Renal Physiology

1. Mechanism of Formation of Urine
Dr Ambika Jawalkar

2. Mechanismof Formation of Urine
1. Glomerular filtration.
2. Tubular reabsorption
3. Tubular secretion
4. Concentration & acidification of urine

4. Glomerular filtration. –
 = blood – [ cells + plasma proteins]
 Ultrafiltration of plasma - of water & solutes  4nm.
GFR –
 Rate at which plasma is filtered in all the nephrons of both
kidneys in one minute.
NORMAL VALUE –
 125 ml /min.
 i.e. 180 liters /day.
Urine excretion -
 1 - 2 liters /day.
Note –
 i.e. 178 liters /day is reabsorbed in renal tubules.

5. Factors influencing GFR
1. Net filtration pressure
2. Permeability of glomerular
membrane
3. Surface area of filtering membrane
4. Age

6. Glomerular filtration - across glomerular membrane.
Mechanism – Starling’s hypothesis.[same as tissue fluid formation]
GFR = Kf X NFP
Kf = the glomerular ultrafiltration coefficient, [is the product of the
glomerular capillary wall hydraulic conductivity (ie, its permeability)
and the effective filtration surface area.]
PGC is the mean hydrostatic pressure in the glomerular capillaries,
PT the mean hydrostatic pressure in the tubule,
GC the osmotic pressure of the plasma in the glomerular capillaries,
and
T the osmotic pressure of the filtrate in the tubule.

7. FactorsinfluencingGFR
1. Net filtration pressure [NFP] =
[GBHP + TCOP] - [CHP + BCOP]
 GBHP =
 Glomerular blood hydrostatic pr.
 [favouring GF]
 TCOP =
 Tubular colloid osmotic pr. =0;
 due to protein free filtrate
 CHP =
 Capsular hydrostatic pr.
 [opposing GF]
 BCOP =
 Blood colloidal osmotic pr.
 [opposing GF]
GFR = Kf X NFP
 [ Kf =
 ultrafiltration coefficient =
 intrinsic permeability of glomerular membrane]

8. FactorsinfluencingGFR–solvetheproblem
1. Net filtration pressure [NFP] =
[GBHP + TCOP] - [CHP + BCOP]
 Question -
 GBHP = 60 mm Hg. ; CHP = 18 mm Hg.; BCOP = 32 mm Hg.
Answer –
NEP =
 [GBHP + TCOP] - [CHP + BCOP] =
 [60] – [18 +32] =
 60 - 50 =
 10 mm Hg
GFR = Kf X NFP
 [ Kf =
 ultrafiltration coefficient =
 intrinsic permeability of glomerular membrane]

18. FactorsinfluencingGFR [contd]
2. Permeability of glomerular membrane. –
Glomerular capillary –
 50 times more permeable than other capillaries.
Glomerular membrane –
 It has pore size of 8 nm. &
 Is – vely charged due to presence of sialproteins.
[NOTE -
Size –
 upto 8 nm filtration of neutral charged particles.
As it is –vely charged &
 it repels –ve charged particles like albumin [plasma protein]
 [ which is absent in filtration.]

19. Applied –
in glomerular membrane damage e.g.
glomerular nephritis & nephrotic syndrome 
Loss of –ve charge of glomerular filltering
membrane 
Albuminuria Or proteinuria. 
Hypoproteinaemia 
 in colloidal osmotic pr of plasma 
  in blood volume + Interstitial oedema.

21. FactorsinfluencingGFR [contd]
3] Surface area of the Filtering membrane
 in Surface Area –
 in mesangial cells contraction by action of Angiotensin II
+ thromboxane A2.
 [Note – mesangial cells are contractile cells in between
capillaries of glomerulus & provide support.]
Applied –
 mesangial cells responsible for development of
glomerulonephritis.
4] Age –
 after 30 yrs – gradual decrease in GFR

22. Determinants
of GFR
(1) the sum of the
hydrostatic and colloid
osmotic forces across the
glomerular membrane,
which gives the net
filtration pressure, and
(2) the glomerular
capillary filtration
coefficient, Kf.

27. MEASUREMENT OF GFR
1. DIRECT METHOD –
 Micropuncture technique.
2. INDIRECT METHOD –
 By clearance measurments –

28. Definition –
Clearance of a substance is
 the volume of plasma cleared of the substance in unit time.
 [E.g. --- ml of plasma/min]
C = UV / P
C = Clearance of a substance
U = Concentration of substance in urine
V = volume flow rate
P = Concentration of the substance in plasma

29. C = clearance of a substance
C = GFR
[ no tubular secretion + no reabsorption]
e.g. Inulin
C > GFR
[net tubular secretion]
e.g. PAH
C  GFR
[net tubular reabsorption]
e.g. Urea.

30. CriteriaofsubstanceusedformeasurementofGFR
I. Is freely filtered by glomerular membrane
II. Is neither reabsorbed nor secreted
III. Is not metabolized, stored or synthesized by body
IV. Does not bind with protein
V. Does not affect GFR
VI. Is not toxic
VII. Whose concentration is easily measurable in plasma & urine.
E.g.
1. Inulin – polymer of fructose
2. Mannitol
3. Vit B12 labelled with radioactive cobalt

31. PROCEDURE
A loading I.V. dose of inulin followed by
 a sustaining infusion to keep the arterial plasma level constant.
After the inulin has equilibrated with body
fluids,
 an accurately timed urine specimen is collected and
 a plasma sample obtained halfway through the collection.
Plasma and urinary inulin concentrations are
determined and the clearance is calculated. i.e.
UV/P ml/min

32. CALCULATE
THE GLOMERULAR FIRTRATION RATE
Concentration of Inulin in Urine : 35 mg/ml
Concentration of Inulin in plasma : 0.25mg/ml
Rate of Urine flow : 0.9ml/min

34. Measurement of GFR
Creatinine:
 End product of muscle creatine metabolism
Used in clinical setting to measure GFR but less
accurate than inulin method
Small amount secrete from the tubule

36. FILTRATION FRACTION –
expressed as % of ratio of GFR to renal plasma flow
 Filtration fraction = GFR x 100/ Renal plasma flow
 = 130 x100/650
 = 20%
FILTRATION COEFFICIENT – [Kf] is
 GFR of both kidneys per mm hg filtration pressure.
Normal value = 10ml/min/mm of Hg.
[Note – GFR = NFP X Kf]

37. REGULATION OF GFR
1. AUTOREGULATION. – due to
autoregulation of renal blood flow inspite of wide fluctuations
of systemic MAP.
2. HORMONAL REGULATION. – due to
1. Renin –angiotensin – aldosterone mechaism.
2. Atrial natriurtic peptide [ANP]
3. NEURAL REGULATION

39.  GFR
RENIN
Angiotensinogen Angiotensin I Angiotensin II


 

 ACE
Renin Angiotensin Aldosterone Mechanism

40. Angiotensin II
Efferent arteriolar
constriction
Aldosterone from adr cortex
Stimulation of
thirst center of
Hypothalamus
 ADH from
post pit
 Glomerular
hydrostatic pressure
 GFR
Reabsorption of
Na+, Cl- & H2O
blood volume
 Glomerular
hydrostatic pressure
 GFR
Reabsorption of
H2O from
DistalTubule
blood volume blood volume
 Glomerular
hydrostatic pressure
 Glomerular
hydrostatic pressure
 GFR GFR

41. HORMONALREGULATION.–dueto
i]Renin–angiotensin–aldosteronemechaism.ii]Atrialnatriurticpeptide[ANP]
II] ATRIAL NATRIURTIC PEPTIDE [ANP] –
Hormone secreted by atrial cells.
Action –
 diuresis & Natriuresis [  H2O + electrolytes excretion]
Stimulus –
 stretch of atria [due to blood volume]
Receptors –
 stretch receptors.
Effects –
  permeability of glomerular membrane.
 Dilatation of afferent arteriole
  ADH secretion
  aldosterone +  renin
IMPORTANCE – help in hypertension & renal failure by–
  GFR.
  H2O retention + oedema   BP

42. 3] Neural regulation
Moderate Symp. stim. –
 Constriction of both afferent & efferent arterioles
 No change in GFR.
Max symp stim
 e.g. exercise, haemorrhage, stress [fight & flight response] -
Predominance of afferent artereolar
constriction
  GFR

45. Applied Physiology

46. Renal Tubular
Functions

47. RENAL TUBULAR FUNCTIONS
Tubular reabsorption
Tubular secretion
Concentration of urine
Acidification of urine
Aim of tubular functions – modify glomerular
filtrate so that urine contains only waste
materials.

49. Tubularfunctions–1]Tubularreabsorption
99 % reabsorption & 1% excretion
By both active & passive process.

53. Two pathways of the absorption:
Lumen
Plasma
Cells
Transcellular
Pathway
Paracellular
transport

54. Primary Active transport can move a solute against an
electrochemical
gradient and requires energy

55. Transport that is coupled indirectly to an energy
source, such as that due to an ion gradient-
secondary active transport
Na+
glucose
Na+
H+
out in out in
co-transport counter-transport
(symport) (antiport)
Co-transporters will move one
moiety, e.g. glucose, in the same
direction as the Na+.
Counter-transporters will move
one moiety, e.g. H+, in the
opposite direction to the Na+.
Tubular
lumen
Tubular Cell
Interstitial
Fluid
Tubular
lumen
Tubular Cell
Interstitial
Fluid

56. TubularreabsorptioninPCT [proximalconvolutedtubule]
100 % of glucose +Amino acids
80 – 90 % HCO3-
65 % of [H2O + Na+ + K+ ]
50 % Cl- + Urea
No creatinine reabsorption in PCT
MECHANISMS –
 1] Passive diffusion –
 H2O + urea + Cl-
 2] Fascilitated diffusion –
 Glucose , Aminoacids
 3] Active transport –
 Na+ by symport, antiport.
 4] Leakage – thro paracellular spaces i.e. thro leaky tight junctions.
 E.g. H2O & electrolytes.

57. Na+ reabsorption
In PCT – 60%
Passive diffusion or fascilitated diffusion OR secondary active transport.
Active transport –
 Na+ - H+ Exchange mechanism [antiport] – 60%
 Cl- driven Na+ transport
In Loop of Henle – 30%
Thin part of Ascending limb –
 Cl- driven Na+ transport
Thick part of Ascending limb –
 Na+- 2Cl - K+ cotransporter [carrier mediated Na+ transport] – 30%
In DCT – 7%
 Cotransporter Na+- Cl
In Collecting tubule – 3%
 Regulated by Aldosterone Via ENaC [ epithelial Na+ channel]

59. In PCT – 60%
1] Passive diffusion. OR Fascilitated
diffusion OR Secondary active
transport
Electrochemical gradient
 Inside cell  Na+ + negative charge =.
 So Na+ enters in along with glucose OR
amino acid [symport] with
cotransporter protein.
 Energy – by Na+- K+ pump at
basolateral junctions
2] Active transport –
 Na+ - H+ Exchange mechanism
[antiport] – 60%
 Cl- driven Na+ transport – leaky tight
junctions

62. In Collecting
tubule – 3%
 Regulated by
Aldosterone Via
ENaC [epithelial Na+
channel]

63. Fate of Na+ inside tubularcells
1] Na+ – K+ ATPase active pump in basolateral membrane
 Na+ out into lateral intercellular space +
 K+ from interstitium into cell.
Na+ enters peritubular capillaries
2] Low hydrostatic pr + high osmotic pr. of peritubular capillaries [as
glomeruli filters plasma without proteins] favors
 passive reabsorption of Na+ along with water.
As Na+ is main cation in ECF determines the ECF volume.
 So Hyponatraemia[ Na+ in blood]   ECF   BP

65. Factors affecting Na+ absorption
1. GFR
2. Neural factors
3. Hormonal factors
 Renin –Angiotensin aldosterone mechanism
 ANF
4. Starling’s forces
5. Drugs

66. FactorsaffectingNa+ absorption– 1]GFR
Glomerulotubular balance OR Load dependent reabsorption. –
In PCT 65 % of solute reabsorbed is constant. i.e.
  GFR  proportionate in solute +  H2O reabsorption.
Mechanism –
i.  GFR   oncotic pr in peritubuar capillaries.
 Due to Starling forces   Na+ & H2O reabsorption.
ii.  Surface area [SA] due to microvilli 
  Na+ & H2O reabsorption.
iii. Leaky tight junctions in PCT [90% more permeable than others]
Significance of Glomerulotubular balance -
 Prevention of overloading on Distal tubule function on  in GFR

67. FactorsaffectingNa+ absorption–2]Neuralfactors
Regulation by ECF volume
 ECF  Direct  Symp stim of kidney 
  Na+ absorption at PCT +  Renin secretion 
 Retention of Na+ & H2O   ECF
Vice versa i.e.
 ECF  thro baroreceptor  Symp tone 
  Na+ absorption at PCT +  Renin secretion 
  Excretion of Na+ & H2O   ECF

68. FactorsaffectingNa+ absorption
3]Hormonal factors
 i] Renin –Angiotensin aldosterone mechanism
Actions of Aldosterone –
a)  luminal permeability for Na+
b) Stimulate Na+ K+ ATPase 
  intracellular Na+ 
 with gradient Na+ enters into cell from tubular lumen.

69.  Na+ intake
 ECF volume
Angiotensinogen Angiotensin I Angiotensin II


 


ACE
Renin Angiotensin Aldosterone Mechanism
RENIN
 Renal arterial mean pr.
Stimulate JGA


70. Angiotensin II
Aldosterone from adr cortex
Reabsorption of Na+ Cl- & H2O in DCT
ECF volume
 Renal arterial mean pressure
RENIN
Reabsorption of Na+ & H2O from PCT
ECF volume
 Renal arterial mean pressure
 RENIN

71. FactorsaffectingNa+ absorption–
3] Hormonal factors [contd]
ii] ANP – [Atrial natriuretic peptide]
  plasma vol   atrial stretch   secretion of ANP
Actions of ANP –
a) Dilate afferent arteriole   GFR
b) Relax mesangial cells to   SA for filtration   GFR
c) Direct action on adrenal cortex  aldosterone  
Na+ reabsorption in collecting duct.
d)  renin secretion
e)  stim of renal sympathetics

72. FactorsaffectingNa+ absorption4]Starling’sforces
According to STARLING’ FORCES -
 peritubular capillary hydrostatic pr & / or  in
peritubular capillary oncotic pr 
 reabsorption of fluid into capillaries. [more in
PCT] 
 excretion of Na+ & H2O

73. FactorsaffectingNa+ absorption5] Drugs
a. Xanthines e.g.
 caffeine, theophylline   GFR +  tubular reabsorption of Na+
b. Carbonic anhydrase inhihitors –e.g.
 acetazolamide [Diamox]   H+ secretion   Na+ + K+ excretion
c. Thiazides –
 inhibit Na+ Cl- cotransporter in distal tubule
d. Loop diuretics e.g.
 frusemide [Lasix] – inhibit Na+ K+ 2Cl- cotransporter in thick ascending
limb of loop of Henle
e. K+ sparing diuretics e.g.
 spironolactone [Aldactone = antagonist of aldosterone],
 Trimterine, amiloride [inhibit EnaC] etc. inhibit Na+ -K+ exchange in
collecting duct

74. Carbonic anhydrase
inhibitor
 e.g.
 acetazolamide
[Diamox] 
 H+ secretion 
 Na+ + K+ excretion

76. K+ sparing diuretics
e.g.
 spironolactone
 [Aldactone =
antagonist of
aldosterone],
 Trimterine,
 amiloride [inhibit
EnaC] etc.
o inhibit Na+ K+
exchange in
collecting duct

78. Sodium Reabsorption

79. Glucose reabsorption
Normal –
 Filtration rate – 100mg /min
PCT - 100% reabsorption of filtered load
 by secondary active transport.
 Symport with Na+ by SGLT2 present in luminal membrane
TMG[tubular maximum transport of glucose] = 375 mg /min.
 When tubular conc. exceeds TMG value glucose appears in urine
[glycosuria].
Renal threshold for glucose = TMG / GFR X100
= 375mg/min / 125ml/min X 100
= 300mg /100ml of plasma

80. Transport maximum
For most substances that are actively reabsorbed or
secreted, there is a limit to the rate at which the solute
can be transported, often referred to as the transport
maximum.
 It is dependent on substances transported by
TRANPORTERS [transport proteins]
 At higher conc. of substance the transport
mechanism is saturated & there is no further increase
in transport.

81. RENALTHRESHOLD
Substances with Tubular Maximum value have a threshold
value in plasma.
It can be calculated with the help of TM value.
Below threshold level –
 complete reabsorption of the substance & it is absent in urine.
Above threshold level,
 excess amount is not reabsorbed & appears in urine.
Renal threshold for glucose = 180mg /100 ml of plasma.
i.e.
 Glucose conc. upto 180 mg /100ml of plasma =
 all reabsorbed +
 no glucose in urine.
 Glucose conc. more than180 mg /100ml of plasma =
 375 mg /min is reabsorbed +
 excess glucose appear in urine. [glycosuria]

82. Splay
Renal threshold for glucose is plasma glucose at which glucose
first appears in urine.
Renal threshold = TMG / GFR X 100
= 375 mg/min /125ml/min X 100
= 300mg /100 ml of plasma.
This is theoretical value.
The "ideal" curve shown in diagram would be obtained if the TmG in all
the tubules was identical and if all the glucose were removed from each
tubule when the amount filtered was below the TmG.
Actual value of renal threshold is 180 mg /dl of venous blood
[corresponds to 200 mg / dl of arterial blood] & is less than predicted
theoretical value.

83. If graph is plotted with plasma glucose in X axis, amount of glucose
reabsorbed in Y axis, curve appears to be rounded & deviated
considerably from the ideal or theoretical curve.
This deviation is called Splay.
The magnitude of the splay is inversely proportionate to the avidity
with which the transport mechanism binds the substance it
transports

84. Reabsorption of Amino Acids
100 % Reabsorption of filtered load of
AA
At PCT
 Secondary active transport.
 Symport with Na+ .
Transport to peritubular space by
 simple diffusion OR
 Facilitated diffusion

85. Chloride Reabsorption
By Passive diffusion
1. With Na+
2. PCT – thro leaky tight junction

86. Chloride Reabsorption

87. Ca2+reabsorption
Normal plasma Ca2+ =
 9 -11 mg/100ml
Reabsorption of 99% of filtered load of Ca2+ +
1% excretion in urine.
Urinary excretion =
 200mg /day
Mechanism –
80% - passive
20% -via Ca2+ channels
Active process – from cell to interstitium
Regulated by
 Parathormone,
 Calcitonin &
 Calcitrol
Site of action –
 ascending limb of loop of Henle & Distal tubule.

88. Ca2+&Pi[inorganic]reabsorption[contd]
Normal plasma Pi [inorganic] =
 4 mg/100ml
Reabsorption of 90% of filtered load of Pi[inorganic] +
10% excretion in urine.
Pi [inorganic] –
 imp buffer to maintain acid base balance.
Hormonal regulation –
1. Parathormone –
  inhibits reabsorption at PCT
2. Growth hormone –
  reabsorption at PCT.

89. K+ Reabsorption-
Reabsorption
100% of filtered load
Urinary excretion =
2gm/day
Due to secretion of K+
in distal tubule under
influence of
 Aldosterone as antiport
with Na+

90. Urea reabsorption
Normal blood urea –
 20 - 40 mg/100ml of blood.
[Note – Uraemia or Azotaemia =
 ↑↑ blood urea level]
Urinary excretion –
 25gm/day
Urea excretion depends on
 urea formation in turn
 depends on protein ingestion.
o[Note – urea is breakdown product of protein]
 Urea secretion in
 thin ascending limb of loop of Henle.
**only about one half of the urea that is filtered by
the glomerular capillaries is reabsorbed from the
tubules.**

91. FactorsdeterminingUreaReabsorption
1.  H2O reabsorption 
  urea reabsorption 
  excretion of urea
2.  urine flow rate 
  excretion of urea
i.e.
 Maximum urea clearance = UV/ P
=75 ml/min
 [Note - when urinary output i.e.
 V = more than 2 ml /min ]

92. Reabsorption& secretionof Uric acid
98% of filtered load -
 reabsorbed.
80% of uric acid in urine is
 secreted by tubules
Normal value –
Plasma conc. – 3 – 6 mg /100 ml
Uric acid excretion – 1gm /day
 in plasma uric acid due to
1.  excretion e.g. treatment with thiazide diuretics.
2.  production – e.g. leukaemia, pneumonia etc due to [] increased
breakdown of uric acid rich WBC.
What is Gout?
Defn – Group of disorders like arthritis, renal stones due
to Hyperuricaemia]
Mechanism of action of Drugs used in Gout is by
 inhibition [] of reabsorption of uric acid at renal tubules 
  excretion of uric acid

93. Waterreabsorption
180 L/day GFR to 1 -1.5 L /day urine
 99.7 % reabsorption in tubules.
1. PCT – 65%
2. Loop of Henle – 15%
3. DCT - 5%
4. Collecting tubule –
a) Cortical part -10%
b) Medullary part – 4.7%
2 types –
I. Obligatory water reabsorption –
 PCT + Loop Of Henle
II. Facultative water reabsorption –
 DCT + CT [under influence of ADH]

94. Obligatory water
reabsorption [90%]–
 PCT + Loop Of Henle.
 Because water is obliged
to follow the solutes.
90% By osmosis
 along with reabsorption of
solutes e.g.
 Na+, Cl-, Glucose etc.
2 routes –
a) Paracellular route
b) Trans cellular route

95. Facultative water reabsorption –
DCT + CT
 [under influence of ADH i.e. water conserving
hormone]
Homeostasis maintained by
 a negative feedback system regulating
 ADH stimulated water reabsorption.
On stim of osmoreceptors [hypertonicity] in
Hypothalamus
 thro supra optic & paraventricular nuclei there is
  ADH   water reabsorption in DCT +CT
  normotonicity.

96. ADH

97. Mechanismof actionof ADH
Site of action –
 distal tubule [collecting duct]
 [Aquaporin -2]
Aquaporins –
 protein water channels on cell membrane.
 Help in  diffusion of water across cell membrane.
4 types -
1. Aquaporin -1 –present in PCT
2. Aquaporin -2 – present in Collecting duct.
3. Aquaporin-5
4. Aquaporin -9
[note – aquaporins present in kidneys, liver, lungs, spleen, salivary & lacrimal
glands.]
MECHANISM –
 Aquaporin -2 in CD is stored in vesicles of cytoplasm of principal cells
 ADH – via V2 receptors, insert aquaporin - 2 on cell membrane.

100. Diabetes Insipidus
Diabetes =
 polyurea [ urine volume]
Insipidus =
 tasteless.
Due to deficiency of ADH 
  volume of hypotonic urine.
Note =
a) Normal urine osmolarity =
 1400 mosm/ kg of water
a) In DI urine osmolarity =
 30 mosm/ kg of water]
2 causes –
 1]  ADH from Post pituitary. – Central Diabetes Insipidus
 2] Nephrogenic DI = CD of kidney fail to respond to ADH.
Due to Mutation of gene coding for
i. V2 receptors or Aquaporin -2

101. Water intoxication
Normal urine flow rate –
 2 ml/min [1.5 to 2L/day]
Max. urine flow rate –
 16 ml /min [18 to 20L/day]
If water ingestion exceeds this limit 
 swelling of cells in hypotonic ECF.
Signs –
1. Convulsions, coma etc
2. Death due to swelling of brain cells.

102. TUBULAR SECRETION

103. Mechanismof Formation of Urine
1. Glomerular filtration.
2. Tubular reabsorption
3. Tubular secretion
4. Concentration & acidification of urine

104. 3] TUBULAR SECRETION
It is movement of substances from blood
to tubular fluid.
E.g. –
i. H+, K+, NH3, Creatinine, Steroids
ii. Drugs like Penicillins, Salicylates etc

105. K+ secretion
Reabsorption =
 100% of filtered load of K+
DCT & CD -
 Secretion of K+
 [maintain contant conc of K+ in body fluids].
 Urine flow rate 
  K+ secretion
Because with rapid flow,
 less chance for tubular K+ conc to rise to value
 that inhibits further secretion of K+ .

106. Regulation of K+ secretion
i.  aldosterone   K+ secretion
ii.  K+ conc   K+ secretion
iii.  Na+ reabsorption in DCT – by Na+ K+
antiport    K+ secretion
iv.  urine flow rate   K+ secretion
v.  H+ secretion   K+ secretion
[competetion for carrier protein]

107. Importanceof K+ secretion
Normal K+ excretion = 2-3 g/day
Secretion of K+ = K+ intake
1. Hyperkalaemia =  in plasma K+ [serious] 
 cardiac arrest [ occurs in impaired renal function].
2. Hypokalaemia =  in plasma K+ [Common]
Causes of hypokalaemia
i. Loss of K+ e.g. severe vomiting, diarrhea, polyurea etc.
ii.  dietary intake of K+
iii. Drugs like
Steroids
Insulin shifts K+ intracellularly
b–adrenergic agonists
Loop diuretics[inhibit Na+ K+ 2Cl-cotransport]
Carbonic anhydrase inhibitors

108. H+ secretion
PCT –
 Secondary active transport –
 for each H+ secreted one Na+ & one HCO3 enter interstitial fluid.
DCT -
 By Aldosterone – act on H+ K+ ATPase   secretion of H+

109. NH3 secretion
1. Glutamine  glutamate + NH3
2. Glutamate  a –
ketoglutarate + NH3
3. NH4  NH3 + H+
NH3 formed inside tubular cells is
secreted & is converted to NH4
maintaining conc gradient for
diffusion of more NH3 into urine
[nonionic diffusion]

110. Production & buffering action of Ammonium [NH3]

111. Production & buffering action of Ammonium [NH3]

113. Concentration &
Dilution of Urine

114. Concentration & dilution of Urine
Total volume of body fluids remains constant inspite of
 fluctuations in intake of fluids ,
 because of regulatory mechanism at kidney.
i. Urine osmolarity vary –
 50 -1200 mOsm /L
ii. Corresponding urine volume –
 18L/day to 0.5L/day.
Diuresis
  fluid intake   vol of urine + dilution of urine
Antidiuresis = conservation of body fluids.
  fluid intake OR  fluid loss[e.g. heavy sweating, vomiting, diarrhea
etc]   vol of urine + conc of urine

115. Why urine is concentratedOr diluted?
Kidney is the major regulator of water loss from body
 as other routes of water loss like sweating, thro respiratory passages, GIT etc are not
under regulation.
Conservation of water
 in times of Hypotension OR Hyperosmolarity.
Mainly by influence of ADH [water conserving hormone] on DCT.
Water moves across tubular membrane with osmotic gradient.
 So Hyperosmotic environment is created in interstitial fluid of Renal medulla
Normal solute conc of interstitial fluid
 300 msmO/L in renal cortex 
 1200 mOsm/L in renal medulla.
Major solutes contribution is
 NaCl & Urea
Major role in maintainance of osmotic gradient is
 Thick ascending limb of Loop Of Henle

117. Factorsresponsiblefor Production&
Maintenanceof Osmotic gradient
1] For Production of Osmotic gradient –
 Differences in water & solute permeability in different segments of
nephron
2] For Maintenance of Osmotic gradient –
 Countercurrent mechanism operating in loop of Henle & vasa
recta

118. 1]ForProductionofOsmoticgradient–Differencesinwater&solutepermeabilityin
differentsegmentsofnephron
i. PCT –
 Free permeable to both . So Isotonic.
ii. Descending Limb of Loop Of Henle –
 permeable to water, not to solutes.
 So Hypertonic at hair pin bend of Loop Of Henle
 [note – greater length of Loop Of Henle - greater osmolarity at hair pin bend of Loop Of Henle
]
iii. Ascending limb –
 a] Thin ascending limb – impermeable to water but permeable to solutes.
 [Hypotonic gradient]
 b] Thick ascending limb – impermeable to water but permeable to solutes by
active reabsorption of Na+ K+ 2Cl– [symporter]. &
 is responsible for concentration of solutes in medulla &
 setting up of Osmotic gradient [hypotonic] = 150 mOsm /L at entry of DCT.
iv. DCT – not permeable to water.

119. Isotonic
Hypertonic
Hypotonic
Hypertonic

120. 1]ForProductionofOsmoticgradient–Differencesinwater&solutepermeabilityin
differentsegmentsofnephron[contd]
vi] Collecting Duct –
 reabsorption of water + Na+ + urea
Principal cells of collecting duct –
 highly permeable to water under influence of ADH.
Tubular fluid –
 highly hypertonic.
 [ note – ADH + V2 receptors  activation of adenyl cyclase  insertion of Aquaporins
-2 into luminal membrane of principal cells]. 
Water reabsorption along with osmotic gradient of
hypertonic gradient.
 [note – hypertonicity of plasma is major stimulus of ADH . & effective
osmolarity of plasma determined by plasma Na+ conc as it is the ECF
major solute.]

122. 1]ForProductionofOsmoticgradient–Differencesinwater&solutepermeabilityin
differentsegmentsofnephron[contd]
Urea recycle -
 On water reabsorption under influence of ADH   urea conc of
tubular  diffusion of urea by Facilitated diffusion   in medullary
interstitium.
 From medullary interstitium urea enters into ascending limb & thin limb
of descending limb.
 Thus constant transfer of UREA from between different segments of
renal tubule & medullary interstitium.
 Reabsorption of water from tubular fluid of renal medulla   urea
conc. of medullary interstitium  further facilitating reabsorption from
collecting duct & help in concentration of URINE.

123. Mechanismof excretionof Dilute Urine
Low plasma osmolality [e.g. Hypervolemia, OR plasma Na+ is
 135 mmol /L] 
 No ADH. 
 No reabsorption of water from CD.
Note –
 Reabsorption of NaCl continues
 So tubular fluid becomes progressively HYPOOSMOTIC with  Na+ + 
Urea
In absence of ADH
 Max vol [] of urine = 18L/day
 & [] Urine osmolarity = 50 mosm/L

124. Less Hypertonic

125. Countercurrent
Mechanism

126. Countercurrent Mechanism
Defn – A system when inflow runs
Parallel to,
Counter to &
In close proximity to out flow.
Sites of CCM in kidney –
 1] Loop of Henle
 2] Vasa Recta.
[note – if CCM absent in Vasa recta - loss of medullary osmotic gradient by
washing away of solutes + urea]
CCM in Vasa Recta allows some reabsorption of water.
So fluids in
i. descending limb of Loop Of Henle,
ii. medullary interstitium,
iii. descending limb of Vasa Recta
= same osmolarity

127. CCM multiplier system – Loop Of Henle

128. CCM exchanger system – Vasa recta

129. ImportanceofDiluting,ConcentratingmechanismsofKidney.
Plasma Hypo osmolarity 
Water enters cells  cell swelling
Brain cell swelling  nausea, headache,
confusion, coma etc.
Plasma Hyper osmolarity 
Loss of water from cells  cells shrink.
Brain cell shrinking  weakness, seizures, coma &
death

130. Factors affecting ADH secretion
STIMULANTS OF []ADH
SECRETION
Hyperosmolarity of
body fluids.
 blood volume & 
BP
Angiotensin II
Nicotine
INHIBITORS OF [] ADH
SECRETION
Hypo-osmolarity of
body fluids.
 blood volume & 
BP
Atrial natriuretic
peptide [ANP]
Alcohol

131. Osmotic control of ADH secretion –
1] Hyperosmolarity
Osmoreceptors of Hypothalamus –
i. Sense hyperosmolarity due to shrinking of
Osmoreceptors.
ii. Very sensitive & sense 1% change in osmolarity.
iii. Effective osmole is Na+
iv. Ineffective osmoles are glucose, urea.
Send impulses to SON & PVN of hypothalamus   ADH secretion
2] Hypo –osmolarity – osmoreceptors swell  no impulse  no ADH
secretion.
½ life of ADH is very less.

134. HaemodynamiccontrolofADHsecretion
 Blood volume &  BP   Baroreceptor
or stretch receptors stimulation   ADH
secretion
Low pr. receptors - Sensitive to Blood
volume changes are in Lt atrium,
pulmonary vessels
High pr. receptors - Sensitive to arterial
Blood pressure changes are in carotid
sinus & aortic arch.
Thro CN IX & X reach brainstem  SON
&PVN of hypothalamus   ADH

135. Haemodynamic control of ADHsecretion
Is less sensitive as compared to Osmoreceptor control.
5 -10 % of Blood Volume & BP change is necessary to cause
stimulation.
[Note –
 ADH thro V1 receptors on blood vessels  vasoconstriction
 ADH [Arginine vasopressine ]   BP ]

136. Abnormalities of ADH secretion
1] Neurogenic diabetes Insipidus OR
[Pituitary Diabetes] OR
[Central diabetes Insipidus.]
 Inadequate secretion [] of ADH from Post. Pit. 
 Polyurea [ i.e.  water retention in body.   urine vol.] +
 Polydipsia [i.e. hyper osmolarity   stim of thirst center at
Hypothalamus ]
Note –
 Osmotic threshold for thirst = 295 mosm / L &
 NaCl is most effective osmole

137. AbnormalitiesofADHsecretion[contd]
2] Syndrome of Inappropriate ADH
secretion [SIADH]
 in Plasma ADH. 
More [] water reabsorption by distal
tubule.
If no restriction of water intake
hypo - osmolarity

138. AbnormalitiesofADHsecretion[contd]
3] Neprhogenic Diabetes Insipidus –
Normal ADH . But no response on kidney  i.e.
 no reabsorption of water at distal nephron.
Concentration of urine not possible 
 polyurea + polydipsia.
 Etiology –
i. Metabolic disorders like Hypercalcemia,
ii. Due to drugs like Lithium.,
iii. Rarely mutation of V2receptors OR Aquaporin -2.

139. ACID BASE BALANCE

140. Acid Base balance means
Excess acid addition to body is balanced by it’s
excretion
a) thro Lungs [Volatile acids] OR
b) kidneys [ Nonvolatile acids]
If  in acid excretion  acidosis
Sources of Acids in the Body
i. Dietary sources
ii. Cellular metabolism

141. I] Production of volatile acids –
 1] Aerobic metabolism of carbohydrates + fats
II] Production of non -volatile acids –
 2] Metabolism of Sulphur containing AA
 3] Metabolism of Lysine, Arginine & Histidine
[Note – A nonvegetarian diet  production of [] nonvolatile acids
than a vegetarian diet.]
4] In Diabetes Mellitus –
  Insulin  production of [] Ketoacids
5] In Hypoxia 
 production of [] Lactic acid.

142. Contd -
I] Production of volatile acids –
 1] Aerobic metabolism of carbohydrates + fats =  [] CO2
production of[]volatile Carbonic acid
II] Production of non -volatile acids –
 2] Metabolism of Sulphur containing AA e.g.
Cysteine,methionine etc  production of []H2SO4
 3] Metabolism of Lysine, Arginine & Histidine  production of []
HCl
[Note – A nonvegetarian diet  production of [] nonvolatile acids than
a vegetarian diet.]
4] In Diabetes Mellitus –
  Insulin  production of [] Ketoacids like acetic acid , aceto acetic
acid & b –hydroxybutyric acid
5] In Hypoxia 
 production of [] Lactic acid.

143. AcidificationofUrine
Acid= [] H+ conc
Alkali=  H+ conc.
Normal body pH [ECF] = 7.4
Metabolic functions of body are highly sensitive to pH.
Compatible for life = pH range 6.8 -7.8 [ECF]
Acid –Base balance is co–ordinated function of lungs & kidney.
Lungs –
Major excretory route of volatile acids e.g. carbonic acid.
Kidney –
pH of urine range – 4.5 to 8. [depend on rate of acid secretion]
When body pH changes  kidney excretes acidic OR alkaline urine 
maintain Acid base balance of ECF.

144. Buffers in blood –
NaHCO3 buffers strong acids e.g.
H2SO4 + 2 NaHCO3 Na2SO4 + 2CO2 + 2H2O
HCl + NaHCO3  NaCl + CO2 +H2O
Functions of kidney –
The acid salts are excreted by kidney
Replacement of blood buffer [NaHCO3]

145. Buffer systemof Kidney
H+ secretion into tubular fluid is
buffered by 3 imp. buffers in kidney.
1. HCO3
- buffer system
2. PO4
- buffer system
3. NH3
- buffer system

146. 1] HCO3
- buffer system
It is regulated both by Lungs & kidneys.
 in plasma HCO3
- buffer  metabolic
acidosis.
[] in pCO2  respiratory acidosis
Note –
Kidney regulate plasma HCO3
- buffer
Lungs regulate plasma pCO2 changes.

148. In PCT –
For secretion of one H+ ion into
tubule there is gain of one Na+ +
one HCO3
- in plasma.
H+ secretion is in exchange for
Na+ by
1] secondary active transport.
&
2] active transport of H+
ATPase

149. Note –
For one H+ secretion = one HCO3- gain in plasma
Normal plasma HCO3- = 26 mEq/L
Renal plasma threshold for HCO3- is = 28mEq/L
If more than 28mEq/L = HCO3- appears in urine [alkaline urine]
Limiting pH
for PCT = 6.9 &
for Distal tubule = 4.5
H+ secretion stops at limiting pH.

150. FactorsaffectingH+ secretion
[] H +secretion [] H +secretion
1] [] In intracellular pH 1] [] In intracellular pH
2] [] intracellular PCO2 2] [] intracellular PCO2
3] [] in filtered load of HCO3 3] [] in filtered load of HCO3
4] [] in ECF volume 4] [] in ECF volume
5] [] in Aldosterone 5] [] in Aldosterone
6] Hypokalemia 6] Hyperkalemia
7] [] in Carbonic anhydrase 7] [] in CA = CA inhibitors e.g.
acetazolamide [Diamox]

151. PO4 Buffer system
Primary urinary buffer system.
Derived from diet.
Distal nephron –
 Alkaline PO4 + H+  Acidic PO4 i.e.
 H+ + HPO4
2-  H2PO4
-
NOTE –
Titrable acidity = PO4 buffer system. [not measure HCO3 & NH3
buffers]
 It is Amount of alkali added to raise pH of urine to 7.4
 Substances contributing to titrable acidity = excreted PO4 +
ketoacids + lactic acid + creatinine

152. NH3 Mechanism
Production in Kidney.-
In PCT & DCT
By metabolism of AA Glutamine
NH3 is lipid soluble  free passage across tubular membrane.
NH3
+ + H+  NH4
Trapping of NH4 = Non ionic diffusion Or Diffusion trapping
In acidosis  [] NH4 in urine

153. Compensatory Responsesof the body
in Acid –Base disturbances
1. Intracellular & Extracellular
buffering.
2. Changes in ventilation.
3. Renal adjustments

154. CompensatoryResponsesofthebodyinAcid–Basedisturbances
1] Intracellular& Extracellularbuffering.
A. ECF buffers –
 HCO3 buffer
 Plasma protein buffer system
B. Intra cellular buffers –
 HCO3 buffer
 PO4 & histidine group of proteins
 Reduced Hb.

155. CompensatoryResponsesofthebodyinAcid–Basedisturbances
2] Changes in ventilation.
Depend on pCO2 level
1.  in pCO2  respiratory acidosis 
 stimulation of peripheral & Central chemoreceptors 
 [] hyperventilation
2.  in H+  metabolic acidosis 
  stim of Central chemoreceptors 
 [] hyperventilation.
 E.g. Diabetic ketoacidosis.  Kussmaul breathing.

156. CompensatoryResponsesofthebodyinAcid–Basedisturbances
3] Renal adjustments
In acidosis  due to  NH4 secretion
 H+ secretion   production of HCO3 
  buffering capacity of blood