodilation by release of nitric oxide and prostaglandins and increases RBF and GFR.
• Dopamine increases RBF and inhibits renin secretion.
• Endothelin causes profound vasoconstriction of afferent and efferent arterioles and decreases RBF and GFR.
• Histamine increases RBF by decreasing afferent and efferent arteriolar resistance and maintains GFR.
• Nitric oxide increases vasodilation of afferent and efferent arterioles
• Prostaglandins dampen vasoconstriction caused by sympathetic nerves and angiotensin II and prevent harmful vasoconstriction and renal ischemia.
• Urodilatin inhibits sodium and water reabsorption and increases diuresis.

Renin-Angiotensin-Aldosterone System (RAAS) Overview

• The RAAS is a major hormonal regulator of renal blood flow (RBF), systemic arterial pressure, sodium and water reabsorption, and renal blood flow itself. It plays a crucial role in stabilizing blood pressure, regulating extracellular fluid volume, and maintaining electrolyte balance.

Renin-Angiotensin-Aldosterone System (RAAS) Cascade

• Renin is released into the bloodstream to start the renin-angiotensin cascade.
• Renin cleaves angiotensinogen (produced by the liver) into angiotensin I.
• Angiotensin I is converted to angiotensin II by the enzyme angiotensin-converting enzyme (ACE), which is primarily found in the pulmonary and renal endothelium.

Effects of Angiotensin II

• Angiotensin II is a potent vasoconstrictor promotes vasoconstriction of systemic arterioles, increasing glomerular filtration pressure and systemic vascular resistance.
• Stimulates aldosterone secretion which increases sodium reabsorption in the kidneys, leading to water retention and increased blood volume.
• Stimulates antidiuretic hormone (ADH) which increases water reabsorption in the kidneys' collecting ducts.
• Stimulates thirst to encourage fluid intake.
• Increases sympathetic nervous activity, further increasing blood pressure.

Aldosterone

• Aldosterone promotes sodium reabsorption, water retention and increased blood volume.
• It also promotes potassium excretion and hydrogen ion excretion.

Antidiuretic Hormone (ADH) / Vasopressin

• ADH promotes water reabsorption in the kidneys by increasing the permeability of the collecting ducts through aquaporin channels.
• In higher concentrations, ADH also acts as a vasoconstrictor.

Natriuretic Peptides

• Natriuretic peptides act as natural counter-regulators to the RAAS and help reduce blood volume and blood pressure.
• Atrial Natriuretic Peptide (ANP) Inhibits Na+ and water reabsorption in the kidneys and Inhibits renin and aldosterone secretion.
• Brain Natriuretic Peptide (BNP) Has similar effects to ANP, promoting natriuresis, diuresis, and vasodilation.
• C-type Natriuretic Peptide (CNP) primarily acts as a vasodilator, aiding in blood pressure regulation.
• Urodilatin: A renal-specific natriuretic peptide that enhances renal blood flow and promotes diuresis.

Clinical Relevance

• Overactivation of the RAAS system contributes to conditions like hypertension, heart failure, and chronic kidney disease.
• Medications that block the RAAS (ACE inhibitors, ARBs, and aldosterone antagonists) are commonly used to treat these conditions.
• In heart failure, the heart’s ability to pump blood is impaired, leading to activation of RAAS, which exacerbates fluid retention and worsens symptoms. Natriuretic peptides (ANP, BNP) are elevated in heart failure as part of the body’s attempt to counteract this activation.

Renal Hormones

• Renin: Enzyme formed and stored in granular cells of afferent arterioles of the JGA.
• Release is triggered by decreased blood pressure in the afferent arterioles
• Angiotensin I: Formed when renin separates an α-globulin (produced by liver hepatocytes) in the plasma
• Angiotensin-converting enzyme (ACE): Produced in the pulmonary and renal endothelium, interacts with angiotensin I to form angiotensin II
• Angiotensin II stimulates secretion of aldosterone by the adrenal cortex. Natriuretic Peptides are a group of peptide hormones.
• Atrial Natriuretic Peptide (ANP): secreted by myocardial cells in the atria & inhibits Na+ and water absorption by kidney tubules.
• Brain Natriuretic Peptide (BNP): secreted from myocardial cells in the cardiac ventricles & inhibits Na+ and water absorption by kidney tubules.
• C-Type Natriuretic Peptide: secreted from vascular endothelium and in the nephron and causes vasodilation.
• Urodilatin: secreted by the distal convoluted tubules and collection ducts and causes vasodilation and natriuretic and diuretic effects.
• Renalase: Hormone produced by the kidney that degrades catecholamines and regulates blood pressure.
• Norepinephrine & Epinephrine Released by adrenal medulla promotes afferent arteriolar vasoconstriction and decreases GFR and RBF
• Antidiuretic Hormone (ADH) Secreted from the posterior pituitary or neurohypophysis, increases water permeability in the last segment of the distal tubule and along the entire length of the collecting ducts and is secreted due to presence of high osmotic gradient in the medullary interstitium
• Vitamin D Hormone obtained in the diet or synthesized by the action of ultraviolet radiation on cholesterol in the skin. Active form is calcitriol

Aldosterone Details

• Initial stage of synthesis occurs in the zona fasciculate and zona reticularis and final conversion occurs in the zona glomerulosa
• Is regulated by the RAAS especially Angiotensin II and maintains extracellular volume and acts on distal nephron epithelial cells to increase Na+ reabsorption and potassium, and H+ excretion
• Synthesis and secretion are regulated by the RAAS
• Other effects: enhancement of cardiac muscle contraction, stimulation of ectopic ventricular activity, stiffening of blood vessels with increased vascular resistance, and decreased fibrinolysis and implicated in myocardial changes associated with heart failure.

Protein Metabolism

• Urea: end-product of protein metabolism and major constituent of urine.
• The glomerulus freely filters urea
• The tubular reabsorption of urea depends on the urine flow rate
• Approximately 50% of urea is excreted in the urine while 50% is recycled in the kidneys
• Recycling urea contributes to osmotic gradient and individuals with protein deprivation cannot maximally concentrate their urine.

Glomerular Filtration Rate

• Glomerular Filtration Rate is the best indicator of renal function.
• It is the volume of plasma that the kidneys filter through the glomeruli per unit time.
• Damage to the glomerular membrane or loss of nephrons decreases GFR.
• The measurement of GFR requires a substance characteristics of insulin: Stable plasma concentration, it is not protein bound, freely filtered at the glomerulus & Does not influence GFR & is not secreted, reabsorbed, or metabolized by the tubules
• Creatinine clearance provides a good estimate of GRF because only one blood sample is required in addition to a 24-hour volume of urine
• GFR gradually decreases as a person ages due to the loss of active nephrons, average volume of plasma filtered by glomeruli in a young adult is 90-120 ml/min

Specific Gravity

• Specific gravity is an estimated measure of the solute concentration of the urine
• Measurement of specific gravity of any solution is comparing the weight of the solution with an equal volume of distilled water. It also Correlates well with osmolality as a useful clinical tool
• It is measured with a hydrometer in a cylinder of urine with a normal value in between 1.016 to 1.022

Glucosuria

• Reabsorption of molecules such as Na+ , water urea, K+, glucose, bicarbonate, Ca+, phosphate, amino acids, and uric acid occur at end of the proximal convoluted tubule
• Active transport in renal tubules is limited as carrier molecules become saturated, such as the development of hyperglycemia w/ serum glucose values of 180 mg/dl or greater which is when excess glucose is excreted in the urine

Bladder Fullness

• Stretching of tissue in bladder from an accumulation of 250 to 300ml of urine signals to feel bladder fullness
• Mechanoreceptors sends impulses to stimulate spinal reflex arc which bladder contracts and internal urethral sphincter relaxes (micturition reflex)
• Micturition reflex can be inhibited or facilitated by impulses coming from the brain

Aging and Renal Function

• The kidney increases workload results in a compensatory hypertrophy resulting in glomeruli increase in diameter and tubules enlarge effectively to maintain the regulatory function of the kidney
• There is a reduction in size decrease in renal blood flow with change in renal vasculature and perfusion patterns but is less pronounced in healthy individuals
• Rate of nephron loss accelerates after 50 years of age and has primary mechanism of Atherosclerosis
• Degenerative changes to nephrons become sclerotic, arcuate and interlobular arteries become tortuous, causing Ischemia
• Tubular transport adaptations become difficult so glucose, bicarbonate, and Na+ are not efficiently reabsorbed with pH imbalances
• Decrease in renal activation of vitamin D causes decreased absorption, so older adults require more vitamin D
• Patients experience Bladder symptoms (frequency, urgency, and nocturia due to factors such as ischemic-induced neurogenic and myogenic changes in bladder structure and neurotransmission slowing influences micturition reflex

Exercise and Renal Blood Flow.

• There is more blood flow directed towards skeletal muscles, skin and the heart. Reduction in renal blood flow occurs due to vasoconstriction.

Body Position Effect on Renal Blood Flow.

• Supine, lying down position results in venous return to the heart increases results in slight increase in renal blood flow.
• Standing up position results in blood pools causing a decrease venous return, cardiac output also renal blood flow