Physiology 31: Diuretics, Kidney Diseases
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Many diuretics decrease Na reabsorption -> natriuresis which causes diuresis
o May raise renal output of K, Cl, Mg and Ca, too
o Effect of diuretics subsides within few days (activation of other compensatory
mechanisms)
Injection of urea, mannitol, and sucrose (not reabsorbed) into blood or excess glucose in DM
cause increase in osmotically active molecules in proximal tubule -> reduces water reabsorption
= osmotic diuretics
Furosemide, ethacrynic acid, and bumetanide decrease reabsorption in thick ascending limb of
loop of Henle (block 1-sodium, 2-chloride, 1-potassium cotransporters) = loop diuretics
o Increased solutes reaching distal nephron prevent H2O reabsorption
o Disrupt countercurrent multiplier system (decreasing osmolarity of medullary interstitial
fluid) so can’t concentrate or dilute urine
Thiazide diuretics (chlorothiazide) act on early distal tubule blocking Na-Cl cotransporter
Acetazolamide inhibits carbonic anhydrase so no reabsorption of HCO3 in proximal tubule (site
of action of carbonic anhydrase inhibitors) and also low Na reabsorption (osmotic diuresis)
o Cause some degree of acidosis
Spironolactone and eplerenone = mineralocorticoid receptor antagonists (competitive inhibitors
of aldosterone) so decrease Na reabsorption and K secretion in collecting tubule
o Osmotic diuresis and K movement from ICF to ECF = potassium-sparing diuretics
Amiloride and triamterene inhibit Na reabsorption and K secretion in collecting tubules (block
entry of Na into Na channels so ↓ Na-K-ATP pump activity = potassium-sparing diuretics
Acute renal failure = kidneys abruptly stop working may recover
o Prerenal acute renal failure -> ↓ blood supply to kidney reduced GFR (↓ urine output =
ologuria or anuria)
 Can usually be reversed if BF doesn’t fall below 20-25% normal (large range due
to E sparing from low NaCl reabsorption)
o Intrarenal acute renal failure -> abnormalities within the kidney from 1) injured
glomerular capillaries, 2) damaged renal tubular epithelium, 3) damage to renal
interstitium
 Glomerulonephritis = immune reaction damaging basement membrane of
glomeruli (group A beta streptococci); mesangial cells proliferate blocking
glomeruli (subsides within 2 weeks but may lead to chronic renal failure)
 Tubular necrosis = destruction of epithelial cells from…
 Severe ischemia -> circulatory shock, tubular cells “slough off” and plug
nephrons so anuria
 Poison, toxins, or medications -> carbon tetrachloride, heavy metals ,
ethylene glycol (in antifreeze), insecticides, tetracyclines, cis-platinum
o If basement membrane intact, may regrow epithelium
o Postrenal acute renal failure -> abnormalities in lower urinary tract (i.e. bilateral
obstruction from stones or blood clots, bladder obstruction, urethra obstruction)
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Effect of acute renal failure = retention of water, waste products and electrolytes
(edema and hypertension). Hyperkalemia (>8 mEq/L) can be fatal, metabolic acidosis
can aggravate.
Chronic renal failure = progressive and irreversible loss of nephron (70-75% below normal)
o Causes = DM, obesity, amyloidosis, hypertension, atherosclerosis, PAN, lupus
erythematosus, glomerulonephritis, pyelonephritis, tuberculosis, nephrotoxins, renal
caliculi, prostatic hypertrophy, urethral constriction, polycystic disease, renal hypoplasia
o End-stage renal disease (ESRD) = deterioration to point of dialysis or transplant
 Surgical removal of diseased portion causes other portion to hypertrophy but
eventually additional injury may occur from chronic increase in pressure
(sclerosis)
 To slow ESRD, lower BP and glomerular hydrostatic pressure (ACE inhibitors)
 Diabetes and hypertension are the leading causes of ESRD with obesity being
the highest risk factor
Atherosclerosis of large arteries, fibromuscular hyperplasia, and nephrosclerosis of smaller
arteries can lead to renal ischemia
o Atherososclerosis and hyperplasia frequently unilateral diminished fxn
o Benign nephrosclerosis (most common kidney disease) -> in interlobular arteries and
afferent arterioles, leakage of plasma with fibrinoid deposits leading to
glomerulosclerosis (↓GFR and renal BF)
 If with sever hypertension -> malignant nephrosclerosis (large amount of
fibrinoid deposit in arterioles). Higher in blacks
Chronic glomerulonephritis is slowly preogressive (irreversible renal failure)
o May be secondary to lupus erythematosus with accumulation of antigen-antibody
complexes
Interstitial nephritis = disease of renal interstitium destroying individual nephrons
o Caused by bacterial infection especially E. coli -> pyelonephritis (begins in renal medulla
so counter-current multiplier affected -> can’t concentrate urine)
o Inability of bladder to empty and obstruction of urine flow interfere with flushing of
bacteria out -> bacteria multiply (cystitis)
 Vesicoureteral reflux -> ascension of urine up ureters during micturition
(allowing bacteria to reach renal pelvis)
Nephrotic syndrome = loss of large quantities of plasma protein in urine (increased permeability
of glomerular membrane)
o Caused by: chronic glomerulonephritis, amyloidosis, minimal change nephrotic syndrome
(loss of negative charges in basement membrane usually in children 2-6 y and may cause
severe edema)
Reduction of nephrons below 20-25% normal may lead to edema and death
o Waste products accumulate in proportion to number of nephrons destroyed (urea and
creatinine) because kidney excretion is only route to remove
o Phosphate, urate and H+ maintained near normal until GFR below 20% normal (excrete
large fractions of solutes by decreasing reabsorption)
o
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Na and Cl maintained constant by decreasing reabsorption (nephrons excrete more Na
and water)
 Adaptation from increased GFR and BF to surviving nephrons (hypertrophy)
o Isothenuria = inability to concentrate or dilute urine
 Concentration impaired because rapid flow through collecting ducts of
remaining nephrons prevents adequate H2O reabsorption and prevents
countercurrent mechanism from being effective (urine osmolarity and specific
gravity approach those of glomerular filtrate) -> effected more than dilution
 Diluting impaired because rapid fluid and high solutes in loop of Henle
Renal failure effect depends on H2O and food intake and degree of impairment.
With normal intake following failure -> generalized edema, acidosis, high concentration of
nonprotein nitrogens (urea, creatinine, uric acid), high concentrations of phenols, sulfates,
phosphates, potassium and guanidine bases = uremia
o May limit with water intake restriction
o Not severe until kidney function falls to 25% of normal
Chronic renal failure may lead to severe hypertension from excessive renin secretion (remove
Na and ECF by dialysis)
Nonprotein nitrogens are end products of protein metabolism must be removed
o Concentrations rise in proportion to degree of impairment (measuring them assesses
degree of renal failure)
Buffers of the body normally bugger 500-1000 mmoles of acid and phosphate in bones can
buffer few thousand mmoles (all used up with renal failure)
Decreased secretion of erythropoietin in renal failure -> anemia
Prolonged renal failure -> osteomalacia (due to reduction in active vitamin D and rise in serum
phosphate from decreased GFR -> decreases plasma serum ionized Ca stimulates PTH)
Hypertension is major cause of ESRD but can also be caused by damage (vicious cycle)
o Renal lesions decreasing ability to excrete Na and H2O cause hypertension (decrease
GFR or increase tubular reabsorption)
 Increased renal vascular resistance (renal a stenosis)
 Decreased Kf reduces GFR (chronic glomerulonephritis)
 Excessive tubular Na reabsorption (excess aldosterone)
o Hypertension returns excretion levels to normal (pressure naturesis and diuresis)
o Patchy renal damage from ischemia increase secretion of renin -> hypertension
Loss of nephrons may lead to renal failure if large enough but if remaining nephrons normal may
not cause hypertension if salt is restricted
Renal glycosuria = failure to reabsorb glucose
Aminoaciduria = failure to reabsorb AAs
o Generalized aminoaciduria -> all AAs involved
o Essential cystinuria -> failure to reabsorb cystine
o Simple glycinuria -> failure to reabsorb glycine
o Beta-aminoisobutricaciduria
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Renal hypophosphatemia = failure to reabsorb phosphate (over long period decreases bone
calcification -> rickets refractory to vitD therapy)
Renal tubular acidosis = failure of tubules to secrete H+ (NaHCO3 lost in urine)
o Continuous state of metabolic acidosis
Nephrogenic diabetes insipidus = failure to respond to ADH (must supply with plenty of water)
Fanconi’s syndrome = generalized reabsorptive defect with increased excretion of all AAs,
glucose and phosphate (proximal tubules esp affected)
o if sever -> failed NaHCO3 reabsorption, excretion of K and Ca and nephrogenic diabetes
insipidus
o Causes = hereditary, toxins or drugs, ischemic injury
Bartter’s Syndrome = decreased Na, Cl, and K reabsorption in loops of Henle (impaired 1sodium, 2-chloride, and 1-potassium cotransporters) -> hypokalemia and metabolic alkalosis
Gitelman’s Syndrome = decreased NaCL reabsorption in distal tubules; disorder of thiazidesensitive Na-Cl cotransporter (cannot be corrected so replace lost NaCl and K)
Liddle’s Syndrome = increased Na reabsorption (mutations in amiloride-sensitive ENaC in distal
and collecting tubules -> hypertension and metabolic alkalosis and decreased aldosterone levels
Transplantation of kidnery to patient with ESRD can restore normal homeostasis
o Maintain on immunosuppressive therapy (increased risk for infection and cancer)
Dialysis used as alternative to remove waste products (health impaired tho because can’t
replace all functions of kidney)
o Pass blood through channels of thin membrane with dialyzing fluid on other side (waste
products diffuse across). Prevent coagulation, infuse heparin. Maximize diffusion with
hydrostatic pressure force = bulk flow
o Rate of diffusion depends on [] gradient, permeability or membrane to solute,
membrane surface area, and length of time blood in contact with membrane
 Maximum when dialysis is begun but can be adjusted more with hemodialysis
(flowing system)
Dialyzing fluid = ion levels adjusted to allow movement of H2O and solutes (no phosphate, urea,
urate, sulfate, or creatinine)
o Effectiveness is by amount of plasma cleared of different substances each minute
o Most clear urea at rate of 100-225 ml/min but used 4-6 hrs/day, 3 times/wk