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function of the nephron

The nephron is the functional unit of the kidney.
It has three roles:
2.Selective Reabsorption


functions of the kidney

 Maintenance of Extracellular Fluid Volume (ECFV) – sodium and water (therefore maintaining blood pressure)
 Acid-base balance regulation - therefore normally preventing acidosis/alkalosis
 Excretion of metabolic waste – urea and creatinine
 Endocrine secretion
 Renin-angiotensin system (for sodium regulation of blood pressure)
 Erythropoietin (for RBC production and regulation)
 Vitamin D (for calcium regulation)


the nephron is divided into

 Glomerulus - filtration
 Proximal Convoluted Tubule – selective reabsorption of water, ions, and all organic nutrients
 Descending Limb of Loop of Henle – selective reabsorption of water
 Ascending Limb of Loop of Henle – selective reabsorption of sodium and chloride ions
 Distal Convoluted Tubule – secretion of ions, acids, drugs, toxins/ variable reabsorption of water sodium and calcium ions
 Collecting Tubule – variable reabsorption of water and reabsorption/secretion of sodium, potassium, hydrogen and bicarbonate ions


blood supply of the kidney

• The average cardiac output is 5 litres/min. The kidneys receive 20% of this (1 litre/min).
• The renal blood flow (RBF) is about 10-50 times greater than other the blood supply of other organs.


kidney main function

• The kidneys are the primary means for eliminating waste products of metabolism that are no longer needed by the body.
• These products include urea (from the metabolism of amino acids), creatinine (from muscle creatine), uric acid (from nucleic acids), bilirubin (from Hb breakdown), and metabolites of various hormones.
• The kidneys also eliminate most toxins and other foreign substances that are either produced by the body or ingested, such as pesticides, drugs, and food additives.



• The glomerulus allows for filtration of contents of the blood into the proximal convoluted tubule (PCT).
• Proteins larger than the size of albumin can’t pass into the PCT.
• The fluid must cross:
 Wall of glomerular capillary
 Basement membrane
 Inner layer of Bowman’s capsule
(Podocytes, Pedicels, Filtration slits)
• The glomerulus provides a size and a charge barrier.
• It allows small positive molecules through.
• Large or negatively charged molecules are repelled.


glomerular filtration rate

GFR= K_f ∙[P_GC-(P_BC+π_GC )]
There are certain factors that affect the GFR:
Kf = filtration coefficient
PGC = glomerular capillary hydrostatic pressure (favours filtration)
π GC = glomerular capillary oncotic pressure (opposes filtration)
Oncotic pressure is a form of osmotic pressure exerted by proteins, notably albumin, in a blood vessel that pulls water into the circulatory system.
PBC = Bowman's capsule hydrostatic pressure (opposes filtration)


autoregulation-maintaining GFR

• Autoregulation is the process by which the RBF and GFR are maintained despite changes in systemic pressure.
• This graph shows that when the blood pressure increases, the vascular resistance of the afferent arteriole increases too.
• This maintains the RBF and the GFR.
• Autoregulation (the increased vascular resistance) occurs in two ways:
 Myogenic – vascular smooth muscle responds to stretch by vasoconstricting.
 Tubuloglomerular feedback – distal tubular flow regulates vasoconstriction.


tubuloglomerular feedback

• This process involves the macula densa.
• The macula densa is a collection of densely packed epithelial cells at the junction of the thick ascending limb (TAL) and distal convoluted tubule (DCT).
• As the TAL ascends through the renal cortex, it encounters its own glomerulus, bringing the macula densa to rest at the angle between the afferent and efferent arterioles.
• The macula densa's position enables it to rapidly alter glomerular resistance in response to changes in the flow rate through the distal nephron.
• The macula densa uses the composition of the tubular fluid as an indicator of GFR.
• A large sodium chloride concentration is indicative of an elevated GFR.
• A low sodium chloride concentration indicates a depressed GFR.


machanism of tubuloglomerular feedback e.g inc GFR

• Increased arterial pressure causes increased glomerular pressure and plasma flow.
• This increases the GFR.
 The plasma colloid osmotic pressure increases to limit the increased GFR.
• The increased GFR increases the tubular flow to the proximal convoluted tubule
 This leads to increased reabsorption of water and ions in the proximal convoluted tubule and the loop of Henle.
• The increased GFR increases the tubular flow to the early distal convoluted tubule.
 There is increased osmolarity of the tubular fluid (i.e. increased NaCl).
• This is sensed by the macula densa by an apical Na-K-2Cl cotransporter (NKCC2).
• The juxtaglomerular cells in the macula densa secrete renin, which results in afferent arteriole constriction.
• This increases the preglomerular resistance, thus decreasing the GFR and keeping it maintained at a steady level.


measurement of GFR

‘Renal Clearance’ – volume of plasma which is cleared of substance x per unit time
Renal Clearance= (Ux V)/Px
Ux = urinary concentration of ‘x’
V = urine volume per unit time
Px = plasma concentration of ‘x’
Markers of GFR:
Features of a good marker:

Freely filtered
Not reabsorbed
Not secreted
Excreted in urine

Creatinine is the marker used in clinical practice.
It is a by-product of muscle breakdown.
It is affected by: age, gender and ethnicity.


selective reabsorption-sodium regulation

• We reabsorb about 1.5kg of Na+ ions a day.
• We excrete about 9g of Na+ ions a day.

• Plasma [Na+] determines
 Extracellular fluid volume
 Arterial blood pressure
• Less “expensive” than active water transport. This is because it is easier to transport Na+ ions and allow other things (like water and glucose) to follow. This way we don’t expend excess amounts of ATP.
• Linked to most other renal transport processes e.g. glucose reabsorption.


bulk reabsorption vs fine tuning

• Proximal convoluted tubule – 67% Na+ reabsorbed
• Loop of Henlé – 25% Na+ reabsorbed
 This occurs via the Na+-K+-Cl- Cotransporter (NKCC2) in the ascending loop of Henle.
• Distal convoluted tubule & collecting duct – 8% Na+ reabsorbed

1. The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell.
2. This allows the Na+-H+ exchanger on the apical membrane to take up Na+ ions from the urine.
3. The anion-Cl- exchanger allows the uptake of HCO3- ions in exchange for Cl- ions.
 Therefore, both Na+ ions and HCO3- ions are reabsorbed.

1. The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell.
2. Aldosterone combines with a cytoplasmic receptor.
3. Hormone-receptor complex initiates transcription in the nucleus.
4. New protein channels (ENaC – epithelium sodium channel) and pumps are made.
5. Aldosterone-induced proteins modify existing proteins.
6. Result is increased Na+ reabsorption and K+ secretion.


glucose transport

• There are three transport protein families that are involved in glucose transport:
1. SLC – solute carrier family
 SLC5: sodium-linked cotransporters
 SGLT1 - transports 1 glucose: 2 Na
 SGLT2 – transports 1 glucose: 1 Na
 GLUT1 and GLUT2


early proximal convoluted tubule

 The early proximal convoluted tubule is involved in the mass reabsorption of glucose.
 The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell.
 This allows the Na+-glucose SGLT2 cotransporter on the apical membrane to take up Na+ and sodium from the urine.
 Next, the GLUT2 protein allows passage of glucose from inside the cell into the blood.
 These have a low-affinity but high capacity because there is a lot of glucose available and these transport proteins allow for mass reabsorption of glucose


late proximal convoluted tubule

 The late proximal convoluted tubule is involved in the fine reabsorption of glucose.
 The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell.
 This allows the Na+-glucose SGLT1 cotransporter on the apical membrane to take up Na+ and sodium from the urine.
 Next, the GLUT1 protein allows passage of glucose from inside the cell into the blood.
 These have a high-affinity but low capacity because glucose has already been mass absorbed and so there is less glucose left in the tubular fluid. These transport proteins allow for fine-tuning reabsorption of glucose.


Glucose excretion: Tm

• Fasting glucose ~ 5 mmol/L and GFR = 125 ml/min
• Filtered glucose = 5 x 0.125 = 0.63 mmol/min
• Transport maximum (Tm) ~ 1.25 mmol/min Plasma glucose ~ 10 mmol/L

• This graph shows that once the Tm is reached, no more glucose can be reabsorbed.
• The excess glucose must be excreted (the point of intersection of the lines).



• The kidney itself is a source of glucose via gluconeogenesis.
• The kidney makes around 20% of all glucose in the body, but it then breaks it back down.


water balance-concentrating urine

• Water reabsorption occurs in the descending loop of Henle.
• The longer the loop of Henle, the greater the amount of water that is reabsorbed.
• If the need to reabsorb more water occurs, this is mediated by the effect of ADH/ Vasopressin.
• ADH inserts aquaporins (AQP2) in the apical membrane of the cells in the late distal convoluted tubule and the cells of the collecting tubule.
 This allows water to be reabsorbed from the cells back into the body.
 The water will only flow through these channels in the presence of an osmotic gradient caused by Na+ ions.
• AQP3/4 are already present on the basolateral membrane of these cells.
• Aldosterone (via ENaC) also allows reabsorption of water.


calcium ions and magnesium ions

• PCT & Loop of Henlé
 91% Ca2+ reabsorbed – paracellular route (passive reabsorption)
 89% Mg2+ reabsorbed – paracellular route (passive reabsorption)
 3-7% Ca2+ reabsorption
 5-6% Mg2+ reabsorption


calcium reabsoption

• In the PCT and Loop of Henle, Ca2+ ions are passively reabsorbed.
• In the DCT, Ca2+ ions require transport proteins to be reabsorbed.

• Ca2+ ions enter the cell via TRPV5 transport protein channels.
• Because Ca2+ is an intracellular signalling molecule, we can’t have free Ca2+ in the cell as it would trigger other signalling pathways.
• Therefore, Ca2+ needs to be chaperoned from the apical membrane to the basolateral membrane where they would then enter blood.
• Ca2+ ions bind to an intracellular protein called Calbindin-D28K.
• This allows Ca2+ ions to move to the basolateral membrane.
• Once at the basolateral membrane, these ions can exit the cell into the bloodstream via two transport proteins: (1) Na+/Ca2+ exchanger [NCX1] and (2) plasma-membrane-calcium-ATPase-pump [PMCA1b].


TRPV5 can be regulated by

 Parathyroid hormone
 Vitamin D – the kidneys activate vitamin D which stimulates TRPV5 in the DCT
 Sex hormones
 Klotho – this is a protein that’s associated with longevity.


magnesium reabsorption

• Mg2+ reabsorption is less known.
• There is a ROMK potassium channel on the apical membrane of these cells.
• This causes the movement of K+ ions out of the cell and into the tubular fluid.
• This makes the tubular fluid positively charged.
• This favours the movement of Mg2+ ions into the cell via TRPM6 transport protein channels.
 This is activated by epidermal growth factor.
• There is a Mg2+ exchanger on the apical membrane but we don’t know what Mg2+ is exchanged for.


secretion-potassium ions

• We absorb potassium from our diet.
• It enters the ECF.
• It is taken up by cells by a Na+-K+ pump. This pump is activated by insulin.
• 98% of the potassium ions is taken up by the cells and 2% remains in the ECF.
• Proximal Convoluted Tubule takes up 65% of K+ ions.
• Loop of Henlé takes up 25% of K+ ions.
• Distal Convoluted Tubule & collecting duct have variable K+ reabsorption and secretion. Here, you either get net reabsorption or net secretion.

• 92% of the potassium is excreted by the kidneys.
• 8% of the potassium is excreted by the colon.
• Potassium needs to be carefully regulated because both hypokalaemia and hyperkalaemia can be fatal.
• Hypolkalaemia causes excess hyperpolarisation which leads to paralysis and so death.
• Hyperkalaemia causes excess depolarisation which also leads to paralysis and so death


proximal convoluted tubule

• On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions.
• These can leave via a K+ channel on the basolateral membrane.
• The net effect is the recycling of K+ ions.
• On the apical membrane there is a K+ channel.
• This allows the outflow of K+ ions, into the urine.
• As the tubular fluid continues through the PCT, there is a gain in the charge of the fluid because of the secretion of positively charged ions into the tubular fluid.
• This causes K+ ions to diffuse through the tight junctions between cells, back into the blood (down an electrochemical gradient).
• This is unregulated.
• In this way, most of the K+ ions are secreted into the tubular fluid, however, some diffuse back into blood.


ascending limb of loop of henle

• On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions.
• These can leave via a K+ channel on the basolateral membrane.
• The net effect is the recycling of K+ ions.

• On the apical membrane there are two K+ transport proteins.
• The NKCC2 is a sodium-potassium- 2 chlorine cotransporter.
• It allows the entry of potassium ions into the cell.
• The ROMK2 potassium channel causes an outflow of K+ ions.
• This causes recycling of K+ ions on the apical membrane, similar to that on the basolateral membrane.
• The net movement of potassium ions favours the influx via NKCC2.


collecting duct

• The collecting duct has two populations of cells: (1) Principal Cells (2) Intercalated Cells.
• Principal cells are involved with the secretion of K+ ions into urine.
• Intercalated cells are involved with the reabsorption of K+ ions from the urine


principle cells

 On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions.
 There is another K+ channel that allows the uptake of K+ ions form the blood into the cell.

 On the apical membrane, there is a K+/Cl- cotransporter which causes the secretion of both K+ and Cl- ions into the urine.
 There is also a K+ channel (ROMK1) that allows secretion of K+ ions.
 The ROMK1 channel can be stimulated by aldosterone or high plasma K+ (hyperkalaemia).


intercalated cells

 On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions.

 On the apical membrane, there is a K+/H+ exchanger which causes the reabsorption of K+ ions.
 There is also another H+ channel which causes the outflow of H+ ions.
 Acidosis or hypokalaemia activate the intercalated cells.


acid base balance in the kidneys

• Normally, there is around 15,000mmol of CO2 produced per day. This is ‘potential acid’, but it usually isn’t a problem as it is efficiently excreted by the lungs.
• Metabolism also produces ~40 mmol H+ per day (‘non-volatile acids’: sulphuric, phosphoric, organic acids).
• There is also a net uptake of ~30 mmol H+ per day by GI tract
• So the kidney has to:
 Excrete ~70 mmol H+ per day
 Reabsorb all the filtered HCO3 -

• Excess H+ ions in the urine can cause the urine to become very acidic (pH = 1.3), thus painful.
• Therefore, in the urine, the H+ ions needs to be buffered.


concept of carbonic anhydrase enzyme

• These are enzymes that contain Zn.
• There are at least 16 isoforms, but two important isoforms reside in the kidneys:
 CA II – soluble cytoplasmic (found freely dispersed in the cytoplasm)
 CA IV – extracellular, linked to cell membrane (by a GPI anchor)
• They catalyse the hydration of CO2. But, this is what actually happens…
• Carbonic anhydrase (CA) catalyses the second reaction (CO2 + OH-…)


reabsorption of HCO3

• HCO3- in the tubular fluid is converted to CO2 and OH- ions as a result of CA IV.
• The CO2 diffuses into the cell.
• The OH- ions combine with the H+ ions in the tubular fluid to form water.
• This water diffuses into the cell via osmosis.
• Once in the cell, the water breaks down again into H+ and OH- ions.
• The CO2 combines with the OH- (via CA II) ions to from HCO3- ions.
• At the basolateral membrane, the HCO3- ions exit the cell and enter the blood.
• The net movement of HCO3- ions is from the tubular fluid into the blood.
• This process uses a lot of ATP.


sites of HCO3 reabsorption

• HCO3- ions are reabsorbed throughout the nephron:
 PCT = 80%
 Thick ascending loop of Henle (TAL) = 10%
 DCT = 6%
 Collecting duct = 4%
• Less than 0.01% is excreted


proximal convoluted tubule of HCO3

• HCO3- in the tubular fluid is converted to CO2 and OH- ions as a result of CA IV.
• The CO2 diffuses into the cell.
• The OH- ions combine with the H+ ions in the tubular fluid to form water.
• This water diffuses into the cell via osmosis.
• Once in the cell, the water breaks down again into H+ and OH- ions.
• The CO2 combines with the OH- (via CA II) ions to from HCO3- ions.
• At the basolateral membrane, the HCO3- ions exit the cell via a ‘kidney variant of Na+/ HCO3- cotransporter’ (kNBCe1) and enter the blood.
• The H+ ions are secreted from the cell via a H+-ATPase pump and via a Na+/H+ exchanger (NHE3).
• The net movement of HCO3- ions is from the tubular fluid into the blood.
• This process uses a lot of ATP.

• The NHE3 is dominant in proximal tubule. It has a large capacity but limited gradient generation (from 7.35 to 6 pH). This is because the Na+ ions move over a small gradient and so only small amounts of H+ are exchanged (secreted), therefore the pH only decreases by a small amount.
• V-type (vacuolar) H+-ATPase can generate a bigger gradient (from 7.35 to 4/5 pH).

• 1:3 stoichiometry of kNBCe1 makes it electrogenic.
 It allows HCO3 - efflux from the cell because of extra drive from membrane potential.
 This is because there is a net efflux of 2- charge. This gives the protein the extra drive.


proximal renal tubular acidosis

Proximal Renal Tubular ACIDOSIS (RTA)
• Rare autosomal-recessive disease
• Impaired HCO3- reabsorption in PCT
• Not treatable by HCO3- supplementation
• Attributed to mutations in kNBCe1
• Ocular abnormalities too because of kNBCe1 and pBNCe1 expression there too


thick ascending loop of henle and distal convoluted tubule in hco3

• The transport protein for HCO3- ions at the basolateral membrane differs to that in the PCT.
• Here, it is an anion-exchanger (AE2).
• It exchanges HCO3- ions for Cl- ions.


α – Intercalated Cells of the Collecting Tubule and Duct Cells

• The H+ pump at the apical membrane is electrogenic.
• The H+/K+ -ATPase pump at the apical membrane is not electrogenic, therefore allowing transport of H+ ions up a steep gradient.
• The kAE1 exchanger protein at the basolateral membrane exchanges HCO3- ions for Cl- ions.


Distal Renal Tubular ACIDOSIS (dRTA)

• Inability to acidify urine (acid not secreted) – serious systemic consequences
• Treatable with HCO3- supplementation
• Dominant and recessive patterns
• Several transporter mutations – mainly affecting the α – intercalated cells: kAE1, V-type H+ -ATPase, CA II (proximal effects too)


excretion of H+ as titratable acid TA

• The water that diffused into the cell during reabsorption of HCO3- ions split into H+ and OH- ions.
• These H+ is secreted back out of the apical membrane into the tubular fluid.
• Once in the tubular fluid, the H+ ions are buffered by filtered phosphate (HPO42-) into H2PO4-.
• At the same time, HCO3- enters the tubular fluid after being filtered by the glomerulus, which further neutralises it.


excretion of H+ as NH4+

• An alternate way of secreting H+ ions is to utilise the ammonium (NH4+) ions synthesised in the cell during glutamine metabolism.
• Glutamine metabolism produces NH4+ ions and OH- ions.
• The OH- ions can combine with CO2 (via CA II) to form HCO3- ions that can enter the blood.
• The NH4+ ions split into ammonia (NH3) and H+ ions.
• NH3 and H+ ions are secreted into the tubular fluid where they both combine again to form NH4+ for excretion in urine.


sites of net acid secretion

• Acid (H+ ions) is secreted throughout the nephron:
 PCT = 40mmol NH4+ and 15mmol titratable acid (TA)
 DCT = 5mmol TA
 Collecting duct = 10mmol TA
 Small amounts of this acid is recycled in the medulla of the kidneys.
 Excreted = 40mmol NH4+ and 30mmol TA.


NH4 reabsorption in the thick ascending loop of henle

• On the apical membrane, there is a Na+/K+/Cl- cotransporter (NKCC1).
• There is a lack of selectivity for the K+ ion and instead NH4+ can be selected for.
• Also, there is a ROMK2 channel on the apical membrane.
• This is a K+ channel but can also select for NH4+ ions.
• Once in the cell, NH4+ splits into H+ ions and NH3.
• NH3 can now diffuse into the blood.


respiratory acidosis

Cause: hypoventilation/inc PCO2. Compensation: inc HCO3 reabsorption to react with excess H+.


respiratory alkalosis

hyperventilation/dec PCO2. compensated by dec HCO3 reabsorption.


metabolic acidosis

cause: dec HCO3 reabsorption, causes a build-up of H+ ions in the blood as HCO3- can’t react with it. Compensation: hyperventilation/dec PCO2 to get rid excess H+.


Metabolic alkalosis

cause-inc HCO3 reabsorption


metabolic acidosis details

is a condition that occurs when the body produces excessive quantities of acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low (less than 7.35) due toincreased production of hydrogen ions by the body or the inability of the body to form bicarbonate (HCO3−) in the kidney. Its causes are diverse, and its consequences can be serious, including coma and death. Together with respiratory acidosis, it is one of the two general causes of acidemia. Symptoms are not specific, and diagnosis can be difficult unless the patient presents with clear indications for arterial blood gas sampling. Symptoms may include chest pain, palpitations, headache, altered mental status such as severe anxiety due to hypoxia, decreased visual acuity, nausea, vomiting, abdominal pain, altered appetite and weight gain, muscle weakness, bone pain and joint pain. Those in metabolic acidosis may exhibit deep, rapid breathing called Kussmaul respirations which is classically associated with diabetic ketoacidosis. Rapid deep breaths increase the amount of carbon dioxide exhaled, thus lowering the serum carbon dioxide levels, resulting in some degree of compensation. Over compensation via respiratory alkalosis to form an alkalemia does not occur


extreme acidemia leads to neurological and cardiac complications

Neurological: lethargy, stupor, coma, seizures.
Cardiac: arrhythmias (ventricular tachycardia), decreased response to epinephrine; both lead to hypotension (low blood pressure).
Physical examination occasionally reveals signs of disease, but is otherwise normal. Cranial nerve abnormalities are reported in ethylene glycol poisoning, and retinal edema can be a sign of methanol (methyl alcohol) intoxication. Longstanding chronic metabolic acidosis leads to osteoporosis and can cause fractures.


diagnosis of metabolic acidosis

Arterial blood gas sampling is essential for the diagnosis. If the pH is low (under 7.35) and the bicarbonate levels are decreased (


anion gap

( [Na+] + [K+] ) − ( [Cl−] + [HCO3−] )

As sodium is the main extracellular cation, and chloride and bicarbonate are the main anions, the result should reflect the remaining anions. Normally, this concentration is about 8-16 mmol/l (12±4). An elevated anion gap (i.e. > 16 mmol/l) can indicate particular types of metabolic acidosis, particularly certain poisons, lactate acidosis and ketoacidosis.

As the differential diagnosis is made, certain other tests may be necessary, including toxicological screening and imaging of the kidneys. It is also important to differentiate between acidosis-induced hyperventilation and asthma; otherwise, treatment could lead to inappropriate bronchodilation


causes of metabolic acidosis

Metabolic acidosis occurs when the body produces too much acid, or when the kidneys are not removing enough acid from the body. There are several types of metabolic acidosis. The main causes are best grouped by their influence on the anion gap.

It bears noting that the anion gap can be spuriously normal in sampling errors of the sodium level, e.g. in extreme hypertriglyceridemia. The anion gap can be increased due to relatively low levels of cations other than sodium and potassium (e.g. calcium or magnesium). Compensatory mechanisms
Metabolic acidosis is either due to increased generation of acid or an inability to generate sufficient bicarbonate. The body regulates the acidity of the blood by four buffering mechanisms: bicarbonate buffering, respiratory, renal compensation


bicarbonate buffering system

Intracellular buffering by absorption of hydrogen atoms by various molecules, including proteins, phosphates and carbonate in bone


treatment of metabolic acidosis

A pH under 7.1 is an emergency, due to the risk of cardiac arrhythmias, and may warrant treatment with intravenous bicarbonate. Bicarbonate is given at 50-100 mmol at a time under scrupulous monitoring of the arterial blood gas readings. This intervention, however, has some serious complications in lactic acidosis and, in those cases, should be used with great care.

If the acidosis is particularly severe and/or there may be intoxication, consultation with the nephrology team is considered useful, as dialysis may clear both the intoxication and the acidosis. Complications
The major problem is suppression of myocardial contractility and unresponsiveness to catecholamines caused by the acidaemic state. This may lead to a vicious cycle of hypoperfusion, worsening lactic acidosis and further cardiac suppression, causing multi-organ failure. If pH is



The bladder fills progressively until the tension in its walls rises above a threshold•This elicitsthe micturition reflex that empties the bladder or, if this fails, causes a conscious desire to urinate. The micturition reflex is an autonomic spinal cord reflex,butit can also be inhibitedor facilitated by centers in the cerebral cortexor brain stem.The urinary bladder is a smooth muscle chamber composed of: •The bodycollectsurine•The neckconnects with the urethraSmooth muscle cells of the detrusor musclefuse with one another so that electrical pathways exist from one muscle cell to the other. Therefore, an action potential causescontraction of the entire bladder at once.At the trigonethe bladder neck opens into the posterior urethra and the two ureters enter the bladder. The trigone mucosa is smoothin contrast to the remaining mucosa, which is folded to form rugae.The neck wall composed of detrusor muscle(internal sphincter)interlaced with elastic tissue. Its natural tone normally keeps the bladder neck empty ofurineAn extension of the urogenital diaphragmforms the external sphincter. Thisis under voluntary control of the nervous system and can be used to consciously prevent urination.


transport of urine

The walls of the ureterscontain smooth muscleand are innervated by both sympathetic and parasympathetic nerves, as well as by an intramural plexus of neurons and nerve fibers that extends along the entire length of the ureters. Normally, the ureters course obliquely through the bladder wall. The normal tone of the detrusor muscle in the wall tends to compress the ureter, thereby preventing backflow of urine from the bladder when pressure builds up in the bladder. Each peristaltic wave along the ureter increases the pressure within the ureter so that the region passing through the bladder wall opens and allows urine to flow into the bladder.Ureter painprovokes a ureterorenal reflex. This isa sympathetic reflex back to the kidney to constrict the renal arterioles, thereby decreasing urine output from the kidney


concentrated uring

The requirements for formingconcentrated urine are •Ahigh level of ADH•Ahigh osmolarity of the renal medullary interstitial fluidThe renal medullary interstitium surrounding the collecting ducts is normally hyperosmotic, so when ADH levels are high, water moves through the tubular membrane by osmosis into the renal interstitium; from there it is carried away by the vasa recta back into the blood.


counter current mechanism

The osmolarity of the interstitial fluid in the medulla of the kidney is much higherthan normal interstitial fluidand increasesprogressively in the pelvic tip of the medulla. Once the high solute concentration in the medulla is achieved, it is maintained by a balanced inflow and outflow of solutes and water in the medulla.The major factors that contribute to the buildup of solute concentration into the renal medulla are as follows:•Active transportof sodium ions and co-transport of potassium, chloride(NKCC pump), and other ions out of the thick ascending limb –This is the most important factor•Active transport of ions from the collecting ducts•Facilitated diffusion of ureafrom the inner medullary collecting ducts•Diffusion of only small amounts of water from the medullary tubules•Passive reabsorption of sodium chloride from the thin ascending limb The descending limb is very permeable to water, and the tubular fluid osmolarity quickly becomes equalto the renal medullary osmolarity. The repetitive reabsorption of sodium chloride by the thick ascending loop and continued inflow of new sodium chloride from the proximal tubule into the loop is called the countercurrent multiplier.


urinary tract obstruction

Obstruction increases susceptibility to infection and to stone formation, and unrelieved obstruction almost always leads to permanent renal atrophy(hydronephrosis).Obstruction may be sudden or insidious, partial or complete, unilateral or bilateral; it may occur at any level of the urinary tract from the urethra to the renal pelvis. Hydronephrosisis dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to obstruction to the outflow of urine. Even with complete obstruction, glomerular filtration persists for some time because the filtrate subsequently diffuses back into the renal interstitium and perirenal spaces, where it ultimately returns to the lymphatic and venous systems. Because of this continued filtration, the affected calyces and pelvis become dilated, often markedly so. The high pressure in the pelvis is transmitted back through the collecting ducts into the cortex, causing renal atrophy, but it also compresses the renal vasculature ofthe medulla, causing a diminution in inner medullary blood flow. The medullary vascular defects are initially reversible, but lead to medullary functional disturbances. Accordingly, the initial functional alterations caused by obstruction are largely tubular, manifested primarily by impaired concentrating ability. Only later does the GFR begin to fall. Obstruction also triggers an interstitial inflammatory reaction, leading eventually to interstitial fibrosis


clinical features of urinary obstruction

Acute obstructionmay provoke pain attributed to distention of the collecting system or renal capsule. Most of the early symptoms are produced by the underlying cause of the hydronephrosis. Unilateralcomplete or partial hydronephrosis may remain silentfor long periods, since theunaffected kidney can maintain adequate renal function. Ultrasonographyis a useful noninvasive technique in the diagnosis of obstructive uropathy.In bilateral partial obstructionthe earliest manifestation is inability to concentrate the urine, reflected by polyuriaand nocturia.Complete bilateral obstructionresults in oliguriaor anuriaand is incompatible with survival unless the obstruction is relieved. Curiously, after relief of complete urinary tract obstruction, postobstructive diuresisoccurs.This can often be massive, with the kidney excreting large amounts of urine that is rich in sodium chloride.



Prostatic parenchyma can be divided into: the peripheral, central, and transitional zones, and the region of the anterior fibromuscular stroma.•Most hyperplasiasarise inthe transitional zone•Most carcinomas originate in the peripheral zoneHistologically the prostate is composed of glands lined by: a basal layer of low cuboidal epithelium covered by a layer of columnar secretory cells. In many areas there are small papillary infoldings of the epithelium. These glands are separated by abundant fibromuscular stroma. Testicular androgens control the growth and survival of prostatic cells. Benign Prostatic Hyperplasia (BPH) or Nodular HyperplasiaBPH is an extremely common disorder in men over age 50. It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodulesin the periurethral region of the prostate. When sufficiently large, the nodules compress and narrow the urethral canal to cause partial/complete, obstruction of the urethra.


Eitiology and pathogenesis of prostate

There is an overall reduction of the rate of cell death, resulting in the accumulation of senescent cells in the prostate. Androgens, which are required for the development of BPH, can not only increase cellular proliferation, but also inhibit cell death.Themain androgen in the prostate is dihydrotestosterone (DHT). It is formed in the prostate from the conversion of testosterone by type 2 5α-reductase.This enzyme is located in stromal cells.•Type 1 5α-reductasemay produce DHT from testosterone in liver and skin, and circulating DHT may act in the prostate by an endocrine mechanism.DHT binds to the nuclear androgen receptor(AR) present in both stromal and epithelial prostate cells. This activatesthe transcription of androgen-dependent genes. DHT results in the increased production of several growth factors and their receptors. FGF-7, produced by stromal cells, is the most important factor mediating the paracrine regulation of androgen-stimulated prostatic growth. Other growth factors produced in BPH are FGFs 1 and 2, and TGFβ, which promote fibroblast proliferation.



The early nodules are composed almost entirely of stromal cells, and later predominantly epithelial nodulesarise. From their origin in this strategic location the nodular enlargements may encroach on the lateral walls of the urethrato compress it to a slitlike orifice. Microscopically, thehallmark of BPH is nodularity.


stages of chronic kidney disease

based on GFR. 5 stages, normal in 1 with observation and control BP, and minimally reduced in 2. 3-moderatly reduced, 4 serverly reduced plan for endstage renal failure. 5 GFr below 15 on dialysis. endstage kidney failure treatment choices


diabetic nephropathy- glomerular pathology

• A common cause of nephropathy is damage to the glomerular filtrate.
• There can be damage to the:
 Endothelium (pre-eclampsia)
 Glomerular basement membrane
 Podocytes – this is due to genetic mutations. The podocytes ‘drop off’ the basement membrane and flow in the blood until they are removed from the system.

• This damage leads to a faulty barrier, which allows larger molecules such as albumin and glucose to pass through into the kidneys.
• Chronic damage to the glomerular filter leads to kidney dysfunction.


nephrotic syndrome

disease where there is loss of protein


nephritic syndrome

disease where there is a loss of blood



• Proteinuria is the presence of protein in the urine.
• Protein:creatinine ratio (PCR) in the urine:
 300 μg/mg (albuminuria


epidemiology of diabetic nephropathy

 2025: 300 million with diabetes (WHO)
 40% develop nephropathy – Genetic susceptibility
 Commonest cause of kidney failure worldwide

• Type 1 and 2 diabetes both share the same pattern for nephropathy.
• Diabetic nephropathy is linked to mortality. Of all the people who develop nephropathy, diabetics have one of the worst prognosis.
 Albuminuria persistency means increased risk of developing a heart attack.
• Genes can cause increased susceptibility towards this development or protection against developing nephropathy.


stages of injury in nephropathy

 Hyperfiltration
 Microalbuminuria
 Macroalbuminuria
 Proteinuria
 Declining renal function


glomerular compartment

 Endothelial cells
 Glomerular basement membrane
 Podocytes
 Mesangial cells
 Mesangial cell deposit


pathology of nephropathy

 GBM thickening
 Mesangial expansion
 Nodular sclerosis
 Advanced renal sclerosis


treatment for diabetic nephropathy

• Aims of treating Diabetic Nephropathy:
 Glycaemic control
 Blood pressure control – these drugs help to delay the progression of kidney diseases by blocking the renin-angiotensin aldosterone system(RAAS):
o ACE inhibitors
o Angiotensin-2 receptor blockers (ARB) - Losartan
o Renin-inhibitors – Aliskiren
 These drugs delay the progression because they lower the blood pressure which in turn lowers the GFR.
• Secondary treatments:
 Lipid lowering
 Reduce other CV risks



• Reduce extracellular fluid volume
• Lower blood pressure
• Augment effects of RAAS inhibitors
• Choice of diuretic agents depends on renal function:
1) Osmotic Diuretics (e.g. mannitol) – these work on the late PCT and the Descending loop of Henle.
2) Loop diuretics (e.g. furosemide) – these work on the ascending Loop of Henle
3) Thiazide diuretics (e.g. bendroflumethiazide) – these work on the DCT
4) Potassium-sparing – these work on the late DCT and early collecting tubule.



• Waste, excess fluids and salts are removed from the body by passing the blood over a dialysis membrane.
• This allows the exchange of substances between the blood and the dialysis fluid, which has the same concentration of substances as blood plasma.
• Substances diffuse from both sides to create the correct concentration of substances.


peritoneal dialysis

• Immediate use reduces fluid overload.
• No anticoagulation.
• Cheaper and can be used at home.
• Continuous
• Least likely to cause fluid shifts and hypotension



• Specialist nursing care
• Tertiary units
• Need for good central venous access
• High and efficient solute clearance
• Anticoagulation (heparin) required.
• Intermittent: not tolerated when haemodynamically unstable.
• Continuous Hemofiltration



• Kidney
• Combined kidney and pancreas – in the case of severe diabetes
• Islet cell


epidemiology of obesity

• Epidemiology:
 Obesity has been on the rise.
 In 2012:
 25% of adults (>16) in England were obese - an overall increase from 15% in 1993.
 19% of children (yr 6) were obese


adipose tissue

• Adipose tissue is deposited in two places:
 Subcutaneous fat – storage
 Visceral/omental fat – endocrine tissue

• Adipose tissue is used for energy balance and for monitoring appetite


visceral fat - endocrine tissue

• This type of adipose tissue secretes the following:
1. Inflammatory mediators:
 TNFa – induces insulin resistance by promoting serine-phosphorylation of IRS-1, which impairs insulin signalling
 Resistin – neutralising antibodies reduces insulin resistance
 IL-6 – direct correlation between IL-6 and insulin resistance/ visceral fat secrets 2x more IL-6 than subcutaneous fat
2. Adiponectin (Acrp30) – this stimulates adipose tissue to function correctly. Obesity reduces Acrp30.
3. Leptin
 This signals the adipose tissue mass size to the CNS (hypothalamus).
 Increased leptin = reduces food intake + increases energy expenditure.
 Obesity increases adipose tissue mass.



• Leptin secretion sends signals to the hypothalamus.
• This causes inhibition of feeding and increased sympathetic output.
• The increase of sympathetic output causes B-cells to decrease insulin synthesis and secretion.
• This leads to increased lipolysis and decreased lipogenesis.

• Leptin decreases gluconeogenesis.
• Leptin increases glycogenolysis.
• Leptin increases B-oxidation.
• Leptin increases glucose uptake.
• Leptin increases glycogenolysis
Obese people are leptin resistant. This means that they have an increased appetite and they don’t expend much energy. This means that they get fatter and secrete more TNF-a and so more insulin resistance manifests, increasing the risk of insulin resistance.


is insulin resistance and diabetes an inflammatory condition

• High doses of salicylates (aspirin)
 Reverse insulin resistance and diabetes
 Preserve β-cell function

• High-fat diets or obesity activate NF-κB and increase production of IL- 6, IL- 1β and TNFα.
 When these reach their targets (e.g. liver) they cause a further increase in NK-KB.
• Activation of NF-κB in liver results in liver and muscle insulin resistance and diabetes.
• Antibody-mediated neutralization of IL- 6 in high-fat fed animals partially restores insulin sensitivity.



is a protein that controls transcription of DNA. It plays a key role in regulating the immune response to infection. Incorrect regulation of NF-kB has been linked to inflammatory diseases. NF-kB is the protein responsible for cytokine production and cell survival.


mechanism of action of thiazolidinediones

• These drugs are PPARϒ agonists.
• PPARϒ are nuclear hormone receptors that cause an increase in adipogenesis in fat cells.
• This causes an increase in glucose uptake for adipogenesis, thus reducing the blood glucose level, without the need of insulin secretion.

• These drugs also activate AMP-Kinase.
• Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation


thiazolidinediones (inc insulin sensitivity)

• These are a form of drug used to treat type 2 diabetes.
• They work by increasing the sensitivity of cells to insulin (that are insulin resistant).
• These provide:
 Improvement of fasting plasma glucose.
 Improvement of lipid profile – lower NEFA/ TG/ cholesterol
 Improvement of B-cell function


advanced glycation end products (AGE)

• AGEs are substances that can be a factor in the development or worsening many degenerative diseases, such as diabetes.
• These compounds can affect nearly all types of cells and molecules in the body.
• They are thought to play a causative role in the blood vessel complications of diabetes.
• AGEs are seen as speeding up oxidative damage to cells and in altering their normal behaviour


AGE formation in diabetes

• Normally, AGE is produced in the body due to the combination of proteins and glucose.
• In type II diabetes, a state of hyperglycaemia develops intracellularly because on increased uptake of glucose (due to the increased levels of insulin), even though the intracellular mechanisms are abnormal (insulin resistance).
• This leads to increased levels of NADH and FADH.
• This increases the proton gradient in the oxidative phosphorylation.
• This results in mitochondrial production of reactive oxygen species which damage the DNA.
• These reactive oxygen species also cause accumulation of metabolites, which activate multiple pathogenic mechanisms.
• One of these mechanisms includes increased production of AGEs.


intracellular effects of AGE

• Causes activation of NF-kB, which results in the production of cytokines, and therefore is proinflammatory.
• Main targets are endothelial cells and smooth muscle.


extracellular effects of AGE

• Crosslinking key basement membrane molecules.
• Targets:
 collagen I and IV, vitronectin, laminin, elastin
 Lipid linked LDL
• Consequences:
 Increased vascular stiffness
 Increased synthesis of several ECM components
 Reduced endothelial cell adhesion
 Reduced NO (muscle relaxant) production and clearance of LDL


AGE and macrophage

• Basement membrane AGEs inhibit monocyte migration - “apoptaxis.”
• Soluble AGEs activate monocytes.
• AGE binds to receptors on monocytes.
• This causes increased expression of macrophage scavenger receptor (MSR) class A receptors and CD36 receptors on the monocyte cell membrane.
• As a result more Oxidised LDL (OxLDL) is taken up, thus increasing the concentration of LDL inside the cell.
• This leads to foam cell formation


AGE and AGE receptor RAGE summary

• AGE generation by hyperglycaemia underpins development of diabetic complications, such as kidney disease and atherosclerosis.
• Glucose forms adducts, causes protein crosslinking and changes in structure.
• AGE will:
 Target vascular tissue and beta cells
 Trigger inflammatory reactions
 Trigger atherosclerosis
 Induce apoptosis
 Change cell adhesion properties
 Cause vascular stiffness and vasoconstriction
 Change basement membrane properties – kidney function

• Overall, in diabetes, AGE is responsible for the chronic effects:
 Vascular damage
 Kidney dysfunction
 B-cell damage


Type I Diabetes - Lack of Insulin Production by Beta Cells of the Pancreas

• Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I diabetes.

• Causes of Type 1 Diabetes:
o Autoimmune disorders - destruction of beta cells.
o Viral infections – destruction of beta cells.
o Genes play a role in the susceptibility of developing Type 1 Diabetes.

• 90% of the islet of Langerhans need to be destroyed to develop type 1 diabetes. Therefore, the usual onset of type I diabetes occurs in teenage years - “juvenile diabetes mellitus”

• Type I diabetes may develop very abruptly, over a period of a few days or weeks, with three principal sequelae:
1. Increased blood glucose
2. Increased utilization of fats for energy for formation of cholesterol by the liver.
3. Depletion of the body’s proteins for use of energy within the cells themselves


glucose in the urine and dehydration

• The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine.
• The very high levels of glucose can cause dehydration.
 This occurs partly because glucose does not diffuse easily through the pores of the cell membrane, and the increased osmotic pressure in the extracellular fluids causes osmotic transfer of water out of the cells.

• In addition to the direct cellular dehydrating effect of excessive glucose, the loss of glucose in the urine causes osmotic diuresis.
 That is, the osmotic effect of glucose in the renal tubules greatly decreases tubular reabsorption of fluid.
 The overall effect is massive loss of fluid in the urine (due to glucose drawing in water into the urine), causing dehydration of the extracellular fluid, which in turn causes compensatory dehydration of the intracellular fluid.
• Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes


chronic high glucose concentration causes tissue injury

• Chronic high glucose concentration (i.e. in diabetes mellitus) causes blood vessels in multiple tissues throughout the body to function abnormally and undergo structural changes that result in inadequate blood supply to the tissues.
 This in turn leads to increased risk for:

 Heart attack
 Stroke
 End-stage kidney disease
 Retinopathy and blindness (eyes)
 Ischemia and gangrene of the limbs
 Peripheral neuropathy
 Autonomic nervous system dysfunction

• Peripheral neuropathy, which is abnormal function of peripheral nerves, and autonomic nervous system dysfunction can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in the extremities, and other symptoms of peripheral nerve damage.
• In addition, hypertension, secondary to renal injury, and atherosclerosis, secondary to abnormal lipid metabolism, often develop in patients with diabetes and amplify the tissue damage caused by the elevated glucose.


diabetes mellitus causes inc utilization of fats and metabolic acidosis

• The shift from carbohydrate to fat metabolism in diabetes increases the release of keto-acids, such as acetoacetic acid and b-hydroxybutyric acid, into the plasma more rapidly than they can be taken up and oxidized by the tissue cells.
• As a result, the patient develops severe metabolic acidosis from the excess keto-acids, which, in association with dehydration due to the excessive urine formation, can cause severe acidosis.
• This leads rapidly to diabetic coma (pH


diabetes mellitus causes depletion of the bodys proteins

• Failure to use glucose for energy leads to increased utilization and decreased storage of proteins as well as fat.
• Therefore, a person with severe untreated diabetes mellitus suffers rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia).
• Without treatment, these metabolic abnormalities can cause severe wasting of the body tissues and death within a few weeks.


pancreas transplant

A pancreas transplant allows patients with type 1 diabetes to get a new source of insulin from a donated pancreas.
Most pancreas transplants are performed on people with type 1 diabetes who also have kidney failure. This means a pancreas transplant is usually performed at the same time as a kidney transplant.
Pancreas transplants are also given to diabetic patients who don’t need a kidney, but who have life-threatening hypoglycaemic attacks.
Hypoglycaemic attacks are a serious complication of diabetes caused by low levels of glucose in the blood. About one in 10 pancreas transplants are carried out for this reason.
Pancreas transplantation is less common than kidney or liver transplantation, and only 200 such transplants are performed in the UK each year with more than 300 people on the waiting list.
The waiting time for a pancreas transplant is between one and two years because there is a shortage of suitable donor organs.


types of pancreas transplant

Simultaneous Kidney Pancreas Transplant (SPK) – both the pancreas and kidneys are transplanted together, from the same donor. This is the most common type, accounting for nine out of 10 transplants. It is used in people who have kidney disease as a result of type 1 diabetes.
Pancreas after Kidney Transplant (PAK) – a person first receives a kidney transplant from a living or deceased donor. This is then followed by a pancreas transplant from a deceased donor.
Pancreas Alone Transplant (PTA) – only the pancreas is transplanted. This is a treatment for patients with very poorly controlled type 1 diabetes who have hypoglycaemic attacks without warning, and which may threaten their life.


complications of pancreas transplant

A pancreas transplant is a complicated operation and, like other types of major surgery, there is a risk of complications.
About one person in five needs further surgery in the first few days after transplantation to deal with problems such as infection and bleeding.
There is also the risk of rejection. This is when the immune system (the body’s defence against infection) thinks the transplanted pancreas is a foreign body and attacks it.
To prevent rejection a type of medication is given to suppress the immune system (immunosuppressants). These need to be taken for the rest of the person's life.
Long-term use of immunosuppressants carries its own risk of complications, such as increased vulnerability to infection and cancer.



Diuretic drugs increase urine output by the kidney (i.e., promote diuresis). This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase. Most diuretics produce diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system. Sometimes a combination of two diuretics is given because this can be significantly more effective than either compound alone (synergistic effect). The reason for this is that one nephron segment can compensate for altered sodium reabsorption at another nephron segment; therefore, blocking multiple nephron sites significantly enhances efficacy.


loop diuretics

inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb (see above figure). This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct. This altered handling of sodium and water leads to both diuresis (increased water loss) and natriuresis (increased sodium loss). By acting on the thick ascending limb, which handles a significant fraction of sodium reabsorption, loop diuretics are very powerful diuretics. These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow.


thiazide diuretics

which are the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule. Because this transporter normally only reabsorbs about 5% of filtered sodium, these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. Nevertheless, they are sufficiently powerful to satisfy most therapeutic needs requiring a diuretic. Their mechanism depends on renal prostaglandin production.


complications of loop and thiazide diuretics

Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine. The increased hydrogen ion loss can lead to metabolic alkalosis. Part of the loss of potassium and hydrogen ion by loop and thiazide diuretics results from activation of the renin-angiotensin-aldosterone system that occurs because of reduced blood volume and arterial pressure. Increased aldosterone stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into the urine.


potassium sparing diuretics

. Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport. Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) at the distal segment of the distal tubule. This causes more sodium (and water) to pass into the collecting duct and be excreted in the urine. They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics. The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine. Other potassium-sparing diuretics directly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore have similar effects on potassium and hydrogen ion as the aldosterone antagonists. Their mechanism depends on renal prostaglandin production. Because this class of diuretic has relatively weak effects on overall sodium balance, they are often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia.


carbonic anhydrase inhibitors

inhibitors inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine. These are the weakest of the diuretics and seldom used in cardiovascular disease. Their main use is in the treatment of glaucoma.


cardiovascular effects of diuretics

Through their effects on sodium and water balance, diuretics decrease blood volume and venous pressure. This decreases cardiac filling (preload) and, by the Frank-Starling mechanism, decreases ventricular stroke volume and cardiac output, which leads to a fall in arterial pressure. The decrease in venous pressure reduces capillary hydrostatic pressure, which decreases capillary fluid filtration and promotes capillary fluid reabsorption, thereby reducing edema if present. There is some evidence that loop diuretics cause venodilation, which can contribute to the lowering of venous pressure. Long-term use of diuretics results in a fall insystemic vascular resistance (by unknown mechanisms) that helps to sustain the reduction in arterial pressure


renin angiotensin aldosterone pathway

dec volume and BP-release renin from juxtaglomerular cells in kidneys and angiotensinogen from the liver, combine make angiotensin i, ACE to angiotensin II, cause vasoconstrict, increase aldosterone which increaes Na and H2O reabsorption inc sec K+. Inc blood vol.