Renal Tubular Acidosis & Potassium Disorders 10-3

Terms in this set (35)

Understand the role of the proximal tubule in bicarbonate reabsorption.
The majority of bicarbonate reclamation occurs in the proximal tubule through the Na+/H+ exchanger
Understand how the kidneys excrete hydrogen ions through ammoniagenesis.
Active transporters in the distal tubule secrete hydrogen ion against a concentration gradient.
Also, NH3 is generated in the proximal tubule by the deamidation of glutamine to glutamate, which is subsequently deaminated to yield NH3 and α-ketoglutarate. The enzymes responsible for these reactions are up-regulated by acidosis and hypokalemia. NH3 builds up in the renal interstitium and passively diffuses into the tubule lumen along the length of the collecting duct, where it is trapped by H+ and excreted as NH4.
Understand the clinical utility of urine anion gap.
It is an estimate of NH4+ excretion, which accounts for the majority of acid excretion.

-if Cl- is the anion balancing the charge of NH4+, the gap is negative b/c the chloride is greater than the sum of Na+ & K+ (which are also large components of urine)
UAG = (Na+ + K+) - Cl-
Understand the collecting tubule mechanism and stimuli for hydrogen ion and potassium secretion.
Aldosterone directly increases the activity of the Na+-K+-ATPase in the collecting duct cells, stimulating secretion of K+ into the tubular lumen.

Reabsorption of sodium in the collecting duct occurs through selective sodium channels, which create an electronegative charge within the tubular lumen relative to the tubular epithelial cell, which in turn promotes secretion of H+ and K+ into the lumen.
Be familiar with the renal causes of normal anion gap (hyperchloremic) metabolic acidosis including:
1. defective ammoniagenesis
1. due to chronic kidney disease. As the # of nephrons decrease w/progression, there is a proportional decrease in production of ammonia.
-when GFR falls to < 40 ml/min, kidney can't excrete acid load & serum [HCO3-] declines & there is an increase in serum [Cl-] -> hyperchloremic metabolic acidosis (HCMA).
-UAG will be positive b/c of decreased ammonia excretion, but the urine pH will be < 5.5
Be familiar with the renal causes of normal anion gap (hyperchloremic) metabolic acidosis including:
1. hypoaldosteronism
1. can be primary or secondary (due to ACEI/ARB)
-most often seen in pt's w/diabetes & mild CKD.
-may be due to chronic volume overload. The acidosis is caused by decreased ammoniagenesis due to hyperkalemia induced by aldosterone deficiency (causes defects in Na+ reabsorption and in K+ and H+ secretion and excretion.), thus leading to less NH4+ excretion.
-> urine pH is usually < 5.5

Rx = loop, K restriction, bicarb supps
Be familiar with the renal causes of normal anion gap (hyperchloremic) metabolic acidosis including:
1. proximal tubule disorders
1. defect in the ability of PCT to reclaim filtered bicarb. There can also be diminished reabsorption of other solutes across the PCT -> inappropriately excrete amino acids, glucose, phosphorus & uric acid as well (seen in Fanconi's)

Hereditary = mutation in Na/H exchanger on luminal membrane, Na-HCO3 cotransporter on basolateral membrane & cystosolic carbonic anhydrase.

Fanconi's Syndrome = generalized transport defect
- decrease in ATP production -> reduction of Na/K ATPase is presumed cause of this global transport defect

other etiologies = Wilson's Dz, Lowe's syndrome, Multiple Myeloma or IgA Nephropathy

*when [HCO3-] is below the lowered threshold seen in these disorders urine pH < 5.5. when above the threshold, urine is > 6.5
- fractional excretion of > 15% w/admin of supp bicarb is diagnostic
Understand the underlying pathophysiologic mechanism causing each type of RTA.
1. proximal tubule disorder
2. distal w/hypokalemia
3. distal w/hyperkalemia
1. defect in the ability of the proximal tubule to reclaim filtered bicarbonate.

2. inability of the distal tubule to acidify the urine due to dysfunction of luminal H+-ATPase and the basolateral Cl-/HCO3- exchanger.

3. defect in distal tubular H+ and K + secretion or a primary defect in Na+ transport
Be familiar with the urine pH and serum potassium findings for each type of RTA.:
1. Proximal
2. Distal
1. < 5.5 when serum [HCO3-] between 15-18 mEq/L.. when bicarb is above resorptive threshold - ph > 6.5

2. > 5.5
Recognize conditions associated with each type of Renal Tubular Acidosis.
1. Proximal RTA
2. Distal RTA
1. Fanconi's Syndrome is associated with patients with cystinosis, Wilson's disease, Lowe's syndrome, Multiple Myeloma or light chain disease

2. recessive pseudohypoaldosteronism (PHA) type I
PHA Type II, (Gordon's syndrome)
Understand the underlying defect and clinical presentation for each type of pseudohypoaldosteronism (PHA).:
1. type I
2. type II (Gordon's syndrome)
1. mutation in the renal mineralcorticoid receptor that results in a decreased affinity for aldosterone.
- child with hyperaldosteronism, hyperkalemia, metabolic acidosis, salt wasting, and hypotension.

2. Mutations in WNK1 and WNK4 -> increase NaCl transporters in DCT & thus NaCl reabsorption
-Patients have mild volume overload with suppressed renin and aldosterone, hypertension, hyperkalemia and metabolic acidosis
Understand the intracellular and extracellular distribution of potassium under normal conditions.
[K+]
ECF = 4 mEq/L
ICF = 150 mEq/L

-a relatively small shift from ICF -> ECF can cause marked increase in serum [K+]
Understand the role of the kidneys in maintaining potassium homeostasis.
Reabsorption of sodium in the collecting duct occurs through selective sodium channels, creating an electronegative charge within the tubular lumen relative to the tubular epithelial cell, which in turn promotes secretion of H+ and K+ into the lumen.
Understand the role of the GI tract in maintaining potassium homeostasis.
The small intestine and colon can secrete K+ and this can also be stimulated by aldosterone.
In normal individuals, intestinal potassium excretion plays a minor role in potassium homeostasis. In patients with chronic renal failure, intestinal K+ excretion is increase threefold to fourfold, is often inadequate to compensate for the loss of kidney function.
Understand the effect of alkalosis on serum potassium concentration.
shifts K+ into the cells in exchange for H+ to correct high pH -> hypokalemia
Understand the effect of acidosis on serum potassium concentration.
shifts K+ out of the cells in exchange for H+ into cell to correct low pH -> hyperkalemia
Understand the effects of aldosterone presence on potassium secretion at the collecting tubule.
directly increases the activity of the Na+-K+-ATPase in the collecting duct cells, stimulating secretion of K+ into the tubular lumen.
Understand the effects of aldosterone absence on potassium secretion at the collecting tubule.
decrease potassium excretion by the kidneys and increase risk of hyperkalemia.
Understand the effects of insulin and beta-agonists on serum potassium concentration.
they stimulate Na+/K+ATPase, primarily in skeletal muscles causing transfer of K+from ECF to ICF
Differentiate between renal and non-renal causes of potassium loss.
non = prolonged vomiting (due to 2ndary hyperaldosteronism from volume depletion), severe diarrhea (high K+ loss stool)

renal = ass'd w/HTN
primary hyperaldosteronism
glucocorticoids
renovascular HTN
renin-secreting tumore
malignant HTN
11B-hydroxysteroid dehydrogenase deficiency
congenital adrenal hyperplasia
Liddle's syndrome

normal BP
type I (distal) RTA
type II (proximal) RTA
Bartter's Syndrome
Gitelman's syndrome
Familial Hypokalemic Periodic Paralysis
thyrotoxic hypokalemic paralysis
Describe hyperaldosteronism and its pathophysiology
autonomous secretion of aldosterone by the adrenal cortex, resulting in avid sodium retention and potassium secretion by the distal nephron.
presents with:
volume dependent hypertension, hypokalemia, and metabolic alkalosis.

Labs show an elevated aldosterone and suppressed renin. Abdominal CT scan may reveal either a unilateral adrenal adenoma or bilateral adrenal hyperplasia.
Describe glucocorticoid-remedial aldosteronism and its pathophysiology
rare, autosomal-dominant condition in which there is fusion of 11β-hydroxylase and aldosterone synthesis genes. -> aldosterone secretion is stimulated by ACTH, and can be suppressed by an exogenous mineralcorticoid, dexamethasone.
These patients present similar to primary hyperaldosteronism but are younger and have a family history.
Describe 11-beta hydroxysteroid dehydrogenase deficiency and its pathophysiology
rare genetic disorder that prevents the conversion of cortisol to cortisone in peripheral tissues resulting in high cortisol levels that bind the mineralcorticoid receptors producing hypertension and hypokalemia.
These patients have low renin and aldosterone levels.
There are also acquired forms (chew tobacco, licorice)
Describe congenital adrenal hyperplasia and its pathophysiology
deficiency of 11β-hydroxylase, an enzyme required in the common pathways of mineralcorticoids and glucocorticoids. These patients have low renin and aldosterone and high levels of deoxycorticicosterone acetate and androgen.
Males exhibit early puberty and females exhibit virilization.
This improves with administration of exogenous steroids to suppress ACTH.
Describe Liddle's syndrome and its pathophysiology
rare autosomal-dominant disorder caused by a defect in sodium channels resulting in increased sodium reabsorption and potassium secretion in the collecting duct. Patients present with hypokalemia, hypertension, and volume overload. They have low levels of renin and aldosterone.

They improve dramatically with sodium channel inhibitors, such as amiloride.
Describe Bartter's syndrome and its pathophysiology
rare familial disease characterized by hypokalemia, metabolic alkalosis, hypercalciuria, and normal blood pressure. They have high levels of renin and aldosterone. It has been associated with a number of mutations that inhibit Na+ reabsorption in the thick ascending limb of the loop of Henle.
Patients appear as if they are chronically ingesting loop diuretics.
Describe Gitelman's syndrome and its pathophysiology
It is linked to a mutation in the thiazide sensitive Na+Cl- cotransporter in the distal convoluted tubule. They have hypocalciuria, hypomagnesemia, and hypokalemic metabolic alkalosis.
These patients appear as if they are chronically ingesting thiazide diuretics.
Understand the acute management of severe hyperkalemia.
1. Stabilize the myocardium with IV calcium gluconate
2. Shift potassium from the ECF to ICF by administering any or all of the following:
a. IV Insulin
b. Inhaled β2 agonist
c. IV sodium bicarbonate
3. Remove potassium from the body
a. Diuretics
b. Sodium polystyrene sulfonate (Kayexalate) : a resin exchanger that removes potassium from the blood into the gut for equal parts of sodium (slow acting)
c. Hemodialysis

For patients with moderate hyperkalemia not associated with EKG changes it is often sufficient to discontinue drugs promoting hyperkalemia.
what physiologic factors stimulate distal K+ secretion (thus increasing excretion)?
aldosterone
high distal sodium delivery
high urine flow rate
high [K+] in tubular cell
metabolic alkalosis.
Briefly describe autosomal dominant pseudohypoaldosteronism type I (PHA)
mutation in renal mineralcorticoid receptor -> decreased affinity for aldosterone.
manifests in childhood w/hyperaldosteronism, hyperkalemia, metabolic acidosis, salt wasting & hypostension.
Describe the Classic Distal Renal Tubular Acidosis w/Hypokalemia (aka type I RTA)
due to inability of the distal tubule to acidify the urine & can be congenital or acquired
-abnormality in luminal H+ ATPase & basolateral Cl/HCO3- exchanger.

acquired = due to SLE, Sjogren's, lithium, amphotericin

- inappropriately high urine pH > 5.5.. b/c H+ secretion is defective, less NH4+ is trapped in lumen of tubule -> decreased excretion & thus a positive UAG (distinguishing factor that differentiates lab findings from diarrhea which would have high NH4+ excretion & (-) UAG.

hypokalemia is seen due to augmented distal K+ secretion in place of H+ secretion in exchange for Na+ reabsorption.
Also hypocitraturia, hypercalciuria, and nephrocalcinosis seen.
Describe Distal Renal Tubular Acidosis with Hyperkalemia
generalized defect in distal tubular H+ & K+ secretion or primary defect in Na+ transport (voltage defect) which are associated w/obstruction & interstitial kidney Dz

Autosomal recessive pseudohypoaldosteronism (PHA) type I causes a loss of function of the ENaC in the distal tubule -> childhood hyperkalemia, metabolic acidosis, hyperaldosteronism, salt wasting, & other symptoms.
- similar picture seen w/amiloride

PHA type II (Gordon's syndrome) = mutations in WNK1 & WNK4 -> increase in # of NaCl transporters -> increased NaCl transport across the DCT. this leads to less Na delivered distally & thus less lumen negative potential & decreased K+ & H+ secretion.
- these pt's have mild volume overload w/suppressed RAAS, HTN, hyperkalemia, acidosis
-treat w/thiazides
Describe Drug induced Hypokalemia
occurs with drugs that stimulate renal potassium excretion such as mineralcorticoids (mimic effects of aldosterone) and diuretics (except potassium sparing types).
Describe Familial Hypokalemic Periodic Paralysis and its pathophysiology
Rare autosomal dominant disorder in which affected individuals develops episodes of severe muscle weakness in association with profound hypokalemia, caused by rapid shifts of potassium from the ECF to ICF.
This resolves within hours of potassium ingestion. They are asymptomatic with a normal potassium level between episodes.
Describe Thyrotoxic hypokalemic paralysis and its pathophysiology
unusual manifestation of hyperthyroidism, seen mostly in Asian patients. Episodes are similar to that of periodic paralysis except that the episodes cease when hyperthyroidism is corrected.
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