Case 9: CKD Flashcards
What parameters are used to indicate poor kidney function?
- Serum creatinine
- Proteinuria
What are the 4 steps in kidney filtration?
- Ultrafiltration
- Reabsorption
- Secretion
- Excretion
What is ultrafiltration based on?
- Size
- Charge
What protein is always secreted by tubular epithelium into urine?
Tamm-Horsfall Protein /Uromodulin
What is the purpose of uromodulin?
It exhibits anti-microbial properties
Roughly, how much protein is lost in urine per day?
150 mg
How much of the 150 mg is attributed to Albumin?
<30mg but ideally <10mg
What is the loss of albumin between 30-300 mg/day called?
Moderate albuminuria/ microalbuminuria
What counts as severe/macro albuminuria?
Losing more than 300mg of Albumin a day
What can act as a good diagnostic marker of CKD and vascular health in people with Diabetes?
Moderate albuminuria
Describe types of albuminuria in terms of albumin:creatinine ratio in mg/g
NORMAL: <30mg/g
MA: 30-300 mg/g
SA: >300 mg/g
Describe types of albuminuria in terms of albumin:creatinine ratio in mg/mmol
NORMAL: <3mg/mmol
MA: 3-30 mg/mmol
SA: >30 mg/mmol
Why are urine dipsticks rarely used to diagnose albuminuria?
It is not a sensitive test so it cannot detect moderate albuminuria (when the amount of protein is just above the threshold).
What are the 3 types of proteinuria?
- Overflow
- Glomerular
- Tubular
What is overflow proteinuria?
- High circulating protein concentration so more is filtered out by nephrons.
- However, there is a limit to how much protein can be reabsorbed (blood is saturable) so some protein is left and excreted.
Give an example of overflow proteinuria
Rhabdomyolysis- rapid breakdown of skeletal muscle due to trauma/excess exercise. Proteins that may be found in excess in urine include…
- myoglobin (can also cause AKI as it is toxic)
- free haemoglobin (haemoglobinuria)
What is glomerular proteinuria?
Damage to the glomerular barrier meaning that larger proteins can filter through.
Give an example of glomerular proteinuria
Diabetic Nephropathy, a type of secondary glomerulopathy as the damage occurs secondary to a condition like diabetes/drugs.
ALBUMIN is LOST.
Give an example of tubular proteinuria (which is caused by diseased tubes)
Acute tubulointerstitial nephritis- inflammation due to nephrotoxic drugs
Give examples of nephrotoxic drugs
- NSAIDs
- Aminoglycosides
- Contrast agents
- ACE inhibitors
Which protein is capable of the biggest protein loss?
Albumin
How can GFR be calculated?
Renal clearance of creatinine
What formula can be used to calculate GFR without the need for urinary creatinine?
MDRD formula
What is the most commonly used method of monitoring/screening proteinuria?
Through Albumin: Creatinine ratio of urine sample
In what ways can hyperglycaemia cause chronic kidney disease?
It causes…
- narrowing of efferent arteriole (through glycation of the endothelial cells)
- activation of RAA system (⬆️ angiotensin II, ⬆️ upstream pressure in efferent arteriole through vasoconstriction)
- alteration in the tubuloglomerular feedback
- ⬆️ TGF-beta secretion -> ⬆️ ECM -> scarring
How does dysfunctional tubuloglomerular feedback result in protein loss?
- Increase in BP due to hypertension which many people with diabetes have.
- BP increase cannot be dealt with as easily because of dysfunctional tubuloglomerular feedback.
- More Glucose is filtered out into the Bowman’s capsule.
- Increased glucose + Na+ (glucose cotransporter) reabsorption in PCT
- Less Na+ in Loop of Henle so less taken up by macula densa cells
- Less stimulation of afferent arteriolar vasoconstriction
- Afferent and efferent arteriolar dysregulation initially result in increased filtration pressure across the glomerulus
- Greater protein loss
Initially, the glomerular filtration rate increases but then it decreases. Why does it decrease?
- Hypertensive-related changes in the afferent arteriole result in vessel thickening and reduced lumen diameter.
- Ischaemiaof kidneys due to reduction in blood supply.
- Macrophage recruitment -> TGF-beta secretion -> mesangial cells secrete excess ECM.
- Hardening and scarring within the glomerulus.
- Reduced capacity for filtration.
What is hardening and scarring within the glomerulus known as?
Glomerulosclerosis
How does hyperglycaemia affect the glomerular filtration membrane?
It causes…
- thickening of the glomerular filtration membrane
- damage to the slit diaphragm
- glomerulosclerosis
- reduced nephrin expression
- glycated, dysfunctional nephrin
What is the purpose of nephrin?
It is a major protein component of podocytes. If it is expressed incorrectly, it can cause protein to leak into the bowman’s capsule.
What are some causes of chronic kidney disease?
- Diabetic Nephropathy
- Hypertension
- Glomerulonephritis
Describe the pathogenesis of CKD
- If 50% of nephrons lose their function, the remaining nephrons undergo adaptive hyperfiltration (as compensation). Renal blood is directed to these nephrons.
- Prolonged hyperfiltration puts pressure on the glomerular capillaries.
- This causes glomerulosclerosis which results in ischaemic injury.
- More nephrons are lost and more undergo hyperfiltration.
What type of adaptation is hyperfiltration?
Maladaptive because it accelerates damage to nephrons.
How is CKD diagnosed?
- Moderate albuminuria for > 3 months
- Reduced GFR + ACR ratio
- Electrolyte/ structural abnormalities upon imaging
What are some factors that affect GFR?
- Age
- Gender
- Ethnicity
When might it be unreliable to use a creatinine based formula to calculate GFR?
When creatinine levels are unstable.
- In AKI, serum creatinine can remain elevated even as GFR improves.
- Pregnancy
- End stage CKD
What factors can increase serum creatinine?
- muscle mass and diet so it’s important to take that into account. E.g. body builders have more creatinine in their blood.
- drugs
- muscle wasting due to hospitalisation
- sepsis
Why can End stage CKD not be diagnosed using creatinine based GFR?
Secreted creatinine increases while filtered creatinine falls.
For GFR, creatinine should mainly be freely filtered and only negligibly secreted so an increase in secreted creatinine can make the estimate unreliable.
What is the treatment for a Type 2- diabetic with mild CKD?
Treat…
- hyperglycaemia: insulin (reduces vascular + kidney damage)
- hypertension: ramipril (ACE inhibitor which also reduces inflammation)
- dyslipidaemia: atorvastatin (reduces sclerosis by reducing LDL and inflammation)
- smoking cessation
What are the systemic complications of untreated CKD?
- Decreased excretion (more retention)
- Decreased biosynthesis
- Altered metabolism
What does decreased excretion entail?
- Oedema + heart failure (⬆️ water + salt)
- Arrhythmias + cardiac arrest (⬆️ potassium)
- Metabolic acidosis (⬆️ H+)
- Encephalopathy, pericarditis (⬆️ urea)
- Gout (⬆️ uric acid)
- Hyperparathyroidism + renal bone disease (⬆️ phosphate)
What does decreased biosynthesis entail?
- Normacytic Anaemia (⬇️ erythropoietin so patient can produce normale RBCs but not enough)
- Hyperparathyroidism + renal bone disease (⬇️ Calcitriol)
What does altered metabolism entail?
- dyslipidaemia and CVD (⬆️ lipids)
- hypogonadism (⬇️ sex hormones)
How can CDK lead to renal osteodystrophy/ renal bone disease?
- Reduced calcitriol synthesis due to dysfunctional kidneys. This results in low serum calcium.
- Low serum calcium is detected by the chief cells in the parathyroid glands and they produce Parathyroid hormone in response.
- Parathyroid hormone stimulates calcium resorption and bone breaks down.
- High serum phosphate (due to decreased kidney excretion) further depletes serum calcium by binding to it.
- Phosphate also stimulates PT gland and PTH synthesis so more bone is broken. The calcium that is lost, is replaced with fibrous tissue. This is known as Osteitis Fibrosa.
FGF23 production is also increased in CDK. What does this cause?
- Tertiary hyperparathyroidism (when PT gland produces PTH autonomously without a stimulus). This is a result of ⬆️ phosphate secretion.
- ⬇️ Calcitriol synthesis
What is key in preventing severe end-stage CDK?
Early recognition (screening for proteinuria)
Reducing hypertension, hyperglycaemia and dyslipidaemia are all crucial in slowing the decline of GFR. However, decline in GFR is ________.
Inevitable
