The Urinary System - LUSUMA

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					The Urinary System
Adults are about 60% water (63% in men & 52%), distributed between extracellular & intracellular
spaces, in the ratio of about 1:2.5. There is also a small volume in ‘transcellular’ fluids such as CSF &
gastric secretions.

Extra-cellular fluid about 12L outside of the circulation plus about 3l in plasma

Functions: The kidney filters very large amount of extra cellular fluid. Ultra- filtrate, water, ions & all
small molecules. 180l.d-1 every litre filtered ten times a day. But only 1.5l per day of urine.

In normal water & electrolyte balance

    –   Over 99% of filtered water recovered
    –   Over 99% of filtered sodium & chloride recovered
    –   100% of hydrogen carbonate recovered
    –   50% of urea excreted.
    –   100% of phenol excreted
    –   100% of glucose & amino acids recovered
    –   Just a few waste products not recovered
    –   Some substances (eg H+, actively secreted, so lose more than filtered)

Metabolically demanding uses 25% of cardiac output at rest.

The kidney are paired organs behind the peritoneal (retroperitoneal) & weigh 150g.
Microscopically that kidney is made up of an outer cortex & inner medulla, surrounding the renal
pelvis which is connected to the ureters. Each kidney has about 1-1.5 million nephrons.

Proximal convoluted tubule

Major site of reabsorption

   – 60-70% of sodium & water
   – 80-90% of potassium
   – 90% of hydrogen carbonate
   – Normally, 100% of glucose & amino acids
Water follows osmotic gradients, so filtrate remains isotonic. Reabsorbed materials leave by peri-
tubular capillaries.

The membrane facing the filtrate – the apical or luminal membrane, & that facing the extra cellular
space – the serosal or basolateral membrane.

The loop of Henle: Counter-current multiplication.

The distal tubule: major site of variable reabsorption of electrolytes & water. Fluid leaving loop of
Henle is hypotonic. Distal tubule removes yet move sodium & chloride. Also actively secretes H+.
Water may or may not follow reabsorption. If it does not – diuresis

The collecting duct passes through the high osmolarity environment of the medulla. If water can
cross the epithelium it will leave the urine down the osmotic gradient – producing low volume of
concentrated urine. If it cannot urine remains dilute.

Overall, the kidney does:
    Excretes waste products by filtering & not reabsorbing them.
    Recovers essential molecules such as glucose which have been filtered
    Controls the osmolarity of body fluids by variable excretion of water
       controls the volume of extra cellular fluid by the variable secretion of salts
       Controls the pH of ECF by variable excretion of H+

The right kidney is about 1cm lower than the left kidney.

Upper right pole T12 Right anterior organs – liver supra-renal at the top; duodenum in the middle,
possibly with pancreas; right colonic flexure.
Left anterior organs – spleen supra-renal at the top; pancreas in the middle, with possibly stomach,
possibly lower pole of splenic flexure, possibly some small bowel. Left kidney T11

Each kidney is enclosed by a tough capsule & surrounded by perinephric fat. The renal fascia holds
the kidney in position & separately enclose the adrenal gland. The kidneys lie on a bed which starts
with psoas muscle medially & then passed out over the diaphragm which is attached to the 12th rib
& beneath the 12th rib the quadrates lumborum muscle. The upper part of the kidney lies over the
lower 2 ribs.

The ureter is 25 cm long & runs downwards vertically, blended with the peritoneum on psoas major,
just medial to, & parallel with, the tips of the lumbar transverse processes. The ureter enters the
pelvis by crossing the bifurcation of the common iliac artery, anterior to the sacroiliac joint where a
narrowing may be present as it passes over the pelvic brim. It then runs downwards & backwards to
the region of the ischial spine, where it turns forwards & medially to enter the bladder. It traverses
the bladder wall in an oblique manner, this intramural part being the narrowest point of the ureter.

Session 2

Development of the Urinary System
The kidney & ureters develop from intermediate mesoderm at the urogenital ridge.

After Gastrulation, a trilaminar embryo has formed, the mesoderm formed rapidly undergoes
organisation. The primordum of the gut is forced during embryonic folding. After gastulation there
are two areas where mesoderm does not separate ectoderm & endoderm (the buccopharyngeal
membrane & the cloacal membrane).

3 systems develop sequentially, disappearance of one system makes the onset of development of
the next developmental stage. 1st appears in the cervical region, the pronephros.

Structure        Appears          Regresses      Functional     Comment
Pronephros       start week 4     end week 4     no
Mesonephros      End week 4       End of         Yes, no        Mesonephric duct has a role in the
                                  week 8         water          development of the duct system of the
                                                 conserving     male reproductive tract. It sprouts the
                                                 mechanism      “ureteric bud”, the primordum of the
                                                                collecting duct
Metanephros      Week 5           No             Yes, from      The “definitive kidney”. Collecting system
                                                 end of 1st     develops from ureteric bud & the
                                                 trimester      excretory system develops from
                                                                “metanephric tissue cap”
The pronephric duct extends from the
cervical region to the cloaca & drives the
development of the next stage.

Urogenital ridge – Region of intermediate
mesoderm giving rise to both the
embryonic kidney & the gonad. The two
systems are intrinsically fused.

The Mesonephric tubules develop caudal to
the pronephric region. Mesonephric
tubules + Mesonephric duct = embryonic
kidney. No water concentration so very big.

The ureteric bud induces development of
the definitive kidney within intermediate
mesoderm of the caudal region of the

The ureteric bud drives the development of
the definitive kidney. The collecting system
is derived from the ureteric bud itself. The excretory component is derived from intermediate
mesoderm under the influence of the ureteric bud.


During its development the kidney undergoes a dramatic shift in position from the pelvis to the
abdomen. This arises because of migration & expansion of the caudal region of the foetus. Migration

    1. Cranio-caudal shift from L4 to L1/T12
    2. Lateral displacement (meeting up with the adrenal glands in the process)
    3. A 90o rotation so the renal pelvis faces the midline.

                                                                When things go wrong...

                                                                Ureteric bud fails to interact with
                                                                intermediate mesoderm renal
                                                                agenesis (complete absence)
                                                                Migration goes awry. Wilm’s
                                                                tumour. Duplication defects,
                                                                ectopic ureter. Cystic disease.

                                                                Bladder & urethra
                                                                Early in development the GI, urinary
                                                                & reproductive tracts end at a
                                                                single structure  THE CLOACA.
                                                                The bladder is a hind-gut derivative
                                                           i.e. it is derived from the caudal portion of
                                                           the primitive gut tube firmed during
                                                           embryonic folding in the 4th week of
                                                           development. Also involved is the
                                                           allantois, which is a supero-ventral
                                                           diverticulum of the hind-gut & extends
                                                           into the umbilical cord. The lumen of the
                                                           allantois becomes obliterated to becomes
                                                           the urachus, which is the median
                                                           umbilical ligament in adults. The cloaca
                                                           becomes divided by the urorectal septum
                                                           into the urogenital sinus & anorectal

The female urethra is formed b the pelvic part of the urogenital sinus. The male is divided into 4
parts: the pre-prostatic, prostatic, membranous, spongy (only big in the phallic part). The distal
portion of the urethra develops as the external genitalia change from an indifferent starting point to
the morphology dictated by the genotype of the embryo. Thus, in the male, the distal urethra is
elongated (becoming the spongy urethra) as the penis develops from fusion of the urethral folds
under the influence of testosterone. In female the urethra opens into the vestibule because the
urethral folds do not fuse.

Wrong un’s: Fistulae, exstrophy of the bladder – bladder opens onto abdominal wall, ectopic
urethral orifices (hypospadias)

Hypospadias  defect in fusion of urethral folds, urethra opens onto the ventral surface rather than
at the end of the glans.

Renal agenesis. This is due to failure of development of the metanephros or failure of the ureteric
bud from the mesonephric duct to reach the metanephric mass.

Ectopic kidney. This arises from failure of ascent of adult metanephros to the normal region of the
posterior abdominal cavity at approximately the level L1.

Horseshoe kidneys. The lower pole of the developing kidneys fuse in the pelvic region & ascend into
the adult position with the lower poles fusing, forming the characteristic horseshoe shape.

Polycystic kidneys. Thought possibly to be due to failure of the ureteric bud to anastomoses
appropriately to the nephron tubules. This is probably an over implication.

Ureters duplex. Instead of a single ureteric bud arising from a mesonephric duct, there are two of
these & they ascend to the metanephric mass as two ureters forming the so-called duplex system.

Ectopic ureter - normally both ureteric orifices of a duplex system enter the bladder through the
area of the trigone. If there is further absorption of the mesonephric duct & the ureteric buds into
the urinary pathway, the duplex ureter of the upper moiety (i.e. upper part of the kidney) may enter
beneath the sphincter zone of the urethra, or indeed, into the vagina. In these circumstances the
patient will experience incontinence.
Functional Histology of the urinary tract
The renal corpuscle = the glomerulus + bowman’s capsule, it produces ultra filtrate of the plasma.
Parietal layer of Bowman’s capsule consists of simple squamous epithelium. Filtration barrier
produced by capillary endothelium & visceral layer of Bowman’s capsule. The visceral layer of
Bowman’s capsule wraps around the capillary endothelium – podocytes. The parietal layer of
Bowman’s capsule makes a ‘funnel’ to collect the ultrafiltrate which drains into the proximal
convoluted tubule at the urinary pole.

Capillary endothelium is fenestrated podocytes invest the capillary endothelium. Making filtration
slits spaces between the podocytes processes. Endothelium & podocytes share a basement

Proximal convoluted tubule
Longest most convoluted section of the tubule, reabsorption begins. Simple cubiodal epithelium
with pronounced brush border.
The loop of Henle
     Thin descending limb dipping down into the medulla, simple squamous epithelium. There is
        no active transport, looks a lot like a small capillary but no RBC’s & no brush border.
     Thick ascending limb – best seen in the medulla, simple cubiodal epithelium with no brush
        border, active transport.

Distal convoluted tubule: Makes contact with glomerulus, contain numerous mitochondria, no
brush border, but larger lumen the proximal part.

The juxtaglomerular apparatus: consists of the macula densa of distal convoluted tubule, the
juxtaglomerular cells of afferent arteriole of glomerulus, the extraglomerular mesangial cells.

Collecting Duct: continuation of DCT via collecting tubule, similar appearance to the thick limbs of
henles loop. But lumen is larger & tends to be more irregular than circular.

Renal pyramid – formed by progressively larger ducts that are formed by merging collecting ducts
contents empty at renal papilla.

Ureter is a muscular tube, with 2 layers of smooth muscle, lined by transitional epithelium

Session 3- Filtration
What is filtered & how?

The glomerulus filters the plasma in blood. The afferent arterioles bring blood in – sympathetic
innervation for control of renal blood flow & plasma filtration. Glomerular tuft  very leaky.
Efferent arteriole – blood flow out & not regulated.

The glomerulus filters approximately 20% of plasma each time it passes through. This is 125 ml of
plasma per min or 180 litres per day. So the total circulation of 3-5 litres is filtered 65 times a day.

The barrier
    1. Capillary endothelium permeable to water, salts, glucose
    2. Basement membrane – consists of an acellular gelatinous layer of collagen/glycoproteins,
       permeable to small proteins but glycoproteins repel protein movement.
    3. Podocyte layer  pseudopodia interdigitate forms filtration silts

Small mol.Wt. & effective radius >1.48nm concentration in plasma = filtrate

Mol wt <69kDa & effective radium <1.48nm cannot get through

Proteinuria  in many disease processes the negative charge on the filtration barrier is lost so that
proteins are more readily filtered

Glycosuria occurs when urine in the plasma concentration has reached 10mmol/l, but this is
variable, some people as low as 7mmol/L or may be absent at 13mmol/l. Only when 16mmol/l or
greater is the reabsorptive capacity of all nephrons reached.

Physical forces involved in the filtering of plasma form tubular fluid.
   1. Hydrostatic pressure in the capillary which is regulated (favours filtration)
   2. Hydrostatic pressure in the Bowman’s capsule (opposes filtration)
   3. Osmotic pressure difference between the capillary & the tubular lumen opposes filtration

Glomerular filtration rate
Defined: The volume of plasma from which any substance is completely removed by the kidney in a
given amount of time e.g. normally 65ml/min

To find GFR need a molecule which is not reabsorbed such as inulin, Inulin expensive so creatinine.

Clearance – the volume of plasma from which a substance X can be completely cleared to the urine
per unit time.

All plasma constituents are at the same concentration in the glomerular filtrate as in the plasma.
Movement can be transcellular or paracellular but transport occurs primarily through cells unlike
filtration. Channels & transports promote trans-membrane flux of solute that cannot pass through
lipid bi-layer this is energy dependent. Water & solute reabsorbed into interstitium is driven into
capillary by staling forces.

Regulation of GFR
Auto-regulatory mechanisms keep GFR within normal limits. Autoregulation of the afferent
arterioles :

       increased blood pressure  afferent arteriole constriction (GFR unchanged)
       decreased blood pressure  afferent arteriole dilatation (GFR unchanged)
       Autoregulation is able to maintain GFR when blood pressure is within 80 – 180 mmHg
Macula densa cells are sensitive to the ionic content & water volume of the fluid in the DCT,
producing molecular signals that promote renin secretion by granular cells of the juxtaglomerular

Increase arterial pressure  increase glomerular capillary pressure  increased GFR

Increased GFR  increased Na & Cl in distal tubule

Tubular secretion
Like tubular reabsorption, tubular secretion involves Transepithelial transport mechanisms. This
provides a second route of entry for solutes that need to be secreted into the tubular fluid. This is
useful since only 20% of the plasma is filtered each time blood passes through the kidney:
Substances secreted into the tubular fluid as protons, potassium & organic anions & cations.

Organic cations are secreted due to entry by passive carrier  mediated diffusion across the
basolateral membrane down favourable concentration & electrical gradients created by the Na-K-
ATPase pump. Then secretion into the lumen occurs by a H-OC+ exchanger that is driven by the H
gradient created by the Na-H antiporter.

                                                                       Several organic cation
                                                                       transporters analogous to
                                                                       organic anion transports.
                                                                       Cations compete with each
                                                                       other for transport this limits it.
Session 4 – Changes in plasma Volume
Major osmotically effective solute in the ECF is Na+ thus water in the ECF compartment depends on
the [Na] change the Na results in effect on the effective circulating volume.

Sodium balance: independent control of sodium reabsorption allows kidney to compensate for the
fact that sodium ingestion is variable. Control of total body sodium controls the effective circulating
volume. Independent control occurs in the distal tubule via the hormone aldosterone.

If sodium excretion is less than intake then a patient is in positive balance. In this case, extra sodium
is retained in the ECF. When Na+ content of the ECF ↑there is corresponding ↑in ECF volume as
water from the nephron is drawn out, blood volume & arterial pressure ↑& oedema may follow. If
sodium excretion is greater than ingestion then a patient is in negative balance. Excess Na+ is lost
from the body, the sodium content of the ECF ↓& water remains in the nephron, ECF volume ↓as
does blood volume & arterial pressure. Different nephron segments use different apical transporters
or channels for transcellular Na2+ reabsorption.

S1 segment first part of proximal tubule

       Basolateral Na/K/ATPase (34%)
       Apical
             o Na/H exchange (25%)
             o Co-transport with glucose (5%)
             o Co transport with AA or carboxylic acids (3%)
     Urea & Cl concentrations increases down S1 compensating for loss of glucose.
     So reabsorbs 67% of total
The driving force is osmotic gradient established by solute absorption e.g. osmolarity in tubule
decreases as osmolarity in interstitial spaces increases. Proximal tubule is highly water permeable.
Accumulation of water & solutes in intracellular spaces increases hydrostatic pressure forcing
solutes & water into capillaries. Reabsorption is isosmotic with plasma./

S2 segment end of tubule & start of descending limb of Henle.

       25% Na reabsorbed
       Apical
            o Parallel Cl-/formate
            o Na/H exchange
            o ~4mOsmol gradient favouring water uptake from lumen.
Loop of Henle

Thick ascending limb
     From lumen to cells via NaK2Cl transporter
     Na moves into interstitium due to action of Na/K/ATPase
     K diffuses via ROMK back into lumen & interstitium & Cl moves  interstitium.
Bartter’s Syndrome  loss of function of the NaK2Cl channel or ROMK or Cl channels so results in
loss of Na, to urine & hypovolaemia  this stimulates the RAAS  hypokalaemia.

Descending limb reabsorbs water but not NaCl ascending limb reabsorbs NaCl but not water. For this
reason ascending limb is known as the diluting segment. Tubule fluid leaving loop is hypoosmotic
(more dilute) compared to plasma.
Distal convoluted tubule
Hypoosmotic fluid enters
     Active transport of 8% of Na+
     NaCl enters across apical membrane via NCC symporter leaves Na/K/ATPase in Basolateral
        membrane & water permeability is fairly low
     More hypoosmotic fluid leaves...Further dilution.

Collecting Tube & Duct
     Principle cells (70%)
           o Reabsorb via ENaC in apical membrane (Na/K/ATPase in Basolateral)
           o Chloride reabsorption
           o Active Na into the cell produces a lumen charge providing a driving force for Cl-
              uptake via paracellular route
           o Variable H2O uptake through AQP-2 & 3 channels depending on action of ADH
     Intercalated Cells
           o Secrete H+ or HCO3-

Angiotensin converting enzyme is present in all vascular tissue, but endothelial cells in lungs are

Proteolytic enzyme from juxtaglomerular cells responds to perfusion pressure or/& sympathetic
&/or NaCl to macula densa.

LEADS TO decrease in Na+ excretion & therefore decrease in H2O

Angiotensin II:
      Responds directly to pressure changes in the glomerular afferent arteriole
      Decreases in pressure  stimulates release of rennin  RAAS
Aldosterone  from the zona glomerulosa of adrenal cortex, promotes active Na,Cl reabsorption &
secretion of K & H in DCT & CD. Competes with cortisol to bind to its receptor on principle cells.
Receptor bound aldosterone increase transcription ENaC results in increase extrusion of Na from
cells into interstitium & secretion of K, H, into lumen.

Aldosterone controls up to 2% of the sodium. That equates top 30g/day therefore control via
aldosterone from min to max finely adjusts excretion of sodium.

Factors which cause aldosterone release:

     Increased Angiotensin II Na reabsorption in kidney, colon & stomach
     Decreased ECF  results in increased ECF volume & increased K secretion
     Decreased plasma (Na)  increased K & H excretion
     Increased K (plasma)  decreased plasma K+
Liddle’s Syndome  Mutations in the genes that codes for the β subunit of ENaC results in
constitutively active ENaC in collecting ducts, results in Na retention & hence hypertension.

Neural mediators: sympathetic efferent’s reach the kidney
    Granular cells of juxtaglomerular apparatus via renal nerve mediate renin release (
       ↑sympathetic stimulation = ↑renin = ↑Na uptake)
    Release of catecholamine’s stimulation of PCT Na/K/ATPase
Vascular low pressure sensing

The baroreceptors located in the low pressure side of the circulation sense fullness respond to
decreases in volume.
Afferent fibres from high pressure baroreceptors in glossopharyngeal & vagus nerves to brainstem
where an increase in pressure causes a ↓in sympathetic stimulation so ↓in ADH and ↑in PSNS
stimulation. Changes s of 5-10% in volume triggers both low & high pressure sensors.

Calcium & Renal stones
Total calcium 25-35 mol but more than 99% in the
skeleton leaving 0.1% in the ECF.

Absorption under 1,25-(OH)2D control (vitamin D
derivative). 20 dietary Ca absorbed. Absorption
increases in growing children, pregnancy, lactation
& decreases with advancing age. 2-5mmol
secreted back into gut. Complexing calcium e.g.
with phytates, oxalates reduced absorption.

The kidney filters 250mmol calcium per day, of
that 95-98% reabsorbed.
     65% in proximal tubule with associated Na
        & H2O intake.
     20-25% recovered in ascending loop of
     10% recovered in distal convoluted tubule under parathyroid hormone control
     24 Hour calcium excretion <10mmol

        45% ionised calcium
        45% protein bound of which 70% to albumin
        10% Complexed to citrates, phosphate, etc
        Ionised calcium ref range: 1.1-1.3 mmol/l
        Total adjusted calcium ref range 2.1-2.6 mmol/l

Adjusted calcium = measured calcium + 0.02(40-measured Albumin)
Actions of C1,25-(OH)2D:
     BONE: it ↑the availability of calcium & phosphate via intestinal uptake & promote
        osteoblasts activity & maturation of osteoclasts precursor cells
     KIDNEY: inhibition of renal 1 α-hydroxylase by intestinal absorbed phosphate. Promotes
        synthesis of 24,25-(OH)2D. Lastly, small effect on renal calcium & phosphate reabsorption
     OTHER actions

PTH on Bone  aids bone remodelling by stimulation osteoclasts activity, increasing plasma calcium
& phosphate. Slowly stimulate osteroblast activity.

PTH on kidney  increases calcium & magnesium reabsorption, decrease phosphate & bicarbonate
reabsorption. Stimulates conversion of 25-OHD to 1,25-(OH)2D by alpha hydroxylase

Main causes of hypercalcaemia  Primary hyperparathyroidism (about 1 in 100 people).
Haematological malignancies. non-haematological malignancies.

Clinical manifestations of hypercalcaemia: anorexia, nausea/vomiting, constipation, hypertension,
short QT interval on ECG, enhanced sensitivity to digoxin, Polyuria & Polydipsia, occasional
nephrocalcinosis, cognitive difficulties & apathy, drowsiness & coma.

      Primary hyperparathyroidism  ↑plasma calcium
      Secondary hyperparathyroidism  ↓or normal plasma calcium
      Tertiary hyperparathyroidism  ↑plasma calcium.

Hypercalcaemia of malignancy –parathormone-related peptides; Cytokines such as TNF & IL-1; TGFα
& prostaglandins

Renal stone formation
Approximately 20% men & 5-10% women will develop renal stones. 50% recurrence rate within 5
years from first stone. After 8 years 3% men & 18% women form additional stones. They can lead to
renal failure.

Symptoms: sometime none – incidental finding on x-ray, haematuria & pain & associated
complications of an obstruction in the renal tract.

Management  increase fluid intake, urine output >2L daily, dietary restriction of oxalate & sodium
for all, & perhaps calcium & animal proteins

Hypocalcaemia caused by alkalosis, Hypercalcaemia by acidosis this is due to H+ binding to proteins &
releasing free ionised calcium. In alkalosis this is opposite & more calcium binds to proteins, as H+
concentration falls. Management of acute hypocalcaemia  hydration, loop diuretics,
bisphosphonates, calcitonin & glucocorticoids & treat underlying condition

Session 5 – Thirst, osmoreceptors, long & short loops
Osmolarity  The osmotic concentration of a solution expressed as osmoles of solute per litre of
solution. I.e. 1 mole of glucose in 1 litre = 1 osmole of glucose.

Osmolarity changes in EFC
Disorders of water balance manifest as changes in body fluid osmolarity. Usually measured as
changes in plasma osmolarity. As the major cation of the ECF is Na+ then changes in [Na+] are seen.
This is not a problem with Na+ balance as Na+ balance changes volume. It is a problem with
osmolarity affecting water balance.

Increasing osmolarity if intake is less than loss  osmolarity increases

Decreasing osmolarity if intake exceeds loss  osmolarity decreases.

Average Diet: most people on average urinate 1-1.5 L/d & ingest 600-1000 mOsm/d thus usual
urinary osmolarity = 500-700 mOsm/L

Body fluid osmolarity is maintained by osmoregulation at about 282-295 mOsm/l. Even small
changes stimulate the hormonal processes.

What is sensed                                   Plasma osmolarity
Sensors                                        Hypothalamic osmoreceptors
Efferent pathways                              ADH                   Thirst
Effector                                       Kidney                Brain: drinking
What is affected?                              Renal water           Water intake.
Effectors form negative feedback loops that begin within the hypothalamus. Osmolarity increase
stimulates osmoreceptors. Secretion of ADH &/or trigger thirst.

Result = the two complementary feedback loops stabilise osmolarity & thus [Na+]

Large deficits in water (or salt) only partially compensated for in the kidney. Ingestion is the ultimate
compensation. Stimulation by increased fluid osmolarity (also by reduced ECF volume). Salt ingestion
is the analogue of thirst.
      Drinking behaviour. Dehydration leads to thirst  rapid ingestion of water.
      Affect of thirst is increased water intake. The stimulus for thirst response required significant
         increase in osmolarity or decrease in volume (<10% changes)
Secondary & primary thirst
      Primary thirst results from an absolute decrease in body content i.e. hypovolaemia
      Secondary thirst is drinking to prevent thirst rather than to alleviate it.
Although the sensation of thirst is usually perceived peripherally, as in drying of the oral mucosa, it is
regulated centrally by the so-called ‘drinking centre’ in the lateral pre-optic area of the
hypothalamus. This centre is responsive to raised plasma osmotic pressure & reduced ECF volume.

Under conditions of predominant ‘loss of water’ osmoreceptors in hypothalamus initiate release of
ADH. Increase in osmolarity (i.e. loss of water) stimulated ADH (1% change) decrease osmolarity
inhibits ADH secretion.

ADH is synthesized in the neuro-endocrine cells located in the supraoptic & paraventricular nuclei of
the hypothalamus. The synthesised hormone is packaged in granules & transported down the axon
to nerve terminals located in the posterior pituitary gland. Here the ADH is stored until it is released.
Release of the ADH follows action potential stimulated of Ca2+ influx & exocytosis.

ADH is a small peptide 9 AA long

If plasma ADH is low = large volume of urine (water diuresis)

If plasma ADH levels are high a small volume of urine is excreted (anti-diuresis). ADH increase the
permeability of the collecting duct to water also permeability of urea.

ADH targets the principle cells of the collecting duct. Primary action of ADH is to increase
permeability of the collecting ducts to water. In addition ADH increases the permeability of the
collecting duct to urea. ADH binds to the V2 receptor on the basolateral membrane & stimulates via
G-protein coupled receptor cascade the insertion of Aquaporin 2 channel in the apical membrane. As
the basolateral membrane always contain Aquaporin 3 + 4 & is therefore freely permeable to water
addition of Aquaporin 2 to the apical membrane allows free uptake of water. With the removal of
ADH the AQ2 channel is retrieved from the apical membrane by endocytosis.

Also, acts on thick ascending limb – stimulates apical Na/K/Cl co-transporter.
Renal water excretion if osmolarity increases renal water excretion decreases
      Less water in ECF
      Water is conserved
If osmolarity decreases renal water excretion increases
      More water in ECF
      Water is lost
Osmolarity Decreases
Production of hypo-osmotic urine  Reabsorb solute from nephron no ADH stimulation means no
ADH stimulation means no Aquaporin 2 inserted in the DCT & collecting ducts. Limited water
reuptake in DCT & collecting duct (about 2% without ADH). Tubular fluid rich in water passes
through the hyperosmotic renal pyramid with no change in water content. This all means a loss of
large amount of dilute urine.

ANP is produced, stored & released atrial cells & released in response to atrial stretch induced by
hypovolaemia. Sympathetic stimulation of beta-receptors.

    Causes a reduction in blood volume
          o Renal sodium reabsorption is decreased
          o Dilates afferent arteriole, constricts efferent glomerular: increasing GFR  resulting
               in greater excretion of Na & water
          o Decreases sodium reabsorption in the distal convoluted tubule via ENaC
          o Inhibits rennin secretion, thereby inhibiting the RAAS
          o Reduces aldosterone secretion by the adrenal cortex
    More urine production.
Nephrogenic diabetes insipidus

Caused by ADH deficiency.

So collecting ducts do not respond to ADH: two forms of disease

    1. Gene for V2 receptors is mutated making it inactive V2 gene on X chromosome inheritance is
       sex linked.
    2. Autosomal gene for AQP-2 is mutated.
Plasma osmolarity increases

Body needs to produce hyperosmotic urine. The kidney must reabsorb as much water as possible
from the kidney tubule.

Urea is the major osmole in urine: Urea reabsorption from CD. Movement
into interstitium & diffusion back in loop. Under the influence of ADH
fractional excretion of urea decreases & urea re-cycling increases.

Conc grad is produced by the loop of Henle acting as a counter-current
multiplier. Maintained by the vasa recta acting as a counter-current

Ascending limb is impermeable to H2O but it is permeable to NaCl & urea. As
urea is high in tissue & low in tubular fluid it moves in passive processes. At
bend tubular fluid & surrounding tissue are iso-osmotic but tubular fluid
contains NaCl & tissue has urea as its osmole.

Longer loop more reabsorption. As more concentrated interstitium so in the presence of ADH more
water flows out of the collecting duct.

Post-operative fluid replacement
Fluid & electrolytes are not infrequently lost from the body in excess of the normal losses. That
serves to maintain the balance between input & output, & thus maintain constancy of body fluid
volume & composition. If there is not severe restoration of fluid & electrolyte homeostasis is readily
effected without therapeutic intervention. But more severe losses by be required replacement by IV
infusion, & this also applied to losses occurring during surgery & attendant procedures such as
nasogastric drainage.

Volume determined by loss of water & electrolyte. The ratio of the water-to-electrolyte losses is
important, since this will determine the osmolarity of the fluid lost. Normally fluid is isosmotic so,
controlled infusion of normal saline plus 5% dextrose will be sufficient. In complicated loss or on
going loss need to monitor.

Under controlled conditions the following calculations can be made –

Add up fluid losses (e..g. urine, surgical drains, gastric suction) on a daily basis.

If applicable, add to this 100ml for each degree rise in temperature above 37oC. Add a further 500ml
for a normal sized adult. Although this is less than the daily insensible fluid loss through sweat
(approx. 1 litre), 500ml will also be available from metabolic breakdown

A complicating factor is that the lost fluid is frequently hypoosmotic. But IV infusion of hypoosmotic
fluids is ruled out, since this would lead to osmotic cell swelling & potentially fatal cerebral oedema
& rise in intracranial pressure.

Hypertension & the control of Blood pressure
BP = CO X TPR             CO = SV X HR

Both short & long term regulation

Short term regulation via the baroreceptors reflex.

     Adjust sympathetic & parasympathetic inputs to the heart to alter CO
     Adjust sympathetic input to peripheral resistance vessels to alter TPR
Nerve endings in the carotid sinus & aortic arch are sensitive to stretch. Increased arterial pressure
stretches these receptors.

Bradycardia & vasodilation counteract increased

The baroreceptors reflex controls acute changes in BP. Produces rapid response to changes in BP.
Does not control sustained increases because the threshold for baroreceptors firing resets

Medium & long term control of BP

Complex interaction of neurohumoral responses directed at controlling sodium balance & thus ECF

Plasma is part of the ECF compartment:
     Control of ECF volume controls plasma volume
     Water follows Na+ therefore controlling total body Na+ controls plasma volume
Neurohumoral factors controlling BP: RAAS, SNS, ADH & ANP

Reduced perfusion pressure in the kidney causes the release of renin as there are baroreceptors in
the afferent arteriole. Sympathetic stimulation to juxtaglomerular apparatus increases release of
rennin. Renin released from granular cells of the JGA.

Decreased circulating volume stimulates renin release. Decreased NaCl concentration at the macula
densa, sympathetic stimulation to JGA, decreased renal perfusion pressure

Angiotensin II receptors either AT1 & AT2

Main actions via AT1 receptor which is a G-protein coupled receptor,

Site                                              Action
Arterioles                                        Vasoconstriction
Kidney                                            Stimulates Na+ reabsorption at the kidney
Sympathetic NS                                    Increased release of NA
Adrenal cortex                                    Stimulates release of aldosterone
Hypothalamus                                      Increases thirst sensation (ADH ↑)
Also vasoconstriction in kidney particularly of the efferent arteriole, this enhances Na+ reabsorption
at the PCT as it stimulates Na-H exchanger in apical membrane.

      Stimulates Na+ therefore water reabsorption
      Acts on principal cells of collecting ducts
      Activates apical Na+ channel (ENaC) & apical K+ channel
      Also increases Basolateral Na+ extrusion via Na/K/ATPase
Bradykinin is a vasodilator. The vasoconstriction effects of AngII are further augmented because ACE
is also one of the kininase enzymes which deactivates Bradykinin into peptide fragments.

Response to increased sympathetic NS stimulation:
    High levels of sympathetic stimulation ↓renal blood flow & ↓GFR – ↓Na+ excretion.
    It activates apical Na/H-exchanger & Basolateral Na/K ATPase in PCT.
    Stimulates renin release from JG cells leading to increased AngII & aldosterone levels.

ADH increases Na+ reabsorption main role is formation of [urine] by retaining water & control
plasma osmolarity. ADH release is stimulated by increases in plasma osmolarity or severe
hypovolaemia. Also stimulates Na+ reabsorption. Acts on thick ascending limb – stimulates apical
Na/K/Cl co-transporter.

ANP promotes Na+ excretion this is synthesised & stored in atrial myocytes then released from atrial
cells in response to stretch. Low pressure volume sensors in the atria reduced effective circulating
volume inhibits the release of ANP.

So causing renal vasodilation, both afferent & efferent, increase blood flow increases GFR also
inhibits Na+ reabsorption along the nephron.
Prostaglandins more important clinically than physiologically they act as vasodilators, Locally acting
prostaglandins enhance GFR & reduce Na+ reabsorption. Act as a buffer to excessive vasoconstriction
produced by the SNS & RAAS.

They help to maintain renal blood flow & GFR in presence of vasoconstrictors. NSAIDs inhibit cyclo-
oxygenase pathway involved in formation of prostaglandins. Administration of NSAIDs when renal
perfusion is compromised can further decrease GFR  acute renal failure

        Classification                   Systolic                            Diastolic
     Mild hypertension                   140-159                              90-99
  Moderate hypertension                  160-179                             100-109
    Severe hypertension                   >180                                 >110
Essential hypertension 95% cause is unknown

Secondary hypertension where cause is known e.g. renovascular disease, chronic renal disease,
aldosteronism, Cushing’s syndrome... Treat primary cause.
     Occlusion of the renal artery (stenosis) causes a fall in perfusion pressure in that kidney
     Decreased perfusion pressure leads to increased renin production
     Vasoconstriction & Na+ retention at other kidney

In renal artery stenosis the afferent arteriole dilates & filtration pressure is maintained by efferent
arteriolar constriction, which is itself due to the action of AII. Blockade of AII production by ACE
inhibitors leads to relaxation of the efferent arterioles to the level where glomerular capillary
hydrostatic pressure is insufficient to maintain filtration - i.e. the kidney becomes non-filtering,
although renal blood flow is maintained.

Renal parenchymal disease earlier stage may be a loss of vasodilator substances in later stage Na+ &
water retention due to inadequate glomerular filtration.

Adrenal causes of hypertension:
    Conn’s syndrome – aldosterone secreting adenoma  HT & hypokalaemia
    Cushing’s syndrome – excess secretion of glucocorticoid cortisol – at high conc acts on
       aldosterone receptors – Na+ & water retention
    Tumour of the adrenal medulla – pheochromocytoma – secretes NA & A.

Treating Hypertension
ACE actions
     ACE inhibitors prevent production of AngII from AngI
     AngII receptor antagonists (or ARB (blockers)
     Blocking production or action of AngII has diuretic & vasodilator effects.
     Thiazide diuretics reduce circulating volume
     Inhibit Na/Cl co-transporter on apical membrane of cells in distal tubule
     Other diuretics e.g. aldosterone antagonists (spironolactone) will also lower BP.
L-type Ca Channel blockers  reduce Ca2+ entry to vascular smooth muscle cells. Relaxation of
smooth muscle, vasodilation

Alpha 1 receptor blockers  reduce sympathetic tone (relaxation of vascular smooth muscle)

Beta blockers  blocking B1 receptors in the heart will reduce effects of sympathetic output. Not
used in first line treatment but used if there are other indications such as previous MI.

Other management approaches: exercise, diet reduced salt, reduced alcohol, failure to implement
lifestyle changes could limit the effectiveness of antihypertensive therapy.

Session 6 – Renal Control of Acid & Base
The kidneys control plasma pH by filtering & variably recovering HCO3- & active secretion of H+.
Plasma pH -7.38-7.42

Greater than 7.42 – alkalaemia

Less than 7.38- Acidaemia

Alkalaemia  lowers free Ca thus increases excitability of nerves if pH greater than 7.45,
paraesthesia & tetany occur. At pH 7.55, mortality is 45% & 80% if pH exceeds 7.65.

Acidaemia  affects many enzymes:
        Reduced cardiac & skeletal muscle contractility
        Reduced glycolysis in many tissues
        Reduced hepatic function
        Increased plasma K

Effects severe below pH 7.1 & life threatening below pH 7.0

pH = 6.1 + log ([HCO3-]/(pCO2 X 0.23))
20 times more HCO3- than pCO2

Log 20 = 1.3  pH = 6.1 + 1.3 = 7.4

Hypoventilation leads to hypercapnia  pH falls  respiratory acidosis

NOTE: recovery of HCO3- occurs in PCT (80-90%) & the rest in thick ascending limb.

Hyperventilation lead to Hypocapnia  pH rises  respiratory alkalosis
Chemoreceptors: central chemoreceptors normally control pCO2 within tight limits. Respiratory
changes correct respiratory disturbances of pH.

Peripheral chemoreceptors enable changes in respiration driven by changes in plasma pH.

Changes in pCO2 can be compensated by changes in HCO3-. This is controlled by the kidney.

Respiratory acidosis is compensated by the kidneys ↑HCO3-

Respiratory alkalosis is compensated by ↓HCO3-

Metabolic Alkalosis  if plasma HCO3- rises (e.g. after vomiting) plasma pH rises  metabolic
alkalosis  can only be partially compensated by decreasing ventilation. Respiratory driven changes
in pH compensated by the kidney, metabolic changes in pH compensated by breathing.

Renal correction – the kidneys correct metabolic disturbances of pH by variable excretion or
creation of HCO3-. Large quantities of HCO3- filtered each day, 4500mmol, should be able to lose
HCO3- very easily. If need to increase HCO3- must recover all filtered HCO3- & make new. Metabolic

activity of kidney produces large quantities
of CO2 this can react with water to produce -> HCO3- (to plasma) & H+ to enter urine.

Metabolic Acidosis  If the tissues produce acid, this reacts with HCO3-. The fall in HCO3- leads to a
fall in pH  metabolic acidosis, this can be compensated by changing ventilation by the peripheral
chemoreceptor – lowers pCO2  restores pH towards normal.

Recovery H+ exported from cell into lumen, up a conc. grad, energy from movement of Na+ down
concentration gradient. Produced by sodium pumps on Basolateral membrane. H+ reacts with HCO3-
making CO2 which can cross the plasma membrane. This reacts with H2O to make H+ which is
exported again. Leaving HCO3- to leave by Basolateral membrane to ECF

80-90% in PCT & remainder in thick limb of Henle

Creation of HCO3- occurs in the PCT & DCT

In PCT -> glutamine broken down to produce  α-ketoglutarate which makes 2 HCO3- & NH4+. HCO3-
goes into ECF & NH4+ into lumen.
In DCT  By distal tubule all filtered HCO3- normally recovered. Na grad insufficient to drive H+
secretion. Need active secretion of H+ into lumen. Where it is buffered by filtered phosphate (PO43−)
& excreted NH4+. H+ generated from metabolic CO2 producing HCO3- which enters ECF.

Acid excretion… minimum urine pH is 4.5 where [H+] is 0.04 mmol.l-l. No HCO3- some H+ buffered by
phosphate. Rest attached to ammonia as ammonium. Total acid secretion 50-100 mmol H+ per day.
Keep plasma HCO3- normal.

Control of H+ excretion occurs by stimulus to changes in acid excretion, probably changes in
intracellular pH of tubular cells. Due to changes in rate of HCO3- export to ECT produced by changes
in ECF [HCO3-].

Cellular responses to acidosis… enhanced H/Na exchange full recovery of all filtered HCO3-,
enhanced ammonium production in PCT. This increases activity of H ATPase in DCT. Thus, increased
capacity to export HCO3- from tubular cells to ECF.

Metabolic acidosis  acids produced metabolically, produce H+ & an anion (lactate, etc) H+ reacts
with HCO3- producing CO2 which is breathed out. So some HCO3- replaced by anion from acid.

The anion gap indicated whether any HCO3- has been replaced with something other than Cl-. =
([Na+] + [K+])-([Cl-]+ [HCO3-]_ i.e. Unaccounted anions. This should be 10-15 mmol.l-1. It is increased if
                                                            anion from metabolic acid has replaced
                                                            plasma HCO3-. Sometimes renal problems
                                                            can reduce [HCO3-] without increasing the
                                                            anion gap as it is replaced with Cl-.

                                                             Metabolic alkalosis should be very easy to
                                                             correct, HCO3- infusions excreted
                                                             extremely rapidly  rise in intracellular pH
                                                             reduced H+ excretion & HCO3- recovery.

                                                             BUT if there is also volume depletion,
                                                             capacity to lose HCO3- is less, because of
                                                             high rates of recovery of Na+ favouring
                                                             HCO3- recovery as well.

Metabolic acidosis is associated with Hyperkalaemia, as K+ moves out of cells, more K+ reabsorption
in distal nephron. Hyperkalaemia makes intracellular pH alkaline as it favours HCO3- excretion &
therefore metabolic acidosis.

Metabolic alkalosis is associated with hypokalaemia because K+ moves into cells so less K+
reabsorption. Hypokalaemia makes intracellular pH of tubule cells acid as it favours H+ excretion &
HCO3- recovery & therefore metabolic alkalosis.

Control of Potassium
Intracellularly the major cation is K+ maintenance of K+ is essential for life.

Plasma 4-5 mmol/l & intracellular 150- 160 mmol/l
Normal diet contains 40-130mmol K+ - more than enough to satisfy the needs of the body; hence
maintenance of K+ balance is brought about by regulation of K+ excretion.

Intracellular stores buffer any changes in plasma [K+]. I.e. if decrease in plasma [K+], there is
movement of K+ out of cells & hence change in plasma [K+] is minimised. Implies that for K+ control
to be effective, very small changes in plasma K+ must be able to provide the stimulus for excretion to
be adjusted.

Na & K intake roughly the same. So to maintain K+ balance there must be a higher fractional
excretion of K+ than Na+.

Proximal tubule – around 80% of filtered is reabsorbed, this is predominantly passive, mainly
through the tight junctions with small active component.

Some K+ secretion in the descending thin limb

K+ reabsorbed from the ascending limb together with Na+ & Cl-.

Although some leaks back into the ascending limb a proportion enters the Medullary interstitium &
hence the descending limb  K+ recycling

DCT – early tubule is functionally similar to the thick ascending limb.

Reabsorption of Na+, Cl- & K+ leakback & reabsorption similar so little change in tubular [K+]. Late
tubule & subsequent segments of collecting-duct system, K+ is secreted into the tubular fluid. This
late secretion accounts for K+ passive process, driven by electrochemical gradient between principal
cells & the lumen.

The [K+] in the distal tubule produced by a given rate of distal K+ secretion, will be determined by the
flow rate in the distal tubule. Thus diuretics, which increase distal tubular flow, can increase the rate
of K+ secretion by lowering tubular K+ concentration (as well as increasing Na+ delivery to the distal

           PCT – predominantly passively reabsorbed
           Descending thin limb –some K+ secretion
           Ascending thick limb – K+ reabsorbed from the ascending limb
           DCT – reabsorption of K+
           Collecting tubule – K+ is secreted into the tubular fluid where the rate of K+ section is
            dependent on  Na+ absorption, changes in cellular [K+] & changes in DCT lumen [K+].

ADH  stimulates K+ secretion & prevents changes in urine volume from disturbing K+ homeostasis.

Aldosterone works in the distal nephron (see above) in terms of potassium it:
        Increases the number of K+ channels in the apical membrane & hence enhances K+
           secretion. Aldosterone enhances H+ secretion by
        Increasing Na H exchange in principal cells & by
        Increasing H ATPase activity in intercalated cells.
Increases in plasma [K+] act directly on the adrenal cortex to increase aldosterone output &
decreases in plasma [K+] reduce aldosterone output. Aldosterone constitutes the only hormonal
control over K output, whereas it is only one of many factors regulating Na+ output.

Hypokalaemia generally due to renal of GI losses –
    Diarrhoea – Faecal loss of K+ from GI secretions
    Vomiting – direct K+ loss in vomit & urinary K+ excretion.
    Insulin – increases K+ entry into cells (of skeletal muscle & liver) via the Na K ATPase. Total
      body K+ unaltered but extracellular K+ decreases.

Hypokalaemia  most subjects symptom free until down to 2-2.5 mmol/l

       Initial symptom is muscle weakness, usually affecting the lower extremities & gradually
        extending upwards, death occurs when respiratory function is affected.
       Also, synthesis of liver & muscle glycogen required K so hypoK produces an abnormal
        glucose tolerance.
       Vasoconstriction occurs
       Polyuria & thirst – renal response to ADH is impaired so patients are unable to produce
        concentrated urine.
       Metabolic alkalosis – since the K+ deficit tends to cause increased H+ secretion

Management – ECG monitoring & muscle strength,.

Cardiac muscle is an excitable tissue dependent on K. After excitation, the repolarisation of the
muscle is brought about by an increase in K+ permeability, causing K+ to move out of the cells, in
hypoK the time for cardiac to repolarise is prolonged. ECG changes at 3 mmol.

Treatment  IV K+ salt.

Renal function changes. Initially, the kidney does not immediately conserve K+ effectively & urinary K
output remains high for 2-3 weeks. Thus hypoK & low urinary K output is indicative of long-standing
K depletion, caused by extra-renal factors.


Excess K+ is normally removed from the body by renal secretion. Ingestion causes a small rise, and
then ↑plasma K stimulates the release of aldosterone from the adrenal cortex, which K+ secretion.

Normal people can tolerate tenfold increase in K+ intake.

Acidosis can cause hyperK even when the body’s K stores are normal. Insulin promotes K entry into
cells, so insulin deficiency can lead to Hyperkalaemia. Another cause of hyperK is excessive
breakdown of cells.

However, patients with impaired kidney function, or infants may suffer hyperK which can be fatal
    The reduction in the kidney’s ability to excrete K in oliguric renal failure is probably due to
      decreased fluid (& Na) delivery to the distal K-secreting site.

           Loop diuretics to promote K excretion
           Insulin (with dextrose) to promote intracellular entry of K
           The effects of hyperK on muscle function can be corrected even in the continuing
            presence of hyperK, by administering Ca2+. This makes the threshold potential less
            negative & restores the normal gap with the resting membrane potential.

Session 7- Micturition & the Nervous System
Two phases urinary storage & urinary voiding. The bladder has a capacity of around 550 ml (350-
750ml). Urinary voiding occurs at intervals of several hours. Urge to urinate at 150ml.

Storage in the bladder:
It is under the control of the NS. There is a dedicated & independent neural apparatus that promotes
storage of urine within the urinary bladder. Urine is produced at the rate of 60ml/hour. Depending
on the state of water loading. The storage phase of urine can last up to 9 hours before the urge to
void. It can last for a maximum of 4 hours when there is pathology to the neural storage apparatus.

                                                           Voiding: it is mediated by an independent
                                                           neural apparatus. Generally it is short
                                                           lasting event. Urinary flow rate in a full
                                                           bladder is about:

                                                                20-25ml/s in men (lasting about
                                                                -25-30 ml/s in women (lasting
                                                           around 22s)

                                                           Flow rates of 15 ml/s or less would be
                                                           taken to suggest an obstruction to urinary

                                                           Flow rate <10ml/s are taken to indicate
                                                           evidence of a definite obstruction to
urinary flow.

General anatomy of the bladder

A hollow muscular distensible pouch. Neck connects bladder to the urethra. Have 3 muscles detrusor
muscle, internal urethral sphincter, & external urethral sphincter.

Detrusor muscle is a smooth muscle, a syncytium. A mass contrating muscle which has no peristaltic
activity. Urinary bladder form & size is similar in both sexes. It is supplied by the ANS.
Functions of bladder:

       To store urine by the cerebral cortex, that contracts & closes the external urethral sphincter.
        The sympathetic division of the ANS, spinal root values T10-L2.
            o  Cerebral cortex signals storage centre (pontine continence) signals sympathetic
               nuclei in cod signals detrusor muscle & external urethral sphincter motor neurones
               in sacral cord.
           o Neural apparatus prescribing for urinary storage are known as continence circuits.
               Bilateral outputs from the pons. Descending outputs do not decussate. Their actions
               bring about silencing the detrusor muscle, relaxation of the detrusor muscle.
               Increase in urethral sphincteric pressure, therefore storage of urine.
           o Spinal urinary continence controlled by the sympathetic NS. Spinal motor outflow
               from as Onuf’s nucleus of the ventral horn of the cord. Supplies sphincter to
               contract, constrict & close it. S2-S4 -: promotes bladder filling.
           o Walls of the bladder are highly folded rugae, making them distensible. As the
               bladder fills with urine the internal urethral sphincter tightens. AS the bladder fills,
               rugae flatten, capacity increases. As the bladder fills up with urine, intravesical
               pressure hardly changes.
       To expel urine
           o A different set of neurones promote the bladder to void urine.
           o Cerebral cortex : to relax & thereby open the external urethral sphincter, spinal
               root values S2-S4. The parasympathetic division of the ANS  spinal root values S2-
           o Cerebral cortex signals the pons signals sacral levels of parasympathetic outflow
               signals external urethral sphincter & detrusor muscle.
           o Their actions bring about. Strong contraction of detrusor muscle  increase
               intravesical pressure, relaxation of the internal urethral sphincter, voluntary
               relaxation of the external urethral sphincter  expulsion of urine.

Urinary voiding is mediated by the PSNS neurones arise from the ventral horn of the sacral cord also
known as Onuf’s nucleus. Promote bladder voiding by contracting detrusor muscle & relaxing
urethral sphincter.

External urethral sphincter essentially muscles of the pelvic flow. Supplied by the perineal branch of
the pudendal nerve root values S2-S4. Constricts urethra for maintenance of continence. Relaxation
promotes voiding.

Sensory functions of the bladder: Afferent nerves originate in bladder wall, thought to be stretch
receptors. Signal extent of bladder filling, pain sensation from irritation of bladder, temperature
sensation. Travel principally with PS nerves some limited routing with SNs. Pain sensation in bladder
is well localised i.e. bladder pain is not referred.

The two sphincters control bladder outlet. The Internal sphincter is closed during bladder filling. This
contraction of the sphincter is due to sympathetic stimulation via hypogastric nerve & alpha 1
adrenorecptors stimulation. The external sphincter is voluntarily contracted via stimulation from
pudendal nerve during bladder filling. For micturition the supraspinal centres block stimulation of
the pudendal & hypogastric nerves & parasympathetic stimulation dominates. Thus detrusor muscle
contracts. The sympathetic stimulation of internal sphincter is inhibited & therefore internal
sphincter relaxes & the external sphincter is consciously relaxed allowing voiding.

Another way:
The micturition reflex involves impulses travelling from the bladder to the sacral region of the spinal
cord & from the sacral region of the spinal cord back to the bladder. It is coordinated by neurons in
the spinal cord & can be influenced by signals from the brain. When the urinary bladder becomes
stretched there is an increase in the frequency of action potentials carried from the bladder wall to
the sacral region of the spinal cord. In response, parasympathetic neurons from the spinal cord to
the bladder are activated, & this causes the smooth muscle on the bladder wall to contract. The
sensory signals to the sacral region of the spinal cord also stimulate ascending pathways to the pons
& cerebrum, which results in a conscious desire to urinate. if urination is inconvenient, the brain
sends impulses down the spinal cord to inhibit the micturition reflex. Impulses via somatic motor
neurons keep the external urinary sphincter contracted, which also prevents urination. When
urination is desired, signals from the brain stimulate the micturition reflex. The brain also decreases
action potentials in the somatic motor neurons to relax the external urinary sphincter.


       Incontinence – involuntary loss of urine
       Urge incontinence – involuntary loss of urine, a sudden, strong desire to void
       Stress incontinence – involuntary loss of urine during cough, sneeze & physical exertion
       Mixed – coexistence of the above
       Overflow incontinence with chronic urinary retention
       Passive incontinence via a fistula

Severely affects quality of life. Common approx. 35% of women at varying frequencies

Physical examination:

Vulval skin – oestrogen deficiency, assessment of SUI., assessment of prolapse, pelvic tone, perineal
sensation, spreading of toes to test S3.

Urodynamics – Rectal (abdominal) pressure probe, bladder (vesical) pressure probe, infusing
catheter, flow meter (Q). Detrusor pressure is calculated: Pdet=Pabd-Pves

Urodynamic assessment - Independent urine flow rates, Abdominal pressure, Bladder pressure,
Subtracted pressure (detrusor), Residual urine, Bladder capacity, pressure of bladder at inflow
cystometry, Pressure at voiding, combined result of voiding & detrusor pressure

Worrying signs – microscopic haematuria in women over 50, palpable bladder after voiding, palpable
pelvic mass, bladder pain, neurological problem, symptomatic prolapse beyond introitus

Management: depends on symptoms: degree of bother, effects of treatment on other symptoms,
previous or current treatments

Urge incontinence – freq. normal=4-8 voids per day, urgency with or without incontinence (30%),
+/- nocturia.

conservative management – lose weight, stop smoking, vaginal oestrogens, pelvic floor exercises.

Antimuscarinics side effects: dry mouth, dry eyes, drowsiness, constipation.
Botox into the bladder

Stress urinary incontinence – management much the same, drug: duloxetine

Various procedures – burch colposuspension

Session 8 - Malignancy of the Urinary Tract
Prostate cancer is the most common cancer in men in UK & 2nd most common cause of death from
cancer in men. Most men diagnosed with CaP are more likely to die with & not from CaP.

Risk factors:
      Age – urinary symptoms, benign enlargement of prostate, CaP
      Family history – 4 times more risk if
             o one 1st degree relative diagnosed with CaP before age 60
             o Or if 2 or more 1st degree relatives diagnosed with CaP at any age
      Race  Afro-Caribbean’s most likely, then whites, then Asians
Clinical presentation
      Asymptomatic
      Urinary symptoms – benign enlargement of prostate/bladder over activity
      Bone Pain
Unusual – haematuria

Prostate specific antigen is often elevated in the presence of prostate cancer & BPH

Diagnostic Pathway

Digital rectal examination (smooth benign, rough metastatic) & serum PSA  TRUS (transrectal
ultrasound) – guided biopsy of prostate

Lower urinary tract symptoms  Transurethral resection of prostate

Factors influencing treatment decisions: Age, DRE – staging, PSA level, biopsies (gleason grade &
extent), MRI Scan & bone scan – nodal & visceral metastases.

Localised CaP – Treatment

Establish treatments – surveillance, radical prostatectomy (open, laparoscopic or robotic),
radiotherapy (external beam or low dose rate brachytherapy [where a radioactive source is placed
inside of next to the area requiring treatment])

Developmental treatments - high intensity focused ultrasound, primary cryotherapy, high dose rate

Metastatic CaP – Treatment

Hormones – surgical castration, medical castration – LHRH agonists

Palliation – single-dose radiotherapy, bisphosphonates – Zoledronic acid, chemotherapy (docetaxel).

Bone metastases – sclerotic, hot spots on bone scan, but highly unlikely if PSA <1-ng/ml
Locally advanced CaP – Treatment – Surveillance, hormones & radiotherapy (mixture of above)

Prostatic hypertrophy – usually causes CRF, but symptoms are a hesitant, interrupted, weak stream
with urgency & leaking or dribbling, with more frequent urination, especially at night.


Differential diagnosis:
     Cancer
             o Renal cell carcinoma
             o Upper tract transitional cell carcinoma
             o Bladder cancer
             o Advanced prostate carcinoma
     Other
             o Stones, infection, inflammation, benign prostatic hyperplasia
Nephrological causes – e.g. IgA nephropathy post-streptococcal glomerulonephritis, nephritic

        History – smoking, occupation, painful or painless, other LUTS, FH
        Examination – BP, abdominal mass, Varicocoele, leg swelling, assess prostate DRE.
        Investigations – FBC, U & E, Ultra sound, endoscopy, urine culture & cytology.

Bladder cancer – 5th most common cancer in UK incidence is falling. 3 males to 1 female & 90% are
transitional cell carcinoma.

Risks – smoking, rubber or plastic manufacture, handling of carbon, crude oil, painter, mechanics,
hairdressers & lastly caused by Schistosomiasis

                                                      Initial treatment – Trans-urethral resection of
                                                      bladder tumour

                                                      Staging. 75% are Ta or T1, 5% are Tis & 20% are
                                                      muscle invasive. T2-T4

                                                      Grading related to how differentiated the
                                                      tissue is. Low grade low stage  check

                                                      High risk non muscle invasive  check
                                                      cystoscopies, intravesical

                                                      Muscle invasive transitional cell carcinoma 
                                                      neoadjuvant chemo & radical cystectomy or
Radical cystectomy, a illeal conduit or reconstruction needs to occur.
Renal cell carcinoma – 13th most common cancer in UK but 95% of all upper UT tumours, incidence
& mortality are increasing 2 males to 1 female. 30% metastases on presentation.

Causes – smoking, obesity, dialysis.

Spreads to lymph nodes, perinephric spread (bulging out of kidney(, or IVC spread to RA

Ultrasound & CT will be done.

Treatment – radical nephrectomy – kidney, adrenal, surrounding fat & upper ureter & all taken.

OR partial nephrectomy

Palliative care- immunotherapy such as INFα & IL-2. Molecular therapies targeting angiogenesis such
as sunitinib & sorafenib.

It is relatively chemo & radio resistant.

Upper Tract Transitional cell carcinoma – only accounts for 5% of all UT carcinomas. Caused by
smoking, phenacetin abuse, Balkan’s nephropathy. It is much more likely that an UUT carcinoma will
spread down than it is for one to spread up.

Investigation – ultrasound, CT, retrograde pyelogram, ureteroscopy for biopsy & washings for

Treatment – Nephro-ureterectomy (kidney, fat, ureter, cuff of bladder)

Glomerular Disease
Nephrotic syndrome: Triad  proteinuria, hypoalbuminaemia, oedema also hypercholesterolaemia.

Pathognomonic of glomerular disease & required renal biopsy for diagnosis

GASH’D  minimal change Glomerular nephritis, amyloidosis, SLE, Henloch-Schonleich purpura,
Diabetes mellitus (or drugs)

Nephritic Syndrome: The classic syndrome is that which accompanies post-streptococcal
glomerulonephritis in children, but can be as a result of other glomerulonephritides, often self-
limiting. Features: haematuria with/without proteinuria, renal impairment, salt & water retention, &

PAIRS – Post-streptococcal GN, Alport’s syndrome, IgA nephropathy, RPGN, SLE

Filters can clog – renal failure

Filters can leak – Proteinuria, haematuria

The glomerulus can be injured at subepithelial, within basement membrane, subendothelial &
Mesangial (& paramesangial)
Minimal change glomerulonephritis - nephritis marked by inflammation of the glomeruli of the
kidney; characterized by decreased production of urine & by the presence of blood & protein in the
urine & by oedema –

Seen in children, nephrotic range proteinuria is seen & responds to steroids (usually)

There is no antibody deposition, only abnormality is damage to podocytes (could be due to
circulating factor or produced by T cells)

IgA nephropathy – occurs at any age presents with haematuria, may get worse at time of mucosal
infections, significant proportion progress to renal failure.

Very variable Glomerular changes – Mesangial proliferation deposits of IgA-containing immune
complexes in mesangium.

Post-streptococcal glomerulonephritis  any age, presents with acute oliguric renal failure with
haematuria – Nephritic syndrome,  2 weeks after a streptococcal infection & it usually gets better.

Membranous glomerulonephritis  commonest cause of nephrotic syndrome in adults, one 1/3
remit, 1/3 continue & 1/3 progress to renal failure. May be secondary to SLE, infections, cancer,
some drugs.

No increased cellularity, capillary loop immune complex deposits, ‘subepithelial spikes’ probably

Goodpasture syndrome  catastrophic nephritic presentation, with haemoptysis if a smoker,
autoantibody against basement membrane, treatable if caught early
Systemic Lupus erythematosis  systemic MOD, kidney involvement – is bad prognostic sign.
Produces almost any pattern of glomerular damage, usually massive immune complex deposition

Vasculitis  Systemic disorders, no antibody deposition, associated with anti neutrophils
cytoplasmic antibodies, nephritic presentation, needs to be caught early.

Diabetes Mellitus  causes BM thickening, Mesangial sclerosis – may become nodular, arteriolar
hyalinosis, progressive proteinuria & progressive renal failure.

Amyloidosis multi-organ deposition, in the glomerulus, a little bit of amyloid can cause a lot of

Session 9: Acute Kidney Injury
It is a clinical syndrome characterised by an abrupt decline of GFR. Upset of ECF volume, electrolyte
& acid/base homeostasis. Accumulation of nitrogenous waste products, acute renal failure increases
                                                             morbidity & mortality.

                                                             Incidence difficult to assess – variable
                                                             criteria approximately 200pmp/yr, &
                                                             50pmp/yr need renal replacement
                                                             therapy. 5% of hospitalised patients. 25-
                                                             30% of patients admitted to ICU

                                                             ARF is a medical emergency; delayed
                                                             treatment leads to irreversible renal

                                                              Pre- renal acute renal failure caused by a
                                                              reduction in renal perfusion, unless the
                                                              cause of poor renal perfusion is
                                                              recognised & promptly treated then
acute tubular necrosis will develop. Causes split into reduced effective EFV due to hypovolaemia,
cardiac failure or systemic vasodilatation (septic shock), or due to impaired renal autoregulation
such as preglomerular vasoconstriction (due to sepsis, hyperC, NSAIDs) & due to postglomeruler
vasodilatation from ACE inhibitors.

Intrinsic acute kidney injury

Acute tubular necrosis – severe acute ischaemia can occur if the fall in renal perfusion is not treated.

Toxic acute tubular necrosis – Nephrotoxins damage the epithelial cells lining the tubules & cause
cell death & shedding into the lumen. Nephrotoxins can be endogenous or exogenous.

ATN is much more likely if there is reduced perfusion & a nephrotoxin.

Endogenous nephrotoxins: myoglobin (from rhabomyolysis), urate, bilirubin
Exogenous nephrotoxins: endotoxin, X-ray contrast, Drugs (ACEi, NSAIDS, aminoglycosides,
Gentamicin) other poisons.

Glomerular & arteriolar disease

Acute glomerulonephritis – immune disease affecting the glomeruli, can be – primary: only the
kidneys or secondary: kidneys are involved as part of a systemic process.

Other causes – haemolytic uraemic syndrome, malignant hypertension, pre-eclampsia

Caused by endothelial damage  platelet thrombi  partial obstruction of small arteries 
destruction of RBC’s, microangiopathic haemolytic anaemia

Acute tubule-interstitial nephritis caused by acute pyelonephritis or toxic antibiotics, & NSAIDs.

Post-Renal failure

Accounts for 10% of ARF cases & much more common in the elderly.

Obstruction with continuous urine production causes: a rise intraluminal pressure  dilatation of
renal pelvis  decrease in renal function.

Causes grouped into: within the lumen OR within the wall OR pressure from outside

Within the lumen – calculi, blood clot, papillary necrosis, tumour (of renal pelvis, ureter, or bladder).
To cause ARF, stones must be in both renal pelves & ureters OR neck of the bladder OR urethra,
stones > 10mm will usually not pass. Pain &/or haematuria is common.

Within the wall – congenital causes – pelviureteric neuromuscular dysfunction, megaureter,
neurogenic bladder.

        -   Ureteric stricture (post- TB)
        -   Within the wall causes usually cause CRF & not ARF.

Pressure from outside – prostatic hypertrophy, tumours, aortic aneurysm, diverticulitis, accidental
ligation of ureter

Examination & further analysis of AKI

Is the patient volume depleted? cool peripheries, increased pulse, low BP, postural hypotension, Low
JVP, increased skin turgor, dry axillae

In cardiac failure – a cause of renal underperfusion or as a result of ARF  gallop rhythm, raised BP,
raised JVP, pulmonary oedema- basal crackles & dyspnoea, peripheral oedema.

Signs of sepsis – pyrexia & rigors, vasodilatation (warm peripheries), bounding pulse, rapid capillary
refill, hypotension

Test for urinary tract obstruction: suspect in: anuria, single functioning kidney, Hx of stones, old man
Examine for- palpable bladder, pelvic or abdominal masses, enlarged prostate.

Serum biochemistry: increased urea & creatinine in all causes of ARF. Test for hyperkalaemia,
hyponatraemia, hypocalcaemia & hyperphosphataemia.

ECG signs in hyperkalaemia tall T waves, small or absent P waves, increased P-R interval, wide QRS
complex, ‘sine wave’ pattern, asystole.

Urine testing – stick for detection of blood, protein, leucocytes, & urine microscopy & urine

Soluble immunological tests of circulating autoantibodies: anti-nuclear antibody, anti-neutrophil
cytoplasmic antibody, anti-glomerular basement membrane antibodies.

Imaging ultrasound scan for renal size & presence of obstruction

Chest X-ray for pulmonary oedema

Renal histology obtained when- pre & post ARF ruled out OR a confident diagnosis of ATN (acute
tubular necrosis) cannot be made or systemic inflammatory symptoms are present

Management of Acute Renal Failure

Prevention of acute tubular necrosis: Identify pre-renal state/correct aggressively

Contrast: volume expand

Drugs: avoid nephrotoxins, dose, drug levels

Myoglobin: forced diuresis

Furosemide, mannitol, dopamine  no benefit in trails

Established ARF

Volume overload  restrict Na & water <1l/day, diuretics

Hyperkalaemia  restrict dietary K, stop K sparring diuretics & ACEi, exchange resin, dextrose &
insulin, sodium bicarbonate, B2 agonists, Ca gluconate

Acidosis  protein restrict, sodium bicarbonate

Nutrition  catabolic: enter/parenteral nutrition

Indications for dialysis

Usually haemodialysis in ARF

They are: hyperkalaemia, pulmonary oedema, pericardial rub, uraemic symptoms, metabolic
acidosis, azotaemia, presence of a dialyzable nephrotoxin.

Management of Rapid progressive glomerular nephritis:
Usually involves steroids & cyclophosphamide & plasma exchange for ANCA-positive vasculitis &


Different Presentations of Renal Disease
Presentation of kidney disease ranges from:

       Asymptomatic individual with proteinuria & haematuria or low eGFR detected n routine
       To a patient with fulminant disease comprising AKI together with life threatening extrarenal

Asymptomatic presentations are more common but less specific. Asymptomatic urinary
abnormalities may indicate a wide range of other UT diseases.

Most disease without symptoms found incidentally by urinalysis or when blood tested for other

Microscopic haematuria common 22% may be due to: UTI, polycystic kidneys, stones, tumours,
arteriovenous malformations as well as glomerular disease. Kidney disease is more likely if
proteinuria & hypertension are present.

Macroscopic haematuria episodic macroscopic haematuria associated with glomerular disease is
often brown or smoky in colour rather than red, clots are very unusual. Other causes of red or brown
using are: haemoglobinuria, myglobinuria or consumption of food dyes.

Usually painless, commonest glomerular cause is IgA nephropathy occurs within 24 hours of URTI.

Isolated asymptomatic proteinuria normal urine protein excretion <150mg/24 hours,
microalbuminuria is defined as 30-300mg albuminuria/24hours. May be associated with conditions
other than glomerulonephritis

Nephrotic syndrome: Triad  proteinuria, hypoalbuminaemia, oedema also hypercholesterolaemia.

Pathognomonic of glomerular disease & required renal biopsy for diagnosis

GASH’D  minimal change Glomerular nephritis, amyloidosis, SLE, Henloch-Schonleich purpura,
Diabetes mellitus (or drugs)

Nephritic Syndrome: The classic syndrome is that which accompanies post-streptococcal
glomerulonephritis in children, but can be as a result of other glomerulonephritides, often self-
limiting. Features: haematuria with/without proteinuria, renal impairment, salt & water retention, &

PAIRS – Post-streptococcal GN, Alport’s syndrome, IgA nephropathy, RPGN, SLE

Manifest as: rapid onset, oliguria, HT, oedema, haematuria with smoky brown urine, normal serum
albumin, variable renal impairment, urine contains blood protein & red cell casts. Biopsy required.
Rapidly progressive glomerulonephritis –A clinical situation in which glomerular injury is so severe
that renal function deteriorates over days. Patient may present as a uraemic emergency, with
evidence of extrarenal disease. Associated with crescentic glomerulonephritis. Biopsy required.

Session 10: Urinary Tract Infections
1-3% prevalence in adult women. Up to 50% of all women may suffer from symptomatic UTI at some
time in their life; it is a common source of gram-negative septicaemia.

Women more likely because of shorter urethra. More likely in obstructed urethra in times of
enlarged prostate, pregnancy, stones & tumours. It is more likely with neurological problems due to
                                                incomplete emptying, or ureteric reflux,
                                                ascending infection from bladder especially in

                                                        A.   PUJ: calculi
                                                        B.   Ureter: calculi, Ca, retroperitoneal fibrosis
                                                        C.   Bladder: neuropathic bladder
                                                        D.   VUJ: calculi
                                                        E.   Bladder neck: hypertrophy
                                                        F.   Prostate: BPH/Carcinoma
                                                        G.   Urethra: stricture

                                                    Bacterial factors: fimbriae allow attachment to
                                                    host epithelium. K antigen permits production of
                                                    polysaccharide capsule. Haemolysins damage
                                                    host membranes & cause renal damage. Urease
                                                    breaks down urea creating a favourable
                                                    environment for bacterial growth.

                                                    Lower UTI - sometimes low grade fever, dysuria,
                                                    frequency & urgency.

Upper UTI (pyleonephritis) – FLAVOR fever, loin pain, ARF, Vomiting, Oliguria (if ARF), Rigors may
have dysuria & frequency.

Investigation of UTI – in healthy women ‘uncomplicated UTI’ no need to culture urine – infection
indicated by nitrite/leucocyte esterase dipstick. Culture urine in ‘complicated UTI’ when patient
either pregnant or treatment failure, suspected pyleonephritis, complications, male or children.

MSU –cleansing not required in women. Clean catch in children – no antiseptic. Or from collection
bad, catheter sample or supra-pubic aspiration. Transportation: 4Co & with/without boric acid.

Screening for turbidity, dipstick testing, leucocyte esterase, nitrite, haematuria & proteinuria

Microscopy is needed when – kidney disease – loin pain, nephritis, hypertension, toxaemia, renal
colic, haematuria, renal TB, casts. In suspected endocarditis, children under 6, Schistosomiasis or
suprapubic aspirates or when requested
Significant bacteriuria - asymptomatic females compared with females with pyelonephritis. > 105
cfu/ml distinguishes bacteriuria from contamination. Single specimen 80% predictive in females

Culture needed investigation of children, males & complicated infections. Increased sensitivity
(down to 102 cfu/ml). Get an epidemiology of isolates, susceptibility, control of specimen quality

Of symptomatic adult women

50% significant bacteriuria the other 50% urethral syndrome which is:
    Low-count bacteriuria
    Fastidious organisms
    Vaginal infection/inflammation
    Sexually-transmitted pathogens – urethritis
    Mechanical, physical & chemical causes.

Sterile pyuria (sterile urine with pus in it) – required antibiotics, could be due to urethritis
(Chlamydia/gonococci) or vaginal infection, chemical inflammation, TB, appendicitis.

Treatment of UTI  increase fluid intake, address underlying disorders.

3 day course of trimethoprim or nitrofurantoin for uncomplicated UTI

7 day course for complicated UTI – Trimethoprim, nitrofurantoin or cephalexin may be used.
Amoxicillin not appropriated because 50% of isolates resistant. Post treatments follow up in children
& pregnant women.

CSU: only treat if systemically unwell.

Treatment of pyleonephritis/septicaemia: pyelonephritis 14 day course of antibiotics use agent
with systemic activity. Possibly IV initially unless good PO absorption & patient well enough. Typical
antibiotics: ciprofloxacin, cefuroxime or Gentamicin – IV only, & nephrotoxic

Prophylaxis is given in patients with 3 or more episodes in 1 year with no treatable underlying
condition, either trimethoprim or nitrofurantoin, just one single nightly dose, ensure all
breakthrough infections are documented.

Complications of UTI – pyelonephritis, risk of early pregnancy, life-threatening gram-negative
septicaemia, renal failure

UTIs in catheterised patients should only be treated if patients have systemic features. Whenever
possible the catheter should be removed before treatment. Where indicated, use antibiotics
determined by susceptibility testing. Do not use prophylaxis in catheterised patients as this generally
leads to the emergence of resistance. A catheter/catheterisation policy should address the basic
issues, including the following points to reduce catheter- associated UTIs:

        1.   Only catheterise when absolutely necessary
        2.   Remove catheter as soon as possible
        3.   Use intermittent rather than continuous catheterisation
        4.   Insert catheter with good aseptic technique
        5. Use closed sterile drainage system
        6. Ensure urine drains by gravity to avoid reflux

Diuretic - A substance/drug that promotes a diuresis ↑ renal excretion of water & sodium ↓
reduction of ECF volume

Different segments of the tubule have different types of sodium transporters & channels in the
apical membrane.

       Proximal Tubule – Na-H antiporter
       Loop of Henle – NaK2Cl symporter
       Early Distal Tubule – Na-Cl symporter
       Later Distal Tubule & Collecting Duct – ENaC

Tubular reabsorption of sodium & secretion of potassium by the principal cells in the late distal
tubule & collecting duct.

Na-K ATPase in basolateral membrane Na enters via ENaC. Aldosterone increases both expression of
Na-K ATPase & ENaC. Principal cells also secrete K through a separate channel. Na reabsorption
favours K secretion by creating a lumen negative potential for K secretion. Hence diuretics blocking
ENaC also reduces K secretion. I.e. potassium sparring diuretics

Mechanism of Diuretics

By direct action on cells to block Na transporters in the luminal membrane
   Loop diuretics – act on L of Henle block Na-K-2Cl symporter (Furosemide, Bumetanide)
   Thiazide diuretics – act on the early DT & block Na-Cl symporter. (Bendroflumethiazide,
   K+ sparring diuretics – Act on late DT & CD block ENaC (Amiloride, Trimterene)

By antagonising the action of Aldosterone, Aldosterone acts on principal cells of Late DT & CD to
increase Na reabsorption via ENaC, NaK ATPase & ROMK. Aldosterone antagonists – competitive
inhibition of Aldosterone receptor decreases Na reabsorption. (Spironolactone)

By modification of filtrate content – osmotic diuretics (Mannitol –class not currently used as a
     Filtered at glomerulus
     Increase osmolarity of filtration
     Decrease water & sodium reabsorption throughout tubule
     Used to treat cerebral oedema
     Increases plasma osmolarity thus drawing out fluid from cells, freely filtered at the
         glomerulus, & increases the osmolarity of the filtrate. Acts by altering the driving force for
         renal water absorption, which is osmolarity. Not inhibitors of enzymes or transport proteins.
         Causes loss of water, Na & K in the urine.
By inhibiting activity of enzyme carbonic anhydrase – carbonic anhydrase inhibitors -
(acetazolamide – class not currently used as a diuretic)

        These acts on PCT inhibits enzyme that interferes with Na & HCO3- reabsorption.

        Used to treat Glaucoma, can cause metabolic acidosis due to loss of HCO3- in urine

Loop diuretics

Very potent– 25-30% of filtered sodium reabsorbed in LOH, loop diuretics block this absorption.
Segments beyond have limited capacities to reabsorb the resulting flood of Na & water.

Used in Heart Failure – diuretic effect cause vaso & venodilatation (decrease after & pre load). In
acute pulmonary oedema Furosemide given IV for rapid action

Also used in nephrotic syndrome, renal failure, cirrhosis of liver

Hypercalcaemia – loop diuretics promote Ca2+ excretion by the loop of Henle

Thiazide diuretics act on the early DT

Less potent diuretics than loop diuretics only 5% of Na reabsorption inhibited. Ineffective in renal
failure, widely used in hypertension (vasodilatation) higher incidence of hypokalaemia

Late distal tubule & collecting duct diuretics

Potassium sparing diuretics & Aldosterone antagonists

Both types reduce Na+ channel activity. Both reduce the loss of K & are called potassium sparing
diuretics. Both are mild diuretics affecting only 2% of Na reabsorption.

Aldosterone antagonists are the best drug for treatment of hypertension due to primary
hyperaldosteronism. E.g. Adrenal hyperplasia/tumour  increased secretion of Aldosterone  HT.

Aldosterone antagonists are also preferred drug for Ascites & oedema in cirrhosis & used in addition
to loop diuretics in heart failure.

Diuretic Therapy & Potassium

Loop diuretics & Thiazide diuretics increase the loss of K in the urine  may cause hypokalaemia

K sparing diuretics & Aldosterone antagonists reduce excretion of K in the urine  may cause

K secretion in DT & CD – Is a passive process, driven by electrochemical gradient for K between
principal cells & lumen. Rate of K secretion depends on

    1. Intracellular K concentration
    2. K concentration in fluid in lumen affected by the rate of flow of filtrate in lumen
    3. Sodium absorption the inward movement of Na+ creates a favourable lumen negative
       potential for K+ secretion.
Also contributing to hypoK... diuretics reduce ECF volume  activation of RAAS  increase
Aldosterone secretion  increased Na & K secretion  Hypokalaemia.

Therefore we need to monitor electrolyte levels during diuretic therapy. Loop/Thiazide diuretics may
necessitate K supplements OR the combination of Loop/Thiazide diuretic with a K sparing diuretic
can be used to minimise changes in K.

Side Effects
     Hypovolaemia – especially loop diuretics
             o Decreased ECF volume due to excessive loss of water & Na
            o Monitor – weight, for signs of dehydration, BP (look for postural drop)
       Hyponatraemia
       Increase uric acid levels in blood- can precipitate attack of Gout
       Glucose intolerance
       Increased LDL levels.

Alcohol – inhibits ADH release. Caffeine – increased GFR & decreased tubular Na reabsorption

Other drugs: Lithium & demeclocycline both inhibit ADH action on CD

ACE inhibitors will result in depressed aldosterone secretion, hence K retention & hyperkalaemia.
Late distal diuretics also dispose towards hyperkalaemia, & this is why these drugs must never be
administered in parallel.

Session 11 – Chronic Kidney Disease
Normal GFR 90- 120/ml/min/1.73m2 from 2 X 106 nephrons of which we only need 2% to survive.

CKD is the progressive & irreversible loss of renal function over a period of months to years. Renal
tissue is replaced by extracellular matrix in response to tissue damage (this is bad). This results in
progressive chronic kidney disease – the uraemic syndrome.

Aetiology: immunological (glomerulonephritis), infection (pyelonephritis), genetic – PCK, Alport’s,
reflux. Obstruction, hypertension, vascular, systemic disease (diabetes), myeloma, or of unknown

Stage    GFR            Description
1        >90            Kidney damage with normal or         Need other evidence of kidney damage
                        increased GFR                        (U/A or USS)
2        60-89          Kidney damage with mild GFR          Need other evidence of kidney damage
                        fall                                 (U/A or USS)
3        30-59          Moderate fall in GFR                 Symptoms +
4        15-29         Severe fall in GFR               Symptoms ++
5        <15 or RRT Established renal failure           Symptoms +++
End stage kidney disease is caused by common conditions which are frequently seen. Less than 10%
have a glomerulonephritis.

85% of patients with CKD will be identified by looking in registries for diabetes, hypertension, IHD. It
is more common in the elderly, ethnic minorities & the social disadvantaged.

Incidence – 100 pmp taken on to dialysis. High cardiovascular morbidity & mortality, understanding
pathophysiology may allow prevention or at least delay progression.

Patients with CKD are more likely to die than require dialysis.

CKD is an independent & major risk factor for cardiovascular disease.

Measuring renal function
Serum creatinine – normal range 80 – 120 µmol/l

GFR – normal range 80 – 120 ml/min (% normal function). Either by inulin clearance or creatinine
clearance (24hours)

But creatinine concentration determined by renal function & muscle mass which in turn is
dependent on age, sex & race.

Estimated GFR reporting

Modified MDRD... GFR (ml/min/1.73m2) = 186 X {[serum creatinine (µmol/l)/88.4]-1.154} X age-0.203 X
0.742 (if female) X 1.21 if black.

Problems: only accurate in adults correction needed for black patients. It defines chronic kidney
disease & is not useful in acute renal failure.

Assessment of cause of CKD – auto antibody screen, complement, immunoglobulin, ANCA< CRP,
Serum Protein Electrophoresis/urine protein electrophoresis

Imaging: Ultrasound for size & hydronephrosis then either CT or MRI

If the kidneys are normal in size & the cause of CKD is not obvious a renal biopsy should be

Complications of CRF

Anaemia due to decreased erythropoietin production, resistance to erythropoietin, decreased RBC
survival & blood loss.

Renal bone disease

Renal osteodystrophy, rugger jersey spine, erosion to terminal phalanges & bone cysts


Change lifestyle, treat diabetes, & treat BP, ACE inhibitors/ARBs, & lipid lowering drugs.

Renal replacement therapy is required when native renal function declines to a level no longer
adequate to support health, usually when GFR < 10ml/min.
Indications for initiation of dialysis – uraemic syndrome, acidosis, pericarditis, fluid overload,

Haemodialysis, continuous ambulatory peritoneal dialysis, or renal transplantation

Haemodialysis requires: HD machine, highly purified water, vascular access, anti-coagulation, &
logistics. Usually a primary arteriovenous radiocephalic fistula is done.

Advantages: effective survivors can live 25 years. 4/7 days free from treatment. Dialysis dose easily

Disadvantages: fluid/diet restrictions, limits holidays, access problems, CVS instability, high capital
costs, hospital based.

Peritoneal dialysis requires: peritoneal membrane, perfusion & peritoneal dialysis fluid.

Advantages: home technique, easily learned, allows mobility, CVS stability, & better for elderly &

Disadvantages – frequent exchanges, no long term survivors, frequent treatment failures, peritonitis,
limited dialysis dose range, high revenue costs.


All patients with progressive CKD or end stage renal failure should be considered for transplantation.
Sources are cadaver donors, non-heart beating donors, living related donors & living emotionally
related donors.

Advantages: restores near normal renal function, allows mobility & rehab, improved survival, good
long term results, & is cheaper than dialysis

Disadvantages: not all are suitable, limited donor supply, operative morbidity & mortality, lifelong
Immunosuppression, still left with progressive CKD.

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