MET2 Revision7 Flashcards
What are the two pathways of allorecognition?
Direct:
* Recipient T-cells recognise allogenic APC (donor APCs) and cause aggressive imune response to foreign HLA
Indirect:
* The allogenic APCs are replaced with auto-APCs
* Some of the peptides presented by new auto-APCS are derived from shed HLA molecules
* Causes a more gentle immune response
What are the sites of action used for immunosuppressive drugs? [3] and what drugs used?
Calcineurin inhibitors:
* Calcineurin is an enzyme that activates T-cells of the immune system.
* E.g. Cyclosporin and tacrolimus (learn !)
Anti-proliferative drugs:
* (target nucleus at end stage of T cell activation)
* e.g. Azathioprine and Mycophenolic acid
Prevent cytokine (IL-2) gene activation
* Use cortiosteroids
* e.g. Prednisolone
Standard treatment: Calcineurin inhib, steroid and anti-proliferative drugs
KEY In: Male and female [] ducts form embryonic and parts of adult kidney
In: Male and female mesonephric ducts form embryonic and parts of adult kidney
Explain how can you prevent acute rejection of transplants? [2]
HLA matching (make sure that not positive for match)
Minimising ischaemia-reperfusion injury:
- Ischaemia causes upregulation of adhesion molecules, which increases adhesion of leukocytes when blood is reperfused.
- More leukocytes increases chance of rejection, SO try and limit ischaemia time.
- Cold ischaemia time: 12 hrs
- Warm ishaemia time: 1 hour
Explain how activation of a helper T cell / CD4 cell occurs [3]
- T helper cell receptor recognising antigen from HLA
- Co-stimulation from another molecule
Both these signals activate nucleus to make IL-2.
IL-2 binds to IL-2 receptor on different T helper cell. [3]
Causes signal at nucleus to make proliferation of T-helper cells
In the embryo, 3 kidneys form:
pronephric, mesonepheric and metanepheric kidneys.
Two are non functional and dissapear
One is functional and remains - Which?
Metanephric kidney
Metanephric kidney develops from [] duct
Metanephric kidney develops from Mesonephric duct
How does the metanephric kidney develops from which two structures? [2]
How? [1]
Uteric bud and fuses with mesenchyme (metanephric bud). Mesenchyme elongates and fuses to collecting tubules to make the excretory system.
Bifurciates to make major calyx.
Bifucates again to make minor calyx
Bifucates x lots to make
During renal development:
- the uteric bud becomes which overall part of kidney?
- the metanephric system becomes which overall part of kidney?
Uteric bud: collecting system (ureter, renal pelvis, major and minor calyxes, CD)
metanephric system: excretory system (Renal glomerulus -capillaries
Bowman’s capsule. PCT
LoH, DCT)
Describe the ascent of the kidneys during development:
Where do they start from? [1]
Where do they finish? [1]
(Include vert levels)
Describe the ascent of the kidneys during development:
Where do they start from? [1]
Sacral region S1
Where do they finish? [1]
Lumbar region T12
(Include vert levels)
Why wont babies survive bilateral kidney agenesis? [2]
If kidneys dont develop then effects creation of amniotic fluid (reduced: oligohydramnios)
This causes failure of lung development
What are two types of ectopic kidney? [2]
Pancake kidney: Usually (one) kidney remains in pelvic region
Horseshoe kidney: kidneys fuse in pelvice region and form a single U. Can’t ascend because of IMA
Describe pathophysiology of autosomal dominant polycystic kidney disease
How do cysts grow? [4]
Mutation on polycystin gene: involved in production in primary cilia (ciliopathy)
Primary cilia involved in cell adhesion, calcium transport and cell cycle.
Cysts growth:
- Cysts originates as dilations of intact tubule
- Increased proliferation of cyst epithelium
- Cyst epithelium becomes secretory resulting in increased fluid secretion into lumen of cyst
- Cyst enlarges and loses contact with nephron
Define GFR
GFR = Clearance of substance
Total amount of fluid that is filtered through the glomerulus
What is creatinine a breakdown product of? [1]
creatine phosphate: found in muscle
Found at a steady-state concentration in the blood
What are 4 disadvantages of using creatinine to eGFR? [3]
using creatinine to estimate GFR underestiamtes GFR by 10-20%
underestimated in black ethnicities
malnourished patients have low muscle mass so overestimates eGFR
muscular individuals have raised muscle mass so underestimates GFR
How is creatinine clearance measured?
Cr Clearance = ( [U] / [P] ) x Volume
(Urine conc / plasma conc) x volume of urine
Which variables are used for MDRD equation to measure clearance? [4]
Need:
Cretinine
Age
Gender
Ethnicity
Explain the MoA of Kidney absorption
Reduce volume of water and solutes within urine but without changing the concentration: make a hypertonic medulla
MoA:
At thin descending loop
* Water pumped out via aquaporins due to increased osmolality produced by thick ascending limb pumping out Na+
At thick ascending limb
* Na is actively pumped into medullary space via Na/K channel
* Paracellular transport of Na, Ca and Mg down a electrochemical gradient
* This wall is impermeable to water.
At distal convoluted tubule:
* Aldosterone works to increase Na absorption
At collecting duct:
- ADH opens aquaporins to reabsorb more water
- Fluid passes down from here to ureter and ladders
ADH acts via which receptor to cause aquaporin insertion? [1]
ADH acts via V2 receptor to cause aquaporin 2 insertion and fluid movement from collecting duct to intersitium down osmotic gradient.
What plasma concentration of glucose exceeds renal threshold, so glycosuria occurs / glucose threshold?
At a plasma glucose level of about 10 mmol/L
`Label the class of drugs found at A, B & C [3]
A: Carbonic anhydrase inhibitors
B: Loop diuretics
C: Thiazides
Name and explain which transport protein in the thick ascending loop of Henle assists NaKCl2 transporter
Renal Outer Medullary potassium channel or ROMK
- K is AT pumped into the tubular lumen / urine to generate positive voltage within the cell (because less K+ in)
- This creates an overall voltage gradient of +80mV; from +10mV in the tubular lumen to -70mV in the tubular cell
- This voltage difference drives Na into the tubular cell via NaKCl2 transporter
Which transporter do thiazide diuretics inhibit? [1]
Where is this transporter located? [1]
Block Na+/Cl− cotransporter at distal convoluted tubules
which arteries supply the kidneys?
from what origins?
what vertebral level found?
renal arteries
- L1-L2 level
- come from thoracic aorta
- lie inferior to superior mesenteric artery
what other function do macula dense cells do ? / what do they produce?
The macula densa cells also tonically produce prostaglandin PGE2
which acts on juxtaglomerular cells to stimulate renin release
low sodium levels = More prostaglandin = more renin
what does clearance of PAH (para-amin-hippuric acid) measure?
Clearance of PAH (para-amin-hippuric acid) measures renal plasma flow (RPF) because all PAH is secreted into blood, therefore all blood passing through kidney is ‘cleared’ of PAH.
what is the location, function and mechanism of action for the NKCC2 channels?
NKCC2 (Na-K-Cl cotransporter channel
- location: thick ascending limb of the loop of Henle
- function: to get Na / Cl out of the ascending limb and into extracellular fluid
-
mechanism of action:
i) luminal walls of the epithelial cells allows sodium, potassium & chloride ions to move passively together down their concentration gradient into the cells that make thick ascending limb
ii) then, sodium is actively transported out into extracellular space by Na/K ATP-ase
iii) Cl- moves passively with the sodium
iv) most of K+ ions diffuse back into the lumen via K ion channels
https://www.youtube.com/watch?v=sapTNUtrPdY
what would happen if you blocked NKCC2, Cl- or K+ channels in ascending loop of Henle??
- leads to reduction of Na / Cl reabsorbtion
- decreases **interstitial osmolality
- get less waterereabsorbtion** in descending limb of Loop of Henle
- causes an increased excretion of water = diuresis
Diuresis is a condition in which the kidneys filter too much bodily fluid. That increases your urine production and the frequency with which you need to use the bathroom.
which pump assists the NKCC2 pump?
explain how xix
Renal Outer Medullary potassium channel or ROMK (royal orders make knights)
- K+ out of the tubule cells into the lumen (where fluid is)
- generates postive voltage: 10mV in tubular lumen
- creates an overall voltage difference of 80mV between tubular lumen and tubular cell
- this voltage difference helps propel sodium via NCKK2 transporter into tubular cells
Furosemide:
indications?
MoA?
_Furosemide removes excess water in the body
indications:_
- oedema
- resistant hypertension
mechanism of action:
- blocks the transport of sodium (and chloride) out of the loop of Henle and into interstitial fluid of medulla
- causes a lower concentration of sodium & other solutes in interstial fluid
- SO, less water is reabsorbed in descending loop of Henle (remember, water follows Na)
- means Na, & water is kept in the urine: prevents reabsorbtion of 20% Na & 15% H20
- SO, more water excreted
* furosemide, and other loop, diuretics act independently of ADH *
where in body are cells that detect stretch - and what does this cause a release of?
Specialised muscle cells: right atrium and inferior vena cava.
In response to stretch (indicating increased preload) these cells release atrial natriuretic peptide (ANP)
Name 2 sreening methods used (by Bart’s Health Trust) for nutritional screening for adults [1] and children [1]?
MUST (adults) and STAMP (paedatrics - Screening Tool for the Assessment of Malnutrition in Paediatrics)
How often should you repeat MUST assessment? [1]
weekly
How would you calculate a MUST score? [3]
How do you work out an Action Plan for MUST? [1]
MUST:
1. BMI
2. Weight Loss
3. Acute disease effect
4. Add scores for 1-3
5. Action Plan
Whats important to think when assessing malnutrition? [1]
Often missed in overweight patient (high BMI would be scored agaisnt in MUST)
What is a surrogate measure for measuring weight? [1]
Mid upper arm circumference (MUAC) [1] (can measure in supine position)
If MUAC is less than [], BMI is likely to be underweight (<20 kg/m2)
If MUAC IS over [], BMI is likely to be overweight ( >30 kg/m2)
.
If MUAC is under 23.5, BMI is likely to be under 20 (underweight)
If MUAC IS >32, BMI is likely to be >30 (overweight)
What does Handgrip Dynamometry (HGD) or Grip Strength measure? [1]
How do you take? [3]
Measures muscle strength & endurance: predictor of mortatility
Can be measured
* -supine or sitting position
* -dominant or non-dominant side
* -repeated measures to mirror original position
It is a widely held belief that low albumin arises because of inadequate protein intake.
Explain what causes Hypoalbuminaemia in hospital? [2]
Cause in hospital: is inflammation and sepsis:
- increased C-Reactive Protein
- White Cell Count
- pyrexia
- infection
In these patients capillary walls become more ‘porous’ and albumin drifts out –> low plasma albumin
Low albumin often occurs in sick, malnourished patients, but it is not caused by poor intake
Describe changes that occur when refeeding occurs in refeeding sydrome
What do you become reduced in? [4]
Metabolism changes from fatty acids to carbohydrates
Raised insulin secretion
Insulin stimulates K+, P04-, Mg2+ to return to cells
∴ intracellular stores are replenished but at the expense of plasma concentrations.
See:
* Hypokalaemia
* Hypomagenesiumia
* Hypopohopshataemia
* Thiamine deficiency
Which Ptx are at risk of refeeding syndrome? [1]
Which Ptx are at high risk of refeeding syndrome? [4]
Which Ptx are at very high risk of refeeding syndrome? [4]
Risk
* Any ptx with very little food for more than 5 days
High risk
ONE OF:
Any one the following;
* BMI less than 16
* Unintentional weight loss >15% in last 3-6 months
* Little or no nutritional intake for more than 10 days
* Low levels of K, PO, Mg prior to feeding
Very high risk
TWO OF THE FOLLOWING:
* BMI less than 18.5
* Unintentional weight loss >10% in last 3-6 months
* Little or no nutrition for more than 5 days
* A history of alcohol abuse or drug use including chemotherapy, antacids or diuretics
How can you provide nutritional support from supplemental drinks? [3]
Milkshake style
* Calorie content varies
* Ready made
Juice based
* Fat free
Powdered
* Not nutritionally complete
* Is the patient able to mix it
What nutritonal supplements could you provide for ptx with dysphagia? [5]
- Pre-thickened drinks
- Thickening of supplement drinks with a thickener
- Yoghurt style drinks
- Smoothie style drinks
- Yoghurt/dessert pot type supplements
What are the three types of immunological rejection? [3] xx
Hyperacute: minutes to hours
Acute: one to six weeks
Chronic: months to years
(Defined on basis of time to occurrence)
What are two mechanisms that acute rejection occurs?
Acute rejection can be either via:
Acute Cellular Rejection (ACR)
- Cytotoxic T lymphocyte response
- Macrophage response
OR
Acute Antibody Mediated Response (AMR)
- B lymphocyte response making antibodies (agaisnt MHC Class 1 /2 antigens or ABO blood group antigens)
Antibody-mediated rejection (AMR):
What are the main antigens targets of antibodies? [3]
Where does this mainly occur? [1]
Antibody targets:
* MHC (Class I & II): HLA antigens:
* ABO antigens
* MHC class I-related chain A (MICA)
Target location: endothelium - targets arteries and capillaries (because these are the cells first meet after transplantation)
With regards to acute rejection of transplants, how would you detect antibody prescence?
Detect antibody presence with complement: C4d
- The antibody-antigen complex activates the compliment system
- This produces C4d molecules (which forms covalent bonds with endothelial cells)
- C4d molecules are stained easily
- This shows that acute rejection has occurred
Staining for C4d is a very good proxy for detecting antibodies
Acute antibody mediated transplatn rejecton:
there is a very good correlation between high [] levels and [] antibodies.
there is a very good correlation between high C4d levels and donor specific antibodies.
What is criteria for diagnosis of acute antibody rejection? [3]
Evidence of acute renal injury on histology (often microvascular inflammation)
Evidence of antibody activity C4d staining in peritubular capillaries
Circulating anti-donor specific antibodies
Explain how AMR causes damage in hyperacute rejection
change from anti-coagulant to pro-coagulant state:
- antibodies bind to surface of epithelial cells: become pro-coagulant and clots form
- causes downstream infarction
- causes haem.
Summary of hyperacute rejection:
Within 1 hr you get [] infiltrate of peritubular capillaries
Within 12-24 hrs you get what effects? [2]
Within 1 hr you get neutrophils infiltrate of peritubular capillaries
Within 12-24 hrs you get intravascular coagulation and cortical necrosis
How can we prevent hyperacute rejection? [3]
- Use somone who is ABO compatabile (O is universal donor)
-
screen for preformed antibodies:
* Direct cross match: mix donor cells and recipient serum. Look for complement activation (positive is bad)
* Beads with bound HLA: look to see if recipient serum binds to HLA beads
What are the most important HLAs? [3]
HLA A
HLA B
HLA DR
Each have two genes
What kidney pathology is depicted? [1]
Pancake kidney
What kidney pathology is depicted? [1]
Pancake kidney
What kidney pathology is depicted? [1]
Horseshoe kidney
What kidney pathology is depicted? [1]
Polycystic kidney disease
Name the gene that has a defect to cause this pathology [1]
Polycystin gene
Abdominal CT showing []
Abdominal CT showing polycystic kidneys
Label A & B of developing kidneys
A: mesonephric bud
B: uteric bud
What type of renal pathology is depicted here?
IgA neuropathy
Membrane change disease
Glomerulonephritis
Acute rejection from kidney transplant
What type of renal pathology is depicted here?
IgA neuropathy
Membrane change disease
Glomerulonephritis
Acute rejection from kidney transplant
Focal glomerulitis in active antibody mediated rejection-Banff score g3. Dilated glomerular capillaries are filled with swollen endothelial cells and inflammatory cells (PAS, 200×).
Describe what pathology is occuring at the arrow heads in this renal artery
Inflammatory cells (arrows) infiltrate the intima in intimal
arteritis, due to acute cell mediated rejection
