GEP (Life Maintenance) Week 4

Question 1

What are the fluid compartments divided into and how

Answer 1

60-40-20 rule:-

60% refers to the total body water content.

40% is based ontheICF making up 2/3 of thetotal body water (i.e. 40% of the overall body).

20% is based onthe ECF making up 1/3 ofthe total bodywater (i.e. 20% of the overall body).

Question 2

What minerals and ions in the compartments of

Answer 2

• The ECF itself can be subdivided into comprising ~80% interstitial fluid and ~20% plasma (there are other smaller areas of fluid such as lymph and the CSF- not your problem yet).
• The differences in composition between these two is important in preventing oedema. Crucially, the plasma contains a higher protein concentration- most notably of albumin- which maintains an oncotic pressure gradient and draws water back into the capillaries.

Potassium is themajorintracellular cation, whilst sodium is the majorextracellular cation.

Question 3

What is Tonicity and Osmolality/Osmolarity

Answer 3

• Osmolality- ‘the number of solute particles in 1kg of solvent.’
• Osmolarity- ‘the number of solute particles per 1L of solvent.’
• Tonicity- ‘a measure of the osmotic pressure gradient.’ I.e. what impact a solution will therefore have on a cell’s contents as determined by its relative osmolality.

Question 4

Describe the gross anatomy of the kidney

Answer 4

• Retroperitoneal structure found around vertebral level T12-L3 (i.e. around the level of the aortic hiatus).
• The right kidney is typically slightly lower due to the presence of the liver.

Question 5

Identify the anatomical structures and vasculatures of the kidney

Answer 5

Question 6

What is the vasculature of the kidney and how blood flows through the kidney

Answer 6

• The renal arteries arise from the abdominal aorta distal to the superior mesenteric artery. As the AA is slightly left of the midline, the right renal artery is longer.
• At the hilum, anterior and posterior divisions are formed which provide 75% and 25% of renal blood supply respectively, and from which 5 segmental arteries originate.
• The L+R renal veins leave the hilum anteriorly to the arteries and drain directly into the IVC.
• As the IVC is slightly to the right, the left renal vein is longer.

Question 7

What is the ureter, where does it arise from, and its anatomical locations

Answer 7

• Arise from the renal pelvis and descend through the abdomen, initially retroperitoneally, along the anterior surface of the psoas major muscle.
• At the sacroiliac joints, the ureters cross the pelvic brim and the bifurcation of the common iliac arteries to enter to pelvic cavity.
• Here, they travel down the lateral pelvic walls and turn to move transversely toward the bladder at the level of the ischial spine towards the bladder. This course gives rise to 3 key points of constriction where kidney stones can potentially lodge. (Origin, pelvic brim and vesico ureteric junction).
• Their proximity to pelvic structures means that there is risk of damage during pelvic surgery:-
  -The vas deferens crosses the ureters anteriorly in males.
  -The ureters are proximal to the ovaries at the pelvic brim and run underneath the uterine artery ~2cm superior to the ischial spine in females (‘’Water under the bridge’’).

Question 8

How do the kidney ascent from embryo to infant

Answer 8

• During development, the kidneys undergo an ascending retroperitoneal course from the pelvis to their ultimate destination around the lumbar region.
• As this occurs, branches of the iliac vessels and aorta continuously supply the kidneys- with these changing dependent on layer and those lower down typically atrophying.
• Excess arteries may remain present- accessory arteries.
• Accessory arteries which don’t enter through the hilum are described as aberrant.

Question 9

What structures are anatomically anterior and posterior to the left and right kidney

Answer 9

Question 10

What are the innervation of the kidney

Answer 10

• Parasympathetic from the pelvic splanchnic nerves.
• Sympathetic from lumbar splanchnic nerves.
• Lack of superficial innervation means that kidney pathology can be associated with poorly localised visceral pain of anything innervated by nerves branching at level T12-L3. As such, pain can arise at the costovertebral/renal angle- where the bottom of the ribcage meets the spine.

Question 11

What are the roles of the kidney

Answer 11

• Involved in vitD metabolsim
• Produces erythropoeitin (EPO) to stimulate RBC production
• Excretion of metabolic waster products and water
• Regulation of blood pressure
• Influence on Blood PH

Question 12

What is the functional unit of the kidney and its anatomy

Answer 12

Question 13

What are the 2 types of Nephrons

Answer 13

• You have the Juxtamedullary Nephron which make up 15% of Nephrons
  -They have long loop of henle deep in the medulla
  -The major functiopn is the concentration of urine- the long loop of henle facilitates counter-current mechansism.
  -Juxtamedullary nehrons have long vasa recta descending thier loop of henle
• You have the Cortical Nephrons which make up 85% of Nephrons
  -They have a short loop of henle deep into the medulla
  -A major function is excretion of waste products
  -Cortical nephrons ahve short pertubular cappillaries

Question 14

What is the filteration barrier and what are the components of it

Answer 14

**There are 3 components **:
1) Endothelial cells of glomerular capillaries
-Perforations (fenestrae)
-Do not restrict water, proteins, large molecules
-Prevent filtration of RBC
2) Glomerular basement membrane
-Type IV collagen, Heparan sulfate proteoglycans, lamin
-Limits intermediate/large sized soltes
3) Epithelial cells of bowma’s caosule (Podocytes)
-Specialised ‘foot-like’ Epithelial cells
-main barrier to proteins
-Negatively charged (proteins are generally anions)

Question 15

What is ultrafiltration

Answer 15

• Ultrafiltration is filtration under pressure, in this case from our glomerular capillaries to the Bowman’s capsule.
• Moderated by our afferent and efferent arteriole.

Question 16

What is GFR

Answer 16

• GFR = measure of blood being ‘cleaned’ by kidneys per minute.
• I.e. it is the amount of blood filtered from the glomerular capillaries into the Bowman’s capsule.
• GFR is impacted by different factors, but most importantly is difference in ‘tone’ of afferent and efferent.
• V. difficult to directly measure; estimations from serum creatinine used instead (eGFR).

Question 17

What is eGFR

Answer 17

• Serum creatinine is a very useful estimate of GFR.
• Creatinine is created when creatine phosphate is broken down in muscle.
• Creatinine is freely filtered by the glomerulus (but also actively secreted by peritubular capillaries).
• This means eGFR using creatinine slightly overestimates actual GFR…
  **
  Inulin**
  Gold-standard for calculating eGFR.
  100% of filtered inulin stays in the nephron lumen – none is reabsorbed or secreted after glomerular filtration.

Question 18

What occurs in the renal tubules, what its principles

Answer 18

-We want to retain most of the substance that we filter across the glomerulas
-Secretion: Unfiltered substances move from blood into renal tubule
-Reabsorption: Filtered substances in the renal tubule move back into the blood

~180L a day pass through the nephrons; want to reabsorb most of that.
Different parts of the nephron specialised for different aspects of reabsorption/secretion.

Question 19

What is the PCT (proximal convoluted tubule)

Answer 19

Has 2 layers:
* Apical membrane – faces into lumen of PCT (has microvilli brush-border)
* Basolateral membrane – faces towards bloodstream

Majority of reabsorption occurs in the PCT:
~ 65% of H2O, Na+, K+, Cl-
100% of glucose, amino acids
85-90% HCO3-

Driving force is Na+ ; wants to go into the cell.
Facilitated by Na+/K+ ATPases on the basolateral membrane – pumps 3 Na+ into interstitium (towards blood), in exchange for 2 K+.
Creates electrochemical gradient for Na+.
Lots of Na+ - linked symporters co-transports Na+ with substances from the lumen into the cell.
E.g. Sodium-Glucose linked transporter 2 (SGLT2)
Same principal as in ORT (which uses SGLT1 in the gut).
Water follows sodium (majority of water reabsorbed here).

Secretion of H+ helps maintain acid-base balance (more later on).
For 1 H+ secreted, 1 Na+ and 1 HCO3- is reabsorbed.

Question 20

What is the loop of henly, what are the different areas on it and its function

Answer 20

• Thin Descending Limb
• Thin Ascending Limb
• Thick Ascending Limb
  Work together to create Counter-current Multiplication

Question 21

What occurs in the thick ascending limb of of the loop of henle (LoH)

Answer 21

Na+ K+ 2Cl- pump (NKCC2) moves ions from lumen into the cell.

This is the site of action of loop diuretics (e.g. furosemide)

Question 22

What occurs in the Distal Convoluted Tubule (DCT)

Answer 22

• Split into ‘early’ and ‘late’ (Late v. similar to Collecting duct)
• Early DCT is impermeable to water.
• Most important aspect is Na+/Cl- transporter (NCC).
• Macula Densa cells are found here (more later).

Question 23

Describe what the late DCT and collecting duct do

Answer 23

Two main cell types: Principal Cells (majority) and Intercalated Cells.

Principal cells = eNaC to reabsorb Na+

Intercalated cells = active H+ secretion, reabsorb HCO3- (acid-base control)

Main role of Collecting Duct is to reabsorb water.
Aquaporin 2 channels
ADH increases expression of these
in apical membrane

Question 24

What is the Normal PH and how is the Acid-Base Balance kept

Answer 24

Normal pH= (7.35-7.45)
* The kidneys metabolically compensate to maintain this range. (lungs = respiratory).
* The kidneys control reabsorption of HCO3- and secretion of H+.

Question 25

How does the bicarbonate buffer system work

Answer 25

* Back to the PCT… * Main site of this system due to the CA enzyme being present. * (Small amount of BBS occurs in thick LoH)

Question 26

Describe the Ammonia and Phosphate Buffer System

Answer 26

Question 27

What is the RAAS system

Answer 27

RASS (Renin-Angiotensis-Aldosterone System) * Essential for regulation of fluid balance and blood pressure. * Fundamentally, low BP activates RAAS to increase BP.

Question 28

Where is renin released and how is it initiated.

Answer 28

* It starts with renin release from the Juxtaglomerular (JG) cells. **3 ways this is initiated:** * Reduced Na+ at DCT detected by Macula Densa cells. These secrete prostaglandins, causing JG cells to release renin. * Reduced BP detected by baroreceptors in afferent arteriole. * Sympathetic stimulation of JG cells when baroreceptors elsewhere detect reduced BP. All of these typically occur in response to low BP and cause renin release from JG cells

Question 29

What affects does the RASS system have on the body

Answer 29

Question 30

What affects does NSAIDs and Prostaglandins have on the kidney

Answer 30

Earlier we talked about the afferent and efferent arterioles moderating blood flow… Normally, our afferent arteriole is more dilated than the efferent – increases hydrostatic pressure in glomerulus. At low BP, angiotensin II constricts both afferent and efferent to maintain good kidney perfusion. Macula Densa cells will also release PGs – these preferentially dilate the afferent – helps maintain GFR. NSAIDs disrupt the compensatory vasodilation response of renal prostaglandins to vasoconstrictor hormones released by the body. Inhibition of renal prostaglandins results in acute deterioration of renal function after ingestion of NSAIDs.

Question 31

What do the NSAIDs particularlly affect

Answer 31

They inhibit cox1 and cox2, which inhibits prostagladin synthesis. Leads to: * JG cells cannot release PG at low BP Reduces renin release. Afferent is more vasoconstricted (reduced blood flow to kidney). * Hyperkalaemia, as decreased blood flow = decreased Na+ = decreased K+ exchange ## Footnote NSAIDs exacerbate effects of low fluid volume on the kidneys

Question 32

What is an acute kidney injury (AKI)

Answer 32

* ‘An acute decline in kidney function, leading to a rise in serum creatinine and/or a fall in urine output.’ Ultimately, it can present as on a spectrum from mild to severe failure as long as it shares this characterisation. So therefore defined as any of (KDIGO staging):- Increase in serum creatinine by ≥26 micromol/L (≥0.3 mg/dL) within 48 hours. Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days. Urine volume <0.5 mL/kg/hour for 6 hours Whilst the key presenting feature can be urine output, also suspect potential AKI in patients with hypotension; or known risk factors/history of kidney insults. Non-specific symptoms include nausea/vomiting, diarrhoea, dehydration, confusion and drowsiness.

Question 33

What are the different areas of AKI and the mechanism and case of it.

Answer 33

Given its association with reduced kidney perfusion, prerenal can often be identified by the clinical features of the underlying cause- for example hypovolaemic causes will see marked hypotension, cool peripheries and a low JVP. There are baseline tests which should be undertaken, after which specific investigations can then be tailored to results, signs and symptoms seen… ## Footnote Always consider history first- could there, as a completely random example, be a factor such as NSAIDs?

Question 34

What are the investigations for AKI

Answer 34

* U&E’s- creatinine, potassium, bicarb, sodium, calcium, BUN. * FBC– leucocytosis- infection/sepsis? Anaemia secondary to potential AKI causes? TCP- eg haemolytic uraemic syndrome. * CRP-infection. Blood culture- sepsis? * CXR/ECG may indicate a pre-renal cardiac aetiology-or changes associated with hyperkalaemia. * Further imaging is typically only indicated if no cause has been identified or obstructive cause specifically suspected- in which case renal tract ultrasound/CT abdo. * Urinalysis is typically key to identifying causes… *

Question 35

What is a urine dipstick test and what are you looking for and indicating

Answer 35

* Midstream clean-catch specimen ASAP and dip. * If both proteinuria and haematuria, consider intrinsic cause if no obvious indication such as catheter trauma or evidence of UTI. Can potentially indicate glomerular disease. * Urine culture if signs of UTI/haematuria, proteinuria, nitrites or leukocyturia. * Urine output (fluid balance). * Fluid challenge- positive response indicative of a pre-renal cause.

Question 36

What is urine Microscopy and how is it used to differentiate AKIs

Answer 36

* Prerenal- typically little to no signs. * Intrinsic can show epithelial cell, muddy brown or granular casts; or renal tubular epithelial cells. * Postrenal- evidence of blockage such as crystals, WBCs, RBCs, bacteria. * Casts arise from solidification of protein in the lumen of the DCT or collecting duct only. * Muddy brown casts are notably associated with one of the most common causes of AKI- acute tubular necrosis (ATN)- wherein death of the tubular epithelial cells and is diagnosed by the casts alongside FENa. Can arise from ischemia or toxicity. ## Footnote Casts= the result of protein aggregation in the tubules.

Question 37

What are the initial management of AKI

Answer 37

* Approach essentially comprises identifying and removing/managing causative factors whilst providing specific support for the AKI- diuretics in fluid overload such as pulmonary oedema; immunosuppression in nephritis; catheterisation to manage obstruction if appropriate. * Follow an appropriate care package- STOP AKI. Hypovolaemia is particularly common so immediate IV fluid resus followed by crystalloid bolus dose with close monitoring. * Hypervolaemia- typically a loop diuretic such as furosemide. * Consider whether RRT (renal replacement therapy) is necessary.

Question 38

What are the indications for Dialysis/RTT

Answer 38

* When to dialyse- severe cases of AKI- * Metabolic acidosis pH < 7.15 or worsening acidaemia * Refractory electrolyte abnormalities (hyperkalaemia >6.5mmol) * Presence of dialysable toxins (toxic alcohols, aspirin, lithium) * Refractory fluid overload (diuretic resistant fluid overload in setting of AKI) * End-organ uraemic complications (e.g. pericarditis, encephalopathy, uraemic bleeding) ## Footnote The choice of technique depends on multiple factors, including the primary need (eg, solute or water removal or both), underlying indication (eg, acute or chronic kidney failure, poisoning), vascular access, hemodynamic stability, availability, local expertise, and patient preference and capability (eg, for home dialysis)

Question 39

What are the principles of Dialysis

Answer 39

* Similarly to the LoH, utilises counter current flow to maintain concentration gradient across a semi-permeable membrane. * Dialysate pressure can be altered to increase hydrostatic pressure and therefore pressure gradient. * Composition of dialysate is dependent on blood levels, with primary aims being removal of waste products such as potassium, phosphate and urea whilst concentrations of other ions such as sodium and chloride are equivalent to that of blood to ensure these aren’t lost.

Question 40

What is peritoneal dialysis and how is it performed

Answer 40

* Follows the same principles but uses the peritoneum as the semipermeable filtration barrier. * Can be more lifestyle compatible- allow for on/off home dialysis rather than outpatient visits. * Is however associated with additional complications such as peritonitis and herniation; and is not viable in patients with ongoing/previous abdominal pathology/surgery.

Question 41

What is Haemofiltration

Answer 41

* The form of RRT used more prevalently in an acute/ICU setting. * Operates on the basis of convection as opposed to diffusion. No dialysate is used. * Larger molecules can be removed, as the process is a function of ultrafiltration and therefore pore size and molecular shape/size. For example, inflammatory mediators in septic patients. * Consider the process similar to that which occurs at the glomerulus/Bowman’s capsule.