KIDNEY GENERAL FUNCTIONS OF KIDNEY 1.

HOMEOSTASIS FUNCTION - maintains the constancy of the internal environment by excretion of urine - kidneys maintain : water balance electrolyte balance blood pH 2. ENDOCRINE FUNCTION 1. Renin Juxta-glomerular cells 2. Erythropoietin 3. converts vit D3 to 1,25 DHCC (active form) 4. secretes prostaglandins *Excreted urine normally contains 1. Surplus water 2. Surplus electrolytes 3. Surplus acids & alkalis 4. Metabolic waste products 1. Urea from amino acids that used for heat & energy 2. Uric acid from nitrogen from nucleic acid/purines *excessive production gout 3. Creatinine from creatine in the muscle *presence in urine represents loss of nitrogen from body 5. Abnormal constituents (clue for underlying disorder) 1. Glucose (DM) 2. Ketone bodies (ketosis ) 3. Albumin(kidney disease ) 4. Red blood cells (kidney disease ) 5. Galactose (galactoseamia ) 6. Phenylketones (phenylketonuria ) 6. Metabolic products of all drug *hormone chorionic gonadotrophin in urine of pregnant women 1. renal artery 2. 3-5 interlobar arteries 3. arcuate branches 4. inter-lobular arteries RENAL CIRCULATION in the medulla pass between pyramids at bases of pyramids, at cortico-medullary junction ascend through the cortex, between adjacent medulllary rays to end as capsular capillaries during the course in cortex a tuft of coiled capillary network *glomerular filteration!

formation of angiotensin II regulate ABP stimulate BM RBC regeneration promotes Ca reabsoprtion from intestine

5. afferent arterioles 6. glomerular capillaries [1st capillary network] 7. efferent arterioles 8. [2nd capillary network] *differs according to position of corpuscles - peritubular capillaries - subcapsular & intermediate corpuscles - vasa recta - juxtamedullary corpuscles 9. interlobular veins arcuate veins interlobar veins renal veins *see histo!

Characters of renal circulation 1. Almost, all renal blood has to pass through the glomeruli 2. Renal circulation is a portal circulation - blood circulates into two capillary networks (glomerulus + peritubular capillaries) - portal renal system has 2 functions : Filtration through glomerular capillaries. Reabsorption and secretion through peritubular capillaries . 3. High blood flow rate - 1/4 of COP passes into the kidney (1300 ml blood/ minute) 4-The high renal blood flow is not due to high o2 consumption of kidney - utilize only 8% of total o2 consumption of body - BF is related to homeostatic function of the kidney allowing high GFR 700 ml of plasma passes through glomeruli 120 ml are filtered per minute 180 L/day , 99% of the filtrate is reabsorbed by the renal tubules leaving behind unwanted substances to be excreted Pressures in renal circulation The 2 areas of resistance to blood flow in nephron = afferent & efferent arterioles in afferent arterioles in efferent arteriole pressure falls from 100 mmHg at pressure falls 47 mmHg to be beginning to 60 mmHg in glomerulus 13 mmHg in peritubular capillaries leads to filtration leads to reabsorption

FORMATION OF URINE Urine is formed by 3 main processes : 1. Glomerular filtration of plasma colloids . 2. Tubular reabsorption of wanted substances . 3. Tubular secretion of unwanted substances. GLOMERULAR FILTRATION glomerulus acts as a simple filter between the blood & the tubule its permeability is 100-500 times permeability of usual capillary filtration is a passive process! driving force = the high capillary BP in the glomeruli fluid that filters through the glomeruli = glomerular filtrate which is plasma (minus) colloids;fats and proteins Fenestrated capillary endothelium + glomerular basement membrane + filtration slits between feets processes of podocytes = have no function in reabsorption & secretion = act only as a filter/sieve, restricting the passage of large molecules with MW > 70,000 Dynamics of Glomerular Filtration Glomerular pressure : 60 mmHg Pressure in Bowmans capsule : 18 mmHg Colloid osmotic pressure in glomerulus : 1/5 of plasma in capillaries filters into capsule protein concentration increases about 20% if the normal colloid osmotic of blood at beginning of glomerulus is 28 mmHg, it increases to 36 mmHg at end of it the average is 32mmHg Filtration pressure = glomerular pressure (minus) glomerular colloid osmotic pressure (minus) capsular pressure 60 -32 -18 =10 mmHg *glomerular pressure causes fluid to filter into Bowmans capsule *colloid osmotic pressure of blood & pressure in Bowmans capsule both oppose the filtration Filtration coefficient : Kf : = GFR for both kidneys per mmHg of filtration pressure GFR = Filtration pressure x Kf Kf = 12.5 ml per minute Filtration pressure = 10mmHg GFR = 10 times 12.5 = 125 ml / minute / mmHg of filtration pressure Glomerular Filtration Rate (GFR) = quantity of glomerular filtrate formed each minute in all nephrons of both kidneys averages : 125 ml /minute 180 L /day Over 99 % of filtrate is reabsorbed in tubules & the remainder passes into urine

High rate of glomerular filtration is due to : 1. High capillary blood pressure -higher than any other capillaries in the body, dt special arrangement of the renal arteries system: renal artery afferent glomerular arteriole -short, wide - shorter & wider than efferent - arise directly from abdominal aorta arteriole leads to high pressure in afferent creates high glomerular capillary glomerular arteriole pressure cause filtration through capillary membrane 2. High glomerular filtration coefficient -depends upon Surface area of filtering membrane = 2 m2 Permeability of filtering membrane = high high GFR can be accounted for by high hydrostatic pressure forcing through a large membrane with high permeability.

Factors affecting Glomerular Filtration Rate (GFR) 1. Renal blood flow 2. Diameter of glomerular vessel - RBF, GFR - RBF, GFR Afferent arteriole BF, glomerular press, GFR BF, glomerular press, GFR Efferent arteriole glomerular press, GFR

dilatation

constriction

- mild constriction, GFR - moderate or severe constriction, glomerular flow rate, GFR

1. plasma will remain for a longer time in glomerulus large amounts of plasma will filter out 2. this increases plasma colloid osmotic pressure paradoxical decrease in GFR occurs despite the increase in glomerular pressure 3. Sympathetic stimulation 4. Arterial blood pressure causes constriction of afferent glomerular arterioles decreases renal BF & GFR *very strong stimulation glomerular flow & pressure greatly urinary output can fall to zero - autoregulation of GFR occurs between ABP 70 -160 mmHg prevent significant rise in glomerular pressure corresponding to rise in systemic BP - BP automatic afferent arteriolar constriction keep GFR constant *GFR only a few percent if in BP is not severe - BP afferent dilatation ( BF, GFR) - in renal pelvic pressure due to stone or tumour intracapsular pressure & GFR - pressure higher than 28 mmHg will stop filtration - colloid osmotic pressure of plasma proteins antagonizes filtration -hypoproteinaemia increases GFR permeability GFR and vice versa

5. Intrapelvic pressure 6. Colloid osmotic pressure 7. Permeability of glomerular capillaries

Permeability of glomerular capillaries & Bowmans capsule -absent for substance of MW > 70,000 plasma protein serum albumin MW 70,000 in diseased kidney - can pass through permeability increases, serum - but amount filtered is very small, albumin appear in urine in large therefore would be reabsorbed back in amount! renal tubules (normal urine is devoid of plasma protein) - cannot pass through will appear in urine in advanced case will never appear in urine -protected by being enclosed inside the - if hemolysis occurs, Hb will be set membrane of RB free will pass through the glomeruli *DANGEROUS! - in the renal tubule, the reaction is acidic Hb will be precipitated as acid haematin which blocks the renal tubules anuria death

serum globulin serum fibrinogen haemoglobin

165,000 200,000 68,00

THE CONCEPT OF PLASMA CLEARANCE Plasma clearance = the ability of the kidney to clean or clear the plasma of various substance Measured by measuring the volume of plasma cleared from this substance per minute rate of clearance of a substance from plasma = rate of excretion of this substance in urine
rate of clearance of a substance from plasma = concentration of substance in x volume of plasma cleared from this plasma (P) substance per minute (C)

rate of excretion of this substance in urine = concentration of substance in urine (U) x volume of urine per minute (V)

PxC=UxV P x plasma clearance of a substance (ml/min) = U x V plasma clearance of a substance (ml/min) = (U x V)/ P INULIN CLEARANCE - inulin is a polysaccharide having the following characters: has MW of 5200 freely filtered through the glomeruli NOT bound to plasma protein concentration in glomerular filtrate = concentration in the blood can be estimated chemically in plasma & urine with high degree of accuracy NOT toxic neither absorbed nor secreted by renal tubules amount of inulin filtered /min = amount of inulin excreted in urine
amount of inulin filtered/min = inulin concentration in filtrate (P) x vol. of glom filtrate/min(GFR)

CREATININE CLEARANCE (Ccr) - also used to determine GFR - some are normally secreted by PCT endogenous creatinine is frequently used to measure the GFR - the values agree quite well with the GFR measured by inulin
*even the value of urinary creatinine is high (dt tubular secretion), value of plasma creatinine is also high (dt non specific chromogen, present in the blood, attached to creatinine, cannot be separated from each other) high urinary creatinine is abolished
- Average PAH extraction ratio (ER) = 0.9 * Actual RPF = ERPF = 630 =700 ml/min ER 0.9 *from RPF, renal BF can be calculated; If hematocrit = 45%, RBF = RPF 1 = 700 x 1 = 1273ml/min (1-Ht) 0.9 *Filtration fraction = ratio of GFR to RPF (125/700) = 0.18%/20%

PARA-AMINO HIPPURIC ACID (PAH) CLEARANCE - renal plasma flow (RPF) is commonly measured by infusing PAH at low doses (<3mg/100ml) - PAH is cleared from plasma by filtration through glomeruli & secretion in the PCT its exctraction ratio ( arterial conc-venous conc/arterial concentration) is high - about 90% of PAH in arterial blood is removed in a single circulation, only 1/10 remains in venous plasma when the blood leaves the kidney
- effective RPF is obtained by dividing amount of PAH in urine by plasma PAH level ERPF indicates the plasma flowing through functioning nephrons, so cleared from PAH *the rest of plasma passes to areas that do not contain functioning nephrons (medulla, capsule, perirenal fat) PAH clearance = Effective Renal Plasma Flow UPAH x V = 630 ml/min PPAH - ERPF can be converted to actual renal plasma flow (RPF)

amount of inulin excreted/min = inulin concentration in urine (U) x volume of urine/min (V)

GFR = U x V P - inulin clearance = 125 ml/min used a measure for GFR behaviour of other substances is compared to it - clearance < inulin (GFR) = substance is reabsorbed - clearance > inulin (GFR) = substance is secreted

AUTOREGULATION Autoregulation of Glomerular Filtration Rate (GFR) mechanism of autoregulation is uncertain it is definitely intrinsic to the kidneys , since autoregulation can be demonstrated in transplanted, denervated kidneys 1. MYOGENIC HYPOTHESIS increase ABP causes stretch of smooth muscle of afferent glomerular arteriole this causes reflex constriction of afferent arteriole decrease ABP decreases stretch on afferent smooth mucsle leads to afferent dilatation
2. JUXTA-GLOMERULAR / TUBULO-GLOMERULAR HYPOTHESIS In hypotension (means BP decreases below 100mmHg till 70 mmHg ), 2 feedback mechanisms occur :

Autoregulation of Renal Blood Flow (RBF) RBF is constant between mean ABP 70-160 mmHg it is mainly an afferent arteriolar mechanism - if the mean ABP is , RBF GP GFR - the concentration of Na+ and Cl- ions at macula densa causes afferent arteriolar dilatation that RBF and GFR back to normal -however , if mean ABP is it RBF and GFR - the concentration of Na+ and Cl- ions at macula densa causes afferent constriction that decreases the GFR and RBF to normal * if ABP remains low for 10-20 minutes , RBF autoregulation disappears = regulation mechanisms are switched! - efferent arteriolar constriction mechanism becomes more potent RBF allows GFR to remain constant - marked decrease in RBF helps ABP to return back to normal

afferent arteriolar vasodilator feedback - ABP GFR slow passage of filtrate in tubules & over reabsorption of Na+ and Cl- ions in thick ascending limb in loop of Henle Na+ and Cl- at macula densa - ion concentration causes afferent dilatation rate of blood flow in glomerulus glomerular pressure GFR back to normal

efferent arteriolar vasoconstrictor feedback - too low GFR causes over reabsorption of Na+ and Cl- ions from filtrate Na+ and Clat macula densa - concentration of ions at macula causes JG cells to secrete renin from their granules formation of angiotensin II - angiotensin II constricts the efferent arterioles the glomerular pressure GFR to return back to normal * in case of ABP, GFR Na+ and Clconcentration in the macula densa causes afferent constriction subsequent in GFR the concentration of Na+ and Clentering the tubular lumen

Transport through renal tubules

PRIMARY PRIMARY ACTIVE REABSOPRTION (PCT) - depends on transport of substances by carrier proteins in cell membrane - give energy to substance to move it against electrochemical gradient - have an ATPase activity they cleave ATP to ADP or AMP and energy 1. Active reabsorption of sodium - basolateral surface of cell membrane contains extensive Na-K ATPase that cleaves ATP highly permeable to potassium -released energy transport : sodium ions out of the cell to interstitium (blood) potassium ions from interstitium to interior cell * K+ diffuses back into the interstitium (dt hi permeability) - Na+ transport out of cell its concentration & negativity inside cell to -70 millivolts Na+ diffuses from tubular lumen to inside of cell by electrochemical gradient, *but it needs a carrier to facilitate its diffusion through membrane by a process called facilitated diffusion PRIMARY ACTIVE SECRETION (late DCT and cortical CD) 1. Primary active secretion of potassium - basolateral border of principal cell of CT Na+ ions are pumped to interstitium by Na-K ATPase K+ ions are transported to interior of cell * luminal border is very permeable to K+ passes to lumen 2. Primary active secretion of hydrogen - intercalated cells or dark cells secretion of hydrogen ions by primary active secretion in the presence of H+-ATPase

SECONDARY SECONDARY ACTIVE REABSORPTION (Na Co-transporter) - glucose & amino acids are transported from tubular lumen through brush border by a process called sodium Co-transport - glucose or AA binds with same sodium carrier in brush border sodium diffuses inward through membrane and pulls glucose or amino acid along with it - inside the cell, sodium and glucose or AA split from carrier - glucose or AA diffuses through basal membrane of cell into peritubular capillaries by a carrier down their concentration gradient facilitated diffusion * glucose or AA diffuse from lumen to inside of cell by energy of diffusion of sodium against concentration gradient

SECONDARY ACTIVE SECRETION (PCT) Secondary active secretion of hydrogen ions - hydrogen ions combine with carrier proteins on cell membrane which transports Na+ to inside of cell hydrogen ions from cell to lumen of tubule *this is called Na-H counter-transport

Diffusion means free movement of substance by a concentration gradient as well as chemical, electrical or electrochemical gradient 1-Passive absorption of water by osmosis - when different solutes are transported out of the tubule their total concentration decreases inside the tubular lumen, but increases in the renal interstitium - the concentration difference cause osmosis of water in the same direction with the solutes * different portions of renal tubules have different permeabilities to water 2-Passive absorption by diffusion - when water is reabsorbed by osmosis, the urea in tubular fluid remains behind - urea concentration increases in lumen urea diffuses from lumen to interstitium *however ,permeability of membrane for urea in most parts of renal tubule is far less than that of water a large proportion of the urea remain in the tubules and is lost in urine (usually > 50 % of all that enters the glomerular filtrate) 3-Diffusion caused by electrical difference across tubular membrane Secondary ion reabsorption - negative ions tend to follow the positive sodium ions by electrostatic attraction - when active absorption of sodium takes place chloride ions are absorbed with it to keep electrical neutrality Passive secretion : Ammonia is synthesized inside the tubular cells and diffuses into the tubular lumen by a concentration gradient

Active transport 1. Reabsorption - primary Na+ - secondary AA & glucose (Na-Cotransporter) 2. Secretion - primary K+, H+ - secondary H+ (Na-H counter transport)

Passive transport 1. osmosis of water (65%) H+ secretion DCT, CT (intercalated) PCT 2. urea (50% reabsorption) H+ ATPase no specific ATPase 3. passive transport of Cl- & HCO34. passive secretion of ammonia

1ry active 2ry active

TUBULAR TRANSPORT MAXIMA Definition :The maximum amount of a substance in mg. which can be reabsorbed or secreted per minute * under normal condition, it remains constant for the individual Glucose tubular maximum (TmG) maximum amount of glucose reabsorbed in mg. per minute in the renal tubules / maximum capacity of tubular cells to reabsorb glucose measures the absorbing power of the renal tubules 1. increasing the plasma glucose concentration in steps 2. determining the amount of glucose excreted in urine the difference between the quantities of glucose filtered and those excreted represents = the amount reabsorbed by the tubules *the amount of glucose filtered per minute = concentration of glucose per ml plasma x GFR *the amount of glucose excreted in urine= concentration of glucose per ml urine x volume of urine per minute Para-amino hippuric acid tubular maximum (TmPAH)

definition measures determination

measures the secretory power of the renal tubules * if PAH is administered intravenously in small amount (to maintain a low concentration in blood) it is found that that blood leaving the kidney in renal vein contains 10% of PAH - the remaining 90% of PAH is removed from the renal blood in single circulation by filtration and secretion

- if PAH concentration in plasma is increased in steps the rate of tubular secretion increases until a maximum is reached & no more increase of secretion occurs denotes - within the physiological range of BG level (80-180 mg/100ml) all glucose filtered is that the tubules have a limit for secretory power reabsorbed by the tubules - at the threshold level (about 180mg%) glucose starts to be excreted in urine (renal threshold the amount of PAH secreted/min = (amount of PAH excreted/min) ( the amount of PAH of glucose) because the absorbing power of some tubules becomes saturated filtered/min) - with gradual increase of BG level, more renal tubules become saturated until all the tubules TmPAH=75mg/min become saturated and no increase in glucose absorption occurs * excess glucose filteres is excreted in urine because the tubules reach their maximum absorbing capacity which is about - 375mg/min for men - 300mg/min for women

PROXIMAL CONVOLUTED TUBULES

LOOP OF HENLE THIN DESCENDING THIN ASCENDING THICK ASCENDING

DISTAL CONVOLUTED TUBULE

COLLECTING DUCT

Reabsorption of about 65% of the GF: 1. 1ry active reabsorption of 65 % of Na

+

1. active reabsorption of 8-10% of filtered Na+ 2. active secretion of K+ and H+ controlled by aldosterone 3. reabsorption of up to 15% of filtered water [FACULTATIVE WATER REABSOPRTION] under effect of ADH 4. Reabsorption of urea facilitated by ADH *other parts of tubular epithelium is IMpermeable to urea

2. 2ry active reabsorption of glucose & AA [ Na-Co transport] 3. 2ry active reabsorption of 65% of K+ 4. 2y active reabsorption of phosphate under the control of PTH (inhibition) 5. reabsorption of 65% of water [OBLIGATORY WATER REABSOPRTION] * wall is freely permeable to water not under the control of ADH 6. passive reabsorption of Cl- and HCO3 Secretion of 1. 2ry active secretion of H+ [Na-H counter transport] 2. secretion of diodrast , PAH, and penicillin 1-Reabsorption of 15-20 % of filtered water 2-Reabsorption of 25 % of filtered Na+ 3-Reabsorption of 25 % of filtered K+ 4- Reabsorption of chloride 5-Has an important role in concentration and dilution of urine - permeability to water - permeability to solutes *osmolality of tubular fluid - IMpermeable to water - permeability to sodium & chloride [passive diffusion] 1. active reabsorption of sodium 2. 2ry active reabsorption of chloride & potassium [Na-Co transport] *osmolality of tubular fluid (hypotonic)

osmolality Definition: measure of total concentration of discrete solute particles in solution Posm = Osmolality of electrolytes + osmolality of glucose + osmolality of urea Osmolality of electrolytes = osmolality of NaCl Na+ and Cl- dissociate Na+ ions in ECF=140mEqL per litre=140mosm per litre Cl- concentration are also140 mEq per litre =140mosm per litre Osmolarity of Nacl =280 mosm per litre Glucose and urea will add 20 m0sm to it so Posm= 300mosm per litre Normal osmolality of ECF and ICF is about 300 milliosmoles per Kg water DILUTING MECHANISM OF THE KIDNEY In case of haemodilution, plasma osmolality decreases and this decreases ADH and absorption of solutes takes place at : thick portion of the loop of Henle & first segment of the DCT (diluting segment) late DCT and CD - active reabsorption of sodium ions - secondary active absorption of chloride and potassium ions osmolality of the fluid in the ascending limb decreases to about 100 milliosmoles per Kg water

- active absorption of sodium - passive absorption of chlorides *IMpermeable to water in the absence of ADH! (facultative)

osmolality decreases to 70-65 mosm /Kg water

Concentrating mechanism of the kidney In case of inadequate water supply or excess intake of electrolytes (hemoconcentration) the kidney excretes concentrated urine (excess solutes are excreted with little loss of water) Kidneys have developed a special mechanism for concentrating urine, called the counter current mechanism of the kidney It depends on the special anatomical arrangement of the loops of Henle and the vasa recta in juxtamedullary nephrons in which the loop of Henle dip in the medulla loops are parallel to vasa recta counter-current mechanism = a system in which INFLOW runs (1)PARALLEL, (2)COUNTER TO & (3) ADJACENT to the OUTFLOW 1. the first step in the concentration of urine is to create the hyperosmolality of the medullary interstitial fluid (IF) 4 different solute-concentrating mechanisms are responsible for this osmolality : thick ascending limb of loop of Henle * principal cause thin ascending limb of loop of Henle - active reabsorption of sodium ions increases osmolality of outer medulla interstitial fluid - secondary active reabsorption of chloride and potassium - passive reabsorption of sodium and chloride ions *depends on prior existence of medullary gradient to reabsorb water from thin descending limb
thereby increasing the concentration of sodium & chloride ions in the tubular fluid delivered to thin ascending limb

inner medullary part of the collecting ducts collecting duct

reabsorption of urea (helped by ADH) increases the inner medullary interstitial fluid osmolality - active reabsorption of sodium - electrogenic passive absorption of chloride the net result of these mechanisms = increase in the osmolality of medullary interstitial fluid to 1200-1300 mosm/Kg water in the pelvic tip of medulla The combination of these mechanisms is called counter-current multiplier mechanism because it multiplies the osmolality of the renal medullary interstial fluid *In haemoconcentration, Concentration of ADH & act on epithelium of late DCT and CD its permeability to water water is reabsorbed into the highly concentrated medulla

2 characteristics of medullary blood flow for maintaining the high solute concentration in the medullary IF

1. medullary blood flow is very small in quantity (about only 1-2% of total BF to the kidney) because of the small and sluggish blood flow, removal of solutesis minimized 2. vasa recta functions as counter current exchanger (prevents washout of solutes from the medulla) * walls of the vasa recta are highly permeable to NaCl and water

1. as blood flows down the descending limb of the vasa blood osmolality is slightly lower than the recta ( which is parallel to the ascending limb of the tubule) osmolality of medullary IF 2. at the tip of vasa recta, the blood osmolality increases to 1200 mosm/Kg water 3. as blood flows up back to the ascending limb blood osmolality is slightly higher than the osmolality of medullary IF

Na, Cl & urea diffuse out from the IF into blood water diffuses out of blood into IF

Na, Cl & urea diffuse back out of the blood into IF water diffuses back into the blood Net result blood of the vasa recta removes a little amount of solutes can maintain high solute concentration in medullary IF

Operation of vasa recta as counter current exchangers in the kidney 1. NaCl & urea diffuse out of ascending limb of vessel into the descending 2. water diffuses out of descending and into the ascending limb of vascular loop (vasa recta)