Week 9 The Kidney

Question 1

Homeostasis

Answer 1

In order for our body cells to function properly, they must be surrounded by extra-cellular fluid which is relatively constant with regard to osmolality (280mosmol/l)
•control of pH, temperature and oxygen concentration is also important
•The kidneys, together with neural and endocrine systems regulate the volume and osmolality of the ECF by altering the amount of electrolytes and water excreted

Question 2

Where’s the kidney located?

Question 3

Blood order

Answer 3

Aorta> renal artery> segmental artery > interlobar artery > arcuate artery >cortical radiate artery>(afferent arteriole > glomerulus (capillaries)>efferent arteriole >pertitubular capillaries or vasa recta ) > cortical radiate vein > arcute vein> interlobal vein > renal vein > inferior vena cava

(Nephron acciacted blood vessels)

Question 4

Innervation of the Kidney

Answer 4

Autonomic nerve fibres anf ganglia control the kidney and ureter
Network of fibres located at the renal plexus
Sympathetic vasomotor fibres enter the kidney from the inferior thoracic and lumbar splanchnic nerves.

Follow the route of the arteries through out the kidney Regulates the kidney in several ways:
Decreases the rate of blood flow to the glomerulus through contraction of precapillary sphincters. Sympathetic nervous system is stimulated by renin ,which is released by the kidney.
Causes changes in water and sodium reabsorption by the nephron.

Question 5

The nephron

Answer 5

The functional unit of the kidney
Responsible for blood processing
Change in the types of cells along the length of the nephron to enable it to perform its function

3 main areas
Renal corpuscule
Renal tubule
Collecting duct

Cortical nephrons = 85% of the nephrons only just dip into the medulla. The pertitubular capilares encircle all the nephron

Juxtamedually nephrons:
15% of nephrons extend deep into the medualla. Vascular loops called vasa recta extend to encircle the loop of Henley

Question 6

Four principles to the kidney

Answer 6

Filtration – movement of fluid from glomerulus into lumen of Bowman’s capsule (and then proximal convoluted tubule)

Reabsorption – fluid in the tubule lumen is now ‘external’ to the body unless it is reabsorbed and returned into system via peritubular capillaries, lymph and vasa recta

Secretion – removes molecules from blood and secretes them into lumen
There processes which take place in the nephron are related to the types of epithelial cells which we discussed in the lecture on structure

Fitration – through the squamous epithelia,
reabsorption – columnar epithelia
Secretion – very selective –uses membranous transport proteins sometimes scattered along the nephron in individual cells

Question 7

Glomerular filtration

Answer 7

Occurs at the Renal Corpuscle, where plasma moves from the blood vessels of the glomerulus into the lumen of Bowmans Capsule.

20% plasma moves into Bowmans Capsule, most of this is reabsorbed further along the nephron.

80% proceeds to the peritubular capillaries where secretion of desired solutes into the nephron lumen occurs, ready for excretion

Question 8

The Renal Corpuscle & Glomerular Filtration

Answer 8

Glomerulus has a “fenestrated endothelium” meaning it contains pores, which increases its permeability.

20% plasma moves into Bowmans space this is dependent on hydrostatic pressure  Colloid osmotic pressure  Hydrostatic fluid pressure

Question 9

Control of Glomerular Filtration Rate

Answer 9

Generally, Glomerular Filtration Rate (GFR) is relatively constant.
GFR is controlled by 2 factors:

Net filtration
Changes in renal blood flow and blood pressure

Filtration Coefficient
Changes in diameter of the afferent and efferent arterioles to alter the GFR

These changes can be actioned in 3 ways:
Hormonal
-Angiotensin II
-Prostaglandins

Nervous
-Sympathetic nerves release noradrenaline
-> arteriole constriction

Autoregulation
-Myogenic response - response to pressure changes
-Tubuloglomerular feedback – macula densa release of hormones due to physical changes in afferent and efferent arterioles and ascending limb of loop of Henle

Question 10

Control of Glomerular Filtration Rate

Answer 10

Generally, Glomerular Filtration Rate (GFR) is relatively constant.
GFR is controlled by 2 factors:

Net filtration
Changes in renal blood flow and blood pressure

Filtration Coefficient
Changes in diameter of the afferent and efferent arterioles to alter the GFR

These changes can be actioned in 3 ways:
Hormonal
-Angiotensin II
-Prostaglandins

Nervous
-Sympathetic nerves release noradrenaline
-> arteriole constriction

Autoregulation
-Myogenic response - response to pressure changes
-Tubuloglomerular feedback – macula densa release of hormones due to physical changes in afferent and efferent arterioles and ascending limb of loop of Henle

Question 11

Tubuloglomerular feedback

Answer 11

GFR increases
Flow through tubule increases
Flows past macula densa increases
Paracine from macula densa to afferent arteriole
Afferent arteriole constricts
Resistance in afferent arteriole increases
Hydrostatic pressure in glomerulus decreases
GRF decreases

Question 12

Filtrate composition

Answer 12

Filtrate
Plasma, glucose, amino acids, most hormones, urea, uric acid, creatinine, ions and water

Not filtered (too big)
Red blood cells , platelets, plasma proteins - albumins, globulins

Question 13

Glomerular filtration rate (GFR)

Answer 13

The amount of filtrate the kidneys produce per minute

Averages around 125 ml per minute

Approx 180 litres filtrate produced per day
1300g-1500g NaCl
400g NaHCO3
150g glucose
800 mmol potassium
Only approx 1 litre of urine produced

99% of filtrate reabsorbed

Pl Na level = 140mmol/l
GFR = 125ml/ min
how much filtrate is formed per day?
=
How much sodium would be lost per day if none of this was reabsorbed?
=
how many g NaCl? =

Question 14

Tubular Reabsorption

Answer 14

The process by which substances in the renal tubules are transferred back into the bloodstream.

-Most reabsorption takes place in the Proximal Convoluted tubule

Highly selective process.

More important than secretion for MOST nutrients & ions.

Allows for easy tuning of ion and water balance.

Nutrients are reabsorbed first (e.g. glucose and
amino acids).

Then ions such as Na+, HCO -, Cl-, (rate depends on bodily requirements).
Na+ is key to the transport of many substances.

This then generates a concentration gradient so that water is reabsorbed by osmosis.
Poor reabsorption of waste products

Question 15

Loop of Henle

Answer 15

By the time filtrate reaches loop of Henle 60-70% of filtrate reabsorbed via PCT

Descending limb = thin walls
Ascending limb = thin walls then thick walls (finishes with Macula Densa)

Loop of Henle reabsorbs:
Half the remaining water
2/3 of remaining ions
Achieved by counter-current multiplication

Question 16

Countercurrent multiplication

Answer 16

Na and Cl pumped out of ascending limb
V
Increase in Na and Cl concentration outside
V
Water leaves descending limb by osmosis
V

High concentration of Na and Cl in ascending limb

Question 17

Why use countercurrent system

Answer 17

Efficient way of reabsorbing solutes and water

Establishes a concentration gradient which allows reabsorption of water in the collecting system

Question 18

Control of blood volume; Specialist cells which support nephrons

Answer 18

Juxtaglomerular apparatus: The JGA is part of a complex feedback mechanism that regulates renal blood flow and filtration rate

The macula densa is a region of specialised epithelial cells of the Thick Ascending Limb where it comes back into contact with its glomerulus.
The granular cells are in the wall of the afferent arteriole; they are smooth muscle cells which produce, store and release renin.

Question 19

Maintaining blood volume eg D&V

Answer 19

Fluid and salt loss
decrease in ECF volume
JGA pf the nephrons
Renin released
Angiotensinogen- angiotensin 1
AT converting enzyme ACE = angiotensin II
Aldosterone released (adrenals)
Sodium reabsorbed from distal tubule
Increase in osmolality
(Detected by hypothalamus)
ADH released, thirst stimulated

Question 20

Angiotensin II:

Answer 20

constricts arterioles closing down capillary beds (thus decreasing GFR)
stimulates proximal tubules to reabsorb sodium
stimulates adrenal cortex to release aldosterone from adrenal gland (which increases sodium and water retention and potassium secretion)
increases strength of heartbeat
stimulates pituitary to release antidiuretic hormone (ADH)

ACE inhibitors are a range of powerful antihypertensive drugs. They have been shown to decrease rate of progression of renal failure by their effect on blood pressure and also by reducing damage to filtration system of the Bowmans capsule; reduction in proteinurea is measured. As they will have an effect in reducing aldosterone release, a side effect of the ACE inhibitors is that the K+ level in the blood increases

Question 21

ADHAnti-diuretic hormone

Answer 21

Controls water reabsorption in DCT and collecting system

Without ADH, tubule walls impermeable to water

ADH creates water channels, increasing permeabilty

Therefore ADH stimulates water reabsorption, and controls blood volume

Question 22

Action of ADH on water channels

Answer 22

ADH is a 9 aa peptide produced in the hypothalamus
release is sensitive to changes in osmolarity.
Regulates water permeability in Distal nephron = DCT, CD
Binds to basolateral side, but acts on apical side
results in 20 fold increase in water permeability

The concentration of urine is finally affected by the action of ADH on the collecting ducts. As the CD passes through the highly concentrated medulla, water will be pulled out only if the tubules are permeable. This is controlled by ADH (post pit) which signals aquaporins (held in endosomes ) inside the cell to be inserted into the lumen side of the cell wall water pores are open

Question 23

End result…

Answer 23

Electrolytes, body fluid return to normal (may need help from rehydration fluids in severe cases or vulnerable people; young, elderly)
Consider other case studies eg elderly person – not really drinking enough (too much effort to make drinks plus go to the loo)
Gets norovirus (D&V)
Quite easily end up hospitalised as renal function declines as we get older : 4% of population have GFR < 60ml/min

Question 24

Control of high blood pressure

Answer 24

Overall, the prevalence of hypertension (at least ≥140/90 mm Hg or on treatment for hypertension) in those aged over 35 was 32% in men and 27% in women.HSE 2009
The prevalence significantly increased with age in both sexes:
About 73% of men and 64% of women aged ≥75 years or older have hypertension.
often combinations of medications which act at different points of the nephron are used together: eg an ACE inhibitor and a diuretic
NICE guideline 127 2011

Stage 1 hypertension Clinic blood pressure is 140/90 mmHg or higher
and subsequent ambulatoryblood pressure monitoring (ABPM) daytime average or home blood pressure monitoring (HBPM)
average blood pressure is 135/85 mmHg or higher.
Stage 2 hypertension Clinic blood pressure is 160/100 mmHg or higher and subsequent ABPM
daytime average or HBPM average blood pressure is 150/95 mmHg or higher.
Severe hypertension Clinic systolic blood pressure is 180 mmHg or higher, or clinic diastolic blood
pressure is 110 mmHg or higher.

Question 25

Blood pressure tablets: ACE inhibitors & A II Receptor Antagonists /blockers (ARBs)

Answer 25

ACE inhibitors are a range of powerful antihypertensive drugs. They have been shown to decrease rate of progression of renal failure by their effect on blood pressure and also by reducing damage to filtration system of the Bowmans capsule; reduction in proteinurea is measured. As they will have an effect in reducing aldosterone release, a side effect of the ACE inhibitors is that the K+ level in the blood increases
Release of renin stimulated by:
A decrease in delivery of Na Cl to MD
SNS activation
decreased flow rate in the distal tubule. To differentiate these two mechanisms is difficult.
Stretch receptors in afferent arteriole granular cells detect drop in circ vol

Leading to release of aldosterone

JG cells release renin which converts angiotensinogen (produced by liver) to angiotensin 1
A1 is converted to A2 by ACE found in capillaries

fine tuning of Na balance - aldosterone responsible for 2% of Na handling (400mmol/d)
Increases Na pumps in distal tubule therefore more Na reabsorbed

ACE also has protective effect on kidney reduces microalbuminuria (protein loss in urine)
Angiotensin 2 receptor antagonists sometimes called blockers AIIRBs

Additionally:
Aldosterone is released from adrenal cortex mainly in response to low blood pressure

Question 26

Most Diuretics target Na+ transporters

Answer 26

Eighty-five percent of potassium is excreted by the kidneys and only fifteen percent excreted by the intestines. Although the kidneys are the organ most responsible for elimination of potassium; in the face of hypokalemia the kidneys are not efficient at conserving potassium.

Potassium losing
Thiazides eg bendrofluazide targets Na/Cl co transporter in the Distal convoluted tubule. Act within 1 – 2 hours,last for 12 – 24 hours take in the am so your not going to loo ++ at night
Taken for oedema of chronic heart failure and moderate HT
Metolozone, Indapamide
All thiazides can cause K loss

Loop diuretics act on the loop of Henle: Na K Cl cotransporter affected
Frusemide, bumetanide
Good for pulmonary oedema (relieves breathlessness, Left ventricular failure); inhibits reabsorption from ascending loop of henle – can cause hypo kalaemia and hyponatraemia

Potassium sparing
Spironolactone antagonises aldosterone (which acts on the Distal Convoluted Tubule and CT to reabsorb Na) useful in oedema caused by liver cirrhosis and primary hyperaldosteronism (Conns syndrome – one of the causes of hypernatraemia )
Amiloride blocks Na channel in the CD; can cause hyperkalaemia, and hyponatraemia

Macula densa;
a decrease in NaCl concentration at the MD will stimulate renin secretion (and vise versa)
Baroreceptors; renin secretion is stimulated by a decrease in arterial pressure sensed by a receptor in the afferent arteriole
ANF; released in response to atrial distension -
inhibits Na absorption along the CD

ADH (released when osmolality increases above 285mmol/l) opens aquaporins in DCT and CD so water is pulled out into the hypertonic tissue surrounding the tubules

Question 27

Abnormalities in bone mineral metabolism in Chronic Kidney Disease

Answer 27

During CKD, one of the main abnormalitites observed in bone mineral homeostasis/metabolism is the inadequate excretion of phosphate from the blood stream, which in turn leads to hyperphosphataemia.
Alongside this, there is insufficient hydroxylation of vitamin D, which can lead to low serum calcium levels. This in turn stimulates parathyroid hormone (PTH) to be released into the circulation, to correct the serum calcium levels. Over time, excess secretion of PTH into the blood stream leads to hyperparathyroidism.
Clinical features of hyperparathyrodism include raised serum calcium levels, and this combined with raised serum phosphate levels results in vascular and soft tissue calcification

Question 28

Aetiology and Diagnosis of anaemia

Answer 28

Erythropoietin (EPO) is essential for the maturation of erythrocytes.
Produced by peritubular cells in the cortex of the kidney.
Hb < 115g/l females
Hb < 135g/l in males
% hypochromic RBC > 10%
Ferritin < 100µg/l?
Anaemia tends to develop after GFR drops below 30ml/min
patients with DM tend to develop anaemia earlier
Symptoms: mild breathlessness (SOBOE), lethargy
Complications; cardiac enlargement (LVH), heart failure, cognitive impairment, failed menstrual cycles, impaired immune response

Question 29

Saturation of renal transport – another important concept in kidney function

Answer 29

Because much of the transport is mediated by proteins in the membrane – the transport system exhibits specificity, saturation and competition
Saturation: below saturation point transport rate of glucose is related to the substrate concentration ie glucose filtered = glucose reabsorbed (none excreted)
Above saturation point (amount filtered > 200mg/dl = 11mmol/l ) amount reabsorbed stays the same and amount excreted starts to rise

Question 30

Summary

Answer 30

The cells are not tolerant to changes in their environment, therefore mechanisms evolved to maintain composition of ECF within narrow ranges

The kidneys play an important part in regulation of homeostasis as well as producing hormones which have an impact on bone, RBC production and blood pressure