RENAL SYSTEM

RENAL SYSTEM• Kidneys - function as filters, removing

metabolic products and toxins from the body and excreting them through urine

- play a key hemostatic role by regulating body’s fluid status, electrolite balance, acid-base balance

- produce hormons involved in erythropoesis, calcium metabolism, and the regulation of blood pressure and blood flow

RENAL SYSTEM

The kidneys -Are paired, bean-shaped organs - lie on the posterior wall of the abdomen behind the peritoneum on either side of the vertebral column. - In an adult human, each kidney weighs between 115 and 170 g and is approximately 11 cm long, 6 cm wide, and 3 cm thick. - Each kidney is covered by a fibrous, almost nondistensible capsule- In the middle of their concave surface there is a slit in the capsule, the hilus, the port of entry for the renal artery and nerves and site of exit for the renal veins, the limphatics and the ureter.

RENAL SYSTEM

• A cut section through the kidney reveals

- the cortex , an outer granular region with glomeruli and a large number of convoluted tubules, and

- the medulla, darker inner region consisting of parallel arrangements of tubules and small vessels. It lacks glomeruli

RENAL SYSTEMThe medulla in the human kidney is divided into conical masses called renal pyramids (8-18). The base of each pyramid faces the corticomedullary border, and the apex terminates in a papilla, which lies within a minor calyx. Minor calyces collect urine from each papilla. The numerous minor calyces expand into two or three open-ended pouches, the major calyces. The major calyces feed into the pelvis. The pelvis represents the upper, expanded region of the ureter, which carries urine from the pelvis to the urinary bladder. The walls of the calyces, pelvis, and ureters contain smooth muscle that contracts to propel the urine toward the urinary bladder.

RENAL SYSTEM• Blood flow to the two kidneys is equivalent to

about 25% (1.25 L/min) of the cardiac output in resting individuals.

• About 90% of the blood entering the kidneys perfuses superficial glomeruli and renal cortex; only 10% perfuses juxtamedullary glomeruli and medulla

• The renal artery branches progressively to form the interlobar artery, the arcuate artery, the interlobular artery, and the afferent arteriole, which leads into the glomerular capillaries (i.e., glomerulus).

• The glomerular capillaries come together to form the efferent arteriole, which leads into a second capillary network, the peritubular capillaries, which supply blood to the nephron or vasa recta which provide blood for tubules located in the medulla.

RENAL SYSTEM• The vessels of the venous

system run parallel to the arterial vessels and progressively form the interlobular vein, arcuate vein, interlobar vein, and renal vein, which courses beside the ureter.

• Lymph vessels drain the interstitial fluid of the cortex ( they are absent in the renal medulla) and leave the kidney following arteries towards the hillus

RENAL SYSTEMUltrastructure of the Nephron• The functional unit of the

kidneys is the nephron.• Each human kidney contains

approximately 1.2 million nephrons, hollow tubes composed of a single cell layer.

• The nephron consists of - renal corpuscle, - proximal tubule, - loop of Henle, - distal tubule, and - collecting duct system.

RENAL SYSTEMThe renal corpuscle components:A.Vascular elementsB.The mesangium C. The Bowman capsule and space

A.The vascular elements form the glomerulus, a network of capillaries supplied by the afferent arteriole and drained by the efferent arteriole. It is surrounded by Bowman’s capsule.

• The capillaries are coverd by podocytes, epithelial cells that form the visceral layer of Bowman’s capsule

• The space between the visceral and parietal layer of Bowman ‘s capsule joins the proximal tubule

• Endothelial cells of glomerular capillaries lie on a basement membrane that is surrounded by podocytes

RENAL SYSTEMVascular elementsThe glomerular filtration barrier consists of: - endothelial cells of glomerular capilaries, - basement membrane - the layer of epithelial podocytes1.Endothelial cells-almost completely surrounded by glomerular basement

membrane-contain large fenestration (70nm holes) with no restriction to

the movement of water and small solutes, including proteins and other large molecules; they serve only to limit the filtration of cellular elements.

-filtration occurs at the peripheral portion of the capillary wall, which is covered with basement membrane and podocytes

- There is a small region towards the center of the glomerulus where endothelial cells come into direct contact with smooth-muscle-like mesangial cels

-

RENAL SYSTEM2.Basement membrane -separates endothelial layer from

epithelial layer in all parts of the glomerulus

- has three layers: lamina rara interna, lamina densa, lamina rara externa

- has important contribution to the permeability characteristics, restricting intermediate to large sized solutes

-it is a site of strongly anionic charges (sialic and dicarboxilic aminoacids residues and function primarily as a charge-selective filter in which the ability of proteins to cross the filter is based on charge

RENAL SYSTEM3.Podocytes-Have foot processes that interdigitate and cover the basement membrane-Foot proceses are separated through filtration slits which are connected by a thin diaphragmatic structure with pores ranging 4-14 nm, composed of several proteins , nephrin, podocin, alfa-actinin, CD2-AP with key role in podocyte function.-Filtration slits function primarily as a size selective filter keeping the proteins and macromolecules that cross the basement membrane from entering Bowman’s space-Glycoproteins with negative charges cover podocytes, filtration slits and slits diaphragms.-Negative charges favour the filtration of positively charged solutes

RENAL SYSTEMB. Contractile mesangial cells- Form a network of support for the glomerular capillary

loops- Posess properties of smooth muscle cells- Is continuous with the smooth muscle cells of afferent

and efferent arteriole- Secrete the extracellular matrix- Exibit fagocytic activity- Secrete prostaglandins and citokines- Regulate blood flow by altering the capillary surface

area(influence filtration rate)

Juxtaglomerular apparatus (JGA) -Part of the complex mechanism that regulate renal blood

flow, filtration rate, modulates Na + balance and systemic blood pressure

- includes: extraglomerular matrix, macula densa, granular cells

Macula densa=region of specialised epithelial cells of the thick ascending limb where it contacts its glomerulus

Granular cells, specialized smooth muscle cells in the wall of afferent arteriole which produce, stores and regulate renine release

BM, basement membrane; BS, Bowman's space; EA, efferent arteriole; EN, endothelial cell; FP, foot processes of the podocyte; M, mesangial cells between capillaries; P, podocyte cell body (visceral cell layer); PE, parietal epithelium; PT, proximal tubule cell.

RENAL SYSTEMTubule segment of the nephron:- Proximal convoluted tubule- Proximal straight tubule- Thin descending limb of loop of

Henle- Thin ascending limb of loop of

Henle- Thick ascending limb of loop of

Henle- Distal convoluted tubule- Connecting tubule- Initial collecting tubule- Cortical collecting tubule- Outer medullary collecting duct- Inner medullary collecting duct

RENAL SYSTEMEach nephron segment cells are uniquely suited to perform specific transport functions.• Proximal tubule cells -extensively amplified apical membrane (the urine side of the cell) called the brush border, - highly invaginated basolateral membrane (the blood side of the cell) with many

mitochondria. • the descending and ascending thin limbs of Henle's loop - poorly developed apical and basolateral surfaces and few mitochondria. • The cells of the thick ascending limb and the distal tubule - abundant mitochondria and extensive infoldings of the basolateral membrane. • The collecting duct has two cell types: principal and intercalated. – Principal cells- moderately invaginated basolateral membrane, contain few

mitochondria, play an important role in reabsorption of NaCl and secretion of K+

– Intercalated cells,-high density of mitochondria, play an important role in regulating acid-base balance. One population secretes H+ (i.e., reabsorbs HCO3

− ) and a second population secretes HCO3

−

RENAL SYSTEM

• All cells in the nephron, except intercalated cells, have in their apical plasma membrane a single nonmotile primary cilium that protrudes into the tubule fluid

• Primary cilia are - mechanosensors ( they sense changes in the rate of flow of

tubule fluid) and - chemosensors (they sense or respond to compounds in the

surrounding fluid), - they initiate Ca++ dependent signaling pathways, including

those that control kidney cell function, proliferation, differentiation, and apoptosis (i.e., programmed cell death).

RENAL SYSTEM

• Kidneys are also endocrine organs:- granular cells of JGA produce Renine- Proximal tubule cells convert circulatig 25-hydroxivitamin D

to the active metabolite 1,25-dihydroxivitamin D (controls calciu and phosphorus metabolism)

- Fibroblast-like cells in the interstitium of the cortex and outer medulla secrete erythropoetin in response to a fall in local tissue PO2

- Tubule cells secrete angiotensine, bradykinin. cAMP, ATP - Kidney release prostaglandins and several kinines acting as

local control circulation hormons

RENAL SYSTEM

Urine formation consists of three general processes:- Glomerular filtration- Reabsorbtion of the substance from the tubular

fluid back into blood- Secretion of some substance from blood into the

tubule fluid

RENAL SYSTEM• Glomerular filtration is a passive movement of plasma ultrafiltrate from the glomerular

capilaries into Bowman’s space which is contigous with the lumen of proximal tubule.• plasma ultrafiltrate is devoided of cellular elements (red and white blood cells and

platelets) and essentially protein free; it has the same concentration of salts and organic molecules, as plasma.

• Molecules filtration depend on their sizes and electrical charge: - neutral molecules with radius < 20 Å are filtered freely(water, glucose, sucrose,

creatinine, and urea) - molecules between 20 and 42 Å are filtered to various degrees - molecules larger than 42 Å are not filtered - for any given molecular radius, cationic molecules are more readily filtered than

anionic molecules, explained by the presence of negatively charged glycoproteins on the surface of all components of the glomerular filtration barrier.

- because most plasma proteins are negatively charged, the negative charge on the filtration barrier restricts the filtration of proteins that have a molecular radius of 20 to 42 Å or greater.

molecules must travel through several barriers to move from the capillary lumen to Bowman's space (fenestrated epithelium → basement membrane → between podocytes → filtration slit → Bowman's space),

RENAL SYSTEM

• Glomerular filtration dynamic is governed by pressures: - glomerular capillary hydrostatic pressure (HPGC) forcing fluid out

of the capillary, - glomerular capillary oncotic pressure (πGC) attracting fluid into

the glomerular capillary, - Bowman's space hydrostatic pressure (HPBS) opposing capillary

hydrostatic pressure, and - Bowman's space oncotic pressure (πBS) attracting fluid into

Bowman's space (typically there is negligible protein in the Bowman's space, so πBS is not significant).

Net filtration pressure = (HPGC – HPBS) – πGC

•

RENAL SYSTEM• additional points concerning Starling forces and this pressure change are also

important. - HPGC decreases slightly along the length of the capillary because of the resistance to

flow along the length of the capillary. - πGC increases along the length of the glomerular capillary. Because water is filtered and

protein is retained in the glomerular capillary, the protein concentration in the capillary rises, and πGC increases.

- the glomerular capillaries are different from other capillaries (which have significantly reduced pressures at the distal end of the capillary), because the efferent arteriole (at the other end of the glomerulus) can constrict and maintain pressure in the glomerular capillary.

- there is very little reduction in HPGC through the capillary, and filtration can be maintained along its entire length.

- afferent and efferent arteriolar resistance can be controlled by neural influences, circulating hormones (angiotensin II), myogenic regulation, and tubuloglomerular feedback signals, allowing control of glomerular filtration by both intrarenal and extrarenal mechanisms.

RENAL SYSTEMGlomerular filtration rate (GFR) • GFR is the amount of plasma (without protein and cells) that is filtered

across all of the glomeruli in the kidneys, per unit time. • GFR is equal to the sum of the filtration rates of all functioning nephrons,

an index of kidneys function• In a normal adult, GFR is 100 to 125 mL/min, with men having higher GFR ∼

than women. • Many factors contribute to the regulation of GFR, which can be maintained

at a fairly constant rate, despite fluctuations in mean arterial blood pressure (MAP) from 80 to 180 mm Hg

Maintaining normal GFR is critical for eliminating excess fluid and electrolytes from the blood and maintaining overall homeostasis. Significant alteration of any of the parameters in the equation above can affect GFR.

RENAL SYSTEM

• GFR is proportional to the sum of the Starling forces that exist across the capillaries [(HPGC − HPBS )-σ(πGC-πBS)] multiplied by the ultrafiltration coeficient Kf

– Kf represents the intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration; Kf is approx 100 times greater in glomerular capilaries compared to systemic capillaries;

– HPGC is aprox twice HP in systemic capillaries i

– GFR can be altered by changing Kf or any of the Starling forces; Alteration in HPGC can be induced through:

1. changes in afferent arteriolar resistance (↓resistance =>↑HPGC, ↑GFR; ↑resistance =>↓HPGC, ↓GFR )

2. changes in efferent arteriolar resistance (↓resistance =>↓HPGC, ↓GFR ; ↑resistance =>↑HPGC, ↑GFR; )

3. changes in renal arteriolar pressure transiently change HPGC.

RENAL SYSTEM

RENAL SYSTEMRenal plasma flow (RBF)

- determins indirectly the GFR - delivers substrates for excretion in urine - delivers O2, nutrients, hormons to the nephron cells, returns CO2 and reabsorbed fluid and solutes to general

circulation - modifies the rate of solute and water reabsorbtion by the proximal tubule - participates in the concentration and dilution of urine

• Whole blood enters the renal arteries but only plasma is filtered at the glomerular capilaries.• Renal blood flow (RBF) is approx. 1 l/min• Renal plasma flow (RPF)= RBF x (1-Ht)• RPF = 1l/min x 0.6 = 600 ml/min• Not all the plasma presented to the capillaries is filtered.• The filtration fraction FF is the proportion of RPF that becomes glomerular filtrate: FF = GFR/RPFIn the normal adult FF = (125 ml/min: 600 ml/min) x 100 = ~ 20%The unfiltered plasma (approx. 80%) exits the efferent arteriole to the peritubular capilaries

RENAL SYSTEM

• Renal clearance is the volume of plasma cleared of a substance per unit time

• The renal clearance can be used to measure GFR, RBF, RPF, and determine weather a substance is reabsorbed or secreted along the nephron .

• The clearance equation incorporates the urine and plasma concentrations of the substance, and the urine flow rate and is usually reported in mL/min or L/day:

U = urine concentration of the cleared substanceP = plasma concentration of the cleared substanceV = urine flow

RENAL SYSTEM– Any substance that meets the following criteria can serve as an

appropriate marker for the measurement of GFR. 1.Be freely filtered across the glomerulus into Bowman's space2.Must be neither reabsorbed nor secreted by the renal tubules3.must be neither metabolized nor produced by the kidney4. Must be physiologicaly inert (not toxic, not to alter the GFRThese criteria are met by inulin, a polyfructose. To measure inulin

clearance it is infused intravenously, and when stable plasma level is achived, timed urine collection are made. C inulin= GFR. Infusing inulin is not rutinely used becouse of the invasive nature of the procedure. Instead the renal clearance of endogenous substance creatinine is used

Creatinine, a byproduct of skeletal muscle creatine metabolism, can be used to measure GFR

Creatinine is freely filtered across the glomerulus into Bowman's space, and to a first approximation, it is not reabsorbed, secreted, or metabolized by the cells of the nephron .(there is 10% secretion into the renal tubules from the peritubular capilaries

Accordingly, the amount of creatinine excreted in urine per minute equals the amount of creatinine filtered at the glomerulus each minute

NV=125ml/min for a body surface area of 1.73 m2

RENAL SYSTEM• Regulation of the GFR occurs by changes in blood flow to the glomeruli

via:a)intrinsic feedback systems,b) Hormones and vasoactive substances, andc) renal sympathetic nerves.

a)Intrinsic systems include: 1.myogenic mechanism and2. tubuloglomerular feedback

These systems allow minute-to-minute regulation of GFR over a wide range of systemic blood pressures (MAP 80 to 180 mm Hg).

The kidney is unique in that the glomerular capillaries have arterioles on either end of the capillary network. Constriction of the afferent or efferent arterioles can elicit immediate effects on the HPGC, controlling GFR

RENAL SYSTEM

a)intrinsic feedback systems 1.myogenic mechanism, (tendency to contract when

stretched)- makes the renal arteries and arterioles respond directly

to increases in systemic blood pressure by constricting, thereby maintaining constant filtration pressure in the glomerular capillaries.

- Increase in vessel diameter opens strech activated, nonselective cation channels in vascular smooth muscle, depolarizing the cell and leading to an influx of Ca2+ that stimulate contraction

RENAL SYSTEMa)intrinsic feedback systems 2.Tubuloglomerular feedback (TGF), is a regulatory mechanism that involves the

macula densa of the juxtaglomerular apparatus.. - As juxtaglomerular apparatus functionally associates the distal tubule to the

afferent arteriole, the tubular flow past the macula densa can control afferent arteriolar resistance.

- If distal tubule flow or tubular fluid sodium concentration decrease, afferent arteriolar resistance decreases which increases GFR

- if distal tubular flow or osmolarity is high, TGF will increase afferent arteriolar resistance, decreasing GFR.

- Macula densa does not sense flow per se, but the higher luminal [Na+] or [Cl-] resulting from high flow; there is an activation of nonselective cation channels allowing Ca 2+to enter macula densa cells. The increase Intracellular Ca2+

concentration causes macula densa cells to release paracrine agents (adenosine, tromboxane, ATP) that may trigger contraction of nearby vascular smooth muscle cells

RENAL SYSTEM

RENAL SYSTEMb) Hormones and vasoactive substances • The renin-angiotensin-aldosterone system (RAAS) - activated in response to low renal vascular flow. Renal vascular baroreceptors stimulate

renin secretion by the juxtaglomerular cells at the ends of the afferent arterioles. This, in addition to the modulation of renin secretion by the macula densa, will activate the RAAS . The renin will act locally and through the systemic circulation to produce angiotensin II, and thus control GFR.

• Angiotensin II - is produced systemically and locally within the kidneys

- exerts both direct and indirect effects on the GFR. - It is a vasoconstrictor, and in the kidneys, it acts directly on the renal arteries, and to a

greater extent at the afferent and efferent arterioles, increasing resistance, reducing HPGC, and decreasing GFR;

- angiotensin II actually has greater effect on the efferent arteriole than afferent arteriole. At the same time, it can constrict glomerular mesangial cells, reducing Kf, and thus, GFR.

RENAL SYSTEM

b) Hormones and vasoactive substances • Endothelin - secreted by endothelial cells of the renal vessels, mesangial cells, and distal

tubular cells in response to angiotensin II, bradykinin, epinephrine, and endothelial shear stress.

- causes profound vasoconstriction of the afferent and efferent arterioles and decreases GFR and RBF.

- this potent vasoconstrictor may not influence GFR and RBF in resting subjects, - production of endothelin is elevated in a number of glomerular disease states• Adenosine - produced within the kidneys - causes vasoconstriction of the afferent arteriole, thereby reducing GFR and

RBF. - adenosine may play a role in tubuloglomerular feedback.

RENAL SYSTEMb) Hormones and vasoactive substances

• Atrial natriuretic peptide (ANP) - is released from the right cardiac atrial myocytes in response to stretch (at high blood volume). - dilates the afferent arteriole, and constricts the efferent arteriole, increasing HPgc, and thus, GFR.

- The enhanced flow increases sodium and water excretion, reducing blood volume.

• Intrarenal prostaglandins (PGE2 and prostacyclin [PGI2])

- Prostaglandins do not play a major role in regulating RBF in healthy, resting people - Synthesis of prostaglandins is stimulated by dehydration and stress (e.g., surgery, anesthesia), angiotensin II,

and sympathetic nerves. during pathophysiological conditions such as hemorrhage. Prostaglandins are produced locally within the kidneys, and they increase RBF without changing GFR.

- Prostaglandins increase RBF by dampening the vasoconstrictor effects of sympathetic nerves and angiotensin II. This effect is important because it prevents severe and potentially harmful vasoconstriction and renal ischemia.

- are vasodilators and serve to counteract primarily angiotensin II-mediated vasoconstriction, acting at the level of the arterioles and glomerular mesangial cells.

- Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin will block prostaglandin synthesis and restrict the compensatory renal vasodilation. Thus, administration of these drugs during renal ischemia and hemorrhagic shock is contraindicated because by blocking the production of prostaglandins, they decrease RBF and increase renal ischemia.

Prostaglandins play an increasingly important role in maintaining RBF and GFR as individuals age. Accordingly, NSAIDs can significantly reduce RBF and GFR in the elderly.

RENAL SYSTEMb) Hormones and vasoactive substances • NO, an endothelium-derived relaxing factor - important vasodilator under basal conditions; Increased production of NO causes dilation of

the afferent and efferent arterioles in the kidneys. Whereas increased levels of NO decrease total peripheral resistance, inhibition of NO production increases total peripheral resistance.

- it counteracts the vasoconstriction produced by angiotensin II and catecholamines. The factors stimulating NO production: - blood flow increase with greater shear force acting on endothelial cells in the arterioles - vasoactive hormones, including acetylcholine, histamine, bradykinin, and ATP, facilitate the

release of NO from endothelial cells. Adenosine Triphosphate– Cells release ATP into the renal interstitial fluid. – ATP has dual effects on GFR and RBF. – Under some conditions, ATP constricts the afferent arteriole, reduces RBF and GFR, and

may play a role in tubuloglomerular feedback. – ATP may stimulate NO production and increase GFR and RBF.

RENAL SYSTEM

c) Innervation of the kidneysSympathetic nerve fibers - originate in the celiac plexus,- lie adiacent to the smooth muscle cells of the branches of

the renal artery and the afferent and efferent arteriole- Innervate the renin producing granular cells of afferent

arteriole; - Innervate also proximal tubule, loop of Henle, distal tubule,

collecting duct; - Release norepinephrine and dopamineThere is no parasympathetic innervation

RENAL SYSTEMMajor effects of simpathetic stimulation:- vasoconstriction- Strongly enhance Na+ reabsorbtion of proximal tubule cells- stimulate renine secretion because the dense accumulation of fibers near the

granular cells of JGA- A few myelinated fibers conduct baroreceptor and chemoreceptor impulses that

originate in the kidney• Sympathetic nerves and catecholamine secretion (NE and Epi) are stimulated in

response to reductions in systemic blood pressure and cause vasoconstriction of the renal arteries and arterioles.

• At tonic levels of sympathetic nerve activity, the intrarenal systems will counteract this effect, to ensure the kidney vasculature remains dilated, preserving GFR.

• During high sympathetic nerve activity (hemorrhage, strenuous exercise), sympathetic nerve activity overrides the intrarenal regulatory mechanisms and reduces renal blood flow and GFR

RENAL SYSTEM