Basics Flashcards
Total Blood Osmolaity
2([Na+]blood) + (blood glucose / 18) + (BUN / 2.8)
Effective Osmolality
2([Na+]blood) + (blood glucose / 18)
- created by effective solutes, which cannot passily diffuse across cell membranes
Effective Circulating Volume
the blood volume that is required for adequate perfusion of the vital organs
What do the kidneys regulate?
- plasma volume
- blood pressure (BP)
- waste excretion
- electrolyte balence
- plasma pH
What 3 things mediate renal function?
- internal mechanisms
- extra- and intrarenal endocrine systems (e.g.: aldosterone, arginine vasopressin, angiotensin, and atrial natriuretic peptide)
- the autonomic nervous system (SNS)
Describe the ANS control in the kidney.
SNS activity controls
- vasoconstriction of the renal microcirculation
- Na+ reabsorption
- stimulates the secretion of renin
What is filtration?
the movement of plasma constituents (e.g.: H2O, ions, glucose, urea, and very small proteins) from the glomerulus into Bowman’s capsule
What is reaborption?
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
What is secretion?
movement of constituents from renal circulation, interstitium and/or tubule epithelium into the forming urine
What is the significance of GFR?
- 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
What pathophysiologic factors will affect GFR?
- 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
Explain glomerular regulation of intraglomerular pressure
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
What values of GFR are at risk?
- 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
How do we measure GFR?
creatinine
assuming steady state:
Scr (serum/plasma creatinine) generally fall in standard range: (~0.4-1.5 mg/dl)
What factors affect creatinine levels?
HEALTHY PATIENT:
- inceased GFR will induce a decreased in Scr
- decreased GFR will cause increased Scr 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 Scr:
- 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 Scr:
- Race: hispanic, asian
- Low muscle mass
- Vegetarian diet
- Malnutrition
What is BUN and what affects it?
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
Explain fluid dynamics (forces) within the nephron
- Within the afferent arteriole (and esp glomerular capillary), the hydraulic forces (Pcap +πBowman’s) that favor ultrafiltration win-out –> FILTRATION OCCURS
- As plasma enters the efferent arteriole, the opposing forces (PBowman’s + πcap) increase concomitant with a decrease in thehydraulic forces; these forces oppose filtration)
What regulates input to the nephron?
- systemic BP which afects:
- blood flow (ie BP and renal perfusion) with in the afferent arteriole
- glomerular P which dictates GFR
- vasomotion within the afferent and efferent arterioles
*Afferent arteriole is key:
What is the role/significance of the afferent arteriole?
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
What does “autoregulation” respond to?
- 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
- pressure-induced distension of both the vascular smooth muscle and the vascular endothelium within the afferent arteriole
- the tubular-glomerular feedback system
What regulates the tubular-glomerular-feedback (TGF) system?
concentration of Na+ (or NaCl) in the forming urine as it reaches the cortical thick ascending limb (TAL)
What is PRA?
Plasma Renin Activity
volume depletion leads to lowered BP, this would cause the secretion of renin with a subsequent increase in PRA
How does ACE support vasoconstriction?
- production of AII
- degradation of bradykinin (a vasodilator)
Explain mobilization of the RAS during periods of hypovolemia
(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
What is AT1?
- 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
What happens in a state of diminished ECV (ie low BP)?
- 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
What is the role of AII?
- 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
Osmoles
total particles in solution
Osmolarity
total moles in solution
Osmolality
Solute/Kg H2O
Osmosis
Diffusion of H2O through a semipermeable membrane; from an area of high random motion to area of less random motion
Osmotic Pressure
created by effective osmoles; driving forve for osmosis
osmotic equilibrium
osmotic pressure = hydrostatic pressure
Explain the SNS response to Low BP
* To Conserve, we increase GFR *
- Low BP (threshold)
- SNS tone increased
- AII production
- Selective constriction of efferent arterioles (major effect)
- Increases/maintains glomerular pressure
- Increase GFR
- maintain optimal reabsorptive gradients (conserve)
Volume Decrease and Osmole System
Note: Osmole receptor system is not coupled to volume decrease due to dehydration or GI fluid loss.
What are the intrarenal and extrarenal effects of AT1-R?
Pathophysiologic?
- Intrarenal (in kidney):
- vasocontriction
- Na+ reabosorption
- Extrarenal effects:
- vasoconstriction
- aldosterone secretion
- Pathophysiologic:
- LVH
- Fibrosis (cardiac, renal)
- Athrosclerosis
What does evidence suggest is the role of AT2-R?
- Bradykinin synthesis (vasodilation)
- Reverse/block fibrosis
- Anti-inflammatory
- Proapoptotic (heart, favorable remodeling)
Wht are the physiologic and pathophysiologic effects of aldosterone?
- 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
What occurs in the proximal tubule?
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)
-
Na+/K+ ATPase (Na+ reabsorped and K+ secreted into cytoplasm)
What happens in the Distal Nephron’s Thick Ascending Limb?
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
What happens in the distal convoluted tubule?
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
Diuretics
-
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
- block aldosterone
-
HCTZ
- weak; blocks Na+ and Cl- reabsorption
- stimulates K+ secretion; stimulates Ca2+ reabsorption
Aldosterone (simplified)
- stimulated by:
- elevated AII
- Hyperkalemia
- Causes:
- Na+ reabsorption
- K+ secretion
1:42
Glomerulosa
- where aldosterone is synthesized
- high [AT1-R]
- this is how AII stimulates secretion of aldosterone from adrenal cortex (targeting AT1-R in zona glomerulosa)
Mineralicorticocoids
a family of steriods that include aldosterone
