KIDNEY 2024

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 Functions of the kidney

• Maintain constant internal environment= homeostasis

1. Regulation of
• Water, electrolyte balance (excretion matched to intake)

• Arterial blood pressure

➢ Short term regulation via (renin-angiotensin-aldosterone system)

➢ Long term regulation via (excreting variable amount of Na & H2O).

• Acid-base balance via:

➢ Regulation of buffer stores

➢ Excretion of acids produced from protein metabolism e.g. sulphuric & phosphoric acid acid
2. Excretion of

• Metabolic waste products e.g. urea, uric acid, creatinine, bilirubin, metabolites of hormones

• Foreign chemicals e.g. drugs, food additives

3. Endocrine: secrete

• Erythropoietin: stimulate erythropoiesis (anemia in kidney disease), treated by EPO injection

• Renin (regulation of RAAS): see later

• Prostaglandins (PGE2, PGl2), bradykinins (paracrine hormones): regulate renal blood flow

• Active form of Vitamin D (1,25 dihydroxycholecalciferol)

by hydroxylating vitamin at number (1) position

→ control plasma Ca2+, PO-4 homeostasis

Renal osteodystrophy in Chronic renal failure , due to

➢ ↓Activation of vitamin D →impair intestinal absorption of calcium

➢ Retention of phosphate →disturb calcium level
→ Cause 2nd hyperparathyroidism to correct the calcium level
→ Leads to bone weakness & ↑ incidence of fracture

4. Gluconeogenesis (synthesize glucose from amino acids) during fasting to maintain blood glucose level

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 Causes of anemia in CKD

1. EPO deficiency = predominant cause → leading to normocytic normochromic anemia

2. Uremia →inhibit erythropoiesis
3. Shortened RBC’s life span
4. Nutritional deficiencies of folate and vitamin B12, due to anorexia & dialysis losses
5. Iron deficiency:
a) Chronic bleeding from uremia-associated platelet dysfunction,
b) ↓iron absorption, especially in hemodialysis patients due to ↑Hepcidin due to
• ↑expression by inflammatory cytokines
• ↓renal clearance
❖ Oral iron is less effective than IV iron for improving anemia in hemodialysis patients

• In impaired renal blood flow (as if there is systemic hypotension) due to

• Atherosclerosis
• Bilateral renal artery stenosis
• Diabetes mellitus
➢ kidney correction →via ↑renin angiotensin formation→ cause hypertension
➢ Main line of treatment of hypertension in these cases is
• Inhibition of angiotensin II formation or
• Blocking its receptors

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 Physiologic Anatomy of Kidney

Site: on posterior abdominal wall outside peritoneal cavity

Size 150 grams = size of clinched fist, 12 cm in length and < 8 cm in width

• Surrounded by thin, = tough capsule.

• Renal artery, vein, lymphatics, nerve supply and ureter enter the kidney at the hilum on its medial side.

Structure: formed of

Outer cortex Inner medulla

Granular, deeper in color Striated, paler in color

Divided into renal pyramids→

Tapers to form renal papilla,

Projects into pelvic space via minor calyx

➢ Minor calices converge into 2 or 3 major calices (chambers)

➢ Major calices converge to form the pelvis of ureter.
➢ Calices, renal pelvis and ureters are surrounded by smooth fibers,
→force the urine from the pelvis to the urinary bladder by
peristaltic contractions

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 Nephron
• Functional unit of the kidney (forming urine),
• 1.3 million nephrons in each kidney,
• Consists of

1. Renal Glomerulus

• Tuft of glomerular capillaries (supplied by afferent arteriole & drained by efferent arteriole)
• Within Bowman's capsule (dilated end of renal tubule)
• High pressure capillary bed= 60 mmHg

2. Renal tubule: thin

A- Proximal Convoluted Tubule= 15 mm in cortex,

Made up of a single layer of cells

At apex At base
Tight junction between cells lateral intercellular space (extensions of the extracellular space)
Brush luminal border (microvilli)
B- Loop of Henle= U-shaped extension of PCT that dips in the medulla, consists of
Descending Ascending limb
Lower half Upper half (its way back to the cortex
Thin segment of loop of Henle Thick segment of loop of Henle
(attenuated flat epithelium) cuboidal cells with extensive basilar

C- Distal Convoluted Tubule: 5 mm in cortex

• Made of epithelium is lower than that of the proximal tubule.
• No distinct brush border, (few microvilli)
D- Collecting Ducts: distal tubules coalesce to form collecting ducts = 20 mm long
→ pass through renal cortex , medulla to empty into the pelvis at the apexes of the medullary pyramids.
• Lined by 2 types of cells

Principal cells (P cells) Intercalated cells (I cells)

Predominant relatively tall cells Smaller number, found also in DCT
Concerned with Concerned with H secretion
+
Na reabsorption in exchange with K or H,Controlled by aldosterone
Water reabsorption controlled by ADH

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 Types of nephrons

According to location of glomeruli in cortex

Cortical nephron (85 %) Juxtamedullary (15 %)

Glomeruli In outer cortex, close to surface In inner cortex (deep), near to medulla
Loop of Henle Short Long
Penetrate short distance in medulla Penetrate long distance in medulla
no further than the junction between (dips deeply)
inner & outer medulla
Capillaries Network of peritubular capillaries Vasa recta
surround tubule (specialized U shaped peritubular capillaries)
(lie side by side with loop of Henle)
Special Function Play a role in concentration of urine

Juxtaglomerular Apparatus

Definition

Specialized tubular and vascular cells at vascular pole

where afferent & efferent arterioles enter and leave the glomerulus

Function

1. Autoregulation of renal blood flow & GFR during changes in ABP

2. Regulation of ABP via RAAS

Consists of

1- Macula densa 2- Juxtaglomerular cells

Modified tubular cells in early (initial) distal tubule Epithelioid granular cells in the media of afferent

that comes in contact with afferent & efferent arterioles.arterioles (lesser in efferent arterioles).

Function: chemoreceptor: monitor composition of the Function: baroreceptors, stimulated by ↓ renal

tubular fluid (NaCl load) perfusion pressure or hypovolemia→ secrete
renin

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 Renal blood flow 1.2 -1.3 liter / minute = 21 % of cardiac output.

• Two capillary beds associated with nephron:

Glomerular capillary bed Peritubular capillary

Arise from afferent arteriole. Arise from efferent arteriole.

High pressure = 60 mmHg→ cause rapid filtration Low pressure =13 mmHg
→ cause fluid reabsorption from ISF to blood

✓ Highest capillary pressure due to:

• Renal artery: direct branch of abdominal aorta

• Afferent arterioles: short, straight branches of

interlobular arteries

• Efferent arterioles resistance higher than afferent

arteriole

• Regional Blood Flow

➢ Renal cortex: receive 98 % of RBF for filtration

➢ Renal medulla: receive 2 % (sluggish blood flow) to form concentrated urine

• Measurement of RBF: see later

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 Regulation of the renal blood flow

1. Autoregulation of the renal blood flow & GFR:

• Renal blood flow & GFR are kept constant
despite marked changes in ABP (90 – 220 mmHg)
by auto-regulatory mechanisms (by change in vascular resistance)
• Present in denervated & isolated kidney (independent on nerves or hormones)

A- Myogenic autoregulation: 1st line rapid defense against rapid change in ABP

➢ ↑ABP up to 200 mmHg→ stretch afferent arteriole→ open Ca++ channels

→ VC →↑resistance →prevent excessive increase in flow (vice versa)
➢ At low pressure: VD (relaxation) →↓resistance→ maintain constant flow

B- Tubulo-glomerular balance (feedback mechanism) buffer changes of ABP on GFR

↑ ABP→↑RBF & GFR ↓ABP→↓ RBF & HPGC →↓GFR

→ ↑Solutes, H2O delivery at macula dense → ↓ flow rate at loop of Henle

→ macula dense cells ↑active Na →↑ Na, Cl reabsorption in ascending loop of Henle →

reabsorption with ↑production of adenosine ↓Na, Cl at macula dense
by breakdown of ATP → Macula dense stimulate release of renin from JGC
→ that cause VC of afferent arterioles → ↑ formation of angiotensin I, converted to AgII→

→↓RBF, HPGC, GFR back to normal → VC of efferent arteriole→↑ HPGC & ↑GFR

+ VD of afferent arteriole

• Aim: maintain constant GFR & precise control of renal excretion of water and solutes
despite marked changes in ABP
2. Nervous regulation (sympathetic) of renal blood flow (α receptor)→ cause VC
→↓ RBF & GFR
as in (exercise & hypovolemic shock)

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 Formation of urine

1- Glomerular filtration 2- Tubular reabsorption 3- Tubular secretion

From glomerular capillaries into Transfer of water & solutes From Transfer of solutes From peritubular
Bowman's capsule tubular lumen (filtrate) back into capillaries into tubular lumen.
Fluid free of proteins (colloid). peritubular capillaries

Urinary excretion rate = Filtration rate - reabsorption rate + secretion rate

Glomerular membrane

o Separates blood in capillaries from filtrate in Bowman's capsule (3 layers)

1- Capillary endothelium 2- Basement membrane 3- Podocytes

Have relatively large fenestration Meshwork of Collagen & Epithelial cells line outer surface
(holes) (perforation) -ve charges proteoglycan fibril Have many pseudopodia
70-90nm (have large spaces) → Interdigitate to form slit pores
→ Not barrier for filtration of Major barrier (25 nm)
proteins prevent filtration of proteins

Total surface area of glomerular membrane= 0.8m2

Mesangial cells: stellate contractile cells between basement membrane & endothelium
at bifurcation of the capillaries
• Functions of the mesangial cells:
1. Regulation of GFR: Have receptors for vasoactive substances
• Contraction of mesangial cells →↓surface area →↓filtration (vice versa).
2. Immune function→ Take up immune complexes and secrete cytokines

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 Permeability of glomerular membrane

50 times > capillaries in skeletal muscle.

Highly selective: determined by

A- Size of solutes

Neutral substances < 4 nm Neutral substances > 8 nm

Freely filtered (Na, glucose: freely filtered) Not filtered

Between values, filtration is inversely proportionate to diameter

B- Charge of solutes

o -ve charged are filtered less easily than +ve charged molecules of equal diameter
due to -ve charges in basement membrane
o Albumin glomerular concentration = 0.2% of its plasma concentration
in spite of its effective molecular diameter of 7 nm (due to its negative charge).
o In kidney diseases: -ve charge are lost without ↑in pores size → cause Albuminuria

Glomerular filtration rate (GFR)

Definition Volume of filtrate formed by glomeruli of both kidneys/minute

Normal GFR 125 ml/min in men. 10% less in women.

➢ 125 ml/min = 7.5 L/h =180 L/day. (60 times plasma volume) Whereas normal urine volume is 1 L/day,

➢ ≥ 99% is reabsorbed

• Both blood urea nitrogen and plasma creatinine ↑when GFR ↓.

• GFR ↓ by 1 ml/min/year with age, although plasma creatinine remains constant
because of ↓muscle mass.
• GFR = best kidney function test

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 Control of GFR (forces)

Starling equation: GFR = KF (HPGC - HPBC) - (GC - BC) = KF (HPGC — HPBC — GC +  BC)

1. Hydrostatic pressure gradient across capillary wall

➢ HPGC= hydrostatic pressure in glomerular capillaries (mmHg).
➢ HPBC= hydrostatic pressure in Bowman's capsule
2. Osmotic pressure gradient across capillary wall
➢ GC = osmotic pressure of plasma proteins in glomerular Capillaries
➢ BC = osmotic pressure of proteins in the filtrate
3. KF = glomerular ultrafiltration co-efficient (ml/min/mmHg), depends on
➢ Permeability of glomerular membrane 3
➢ Effective surface area 4
• Not measured directly
• GFR = KF X NFP
125 𝑚𝑙 /𝑚𝑖𝑛
• KF= GFR/ NFP= = 12.5 ml/min/1mmHg = GFR / 1mmHg of filtration pressure.
10 𝑚𝑚𝐻𝑔

Forces favoring filtration (mmHg): Forces opposing filtration

HPGC =60 mmHg HPBC = 18 mmHg

BC= 0 mmHg (no protein is filtered) (repelled by –ve charge) GC = 32 mmHg.

Net filtering pressure = 60 - 18 - 32 = 10 mmHg.

Measurement of GFR: see later

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 Factors affect GFR

Starling equation:…….
1. Filtration coefficient (Kf):

o ↑KF→ ↑GFR (vice versa)

o Depends on Permeability & Surface area
• Permeability: ↑thickness of glomerular membrane (as in uncontrolled DM & HTN)→↓permeability
• Surface area of glomerular capillaries: affected by
A- Contraction of mesangial cells B- Relaxation of mesangial cells
At point where capillary loop bifurcate
shift blood from some capillary

e.g. by Vasopressin, Norepinephrine, Endothelin, e.g. by ANP, CAMP, PGE2,

thromboxane, leukotrienes A, D, histamine, PGF2 dopamine

↓surface area→↓ GFR ↑surface area→↑ GFR

C- Some diseases as chronic uncontrolled DM→↓ number of functional capillaries→ ↓surface area

2. Glomerular capillary hydrostatic pressure ↑ HPGC→ ↑ GFR:

Diameter of afferent arteriole Diameter of efferent arteriole Arterial blood pressure

• VD: bradykinins, PGE2, PGI2 Renal blood flow & GFR are
kept constant despite marked
→ ↑HP GC →↑ GFR
changes in ABP (90 – 220
• VC: noradrenaline (sympathetic) • Moderate VC (angiotensin II) →↑
mmHg) by auto-regulatory
→ ↓ HPGC → ↓ GFR resistance→↑ HPGC → slight
mechanisms.
• ↑ Sympathetic e.g. during ↑GFR.
When Mean systemic
exercise→↓GFR < 50% of normal
pressure drop < 75 mmHg→
sharp drop in GFR
Mechanism of Auto-regulation of RBF & GFR: Myogenic autoregulation & Tubulo-glomerular feedback
see before

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 3. Bowman’s capsule hydrostatic pressure

o ↑ HPBC e.g., stone in ureter→↓GFR

2. 4. Glomerular colloid osmotic pressure concentration of plasma proteins

↑ GC e.g., dehydration → ↓ GFR ↓ GC e.g., hypoproteinemia→↑ GFR.

5. Renal Vasodilators:

o PGE2, PGl2 & bradykinin → cause VD →↑ RBF and GFR.

o Anti-inflammatory drug (aspirin & ibuprofen)

→↓PG formation

→↓GFR
→ may lead to renal failure
o Sympathetic & angiotensin II→↑PG synthesis

→ protect kidney from severe VC as in severe CVS stress like hemorrhage.

6. Autonomic nerves (sympathetic) (α receptor)

→ cause VC →↓ RBF & GFR
7. Effect of protein intake ↑RBF and GFR.

o ↑protein intake →↑amino acids in blood→ filter in Bowman's capsule

→↑ amino acids and Na+ reabsorption in proximal tubules (cotransport)

→↓ Na delivery at macula dense→ tubule-glomerular feedback

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 Plasma Clearance/ Renal Clearance of a substance

Definition volume of plasma cleared from certain amount of substance excreted in urine / minute.
Volume of the plasma necessary to supply the amount of substance excreted in urine / unit time
Calculation
• Amount of substance (X) cleared from plasma / min = amount of substance (X) excreted in urine / min
𝑈 ×𝑉
• CX X PX= UX X V C (clearance) =
𝑃
✓ CX= Cleared volume of plasma from X / minute.
✓ PX = Plasma concentration of X / ml plasma
✓ UX= Urine Concentration of X / ml urine.
✓ V = Volume of urine / min. (Urine flow rate)

Importance
1- Study tubular handling of different substances in the filtrate
Substance Clearance ml / min Tubular Handling

Inulin 125 Neither reabsorbed nor secreted

Urea < 125 Partially reabsorbed

Glucose 0 Completely reabsorbed

Creatinine 125-650 Partially secreted

PAHA 650 Completely secreted

2- Measurement of GFR
A- Inulin Clearance test

Steps

• large dose of inulin is injected IV followed by sustained infusion →to keep constant arterial plasma level
• After equilibration, urine and plasma samples are collected to determine inulin conc.

Characters of Inulin

• Polymer of fructose , with M.W. 5200, found in dahlia tubers

• Easy to measure in plasma and urine
• Not metabolized, No effect on GFR
• Freely filtered (not bound to plasma proteins)
Concentration of inulin in plasma = concentration of inulin in filtrate.
• Not reabsorbed or secreted.
Amount filtered/min = amount excreted in urine / min. Cin X Pin= Uin X V
• Not stored in the kidneys

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B- Creatinine Clearance = Creatinine is an endogenous substance formed from creatine in muscle at constat rate

Characters of creatinine

• Easy to measure, Endogenous→ used as an index of renal function

• Freely filtered
• Not reabsorbed
• Partially secreted → GFR measured by creatinine clearance is slightly higher than GFR measured with inulin

Cockcroft and Gault formula: estimate creatinine clearance (GFR) from plasma creatinine level

without any urinary measurement.

(140−𝑎𝑔𝑒)𝑋 𝑤𝑒𝑖𝑔ℎ𝑡 (𝐾𝑔)
𝐆𝐅𝐑 = ( X 0.85 For woman), because of less muscle mass
𝑷𝒄𝒓 𝑿 𝟕𝟐

3- Measurement of renal plasma flow

Para-amino Hippuric acid (PAH) clearance

Characters of Para-amino Hippuric acid
• Freely filtered
• Not reabsorbed
• Completely secreted (from peritubular capillaries) in a single circulation via the kidney.
▪ Extraction ratio of PAH =90% (Only 90% of PAH in renal arterial blood is removed in a single
circulation through the kidney)
▪ Amount of PAH in the effective plasma of renal artery = amount of PAH excreted in urine.
▪ U X V
ERPF = PAH
CPAH = effective renal plasma flow (ERPF)
PPAH
▪ Actual renal plasma flow (RPF) = ERPF / extraction ratio
▪ Renal blood flow = RPF /1 – Hematocrit Value

4. Calculation of filtration fraction: ratio of the GFR to the renal plasma flow. (fraction of RPF that is filtered)
• GFR is determined by inulin clearance/ RPF is determined by PAH clearance.
• Normal value = 0.16 - 0.20 filtered, (remaining 80% pass via efferent arteriole)
Problem
• Concentration of PAHA in urine (UPAH) = 14 mg/ml 14 x 0.9
ERPF = = 630 ml/min.
• Urine flow (V) = 0.9 ml/min 0.02

• Concentration of PAHA in plasma (PPAH) = 0.02 mg/ml RPF = 630 / 0.9 = 700 ml/min .
• Extraction ratio = 0.9
• 700
HV = 45% RBF = = 1273 ml/min.
1 - 0.45
Calculate the RBF

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 Tubular Processing of the Glomerular Filtrate

• Result in
➢ ↓volume
➢ Change composition by processes of tubular reabsorption and secretion
• Urinary excretion rate: see before
Tubular Reabsorption involves:

• Transport of the substance across tubular epithelium into ISF

• Transported from ISF into peritubular capillaries.
Type of transport across the tubular epithelium

• Transcellular: Solutes are reabsorbed or secreted through cells

• Paracellular: solutes are reabsorbed or secreted through the tight junctions between cells.

Mechanism of tubular transport

Active transport Passive transport

Primary active transport Secondary active transport

Co-transport Counter-transport

A. Active transport: against concentration or electrical gradient

1- Primary active transport

• Energy: from ATP hydrolysis by membrane bound ATPase (component) of a carrier (transporter)
that binds and moves solutes across the cell membrane.
• Example: Sodium reabsorption across PCT

At the basolateral border At the luminal border

Na+ - K+ ATPase pump: Na+ diffuses across the luminal membrane
Extrudes 3 Na+ into ISF in exchange for 2 K+ in → from the tubular lumen into the cell
• Creating a negative potential - 70 mV within the cell. due to electrochemical gradient
• Low intracellular Na+ concentration

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2. Secondary active transport:

• Energy: not directly from ATP or high-energy phosphate sources.

• 2 types:
A- Co-transport: reabsorption of glucose is linked to passive reabsorption of sodium
dependent on active sodium potassium pump at basolateral border
At the luminal border At the basolateral border
Glucose and Na+ bind to a common carrier SGLT-2 Na+ is pumped out of the cell into lateral
in the luminal membrane. intercellular spaces.
As Na+ diffuses along its electrochemical gradient Glucose is transported by GLUT-2 into ISF by
Glucose is introduced into the cell. facilitated diffusion

B- Counter transport: reabsorption of one substance is linked to secretion of another substance

secondary active secretion of H + into the tubule
At luminal membrane, of PCT
Sodium - hydrogen counter transport
As Na+ is carried to the interior of the cell,
H+ is forced outward in opposite direction into the lumen

B-Passive Reabsorption:
1. Passive Reabsorption of Chloride: via paracellular pathway following Na+ reabsorption.
• Reabsorption of Na+→ create negatively charged lumen → causes passive diffusion of Cl
2. Osmosis of Water
• Reabsorption of solutes → ↓ their concentration inside the tubule & ↑ in ISF
→creates concentration gradient
→causes osmosis of water from the tubular lumen into ISF mainly through paracellular route.
3. Passive Reabsorption of Urea
• Reabsorption of water→↑urea concentration in tubular lumen
→ creates concentration gradient →favoring reabsorption of urea.
• About 50% of the filtered urea is passively reabsorbed from tubule
and the remainder passes into urine.

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Tubular Transport Maximum→ maximum transport rate for actively transported substances (mg/minute).
Require specific carriers and enzymes
When carrier system is saturated→ Tm is reached→ no further increase in transport as tubular load
increase.
Glucose reabsorption exhibit Tm
Threshold for substances that have a tubular maximum: threshold concentration in plasma
• Below which→ none of substance appears in the urine
• Above which → progressively large quantities appear in urine

Gradient - time Transport (For passively transported substances by diffusion), determined by:

1. Electro-chemical gradient for the substance across the membrane.

2. Tubular flow rate (the time that the fluid containing the substance remain within the tubule)

Na+ obey gradient-time transport in PCT (Despite actively transported),

as rate of active transport at basolateral borders > >>> rate of its diffusion at brush border

Absorption by peritubular capillaries by bulk flow as venous end of capillary

Forces favor reabsorption Forces oppose reabsorption

Hydrostatic pressure in renal ISF (6mmHg) Hydrostatic pressure inside peritubular capillaries (13mm).

Colloidal osmotic pressure of peritubular Colloidal osmotic pressure of renal ISF

capillaries (32 mmHg) (15mmHg)

Net reabsorptive Force = (32 + 6) - (13 + 15) = 38-28= 10 mmHg

Uptake of fluid & solutes by the peritubular capillaries is matched to the net reabsorption of water & solutes
from tubular lumen into ISF

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Na+ Handling / Reabsorption by the Renal Tubule
Na is the main ECF cation, 90 % of osmotically active solutes→ maintain ECF volume

Na+ is reabsorbed at all segments except descending segment of loop of Henle

1. Proximal Tubule reabsorb 65% of filtered Na+ (not depend on aldosterone)

Mechanism of Na reabsorption Primary active transport (obey gradient time transport)

➢ At basolateral border: Na+ K+ ATPase pump → keep low intracellular Na+ concentration
➢ At luminal border: Na+ diffuses from tubule into cell (electrochemical gradient)
First half= early PCT Late half
Na+ reabsorbed by Na+ is reabsorbed with
• Co-transport with (sulphate, PO4, organic acid (lactate, citrate) • Cl- (passive diffusion)
• Co-transport with all filtered glucose, amino acids through paracellular route
• Responsible for reabsorption of HCO3 (85-90 %), consequent with

H secretion

• Counter-transport with H+ via (Na+ - H+ exchange)

2. Loop of Henle &early distal tubule:

Thin descending limb Ascending limb =25%
No capacity to reabsorb Na+ Thin part:

(Absence of Na+ channel Reabsorb NaCl passively / impermeable to water→↓ tubular osmolarity
Thick part:
from luminal membrane)
Reabsorb 25% of filtered Na via 1Na+, 1K+ & 2Cl- co-transport

Reabsorb water in luminal membrane (2nd active transport)

Most K+ that enters the cell, refluxes back into lumen via K+ leak channels to:
a) Ensures sufficient K+ conc. for optimal function of co-transporter.
b) Cause Net positive potential in lumen
→ facilitates paracellular reabsorption of several cations as Ca++, Mg++ ,Na+, 1K
Bartter's Syndrome
Cause Defect in Na+ - K+ - 2 Cl- cotransporter in luminal membrane of thick ascending limb
Result Loss of Na+, K+, Cl-, ca2+ → salt wasting, volume depletion, hypercalciuria, hypokalemia,
metabolic alkalosis.

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3. Early distal tubule
Cortical diluting segment.

▪ Reabsorption NaCl by Na+-Cl- cotransporter

▪ impermeable to water

(Ascending limb and early distal tubule are called diluting segment)

4. Late Distal Tubule and Collecting Duct:

Final adjustment, under hormonal control (aldosterone) to achieve (Na homeostasis)

▪ Principal cells: reabsorb < 10 % of filtered Na+ in exchange with K+ secretion

▪ Mechanism:

➢ At basolateral membrane: Na+ - K+ ATPase?

➢ In luminal membrane: Na+ and K channels
o Na diffuse into P-cells (electrochemical gradient) , K diffuse out in ISF (chemical gradient)
o Concomitant paracellular passive reabsorption of Cl
(as a result of luminal negative potential caused by Na transport)

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 Regulation of Na+ Excretion

• Amount excreted (1 – 400 mEq/L) adjusted to the amount ingested

• Variation in Na excretion: affected by (amount filtered , amount reabsorbed)
• Factors affecting GFR, tubular reabsorption will affect renal excretion of Na
1. GFR: "Glomerulo-tubular Balance"
• ↑GFR → ↑ filtered Na+ →↑reabsorption of Na+ (solutes), H2O →slight ↑in excreted Na.
Mechanism in isolated kidney (independent of hormones)
Renal tubules reabsorb constant % of filtered Na + (2/3 or 65%) rather than a constant amount
Site PCT mainly, Loop of Henle
Importance

a. Prevent overloading of DCT when GFR increase

b. Prevent inappropriate losses of Na+ and water in urine when GFR suddenly increase
2. Rate of Tubular Flow Slow flow rate (as in ↓GFR) →↑tubular reabsorption of Na+
3. Effect of ABP on tubular reabsorption "Pressure Natriuresis & Diuresis " ↑ABP →↑ Na+ & H2O excretion
Mechanism compensatory mechanism for regulation of ABP independent of nervous or hormone

1. ↑ABP →↓angiotensin II secretion

2. ↑ ABP →↑hydrostatic pressure in peritubular capillaries

→ ↑hydrostatic pressure in ISF

→enhance back leak of Na+ into lumen

→↓net reabsorption of Na & H2O→↑urine output

4. Hormonal Control:
Hormones →↑Na+ reabsorption
Aldosterone (mineralocorticoid) Mechanism: Acts on P cells on DCT & CD
o At basolateral membrane: ↑Na-K ATPase
o In luminal (apical) membrane: ↑ Na+ channel

→ ↑Na+ reabsorption in exchange with K+ or H+

Glucocorticoid Mechanism: weak mineralocorticoid effect=↑Na+ reabsorption

Sex Hormones (estrogen) ↑Na+ reabsorption

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Angiotensin II: Mechanism: ↑Na+ reabsorption

Most powerful Stimulates aldosterone secretion

Direct action on PCT: Stimulates Na+ - K+ ATPase pump.
sodium-retaining hormone
Stimulates Na+ - H+ counter transport.
VC of efferent arterioles
→ ↓hydrostatic pressure, ↑osmotic pressure of peritubular capillaries
(through increasing filtration fraction)
Hormones →↓Na+ reabsorption

Atrial natriuretic peptide (ANP) Mechanism:

↑ NaCL & water Excretion in case of ✓ ↑ GFR → ↑filtered Na+ →↑Na+ excretion via
marked expansion of ECF. • Relaxation of mesangial cells→↑ surface area
• VD of afferent
✓ Inhibit renin secretion →↓angiotensin-II & aldosterone.
✓ On collecting ducts: Inhibit Na+ channels & Na+ - K+ ATPase

PGE2 ↑Na+ excretion through:

o At basolateral membrane: Inhibit Na+ - K+ ATPase.
o At apical membrane: Inhibit Na+ channels.

Endothelin ↑PGE2.

5. Sympathetic stimulation: ↑Na+ reabsorption &↓Na+ excretion by

• VC of renal vessels (via 1 receptor) →↓RBF and GFR
• ↑renin ((via 1receptors on Juxtaglomerular apparatus) & angiotensin II
• Direct action on renal tubule (Via  & ) →↑ Na reabsorption
6. Diuretics →↑ Na+ excretion
• Carbonic anhydrase inhibitor= acetazolamide = Diamox:↓ H secretion + ↑ Na, K, HCO3 and water loss
• Loop diuretic= Lasix (furosemide): inhibit Na+ K+2Cl- at thick ascending limb of loop of Henle
→ ↑ electrolyte excretion in urine
• Thiazide diuretic: inhibit NaCl reabsorption by early DCT
• Aldosterone inhibitor= Aldactone: inhibit Na- K exchange at DCT & CD→ ↑Na excretion & K retention
• Xanthine as caffeine: ↑GFR + ↓Na reabsorption by renal tubule
• Ethanol: inhibit ADH secretion

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 Tubular Handling of K+ by the Renal Tubule

✓ Both reabsorbed and secreted

✓ Normal rate of k+ filtration = 756 mEq/day (GFR x plasma K+ level = 180 x 4.2).

1. PCT
• Reabsorb 65% of filtered K+

2. Thick ascending limb of Loop of Henle

• Reabsorb 25% of filtered K+ actively with Na+ and Cl- (co-transport)

3. Distal tubule and Collecting Tubule

• Reabsorb or secrete K+ depending on dietary intake.

A- K+ reabsorption by intercalated cells: Occurs only on a low K+ (K+ depletion)

• Reabsorb 5% of filtered K+ actively (1ry)
• Mechanism
A- At luminal membrane: ATP dependent K+ - H+ antiporter
B- At basolateral membrane: K+ channels

B- K+ Secretion by principal cells into tubular lumen in late DCT & collecting tubule
• Amount: variable, depends on dietary K+, aldosterone level, urine flow rate and acid-base status
• Mechanism: under effect of aldosterone
A. At basolateral membrane:
o Na+-k+ ATPase pump Na+ into ISF & K+ into cell
→ ↑intracellular K+ conc.
B. At luminal membrane: K+ diffuses through
o K+ - channels (electrochemical gradient)
o K+ Cl- co-transporter

22
Regulation of Tubular Potassium Secretion: DCT, CD

1. Plasma Potassium Concentration

• ↑ plasma K+ conc. →↑ K+ secretion
• Mechanism:
a) At basolateral membrane: ↑activity of Na+ - K+ ATPase by:
➢ Direct effect of extracellular K+
➢ ↑aldosterone secretion (by ↑K+ level).
b) At luminal membrane: ↑number of K+ channels by aldosterone.

2. Flow rate in the distal tubule

• ↑flow rate → flushing down the secreted potassium
→ ↓K+ conc. in the tubular lumen
→ enhance the diffusion gradient
→↑ K+ secretion
• Diuretic therapy → cause K+ depletion.

3. Aldosterone
• Hyperaldosteronism→↑K+ secretion→ cause hypokalemia (vice versa)

4. Acid - Base Status

• Acidosis: ↓K+ secretion. (vice versa)
• Mechanism:
Acidosis→ ↓ intracellular K+ concentration in P-cells
→↓ diffusion gradient
→↓ K+ secretion via
➢ Inhibition of Na+ - K+ ATPase
➢ efflux of K+ and uptake of H+ from ECF

23
 Glucose reabsorption by renal tubules

Site all filtered glucose is reabsorbed in early proximal tubule

urine is nearly free of glucose

Mechanism: 2nd active transport

At luminal brush border 2nd active transport

• Glucose & Na+ bind SGLT-2 (sodium dependent glucose transporter) (97 %), SGLT-1 in late PCT reabsorb 3 %

➢ As Na+ diffuse along its electrochemical gradient

➢ glucose is carried into the cells against concentration gradient

• Glucose transport at luminal border is blocked by:

o Ouabain: blocks Na+ - K+ ATPase.

o Phlorizin: competes with glucose for SGLT-2 carrier
At basolateral border Glucose is carried into ISF by GlUT-2 (facilitated diffusion down chemical gradient)

↑glucose reabsorption maintain hyperglycemia in type II DM

Management: SGLT-2 inhibitors as canagliflozin, dapagliflozin

Transport Maximum of glucose (TmG)

Definition maximum amount of glucose (in mg) reabsorbed / minute.

• Indicator of reabsorptive capacity of the kidney

• Determined by number of glucose carriers in PCT

Value

• 300 mg / min in female

• 375 mg /min in male

Renal threshold for glucose

Definition plasma glucose level at which glucose appears in urine rather than normal minute amount

Value

• Arterial blood: 200 mg / dl

• Venous blood: 180 mg % ( at lower plasma conc. Than Tm)

24
 Glucose Titration Curve and Tm

• Relationship between plasma glucose concentration and glucose reabsorption, filtration and excretion
• Obtained experimentally by infusion of glucose
• Measuring rate of reabsorption as plasma concentration is increased.
A- Filtered load of glucose = GFR x [P] glucose as Glucose is freely filtered
• ↑plasma glucose concentration →↑filtered load linearly.
B- Reabsorption of glucose
At plasma glucose At plasma glucose At plasma glucose concentrations
concentration < 200 mg/dl concentration > 200 mg/dl > 300 mg/dl

All filtered glucose is reabsorbed Some filtered glucose is not no↑ in rates of reabsorption as
(many Na+ glucose carriers) reabsorbed as some carriers Carriers are fully saturated
are saturated (limited number)

Reabsorption curve is identical to Reabsorption curve bends Reabsorption reaches maximal

filtration curve value Tm
(reabsorption = filtration)

C- Excretion of glucose
At plasma glucose concentration At plasma glucose concentrations At plasma glucose conc.
< 200 mg/dl > 200 mg/dl > 300 mg/dl
All filtered glucose is reabsorbed Most filtered glucose is reabsorbed, Additional filtered glucose is
None is excreted Some is excreted excreted in urine
Excretion curve increases
linearly paralleling that for
filtration.
➢ Tm for glucose is reached gradually, rather than sharply producing splay
➢ Splay bending of reabsorption curve between threshold (200) and Tm (300)

(as reabsorption is approaching saturation)

Explanation: due to heterogeneity of nephrons

• Tm reflects the average Tm of all nephrons

• Some nephrons reach Tm at lower plasma concentration than others,
and glucose will be excreted in urine before the average Tm is reached.

25
Glycosuria
Definition excretion of glucose in urine in considerable amounts.
Causes

Diabetes Mellitus Renal glucosuria (congenital defect in glucose transport)

Blood glucose level > renal threshold Glucosuria at Normal plasma glucose level
Renal threshold for glucose is ↓ < 180 mg %
TmG is markedly ↓
Excretion of osmotic active glucose → cause loss of water
(osmotic diuresis), Na+ , K+

26
 H2O reabsorption

➢ Passive process throughout the whole nephron except ascending loop of Henle
2 types

A- Obligatory water reabsorption 87% of filtered water reabsorbed by osmosis independent of ADH

1- Proximal tubule (65%) 2- Loop of Henle: (15%) 3- Early Distal tubule

Main site Descending limb Ascending limb

Reabsorb 65% of solutes No solutes Actively reabsorb solutes Reabsorb Solutes

(create osmotic gradient) (Na+) reabsorption (Na+ Cl-, K+ , Ca++) into

medullary ISF
Highly permeable Highly permeable Impermeable Relatively impermeable

Reabsorb 65% of H2O Reabsorb 15% of H2O by No H2O reabsorption to H2O

via aquaporin-1 channel in osmosis into hypertonic

the luminal membrane) medullary ISF

Osmolarity of tubular Osmolarity of tubular fluid = Osmolarity of tubular Osmolarity of tubular fluid
fluid = Plasma hypertonic medullary ISF fluid is ↓= very diluted is ↓= diluted

(iso-osmotic) (Equilibrium) (100 mOsm/L), (60 mOsm/L.).

(300 m Osmo/L) 1200 -1400 at end of by end of ascending limb

descending limb of juxta
medullary nephron

Diluting segment?

B- Facultative water reabsorption: 13% of filtered water is controlled by ADH in late DCT, collecting duct
• Final adjustment of water according to body needs

• Role of ADH

➢ ADH ↑ H2O permeability via insertion of aquaporin-2 channel in luminal membrane of principal cells

of late DCT, cortical, medullary CD

➢ Water diffuse from the cell into ISF through aquaporin-3,4 at basal border of P cells

until osmotic equilibrium is reached (same as medullary ISF)

27
 Urine concentration and dilution

• Depends only on the extent of facultative water reabsorption.

• In dehydration: water is conserved,
concentrated urine with high osmolarity is excreted (vice versa)
Requirements for excreting concentrated urine
1. High ADH: (role of ADH)?
2. Hyperosmotic renal medulla
a. Osmolarity of medullary ISF increases from 300 mOsm/L in superficial layer of medulla
to 1200 mOsm/L in deep parts in the tips of papillae.
b. High osmolarity →cause H2O osmosis from renal tubule into renal ISF (carried by vasa recta)

Mechanisms produce hyperosmotic renal medullary ISF

1. Countercurrent multiplier system

inflow runs parallel to, counter to , in close proximity to outflow for some distance.
Function of loop of Henle of juxtamedullary nephron
• Adds solutes to medullary ISF→ creates medullary hyperosmolarity
Ascending limb Descending limb

Thick segment: Much less Impermeable to Na+, Cl, urea

At basolateral border: Na K ATPase pump

At luminal border: Na+, K+ and Cl- are co transported

Ca, HCO3, Mg are also reabsorbed

Thin segment: passive reabsorption of Na+ & Cl

Down conc. gradient

Impermeable to water Permeable to water

(H2O diffuse from into medullary ISF by osmosis)

↑ Osmolarity of medullary ISF to 1200 at the tip ↑ Osmolarity of Tubular fluid from 300 to 1200
Tubular fluid → become diluted (100 mosm/L) at tip of the loop

as it enter DCT = reach osmotic equilibrium with medullary ISF

(cause ???)

28
2. Countercurrent exchange system of (U shaped Vasa recta
Highly permeable to water and solute
Descending limb of the vasa recta Ascending limb of vasa recta

Na+, Cl (solutes) diffuse from medullary ISF into Na+, Cl diffuse back from blood into medullary ISF
blood along concentration gradient along concentration gradient

H2O diffuses from blood into ISF H2O diffuses from ISF into blood (vasa recta)

Blood is hypertonic at tip of vasa recta= 1200 mOsm /L

(Reach osmotic equilibrium with medullary ISF).

• Vasa recta does not create medullary hyperosmolarity but prevent it from being lost (dissipated)
(minimize loss of solute)
• Fluids & solutes is reabsorbed into blood by bulk flow through colloid and hydrostatic pressures

3. Role of urea to hyperosmotic renal medullary ISF: urea cycling (trapping) (urea handling)
a. 40 % of the filtered Urea is passively reabsorbed n PCT
Mechanism: as water is reabsorbed→↑ urea concentration in the tubular fluid
→ create concentration gradient→ favoring passive reabsorption of urea
b. Loop of Henle is slightly permeable to urea (from ISF to renal tubule)
c. Late DCT, cortical collecting duct, outer medullary collecting ducts are relatively impermeable to urea
→↑ urea conc. When ADH is present.
d. At inner medullary CD→ urea is reabsorbed (diffuse) into medullary ISF
(facilitated by ADH through insertion of UT-1 and UT-3)
→ adding 50% of osmolarity (500 mOsm/L) of renal medullary ISF
• High protein diet →↑ability of the kidney to form concentrated urine in CD (vice versa)
e. Urea cycle: urea diffuses back from medullary ISF into thin loop of Henle
→ then back to medullary CD again
Circulate through theses terminal parts several times before it is excreted

4. Sluggish medullary blood flow receive 1-2 % of total renal blood flow
→ minimize solute loss from medullary ISF

29
 Requirements for Excreting a Dilute Urine

• Solutes are reabsorbed > water in certain segments of renal tubule.

Ascending limb of the loop of Henle DCT, cortical collecting duct, medullary collecting ducts
Impermeable to water Impermeable to water in absence of ADH
Reabsorb Na+, K+, Cl- Reabsorb NaCl.
Tubular fluid → become dilute as it enters DCT Tubular fluid → become more diluted
(Osmolarity = 100 mOsm/L) (osmolarity =50 mOsm/L)

Disorders of urinary concentration

A- Diabetes Insipidus
Causes
Central diabetes insipidus Nephrogenic diabetes insipidus

Deficiency of ADH secretion due to lesion of Inability of the kidney to respond to ADH due to
Hypothalamus Congenital defect in V2 receptors in collecting duct
Hypothalamo-hypophyseal tract
posterior pituitary
Manifestations
a. Polyuria: large amounts of dilute urine.

b. Polydipsia: Drinking of large amounts of fluid→ keeps patients alive.

If sense of thirst is depressed by loss of consciousness→ fatal dehydration.

B- Syndrome of inappropriate ADH secretion (SIADH)

Cause; Excessive secretion of ADH from
➢ Posterior pituitary
➢ Ectopic source as malignant tumor (e.g. bronchogenic carcinoma)
Manifestations

a. H2O retention→ expansion of ECF volume.

b. Hyponatremia
Cause: water retention →↓aldosterone secretion →↑urinary excretion of Na+
c. ↑urine osmolarity: because of ↓ H2O excretion & continuous excretion of Na+
d. Edema: due to ↓plasma osmolarity → water shift into the interstitial space.
Treatment: drugs block ADH receptors.

30
 Diuresis (↑rate of urine output )
Types
1. Water diuresis
Cause drinking of large volume of H2O or hypotonic fluid.
Onset start 15 min after drinking of water load → reaches maximum in 40 min.
Mechanism ↓plasma osmolarity →Inhibit ADH →↓ facultative H2O reabsorption (impermeable CD)
Result excretion of large volume of hypotonic Urine

2. Osmotic diuresis
Cause presence of large amount of Un-reabsorbed solutes in renal tubule: e.g.
a. ↑ filtered glucose (Uncontrolled diabetes mellitus)
b. Infusion of large amounts of urea
c. Infusion of osmotically active substances, not reabsorbed by renal tubule (as Mannitol)
Mechanism
a. Un-reabsorbed Solutes in PCT →hold water →↓ obligatory H2O reabsorption.
b. H2O retention→↓Na+ concentration in tubular fluid → ↓ active Na+ reabsorption→ leads to
• Na+ retention in the renal tubule & consequently water.
• ↓medullary osmolarity due to ↓ active Na+ reabsorption from ascending loop of Henle
→ ↓ H2O reabsorption in collecting duct & descending limb of loop of Henle
→↓ facultative H2O reabsorption.
Result excretion of large volume of isotonic or hypertonic Urine (↑Na+ & electrolytes excretion)
H2O diuresis Osmotic diuresis
Production Drinking of large volume Presence of large amount of un-
of H2O reabsorbed solutes in renal tubule.
ADH secretion Inhibited Normal or increased
H2O reabsorption ↓Facultative ↓Facultative and obligatory
Solute excretion Not increased. Increased.
Maximal urine flow Large volume 16 mL/min Large volume.
Osmolarity of urine Hypotonic Isotonic or hypertonic
3.
3. Pressure diuresis see before.
4. Diuretic drugs see before

31
 Secretion of Hydrogen & Reabsorption of Bicarbonate (Renal Control of Acid - Base Balance

• Most powerful (efficient) buffer mechanism.

Site
• H+ is secreted in all renal tubule except descending and ascending thin limbs of the loop of Henle
• For each H+ secreted, one bicarbonate is reabsorbed.
• Bicarbonate is reabsorbed mainly by
o Proximal tubule (85%)
o Thick ascending loop of Henle (10%)
o Collecting duct (4.8%)
• Renal tubules are poorly permeable to HCO3-.
• Reabsorbed HCO3- is formed in tubular epithelium from CO2
CA
o CO2 (coming from the blood or formed by metabolism) + H2O→ H2CO3 →H+ + HCO3-
H+ are secreted into tubular fluid →buffered by
➢ Bicarbonate/ Phosphate buffer in tubular fluid
➢ Ammonia synthesized by tubular epithelium

Mechanism of H+ secretion and HCO3 reabsorption

Secondary active transport Primary active secretion
A- In PCT (85 %) C- in late DCT and collecting ducts. (4.8%)
B- loop of Henle (thick ascending) and initial DCT (10 %) • H+-ATPase pump at the luminal membrane
• Counter-transport mechanism of the intercalated cells
Antiport carrier at luminal borders ➢ H+ is actively secreted
→ binds H+ and Na+ ➢ Na+ - independent
➢ Na+ diffuses into tubular cell ➢ Stimulated by aldosterone →↑900 folds.
➢ H+ diffuses into tubular lumen. • For each H+ secreted, one bicarbonate is
No H handling in……………………. reabsorbed

Hydrogen secretion by these segments represent the fixed acids produced from metabolism of ingested
proteins and phospholipids and responsible for regeneration of new HCO3
• Hydrogen secretion in PCT, returns back the filtered HCO3 to the blood
• Hydrogen secretion by DCT, collecting duct generate new HCO3

32
 Fate of H+ secreted

1. In PCT by NaHCO3 buffer (as before)

2. In Distal tubule and collecting duct
A- Buffering by phosphate buffer
a) 30 - 40 mEq of Na2HP04 is available/ day→ concentrated as it reaches DCT and collecting duct.
b) H+ + Na2HP04→ NaH2PO4 + Na+
c) NaH2PO4 is excreted → cause most of titratable acidity in urine
d) Na+ is reabsorbed with intracellular HCO3-
e) Results: H+ secretion + net reabsorption of newly synthesized HCO3-
B- Buffering by ammonia (NH3)
a. NH3 is formed from glutamine
Glutaminase
i.
Glutamine ⎯⎯⎯⎯⎯⎯⎯→Glutamic acid + NH3
b. NH3: is lipid-soluble →diffuses into tubular fluid
c. H+ + NH3 → NH4+
d. NH4+ + Cl → NH4Cl (excreted in urine)
e. Na+ is reabsorbed with intracellular HCO3-

Importance of H+ buffering
o H+ secretion in DCT and collecting ducts as long as
▪ pH of the fluid in these segments > 4.5 (limiting pH for H+ secretion).
o If secreted H+ is not buffered→ this pH is reached rapidly → cause stop of H+ secretion.

Factors affecting acid secretion

1. Aldosterone: ↑ H+ secretion in exchange with Na
2. Intracellular PCO2: ↑PCO2 (respiratory acidosis) →↑ intracellular H2CO3→↑ H+ secretion.
3. ECF K+ concentration: in hyperkalemia →↓H+ secretion (since both compete for secretion in DCT, CD)
4. Carbonic anhydrase inhibitor: inhibit hydrogen secretion

33
 Kidney Function Tests

1. Blood Analysis
A- Blood urea & blood urea nitrogen (BUN)= amount of nitrogen contained in urea.
o Normal blood urea =20-40 mg/dL.
o Importance: Poor guide to renal function as it varies with
• Protein intake
• Liver metabolic capacity
• Impaired kidney function.
B- Plasma creatinine: Produced from muscle at a constant rate and completely filtered at glomerulus and
very little is secreted by renal tubule.
o Normal level= 0.6 - 1.5 mg/dL
o Important measure of kidney function
• Normal BUN: creatinine ratio = 10:1 .
• With dehydration, ratio = 20:1 or higher due to ↑urea reabsorption.
C- Potassium level = 3.5- 5 mEq/L. (↑in renal insufficiency)
D- Blood pH: Arterial pH = 7.4 Venous pH = 7.35 (Acidosis in renal failure)

2. Urine Analysis:
A- Volume: normal 500 - 1500 ml/day
I- Polyuria: ↑volume of urine= urine output > 3 L/day
or > 40 ml/kg/24hrs in adults
or > 2 L/m 2/24 hrs in children.
❖ Must be differentiated from frequency or nocturia,
which may not be associated with an ↑in total urine output.
❖ Possible causes

• ↑fluid intake.
• Osmotic diuresis "diabetes mellitus"
• Diabetes insipidus.

34
 II- Oliguria: decreased volume of urine= Urinary output < 400,ml per day in adult
Or < 0.5 ml/ kg/h in children ,
< 1 mL/kg/h in infants
❖ Importance:
• one of the earliest signs of impaired renal function or acute kidney injury (AKI)
❖ Classification and causes

• Prerenal causes e.g. dehydration

• Intrinsic causes due to parenchymal damage e.g. glomerulonephritis
• Postrenal causes (obstructive uropathy): 2nd to urinary retention e.g. benign prostatic hypertrophy .
III- Complete anuria: Acute vascular thrombosis, Total urinary obstruction.
B- Presence of proteins in urine is indicative of glomerular damage.

C- Specific gravity: normal 1010 -1020

• Low: diabetes insipidus.

• High: diabetes mellitus
• Low fixed specific gravity (1010) occurs in chronic renal failure.
3. Tests depending on blood and urine analysis (Plasma Clearance):
Creatinine clearance: best index for kidney function & GFR measurement.
• ↓in renal dysfunction
• Used in follow up in chronic kidney disease and to determine the proper time for initiation of dialysis
or replacement therapy.
4. Imaging Techniques:
• Plain - X-Ray→ shows opaque calculi and calcifications in the urinary tract.
• Intravenous urography: injection of iodine -containing compound that is excreted by kidney e.g. diodrast.
Radiographs are taken at intervals after injection
→ detects non - opaque calculi, strictures of urinary tract.
• Ultrasonography→ shows
➢ Renal size and position.
➢ Dilatation of the collecting system suggesting obstruction.
➢ Tumors and cysts.
• Computed Tomography (CT): detect tumors

35
 Physiologic Anatomy of the urinary bladder

1. Body: smooth muscles = detrusor muscle

→ functional syncytium →↑ pressure in the bladder to 40-60 mm Hg

→ to cause emptying of the bladder.

2. Neck: 2-3 cm funnel - shaped extension of the body,

surrounded by internal urethral sphincter (extension of the detrusor muscle)

Functions of the internal sphincter

a. Its natural tone→ keeps the posterior urethra empty of urine
→ prevents emptying of the bladder until the pressure in the bladder body rises > threshold level.

b. Prevents reflux of semen into the bladder during ejaculation.

External urethral sphincter voluntary skeletal muscle →consciously controls micturition.

Innervation of the bladder and sphincters

Parasympathetic Sympathetic Somatic
Supplies Urinary bladder wall internal urethral External urethral
(detrusor muscle) sphincter sphincter.

internal urethral sphincter

Origin S2 and S3 L2 S2 and S3
Afferent 1. Detect stretch in the 1. Fullness Sensation Transmits sensation of urine
bladder & posterior urethra 2. Pain sensation due to flow from stretch receptors
initiate micturition reflex over stretch or infection. in posterior urethra

Efferent Contraction of bladder wall Contraction of internal Control external urethral

urethral sphincter to sphincter

Relaxation of internal prevent reflux of semen

urethral sphincter. into the bladder during

ejaculation

36
Micturition is emptying of urinary bladder when it becomes filled. 2 steps:
1- Filling of the bladder,
2- Micturition reflex: see later
Mechanism of Bladder filling
▪ Peristaltic contractions along the ureter → force the urine from renal pelvis towards the bladder.

▪ Backflow (reflux) of urine from the urinary bladder into the ureters is prevented as

✓ Oblique course of ureters through the bladder wall for several cms and 1-2 cm beneath the
bladder mucosa

✓ Normal tone of detrusor muscle compresses the ureters with ↑of pressure.

▪ Not much increase in intravesical pressure until the bladder is well filled.
2T
Explained by Laplace law: P=
r
✓ With bladder filling →↑ wall tension & radius→ slight ↑pressure

✓ At certain volume, T markedly increases & intravesical pressure increase sharply

Cystometrogram
Intravesical pressure = 0 when there is no urine in the bladder.

Volume of urine intravesical pressure

Segment la 50 ml ↑to 5-10 cm water

Segment Ib ↑ to 200 - 300 ml Small ↑in pressure

Segment II 400 ml Sharp rise in pressure

➢ 1st urge to void is felt at a bladder volume of 150 ml

➢ Marked sensation of fullness at 400 ml.

37
Micturition reflex
• Spinal autonomic reflex, initiated when tension in the wall rise > threshold level
as volume reach 300 - 400 ml (in adult)

• Can be inhibited or facilitated by higher centers in cerebral cortex or brain stem

• Components:
1. Receptors: stretch receptors in the bladder wall and posterior urethra.

2. Afferent: Pelvic parasympathetic.

3. Center: S2 and S3.

4. Efferent: pelvic parasympathetic.

5. Effector and response: Detrusor muscle: contraction.

Internal urethral sphincter: relaxation.

Micturition reflex is self-regenerative:

o Once it begins, Contraction of the bladder further activates the stretch receptors
→ further ↑in sensory discharge from the bladder & posterior urethera
→further ↑in reflex contraction of the bladder.

▪ Once the micturition reflex becomes powerful enough, it causes another reflex

→ passes through pudendal nerve→ inhibit the external urethral sphincter

Higher control of the micturition reflex in cerebral cortex & brain stem
 Cortical Micturition Centre (CMC): in superior frontal gyrus →facilitate or inhibit micturition reflex.

• Facilitatory centers: a) Pontine centers: b) Posterior hypothalamus

• Inhibitory center: mid-brain

Control micturition in the following way

a) Partially inhibit micturition reflex except when micturition is desired.

b) Prevent micturition even if micturition does occur by contraction of the external urethral sphincter.

c) at appropriate time, cortical areas facilitate sacral centers to initiate micturition reflex & inhibit external
urethral sphincter.

38
Mechanism of initiation of voluntary urination
1. Relaxation of the pelvic floor muscles

leads to downward tug on detrusor muscle to initiate its contraction.

2. Voluntary contraction of the abdominal muscle→↑intravesical pressure

→ entry of urine in the bladder neck→ stretch of the bladder neck

→ stimulate stretch receptors→ excite micturition reflex.

3. Simultaneous relaxation of the external urethral sphincter.

• After urination, the female urethra empties by gravity.

• urine remaining in the male urethra is emptied by contraction of the bulbocavernosus muscle.

Abnormalities of micturition =Urinary incontinence

Deafferentation Denervation Spinal Cord damage
Cause Damage of dorsal root by e.g. Destruction of Transection of the spinal cord
syphilis (Tabes dorsalis) afferent & efferent leaving sacral segments intact.

Micturition Abolished. Abolished 1.Spinal shock: lost.

reflex 2.Recovery stage: return.

Voluntary Lost. Lost. Lost.

control
Bladder Thin-wall Thick-wall Shock stage: Flaccid.
Distended shrunken
hyperactive. Recovery stage: Hypertrophied
Hypotonic.
(denervation with reduced capacity.
Hypersensitivity)
Urination The bladder fills to capacity Hyperactive Retention with overflow in
and overflows few drops at a bladder expels shock stage.
time because of intrinsic dribbles of urine. Automatic bladder in recovery
response of detrusor muscle stage.

hypersensitivity)
39
 Acid Base Balance

❖ Total amount of H+ in ECF= very small compared to the amount produced / day.
❖ pH=-l og10 (H) =- Log 0.00004= 7.4
• Slightly alkaline.
• Life is compatible within narrow range of pH= 7.35-7.45
• Death occurs if the pH < 6.8 or > 8.0
❖ Regulation of Abid - Base Balance (pH): 3 major systems
1. Buffer systems: minimize change in free H + concentration.
2. Respiratory system: eliminates H + derived from C02.
3. kidneys: excrete fixed acids and restores ECF buffers.

Buffer System

• Combination of many buffers in the body, determines free H + concentration.

• Relation between pH and ratio of concentration of the buffer members.
𝒔𝒂𝒍𝒕
Expressed by: Henderson-Hasselbalch equation: pH of a buffer = pK+ log 10𝒂𝒄𝒊𝒅
pK: minus log dissociation constant.
✓ When Henderson-Hasselbalch equation is applied to the bicarbonate-carbonic acid buffer:
▪ [HCO3] = 24 mmol/L
▪ [H2C03] = PC02 x solubility co-efficient (0.03ml carbonic acid formed for each 1 mmHg PC02) =40 x 0.03
▪ pK= 6.1
𝑯𝑪𝑶𝟑 (𝟐𝟒)
▪ pH of arterial blood = 6.1 + Log10 𝑯𝟐𝑪𝑶𝟑 (0.03 X40) = 6.1 + 1.3= 7.4

• The effectiveness the buffer depends on:

a) Amount of the buffer pair.
b) PK of the buffer system: The buffer is most effective when its pH = PK.
The nearer the PK to the pH of ECF→ the more is the effective of the buffer
• Role of buffers in regulation of acid-base balance
Immediately trap H+ temporarily until respiratory and renal mechanisms act.
They Only minimize the change in H + concentration.

40
• Types of buffer systems:
1. Bicarbonate buffer system H2CO3/ BHCO3 B= Na or K

2. Phosphate buffer system BH2PO4/ B2HPO4

3. Protein buffer system:

a) Plasma proteins.
b) Hemoglobin
c) Tissue proteins.

• Physiological importance of main buffers:

• Bicarbonate Buffer

1- Its concentration in ECF = 24mmol/L

2- Very effective buffer as its components can be controlled
• HCO3] is regulated by the kidneys.
• [H2C03] is regulated by the respiratory system.

3- Changes in pH that result from an alteration in either HC03- concentration or PC02

can be corrected by changing the other variable to preserve the buffer ratio.

• Hemoglobin Buffer: plays an important role in buffering C02 produced at the tissues

(chloride shift phenomenon).

41
Respiratory control of pH ((

Mechanism

A- in metabolic acidosis:
• H+ stimulates R.C. via peripheral chemoreceptors→ Hyperventilation →↓C02 →↓carbonic acid and
H + concentration
incomplete correction of pH is but it is compatible with life.
Final correction is brought about by the kidney
B- In metabolic alkalosis: vice versa

Effectiveness:

• Respiratory system return [H+] and pH 2/3 the way back to normal within minutes to hours after a
sudden disturbance
• Buffering power = 1 - 2 times as all the chemical buffers combined, but has limited ability.

Renal control of pH
• kidneys return pH back to normal within 12-24 hours in most cases.
( when respiratory system fails to completely restore [H+] to normal)

• Most efficient & powerful buffer mechanism through:

➢ Reabsorption of nearly most of the filtered HCO3
➢ Regeneration of new HCO3 with secretion of fixed acids

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 𝑯𝑪𝑶𝟑
Acid - Base disturbance pH depends on ratio 𝑷𝑪𝑶𝟐 Acidosis (Arterial pH < 7.35) Alkalosis (pH > 7.45)

Primary change is in PCO2 Primary change is in HCO3

Respiratory acidosis Respiratory alkalosis Metabolic acidosis Metabolic alkalosis

Causes pH?? pH ?? PH pH
↑ arterial PCO2 >45 ↓ arterial ↓ plasma HCO3<22 ↑ plasma HCO3>28
Respiratory centers PCO2<35 1. ↑production of 1.Persistent vomiting
depression High altitudes fixed acids H+ and Cl- are lost in
Narcotics a) DKA: acetoacetate, vomitus & HCO3- is
Excess sedation Psychological B-hydroxybutyrate added to plasma.

Air way obstruction dyspnea (anxiety) b) Shock: ↑lactic acid 2.↑intake of alkali
Bronchial asthma c) Aspirin poisoning to treat peptic ulcer.
Emphysema Fevers → Salicylic acid. 4. Cushing syndrome.
Asphyxia d) Methanol poisoning 5. Conn's syndrome.
Paralysis of respiratory → formic acid.
muscles K+ leaves the cells in
2. ↓ elimination of exchange with H+
fixed acid::Renal failure 6. Diuretics except
3. Loss of HCO3- carbonic anhydrase
a) Severe diarrhea. inhibitors.
b) Pancreatic fistula
c) Addison's disease

Compensation Renal Renal Renal Renal

• ↑PCO2 →↑ • ↓PCO2 →↓ • ↑ generation and • ↓ generation and
generation of H+ and generation of H + reabsorption of reabsorption of
HCO3- in renal and HCO3 in renal [HCO3-] +H secretion
- [HCO3-] + ↑loss of
tubular cells. tubular cells. Respiratory HCO3-in urine
• H+ is secreted + • ↓Reabsorption • ↑H+ →↑ ventilation Respiratory
HCO3- is reabsorbed of filtered HCO3 via peripheral • ↓ [H+] →
• ↑plasma HCO3 ↓plasma HCO3 chemoreceptors→↓ →↓ventilation →↑
PCO2, H+ PCO2 (potent stimulus
However, ↑ventilation to ↑ventilation,
• Thus PCO2 slightly
is insufficient to return
plasma H+ to normal
↑(respiratory
→metabolic acidosis component is not so
with respiratory
powerful as in
compensation
acidosis

43
 pH

< 7.35 >7.45

Acidosis Alkalosis

HCO3< 22 mEq/L PCO2>45 mmHg HCO3> 28 mEq/L PCO2<35 mmHg

Metabolic respiratory Metabolic respiratory

If ↓PCO2 if ↑HCO3 if ↑PCO2 if ↓HCO3

Metabolic acidosis Respiratory acidosis Metabolic alkalosis Respiratory alkalosis
With respiratory compensation with renal compensation with respiratory with renal compensation
compensation

Acid base disturbance , caused by one system, results in compensation by complementary system e.g. see before
Compensation restore pH towards normal, even though HCO3, PCO2 are still disturbed

Arterial venous
pH 7.35-7.45 7.32-7.43
PO2 80-95 mmHg 20-49 mmHg
PCO2 30-45 mmHg 41-51 mmHg
HCO3 21-28 mEq/l 24-28 mEq/l

44
 Stimulus for Time
Hormone Mechanism of Action Actions on Kidneys
Secretion Course
PTH plasma [Ca2+] Fast Basolateral receptor
Adenylate cyclase→ .  PO4 reabsorption (PCT)
cAMP . Ca2+ reabsorption (DCT)
. Stimulates 1 hydroxylase (PCT)

ADH  Plasma Fast V2 receptor  H2O permeability (late DCT & CD; P-
osmolarity Adenylate cyclase cells).
 Blood volume cAMP

blood volume Slow New protein Na+ reabsorption (DCT; P-cells).

(via rennin- synthesis K+ secretion (DCT; P-cells)
Aldosterone
angiotensin II)
plasma [K+]
Fast Guanylate cyclase  GFR
ANP atrial pressure
cGMP. Na+ reabsorption
Angiotensin blood volume Fast Na+-H+ exchange & HCO3- reabsorption
II (via renin) (PCT)

45
 Name Equation Units Comments

Clearance [U] x V ml/ min X is any substance

Cx =
[P] x
Glomerular [U]Inulin V ml/ min Equals Cinulin
filtration rate GRF =
[P]Inulin

Estimated GFR (140−𝑎𝑔𝑒)𝑋 𝑤𝑒𝑖𝑔ℎ𝑡 (𝐾𝑔) ml/min ( X 0.85 For woman),

𝐆𝐅𝐑 = 𝑷𝒄𝒓 𝑿 𝟕𝟐

Effective renal Effective RPF = ml/ min

plasma flow [U] PAH V
[P] PAH
True Renal plasma ERPF/ extraction ratio ml/min
flow

Renal blood flow RBF ml/ min HV is fraction of blood volume

RBF = x 100
100 - HV that is RBC’s.

Filtration fraction GFR None

FF =
RPF
Filtration load Filtered Load = GFR x [P] X mg/ min

Excretion rate Excretion = V x [U] X mg/ min

Reabsorption or = filtered load - excretion mg/ min If positive, net reabsorption

secretion rate If negative, net secretion

46
 Handling of important solutes and water by PCT & Loop of Henle of the nephrons
PCT Descending Ascending Loop of Henle
LOOP of Henle and early distal tubules

Na+ 65% No capacity to 25%

reabsorb Na+
Primary Active No Na+ channels Passive: thin part
on the luminal Active: thick part & early
border distal
H2O 65% Obligatory 15% Obligatory
Passive (osmosis) Passive (osmosis)
AQP-I
K 65% 25 %

Active Active (thick part)

Glucose All

Secondary active
transport
Urea 40 % relatively relatively impermeable
impermeable to to urea.
Passive urea.
HC03 85- 90% 10% (thick part)
Accompanied with H + Accompanied with H +
secretion secretion
Amino acids All
Secondary active
transport
Osmolarity 300 1200-1400 at 100 at the end of loop
mosm/L bottom 60 at the end of early
distal tubules
Iso-isomotic Concentrating Diluting segment
segment

47
Handling of important solutes and water by late distal tubule collecting ducts of the nephrons

48