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RENAL PHYSIOLOGYRENAL PHYSIOLOGY

LECTURE 1&2:LECTURE 1&2:

Kidney Structure, Functional RelationshipKidney Structure, Functional Relationship& Glomerular filtration& Glomerular filtration

By

DR. P MURAMBIWA

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“Kidneys  are master  chemists with main  roles 

of protecting us from pleasures of eating and 

drinking,  and  thus  their  dysfunction  speeds 

our early death." 

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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.

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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.

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Renal Cortex

Renal Medulla

Minorcalyx

Renal PelvisRenal Artery

RenalPyramid

Renal Vein

Ureter

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         Two distinct regions;  

    The cortex, darker outer region                     Medulla a pale inner region 

 

The medulla further subdivides into conicalareas called pyramids.  

RenalCortex

RenalMedulla

CorticalNephron

JuxtamedullaryNephron

osmotic gradient formation

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EfferentArteriole

Peritubularcapillaries(cortical nephrons)

VasaRecta(juxtamedullarynephrons)

collectingduct

Loop ofHenle

• The vasa recta plays a critical role in urine formation.

Blood Supplyto the Nephrons

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

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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      

       

    the kidney.  

Total renal blood flow is decreased in most                    

    stressful situations

A number of substances also affect renal blood                    

    flow

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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

 

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Regulation  of  plasma  [bicarbonate]  and therefore the hydrogen ion concentration           

   The  kidneys  eliminate  metabolic  waste 

products such as urea. 

They also  eliminate many  foreign compoundsfrom  the  body,  including  drugs  such  as penicillin. The  kidneys  produce  erythropoietin,  renin, 

kallikrein,  that  leads  to  the  formation  of  kinins and various prostaglandins 

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 ♦ Kidneys have several special metabolic functions. 

They are responsible for converting the inactive form of vitamin D to its active form, 1,25-dihydroxy-

vitamin D3. 

The kidneys synthesize ammonia from amino acids.  

The kidneys can synthesize glucose from      non-carbohydrate sources. 

Kidneys are sites for degradation of several polypeptide hormones, including insulin, glucagon, 

and parathyroid hormone. 

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OBJECTIVES 2:OBJECTIVES 2:  

Define the basic processes of GFR •   State  the  sites  in  the  glomerulus  for  restriction  of macromolecules

 •  State the determinants of GFR.  •   Why is renal auto-regulation important?

Summary-Processes occurring in the Nephron

Filtration

Reabsorption Secretion

Excretion

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GLOMERULAR FILTRATIONGLOMERULAR FILTRATION

• Filtration  =  the  bulk  flow  of  a  solvent             through  a  filter  carrying  with  it 

            substances  small  enough  to        pass through the filter. 

• Kidney      =  separation  of  compounds  into 

    glomerular filtrate.

The Renal CorpuscleComposed of Glomerulus and Bowman’s capsule

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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.

Glomerular filtration barrier

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RENAL PHYSIOLOGYRENAL PHYSIOLOGY

LECTURE 1 & 2 CONT’D:LECTURE 1 & 2 CONT’D:

Kidney Structure, Functional RelationshipKidney Structure, Functional Relationship& Glomerular filtration Rate& Glomerular filtration Rate

By

DR. P MURAMBIWA

Glomerular Filtration barrier

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

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

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.

Forces governing GFR and RBF

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

FORCES FAVOURING FILTRATION

• Glomerular capillary pressure

FORCES OPPOSING FILTRATION

• Fluid pressure in bowman space

• Osmotic force due to protein in plasma

NET FILTRATION PRESSURE IS POSITIVE-FAVOURS FILTRATION

CONTD

• Osmotic force due to protein higher than in all other arterioles because of loss of large quantities of water by glomerular filtration process

GLOMERULAR FILTRATION RATE

• It refers to VOLUME of fluid filtered from the glomerulus into bowman space PER UNIT TIME.

FACTORS AFFECTING GFR

• Changes in renal blood flow

• changes in glomerular capillary hydrostatic pressure due to

1) changes in systemic blood pressure2) afferent or efferent arteriolar

constriction

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

SUMMARY OF FACTORS AFFECTING GFR

• Net filtration pressure.

• Permeability of corpuscular membrane

• Surface area available for filtration to occur

PHYSIOLOGICAL REGULATION OF GFR

• It is not fixed but regulated by1) hormones2) neural input to the 2 arterioles3) neural and hormonal input to

mesangial cells

GFR DECREASED BY

Constriction of AADilatation of EAContraction 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

AGENTS CAUSING CONTRACTION OF MESANGIAL

CELLSAngiotensin IIVasopressinNor-epinephrineHistamine

AGENTS CAUSING RELAXATION OF MESANGIAL CELLS

ANPDopaminecAMP

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

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        CONCEPT OF CLEARANCECONCEPT OF CLEARANCE RBF and GFR can be measured by clearance methods.

   Clearance of a substance is the volume of blood cleared of the substance in unit time. 

        The units of clearance are usually volume/time, (ml/min).

Renal handling of different substances

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To calculate the clearance of a substance three values must be measured.

[Substance]  in  plasma

=

Px

   

[Substance]  in  urine

=

Ux

   

Urine  flow  rate 

=

V

 

Amt  excreted/  min

=

Ux     V

           Clearance

           

 = C= UxV ml/ time

                                               

                                 Px 

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Clearance of Na+ when given the following: PNa+ 

=     142 mmol/lUNa+ 

=      71 mmol/lV

=        1 ml/min Clearance  of  Na+

=       71   1                                         

            142                                                         

                

=    0.5 ml/min

Glomerular filtration rate (GFR) measured byclearance methods.

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GFR MEASUREMENTGFR MEASUREMENT

GFR = amount of  filtrate  that  flows out of the  renal  corpuscles  of  both  kidneys every minute. 

How do we measure GFR?

Substance  used  must  have  the  following  properties:

freely  filtered, small and must not bind  to plasma protein.

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♣  

must  not  be  secreted  or  reabsorbed  (  actively  or 

passively )                   

 

must not be toxic.                   

 

must not be metabolized. 

 

The substance must be present in the filtrate at 

the same concentration as in plasma. 

 

When  99%  of  the  filtrate  is  reabsorbed  the 

substance  will  remain  in  the  tubule  and  excreted 

in  the  urine.

 

 

Therefore,  concentration  of  substance  in  the 

filtrate  =  concentration  of  substance  in  the 

plasma.

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MEASUREMENTMEASUREMENT  WITH INULINWITH INULIN   Inulin is not a normal constituent of the body.

     Inulin (MW 5500) is freely transferred  across the glomerular membrane in the  same way as  small molecules such as urea or Cl-. 

    Molecular weights have shown that molecular weight of 10,000 pass freely

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We need to know the following:     

  Urine    [inulin] 

(  UIn  )        =

60 mg/ml     

Urine  flow  rate

(V  )

    =

1.1 ml/min        

Plasma  [inulin]

(PIn  )          =

0.5 mg/ml         

GFR  =

UIn   V  =  60 x 1.1 = 132 ml/min 

                                       

      PIn        0.5

    

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  Normal GFR is 125 ml/min (180 litres/day) in a normal man.     Varies with body size; therefore the value is normally  given  as  125 ml/min/1.73 m2  body  surface  in young  man,  the  body  surface  area  is  10%  less  in females.    GFR is low in infants and decreases in old age.  

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

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  MEASUREMENT OF RENAL BLOOD FLOW (RBF)MEASUREMENT OF RENAL BLOOD FLOW (RBF)

Using indirect methods.  

substance should meet the following criteria:

 

totally cleared by filtration.

 

not reabsorbed.  

not metabolized.

 

not toxic.  

[substance]  should  not  exceed  the  transport maximum 

(Tm).  

  

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Para-amminohippuric acid (PAH) is widely used to    estimate RBF.  [PAH]  should  not  exceed  the  Tm  since  the  substance  is 

eliminated from the kidney by both filtration and secretion 

The amount of PAH excreted =  amount of PAH filtered + the amount that is being secreted.   

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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. 

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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."         

  

Mechanisms of glomerulotubular balance and tubuloglomerular feedback-Intra-renal mechanism

2934

Tubuloglomerular feedback

Myogenic mechanism of the autoregulation

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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 PROXIMAL TRANSPORT PROCESSES IN THE PROXIMAL TUBULETUBULE

By

DR. P MURAMBIWA 

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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.

74

INTRODUCTIONINTRODUCTION

The proximal tubule = a major site where many

substances are reabsorbed such as :

Na+

Cl-

H2O

HCO3-

Glucose

Amino acids

Urea

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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

Renal handling of different substances

Summary-Processes occurring in the Nephron

Filtration

Reabsorption Secretion

Excretion

PROXIMAL CONVOLUTED TUBULE (PCT)

Found in cortex15 mm long and 55µm in diametersingle layer of cellsluminal edges with brush borderconvolution increases length hence

increase contact between tubular cells and luminal fluid thereby facilitating reclamation

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SODIUM AND WATER REABSORPTION

REABSORPTION OF SODIUM

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% NaCl Reabsorbed

♦Proximal Tubule 67% Loop of Henle (Ascending) 25%

Distal Tubule 5%Collecting Duct 2% Excreted in Urine % Variable

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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

Two pathways of the absorption

Lumen

Plasma

CellsTranscellular

Pathway

Paracellular

transport

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Passive Transport

Diffusion

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NaNa++ HANDLING HANDLING

Reabsorption of 60 - 70% Na+ is by active process. The Na+ reabsorption is associated with Cl- and

HCO3- and H2O.

The reabsorption of Na+ is primary and active and is shown by many arguments.

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.

COUPLING OF WATER TO SODIUM REABSORPTION IN PCT

COUPLING OF WATER TO SODIUM

REABSORPTION IN PCT

Na+ reabsorption in PCT

Primary Active Transport

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 CellInterstitial

Fluid

Tubular

lumen

Tubular CellInterstitial

Fluid

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Transport is abolished by cooling.

Replacement of sodium by any other cation (Lithium) greatly reduces reabsorption of H2O and other solutes.

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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.

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Na+ EXTRUSION Cl- REABSORPTION

H2O REABSORPTION

UPTAKE OF NaCl AND H2O

The uptake of Na+, Cl- and H2O from lateral intercellular spaces into peritubular capillaries

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Na+

Cl-

Na+

Cl-

H2O 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)

H2OπLIS

πcap

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RENAL PHYSIOLOGYRENAL PHYSIOLOGY

LECTURE 3 & 4: CONT’D

TRANSPORT PROCESSES IN THE PROXIMAL TRANSPORT PROCESSES IN THE PROXIMAL TUBULETUBULE

By

DR. P MURAMBIWA 

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GLUCOSE AND AMINO ACID REABSORPTION

Glucose & amino acidsCo-transported with sodium

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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

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+.

Tubular

lumen

Tubular CellInterstitial

Fluid

Tubular

lumen

Tubular CellInterstitial

Fluid

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

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GLUCOSE TRANSPORT & CONCEPT OF TRANSPORT MAXIMUM

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HYDROGEN ION SECRETION AND HYDROGEN ION SECRETION AND BICARBONATE REABSORPTIONBICARBONATE REABSORPTION

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:

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• 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.

BICARBONATE REABSORPTION

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BICARBONATE REABSORPTION

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

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

ADDITION OF NEW BICARBONATE TO PLASMA

COMBINATION OF SECRETED

BICARBONATE WITH NON

BICARBONATE BUFFERS

RENAL PRODUCTION AND

SECRETION OF AMMONIUM occurring

in the PCT

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

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

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ACID PHOSPHATE EXCRETIONACID PHOSPHATE EXCRETION

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REABSORPTION OF UREAREABSORPTION OF UREA

• 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.

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

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RENAL PHYSIOLOGYRENAL PHYSIOLOGY

LECTURE 5&6: LECTURE 5&6:

COUNTER-CURRENT MULTIPLIER AND EXCHANGE SYSTEMS COUNTER-CURRENT MULTIPLIER AND EXCHANGE SYSTEMS

By

DR. P MURAMBIWA

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CORTEX

MEDULLA

Early diluting segment

Cortical collecting tubule

Outer medullary collecting duct

Inner medullary collecting duct

Thin ascending limb

Thick ascending limb

Thin descending limb

Proximal straight tubule

Proximal convoluted tubule

Bowman’s capsule

Macula densa

Late diluting segment

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INTRODUCTIONINTRODUCTION

The fluid entering the loop of Henle is isotonic toplasma

Animals such as birds and mammals, those with longloops of Henle, urine produced may be moreconcentrated 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-currentMultiplier Systems.

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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.

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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)

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Operation of the loop of Henle as a countercurrent multiplier system

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ASCENDING LIMBASCENDING LIMB 

  Actively extrudes NaCl into the medullary          interstitium, but is impermeable to water.   Process uses a Na+ - K+ ATPase   Cl- is actively transported.     Stoichiometry of 1Na+, 2Cl- and lK+  

     

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Much of the K+ leaks back into the tubular      lumen so that it is predominantly NaCl that    accumulates in the medullary interstitium.  Osmolality in the medullary interstitium is    increased and that of the fluid in the   ascending limb is decreased.

NaCl transport in the thick ascending limb of the loop of Henle

Na+ reabsorption in thick ascending loop of Henle

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THE DESCENDING LIMBTHE DESCENDING LIMBHighly permeable to H2O and to a lesser extent to  NaCl Urea  is  added  to  the  medullary  interstitium  from  the collecting  duct by diffusion down a concentrationgradient  Collecting  duct  tubules  urea  concentration  rises       because of water reabsorption.  The medullary collecting tubule is permeable to urea in the presence of antidiuretic hormone (ADH). 

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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]

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• 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.

Na+ Reabsorption-Cortical Collecting Duct

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  UREA AND COUNTER-CURRENTUREA AND COUNTER-CURRENT  MULTIPLICATIONMULTIPLICATION ♦Urea is delivered to the distal tubule and hence the    collecting ducts.  ♦ In the presence of ADH water is reabsorbed.  ♦ In the medullary collecting ducts ADH causes the   urea and water reabsorption.  ♦The high interstitial urea concentration leads to the   diffusion of some urea into the loop of Henle, to   return to the collecting duct.

ADH/Arginine vasopressin

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.

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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)

apposition of the vasa recti (vessels originating from the efferent arteriole-hairpin turn of the vasa recti)

the thin descending limb is impermeable to sodium chloride but permeable to water

the thin ascending limb is impermeable to both sodium chloride and  water and has no active transport mechanism for sodium chloride

The thick ascending limb is impermeable to both water and sodium chloride but has active transport for sodium chloride

the distal tubule has active transport for sodium chloride but is impermeable to water

the cortical collecting duct is permeable to water, & has active transport for sodium chloride

Both medullarly and cortical  collecting ducts are controlled by vasopressin. 

urea, a freely permeable and highly filtrable substance also helps in the maintenance of a hyper osmotic intestitium in the medulla.

Countercurrent exchanger system- Vasa recta

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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.

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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.

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.

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  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.

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ACTIVITY 4ACTIVITY 4 

 

 

1.  How do processes for sodium and water     reabsorption in the collecting ducts and       proximal  convoluted tubules differ? 

 2.  Describe the role of counter-current 

multiplier system in  urine concentration. 

3.  State how changes in medullary blood flow or loop flow rates may impede concentration of 

      urine. 

4.  State the action of ADH and the nephron sites      on which it  acts. 

        

RENAL PHYSIOLOGYRENAL PHYSIOLOGY

LECTURE 7 & 8:

THE RENAL CONTROL OF SODIUM AND POTASSIUM EXCRETION

&RENAL ACID BASE BALANCE

By

DR. P MURAMBIWA

OBJECTIVESOBJECTIVES:

1a. Explain renal sodium and potassium handling and factors that control their handling.

1b. What determines the effectiveness of a pH buffer?

2. List chemical buffers present in:

(a)   extracellular fluid (b) intracellular fluid (c) bone (d) urine

   

3. What  leads  to  the  generation  of  new  bicarbonate  in  the kidney to replace depleted plasma bicarbonate reserves?

 

4. Which  process  in  the  kidney  consumes  most  of  the hydrogen ions secreted by the tubular epithelium? 

THE RENAL CONTROL OF SODIUM AND POTASSIUM EXCRETION

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 • In several types of disease, Na+ balance becomes deranged by the failure of the kidneys to excrete Na+ normally. 

• The processes involved in renal Na+ handling are discussed  in  this  Lecture  to  enable  you  to understand  underlying  factors  that  may  be associated with impairment in kidney function.

 

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• Conditions associated with  NaConditions associated with  Na++ Deficiency. Deficiency. ♠ Disorder Manifestation                               

• Severe diarrhoea hyponatremia   especially 

infants                                                                          • Diuresis  hyponatremia• Severe sweating hyponatremia• Adrenal insufficiency hyponatremia •  SIADH  (  Inappropriate hyponatremia

ADH secretion).                      

                

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• Diseases associated with KDiseases associated with K++ deficiency. deficiency.♥ Disorder Manifestation.

  • Laxatives   hypokalaemia • Vomiting  hypokalaemia• Diarrhoea hypokalaemia• Gastrointestinal hypokalaemia• Surgical drainage loss hypokalaemia• Metabolic alkalosis hypokalaemia• Metabolic acidosis hyperkalaemia 

 

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    TUBULAR NaTUBULAR Na++ REABSORPTION REABSORPTION

 • Controlled by both humoral factors and   physical factors. 

 • Sites = proximal tubule, ascending loop of        Henle,  distal  tubule  and  the  collecting duct or a combination of these sites.

 

 An alteration in GFR changes the filtered 

 Na+ load 

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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.  

 

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•  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  dogsinduced by either Ach or prostaglandin has                     

been noted to increase Na+ excretion and urine           flow without changes in GFR.

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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.

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• 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.

 

 

 

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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.  

 

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♥ Sympathetic fibres from the splanchnic nerves enter the kidney as a nerve plexus along the walls of the renal artery.

 

• Sympathetic  fibres  from  the  splanchnic  nerves innervate three distinct structures             

♥ the  renal  vasculature,  particularly  along    the arteries and arterioles;

♥ the juxtaglomerular apparatus;

♥ the proximal tubule and other parts of

the nephron.

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– The nerve-mediated Na+ reabsorption involves an initial activation of ∝ 1

adrenoceptors.

 

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♦ HORMONAL REGULATION 

Condition  Na+

mmol/l K+

mmol/l Cl- mmol/l 

HCO3-

mmol/l

Normal

Adrenal insufficiency (Addison’s disease)

Primary Aldosteronism 

142 

120 

148 

4.5     

 6.7 

 2.4 

105     85 

 96 

25   

25 

41

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• Aldosterone is involved in the regulation of Na+ reabsorption.  

             

• Site of action is the epithelial cells of the distal convoluted tubules and collecting ducts.

• Glandular epithelial cells  in the bowel mucosa, salivary and sweat glands.   

 

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• 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.

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Nuclear membraneCell membrane

(Transcription)

(TRANSLATION) mRNA ribosomesavidin

DNAAcidic protein

               

          

             

 

♦ MECHANISM OF ALDOSTERONE  ACTIONMECHANISM OF ALDOSTERONE  ACTION 

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• 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 

 

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•  Angiotensin II and plasma levels of Na+ or K+ 

 

 •  Plasma sodium (PNa+ )

 

• K+  ions  also  exert  a  stimulatory  effect  on aldosterone biosynthesis by acting directly  on the zona glomerulosa cells 

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♦♦RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)(RAAS)

Influences Na+ excretion in two different ways.

   A direct renal action of AII

   An influence of AII over aldosterone synthesis 

 

   AII acts directly on the adrenal cortex to enhance

   aldosterone synthesis.

  Macula densa cells within the distal tubule are

  believed  to act as sensors.

Maculadensa(vasoconstrictorsand vasodilators)

Efferentarteriole

Glomerularcapillaries

Proximaltubule

Bowman’s capsule

Urinary space

Juxtaglomerular(Granular) cells(renin)

Renalnerves

Afferent arteriole

Distaltubule

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• 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

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♦♦ 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). 

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Sympathetic  nerve  activity  causes  renin  release, mediated  by  α 1-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

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• 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.

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♦♦ 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.

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2934

Tubuloglomerular feedback

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• 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). 

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• Atrial extracts increase GFR in  isolated perfused kidney.  

 

• A  high  density  of  ANF  receptors  has been  seen  in  adrenal  glomerulosa membranes.  

    

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♥♥ ACTIONS OF ANPACTIONS OF ANP

♠Inhibition of aldosterone secretion

♠Reduction of renin release

♠Reduces the release of vasopressin

♠Natriuresis and diuresis.

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▲ ▲ ANP/ALDOSTERONEANP/ALDOSTERONE

• A high density of ANF receptors has been seen in adrenal glomerulosa membranes.

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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.

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• 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.

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♦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.

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KK++ EXCRETION EXCRETION

• 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.

Summary of Na+ and K+ handling

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+)

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• 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.

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• 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.

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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.

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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.

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• 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.

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EFFECTS OF HYPERKALAEMIAEFFECTS OF HYPERKALAEMIAExcitable 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.

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♦♦ 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.

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• 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.

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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.

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♦♦ HANDLING OF PHOSPHATEHANDLING OF PHOSPHATE

Two forms acid phosphate,

• Acid H2PO4- 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.

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• 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.

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.

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SUMMARY-CONTRIBUTION OF THE SUMMARY-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 H2O

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• 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 H2O.

Major site of active regulation of magnesium excretion

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• 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

RENAL ACID BASE BALANCE

WHY MAINTAIN ACID WHY 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.

BICARBONATE BUFFER SYSTEMBICARBONATE BUFFER SYSTEM          

[H+] nmol/l

pH pCO2

(mm-Hg)[HCO-

3]

m mol/l

Arterial 40 7.42 40 24

Venous 46 7.35 46 25                        

MAJOR SOURCES OF ACIDMAJOR SOURCES OF ACID CO2 + H2O ⇔ H2CO3 ⇔ 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.

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.

BUFFERS OF THE KIDNEY

HCO-3/CO2

Phosphate

Ammonia

HCO-3/CO2

Phosphate

Ammonia

CO-3/CO2

HCO-3 regulated in proximal tubule – distal

tubule and collecting duct

PhosphateTwo phosphate salts disodium hydrogen phosphate (alkaline) Na2HPO4

Sodium dihydrogen phosphate (acid) NaH2PO4 .

The normal ratio 4 :1 alkaline to acid and can be changed H+ secretion - mainly distal tubule

AmmoniaConversion 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.

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.

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.

RESPIRATORY ACIDOSIS♣ The respiratory system is unable to remove sufficient pCO2 from the body to maintain normal pCO2.

[CO2] + H2O ⇔  H2CO3 ⇔ HCO-

3 + H+

♣ Consequence = ↑↑  [H] and ↑ [HCO-3] pH

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.

♣ 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.

♥ 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

RESPIRATORY ALKALOSISRESPIRATORY ALKALOSIS♣ Excessive removal of CO2 from the

body = arterial pCO2 below 35mmHg.

↓CO2 + H2O ⇔ H2CO3 ⇔ ↓ ↓ H+ +

↓HCO3-

↓

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.

METABOLIC ALKALOSISMETABOLIC ALKALOSIS♣ Acid base disturbances by means other

than altering the pCO2

= pH = H+ in the blood = H+

secretion = HCO3- re-absorption.

H2O + CO2 ⇔ H2CO3 ⇔ H+ + ↑↑ HCO3

-

+ OH-

♣ Metabolic alkalosis = addition of OH-

ions

♣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.

 

 

♣ 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

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 + H2O ⇔ H2CO3 ⇔ H+ + ↓↓ HCO3-

+ H +

 

♣ 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.

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 ingestedpotassium.

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.

 • 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

• A diuretic is a substance that increase the rate of urine output.

• It cause natriuresis (increased sodium output), and this in turn cause diuresis (increased water output)

Diuretics and their mechanisms

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

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)

• Basic processes involved in the filling and emptying of the bladder

3 muscles are involvedDetrusor muscle-smooth 

(parasympathetic)Internal urethral sphincter-smooth 

(sympathetic)External urethral  sphincter-skeletal 

(somatic motor neurone)

MICTURITION OR URINATION

Micturition reflex

stretchreceptors

• 1) APs generated by stretch receptors

• 2) reflex arc generates APs that

• 3) stimulate smooth muscle lining bladder

• 4) relax internal urethral sphincter (IUS)

• 5) stretch receptors also send APs to Pons

• 6) if it is o.k. to urinate

– APs from Pons excite smooth muscle of bladder and relax IUS

– relax external urethral sphincter

• 7) if not o.k. inhibitory impulses from pons inhibit micturition

–

Micturition reflex

THE END