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Kidney Lect 7
Disorders of Volume Homeostasis
Question | Answer |
---|---|
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 |