wk 11, lec 2 Flashcards
therapeutics for hypertesnion
ARBs, ACE - reduce RAAS
diuretic- lose water and salt in urine
calcium channel blocker- vasodilate
hypertension and arteriole tone
increased arteriole wall responsiveness to vasoactive stimuli –> vasoconstriction
increase resistance via lumen narrowing (arteriosclerosis)
hyaline deposite; brain, heart, renal
less vasodilation (i.e NO)
arteriosclerosis in HTN
deposit ECM, hypertrophy and hyperplasia of smooth muscle cells
hypertension and intravascular volume
Na+ and cant excrete; increase blood volume and mean arterial pressure
if not hypertensive then would down regulate Na/H and Na/Cl transporters if eat too much salt; but not in HTN
increased pressure causes atrophy and ischemic damage , glomerulosclerosis
hypertesnion and autonomic nervous system
increase SNS and reset baroreceptor
- Vasoconstriction of systemic arterioles (alpha-1 receptors)
- Increased ADH release (increased water retention)
- Increased release of renin and AT2
renal denervation in hypertesnion
a procedure to ablate/ destroy SNS outflow to kidneys
to lower blood pressure and resistance
hypertesnion and RAAS
both after ATII
AT2 receptors: vasodilation, sodium loss (natriuresis), NO proaction
AT1 receptors: vasoconstriction, increase BP, hypertesnion
activated via glomerular hypo perfusion or increase SNS
hypertesnion and infalmmation
leukocytes
-activated by increase extraecullar sodium
-ILC3 and Th17 c ells for vascular remodelling esp in kidneys
insulin resistance and obesity in hypertension
impair vasodilation
SGLT2 (sodium glucose) impacted
antihypertesnives ACE and ARBs
ACE inhibitors: block angiotensin into ATII –> no vasoconstriction and Na+ retention
ARB (ATII receptor blockers): block AT1 receptors –> leads to dilation and block aldosterone secretion
both are potassium sparing diuretics
loop and thiazide diuretics in hypertesnion
loop diretics: thick ascending limb block NKCC transporter, can cause hypokalmeia
thiazide diuretics: act on Na/Cl transport in DCT, less severe hypokalemia
tubulointerstitial nephritis
causes
characteristics
cause acute kidney injury
- Inflammation of the renal intersitium with variable
damage to the epithelial cells of the tubules - quick - Fibrosis of the renal interstitium as a consequence
of inflammation - slow - Atrophy/death of cells in tubular compartment –
can be quick, but slower than inflammation
major causes of acute kidney injury
ATN, acute tubular necrosis;
DIC, disseminated intravascular
coagulation;
HTN, hypertension;
PCN, penicillin; PPI, proton pump inhibitors;
TTP/HUS, thrombotic
thrombocytopenic
causes of acute tubulointerstitial nephritis
**vancomycine, iodinated IV contrast agents
medications (NSADIS, IV contrast, beta lactam, diuretics)
pyelonephritis
autoimmune
crystal nephroblathy
myoglobin from rhabdomylosos
allergic interstitial nephritis (acute tubulointerstitial nephritis)
triad sx
allergy mediated
i.e. drug allergies (beta lactic, sulfonamid)
triad: eosinophilia, fever, skin rash
lupus nephritis and sjogre syndrome causing tubulointerstitial nephritis
sjogren: lymphocytic invasion and chronic
fibrotic destruction of a variety of exocrine glands (especially eyes/ lacrimal, salivary glands) (infiltrate interstitiation and fibrous of tubules
lupus: Immune complex formation and tubulointerstitial
inflammation
tubulointersitial nephritis clinical findings
cant concentrate urine (polyuria, nocturia)
salt wasting
cant excrete acids (metabolic acidosis) (hyperkalemia)
defects in tubular reabsorb and secrete
Acute Tubular Necrosis
ischemia
tubular: mitochondrial injury, lose polarity, apoptosis and necrosis, desquamation of cells
microvascular: vasoconstriction increase, smooth muscle damage, leukocyte adhesions
acute tubular necrosis pathophysio
mitochondria dysfunction, ROS
cant absorb salt and water; increase vascular resistance, reduce blood flow, more ROS and cytoksletal rearrange
cells detach from basement membrane and die; tubular back leak; edema
pathogenesis of acute tubular necrosis
Causes of Tubular Injury:
Toxic Injury (e.g., drugs, myoglobin, hemoglobin)
Ischemia (low blood flow) → leads to vasoconstriction and worsens injury
Results of Tubular Injury:
Tubular cells die and slough off
Leads to:
Tubular back-leak (fluid leaks into tissues instead of forming urine)
Obstruction (dead cells clog the tubule)
Interstitial inflammation
Decreased glomerular filtration rate (GFR) → less blood filtered
Clinical Effects:
Decreased urine output (oliguria)
Decreased GFR → worsened kidney function
injury causing acute tubular necrosis
drugs, myoglobin, hemoglobin
findings in acute tubular injury
rupture basement mamebrnae
necrosis
lose brush borders adn polarization
casts- granular proteinaceous mass of Tamm Horsfall protein (uromodulin)
leukocytes in vasa recta
casts in acute tubular injury
casts- granular proteinaceous mass of Tamm Horsfall protein (uromodulin)
3 phases of acute tubular injury
- initiation phase: decrease urine output, increase BUN
- maintenance phase: oliguria, salt and water overload, hyperkalemia, metabolic acidosis
- recovery phase: increase urine volume, Na K and H2o loss due to loss of tubular function
Tubulointerstitial Nephritis (TIN) -
Chronic
causes
Vesico-ureteric reflux
Chronic exposure to medications
toxins (leads, cadmium)
Hyper-uricemia or hyperoxaluria (crystal-induced)
▪ Chronic glomerulonephritis
▪ Chronic UTIs/pyelonephritis
▪ Long-term ischemia
▪ Sickle-cell disease
Tubulointerstitial Nephritis (TIN) -
Chronic
appearance
- Over time, fibrosis and tubular atrophy leads to
shrunken kidneys macroscopically and a
disorganized, cell-poor appearance
microscopically
▪ Tubulointerstitial fibrosis
vesicoureteric reflux causing Tubulointerstitial Nephritis (TIN) -
Chronic
Retrograde flow of urine from bladder to ureter
detrusor muscle no longer effective valve
chronic pyelonephritis; impaired filtration and atrophy
thinned cortex
hypertesnion and protreinuria
sickle cell nephropathy causing chronic Tubulointerstitial Nephritis
sickling events –> necrosis and inflammation–> atrophy and scarring
hypertonic medulla
proteinuria, hematuria, and reduced
concentrating ability
urate nephropathy causing chronic Tubulointerstitial Nephritis
high levels of uric acid
crystalline deposits in kidney parenchyma
benign nephrosclerosis
thickening of arteries in kidneys –> ischemia
▪ Glomerulosclerosis and chronic tubulointerstitial
injury (ischemic) result
▪ Renders nephrons less effective
risks: hypertesnion and diabetes
benign nephrosclerosis patholgoy
thicken tunica media and intima
hyaline deposits, increase basement membrane
shrink cortex, scarred
narrow lumens
ischemia: atrophy, necrosis, fibrosis
impacts of benign nephrosclerosis
Despite the many
morphological changes, usually
does not cause renal
insufficiency or uremia, by itself
small decrease in GFR and tubular function,
common causes of urianry tract obsructuoon
congenital anomalies
urinary calculi
benign prostatic hypertrophy
tumors
prenngacy
uterine prolapse
infalmmation (ie. prostatic)
functional: diabetic nephropathy, spinal cord damage
sloughed papillae
consequences of urinary tract obsruction
infections,
stone formation
renal atrophy ( hydronephrosis or obstructive uropathy)
–>Dilation of the renal pelvis + calyces due to
obstructive outflow of urine
acute vs chronic urinary tract infection
acute: pain, distention, oliguria
chronic: hypertension, tubulointersitial nephritis, cant concentrate urine; polyuria, salt wasting
urolithiasis (kidney stones) types and most common
Calcium stones (70%) – calcium oxalate
Struvite stones (15%) – magnesium ammonium
phosphate
Uric acid stones (5-10%) – associated with gout
Cysteine (1-2%)
calcium oxalate stones
only 5% hypercalcemia
mostly hypercalcuria (in urine) but serum is normal
Calcium inhibits oxalate absorption from the intestine
–>Therefore low calcium diets and/or high oxalate diets tend to greatly increase the risk of stone formation
struvite stones
cause
kidney stones from bacterial infection; turn urea into ammonia
urine is alkaline and precipitate magnesium salts
cause: proteus mirabilis
largest stones; stag horn calculi
uric acid stones
hyperuricemia (high uric acid) with or without gout, leukemia, Lesch-Nyhan syndrome
1/2 have normal serum uric acid
cystine stones
worse with acidic urine
cysteine not reabsorbed but also other amino acids: ornithine, lysine, arginine
features of urolithiasis (kidney stones)
colicky and constant pain, N/V
Smaller stones tend to be more dangerous acutely, since they will migrate down the ureters and cause obstruction as well as renal colic
Larger and smaller stones can result in hematuria
complication in urolithiasis
unilateral so usually dont cause acute renal failure
predispose pt to infection
Autosomal-dominant polycystic
kidney disease
gene mutation in??
Mutations in polycystin-1, polycystin-2, or fibrocystin
Mutation of polycystin-1, which is an integral
transmembrane protein that interacts with components of
ECM
- Can also be caused by mutation of polycystin-2, which is a
calcium channel found in renal tubules
pathophysiology in Autosomal-dominant polycystic
kidney disease
Altered mechanosensation by tubular cilia (sensing fluid flow is impaired)
Altered calcium signaling (flux) inside kidney cells
Both changes lead to altered tubular epithelial growth and differentiation, causing:
Abnormal extracellular matrix production
Excessive cell proliferation
Excess fluid secretion into the tubules
Result:
Cyst formation in the kidneys
Over time, cysts cause:
Glomerular and blood vessel damage
Inflammation and fibrosis (scarring) in the kidney tissue
Autosomal-dominant polycystic
kidney disease
clinical features
massive kidneys
azotemia and uremia and hematuria
liver cysts
real failure
dialysis and transplant needed
