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Kidney Lect 7

Disorders of Volume Homeostasis

QuestionAnswer
The loss of fluid from the intravascular space is detected by “volume” sensors that are present in... in the vascular bed (both venous and arterial beds), heart, liver, and kidneys.
The reduction in the extracellular fluid volume (and intravascular volume) leads to activation of... the sympathetic nervous system (SNS) and the renin-angiotensin system, with the release of renin, conversion of renin substrate to Angiotensin I and Angiotensin II, and secretion of aldosterone.
Significant reductions in extracellular fluid volume are associated with the clinical findings of: a reduction in blood pressure (hypotension), increase in heart rate (tachycardia), dry mucous membranes, and a decrease in skin turgor
As the extracellular fluid volume is reduced, a fall in blood pressure and increase in heart rate may be manifested with what maneuver? patients change from a supine to upright position (orthostatic hypotension).
Loss of ECF volume will be reflected in a reduction in ___. weight
How is GFR affected when ECF goes down (in physiological response)? What about when volume depletion is severe? In states of moderate volume depletion GFR is maintained by physiological mechanisms; In states of severe volume depletion, GFR falls
What lab findings do you see with severe volume depletion? An elevated BUN/Creatinine ratio (>20:1) and elevated plasma uric acid are often observed in the setting of volume depletion.
Low volume as well as high serum osmolarity stimulates... arginine vasopressin leading to water reabsorption in the collecting duct
Renal vasoconstriction is mediated by ... the SNS and Angiotensin II.
Efferent arteriolar vasoconstriction will result in... decrease in renal plasma flow and a subsequent increase in glomerular capillary hydrostatic pressure.
increase in glomerular capillary hydrostatic pressure will tend to ___ GFR and vice versa increase
in severe volume depletion, GFR as well as renal blood flow will fall. This is due to... the effects of high levels of circulating angiotensin II which eventually cause both afferent and efferent arteriolar constriction. Additionally, as the systemic blood pressure falls, overall renal perfusion falls.
Changes in the peritubular oncotic pressure (increased) and in the peritubular hydrostatic pressure (decreased) will favor an ____ in rates of proximal tubular Na reabsorption increase
Associated with increases in proximal tubular reabsorption of Na and water are ____ in the reabsorption of urea and uric acid. increases
An elevated BUN/Creatinine ratio (>20:1) and an elevated plasma concentration of uric acid are often observed in the setting of a ____ ECF volume. decreased
Where is vasopressin released from? What triggers its release? Pituitary gland; This non-osmotic secretion of vasopressin occurs as a result of a low volume state (despite a normal or low plasma osmolality)
How does vasopressin increase blood pressure? Secretion of vasopressin from the posterior pituitary gland increases Na retention by activating the Na,K,2Cl co-transporter in the thick ascending limb of the loop of Henle and ENaC in the collecting duct
What effect does renal perfusion have on renin release? A decrease in renal perfusion enhances renin release and starts the cascade that leads to the formation of angiotensin II
What proteins does aldosterone activate? Aldosterone activates the Na,Cl co-transporter and the Na channel (ENaC); Additionally, it activates the basolateral Na,K ATPase in the distal tubule and collecting duct
How does a decreased ECFV sinfluence urinary concentration? A clinical hallmark of a decreased ECFV is a low urinary Na concentration; If the decrease in ECFV is associated with renal Na wasting, the urinary Na concentration may not be low.
What clinical findings are associated with a decresed ECF volume: blood pressure, mucous membranes, skin turgor, weight, BUN/creatinine, serum uric acid, urinary [Na]? • Orthostatic hypotension (or frank hypotension) • Dry mucous membranes • Decreased skin turgor • Decreased weight • Elevated BUN/Creatinine ratio • Elevated serum uric acid • Low urinary [Na] (except in the setting of renal Na wasting)
How will a decrease in effective circulating volume change sympathetic volume (4) steps? Decrease ECV-->decreased venous return-->decrease cardiac output-->decrease blood pressure-->increased baroreceptor stimulus-->increased sympathetic tone
What (5) direct effects will increased sympathetic tone have on vascular flow and kidney function? + arterial and venous constriction, + cardiac contractility, + renin release, + tubular Na+ reabsorption
How can the body increase the effective circulating volume? Increased Na+ reabsorption and drinking more fluids
How can the body increase cardiac output? Venous constriction, increased heart rate, and increased effective circulating volume
How can the body increase blood pressure? increase vascular resistance and increased cardiac output
What are the clinical settings associated with decreased ECF volume? • GI losses • Renal losses o Diuretics, osmotic diuresis, renal salt wasting disorders • Skin/respiratory losses • Fever, excessive sweating, burns • Sequestration of fluids in third spaces • Bleeding, pancreatitis, venous obstruction
What diuretics are associated with Na wasting (if overused)? inhibitors of the ascending loop Na,K,2Cl co- transporter, distal convoluted tubule Na,Cl co- transporter, collecting duct epithelial Na channel, aldosterone receptor antagonists
Overuse of glucose and mannitol can lead to... Osmotic diuresis
Low renin and hypoaldosteronism can lead to... renal Na wasting
Barrter's syndrome, gitelman's syndrome, and pseudohypoaldosteronism are all... inherited disorders associated with renal wasting
Barttter's syndrome is caused a defect in which part of the kidney? How is normal kidney function affected? Loss of Na, Ca and Mg absorption in the ascending limb of the loop of Henle
What mutations are associated with Bartter's syndrome? Mutations can either occur in: o In the Na, 2Cl-,K Transporter itself o The Apical ROMK channel o Basolateral chloride channel
Bartter's syndrome mutations resemble overdose with which type of drug? All these mutations lead to a loss of Na reabsorption in the thick ascending limb and resemble treatment with a LOOP DIURETIC
Low-normal ECFV, Low-normal BP, Low [K], Elevated plasma renin and aldosterone, HYPERCALCIURIA, Metabolic alkalosis, Marked defect in urinary concentration, Polyuria/polydipsia, Presents early in life (before age of six), Growth and mental retardation Bartter's syndrome
Giterlman's syndrome: what causes it? It resembles treatment with which type of drug? • Loss of function mutation from the Na,Cl co-transporter in the early, distal tubule • Resembles treatment with a thiazide diuretic
o Low-normal ECF volume o Low-normal blood pressure o Elevated renin and aldosterone levels o Low potassium o HYPOCALCIURIA o Metabolic alkalosis o Hypomagnesemia o URINE CONCENTRATION ABILITY IS MAINTAINED Gitelman's syndrome (resembles treatment with thiazide diuretic)
Gitelman's syndrome may be due to mutations in the gene encoding... the Na,Cl transporter (NCC)
Why is hypomagnesia seen in Gitelman's syndrome/chronic overdose with thiazide diuretics? Why are calcium levels affected? Hypomagesemia is observed and may be due to dysfunction of the magnesium channel; Increased calcium reabsorption in this disorder is probably due to increased proximal reabsorption of calcium.
Pseudohypoaldosteronism: genetic inheritance? What causes it? autosomal recessive disorder; Caused by a loss of function mutations of either the epithelial Na channel or the mineralocorticoid receptor. Either mutation makes the collecting tubule unable to respond to aldosterone
o volume depletion o hypotension o hyperkalemia despite elevated plasma aldosterone levels Pseudohypoaldosteronism
What are the characteristics of hypoaldosteronism? o volume depletion o hypotension o hyperkalemia despite elevated plasma aldosterone levels
CHF, cirrhosis and nephrotic syndrome are conditions associated with both an __ of extracellular fluid volume and an ___ ___ of the arterial bed expansion; under filling
What is the definition of edema? Edema is defined as expansion of the interstitial space
What causes edema? Edema formation is caused by retention of sodium and water in conjunction with a change in Starling forces. This results in fluid movement out of the capillary bed and into the interstitial space
Certain disease states are associated with BOTH an expansion of the extracellular fluid volume, AND with an underfilling of the arterial bed. This clinical setting is often referred to as a ______. decreased “effective” arterial volume
In CHF, cirrhosis and nephrotic syndrome, excess fluid often accumulates in the... lower extremities (peripheral or dependent edema), based on gravity
. If patients are bed ridden, fluid accumulation often occurs in the... low back
Fluid accumulation in the peritoneum (ascites) is often found in patients with ____, whereas excess fluid accumulation in the lung is seen in patients with ___ liver failure; left sided congestive heart failure
There are two key factors that are involved in the formation of edema: (1) Renal retention of Na (and H 2 O) and (2) A change in capillary Starling forces that results in a net movement of fluid out of the capillary bed and into the interstitial space.
It takes about ___ liters of excess fluid accumulation in order to develop clinical findings associated with peripheral edema, as a result of renal retention of Na and water. 2.5 to 3
The movement of fluid between the capillary bed and interstitial space is dependent on: 1) Starling forces 2) the permeability of the capillary wall (Lp), 3) the capillary surface area (S).
The reflection coefficient (σ) is an indication of ___. A value of 0 indicates that the capillary wall is completely permeable; a value of 1 indicates that that the capillary wall is... how porous the capillary wall is to albumin; completely impermeable.
Under normal circumstances there is a small pressure gradient favoring net fluid movement in which direction? out of the vascular space and into the interstitial space.
The “extra” fluid is returned to the vascular space via ___, which prevents excess fluid from accumulating in the interstitial space. lymphatics
Hypoalbuminemia: what diseases is it associated with? What symptom will it cause? (low albumin levels in the blood) in the setting of liver failure or nephrotic syndrome will lead to a reduced capillary oncotic pressure (πcap ), and may also contribute to the development of edema
___ is accompanied by a decrease in filling of the arterial bed with a resultant activation of baroreceptors and increase in sympathetic tone CHF
States associated with expansion of both the intravascular and extravascular fluid volume: o Hyperaldosteronism o Syndrome of apparent mineralocorticoid excess/11-beta-hydroxysteroid dehydrogenase inhibitors o Liddle’s Syndrome o Gordon’s syndrome o High sodium intake o Renal failure
What common themes lead to both increased intravascular and extravascular fluid expansion? (1) increased Na intake or (2) reduced Na excretion.
What symptoms and clinical findings are seen in patients with intravascular and extravascular fluid expansion? • Clinical findings may include an elevated blood pressure and peripheral or pulmonary edema. • Patients often present with a history of weight gain in association with increases in the ECF volume.
Expansion of the extracellular fluid volume occurs when Na ___ > Na ____. intake; excretion
What casues hyperaldosteronism? Hyperaldosteronism is due to adrenal hyperplasia, aldosterone secreting tumors, or ingestion of mineralocorticoid agonists
Excess aldosterone leads to ... increased Na retention
Patients with hyperaldosternism preset with... o Hypertension o High serum aldosterone levels o Low renin levels o Low potassium levels
11β OHSD type 2 an enzyme that prevents circulating glucocorticoids (cortisol) from activating the mineralocorticoid (aldosterone) and glucocorticoid receptors
If 11β OHSD is mutated so that it cannot function or if it is inhibited... it is unable to break down cortisol into cortisone. (Cortisone is not capable of activating the mineralocorticoid or glucocorticoid receptors)--> cortisol is able to activate the mineralocorticoid receptor
Without 11β OHSD... cortisol (which circulates at levels that are several orders of magnitude greater than circulating levels of aldosterone) would chronically activate mineralocorticoid sensitive principal cells
Chronic activation of minealocorticoid sensitive principal cells would result in... increased Na reabsorption through the epithelial sodium channel (ENaC)
glycyrrhizic acid found in certain types of natural licorice-->inhibits 11β OHSD-->chronic activation of mineralocorticoid receptors
What are the clinical presentations of Syndrome of Apparent Mineralocorticoid Excess (AME) /11 beta hydroxysteroid dehydrogenase (11β OHSD) inhibitors? o Hypertension o Low aldosterone levels o Low renin levels o Hypokalemia
Liddle’s syndrome: caused by... over activity of ENaC in the distal tubule (gain of function mutation of ENaC)
What do patients with Liddle's syndrome present with? o Hypertension o Low renin levels o Low aldosterone levels o Hypokalemia o Positive genetic testing for a Liddle’s mutation o Spironolactone is ineffective in Liddle’s syndrome (defect in channel, not mineralocorticoid signaling)
Gordon's syndrome is caused by... over activity of the Na,Cl co- transporter in the distal tubule and inhibition of ROMK
How is Gordon's syndrome inherited? What defects is it seen with? Autosomal dominant form of severe hypertension that is associated with hyperkalemia (Familial Hyperkalemic Hypertension)
What clinical findings are seen in Gordon's syndrome? Presents with severe hypertension associated with hyperkalemia and abnormally low renin levels
If a high sodium diet is abruptly started in a patient previously on a low sodium diet, only about ____ is excreted on the first day half the excess intake
How does the body respond to a sudden increase in sodium in the diet? reduced activity of the SNS, increased thirst and secretion of ADH (due to increased plasma osmolality), renin release inhibited, decreased sodium reabsorption and increased sodium excretion
How does the body try to decrease an excess of Na+ in the serum? Less renin-->no RAAS cascade-->less absorption in nephron; ANP secretion increases GFR and decreases distal reabsorption of Na; ouabain-like factors decrease distal NaKATPase activity
Created by: karkis77