Case 9 Flashcards
What is glomerular filtration based on?
Size and charge
What occurs in reabsorption?
Epithelial cell of renal tubules perform reabsorption.
In PCT, large amounts of electrolytes, glucose and filtered proteins are reabsorbed by active transport/passive diffusion
In DCT and collecting duct, epithelial cells respond to hormonal influences to reabsorb water and electrolytes
What occurs in secretion?
Tubules secrete substances from bloodstream into urine via tubular cells
Whta is excretion
Anything filtered and not reabsorbed is excreted as waste in urine
What is high creatinine levels indicative of?
Means there is a problem with the nephrons
Why is proteinuria unnatural?
Low molecular weight proteins pass easily through glomerular filtration barrier. Large proteins shouldn’t be able to pass through.
Proteins which pass the barrier are carried through renal tubules wit filtrate. Proteins are usually reabsorbed by endocytosis by renal epithelial cell (particularly in PCT) where they are hydrolysed into AAs and return to circulation.
Almost all filtered protein is reabsorbed but a very tiny amount is excreted (eg Tamm- Horsfall protein aka uromodulin)
How much protein is lost in a healthy individual in 24hrs?
<150mg
What are the classifications of proteinuria?
Overflow e.g. Rhabdomyolysis
Glomerular eg diabetic nephropathy
Tubular eg acute tubulointestinal nephritis
What is overflow proteinuria?
Excess low molecular proteins means more proteins are crossing the glomerular barrier so more is being excreted
Can be excess myoglobin, haemoglobin (due to rapid intravascular haemolysis)
What is rhabdomyolysis?
Rhabdomyolysis is a rapid breakdown of excess skeletal muscle - can cause excess myoglobin to be released (myoglobin is toxic so can cause acute kidney injury)
Whats the difference between haematuria and haemoglobinuria?
Haemaglobinurea is due to overflow
Haematurea is due to bleeding in the urinary tract
What is glomerular proteinuria?
Due to damage to the glomerulus allowing larger than normal proteins to be let through
Albumin is predominantly lost (its about the same size as the normal glomerular pores and has flexible ellipsoid shape)
What is diabetic nephropathy?
A secondary glomerulopathy
glomerular damage occurs secondary to something else
What is tubular proteinuria?
Can occur f tubules are diseased or damaged and not able to reabsorb filtered proteins as well as normal
What is tubulointerstitial nephritis?
Tubulointerstitial = kidney disease that involve structures around glomerulus
Can lead to tubular dysfunction with or without renal failure
Can be acute or chronic. Acute caused by drugs (nephrotoxic drugs)
What are 4 nephrotoxic drugs that are the most common cause of acute kidney injury in hospitalised patients?
NSAIDs
ACE inhibitors
Aminoglycoside antibiotics eg gentamicin
Contrast agents
What mechanism leads to the greatest protein loss?
Glomerular proteinurea
How does hyperglycaemia affect the kidneys?
Mainly effects efferent arteriole where non-enzymatic glycation of endothelial cells can lead to stiffening and narrowing of the vessel.
It can also directly activate the renin-angiotensin-aldosterone system in the kidney
Angiotensin II has vasoconstrictive action on efferent arteriole increasing upstream pressure in the glomerulus
How does hypertension affect the kidneys?
Leads to increased flow in afferent arteriole increasing glomerular pressure further
Auto-regulation which normally protects from increased pressure, is altered in diabetes
How does diabetes effect sodium levels?
PCT work hard to reabsorb excess glucose which leads to increased Na reabsorption (co-transported).
Less sodium is delivered to macula dense in DCT meaning less stimulation if afferent arteriole vasoconstriction
What happens over time with hypertensive changes in the afferent arteriole?
Can result in vessel thickening and reduced lumen diameter meaning less blood supply to kidneys so ischaemia
What occur in relative ischaemia?
It recruited macrophages which secrete TGF-B causing menengial cells to secrete more ECM.
Excessive ECM leads to hardening and scarring in the glomerulus- glomerulosclerosis- which can lead to reduced capacity for filtration
What makes up the glomerular filtration barrier?
The glomerular capillary endothelial cells
Glomerular basement membrane
Podocytes
How is the glomerular filtration barrier effected in diabetic nephropathy?
Hypertension and hyperglycaemia changes can result in damage to glomerular endothelial cells
Can also cause changes in the glomerular basement membrane- can become thickened and leaky
How are podocytes affected in diabetic nephropathy?
Podocytes have foot processes (projections) connected by silt (nephrin is a key component)- damage to silt diaphragm can contribute to protein leak and mesangial expansion.
Reduced nephrin has been observed in diabetic nephropathy.
Podocytes can be damaged directly by advanced glycation end-products as a result of hyperglycaemia
The presence of what indicates a defect n one of the glomerular barrier layers?
Albuminurea
What are the three most common causes of chronic kidney disease?
Diabetes
Hypertension
Glomerulonephritis
What happens when you have damaged nephrons in the kidneys?
Damaged nephrons will filter poorly
The functional nephrons will undergo adaptive hyperfiltration where blood flow is shunted to them.
Adaptive hyperfiltatration in working nephrons puts excessive pressure on their glomerular capillaries leading to glomerulosclerosis -> ischaemic nephron injury -> loss of filtration and eventually nephron loss
Adaptive hyperfltation can be maladaptive because it can lead to accelerated damage to working nephron
What is the best way to monitor and screen for proteinuria in diabetes?
Albumin creatinine ratio of urine sample
Accounts for differences in urine conc.
Provides reasonable estimate of protein loss
ACR is used in diabetes- greater sensitivity (PCR is used as alternative to ACR in those without diabetes and with high levels of proteinuria)
Why is a urine dipstick test not used to screen for proteinuria?
Poor sensitivity
Might miss causes
Why is a 24 hour urine test not primarily used to screen for proteinuria?
Total protein should be <150g per 24hr
Total albumin should be <30mg per 24hr
Impractical, often not collected accurately
Why is random albumin conc. not used to test for proteinuria?
Unreliable as depends on conc. of urine
Depends on patients hydration
Why check for albuminuria in diabetes?
Albumin feels are a good predictive and prognostic marker of CKD
Moderate albuminuria that persists for 3 months + is a diagnosis of CKD
Can reflect the integrity and health of the systemic vascular endothelium- predictor of CVD mortality in T1 and T2 diabetes
What is microalbuminuria?
AKA. moderate albuminuria
Albumin loss between 30 and 300mg a day
What is macroalbuminuria?
AKA. Severe albuminuria
Albumin loss greater than 300mg a day
Wha is GFR?
Tells us volume of fluid filtered from glomerular capillaries into bowman’s capsule per unit time
Its proportional to the clearance rate of any substance that is freely filtereted and neither reabsorbed or secreted by the kidneys
How is GFR calculated?
Clearance = urinary substance conc x urine production rate / plasma substance conc
Why is creatinine used to measure GFR?
Its freely filtered from the kidney and is not reabsorbed. A little of it is secreted but this is accepted
Clearance of creatinine is roughly proportional to GFR
We use evidence based formulas that use serum creatine without need for urinary creatinine to estimate GFR
What formula is commonly used to measure creatinine clearance?
MDRD formula
By what method is GFR tested?
Isotopic method where radioactive tracer is injected into patient through IV and serum conc. of tracer measured sequentially to measure GFR
This is done in renal clinics when creatinine estimation aren’t reliable
What does the MDRD formula take into account?
-Age
-Ethnicity
-Gender
(muscle mass differs between gender, age and ethnicity- young males of afro-caribbean descent have greater muscle mass so greater creatine levels)
-ACR
-Creatinine
What group of patients should you be cautious of when measuring creatinine levels?
Dietary consumption- some AAs are creatine precursors
Should be careful using formula in individuals with extras in weight or nutrition e.g. body builders
What are markers of CKD?
Albuminuria Electrolyte abnormalities Abnormalities on histology Structural abnormalities Kidney transplantation
In what patient is using a creatinine based formula less reliable?
An elderly patient with acute kidney injury
A pregnancy lady
A patient with end stage renal failure about to start dialysis
Why can’t we measure serum creatinine in an acutely unwell patient?
rate of increase in serum creatinine doesn’t parallels fall in GFR (can take time for serum creatinine to build up)
Trauma, certain drugs (eg trimethoprim which can inhibit secretion of creatinine in tubules) malnutrition or muscle waste or sepsis can impact serum creatinine
How does pregnancy affect serum creatinine?
GFR increases so drop in serum creatinine may not be seen
Why can creatinine measurements be unreliable in a patient with end stage CKD
Creatinine calculations are overestimations as they take into account the amount of creatinine secreted
As GFR falls, proportion of creatinine that comes from secretion increases and becomes less form what is filtered
With a very low true GFR, creatinine clearance may be unreliable
What drugs should be given to Mr Stanworth for optimal management?
Insulin
Ramipril
Atorvastatin
These taget hypertension, hyperglycaemia and dyslipidaeia which all contribute to CKD
What is ramipril?
An ACE inhibitor and one of the first line treatments for CKD- has a dual benefit in patients with proteinuria CKD as it has a general effect on hypertension and a specific positive effect in the kidney
Ramipril reduces arterial perfusion pressure and relax efferent arterial so can reduce glomerular pressure, glomerular injury and reduce proteinuria
Has anti-inflammatory effects
Why is insulin used to treat CKD?
Used to treat hyperglycaemia which can cause damage to the microvasculature
Why is atorvastatin used int he treatment of CKD?
High blood cholesterol is associated with atherosclerosis and sclerotic glomeruli are observed in CKD
Atorvastatin can treat this by lowering blood cholesterol
Has anti-inflammatory effects
What are the consequences of CKD?
Decreased excretion
Decreased biosynthesis
Altered metabolism
What are the consequences of decreased excretion?
A patient with mild- moderate CKD is less able to respond to rapid intake of sodium therefore more prone to fluid overload
Patients with volume overload respond to fluid restriction, slat restriction and a daily loop diuretic
Potassium levels are normally maintained but hyperkalaemia develops in patients with advanced CKD who don’t make much urine or have high potassium diet- ACE inhibitors can worsen hyperkalaemia
Increased tendency to retain H ions in CKD can lead to metabolic acidosis- may be treated with bicarbonate supplements
Levels of urea rise with CKD- may need dialysis treatment if serious
Other molecules that can be retained as filtration falls: uric acid (builds up in joints and cause gout), phosphate (increased production in PTH)
What are consequences of decreased biosynthesis?
Kidney produces erythropoietin- CKD can lead to normocytic, normochromic anaemia (don’t produce enough RBCs)
Treatment means replete lives of vit B12, folate and iron
Kidney performs second hydroxylation of vitamin D
CKD can lead to a lack of vit D
Can be treated with administration of alphacalcidiol (1-alpha-hydroxycholecalcifero)
What are consequences of altered metabolism
CKD is associated with elevated levels of lipids
Altered metabolism of sex hormones can lead to reproductive function abnormalities
What is the impact of CKD on calcium levels in the body?
The kidney releases vitamin D which acts on the gut to please calcium into the blood (in CKD less vit D is released so less calcium is released in the blood)
If calcium levels are low in the body this is detected by the parathyroid gland which leads to increased secretion of parathyroid production which acts on the bone to cause increase release of calcium in the blood.
The kidney also releases phosphate which binds to PTH to reduce levels of free calcium in circulation (in CKD phosphate is increased because it isn’t filtered)
Phosphate also stimulates the release of PTH from the parathyroid gland (secondary hyperparathyroidism)-in CKD this leads to reduced calcium in bone known as osteitis fibrosa (bone replaced by fibrous tissue)
In CKD FGF-23 is also elevated which leads to increased secretion and decreased absorption of phosphate
Ongoing stimulation of parathyroid glands can lead to PTH being released autonomously and spontaneously
How may Mr Stanworth’s CKD progress over the next 10 yrs?
He would progress to stage 3A very quickly (within 2 yrs) and will progress to CKG 3B within 10 yrs
How do different types of albuminuria progress over time?
Theres not a large difference in progression with those with normoalbuminurea and moderate albuminirea whereas severe albuminuria have much faster decline in kidney dysfunction
Slight improvement in kidney function in the first year or two is most likely due to initiation of drug treatment- drugs don’t prevent the eventual progression of kidney dysfunction, just slow it
