Block 4 Exam Flashcards
BUN equation
Plasma osmolality = 2[Na+] + glucose/18 + BUN/2.8
Capillary filtration equation
Kf[(Pc - Pi) - sigma( Pi(c) - Pi(i))]
Kf
Filtration coefficient
Pc
Capillary hydrostatic pressure
Pi
Interstitial hydrostatic pressure
Pi(c)
Capillary oncotic pressure
Pi(i)
Interstitial oncotic pressure
Sigma
Protein reflection coefficient
Primary functions of the kidneys
Filtration
Reabsorption
Secretion
Afferent arteriole resistance
high
Glomerular capillaries resistance
low
Efferent arteriole resistance
high
Vasa Recta resistance
low
Vasa recta capillaries resistance
low
Renal veins resistance
low
Afferent arteriole pressure
high
Glomerular capillaries pressure
high
Efferent arterioles pressure
high
Vasa recta pressure
low
Vasa recta capillaries pressure
low
Renal veins pressure
low
Leaky epithelia electrical resistance
low
Leaky epithelia transport rate
high
Leaky epithelia chemical gradient
low
Leaky epithelia transepithelial voltage
low
Leaky epithelia tight junction structure/selectivity
limited
Leaky epithelia membrane infolding
extensive
Leaky epithelia mitochondria
a lot
Tight epithelia electrical resistance
high
Tight epithelia transport rate
low
Tight epithelia chemical gradient
high
Tight epithelia transepithelial voltage
high
Tight epithelia tight junction structure/selectivity
extensive
Tight epithelia membrane infolding
Limited
Tight epithelia mitochondria
fewer
Proximal tubule Na+ reabsorption
60-70% of filtered Na+
Proximal tubule Water reabsorption
60-70% of filtered water
Proximal tubule sugar reabsorption
All of the glucose and most other sugars
Proximal tubule Protein reabsorption
Nearly all amino acids, peptides and protein by secreting proteases
Proximal tubule Phosphate and sulfate reabsorption
Nearly all of both
Proximal tubule organic cations and anions reabsorption
reabsorps
Proximal tubule HCO3 - reabsorption
80-90% of filtered HCO3 -
Proximal tubule Ca2+ and Mg2+ reabsorption
50% of filtered
Proximal tubule Cl- reabsorption
50% of Cl-
Proximal tubule secretions
Toxins
Ammonium
What does the proximal tubule synthesize
Glucose
Proximal tubule apical membrane in-foldings
extensive
Proximal tubule basolateral membrane in-foldings
Extensive
Proximal tubule nucleus
Large
Proximal tubule mitochondria
Numerous located to basolateral in-foldings
S1 location
Renal cortex
Lumen negative
S2 location
Medullary ray
Lumen negative
S3 location
Outer medullae
Lumen Positive
What does the loop of Henle include?
S3 segments of proximal tubules
Thin descending limbs
Thin ascending limbs
Thick ascending limbs
Thin descending limb cells
Thin
Thin descending limb mitochondria
Few
Thin descending limb membrane in-foldings
None
Thin ascending limbs location
Deep nephrons only
Thin ascending limb cells
Thin
Thin ascending limb mitochondria
few
Thin ascending limb membrane in-foldings
None
What does the Thick ascending limb reabsorb
20-30% of NaCl K+ Ca2+ Mg 2+ HCO3 -
What does thick ascending limb secrete
Tamm-Horsfall protein
Tamm-Horsfall protein
Plays a role in immunity and stone prevention
Another name for thick ascending limb
Diluting segment
Thick ascending limb mitochondria
Lots
Thick ascending limb apical membrane in-foldings
Modest
Thick ascending limb basolateral in-foldings
Lots
Macula densa nuclei
Large
Macula densa mitochondria
lots
Distal convoluted tubule divisions
Early of Classical DCT
Late or not really the DCT DCt
How much NaCl does the classical DCT reabsorb?
5-10%
What does the Early DCT reabsorb?
NaCl
Ca2+
K+ sometimes
What does the early DCT secrete?
K+ sometimes
How much NaCl does the late DCT reabsorb?
5-10%
What does the late DCT reabsorb?
NaCl
K+ sometimes
What does the late DCT secrete?
K+ sometimes
DCT apical membrane in-foldings
Some
DCT mitochondria
Numerous
DCT basolateral membrane in-foldings
Intermediate amount
Collecting ducts cells
Principal cell
Alpha intercalated cel
Beta intercalated cell
Inner medullary collecting ducts mitochondria
Few
Inner medullary collecting ducts membrane in-foldings
None
Inner medullary collecting ducts tight junctions
Tightest of any segment
Inner medullary collecting ducts gradients
large
Inner medullary collecting ducts Na+ transport rates
Low rates
Inner medullary collecting ducts other transport
High rates of urea, ammonia, and water
Renal clearance
Volume of plasma totally cleared of a substance in a given time
GFR in healthy individuals
Greater than 90mL/min/1.73m^2
Use eGFR to assess renal function in:
Chronic Kidney Disease (CKD)
Serum creatinine must be used to assess renal function in
Acute Kidney Injury (AKI)
Albuminuria
Pathological condition wherein the protein albumin is abnormally present in the urine
24-hour urine collection Albuminuria
> 30 mg albumin/24 hours
Spot collection Albuminuria
Urine albumin/creatine > 30 mg/g
Heamturia
Presence of red blood cells in urine
Hemoglobinuria
Presence of hemoglobin in the urine
Dysmorphic erythrocyte means
Damage to glomeruli
CKD Stage 1 GFR
Greater than or equal to 90
CKD Stage 2 GFR
60-89
CKD Stage 3a GFR
45-59
CKD Stage 3b GFR
30-44
CKD Stage 4 GFR
15-29
CKD Stage 5 GFR
Less than 15
CKD Primary risk factors
Diabetes
Hypertension
CKD Other risk factors
Family history of CKD Advancing age Systemic infections Loss of kidney mass Autoimmune disease
Acute Kidney Injury (AKI)
Rapid deterioration of kidney function manifested by an increase in SrCf > 0.3 mg/dl < 48 hr OR increase in SrCr > 50% in < 48 hr
Patients who develop AKI may experience:
Complete recovery of renal function
Development of progressive chronic kidney disease (CKD)
Exacerbation of the rate of progression of preexisting CKD
Irreversible loss of kidney function and evolve into ESRD
Normal kidney size
10-12 cm
Kidney size in AKI
Normal or hydronephrotic
Kidney size in CKD
Reduced
Causes of prerenal AKI
Decreased ECV
Renal vasoconstriction
Large vessel disease
Causes of Acute tubular necrosis (ATN)
Ischemic progression of prerenal AKI
Nephrotoxins
Contrast media
Causes of Acute interstitial nephritis (AIN)
Allergic reactions
Infection
Infiltrative
Autoimmune
Causes of ureteral AKI
Stone
Neoplasms or tumors
Severe constipation
Causes of bladder neck AKI
BPH
Prostate cancer
Neurogenic bladder
Postrenal AKI
Ureteral
Bladder neck
Intrinsic (renal) AKI
Acute tubular necrosis (ATN)
Acute interstitial nephritis (AIN)
Glomerulonephritis
Prerenal AKI diagnosis
FENa <1.0%
BUN/Cr > 20:1
Bland sediment
+/- Hyaline casts
Acute tubular necrosis (ATN) diagnosis
FENa > 2.0%
BUN/Cr < 20:1
Muddy brown casts
+/- RBCs
Acute interstitial nephritis (AIN) diagnosis
WBC casts
WBCs
+/- RBCs
Glomerulonephritis diagnosis
Dysmorphic RBCs
RBC casts
Postrenal AKI diagnosis
Bland sediment
+/- nondysmorphic RBCs
+/- hydronephrosis by US
Azotemia
A build-up of nitrogenous waste in blood (BUN and SrCr)
Uremia
A constellation of symptoms and signs of multiple-organ dysfunction caused by retention of “uremic toxins”
Kidney transplant
Best option for renal replacement therapy
Three year mortality in ESRD
~50%
Renal Hemodynamics
Volume of plasma filtered/unit time
Renal Plasma Flow (RPF)
Rate of plasma flowing through the vasculature (~400-600 mL/min) or 600-900 L/day
Glomerular filtration
Filtration of plasma & non-protein constituents into Bowman’s space
Ultrafiltration
Leaves proteins and RBCs in blood because they cannot pass through the selective glomerular filtration barrier
Glomerular filtration rate
Rate of fluid movement from capillary space into Bowman’s space
Molecules to measure GFR criteria
Substance must be freely filterable in glomeruli
Substance must be neither reabsorbed nor secreted by the tubules
Substance must not be synthesized, broken down or accumulated by the kidney
Physiologically inert
Physiologically inert
Not toxic and without effect on renal function
GFR equation
GFR = Ux*V/Px
Amount of inulin filtered
P(in) * GFR
Amount of inulin excreted in the urine
U(in) * V
Same as amount filtered
Metabolism of creatine phosphate in men
20 to 25 mg/kg/day
Metabolism of creatine phosphate in women
15 to 20 mg/kg/day
Filtration barrier components
Slit diaphragm
Basement membrane
Fenestrated endothelium
GFR influenced by:
Blood pressure and blood flow
Obstruction to urine outflow
Loss of protein-free fluid
Hormonal regulation
Hormonal regulation
Renin-angiotensin
Aldosterone
ADH
ANP
P(gc)
Glomerular capillary hydrostatic pressure
Pi(bs)
Bowman’s space oncotic pressure
P(bs)
Bowman’s space hydrostatic pressure
Pi(gc)
Glomerular capillary oncotic pressure
Renal plasma flow equation
RPF = (1-Hct)*RBF
Normal Renal plasma flow
600 mL/min given a hematocrit of 40%
Filtration fraction equation
FF = GFR/RPF
Filtration fraction
Volume of filtrate that forms from a given volume of plasma entering the glomeruli
Increase AA resistance
Decrease P(gc) Decrease RBF
Increase EA resistance
Increase P(gc) Decrease RBF
Increase AA and EA resistance
Decrease RBF Unchanged P(gc)
Diabetes
Fasting blood glucose > 126mg/dl
Random glucose >200 mg/dl
HbA1c > 7.0%
Type 1 Diabetes (juvenile onset)
Complete loss of insulin production
Likely due to inflammatory/immune-mediated insult
Type 2 diabetes (adult onset)
Initial insulin resistance
Eventual beta-cell failure and decreased insulin secretion
Low glomerular filtration rate
Generally GFR < 60 mL/min
Albuminuria or proteinuria
Detectable at 1+ or 30 mg/dl on dipstick
Measured in urine @ >30 mg albumin or 300 mg protein per 24 hrs
Clinical risk factors of DKD
Race/genetics Gender Obesity Poor glycemic control Hypertension Other diabetic microvascular end organ complications
Hemodynamic
Intraglomerular hypertension/hyperfiltration
Hyperglycemia
Advanced glycation end products
Increased flux through polyol and hexosamine pathways
Growth Factors and Cytokines Associated with DKD
Angiotensin II Transforming Growth Factor-beta Endothelin Platelet-Derived Growth Factor Insulin-like Growth Factor Tumor Necrosis Factor Interleukin-1
Reactive Oxygen Species Enzymatic
Catalyzed by NADPH oxidase
Reactive Oxygen Species Non-enzymatic
Leakage from mitochondrial electron transport chain
Mechanisms targeted by current treatments
Glucose
Blood pressure
SGLT2
Glucose targets
Goal of Hgb A1c ~7.0%
Blood pressure with T2DM
130/80-85 is just right
60% of TBW
Intracellular Fluid
40% of TBW
Extracellular Fluid
20% of ECF
Plasma
Plasma
Noncellular, protein rich fluid
Is Na permeable to plasma membranes?
No (unless using facilitated diffusion, secondary active transport, or primary active transport)
Does Na+ contribute to tonicity?
Yes, because it is an effective osmolyte
What is tonicity
The concentration of effective osmolytes. They cause water shifts from one compartment to another assuming water is permeable across the membrane that separates those compartments
Does Na+ contribute to the ECF osmolality
Yes
Does urea cross plasma membranes
Yes
Does urea contribute to plasma osmolality
Yes
Importance of filtration
Need to remove metabolic waste and toxins
Importance of reabsorption
Maintains plasma Na+ concentrations
Maintains water balance
Regulates plasma pH
Regulates balance of other solutes
Importance of secretion
Removes toxins
H+, K+ and more
Hilus
Renal artery and nerves enter here
Renal vein, lymphatics, and ureter exit here
Cortex
Outer layer
Medulla
Inner layer
Striated due to renal pyramids
Can be highly concentrated, even if plasma is very dilute
Glomerular Filtration Barrier
Glycocalyx Endothelial cells of glomerular capillaries Basement membrane Slit diaphragm Podocytes
Basement membrane
Lamina rara interna
Lamina densa
Lamina rara externa
Claudins
Arranged like pearls on a string
Strands are NOT continuous
Direct relationship between selectivity/resistance and # of strands
Thin Descending Limb Reabsorption
5% filtered water
NKCC2 in Thick ascending limb is inhibited by what
Loop diuretics
Macula densa functions
Sense luminal NaCl as part of tubuloglomerular feedback
Regulate renin release from juxtaglomerular cells
Release paracrine factors that regulate afferent and efferent arteriolar tone
What increases NaCl reabsorption in the DCT
Aldosterone
What causes the DCT to reabsorb water
ADH/vasopressin
DCT Transport rates
Moderately low
DCT transepithelial voltages
Moderate
Collecting Duct Reabsorbtion
0-5% filtered NaCl
What does ADH cause the collecting duct to reabsorb
Urea
Water
What causes an increase in Na+ reabsorption in the collecting duct
Aldosterone
What causes a decrease in Na+ reabsorption in the collecting duct?
NO
Endothelin
Bradykinin
ANF
Collecting duct Secretion
K+
H+
NH4 +
What causes an increase in K+ secretion in the collecting duct
Aldosterone
What inhibits the ENaC channel in the collecting duct?
Amiloride
Collecting duct Membrane in-foldings
Limited
Collecting Duct mitochondria
Some
Collecting duct transport rate
low
collecting duct transepithelial voltage
high
Collecting duct transepithelial resistance
moderately high
Detrusor muscle inhibition of NE release
Contraction
Internal sphincter inhibition of NE release
Relaxation
P(uf) > 0
Filtration
P(uf) <0
Reabsorption
Permselectivity
Ratio of Ufx/Px
Clearance ratio
How well the kidney clears solute X from the blood compared to inulin (completely cleared)
Clearance ratio = 0
Solute is not freely filtered or excreted
Clearance ratio > 1
NET secretion of substance X along nephron
Clearance ratio < 1
NET reabsorption of substance X along nephron
Maintaining GFR
Maintaining stable and optimal extracellular levels of solutes and water (maintains homeostasis)
Normal GFR
125 mL/min
Peritubular capillaries originate from
Efferent arterioles of superficial/cortical glomeruli
Vasa recta originate from
Efferent arterioles of juxtamedullary glomeruli
2 main functions of peritubular capillaries
Deliver oxygen and nutrients to epithelial cells
Reabsorption of fluid and solutes from interstitium
Cells of the Juxtaglomerular apparatus
Mesangial cells
Macula densa cells
Granular cells
Mesangial cells
Secrete the extracellular matrix
Macula densa cells
Specialized epithelial cells
Located at transition between TAL and distal tubule
Basolateral aspects are in contact with mesangial cells of glomerulus, afferent and efferent arterioles
Granular cells
Located in the wall of AA
Specialized smooth-muscle cells that produce, store, and release renin
JGA
Helps regulate blood flow and filtration rate, modulate Na+ balance and systemic BP
Apical & Basolateral infoldings
Increased surface area to accommodate more transporters on that membrane
More mitochondria
High need for ATP
Proximal Tubule Na+ Transport Primary mechanism
Na+/H+ exchange (apical)
Na+/K+ ATPase (basolateral)
Na+/HCO3 - (basolateral)
S1/S2 Na+ Transport
Na+ and H+ gradients favor H+ efflux and Na+ influx
S3 Na+ transport
NHE makes up majority of Na+ reabsorption
Proximal tubule Solvent drag Na+ reabsorption
30% of NaCl reabsorption in PT
Proximal Tubule Cl- Transport S1/S2
Solvent drag
Electrochemical gradient
Proximal tubule Cl- reabsorption Solvent drag
Na/HCO3 cotransporter (basolateral) creates osmotic gradient drives water reabsorption Lumen - voltage Chloride reabsorbed paracellularly
Cl- reabsorption S3
Cl-/HCO3 anion exchange (apical) KCl cotransporter (basolateral) Paracellular reabsorption
NaCl Transport Early TAL
Na+ reabsorbed passively
NKCC2 (apical)
Na+/K+ ATPase (basolateral)
NaCl Transport Late TAL
Na+ can be passively secreted
NKCC2 (apical)
Na+/K+ ATPase (basolateral)
Chloride Transport in Thick ascending limb
NKCC2 (apical)
KCl cotransporter (basolateral)
Cl- channel (basolateral)
Paracellular transport
Classical or Early DCT NaCl Transport
NCC (Apical)
KCC (basolateral)
Cl- channel (basolateral)
Na/K ATPase (basolateral)
What inhibits NCC in the Classical DCT
Thiazide diuretics
Late or not really the DCT DCT NaCl Transport
NCC (apical) ENaC (apical) Na/K ATPase (basolateral) KCC (basolateral) Cl- channel (basolateral)
What inhibits ENaC in the late DCT
Amiloride diuretics
Paracellular transport in DCT
Cl- ions due to lumen negative charge
Collecting Duct Principal Cell Transport of Na+
ENaC (apical)
Na/K pump (basolateral)
Collecting Duct Principal cell Transport of Cl-
Paracellular driven by lumen negative voltage
Collecting Duct Beta Intercalated Cell Cl- Transport
Transcellular Anion exchange (Apical) Cl- channel (basolateral)
Inner medullary collecting ducts Na+ Reabsorption
ENaC (apical)
CGGC (apical)
NBC (Apical)
Na/K pump (basolateral)
Inner medullary collecting ducts Na+ Secretion
Paracellular driven by electrochemical gradient
Inner medullary collecting duct Cl- Reabsorption
Anion Exchange (apical) Cl- channel (basolateral) Paracellular
Inner medullary collecting duct Cl- Secretion
NKCC1 (basolateral)
CFTR (apical)
Components of glomerulus
Endothelial cells
Mesangial cells
Glomerular epithelial cells (podocytes)
ESRD pathology
Tubular atrophy and interstitial fibrosis
Glomerular cap pathology
Expansion of mesangial matrix
Kimmelstiel-Wilson lesions
Arteriolar hyalinosis
Expansion of the mesangial matrix
Cytokines and growth factors => profibrotic
Kimmelstiel-Wilson lesions
Increases in mesangial matrix from damage as a result of glycation of proteins
Podocyte pathology
Thickened basement membrane
Disrupted foot processes
DKD progression
Hyperfiltration
Microalbuminuria
Macroalbuminuria
Increasing albuminuria
Hyperfiltration
GFR increases
Macroalbuminuria
Nephrotic syndrome
>3.5g/day of albumin being excreted in urine
Increasing albuminuria
Decrease in GFR
FATP2
Expressed in luminal membrane of PT and takes up fatty acids
Progression of Renal Insufficiency
HTN => Increase PTH => Anemia => Increase Phosphorus => Acidosis, hyperkalemia => Uremic syndrome
Consequences of AKI
Accumulation of nitrogenous wastes
Disturbances in fluids/electrolytes
Acid-base disorders
Anuria
Less than 50mL of urine output in 24 hours
Drugs Targeting RAAS
ACE inhibitors
ARBs
Renin inhibitors
Renin Target
Cortical collecting duct
Effect of renin on CCD
Increased cAMP and PKA
Low end of [ANGII] effect
Maintain GFR because efferent arterioles will constrict more than afferent arterioles
High end of [ANGII] effect
GFR will fall because of too much constriction of both afferent and efferent arterioles
ANGII effect on PT
Stimulates or inhibits Na+ reabsorption
ANGII effect binding AT1R on THAL
Stimulates Na+ reabsorption via NKCC2
ANGII effect binding AT2R in THAL
Inhibits Na+ reabsorption via NKCC2
ANGII effect on DCT
Stimulates NaCl reabsorption by increasing apical NCCs & increasing phosphorylation of NCCs
ANGII effect on CD
Increases Na+ reabsorption via ENaC
ANGII effect on Adrenal cortex
Stimulates aldosterone release
ANGII effect on Granular cells
Inhibits release of renin
ANGII effect on vasculature
Vasoconstriction
ANGII effect on OVLT & SFO
Stimulates thirst & AVP release
Aldosterone effect on DCT
Stimulates NaCl reabsorption via NCC
Aldosterone effect on CD
Stimulates Na+ reabsorption & K+ secretion
Low levels of RSN activation
Sodium reabsorption
Medium levels of RSN activation
Renin release
High levels of RSN activation
Increased renal vascular resistance
RSNA effect on PT
Increases Na+ transport
RSNA effect on THAL
Increases or decreases Na+ transport
RSNA effect on collecting duct
Complicated
RSNA effect on JGA granular cells
Increases prorenin release
RSNA effect on OVLT & SFO
Stimulates thirst centers and release of AVP
ANP/BNP effect on vasculature
Vasodilation
ANP/BNP effect on JGA granular cells
Decrease prorenin release
ANP/BNP effect on PT
Decreases Na+ reabsorption
ANP/BNP effect on THAL
Decreases Na+ reabsorption
ANP/BNP effect on Macula densa
Decreased Na+ reabsorption and TGF
ANP/BNP effect on CCD
Decreased Na+ reabsorption
ANP/BNP effect on IMCD
Decreased Na+ reabsorption
High [ET-1] effect on PT
Inhibits NHE3 leading to decreased Na+ reabsorption
Low [ET-1] effect on PT
Increase PKC leading to increased Na+ reabsorption
Endothelin effect on THAL
Decreases Na+ reabsorption
Endothelin effect on CD
Decreases Na+ reabsorption
Nitric oxide effect on PT
Inhibits Na+ reabsorption
Nitric oxide effect on TAL
Inhibits Na+ reabsorption
Nitric oxide effect on CD
Inhibits Na+ reabsorption
Cadmium
Causes Fanconi Syndrome
PT damage
Inhibits Na/K ATPase
Inhibits SGLTs and NaPis in PT
Fanconi syndrome
Loss of PT function
Decreased GFR
Increased urinary flow rate
Excessive loss of major ions