Basics

Question 1

Total Blood Osmolaity

Answer 1

2([Na⁺]_blood) + (blood glucose / 18) + (BUN / 2.8)

Question 2

Effective Osmolality

Answer 2

2([Na⁺]_blood) + (blood glucose / 18)

• created by effective solutes, which cannot passily diffuse across cell membranes

Question 3

Effective Circulating Volume

Answer 3

the blood volume that is required for adequate perfusion of the vital organs

Question 4

What do the kidneys regulate?

Answer 4

• plasma volume
• blood pressure (BP)
• waste excretion
• electrolyte balence
• plasma pH

Question 5

What 3 things mediate renal function?

Answer 5

1. internal mechanisms
2. extra- and intrarenal endocrine systems (e.g.: aldosterone, arginine vasopressin, angiotensin, and atrial natriuretic peptide)
3. the autonomic nervous system (SNS)

Question 6

Describe the ANS control in the kidney.

Answer 6

SNS activity controls

• vasoconstriction of the renal microcirculation
• Na+ reabsorption
• stimulates the secretion of renin

Question 7

What is filtration?

Answer 7

the movement of plasma constituents (e.g.: H2O, ions, glucose, urea, and very small proteins) from the glomerulus into Bowman’s capsule

Question 8

What is reaborption?

Answer 8

the movement of constituents from teh tubule lumenal fluid (ie: forming urine) into the renal interstitium; and/or recycling of these substances back into circulation

Question 9

What is secretion?

Answer 9

movement of constituents from renal circulation, interstitium and/or tubule epithelium into the forming urine

Question 10

What is the significance of GFR?

Answer 10

• it is the product of a single nephron
• it will decrease prior to the onset of symptoms of renal disease
• it decreases in direct correlation with the pathological severity of kidney disease
• *can only be assessed in patients who are at some steady state

Question 11

What pathophysiologic factors will affect GFR?

Answer 11

• kidney disease
• pregnancy
• reduced kidney perfusion
• marked changes in extracellular fluid volume
• non-steroidal anti-inflammatory drug (NSAID) use
• acute/habitual elevated protein ingestion
• blood glucose
• arterial BP

Question 12

Explain glomerular regulation of intraglomerular pressure

Answer 12

Generally,

• self-governing:
• increased systemic BP induces a myogenic response within the afferent arterioles
  
  • resultant vasoconstriction of the afferents prevents potentially damaging inceases in glomerular pressure, and sustains GFR within optimal limits
• Very low BP sensed within the kidney:
  
  • in response: hormonal mechanisms are mobilized to induce vasoconstriction within the efferent arterioles
  • maintains glomerular pressure within the fairly narrow range that is conducive to healthy GFR

Question 13

What values of GFR are at risk?

Answer 13

• GFR<60 is associated with a high risk for the development of cardiovascular disease and mortality from CV disease exceeds the risk of progression to renal failure
• GFR<15 ml/min/1.73m³ indicates renal failure and would require replacemet via dialysis or kidney transplant

Question 14

How do we measure GFR?

Answer 14

creatinine

assuming steady state:

S_cr (serum/plasma creatinine) generally fall in standard range: (~0.4-1.5 mg/dl)

Question 15

What factors affect creatinine levels?

Answer 15

HEALTHY PATIENT:

• inceased GFR will induce a decreased in S_cr
• decreased GFR will cause increased S_cr and increased BUN

General Levels:

• Men excrete: 20-25 mg creatinine/kg/day
• Women excrete: 15-20 mg creatinine/kg/day
• *obesity has no effect on levels

Factors that Increase S_cr:

• Race: black
• Kidney disease
• Crushing injury (rhabdomyolysis)
• Ketoacidosis (interferes with assay)
• Ingestion of cooked meat (transient increase)
• Large muscle mass
• Various medications

Factors that Decrease S_cr:

• Race: hispanic, asian
• Low muscle mass
• Vegetarian diet
• Malnutrition

Question 16

What is BUN and what affects it?

Answer 16

Blood Urea Nitrogen

• a product of protein metabolism
• levels fluctuate with changes in diet, metabolism, and volume status
• high protein diet and volume depletion will each raise BUN
  
  • This effect is see in volume depletion bc of increased renal tubule reabsorption of urea accompanies Na+ and H2O reabsorption
  • thus elevation in BUN is not reliable indicator of GFR

Question 17

Explain fluid dynamics (forces) within the nephron

Answer 17

• Within the afferent arteriole (and esp glomerular capillary), the hydraulic forces (P_cap +π_Bowman’s) that favor ultrafiltration win-out –> FILTRATION OCCURS
• As plasma enters the efferent arteriole, the opposing forces (P_Bowman’s + π_cap) increase concomitant with a decrease in thehydraulic forces; these forces oppose filtration)

Question 18

What regulates input to the nephron?

Answer 18

1. systemic BP which afects:
2. blood flow (ie BP and renal perfusion) with in the afferent arteriole
3. glomerular P which dictates GFR
4. vasomotion within the afferent and efferent arterioles

*Afferent arteriole is key:

Question 19

What is the role/significance of the afferent arteriole?

Answer 19

Significance:

• GREATEST pressure drop occurs between the afferent arteriole and glomerulous
• virtulally no pressure drop occurs between afferent and efferent end of the glomerulus
• thus, vasoconstriction and vasodilation of the afferent arteriole has major impcat on renal perfusion and GFR

Role:

• So goes the afferent arteriole, so does GFR
  
  • ​constriction of the efferent arteriole will cause back pressure within the glomerulus
  • healthy pt: any incrase in pressure wthin the glomerulus will incrase GFR
  • low pressure and high resistance (esp compared to systemic capillary network)
    
    • enables filtration of ~180 L of plasma/day

Question 20

What does “autoregulation” respond to?

Answer 20

• autoregulation fuctions via the concertes actions of SNS, natriuretic peptides, paracrine factors, and RAAS
• via autoregulation, GFR and RBF can be maintained within a narrorw rainge even in face of markedly changing MAP

​Autoregulation responds to

1. ​pressure-induced distension of both the vascular smooth muscle and the vascular endothelium within the afferent arteriole
2. the tubular-glomerular feedback system

Question 21

What regulates the tubular-glomerular-feedback (TGF) system?

Answer 21

concentration of Na+ (or NaCl) in the forming urine as it reaches the cortical thick ascending limb (TAL)

Question 22

What is PRA?

Answer 22

Plasma Renin Activity

volume depletion leads to lowered BP, this would cause the secretion of renin with a subsequent increase in PRA

Question 23

How does ACE support vasoconstriction?

Answer 23

1. production of AII
2. degradation of bradykinin (a vasodilator)

Question 24

Explain mobilization of the RAS during periods of hypovolemia

Answer 24

(measured by incrased PRA)

• AII induces vasoconstriction of systemic arterioles, this raises BP
• AII targets the renal arteriole –>2-prong approach to stopping and correcting volume depletion
  
  • 1) AII-dependent constriction of the efferent arteriole steadies glomerular P. With constriction of the efferent arterioles by AII, renal perfusion is reduced, leading to lowered P within the peritubualr capillaries
  • 2) conservation mechanism: reduced perfusio allows hemodynamics that favor reabsorption of Na+ and H2O from the glomerular filtrate into the renal interstitium and back into circulation

Question 25

What is AT₁?

Answer 25

* AII receptor * **predominant AT receptor isoform expressed in humans** * **expressed within smooth msucls of afferent and predominately efferent arterioles, renal tubules, and peripheral vasculature** * expressed witin renal tubules and cells within the adrenal zona glomerulosa * likely coupled to Na+ reabsorption * regionally expressed within renal tubule epithelium and JG cells * **AT₁ is known to mediate AII-dependent vasoconstriction in the renal arterioles (predominant effect) and AII-stimulated Na+ reabsorption from the tubules**

Question 26

What happens in a state of diminished ECV (ie low BP)?

Answer 26

* **AT binds and activates AT₁ within the efferent arteriolar vascular smooth muscle** * This induces efferent vasoconstriction and maintains glomerular pressure in order to sustain optimal ultrafiltration across the glomerular capillaries

Question 27

What is the role of AII?

Answer 27

* stimulates renal Na+ reabsorption by activating transporters (NHE3, NKCC2, NCC, and ENaC) * likely stimulates the Na+/K+ ATPase within the tubule epithelium * this collectively allows for the reabsorption of Na+ from forming urine back in to ciculation

Question 28

Osmoles

Answer 28

total particles in solution

Question 29

Osmolarity

Answer 29

total moles in solution

Question 30

Osmolality

Answer 30

Solute/Kg H2O

Question 31

Osmosis

Answer 31

Diffusion of H2O through a semipermeable membrane; from an area of high random motion to area of less random motion

Question 32

Osmotic Pressure

Answer 32

created by effective osmoles; driving forve for osmosis

Question 33

osmotic equilibrium

Answer 33

osmotic pressure = hydrostatic pressure

Question 34

Explain the SNS response to Low BP

Answer 34

***\* To Conserve, we increase GFR \**** 1. Low BP (threshold) 1. SNS tone increased 2. AII production 3. **Selective constriction of efferent arterioles (major effect)** 4. Increases/maintains glomerular pressure 5. Increase GFR 1. maintain optimal reabsorptive gradients (conserve)

Question 35

Volume Decrease and Osmole System

Answer 35

*Note: Osmole receptor system is not coupled to volume decrease due to dehydration or GI fluid loss.*

Question 36

What are the intrarenal and extrarenal effects of AT1-R? Pathophysiologic?

Answer 36

* Intrarenal (in kidney): * vasocontriction * Na+ reabosorption * Extrarenal effects: * vasoconstriction * aldosterone secretion * Pathophysiologic: * LVH * Fibrosis (cardiac, renal) * Athrosclerosis

Question 37

What does evidence suggest is the role of AT2-R?

Answer 37

* Bradykinin synthesis (vasodilation) * Reverse/block fibrosis * Anti-inflammatory * Proapoptotic (heart, favorable remodeling)

Question 38

Wht are the physiologic and pathophysiologic effects of aldosterone?

Answer 38

* secreted from adrenals * myocardial production * mineralcorticoid receptor **_Physiologic:_** * Na+ conservtaion * K+ elimination * vasoconstriction **_Pathophysiologic:_** * direct vasoconstrictor * HTN * induces vascular inflammation * increases collagen synthesis in cardio fibroblasts * induces cardiomyocyte apoptosis

Question 39

What occurs in the proximal tubule?

Answer 39

Na+ and glucose reabsorption _Lumen to Cyto Side_ * **SGLT:** Na+ and Glucose **reabsorbed** into epithelial cytoplasm from forming urine (lumen) * **NHE-3:** Sodium/proton epithelieal trans * trades **sodium reabsorption** into epithelial cell for **proton secretion** into lumen * *\*Important for acid-base balence* * **AT₁-Receptors**: respond to reabsorb AII * coupled to/driving NHE-3 **_Cyto to Intersitium (vehicle to plasma)_** * **GLUT:** Glucose to plasma * Na+ has several options * **Na+/K+ ATPase** (**Na+ reabsorped and K+ secreted into cytoplasm)** * **​***activity of Na+/K+ ATPase may be upregulated by AII* * **Na+/HCO3- transporter** (**reabsorption of both)**

Question 40

What happens in the Distal Nephron's Thick Ascending Limb?

Answer 40

Na+ and K+ handling _Lumen to Cytoplasm (apical):_ * **NKCC**: grabs Na+, K+, and 2 Cl-s to reabsorb them * driven by AII and * faciliated by K+ secretion - creates gradient dynamics * targeted by loop diuretics * **ROMK2**: K+ secretion that facilitates NKCC (K+ cycling) * **NHE**-3: think acid-base and Na+ reabsorption _Cyto to interstitum (basolateral):_ * **HCO3-/Cl- exchanger** (bicarb reabsorption and Cl secretion into lumen) * mechaism for Cl- reabsorption * also a **K+ leak** into interstitum * **Na+/K+ ATPase**

Question 41

What happens in the distal convoluted tubule?

Answer 41

Na+, Cl-, and Ca2+ Reabsorption _Lumen to Cyto (apical)_ * **_NCC_**: reabsorps Na and 2 Chlorides * driven by AII * target for Thiazide diuretics * Ca2+ transporter - reasoprtion * primary place for Ca2+ regulation * **ENaC**: Na+ reabsorption * targeted/stimulated by AVP and AII _Cytoplasm to Interstitium (basolater:_ * Ca+/Na+ transporter (Na+ secreted into cytoplasm; Ca2+ reabsorbed) * Na+/K+ ATPase * Cl- transporter (reabsorption) * K+ reabsorbed

Question 42

Diuretics

Answer 42

* **Acetazolamide**: * Carbonic anhydrase inhibitor, thus impairing the formatin of bicarbonate, and thus becomes useful as diuretic in certain acid-base disorders * **Furosemide** * blocks NKCC * by keeping more charged substances in the forming urine --\> acts as effective osmole * wherever there is a charge, that is where water wants to go * so if you keep more stuff in forming urine, water will be there --\> diuresis * *also screws up Ca2+ reabsorption bc changes charge gradient* * *when using furosemide, be careful with Ca2+ status of pts, esp if they are hypocalcemic* * *​*potent; uses reserved for pleural edema, etc * Ca2+ wasting * **Thiazides** * **​**blocks NCC transporter * changes electrochemical gradient, thiazides stimulate * K+ secretion - *be careful if ppl have K+ or Ca2+ issues* * Ca2+ reabsorption * **Amiloride** * K+ sparing (helps us hang onto K+) * blocks Na+ chanel in collecting tubules * **Eplerenone and Spironolactone** * block aldosterone * mineralocotoricoid receptor antagonists * **HCTZ** * weak; blocks Na+ and Cl- reabsorption * stimulates K+ secretion; stimulates Ca2+ reabsorption

Question 43

Aldosterone (simplified)

Answer 43

* stimulated by: * elevated AII * Hyperkalemia * Causes: * Na+ reabsorption * K+ secretion

Question 44

1:42

Question 45

Glomerulosa

Answer 45

* where aldosterone is synthesized * high [AT1-R] * this is how AII stimulates secretion of aldosterone from adrenal cortex (targeting AT1-R in zona glomerulosa)

Question 46

Mineralicorticocoids

Answer 46

a family of steriods that include aldosterone