Diabetic nephropathy Flashcards
fWhat is the structure of the nephron?
Afferent and efferent blood vessels in and out of the glomerulus
Renal corpuscle
PCT
Descending limb
Loop of Henle
Ascending limb
DCT
Collecting tubule
What is the structure of the renal corpuscle?
Vascular and urinary pole
Visceral layer of Bowman’s capsule - podocytes
Parietal layer of Bowman’s capsule
Basement membrane of capsule and vessels
Intraglomerular mesangial cells between capillaries
Macular densa cells in wall of DCT (monitor Na+ conc) adjacent to:
Juxtaglomerular cells - modified smooth muscle cells in wall of afferent arteriole (release renin)
What is the structure of the glomerular filter?
Fenestrated endothelium
Glomerular basement membrane
Podocytes creates filtration slits
What is the process of glomerular filtration?
Blood enters afferent arteriole by ultrafiltration due to high hydrostatic pressure > afferent dilates, efferent constricts
Neg charged large molecules filter slower than pos charged
Filtered into Bowman’s capsule
Filtrate moves to PCT
What epithelial cells line the PCT?
Simple cuboidal with brush border on apical side
What channels are present in the PCT? what do they filter, where are they found in PCT (7)
SGLT2 - early PCT apical memb - glucose and Na+ - 90% glcucose reabosrption
Na+/K+ ATPase pumps - basolateral memb - 3Na+ out cell, 2K+ in cell, out of blood
GLUT2 - early PCT basolateral memb- glucose out of cell
SGLT1 - late PCT apical memb - reabsorbs remaining glucose
GLUT1 - late PCT basolateral memb - glucose out cell
Na+/amino acid symptorters - apical
Na+/H+ antiporter - apical
Osmolarity vs osmolality
Osmolarity: number of particles of solute per litre
Osmolality: number of particles of solute per kg of solvent
What happens in the counter-current multiplier system in the Loop of Henle?
Thick ascending limb - Na+ pumped out and negative ions follow e.g. Cl-. Makes medulla concentrated - creates gradient
Water leaves passively from thin descending limb due to high salt conc of surroundings - increases conc of filtrate - to equilibrate between filtrate and medulla
As filtrate is flowing all the time, there is a gradient of increasing osmolarity into the medulla
Facilitates water moving out of CT and concentrating urine
What transport occurs in the overall generally DCT and specifically in the early DCT?
Reabsorption of sodium, chloride, potassium, calcium, magnesium and bicarbonate ions
NO WATER is reabsorbed
Early DCT
Na+/K+ ATPase - Na+ into ECF, K+ into cell. Creates gradient for Na+ to be reabsorbed into cell via apical channels
What transport occurs in late DCT and CD? What cells are involved?
Late DCT
- Principle cells - Na+/K+ ATPase pump - uptake sodium, accumulation of potassium basolaterally and extrude potassium and sodium
- Type A intercalated cells - H+/K+ ATPase secrete H+ into lumen. K+ Cl- cotransporter allows leakage into ECF
- Type B intercalated cells - secrete bicarbonate and reabsorb H+
CD
reabsorption of water via ADH and aquaporins
What generally occurs in type 1 diabetes?
Autoimmune destruction of Beta cells
Cause low insulin levels
What is the pathophysiology of type 1 DM?
How is type 1 DM treated?
What is the pathophysiology of type 2 DM?
What is the pathophysiology of CKD?
What is the pathophysiology of diabetic nephropathy?
What are the main kidney tests?
GFR
Urine albumin: creatinine ratio
Serum creatinine
BUN
Creatinine clearance
Imaging studies
Creatinine in blood tests for kidney function
Product of muscle breakdown
Normally filtered from blood via kidneys out through urine
Coincides with decrease in GFR
Diet and muscle mass can affect creatinine - so not accurate measure of kidney health
Urea in blood tests as test for kidney function
Decreased renal function prevents loss of toxic nitrogenous waste
Build up in blood rather than excreted by kidneys
Symptoms like itching - uremic pruritis
eGFR for creatinine for kidney function
Severe damage to kidney will reduce GFR - elimination of waste products is impaired
Calculated from serum creatinine level, age, sex and race
Adjusted calcium for kidney function
Adjusted calcium: free calcium and calcium bound to albumin
FGF23 is very high in end stage kidney disease - promotes suppression of vitamin D production and leads to less Ca2+ absorption
Hyperphosphatemia leads to binds to serum Ca2+ - decreased availability of free Ca2+
Inorganic phosphate for kidney function
Failure to excrete phosphate - hyperphosphatemia
Phosphate binds to serum Ca2+ - decreased availability of ionised free Ca2+
Increased bone resorption also releases phosphate
High levels of FDF23 increases phosphate
Alkaline phosphatase for kidney function
Enzyme from liver and bone - hydrolysis of organic phosphate
Increase in secondary hyperparathyroidism - related to decreased calcium and increased phosphate levels
The enzyme functions to catalyse the hydrolysis of phosphate
Higher in kidney damage
Vitamin D levels for kidney function
Inactive form of vitamin D - depends on intake from diet, sunlight etc.
Vitamin D3 for kidney function
Active form of Vitamin D
Needs enzyme from kidneys to be converted into active form
Kidney damage = failure to produce this enzyme -> less Ca2+ absorption and Vit D deficiency
PTH for kidney function
Enzyme high in CKD as hyperphosphatemia binds to calcium - less free Ca2+
PTH levels rise to try increase serum C2+
Albumin:creatinine ratio in urine for kidney function
Sensitive for glomerular disease/damage
Looking for protein in the blood
Protein would increase if glomerulus damaged and barrier is more leaky
Good measure of GFR but requires 24 hour urine collection and blood sample
What clinical imaging can be taken to assess kidney health?
US scan - size/shape/position, stones, lesions etc
Doppler US of renal vessels - thrombosis, renovascular disease
CT of kidney ureter bladder (KUB) - renal colic, KUB stones
CT urogram - malignancy
Angiography - hypertension and or renal failure
Renal biopsy - parenchymal renal disease
Normal vitamin D processing in the body?
SKIN/DIET
Vitamin D3 obtained from synthesis in the skin from sunshine/supplements
LIVER
Vitamin D2 and D3 converted to calcidol by enzyme in the liver
KIDNEY
Calcidol converted to calcitrol by enzymes from kidney, stimulated by PTH, opposed by FGF23
INTESTINES
Active vitamin D (calcitriol) increases absorption of calcium and phosphorus
Bone breakdown which releases Ca2+ and phosphorus into blood
Normal calcium processing in the body in bone homeostasis
- PTH secreted from chief cells in parathyroid gland in response to low serum Ca2+
- No PTH receptor on osteoclasts so PTH binds to osteoblasts
- Osteoblasts activate RANKL and M-CSF > activate pre-osteoclasts > activate osteoclasts
- Osteoclasts stimulate bone resorption - release Ca into blood
- Calcitonin released in response to high Ca
- Secreted from parafollicular cells in thyroid glands
- Antagonises PTH = inhibits bone resorption, increases urinary excretion Ca and PO4
What is the effect of CKD on the bones? calcium
Cannot synthesise calcitriol:
Cannot convert calcidol from liver to calcitriol as inhibits converting enzyme
No active vitamin D = cannot absorb Ca from intestines into circulation = hypocalcaemia
Hypocalcaemia = reduced bone mineralisation
Hypocalcaemia > PTH secretion > increased bone resorption > osteomalacia
What is the effect of CKD on the bones? phosphate
Renal pathology reduces excreted of PO4 > hyperphosphatemia
Excess PO4 binds to free Ca > further reduces availability of free/ionised Ca > hypocalcemia > PTH secretion = secondary hyperparathyroidism
FGF23
Produced by osteoblasts in bone
Secreted as a compensatory mechanism in response to hyperphosphatemia in CKD
Increases PO4 excretion in urine
Inhibits 1-a-hydroxylase = inhibits vitamin D activation from calcidol to calcitriol
> Reduces intestinal Ca and PO4 absorption > increased PTH > secondary hyperparathyroidism
Summary: what are the levels of parathyroid hormones, serum calcium and phosphate in hyperparathyroidism?
Parathyroid hormone: high
Serum calcium: decreased/normal
Phosphate: Increased/normal
What is the cause of secondary hyperparathyroidism and its symptoms?
Cause: vit D deficiency/impaired production OR end stage kidney disease
Symptoms:
- Osteoporosis
- Renal stone
- Bone and joint pain
How is secondary hyperparathyroidism treated?
Vitamin D supplement - cholecalciferol
Treat underlying cause
How is CKD clinically shown?
Gradual loss in kidney function, with GFR under 60mL/min per 1.73 m2, or markers of kidney damage, or both for at least 3 months duration
What are the main causes of CKD?
Hypertension in the afferent arteriole
Diabetic nephropathy
Glomerulonephritis
How does hypertension in affernet arteriole cause CKD?
Constantly high BP causes sclerosis in renal arteries
Less oxygen is delivered to mesangial cells (make up the glomerulus) which causes ischaemia and necrosis
Triggers macrophages to secrete growth factors - TGF-B - causing fibrosis of glomerulus, decreases GFR
How does diabetic nephropathy cause CKD?
Increase in blood glucose causes glycosylation non-enzymatically
This therefore stimulates pro-inflammatory molecules, damaging efferent arteriole and causing back pressure
Stimulates mesangial cells to secrete growth factors which leads to glomerusclerosis
How does glomerulonephritis cause CKD?
Antibodies attack the membrane and inflammatory response causing lesions of the glomerular basement membrane
What are the symptoms of CKD?
Pulmonary and peripheral oedema, hypertension
Encephalopathy
Pericarditis
Uremic frost
Platelet dysfunction
Uremic odour
Anaemia
Itches and cramps
Bone disorders
Diabetic acidosis
Haematuria, proteinuria, nocturia, oliguria
How is pulmonary and peripheral oedema caused by CKD?
Decreased GFR, inhibits water filtration causing retention which causes accumulation of water
Increased albumin excretion in kidneys amplifies volume overload = oedema
How does CKD cause encephalopathy, pericarditis, uremic frost, platelet dysfunction and uremic odour?
Urea build up leads to uremia which causes all these symptoms
Breakdown of urea by saliva causes uremic odour of breath
How does CKD cause anaemia?
Inhibition of the hormone EPO which is normally released from kidneys, reduces erythropoiesis causing anaemia
How does CKD cause itches and cramps?
Toxin deposition, peripheral neuropathy, immune system dysregulation and opioid imbalance can lead to pruritis - itches and cramps
How does CKD cause bone disorders?
Inability to activate vitamin D in the kidneys - decreases calcium absorption
Stimulayes secondary hyperparathyroidism in response to low calcium, releasing PTH which promotes bone resorption - increases risk of bone disorder
How does CKD cause diabetic acidosis?
Damage to specific cells in kidneys that release protons and absorb bicarbonate ions, causing H+ accumulation which may lead to diabetic acidosis
How does CKD cause haematuria, proteinuria, nocturia and oliguria?
Damage to glomerulus
What are the diagnostic tests for CKD? and what will they show in CKD?
Blood and urine tests:
K+ and PO4, urea and creatinine: increased in blood due to decreased excretory function of kidney
PTH: increase in response to Ca2+
Albumin in urine: increased due to glomerular damage
Calcium: decreased due to inability to activate vitamin D
eGFR: decreased fibrosis of glomerulus
What is shown on renal US with CKD?
Smaller due to fibrosis
Reduced renal vascularity
Marginal irregularities
Poor visibility of structures
What is shown in biopsy in a kidney with CKD?
More collagen deposition (blue)
Increased recruitment of macrophages
What type of drug is dapagliflozin?
Reversible sodium-glucose linked transporter 2 (SGLT2) inhibitor
‘-gliflozin’
What is the mechanism of dapagliflozin?
Inhibits SGLT2 channels on apical membrane of principle cells in PCT
So sodium and glucose cannot be pumped out of the filtrate into the blood > increases urinary glucose excretion
Reduces hyperglycaemia due to insulin resistance in diabetes type 2 which causes blurred vision, MI, neuropathy
What type of drug is metformin?
Biguanide antihyperglycemic agent
What is the mechanism of metformin?
OCT1 takes up metformin into hepatocytes
Metformin accumulates in mitochondria due to positive charge
Inhibits mitochondrial complex I
- reduces ATP production
- activates glucose metabolism
- inhibits gluconeogenesis
Increases anaerobic glucose metabolism in enterocytes > reduces glucose uptake
Increases peripheral glucose uptake > decreases blood glucose
What type of drug is ramipril?
ACE inhibitor
What is the mechanism of action of ramipril?
Metabolised to ramilprat in liver
Binds to ACE and inhibits action > prevents conversion of angiotensin I to angiotensin II
> Less vasoconstriction, fibrosis, inflammation, oxidative stress
> reduced sodium and water reabsorption
> lowers BP
What type of drug is atorvastatin?
HMG-CoA reductase inhibitor
What is the mechanism of atorvastatin?
Works in the liver
Prevents HMG-CoA conversion to mevalonate
Mevalonate would then be converted to cholesterol
Prevents cholesterol production in the liver
Reduces risk of CVD
What type of drug is Alfacalcidol
Analogue of Vitamin D
What is the mechanism of alfacalcidol?
Alfacalcidol is used in the kidneys failure because it does not require enzymatic activation by the kidneys
Rapidly converted into calcitriol - active Vitamin D
How do phosphate binders work?
Used to reduce lower serum phosphate levels by:
forms nonabsorbable compound with an active cation which bind to phosphate
Reduce intestinal absorption of dietary phosphate
Compound then excreted in faeces
