Case 9 Flashcards
whats the prevalence of people with diabetes will go on to develop diabetic nephropathy? what can you do about this?
20%
if spotted early enough, it can be slowed down with treatment
What causes kidney disease? In diabetic nephropathy
High blood glucose levels damage the small blood vessels and tiny filters in your kidney.
High blood pressure also does this.
This causes the kidney to leak and then abnormal amount of protein can leave the body in your urine.
What are the signs and symptoms of kidney disease ?
what may cause them?
- Swollen ankles, feet and hands
- Hameaturia
- lethargic
- shortness of breath
- feeling sick
this may be because your kidneys are struggling to clear extra fluid and waste from the body. However, it can also be caused by other conditions
Are all symptoms of kidney disease visible ?
No, that’s why you need tests every year so that it cn be spotted early and slowed down with treatment
How can you reduce your risk of kidney disease?
- Keep blood sugar levels within target range
- Keep blood pressure down
- Get support to stop smoking
- eat healthily and keep active
- go to all your medical appointment
What are the 2 tests for kidney disease included in your annual review?
Urine test (ACR)
Blood test (eGFR)
Part of your 15 healthcare essentials you should have both tests for kidney disease every year
What does the urine test (ACR) look for?
Albumin: creatinine ratio looks for signs that protein is leaking into the urine.
This is often an early sign of kidney disease.
Describe the relevant details of the blood test (eGFR)
It tests for the wate product creatinine.
Creatinine levels and other info like age, sex and ethnicity are used to estimate you GFR.
Your GFR is a measure of how well your kidneys are working.
What are the treatments for kidney disease?
It all depends on what stage you are in the kidney disease.
ACE inhibitors and ARBs are used to lower BP, hence can protect the kidney from further damage.
Advice on what food to eat will help a lot. Change in diet is essentiak
If it gets to late stage kidney disease, you may need dialysis or kidney transplant. However theses are rare with new technology and early detection.
Where can you get support and more info for kidney disease as a pt
- Your diabetes team - they’ll answer most of your questions
- A helpline call is available if you just want someone to listen to. They are highly skilled and have an extensive knowledge of diabetes.
- National kidney federation -
- British Kidney patient association- offers telephone counselling
- Kidney research UK - future and current research for kidney disease
What are the 3 compoents of the filtraiton barrier of the glomerurlus
- Endothelial of glomerular capillaries
- Glomerular basement membrane
- Epithelial cells of bowman’s capsule- podocytes
Descirbe the structure of the endothelial cells of glomerulus. Link it to their functions?
Has many 70nm sized fenestrae- they limit filtration of cellular components like RBCs.
It has glycocalyx that surrounds the luminal side of endothelial cells- they hinder diffusion of negatively charged particles.
Glycocalyx is made up of negatively charged GAGs
Describe the structure and function of the glomerular basment membrane
It surrounds the endotheliuem.
It’s made up of type 4 collagen, heparan sulfate proteoglycans and lamina.
The heparan sulfate proteoglycan restrict movement of negatively charged molecules across the basement membrane.
The basement membrane consists of 3 layers
What is the function of the 3 layers of the basment membrane and what are they?
The layers are:
- inner thin layer (lamina rara interna)
- A thick layer (lamina densa)
- an outer dense layer (lamina rara externa)
these layers help to limit filtration of intermediate to large sized solutes
What are podocytes and what features help them in ultrafiltration?
They are speicalised epithelial cells of bowman’s capsule which form the visceral layer of the capsule.
Foot like processes project from these podocytes and interdigitate to form filtration slits.
The filtration slits are bridged by the slit diaphragm.
The slit diaphragm has ver small pores preventing large molecules from crossing.
Podocytes have negatively charged glycoprotein covering it- they restrict filtration of large anions.
Describe the relationship between filtration rate and characteristics of molecules
The filtration rate is inversely proportional to the size of the molecules (molecular weight).
Glcuose (180Da) will easily cross the barrier than albumin (69kDa).
Negatively charged molecules are less easily filtered than positively charged molecules of the same size
What are the signs and symptoms of Alpert syndrome and what mutation causes it ?
Genetic disease that is usually inherited via X-linked.
There are mutations in gene coding fo the a5 chain of type 4 collagen.
This is a chronic kidney disease with symptoms like:
- haematuria
- sensorineural deafness
- ocular abnormalities
Descirbe the effects of the mutation that leads to Alpert syndrome and discuss the management options for this disease
This mutation results in thinning of the lamina densa of GBM with areas of multi-layering producing a basket weave appearance.
There’s no definitive treatment but ACE inhibitors are given to help reduce proteinuria and progression of renal disease.
ACE inhibitors also control hypertension
In later stages of Alport syndrome, what occurs
- Glomerulosclerosis
- Interstitial fibrosis
- Tubular atrophy
What is minimal change glomerulonephtirs
This is resposnible for 10-25% of nephrotic syndrome.
No visible change under rlight microsope but electron microsope shows changes in glomeruli
There’s diffuse effacement of foot process of podocytes - in which there’s widening of filtration slits.
Microvillus change seen on the podocytes.
What is thought to be the cause of minimal change glomerulonephritis ?
Considered idiopathic.
However, it is thought to be due to a T-cell derived factor
Describe the management of minimal change glomerulonephritis and how pts respond to it.
Steroid therapy - Most pts respond well to steroids but symptoms may relapse if they come off steroid therapy.
Some pts become come steroid dependent but most of them do not progress to chronic renal failure.
The steroid dpeepdnent pts that progress to chronic renal failure usually have focal segmental glomeruloscelosis as well .
What are the common symptoms of nephrotic symptoms ?
- Proteinuria
- hypoalbuminaemia
- oedema
What molecule inhibits renin secretion. When and where is the molecule made ?
Atrial natriuretic peptide (ANP).
it is released by stretched atria in response to increased blood pressure
Where is ACE made?
Ang-1 is converted to Ang-2 in lungs where most if the ACE is made.
ACE is made in the vascular endothelial cells of lungs
although a little is generated within the renal endothelium ?
Ang-2 binds to 2 recpetors. What are they and in what majority ?
AT-1 and AT-2 receptors.
They are GPCRs. they bind to one of the 2 GPCRs
Most actions occur via AT1
What are the main sites and actions of Ang-2 around the body ?
Explain the cardiovascular effects of Ang-2. Describe the mechanisms?
Ang-2 binds to AT1 on the endothelium of arterioles through out circulation to cause vasoconstriction.
the signallingpathwya involved is via Gq receptors in which PLC and subsequently intracellular Ca2+ is made.
The net effect of this is increase in TPR and hence increase in BP
Describe and explain the effects of Ang-2 on hypothalamus
Acts as hypothalamus to stimulate thirst sensation and hence increase volume consumption.
This can also lead to secretion of ADH from neurohypophysis.
Higher concentration of urine made and less fluid lost from urination.
this maiantains circulating volume
How does the Ang 2 affects the autonomic nervous system (neural effects)?
Acts on hypothalamus to stimulate the sympathetic nervous system.
there’s release of NA and hence can activate RAAS and:
- increased cardiac output
- vasoconstriction of arterioles
- rel;ease of renin
What are the renal effects of Ang-2?
Afferent and efferent arteriole constriction.
Increased Na+ Reabsorption in PCT
What mechanism is Ang-2 important in which maintain a stable GFR? What other mechanism is vital to this process?
Tubuloglomerular feedback mechanism
The local release of prostaglandins which result in preferential vasodilation to the afferent arteriole in the glomerulus is also vital to Tubuloglomerular feedback
What is the action and mechanism of Ang 2 in these 2 targets?
Renal artery and afferent arteriole
efferent arteriole
Describe the action and mechanism of Ang 2 in these 2 targets:
- Mesangial cells
- PCT
Where does aldosterone act and describe the effects in the body ?
Act on principal cells of DCT and collecting duct .
effect: increase serum Na and decrease serum K and H
*revise endo and cardio and renal
Summarise RAAS
Give examples of ACE inhibitor and they are used for treatment of what disease?
E.g are ramipril, lisinopril and enalapril
used in treatment of hypertension and heart failure
What are the physiological effects of ACE inhibitors
- Decrease arteriolar resistance
- decreased arteriolar vasoconstriction
- Decrease cardiac output
- Reduced potassium excreiton in kidneys
these actions help to lower BP in hypertensive pts and improve outcomes in conditons such as heart failure
What are the typical side effects of ACE inhibitors ?
- Dry cough
- hyperkalaemia
- headache
- dizziness
- fatigue
- renal impairment
- RARELY angioedema
what are the 2 most important prognostic factor in chronic kidney disease ?
Hypertension
Proteinuria
What kidney diseases can ACE inhibtors be used to manage ? Why?
Diabetic nephropathy and other forms of chronic renal impairment.
This is becuase they both reduce systemic blood pressure and reduce urinary protein excretion
Describe the mechanism in which ACE inhibitor can reduce proteniuria ?
It is liely related to inhibition of the prefenrtial vasoconstriciton that occurs in the efferent arteriole in the glomerulus.
this reduces GFR and hecne reducing urinary protein excretion
In what pts must ACE inhibtor be used wiht caution? Why?
Those with:
- bilateral renal artery stenosis
- acute kidney injury
This is becuase the reduction in GFR can pronounced and be harmful to them
what are the 2 parameters the GP used to indicate the concern of Mr Stanworth kidney function?
- Proteinuria - quite leaky urine
- High serum creatinine - which shows a fall in GFR
Describe the 4 processes that substances undergo in the kidney ?
- Filtration
- Reabsorption
- Secretion
- excretion
Describe the relevant features of secretion process
Occurs via tubular cells
They secrete drugs and ions like hydrogen according to need
Descirbe the relevant features of reabsorption process
In PCT, epithelial cells carry this out by active transport and diffusion. glucose and amino Acids are reabsorbed
in DCT, electrolytes and water are reabsorbed accoding to the body’s need. there’s hormone signalling
Describe filtration and what substances can pass through glomerulus
Molecules are filtered according to size and charge.
cells and large proteins can’t pass through. Filtration pressure also affects rate of filtration
Describe the process of how proteins can be processed in the kidney.
Small proteins are filtered. Medium are filtered sometimes and large proteins doesn’t cross the filtration barrier at all.
All proteins are reabsorbed in PCT via endocytosis- proteins are taken up into cells and it is hydrolysed into amino acids and it crossed the basolateral membrane into the blood.
The process can be saturated but in healthy conditions, all proteins are reabsorbed
What are the 3 classification of proteinuria
- Overflow
- glomerular
- tubular
What are the most common causes of CKD in the western world
- Diabetes
- Hypertension
- glomerulonephritis
the other 2 in the list are important so learn it but the 3 above are the most common
Descirbe the course of CKD regardless of aetiology ?
When one nephron is damaged, nothing happens. However when half of nephrons are damaged ,
the remaiiang healthy ones undergo adaptive hyperfiltraiton.
Blood is shunted from damaged nephrons to working ones- this will maintain the normal filtration rate and capability of plasma
Overtime there’s too much pressure on capillaries and leads to ischaemia and leds to loss of filtration and nephron loss.
This shows that regardless of aetiology of kidney damage, when half of nephron is lost, the kidney disease progress in a similar manner
What is the best way for monitor/screen for proteinuria in diabetes
Albumin:creatinine concentration .
This uses a single urine sample. It uses creatinine to correct the amount of albumin that should be there.
There are other tests that aren’t very useful for screening for proteinuria in diabetes . What are they? And describe why they aren’t useful.
PCR: only used to monitor protein loss in those without diabetes and with higher levels of proteinuria
Also PCR may be used if ACR can’t be done.
What is microalbuminuria /moderate albuminria and descirbe what it predicts
When theres 30-300mg of albumin in urine per day.
it is a predictor of kidney disease and an indicator of vascular health
Albumin loss is a predictor of cardiovascular mortality in type 1 and 2 diabetes
if blood vessles in kidneys are changed due to diabetic nephropathy , then chances are, other parts of the body are changing also . Ie. Shows the health of systemic endothelium
What is Macroalbuminuria ?
More than 300mg of albumin lost a day
Does the urine dipstick always show moderate albuminuria
No, can have false negatives
How do you estimate GFR normally?
Using creatinine clearance.
An evidence based formula that uses serum creatinine is used,
This can be calculated using the MDRD formula (modification of diet in renal disease).
Serum creatinine is more practical to calculate and analyse than urine sample .
What stage of CKD was Mr stanworth in?
G2A2
it is better to check and screen early in order to try and prevent further deterioration.
*learn diagram and it’s meaning*
How does having having an acute kidney disease affect the reliability of the serum creatinine ?
In an acute scenario, things are rapidly changing. The fall in GFR doesn’t match with the rise in serum creatinine.
Serum creatinine starts to rise 2 days after the fall in GFR.
What are the consequence of CKD
Decreased excretion of : urea, potassium, water, sodium, hydrogen ions and phosphate.
Decreased biosynthesis of erythropoietin and calcitriol
Altered metabolism of lipids and sex hormones
Descirbe the consequences of altered metabolism of lipids and sex hormones . And also explain what causes it
It’s complex and multifactorial
Also all pt with diabetic nephropathy should be on statins
What conclusions can you make From the image and graph below
- At the start there’s a slight increase (1st year)- due to being put on drugs like ramipril. Eventually and inevitably eGFR will fall.
- Mr stanworth is in th dark blue line and there’s not that much difference in the rate of decrease of eGFR b/w normoalbuminuria and moderate albuminuria.
- The blue lines must’ve had the albuminuria for 3 months before diagnosis
- those with severe albuminuria declined a lot faster than others (cross stage 3b barrier 3 yrs before others).
- it didnt show how quickly the deterioration will be without treatment.
- CKD causes mortality and risk of hospitality increases as GFR declines
What is the earliest identifying factor for those with CKD?
what can you do to help slow the rate of GFR decline ?
Moderate albuminuria - early recognition is key
reducing the following will help to slow the rate of GFR decline:
- hypertension
- hyperglycaemia
- dyslipidaemia
Educate, engage and empower mr stanworth in order to manage his treatment efficiently
Explain how secondary hyperparathyroidism occurs in CKD, and describe what disease that could lead to?
Low Vit D biosynthesis and phosphate retention ultimately reduces serum calcium levels.
There’s also high serum phosphate levels.
All these stimulate parathyroid gland to make PTH (still need stimulation to make it ) to try and correct the imbalances.
Secondary hyperparathyroidism leads osteitis fibrosa
*learn diagram*
Explain the role of FGF23 in CKD?
A hormone that is made by bone and acts on kidneys. It is elevated in CKD for unknown reasons.
it is responsible for phosphate balance by:
- Decreases reabsorption of phosphate ions in kidney and hence increases it’s secretion and excretion. it tries to decrease serum phosphate levels.
- it reduces calcitriol synthesis (reduced renal mass and high phosphate levels also do this)
The activity of FGF23 coupled with prolonged secondary hyperparathyroidism processes all causes the parathyroid gland to act autonomously.
this leads to tertiary hyperparathyroidism
Explain how tertiary hyperparathyroidism emerges in CKD
There is prolonged secondary hyperparathyroidism. The increased blood phosphate levels causes hyperplasia of chief cells of parathyroid gland.
The hyper plastic parathyroid gland now have less Vit D and FGF23 receptors. Also there’s reduced calcium sensitivity of the parathyroid gland and this leads to continued PTH release even in the presence of hypercalcaemia
How does renal osteodystrophy arise in CKD
There’s Hypocalcaemia due to low Vit D made and more phosphate retention.
there’s hyperparathyroidism seocndary to high phosphate levels
there’s also uraemia related phosphate retention
What big 6 things can you do to manage your kidney in early stage kidney disease
- Stop smoking
- stop alcohol
- exercise regular
- eat healthily
- Keep you blood pressure down and you may need tablets
- Keep diabetes under control is your diabetic
the medical team can help you achieve this by offering advice and services if possible.
This is very relevant for Mr Stanworth
Why is creatinine used as the comparison molecule in urine ACR
Serum creaitnine doesn’t change that much if GFR decreases a lot.
Hence very useful in comparing with albumin in urine
