RENAL PHYSIOLOGY

Dr. Mayuri Golhar

INTRODUCTION• The kidneys contain approximately 2 million

nephrons, consisting of a glomerulus and a tubule, which empties into a collecting duct.

• Together they regulate intravascular volume, osmolality, and acid-base and electrolyte balance and excrete end products of metabolism and drugs.

• Urine is formed by the combination of glomerular ultrafiltration and tubular reabsorption and secretion.

FUNCTIONS

• Functions of the nephron: elaborates hormones that contribute to 1) fluid homeostasis (renin, prostaglandins, kinins)

• 2) bone metabolism (1,25-dihydroxycholecalciferol)• 3) hematopoiesis (erythropoietin)

ANATOMY & PHYSIOLOGYThe Glomerulus (Renal Corpuscle) The glomerulus consists of five distinct components:

1)capillary endothelium, 2)glomerular basement membrane, fiteration barrier3)visceral epithelium 4)parietal epithelium (Bowman's capsule),5) mesangium (interstitial cells).The glomerular tuft, a

highly convoluted series of capillary loops, is fed by the afferent arteriole and drains into the efferent arteriole

• The capillary endothelium synthesizes nitric oxide and endothelin-1, which governs vasodilation & vasoconstriction renal blood flow. It has fenestrations about 70 to 100 nm in diameter and lies atop the glomerular basement membrane, which has a total cross section of about 350 nm.

• visceral epithelium, which lies underside the basement membrane, consists of podocytes with filamentous, interdigitating foot processes that contain contractile actin filaments. Filtration slits form 25- to 60-nm gaps between the foot processes.

ANAT & PHYSIO cont..• The blind parietal epithelial sac of the renal tubule is

invaginated around the capillary tuft as Bowman's capsule and meets the visceral epithelium at the vascular pole of the glomerulus. Bowman's space, between the visceral and parietal layers of the capsule, becomes the lumen of the proximal tubule at the urinary pole of the glomerulus.

• The central or interstitial mesangial cells are specialized pericytes with numerous functions structural support, matrix elaboration, and phagocytosis. They contain myofilament-like threads of actin and myosin

• ANGII contraction restricts BF to cap loops regulates fileration & permeablitiy

Formation of the Glomerular Ultrafiltrate:• The molecules of the ultrafiltrate pass in succession thru-

endothelial fenestrations restricts the passage of

FITERATION glomerular BM cells & negatively char-

BARRIER visceral epithelium ged proteins.

Thus the filtration barrier is size & charge selective.The size of the molecules which are filtered range

between(1.8-3.6nm) & depends on their charge. Thus Hb & albumin( 3.6nm) are not filtered.

Fitration is governed by Starlings forces which states that-Glomerular filtration rate (GFR) depends on the permeability of the

filtration barrier and the net difference between the hydrostatic forces pushing fluid into Bowman's space and the osmotic forces keeping fluid in the plasma.

JUXTAGLOMERULAR APPARATUS

• The juxtaglomerular apparatus consists of a integration of tubular and glomerular structure and function.It is a modified portion of the thick ascending limb, between the afferent and efferent arterioles.

• The cells of the macula densa are chemoreceptors and sense the tubular concentration of sodium chloride (NaCl).

• The juxtaposed segments of the afferent and efferent arterioles contain modified smooth muscle cells (granular cells), which produce renin. The arterioles are innervated by sympathetic nerve fibers and contain baroreceptors that respond to changes in intraluminal blood pressure.

• Renin catalyzes the formation of angiotensin, which modulates efferent and afferent arteriolar tone and GFR

Afferent and Efferent Arteriolar Control Mechanisms• The determinant of GFR is glomerular filtration pressure (GFP)GFP depends on- renal artery perfusion pressure - balance between efferent &afferent arteriolar tone. In the presence of decreased afferent arteriolar pressure or blood

flow, low levels of catecholamines, angiotensin, and arginine vasopressin (AVP) induce preferential efferent arteriolar constriction, which maintains glomerular filtration pressure.

This is reflected by an increase in calculated filtration fraction (FF), which is the GFR expressed as a fraction of the renal plasma flow (RPF), that is, FF = GFR/RPF

High levels of catecholamines and angiotensin (but not AVP) increase afferent arteriolar tone and decrease glomerular filtration pressure (and GFR) out of proportion to RPF, and FF decreases

Tubuloglomerular Feedback• Tubuloglomerular feedback may be a primary mechanism in

renal autoregulation. GFR increases

distal tubular NaCl delivery is enhanced

increase chloride is sensed by macula densa

renin is released from the afferent arteriole

angiotensin is released causing vasoconstriction

dereases the GFR

Renal Autoregulation

• Autoregulation enables the kidney to maintain solute and water regulation independently of wide fluctuations of arterial blood pressure. The kidney maintains a constant renal blood flow and GFR through an arterial pressure range of 80 to 180 mm Hg .

increase in the GFR the arterial pressure rises NaCl concentration in the tubules raises sensed by the chemosensors of the macula densa releases ATP & Adenosine stimulates the adenosine A1 receptors afferent arteriolar constriction & its resistance increasesThus reduces the RBF & GFR back to previous levels.

THE TUBULE

• The tubule has four distinct segments: 1 the proximal tubule,2 loop of Henle, 3 the distal tubule, and the 4 connecting segment.

• The loop of Henle itself is divided into - the pars recta (the straight portion of the proximal tubule),

- the descending & the thin & thick ascending limbs. • Each distal tubule drains into a collecting duct, which

courses through the cortex, outer medulla, and inner medulla before entering the renal pelvis at the papilla

TUBULES• There are two populations of nephrons. 1)The cortical

nephrons populate the outer and middle renal cortex, are far more numerous, receive about 85% of the renal blood flow, and have short loops of Henle.

2)The juxtamedullary nephrons populate the inner renal cortex, receive about 10% of the RBF, and have larger glomeruli and long loops of Henle, which dive deeply into the inner medulla.

• Although the vasa recta receive less than 1% of the RBF, they play an important role in generating the countercurrent mechanism for medullary hypertonicity and renal concentrating ability

Tubular reabsorption & secretion• The tubule has an enormous capacity for reabsorption

of water and NaCl. Each day, 180 L of protein-free glomerular ultrafiltrate is formed, of which almost 99% of the water and 99% of the sodium is reabsorbed.

• Glucose have a maximum rate of tubular reabsorption (tubular maximum). Tubular reabsorption of glucose increases at a rate equal to that of the filtered load. If the GFR is constant, the rate is directly proportional to the plasma glucose. Once plasma glucose exceeds the tubular maximum (375 mg/dL), no further glucose is reabsorbed and glycosuria results.

Tubular reabsorption &secretion• Many important endogenous and exogenous solutes are

secreted into the tubular lumen from the capillary blood.

• The most metabolically active components of the tubule are the proximal tubule, the thick ascending loop of Henle, and the first part of the distal tubule.

• The cells of the proximal tubule have a brush-border whereas the cells of the descending and thin ascending loops of Henle are flattened with few mitochondria. The intercalated cells of the distal tubule have many mitochondria; the principal cells are few.

Tubular reabsorption & secretion

• Active transport systems that move solutes in the same direction into or out of the cell are called symporter systems, whereas those that move solutes in opposite directions are called antiporter systems. Solutes are transported by active and passive mechanisms, but water always diffuses passively along an osmotic gradient.

• The most important is the sodium-potassium adenosine triphosphatase (Na+-K+-ATPase) system, situated in the basolateral membrane.

Na is pumped out of the cell passive reabsorption of Na from the lumen into the cell.K is exchanged inside the cell decrease in the intracellular Na conc

Proximal tubule• The first part of PCT reabsorps 100% glucose ,lactate, AA & phosphate.H+ ions are excruded into the tubule in exchange of bicarbonate

( Na+ H+ antiporter)

High chloride conc downstream & passive ingress of chloride.

Tubular fluid becomes positively charged.

This promotes further Na movement into the cell from the tubular fluid.The Na+/K+-ATPase system pumps sodium into the interstitial space, and a

K+/Cl- symporter system pumps chloride. The resulting increase in osmolality draws water across as well.

Secretion of many endogenous anions (bile salts, urate), cations (creatinine, dopamine), and drugs (diuretics, penicillin, probenecid, cimetidine)

Thick ascending loop of Henle

• Thick loop of henle absorbs 20% of Na , chloride, K & bicarbonate.

• Only descending loop of henle is permeable to water.

• In the water-impermeable thick ascending limb Na is actively reabsorbed.

• This is called the diluting segment of the kidney.• The tubular fluid osmolality decreases to less than

150 mosmol/kg water.

Oxygen Balance in the Medullary Thick Ascending Loop• Kidneys receive 20% of the total cardiac output but relatively

little amount of oxygen.• Renal atriovenous [(a-v)O2.] oxygen difference is 1.5 ml/dl.• The medulla receives 6% of RBF &O2 tension (PO2) of

8mmhg.• So severe hypoxia can develop in the medulla despite of

adequate RBF & thick loop of henle is particularly vulnerable to hypoxic injury.

CORTEX MEDULLAPercent of renal blood flow

94 6

Blood flow (mL/min/g) 5.0 0.03

PO2 (mm Hg 50 8

O2 extraction ratio (VO2/DO2)

0.18 0.79

Distal Tubule and Collecting Duct

• Sodium reabsorption is mediated by an apical cell membrane NaCl symporter system, which is the site of action of thiazide diuretics.

• The last part of the distal tubule is composed of two types of cells. Principal cells reabsorb sodium and water and secrete potassium via the Na+/K+-ATPase pump, and intercalated cells secrete H+ and reabsorb bicarbonate by an H+-ATPase pump in the apical cell membrane.

Osmotic equilibrium• The ability of the kidney to concentrate urine is

dependent on the interaction of at least three processes:

• (1) the generation of a hypertonic medullary interstitium by the countercurrent mechanism and urea recycling,

• (2) concentration and then dilution of tubular fluid in the loop of Henle, and

• (3) the action of antidiuretic hormone in increasing water permeability in the last part of the distal tubule and collecting ducts.

1) Tubular fluid enters the distal proximal tubule iso-osmotic with plasma (300 mOsm/kg). In the descending limb of Henle (2), water rapidly diffuses out into the increasingly hypertonic medulla and is removed by the vasa recta so that the tubular fluid becomes hypertonic, owing largely to concentration of sodium chloride (NaCl). Urea diffuses in from the hypertonic interstitium, further increasing tubular fluid osmolality (1200 mOsm/kg). In the thin ascending loop of Henle (3), NaCl passively diffuses into the interstitium along its concentration gradient but water is trapped in the water-impermeable tubule, which progressively decreases tubular fluid osmolality. Urea passively diffuses into the tubular fluid (urea recycling). Tubular dilution is accelerated by active reabsorption of NaCl in the thick ascending loop (the diluting segment) and proximal distal tubule (4). The fluid entering the distal tubule is quite hypo-osmotic (100 mOsm/kg). In the collecting segment (5), the osmolality of the tubular fluid returns to that of plasma (300 mOsm/kg) but, unlike the contents of the proximal tubule, the solute component consists largely of urea, creatinine, and other excreted compounds. Increased plasma antidiuretic hormone renders the cortical and medullary collecting ducts (6) permeable to water, which passively diffuses into the hypertonic medullary interstitium. Even though some urea diffuses out into the medulla, the maximal osmolality of concentrated urine (7) approaches that of the hypertonic medullary interstitium, about 1200 mOsm/kg. In the absence of antidiuretic hormone, the collecting ducts remain impermeable to water and the urine is diluted

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