UT Southwestern School of Medicine renal physiology block 3

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4 unique features of renal circulation

1 no anastamoses, 2 highest flow/gram tissue, 3 arteriovenous shunts, 4 multiple capillaries in tandem

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Loop of Henle main function

Reabsorption: Na/K/HCO3/Cl/Ca/Mg. Dilution of filtrate.

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Thin descending and ascending limb main fxns

descending: water reabsorption & urea secretion. ascending: Na/Cl/K reabsorption

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Thick ascending limb fxn

Reabsorption of Na/K/Cl/HCO3/Ca/Mg (secondary active transport & paracellular)

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Distal convoluted tubule fxn

Reabsorption of Na/Cl/Ca/Mg

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Collecting Tubule cell types

Principal cells, Intercalated cells (alpha all along collecting duct, beta only in cortical region)

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Medullary Collecting Tubule

Inner Medullary Collecting Duct (IMCD). fewer intercalated cells (some alpha remain). Reabsorption of Na/K/Cl/urea, Secretion of: H. ADH-sensitive.

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mesangium

mesangial cells + sulfated GAG's & collagen.

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mesangial cell fxn

support, regulate capillary flow, produce matrix, phagocytic, paracrine (e.g. prostaglandins)

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fractional urinary excretion (equation)

= amount excreted/amount filtered

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renin

maintains constant GFR. stimulated by 1) sympathetics, 2) JG cells (low salt in macula densa OR low pressure @ JG cells). Feedback inhibition by AngII.

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Where is erythropoeitin made?

kidney cortical interstitial cells

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1-alpha-hydroxylase

enzyme in proximal tubule cells generates 1,25 (OH)2 vitamin D3 (active form).

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What is normal renal blood flow?

20% of CO, ~1.1 L/minute.

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What is normal renal plasma flow (RPF)?

600 ml/minute (hematocrit = 40%)

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What is normal GFR?

100-130 ml/minute, (180 L/day). Babies < 10 ml/minute up to adult values @ 2 years old. vegetarians = 30-50% lower than normal.

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Filtration Fraction equation & normal value

= GFR (ml/min)/RPF (ml/min). normal = 125/600 = 0.2 Efferent arteriolar resistance ONLY alters filtration fraction.

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What is the pressure drop from the renal artery to the renal vein?

90 mm Hg !!! 100 mmHg (renal artery)-> 50 (glomerular capillary)-> 20 (peritubular capillary)-> 10 (renal vein)

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GFR equation

GFR = Kf*(capillary hydrostatic P - Bowman's space HP - capillary colloid osmotic P). Kf = ultrafiltration coefficient. hydrostatic pressure relatively constant along capillary, but colloid pressure increases

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Ultrafiltration coefficient (Kf)

determines surface area available & water permeability

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Factors affecting GFR

1) glomerular hydrostatic P, 2) Bowman's hydrostatic P, 3) plasma colloid P, 4) Kf, 5) arteriolar resistance

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filtration equilibrium point

where there is no net filtration pressure in the glomerulus. higher blood flow decreases plasma oncotic pressure & delays the equilibrium point. lower renal blood flow hastens it.

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autoregulation of GFR

1) Myogenic (pressure-dpdt changes in in arteriolar contractility via Ca & cation Ch's), 2) Tubuloglomerular Feedback (macula densa senses low Na/Cl -> paracrine adenosine/NO -> modified Afferent arteriolar tone)

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How does EABV alter the sensitivity of GFR?

GFR is fine-tuned by increased/decreased arterial volume. high arterial volume -> decreased sensitivity.

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Measuring GFR with inulin

GFR * plasma-inulin = urine flow * urine-inulin. rate filtration === rate excretion.

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clearance definition

volume plasma from which substance is completely cleared by kidneys per time. (for inulin, clearance ==GFR since all filtrate is cleared of inulin)

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Clearance Equation for inulin

Clearance = urine [inulin] x Volume urine/plasma [inulin]

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creatinine as marker substance

released into blood @ constant rate (v. little change in plasma levels. creatinine is filtered AND secreted, s o GFR is overestimated. serial measures = best estimate (average). @ v. low GFR, secretion effect magnified.

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Cockcroft-Gault equation

estimates creatinine clearance NOT GFR (overestimates)

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PAH method to estimate RPF

Paraminohippurate (PAH) = synthetic. 100% filtered + secreted. [PAH] must be <12 mg/dL. clearance == RPF. 10% underestimate b/c some blood doesn't contact glomerulus.

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PAH equation for effective RPF

urine PAH x urine rate/Plasma PAH = "effective" RPF.

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PAH equation for true RPF

urine PAH x urine rate/(renal artery PAH - renal vein PAH). best for PAH because artery & vein have huge difference.

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equation to calculate renal blood flow from hematocrit

RPF/(1-hematocrit %) = RBF/1

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equation for filtration fraction

FF = GFR/RPF. = fraction plasma flowing through kidneys.

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FEx (fractional Excretion) equation

FEx = amt. excreted/amt. filtered * 100. Na = used to identify reason for kidney failure (tubule injury) Mg or PO4 low -- is kidney cause/GI tract? Can exceed 100% if net secretion.

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body fluid distribution for a 70 kg male

70 kg male ~60% water (40% intracellular/20% extracellular). extracellular = 15% interstitial/5% intravascular. woman = 55% aqueous due to more fat.

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body fluid distribution, general

2/3 of water = intracellular. remaining = extracellular: 3/4 interstitial, 1/4 intravascular.

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Na resorption in different areas of the nephron

proximal = 67%, Loop of Henle 25%, Distal Tubule 5%, Collecting Duct 3%, Excreted < 1%

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Na transport mechanisms

mostly transcellular. Antiporter: Na/H. Coporters: Na/glucose, Na/phosphate, Na/aa, Na/K/2Cl, Na/Cl. Na channels & nonspecific ion channels

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mechanism for paracellular Na resorption

driven by (+) potential in lumen after Cl leaves paracellularly

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Cl resorption mechanisms

paracellular in proximal tubule & collecting duct. Transcellular in DCT (NaCl coporter), TAL (Na/K/2Cl), Na/H + Cl/base exchangers in late proximal & distal convoluted tubules.

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Basal membrane Cl transport

Cl channels or KCL coporter

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proximal tubule reabsorption

site of highest reabsorption of Na, Cl, K, Ca, urea, phosphate, bicarb, aa's, glucose. isosmotic water absorption. Bicarb absorbed v. proximal & cl absorbed more distal.

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TF/P ratio

tubular fluid: plasma ratio.

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AngII

1) efferent > afferent constriction, 2) increased prox. tubule Na/H exchanger. 3) stimulates Aldo-> Na reabsorption in CCD. 4) increased sympathetics. 5) peripheral vasoconstriction. AT1 Receptor.

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effects of high filtration fraction on peritubular capillaries

increases colloid osmotic pressure of peritubular capillaries -> facilitates NaCl reabsorption

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effects of low Effective Arterial Blood Volume (EABV)

renal nerve activity & endothelin release, RAAS, myogenic reflex.

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What do ANP/BNP do? (also C-type NP & Urodilatin)

1)inhibit Na/H in prox tubule, 2) directly inhibit renin & Aldo. 3) directly inhibit Na reabsorption in IMCD 4) relaxes efferent arteriole. 5) more blood to medulla-> washout -> less Thin AL Na passive reabsorb.

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effects of metabolic acidosis on ion reabsorption in the proximal tubule

less HCO3- reabsorbed -> less water reabsorbed -> lower Cl concentration -> less NaCl absorbed paracellularly

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NaCl absorption in the thick ascending limb "diluting segment"

major site of NaCl transport in loop of Henle. Na/K/2Cl apical + ROMK (leak channel). paracellular pathway more permeable to cations. NO H2O permeability.

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***ADH

1) activates Na/K/2Cl & ROMK in Thick AL. 2) opens more ENaC in apical principal cells of IMCD. 3) Causes AQP2 insertion in CD. 4) High [ADH] -> systemic vasoconstriction.

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Bartter Syndrome

=Mutation in Na/K/2Cl, apical K Ch., basal Cl channel, Barttin (chaperones Cl channel to membrane). autosomal recessive, no salt transport in thick ascending limb. renal salt wasting & low BP, hypokalemic metabolic alkalosis, hypercalciuria.

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Na transport in distal convoluted tubule

1) Na/Cl coport. 2) Na/H + Cl/Base antiporters. 3) passive Na Channel + paracellular Cl

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Gitelman Syndrome

defective thiazide-sensitive NaCl coporter in DCT-> hypocalciuria (high Ca resorption), downregulated TRPM6 (low Mg resorption). salt wasting.

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***Gordon Syndrome (Distal Convoluted Tubule & Collecting Duct)

pseudohypoaldosteronism type II. WNKIV mutation -> 1) disinhibits NaCl Coporter 2) endocytosis of ROMK Ch.-> hyperkalemia. 3) increased P'ation of claudins -> increased paracellular Cl reabsorption. 4) inhibits DCT Ca reabsorption

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WNK4 ("with no lysine" kinase)

-> decreases NaCl coporter (NCC) expression. normally dephosphorylates claudins1-4 & decreases Cl reabsorption. inhibited by WNK1.

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Collecting Duct Na regulation

ENaC

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ENaC Channel

alpha subunit required for channel fxn. beta & gamma increase conductivity

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Liddle Syndrome

mutations in beta and gamma subunits PY motif where normally Nedd4-2 ubiquitinates for internalization & degradation. Hypertension due to high Na resorption

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Nedd4-2

marks normal ENaC for degradation. inhibited by SGK1 (serum & glucocorticoid-stimulated kinase) which is stimulated by Aldo.

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Aldosterone: K secretion & Na/H2O absorption in collecting duct & distal nephron

high plasma K & AngII-> Aldo released by zona glomerulosa of adrenal Cx. upregulates SGK1 -> inhibits Nedd4-2 -> more ENaC channels (quick). increases ENaC alpha subunit & Na/K pump expression (slow). Activates apical Na ch. & basal Na/K pump.

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11-beta-HSD

present in tissues unresponsive to cortisol, converts cortisol to inactive cortisone. permits aldosterone to activate R. inhibited irreversibly by licorice, loss of fxn mutation in Apparent Mineralocorticoid Excess. Overwhelmed w/Cushings.

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What effects does renal nerve activation have on Na reabsorption in the nephron?

low arterial blood volume -> high renal nerve activity -> AngII secretion -> Aldo secretion -> collecting duct Na reabsorption

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What is the major contributor to water movement b/tw vascular & extravascular spaces?

Oncotic Pressure! protein: vascular = 1.0 mmol/L, extravascular 0.1 mmol/L

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reflection coefficient

sigma. measures IMPERMEABILITY. when 0 = 100% permeable. when 1 = impermeable (but still adds molarity & osmotic pressure). When 0<sigma<1 adds osmolarity AND tonicity.

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Flux (Jv)

Jv = Lp*RT*sigma*deltaC. sigma = reflection coefficient. Lp = permeability.

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major determinant of water movement between ICF & ECF

NaCl: sigma ~1, largest extracellular concentrations

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IV fluids that spread to the ECF

Normal Saline, Lactated Ringer's

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Which IV fluids spread to the ICF?

5% Dextrose (D5W), 1/2 Normal Saline

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Which IV fluids stay intravascular?

Whole Blood, Packed Red Cells, Plasma, Albumin

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Which compartments lose volume during hypovolumia?

All compartments lose water (Total Body Water = ECF, ICF, intravascular)

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early vs. late proximal tubule Na reabsorption

early, transported w/HCO3-. late, transported w/Cl paracellular 1/3 transcellular 2/3.

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WNK kinases

WNK4 downregulates NaCl coporter in DCT (WNK1 inhibits WNK4)

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determinants of ECF volume

balance b/tw Na inake and excretion

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abrupt decrease in dietary Na effects:

ECF volume decreases -> EABV decreases -> decreased urinary Na excretion -> several days to achieve new Na balance.

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Where are pressure sensors affecting renal performance located?

1) Low pressure receptors in veins/atria/lungs, 2) High pressure receptors in aorta/carotid sinus, 3) Intrarenal mechanoreceptors, 4) Hepatic volume receptors, 5) CNS volume receptors

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low-pressure volume sensor reflex to kidneys

1) VENOUS: signaling decreases when low volume-> vagus-> hypothalamus -> Sympathetic Integrative Centers are released from tonic inhibition-> increased sympathetics. 2) ATRIAL: less distension-> ADH & renin increase (indirect).

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***What are the 2 types of intrarenal receptors?

1) Mechanoreceptors in afferent arteriole (sense changes in perfusion pressure independent of EABV). 2) Chemoreceptor senses renal ischemia & interstitial environment

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renal autoregulation

myogenic reflex dilates afferent arteriole when low renal artery pressure & constricts when high pressure to maintain constant flow

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tubuloglomerular feedback system

macula densa signals lower lumenal [NaCl] concentration -> afferent artery vasodilation & high GFR.

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juxtaglomerular apparatus reflex (to decrease GFR when high NaCl delivery to macula densa)

long-term high NaCl suppresses renin release -> low AngII & Aldo AND -> afferent arteriole constriction (adenosine) (if low flow NO for dilation)

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hepatic sodium sensors

osmoreceptors & NaCl receptors in liver -> nucleus of the solitary tract -> decreases renal sympathetic activity -> increased salt excretion

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hepatic baroreceptors

reflexively decrease renal sympathetic nerve activity

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FX of low EABV on kidneys

-> NE release, renin -> AngII-> Aldo, ADH released, sympathetic activated. In edema, this state persists. Aldo + ADH = simultaneous salt & water retention.

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***filtered load

= GFR * plasma [ ] - amt. reabsorbed

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glomerulo-tubular balance

nearly constant fractional excretion of Na despite changes in GFR due to proximal tubule salt reabsorption.

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effects of salt restriction on GFR

-> low EABV -> low renal plasma flow -> low afferent signaling -> ADH release. RAAS -> efferent arteriole constriction -> GFR maintained + peritubular hydrostatic P decreases -> higher Na resorption

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What causes Wash Out of medullary gradient, and what are the proximal effects?

Caused by volume expansion, water diuresis, prostaglandins, ANP -> lower water extraction from thin descending limb -> less NaCl entering thin AL -> less passive NaCl reabsorption

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conditions in which more Na is reabsorbed proximally

low EABV. high Aldo does NOT cause K loss.

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conditions when distal Na delivery is more plentiful

ECF volume expansion. Aldo is suppressed & K is not lost @ higher rates.

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When are prostaglandins released in the kidney?

renal vasodilator when renal ischemia & hypovolemia! low EABF -> AngII/AVP/NE-> PGI2 (Cx) PGE2 (medulla) -> renal vasodilation. NSIDs inhibit.

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How do prostaglandins moderate blood flow & sodium retention during high RAAS activity?

1) Efferent & total renal Vasodilation-> increased renal blood flow & decreased filtration fraction. 2) Increased medullary blood flow (wash-out)-> less salt absorption in thin AL [->renin]. 3) Directly inhibits Na reabsorption in ThickAL & CD (saves ATP)

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ANP general rules

Diuresis, natriuresis, vasorelaxation. BUT NP's are only modulators! Their levels are sky high when heart failure, but patients still retain salt & water (AngII & sympathetics win)

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CNP

released by vascular endothelium as local paracrine

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diuretic-induced diuresis

when diuretics result in an increase in solute AND water excretion

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K-sparing diuretics

Aldo antagonists. intracellular site of action.mild b/c collecting duct only reabsorbs 1-3% filtered Na.

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Carbonic Anhydrase Inhibitors

Lumenal + Intracellular access @ PCT. eg Acetazolamide. inhibits bicarb absorption -> decreases Na/H exchange. Thick AL compensates = weak, but good for glaucoma & metabolic alkalosis (due to other diuretics).

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Thiazide diuretics

lumenal action @ DCT. filtered + actively secreted. inhibit Cl binding to NaCl coporter. 1) limit urine dilution but not concentration! 2) increase Ca reabsorption. used for hypertension & Ca kidney stones. don't work @ low GFRs!

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Loop diuretics

lumen action @ Thick AL. inhibit Na/K/2Cl (inhibit binding of 2nd Cl). 1)dissipates osmolality & + potential, 2)impair urine concentrating & diluting ability. 3) block Ca and Mg reabsorption (note thiazide diuretics INCREASE Ca reabsorption)

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Types of loop diuretics

1) sulfonamide derivatives e.g. furosemide/bumetanide/torsemide. 2) non-sulfonamide derivatives e.g. ethacrinic acid.

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When to prescribe loop diuretics

for treatment of volume overload eg congestive heart failure, nephrotic syndrome, cirrhosis + ascites. Also for hypercalcemia, hypertension + low GFR. STEEP dose response curve -> if ineffective increase dose not freq.

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furosemide dosing

must enter ultrafiltrate to reach site of action. patients w/low GFR need higher dose (right shift in dose-response curve). must be given frequently or body tries to reabsorb Na in between doses. dose slowly over 30 min to prevent toxicity.

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side effects of loop diuretics

bumetanide most potent. causes low K/Mg, low ECF, metabolic alkalosis. Direct ototoxicity due to high dose required (esp. for ethacrynic acid)

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Thiazide indications

treats hypertension + kidney stones caused by hypercalciuria. less bioavailability in congestive heart failure, cirrhosis, kidney disease. causes low K & Na, hyperuricemia, metabolic alkalosis

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Mechanism for Thiazide-induced decreased Ca secretion

lowers EABV -> increases Ca++ reabsorption in proximal tubule & decreases Ca++ secretion. NO FX on Mg b/c DCT reabsorbs v. small % of filtered Mg.

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What are the K-sparing diuretics (non-mineralocorticoid)?

Triamterene & Amiloride. Block ENaC @ apical DCT & principal cells of collecting duct -> blocks ROMK. secreted & filtered. side effect = hyperkalemia in patients w/advanced kidney disease.

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K-sparing diuretics that act as aldo/androgen/progesterone R agonists

1) spironolactone (side effects = gynecomastia, impotence, menstrual irregularity). 2) epleronone = mineralocorticoid R antagonist. side effects = high K.

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What is a good surrogate estimate of plasma osmolarity?

2 x plasma [Na+] = surrogate for plasma osmolarity (b/c Na ~1/2 of overall osmolarity in ECF). Changes in plasma osmolarity are sensed by ALL CELLS.

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ADH production

Small changes in ECF volume cause large changes in ADH secretion. stimulated by cardiac/arterial/venous baroR's + hypothalamic osmoR's -> ADH release from the SON & PVN.

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osmo vs. baroreceptors & ADH

small changes = osmoreceptors win. large changes = baroreceptors change. circulation most important to maintain

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thirst stimulation

1) threshold higher than ADH threshold, 2) stimulated by high osmolarity & low blood volume, 3) volume trumps osmolarity

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thirst inhibition

1) low osmolality, 2) oropharyngeal reflex (water @ back of oropharynx temporarily blocks thirst, 3) volume expansion

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free water

300 mOsm * x L = total mOsm of urine. total volume of urine - x L = free water. kidney capacity to excrete free water = v. high

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free water generation

kidney has low capacity to produce free water to hydrate the body, and it is only a temporary fix. Thirst has unlimited capacity, but rarely available.

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4 requirements for regulating water excretion

1. glomerular filtration, 2. ADH-renal axis, 3. medullary interstitial osmolality, 4. specialized permeabilities in different regions of the nephron

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osmolarity of ultrafiltrate in different regions of the nephron

1) glomerulus 300, 2) Loop of Henle 1200, 3) thick ascending branch 300, distal convoluted tubule 50

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mechanism for aquaporin 2 insertion

ADH binds basal V2 R -> Gs -> PKA -> Aquaporin 2 inserted apical membrane (microtubule-dpdt)

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alternate aquaporins

3 & 4 exist in basal membrane of principal & IMCD cells, but water cannot flow w/out apical 2

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Hyponatremia

defective urinary dilution. too much water in system.

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Hypernatremia

defective thirst/urinary concentration.

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normal interstitial vs. intracellular Na

interstitial ~145 (same as plasma). intracellular 10.

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normal interstitial vs. intracellular K

interstitial ~4 (same as plasma). ICF 150.

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normal interstitial vs. ICF Ca

interstitial ~ 2 (same as plasma). ICF 10^-7

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normal interstitial vs. ICF Mg

interstitial ~1 (same as plasma). ICF 2.

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normal interstitial vs. ICF [Cl]

interstitial ~110 (same as plasma). ICF 4.

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normal interstitial vs. ICF [protein]

interstitial 0.1 (NOT SAME AS PLASMA 1.0). ICF 50.

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normal interstitial vs. ICF HCO3

interstitial 24 (same as plasma). ICF 12.

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steady state vs. balance

steady state = variable of interest doesn't vary. Balance = variable doesn't change specifically because inputs = outputs.

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Pool vs. Flux

Pool = volume of body fluid affected by inputs & outputs (homeostatically regulated). Flux = amt. solute/solvent put in/taken out of the pool/time.

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Buffers

instantly remove acid/base, but only temporary fix.

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Balance types

1) External = net gain/loss b/tw person & environment. 2) Negative = net loss. 3) Zero = no net change (steady state = freq. associated w/Zero Balance). 4) Excess = more than healthful need,Deficiency = less

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pH & pK

pH-pK = log [acid]/[base]. strong acids completely dissociate @ pH7, whereas strong bases completely associate @ pH7.

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significance of urine sulphate levels

direct reflection of amount of sulphur-containing aa's digested = amount of acidic aa's consumed

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"loads"

acidic aa's = base loads. basic aa's = acid loads. organic anions = alkali loads. NOTE: if you eat an acid, it must be metabolized by consuming H+ -> net generation of base!!!

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dietary source of acids & bases

1) acids from proteins. 2) bases from produce.

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3 components of homeostatic response to metabolic acids

1) Buffer, fast. 2) Respiration, removes volatile acids to restore balance. 3) Metabolic & Renal

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Buffer mechanism

Moderate pH change, but do not add/remove acid/alkali. If pH = buffer pK, only 1/2 of buffer carries H+. Want pH to be less than pK by several points.

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Buffer stats

1) conc. & pK, 2) Distribution (ICF focused on acids; ECF focused on bases; urine = finite vol. so acid must be buffered). 3) Bicarb vs. non. 4) Open vs. Closed

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Buffer Capacity

in units of Eq/l/pH unit. = amt. strong acid/base required to change 1 L solution x 1 pH point.

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Ampholyte

both acid and base

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Bicarbonate as buffer

not good base @ physiologic pH but equilibrium skewed by lungs exhaling CO2. H2CO3 dehydrates spontaneously but VERY slowly to CO2 (need CA).

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Open vs. Closed Buffers

Closed = total concentration fixed. Open = part/all can leave system, concentration maintained in balance (e.g. CO2/HCO3: CO2 & H2CO3 levels remain constant w/respiration, but HCO3 levels change to buffer)

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Good organic non-bicarb buffers

pK = 6.9 so good buffer @ 7.4. Histidine has pK close to 7.4 so proteins w/lots of histidine = good buffer (e.g. Hb).

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Acid-Alkali Transport Buffers

Cells take up acid in order to buffer pH changes in ECF. Intracellular Buffers prevent cellular pH changes. e.g. Bone releases large alkali reserve via clasts

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Henderson-Hasselbalch Equation

pH = 6.1 + log [HCO3]/alpha*PaCO2 . (alpha = 0.03 solubility of CO2). Compensations = when changes in PCO2 return bood pH to normal.

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respiratory alkalosis

pH > 7.7, PCO2 20 (low), [HCO3] 24 (normal)

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respiratory acidosis

pH < 7.12, PCO2 60 (high), [HCO3] 24 (normal)

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metabolic acidosis

pH < 7.1, PCO2 40 (normal), [HCO3] 12 (low). Caused by increased acid production OR decreased renal excretion of acid.

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metabolic alkalosis

pH > 7.57, PCO2 40 (normal), [HCO3] 36 (high). Can ONLY be caused by abnormal kidneys. NORMAL: inhibited reabsorption with high plasma [bicarb]. ABNORMAL: _increased_ reabsorption with HIGH plasma [bicarb].

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Metabolic compensation for primary respiratory alkalosis/acidosis

changes [HCO3] which alters PCO2 levels in oposite direction.

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Respiratory Compensation for primary metabolic acidosis/alkalosis

changes PCO2 which alters [HCO3] in opposite direction

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balanced acid/base but chronic metabolic acidosis

e.g. diarrhea -> acidosis but kidneys increase acid excretion -> high [HCO3] to sustain acid excretion.

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net nonvolatile acid production

chronic but small net acid load. 0.5-1 mEq/kg/day from diet (plus lactic acid can contribute (from glucose)). HCO3 lost in feces.

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kidney reclamation vs. regeneration of H+ (RENAL ACIDIFICATION)

Reclamation = HCO3 reabsorption. kidney secretes 4300 mEq/day of H+ to reclaim HCO3. Regeneration = Secretion of H+ creates new HCO3. kidney secretes 35-70 mEq/day of H+ to regenerate HCO3.

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normal ultrafiltrate bicarb

~24 mEq/L, filtered load ~4000 mEq/day entering Bowman's space

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pH buffers in urine

ammonia + "titratable acidity" (closed buffers filtered @ pH 7.4, so pK must be similar). e.g. HPO4-- pK = 6.9

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ammonia as urine pH buffer

high pK (9), high rate of production, open buffer (synthesized in proximal tubule from glutamine metabolism). Amount excreted depends on: 1) low ultrafiltrate pH & 2) [NH3] in interstitium (determined by rate of prox. tubule NH4 generation & transport)

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ammonia transport into lumen

NHE3 transporter antiports NH4+ against Na, or NH3 diffuses through & binds H in lumen.

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***NAE (net acid excretion)

NAE (net acid excretion) = urinary vol*(NH4 + TA + H - HB) = urinary vol*(NH4 + TA - HCO3)

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nephron contributions to urine acidity

Collecting Tubule > Proximal Tubule.

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Proximal Tubule & ThickAL Bicarb metabolism

Reabsorbs 70-80% filtered bicarb. 2/3 H+ secretion = Na/H, 1/3 H+ secretion = V-type H pump. Thick AL = 5-10% HCO3 reabsorption

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alpha cell

apical V-type pump, K/H pump, basal anion exchanger, K-leak, Cl-leak, intracellular CA. increase in number b/tw IMCD & CCD. generates lumen + potential.

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beta cell

CCD. electroneutral lumen. apical anion exchanger. cytoplasmic CA. basal Cl leak, K leak, H/K pump.

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Metabolic Acidosis

LOW BICARB caused by overproduction of acid (from metabolism/intake/excessive base loss). >400 mmoles/day or reduced capacity (e.g. renal failure)

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Metabolic Alkalosis

HIGH BICARB. Generation Phase = excess alkali added to ECF. Rapidly excreted normally, but 2nd defect in Maintenance Phase must prevent renal excretion.

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Respiratory Acidosis

Impaired Alveolar Ventilation -> HIGH CO2. wouldn't/couldn't/shouldn't breathe = central disorder/peripheral neural lesion/physiological suppression.

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Respiratory Alkalosis

LOW CO2. Ventilation beyond what is needed for CO2 clearance

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Acid-Base disorders that CANNOT coexist

ONLY Respiratory Acidosis with Respiratory Alkalosis. all others can exist in combination.

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Henderson Equation

[H] = 24* PCO2/[bicarb]

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Anion Gap ****

=[Na]-[Cl]-[bicarb] . estimate of anion that originated with the acid causing the problem. Poor estimate. (normal = 12-14, larger = unidentified anion such as ketoacids is present). Rise in anion gap should have decrease in HCO3!!!

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renal vasculature

renal artery -> segmental branches -> interlobar -> arcuate (cortico-medullary jxn) -> cortical ascending -> afferent arteriole -> efferent arterioles

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What happens if one renal artery is occluded?

half of kidney receives no blood. NO ANASTAMOSES.

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organ with the highest VO2

kidney (extracts only 10-15% of O2 that passes through)

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Renal AV shunt

FUNCTIONAL: O2 diffuses from artery straight to vein b/c so closely apposed + Vasa recta blood doesn't supply kidney tissues (goes straight to veins)

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normal glomerular capillary pressure

HIGH ~50 mm Hg (normal = 25). primary driving pressure for GFR.

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glomerular capillary hydrostatic P

primary determinant of GFR (afferent arteriolar dilation/efferent constriction -> higher GFR)

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components of juxtaglomerular apparatus

macula densa, afferent arteriole smooth muscle cells that produce renin, extraglomerular mesangium

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Chronic high volume/salt (e.g. eat greasy Chinese food every day for a week) ->

1) decreased sensitivity of tubuloglomerular feedback, 2) decreased renin release (to clear excess Na)

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Effects of low ECF volume (e.g. diarrhea) on Renal blood flow

GFR declines (systems activated to bring back up, but not quite back to normal). Renal blood flow declines more (AngII-> efferent declines more than afferent arteriolar resistance) -> INCREASED filtration fraction (want to reabsorb more salt)

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MDRD estimate of GFR

most accurate, but developed for patients w/kidney disease (GFR < 60 ml/min). Doesn't work if GFR close to normal range.

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osmolarity

mmol/kg water

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osmolality

mmol/L water

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Tonicity

mmol "effective solute"/L . some solutes have 100% permeability so 0 tonicity because do not contribute to flux.

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water vs. Na dysregulation

changes in ECF volume due to changes in Na concentration, but hypo/hypernatremia due to altered water content.

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regulation of ADH release by osmolarity

mediated by volume & pressure. ALWAYS give priority to volume over osmolarity & P.

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tonicity of loop of Henle

up to 1200 mosm (600 urea, 300 Na, 300 Cl)

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K partitioning in the body

most ICF, 65 mEq in ECF, 100 mEq excreted daily (feces & urine)

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lines of defense against K overload

1) cellular uptake, 2) renal excretion (works over hours), 3) colonic seretion (for chronic high K, low capacity)

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Hypokalaemic Periodic Paralysis

K deficiency due to too much in ICF

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renal K wasting

both ICF & ECF K is low. cell voltage stays ~ same b/c ratio of ICF to ECF is most important.

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control of K homeostasis

1) Aldo -> K excretion. 2) insulin -> HIGH Na/K pump activity (K enters ICF) & relieves acute dietary hyperkalemia, 3) Epi & NE -> K enters ICF 4) pH

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diabetes & K regulation

low insulin -> high ECF [K]. When treated, K shifts back into ICF but not enough (hypoK). insulin release involves ATP closing the K SUR channel. high ECF K -> channel stays open & high K depolarizes cell

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Epi/NE & K management

impt't for exercise. beta2 R activates Na/K pump (prevents hyperkalemia) -> K enters iCF. alpha R's -> K leaves cells post-exercise.

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pH effects on K management

H enters cell (electrogenic)-> displaces K from buffer-> K leaves cell-> lower Vrest. NOT for organic acids (eg lactate freely diffuses; ketoacids form in ICF & carry H out). same pH but low bicarb -> lower ECF K. acidemia>alkalemia. acute>chronic.

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colon K secretion

Basal: NaK2Cl, Na/K pump, K-leak. Apical: K-leak, Na-leak (comes in).

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colon K absorption

Basal: Na/K pump, K-leak. Apical: K/H ATPase (K comes in). Colon normally net absorbs K, but in kidney failure, colon switches to secreting K (small effect, but helps). constipation -> impaired K excretion (concentration builds up in lumen).

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renal K absorption

90% reabsorbed by end of Loop of Henle. only steep decline in GFR changes excretion. CCD: K secretion + alpha cells reabsorb in chronic K deficiency w/upregulated colonic H/K pump. Kidneys cannot lower urinary K to 0.

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K secretion in CCD

Basal: anion exchanger, K-leak, Cl-leak. Apical: K/H, V-type pump. Higher flux w/ high apical K conductance, high [K]in, low [K]out, (-) filtrate potential. low lumenal [K] stimulates secretion.

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volume contraction effects on Na reabsorption

increased reabsorption in proximal nephron, decreased Na reabsorption in distal nephron.

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***chronic high dietary K effects on kidneys

-> CCD principal cell 1) more basal Na/K pumps, 2) increased basal surface area

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***chronic low dietary K effects on kidneys

-> CCD alpha cell 1) more H/K pumps, 2) increased apical surface area

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Direct effects of plasma K on secretion in CCD

increased peritubular K 1) activates apical K & Na channels, 2) activates basal Na/K pump

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Effects of pH on renal K

alkalosis directly stimulates apical ROMK Ch's & secretion. acidosis directly inhibits " ".

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effects of low Effective Arterial Blood Volume (EABV) on Na & K

1) increased Aldo -> increased K secretion & proximal Na reabsorption. 2) Low filtrate [Na] due to increased proximal reabsorption -> decreased K secretion. OVERALL: NO CHANGE in K handling.

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Cause of most abnormalities in renal K handling

mineralocorticoids & distal Na delivery change IN THE SAME DIRECTION. K-wasting: 1) edema/high BP + proximal CCD diuretic, 2) hyperaldosteronemia, 3) Bartter Syndrome. K-saving: 1) Addison's, 2) Acute renal failure (low filtrate [Na])

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effects of edema/high BP + diuretics that work proximal to the CCD

Primary Increase in Distal Na Delivery: diuretics inhibit renal Na reabsorption -> NaCl+H2O excretion-> decreased blood volume -> AngII & Aldo. Low filtrate [Na] + Aldo -> K wasting.

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Calcium Stats

2% body weight (99% in skeleton), intake= 800-1200 mg/day but only 175 mg/day absorbed, 8.8-10.6 mg/dL in blood (40% w/albumin, 50% ionized)

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Blood calcium

10% complexed to anions, 50% freely ionized, 40% bound to plasma protein

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Renal calcium handling

98% reabsorbed normally. 65% prox tubule, 25% Thick AL, 8% DCT & CD. Only 60% of ECF Ca can be filtered.

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Proximal Tubule Ca reabsorption

1) 65% Ca reabsorbed in prox. tubule (80% of this paracellular). 2) High Na/H2O reabsorption concentrates Ca -> increased reabsorption + solvent drag. 3) Increased reabsorption w/volume contracton.

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Thick Ascending Limb Ca reabsorption

25% of filtered Ca reabsorbed in Thick AL. mostly passive, driven by lumen + charge. - Feedback: Ca binds to sensor -> inhibits ROMK -> decreased Ca reabsorption.

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renal Ca sensor

basal side of thick AL, blood-derived Ca & Mg binds -> AA metabolite 20-HETE released & Gi decreases cAMP-> inhibits apical ROMK -> dissipates lumen + potential

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Distal Convoluted Tubule Ca Reabsorption

Active transcellular (no para). Apical TRPV5/6 -> Calbindin sequesters -> Ca exits @ basal 3Na/1Ca (major) or Ca ATPase pump (minor).

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Control of Ca reabsorption

Increased: PTH, alkalosis (distal nephron), low ECF volume (proximal nephron). Decreased: ECF volume expansion (proximal tubule, secondary to low NaCl reaborption), low PO4, acidosis (distal)

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PTH (parathyroid hormone) in kidneys

D3 is permissive!! 1) Increases Ca reabsorption in DCT (increased transporter expression). 2) Decreases PO4 absorption in PCT (Binds NaPi-> endocytosed & degraded). 3) makes more PCT D3 (activates 1-alpha-hydroxylase). 4) decreases PCT bicarb reabsorption

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Mg stats

54% in skeleton, 45% in ICF, only 1% in ECF. 120 mg/day net absorbed from diet & net secreted. kidney Thick AL = major site of regulation. Normal [Mg] = 1.8-2.2

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Renal Mg Handling

70% plasma Mg filtered. Of this 15% reabsorbed in proximal tubule, 70% reabsorbed in Thick AL, 10% reabsorbed in DCT & CD. Overall 97% reabsorbed

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Mg reabsorption in proximal convoluted tubule

paracellular driven by + lumen potential BUT PCT not v. permeable to Mg. 15% of renal Mg reabsorption.

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Mg reabsorption in thick ascending limb

mostly paracellular driven by lumen + potential. 70% of renal Mg reabsorption. Mg binds Ca sensor -> decreased reabsorption.

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Claudin 16 & 19

tight jxn protein. mutation-> impaired Ca & Mg reabsorption in Thick AL. Claudin 16 permits Na backleak to increase + lumen potential. Claudin 19 prevents Cl from following. "DILUTION POTENTIAL"

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TRPM6 vs. TRPV5/6

TRPM6 = DCT apical Mg Channel. TRPV5/6 = DCT apical Ca Channel.

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causes of hypomagnesemia

1) primary intestinal w//2ndary hypocalcemia = TRPM6 mutation affecting GI tract & kidney. 2) Isolated dominant hypomagnesemia = due to mutation of gamma subunit of Na/K pump (expressed only in DCT)

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modulation of kidney Mg reabsorption

Increase: ECF volume contraction (prox. tubule). Decrease: ECF volume expansion (proximal tubule), Loop Diuretics (Thick AL). hyper/hypomagnesemia -> altered Thick AL reabsorption.

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PO4 stats

80-85% in bones, 14% in ICF, 1% in ECF. net GI tract absorption = 900 mg/day (excreted via kidneys). food preservative & in protein. 80% divalent form (2-). highly regulated amt in blood.

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Normal plasma PO4

2.5-4.5 mg/dL (0.8-1.5 mM). Divalent form dominant (80%) @ pH 7.4. 10-15% protein-bound. low [] in morning, increases until late @ night. 85-90% filtered @ glomerulus -> 80-97% reabsorbed.

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Renal PO4 Handling

85-90% filtered @ glomerulus, 80-97% of this is reabsorbed. transporters quickly saturated (Tm v. modifiable by regulators eg. PTH)

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Na+PO4 coporter types

1) NaPiIIa = 70-80% of PCT apical entry (rate limiting, electrogenic). 2) IIb = GI tract only. 3) IIc = 20-30% of renal apical transport (electroNEUTRAL). 4) PiT2 (type III, apical). PTH only works on IIa, IIc, Pit2.

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modulation of renal PO4 reabsorption

1) Low dietary PO4 increases Type IIa transporter expression (reverse for high dietary PO4). 2) PTH decreases activity (endocytic retrieval). 3) FGF-23 downregulates Type IIa & IIc transporters.

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FGF-23

1) Inhibits 1-alpha hydroxylase (low vitamin D3 = no absorption in intestine), 2) Removes NaPiIIa from membrane (no renal reabsorption). Receptor must bind Klotho to be fxnl. full-length transcript = active (O-linked glycosylation prevents cleavage).

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What is Familial Tumoral Calcinosis?

FGF23 levels too low -> too high PO4 reabsorption. mutations preventing O-linked glycosylation of FGF23 (causes functional knock out = faster cleavage of FGF23)

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PO4 modulation in ECF/ICF

1) respiratory alkalosis -> PFK -> making ATP uses up Pi -> PO4 moves to ICF 2) refeeding syndrome (after starvation) = dangerously low PO4 & K enters ICF when glucose & K are eaten -> hypophosphatemia

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EGF & Mg

EGF synthesized by DCT & tethered to basal membrane. When cleaved -> binds R on same cell (autocrine)-> stimulates TRPM6 activity.

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1-alpha hydroxylase

converts & activates vitamin D3

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Oncogenic Hypophosphatemic Osteomalacia (OHO)

Overproduction of FGF23 -> PO4 wasting via NaPi IIa & downregulated 1-alpha-hydroxylase (low Vitamin D)

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Solute-Free Water Excretion Equation

Excretion =~ Urine Volume*(1-[urinary Na + k]/[plasma Na + K])

🗑

normal amt. total body water ***

42 L

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thiazide diuretic problems

1) blocked Na reabsorption in DCT -> Na wasting, 2) fluid reabsorption in PCT increases. 3) low Na + low volume -> volume wins -> ADH released. net effect = hyponatremia. Treat by stopping Thiazide! or else CPM

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Central Pontine Myelinolyis (CPM)

someone is used to living w/hyponatremia gives Na too quickly -> cells of brain shrink quickly

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hyponatremia leading to acute brain swelling

morphine-induced nausea causes overproduction of ADH -> generation of excess free body water.

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urea diuresis

When very sick patient is given high protein, the protein is just broken down into urea. Massive urea diuresis. generates extra elecrolyte-free water -> hypernatremia. patient can't drink b/c obtunded.

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2 situations in which there is a - K balance without total body K deficiency

1) massive tissue death (hammer to biceps). high plasma K but dead tissues don't need it -> excretion. 2) recovery following K intoxication. A (-) balance does not = deficiency!

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First sign on EKG of hypo/hyperkalemia

1. hyperkalemia -> peaked T-wave. 2. hypokalemia -> flattened T-wave. Due to changes in resting potential of cardiomyocytes influencing likelihood of firing an action potential

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Which agents shift K into cells?

Beta 2 agonists, sodium bicarbonate, insulin (beta2 agonist & hypertonic solution shifts K out of cells)

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What is the ratio of paracellular to transcellular Na transport in the PCT vs. Thick AL?

PCT: 2/3 transcellular. Thick AL: 1/2 transcellular.

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What Ca Sensor mutation causes Bartter Syndrome & why?

An activating mutation of the Thick AL basal Ca sensor. Normal sensor signaling inhibits ROMK

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Why is it dangerous for someone with heart failure to take an NSID?

It prevents the modulatory effects of prostaglandins on the kidneys, permitting excessive salt reabsorption and edema.

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What is a natriuretic?

A substance that causes excess salt excretion in the urine.

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Where is brain natriuretic peptide (BNP) primarily released from?

heart ventricles

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How do ANP/BNP inhibit salt reabsorption in the IMCD?

bind a guanylyl Cyclase R -> cGMP generation -> PKG inhibits nonspecific cation Ch and Na/K pump.

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Which diuretics are protein-bound in the blood?

NOT filtered @ Bowman's capsule! loop diuretics & thiazide diuretics. Proximally secreted into lumen.

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What is acetazolamide?

CA inhibitor diuretic

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What is furosemide?

LOOP DIURETIC! e.g. LASIX. protein-bound (actively secreted into kidneys).

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Why do loop diuretics disrupt tubuloglomerular feedback?

They prevent Na reabsorption in the Thick AL -> inhibit renin secretion independently of filtrate flow.

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Which is the most potent loop diuretic?

bumetanide > torsemide > furosemide (1 : 10 : 40)

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What is unique about the dose-response curve of furosemide?

Threshold effect, lasts 6 hours (half life 90 minutes), rapid onset & offset. MUST be given 2x/day.

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Why must furosemide be given 2x daily?

1. natriuretic FX -> activation of RAAS. early salt wasting can be counterbalanced by late salt saving. 2. Furosemide has short duration FX & steep onset/offset kinetics. 3. Need MUCH higher dose for kidney failure patients.

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What are side effects of loop diuretics?

1) volume contraction & low GFR. 2) (higher Na delivery to CCD) + high Aldo (volume contraction) -> K wasting. 3) metabolic alkalosis in CCD. 4) oto/vestibular toxicity (>4 mg/min IV) disrupts endolymph in inner ear.

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What is hydrocholorothiazide?

Thiazide diuretic.

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What is metozolone?

Thiazide diuretic that DOES work @ low GFR

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Why do Thiazide diuretics increase Ca reabsorption?

1) indirect effect: by lowering EABV, they increase salt reabosorption @ PCT, including Ca. 2) They also have a direct effect @ DCT through unknown mechanisms.

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What are side effects of thiazide diuretics?

1) increase Na delivery to collecting duct, 2) volume contraction -> Aldo, 3) raise serum HCO3 (usually harmless), 4) hyponatremia (water highly reabsorbed in a small fraction of patients)

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What is the major influence on proximal tubule salt and water reabsorption?

VOLUME STATUS (EABV)

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What is amiloride?

K-sparing diuretic blocks ENaC @ CCD & DCT

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What is triamterene?

K-sparing CCD diuretic blocks ENaC @ CCD & DCT

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What are spironolactone & epleronone?

mineralocorticoid receptor antagonists. used to treat cirrhosis. Epleronone more expensive BUT specific inhibitor. Spironolactone = generic, but also inhibits androgen R (-> gynecomastia) & activates progesterone R.

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What are modulators of ADH release?

v. sensitive to low volume. less sensitive to low pressure. v. sensitive to high osmolarity (more sensitive than thirst).

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What are modulators of thirst?

v. sensitive to low EABV. less sensitive to hypertonicity.

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If someone has a serum Na of 154 mM and they have lost 4 L of water, does water/Na/both need to be replaced?

water. Calculate: 42L-4L=38L fluids in body. 42/38 * 140 mM Na (normal) = 154 mM. Therefore replacing lost water will restore normal Na molarity.

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What are 2 causes of organic acidosis seen in disease states?

1) generate H+ & organic anion more quickly than they can be metabolized. 2) kidney flushes organic anion more quickly than they can be metabolized. e.g. glucose/fat/ketoacids/lactic acid

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Why does citrate in lemons vs. oranges have different metabolic effects on acid/base?

in oranges, K-citrate generates net 3 bicarbonates (base load). in lemons, citrate comes accompanied by H+ -> no net change.

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For a closed system, what are the primary determinants of the contribution of a given buffer?

1) pK of the buffer. 2) concentration of the buffer.

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What provides the energy for the basal Na/3HCO3- pump in the PCT?

although extracellular Na is high (reverse chemical gradient), the electrical gradient drives transport: 1 Na and 3 HCO3- relieves some of the - potential of the cell.

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Which aa is used to produce renal ammonia, and how does it get to the kidney?

NORMAL: 20% glutamine is filtered, 17% is reabsorbed -> net 3% enters filtrate -> NH3. ACIDOSIS: glutamine is secreted from the liver -> 20% filtered + 10% actively secreted = 30% converted to NH3.

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What is the equation for urinary net acid excretion?

UNAE = urine volume * ([NH4 + titratable acid] - [citrate + HCO3])

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Can A- (inorganic anion) be excreted into the gut?

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***In respiratory compensation for metabolic acid/base disorders, how much of a change in CO2 is required to change HCO3?

To change HCO3 by 1 mM... ACIDOSIS: increase ventilation 1.2-1.5 mm Hg pCO2. ALKALOSIS: decrease ventilation 0.6 mm Hg PCO2. Harder to decrease than to increase breathing rate b/c hypoxemia.

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***In metabolic compensation for respiratory acid/base disorders, how much of a change in HCO3 is required to change PCO2?

To change CO2 by 10 mmHg...ACIDOSIS: reabsorb 1 mM (acute) or 3 mM (chronic) HCO3. ALKALOSIS: secrete 2 mM (acute) or 5 mM (chronic) HCO3.

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Why does urine get cloudy at high altitude?

Hyperventilate to get more oxygen -> low CO2. Body tries to excrete HCO3 because of respiratory alkalosis and Ca++ (cloudy) gets excreted as well.

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If pH is low, CO2 is high, and HCO3 is low, what is the diagnosis?

Metabolic acidosis + Respiratory acidosis

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If there is a large anion gap but normal bicarb levels, what is wrong?

There was a preexisting metabolic alkalosis that is being masked by bicarb generation from excess anions being neutralized in the blood stream.

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What if CO2 rises more than predicted for a correction of metabolic alkalosis?

= respiratory acidosis. NOT compensation!!!

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What are the variables that should be assessed for acid-base disturbances?

1) pH 2) bicarb 3) pCO2 4) anion gap 5) predicted vs. actual change in bicarb or CO2 (determines whether compensation or additional disturbance)

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What is the size of the pool and the flux for H in the body?

1.6-1.7 micromoles of protons, flux = several hundred miromoles

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***How much K is in ECF vs. ICF?

65 mEq in ECF, 3400 in ICF. flux = 50-100 mEq/day (5% in stool, 95% in urine).

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What is the definition of balance, steady state, and excess/deficiency?

Balance: in=out, Steady State: value is constant with time. Sufficiency/Excess/Deficiency = value is enough, too much, or not enough. e.g. changes to ICF K levels do not alter ECF levels -> can have excess K but still be @ steady state.

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What are the 3 ways to alter ECF potassium?

cellular uptake, colonic excretion, renal excretion

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What is the Nernst equation?

Eion = 61.5mV*log [out]/[in] . = potential difference generated by given charged particle across a membrane WHEN THERE IS NO FLUX.

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Why do you prescribe patients polystyrene?

sulfate + polystyrene binds K @ high affinity -> increases K secretion in colon.

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Where is K stored in the body?

skeletal muscle > bone (inaccessible) > liver > RBCs > ECF

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What is the body's acute reaction to receiving a dietary K load?

K moves into ICF until it can be excreted by the kidneys

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Which factors move K into the ICF?

1) insulin, 2) bicarb, 3) beta2 adrenergic R. (alpha adrenergic R moves K -> ECF)

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How is K reabsorbed/secreted in segments of the nephron?

PCT: paracellular (early = [ ] gradient, late = [ ] & lumen + potential). Thick AL: 50% para-, 50% transcellular (lumen + potential). CD: PRINICPAL secretes (lumen - potential pulls K out of ROMK apically), ALPHA reabsorbs (H/K ATPase transporter).

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What are the major regulators of K secretion in CD principal cells?

1) Aldo, 2) distal Na delivery, 3) plasma K, 4) pH

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What effect does high flow rate have on renal K handling?

Greater flow rate -> more distal Na delivery & more K secretion in CD

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How does elevated serum K alter renal K handling?

Directly activates ROMK, ENaC, Na/K pump. high K diet -> better ability to excrete K @ ANY plasma K level (increased principal cell basal infoldings w/in days)

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How does plasma pH alter renal K handling?

alkalosis -> excretion. Acidosis -> reabsorption. intracellular H -> decreased ROMK open probability & decreased channel insertion in the membrane.

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How do loop/thiazide diuretics alter renal K handling?

Elevated Aldo and increased distal Na delivery -> more K excretion

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How much lumenal Na is required for distal K secretion?

25-35 mM

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What is the ECF Ca++ pool & flux?

1 kg (almost all in skeleton), ~1 g in ECF (40% bound to albumin = not filtered, 10% bound to other ions, 50% alone & freely filtered). Daily intake ~1 g.

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How does pH affect ECF Ca?

H displaces Ca from albumin -> more ionized Ca is bioavailable. When patient has hypocalcemia & acidosis, correct Ca first & pH second b/c low pH helps make Ca available.

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What are the systemic effects of PTH?

(D3 = permissive!) -> bone reabsorption, intestinal Ca reabsorption (via D3), DCT Ca reabsorption

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Why is renal PO4 reabsorption inhibited by PTH?

D3 increases Ca AND phosphorous reabsorption from small intestine. Need a way to independently increase Ca.

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How is PTH expressed & released?

1) low ionized Ca @ G-coupled sensor-> increased PTH expression & release. 2) D3 transcriptionally activates PTH, 3) low Ca or high PO4 -> protein expression that binds & stabilizes PTH mRNA.

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What is Familial Hyocalciuric Hypercalcemia (FHH)?

inactivating mutation of calcium sensor in Thick AL -> too much Ca reabsorption

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How does pH alter Ca reabsorption in the DCT?

low pH -> TRPV5/6 decreased expression & membrane insertion -> decreased Ca reabsorption. High pH -> increased Ca reabsorption.

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What does PTH stimulate expression of in the DCT?

calbindin, TRPV5/6, Na/Ca exchanger, Ca ATPase

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How do you treat hypercalcemia?

NaCl -> expands ECF volume. Loop diuretic -> blocks Thick AL Ca reabsorption. (if no NaCl, loop diuretic -> decreased EABV -> increased PCT Ca reabsorption).

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What is Isolated Recessive Hypomagnesemia?

mutated pro-EGF type 1 membrane protein. Normally binds basal EGFR in DCT -> TRPM6 activation. Autocrine.

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What is the difference in genetic disorders of Mg handling in the Thick AL & DCT

Thick AL mutation -> hypercalciuria. DCT mutation -> hypocalciuria.

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How is DCT Ca modulated by Mg reabsorption?

Intracellular Mg inhibits TRPV5/6 -> inhibits Ca reabsorption

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What are the factors that alter PO4 reabsorption?

1) dietary intake of PO4, 2) PTH, 3) FGF23 hormone

🗑

How does dietary PO4 alter reabsorption in the PCT?

Microtubule-dpdt removal of NaPiIIa from apical membrane (depends on terminal 3 aa's, bind PDZs that stabilize in membrane). Also long-term changes in mRNA & protein. NaPiIIc PDZs are different & much slower.

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How does PTH modify PO4 reabsorption in the PCT?

endocytosis of NaPis via clathrin-coated pits & microtubules. Dependent on 2 aa's (KR) in intracellular loop (not present in intestinal IIb). DEGRADATION, no recycling.

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What are examples of primary & secondary edema?

Primary (overfill): kidney failure. Secondary (underfill): congestive heart failure, Cirrhosis, normal kidney fxn.

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How do burns alter total body water?

Kidneys retain salt & water -> edema. Retain fluid in body compartments that are isolated from the vasculature (blisters) -> low EABV. "Starling Block".

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How does heart failure alter total body water?

total blood volume remains high, but fraction in arteries decreases as blood pools in veins. Kidneys retain salt & water.

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How does liver failure alter total body water?

Kidneys retain salt & water. Ascites. Arterial Blood Volume is high, but EFFECTIVE ABV is low (high pressures in portal vein -> NO production -> generalized vasodilation). "Relative Underfilling". Arterio-venous fistulas develop.

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What causes a Starling block?

AV fistula formation ("arteriolar runoff"), relative underfilling of the arteries, Generalized vasodilation.

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What are features of low EABV?

persistent low volume signal due to derangement in ECF. Functional Equivalent of low total body salt.

🗑

Beri Beri

Thiamine deficiency. high CO, expanded total blood volume but LOW effective volume b/c of generalized vasodilation due to lack of thiamine.

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Hadget's Disease

Widespread A/V fistula formation (rheumatologic disorder of bone marrow cells) -> signals low EABV to kidney.

🗑

What are urine salts for someone on loop diuretics?

high Na, K, & Cl in urine (K-wasting). Co-treat with ACE inhibitor to prevent high Aldo & decrease afterload (causes vasodilation).

🗑

What diuretics cause metabolic alkalosis?

Loop Diuretics. High Aldo, high distal Na delivery -> more Na absorption -> more lumen - potential -> alpha intercalated cells secrete more H (electrical gradient high) & generate more bicarb.

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How does low EABV alter renal bicarb handling?

stimulates proximal bicarb reabsorption.

🗑

Where is free water generated in the nephron?

Loop of Henle (where salt and water are separated & separately absorbed).

🗑

How does heart failure cause hyponatremia?

Low EABV -> increased proximal salt reabsorption -> low distal salt delivery -> low free water formation b/c less NaCl reabsorption in Thick AL, + High ADH -> super concentrated urine

🗑

Do AngII, tubuloglomerular feedback, sympathetic signaling, & prostaglandins work at the afferent or efferent arteriole?

AngII and Sympathetics: constricts Efferent more than Afferent. Tubuloglomerular Feedback: low NaCl dilates Afferent (NO) & high NaCl constricts (adenosine). PGE/I2: dilates Efferent.

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What is unique about paraaminohippurate that makes it helpful in assessing kidney function?

100% clearance rate. Can be used to calculate renal plasma flow.

🗑

How can RPF be approximated?

C_pah = (U_pah x Volume)/P_pah = Effective RPF

🗑

***What are sympathetic NS effects on renal filtration?

NE -> 1) Increased filtration fraction (efferent>afferent constriction). 2) Increased Na/H & Na/K pump activity!!! (alpha adrenergic R) in proximal tubule. 3) Increased renin release.

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What are endothelin effects on renal filtration?

stimulates proximal tubule Na/H pump

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Created by: rbxbrown