Renal Final 2.1

what does an increased RBF cause in the kidneys? what is the compensation?

• inc. RBF → inc. GFR + inc. O2 delivery → inc. Na load + RA → inc. O2 demand → m. hypoxia

• inc. EPO + dec. RBF (to conserve energy)

why does an increase in Na RA result in a depletion of renal O2 levels?

• inc. Na RA @ mTAL → inc. Na/K ATPase → inc. O2 demand in hypoxic m.

• mTAL → site for ischemic injury

what would a partial loss of nephrons cause?

• hypertrophy of remaining nephron

• inc. GFR per nephron

• inc. Na RA

• inc. O2 demand

• inc. risk of AKI + ischemia

why is the inner medulla hypoxic? how does this contribute to concentrated urine?

• countercurrent XC: (+ low RBF → osmotic gradient)

  • O2 out of desc. c. → into asc. c. (doesn’t reach deeper tissue)

  • loses H2O + gains solute desc. → loses solute + gains H2O asc. (from TDL (from IS) + CD) (traps solute)

• hypoosmotic in TAL → hyperosmotic in CD → conc. urine

  • via H2O RA (AQP, ADH, VR)

how does a high Na filtered load cause medullary hypoxia?

• high Na at PCT → more O2 consumption at cortex → less O2 at medulla

• high Na in filtrate still after PCT → higher demand on mTAL

  • high NaCl at medulla → TGF → VC AA (dec. O2 supply)

what factors control RBF levels?

• myogenic autoregulation: inc. stretch/BP → AA constriction (opp. true too)

• tubulo glomerular feedback: MD @ end of TAL sense NaCl

• vasoconstrictors + dilators

what is the difference of vasodilator and vasoconstrictor effect on RBF?

• dilators → inc. O2 supply + dec. O2 demand

• constrictors → inc. O2 demand + dec. O2 supply

what are the vasodilator stimuli?

• NO

• adenosine (A2AR)

• PG

what is the effect of NO on RBF? what occurs of NO synthase is inhibited?

• higher in medulla

• dec. NKCC2 @TAL (dec. Na RA) + CD → dec. O2 demand

• NO synthase inhibition → dec. perfusion → dec. mPO2 (+ inc. NKCC2) → ischemia

what are the vasoconstrictor stimuli?

• Ang. II (AT1)

• adenosine (A1AR)

• endothelins

• NE

• vasopressin (ADH)

what is the effect of Ang II on RBF?

• VC EA → inc. GFR BUT dec RBF @ cortex

  • inc. Na RA → inc. O2 demand

  • @ high conc. also VC AA → dec. GFR

• indirect VD via inc. PG + NO @ medulla

• balance of VD + VC prevents ischemic injury

what is the relationship between adenosine and RBF?

• high NKCC2 (via high NaCl) → ATP cons. inc. = inc. adenosine by MD

  • TGF response (dec. GFR) → VC AA + inhibits renin

• stimulates Na RA @ c. PCT (reduce load) but inhibit @ m. TAL (conserve O2)

what is the difference between adenosine (A1AR) and (A2AR)?

• A1AR: (superficial)

  • AA constrict via high NaCl→ dec. GFR + dec. RBF

  • inc. Na RA @cPCT

• A2AR: (jxtmed)

  • dilates EA → inc. RBF BUT dec. GFR

  • dec. Na RA @mTAL

what effects the regional pO2?

• rate of O2 delivery

• rate of O2 consumption

• rate of O2 removal → via O2 shunting → hypoxia if dec. RBF

what can increase O2 consumption/regional pO2?

• inc. GFR → inc. O2 cons.

• inc. diet Na/diuretic (acetazolamide) → inc. O2 demand @ TAL

• inc. glucose filtered load (via DM) → inc. RA → inc. O2 demand

what changes in blood property can effect pO2?

• alkalosis → inc. Hb affinity + dec. O2 dissociation

• fibrosis → dec. O2 diffusion

how does pregnancy cause dysregulation? what factors can cause ischemia?

• inc. VD (relaxin + progesterone) → inc. GFR + RBF → inc. O2 demand

• ischemia: → proteinuria + dec. RBF

  • vol. depletion

  • preeclampsia (HTN + endothelial swelling)

  • HELLP (hemolysis, ele. liver enzyme, low platelet) → renal insuff.

how does strenuous exercise cause dysregulation?

• compound hypovolemia (via sweating) → act. SNS

  • VC (via NE) → blood shunt to muscle → dec. RBF

  • act. RAAS → VC, Na retention, inc. fluid vol. (HTN)

    • inc. Na RA → inc. O2 demand

how does high altitude cause dysregulation?

• acute:

  • resp. alk. → diuresis (HCO3, H2O, Na sec.) → blood conc. → inc. Hb (dec. O2 diss.) + dec. RBF

• chronic:

  • inc. NE → VC (dec. RBF → dec. GFR → dec. O2 cons.)

  • inc. EPO (inc. Hb → thicker blood) → fluid retention → inc. Na RA

how does blood glucose cause dysregulation? what occurs if there are SGLT2 inhibitors?

• diabetes → inc. Na RA @ PCT via SGLT2 → hypertrophy (Na backflow → inc. mTAL load) + inc. O2 demand → AKI

• SGLT2 inhibitor → glycosuria + natriuresis (dec. Na RA @ PCT)

  • inc. Na to MD → TFG → VC AA → dec. RBF (dec. O2 demand)

how do NSAIDs cause dysregulation?

• inhibit COX → dec. PG (VD)

• inc. unopposed VC → dec. RBF → ischemia @ mTAL

how do diuretics (acetazolamide + furosemide) cause dysregulation?

• acetazolamide (CA inhibitor) → inhibit cPCT Na RA (via NHE3) → inc. Na to mTAL → inc. O2 demand → AKI

• furosemide (loop diuretic) → dec. Na RA @ mTAL (via NKCC2)→ protection (inc. Na @ MD → AA constrict → dec. GFR → dec. O2 demand)

how does low-dose dopamine cause dysregulation? what does a higher dose cause?

• lower dose (acts on DA-1 R) → inc. perfusion

  • AE VD → inc. RBF

  • inhibits NHE3 (dec. Na RA @ PCT) → natriuresis/inc. load → inc. O2

• high dose → VC → dec. RBF

what is the multi hit for dysregulation? what does it cause?

• dec. perfusion

• diabetes

• risky procedures

• tubulo interstitial disease

• cause → VC, tub. toxicity, oxidative stress

what increases RBF post surgery?

• ANP → VD AA /VC EA + dec. RAAS → inc. RBF + natriuresis

• DA-1 agonist (VD)

• furosemide → block NKCC2 → VD AA

• ACE inhibition → dec. Ang II (VC)

• corrective VC via adrenergic agonists → dec. RBF + inc. O2

what is renal clearance defined as?

• rate at which plasma volume is cleared of a substance

• (urine conc. x urine vol.)/plasma conc.

what is GFR equivalent to?

• renal clearance

• Kf (SA+ perm) x NFP

• UxV/P

what substances are eliminated only via glomerular filtration and can assess GFR? Describe both?

• inulin → exactly, freely filtered + NO degradation/sec./RA

• creatinine → almost equal, secreted (so less accurate)

what decreases creatinine clearance?

• age

• dec. muscle mass

• sclerosis → dec. RBF → dec. GFR

• low cardiac output

when does clearance of creatinine increase? how is this different from inulin?

• inc. GFR (dec. P conc.) → sec. inc. → inc. Cr Cl

• inulin NOT impacted by P conc. (only filtered)

how do GFR changes impact plasma creatinine?

• if GFR compromised → inc. creatinine in plasma

• inc. GFR → inc. clearance → dec. creatinine in plasma

how to calculate free water clearance? what do the values indicate?

• CH2O = U (urine flow rate L/day) x (1 -(Uosm/Posm)) (clearance of osmoles)

  • gain/loss of H2O via excretion of dilute/conc. urine

• (-) → urine hypertonic/hyperosmolar (conc.)

• (+) → urine hypotonic (e.g diabetes) (dilute)

what is the filtration fraction (FF)?

• portion of RPF that is filtered via glomerular filtration (20%)

• GFR/RPF

how does PAH calculate RPF? what is the reasoning behind the actual RPF value?

• effective RPF → CPAH

• actual RPF → CPAH/0.9 (renal clearance of PAH is 90% of RPF since PCT secretes PAH)

what can cause inaccurate readings of RPF using PAH?

• metabolic alkalosis: PAH clearance overestimates RPF

• diabetic KA: ketones compete w/ PAH for BL OAT into filtrate + H neutralizes PAH → lower clearance → underestimates RPF

• high PAH → transport saturation =dec. PAH extraction ratio

how to calculate RBF?

RBF = RPF/(1-hematocrit)

what is filtered load? what occurs if filtered load exceeds urinary excretion? what occurs if urinary excretion exceeds filtered load?

• GFR x P conc.

• FL > UE → RA

• FL < UE → excretion

what is the difference of transport max for reabsorption and secretion?

• Tm for RA → (GFRxP) - (UxV)

  • filtered load (larger)- urinary excretion

• Tm for secretion → (UxV) - (GFRxP)

  • urinary excretion (larger) - filtered load

what is renal threshold? what is the threshold?

• plasma conc. at which fully RA substance starts to appear in urine

• renal threshold > plasma conc. → substance RA

• renal threshold < plasma conc. → substance excreted

what does the titration curve of glucose show?

• renal threshold → P conc. @ which fully RA substance appears in urine

  • Tm splay starts → no more RA + inc. excretion (since it’s appearing in urine)

• filtration is proportional to P conc

• glucose RA @ PCT (if SLGT2 inhibited → excreted)

what does the titration curve of PAH show?

• Tm via saturation → excretion inc. (filtration + secretion) BUT at lower rate

  • secretion plateaus @ Tm

• inc. P conc. → inc. filtered amount

• PAH sec. @ PCT

what does this graph describe about the relationship between plasma concentration (mg/dL) and clearance (mL/min) of the following substances?

• PAH: secreted, high clearance @ low P conc. → OAT saturate @ high P conc.

• creatinine: filtered + slight sec., slightly higher clearance @ low P conc. (slightly overestimates clearance/GFR)

• inulin: filtered, NOT sec./RA; clearance constant

• urea: filtered, slight RA; low clearance (depends on hydration)

• glucose: completely RA; 0 clearance @ low P conc. (clearance inc. in diabetes)

how is urea recirculated? what is its importance?

• liver protein metabolism

• freely filtered → RA @ PCT → sec. @ TDL

• maintains high solute conc. in medulla (med. osm)

  • UT-A1 (apical) + UT-A3 (BL) (via ADH)→ urea RA @ CD

  • RA H2O @ CD

what does it mean if there is increased BUN in the blood? decreased BUN?

• inc. BUN

  • dehydration → inc. UT-A T (via inc. ADH) → inc. urea RA @ CD → urine conc. (via H2O RA following urea)

    • renal failure → dec. filtration + clearance

• dec. BUN

  • low protein met.→ less urea → can’t conc. urine

what is FA oxidation? what is it the main source of energy for?

• FA broken down for energy

• main energy source for segments w/ high ATP demand + high O2 supply (PCT)

  • medulla less FAO → via low O2 tension

what is glycolysis? what is it the main source of energy for?

• glucose → pyruvate

• main energy source for high energy demand + low O2 supply (m. TAL + m. CD)

  • medulla

what is gluconeogenesis? what are the precursors? where is the localization?

• glucose from non-carb precursors (@ c. PCT)

• lactate > glutamine > glycerol > alanine

• localization: mit., cytosol, ER in liver > kidney > SI

what is the process of lactate metabolism in GNG? what occurs when lactate is the substrate?

• lactate → pyruvate → oxaloacetate → PEP → F-1,6BP → F-6P → G-6P → glucose

• cytosolic NADH/NAD high → (OAA → PEP) via PEPCK-M @ mit. → PEP diffuse to cytosol

what is the process of glutamine metabolism in GNG? what does glutamine metabolism generate?

• glutamine uptake (SNAT)→ glutamate →

  • a-KG → OAA → malate → pyruvate + HCO3

  • a-KG → OAA → PEP → glucose

• HCO3 + NH3 (ammonia genesis)→ counteract met. acidosis

what is the process of glycerol metabolism in GNG?

triglyceride → glycerol → glycerol 3-P → DHAP → F1,6 BP → F-6P → G-6P → glucose

what is aa metabolism in GNG? what happens when alanine is the substrate?

• alanine + a-KG→ pyruvate + glutamate via ALT

  • low c. NADH/NAD → forms malate to transport OAA from mit. to c. → PEPCK (OAA → PEP)

• aspartate + a-KG → OAA + glutamate via AST

how does EtOH metabolism disrupt GNG?

• high NADH, lactate, & malate + low glucose production

  • via pyruvate → lactate ; OAA → malate

  • dec. pyruvate + dec. OAA → no GNG → hypoglycemia + lactic acidosis

what is the function of pyruvate carboxylase? what is its cofactor? what is an allosteric activator?

• pyruvate → OAA (glycolysis → GNG)

• biotin → avidin in raw egg white inhibits it

• Acetyl CoA → ADP inhibits it

what is the function of PEPCK? what is it stimulated + inhibited by? what does it use as an energy source?

• OAA → PEP

• stim: glucocorticoids, glucagon, epinephrine during fasting to sustain GNG

• inhibit: insulin during eating, dec. glucose prod.

• GTP

what is the function of F1,6- bisphosphatase?

F 1,6-BP → F 6-P

what is the function of PFK-1? what is it inhibited + activated by?

• F6-P → F1,6-BP backwards

• inhibit: citrate + ATP

• act. : AMP + F2,6 BP (most potent)

  • inc. F2,6 BP → inc. glycolysis + dec. GNG (via inhibition of F2,6 BP)

what is the function of G 6-phosphatase?

• G 6-P → glucose

• in ER

what is the function of pyruvate kinase (PK) and pyruvate dehydrogenase (PDH) in glycolysis and GNG?

• both glycolysis enzymes need to be INACTIVATED for GNG to progress

  • inhibited in fasting states

• PK: PEP → pyruvate

  • inhibited via ATP, NADH, acetyl coa

• PDH: links glycolysis to TCA cycle

  • inhibited by ATP, alanine, glucagon, NE