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UTSW Physio Block 3
UT Southwestern School of Medicine renal physiology block 3
| Question | Answer |
|---|---|
| 4 unique features of renal circulation | 1 no anastamoses, 2 highest flow/gram tissue, 3 arteriovenous shunts, 4 multiple capillaries in tandem |
| Loop of Henle main function | Reabsorption: Na/K/HCO3/Cl/Ca/Mg. Dilution of filtrate. |
| Thin descending and ascending limb main fxns | descending: water reabsorption & urea secretion. ascending: Na/Cl/K reabsorption |
| Thick ascending limb fxn | Reabsorption of Na/K/Cl/HCO3/Ca/Mg (secondary active transport & paracellular) |
| Distal convoluted tubule fxn | Reabsorption of Na/Cl/Ca/Mg |
| Collecting Tubule cell types | Principal cells, Intercalated cells (alpha all along collecting duct, beta only in cortical region) |
| 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. |
| mesangium | mesangial cells + sulfated GAG's & collagen. |
| mesangial cell fxn | support, regulate capillary flow, produce matrix, phagocytic, paracrine (e.g. prostaglandins) |
| fractional urinary excretion (equation) | = amount excreted/amount filtered |
| 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. |
| Where is erythropoeitin made? | kidney cortical interstitial cells |
| 1-alpha-hydroxylase | enzyme in proximal tubule cells generates 1,25 (OH)2 vitamin D3 (active form). |
| What is normal renal blood flow? | 20% of CO, ~1.1 L/minute. |
| What is normal renal plasma flow (RPF)? | 600 ml/minute (hematocrit = 40%) |
| 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. |
| Filtration Fraction equation & normal value | = GFR (ml/min)/RPF (ml/min). normal = 125/600 = 0.2 Efferent arteriolar resistance ONLY alters filtration fraction. |
| 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) |
| 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 |
| Ultrafiltration coefficient (Kf) | determines surface area available & water permeability |
| Factors affecting GFR | 1) glomerular hydrostatic P, 2) Bowman's hydrostatic P, 3) plasma colloid P, 4) Kf, 5) arteriolar resistance |
| 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. |
| 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) |
| How does EABV alter the sensitivity of GFR? | GFR is fine-tuned by increased/decreased arterial volume. high arterial volume -> decreased sensitivity. |
| Measuring GFR with inulin | GFR * plasma-inulin = urine flow * urine-inulin. rate filtration === rate excretion. |
| 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) |
| Clearance Equation for inulin | Clearance = urine [inulin] x Volume urine/plasma [inulin] |
| 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. |
| Cockcroft-Gault equation | estimates creatinine clearance NOT GFR (overestimates) |
| 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. |
| PAH equation for effective RPF | urine PAH x urine rate/Plasma PAH = "effective" RPF. |
| 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. |
| equation to calculate renal blood flow from hematocrit | RPF/(1-hematocrit %) = RBF/1 |
| equation for filtration fraction | FF = GFR/RPF. = fraction plasma flowing through kidneys. |
| 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. |
| 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. |
| body fluid distribution, general | 2/3 of water = intracellular. remaining = extracellular: 3/4 interstitial, 1/4 intravascular. |
| Na resorption in different areas of the nephron | proximal = 67%, Loop of Henle 25%, Distal Tubule 5%, Collecting Duct 3%, Excreted < 1% |
| 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 |
| mechanism for paracellular Na resorption | driven by (+) potential in lumen after Cl leaves paracellularly |
| 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. |
| Basal membrane Cl transport | Cl channels or KCL coporter |
| 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. |
| TF/P ratio | tubular fluid: plasma ratio. |
| 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. |
| effects of high filtration fraction on peritubular capillaries | increases colloid osmotic pressure of peritubular capillaries -> facilitates NaCl reabsorption |
| effects of low Effective Arterial Blood Volume (EABV) | renal nerve activity & endothelin release, RAAS, myogenic reflex. |
| 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. |
| effects of metabolic acidosis on ion reabsorption in the proximal tubule | less HCO3- reabsorbed -> less water reabsorbed -> lower Cl concentration -> less NaCl absorbed paracellularly |
| 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. |
| ***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. |
| 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. |
| Na transport in distal convoluted tubule | 1) Na/Cl coport. 2) Na/H + Cl/Base antiporters. 3) passive Na Channel + paracellular Cl |
| Gitelman Syndrome | defective thiazide-sensitive NaCl coporter in DCT-> hypocalciuria (high Ca resorption), downregulated TRPM6 (low Mg resorption). salt wasting. |
| ***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 |
| WNK4 ("with no lysine" kinase) | -> decreases NaCl coporter (NCC) expression. normally dephosphorylates claudins1-4 & decreases Cl reabsorption. inhibited by WNK1. |
| Collecting Duct Na regulation | ENaC |
| ENaC Channel | alpha subunit required for channel fxn. beta & gamma increase conductivity |
| Liddle Syndrome | mutations in beta and gamma subunits PY motif where normally Nedd4-2 ubiquitinates for internalization & degradation. Hypertension due to high Na resorption |
| Nedd4-2 | marks normal ENaC for degradation. inhibited by SGK1 (serum & glucocorticoid-stimulated kinase) which is stimulated by Aldo. |
| 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. |
| 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. |
| 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 |
| 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 |
| 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. |
| Flux (Jv) | Jv = Lp*RT*sigma*deltaC. sigma = reflection coefficient. Lp = permeability. |
| major determinant of water movement between ICF & ECF | NaCl: sigma ~1, largest extracellular concentrations |
| IV fluids that spread to the ECF | Normal Saline, Lactated Ringer's |
| Which IV fluids spread to the ICF? | 5% Dextrose (D5W), 1/2 Normal Saline |
| Which IV fluids stay intravascular? | Whole Blood, Packed Red Cells, Plasma, Albumin |
| Which compartments lose volume during hypovolumia? | All compartments lose water (Total Body Water = ECF, ICF, intravascular) |
| early vs. late proximal tubule Na reabsorption | early, transported w/HCO3-. late, transported w/Cl paracellular 1/3 transcellular 2/3. |
| WNK kinases | WNK4 downregulates NaCl coporter in DCT (WNK1 inhibits WNK4) |
| determinants of ECF volume | balance b/tw Na inake and excretion |
| abrupt decrease in dietary Na effects: | ECF volume decreases -> EABV decreases -> decreased urinary Na excretion -> several days to achieve new Na balance. |
| 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 |
| 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). |
| ***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 |
| renal autoregulation | myogenic reflex dilates afferent arteriole when low renal artery pressure & constricts when high pressure to maintain constant flow |
| tubuloglomerular feedback system | macula densa signals lower lumenal [NaCl] concentration -> afferent artery vasodilation & high GFR. |
| 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) |
| hepatic sodium sensors | osmoreceptors & NaCl receptors in liver -> nucleus of the solitary tract -> decreases renal sympathetic activity -> increased salt excretion |
| hepatic baroreceptors | reflexively decrease renal sympathetic nerve activity |
| 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. |
| ***filtered load | = GFR * plasma [ ] - amt. reabsorbed |
| glomerulo-tubular balance | nearly constant fractional excretion of Na despite changes in GFR due to proximal tubule salt reabsorption. |
| 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 |
| 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 |
| conditions in which more Na is reabsorbed proximally | low EABV. high Aldo does NOT cause K loss. |
| conditions when distal Na delivery is more plentiful | ECF volume expansion. Aldo is suppressed & K is not lost @ higher rates. |
| 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. |
| 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) |
| 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) |
| CNP | released by vascular endothelium as local paracrine |
| diuretic-induced diuresis | when diuretics result in an increase in solute AND water excretion |
| K-sparing diuretics | Aldo antagonists. intracellular site of action.mild b/c collecting duct only reabsorbs 1-3% filtered Na. |
| 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). |
| 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! |
| 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) |
| Types of loop diuretics | 1) sulfonamide derivatives e.g. furosemide/bumetanide/torsemide. 2) non-sulfonamide derivatives e.g. ethacrinic acid. |
| 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. |
| 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. |
| 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) |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| osmo vs. baroreceptors & ADH | small changes = osmoreceptors win. large changes = baroreceptors change. circulation most important to maintain |
| thirst stimulation | 1) threshold higher than ADH threshold, 2) stimulated by high osmolarity & low blood volume, 3) volume trumps osmolarity |
| thirst inhibition | 1) low osmolality, 2) oropharyngeal reflex (water @ back of oropharynx temporarily blocks thirst, 3) volume expansion |
| 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 |
| 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. |
| 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 |
| 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 |
| mechanism for aquaporin 2 insertion | ADH binds basal V2 R -> Gs -> PKA -> Aquaporin 2 inserted apical membrane (microtubule-dpdt) |
| alternate aquaporins | 3 & 4 exist in basal membrane of principal & IMCD cells, but water cannot flow w/out apical 2 |
| Hyponatremia | defective urinary dilution. too much water in system. |
| Hypernatremia | defective thirst/urinary concentration. |
| normal interstitial vs. intracellular Na | interstitial ~145 (same as plasma). intracellular 10. |
| normal interstitial vs. intracellular K | interstitial ~4 (same as plasma). ICF 150. |
| normal interstitial vs. ICF Ca | interstitial ~ 2 (same as plasma). ICF 10^-7 |
| normal interstitial vs. ICF Mg | interstitial ~1 (same as plasma). ICF 2. |
| normal interstitial vs. ICF [Cl] | interstitial ~110 (same as plasma). ICF 4. |
| normal interstitial vs. ICF [protein] | interstitial 0.1 (NOT SAME AS PLASMA 1.0). ICF 50. |
| normal interstitial vs. ICF HCO3 | interstitial 24 (same as plasma). ICF 12. |
| steady state vs. balance | steady state = variable of interest doesn't vary. Balance = variable doesn't change specifically because inputs = outputs. |
| 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. |
| Buffers | instantly remove acid/base, but only temporary fix. |
| 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 |
| pH & pK | pH-pK = log [acid]/[base]. strong acids completely dissociate @ pH7, whereas strong bases completely associate @ pH7. |
| significance of urine sulphate levels | direct reflection of amount of sulphur-containing aa's digested = amount of acidic aa's consumed |
| "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!!! |
| dietary source of acids & bases | 1) acids from proteins. 2) bases from produce. |
| 3 components of homeostatic response to metabolic acids | 1) Buffer, fast. 2) Respiration, removes volatile acids to restore balance. 3) Metabolic & Renal |
| 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. |
| 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 |
| Buffer Capacity | in units of Eq/l/pH unit. = amt. strong acid/base required to change 1 L solution x 1 pH point. |
| Ampholyte | both acid and base |
| 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). |
| 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) |
| 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). |
| 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 |
| 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. |
| respiratory alkalosis | pH > 7.7, PCO2 20 (low), [HCO3] 24 (normal) |
| respiratory acidosis | pH < 7.12, PCO2 60 (high), [HCO3] 24 (normal) |
| metabolic acidosis | pH < 7.1, PCO2 40 (normal), [HCO3] 12 (low). Caused by increased acid production OR decreased renal excretion of acid. |
| 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]. |
| Metabolic compensation for primary respiratory alkalosis/acidosis | changes [HCO3] which alters PCO2 levels in oposite direction. |
| Respiratory Compensation for primary metabolic acidosis/alkalosis | changes PCO2 which alters [HCO3] in opposite direction |
| balanced acid/base but chronic metabolic acidosis | e.g. diarrhea -> acidosis but kidneys increase acid excretion -> high [HCO3] to sustain acid excretion. |
| 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. |
| 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. |
| normal ultrafiltrate bicarb | ~24 mEq/L, filtered load ~4000 mEq/day entering Bowman's space |
| pH buffers in urine | ammonia + "titratable acidity" (closed buffers filtered @ pH 7.4, so pK must be similar). e.g. HPO4-- pK = 6.9 |
| 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) |
| ammonia transport into lumen | NHE3 transporter antiports NH4+ against Na, or NH3 diffuses through & binds H in lumen. |
| ***NAE (net acid excretion) | NAE (net acid excretion) = urinary vol*(NH4 + TA + H - HB) = urinary vol*(NH4 + TA - HCO3) |
| nephron contributions to urine acidity | Collecting Tubule > Proximal Tubule. |
| 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 |
| 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. |
| beta cell | CCD. electroneutral lumen. apical anion exchanger. cytoplasmic CA. basal Cl leak, K leak, H/K pump. |
| 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) |
| Metabolic Alkalosis | HIGH BICARB. Generation Phase = excess alkali added to ECF. Rapidly excreted normally, but 2nd defect in Maintenance Phase must prevent renal excretion. |
| Respiratory Acidosis | Impaired Alveolar Ventilation -> HIGH CO2. wouldn't/couldn't/shouldn't breathe = central disorder/peripheral neural lesion/physiological suppression. |
| Respiratory Alkalosis | LOW CO2. Ventilation beyond what is needed for CO2 clearance |
| Acid-Base disorders that CANNOT coexist | ONLY Respiratory Acidosis with Respiratory Alkalosis. all others can exist in combination. |
| Henderson Equation | [H] = 24* PCO2/[bicarb] |
| 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!!! |
| renal vasculature | renal artery -> segmental branches -> interlobar -> arcuate (cortico-medullary jxn) -> cortical ascending -> afferent arteriole -> efferent arterioles |
| What happens if one renal artery is occluded? | half of kidney receives no blood. NO ANASTAMOSES. |
| organ with the highest VO2 | kidney (extracts only 10-15% of O2 that passes through) |
| 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) |
| normal glomerular capillary pressure | HIGH ~50 mm Hg (normal = 25). primary driving pressure for GFR. |
| glomerular capillary hydrostatic P | primary determinant of GFR (afferent arteriolar dilation/efferent constriction -> higher GFR) |
| components of juxtaglomerular apparatus | macula densa, afferent arteriole smooth muscle cells that produce renin, extraglomerular mesangium |
| 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) |
| 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) |
| 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. |
| osmolarity | mmol/kg water |
| osmolality | mmol/L water |
| Tonicity | mmol "effective solute"/L . some solutes have 100% permeability so 0 tonicity because do not contribute to flux. |
| water vs. Na dysregulation | changes in ECF volume due to changes in Na concentration, but hypo/hypernatremia due to altered water content. |
| regulation of ADH release by osmolarity | mediated by volume & pressure. ALWAYS give priority to volume over osmolarity & P. |
| tonicity of loop of Henle | up to 1200 mosm (600 urea, 300 Na, 300 Cl) |
| K partitioning in the body | most ICF, 65 mEq in ECF, 100 mEq excreted daily (feces & urine) |
| lines of defense against K overload | 1) cellular uptake, 2) renal excretion (works over hours), 3) colonic seretion (for chronic high K, low capacity) |
| Hypokalaemic Periodic Paralysis | K deficiency due to too much in ICF |
| renal K wasting | both ICF & ECF K is low. cell voltage stays ~ same b/c ratio of ICF to ECF is most important. |
| 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 |
| 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 |
| 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. |
| 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. |
| colon K secretion | Basal: NaK2Cl, Na/K pump, K-leak. Apical: K-leak, Na-leak (comes in). |
| 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). |
| 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. |
| 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. |
| volume contraction effects on Na reabsorption | increased reabsorption in proximal nephron, decreased Na reabsorption in distal nephron. |
| ***chronic high dietary K effects on kidneys | -> CCD principal cell 1) more basal Na/K pumps, 2) increased basal surface area |
| ***chronic low dietary K effects on kidneys | -> CCD alpha cell 1) more H/K pumps, 2) increased apical surface area |
| Direct effects of plasma K on secretion in CCD | increased peritubular K 1) activates apical K & Na channels, 2) activates basal Na/K pump |
| Effects of pH on renal K | alkalosis directly stimulates apical ROMK Ch's & secretion. acidosis directly inhibits " ". |
| 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. |
| 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]) |
| 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. |
| 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) |
| Blood calcium | 10% complexed to anions, 50% freely ionized, 40% bound to plasma protein |
| Renal calcium handling | 98% reabsorbed normally. 65% prox tubule, 25% Thick AL, 8% DCT & CD. Only 60% of ECF Ca can be filtered. |
| 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. |
| 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. |
| 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 |
| 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). |
| 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) |
| 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 |
| 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 |
| 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 |
| Mg reabsorption in proximal convoluted tubule | paracellular driven by + lumen potential BUT PCT not v. permeable to Mg. 15% of renal Mg reabsorption. |
| Mg reabsorption in thick ascending limb | mostly paracellular driven by lumen + potential. 70% of renal Mg reabsorption. Mg binds Ca sensor -> decreased reabsorption. |
| 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" |
| TRPM6 vs. TRPV5/6 | TRPM6 = DCT apical Mg Channel. TRPV5/6 = DCT apical Ca Channel. |
| 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) |
| 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. |
| 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. |
| 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. |
| Renal PO4 Handling | 85-90% filtered @ glomerulus, 80-97% of this is reabsorbed. transporters quickly saturated (Tm v. modifiable by regulators eg. PTH) |
| 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. |
| 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. |
| 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). |
| 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) |
| 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 |
| EGF & Mg | EGF synthesized by DCT & tethered to basal membrane. When cleaved -> binds R on same cell (autocrine)-> stimulates TRPM6 activity. |
| 1-alpha hydroxylase | converts & activates vitamin D3 |
| Oncogenic Hypophosphatemic Osteomalacia (OHO) | Overproduction of FGF23 -> PO4 wasting via NaPi IIa & downregulated 1-alpha-hydroxylase (low Vitamin D) |
| Solute-Free Water Excretion Equation | Excretion =~ Urine Volume*(1-[urinary Na + k]/[plasma Na + K]) |
| normal amt. total body water *** | 42 L |
| 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 |
| Central Pontine Myelinolyis (CPM) | someone is used to living w/hyponatremia gives Na too quickly -> cells of brain shrink quickly |
| hyponatremia leading to acute brain swelling | morphine-induced nausea causes overproduction of ADH -> generation of excess free body water. |
| 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. |
| 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! |
| 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 |
| Which agents shift K into cells? | Beta 2 agonists, sodium bicarbonate, insulin (beta2 agonist & hypertonic solution shifts K out of cells) |
| 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. |
| What Ca Sensor mutation causes Bartter Syndrome & why? | An activating mutation of the Thick AL basal Ca sensor. Normal sensor signaling inhibits ROMK |
| 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. |
| What is a natriuretic? | A substance that causes excess salt excretion in the urine. |
| Where is brain natriuretic peptide (BNP) primarily released from? | heart ventricles |
| 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. |
| Which diuretics are protein-bound in the blood? | NOT filtered @ Bowman's capsule! loop diuretics & thiazide diuretics. Proximally secreted into lumen. |
| What is acetazolamide? | CA inhibitor diuretic |
| What is furosemide? | LOOP DIURETIC! e.g. LASIX. protein-bound (actively secreted into kidneys). |
| Why do loop diuretics disrupt tubuloglomerular feedback? | They prevent Na reabsorption in the Thick AL -> inhibit renin secretion independently of filtrate flow. |
| Which is the most potent loop diuretic? | bumetanide > torsemide > furosemide (1 : 10 : 40) |
| 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. |
| 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. |
| 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. |
| What is hydrocholorothiazide? | Thiazide diuretic. |
| What is metozolone? | Thiazide diuretic that DOES work @ low GFR |
| 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. |
| 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) |
| What is the major influence on proximal tubule salt and water reabsorption? | VOLUME STATUS (EABV) |
| What is amiloride? | K-sparing diuretic blocks ENaC @ CCD & DCT |
| What is triamterene? | K-sparing CCD diuretic blocks ENaC @ CCD & DCT |
| 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. |
| 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). |
| What are modulators of thirst? | v. sensitive to low EABV. less sensitive to hypertonicity. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
| What is the equation for urinary net acid excretion? | UNAE = urine volume * ([NH4 + titratable acid] - [citrate + HCO3]) |
| Can A- (inorganic anion) be excreted into the gut? | no |
| ***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. |
| ***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. |
| 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. |
| If pH is low, CO2 is high, and HCO3 is low, what is the diagnosis? | Metabolic acidosis + Respiratory acidosis |
| 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. |
| What if CO2 rises more than predicted for a correction of metabolic alkalosis? | = respiratory acidosis. NOT compensation!!! |
| 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) |
| 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 |
| ***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). |
| 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. |
| What are the 3 ways to alter ECF potassium? | cellular uptake, colonic excretion, renal excretion |
| 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. |
| Why do you prescribe patients polystyrene? | sulfate + polystyrene binds K @ high affinity -> increases K secretion in colon. |
| Where is K stored in the body? | skeletal muscle > bone (inaccessible) > liver > RBCs > ECF |
| 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 |
| Which factors move K into the ICF? | 1) insulin, 2) bicarb, 3) beta2 adrenergic R. (alpha adrenergic R moves K -> ECF) |
| 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). |
| What are the major regulators of K secretion in CD principal cells? | 1) Aldo, 2) distal Na delivery, 3) plasma K, 4) pH |
| What effect does high flow rate have on renal K handling? | Greater flow rate -> more distal Na delivery & more K secretion in CD |
| 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) |
| How does plasma pH alter renal K handling? | alkalosis -> excretion. Acidosis -> reabsorption. intracellular H -> decreased ROMK open probability & decreased channel insertion in the membrane. |
| How do loop/thiazide diuretics alter renal K handling? | Elevated Aldo and increased distal Na delivery -> more K excretion |
| How much lumenal Na is required for distal K secretion? | 25-35 mM |
| 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. |
| 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. |
| What are the systemic effects of PTH? | (D3 = permissive!) -> bone reabsorption, intestinal Ca reabsorption (via D3), DCT Ca reabsorption |
| Why is renal PO4 reabsorption inhibited by PTH? | D3 increases Ca AND phosphorous reabsorption from small intestine. Need a way to independently increase Ca. |
| 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. |
| What is Familial Hyocalciuric Hypercalcemia (FHH)? | inactivating mutation of calcium sensor in Thick AL -> too much Ca reabsorption |
| 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. |
| What does PTH stimulate expression of in the DCT? | calbindin, TRPV5/6, Na/Ca exchanger, Ca ATPase |
| 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). |
| What is Isolated Recessive Hypomagnesemia? | mutated pro-EGF type 1 membrane protein. Normally binds basal EGFR in DCT -> TRPM6 activation. Autocrine. |
| What is the difference in genetic disorders of Mg handling in the Thick AL & DCT | Thick AL mutation -> hypercalciuria. DCT mutation -> hypocalciuria. |
| How is DCT Ca modulated by Mg reabsorption? | Intracellular Mg inhibits TRPV5/6 -> inhibits Ca reabsorption |
| 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. |
| 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. |
| What are examples of primary & secondary edema? | Primary (overfill): kidney failure. Secondary (underfill): congestive heart failure, Cirrhosis, normal kidney fxn. |
| 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". |
| 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. |
| 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. |
| What causes a Starling block? | AV fistula formation ("arteriolar runoff"), relative underfilling of the arteries, Generalized vasodilation. |
| 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. |
| 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. |
| 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. |
| 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. |
| What are endothelin effects on renal filtration? | stimulates proximal tubule Na/H pump |
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rbxbrown