Week 2 (Renal)

Question 1

How does the body maintain a low, stable H+ concentration when our daily acid intake is so high?

Answer 1

1) Buffering: bicarbonate (HCO3-)
2) Excretion through kidneys
3) Elimination through lungs

Question 2

Henderson-Hasselbach equation

Answer 2

pH = pKa + log (base/acid)

[H+] = Ka x (acid/base)

Question 3

What happens when you add 1 meq H+?

Answer 3

Lose 1 meq HCO3-

Gain 1 meq CO2

Question 4

Normal values

Answer 4

pH: 7.37 - 7.43

[HCO3-]: 22-26 meq/L

PCO2: 38 - 42 mmHg

CO2 dis: 1.2 meq/L

Question 5

Extracellular and intracellular buffers

Answer 5

Extraacellular: HCO3-, inorganic phosphates, plasma proteins

Intracellular: proteins, inorganic and organic phosphates, hemoglobin, bone

Question 6

Renal acid excretion

Answer 6

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+)

Question 7

What is the anion gap?

Answer 7

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

Question 8

Causes of anion gap metabolic acidosis

Answer 8

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)

Question 9

Lactic acidosis

Answer 9

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))

Question 10

Ketoacidosis

Answer 10

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

Question 11

Renal failure

Answer 11

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

Question 12

Methanol and ethylene glycol toxicity

Answer 12

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!

Question 13

Normal anion gap acidosis

Answer 13

HARD ASS:

Hyperalimentation

Addison’s disease

Renal tubular acidosis

Diarrhea

Acetazolamide

Spironolactone (or hypoaldosteronism)

Saline infusion

Question 14

Renal tubular acidosis Type 1 (distal)

Answer 14

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

Question 15

Renal tubular acidosis Type 2 (proximal)

Answer 15

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)

Question 16

Renal tubular acidosis Type 4 (hyperkalemic)

Answer 16

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)

Question 17

Acetazolamide

Answer 17

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

Question 18

Treatment of acidosis

Answer 18

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

Question 19

K+ and acidosis treatment

Answer 19

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

Question 20

Metabolic alkalosis

Answer 20

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

Question 21

Fluid losses and conditions caused

Answer 21

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

Question 22

Respiratory acidosis

Answer 22

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

Question 23

Control of respiration

Answer 23

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+

Question 24

Respiratory acidosis

Answer 24

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

Question 25

Respiratory alkalosis

Answer 25

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

Question 26

Mixed acid-base disorders

Answer 26

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)

Question 27

Chronic renal failure (CRF) and chronic kidney disease (CKD)

Answer 27

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

Question 28

What things ultimately lead to uremia?

Answer 28

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

Question 29

Stages of CKD

Answer 29

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

Question 30

End stage renal disease (ESRD)

Answer 30

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

Question 31

Common causes of CKD in the US

Answer 31

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

Question 32

Why is kidney disease progressive?

Answer 32

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

Question 33

“Salt sandwich” of CKD

Answer 33

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+!

Question 34

Major signs and symptoms of uremia

Answer 34

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

Question 35

CKD and cardiovascular risk

Answer 35

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

Question 36

Renal osteodystrophy

Answer 36

“Rugger-jersey” spine: alternating sclerosis and porosis

Absorption of distal clavicle

Question 37

Potentially reversible causes of deterioration of CKD

Answer 37

Infection

Urinary tract obstruction

ECF volume depletion

CHF

Hypertension

Nephrotoxins

Pericardial effusion

Hypercalcemia

Severe hyperuricemia

Question 38

Management of CKD

Answer 38

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

Question 39

Options for treatment of advanced CKD

Answer 39

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

Question 40

CO2 dissolved vs. pCO2

Answer 40

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)

Question 41

Other than buffering, how is it that we can add even MORE acid without changing the pH too much?

Answer 41

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

Question 42

After bicarb is filtered into tubular lumen, how is it reabsorbed?

Answer 42

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+??

Question 43

Getting rid of H+ by forming titratable acidity (using HPO4)

Answer 43

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

Question 44

Getting rid of H+ by forming urinary ammonium (NH4+)

Answer 44

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

Question 45

Natural history of diabetic nephropathy

Answer 45

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)

Question 46

How does the diseased kidney maintain salt balance?

Answer 46

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!

Question 47

Pseudohyperkalemia due to thrombocytosis

Answer 47

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

Question 48

Pseudohyperkalemia due to leukocytosis

Answer 48

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

Question 49

Difference between pseudohyperkalemia due to thrombocytosis vs. leukocytosis

Answer 49

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+

Question 50

Pseudohyperkalemia due to hemolysis

Answer 50

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

Question 51

Two ways to get true hyperkalemia

Answer 51

1) Extrarenal causes due to redistribution
2) Renal causes

Note: very hard to get hyperkalemia by eating too much K+

Question 52

What happens with K+ in diabetes and why?

Answer 52

Diabetics get hyperkalemia because have no insulin and insulin usually stimulates Na/K pump to pump K+ into cells

Question 53

What inhibits Na/K pump?

Answer 53

Beta blockers

Digoxin

(Lack of insulin)

Question 54

What happens to K+ during metabolic acidosis?

Answer 54

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+

Question 55

What happens to K+ during lactic acidosis?

Answer 55

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)

Question 56

K+ drag

Answer 56

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

Question 57

How can tissue necrosis cause hyperkalemia?

Answer 57

Tumor lysis

Rhabdomyolysis

In vivo hemolysis

K+ stored in cells so any process that leads to cell necrosis causes hyperkalemia

Question 58

Can you have problems excreting K+?

Answer 58

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)

Question 59

Causes of hypoaldosteronism

Answer 59

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

Question 60

Aldosterone antagonists

Answer 60

Spironolactone

Eplerenone

Question 61

Voltage-dependent secretory defect

Answer 61

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)

Question 62

Diminished effective circulating volume

Answer 62

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

Question 63

Renal failure causing hyperkalemia

Answer 63

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

Question 64

EKG findings in hyperkalemia

Answer 64

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

Question 65

Treatment of hyperkalemia

Answer 65

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+)

Question 66

Pseudohypokalemia due to leukocytosis

Answer 66

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

Question 67

Two causes of hypokalemia

Answer 67

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)

Question 68

Extrarenal causes of hypokalemia

Answer 68

Decreased K+ intake

Increased sweat losses

Redistribution (cells to blood)

Increased GI losses

Question 69

Redistribution (K+ moving into cells) as cause of hypokalemia

Answer 69

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)

Question 70

Increased Na/K exchange causing hypokalema

Answer 70

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

Question 71

What do loop diuretics do?

Answer 71

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

Question 72

Thiazide diuretics

Answer 72

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

Question 73

Primary vs. secondary hyperaldosteronism

Answer 73

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

Question 74

Treatment for hypokalemia

Answer 74

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

Question 75

Tubulointerstitial disease

Answer 75

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)

Question 76

Cystic disease of the kidney

Answer 76

Acquired cysts: simple (majority), dialysis associated

Developmental: renal dysplasia

Hereditary cystic syndromes (ADPKD, ARPKD)

Question 77

Simple cysts

Answer 77

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

Question 78

Dialysis associated cysts

Answer 78

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

Question 79

Autosomal dominant polycystic kidney disease (ADPKD)

Answer 79

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

Question 80

Polycistin 1-2 heterodimer in ADPKD

Answer 80

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

Question 81

Autosomal recessive polycystic kidney disease (ARPKD)

Answer 81

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

Question 82

Cystic renal dysplasia

Answer 82

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

Question 83

Other cystic diseases

Answer 83

Medullary sponge kidney

Nephronophtisis (medullary cystic disease complex)

Question 84

Acute tubular necrosis (ATN)

Answer 84

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

Question 85

What predisposes tubular cells to injury in ATN?

Answer 85

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

Question 86

Reversible structural changes induced by ischemia on tubular epithelial cells

Answer 86

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

Question 87

Pathogenesis of ATN

Answer 87

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

Question 88

Factors that favor the reversibility of ATN

Answer 88

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!

Question 89

Recovery from ATN

Answer 89

Proliferation of epithelial cells (cytokines and growth factors elaborated by injured epithelial cells and inflammatory cells): EGF, TGF-a, IGF, hepatocyte growth factor

Question 90

Histology of ATN

Answer 90

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

Question 91

Causes of ATN associated with specific histologic features

Answer 91

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

Question 92

Oxalosis

Answer 92

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

Question 93

Types of tubulointerstitial nephritis

Answer 93

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

Question 94

Interstitial nephritis

Answer 94

Drugs and toxins cause interstitial immunologic reaction, NOT direct toxicity

Direct injury to tubules usually results in ATN, not interstitial nephritis

Question 95

Drug induced interstitial nephritis

Answer 95

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

Question 96

Histology of drug induced interstitial nephritis

Answer 96

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

Question 97

Pathogenesis of drug induced interstitial nephritis

Answer 97

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

Question 98

Nephropathy due to aristolochic acid

Answer 98

“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

Question 99

Acute pyelonephritis

Answer 99

Suppurative inflammatory process due to bacterial infection

Most associated with UTI (ascending pyelonephritis)

Hematogenous spread: seeding of kidney by organisms in blood stream

Question 100

Ascending pyelonephritis

Answer 100

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)

Question 101

Ascending pyelonephritis from bladder up to kidneys

Answer 101

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)

Question 102

Pyelonephritis by hematogenous spread

Answer 102

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

Question 103

Histology of acute pyelonephritis

Answer 103

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

Question 104

Complications of pyelonephritis

Answer 104

Papillary necrosis (more common in diabetics, obstruction)

Pyonephritis: pelvis filled with puss/neutrophils (obstruction)

Perinephric abscess: infection and inflammation spread into perinephric fat (diabetics)

Question 105

Chronic pyelonephritis

Answer 105

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

Question 106

Obstruction

Answer 106

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

Question 107

Hydronephrosis

Answer 107

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

Question 108

Hypertension

Answer 108

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)

Question 109

Renal artery stenosis

Answer 109

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

Question 110

Mechanisms of secondary HTN

Answer 110

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

Question 111

Malignant HTN

Answer 111

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

Question 112

Factors influencing BP

Answer 112

Blood volume

Na+ content

Vascular resistance: primary arterioles (neural and hormonal control)

Cardiac output

Question 113

Renal influence on BP

Answer 113

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

Question 114

Essential hypertension

Answer 114

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

Question 115

Environmental factors contributing to HTN

Answer 115

Stress, obesity, smoking, physical inactivity, heavy salt consumption

Question 116

Pathology of HTN

Answer 116

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

Question 117

Hyaline arteriosclerosis

Answer 117

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

Question 118

Benign nephrosclerosis

Answer 118

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

Question 119

Hyperplastic arteriosclerosis

Answer 119

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

Question 120

Malignant hypertension

Answer 120

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)

Question 121

Thrombotic microangiopathy (TMA)

Answer 121

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)

Question 122

Pathogenesis of TMA

Answer 122

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)

Question 123

Renal disease in diabetes

Answer 123

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

Question 124

Diabetic nephropathy

Answer 124

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

Question 125

Diabetic nephropathy hyalinosis

Answer 125

Hyalinosis in glomeruli

Trapped plsama proteins in capillary loops: fibrin caps (misnomer because not fibrin)

Insudates in Bowman’s capsule BM (capsular drops)

Question 126

Diabetes pathogenesis

Answer 126

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

Question 127

What are the anions in the “anion gap?”

Answer 127

Proteins, albumin

Question 128

Causes of increased anion gap

Answer 128

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 -)

Question 129

Causes of decreased anion gap

Answer 129

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)

Question 130

Methanol intoxication

Answer 130

Methanol intoxication causes metabolic gap acidosis due to formic acid (which is also toxic)

Causes blindness then death

Question 131

What causes elevated plasma osmolal gap without anion gap metabolic acidosis?

Answer 131

Ethanol intoxication, isopropyl alcohol intoxication, mannitol intoxication and glycine administration

Question 132

What causes anion gap metabolic acidosis with elevated plasma osmolal gap?

Answer 132

Methanol intoxication

Ethylene glycol intoxication

Ketoacidosis

Lactic acidosis

Chronic renal failure

Question 133

What causes non-gap metabolic acidosis and elevated plasma osmolal gap?

Answer 133

Multiple myeloma causing proximal renal tubular acidosis

Question 134

What causes elevated plasma osmolal gap and decreased plasma anion gap?

Answer 134

Multiple myeloma

Patients given IVIG (contains maltose)

Question 135

Salicylate (Aspirin) Toxicity

Answer 135

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

Question 136

What do dysmorphic RBCs and RBC casts indicate?

Answer 136

RBC casts indicate acute glomerulonephritis unless proven otherwise

Both are indicative of glomerular process

Question 137

Tamm-Horsfall protein

Answer 137

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

Question 138

What happens if cells sloughed off tubules but sat for a while before exiting in the urine?

Answer 138

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

Question 139

How can you tell if a patient has AKI on top of CKD?

Answer 139

Change in eGFR vs. time

See progressive decline in eGFR due to CKD, but if AKI then see abrupt drop too

Question 140

Glomerular vs. tubular kidney disease

Answer 140

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

Question 141

Treatment for IgA nephropathy

Answer 141

Fish oil (antiinflammatory and reduces mesangial proliferation)

Hypertension control

ACEI or ARB

Glucocorticoids (if acute only?)

Alkylating cytotoxic agents if progressive disease?

Question 142

Slowing progression of CKD

Answer 142

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)

Question 143

Acute vs. chronic renal failure

Answer 143

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

Question 144

Why don’t some diabetics have small kidneys even in end stage disease?

Answer 144

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

Question 145

Where is erythropoietin made?

Answer 145

Peritubular cells of kidneys

Question 146

Urolithiasis

Answer 146

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)

Question 147

Paraneoplastic syndromes caused by renal cell carcinoma

Answer 147

Polycythemia (EPO)

Hypercalcemia (PTHrP)

Hypertension

Liver dysfunction

Feminization or masculinization

Cushing syndrome

Leukemoid reactions

Amyloidosis