kidney (Q &A)

Q. Describe the functional characteristics of nephronNephron is the functional unit of the kidney, composed of:

a) Renal corpuscle It is formed of Glomerulus (Tuft of capillaries) which lies within the dilated blind end of renal tubule (Bowman’s capsule). These capillaries lies between afferent arteriole and a smaller efferent arteriole►Glomerulus is a high pressure capillary bed (60 mmHg) .

b) Renal tubuleThe total length of renal tubule is 45-65mm

1) Proximal convoluted tubule (PCT)- lies in the cortex.- It coils and twists in the neighborhood of its renal corpuscle.- It is made up of single layer of cells.

2) Loop of Henle- U shaped that dips in the renal medulla.- It is composed of:a) Thin segment i.e. descending limb and lower ½ of ascending limb.It is lined by flat epithelium.b) Thick segmenti.e. rest of ascending limb (lined by cuboid epithelium and contain many mitochondria.3) Distal convoluted tubule DCT- 5 mm long that lies in the cortex.- It opens into the cortical collecting tubule. 4) Collecting ducts - 20 mm that passes through cortex and medulla.

Q. Describe the location and structure of the juxtaglomerular apparatus.Area of contact between the distal convoluted tubule and the afferent arteriole of the same nephron.Present in cortical nephrons only.It consists of;

(1) Macula densa ; (intra-renal chemoreceptors)modified tubular cells in 1st part of DCT secrete a substance directed towards arteriole. Macula densa cells detect changes in volume of Na delivered to the distal tubules.(2) Juxta glomerular cells ; (intra-renal baroreceptors)Granular cellsModified smooth muscle fibres in the wall of afferent arteriole Secrete renin.

Function; - Auto-regulation of renal blood flow and glomerular filtration during changes in ABP.- Regulation of blood pressure and sodium balance.

Q. Compare between different Types of nephrons Items Cortical nephrons Juxtamedullary nephrons

1

kidney (Q &A)

% Of total 85 % 15%

Glomeruli Out part of cortex Inner part of cortex Loop of Hnle Short i.e. dips to the junction between

inner and outer medulla.It has no thin ascending limb. The thin descending limb joins the thick ascending limb at the hairpin loop.

Long i.e. dips deeply into the medullary pyramids to the inner

medulla.The ascending limb is formed of

a thin part and a thick part.Blood supply Peritubular capillaries

No Vasa RectaVasa recta and peritubular

capillariesSpecial function Na reabsorption Urine concentrationAfferent arteriole Thick muscular wall

Very sensitive to symp Stimulation.Have JG apparatus

Exhibit autoregulationLow resistance to blood flow at rest

Thin muscular wallLess sensitive to symp

Stimulation.Have no JG apparatusDo not exhibit autoreg

High resistance to blood flow at rest

Efferent arteriole Thin muscular wallLess sensitive to symp

Stimulation & vasopressin.

Thick muscular wallVery sensitive to symp

Stimulation & vasopressin.Tone decreased by

Prostaglandins (PGs).JG apparatus Present AbsentAutoregulation Present Absent

The efferent vessels of juxtamedullary glomeruli form long looped vessels, called Vasa recta which is important for urine concentration.

Q. Describe Blood supply of the kidneyKidneys receive 20-25% of cardiac output i.e. 1.2-1.3 litre / min. (1200ml/min).90% to the cortex, 9% in outer medulla & 1% in inner medulla.Renal vascular arrangement:

2

kidney (Q &A)

Each renal artery divides to form the interlobar arteries, arcuate arteries (100mmHg) and interlobular arteries afferent arterioles glomerular capillaries (60mmHg) efferent arterioles peritubular capillaries (13 mmHg) (also vasa recta) interlobular veins arcuate veins (5-8mmHg) interlobar veins renal veins.

Glomerular capillary bed

Peritubular capillary bed

1. Receives bl from afferent art. Receives bl from efferent art.2. High presure bed 60 mmHg Low pressure bed 13 mmHg3.Represents arterial end of cap. Represents venous end of cap.4. allows fluid filtration. Allows fluid reabsorption & specialized for O2

supply.►Portal system (capillary beds in series), paralleling the nephron

Renal ==> afferent ==> glomerular ==> efferent ==> peritubular arteries ==> arterioles ==> capillaries ==> arterioles ==> capillaries.

Q. Enumerate Characteristics of renal circulation 1- Very rich, high flow circulation (25% of cardiac output).2- It is a portal circulation i.e. blood flows through 2 sets of capillaries (the glomerular and peritubular capillaries( before it drained by veins. The renal circulation is the only circulation where there are capillaries which are drained by arterioles (glomerular capillaries drain in efferent arterioles).3- High permeability of glomerular capillaries.4- High pressure in glomerular capillaries (glomerular capillary pressure is 50-60 mmHg, in other parts of the body is average 25mmHg) facilitates filtration of plasma.5- Pressure in peritubular capillaries is relatively low which favors reabsorption of solutes and fluids from renal tubular lumen to capillaries.6- High degree of autoregulation.

Q. Mention the effect of Sympathetic stimulation to the kidneyVasoconstriction of afferent & efferent arterioles via receptors.Renin secretion from juxtaglomerular apparatus.Increased Na+ reabsorption of renal tubules.

3

kidney (Q &A)

Q. Discuss how renal blood flow is regulatedKidneys receive 20-25% of cardiac output i.e. 1.2-1.3 litre/min.So renal plasma flow (RPF) about 625 ml/min.90% to the cortex, 9% in outer medulla & 1% in inner medulla.Low medullary blood flow is due to high resistance offered by vasa recta and is important for urine concentration.

A) Autoregulation of the renal blood flow@ DEF; RBF is kept relatively constant between ABP; 80-180 mmHg, It is present in denervated, isolated kidney, This proving that this property is intrinsic property.- Beyond blood pressure range 80 – 180 mmHg, there is no autoregulation.

@ mechanism; by changing the renal vascular resistance.a. Myogenic mechanism- Increased ABP stretch of afferent arteriole increased Ca influx from extracellular fluid into muscle fibre direct vasoconstriction prevent increase in RBF.- Smooth muscles in the wall of afferent arteriole relax when blood pressure decreases leading to vasodilatation causing increase in blood flow and increase in GFR back to normal.

b. Tubuloglomerular feedback- Macula densa in the juxtaglomerular apparatus → release of vasoactive chemicals (in case of increase in blood pressure) → afferent arteriolar vasoconstriction → decrease in RBF & GFR or vasodilator substance leading to afferent arteriolar vasodilatation (in case of decrease in blood pressure) → increase in RBF & GFR.

2-Extrinsic regulation:A- Hormonal regulation: - adrenaline and noradrenaline cause constriction of renal vessels leading to a decrease in RBF.- angiotensin II in high levels constrict both afferents and efferents leading to a decrease in RBF.- prostaglandins may be vasodilators or vasoconstrictors.B- Extrinsic sympathetic nervous control: constricts renal vessels leading to decrease in RBF and decrease in glomerular filtration rate (GFR).

4

kidney (Q &A)

Q. Describe how to measure renal blood flowBy PAH clearance

►The substance used is PAH (paraminohippuric acid) because- If is freely filtered by the glomerulus.- It is completely secreted from the peritubular capillaries into the tubular lumen in single

circulation.►Measurement of the effective renal plasma flow ERPF.The extraction ratio of PAH is 90% i.e. only 90% of PAH in renal arterial blood is removed in a single circulation. This is because only 90% of ARPF go to the nephronsActual RPF = ERPF.x 100/90. ►Measurement of the actual (total) renal blood flow RBF Knowing the haematocrite value ( HV).

RBF = RPF / 1 – HV = about 1200 mL/min

Q. List processes needed for Formation Of Urine1) Glomerular filtration: into Bowman’s capsule.2) Tubular reabsorption : from lumen to peritubular capillaries.3) Tubular secretion : from peritubular capillaries to lumen.

Q. What are the characters of glomerular filtrationa- Contents: - water- ions: Na+, K+, Cl-- freely filtered substances e.g. glucose, amino acids.- 0.03% albumin (molecular weight 6900).b- Osmolality: 300 mosmol/L, isotonic (same osmolality as plasma).C- Specific gravity: 1010Glomerular filtration rate (GFR) In an average man: 125 ml/minute. In women : 10% less. Tends to decrease with advanced age (60% less at 70 years). High renal blood flow (20-25% of cardiac output) needed for high GFR.

5

kidney (Q &A)

GFR equals about 180 L/day so plasma volume (3L) filtered about 60 times daily, this important to excrete large amount of waste products. More than 99% of GFR is normally reabsorbed.

Q. Define Filtration fraction It is the fraction of the renal plasma flow (RPF) that becomes glomerular filtrate. the average filtration fraction about 16-20%. It is calculated as (GFR/RPF X100).

Q. Mention different layers of Glomerular membran (1)Capillary endothelium ; It has small holes (70-90 nm). It does not act as a barrier against plasma protein filtration. (2)Basement membrane ; (BM)filamentous layer attached to glomerular endothelium & podocytes, carry strong-ve charges which prevent the filtration of plasma proteins, but filters large amount of H2O and solutes.(3)Podocytes ; Epithelial cells that line the outer surface of the glomeruli. They have numerous foot processes that attach to the BM, forming filtration slits (25 nm wide).

There are stellate cells called mesangial cells between basal lamina and endothelium. They are contractile cells and play a role in glomerular filtration.

Q. List different Forces (mechanism) that control GFR Forces favoring Filtration: 2Hydrostatic pressure in glomerular capillary = 60 mmHg.Colloidal smotic pressure of proteins in the filtrate = 0 mmHg.Forces opposing Filtration: 2Hydrostatic pressure in Bowman’s capsule= 18 mmHgColloidal osmotic pressure of proteins in glomerular capill= 32 mmHgThe net filtering pressure

60 - 50 = 10 mmHg.

Q. Define Filtration coefficient (Kf)It is the GFR / mmHg of net filtration pressure, it is normally 12.5ml/min/mmHg. It is constant (normally).* Glomerular filtration rate =Net filtration pressure X Filtration coefficientGFR = NFP (l0) X Kf (12.5) = 125ml/min.-Kf is determined by 2 factors:1- The permeability of the capillary bed.2- The surface area of the capillary bed.Kf = permeability of membrane X effective filtration surface area (of both kidneys).

Q. Compare the composition of glomerular filtrate with that of the blood plasma.The glomerular filtrate has about the same composition as what becomes tissue fluid elsewhere in the body.In other words, glomerular filtrate is mostly water and contains essentially the same substances as blood plasma, except for the larger protein molecules.

6

kidney (Q &A)

Q. Mention different Factors that affect GFR (1) Changes in glomerular hydrostatic pressure. (I) Diameter of the afferent arterioles.

a. VD of afferent arterioles Increased Hydrostatic pressure in glomerular capillary Increase GFR.b. VC of afferent arterioles e.g Increased sympathetic activity Decreased Hydrostatic pressure in glomerular capillary Decreased GFR.

(II) Diameter of the efferent arterioles;1. Moderate VC increase glomerular capillary hydrostatic pressure Slight increase of GFR.2. Severe VC decrease RBF decrease GFR.

(III) ABP; Between 70 & 170 mmHg: GFR and RBF are kept relatively constant by autoregulatory mechanisms.

(2) Changes in Bowman’s Capsule hydrostatic pressureIncreased Hydrostatic pressure in Bowman’s capsule e.g. stone in ureter Decrease GFR.

(3) Change in glomerular colloidal osmotic pressure Increased Colloidal osmotic pressure in glomerular capillary e.g in dehydration decreased GFR. Decreased Colloidal osmotic pressure in glomerular capillary e.g in hypoproteinemia increased GFR.

(4) Renal vasodilators - Prostaglandins synthesis in kidneys is increased by haemorrhage (due to sympathetic stimulation and Increased angiotensin II). This may protect the renal vessels from severe VC.

(5) Functioning kidney mass: When the number of functioning nephrons decreases e.g. in renal disease (failure), there is reduction of filtration coefficient (kf) & decrease in GFR (decreasing the filtering surface area).

(6) Changes in filtering surface area : This is changed by contraction or relaxation of mesangial cells.They are contracted by vasopressin (ADH), adrenaline, angiotensin II, prostaglandin F2 and sympathetic stimulation.They are relaxed by prostaglandin E2, dopamine, cAMP and ANP.Contraction of mesangial cells → decrease surface area available for filtration → decrease in K f

& decrease in GFR and vice versa.

(7) Changes in the permeability of glomerular membrane : GFR is directly proportional to the permeability of glomerular membrane e.g. hypoxia, fevers, some renal diseases increases this permeability.

List five conditions in which GFR decreases.1- glomerular hydrostatic pressure is reduced (i.e. hypotensive shock)2-Bowman's space hydrostatic pressure are increase ureteric obstruction.3- plasma oncotic pressure rises to unusually high levels in dehydration. 4- decreased rates of renal blood and plasma flow (e.g. heart failure).5- Reduced permeability and / or total filtering surface area.

Q. How GFR is evaluated

7

kidney (Q &A)

A) Clearance tests: (1) Inulin clearance; Inulin has the following characteristics:

Freely filtered i.e. plasma conc.= filtrate concentration. not reabsorbed or secreted by renal tubules i.e. amount filtered per min.= amount excreted in urine/min. Not metabolized. Not stored in the kidney. Does not affect filtration rate & its conc. is easily measured.

(2) Creatinine clearance Freely filtered Not reabsorbed partially secreted by renal tubules. Endogenous so used easily but inaccurate.

B) Blood tests:

Blood levels of urea and creatinine elevated in severe decrease in GFR.

Q. Discuss Renal Plasma Clearance►DefinitionIt is the volume of plasma that is completely cleared of the amount of substance excreted in urine per minute.►Calculation

Amount cleared from plasma/min= amount excreted in urine /min.C X P = U X V

C= volume of plasma cleared from substance/min.P= conc. of the substance per 1 ml plasma.U= conc. of the substance per 1 ml urineV= volume of urine per minute.

►Importance of the determination of plasma clearanceStudy of tubular handling of different solute in the filtrate

Reabsorbed (glucose, urea, H2O.), Secreted (creatinine, PAH).1-Inulin:

Freely filtered in glomeruli, not reabsorbed and not secreted. All the amount given is completely filtered and completely excreted in urine i.e. the amount of plasma filtered / minute is completely cleared from inulin.

So, CIN = GFR = 125 ml. / min.

2-Urea clearance: Urea is freely filtered, partially reabsorbed and no secretion. So, urea clearance is less than GFR

(the amount of urea excreted in urine is less than that filtered). Curea = 70 ml / min.

3-Glucose: It is freely filtered and completely reabsorbed and no secretion. i.e. all filtered glucose returns back

8

C = U X V

kidney (Q &A)

to plasma and no glucose is excreted. C glucose = Zero / min.

4-Para-aminohippuric acid (PAH) clearance: (Exogenous). It is freely filterable, almost complete secretion in one single circulation (90%) with no absorption.

So, it is used for measurement of RBF. Why? a- It is not metabolized and not stored nor produced by the kidney.

b- It does no affect RBF. c- Its level can be measured easily.

d- 90% is removed from the blood in a single circulation. CPAH = Effective RPF (625 ml/ min.)

-The actual renal plasma flow = 700 ml / min. (90% only filtered in single circulation).By knowing the hematocrit value, RBF can be calculated = 1270

-Diodrast is also handled in the same manner as PAHA so can be used to measure effective renal plasma flow (ERPF).

5- Creatinine clearance: - Mode of handling: complete filtration, partial secretion, no reabsorption. So, creatinine

clearance is more than GFR = 140 ml/min. - It is an endogenous substance coming from creatine metabolism in skeletal muscles. It is

released into blood at relatively constant rate.- It can be used clinically for measuring GFR, it is easier but it is inaccurate.

Q. Describe how substances transported along the renal tubulesTypes of transport across the tubular epithelium 1) Transcellular: through cells.2) Paracellular: through the tight junctions between the cells.

Mechanism of tubular transport A) Active transport; against electrochemical gradient.

(1) Primary active transportRequires energy directly from ATP.ATPase is a component of a carrier (transporter).►Primary active transporter include- Na+ - K+ ATPase for Na+ reabsorption in PCT.

(2) Secondary active transport- It does not require energy directly from ATP.

a) Co-transport Two substances bind to a specific carrier are cotransported in one direction. e.g. secondary active transport of glucose.

b) Counter-transport Two substances bind to a specific carrier are transported in two directions e.g. secondary active secretion of Hydrogen.

B) Passive transport: Down electrochemical gradient.i. Simple diffusion: Transport of substance is down electrochemical gradient e.g. lipid soluble substances.ii. Facilitated diffusion: Transport of substance is down electrochemical gradient and requires a carrier e.g. non- lipid soluble substances.

Q. List different Characteristic features of PCT - PCT is about 15 mm long and 55 μm in diameter.

9

kidney (Q &A)

- PCT wall is lined by single layer of epithelial cells that are connected by tight junctions at their luminal edges, but there is a space between the cells along the rest of their lateral borders (lateral intercellular spaces) which contains interstitial fluid.- The luminal borders of cells have brush border due to presence of large number of microvilli which increase surface area for reabsorption.- The PCT cells have large numbers of mitochondria (energy supply).

Q. Discuss functions of PCT(1) Reabsorption

65 % of filtered Na+ (active), Cl- and water are reabsorbed (passive). The rate of PCT reabsorption of Na+ and water depends directly on GFR. This is called

glomerulotubular balance. 80 % of filtered K+ is actively reabsorbed. About 80 to 90 % of HCO3

- is reabsorbed actively. Reabsorption of 60 % of filtered Ca+2 and 80 % of filtered phosphate.

(parathyroid hormone inhibits phosphate reabsorption). About 50% of the filtered urea is reabsorbed passively because walls are partially permeable

to urea. This is called back diffusion of urea. Glucose, amino acids and trace of proteins are completely reabsorbed by active processes.

(secondary active).

Na reabsorption 65% is reabsorbed by primary active transport.

►At the basolateral border of tubular epitheliumNa+ - K+ ATPase pumpExtrude 3 Na+ ions into the interstitium in exchange with 2 K+ ions that are pumped into the cell.This decreases intracellular Na+ concentration and creates -ve potential.

►At the luminal borderNa+ diffuses from the lumen to the cell passively.

Glucose reabsorption-Complete reabsorption

Site & Mechanism-Site; early portion of the proximal convoluted tubules.-Secondary active reabsorption i.e cotransport with Na.-Cotransport with Na : The glucose and Na bind to a common carrier (called SGLT2) (sodium-dependent glucose transporter). As Na moves down its

10

kidney (Q &A)

electrochemical gradient, glucose is carried into the cells.-This transport is Na+ dependent.-Glucose is transported from cell to interstitial fluid by facilitated diffusion utilizing a carrier called GLUT2 (glucose transporter).Renal threshold for glucose

plasma level at which glucose first appears in urine (180 mg/dl).Tubular maximum for glucose (TmG) The maximum amount of glucose (in mg ) that can be reabsorbed per min.It equals the sum of TmG of all nephrons.TmG not the same in all nephronsIt is an indication of the reabsorptive capacity of the kidney.It is determined by the number of glucose carriers in PCT.The maximum reabsorption rate is reached when all the carriers are fully saturated so they can not handle any additional amounts at that time.Value; 300 mg/min in ♀ , 375 mg/ min in ♂.

GlucosuriaExcretion of glucose in urine in considerable amounts.

►Causes; 1. Diabetes mellitus: blood glucose level > renal threshold.2. Renal glucosuria: It is caused by the defect in the glucose transport mechanism.3. Phlorhizin: A plant glucoside which competes with glucose for the

carrier and results in glucosuria (phloridzin diabetes).4. Pregnancy:due to altered glucose handling in distal nephrons.

Phosphate reabsorptionPhosphate is reabsorbed mainly in PCT (80%), Secondary active transport with Na.PTH inhibit PO4 reabsorption.

Bicarbonate HandlingPlasma HCO3

- plays an important role in the regulation of pH of plasma.

Amino acids and protein reabsorption- Amino-acids are transported by secondary active transport using the same carrier of Na (there are many carriers ,one specific for acidic, other for basic and another for neutral amino acids).- Proteins are transported in the PCT by the process of pinocytosis.

11

kidney (Q &A)

- Proteins in the filtrate about (5mg%).

H2O reabsorption - 65 - 67% of filtered load reabsorbed, Following Na by osmosis.- Sodium absorption → passive water absorption in the proximal tubule (Obligatory reabsorption), this is because:a- The walls of the proximal tubule are highly permeable to water.b- As the solutes are reabsorbed, an osmotic gradient for water is created and water follows the solute. - Since, almost equal amounts of Na & H2O (65 - 67%) of each reabsorbed in proximal CT. The absorbed fluid is iso-osmotic with tubular fuid and Na+ conc. The fluid at the end of proximal tubule → iso-osmotic.

(2) Secretion in the Proximal Convoluted Tubulea- Substances from the blood: e.g. PAH, creatinine (active secretion), drugs.b- Substances formed inside PCT cells: e.g H+ (active), ammonia (passive).

Secretion of H + in PCT This is formed in the tubular cell from dissociation of H2CO3 to H+& HCO3

- then is secreted at the luminal border of the cells by 2 ry active transport in exchange with Na+ reabsorption utilizing an antiport carrier.

Synthesis & secretion of ammonia in PCTThe PCT cells synthesize ammonia (NH3) from glutamine. NH3 & H+ are secreted, combine at the luminal border to form ammonium ion (NH4

+) which excreted in urine in the form of ammonium chloride, sulfate or phosphate.

Q. Describe the mechanisms of glucose reabsorption and explain the meanings of the terms transport maximum and renal plasma threshold.

Q. Describe the permeability characters of Loop Of HenleThe LH constitutes a counter-current system (a system in which the inflow runs parallel, in the opposite direction and close to the outflow).

The LH of the cortical nephrons (conservation of Na + & water ). The LH of juxtamedullary nephrons (urine concentration).

The main function of LH is to create an osmotic gradient in the renal medullary interstitium (in juxta-medullary nephrons).

Descending thin segment-Highly permeable to H2O and reabsorbed 15-20% of filtered H2O.-This is obligatory reabsorption i.e. not controlled by hormones.-The fluid reaching the tip of the loop is hypertonic and reaches equilibrium with medullary interstitium 1200-1400 mosm.

12

kidney (Q &A)

Thin ascending limb of LH Small amount NaCl reabsorbed passively into the medullary interstitium.

Thick ascending limb- 25% - 30% of Na + reabsorbed.- K+ and CL are cotransported at luminal border depending on Na+- K+ pump at basolateral border.- This part is impermeable to water and urea. So the tubular fluid becomes hypotonic 100 mosm.- The 1 Na+, 1 K+ and 2 Cl- co-transporter in the luminal membrane act using the energy released by diffusion of sodium down an electrochemical gradient into the cells. There is a slight backleak of potassium ions into the lumen, creating a positive charge (about +8 millivolts) in the tubular lumen.

- The positive charge (+8 mV) of the tubular lumen relative to the interstitial fluid forces, so cations such as Mg+2 and Ca+2 diffuse from the lumen to the interstitial fluid via the paracellular pathway.

Q. Discuss function of Distal convoluted tubule & cortical CD

ReabsorptionActive reabsorption of Na ; followed by passive chloride & bicarbonate reabsorption, in exchange with H or K+ secretion, under the control of aldosterone.Water reabsorption - Only 5% of filtered water is absorbed by DCT & about 15 % in CD.- The water permeability in DT is low, so little water is absorbed.- ADH increases the permeability of DT & CD to water, so water passes passively down the osmotic gradient in the hypertonic medullary interstitium.

Reabsorption of water in DT & CD is called Facultative water reabsorption but in the proximal tubules is called

Obligatory water reabsorption (65 %).Chloride reabsorption

Passive (down electric gradient) and by secondary active transport with Na.Reabsorption of Ca

By primary active transport (increased by parathyroid hormone).

Secretion

Synthesis of NH 3

increases in cases of acidosis. It combines with H+ and forms ammonium salts.H + Secretion H+ is secreted by 1ry active transport.Potassium (K + ) secretion It is actively secreted in DT & CD.K+ secretion is coupled to Na+ reabsorption, K+ secretion is regulated by aldosterone hormone.

Q. List The characteristics of the late DT and cortical CD1. They are almost completely impermeable to urea.2. They reabsorb sodium ions and Cl- follows passively.3. They actively secrete potassium ions.4. The intercalated cells of these nephron segments secrete hydrogen ions by primary active transport. Both hydrogen and potassium compete for secretion.

13

kidney (Q &A)

The rate of sodium reabsorption and active secretion of potassium and hydrogen is controlled by aldosterone.

5. The permeability of the late distal tubule and cortical collecting duct to water is controlled by the concentration of ADH.

Q. What is the function the inner medullaryCD.1) Urea reabsorption ++ osmolarity of medullary interstitium, which is essential in renal ability to excrete concentrated urine.2) H2O reabsorption ADH causes opening of H2O channeles.

Q. List The major Hormones that affect the renal tubules of the kidney

1- Antidiuretic hormoneIt increases the water permeability of the collecting ducts of the kidney

2- AldosteroneIt stimulates sodium reabsorption in exchange with K or H by the late

distal tubules and collecting ducts.3- Parathyroid hormone

It increases distal renal tubular calcium reabsorption.It reduces the proximal tubular reabsorption of phosphate.

The final composition of urine determined at the level of distal nephron (DCT & CD).

Q. Describe Regulation of tubular reabsorption(1) Glomerulo tubular balance 

►Definition; ++ GFR ++ reabsorption of solutes and, in turn, H2O.►Site; PCT (main site) and loop of Henle.►It is prominent for Na, the renal tubules reabsorb a constant percentageof the filtered Na rather than a constant amount.►mechanism:++ GFR ++ colloidal osmotic pressure in the peritubular capillaries ++ reabsorption of solutes and, in turn, H2O.

(2) Transtubular Physical factors.Reabsorption by the peritubular capillaries

1- Forces that favour reabsorption a) The colloidal osmotic pressure of peritubular capill = 32 mmHg.b) The hydrostatic pressure in renal interstitium = 6 mmHg.2- Force that oppose reabsorptionc) The hydrostatic pressure inside peritubular capill.= 13 mmHg.d) The colloidal osmotic pressure of renal interstilium = 15 mmHgNet reabsorptive force = (32 + 6) – (13 + 15) = 10 mmHg.

(3) Hormonal control; A) Mineralocorticoids e.g Aldosterone. They act on DCT to increase Nareabsorption in exchange with K+ or H+.B) Angiotensin II : most powerful Na+ retaining hormone by direct actionof PCT and via aldosterone.D) ADH; increase H2O reabsorption in DCT and CD.

14

kidney (Q &A)

E) Atrial natriuretic peptide (ANP): inhibiting Na+ reabsorption in distal tubules.

(4) ABP; decrease Na+ excretion via- Inhibition of rennin angiotensin system → ↓ renin and angiotensin II production.- ↑ Hydrostatic pressure in peritubular capillaries which → increase Na+ & H2O excretion.

Q. Describe how the kidney concentrate Urine Renal mechanisms for excreting concentrated urine:(1) High ADH level(2) Hyper-osmotic gradient of renal medulla.Mechanisms that produce hyperosmotic gradient include:(1)The counter current multiplier system.(2)The counter current exchanger system of the vasa recta.(3)Diffusion of large amount of urea from the medullary collecting ducts into medullary interstitium.(4)Sluggish medullary flow 1 - 2 % of RBF, this minimizes solute loss from the medullary interstitium.

Counter Current Multiplier ►Descending limbVery permeable to H2O.Much less permeable to NaCL and urea.Therefore, the tubular osmolarity gradually rises from 300 to 1200 mOsm/L at the tip of the loop due to:

a. Osmosis of H2O out of the descending limb.b. Diffusion of NaCL from the medullary interstitium into the descending limb.

Result; The interstitium fluid makes osmotic equilibration with the descending limb being H2O permeable. Thus the interstitial fluid forms a hyperosmotic gradient starting from 300 mOsm/L at superficial layers of medulla and reaches 1200 mOsm/L at deep layers of the medulla.

►Ascending limb

a) Thick segment It is absolutely impermeable to H2O, but Na +, K+ and Cl- are cotransported

Actively into the renal medulla.b) Thin segment

NaCL is passively reabsorbed into the medullary interstitium Result; The tubular fluid becomes hypotonic 100 mosm as it enters the distal tubule.

15

kidney (Q &A)

Counter Current exchanger (Vasa recta)► In the descending limb of the vasa recta

a)Solutes diffuse from the medullary interstitium to the blood along concentration gradient.b)Water diffuses from the blood to the medullary interstitium.

Result: At the tip of vasa recta, blood osmolality = 1200 mOsm/L. ► In the ascending limb of the vasa recta

a) Most of solutes diffuse back to the medullary interstitiumb) Water diffuses from the interstitium to the blood

► Functions of vasa recta; maintain hyperosmotic gradient via:1- Trapping solutes (NaCL and urea) in the renal medulla.2- Removal of water reabsorbed from interstitium back to the blood.

Role of urea @ Urea contributes 50% of the medullary osmolality i.e. 500 mOsm/L .@ Thus plays an important role in the process of urine concentration:- A high protein diet increases the ability to concentrate the urine.- Protein deficiency impairs the ability to concentrate the urine.

MechanismIn the Inner medullary portion of the collecting duct - Urea diffuses from inner medullary CD into the medullary interstitium to increase its osmolality this leading to more water reabsorption from collecting duct leading to more urine concentration.- Diffusion of urea is facilitated by ADH. NB. Cortical CD not permeable to urea.Role of ADH

(a) Collecting tubule:- ADH increase their permeability to H2O reabsorption of H2O.- Diffusion of urea is facilitated by ADH.- Urea diffuses into the medullary interstitium to increase its osmolality (b) ADH slows the flow in vasa recta:by acting on the efferent arterioles of the juxtamedullary nephrons. This increases the medullary osmolality by decreasing washout of the medullary solutes.

16

kidney (Q &A)

(c) ADH increase efferent arteriolar resistance: of the juxtamedullary nephrons so increases their filtration, this leading to more removal of sodium from the lumen of ascending limb to the surrounding interstitial fluid, further, raises the concentration of sodium ions in the medullary interstitium.

Q. What is Urea & NaCl cycles in the renal tubules

1- NaCl cycles: NaCl is transported from ascending limb of both LH & vasa recta to the interstitium. It then passively diffuses into the descending limb of vasa recta (and may be also slightly into descending limb of LH), then is transported again from ascending limb and so on.

2- Urea cycle: First, it diffuses passively from medullary CD to the interstitium from which it diffuses passively to descending limb of vasa recta & LH, it is then passively transported from ascending limb of vasa recta and from medullary CD to the interstitium again and so on.Q. List different Disorders of urinary concen(A) Diabetes insipidus1. Central DI: Decreased ADH secretion due to lesion of posterior pituitary.2. Nephrogenic DI: Congenital defect in V2 receptors in the collecting duct.

(B) Impairment of the countercurrent mechanism

17

kidney (Q &A)

As in chronic renal failure → damage of renal medulla → the development of hyperosmolality in medulla is poor → loss of concentrating power → iso-osmotic urine (as that of plasma) 300mosmol. & fixed specific gravity.

Q. Describe different types of DiuresisDiuresis is an increase in the rate of urine output.

H2Odiuresis

Caused by drinking large amount of water of hypotonic fluid. It begins after 15 min and reaches its maximum in 40 min.Mechanism; increase H2O intake decrease Osmotic. Pr decrease ADH decrease facultative H2O reabsorption i.e. Urine large volume and hypotonic.

Osmoticdiuresis

Caused by the presence in filterate of large quantities of un-reabsorbable solute e.g. glucose (DM) or mannitol.Mechanism; unreabsorbable solute in PCT decrease obligatory H2O reabsorption decrease Na+ concentration in tubular fluid decrease osmolarity of medullary interstitium decrease facultative H2O reabsorption. - Urine: large volume and isotonic or hypertonic.

Pressure diuresis

Increase in arterial blood pressure leads to:- ↑ GFR.- Inhibition of rennin angiotensin system → ↓ renin and angiotensin II production.- ↑ Hydrostatic pressure in peritubular capillaries which → increase Na+ & H2O excretion.

Diuretic drugs

Thiazides: inhibit Na reabsorption in DCT.Aldosterone inhibitors: (Potassium-sparing diuretics) inhibit Na-K exchange in DCT and collecting tubules decrease serum Na and increase serum K+.Carbonic anhydrase inhibitors e.g. acetazolamide (Diamox).It inhibits carbonic anhydrase enzyme → decrease H+ secretion → decrease Na+ and HCO3

- reabsorption in PCT and increase K+ secretion in DCT → increase Na+, HCO3

- & K+ excretion in urine. May lead to acidosis.Loop diuretics e.g. frusemide (lasix): inhibit Na-K-2Cl cotransporters in the thick ascending limb of loop of Henle.Results:↑ excretion of Na+, K+ & Cl- in urine.↓ solute concentration in MI→↓ osmolality of medullary interstitium →↓ H2O reabsorption from CD → marked diuresis.

Q. Describe Kidney function tests

Assessment of Renal Blood Flow

Volume by PAH clearance- PAH is freely filtered and secreted but not reabsorbed.- About 10-15% of TRPF supplies non secreting parts of kidney (as peripelvic fat and medulla) and this plasma will not lose its PAH by secretion. - The extraction ratio of PAH is 90% i.e. only 90% of PAH in renal arterial blood is removed in a single circulation. This is because only 90% of RPF go to the nephrons.

RPF = = about 625 mL/min.

Inulin - Inulin is: freely filtered in glomeruli, not reabsorbed and not

18

ERPF x 10090

kidney (Q &A)

Assessment of

Glomerular Filtration

clearance

secreted, - measurement of GFR with inulin is inconvenient because inulin is not a normally occurring body substance and method for its measurement is difficult and time consuming.

Creatinine

clearance

is the suitable method for routine useEasy to measureEndogenous substanceIt has disadvantages: 1) a small amount of creatinine is secreted in renal tubules.2) The conventional method for analysis measures other substances in plasma besides creatinine.N.B. Creatinine clearance agree well with GFR because although the amount excreted is high as a result of secretion, the plasma concentration of creatinine is also high as a result of non-specific chromogens and so the error tends to cancel.

Blood urea and

serum creatini

ne

a)blood urea ; normal 20-40 mg/dL (nonspecific test)It varies with protein intake, liver diseases and renal perfusion.b)Plasma creatin in e ; normal 0.6 – 1.5 mg/dL (more accurate).All the above values are increased in renal insufficiency.

Assessmentof

tubular function

Glucose tubular maximu

m (Tm

Glucose)

The reabsorptive power of the tubule can be measured by Tm Glucose.As the glucose concentration is gradually increased from threshold (180 mg%) to a level of about (300 mg%), there is gradual increase of the amounts of glucose filtered, reabsorbed and excreted in urine.

Para-amino

hippuric acid

tubular maximum (Tm PAH)

The secretory power of the tubules can be measured determining Tm PAH. It can be determined by increasing the level of PAH in the plasma above the concentration that can completely removed from plasma by one circulation through the kidney.Tm PAH = 80 mg/min

Q. Mention how pH is Regulated3 major systems

1- The buffer systems : minimize the change in free H+ concentration.2- The respiratory system : removes H+ of volatile acids i.e. CO2.3- The kidneys : remove fixed acids and restore ECF buffers.

19

kidney (Q &A)

Q. Describe different Buffer systemsA buffer is a molecule that combines with or releases a H+.It is composed of weak acid and salt of its conjugate bases.The combination of all buffers determines the pH.

►Henderson- Hasselbalch equation: pH = pK + log 10

► Role of buffers in regulation of acid-base balance:Buffer act within fraction of a second (immediate) to trap H+ temporarily until respiration and renal mechanisms act. They only minimize the change in pH.

►Types of chemical buffer systems:1- Bicarbonate buffer system. 2- Phosphate buffer system. 3- Protein buffer system.

a. Plasma protein.b. Haemoglobin

c. Tissue proteins.

Bicarbonate buffer systemMajor ECF buffer

►Advantage; Its 2 components can be physiologically controlled. (HCO3) by kidneys and (H2CO3) by respiratory system.

►How does a buffer work:Bicarbonate buffer consists of a mixture of carbonic acid (H2CO3) and sodium bicarbonate, (NaHCO3), when a strong acid is added to the same buffere.g: HCl (strong acid) + NaHCO3→ H2CO3 (weak acid) + Na Clwhen a strong base is added to the same buffer:e.g: NaOH (strong base)+ H2CO3 → NaHCO3 (weak base) + H2O

Therefore no marked change in the pH.

Phosphate buffer system- It is a mixture of basis phosphate HPO4 and acid phosphate H2PO4.- Its concentration is high in ICF and tubular fluid (DCT).

Haemoglobin bufferIt plays an important role in CO2 buffering. It has 6 times the buffering power of plasma protein because it is present in larger amount.

20

(salt)(Acid)

kidney (Q &A)

Deoxyhaemoglobin is better buffer than oxyhaemoglobin.

Q. Describe role of respiration in pH regulationRespiration controls pH via controlling blood PCO2.

A decrease in pulmonary ventilation results in an increase in PCO2 and (H+).Mechanism of respiratory control of pH☺ In metabolic acidosis, ++ (H+) stimulates respiratory centers via peripheral chemoreceptors hyperventilation PCO2 -- carbonic acid -- (H+) .☺ In metabolic alkalosis , the reverse occurs.

Effectiveness of respiratory controlThe buffering power of the respiratory control is 1-2 times as that of all the chemical buffers.The respiratory control of the plasma pH has limited ability because the changes in PCO2 have opposite effects on respiration.

Q. Describe role of kidney in pH regulation (1) Reabsorption of essentially all of the filtered HCO3

(2)Production of new HCO 3.

21

kidney (Q &A)

(3) Secretion of H + : in urine by

►mechanism;

1) Secondary active secretion (countertransport with Na+) mainly in proximal nephron.2) Primary active transport by intercalated cells in the distal nephron.►Three important reactions remove the free H+:

(1) H + secretion against reabsorption of filtered HCO 3

►Inside tubular cells: CO2 + H2O CA H2CO3 H2CO3 H+ + HCO3.-H+ is secreted in the tubular lumen in exchange for filtered Na+.

-HCO3 formed inside the cell moves to the blood. ►In the lumen:

H+ (secreted) + HCO3 (filtered) H2CO3 CA (CO2 + H2O).CO2 diffuses into the cells.

(2) Phosphate buffer:

Titrable acid= urinary phosphate buffer that binds to H+ secreted.►Mechanism of formation of titratable acid.►Site: Distal tubules and collecting ducts.►In the tubular cells: CO2 + H2O CA H2CO3 H+ + HCO3.- H+ is secreted into the tubular lumen bind with a titratable acid HPO4

- to form H2PO4 which is excreted in urine.- HCO3 is added to the blood to form NaHCO3.

22

kidney (Q &A)

(3) formation and secretion of ammonia:Ammonia (NH3) is generated from glutamineNH3 acts as a H+ acceptor, it combined with H+. The resulting NH4 ion is lipid insoluble i.e. cannot diffuse back out of the tubular lumen. This is called diffusion trapping, NH4 is excreted in urine and HCO3 is returned to the blood.

Factors affecting (H + ) secretion in the kidney 1- PCO2: When PCO2 is high (respiratory acidosis), more intracellular HCO3

- is available and vice versa.2- K+ concentration: When it increases, H+ secretion decreases since both compete for secretion in DCT & CCDs.3- Carbonic anhydrase: When carbonic anhydrase is inhibited, acid secretion is inhibited.4- Aldosterone: enhances tubular reabsorbtion of Na + and increases K+ and H+ secretion.

Q. Mention detereminants of Acid-base state pH depends on the ratio1- pH values (7.35 to 7.45).2- PCO2; (35 to 45 mmHg).3- (HCO3) ; i.e. alkali reserve (22-28 m Eq/Litre).Acid- base disturbance is caused primarily by change in HCO3 or PCO2 systemThis disturbance is corrected (compensated) by changes in the Second system or both systems to that:

- The ratio (HCO3)/ PCO2 and in turn pH returns to normal.- However, (HCO3) and PCO2 are both increase or decrease.

Q. Discuss different forms of acid-base disturbances

DisorderLab changes Respiratory

compensation

Renal compensationpH PCO2 HCO3

Respiratory acidosis

Caused by decreased alveolar

ventilation due to

respiratory center

depression or chronic

lung disease

-- ++ Nor++

No compensati

on

1) Increase in bicarbonate

reabsorption.2) Increase

excretion of H+

(more acidic urine) leading to increase

titrable acid (NaH2PO4) excretion.

3) Increased ammonia excretion

in urine.Metabolic -- N -- Stimulatio 1. Reabsorptio

23

kidney (Q &A)

acidosisCaused by prolonged starvation,

shock, diabetic

ketoacidosisSevere

diarrhea, renal failure.

Or--

n of respiratory

center & increased alveolar

ventilation

n of all filtered HCO3.

2. Synthesis of new HCO3

In uremic (renal) acidosis,

compensation is not complete

because respiration can

compensate up to 75% only.

Respiratory alkalosis

Caused by hyper-

ventilation due to high altitudes,

CNS disorders or psychological disorders.

++ -- Nor--

No compensati

on

- Decrease reabsorption of

HCO3 and is excreted in urine (alkaline urine)

- Decreased excretion of H in urine in the form of titrable acid (NaH2PO4) and,

ammonium salts. Metabolic alkalosisCaused by

vomiting and diuretic

drugs that result in the excretion of large volume

of acidic urine

++ NOr++

++ Depression of

respiratory center &

decreased alveolar

ventilation

1. Failure of reabsorption of all

filtered HCO3.2. Failure of

Synthesis of new HCO3

Q. Describe how disturbance in ECF K is the cause of ACID – BASE disturbances- K+ and H+ concentration in the ECF parallel each other.

- Potassium depletion (hypokalaemia) produces alkalosis and hyperkalaemia produces acidosis: because when K+ decrease, H+ replaces it inside cells leads to intracellular acidosis which occurs also in tubular cells of the kidney which increases H+ excretion in urine and HCO3

- reabsorption causing alkalosis.

- Conversely when K+ increases (hyperkalaemia) this causes increased K+ excretion (because both K+ and H+ are secreted in exchange with Na+ and compete for the available Na+ in the tubular fluid, H+ secretion is inhibited leading to extracellular acidosis.

24

kidney (Q &A)

Q. What is the Anion GapDefinition

It is the difference between the sum of the concentrations of the major plasma cations and the major anions.The anion gap = [Na+ + K+] – [Cl- + HCO3-].

Normal value 16 mEq/L. Sometimes K+ is omitted from calculation and the anion gap = 12 mEq/L.

ImportanceIn metabolic acidosis, serum HCO3

- decreases.Thus, concentration of another anion must increase to maintain electroneutrality.This anion can be chloride or other unmeasured anions.

The anion gap is increased If concentration of other unmeasured anions is increased as in metabolic acidosis due to renal failure, lactic acidosis and diabetic ketoacidosis.

The anion gap is normal If concentration of chloride increased (hyperchloremic acidosis)as due to ingestion of NH4Cl or carbonic anhydrase inhibitors.

Q. Discuss Mechanism of Micturition1- Filling of the bladder.

2- Micturition reflex: is a spinal autonomic reflex.It is inhibited or facilitated by higher centers in the brain.

Bladder filling The bladder can accommodate large volumes of urine without much increase in intravesical pressure until the bladder is well filled due to La Place’s Law which states that the pressure in spherical viscous equals twice wall tension (2T) divided by its radius (r).

P = 2T r

As urinary bladder fills, T & r both increase and IVP increases only slightly but at a certain volume (400 ml), T increases markedly and IVP rises sharply.Cystometrogram

(Pressure -volume relationship during bladder filling)a plot of the intravesical pressure against the volume of urine in the bladder.

(1) At intravesical pr e ssure O , there is no urine in the bladder.(2) Segment la ; pressure rises to 5-10 cm water by 50 ml of urine has collected.(3) Segment Ib; small additional rise in pressure with further increase in volume to 200-300 ml. This is explained by laplace lawAs the bladder filled with urine, the tension in wall rises but so does the radius. Therefore, the pressure increase is slight until the bladder is relatively full i.e. no increase in Radius.(4) Segment II; sharp rise at a volume of 400 ml. The first urge to void is felt at a volume of 150 ml and marked sensation of fullness at volume of 400 ml.

Micturition reflex ►Stimulus; Volume of urine that initiates micturition reflex is 300-400 ml.►Receptor; stretch receptors in bladder wall.

25

kidney (Q &A)

►Afferen t ; pelvic parasympathetic.►Centre; S2 – S4.►Efferent; pelvic parasympathetic►Response and effectors;

Detursor muscle: contraction.Internal urethral sphincter: relaxation.

Higher control of micturition reflex The reflex is controlled by facilitatory and inhibitory higher centres.►Faciltatory centres : a) Pontine centres B) Post hypothalamus.►Inhibitory centres : Midbrain.

The higher centres exert final control of micturition1- They partially inhibit the reflex except when micturition is desired.1- They can prevent micturition by contraction of external urethral sphinct.2- When it is time to urinate, the cortical areas ;

- facilitate the sacral centre to initiate micturition reflex.- Inhibit thé external urethral sphincter.

Q. List different Abnormalities of MicturitionA) Atonic bladderDamage of the afferent, efferent nerves,or damage of spinal Micturition centre. Manifested by retention with overflow.

B) Automatic bladder Due to complete transection of spinal cord above sacral region.bladder empties reflexely as soon as it is filled to critical capacity, as in infants.

Q. Give short notes on acute & chronic renal failureAcute renal failure

Sudden (days or weeks) and reversible1- Urine: Oliguria < 500 mL/day or even anuria.2- Blood : Hyperkalaemia, metabolic acidosis, hypocalcemia and progressive increase in

blood urea and creatinine.3- Edema and hypertension .

Chronic renal failure Develops over years and irréversible.

(1) Azotemia ; increase in urea, uric acid and creatinine (up to 10 times).(2) Anaemia ; due to decreased erythropoietin secretion.(3) Acidosis : Inability to get rid of H and regeneration of HCO3.(4) Urine osmolarity and specific gravity approach that of glomerular filterate i.e. 290 mOsm and 1010 respectively due to loss of kidney ability to dilute or concentrate urine.(5) Hypertension .(6) Osteomalacia due to:

a) Decreased production of 1,25 dihydroxy cholecalciferol.b) Increased blood PO4 Increase PTH demineralization of bones.

Q. List different Factors controlling ECF volumel) ADH:- Stimuli which increase ADH secretion:

(1) decreased arterial pressure and(2) decreased blood volume

26

kidney (Q &A)

(3) increased osmolarity.- When ECF volume decreases:

ADH causing increase in water reabsorption by distal tubules and collecting ducts of the kidney → increase ECF volume.

- When ECF volume increases: it causes inhibition of ADH secretion that increases water excretion and

decreases ECF volume.

2) Role of the kidney:When ECF volume decreases leads to decrease in blood pressure which decrease glomerular capillary pressure which decreases GFR and decreases the amount of Na+ filtered that leads to increase in tubular reabsorption of Na+ due to stimulation of aldosterone secretion.

Conversely, when ECF volume increases which increases ABP and GFR that increase the amount of filtered Na+ that inhibit release of aldosterone which increase urinary excretion of Na+ and water causing decrease of ECF volume.

3) Renin-angiotensin-aldosterone system:When ECF volume decreases, decrease in blood pressure stimulates renin secretion

from the juxtaglumerular apparatus of the kidney. renin ACEAngiotensinogen angiotensin I angiotensin IIAngiotensin II causes:

a. stimulates aldosterone and ADH secretion.b. stimulates thirst center.

c. vasoconstriction.

4) Thirst mechanism:When ECF volume decrease: this stimulates thirst center in hypothalamus that leads to increase in water intake.

5) Volume receptors: Present in the atria and great veins near the heart. When ECF volume decreases, they send impulses to the hypothalamus causing reflex increase in sympathetic discharge with activation of renin-angiotensin system.

6) Atrial natriuretic peptide (ANP):Increase in ECF volume causes release of ANP which increase Na+ and water excretion.

27