STUDY OF BASIC FUNDAMENTALS OF URINE FORMATION PHYSIOLOGY.pptx
1 mb ch b-pm renal-uz-combined slides-11-3-15
1. 04/07/15 1
RENAL PHYSIOLOGYRENAL PHYSIOLOGY
LECTURE 1&2:LECTURE 1&2:
Kidney Structure, Functional RelationshipKidney Structure, Functional Relationship
& Glomerular filtration& Glomerular filtration
By
DR. P MURAMBIWA
2. 04/07/15 2
“Kidneys are master chemists with main roles
of protecting us from pleasures of eating and
drinking, and thus their dysfunction speeds
our early death."
4. 04/07/15 4
OBJECTIVES 1:OBJECTIVES 1:
• Outline how body fluids are distributed.
• Summarize the ionic composition of intra-
and extracellular fluids.
• Identify the main regions of the kidney.
• Draw a labelled diagram of a nephron.
• Summarize the ultrastructural features of
different parts of the nephron.
• Draw a labelled diagram of the blood supply
of the nephron.
6. 04/07/15 6
Plasma, the extracellular fluid within the
vascular system
Interstitial, the extracellular fluid outside the
fluid vascular system and separated
by the capillary endothelium
Transcellular the extracellular fluid separated
fluids, from the plasma by an epithelial
layer and the capillary endothelium
e.g., synovial fluid, fluids in the
urinary tracts, aqueous & vitreous
humour in the eye and
cerebrospinal fluid.
17. Characteristics of the
renal blood flow:
1.High blood flow.
1200 ml/min, or 20-21 %
of the cardiac output.
94% to the cortex
2. Two capillary beds
High hydrostatic pressure in
glomerular capillary (about
60 mmHg) and low
hydrostatic pressure in
peritubular capillaries (about
13 mmHg)Vesa Recta
18. 04/07/15 18
Why such a high blood flow?
To sustain a high rate of filtration of plasma in
the glomeruli
Blood flow is not distributed uniformly within
19. 04/07/15 19
FUNCTIONS OF THE KIDNEYSFUNCTIONS OF THE KIDNEYS
♦ Regulation of the osmotic pressure of
the plasma and other extracellular
fluids
♦ Regulation of the excretion of sodium
and water and hence the volume of the
extracellular fluid
♦ Regulation of individual concentrations
of many electrolytes in the extracellular
fluid
20. 04/07/15 20
Regulation of plasma [bicarbonate] and
therefore the hydrogen ion concentration
The kidneys eliminate metabolic waste
products such as urea.
They also eliminate many foreign compounds
from the body, including drugs such as
penicillin.
The kidneys produce erythropoietin, renin,
kallikrein, that leads to the formation of kinins
and various prostaglandins
28. 04/07/15 28
FILTRATION IN THE KIDNEYFILTRATION IN THE KIDNEY
Ultrafiltration
At the glomerulus and the Bowman’s capsule =
separation of plasma water and its non-protein
constituents that enter the Bowman's space.
Every minute = 125 ml of plasma is forced through the
glomerular membrane into the tubule by hydrostatic
pressure within the glomerulus.
33. GLOMERULAR
FILTRATION RATE
• It is a bulk flow process in which water
and all low molecular weight substances
including small peptides move together
from the glomerular capillaries into the
bowman”s capsule
34. WHAT SUBSTANCES ARE
FILTERED?
• All plasma constituents except for
• 1) high molecular weight substances such
as plasma proteins like albumins and
globulins i.e. those whose RMM is higher
than 68 000
• 2) substances that are protein bound
such as calcium and fatty acids
35. CONTD
• Large molecules with a net negative
charge because the glomerular surface is
negatively charged hence repulsion
occurs i.e. proteins
• NB THE FILTRATE CONTAINS THE
SAME AMOUNTS OF SUBSTANCES
AS THERE ARE IN PLASMA EXCEPT
FOR PROTEINS AND PROTEIN
BOUND SUBSTANCES.
38. FORCES INVOLVED IN
GLOMERULAR FILTRATION
• Glomerular capillary pressure
=60mmHg
• Fluid pressure in the bowman” s space
=15mmHg
• Osmotic force due to protein in plasma
=29mmHg
40. FORCES OPPOSING
FILTRATION
• Fluid pressure in bowman space
• Osmotic force due to protein in plasma
NET FILTRATION PRESSURE IS
POSITIVE-FAVOURS FILTRATION
41. CONTD
• Osmotic force due to protein higher than
in all other arterioles because of loss of
large quantities of water by glomerular
filtration process
43. FACTORS AFFECTING GFR
• Changes in renal blood flow
• changes in glomerular capillary
hydrostatic pressure due to
1) changes in systemic blood pressure
2) afferent or efferent arteriolar
constriction
44.
45. CONTD
• Changes of hydrostatic pressure in Bowman”s
capsule due to
1) ureteral obstruction
2) edema of kidney inside tight renal capsule
• changes in concentration of plasma proteins
due to
1) dehydration
2) hypoproteinaemia- however, these are minor
factors
46. SUMMARY OF FACTORS
AFFECTING GFR
• Net filtration pressure.
• Permeability of corpuscular membrane
• Surface area available for filtration to
occur
47. PHYSIOLOGICAL
REGULATION OF GFR
• It is not fixed but regulated by
1) hormones
2) neural input to the 2 arterioles
3) neural and hormonal input to
mesangial cells
48. GFR DECREASED BY
Constriction of AA
Dilatation of EA
Contraction of mesangial cells that
surround the glomerular capillaries
thereby reducing the surface area of
capillaries available for filtration, hence
at any given net filtration pressure GFR
will be reduced
51. GFR IS INCREASED BY
• Constriction of EA
• Dilatation of AA
• NB SIMULTANEOUS DILATATION
AND RELAXATION OF THE 2
ARTERIOLES HAS NO NET EFFECT
ON GFR
61. Creatinine is:
End product of muscle creatine
metabolism
Used in clinical setting to measure
GFR but less accurate than inulin
method
Small amount secreted from the
tubule
Creatinine used clinically to measure GFR
64. 04/07/15 64
AUTOREGULATION OF GFRAUTOREGULATION OF GFR
• Changes in blood pressure have little effect on
RBF and GFR.
• In haemorrhage, there are increases in
sympathetic nervous activity to the kidney
causing vasoconstriction.
• Renal vasoconstriction is attenuated by
prostaglandins.
65. 04/07/15 65
The most widely accepted explanation is that of the
myogenic theory.
This states that " Increase in wall distension of afferent
arterioles brought
about by an
increase in perfusion pressure causes automatic
contraction of the smooth muscle fibres in vessel walls
thereby increasing resistance to flow so keeping the
flow constant despite the increase in perfusion
pressure."
71. 04/07/15 71
CONCEPT OF FILTRATION FRACTIONCONCEPT OF FILTRATION FRACTION
Filtration fraction= CI
= 125ml/min
CPAH
600ml/min
~ 20% in normal man
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RENAL PHYSIOLOGYRENAL PHYSIOLOGY
LECTURE 3 & 4:
TRANSPORT PROCESSES IN THE PROXIMALTRANSPORT PROCESSES IN THE PROXIMAL
TUBULETUBULE
By
DR. P MURAMBIWA
73. 04/07/15 73
OBJECTIVES:OBJECTIVES:
1. State major characteristics of proximal-tubular
system for reabsorption and secretion of
electrolytes.
2. What are the pathways for sodium reabsorption
across the proximal tubule epithelium?
3. Describe the renal handling of various organic and
inorganic substances.
76. 04/07/15 76
REABSORPTION AND SECRETIONREABSORPTION AND SECRETION
• Indicate the direction of movement of substances
• Reabsorption = transfer out of the tubular fluid and
returned to peritubular capillaries that surround
tubules.
• Reabsorption is a selective process, and the sites of the
nephron handle the filtrate in tubules differently.
• Secretion = movement of substances across the tubule
epithelium
79. PROXIMAL CONVOLUTED
TUBULE (PCT)
Found in cortex
15 mm long and 55µm in diameter
single layer of cells
luminal edges with brush border
convolution increases length hence
increase contact between tubular cells
and luminal fluid thereby facilitating
reclamation
04/07/15 79
81. REABSORPTION OF
SODIUM
04/07/15 81
% NaCl Reabsorbed
♦Proximal Tubule 67%
Loop of Henle (Ascending) 25%
Distal Tubule 5%
Collecting Duct 2%
Excreted in Urine % Variable
82. 82
Daily sodium intake = daily sodium loss =10.50g
Sodium gain in the body occurs via:
Food intake
Sodium loss in the body can occur via:
menstrual flow in females
feces especially diarrhea
urine
at times GIT loses by vomiting
sweat
hemorrhage where salt and water may be quite high
Daily Sodium Balance
83.
84. Two pathways of the absorption
Lumen
Plasma
Cells
Transcellular
Pathway
Paracellular
transport
87. 04/07/15 87
NaNa++
HANDLINGHANDLING
Reabsorption of 60 - 70% Na+
is by active
process.
The Na+
reabsorption is associated with Cl-
and
HCO3
-
and H2
O.
The reabsorption of Na+
is primary and active
and is shown by many arguments.
88. 88
The net gain and loss of sodium and water are regulated
by the kidney over a wide range
BOTH SODIUM AND WATER ARE:
small
circulate free in plasma
not secreted
reabsorbed above 99% hence their absorption is
linked i.e water reabsorption is dependant on
sodium reabsorption.
93. 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+
.
Tubula
r
lumen
Tubular Cell
Interstitial
Fluid
Tubula
r
lumen
Tubular Cell
Interstitial
Fluid
94. 04/07/15 94
Transport is abolished by cooling.
Replacement of sodium by any other cation
(Lithium) greatly reduces reabsorption of
H2
O and other solutes.
95. 04/07/15 95
Reabsorption continues at almost normal rates after
substitution of Cl- by various other anions, nitrate and
perchlorate.
Replacement of Na+
with HCO3
-
reduces
Na+
reabsorption, but by less than half
Mannitol in the lumen, reduces [NaCl]
Inhibition of Na+ - K+ ATPase by oubain.
97. 04/07/15 97
Na+
EXTRUSION
Cl-
REABSORPTION
H2
O REABSORPTION
UPTAKE OF NaCl AND H2
O
The uptake of Na+
, Cl-
and H2O from lateral
intercellular spaces into peritubular capillaries
98. 04/07/15 98
Na+
Cl-
Na+
Cl-
H2
O πLI
πcap
πLIS
CapillaryLumen
- πcap = capillary hydrostatic pressure
- πLIS = oncotic pressure in the lateral
spaces
+ πLIS = oncotic pressure in the capillary
+ πcap = hydrostatic pressure in lateral
spaces
UPTAKE α (πcap + πLIS) – (πLIS + πcap)
H2O
πLIS
πcap
99. 04/07/15 99
RENAL PHYSIOLOGYRENAL PHYSIOLOGY
LECTURE 3 & 4: CONT’D
TRANSPORT PROCESSES IN THE PROXIMALTRANSPORT PROCESSES IN THE PROXIMAL
TUBULETUBULE
By
DR. P MURAMBIWA
102. 04/07/15 102
Transport processes for amino acid
transport (Tm
limited).
for basic amino acids and cysteine
for glutamic and aspartic acids
for neutral acids
imino acids
for glycine
103. Glucose / Amino acid Co-Transport-PCT
Na+
Glucose or
Amino acid
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+
.
Tubula
r
lumen
Tubular Cell
Interstitial
Fluid
Tubula
r
lumen
Tubular Cell
Interstitial
Fluid
104. CONCEPT OF TRANSPORT MAXIMUM (Tm)
Refers to limit to the amount of substance that the
renal tubule can transport per unit time.
Under normal circumstances Tm is not exceeded but
due to excess ingestion or disease the plasma
concentration of a substance increases and exceed Tm
hence substance appear in urine such as
glycosuria
aminoaciduria
106. 04/07/15 106
HYDROGEN ION SECRETION ANDHYDROGEN ION SECRETION AND
BICARBONATE REABSORPTIONBICARBONATE REABSORPTION
107. BICARBONATE HANDLING
BICARBONATE IS FREELY
FILTRABLE
• it undergoes reabsorption in the
• 1)PCT
• 2)ASCENDING LOOP OF HENLE
• 3)CORTICAL COLLECTING DUCTS
• bicarbonate reabsorption is an ACTIVE
PROCESS VIA:
108. 04/07/15 108
• Processes in the kidney that
consume most of the hydrogen
ions secreted by the tubular
epithelium.
• Processes in the kidney that lead
to generation of new bicarbonate
to replace depleted plasma
bicarbonate reserves.
112. bicarbonate reabsorption is an ACTIVE
PROCESS VIA:
HYDROGEN ION ATPase pumps
HYDROGEN ION/POTTASIUM ION ATPase pumps
SODIUM ION/HYDROGEN ION COUNTER-
TRANSPORTERS
BICARBONATE ION EXCRETION = BICARBONATE
FILTERED + BICARBONATE SECRETED-BICARBONATE
REABSORBED
113. BICARBONATE REABSORPTION STARTS IN THE
CELL
carbon dioxide + water = carbonic acid
carbonic acid dissociates to form bicarbonate ion and
hydrogen ion
bicarbonate ion is transported to the interstitial fluid then to
plasma while hydrogen ion is actively transported into the
lumen to combine with filtered bicarbonate to form water
and carbon dioxide which diffuse back to the cell for use in
the next cycle of bicarbonate reabsorption
114. ADDITION OF NEW
BICARBONATE TO PLASMA
COMBINATION OF SECRETED
BICARBONATE WITH NON
BICARBONATE BUFFERS
RENAL PRODUCTION AND
SECRETION OF AMMONIUM occurring
in the PCT
115.
116. RENAL METABOLISM OF GLUTAMINE AND
EXCRETION OF AMMONIM ION
• Glutamine (amino acid) can be co transported
with sodium or can be from the interstitial fluid
where it is metabolized by the cell to form
ammonium ion and bicarbonate ion
• the ammonium ion is then secreted in counter
transport with sodium to be excreted in urine-
this leads to a net gain of bicarbonate ion
117. Usually about 25 times bicarbonate is filtered
more than any other buffer hence all secreted
hydrogen combine with bicarbonate in lumen
until all has been used up before combining with
other buffers of which hydrogen phosphate is the
most vital
there is a net gain of bicarbonate in this case vital as a
way of compensating acidosis
122. • 50%-reabsorbed by simple
diffusion in the PCT.
• 30% is reabsorbed in the DISTAL
CONVOLUTED TUBULE
• 50% reabsorbed by FACILITATED DIFUSSION
VIA UREA TRANSPORTERS IN THE THIN
ASCENDING LIMBS OF THE LOOP OF HENLE.
123.
124. 124
SUMMARYSUMMARY
This Lecture identified and described the
following:
Pathways for sodium reabsorption across
the proximal tubule epithelium
How Na+
and water reabsorption occur in the
proximal convoluted tubule.
How substances like glucose, aminoacids,
Bicarbonate, urea are reabsorbed
125. 04/07/15 125
RENAL PHYSIOLOGYRENAL PHYSIOLOGY
LECTURE 5&6:LECTURE 5&6:
COUNTER-CURRENT MULTIPLIER AND EXCHANGE SYSTEMSCOUNTER-CURRENT MULTIPLIER AND EXCHANGE SYSTEMS
By
DR. P MURAMBIWA
127. 04/07/15 127
INTRODUCTIONINTRODUCTION
The fluid entering the loop of Henle is isotonic to
plasma
Animals such as birds and mammals, those with long
loops of Henle, urine produced may be more
concentrated than plasma (hypertonic).
This suggests that some processes that influence movement
of water or perhaps some electrolytes.
The loops of Henle are considered to be Counter-current
Multiplier Systems.
128. 04/07/15 128
OBJECTIVES:OBJECTIVES:
What is the difference between Counter-current
Multiplication and Counter-current Exchange Systems?
Describe the role played by:
a) loops of Henle,
b) vasa recta, c) collecting ducts, d) ADH, and
e) urea
in the production of an osmotically
concentrated urine.
129. 04/07/15 129
COUNTER-CURRENT MULTIPLICATION MECHANISMCOUNTER-CURRENT MULTIPLICATION MECHANISM
Hypothesis:
Proposes that the loop of Henle can produce a small
osmotic gradient between the ascending and
descending limbs that can be multiplied into a large
longitudinal gradient by the countercurrent
arrangement in the two limbs.
Wirz, Hargitay & Kuhn (1951)
143. 04/07/15 143
THE OSMOTIC GRADIENTTHE OSMOTIC GRADIENT
• Only juxtamedullary nephrons contribute
• NaCl is added to the medullary interstitium.
• Ascending limb is highly impermeable to H2O.
• H2O extraction from the descending limb
increases the [NaCl]
144. 04/07/15 144
• In the cortical collecting duct system, in the
presence of ADH, the osmolality increases to
become iso-osmotic with plasma.
• High [urea] in the medullary interstitium
provides an osmolality additional to that of
NaCl.
148. UREA DISTRIBUTION
50%-reabsorbed by simple diffusion in the PCT.
30% is reabsorbed in the DISTAL CONVOLUTED
TUBULE
50% reabsorbed by FACILITATED DIFUSSION VIA
UREA TRANSPORTERS IN THE THIN ASCENDING
LIMBS OF THE LOOP OF HENLE.
15% LOST IN URINE DAILY.
151. SUMMARY OF THE FEATURES THAT PROMOTE
COUNTERCURRENT MULTIPLIER
COUNTERCURRENT MULTIPLIER
-basically depends on the ability of the
loops of henle to create and maintain a
hyper-osmotioc medullary interstitium.
Features making this possible are:
apposition of the thin descending and
thin ascending loops of Henle (hairpin
turn of the loops of henle)
156. 04/07/15 156
COUNTERCURRENT EXCHANGE SYSTEMCOUNTERCURRENT EXCHANGE SYSTEM
Vasa recta = capillaries from efferent arterioles of the
juxtamedullary nephrons
Blood flow = 50 - 100 ml/min of which perhaps 5 ml/min
reaches the papillae.
The vasa recta have a hairpin arrangement and dip down
into the medulla.
This arrangement ensures close contact between ascending
and descending vasa recta and between ascending and
descending loops of Henle.
157. 04/07/15 157
The vasa recta, like capillaries, elsewhere are
permeable to water and solutes.
In the ascending vasa recta the plasma regains the
water and solutes.
O2
and CO2
also undergo a countercurrent exchange in
the vasa recta.
As the descending vasa recta enter the increasingly
hypertonic medullary interstitium, water is
osmotically abstracted from the blood vessel, so
that the osmolality of the blood (and its viscosity) are
increased.
158. IN SUMMARY THE COUNTERCURRENT
EXCHANGER-OCCURS IN THE VASA RECTI BY
SIMPLE DIFFUSION OF SODIUM CHLORIDE
INTO, AND WATER OUT OF THE DISCENDING
LIMB WHILE IN THE ASCENDING LIMB THERE IS
DIFFUSION OF SALT OUT, AND WATER INTO THE
LIMB HENCE MEDULLARLY SALT WASHOUT IS
PREVENTED.
160. 04/07/15 160
LECTURE SUMMARY
The Counter-current mechanism permits the kidney to
excrete urine with varying osmolalities.
The primary event in this process is active NaCl
transport out the thick ascending limb of the loop of
Henle into the medullary interstitium.
169. 04/07/15 169
Na+
EXCRETION
• GFR can be altered is by changing
glomerular capillary pressure.
• Hydrostatic and plasma oncotic pressures can
also influence tubular handling of Na+
.
• Hydrostatic and plasma oncotic pressures in
the peritubular.
170. 04/07/15 170
• Increases in blood pressure (30-60mmHg) above
control values (105 - 130 mm Hg) in
anaesthetised rats have been seen to cause
natriuresis.
Suggested that arterial blood pressure wash
out an osmotic gradient to decrease not only in
Na+
reabsorption, but also in the ability of
vasopressin to concentrate urine.
♣ Renal vasodilation in anaesthetised dogs
induced by either Ach or prostaglandin has
been noted to increase Na+
excretion and urine
flow without changes in GFR.
171. 04/07/15 171
PHYSICAL FACTORSPHYSICAL FACTORS
• Changes in the blood perfusing the
kidneys
• Expansion of the ECF volume leads
to increased blood volume and
increased systemic arterial
pressure.
• Increased fluid pressure decreases
proximal tubular Na+
reabsorption.
172. 04/07/15 172
• Increased blood volume also causes a dilution of
plasma proteins by that lowering plasma oncotic
(colloid osmotic) pressure.
Physical factors, HOWEVER, play only a subsidiary
role in regulating sodium excretion.
173. 04/07/15 173
NEURAL CONTROLNEURAL CONTROL
☻Claude Bernad (1859) showed that section of the
greater splanchnic nerve (interruption of a major
part of the sympathetic supply to the kidney)
increased urine flow in the anaesthetised dog.
• Interruption of a major part of the sympathetic
supply to the kidney increases urine flow.
178. 04/07/15 178
• Aldosterone is implicated in instances of fluid and electrolyte
abnormalities associated with some diseases.
• Increased quantities of ALDOSTERONE in the urine of patients
with primary and secondary hypertension, congestive heart
failure, liver cirrhossis and nephrosis
• Elevated levels of aldosterone are also found in the urine of
pregnant women.
• Aldosterone promotes Na+
reabsorption in exchange for
increased excretion of K+
, H+
and NH4
+
ion in humans.
180. 04/07/15 180
• Mineralocorticoid Escape Phenomenon
∀ ♦♦ EFFECTS ON GFR AND RBFEFFECTS ON GFR AND RBF
• Aldosterone and glucocorticoids are necessary
for the maintenance of GFR and RBF.
♦♦ ALDOSTERONE SYNTHESISALDOSTERONE SYNTHESIS
• ACTH promotes steroidgenesis in the
adrenal cortex
187. 04/07/15 187
• Alteration of NaCl concentration is accompanied by
changes in renin secretion.
(plasma globulin synthesized by the liver)
Angiotensinogen
↓ Renin (Aspartyl proteinase)
Angiotensin I (Decapeptide)
↓ Converting Enzyme in Pulmonary
Circulation INHIBITED BY CAPTOPRIL
Angiotensin II (Octapeptide)
↓ INHIBITED BY SARALISIN
Angiotensin III
188. 04/07/15 188
♦♦ RENIN RELEASERENIN RELEASE
• Increased sympathetic activity
Reduction of the extracellular fluid volume and/or the
effective circulating volume will decrease systemic
arterial blood pressure.
• Baroreceptor reflexes will subsequently increase
sympathetic activity to arterioles.
• The main baroreceptors are in the carotid arteries
(carotid sinuses).
189. 04/07/15 189
Sympathetic nerve activity causes renin release,
mediated by α1
-adrenergic receptors and activated
by circulating catecholamines
Decreased wall tension in the afferent arterioles.
• Decreased renal perfusion pressure leads to
increased renin release from the granular cells.
• The macula densa mechanism
190. 04/07/15 190
• Changes in the delivery of NaCl to the
macula densa (composition of fluid in
ascending limb detected)
• The macula densa stimulus releases PGI2
that
acts on the granular cells to release renin.
191. 04/07/15 191
♦♦ EFFECTS RAASEFFECTS RAAS
A II constricts efferent arterioles, to reduce
peritubular capillary pressure.
A II increases reabsorption of Na+
in the
distal tubule.
A II promotes aldosterone synthesis in
the zona glomerulosa.
Stimulates thirst sensation in the brain.
194. 04/07/15 194
• De Bold (1982) demonstrated that the artrial extracts
caused a rapid 30-fold increase in NaCl excretion
coupled with an increase in urine flow in the rat.
• Atrial cardiac cells produce ANP.
• Atrial stretch leads to an increase in the circulating
level of ANP.
• Effects of ANP are modulated via specific cell surface
receptors that when bound to,increase intracellular
levels of cyclic guanosine monophosphate (cGMP).
196. 04/07/15 196
♥♥ ACTIONS OF ANPACTIONS OF ANP
♠Inhibition of aldosterone secretion
♠Reduction of renin release
♠Reduces the release of vasopressin
♠Natriuresis and diuresis.
198. 04/07/15 198
REGULATION OF BODY KREGULATION OF BODY K++
• Body K+
= contains 3 - 4 mmoles
= 2% of this is extracellular and its maintenance
is essential for life.
= Maintenance = regulation of renal excretion.
199. 04/07/15 199
• RENAL HANDLING OF KRENAL HANDLING OF K++
♦In the proximal tubule 80-90% of the filtered
K+
is reabsorbed.
♦In the descending (thin) limb of the loop of
Henle, K+
is secreted, but K+
is reabsorbed
from the ascending limb with Na+
and Cl-
.
♦In the early distal tubule that is functionally
similar to the ascending limb of Henle, Na+
,
Cl-
and K+
reabsorption occurs.
200. 04/07/15 200
♦The late distal tubule and subsequent
segments of the collecting duct system
secrete K+
into the tubular fluid.
♦The rate of K+
secretion is also influenced
by the rate of Na+
reabsorption.
♦Diuretics will increase the rate of K+
secretion.
201. 04/07/15 201
KK++
EXCRETIONEXCRETION
• Aldosterone is the only hormonal control
over K+
output.
• The K+
losing effects of aldosterone do
not exhibit the "escape phenomenon.
• Increases in plasma concentration of K+
directly influence aldosterone synthesis.
206. Strenuous exercise
Cell lysis
Metabolic acidosisMetabolic Alkalosis
B-adrenergic blockadeB-adrenergic stimulation
Aldosterone deficiency
(addison’s disease)
Conn’s syndrome (excess
aldosterone)
Insulin deficiency (diabetes
mellitus)
Insulin
Factors that shift K+ out of
cells (Increase EC K+)
Factors that shift K+ into
cells (Decrease EC K+)
207. 04/07/15 207
• HYPOKALAEMIA CAUSESHYPOKALAEMIA CAUSES
• Gastrointestinal tract or kidneys losses
Persistent vomiting or diarrhoea or the use of diuretics
• Excess insulin.
• Insulin increases K+
entry into cells that the
extracellular levels fall.
• Alkalosis reduces proximal tubular HCO-
3
absorption
and reduces Na+
reabsorption, therefore more NaHCO3
and water in the tubule.
208. 04/07/15 208
• EFFECTS OF HYPOKALAEMIAEFFECTS OF HYPOKALAEMIA
Symptom free until plasma K+
level has fallen to
approximately 2 - 2.5 mmol/l.
• Initial symptom is muscle weakness until death
occurs when the respiratory function is affected.
In hypokalaemia the time cardiac muscle takes to
repolarize = prolonged.
K+
deficiency also causes derangements of metabolism.
209. 04/07/15 209
Hypokalaemia also affects vascular tone,
causing vasoconstriction.
Polyuria and thirst are present because the
renal response to ADH is impaired by
hypokalaemia that patients are unable to
produce urine.
Treatment consists of oral administration of
potassium salt.
210. 04/07/15 210
HYPERKALAEMIA CAUSESHYPERKALAEMIA CAUSES
• Ingestion of excess K+
causes a rise in plasma
levels of K+
.
• Acidosis may also cause hyperkalaemia when the
body's K+
stores are normal.
• Insulin causes entry of K+
into cells, therefore
deficiency will lead to hyperkalaemia.
211. 04/07/15 211
• Another cause of hyperkalaemia is
breakdown of cells as in severe trauma, or
treatment with cytotoxic drugs.
• Hyperkalaemia can also occur due to
decreased K+
excretion in renal failure due
reduction in functioning nephrons.
212. 04/07/15 212
EFFECTS OF HYPERKALAEMIAEFFECTS OF HYPERKALAEMIA
Excitable cells are unable to conduct action
potentials and muscle weakness follows.
Loop diuretics can be used to promote K+
excretion.
Insulin can also be used to promote K+
entry into
cells.
The effects of hyperkalaemia on muscle can be
corrected by Ca2+
administration.
214. 04/07/15 214
♦♦ RENAL CALCIUM HANDLINGRENAL CALCIUM HANDLING
• In the proximal tubule, calcium reabsorption parallels
that of sodium and water.
• Ca2+
is positively charged and therefore entry into the
tubular cell is favoured by the electrical gradient.
• A calcium-activated ATPase facilitates transport.
215. 04/07/15 215
• In addition a Ca2+
counter transport out of the cell
coupled to passive Na+
entry occurs (ratio 3Na+
entering for 1Ca++
leaving).
• Ca2+
reasorption in the ascending limb of the loop of
Henle is similar to that has been described before
for the proximal tubule.
• Furosemide that inhibits NaCl transport in this
region also inhibits Ca2+
reabsorption.
216. 04/07/15 216
A Ca2+
- ATPase facilitates Ca2+
transport in the
ascending limb of the loop of Henle.
Calcium is reabsorbed under the influence of
parathormone.
The physiological regulation of Ca2+
reabsorption
occurs in the cortical thick ascending limb and
distal tubule.
217. 04/07/15 217
♦♦ HANDLING OF PHOSPHATEHANDLING OF PHOSPHATE
Two forms acid phosphate,
• Acid H2
PO4
-
and alkaline phosphate HPO=
4
.
Phosphate is freely filtered in the nephron.
Ratio of 4:1 alkaline to acid phosphate is present in
the filtrate.
• The only hormone that regulates renal tubular
phosphate transport is PTH.
218. 04/07/15 218
• Other hormones such as calcitonin, glucagon and
insulin may also influence renal phosphate
transport.
• PTH, calcitonin and glucagon increase renal
phosphate excretion while insulin reduces
phosphate excretion.
• Hypocalcaemia is common in renal failure patients.
219. 04/07/15 219
• Acidosis decreases the plasma levels of
ionized Ca++
while alkalosis has the
opposite effect.
• The characteristic feature of low plasma
calcium is tetany, convulsions and muscle
cramps.
220. 04/07/15 220
SUMMARY-CONTRIBUTION OF THESUMMARY-CONTRIBUTION OF THE
DIFFERENT NEPHRON SEGMENTSDIFFERENT NEPHRON SEGMENTS
• Nephron segment Major Functions
____________________________________
Glomerulus Forms an ultrafiltrate of
plasma
Proximal tubule Reabsorbs isosmotically
70 percent of the filtered
NaCl and H2
O
221. 04/07/15 221
• Proximal tubule Reabsorbs K+
, glucose amino acids, calcium,
phosphate, magnesium, urea, uric acid,
and bicarbonate (by H+
secretion)
Secretes H+
, ammonia, and organic acids
and bases
• Loop of Henle Countercurrent multiplier; reabsorbs NaCl in
excess of H2
O.
Major site of active regulation of magnesium
excretion
222. 04/07/15 222
• Distal tubule Reabsorb a small
and connecting fraction of filtered
segment NaCl Major site of
active regulation of
calcium excretion
• Collecting tubules Site of final
modification of the
urine;
Reabsorb NaCl; urine
NaCl concentration
can be reduced to less
than 1 mmol/L
224. WHY MAINTAIN ACIDWHY MAINTAIN ACID
BASE BALANCE?BASE BALANCE?
Requirements for normal metabolism
• Fluctuations in pH cause significant
changes in H+
concentrations.
• The pH of the blood of a normal man is
alkaline and it is maintained within a small
range of about 7.37 to 7.42.
227. MAJOR SOURCES OF ACIDMAJOR SOURCES OF ACID
CO2
+ H2
O ⇔ H2
CO3
⇔ H+
+ HCO-
3
In Western diets approximately 40 to 60
mmoles of non-carbonic acids mainly
from protein metabolism.
Phosphoric acid from the catabolism of
phospholipids makes a minor
contribution to daily production of non-
carbonic acids.
228. OTHERSOTHERS
The production of lactic acid during
muscular exercise and during hypoxia
The production of aceto-acetic acid and β-
OH
butyric acid during uncontrolled diabetes
mellitus
Therefore it is vital that a mechanism be
developed to defend the system from
fluctuations in H+
ions.
233. CO-
3
/CO2
HCO-
3
regulated in proximal tubule – distal
tubule and collecting duct
Phosphate
Two phosphate salts
disodium hydrogen phosphate (alkaline)
Na2
HPO4
Sodium dihydrogen phosphate (acid)
NaH2
PO4
.
The normal ratio 4 :1 alkaline to acid and
can be changed H+
secretion - mainly distal
234. Ammonia
Conversion of glutamine to glutamic acid and
α- ketoglutarate
NH3
diffuses into the tubule to combine with H+
forming NH4
+
that has a much lower permeance
than NH3
.
The kidney can greatly increase NH3
production
in acidosis.
This is one of the main ways in which the kidney
responds to an acid load.
235. EFFECTS OF DISTURBANCES OF pHEFFECTS OF DISTURBANCES OF pH
♣ Hyperkalaemia due to movement of potassium
from cells into the extracellular fluid and the
depression of renal secretion of K+
♥ Widespread loss of smooth muscle tone that
produces a severe drop in arterial pressure.
For prolonged periods (weeks to months)
leaching of minerals from bones
(osteoporosis).
Effect of decreased H+
ion concentration raised
pH is tetany or spasm of muscles.
236. ACID BASE DISTURBANCESACID BASE DISTURBANCES
Divided into two categories
♣ Disturbances of Respiratory origin
Respiratory acidosis
Respiratory alkalosis
♣ Disturbances of Non-Respiratory origin
Metabolic acidosis
Metabolic alkalosis
♦ "Metabolic" refers to acid-base disturbances
that effect the CO-
3
/CO2
buffer system by
means other than altering pCO2
.
237. RESPIRATORY ACIDOSIS
♣ The respiratory system is unable to remove sufficient
pCO2
from the body to maintain normal pCO2
.
[CO2
] + H2
O ⇔ H2
CO3
⇔ HCO-
3
+ H+
♣ Consequence = ↑↑ [H] and ↑ [HCO-
3
] pH
238. RENAL COMPENSATIONRENAL COMPENSATION
♦ Definitions
•Compensation is the restoration of
pH towards normal though [HCO-
3
]
and/or pCO2
is still disturbed.
•Correction is the restoration of normal
pH, [HCO-
3
] and pCO2
.
239. ♣ A change in [H+
] = H+
secretion from the renal
tubular cells.
♣ Sufficient to reabsorb HCO-
3
though plasma HCO-
3
is raised – therefore generates increased HCO-
3
for
the plasma.
♣ The increased H+
leading to increased plasma
[HCO-
3
] is the RENALCOMPENSATION for respiratory
acidosis.
♣ The pH is restored to normal but [HCO-
3
] is elevated.
♣ Respiratory acidosis is associated with hypercapnia,
pCO2
= 48 mmHg in arterial blood.
240. ♥ CAUSES OF RESPIRATORY ACIDOSISCAUSES OF RESPIRATORY ACIDOSIS
Chronic bronchitis
Obstruction of airway by a foreign body
Mechanical injuries of the chest
Infections directly affecting the respiratory
centre and brain stem.
Anaesthetics such as morphine barbiturates,
depressants of respiration
241. RESPIRATORY ALKALOSISRESPIRATORY ALKALOSIS
♣ Excessive removal of CO2
from the
body
= arterial pCO2
below 35mmHg.
↓CO2
+ H2
O ⇔ H2
CO3
⇔ ↓ ↓ H+
+
↓HCO3
-
↓
242. pCO2
and consequent in [H+
] in the renal
tubule H+
secretion
♣ Therefore, HCO-
3
is excreted in the urine and
plasma [HCO-
3
] falls further.
♣ In the kidney the defect leads to a change in pH
increasing H+
ions in the blood that will lead to
decreased H+
secretion and therefore HCO3
-
reabsorption.
243. METABOLIC ALKALOSISMETABOLIC ALKALOSIS
♣ Acid base disturbances by means other
than altering the pCO2
= pH = H+
in the blood = H+
secretion = HCO3
-
re-absorption.
H2
O + CO2
⇔ H2
CO3
⇔ H+
+ ↑↑ HCO3
-
+ OH-
♣ Metabolic alkalosis = addition of OH-
ions
244. ♣Hypoxia = respiration = hypocapnia-
hyperventilation = respiratory alkalosis.
♣The decreased level of H+
acts on the chemo
receptors to reduce ventilation resulting in the
increase of pCO2
.
♣This is RESPIRATORY COMPENSATION
for metabolic alkalosis.
245. ♣ This compensation brings down the pH,
but further increases the plasma
concentration of HCO3
-
.
♣ The reduced H+
secretion in the renal
tubules leading to low HCO3
-
is the RENAL
COMPENSATION for renal alkalosis
246. METABOLIC ACIDOSISMETABOLIC ACIDOSIS
♣ Caused by excessive ingestion of acids
and production of H+
ions from the body.
♣ Addition of H+
ions drives the reaction to
the left resulting in the depletion of
plasma levels of HCO3
-
.
CO2
+ H2
O ⇔ H2
CO3
⇔ H+
+ ↓↓ HCO3
-
+ H+
247. ♣ This direct loss of HCO3
-
leads to a
change in pH.
– This change in pH acting on the
chemoreceptors stimulates respiration so
that pCO2
falls. This is respiratory
compensation for metabolic acidosis.
248. 04/07/15 248
SUMMARYSUMMARY
• The kidneys are the major site of sodium output and
regulation of extracellular fluid volume.
• Renal Na+ excretion is influenced by GFR, aldosterone,
peritubular capillary
• Starling forces, renal sympathetic nerve activity, diuretics etc.
• The kidneys normally maintain potassium balance by
excreting most ingested
potassium.
249. SUMMARY CONTINUED
The kidney is involved in the maintenance of pH.
• The processes involved include regulation of
H+
secretion.
• Urinary acidification involves re-absorption of
filtered bicarbonate, excretion of acid and
ammonia.
• The kidneys compensate for acidosis by
adding large quantities of new bicarbonate to
the blood.
250.
• When an individual is acidotic for more than a few
days, there occurs a marked increase in ammonia
synthesis.
• When an alkalosis exists, the kidneys compensate
by secreting too little acid to accomplish complete
re-absorption of filtered bicarbonate, thus leading
to excretion of bicarbonate
252. Early distal tubuleInhibit H secretion
and HCO-3
reabsorption
Thiazides
(chlorothiazides)
Thick ascending
limb
Inhibits Na-K-Cl
co-transport in
luminal membrane
Loop (Furosemide)
Mainly proximal
tubule
Inhibit water and
solute reabsorption
Osmotic
(Mannitol)
Site of actionMechanism of
action
Class of diuretics
253. Collecting tubulesBlock entry of Na
into the channels
of luminal
membrane
Sodium channels
blockers
(Amiloride)
Collecting tubulesInhibit aldosterone
action
Competitive
inhibitors of
aldosterone
(Spironolactone)
Proximal tubuleInhibit secretion of
H+ and
reabsorption of
HCO-3
Carbonic
anhydrase
Inhibitors
(Acetazolamide)
