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 is the most common protein found in urine. Give it’s significant properties and any other relevant features of how it’s found in urine
It’s called uromodulin (THP).
It is secreted from urogenital tract and not fully reabsorbed in kidney.
it is secreted in normal conditions and it is thought to have antimicrobial properties
around (less than 150mg) of uromodulin (around 70mg) is excreted in urine per day
What are the 3 classification of proteinuria
- Overflow
- glomerular
- tubular
Explain the process of overflow proteinuria and give an example of a disease.
There’s excess of low molecular weight protein and they cross the filtration barrier easily.
The tubule is saturated and hence not all is reabdorbed.
An example of a disease is Rhabdomyolysis
Explain the pathophysiology of Rhabdomyolysis and how does it lead to overflow proteinuria
Excess breakdown of skeletal muscle cells
Triggers for this are:
- trauma
- certain toxins
- intense exercise
this can lead to myoglobin (toxic to kidney tubulars cells) in the kidney
Haemoglobin can also be found in urine due to this disease. This arise due to rapid intravascular hameolyisis
What is glomerular proteinuria and what could cause this?
Glomerulus is damaged and larger proteins can cross through barrier. This will oversaturated the tubules and will be found in urine.
Things causing glomerular proteinuria is:
- drugs
- certain infections
- cancers
- diabtetic nephropathy
What is primary glomerulopathy ?
When the problem is Intrinsic to the glomerulus
What is the most abundant protein in the urine as a result of glomerular proteinuria. Give relevant details of this protein
Albumin
ellipsoid shape - intermediate size protein that is normally the same size of a glomerular pores.
Under normal conditions it isn’t filtered as much- but sometimes its filtered but reabsorbed
Explain the mechanism of tubular proteinuria and give a an example of a disease.
Damaged tubules so can’t reabsorbe filtered proteins as much.
e.g. of a disease is Acute tubulointerstitial nephritis - a disease of the kidney outside the glomerulus
Tubulointerstitial nephritis can be acute or chronic.
Acute is normally as a result of nephrotoxic drugs
What are the common stuff in hospital injury that can cause acute kidney disease?
what demographic are more likely to be affected by this more ?
- NSAIDS
- ACE inhibitor
- Aminoglycoside - like gentamicin
- Contrast agents
- Penicillin based antibiotics
- chemotherapy agents like cisplatin
those with CKD are more likely to have acute kidney injury caused by this drugs. However, normal people can still be affected.
Hence those taking these drugs in hospital needs monitoring
What mechanism leads to the most protein loss?
Glomerular proteinuria
anything lower could be overflow or ATN
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.
Why do we look for proteinuria for those with diabetes?
- To look for CVD risk, if there’s proteinuria you can assume that there’s probably vascula disease in the rest of the body.
- it allows us to try and and halt the damage in someone with early proteinuria
- Proteinuria is often seen before any other signs of damage and can predict those that are more likely to progress to CKD.
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
How ca you diagnose CKD from microalbuminuria
You need to have moderate albuminruia for 3 months in order to diagnose CKD.
What is Macroalbuminuria ?
More than 300mg of albumin lost a day
Does the urine dipstick always show moderate albuminuria
No, can have false negatives
What is GFR and what does a fall in it signify
The volume of fluid filtered out of glomerulus into bowman’s capsule per unit time. It can be estimated using creatinine clearance
A reduction in GFR is characteristic of kidney failure - they lack capacity to do their function
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 are the properties of creatinine that allows it to be used to estimate GFR ?
Freely filtered
Neither reabsorbed nor secreted =.
N.b. Some of creatinine is secreted. 10-15% of excreted creatinine is from secretions
What is the gold standard test for GFR calculation ? Explain the features and when should you use this test?
Using isotopic method using chromium EDTA.
it’s a radioactive trace and is administered and monitored intravenously.
serum concentrations are measured sequentially to calculate the clearance.
it should be used in cases where creatinine based GFR aren’t reliable
What factors does the MDRD formula take into consideration when calculating GFR ? why?
- Age
- Ethnicity
- gender
- serum creatinine concentration
all these factors are important as they affect muscle mass. And higher muscle mass increases normal serum creatinine.
If it isnt taken into consideration, then a young black male may be mistaken to have a low GFR; serum creaitnine on it’s own will be higher.
Also an old white lady may be considered to be fine even if she has a kidney disease.
The point is not everyone has a base creatinine concentration and depending on race, gender and age, it chnages. The formula accounts for that when it’s calculating the GFR.
What are the sources of creatinine ?
95%- creatine from muscle
the rest is from dietary proteins which have amino acids that are creaitnine precursors
In what demographic should we be cautious when using the MDRD formla to estimate GFR
- Amputees
- body builders
- people taking creaitnine supplement
- those with malnutrition
- muscle wasting disease
if you’re worried about the reliability then use the isotopic GFR test.
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*
What are the markers of CKD?
- Albuminuria
- Electrolyte abnormalities - if they have tubulointerstitial nephritis
- Abnormalities on histology if biopsies were taken
- Structural abnormalities seen in imaging
- if there’s a history of kidney transplant
remember is there’s moderate albuminuria in first test then he must be re-tested in 3 months time to confirm CKD diagnosis
What physiological states affect the reliability of serum creaitnine ?
Acute kidney disease
Pregnancy
Patient on dialysis with end stage renal failure
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.
In a pt with acute kidney disease, what are the other factors in an unwell patient that can affect creaitnine levels ?
- Trauma- loss of blood and lead to muscle wasting. This will reduce serum creatinine
- sepsis
- Certain drugs like trimethoprim - this inhibits secretion of creatinine in the tubules. This will increase serum creatinine.
- Decondtioning and malnutrition - reduce [serum creatinine]
How does pregnancy affect the reliability of serum creaitnine measurement ?
Filtration rate increases significantly in pregnancy but the corresponding drop in serum creaitnine may not be seen in a couple of days
How does a pt on dialysis with end stage renal failure affect serum [creatinine] measurement
At that end stage (stage 4/5 CKD), GFR and filtration falls and it’s very low.
amount of creatinine filtered is very small.
Hence there’s a very high proportion of creatinine that is from secretion (no longer only 15%); GFR is too Low.
hencre creatine clearance isn’t very reliable in measuring GFR.
What 3 classses of drugs would you give Mr stanworth in order to manage his disease ?
- Ramipril- an ACE inhibitor. (Anti-hypertensive)
- insulin (used to treat hyperglycaemia )
- Atorvastatin - a statin (used to treat dyslipideamia)
tackling hypertension , hyperglycaemia and dyslipidameia will help to reduce proteinuria and stop GFR decline.
Why are ACE inhibitors like ramipril used to manage mr stanworth disease? give relevant features
First line treatment against CKD.
It reduces arterial perfusion pressure and relaxes the efferent arteriole. It has anti-inflammatory effects
Hence it reduces the amount of blood entering the glomerulus and increases amount of blood immediately leaving it.
Hence it reduces :
- glomerular filteration pressure
- glomerular injury
- proteinuria
What’s the effects of using insulin in helping those with CKD especially those with diabetic nephropathy
Reduces blood glucose
reduces damage to glomerular vasculature caused by hyperglycaemia
What’s the effect of Atorvastatin in helping with CKD?
Reduces dyslipidaemia and hence reduces atherosclerosis
this helps to reduce sclerotic glomerulus
it also has anti-inflammatory effects
What are the other lifestyle advice that mr stanworth should do to help with his disease
- Stop smoking if he is
- great diet
revise renal physiology
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
Explain the significance of decreased excretion of water and sodium?
Sodium and water balance are usually maintained up until GFR falls to 10-15ml/min (stage 5 CKD).
However, someone with mild CKD is less able to respond to rapid intake of sodium ions/water to balance it out and hence prone to overdose.
other consequences are:
- hypertension and peripheral oedema
- volume overload with pulmonary oedema and heart failure
What management options are useful for pt with fluid overdose ?
Volume restriction - less water and sodium intake
daily loop diuretic (furosemide)
Explain the consequences of decreased excretion of potassium ions . When does it become more prevalent ? Is it the same for all pt with CKD?
People are still able to maintain K excretion as long as there’s still fluid to DCT and aldosterone activity.
Hyperkalaemia is prevalent in pt with advanced CKD who don’t make enough urine, those with high potassium diet, increased tissue breakdown or hypo aldosteronism
ACE inhibitors and NSAIDS can cause or worsen hyperkalamia
Consequences of hyperkalaemia are:
- weakness and fatigue
- more severe is ECG changes predisposing to arrhythmia and cardiac arrest.
What does decreased excretion of H+ lead to? How can it be managed?
Metabolic acidosis.
they can be treated with bicarbonate supplement to correct serum pH.
Beware of volum overdose as the supplement contains Na+. So continue monitoring the pt
What can decreased excretion of phosphate ions and Uric acid lead to?
Uric acid- gout
phosphate ions- increased production of PTH and it’s a molecule indicated in Renal bone disease
What does decreased excretion of urea lead to?
Urea levels rises slowly.
it becomes a problem at later stages of CKD or if there’s an acute kidney injury on top of CKD.
Consequences are:
- nausea and vomiting , itch , weakness and fatigue
- pericarditis, encephalopathy , bleeding, seizures and coma- these are more serious
all these complications are indicative of dialysis
What are the consequences of decreased biosynthesis of erythropoietin?
It reduces with progressive CKD.
it leads to normocytic normochromic anaemia. There’s not enough erythropoietin to send signal to bone marrow to make more red blood cells.
Treatment are:
- iron, B12 and folic
- at later stages you’ll need erythropoietin supplement.
Descirbe the consequences of less calcitriol made and give treatment.
It wanes with progressive CKD (below 40 GFR). Very low in ESRD especially with phosphate retention and low renal mass
leads to osteomalacia, hyperparathyroidism and renal bone disease
treatment
- Vit D supplement called alfacalcidol
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’s the difference between haamoglobinuria and haematruria ?
Haemoglobinuria- excess of free haemoglobin infringe due to overflow
Haematuria- bleeding from urinary tract itself. There could still be haemoglobin in blood but there’s also intact RBCs
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
Descirbe how changes to glomerular filtration barrier in diabetic nephropathy can lead to proteinuria, particularly albuminuria
Hypertensive changes and hyperglycaemia can damage the glomerular endothelial cells.
Diabetes also result to intramuscular changes in GBM. it becomes thickened in diabetic nephropathy and it also becomes leaky.
there’s reduced nephrin expression in diabetic Nephropathy. There’s also damage to slit diaphragm and mesangial expansion which can lead to protein leak.
finally, podocytes can be DAMAGED by advanced glycation end products (from hyperglycaemia).
Damage to endothelial cellls, GBM or podocytes can contribute to proteinuria. if there’s albuminuria, it means that one of th layers have been compromised
add diagram
What is nephrin ?
A key protein component of the slit diaphragm of the podocytes
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*
What is osteitis fibrosa?
Too much bone resorption occurs and leads to weakening of bone.
This causes bone tissue to be replaced by fibrous tissues.
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
Explain the effects of hyperglycaemia in changing glomerular filtration pressure in diabetic nephropathy
Hyperglycaemia affects the efferent arteriole and causes non-enzymatic glycation of endothelial cells.
This leads to stiffening and narrowing of the vessel.
Hyperglycaemia also active the RAAS within the kidney regardless of volume status. Ang 2 also has vasoconstrictive effect on efferent arteriole
efferent arteriole narrowing increases upstream pressure in gloimerulus
Explain the effects on hypertension on changing the glomerular filtration pressure in diabetic nephropathy
High pressure increase flow through glomerulus, however the auto-regulation and afferent arteriolar constriction is altered in diabetes and excess glucose is filtered in glomerulus.
The proximal tubules work very hard to absorb as much glucose as possible, hence they absorbe much sodium as well via (SGLT2).
less sodium is delivered to macula dense cells in DCT and less sodium uptake occurs there (by the macula dense cells).
this leads to less stimulation of afferent arteriolar vasoconstriction.
All these effects increases glomerular filtration pressure and leads to greater protein loss
Describe how glomerular filtration changes along the course of diabetic nephropathy
At first there’s hyper filtration.
However with time hypertensive change in afferent arteriole causes vessel thickening and reduced lumen diameter.
There’s relative ischaemia which then recruited macrophages that secrete TGF-B.
This causes mesangial cells to secrete more ECM (however hyperglycaemia and pressure damage also triggers this).
Excess ECM deposition leads to glomerulosclerosis and hence eventually lead to reduced capacity for filtration. Hence lowering GFR
What occurs in diabetic nephropathy that leads to proteinuria
Changes in glomerular filtration pressure (increases at first )
Changes to glomerular filtration barrier (more leaky and porous )
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
What is the main disease in which ACE inhibitors are contra-indicated
Renal artery stenosis.
The afferent arteriole cannot work at all and blood flow is dependent on the vasoconstriction of the efferent arteriole (pressure differences).
If ACE inhibitors are used then the efferent arteriole is relaxed. theres no blood flow through kidneys.
always check pt within 7 days of giving ACE inhibitors if they have developed any underlying renal artery stenosis so that AKI can’t occur.
After you’ve calculated GFR, why shouldn’t you be quick to use it to diagnose CKD?
There’s a large variation in GFR for each age group. Hence take an holistic approach and look for other signs like proteinuria and use it in context to diagnose.
n.b CKD could be as a result of low GFR and/OR proteinuria
The general management of the patient with CKD involves the following issues: what are they?
- Treatment of reversible causes of renal failure.
- Preventing or slowing the progression of renal diseases
- Treatment of the complication of renal failure
- Adjusting drug doses when appropriate for the level of estimated glomerular filtration rate
- identification and adequate preparation of the patient in whom renal replacement therapy (dialysis and kidney transplantation) will be required and early plannning for this eventuality
in CKD, what are the reversible causes of renal failure ?
- Decreased renal perfusion
- Administeration of nephrotoxic drugs
- Urinary tract obstruction
what causes the decreased renal perfusion (reversible cause of renal failure)
Hypovolemia- such as vomitng, diarhroea and diruetic use.
Hypotension - due to myocardial dysfunction/pericardial disease.
Infection- sepsis
drugs that lower eGFR like NSAIDs, ACE-Is and ARB
What antibiotic that is usually used for urinary tract infection affects creatinine secretion? Explain
Trimethoprim- does not change filtration rate (true GFR) but may cause increased serum creatinine whilst the pt is taking the drug
it interferes with and reduces creaitnine secretion and therefore impact estimated GFR
Describe what causes urinary tract obstruction and hence how is it measured?
It should always be considered with unexplained worsening renal function.
It blocks and inhibits the flow of urine through the normal path.
E.g. are prostate enlargement, kidney stones, ureteric scars or strictures .
Renal ultrasound shows hydronephrosis when there’s urinary obstruction
Describe the management of anaemia in CKD. How do you diagnose ?
Check Hb every 3-12 months depending on CKD stage. Investigate when Hb falls below 120mg/dL in female and 130 in men.
In order to diagnose it as consequences of CKD you have to exclude non renal causes like:
- Red blood cell indices, serum Fe and transferrin saturation.
- Reticulocyte count, total iron binding capacity , B12 and folate
What are the types of renal bone disease and how do u manage it?
Osteitis fibrosis (most common), osteomalacia and adynamic bone disorders.
PTH levels can be used as earliest marker of bone disease
Manage by:
- Restricting phosphate diet
- Administer oral phosphate binders to reduce absorption of phosphate
- give active Vit D
How do you manage those with Hypertension (in CKD)
Use ACE-Is and ARBs for proteinuric CKD.
Use diuretic , however if GFR is below 20 don’t use Thiazide diuretic alone; not enough filtrate will reach DCT where it acts. It’s better to combine with loop diuretic to get better results
Try to maintain BP to reach guidelines of 130/80mmHg. However specific target should be made tailored to the pt. Based on age, comorbidites, progression of CKD etc.
BP should be maintained becuase the rate of GFR decline is faster when MAP is at or above 100mmHg
What are the therapeutic modalities offer renal protection to slow down rate of CKD progression
- Use ACE-I /ARBs
- Protein restriction
- Stopping smoking
- Treatment of chronic metabolic acidosis
- Control blood glucose
- control alcohol
