Week 2 (Renal) Flashcards
How does the body maintain a low, stable H+ concentration when our daily acid intake is so high?
1) Buffering: bicarbonate (HCO3-)
2) Excretion through kidneys
3) Elimination through lungs
Henderson-Hasselbach equation
pH = pKa + log (base/acid)
[H+] = Ka x (acid/base)
What happens when you add 1 meq H+?
Lose 1 meq HCO3-
Gain 1 meq CO2
Normal values
pH: 7.37 - 7.43
[HCO3-]: 22-26 meq/L
PCO2: 38 - 42 mmHg
CO2 dis: 1.2 meq/L
Extracellular and intracellular buffers
Extraacellular: HCO3-, inorganic phosphates, plasma proteins
Intracellular: proteins, inorganic and organic phosphates, hemoglobin, bone
Renal acid excretion
1) Reabsorption of filtered bicarbonate: 1 meq reabsorbed HCO3- is equilvalent to 1meq decreased H+
2) Excretion of H+ by titratable acidity (combining H+ with urinary buffers like HPO4)
3) Excretion of H+ using ammonia to form ammonium (NH4+)
What is the anion gap?
Unmeasured anions (this increases in anion gap metabolic acidosis)
Weak acids (proteins like albumin)
Anion gap = Na+ - Cl- - HCO3- (or venous CO2) + [2.5 x (normal albumin - measured albumin)]
Normal anion gap is between 10 and 12
Causes of anion gap metabolic acidosis
MUDPILERS:
Methanol (formic acid), metformin
Uremia
Diabetic ketoacidosis
Propylene glycol
Iron tablets or INH or ingestions (paraldehyde)
Lactic acidosis
Ethylene glycol (oxalic acid)
Rhabdomyolysis or renal failure (sulphate, phosphate, urate, hippurate),
Salicylates (late)
Lactic acidosis
TCA cycle requires O2 (aerobic metabolism) so when you don’t have O2, pyruvate can be reduced to lactate and NADH oxidized to NAD+ and lactate accumulates
Altered redox state: decreased oxygen delivery (shock, cardiac arrest, severe hypoxemia, CO poisoning), reduced oxygen utilization (cyanide intoxication, drug induced (zidovudine)), enhanced metabolic rate (grand mal seizure, severe exercise, severe asthma)
Increased pyruvate production: enzymatic defects in gluconeogenesis (Type I glycogen storage disease), pheochromocytoma
Impaired pyruvate utilization: decreased activity of pyruvate dehydrogenase or pyruvate carboxylase (congenital, acquired (Reye’s Syndrome))
Ketoacidosis
Free fatty acids: may be converted to ketoacids, acetoacetic acid, beta-hydroxybutyric acid
This occurs when: excess fatty acid delivered to liver; hepatocyte function reset preferentially converting fatty acids to ketones and not TGs
Insulin deficiency (stimulation of lipoprotein lipase with breakdown of adipose stores), glucagon excess (due in part to insulin deficiency) and increased epi secretion contribute to these changes
Etiology: uncontrolled T1DM (less commonly with T2DM), fasting (usually not severe), excessive alcohol intake
Associated problems: hypovolemia (may exacerbate acidosis), hyperosmolality causing neurologic symptoms
Treatment: insulin, volume replenishment, bicarb therapy for severe acidemia
Renal failure
Metabolic acidosis is common in advanced renal disease
Mechanism: inability to excrete daily dietary acid load (decrease total NH4+ excretion, decrease titratable acidity (phosphate), reduced HCO3- reabsorption
Usually stabilizes with a HCO3- between 12-20 meq/L and dietary protein restriction
Methanol and ethylene glycol toxicity
Can be detected by history, serum assay, presence of significant osmolar gap (difference calculated and measured, in this case measured will be HIGHER because calculation doesn’t include methanol or ethylene glycol): Posm = 2Na + glucose/18 + BUN/28
Both metabolized to acidic agents by alcohol dehydrogenase
Treatment involves administration of ethanol (since alcohol dehydrogenase has tenfold greater binding affinity for ethanol), hemodialysis, and the treatment of the acidosis
If you see osmolar difference in setting of metabolic gap acidosis, think methanol or ethylene glycol toxicity!
Normal anion gap acidosis
HARD ASS:
Hyperalimentation
Addison’s disease
Renal tubular acidosis
Diarrhea
Acetazolamide
Spironolactone (or hypoaldosteronism)
Saline infusion
Renal tubular acidosis Type 1 (distal)
Decreased H+ secretion distal renal tubules
Urine pH >5.5
Caused by: defect H+ ATPase pump, decreased cortical Na+ reabsorption, increase in membrane permeability allowing back diffusion of H+
Can be caused by autoimmune diseases (Sjogrens, lupus), drugs, obstruction
Associated with hypokalemia, increased risk for calcium phosphate stones as result of increased urine pH and bone resorption
Renal tubular acidosis Type 2 (proximal)
Decreased proximal HCO3- reabsorption
Transient and self-limiting
Diagnosis made with trial HCO3- which causes rapid alkalinization of the urine with high fractional urine excretion of HCO3- (difficult to treat because give bicarb but is just secreted out)
Untreated patients typically have urine pH <5.5
Associated with hypokalemia, increased risk for hypophosphatemic rickets
May be seen with Fanconi’s syndrome, multiple myeloma (accumulation of proteins)
Renal tubular acidosis Type 4 (hyperkalemic)
Hypoaldosteronism or lack of collecting tubule response to aldosterone (aldosterone normally induces H+ secretion through stimulation of H+ ATPase pump and increased luminal electronegativity through Na+ reabsorption)
Resulting hyperkalemia (because can’t excrete K+) impairs ammoniagenesis in proximal tubule, leading to decreased buffering capacity and decreased urine pH (more acidic urine)
Acetazolamide
Carbonic anhydrase inhibitor that induces increased excretion of HCO3- and acts as a diuretic
Treatment of altitude sickness by creating metabolic acidosis inducing hyperventilation which improves high altitude adaptation
Anti-glaucoma agent: decreases aqueous humor by 50-60% (mechanism not known)
Anti-urolithic: alkalinization of urine increases uric acid and cystine solubility in the urine
Treatment of acidosis
Treat underlying problem (lactate, ketoacids, diarrhea, etc)
IV NaHCO3 (controversial): advantages are that it improves vital organ perfusion and reduces serious dysrhythmias; disadvantages are that it causes hypernatremia, could overshoot and cause metabolic alkalosis, metabolic acidosis may be protective during ischemia, intracellular acidosis: CO2 accumulation in tissues from buffering of exogenous HCO3- or due to respiratory insufficiency
Most physicians will treat for pH <7.2
K+ and acidosis treatment
Acidosis may result in normal serum K+ with significant total K+ deficit (H+ goes into cells and K+ comes out and is excreted)
This can cause a significant hypokalemia when the acidosis is treated
Metabolic alkalosis
Contraction alkalosis: extracellular volume contraction around constant HCO3- effectively increases HCO3- concentration: loss of fluid containing Cl- and little HCO3-, loop or thiazide diuretics, GI fluid losses, sweat losses in cystic fibrosis
Loss of H+ ion: GI loss (vomiting, antacid therapy), renal loss (loop or thiazide diuretics, mineralocorticoid excess)
Increased exogenous HCO3-: massive blood transfusion (citrate), administration of NaHCO3
Fluid losses and conditions caused
Vomiting: metabolic alkalosis because fluid lost contains excess H+ inrelation to HCO3-
Diarrhea: metabolic acidosis because fluid lost contains excess of HCO3-
Blood loss: no direct change because both H+ and HCO3- are lost in similar proportion to serum levels
Volume depletion: lactic acidosis caused by hypoperfusion; contraction alkalosis
Respiratory acidosis
Rise in PCO2 (hypercapnia) is considered respiratory acidosis
Fall in PCO2 (hypocapnia) is considered respiratory alkalosis
PCO2 is controlled by only one thing: alveolar minute ventilation
Control of respiration
Control of respiration is controlled by two sets of chemoreceptors:
Central (in medullary brainstem): primarily stimulated by increase in PCO2
Peripheral (in carotid and aortic bodies): primarily stimulated by hypoxemia and H+
Respiratory acidosis
Inhibition of central respiratory drive center: drugs (opiates, sedatives, anesthetics), cardiac arrest, central sleep apnea
Disorders of respiratory muscles and chest wall: myasthenia gravis, Guillain-Barre, polio, multiple sclerosis, kyphosis, obesity
Airway obstruction: aspiration, obstructive sleep apnea, laryngospasm
Disorders affecting gas exchange: ARDS, asthma, pulmonary edema, pneumothorax
Mechanical ventilation
Respiratory alkalosis
Hypoxemia: pulmonary disease, CHF, high altitude
Direct stimulation of respiratory center: gram-negative septicemia, hepatic failure, psychogenic, pregnancy, neurologic disorders (stroke, pontine tumors)
Mechanical ventilation
Mixed acid-base disorders
Patient with severe vomiting (metabolic alkalosis) also has uncontrolled insulin dependent diabetes mellitus with ketoacidosis (metabolic acidosis) and may have additional lactate production from the hypovolemia causing reduced tissue perfusion (ALL CAUSE metabolic acidosis).
Finally, there will be a respiratory compensation with hyperventilation (respiratory alkalosis)
Chronic renal failure (CRF) and chronic kidney disease (CKD)
A loss in GFR, often accompanied by albuminuria and caused by a variety of diseases, that is persistent (>3mo), typically slowly progressive and irreversible
Its manifestations, which are often minimal in its early stages, reflect the loss of renal homeostatic, metabolic, and endocrine and excretory functions
What things ultimately lead to uremia?
1) Obstructive uropathy, chronic glomerulonephritis, chronic interstitial nephritis, diabetic nephropathy, hypertension, congenital
2) Inexorable loss of nephrons and renal function
3) Homeostatic, metabolic, endocrine, excretory
4) Uremia
Note: elevated urea is NOT the cause of symptoms! It’s byproducts of protein metabolism, but uremia used as catchall phrase to describe signs and symptoms of CKD (particularly neurologic manifestations) because of ease of measurement and because historically mistakenly thought of as cause of manifestations of CKD
Stages of CKD
Stage 1: normal GFR (>90 ml/min; 120 ml/min), persistent albuminuria = kidney damage with normal filtration
Stage 2: GFR 60-89 ml/min, persistent albuminuria = kidney damage with mildly decreased filtration
Stage 3: GFR 30-59 ml/min = moderately decreased filtration
Stage 4: GFR 15-29 ml/min = severely decreased filtration
Stage 5: GFR <15 ml/min = kidney failure
Note: nothing new is happening in later stages, it’s just a progression
End stage renal disease (ESRD)
The stage in the evolution of CKD (4 and 5) when adaptive mechanisms become inadequate to avoid morbid and potentially life-threatening clinical manifestations
Preparations for alternative supportive therapy (dialysis, transplantation) are required or death will ensue
Note: good news that patients aren’t sick at the beginning even though losing lots of GFR, but also bad news because lose a lot of GFR without having symptoms so don’t come to get treatment until later stages
Common causes of CKD in the US
Diabetes 40%
Hypertension 28%
Clomerulonephritis 12%
Polycystic disease 3%
Urologic 5%
Unknown 12%
Note: approximately 50% of patients present with ESRD without a proven diagnosis
Why is kidney disease progressive?
Reduced nephron population or DM –> glomerular hypertension and/or metabolic and genetic factors –> cause glomerular injury –> glomerulosclerosis –> systemic hypertension and further decrease in total GFR –> intraglomerular hypertension –> vicious cycle
Other mechanisms of how intraglomerular HTN causes glomerulosclerosis:
Endothelial damage and microaneurysm formation cause intraglomerular thrombosis which causes fibrosis and liberation of plateled derived growth factors (PDGF) –> glomerulosclerosis and mesangial expansion
Increased mesangial traffic of macromolecules causes mesangial expansion which causes glomerulosclerosis
Increased number of macrophages causes liberation of growth factors which causes increased hyalin formation and mesangial expansion –> glomerulosclerosis
“Salt sandwich” of CKD
In health, we can eat as much salt as we want because can make very dilute or very concentrated urine = have high salt ceiling and low salt floor
However, in CKD, kidney’s capacity to both retain salt and get rid of it gets worse = ceiling gets lower and floor gets higher –> if eat too much salt will get hypernatremia and/or volume expansion since ADH still working (maintain osmolality but cannot get rid of excess salt)
Note: some people with CKD commit suicide by eating lots of bananas because cannot excrete K+!
Major signs and symptoms of uremia
MSK: renal osteodystrophy, muscle weakness, decreased growth in children, amyloid arthropathy due to beta2-microglobulin deposition
Hematologic: anemia, platelet dysfunction
Electrolytes: hyperkalemia, metabolic acidosis, edema, hyponatremia, hyperphosphatemia, hypocalcemia, hyperuricemia
Neurologic: encephalopathy, peripheral neuropathy
Cardiovascular: hypertension, pericarditis
Endocrine: carbohydrate intolerance due to insulin resistance, hyperlipidemia, sexual dysfunction (incl infertility in women)
GI: anorexia, nausea, vomiting
CKD and cardiovascular risk
Patients with any degree of CKD have a substantial increase in cardiovascular risk that can be explained in part by an increase in traditional risk factors (HTN, DM, anemia) as well as non-traditional risk factors (inflammation/vascular calcification)
Probability of coronary artery calcification increases as time on dialysis increases (so need to get people transplanted)
30yo patient on dialysis has same risk of cardiovascular mortality as 80yo in general population
Renal osteodystrophy
“Rugger-jersey” spine: alternating sclerosis and porosis
Absorption of distal clavicle
Potentially reversible causes of deterioration of CKD
Infection
Urinary tract obstruction
ECF volume depletion
CHF
Hypertension
Nephrotoxins
Pericardial effusion
Hypercalcemia
Severe hyperuricemia
Management of CKD
Treat reversible causes of renal dysfunction
Prevent or slow progression (ACEI/ARB, diet)
Treat HTN
Limit proteinuria
Prevent and treat complications
Identify and prepare patients requiring renal replacement therapy in a timely fashion
Options for treatment of advanced CKD
No intervention –> death from uremia
Hemodialysis (HD): in center (go 4h for 3x per week) or at home
Peritoneal dialysis (PD): CAPD/CCPD; need lots of training to do this so don’t want to make someone go through it if will just be short term
Kidney transplantation: living donor, deceased donor
CO2 dissolved vs. pCO2
CO2 dissolved is dissolved in the plasma = concentration
pCO2 is is a gas (in the lungs?) = partial pressure
CO2 dissolved is in equilibrium with pCO2
pCO2 (mmHg) x 0.03 = CO2 dissolved (concentration)
Other than buffering, how is it that we can add even MORE acid without changing the pH too much?
You can buffer with HCO3, but you can also increase ventilation (blow off CO2)
In the calculation, you don’t add “x” to the numerator or the CO2 dissolved since you’ll just blow that CO2 off with increased respiration
After bicarb is filtered into tubular lumen, how is it reabsorbed?
90% is reabsorbed in PCT and 10% is reabsorbed in collecting tubule
HCO3- in tubular lumen combines with H+ that has been secreted –> H2CO3 –> carbonic anhydrase turns that into CO2 and H2O –> CO2 diffuses into PCT (or collecting tubule) cell
Inside the PCT cell is negative because of Na/K ATPase, and that causes Na/3HCO3- pump to be active in pumping those ions back into peritubular capillary
Because of this, the CO2 that diffused into that cell is converted by carbonic anhydrase to HCO3- and is reabsorbed back into peritubular capillary
Note: similar process for reabsorption in collecting tubule cell but what creates negative charge there is excretion of H+??
Getting rid of H+ by forming titratable acidity (using HPO4)
Most of this happens in collecting tubule (only some in PCT)
Aldosterone stimulates H+ ATPase to secrete H+ from collecting tubule into tubular lumen –> H+ combines with filtered HPO4 and is excreted as H2PO4-
This system is exhausted fast since only a limited amount of phosphate is filtered
Getting rid of H+ by forming urinary ammonium (NH4+)
Ammonia can freely cross into tubular lumen, and comes from most importantly PCT but also collecting tubule cell (intercalated Type A cell)
Slightly more complex in that NH4+ partially reabsorbed in loop of henle, converted back into NH3 and then resecreted in collecting tubule lumen where is converted to NH4+ to get rid of acid
H+ from collecting tubule combines with NH3 to create ammonium (NH4+) and is excreted because ammonium is trapped and can no longer get back into cells
Natural history of diabetic nephropathy
1) Increased GFR 5 years after onset of T1DM, when nephropathy begins (may be due to increased volume due to glucose, may be due to growth factors?) –> begin to get microalbuminuria as well
2) Hyperfiltration
3) Damage to remaining nephrons causes fall in GFR and damage to GBM –> microalbuminuria turns to heavy proteinuria
4) At this point, have 20-30 years until kidney failure (used to be called 20 year renal retinal syndrome, but now we can treat them)
How does the diseased kidney maintain salt balance?
With fewer nephrons, the diseased kidney filters much less Na+ than usual but still excrete the same amount but secreting a higher percent
In advanced renal failure, have very high FENa to stay in salt balance!
Pseudohyperkalemia due to thrombocytosis
Thrombocytosis with platelets > 1,000,000
Elevated serum K+ but normal plasma K+
Due to excessive cellular release of K+ during blood clotting
If put sample into tube with no heparin, you allow cells to clot which causes release of K+ (this is serum K+)
If put sample into tube with heparin, prevent clotting and prevent release of K+ from cells (this is plasma K+)
No therapy necessary, and in fact it is bad if you try to “treat” the patient
Pseudohyperkalemia due to leukocytosis
Leukocytosis with WBC >100,000
Elevated plasma K+ but normal serum K+
Fragile white cells more susceptible to in vitro destruction during centrifugation when they are freely suspended in the plasma
If put sample into tube with no heparin, you allow cells to clot so the cells cannot lyse and get no release of K+ (this is serum K+)
If put sample into tube with heparin, prevent clotting and cells can lyse and have release of K+ from cells (this is plasma K+)
No therapy necessary
Difference between pseudohyperkalemia due to thrombocytosis vs. leukocytosis
With thrombocytosis you get increased K+ during clotting so if you prevent clotting by adding heparin, you’ll see actual K+ in plasma
With leukocytosis you get increased K+ during centrifugation due to cell lysis so if don’t add heparin, you allow clotting, just take the serum and get actual K+
Pseudohyperkalemia due to hemolysis
In vitro hemolysis
Due to mechanical trauma during venipuncture
Know its due to hemolysis because serum has reddish tint due to release of hemoglobin from red cells
Two ways to get true hyperkalemia
1) Extrarenal causes due to redistribution
2) Renal causes
Note: very hard to get hyperkalemia by eating too much K+
What happens with K+ in diabetes and why?
Diabetics get hyperkalemia because have no insulin and insulin usually stimulates Na/K pump to pump K+ into cells
What inhibits Na/K pump?
Beta blockers
Digoxin
(Lack of insulin)
What happens to K+ during metabolic acidosis?
In metabolic acidosis, have too much H+ in the blood, so you bring H+ into the cell but must exchange that for K+ out
K+ leaves cells and enters bloodstream so get increased K+ in blood (LOOKS like hyperkalemia) but normal overall K+
What happens to K+ during lactic acidosis?
In lactic acidosis, too much H+ and lactate- in bloodstream
Lactate follows proton from blood into cell to TRY TO maintain electroneutrality
Still have to kick out some K+, so get a little increased K+ in the blood (but not as much as in non-lactic acid-metabolic acidosis)
K+ drag
When plasma is hyperosmolar, water shifts out of the cells, but water drags K+ with it due to friction
Remember, way more K+ inside cells than outside cells, and at this point (less water inside cells), chemical gradient higher than electrical gradient so K+ exits cells
How can tissue necrosis cause hyperkalemia?
Tumor lysis
Rhabdomyolysis
In vivo hemolysis
K+ stored in cells so any process that leads to cell necrosis causes hyperkalemia
Can you have problems excreting K+?
Yes, decreased urinary K+ excretion by kidneys can cause hyperkalemia by many mechanisms:
Hypoaldosteronism causes hyperkalemia because cannot excrete K+
Aldosterone receptor blockers
Voltage-dependent secretory defect
Diminished ECV
Renal failure (GFR <10)
Causes of hypoaldosteronism
Type IV renal tubular acidosis: hyperkalemia, low renin, low aldosterone; common in patients with diabetic nephropathy of chronic interstitial nephritis
Primary adrenal insufficiency: hyperkalemia, decreased aldosterone production, low cortisol
Drug-induced hypoaldosteronism: NSAIDs (usually stimulate renin production, but decreased renin causes decreased aldosterone), ACEI (inhibit ATII, inhibit aldosterone), ARII-receptor blocker, heparin (including LMW heparin toxic to adrenal gland so inhibit aldosterone), beta blocker (inhibits renin and thus aldosterone production)
Note: usually aldosterone causes Na+ channels to reabsorb Na+ from lumen, leaving negative charge behind due to Cl- which causes K+ to leave the cell and be excreted
Aldosterone antagonists
Spironolactone
Eplerenone
Voltage-dependent secretory defect
Remember that K+ is secreted because Na+ reabsorption creates negative charge in the lumen so K+ wants to go out
So impairment in cortical collecting tubule Na+ reabsorption causes inability of K+ to be excreted, causing hyperkalemia
Type 1 RTA (hyperkalemic form of Type 1; defect in Na+ reabsorption)
Drugs: bactrim, pentamidine, K+ sparing diuretics which block Na+ channel (amiloride, triamterene)
Diminished effective circulating volume
Leads to increased proximal Na+ and water reabsorption
This causes decreased Na+ and fluid delivery to distal K+ secretory site, so less K+ excretion since Na+ reabsorption and K+ secretion linked here
Renal failure causing hyperkalemia
If in renal failure and GFR <10 ml/min:
Decreased K+ filtration
Diminished Na+ and fluid delivery to distal K+ secretory site so less K+ secretion
EKG findings in hyperkalemia
Peaking of T waves
Flattening of P waves
Prolongation of PR interval
Widening of QRS complex (to sine wave)
V-fib or cardiac arrest
Note: these things happen if K+ >6 or 7
Treatment of hyperkalemia
Give Ca2+ (calcium gluconate) to antagonize hyperkalemic actions on cardiac membrane
Drive extracellular K+ into cells: insulin (glucose to prevent hypoglycemia), NaHCO3, beta agonist (albuterol)
Remove K+ from the body: diuretics (lasix, not ACEI or spironolactone), kayexalate (cation exchange resin which does Na+ exchange for K+ across the gut with no fluid loss and in fact Na+ retention causes volume expansion; use if hypovolemic), dialysis if severe (hemodialysis better than peritoneal for clearing K+)
Pseudohypokalemia due to leukocytosis
Remember, leukocytosis can cause pseudohyper AND pseudohypo!
Cells uptake K+ in vitro
Can prevent cellular uptake by rapid separation of plasma from cells or by storage of blood in fridge to slow metabolic activity
Two causes of hypokalemia
1) Extrarenal causes: characterized by K:creatinine ration <13 meq/g creatinine (kidneys trying to conserve K+)
2) Renal causes: characterized by K:creatinine ratio >13 meq/g creatinine (renal K+ wasting)
Extrarenal causes of hypokalemia
Decreased K+ intake
Increased sweat losses
Redistribution (cells to blood)
Increased GI losses
Redistribution (K+ moving into cells) as cause of hypokalemia
Alkalemia (H+ out of cells and K+ in)
Insulin (causes K+ to go into cells)
Elevated beta adrenergic activity (epi, albuterol/beta-agonists cause K+ to go into cells via 3Na/2K pump)
Marked increase in blood cell production (folate replacement causes cell production and those cells take up K+ to cause hypokalemia)
Increased Na/K exchange causing hypokalema
Increased distal delivery of Na+ to collecting tubule will lead to increased K+ secretion
Diuretics
Vomiting
Proximal RTA
Osmotic diuresis (DKA)
Postobstructive diuresis
Diuretic phase of ATN
Mineralocorticoid excess states
What do loop diuretics do?
Block the Na/K/2Cl pump in the thick ascending loop of henle –> cause hypokalemia due to increased loss of K+ and hypercalciuria because can’t reabsorb Ca2+ as well
Mechanism of these findings: usually Na/K/2Cl pump brings those ions in from lumen and K+ is recycled back out to lumen creating positive charge in lumen and Cl- reabsorbed all the way to peritubular capillaries creating negative charge in capillary –> this gradient causes Ca2+, Na+ and Mg2+ to be reabsorbed from lumen to capillary –> but since no more gradient when you have loop diuretics that block that Na/K/2Cl pump, don’t absorb as much Ca2+ and instead get hypercalciuria
Loop diuretics cause metabolic alkalosis
Loop diuretics cause hypovolemia which causes secondary increased renin and increased aldosterone
Thiazide diuretics
Block Na/Cl cotransporter from bringing ions in at the distal convoluted tubule –> hypokalemiaandhypocalciuria
Can cause hypokalemia because less Na+ reabsorption..??
Drop in intracellular Na+ because less Na+ reabsorbed, and this causes Na+ to be put into cells from blood, which in turn causes Ca2+ reabsorption because of Ca/3Na exchanger on capillary side –> see hypocalciuria
Thiazides used in people with kidney stones to stimulate Ca2+ reabsorption
Also get hypovolemia, then increase renin and increase aldosterone
Primary vs. secondary hyperaldosteronism
Both are mineralocorticoid excess states where you have too much aldosterone, but need to figure out etiology!
Key is renin: primary has decreased renin and secondary has increased renin
Both have hypokalemia, metabolic alkalosis (H+ secretion stimulated by aldosterone), high aldosterone
Primary hyperaldosterism because of adrenal adenoma, bilateral adrenal hyperplasia (low renin in response to too much volume retention)
Secondary hyperaldosteronism because of renal artery stenosis (high renin to try to “get volume up” since kidneys/afferent arterioles see low perfusion), seen in diabetics, those with arteriosclerosis
Treatment for hypokalemia
Can switch to K+ sparing diuretic (spironolactone, aldactone) if on thiazide or loop diuretic
Can also use spironolactone/aldactone if primary hyperaldosteronism to block aldosterone action
Can replace KCl
Use amiloride or triamterene (block Na+ channel to block K+ secretion) if volume overloaded and used lasix and became hypokalemic
Tubulointerstitial disease
Cystic diseases: simple cysts, dialysis associated cysts, inherited syndomes (autosomal dominant, autosomal recessive), cystic renal dysplasia
Acute tubular necrosis (ATN)
Tubulointerstitial nephritis: drug induced interstitial nephritis, acute pyelonephritis, chronic pyelonephritis, reflux associated pyelonephritis
Obstruction (hydronephrosis)
Cystic disease of the kidney
Acquired cysts: simple (majority), dialysis associated
Developmental: renal dysplasia
Hereditary cystic syndromes (ADPKD, ARPKD)
Simple cysts
Single or multiple
Most 1-5cm (rarely 10cm)
Lined by single layer of cuboidal epithelium but as cyst expands, this becomes atrophic and flattened
Usually cortical
No clinical significance other than the fact you have to distinguish them from tumors
Usually incidental finding but rarely present with pain due to bleeding and expansion
Dialysis associated cysts
Patients with end stage renal disease, on prolonged dialysis
Cysts in cortex and medulla, not particularly big
Very rarely you can get adenomas and carcinomas within these cysts
Bleeding may cause hematuria
Pathogenesis: obstruction of tubules by fibrosis; is only dialysis related in that dialysis keeps patient alive long enough for cysts to form
Autosomal dominant polycystic kidney disease (ADPKD)
5-10% of renal failure
Two genetic causes: PKD1 = polycystin 1 (cell membrane protein responsible for cell-cell and cell-matrix interactions; 85%); PKD2 = polycystin 2 (cell membrane protein that is a Ca2+ channel; 10-15%)
PKD1 develop end stage disease more rapidly than PKD2
High penetrance
Need mutations in both alleles (either PKD1 OR PKD2, not one of each) to get cyst formation, but you inherit one germ line mutation and acquire a later somatic mutation
Abnormal interaction of tubular epithelial cells with surrounding matrix (may trigger increased prolif of epithelial cells resulting in cystic dilation)
Cells lining cysts have high proliferation rate and immature phenotype
ECM produced by linig cells is abnormal
Cysts detach from tubules and enlarge by fluid secretion (which contains mediators which enhance secretion and induce inflammation)
Massive enlargement with time, up to 4kg, slowly expanding cysts destroy intervening parenchyma, normal renal function for decades then present with renal failure
Extrarenal manifestations: 40% have liver cysts (mostly asymptomatic but occasionally cause obstruction/destruction of intrahepatic biliary tree leading to ESLD), rare cysts in lung and pancreas (inconsequential), berry aneurysms in circle of Willis cause death from subarachnoid hemorrhage 5-15%, mitral valve prolapse, sigmoid diverticulosis
Variably sized cysts, early on parenchyma between cysts normal but then undergoes fibrosis and atrophy causing obstruction and inflammation
Polycistin 1-2 heterodimer in ADPKD
Polycystin 1 and 2 form heterodimer so malfunction of either results in same phenotype: abnormal Ca2+ enters when heterodimer messed up –> problems with cellular proliferation, apoptosis, interaction with ECM, secretory function
Autosomal recessive polycystic kidney disease (ARPKD)
Present in infant/child, is extremely rare
PKHD1 gene with product fibrocystin; expressed in kidney, liver, pancreas; transmembrane protein, extracellular domain has Ig-like structure; most patients compound heterozygotes
Serious dysfunction at birth, most have liver cysts also
Enlarged kidneys with numerous cysts in cortex and medulla, dilated elongated channels virtually replace cortex and medulla
On histology see cylindrical dilation of collecting ducts: nearly all ducts involved, all nephrons involved, renal failure rapid; cysts lined by cuboidal cells
Cystic renal dysplasia
Most common cause of abdominal mass in newborn; this is developmental problem, have persistence of fetal lobar organization; abnormal structures (cartilage, undifferentiated mesenchyme, immature collecting ducts you usually see during pregnancy only!)
Variable degree of atrophy and cyst formation and not all cases are cystic
Can be unilateral or bilateral
Abnormal metanephric differentiation (NOT premalignant, just arranged badly)
Nearly all cases associated with anomaly of urinary tract (ureteropelvic junction (UPJ) obstruction, ureteral agenesis/atresia)
Obstruction in incompletely developed kidney results in abnormal differentiation of mesenchymal elements
Other cystic diseases
Medullary sponge kidney
Nephronophtisis (medullary cystic disease complex)
Acute tubular necrosis (ATN)
Injury to tubular epithelial cells and/or persistent, severe disturbances in blood flow
Acute diminution or loss of renal function (kidneys stop making urine, creatinine shoots up)
Most common cause of acute renal failure, but is reversible
Caused by ischemia, toxic injury, obstruction
Ischemia causes reduced GFR –> intrarenal vasoconstriction –> reduced glomerular blood flow –> reduced blood flow to tubules
What predisposes tubular cells to injury in ATN?
Extensive surface area which is highly charged for reabsorption
Transport system for ions and organic acids
Capability to carry out concentration
Blood supply by efferent arteriole
Reversible structural changes induced by ischemia on tubular epithelial cells
Loss of polarity: redistribution of membrane proteins from basolateral surface to luminal surface
This causes decreased Na+ reabsorption which causes increased Na+ delivery to distal tubules which through macula densa/JGA induces RAAS causing vasoconstriction at glomerular level which results in further decrease in blood flow to tubules
Pathogenesis of ATN
Necrotic epithelial cells sloughed into lumen and may clog tubules (decreases GFR)
Loss of epithelial cells allows fluid to leak across basement membrane into interstitum (increased interstitial pressure further decreases blood flow)
Injured epithelial cells elaborate cytokines
Factors that favor the reversibility of ATN
Patchiness of injury along nephron (especially with toxins that are reabsorbed by one type of PCT cell but not others)
Profound dysfunction of epithelial cells (structural alterations) but doesn’t KILL the cells
High capacity to replace cells that were lost
Note: ATN used to be fatal but now put patient on fluids, dialysis for short time and they go home!
Recovery from ATN
Proliferation of epithelial cells (cytokines and growth factors elaborated by injured epithelial cells and inflammatory cells): EGF, TGF-a, IGF, hepatocyte growth factor
Histology of ATN
Note: histologic severity does NOT correlate well with degree of dysfunction; different types of ATN preferentially damage diff parts of tubules and some causes of ATN have specific histo features and others don’t (most don’t)
Ranges from mild to extensive necrosis with tubular rupture
Skip areas (injury may be specific to certain portion of the nephron (toxins))
Attenuation/loss of brush border
Thinning of epithelial cells
Vacuolization
Sloughing of necrotic cells (necrotic material in tubular lumen)
Mitotic figures/reactive nuclear changes
Edema
Mild mononuclear inflammation
Casts: hyaline, granular pigmented material, varying degrees of Tamm-Horsfall proteins (normal urinary glycoprotein) and plasma proteins
Causes of ATN associated with specific histologic features
Mercuric chloride: nuclear inclusions
Carbon tetrachloride: accumulation of neutral lipids
Oxalosis: primary or secondary, have numerous oxalate crystals
Light chain cast nephropathy (myeloma kidney): cracked casts and giant cells
Oxalosis
Primary oxalosis: mutation in gene in TCA cycle that results in oxalic acid in serum which deposits in kidney and can destroy kidney; presents in infancy; get liver transplant to treat because even though liver looks normal, have biochemical abnormality in TCA cycle; little glomeruli and expanded Bowman’s space since tubules clogged with oxalic acid and necrosis, so as glomerulus kicks out fluid, BS expands
Secondary oxalosis: from ethylene glycol, rhubarb leaves
Types of tubulointerstitial nephritis
Drug-induced interstitial nephritis (most common)
Acute infectious pyelonephritis
Chronic pyelonephritis
Reflux associated pyelonephritis
Acute cell mediated allograft rejection
Terms: interstitial nephritis is noninfectious; pyelonephritis is bacterial infection (but still tubulointerstitial!); both can be acute or chronic
Note: glomeruli are uninvolved until late in disease
Interstitial nephritis
Drugs and toxins cause interstitial immunologic reaction, NOT direct toxicity
Direct injury to tubules usually results in ATN, not interstitial nephritis
Drug induced interstitial nephritis
Caused by synthetic penicillins (methicillin, ampicillin), sulfonamides, rifampin, thiazide diuretics, maybe NSAIDs
Symptoms begin 15 days after exposure: fever, eosinophilia, rash (25%), hematuria, mild proteinuria, acute renal failure (particularly in elderly)
Treatment: do not biopsy to diagnose, just stop drug right away and put patient on steroids
Histology of drug induced interstitial nephritis
Interstitial edema
Interstitial infiltrate: mononuclear cells, eosinophils and neutrophils, granulomas, lymphocytic tubulitis (lymphocytes which cross basement membrane), tubules look farther apart than usual, have inflammatory cells and edema between them
Variable degree of tubular necrosis, rupture and repair
Pathogenesis of drug induced interstitial nephritis
Idiosyncratic reaction (not dose related)
Increased IgE in some patients: delayed type I hypersensitivity
Granulomas: type IV cell mediated response
Drug is reabsorbed, binds to tubular cell protein or matrix protein: acts as hapten
Nephropathy due to aristolochic acid
“Chinese” herb nephropathy, “Balkan” nephropathy
Weeds producing aristolochic acid contaminate food
Now used as herbal weight loss preparation
Patients present in chronic renal failure: interstitial fibrosis with minimal inflammation
Increased risk of transitional cell carcinoma of kidney and urinary tract
Acute pyelonephritis
Suppurative inflammatory process due to bacterial infection
Most associated with UTI (ascending pyelonephritis)
Hematogenous spread: seeding of kidney by organisms in blood stream
Ascending pyelonephritis
Only small % of UTIs result in pyelonephritis
Risk from UTI associated with repeat UTI, instrumentation, anatomic anomalies, congenital or acquired
E. coli most common organism, but als Proteus, Klebsiella, Enterobacter and Psuedomonas
Colonization of lower urinary urethra is fist step: instrumentation and just being a woman (shorter urethra, hormonal changes affect bacterial adherence, traumatic injury from sexual intercourse, prostatic fluid antibacterial)
Note: men have longer urethra and antibacterial prostatic fluid (more protected from UTI than women)
Ascending pyelonephritis from bladder up to kidneys
Multiplication of organisms in bladder: continual flushing and voiding decreases chance of bacterial growth, postvoid residual urine allows growth
Outflow obstruction: prostatic hypertrophy, tumors, stones
Bladder dysfunction: spinal cord injury, diabetic neuropathy
Vesicoureteral reflux: incompetence of vesicoureteral valve allows reflux of urine into ureters; can be due to congenital defects (shortening of intravesicular portion of ureter so don’t close it off as well), infection (bacterial products decrease contractility of bladder wall), spinal cord injury (atony of bladder)
Upper and lower poles more often involved by pyelonephritis because papillae at poles have flattened concave tips (intrarenal reflux) so more susceptible to backflow of urine, papillae in mid zones pointed convex tips so are resistant to backflow (however, this just means poles affected first…eventually will get everywhere)
Pyelonephritis by hematogenous spread
Patients with systemic bacterial infection may develop pyelonephritis via arterial spread of bacteria resulting in scattered small abscesses throughout the kidneys
Get multiple tiny abscesses everywhere when infection comes in through aorta and renal artery
Histology of acute pyelonephritis
Patchy interstitial inflammation, more prominent in medulla (ascending): neutrophils, lymphocytes, macrophages, tubular lumens filled with neutrophils (most specific feature), tubular necrosis, abscess formation if untreated (destruction of tissue)
Note: do not do biopsy to determine if pt has pyelonephritis, this is a clinical diagnosis
Complications of pyelonephritis
Papillary necrosis (more common in diabetics, obstruction)
Pyonephritis: pelvis filled with puss/neutrophils (obstruction)
Perinephric abscess: infection and inflammation spread into perinephric fat (diabetics)
Chronic pyelonephritis
Reflux associated: may be clinically silent, present with renal failure or nephrotic syndrome (secondary FSGS due to subclinical nephron loss), may present with signs of acute pyelonephritis
Chronic obstruction: extensive overlap in pathogenesis and histology
Ex: child has congenital abnormality, gets veiscoureteral reflux, slowly knock off nephrons, child gets bigger so nephrons get increased load, then develop FSGS secondarily –> get 13 year old presenting with nephrotic syndrome of segmentally sclerotic glomeruli w/background of extensive fibrosis
Note: if there is no scarring, most likely primary FSGS
Obstruction
Increases susceptibility to infection
If unrelieved, hydronephrosis develops (obstructive uropathy)
Can occur anywhere: posterior urethral valve stricture, prostatic hypertrophy, tumors in blader, stones in ureter/bladder interface, tumors compressing/inside urethra, infections of urethra, tumors in pelvis
Variability in presentation and severity and outcomes due to sudden vs. insidious onset, partial vs. complete obstruction, unilateral vs. bilateral obstruction
Hydronephrosis
Results in dilation of pelvis and calyces, atrophy or renal parenchyma
GFR reduced but may continue after obstruction
Backflow into kidney increases pressure in collecting tubules and gluid can diffuse into interstitum and then into venous and lymphatic vessels (GFR can continue)
Medullary vasculature becomes compressed
Decreased medullary function and inability to concentrate urine
Triggers inflammation then fibrosis
GFR decreases with time
Get only mild dilation when obstruction is sudden and complete because GFR impaired sooner so don’t get so much fluid buildup
Get lots of dilation and atrophy when obstruction is incomplete or intermittent because GFR less impaired
Hypertension
May be cause or result of renal disease
Complex and multifactorial pathogenesis (genetic and environmental)
95% idiopathic (essential, primary)
5% secondary (renal or adrenal cause)
Renal artery stenosis
Rare but treateble form of secondary HTN
Atheromatous plaque at origin of renal artery
Fibromuscular dysplasia: more common in women, have intimal/medial/adventitial forms, single constriction or a series of constrictions, clinically similar to essential HTN, angiogram for dx; this is NOT related to atherosclerosis
Mechanisms of secondary HTN
Renal artery stenosis: decreased blood flow so decreased pressure in afferent arteriole so increased renin and increased Na+ reabsorption
Pheochromocytoma: adrenal medullary tumor releases catecholamines which cause vasoconstriction
Malignant HTN
Severe HTN: >200/120
5% of hypertensive patients have severe and rapid rise in BP and will die in 2 years if not treated
Most commonly seen in patients with preexisting benign (low grade) hypertension
Factors influencing BP
Blood volume
Na+ content
Vascular resistance: primary arterioles (neural and hormonal control)
Cardiac output
Renal influence on BP
Renin/angiotensin: increase vascular tone, increase distal tubular absorption of Na+
Antihypertensives made by kidney: NO, prostaglandins
Decrease in blood volume detected in kidney: decreased GFR results in increased Na+ reabsorption
Natiuretic factors: made by heart, inhibit Na+ reabsorption
Essential hypertension
Few single gene examples of essential HTN
Most cases represent cumulative effects of several genes and environment
RAAS
Decreased Na+ excretion
increased vasoconstriction
Structural changes to vessel walls
Environmental factors contributing to HTN
Stress, obesity, smoking, physical inactivity, heavy salt consumption
Pathology of HTN
HTN causes injury to large and medium sized vessles accelerating atherogenesis
Small vessel disease is histologically distinct from large vessel disease: hyaline arteriosclerosis (hyalinosis = trapped plasma proteins), hyperplastic arteriosclerosis
Hyaline arteriosclerosis
Homogenous pink, glassy thickening of arterioles
Loss of structural detail (whole wall replaced with hyaline)
Narrowing of lumen
Due to leakage then accumulation of plasma across endothelium
Excess matrix production by smooth muscle cells in media
Arteriolar hyalinosis: insudates of plasma proteins fill arteriolar wall resulting in decreased luminal diameter and decreased contractility
Causes: chronic low grade HTN, but not just HTN: diabetes, aging, chronic calcineurin inhibitor toxicity (cyclosporin, FK506 = tacrolimus)
Results in glomerulosclerosis through ischemia, glomerular scarring results in loss of entire nephron, small foci or scarring replace nephrons, and contraction of kidneys through scarring
Benign nephrosclerosis
Diagnostic term used to describe the changes in the kidney due to long term benign (low grade) HTN
Increasing incidence with age, HTN, AA, diabetics
More frequent renal failure in AAs, diabetics, paeitns with more severe elevation of BP
Small foci of scarring from small vessel injury: foci of tubular atrophy and interstitial fibrosis, glomeruli have wrinkled tufts due to collapsed loops, BS filled with collagen, periglomerular fibrosis
Hyaline arteriosclerosis
Small arteries have medial hypertrophy, duplication of elastic lamina
Granular cortical surface due to small foci of scarring
Hyperplastic arteriosclerosis
Seen in more severe elevations of blood pressure: malignant hypertension, concentric lamination/thickening of arterial walls, progressive narrowing of arterial lumens, smooth muscle cell hypertrophy and hyperplasia, thickened reduplicated BM
Fibrinoid necrosis in severe examples
Malignant hypertension
Usually seen in patients with underlying benign HTN, glomerulonephritis, scleroderma, higher frequency in AAs and men
Pathogenesis: injury to arteriolar walls, increased permeability, endothelial injury, endothelial cell death, platelet aggregation, thrombosis, hyperplasia of intimal cells (narrowing of lumens), ischemia (elevated renin)
Small petechial hemorrhages on surface (due to ruptured arterioles), fibrinoid necrosis of arterioles and glomeruli (early lesion, eosinophilic granular material fills lumen and infiltrates wall, no or minimal inflammation)
Onion skinning (later lesion) of arterioles: intimal thickening through proliferation of concentrically arranged smooth muscle cells, thin layers of collagen (basement membrane), layers of pale staining material (“mucoid intimal proliferation”) of proteoglycans and plasma proteins
Glomerular involvement: early (fibrin in capillary lumens, capillary microaneurysms), later (double contoured capillary loops bc new layers of basement membrane), ischemic wrinkling, collapse of glomerular tuft (from arteriolar occlusion)
Thrombotic microangiopathy (TMA)
Thrombosis in arterioles and capillaries throughout the body, related to hemolytic anemia, thrombocytopenia, renal failure
Malignant HTN can give picture like this, need to take hx to determine
Adult HUS: verotoxin releasing bacteria, antiphospholipid syndrome (Lupus), pregnancy/contraceptives, drugs (chemo), radiation, scleroderma renal crisis (malignant HTN), familial HUS, idiopathic TTP, malignant HTN
Childhood HUS: verotoxin releasing bacteria (E. coli O157:H7, which is on cheeseburgers, apple juice, spinach and bean sprouts)
Familial HUS
TMA morphology: similar to malignant HTN, thrombi in arterioles and glomeruli, swollen endothelial cells, subendothelial fibrin, cell fragments, mesangiolysis (disruption of BM/mesangial connection results in capillary microaneurysms), with time new BM material produced (see multiple layers of BM) by endothelial cell (if it survived) and get double contours (“splitting”) because of damage to endothelial cells (due to HTN or bacterial toxicity in case of HUS)
Pathogenesis of TMA
Endothelial injury: denudation of BM exposes thrombogenic collagen, reduced production of antithrombotic substances by injured endothelial cells, triggers thrombosis
Platelet aggregation: von willebrand factor multimers secreted by endothelial cells, are large and must be cleaved into smaller multimers, large multimers induce aggregation (if cannot break down multimers because of loss of proteases), congenital or acquired loss of specific proteases result in abnormally large multimers and thrombosis, TTP (many of patients deficient in ADAMTS-13, a metalloprotease)
Renal disease in diabetes
Advanced renal disease in 40% of diabetics
Clinical syndromes: nonnephrotic proteinuria, nephrotic syndrome, chronic renal failure
HTN in diabetics increases the risk of developing diabetic nephropathy
Microalbuminuria: 30-300 mg/day of albumin, develops within a few years of diabetes
Overt proteinuria: >300 mg/day develops in 50% of diabetics within 12-22 years, followed by end stage renal disease within 5 years in many patients
Diabetic nephropathy
Glomerular lesions, tubular lesions, vascular lesions, pyelonephritis (papillary necrosis, perinephric abscesses)
Thickened capillary loop BM: changes begin within few years of onset, early changes only on EM, progressive, simultaneous thickening of tubular BMs
Diffuse mesangial sclerosis: mesangial expansion due to increased matrix, mild mesangial cell proliferation early in disease, with progression expansion of mesangial areas becomes nodular, progressive expansion correlates with deterioration of renal function
Nodular glomerular sclerosis: mesangial expansion by matrix appears nodular, mesangiolysis often seen (disruption of sites at which capillaries are anchored to mesangium results in capillary aneurysms (distension of capillary loops due to intraglomerular pressure)), nodules expand and eventually obliterate open loops, Kimmelstiel-Wilson lesions, seen in 25% of patients with diabetic nephropathy
Good glycemic control slows development of diabetic nephropathy, pancreatic transplantation can reverse many of the changes
Diabetic nephropathy hyalinosis
Hyalinosis in glomeruli
Trapped plsama proteins in capillary loops: fibrin caps (misnomer because not fibrin)
Insudates in Bowman’s capsule BM (capsular drops)
Diabetes pathogenesis
Formation of advanced glycation end products (AGE)
Activation of protein kinase C
Intracellular hyperglycemia with disturbances of polyol pathways
Glycosylation of matrix proteins: abnormal matrix-matrix and matrix-cell interactions, decreased endothelial cell adherence to BM (allows increased fluid filtration (hyalinosis)), glycosylated proteins are more resistant to proteolytic degradation (decreased removal of abnormal proteins), glycosylation of BM may cause other proteins to bind
Circulating proteins modified by AGE residues
Proteins with AGE residues bind to AGE receptors on numerous cell types and induce production of cytokines, growth factors, proinflammatory molecules
What are the anions in the “anion gap?”
Proteins, albumin
Causes of increased anion gap
Special types of metabolic acidosis: lactate, ketones, uremia, intoxication with salicylate, methanol, ethylene glycol, paraldehyde (overall remember MUDPILERS)
Decreased K+, Ca2+, Mg2+
Increased albumin
Alkalosis (neutral albumin shifts to albumin -)
Causes of decreased anion gap
Decreased albumin concentration (2.5 mEq/L decrease in AG for every 1g/dL decrease in albumin concentration)
Increase in K+, Ca2+, Mg2+, lithium, bromide
Multiple myeloma (cationic Ig: para-proteins)
Methanol intoxication
Methanol intoxication causes metabolic gap acidosis due to formic acid (which is also toxic)
Causes blindness then death
What causes elevated plasma osmolal gap without anion gap metabolic acidosis?
Ethanol intoxication, isopropyl alcohol intoxication, mannitol intoxication and glycine administration
What causes anion gap metabolic acidosis with elevated plasma osmolal gap?
Methanol intoxication
Ethylene glycol intoxication
Ketoacidosis
Lactic acidosis
Chronic renal failure
What causes non-gap metabolic acidosis and elevated plasma osmolal gap?
Multiple myeloma causing proximal renal tubular acidosis
What causes elevated plasma osmolal gap and decreased plasma anion gap?
Multiple myeloma
Patients given IVIG (contains maltose)
Salicylate (Aspirin) Toxicity
Toxic >40-50 mg/dL
Tinnitus –> vertigo –> N/V –> seizure –> death
In early phase get hyperventilation (respiratory alkalosis)
Blocking oxidative metabolism –> metabolic acidosis because of accumulation of organic acids
Treat with IV bicarb or hemodialysis for severe cases
What do dysmorphic RBCs and RBC casts indicate?
RBC casts indicate acute glomerulonephritis unless proven otherwise
Both are indicative of glomerular process
Tamm-Horsfall protein
This protein is produced in thick ascending limb of loop of henle and is the matrix for all urinary casts (like glue that other cells that sloughed off stick to)
If no cells, you can get hyaline casts that are just pure Tamm-Horsfall proteins
What happens if cells sloughed off tubules but sat for a while before exiting in the urine?
Coarsely granular casts mean sat around for a while (can’t tell what kind of cells they are, just that they’ve been sitting for a while)
Finely granular casts also sat around and waxy casts sat around for longest
How can you tell if a patient has AKI on top of CKD?
Change in eGFR vs. time
See progressive decline in eGFR due to CKD, but if AKI then see abrupt drop too
Glomerular vs. tubular kidney disease
Glomerular: significant proteinuria (>1,000 mg/day; HMW protein that gets through because of GMB damage), dysmorphic RBCs or RBC casts
Tubular: minimal proteinuria (<1,000 mg/day; this is LMW proteins that are normally filtered but now cannot be reabsorbed in PCT because tubules are damaged), muddy brown casts (only see this if get urine right away, might not be there the next day), bland urine
Treatment for IgA nephropathy
Fish oil (antiinflammatory and reduces mesangial proliferation)
Hypertension control
ACEI or ARB
Glucocorticoids (if acute only?)
Alkylating cytotoxic agents if progressive disease?
Slowing progression of CKD
BP control
RAAS inhibitors (ACEI, ARB, if neither of those then mayb RI)
Maintain serum bicarb >22 (chronic metabolic acidosis can interfere with bone and muscle metabolism, can induce interstitial inflammatory changes that make kidney disease progress faster; give NaCHO3 or sodium bicitrate)
Diabetics maintain HbA1C <7%
Avoid NSAIDs (especially long-acting ones like aleeve because those worse for kidney)
Acute vs. chronic renal failure
Acute: acute presentation, significant symptoms, hyperkalemia, normal to large kidneys, normal hb/hct
Chronic: chronic history (of not feeling well for a few months), vague symptoms, normo- to hyperkalemia (gut tries to compensate and secrete K+), small to normal kidneys, low hb/hct, significant bone disease
Why don’t some diabetics have small kidneys even in end stage disease?
Early in disease diabetics have hyperfiltration so have lots of blood in kidney and they get enlarged
Toward end of disease, kidneys sclerose and shrink down but end up being about normal sized
Where is erythropoietin made?
Peritubular cells of kidneys
Urolithiasis
Kidney stones = renal calculi
More common in men, age 20-30
Renal colic due to kidney stones in ureter is horrible pain
Present with flank pain and hematuria (micro or macroscopic)
Calcium stones (70%; are made of calcium oxalate), struvite stones (15%; made of Mg2+, NH4+, PO4 and usually in UTI with Proteus or Staph that convert urea to ammonia), uric acid stones (5-10%; radiolucent and associated with gout and leukemia (rapid cell turnover with uric acid production)), cystine
Mostly due to idiopathic calciuria (high Ca2+ for unknown reason) but can form in those with high Ca2+ due to hyperparathyroidism, sarcoidosis, or due to bowel resection (cannot reabsorb bile acids so more bile acids excreted in gut –> bile acids bind Ca2+ in the gut, so now oxalate cannot bind as much Ca2+ to get excreted in the gut –> oxalate reabsorbed and filtered into urine and higher levels of oxalate being excreted in the urine and can bind Ca2+ and cause precipitation of Ca2+ stones)
Paraneoplastic syndromes caused by renal cell carcinoma
Polycythemia (EPO)
Hypercalcemia (PTHrP)
Hypertension
Liver dysfunction
Feminization or masculinization
Cushing syndrome
Leukemoid reactions
Amyloidosis
