Boards and Beyond: Renal A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 11-27-2017
Read Free For 30 Days
DISCOVER NEW BOOKS
i
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Read Free For 30 Days
DISCOVER NEW BOOKS
ii
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Table of Contents Read Free For 30 Days
Sodium and Water Balance 66 Renal Embryology 1 Sodium Disorders 71 Renal Anatomy 5 Renal Physiology I 6 Glomerular Disease Principles 80 Renal Physiology II 11 Nephritic Syndrome 84 Nephron Physiology 18 Nephrotic Syndrome 91 Renal Endocrinology 26 MPGN 96 Acid Excretion 31 Tubulointerstitial Tubulointerstitial Disease 98 Acid Base Principles 35 Renal Failure 102 Urinary Tract Infections 108 Respiratory Acid Base Disorders 41 DISCOVER NEW BOOKS READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS 43 Cystic Kidney Disease 110 Metabolic Alkalosis Diuretics 112 Renal Tubular Acidosis 47 Metabolic Acidosis 50 Kidney Stones 118 Acid Base Problems 56 Renal and Bladder Malignancy 121 Electrolyte Disorders 60 Rhabdomyolysis 125
iii
Read Free For 30 Days
DISCOVER NEW BOOKS
iv
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Kidney Development Development •
Kidneys derive frommesoderm from mesoderm
•
Three embryonic renal structures form in utero
•
•
First two degenerate Third becomes adult kidney
Read Free For 30 Days
Renal Embryology Jason Ryan, MD, MPH
Kidney Development •
Pronephros •
•
•
DISCOVER NEW BOOKS
READ Formation EVERYWHERE Kidney •
Forms/degenerates week 4
Mesonephros •
Interim kidney 1st trimester
•
Contributes to vas deferens in males
•
Metanephros
BUILD YOUR DIGITAL READING LISTS
Key Structure #1:Ureteric #1: Ureteric bud •
Outgrowth of mesonephric (Wolffian) duct duct
•
Gives rise to ureter, ureter, pelvis, calyxes, collecting ducts ducts
Key Structure #2:Metanephric #2: Metanephric mesenchyme •
Mesoderm tissue
•
Also called metanephric blastema
•
Forms permanent kidney
•
Interacts with ureteric bud
•
Appears 5th week
•
Interaction forms glomerulus to distal tubule
•
Develops into kidney through weeks 32-36
Nephron
Metanephric Mesenchyme
•
Aberrantinteraction kidney malformation
Wilms’ Tumor
Ureteric Bud
•
Most common renal malignancy of young children
•
Proliferationofmetanephric of metanephric blastema •
1
Embryonic glomerular structures
•
Associated with mutations of WT1
•
WT1 expressed in metanephric blastema/mesenchyme
Multicystic Dysplastic Kidney
Renal Agenesis •
•
•
•
Ureteric bud fails to develop Lack of signals to mesenchyme
•
•
If single kidney remaining kidney compensates •
Hypertrophy
•
Hyperfiltration
•
Risk of focal segmental glomerular sclerosis (FSGS) (FSGS)
•
Risk of renal failure after decades decades
•
•
DISCOVER NEW BOOKS
•
•
•
Form of renal dysplasia Kidney replaced with cysts No/little functioning renal tissue
Read Free For 30 Days
Last connection to form form
•
Ureteropelvic junction (UPJ) obstruction •
Common cause single kidney obstruction
•
Narrowing at proximal ureter at junction
•
Hydronephrosis
•
Often detected in utero
•
•
•
•
•
Poor urinary flow kidney stones/UTIs
•
Can be treated with surgery after after birth
•
•
Abnormal closure of ureterovesical ureterovesical junction (UVJ)
•
Occurs in children
•
Associated with duplex ureters
•
•
•
•
High bladder pressure
•
Seen with posterior urethral urethral valves
Hydronephrosis Urinary tract infections Associatedwithvesicoureteral with vesicoureteral reflux
Fetus exposed to absent or ↓ amniotic fluid Amniotic fluid = fetal urine Severe renal malfunction = ↓ amniotic fluid Loss of fetal cushioning cushioning to external forces
•
External compression of the fetus
•
Alteration in lung liquid movement
•
Secondary •
Upper/lowerkidneysform May lead to poor urine flow
Potter’s Sequence
Leads to recurrent urinary tract infections Primary •
Two ureteric buds right or left Or bifurcation ureteric bud
Potter’s Syndrome
Backward urine flowfrom flow from bladder to kidneys
Duplex Collecting System READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Duplicated Ureter
Vesicoureteral Vesicoureteral Reflux •
Abnormal ureteric bud-mesenchyme bud-mesenchyme interaction
If both kidneys: oligohydramnios,Potter’s syndrome
Ureteropelvic Junction •
•
pushes urine backward
•
2
Abnormal face/limb formation Abnormal lung formation formation
Potter’s Syndrome
Oligohydramnios
Signs •
•
•
•
Limb deformities Flat face Pulmonary hypoplasia Often fetal death death
•
First trimester (1-12 weeks): rare
•
Second trimester (13-27 weeks)
•
Third trimester (28 weeks to birth)
•
•
Potter’s Syndrome Causes •
DISCOVER NEW BOOKS
Bilateral renal agenesis
Read Free For 30 Days
Rupture of membranes
Potter’s Syndrome READ EVERYWHERE Causes •
Often detected in utero
•
•
Fetal kidneys seen on ultrasound at 10 to 12 weeks
•
Tissue (valves) obstruct bladder outflow
•
Ultrasound: dilated bladder, bladder, kidneys
•
Both kidneys effected
Autosomal recessiv recessive e polycyst polycystic ic kidney disease
•
Juvenile form of cystic kidney disease
•
Cysts in kidneys and biliary tree
•
Both kidneys affected
•
If severe, may cause oli gohydramnios
•
Less severe
Occurs in males
Horseshoe Kidney
Causes
•
BUILD YOUR DIGITAL READING LISTS
Posterior urethra l valves
•
Potter’s Syndrome •
Decreased formation of fetal urine
•
•
•
renal failure and hypertension in childhood childhood
3
Inferior poles fuse Kidney cannot ascend pelvis retroperitoneum Trapped by inferior mesenteric artery Mostpatients asymptomatic asymptomatic
•
Associated with Turner and Down syndrome
•
Associatedwithvesicoureteralreflux
Urachus •
•
•
Urachal Remnants
Connectsdome Connects dome of bladder to umbilicus Obliterated at birth median umbilical ligament
•
Remnant can lead to adenocarcinoma of bladder
•
Classic case
•
Failed/incomplete Failed/incomplete obliteration obliteration can occur
Key feature: Cancer at dome of bladder bladder
•
Urine can leak from umbilicus
•
Adult with painless hematuria
•
Also can form cyst, cyst, sinus, diverticulum
•
Tumor at dome of bladder
•
Can lead to infections
•
Path showing adenocarcinoma
DISCOVER NEW BOOKS
4
Read Free For 30 Days
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Arterial System Renal Artery
Segmental Artery
Read Free For 30 Days
Renal Anatomy
Interlobar Artery
Jason Ryan, MD, MPH Arcuate Artery
Glomerulus
Special Kidney Features •
Rightkidney slightly smaller •
•
DISCOVER NEW BOOKS
•
Left kidney has longer renal vein •
Often taken for transplant
•
Dead/dying kidney usually not removed removed in transplant
•
New kidney attached to iliac artery/vein
READ EVERYWHERE Aortic Dissection •
Less development in utero due to liver
5
Interlobular Artery
BUILD YOUR DIGITAL READING LISTS
Renal arteries come off abdominal abdominal aorta Aortic dissection can cause renal ischemia
Fluid Compartments
1/4 Plasma
40% Non-Water
1/3For 30 Days Read Free Extracellular
Renal Physiology I
60% Water
Jason Ryan, MD, MPH
Determining Fluid Volume Volume
DISCOVER NEW BOOKS
¾ Interstitial
2/3 Intracellular
READ EVERYWHERE Fluid Compartments
BUILD YOUR DIGITAL READING LISTS
Inulin 40% Non-Water
1gram
1Liter Fluid
1gram
Unknown Volume
60% Water
1g/L
40% Non-Water 60% Water
1/3 Extracellular 2/3 Intracellular
¾ Interstitial
Sample Question 1/4 Plasma
•
Radiolabeled Albumin
1/3 Extracellular 2/3 Intracellular
Radiolabeled Albumin
X grams Inulin infused Equilibrium concentration = Y g/L ECF = X/Y (Liters)
1g/L
Fluid Compartments Inulin
1/4 Plasma
A patient is administered 120mg of inulin. An hour later, the patient has excreted 20mg of inulin in the urine. The plasma inulin concentration concentration is 1mg/100ml. What is the extracellular fluid volume for the patient?
¾ Interstitial
Amount of inulin in body = 120mg – 20mg = 100mg Concentration = 1mg/100ml ECF = 100mg = 10000ml = 10L 0.01mg/ml
10 grams Inulin infused Equilibrium concentration = 0.25 g/L ECF = 10/0.25 = 40L
6
Fluid Compartment Shifts •
Plasma osmolarity about 300mosm/kg
•
Equilibrium between cells and extracellular fluid
•
Fluid Compartment Shifts •
Fluid shifts only if difference in osmolarity
Addition/lossof isotonic fluid •
Change in ECF volume
•
No change in ICF volume
•
Example: Hemorrhage
•
Example:Infusion Example: Infusion of normal saline
•
•
Fluid Compartment Shifts •
•
DISCOVER NEW BOOKS
Example:Infusion Example: Infusion of 5% dextrose •
Hypotonic fluid
•
Increase in in ECF volume
•
Increase in ICF volume
•
•
•
•
Raises plasma osmolarity
•
Remains in the vascular system
•
Decrease i n ICF volume
•
Increase in ECF volume
•
Reduces volume in interstitial space
Low ECV leads to low blood pressure
•
Low ECV activates: •
Sympathetic nervous system
•
Renin-angiotensin-aldost Renin-angiotensin-aldosterone erone system
Extracellular fluid contained in arterial system Maintainstissueperfusion Not necessarily correlated with total body water Modifiedby: •
Volume
•
Cardiac output
•
Vascular resistance
BP = CO X TPR
Effective Circulating Volume •
Increase ECF, no change ICF
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Effective Circulating Volume •
Example: Mannitol infusion
Read Free For 30 Days
Loss of ECF, ECF, no change ICF
Evaluating Kidney Function •
Glomerular f iltration rate •
How much liquid passes passes through the filter (i.e. glomerulus)?
•
Determined from plasma, urine measurements measurements
•
GFR falls as kidneys fail
•
RenalBlood/PlasmaFlow
•
Filtration Fraction
•
•
7
How much blood enters kidney GFR/RPF
Measuring GFR •
Theoretical determination •
•
Theoretical Determination GFR •
Need to know pressures in capillary, Bowman’s capsule
Clinicaldetermination •
•
DISCOVER NEW BOOKS
High pressure drives fluid TOWARD low pressure
Oncotic pressure – concentrated concentrated solution PULLING fluid in •
Hydrostatic pressure
•
Oncotic Pressure
Read Free For 30 Days
Hydrostatic pressure – fluid PUSHING against walls •
•
Need to know plasma concentrations concentrations solutes, urine flow
Capillary Fluid Exchange •
FiltrationDrivingForces
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Capillary Fluid Exchange •
Two forces drive fluid into or out of capillaries
•
Hydrostatic pressure (P)
High pressure draws fluid AWAY from low pressure •
•
Molecules against capillaries walls
•
Pushes fluid out
Oncotic pressure (∏) •
PGC
Solutes (albumin) drawing drawing fluid into capillaries
∏GC
Capillary
∏c
Pc PBC
∏BC Pi
Increase GFR •
PBC
∏i
Raise PGC
Glomerular Filtration Rate PGC
Interstitial Space
∏GC
∏BC
To change GFR: Change PGC or PBC Change ∏GC or ∏GC
8
Dilateafferentarteriole •
More blood IN
•
Increase RPF
•
Increase PGC
•
Increase GFR
•
No change FF
PGC
∏GC
PBC
∏BC
Raise PGC
Raise ∏GC
Increase GFR •
Constrict efferent arteriole
•
Less blood drawn into proximal proximal tubule
•
Less blood out
•
Lower GFR
•
Decreased RPF
•
No change RPF
•
Increase PGC
•
Decrease FF
•
Increase GFR
•
Increase FF
•
•
∏GC
PGC
∏GC
PBC
∏BC
PBC
∏BC
DISCOVER NEW BOOKS
•
•
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Glomerular Flow Dynamics
Increase PBC
Urine backs up behind obstruction
Less GFR PBC No effect RPF Decrease FF
PGC
∏GC
PBC
∏BC
Autoregulation •
Read Free For 30 Days
PGC
Obstruct ureter •
•
Increase protein levels in blood
Blood backs up behind constricted constricted arteriole
Change PBC •
•
•
Myogenic Mechanism
Constant GFR/RBF over range of blood pressures
•
Afferent arterioleconstricts with high pressure •
#1:Myogenic mechanism #2: Tubuloglomerular feedback
•
9
Responds to changes changes in stretch
Result is maintenance of normal GFR/RPF
Tubuloglomerular Feedback
Severe Volume Loss
•
↑ urinary flow in tubule ↑ NaCl to distal tubule
•
•
NaCl sensed by macula densa (part of JG apparatus)
•
•
Macula Densa vasoconstriction afferent arteriole
•
•
•
•
DISCOVER NEW BOOKS
10
Profound loss of fluid (vomiting, diarrhea, etc.) Renal plasma flow falls significantly significantly Auto-regulatory Auto-regulatory mechanisms mechanisms overwhelmed
↓ GFR Read Free ↑ BUN/Cr Pre-renalfailure
For 30 Days
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Renal Function Measurements •
Glomerularfiltrationrate
•
Renal plasma flow
•
Filtration fraction Read Free
•
Renal clearance
•
•
Renal Physiology II
•
Jason Ryan, MD, MPH
How much liquid passes passes through the filter (i.e. glomerulus)? How much liquid does the kidney handle?
For 30 Days
How much of each each blood component gets removed? removed?
ts DISCOVER NEW BOOKS Renal READ EVERYWHERE BUILD YOUR Renal Function Measurements Measuremen Function Measurements Measuremen tsDIGITAL READING LISTS GFR Fluid across Glomerulus
GFR Fluid across Glomerulus
RPF Fluid into Glomerulus
RPF Fluid into Glomerulus
RPF = 5L/min GFR = 2L/min Filtration Fraction=2/5=40% Fraction=2/5=40%
Urine Flow Fluid out of kidney
Renal Function Measurements Measurements
Renal Function Measurements Measurements
GFR Fluid across Glomerulus
GFR Fluid across Glomerulus
RPF Fluid into Glomerulus
GFR = 2L/min [Na] = 2g/L Filtered Load Na = 2*2= 4g/min
Urine Flow Fluid out of kidney kidney
RPF Fluid into Glomerulus Urine Flow = 100cc/hr Urine [K] = 10meq/cc Excretion K = 100 * 10 = 1000meq/hr 1000meq/hr
Urine Flow Fluid out of kidney
11
Urine Flow Fluid out of kidney
Measured Variables
Renal Clearance
1. Plasma concentration (Px = mg/l) •
i.e. Na, Glucose
2. Urine concentration (Ux = mg/l) 3. Urine flow rate (V = l/min)
•
Number determined for blood substance (Na, Glucose)
•
Volume of blood “cleared” of substance X
•
•
Volume of blood that contained amount of X excreted Reported liters/min (volume flow)
Read Free For 30 Days Cx = Ux * V Px
Use these measured variables to get RPF, GFR, etc.
DISCOVER NEW BOOKS
Determining GFR
READ EVERYWHERE Creatinine
BUILD YOUR DIGITAL READING LISTS
•
Inulinclearance used to determine GFR
•
Breakdownproductmuscle metabolism
•
Inulin neither secreted or resorbed
•
Closest naturally occurring substance to inulin
•
•
•
All inulin inulin filtered goes out Amount blood “cleared” of inulin is amount of blood filtered by glomerulus glomerulus Clearance of inulin (liters/min) = GFR
Cinulin = Uinulin * V
•
•
Inulin = All filtered goes out, no secretion/resorption
•
Creatinine = All filtered goes out, small amount amount secretion
Using Cr instead of inulin: •
Secreted Cr will be counted as filtered
•
This will slightly overestimate GFR
= GFR
Pinulin
Creatinine
PCr/GFR Relationship
Cx = Ux * V Px
•
Specialformulas to convert Cr to GFR •
Cockcroft-Gault formula
•
Modification of Diet in Renal Renal Disease (MDRD) formula
•
Use age, gender, gender, Cr l evel to estimate GFR
Amount of Cr out out in urine Equal to amount produced
CCr = UCr * V = GFR PCr
Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) female) / (72 * Cr)
12
Creatinine Clearance
Creatinine
CCr = Constant ≈ GFR
Cr
Read Free For 30 Days
PCr Double [Cr] (1.0 to 2.0)
Half the GFR
GFR
DISCOVER NEW BOOKS
Creatinine •
•
Worsening renal function = high blood Cr level Some sample values: •
Normal kidney function
READ EVERYWHERE Creatinine •
Cr = 0.8 mg/dl
•
Chronic kidney disease
•
End stage renal disease disease (dialysis)
Cr = 2.0 mg/dl
BUILD YOUR DIGITAL READING LISTS
GFR declines with age •
Not always accompanied by rise in Cr
•
Use of formulas is key
•
Must adjust some some medication dosages
Cr = 4.0mg/dl
Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) female) / (72 * Cr)
Renal Function Measurements Measurements
Renal Plasma Flow (RPF)
GFR Fluid across Glomerulus
•
•
•
RPF Fluid into Glomerulus
•
Use para-aminohippuric acid (PAH)to (PAH) to estimate RPF PAH is filtered and secreted 100% of PAH that enters kidney leaves blood in urine Clearance PAH (l/min) = Plasma to kidney (l/min)
CPAH = UPAH * V
= RPF
PPAH
Urine Flow Fluid out of kidney
*PAH clearance underestimates RPF by 10% Not all renal plasma/blood to glomeruli
13
PAH
Plasma versus Blood
Renal Blood Flow (RBF)
•
Blood = Plasma + cells/proteins
•
RBF determined from RPF
•
Renal Blood Flow > Renal Plasma Flow
•
Blood = Plasma + Cells/Proteins Cells/Proteins
•
Separate calculations RBF vs. RPF
•
Cells/Proteins (%) ≈ Hct (%)
Read Free For 30 Days
RPF = RBF (1-Hct)
RBF = 10cc/min 40% if cells (Hct) 60% RBF is plasma RPF = 10 (1- 0.4) = 10 (0.6) = 6cc/min
Renal Blood Flow (RBF) •
•
•
DISCOVER NEW BOOKS
RBF determined from RPF Blood = Plasma + Cells/Proteins
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Renal Blood Flow (RBF) •
•
RPF = 1 liter/min liter/min Hct = 40%
Cells/Proteins (%) ≈ Hct (%)
RPF = RBF (1-Hct) RBF = 1
RBF = RPF
1- Hct
1- Hct
Renal Function Measurements
=
1 = 1.6 l/min 0.6
Other Renal Renal Function Function Variables
GFR Fluid across Glomerulus Inulin/Creatinine
•
RPF Fluid into Glomerulus PAH
•
Urine Flow Fluid out of kidney
14
Filtration Fraction •
How much of plasma to kidney gets filtered?
•
GFR/RPF
•
Normal = 20%
Filtered Load X •
How much of substance X gets filtered?
•
Px * GFR
•
Amount of X delivered to proximal proximal tubule
Quantifying Kidney Function Measured Variables Urine Flow (l/min) Plasma Conc X (mg/l) Urine Conc X (mg/l)
Prostaglandins and NSAIDs
Determined Variables Renal clearance Renal plasma flow Renal B lood Flow Glomerular filtration rate Filtration fraction
•
•
•
•
•
Prostaglandinsdilate Prostaglandinsdilate afferent arteriole ↑ RPF NSAIDs (ibuprofen) block PG production production Afferentarterioleconstricts ↓RPF ↓ GFR --FF ClinicalRead effects: Free For •
Acute renal failure
•
Acute heart failure
30 Days
Inulin Clearance = GFR PAH Clearance = RPF
ACE Inhibitors •
•
•
•
DISCOVER NEW BOOKS
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Secretion and Absorption GFR Fluid across Glomerulus GFR*Px = Filtered Load
AII constricts most blood vessels AII constrictsefferent arteriolepreferentially arteriolepreferentially ACE inhibitors blunt AII effects ↓ GFR ↑RPF ↓ FF
What if Filtered Load ≠ Excretion Urine Flow Fluid out of kidney V*Ux = Excretion
Secretion and Absorption •
•
•
Secretion and Absorption
Excreted = Filtered – Reabsorbed + Secreted
•
Amount filtered (X) = GFR * Px Amount excreted (X) = V * Ux
•
•
Filtered = Excreted if no secretion/resorption Filtered < Excreted if some secreted Filtered > Excreted if some resorbed Example #1: Filtered = 100mg/min Excreted = 120mg/min Additional 20mg/min must be secreted
Example: 10mgX/min filtered, 20mgX/min excreted Additional 10mgX/min must be secreted
Example #2: Filtered = 100mg/min Excreted = 80mg/min 20mg/min must be resorbed
15
Secretion and Absorption
Intake and Output
•
If clearance (x) = GFR no secretion/resorption secretion/resorption
•
•
GFR
•
•
GFR>Cx resorption •
Example #1: GFR = 100ml/min Cx = 120ml/min Additional 20ml/min “cleared” by secretion
•
Amount of any substance in must equal amount out When insults occur (renal failure, diarrhea), there is a transient imbalance that alters plasma levels Steady state returns Read 30 Days Eat 10grams perFree day saltFor 10grams per day excrete
Example #2: GFR = 100ml/min Cx = 80ml/min Additional 20ml/min “uncleared” by resorption
Solutes in Renal Failure •
•
DISCOVER NEW BOOKS
Regulated solutes (Na/K): (Na/K): No concentration change change Unregulated solutes (Cr/Urea): (Cr/Urea): ↑ plasma level
READ EVERYWHERE Question 1 •
BUILD YOUR DIGITAL READING LISTS
A patient has a urine output of 4800cc/day (200cc/hr). Plasma concentration concentration of substance X is 4mg/dL. Urine concentration of X is 8mg/dL. What is the clearance of substance X?
Cx = Ux * V = 8 * 200 = 400cc/hr Px
Question 2 •
4
Question 3
A patient is infused with inulin. At steady state, plasma concentration of inulin is 3mg/dl and urine concentration is 6mg/dl. If the GFR is 200ml/hr, what is the urine flow rate?
GFR = Uinulin * V
•
= Cinulin
A patient is infused with PAH. At steady state, plasma concentration of PAH is 5mg/dl. Urine concentration is 10mg/dl. If the urine flow rate is 200ml/hr and the hematocrit is 0.50, what is the renal blood flow?
CPAH = UPAH * V
Pinulin
= RPF
1- Hct
PPAH
V = GFR * Pinulin = 200 * 3 = 100ml/hr Uinulin
RBF = RPF
RPF = 10 * 200=
6
5
16
400
RBF = 400 = 800ml/hr 1- 0.5
Question 4 •
Question 4
A lab animal has an inulin clearance of 100cc/hr. Plasma concentration of substance X is 4mg/mL. It is known that substance X is not reabsorbed, but is secreted at a rate of 25mg/hr. What is the excretion rate of substanceX?
•
Read Free For 30 Days
Amount filtered (X) = GFR * Px = 100 * 4 = 400mg/hr Excreted = Filtered – Reabsorbed + Secreted Excreted = 400 - 0 + 25 425mg/hr
Amount filtered (X) = GFR * Px Excreted = Filtered – Reabsorbed + Secreted
Key Points •
•
•
A lab animal has an inulin clearance of 100cc/hr. Plasma concentration of substance X is 4mg/mL. It is known that substance X is not reabsorbed, but is secreted at a rate of 25mg/hr. What is the excretion rate of substance X?
DISCOVER NEW BOOKS
If given inulin clearance, that is GFR GFR used to calculate filtered load of other substances
READ EVERYWHERE Key Points •
•
Just need plasma concentration (Px)
•
•
17
BUILD YOUR DIGITAL READING LISTS
Amount filtered = GFR * Px Amount excreted = V * Ux Excreted = Filtered + Secreted - Resorbed For Inulin Filtered = Excreted
Nephron
Nephron Physiology
Read Free For 30
H2O NaCl Days K+ HCO3 Glucose AminoAcids
Jason Ryan, MD, MPH
DISCOVER NEW BOOKS
Transport
READ EVERYWHERE Diffusion
BUILD YOUR DIGITAL READING LISTS
Apical Membrane Basolateral Membrane
Lumen (Urine)
Lumen (Urine)
Interstitium/Blood
Interstitium/Blood
Na
↑[Na]
↑[Na]
↓[Na]
↓[Na] Na
Na
Na
↓[Na]
↑[Na] ATP Na
Osmotic Diffusion
Segments of Nephron Proximal Tubule
Lumen (Urine)
Distal Tubule
Interstitium/Blood
High Osmolarity 1200mOsm
Low Osmolarity (50mOsm) H2O
Collecting Duct
H2O
Descending Limb
H2O
Ascending Limb
18
Proximal Tubule
Proximal Tubule Lumen (Urine)
100% Glucose Amino Acids
Interstitium/Blood Na Na+
67% Water Bicarb NaCl Potassium Phosphate
ATP K+
Glucose
Read Free For 30 Days K +
ClCl
Anions Hydroxide (OH-) Formate Oxalate Sulfate
Anions Glucose H2O NaCl
DISCOVER NEW BOOKS
Glucose
READ EVERYWHERE Pregnancy
•
Completelyreabsorbedproximaltubule
•
•
Na/Glucose co-transport
•
•
•
•
At glucose ~160mg/dl glucose appears in urine Glucose~350mg/dl all transporters saturated
•
•
BUILD YOUR DIGITAL READING LISTS
Pregnancy:some Pregnancy:some glycosuria normal ↑ GFR
↓ glucose reabsorption Serum glucose testing for diabetes
Diabetes mellitus = “sweet” diabetes
Na+ Glucose
Amino Acids •
Lumen (Urine)
All amino acids reabsorbed in proximal tubule •
•
Bicarbonate
Na/AA transporters
Hartnup disease •
No tryptophan transporter in proximal tubule
•
Tryptophan deficiency
•
•
Na+ Interstitium/Blood Na+
HCO3- +
Skin rash resembling pellagra (plaques, desquamation)
H+
H2CO3
Amino acids in urine
CA
H+ + HCO 3-
H2CO3 CA
Na+ CO2 + H2O
CO2 + H 2O
Amino Acids CA = Carbonic Anhydrase
19
Proximal Tubule Bicarbonate
Fanconi Syndrome
Clinical Correlations •
•
Carbonicanhydraseinhibitors
•
•
•
Impaired resorption of solutes solutes
•
•
Result in bicarb loss in urine
•
HCO3-, glucose, amino acids, phosphate
•
Low molecular weight proteins proteins
Type II Renal Tubular Acidosis •
Ion defect
•
Inability to absorb bicarb
•
Metabolic acidosis
Read Free For 30 Days
DISCOVER NEW BOOKS
Polyuria, polydipsia polydipsia (diuresis from glucose) •
•
Loss of proximal tubule functions
Weak diuretics
Fanconi Syndrome •
•
•
Normal serum glucose (contrast with diabetes)
Non anion gap acidosis (loss of HCO 3-) Hypokalemia (↑ nephron flow) Hypophosphatemia Hypophosphatemia (loss of phosphate)
READ EVERYWHERE Fanconi Syndrome •
Inherited or acquired syndrome (rare)
•
Inherited form associated withcystinosis with cystinosis
•
•
Lysosomal storage disease disease
•
Accumulation of cystine
Presents in infancy with Fanconi syndrome
Amino acids in urine
Cysteine
Fanconi Syndrome
Cystinuria •
•
•
•
BUILD YOUR DIGITAL READING LISTS
Acquired Causes
Don’t confuse with cystinosis Proximaltubuledefect Impaired reabsorption of cystine Cystine kidney stones
•
•
•
20
Leadpoisoning Multiple myeloma Drugs •
Cisplatin (chemotherapy)
•
Ifosfamide (alkylating agent) agent)
•
Tenofovir (HIV drug)
•
Valproate
•
Aminoglycoside Aminoglycoside antibiotics
•
Deferasirox (iron chelator)
Cystine
Concentration Changes 50/50
Solute
Concentration Changes 50/50 3.0
Nephron
Na/Cl PAH
Water
Inulin/Cr
2.0 Cl/Urea
50/50
<50/50 Nephron
Read Free For 30Na/K Days
[Tubule] 1.0 [Plasma]
Glucose Bicarb
0.5 50/50
>50/50 Nephron
Inulin Cr
0
Glucose/ Amino Acids/ HCO3Distance Along Proximal Tubule
DISCOVER NEW BOOKS Osmolarity READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS of Nephron Thin Descending Descending Loop Henle •
•
•
•
•
Impermeable to NaCl Concentratesurine Absorbs water Water leaves urine
300mOsm
Cortex
Drawn out by hypertonicity in medulla
600mOsm
Outer Medulla
Inner Medulla
Osmolarity of Nephron •
•
•
•
Thin Descending Loop Henle
Created by Na, Cl, and Urea Urea generated by liver and protein metabolism Reabsorbed by collectingduct •
1200mOsm
300
Cortex
300mOsm
High permeability to urea urea
Essential to maintaining gradients Outer Medulla
H2O H2O H2O H2O H2O
600mOsm
1200 Inner Medulla
Urea
21
1200mOsm
Thick Ascending Loop Henle
Thick Ascending Loop Henle Lumen (Urine)
Interstitium/Blood
120 NaCl NaCl NaCl NaCl NaCl
300 Cortex
Outer Medulla
Na+ Na+
300mOsm + Charge
ATP
K+
Read Free For 30 Days 2Cl K+
-
H2O H2O H2O H2O H2O
600mOsm
K
K
Cl-
1200 Inner Medulla
M
1200mOsm
DISCOVER NEW BOOKS
Distal Tubule
2+ Ca2+
READ EVERYWHERE Collecting Duct Principal Cell
Lumen (Urine) Lumen (Urine)
BUILD YOUR DIGITAL READING LISTS
Interstitium/Blood
Na+
Na+
ENaC Na+
ATP
K+
K+
ATP H2O
K+ Cl-
Interstitium/Blood Na+
Cl-
Intercalated Cell Ca2+
Na Ca2+ ATP H+
Key Points •
•
Collecting Duct Hormones
Collecting duct functions •
Reabsorb Na/H2O
•
Secrete K +/H+
•
•
•
Increased Na delivery to CD increased K excretion •
Contributes to hypokalemia with loops/thiazides loops/thiazides
22
Aldosterone Antidiuretic Antidiuretic hormone (ADH) Regulate collecting duct function
Aldosterone
Collecting Duct Principal Cell
Lumen (Urine) •
•
Steroid(mineralocorticoid)hormone IncreasesNa/K-ATP IncreasesNa/K-ATPase aseprot eins
Interstitium/Blood Na+
Na+ Aldosterone
•
IncreasesNa Increases Na channels (ENaC)of (ENaC) of principal cells
•
Promotes K secretion principal cells
•
Promotes H+ secretion intercalatedcells
ATP
K+
K+
Aldosterone
H2O
Read Free For 30 Days Intercalated Cell
Aldosterone H+
Aldosterone •
•
DISCOVER NEW BOOKS
↑ sodium/water resorption (↑effective circulating volume)
•
↑ K excretion
•
↑H+ excretion
Permeable
•
Angiotensin II
•
High potassium
•
ACTH (minor effect)
•
•
Variable
ADH Water Resorption
Vasopressin
•
Impermeable
Release stimulated by:
Antidiuretic Hormone (ADH) •
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Nephron Water Permeability
Overall effect: •
Cl-
Promotes free water retention (inhibits secretion) Two receptors: V1, V2 •
V1: Vasoconstriction
•
V2: Antidiuretic response
•
•
•
•
Released byposterior by posterior pituitary Two stimuli for release •
Major physiologic stimuli: hyperosmolarity
•
Volume Volume loss: non-osmotic release
V2 receptors: principal cells collecting duct G-protein, cAMP second messenger system Endosome insertion into cell membrane membrane Endosomescontain aquaporin 2 •
•
23
Water channel
Result is ↑ permeability of cells to water
Water Deprivation
Collecting Duct Lumen (Urine)
Principal Cell
High ADH
Interstitium/Blood
AQP-3
H2O
H2O
AQP-4
300
Cortex
ADH
V2
AQP-2 Channel
300mOsm HO Read Free For 30 Days 2
H2O
H2O
Outer Medulla
H2 O H2O
Intercalated Cell
1200
Inner Medulla
High Water Intake
DISCOVER NEW BOOKS
Low ADH
READ EVERYWHERE ADH and Urea •
•
300
Cortex
•
300mOsm
•
NaCl
•
1200mOsm
BUILD YOUR DIGITAL READING LISTS
Key osmole in kidney (with Na, Cl) Medullarycollectingduct permeable to urea ADH increases urea reabsorption reabsorption Urea enters medullary interstitium Thin descending limb transporters “recycle” urea
NaCl
Outer Medulla
NaCl
600mOsm
NaCl
60
Inner Medulla
1200mOsm
Collecting Duct
ADH and Urea
Major Functions •
Resorption Na/H2O
•
Secretion of K+ and H+
•
Urearesorption
•
H2O H2O
H2O Urea
600mOsm
•
Permeable to H20 NOT permeable to Urea
Permeable to H20 AND permeable to Urea
24
Depends on ADH (H2O) (H2O) and Aldosterone (Na) Depends on Aldosterone Aldosterone
Sodium
Water 5%
0%
67%
67% Read Free For 30 8-17% Days
3%
25% 15%
1%
Variable
DISCOVER NEW BOOKS
25
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Renal Hormones •
•
Renal Endocrinology Jason Ryan, MD, MPH
JG Apparatus
DISCOVER NEW BOOKS
Renin (enzyme)
•
1,25 Vitamin D
Act on kidney Read
Free For 30 Days
•
Angiotensin II
•
Atrial Natriuretic Peptide (ANP) (ANP)
•
Antidiuretic hormone (ADH) (ADH)
•
Aldosterone
•
Parathyroid hormone (PTH)
RAAS READ EVERYWHERE Angiotensinogen
BUILD YOUR DIGITAL READING LISTS
Sympathetic System
+ Renin
Modified smooth muscle of afferent arteriole
Macula densa •
•
Erythropoietin
•
JG Cells •
•
•
Renin-Angiotensin-Aldosterone Renin-Angiotensin-Aldosterone System
Juxtaglomerular Juxtaglomerular Apparatus •
Released by kidney kidney
AI
Part of distal convoluted tubule tubule
Renal Na/Cl resorption + ACE
A2 Arteriolar vasoconstriction vasoconstriction
JG cells secrete renin JG Cells
Adrenal aldosterone aldosterone secretion
Net Result ↑Salt/Water Retention ↑BP
RAAS
Stimulation Renin Release
Renin-Angiotensin-Aldosterone Renin-Angiotensin-Aldosterone System
1. Low perfusion pressure •
Low blood pressure pressure or low circulating volume
•
Sensed by afferent afferent arteriole JG cell renin release
•
Renin •
Angiotensin Angiotensin II
•
Aldosterone
•
Sensed by macula densa
JG cell renin release
•
Also constricts afferent arteriole: “tubuloglomerular “tubuloglomerular feedback”
3. Sympathetic activation •
β1 receptors
•
arterioles Also constricts (α) afferent/efferent arterioles
•
Decreases GFR to limit sodium/water excretion
26
Converts angiotensinogen to angiotensin I
•
2. Low NaCl delivery delivery •
Pituitary ADH secretion
Multiple effects
•
Collecting duct effects
•
Resorption of Na
•
Excretion of K, H+
Angiotensin II •
•
•
•
•
Efferent arteriole constriction ↓ RPF ↑ GFR Less renal bloodflow MoreNa/H2O filtration
Capillary Effect •
•
•
•
Angiotensin II •
DISCOVER NEW BOOKS
Increased Na/H2O reabsorption •
Several mechanisms
•
Increased proximal tubule resorption resorption via capillary effect
•
Direct proximal tubule resorption through Na/H+ exchange
•
Stimulates aldosterone release
Read Free For 30 Days
Na/H+ READExchange EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Proximal Tubule Lumen (Urine)
Altered by efferent arteriole constriction
Na+ Interstitium/Blood Na
↓ hydrostatic pressure from less blood flow ↑oncotic pressure from more H2O filtered Net result is that efferent arteriole constriction by AII leads to increased NaClresorption
HCO3- +
H+
H+ + HCO 3-
H2CO3
H2CO3
CA
CO2 + H2O
CA
CO2 + H 2O
CA = Carbonic Anhydrase
Aldosterone •
Synthesized/released Synthesized/released byadrenal byadrenalcortex •
•
•
•
Aldosterone •
Zona glomerulosa cells
•
Freely crosses cell membrane (steroid) Binds to cytosolic protein receptor Activatedreceptormodifies receptor modifies gene expression
•
•
27
IncreasesNa/K-ATP IncreasesNa/K-ATPase aseprot eins IncreasesNa Increases Na channels (ENaC)of (ENaC) of principal cells Promotes K secretion principal cells Promotes H+ secretion intercalatedcells
Collecting Duct
Aldosterone
Principal Cell
Lumen (Urine)
Interstitium/Blood +
Na
•
Na+ Aldosterone
ATP
K+
K+
Aldosterone
H2O •
Intercalated Cell
Overall effect: •
↑ sodium/water resorption (↑effective circulating volume)
•
↑ K excretion
•
↑H+ excretion
ReleaseRead stimulated by: Free •
Angiotensin II
•
High potassium
•
ACTH (minor effect)
For 30 Days
Aldosterone H+
Cl-
RAAS Drugs •
•
DISCOVER NEW BOOKS
ACE-inhibitors
•
Block conversion AI to AII
•
Block sympathetic stim of JG apparatus
•
Lower blood pressure
•
Block renin release
•
Lower blood pressure
Angiotensin receptor blockers (ARBs) •
Block effects of angiotensin II
•
Lower blood pressure
•
Natriuretic Peptides
Aldosterone antagonists •
Spironolactone, eplerenone
•
Lower blood pressure
•
Will ↑K, ↑H+ (↓pH)
•
•
•
•
Potassium-sparing diuretics •
•
BUILD YOUR DIGITAL READING LISTS
BetaBlockers
•
RAA System Drugs •
READ EVERYWHERE RAA System Drugs
Triamterene/amiloride Inhibit ENaC
28
Atrial natriuretic peptide (ANP) Brain natriuretic peptide (BNP) Release in response to volume (myocyte stretch) Oppose actions of RAAS •
Relax vascular smooth smooth muscle via cGMP
•
Vasodilator (↓ SVR)
•
↑ diuresis
Parathyroid Hormone
Parathyroid Hormone Effects
• Maintains calcium levels
•
• Released by chief cells of parathyroid gland •
Main stimulus is ↓ [Ca2+]
• Net Effects: •
•
Kidney: 2+
•
↑ Ca
•
↓ P043- resorption (PCT)
•
↑ 1 ,25 -(0H)2 vitamin D production
resorption (DCT)
Read Free For 30 Days
Also has effects on GI tract and bone
↑[Ca 2+] plasma 3-
•
↓ [P04 ] plasma
•
↑ [P043-] urine
DISCOVER NEW BOOKS
Parathyroid Hormone Lumen (Urine)
PTH
Interstitium/Blood Na
X
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Parathyroid Hormone Lumen (Urine)
Interstitium/Blood Na+
Na
PO4-
Na+
ATP
ATP
K
K+ Cl-
Proximal Tubule
PTH
Distal Tubule Na
↑PO4excretion
Ca2+
++
Ca2+
↑Ca Resorption
EPO
Vitamin D and the Kidney •
Erythropoietin
Proximal Tubule converts vitamin D to active form
•
•
•
PTH
25-OH Vitamin D
+ 1α - hydroxylase
•
•
1,25-OH2 Vitamin D
29
Stimulates red blood cell production in bone marrow Made by interstitial cells peritubular capillary Released in response to hypoxia Decreased production in renal failure Normocyticanemia
Dopamine •
•
•
•
Synthesized in the proximal tubule Dilates afferent and efferent arterioles •
Increased RPF
•
Little change in GFR
Read Free For 30 Days
Promotessodium/waterexcretion(natriuretic) Unclearphysiologic significance significance
DISCOVER NEW BOOKS
30
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Types of Acids •
Two types of acids produced via metabolism •
Volatile acids
•
Non-volatile acids
Read Free For 30 Days
Acid Excretion Jason Ryan, MD, MPH
DISCOVER NEW BOOKS
Volatile Acids •
•
•
CO2 Combines with water to form carbonic acid and H+
•
•
Example: Sulfuric acid
Non-volatile Acids
H2SO4 H+ + SO4-
Proteins Lipids Nucleic Acids
H2SO4 + 2Na+ 2HCO3 Na2SO4 + 2CO2 + 2H2O Sulfuric Acid
Bicarb
↓ HCO3Kidneys
Lungs
Key Points Acid buffered buffered by bicarbonate (no change pH) Bicarbonate must be replenished by kidneys
31
BUILD YOUR DIGITAL READING LISTS
Not from CO2 Derived from amino acids, fatty acids, nucleic acids
Eliminated by lungs (not kidneys)
Non-volatile Acids •
READ EVERYWHERE Non-volatile Acids
Bicarb Reabsorption
Renal Acid-Base Regulation •
•
Proximal Tubule Lumen (Urine)
#1: Reabsorb/Generate bicarb
Na+
Interstitium/Blood
Na
#2: Excrete H+ HCO3- +
H+
H+ + HCO 3-
Read Free For 30 Days H2CO3
H2CO3
CA
CA
CO2 + H2O
CO2 + H2O
CA = Carbonic Anhydrase
Bicarb Reabsorption Reabsorption
DISCOVER NEW BOOKS
Nephron
HCO READ EVERYWHERE 3 Generation
BUILD YOUR DIGITAL READING LISTS
Collecting Duct 6%
Lumen (Urine)
Intercalated Cell
80%
CO2 + H2O CA
4%
H2CO3
10%
H+ + HCO 3ATP H+
HCO3-
0%
HCO3- Generation
Urinary Buffers
Collecting Duct •
•
•
•
•
High H+ low pH damage to nephron Buffers soak u p H+ Protect from low pH Problem: Bicarbonate reabsorbed
•
•
Need other buffers
32
Titratable acids Ammonia
Interstitium/Blood
Titratable Acids
Titratable Acids
•
Urinary substances that absorb H+
•
•
Acids
•
•
Measuredbytitration (“titratable”)
•
•
Titratable Acids •
•
•
DISCOVER NEW BOOKS
HPO4 filtered by glomerulus Form H2PO4 with addition of H+ H2PO4 excreted in urine = excretion of H+
Mostly phosphate Exists in multiple states HPO4 (onehydrogen) H2PO4 (twohydrogens)
Read Free For 30 Days
READ EVERYWHERE Titratable Acids
BUILD YOUR DIGITAL READING LISTS
Interstitium/Blood
Lumen (Urine) HPO4
H+
H+ + HCO 3H2CO3
H2PO4
↑H2PO4 excretion = ↑ H+ excretion
CA
CO2 + H2O
Ammonia •
•
•
•
•
Terminology
Limited supply of titratable titratable acids
•
Varies with dietary intake (especially phosphate)
•
Supply of ammonia (NH3) is adaptable More NH3 generated by kidneys when ↑ H+ Synthesizedfrom glutamine (amino acid)
Glutamine
33
Ammonia = NH3 Ammonium = NH4+
HCO3-
H+ excretion HCO3- generation
Ammonia
Renal Acid-Base
↑NH4+ excretion = ↑ H+ excretion
Summary Non-volatile Acids
Interstitium/Blood
Lumen (Urine)
↓ HCO3NH3
H+
NH4+
HCO3-
H+ + HCO 3-
CO2 + H 2O
H+ excretion HCO3- generation
Net Acid Excretion •
30 Collecting Days
Buffering Tit. Acids NH4+
H2CO3 CA
•
Free For ↑ HCO3- ReadProximal Reabsorption Tubule
DISCOVER NEW BOOKS
Urinary Acid – Urinary Base Positive value indicates acid being excreted
READ Net AcidEVERYWHERE Excretion •
•
Net Acid = Titratable Acids + NH4 + - HCO3Excretion
Duct
↑ H+ Excretion ↑ HCO3- Generated
BUILD YOUR DIGITAL READING LISTS
Acidosis: Increased net acid excretion Alkalosis: Decreased net acid excretion
Net Acid = Titratable Acids + NH4 + - HCO3Excretion
34
Acid-Base Equilibrium
Read Free For 30 Days
Acid Base Principles
CO2 + H2O HCO3 - + H +
Jason Ryan, MD, MPH
Determines pH
Acid-Base Equilibrium
DISCOVER NEW BOOKS
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Acid-Base Equilibrium Low value high H+ (low pH) High value low H+ (high pH)
Maintained by kidneys/metabolism
CO2 + H2O HCO3 - + H +
Maintained by lungs
CO2 + H2O HCO3- + H +
Low value low H+ (high pH) High value high H+ (low pH)
Determines pH
Henderson-Hasselbalch Equation
Acid-Base Equilibrium •
•
pH = 6.1 + log
[HCO3-]
•
0.03*pCO2
35
Normal HCO3- = 22 – 26 mEq/L Normal pCO2 = 35 – 45 mmHg Normal pH = 7.35-7.45
Definitions •
Acidosis/alkalosis •
•
•
Disorder altering H+ levels
•
Acidemia/alkalemia •
•
Acidosis Symptoms
•
Presence of high or low pH in bloodstream
Hyperventilation (Kussmaul breathing) Depressionof myocardialcontractility contractility Cerebral vasodilation •
Can have acidosis without acidemia if mixed disorder •
i.e. acidosis + alkalosis at same same time
Increased cerebral blood flow; Increase Increase ICP
Read Free For 30 Days
CO2 + H2O HCO3 - + H +
Acidosis Symptoms •
•
CNS depression (very high CO2 levels) Hyperkalemia •
•
DISCOVER NEW BOOKS
High H + shifts into cells in exchange for K +
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Alkalosis Symptoms •
Inhibition of respiratory drive
•
Depression myocardial contractility
•
Cerebral vasoconstriction
Shift in oxyhemoglobin oxyhemoglobin dissociation curve •
Bohr effect
•
↓ pH leads to hemoglobin releasing more oxygen
•
•
•
Approach to Acid-Base Problems
Acid-Base Problems 1. Check the pH
3. Determineacid-basedisorder
•
pH < 7.35 = acidosis acidosis
•
•
pH > 7.45 = alkalosis
•
2. Check the HCO3- and pCO2 •
HCO3 from venipuncture; normal 22-28 mEq/L
•
pCO2 from ABG; normal 35-45mmHg
Decrease in cerebral blood flow
Hypokalemia Shift in oxyhemoglobin oxyhemoglobin dissociation curve
•
•
Acidosis + ↓ HCO 3- = metabolic acidosis Acidosis + ↑pCO 2 = respiratory acidosis Alkalosis + ↑HCO3- = metabolic alkalosis Alkalosis+ ↓ pCO 2 = respiratory alkalosis
CO2 + H2O HCO3- + H +
36
Approach to Acid-Base Problems
Approach to Acid-Base Problems
4. For metabolic acidosis only: Calculate anion gap
•
Step 1: What is acid base disorder?
•
Step 2:
5. Use special formulas to check for mixed disorder •
Combined respiratory/metabolic
•
Two metabolic disorders
Compensatory Changes
•
DISCOVER NEW BOOKS
↓ HCO3- = metabolic acidosis
•
•
Compensation = ↓pCO 2
•
•
Is there a second disorder?
•
Is the compensation appropriate?
Read Free For 30 Days
READvs. EVERYWHERE BUILD YOUR DIGITAL READING LISTS Cause Compensation •
•
↑ HCO3- = metabolic alkalosis
•
Metabolic acidosis, respiratory alkalosis, alkalosis, etc.
•
Most acid-base disorders, HCO3- and pCO2 abnormal One is “culprit” that is causing disorder Other is compensatory change
Compensation = ↑pCO 2
↑pCO2 =respiratoryacidosis
•
•
Compensation = ↑ HCO3-
↓pCO2 = respiratoryalkalosis
•
•
Compensation = ↓ HCO3-
CO2 + H2O HCO3 - + H +
Cause vs. Compensation •
•
•
Cause vs. Compensation
Most acid-base disorders, HCO3- and pCO2 abnormal One is “culprit” that is causing disorder
•
•
Other is compensatory change
•
Example 1 pH = 7.30 (acidosis) HCO3- = low pCO2 = low Metabolic acidosis w ith respiratory compensation
Most acid-base disorders, HCO3- and pCO2 abnormal One is “culprit” that is causing disorder Other is compensatory change
Example 2 pH = 7.30 (acidosis) HCO3- = high pCO2 = high Respiratory acidosis with metabolic compensation
CO2 + H2O HCO3 - + H +
CO2 + H2O HCO3- + H +
37
Respiratory Compensation Compensation •
Hyper or hypoventilation hypoventilation
•
Changes pCO2 to compensate for metabolic metabolic disorders
Respiratory Compensation •
Hyperventilation •
•
•
•
Less H+ in blood
•
pH rises
•
•
•
•
Acidosis
Retains CO 2 Plasma CO 2 level rises More H+ in blood pH falls
READDisorders EVERYWHERE Mixed •
BUILD YOUR DIGITAL READING LISTS
Two disorders at same time
•
Excess H+ filtered/secreted filtered/secreted into nephron
•
•
Bicarbonate reabsorbed
•
Metabolic acidosis AND metabolic metabolic alkalosis
•
Urinary buffers excreted
•
Two metabolic acidoses
•
Occurs in many pathologic states states
•
i.e. vomiting and diarrhea
•
•
•
DISCOVER NEW BOOKS
HCO 3 - + H+ CO2For + H30 2ODays Read Free
Hypoventilation •
Renal Compensation
Blows off CO2 Plasma CO 2 level falls
HPO42- excreted as H 2PO4- (phosphate) NH3 excreted as NH 4+ (ammonium)
•
These bind H+ (buffers)
•
Prevent severe drops in pH
•
Alkalosis •
Reverse of acidosis •
Mixed Disorders •
Cannot “compensate” to normal pH
•
Classic scenario: •
pH = normal; HCO 3- and CO 2
•
Mixed disorder
Metabolic acidosis AND respiratory alkalosis/acidosis
To uncover, uncover, determin e “expected” response •
Expected HCO3- for respiratory disorder
•
Expected CO 2 for metabolic disorder
•
Use renal formulas to determine expected response
If actual ≠ expected 2nd disorder present
Mixed Disorders •
abnormal •
If actual ≠ expected, determine abnormality abnormality •
i.e. CO2 higher than expected
•
i.e. HCO3- lower than expected
Usual rules then apply for determining 2° disorders: •
•
•
•
38
↑CO2 = acidosis ↓CO2 = alkalosis ↓ HCO3- = acidosis ↑ HCO3- = alkalosis
Metabolic Acidosis Compensation
Compensation Formulas •
•
•
•
Winter’s Formula Metabolic Alkalosis Formula Acute/Chronic Respiratory Equations Delta-Delta
•
•
•
•
Compensatoryrespiratoryalkalosis (↓ pCO pCO2) Hyperventilation Winter’s Formula: tells you expected pCO2 If actual CO2 ≠ expected, mixed disorder
Read Free For 30 Days
pCO2 = 1.5 (HCO 3-) + 8 +/- 2
Metabolic Acidosis Compensation •
•
•
•
DISCOVER NEW BOOKS
Compensatoryrespiratoryalkalosis (↓pCO2) Hyperventilation Winter’s Formula: tells you expected pCO2 If actual pCO2 ≠ expected, mixed disorder
Metabolic Acidosis READ EVERYWHERE Compensation •
•
•
•
pCO2 = 1.5 (HCO 3-) + 8 +/- 2
BUILD YOUR DIGITAL READING LISTS
Compensatoryrespiratoryalkalosis (↓pCO2) Hyperventilation Winter’s Formula: tells you expected pCO2 If actual pCO2 ≠ expected, mixed disorder
pCO2 = 1.5 (HCO3-) + 8 +/- 2 Example 2 pH = 7.28 (acidosis) HCO3- = 12 mEq/L (nl = 24) pCO2 = 40mmHg (nl=40) Expected pCO 2 = 1.5 (12) + 8 = 26 +/- 2 pCO2>expected Concomitant Respiratory Acidosis Acidosis
Example 1 pH = 7.20 (acidosis) HCO3- = 9 mEq/L (nl = 24) pCO2 = 22mmHg (nl=40) Expected pCO 2 = 1.5 (9) + 8 = 22 +/- 2
Metabolic Alkalosis
Metabolic Alkalosis
Compensation
Compensation
•
•
•
•
Compensatoryrespiratoryacidosis(↑pCO2) Hypoventilation
•
•
↑pCO2 0.7 mmHg per 1.0meq/L ↑ [HCO3-] If actual pCO2 ≠ expected, mixed disorder
•
•
ΔpCO2 = 0.7 * (Δ[HCO3-])
Compensatoryrespiratoryacidosis(↑pCO2) Hypoventilation
↑pCO2 0.7 mmHg per 1.0meq/L ↑ [HCO3-] If actual pCO2 ≠ expected, mixed disorder
ΔpCO2 = 0.7 * (Δ[HCO 3-]) Example 1 pH = 7.50 (alkalosis) HCO3- = 34 mEq/L (nl = 24) pCO2 = 47mmHg (nl=40) Δ[HCO3-] = (34-24) = 10 Expected ΔpCO 2 = 0.7 (10) = 7 Actual ΔpCO 2 = 47-40 = 7 No Secondary Disorder
39
Respiratory Acidosis
Respiratory Acidosis
Compensation
Compensation
•
Acutecompensation •
•
•
Minutes
•
[HCO 3-]
•
Intracellular buffers raise
•
Hemoglobin and other proteins
•
Small ↑pH
•
•
•
•
•
Days
Example 1 pH = 7.15 (acidosis) pCO2 = 80mmHg (nl=40) Acute Δ[HCO 3-] = 40/10 = 4 [HCO3-] = 28; pH = 7.17 Chronic Δ[HCO 3-] = 3.5* 40/10 = 14 14 [HCO 3-] = 38; pH = 7.30
DISCOVER NEW BOOKS
Compensation
•
Read Free For 30 Days
3.5 meq/L ↑ [HCO 3-] for every 10 mmHg ↑pCO2 Δ[HCO3-] = 3.5* ΔpCO 2/10
Renal generation of ↑[HCO3-] Larger ↑pH (but not back to normal!)
Respiratory Alkalosis •
1 meq/L ↑ [HCO 3-] for every 10 mmHg ↑pCO2 Δ[HCO3-] = ΔpCO2/10
Chronic compensation •
Chronic compensation •
Acute compensation compensation
Respiratory Alkalosis READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Compensation
Acutecompensation Chronic compensation
•
Acute compensation compensation •
•
•
2meq/L ↓ [HCO 3-] for every 10 mmHg ↓ pCO2 Δ[HCO3-] = 2*ΔpCO2/10
Chronic compensation compensation •
•
4meq/L ↓[HCO 3-] for every 10 mmHg ↓ pCO 2 Δ[HCO3-] = 4 * ΔpCO2/10 Example 1 pH = 7.65 (alkalosis) pCO2 = 20mmHg (nl=40) Acute Δ[HCO 3-] = 2* 20/10 = 4 [HCO3-] = 20; pH = 7.63 Chronic Δ[HCO 3-] = 4* 20/10 = 8 [HCO3-] = 16; pH = 7.53
Compensation Timeframe •
Acidosis
Respiratory compensation to metabolic disorders •
•
Summary Alkalosis
Rapid
•
Change in respiratory rate
•
Minutes
Respiratory
Metabolic
Respiratory
Metabolic
Metaboliccompensationtorespiratorydisorders •
Acute, mild compensation compensation in minutes from cells
•
Chronic, significant compensation in days from kidneys
Compensation Compensation ↑HCO 3↓pCO 2
Acute/Chronic Formulas
40
Winter’s Formula
Compensation Compensation HCO3↑pCO 2
Acute/Chronic Expected pCO 2 Formulas Formula
Acid-Base Disorders 1. Respiratory alkalosis 2. Respiratory acidosis
Respiratory Acid Base Disorders
4. Metabolic acidosis
Read Free For 30 Days
Jason Ryan, MD, MPH
Respiratory Alkalosis •
•
DISCOVER NEW BOOKS
↓pCO2 pH>7.45
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Respiratory Alkalosis •
Caused by hyperventilation •
Pain
•
Early high altitude exposure
•
Early aspirin overdose
CO2 + H2O HCO3- + H +
High Altitude •
•
•
•
•
•
•
•
Aspirin Overdose
Loweratmosphericpressure Lower pO2 Hypoxia hyperventilation ↓pCO2 respiratory alkalosis (pH rises) After 24-48hrs, kidneys will excrete HCO3pH will fall back toward normal Ventilation rate will decrease Acetazolamide Acetazolamide can augment excretion HCO3-
•
Two acid-base disorders
•
Shortlyafter ingestion:respiratoryalkalosis
•
41
•
Salicylates stimulate medulla medulla
•
Hyperventilation
Hours after ingestion: AG metabolic acidosis •
Salicylates ↓lipolysis, uncouple uncouple oxidative phosphorylation
•
Inhibits citric acid cycle
•
Accumulation of pyruvate, lactate, ketoacids
Aspirin Overdose •
•
Aspirin Overdose
pH
•
•
Variable due to mixed disorder
•
Acidotic, alkalotic, normal
•
•
CO2 •
HCO3-
•
If patent is acidotic: •
•
•
•
•
DISCOVER NEW BOOKS
↑pCO2 pH<7.35
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Respiratory Acidosis •
•
•
-
+
CO2 + H2O HCO 3 + H
Hypercapnia •
•
•
Hypercapnia can affect CNS system Most patients with acute ↑CO2 are agitated Some have depressed consciousness (CO2 narcosis) Δ mental status in patient with respiratory disease: •
PCO2 < Read ExpectedFree For 30 Days Concomitantrespiratoryalkalosis
Winter’s formula predicts predicts CO2 higher than actual CO2 lower than expected for compensation
•
•
PCO2 = 1.5 (14) + 8 +/- 2 = 29
Low due to acidosis
Respiratory Acidosis •
Winter’s formula •
Low due to hyperventilation
•
•
Sample case: pH 7.30, PCO 2 20, HC03- 14 Metabolic acidosis
Consider high CO2
•
Check ABG
•
If CO2 high ventilation
42
Cause by hypoventilation hypoventilation Lung disease (COPD, PNA, Asthma) Narcotics Respiratorymuscleweakness •
Myasthenia gravis
•
Amyotrophic lateral sclerosis
•
Guillain-Barré syndrome
•
Muscular dystrophy
Acid-Base Disorders 1. Respiratory alkalosis 2. Respiratory acidosis 3. Metabolic alkalosis 4. Metabolic acidosis
Read Free For 30 Days
Metabolic Alkalosis Jason Ryan, MD, MPH
Metabolic Alkalosis •
•
DISCOVER NEW BOOKS
↑HCO3pH>7.45
READ EVERYWHERE Metabolic Alkalosis •
Contraction alkalosis
•
Hypokalemia
•
•
•
•
BUILD YOUR DIGITAL READING LISTS
Diuretics Vomiting Hyperaldosteronism Antaciduse
CO2 + H2O HCO3 - + H + Loss of H + from the body or a gain of HCO 3-
Contraction Alkalosis •
↓ECV •
•
•
Proximal Tubule: Bicarb Lumen (Urine)
Renin-Angiotensin-Aldosteron Renin-Angiotensin-Aldosterone e activation
Na+ Interstitium/Blood Na
+
↑H secretion proximal tubule (due to AII) ↑ HCO 3- resorption proximal tubule (due to ↑H+ secretion) ↑H+ secretion collecting duct (due toaldosterone)
HCO3- +
H+
H2CO3 CA
CO2 + H2O
H+ + HCO 3-
H2CO3 CA
CO2 + H 2O
CA = Carbonic Anhydrase
43
Collecting Duct
Hypokalemia
Principle Cell
Lumen (Urine)
Interstitium/Blood +
Na
Na+ Aldosterone
ATP
K+
K+
Aldosterone
•
K+ can exchange with H+ to shifts in and out of cells
•
When ↓ K+ shift K+ out of cells H+ in of cells
•
Hypokalemia alkalosis (vice versa)
H2O
Read Free For 30 Days
Intercalated Cell
HCO3Aldosterone H+
Cl-
Diuretics
DISCOVER NEW BOOKS
Bartter and Gitelman READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Syndromes
•
Loop and thiazide diuretics metabolic alkalosis
•
•
Volume contraction
•
•
•
Hypokalemia ↑Na/H2O delivery to distal nephron ↑K+/H+ secretion •
•
Vomiting
Congenitaldisorders Bartter •
Dysfunction N-K-2Cl pump ascending limb
•
Similar to loop diuretic
Gitelman •
Dysfunction of Na-Cl transport in distal tubule
•
Similar to thiazide diuretic
Both cause hypokalemia/alkalosis
Urinary Chloride
•
Loss of volume contractionalkalosis
•
Useful in metabolic alkalosis unknown cause
•
Loss of HCl
•
Low (<10-20) in v omiting
•
High (>20) in many other causes alkalosis
•
Classicscenario:
•
•
•
↑ production HCl
•
HCO3- generated during production
•
Loss of K+ Urinary chloride is low (<20)
44
Loss of Cl in gastric secretions
•
Young woman with unexplained metabolic alkalosis
•
Urinary Cl is low
•
Diagnosis: surreptitious vomiting
Surreptitious Diuretics
Hyperaldosteronism
•
Intermittent use for weight loss, elimination of edema
•
•
Can cause metabolic alkalosis
•
•
•
•
•
Widely varying urinary chloride levels Initially may cause high urinary chloride Urinary chloride falls to low levels when effects wane
•
•
•
Key test: diuretic screen
•
•
Aldosterone Escape •
•
•
Often no edema in hyperaldosteronism hyperaldosteronism Na/Fluidretention hypertension
•
•
•
•
Increased ANP
Increased sodium and free water excretion Result: diuresis normal volume status
•
•
•
•
Resistant hypertension
BUILD YOUR DIGITAL READING LISTS
Milk-alkali syndrome Excessive intake of: •
Calcium
•
Alkali (base)
Usually calcium carbonate and/or milk Often taken for dyspepsia
Urinary chloride will be increased
Metabolic Alkalosis
Antacid use •
Adrenaladenoma (Conn’s syndrome) ↑ K+/H+ secretion Read Free For 30 Days Hypokalemia Metabolic alkalosis
READ EVERYWHERE Antacid use
Compensatory mechanisms activated •
•
DISCOVER NEW BOOKS
Adrenal overproduction aldosterone Adrenal hyperplasia
Keys to Diagnosis
Hypercalcemia: •
Inhibition Na-K-2Cl in TAL
•
Blockade (ADH)-dependent (ADH)-dependent water reabsorption collecting collecting duct
•
•
History Fluid status •
Results in volume contraction Contraction + alkali = metabolic alkalosis
•
•
45
Volume depleted: vomiting or GI losses
Urinarychloride Low in surreptitious vomiting
IV Fluid Administration Administration •
•
Resolves most forms of metabolic alkalosis •
“Fluid responsive”
•
Diuretics
•
Vomiting
•
Contraction alkalosis
Read Free For 30 Days
Exceptions are hyperaldosteronism, hypokalemia
DISCOVER NEW BOOKS
46
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Non-AG Metabolic Acidosis
Renal Tubular Acidosis
•
Diarrhea
•
Acetazolamide
•
•
•
•
Spironolactone/Addison’s disease Salineinfusion Read Free For 30 Days Hyperalimentation Renal tubular acidosis
Jason Ryan, MD, MPH
Renal Tubular Acidosis •
•
•
DISCOVER NEW BOOKS
Rare disorders of nephron ion channels All cause non-anion-gap metabolic acidosis
•
•
Often present with low [HCO3-] or abnormal K+
•
Type I (distal) RTA •
Very low HCO3- (often <10meq/L)
•
Urine pH is high •
Distal tubule cannot cannot “acidify” the urine
•
Urine is alkaline
•
READ EVERYWHERE Type I (distal) RTA
BUILD YOUR DIGITAL READING LISTS
Distal nephron cells cannot acidify urine excrete H+ (acidemia) Can’t excrete resorb K+ (hypokalemia) Can’t resorb
Type I (distal) RTA •
Diagnosis established if alkaline urine (pH > 5.5) despite a metabolic acidosis (with normal normal kidneys)
•
47
Key symptoms: Chronic kidney stones, Rickets •
Alkaline urine precipitates stones (sometimes bilateral)
•
Acidosis ↑Ca from bones
•
Acidosis suppresses calcium resorption (↑Ca in urine)
Growth failure in children
Type I (distal) RTA
Urine Anion Gap
•
Manyetiologies
•
•
Genetic forms
•
•
Associated with autoimmune diseases
•
•
•
Sjögren's syndrome
•
Rheumatoid arthritis
•
Medications •
Amphotericin B
Urine Anion Gap •
•
DISCOVER NEW BOOKS
In GI metabolic acidosis acidosis (diarrhea): •
•
•
In acidosis, lots of NH4 excreted (removes H+) Can’t measure NH4 directly Urinary anion gap (Na + K – Cl) is a surrogate NH4 leaves with Cl +) being excreted Readnegative Free when For acid 30 (H Days UAG becomes
READ EVERYWHERE Urine Anion Gap •
UAG becomes negative
In distal RTA UAG is positive •
Excretion of NH4 with Cl increases Urine Cl concentration goes up
•
•
•
BUILD YOUR DIGITAL READING LISTS
Kidneys can’t excrete H+ NH4 and Cl - don’t increase increase UAG (Na + K – Cl) does not become negative as it should in acidosis
Can also “challenge” patient with NH4Cl •
Gives an acid load
•
Should lower urine pH
•
In RTA, Urine pH remains >5.3 Negative UAG in acidosis = GI cause Positive UAG in acidosis = RTA
Type I (distal) RTA •
•
Type II (proximal) RTA
Classic case
•
Defect in proximal tubule HC03- resorption UrinepH<5.5
•
Patient with Sjogren’s disease
•
Recurrent bilateral kidney stones
•
•
Very low bicarb on blood work (<10)
•
•
Hypokalemia
•
Urine pH is high (>5.5)
•
UAG is positive
•
If given NH4Cl urine remains with high pH
•
•
•
Treatment: Sodiumbicarbonate bicarbonate
48
Initially, pH may be high due to ↑HC0 3- excretion Distal tubule excretes H+ as acidosis becomes established Urine becomes acidic
Hypokalemia •
Loss of HCO3- resorption
•
Volume contraction
•
↑aldosterone
diuresis
↑K excretion hypokalemia
Type II (proximal) RTA •
•
•
Milder than type I: [HC03-] 12-20
•
•
•
•
No symptoms : routine blood work
•
Secrete acid to compensate
•
Mild weakness (low K)
No kidney stones Can be seen with Fanconi's syndrome •
Generalized failure of proximal tubule
•
Urine loss of phosphate, glucose, amino acids, urate, urate, protein
•
Bone wasting from phosphate loss
•
DISCOVER NEW BOOKS
Distal tubule failure to respond to aldosterone
•
Decreased excretion K+ Only RTA with HYPERkalemia Urine pH usually remains low (<5.4) Impaired ammonium (NH4+) excretion acidosis
•
•
Diabetic with renal insufficiency
•
Unexplained hyperkalemia
Treatment: Fludrocortisone •
Mildly reduced HCO3- (10 – 20)
•
Hypokalemia
•
Urine pH is low (<5.3)
Read Free For 30 Days
Treatment: Sodiumbicarbonate bicarbonate
BUILD YOUR DIGITAL READING LISTS
Decreased aldosterone •
Diabetic renal disease disease
•
ACEi or ARB
•
NSAIDs
•
Adrenal insufficiency
Aldosterone resistance resistance •
Potassium sparing diuretics
•
TMP/SMX
Renal Tubular Acidosis
Classic case: •
•
READ Type IVEVERYWHERE RTA
Aldosterone deficiency/resistance
Type IV RTA •
Sample Case
Distal intercalated cells function normally
•
•
•
•
Type IV RTA •
Type II (proximal) RTA
Mineralocorticoid
49
Metabolic Acidosis •
Most complex set of acid-base disorders
•
Etiology determined by anion gap
Read Free For 30 Days
Metabolic Acidosis Jason Ryan, MD, MPH
The “Chem 7”
DISCOVER NEW BOOKS
Fishbone
READ EVERYWHERE The Anion Gap •
Na+
Cl-
BUN
•
Glucose K+
HCO3-
•
Cr
•
•
140
103
Positive charged ions – negative charged ions = gap Positive charged = Na (don’t count count K+) Negative charged = Cl + HCO3Anion Gap = Na – (Cl- + HCO3-) Normal <12 +/- 4
15
140
100 4.8
26
BUILD YOUR DIGITAL READING LISTS
103
15 100
1.0
4.8
26
1.0
Anion Gap = 140 – (103 + 26) = 11
The Anion Gap •
Results from unmeasured ions
•
Cations: Ca 2+,
•
•
•
Why the Anion Gap Matters •
Mg Mg2+, other minerals
•
Anions:proteins(albumin),phosphates, sulfates A low anion gap can be caused by hypoalbuminemia
•
Also caused by multiple myeloma •
IgG is cationic (+)
•
Will lower measured (+) ions or or increase measured (-) ions
Acidosis from primary loss of HCO3AG = Na + – (Cl- + HCO 3-)
•
Normal anion gap
Acidosis from primary retention of acid •
i.e. ketoacids, lactic acid
•
HCO3- falls without rise in Cl -
•
Rise in A - to compensate for fall in HCO3 -
•
•
50
Body compensates compensates with retention of Cl -
•
AG = Na + – (Cl- + HCO 3-) Result is ↑AG
Why the Anion Gap Matters •
•
•
•
Two Cases
When HCO3- ↓ something negative must ↑ This maintain balance of (-) and (+) charges
134
AG = 10
In normal AG Cl- rises In high AG Unmeasured acids rise
108 pH
7.31
16
Read Free For 30 Days 132
93
AG = 28
pH
7.27
11
Winter’s Formula •
•
•
The Delta-Delta READ EVERYWHERE •
Hyperventilation
•
Winter’s Formula tells you expected ↓pCO2 If actual CO2 ≠ expected, mixed disorder Check Winter’s formula for all metabolic acidoses
•
•
Anion gap ↑ should be similar to HCO3- ↓ ΔAG = AG – 12 Δ HCO3- = 24 – [HCO3-] Ratio ΔAG/ Δ HCO HCO3- assesses for 2° acid-base disorder •
Used to check for 2° metabolic acid-base disorder
•
Winter’s formula assesses for 2° respiratory disorder
ΔΔ=
pCO2 = 1.5 (HCO 3-) + 8 +/- 2
The Delta-Delta •
The Delta-Delta
ΔΔ 1-2 = normal ΔΔ <1 = 2° non-AG metabolic acidosis •
•
•
•
HCO3- too low
•
metabolic alkalosis or pre-existing ΔΔ >2 = 2° metabolic respiratory acidosis •
•
•
HCO3- too high
•
•
ΔΔ=
ΔAG
Δ HCO3-
Delta Ratio •
BUILD YOUR DIGITAL READING LISTS
Delta Ratio
Acidosis:compensatoryrespiratoryalkalosis (↓ pCO pCO2) •
•
DISCOVER NEW BOOKS
ΔAG
•
Δ HCO3-
51
Consider a patient with pH=7.21 (acidosis) HCO3- = 12; Na+ = 150, Cl- = 96 Increased anion gap of 42 Delta AG = 42-12 = 30 Delta HCO3- = 24 – 12 = 12 Delta-Delta = 30/12 = 2.5 HCO3- is too high Concurrent metabolic alkalosis or prior resp. acidosis
Non-AG Metabolic Acidosis •
Diarrhea •
•
Salineinfusion
Lose HCO3- in stool
•
Acetazolamide •
•
•
Blocks formation and resorption HCO 3-
•
•
Loss of aldosterone effects
•
Cannot excrete H + effectively
•
Body retains H +
•
•
↓renin-angiotensinaldosterone activity
•
•
↓ H+ excretion
•
Hyperalimentation
Spironolactone/Addison’s disease •
Anion Gap Metabolic Acidosis
•
Metabolism
•
Lowers pH
•
↑HCl
Anion Gap = Na – (Cl- + HC03-) HCO3- will be low (metabolic acidosis) Some other (-) substance must ↑ to balance Other substance is not Cl-
Read Free For 30anion” Days Other substance is “unmeasuredanion” “unmeasured •
Something with (-) charge that is NOT chloride
Renaltubularacidosis
DISCOVER NEW BOOKS Methanol READ EVERYWHERE Anion Gap Metabolic Acidosis •
•
•
•
Methanol Uremia
•
•
Diabetic ketoacidosis Propylene glycol
•
Iron tablets or INH
•
Lactic acidosis
•
Ethyleneglycol
•
Salicylates
•
•
Methanol •
•
Suspected ingestion (accidental, (accidental, suicide, alcoholic)
•
Confusion (may appear inebriated)
•
Visual symptoms
•
High AG metabolic acidosis
•
•
•
•
Treatment: •
Inhibit alcohol dehydrogenase dehydrogenase
•
Blocks bioactivation of parent alcohol to toxic metabolite
•
Fomepizole (Antizol)
•
Ethanol
Metabolized to formic acid Central nervous system poison Visual loss, coma Found in antifreeze, de-icing solutions, windshield wiper fluid, solvents, cleaners, fuels, industrial products.
Ethylene Glycol
Classic scenario: •
BUILD YOUR DIGITAL READING LISTS
•
52
Metabolized to glycolate and oxalate Both kidney toxins (slow excretion) Glycolate: toxic to renal tubules Oxalate: precipitates calcium oxalate crystals in tubules Also found in antifreeze, solvents, cleaners, etc.
Ethylene Glycol •
•
Classicscenario: •
Suspected ingestion (accidental, (accidental, suicide, alcoholic)
•
Flank pain, oliguria, anorexia (acute renal renal failure)
•
High AG metabolic acidosis
Alcohol Dehydrogenase
Ethanol
Treatment: •
Inhibit alcohol dehydrogenase
•
Blocks bioactivation of parent alcohol to toxic metabolite
•
Fomepizole (Antizol)
•
Ethanol
Methanol
Acetaldehyde
Alcohol Read Dehydrogenase Free For 30Formaldehyde Days
Ethylene Glycol
Propylene Glycol •
•
•
•
•
•
•
DISCOVER NEW BOOKS
Antifreeze (lowers freezing point of water) Solvent for IV benzos
•
•
Metabolized to pyruvic acid, acetic acid, lactic acid Many adverse effects: •
Hemolysis
•
Seizure, coma, and multisystem multisystem organ failure
READ EVERYWHERE Isopropyl Alcohol
•
High AG metabolic acidosis from lactate Main clinical feature of overdose is CNS depression No visual symptoms or nephrotoxicity
•
•
Uremia •
•
•
•
Early kidney disease can can have non-AG acidosis
•
Reduction in H + excretion (loss of tubule function)
•
Increase in HCO3 - excretion
•
Cl- retained to balance charge (normal AG)
Key scenario: ingestion by alcoholic
Converted by ADH to acetone Less toxic than methanol or e thylene glycol Does NOT cause anion gap metabolic acidosis Absence of high AG acidosis acidosis suggest IA ingestion
No role for fomepizole or ethanol Main symptom of ingestion is coma
Diabetic Ketoacidosis (DKA)
Advancedkidneydisease •
Effects similar to e thanol
•
•
BUILD YOUR DIGITAL READING LISTS
Found in many of the same industrial products as methanol,ethyleneglycol •
•
Glycolaldehyde
•
Usually occurs in type I diabetics
•
Insulin requirements rise cannot be met
•
Fatty acid metabolism ketone bodies
•
•
Kidneys cannot excrete organic acids Retention of phosphates, sulfates, urate, others Increased anion gap acidosis
53
Often triggered by infection -hydroxybutyrate, acetoacetate acetoacetate β-hydroxybutyrate,
Diabetic Ketoacidosis Ketoacidosis (DKA)
Lactic Acidosis
•
Polyuria,polydipsia (↑glucose diuresis)
•
Low tissue oxygen delivery
•
Abdominalpain,nausea, vomiting
•
Pyruvate converted to lactate
•
Kussmaul respirations
•
•
•
•
Deep, rapid breathing
•
From acidosis
•
•
•
•
High AG metabolic acidosis from ketones Treatment:
•
•
Shock (↓tissue perfusion)
•
Ischemic bowel
Insulin (lower glucose)
•
Metformin therapy (especially (especially with renal failure)
IV fluids (hydration)
•
Seizures
•
Potassium
•
Exercise
DISCOVER NEW BOOKS
Acute iron poisoning Initial GI phase •
Abdominal pain
•
Direct toxic effects GI tract
READ EVERYWHERE Iron •
BUILD YOUR DIGITAL READING LISTS
AGmetabolicacidosis •
From ferric irons
•
Also lactate (hypoperfusion)
Later (24 hours) •
Cardiovascular toxicity: shock, tachycardia, hypotension
•
Coagulopathy: iron inhibits thrombin formation/action
•
Hepatic dysfunction: worsening coagulopathy
•
Acute lung injury
Weeks later: bowel obstruction Scarring at gastric outlet where iron accumulates
Isoniazid (INH) •
•
•
•
•
High levels (>4.0mmol/L) (>4.0mmol/L) lactic acidosis AGmetabolicacidosis Free For 30 Days ClinicalRead scenarios:
•
Iron •
•
Aspirin Overdose
Tuberculosis antibiotic Acute overdose causes seizures (status epilepticus) Seizures cause lactic acidosis AG metabolic acidosis
•
Two acid-base disorders
•
Shortlyafter ingestion:respiratoryalkalosis
•
54
•
Salicylates stimulate medulla
•
Hyperventilation
Hours after ingestion: AG metabolic acidosis •
Salicylates ↓lipolysis, uncouple uncouple oxidative phosphorylation
•
Inhibits citric acid cycle
•
Accumulation of pyruvate, lactate, ketoacids
Aspirin Overdose •
•
pH •
Variable due to mixed disorder
•
Acidotic, alkalotic, normal
•
•
•
Sample case: pH 7.30, PCO 2 20, HC03- 12 Metabolic acidosis
Winter’s formula •
Low due to hyperventilation
•
HCO3•
•
•
CO2 •
•
Aspirin Overdose
•
PCO2 = 1.5 (12) + 8 +/- 2 = 29
PCO2 < Read ExpectedFree For 30 Days Concomitantrespiratoryalkalosis
Low due to acidosis
Winter’s formula predicts CO2 higher than actual CO2 lower than expected for compensation compensation
DISCOVER NEW BOOKS
55
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Case 1 A 40-year-old man presents to the emergency room with a three day history of severe diarrhea. Several coworkers have been ill with similar symptoms.
Acid Base Problems
An arterial blood gas is drawn showing: Read For 30 Days pH 7.30, pCO2Free 33mmHg Electrolytes are: Na 134, K 2.9, Cl 108, HCO 3- 16
Jason Ryan, MD, MPH
What is the acid-base disorder?
Case 1
134
108
2.9
16
•
Diarrhea non-AG metabolic acidosis
•
No other clues to suggest a 2nd disorder
•
•
•
•
•
•
DISCOVER NEW BOOKS
•
•
•
•
•
•
•
BUILD YOUR DIGITAL READING LISTS
An 80-year-old man with a severe cardiomyopathy cardiomyopathy presents with shortness of breath and edema for the past two days.
pH = 7.30 acidosis HCO3- = 16 (low) metabolic acidosis pCO2 = 33 (low) respiratory compensation Abnormal same direction mixed disorder less likely
An arterial blood gas is drawn showing: pH 7.25, pCO2 62mmHg Electrolytes show: HCO3- 27
Anion gap = 134 – 108 – 16 = 10 (normal) Winter’s formula pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (16) + 8 = 32 +/- 2 Non-AG Metabolic Acidosis
What is the acid-base acid-base disorder?
Case 2 •
READ Case 2 EVERYWHERE
Case 3
CHFexacerbation acuterespiratoryacidosis
A 40-year-old woman with rheumatoid arthritis presents for a routine exam. She has normal vitals and a normal physical exam. She was hospitalized for a
pH = 7.25 (acidosis) (acidosis) pCO2 = 62 (high) respiratory acidosis HCO3- = 27 (high) metabolic compensation Abnormal same direction mixed disorder less likely Acute respiratory acidosis ↑ HCO3- 1/10 ↑CO2 Expected ↑HCO3 = 2 (HCO3- of 26) No concurrent disorder disorder
kidney stone six months ago which has since resolved. Serum electrolytes show: Na 140, K 3.4, Cl 110, HCO3- 16 Because of the low HCO3, an ABG is done: pH 7.25, pCO2 32mmHg What is the acid-base acid-base disorder?
Acute respiratory respiratory acidosis
56
Case 3
140
110
3.4
16
•
pH 7.25 (acidosis)
•
HCO3- 16 (low) metabolic
•
•
•
•
Case 3 pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (16) + 8 = 32 +/- 2
acidosis pCO2 32 (low) respiratory compensation compensation
•
Must consider RTA given RA history/kidney stones
•
UAG should be checked •
Expected PCO2 =32 AG = 140 – 110 – 16 = 14 Non-AG metabolic acidosis
•
Urine Na + K – Cl
•
Should be negative due to acidosis
•
If positive, suggests RTA RTA
Read Free For 30 Days
Acid challenge with NH4Cl should be done •
Urine pH will remain remain >5.3 after NH 4Cl
•
Type I RTA cannot acidify urine
Non-AG metabolic acidosis acidosis
Case 4
DISCOVER NEW BOOKS
75-year-old man has a long-standing history of severe COPD for which he requires chronic oxygen therapy.
140
READ Case 4 EVERYWHERE 4.0 •
•
Serum electrolytes show:
•
Na 140, K 4.0, Cl 94, HCO3- 34 An ABG is done: pH 7.32, pCO2 69mmHg
•
•
•
•
What is the acid-base disorder?
•
94 BUILD YOUR DIGITAL READING LISTS 34
pH = 7.32 (acidosis) (acidosis) PCO2 = 69 respiratoryacidosis HCO3- = 34 metabolic compensation This is chronic Expected Δ[HCO3-] = 3.5* ΔpCO2/10 ΔpCO2 = 69 – 40 = 29 Expected Δ[HCO3-] = 3.5* 29/10 = 10
Actual Δ[HCO3-] = 34 – 24 = 10
Chronic respiratory acidosis
Case 5
Case 5
A 50-year-old man is found obtunded and poorly responsive.
•
•
An arterial blood gas is drawn showing: pH 7.52, pCO2 47mmHg Electrolytes show: Na 140, Cl- 96; HCO3- 34
•
•
•
•
•
pH = 7.52 (alkalosis) (alkalosis) HCO3- = 34 (high) metabolic alkalosis PCO2 = 47 (high) respiratorycompensation ΔpCO2 = 0.7 * (Δ[HCO 3 ]) Δ PCO2 = 47- 40 = 7 Δ[HCO3-] = 34 – 24 = 10
Expected Δ PCO2 = 0.7 * (10) = 7
What is the acid-base acid-base disorder? Puremetabolicalkalosis
57
Case 5 •
Cause? •
•
Case 6 A 59-year-old man with a history of alcoholism and
Contraction alkalosis, hypokalemia, diuretics, vomiting, hyperaldosteronism, antacid use
depression presents with altered mental status. He was found by his ex-wife sleeping in his tool shed. He reports
Need to know volume status •
•
Need to know urinary chloride
•
This disorder often fluid (saline) responsive
•
blurry vision and black spots. Read Free For showing: 30 Days An arterial blood gas is drawn pH 7.30, pCO2 28mmHg Electrolytes show: Na 141, Cl- 102; HCO3- 14
Reduced in contraction, diuretics, vomiting Low with GI losses (vomiting)
What is the acid-base disorder?
141
Case 6 pH = 7.30 (acidosis) (acidosis)
•
HCO3- = 14 metabolic acidosis
•
•
•
•
•
•
DISCOVER NEW BOOKS
14
•
•
102
pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (14) + 8 = 29 +/- 2
READ Case 7 EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
A 50-year-old man with diabetes presents to the emergency room with confusion. His wife says he has been thirsty and urinating frequently. In addition, he takes narcotics for back pain and she believes he has been taking more pills than usual lately for abdominal pain.
pCO2 = 28mmHg respiratory compensation Expected PCO2 = 29 +/- 2 No secondary respiratory disorder
An arterial blood gas is drawn showing:
AG = 141 – 102 – 14 = 25 (high) ΔAG = 25 – 12 = 13; ΔHCO3-=24 – 14 = 10 ΔΔ = 13/10 = 1.3 No secondary metabolic disorder
pH 7.28, pCO2 40mmHg. Electrolytes are: Na 134, K 3.5, Cl 94, HCO - 12 3
What is the acid-base disorder?
AG metabolic metabolic acidosis
Case 7
134 3.5
94
Case 7
12
•
Diabetic, polyuria, polydipsia, abd pain DKA
•
Expect AG metabolic acidosis
•
•
Narcotic use
•
•
•
•
•
•
Possible respiratory depression
•
Respiratory Respiratory acidosis
•
134 3.5
94 12
Winter’s formula pCO2 = 26 pCO2 higher than expected at 40 Concomitantrespiratoryacidosis
pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (12) + 8 = 26 +/- 2
pH = 7.28 acidosis HCO3- = 12 (low) metabolic acidosis pCO2 = 40 (normal) NO respiratory compensation Anion gap = 134 – 94 – 12 = 28 (high)
AG metabolic acidosis with respiratory respiratory acidosis
58
Case 8
Case 8
A 60-year-old woman presents to the emergency room
•
with a massive vomiting for 3 days. On exam, she is hypotensive and tachycardic. Skin turgor is
•
•
diminished. An arterial blood gas is drawn showing: pH7.24, pCO2 24mmHg. Electrolytes are: Na 140, K 3.2, Cl 79, HCO3- 10
•
•
•
•
140
79
3.2
10
Vomiting non-AG metabolic alkalosis Dehydration Possible lactic acidosis pH = 7.24 acidosis HCO3- = 10 (low) metabolic acidosis Read Free For 30 Days pCO2 = 24 (low) respiratory compensation Abnormal same direction mixed disorder less likely Anion gap = 140 – 79 – 10 = 51 (high)
What is the acid-base acid-base disorder?
Case 8 •
•
•
•
•
•
•
140
79
3.2
10
DISCOVER NEW BOOKS
Winter’s Formula pCO2 = 23 +/ - 2 Actual pCO2 = 24 Normalrespiratory compensation compensation ΔAG = 51 – 12 = 39 ΔHCO3- = 24 – 10 = 14 ΔΔ = 39/14 = 2.8 Concurrent metabolic alkalosis
READ EVERYWHERE Summary •
•
pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (10) + 8 = 23 +/- 2
•
•
•
•
•
Diarrhea non-AG metabolic acidosis Acuterespiratoryacidosis Renal tubular acidosis - Urine anion gap Chronicrespiratory acidosis Metabolicalkalosis-Volumestatus/urinechloride Methanol toxicity AG metabolic acidosis with respiratory acidosis •
•
59
Winter’s formula doesn’t match compensation
AG Metabolic acidosis with metabolic alkalosis •
AG Metabolic Metabolic Acidosis Acidosis with metabolic alkalosis
BUILD YOUR DIGITAL READING LISTS
Delta-delta abnormal
Potassium •
•
Needed for HEART and SKELETAL SKELETALMUSCL ES Hypo/hypereffects: •
EKG changes
•
Arrhythmias
•
Weakness
Read Free For 30 Days
Electrolytes Jason Ryan, MD, MPH
Hyperkalemia
DISCOVER NEW BOOKS
Signs/Symptoms •
•
BUILD YOUR DIGITAL READING LISTS
Arrhythmias Arrhythmias •
Sinus arrest
•
AV block
Muscleweakness paralysis •
•
READ EVERYWHERE Peak T waves
Lower extremities
trunk upper extremities
EKG changes •
Peaked T waves
•
QRS widening
Hyperkalemia
QRS Widening
Causes •
Most cases: ↓ K excretion in urine
•
Need aldosterone renal secretion K+
•
•
60
Acute and chronic kidney disease Type IV RTA RTA (aldosterone resistance)
Hyperkalemia
Hypokalemia
Causes
Signs/Symptoms
•
Increased K release from cells
•
Arrhythmias
•
Acidosis
•
PACs, PVCs
•
Insulin deficiency
•
Bradycardia
•
Beta blockers
•
Digoxin
•
Lysis of cells (tumor lysis syndrome)
•
Hyperosmolarity
•
Muscle weakness paralysis
•
EKG changes
•
K K
K
K
K K
K
K K K
K
K
DISCOVER NEW BOOKS
Hypokalemia READ EVERYWHERE
U
•
•
Increased renal losses •
Diuretics
•
Type I and II RTAs
Increased GI losses •
T
BUILD YOUR DIGITAL READING LISTS
Selected Causes
U Wave: Origin unclear May represent repolarization of Purkinje fibers
Flattened T waves waves
K K
U Waves/Flat T waves T
U waves
•
K
K K
•
K K
K
K
K
trunk Read Free Forupper 30extremities Days
Lower extremities
U
Vomiting/diarrhea
Can be normal
Hypokalemia
Hypercalcemia
Selected Causes
Symptoms
•
Increased K entry into cells •
•
•
Hyperinsulinemic states
•
Beta agonists: albuterol, terbutaline, dobutamine
•
Alkalosis
•
•
•
Hypomagnesemia •
Promotes urinary K loss
•
Cannot correct K until Mg is corrected!!
Often asymptomatic May cause recurrent kidney stones Acute hypercalcemia hypercalcemia polyuria
61
Nephrogenic diabetes insipidus insipidus
•
Loss of ability to concentrate urine
•
Downregulation of aquaporin channels channels
•
Excessive free water excretion
•
↓ GFR acute renal failure
Hypercalcemia
Hypercalcemia
Symptoms
Selected Causes
•
•
•
Stones (kidney) •
Polyuria
•
Kidney stones
•
Renal failure
Malignancy
Read Free For 30 Days
Constipation, anorexia, nausea nausea Anxiety, altered mental status
Hypercalcemia
DISCOVER NEW BOOKS
Selected Causes
•
•
Psychiatric overtones •
•
Hyperparathyroidism
Bones (bone pain) Groans (abdominal pain) •
•
•
Hypocalcemia READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
↓ Ca
Signs/Symptoms
Hypervitaminosis D
•
Tetany
•
Massive consumption calcitriol supplements
•
•
Sarcoidosis: Sarcoidosis: Granulomatous macrophages 1α-hydroxylase
•
Calcium blocks Na channels channels in neurons
•
Low Ca easy depolarization
Milk alkali syndrome
Muscle twitches
spontaneous contractions
•
Largely historical (milk/bicarb)
•
High Ca difficult depolarization
•
High intake calcium carbonate (ulcers)
•
Hyper-excitability of neurons and motor endplates
weakness
•
Excess calcium and alkali intake intake
•
Trousseau's sign: Hand spasm with BP cuff inflation
•
Hypercalcemia
•
Chvostek's sign: Facial contraction with tapping on nerve
•
Metabolic alkalosis
•
Renal failure
•
Seizures
Hypocalcemia
Hyperphosphatemia
Selected Causes
Selected Causes
•
•
•
•
•
Hypoparathyroidism(↓ PTH) Renal failure (↓ active vitamin D) Pancreatitis (saponification of Mg/Ca in necrotic fat) Drugs(Foscarnet)
•
•
•
Magnesium: Hypo/Hypermagnesemia
62
Acute and chronic chronic kidney disease Hypoparathyroidism Huge phosphate load
PO4-
•
Tumor lysis syndrome
•
Rhabdomyolysis
•
Large amount of phosphate laxatives (Fleet’s (Fleet’s Phospho-soda)
Calcium-Phosphate in Renal Failure
Hyperphosphatemia Hypoparathyroidism Lumen (Urine)
Sick Kidneys
PTH ↑ Phosphate
↓1,25-OH2 Vitamin D
Interstitium/Blood Na
X
Na
PO4-
ATP K
Read Free For 30 Days Proximal Tubule
↓Ca from plasma
↓ Ca from gut ↑PO4excretion
Hypocalcemia
↑PTH
Hyperphosphatemia
DISCOVER NEW BOOKS
Symptoms •
•
•
Hyperphosphatemia READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Symptoms
Most patients asymptomatic Signs and symptoms usually fromhypocalcemia from hypocalcemia
•
Metastatic calcifications •
Phosphate precipitates serum calcium
“Calciphylaxis”
•
Seen in chronic hyperphosphatemia in CKD
•
Excess phosphate taken up by vascular smooth muscle
•
Smooth muscle osteogenesis osteogenesis
•
Vascular wall calcification
•
Increased systolic blood pressure pressure
•
Small vessel thrombosis
•
Painful nodules, skin necrosis
Hypophosphatemia
Hypophosphatemia
Symptoms
Selected Causes
•
•
Main acute symptom is weakness •
ATP depletion
•
Often presents are respiratory muscle muscle weakness
•
Primary hyperparathyroidism
•
Diabetic ketoacidosis (DKA)
•
Refeeding syndrome in alcoholics
•
If chronic: bone loss, osteomalacia
↑ PO4 excretion
•
Low PO4 from poor nutrition
•
Food intake metabolism
•
Antacids
•
Urinary wasting
•
•
63
Glucose induced diuresis
Ammonium hydroxide Fanconi Syndrome
further ↓ PO4
Hypermagnesemia
Hypermagnesemia
Signs/Symptoms
Selected Causes
•
Mg blocks Ca and K c hannels
•
Neuromuscular toxicity
•
•
•
↓ reflexes
•
Paralysis
•
Renal insufficiency
Read Free For 30 Days
Bradycardia,hypotension,cardiacarrest Hypocalcemia Hypocalcemia (inhibits PTH secretion)
↑ Mg ↓PTH ↓Ca
Hypomagnesemia
DISCOVER NEW BOOKS
Symptoms •
•
•
•
•
Tetany, tremor
Cardiac arrhythmias •
Hypocalcemia Hypokalemia
Low Mg •
↑ PTH release (same effect as calcium)
•
↑ GI and renal magensium along with calcium
Very low Mg inhibits PTH release •
Some Mg required for normal CaSR function
•
Abnormal function
•
Hypocalcemia often seen in severe hypomagenesemia
suppression of PTH release
Hypomagnesemia
Hypomagnesemia
Potassium
Selected Causes
•
•
•
BUILD YOUR DIGITAL READING LISTS
Parathyroid Gland
Neuromuscular excitability •
Hypomagnesemia READ EVERYWHERE
Magnesiuminhibitspotassiumexcretion ROMK •
Renal outer medullary potassium channel
•
Found in cortical collecting duct
•
GI losses (secretions contain Mg)
•
Pancreatitis
•
Renallosses
•
•
K+ won’t correct until Mg2+ corrected
•
•
Interstitium/Blood
Lumen (Urine)
•
Mg2+
X
ROMK
K+
64
Diarrhea Saponification of Mg/Ca in necrotic fat fat Loop and thiazide diuretics diuretics Alcohol abuse (alcohol-induced tubular dysfunction)
Drugs •
Omeprazole (impaired absorption) absorption)
•
Foscarnet
Foscarnet •
•
•
Antiviral pyrophosphate analog Binds/inhibitsviralDNApolymerase Adverseeffects •
Nephrotoxicity (limiting side side effect)
•
Seizures (often related to electrolytes) electrolytes)
•
Hypocalcemia (chelates calcium)
Read Free For 30 Days
•
Hypomagnesemia (induces renal wasting of magnesium)
•
Hypokalemia
•
Hypophosphatemia
•
Hypercalcemia
•
Hyperphosphatemia
Foscarnet
DISCOVER NEW BOOKS
65
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Balance
Sodium and Water Balance
•
Water in = water out “water balance”
•
Sodium in = sodium out
•
Majorregulators:
“sodium balance”
•
Antidiuretic hormone (ADH) (ADH)
•
Sympathetic nervous system (SNS)
•
Renin-angiotensin-aldosterone Renin-angiotensin-aldoste rone system (RAAS)
Read Free For 30 Days
Jason Ryan, MD, MPH
DISCOVER NEW BOOKS Effective READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Effective Circulating Volume Circulating Volume •
•
•
•
Portion of extracellular fluid Contained in arterial system
•
Maintainstissueperfusion Not necessarily correlated with total body water
•
Effective Circulating Volume •
•
•
Modifiedby: •
Volume
•
Cardiac output
•
Vascular resistance
Majordeterminant: sodium •
Excess sodium ↑ ECV
•
Restricted sodium
↓ ECV
Effective Circulating Volume
Low ECV can lead to low blood pressure
•
May cause orthostatic hypotension Dizziness/fainting Dizziness/faintingon standing •
66
Low ECV activates: •
Sympathetic nervous system
•
Renin-angiotensin-aldosterone
Retentionof sodium/water sodium/water
system
Antidiuretic Hormone
Effective Circulating Volume •
•
•
•
ADH; Vasopressin
Some disease states have chronically↓ ECV Chronic activation of SNS and RAAS
•
•
Chronic retention of sodium/water by kidneys
•
May or may not lead to increased total body water
Antidiuretic Hormone
DISCOVER NEW BOOKS
ADH; Vasopressin •
Also released with low ECV “Non-osmotic release” of ADH
•
Second trigger in addition to serum osmolality
•
Only activated with very low ECV
•
•
•
•
Water Balance
Sensed by hypothalamus hypothalamus
•
ADH released by posterior posterior pituitary gland
•
ADH free water resorption by kidneys
•
Water retention adjusted adjusted to maintain normal osmolality
Read Free For 30 Days
READBalance EVERYWHERE Water •
•
Retention of free water Major physiologic trigger is plasmaosmolality
BUILD YOUR DIGITAL READING LISTS
Plasma sodium maintained at ~ 140meq/L Water intake water excretion normal sodium Water balance maintained by ADH ADH retention of excess free water Water balance reflected byplasma by plasma sodium •
Normal sodium: In = Out (in balance)
•
Hyponatremia: In>Out
•
Hypernatremia: In
Water Balance ↓ ADH
Excess Water
Restricted Water
↓ Osmolality
↑ Osmolality
↓ ADH
↑ ADH
↓ Water Resorption
↑ Water Resorption
↑ Water Excretion
↓Water Excretion
V C E / r e t a W y d o B l a t o T
In > Out ↓Posm
Out > In ↑Posm
In = Out
In = Out
ADH = Baseline Posm = Normal
ADH = Baseline Posm = Normal
Time Water Consumption
67
Sodium Balance •
Plasma sodium maintained at ~ 140meq/L
•
Excess sodium ↑ osmolality
•
•
•
Sodium Balance Excess Sodium
↓ Osmolality
↑ Osmolality
↑ osmolality water retention normal sodium Water retention ↑ ECV
↑ ADH Read Free For 30 Days
↓ ADH
Sodium intake expands ECV
Sodium Balance
DISCOVER NEW BOOKS
↑ ADH Na In > Na Out [Na] = Normal ↑Posm ADH = Baseline In = Out Na In > Na Out
•
•
ADH = Baseline
↓ Water Resorption
↑ Water Resorption
↑ Water Excretion
↓Water Excretion
↓ ECV
↑ ECV
READ EVERYWHERE Sodium Balance •
V C E / r e t a W y d o B l a t o T
Restricted Sodium
•
BUILD YOUR DIGITAL READING LISTS
ECV controlled by SNS and RAAS •
Sympathetic nervous system
•
Renin-angiotensin-aldosterone
system
Activated when ECV is low Inhibited when ECV is high Sodium alters ECV alters SNS/RAAS
Time Sodium Consumption
Sodium Balance •
•
•
•
Sodium Balance
Sodium intake Expanded ECV Expanded ECV ↓ SNS and ↓ RAAS Result:Increasedsodiumexcretion Out = In balance restored
68
Restricted Sodium
Excess Sodium
↓ ECV
↑ ECV
↑ SNS/RAAS
↓ SNS/RAAS
↑ Na Retention
↓ Sodium Retention
↓ Na Excretion
↑ Na Excretion
In = Out
In = Out
Sodium Balance
Sodium Balance
Key Points •
↑ ADH Na In > Na Out ↑Posm
V C E / r e t a W y d o B l a t o T
In = Out ADH = Baseline SNS = Baseline RAAS = Baseline
↓SNS/RAAS In = Out [Na] = Normal ADH = Baseline SNS = Decreased RAAS = Decreased
•
High sodium intake expands ECV •
Weight gain
•
May cause hypertension
Low sodium intake contracts ECV
Read Free For 30 Days
•
Weight loss
•
May improve hypertension
Time Sodium Consumption
Out of Balance •
•
Lack of water balance •
Alters plasma sodium level
•
Hypo or hypernatremia
DISCOVER NEW BOOKS
READ EVERYWHERE GILosses •
•
•
Lack of sodium balance •
Alters total body volume/ECV
•
Hypo or hypervolemia
•
•
GI Losses •
•
Hyponatremia oftenoccur •
Drinking free water
•
Not eating (no sodium)
Hypernatremia can occur •
Nausea, vomiting, diarrhea Activation of SNS/RAAS Volume loss •
•
BUILD YOUR DIGITAL READING LISTS
↑ ADH release
Non osmotic r elease of ADH
•
Driven by volume sensors
•
No longer controlled controlled by plasma sodium level
Water balance control by ADH lost Free water always retained by kidneys Plasma sodium determined by relative intake/losses
Heart Failure •
•
•
•
Not taking enough free water
69
Chronically ↓ ECV (low cardiac output) Chronic activation of SNS and RAAS Sodiumchronicallyretained Free water also re tained to balance sodium
Heart Failure •
•
•
•
Sodium balance disrupted Sodium excretion always reduced
•
•
•
•
•
•
High sodium intake intake > excretion Hypervolemiaoften Hypervolemiaoften occurs
Heart Failure •
Heart Failure
•
DISCOVER NEW BOOKS
ADH always high
•
Driven by volume sensors (“non-osmotic”)
•
No longer controlled by plasma sodium level level
•
Failing heart unable to increase increase CO
•
Heart failure patients always have low ECV
Result: Congestion
Read Free For 30 Days
•
Pulmonary edema
•
Elevated jugular venous pressure
•
Pitting edema
SIADH READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Syndrome of Inappropriate ADH Secretion
Water balance disrupted ↓ ECV ↑ ADH release •
ECV does not ↑ normally with fluid retention
•
•
•
Water balance control by ADH lost Free water always retained by kidneys Plasma sodium determined by relative intake/losses intake/losses Hyponatremia often occurs
•
Excessive ADH release Excess water retention hyponatremia Normaltotal Normal total body water •
Water retention ↑ ECV ↓ SNS/RAAS
•
Sodium excretion ↓ ECV (back to normal)
Key findings •
70
Hyponatremia
•
Normal volume status
•
Concentrated urine
Sodium Disorders •
In general, these are disorders ofWATER of WATER not sodium
•
Hyponatremia
•
Hypernatremia
•
•
Sodium Disorders
Too much water
Read Free For 30 Days
Too little water
Jason Ryan, MD, MPH
Sodium Symptoms •
•
•
DISCOVER NEW BOOKS
Fluid into tissues
•
Brain swells
•
•
•
Fluid out of tissues
•
Brain shrinks
Hyponatremia •
•
Malaise, stupor, coma Nausea
High sodium = high plasma osmotic pressure
Plasma Osmolality
Key Diagnostic Tests •
BUILD YOUR DIGITAL READING LISTS
Symptoms
Hypo and hypernatremia effectbrain effect brain Low sodium = low plasma osmotic pressure •
Hyponatremia READ EVERYWHERE
Plasma osmolality Urinary sodium
•
•
Urinaryosmolality
•
•
71
Amount of solutes present in plasma Key solute:Sodium solute: Sodium Osmolality should be beLOW LOW in HYPOnatremia HYPOnatremia st 1 step in hyponatremia is to make sure it’s low
Plasma Osmolality
Plasma Osmolality •
Serum Osmolality = 2 * [Na] + Glucose + BUN 18
2.8
Hyponatremia with HIGH osmolality •
Hyperglycemia or mannitol
•
Glucose or mannitol = osmoles
•
Raise plasma osmolality
•
Water out of cells
hyponatremia Read Free For 30 Days
Normal = 285 (275 to 295)
Plasma Osmolality •
DISCOVER NEW BOOKS
Hyponatremia Hyponatremia withNORMAL with NORMALosmolality osmolality •
Artifact in serum Na measurement measurement
•
Hyperlipidemia
•
Hyperproteinemia (multiple myeloma)
•
“Pseudohyponatremia”
READ EVERYWHERE Plasma Osmolality •
BUILD YOUR DIGITAL READING LISTS
1st step in evaluation of hyponatremia hyponatremia unknown cause Plasma Osmolality
Low
Normal Lipids Protein
High Glucose Mannitol
Further Workup
Urinary Osmolarity •
•
•
•
Urinary Sodium
Concentrations Concentrations of all osmoles in urine (Na, K , Cl, Urea)
•
Varies with water ingestion and urinary concentration Low Uosm = dilute urine (lots of free water in urine) High Uosm = concentrated urine (little free water)
•
•
•
Usually > 20meq/L Varies with dietary sodium and free water in urine Usually high when urine osmolarity is high Key exception: • Sympathetic nervous system (SNS) • Renin-angiotensin-aldosterone Renin-angiotensin-aldosterone system (RAAS) • Activation low urinary sodium with ↑Usom • Hemorrhage, heart failure, cirrhosis
72
Antidiuretic Hormone
Antidiuretic Hormone
ADH; Vasopressin
ADH; Vasopressin
•
•
•
Osmolality sensed by hypothalamus hypothalamus ADH released by posterior pituitary gland
•
Responds to water intake to maintain sodium levels Excess Water
Restricted Water
↓ Osmolality
↑ Osmolality
↓ ADH
↑ ADH
↓ Water Resorption
↑ Water Resorption
↑ Water Excretion
↓Water Excretion
↓ Uosm
↑ Uosm
ADH free water resorption by kidneys
Read Free For 30 Days
Antidiuretic Hormone
DISCOVER NEW BOOKS
ADH; Vasopressin •
•
•
•
Hyponatremia READ EVERYWHERE
Any cause of high ADH can cause hyponatremia Sodium no longer controlled by ADH (always high)
•
Plasma free water varies with intake Increased intake hyponatremia
Urine should be diluted •
More free water than solutes
•
Low urine osmolality osmolality (<100mosm/kg)
•
Low urinary sodium (<30meq/L)
Hyponatremia
Hyponatremia
General Points
Causes
•
•
1. Heart failure and Cirrhosis 2. Kidneys ineffective 3. High ADH 4. Psychogenic polydipsia/Dietary
If urine is diluted •
Kidneys responding appropriately appropriately
•
ADH level is low (as it should should be)
•
Problem is outside the kidneys
If urine is not diluted •
Kidneys are NOT responding appropriately appropriately
•
Too much ADH
•
Or drugs/pathology drugs/pathology interfering with kidney function
BUILD YOUR DIGITAL READING LISTS
General Points
73
Heart failure failure and Cirrhosis Cirrhosis •
Perceivedhypovolemia ADH levels high
•
Urine not diluted (Uosm > 100)
•
Kidneys ineffective •
Clinical signs of hypervolemia
•
Kidneys ineffective •
•
DISCOVER NEW BOOKS
Advancedrenal Advancedrenal failure •
Kidneys cannot excrete free water normally
•
Urine cannot be diluted
•
Minimum Uosm rises even with low ADH
•
Normal <100
•
Greater than 200 to 250mosmol/kg 250mosmol/kg with renal failure
•
Key point: ↑ Uosm indicates abnormal response to ↓Na
Read Free For 30 Days
May occur with euvolemia or hypervolemia
READ EVERYWHERE Diuretics
BUILD YOUR DIGITAL READING LISTS
Diuretics •
Cause sodium and water water loss
•
Most commonly thiazides
•
Can occur with loop diuretics
Cortex
Highlyvariableurinary findings •
↑ sodium and water excretion
•
Dehydration ↑ ADH
•
Water/Na in urine vary by dose, dietary dietary intake
•
Key test: Response to discontinuation discontinuation of drugs
Outer Medulla
Inner Medulla
Diuretics •
•
300mOsm
High ADH
Loopdiuretics
•
Any cause of dehydration ↑ ADH
•
Medullary gradients diminished
•
Vomiting, diarrhea
•
Difficult to reabsorb free water (loops = powerfuldiuretic)
•
Sweat
•
Low likelihood of excess water
hyponatremia
•
Thiazidediuretics •
•
Medullary gradients intact
•
Intact ability to absorb free water
•
More sodium out in urine urine (diuretic effect)
•
Higher likelihood of excess water
hyponatremia
74
Sodium level varies with water intake Free water intake hyponatremia
600mOsm
1200mOsm
SIADH
High ADH •
Adrenal insufficiency •
•
•
Syndrome of Inappropriate Antidiuretic Hormone Secretion •
Cortisol normally suppresses ADH release
•
Loss of cortisol (primary/secondary)
•
Loss of aldosterone aldosterone (pr imary)
•
↑ ADH
•
loss of salt/water ↑ ADH
•
Hypothyroidism SIADH
SIADH
•
•
•
•
DISCOVER NEW BOOKS
Druginduced (carbamazepine, (carbamazepine, cyclophosphamide) cyclophosphamide) Paraneoplastic Paraneoplastic (small cell lung cancer)
•
•
CNS Pulmonarydisease
•
•
SIADH
•
•
Hypotonic hyponatremia hyponatremia (↓Posm ↓Na) Normal liver, liver, r enal, cardiac function function
•
Clinical euvolemia
•
Normal thyroid, adrenal function
•
Urine osmolality > 100 mOsm/kg
30 Days
Heart failure
•
Cirrhosis
•
Dehydration
•
Thyroid/adrenal disease
Fluid retention due to ADH Body responds with ↓RAAS
↓ aldosterone ↑Na in urine (worsens hyponatremia) ↓ aldosterone ↓ water resorption by kidneys Result:normal Result: normal volume status
SIADH
DiagnosticCriteria •
Read Free No other cause for high For ADH
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Volume Status SIADH
•
•
High urinary Na (>40meq/L) High urinary osmolality (>100 mOsm/kg) •
Causes •
Too much ADH released (inappropriate) Causes hyponatremia
•
Common treatment: fluid restriction Specialtreatmentoption: •
Demeclocycline
•
Tetracycline antibiotic
•
ADH antagonist
Demeclocycline
75
Psychogenic Polydipsia
Special Diets
•
Need to drink >18L/day to get hyponatremia
•
Tea and toast
•
Occurs in psychiatric patients (compulsive)
•
Beer drinkers (“beerpotomania”) (“beer potomania”)
•
•
•
Hyponatremia Lowurine osmolality(<100mosm/kg) osmolality(<100mosm/kg) •
Indicates kidneys working
•
Kidneys trying to eliminate free water
•
•
•
•
Water restriction resolves hyponatremia
•
DISCOVER NEW BOOKS
Special Diets •
•
Salt consumed must equal salt excreted Imagine highest water to salt ratio is 10:1
•
•
BUILD YOUR DIGITAL READING LISTS
Normal diet •
1000mOsm/day solute
•
Most dilute urine = 50mOsm/L
•
Max free water output = 1000/50 = 20L/day
Special diet •
250mOsm/day solute
•
Most dilute urine = 50mOsm/L
•
Max free water output = 250/50 250/50 = 5L/day
•
Water intake >5L/day
hyponatremia
Restricted Diet 1 salt 10 water
Special Diets •
Result: hyponatremia
READ Diets EVERYWHERE Special
•
Normal Diet 3 salt 30 water
Very little sodium ingestion Minimum urine osmolality ~60 mosmol/kg Forlimit 30 free Days MinimalRead sodiumFree intake may water excretion Free water intake > output
Hyponatremia
Low urine osmolality(<100mosm/kg) osmolality (<100mosm/kg) •
Indicates kidneys working
•
Kidneys trying to eliminate free water
Free water excretion limited by solute availability
Hypervolemic Cirrhosis CHF
Euvolemic SIADH Hypothyroid
Renal failure
2° Adrenal Disease Disease Renal failure Polydipsia Dietary
76
Hypovolemic Dehydration Diuretics 1°AdrenalDisease
Euvolemic Hyponatremia
Hypovolemic Hyponatremia Hypovolemic
Measure Uosm
Measure UNa
Dehydration Diuretics 1°Adrenal Disease
Read Free For 30 Days Uosm <100 Psychogenic Polydipsia Diet (tea, beer)
↑ ADH and ↑ Uosm
Uosm > 100 SIADH Hypothyroidism Renal Failure
UNa <30 mEq/L Extra-renalcause Vomiting Diarrhea Sweating
DISCOVER NEW BOOKS
Hypervolemic Euvolemic Hypovolemic Cirrhosis SIADH Dehydration CHF Hypothyroid Diuretics Renal failure 2° Adrenal Disease 1°Adrenal Disease
READand EVERYWHERE ADH ↓ ↓ Uosm Hypervolemic Cirrhosis CHF Renal failure
Renal failure Polydipsia Dietary
Euvolemic SIADH Hypothyroid
Renal failure
2° Adrenal Disease Disease
(aldosterone)
BUILD YOUR DIGITAL READING LISTS Hypovolemic Dehydration Diuretics 1°AdrenalDisease
Renal failure Polydipsia Dietary
Hyponatremia
↓ ADH and ↑ Uosm Hypervolemic Cirrhosis CHF
Euvolemic SIADH Hypothyroid 2° Adrenal Disease Disease
UNa > 30 Renal Cause Diuretics 1°AdrenalDisease
Treatment Hypovolemic
•
Dehydration Diuretics 1°AdrenalDisease
•
•
Renal failure Polydipsia Dietary
77
Fluid restriction 3% saline Vaptan drugs (tolvaptan, lixivaptan, and conivaptan) •
Block ADH
•
Main use is in severe hyponatremia hyponatremia of heart failure
Central Pontine Myelinolysis
Hypernatremia
“Osmotic demyelination syndrome”
Symptoms
•
Associated with overly rapid correction ↓Na •
•
•
•
•
Demyelination of central pontine axons Lesion at base of pons Loss of corticospinal and corticobulbar tracts
•
Quadriplegia
•
Can be similar to locked-in syndrome
Hypernatremia
Read Free For 30 Days
DISCOVER NEW BOOKS
Causes 1. Water loss •
Skin and lungs (more H2O than Na)
•
ADH will be high
•
Uosm will high
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Acquired DiabetesInsipidus •
•
•
•
Drugs •
Lithium Amphotericin B
Loss of ADH activity
•
Central: trauma, tumors
•
Congenital nephrogenic (rare)
•
Acquired (nephrogenic): Many causes
Diabetes Insipidus
Diagnosis Diabetes Insipidus
Symptoms
•
Hypercalcemia Hypokalemia •
2. Diabetesinsipidus
•
Irritabilit y, stupor, stupor, coma
Usually >10meq per 24 hours
Polyuriaandpolydipsia Similar to diabetes mellitus via different mechanism
•
Suspected with polyuria and polydipsia
•
Often normal [Na]
•
78
•
Water loss stimulates thirst
•
Hypernatremia occurs if not enoughwater
•
Central lesion (central (central DI) can impair thirst
Urine osmolality low (50-200mOsm/kg)
Diagnosis Diabetes Insipidus
Hypernatremia
Diagnosis
Treatment
•
•
Fluid restriction •
After 8 hours of no fluid, urine should be concentrated
•
If urine is dilute absent/ineffective ADH
•
Water (ideally PO)
•
IV Fluids (D5W)
Administration Administrationof vasopressinor desmopressin •
Should concentrate urine if kidneys work
•
If no concentration
•
If concentration
central DI
Read Free For 30 Days
nephrogenic DI
DISCOVER NEW BOOKS Diabetes READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Diabetes Insipidus Treatments InsipidusTreatments •
Central DI:Desmopressin DI: Desmopressin •
ADH analog
•
No vasopressor effect effect (contrast with vasopressin)
•
•
•
Nephrogenic DI: Thiazides and NSAIDs Thiazides •
Increase in proximal Na/H2O reabsorption reabsorption
•
Less H2O delivery to collecting tubules
•
Paradoxical antidiuretic effect
NSAIDs •
79
Inhibit renal synthesis of prostaglandins (ADH antagonists)
Glomerulus Functions •
Allow “ultrafiltrate” into Bowman’s space •
•
Glomerular Disease Principles
•
•
Water, Water, electrolytes, glucose, amino acids
Prevent filtration of most proteins Prevent filtration of red blood cells Read Free For 30 Days Glomerular pathology •
Proteinuria
•
Hematuria
Jason Ryan, MD, MPH
DISCOVER NEW BOOKS Capillary READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Glomerular Filtration Barrier Endothelium •
•
Capillary Endothelium
•
•
Fenestrated (i.e. has openings) Only small (~40nm) molecules pass through Repels red cells, white cells, platelets First barrier to filtration
Capillary Basement Membrane Podocytes (epithelium)
Bowman’s Space
Basement Membrane
Podocytes
Negativelychargedproteins
•
•
•
•
Type IV collagen
•
Heparan sulfate
•
Repels (-) molecules like albumin Also size barrier
•
•
•
•
•
Only small (~4nm) molecules pass pass through
80
Also called epithelial cells Long “processes” called “foot processes” “foot processes” Wrapcapillaries Slits between foot processes filter blood Further size barrier small (~4nm) molecules
Albumin
Glomerular Diseases
•
Small(~3.6nm)
•
Breakdown of components of filtration barrier
•
Can fit through all size barriers
•
Things in urine that shouldn’t be be there:
•
•
Negatively charged Repelled by GBM charge barrier
•
•
•
Urinalysis Dipstick: tests for the presence of heme
•
Heme has peroxidase activity
•
Heme positive: hemoglobin or myoglobin
•
•
reacts with strip
•
•
Microscopy: red cells visualized
•
•
Glomerular Bleeding •
•
•
•
•
Protein (especially albumin)
READ EVERYWHERE Hematuria
•
•
Red blood cells
•
Read Free For 30 Days
DISCOVER NEW BOOKS
Hematuria
•
BUILD YOUR DIGITAL READING LISTS
Many, many causes Gross: abnormal color to urine from blood Microscopic:Incidentalfindingonurinalysis Can occur after exercise Common causes: •
UTI
•
Kidney stones
Feared cause: bladder cancer Glomerular disease is rare cause
Proteinuria
Red cell casts
•
Dysmorphic red blood cells Acanthocytes Proteinuria Red, smoky brown or ““coca cola”” Clots generally not seen
81
Urinedipstick •
Color change indicates amount of protein
•
Primarily detects albumin (good for glomerular disease!) disease!)
•
1+, 2+, 3+, 4+ 4+
•
Affected by urine concentration
Proteinuria •
Proteinuria
Urine protein-to-creatinine protein-to-creatinineratio
•
24-hour urine collection
•
“Spot urine” “Spot urine”
•
Gold standard for protein evaluation
•
1st or 2nd morning urine sample after avoiding exercise
•
Gives you grams/day or protein excretion
•
Normal ratio less than 0.2 mg/mg
•
Normal is less than 150 mg/day
•
Cumbersome for patients
•
Errors in collection common common
DISCOVER NEW BOOKS
Glomerular Diseases
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Nephrotic Syndrome •
Spectrum
•
•
Nephritic Syndrome RBC casts Mild proteinuria Renal Failure
Nephrotic Syndrome Massive proteinuria Hyperlipidemia •
Nephrotic Syndrome ↓ immunoglobulins immunoglobulins
•
↓protein
↓albumin
Proteinuria Frothy urine
•
↓ ATIII •
↓ ECV ↓GFR
↓ plasma oncotic pressure
↑liver activity
Thrombosis
RAAS
Na/H2O Retention
Edema
Hyperlipidemia
Filtration barrier to protein is lost RBC filtration barrier remains intact Massive proteinuria •
4+ on dipstick
•
>3.5g/day
Triggers cascade of pathology
Urine in Nephrotic Syndrome
•
Infection
Read Free For 30 Days
Fatty casts Oval fat bodies
82
Urinary lipid may be present Trapped in casts (fatty casts) Enclosed by plasma membrane of degenerative epithelial cells (oval fat bodies) Under polarized light fat droplets have appearance of Maltesecross
Nephrotic Syndrome •
Nephritic Syndrome
Classicpresentation •
Frothy urine
•
Swelling of ankles
•
Swelling around eyes (periorbital)
Inflammatory process damages entire glomeruli
•
Filtration barrier to RBCs and protein lost
•
•
Often mistaken for allergic reaction
•
Serum total cholesterol >300mg/dl
•
•
•
Proteinuria (>3.5g/day) •
Nephritic Syndrome Dysmorphic RBCs RBC Casts
↓filtration barrier
DISCOVER NEW BOOKS
↑BUN/Cr
Dysmorphic
•
RBC Casts
Protein in urine •
Less than nephrotic syndrome due to lower GFR
•
<3.5g/day
Classicpresentation •
↓GFR
↑Hydrostatic pressure
Hypertension
Oliguria
Edema
83
Read Free For 30 Days
•
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Nephritic Syndrome •
Proteinuria
Glomerular damage: ↓GFR RBC in urine
Dark urine (RBCs)
•
Swelling
•
Fatigue (uremia)
•
Proteinuria (<3.5g/day)
Nephritic Syndrome
Read Free For 30 Days
Nephritic Syndrome Jason Ryan, MD, MPH
Nephritic Syndrome •
DISCOVER NEW BOOKS
Sites of Glomerular Injury
Classicpresentation •
Dark urine (RBCs)
•
Swelling/edema
•
Fatigue (uremia)
•
Proteinuria (<3.5g/day)
Nephritic/Nephrotic READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS •
Major determinant of whether a disease process leads to nephritic or nephrotic syndrome is the site of glomerular injury
Nephritic/Nephrotic
Nephritic Syndrome
Sites of Glomerular Injury
Major Causes
•
Podocyte injury protein loss only nephrotic
•
Endothelial Endothelial and mesangial cells
•
•
Exposed to blood elements elements
•
Injury lead to inflammation (nephritis)
•
Loss of red blood cells and protein in urine
1. Post-streptococcal 2. Berger’s (IgA)nephropathy 3. Diffuse proliferative glomerulonephritis 4. Rapidlyprogressiveglomerulonephritis(RPGN) 5. Alportsyndrome 6. Membranoproliferative
Most causes of nephritic syndrome related to endothelial/mesangial injury with influx of inflammatory inflammatory cells
84
glomerulonephritis
Post-streptococcal Post-streptococcal GN •
•
Post-streptococcal Post-streptococcal GN
Followsgroup Follows group A β-hemolytic strep infection
•
Impetigo (skin)
•
Circulating antigen-antibodies complexes
•
Pharyngitis
•
In situ formation in kidney
Nephritogenicstrains •
•
Carry specific subtypes of M protein virulence factor
•
•
Post-streptococcal Post-streptococcal GN •
•
Immune complexes deposit in kidney
•
DISCOVER NEW BOOKS
Common in children (can also occur in adults) Classic case •
Fix complement AttractPMNs Read Free
For 30 Days
Hypocomplementemia (also lupus, MPGN)
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Post-streptococcal Post-streptoco ccalGN •
Glomeruli:Enlarged,hypercellular
Child
•
2-3 weeks following strep throat throat infection
•
Nephritic syndrome
Post-streptococcal Post-streptococcal GN •
Subendothelial antibodies/complexes
•
Granular IF (IgG, C3) C3)
Post-streptococcal Post-streptococcal GN •
Electron microscopy: Subepithelial “humps” •
85
Immune complexes
Post-streptococcal Post-streptococcal GN •
Good prognosis in children •
•
Post-streptococcal Post-streptococcal GN
95% recover completely
Many develop renal insufficiency
•
Can be late: 10 to 40 years after initial illness
Spontaneous resolution
•
Can develop RPGN
Read Free For 30 Days
DISCOVER NEW BOOKS
Berger’s Disease
•
•
About 60% recover
•
IgA Nephropathy •
No specific therapy (supportive)
Adults have worse prognosis •
•
•
IgA Nephropathy READ EVERYWHERE
Most common form glomerulonephritis worldwide Repeated episodes of hematuria (nephritic)
•
•
Over time leads to ESRD and HD (50% patients) •
•
•
Overactiveimmunesystem ↑IgA synthesis in response to triggers •
Respiratory infection
•
GI infection
IgA immune complexes mesangium Activate complement •
Alternative and lectin pathways
•
No hypocomplementemia
Glomerular injury occurs
IgA Nephropathy
IgA Nephropathy
Berger’s Disease
Berger’s Disease
•
•
BUILD YOUR DIGITAL READING LISTS
Berger’s Disease
Granular IF Stained for IgA
•
•
Classic case •
Recurrent episodes hematuria hematuria since childhood
•
Episodes follow URI or diarrheal diarrheal illness illness
•
Slowly worsening renal function (BUN/Cr) over time
•
Possible progression to ESRD and HD (20yrs+)
confuse with other glomerular disorders Don’t confuse •
86
Post-strep GN: weeks after infection
•
IgA GN: days after infection
•
Minimal change: nephrotic nephrotic syndrome after URI
DPGN
Henoch-Schonlein Purpura •
IgAnephropathywith extra-renalinvolvement
•
Most common childhood systemicvasculitis
•
•
•
•
•
Diffuse proliferative glomerulonephritis glomerulonephritis •
Skin: palpable purpura on buttocks/legs buttocks/legs GI: abdominal pain, melena Joint pains Diffuse IgA deposition
•
Systemic lupus erythematosus (SLE) •
Most common subtype of SLE renal disease
•
“Type IV Lupus Nephritis”
•
Often presents with other SLE features: fever, fever, rash, arthritis
Immune complex deposition in glomeruli Read Free For 30 Days •
IC inflammatory response
Tissue biopsy: demonstrates IgA
DISCOVER NEW BOOKS
DPGN READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Diffuse proliferative glomerulonephritis glomerulonephritis •
•
Diffuse: More than 50% glomeruli affected affected Proliferative: •
Increase in cellularity cellularity of glomeruli
•
Mesangial cells
•
Endothelial cells
•
Monocyte/neutrophil Monocyte/neutrophil infiltration
DPGN
DPGN
Diffuse proliferative glomerulonephritis glomerulonephritis
Diffuse proliferative glomerulonephritis
•
•
Subendothelial deposits drive immune response •
Anti-dsDNA
•
Hypocomplementemia Hypocomplementemia (also post-strep, MPGN)
GranularIF
•
immunofluorescence “Full house” immunofluorescence •
Classic finding: capillary loops thickened •
•
“Wire looping”
87
IgG, IgA, IgM, C3, C1q
DPGN
RPGN
Diffuse proliferative glomerulonephritis
Rapidly progressive glomerulonephritis glomerulonephritis
•
Mixedclinicalpresentation •
•
•
Proteinuria (sometimes nephrotic)
•
Hematuria
•
Reduced GFR
•
•
DISCOVER NEW BOOKS
Rapidly progressive glomerulonephritis glomerulonephritis •
Monocytes/macrophages
•
Fibrin
RPGN READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Rapidly progressive glomerulonephritis glomerulonephritis
Crescents formed byinflammation by inflammation:: •
Many diseases lead to this this condition
Read Free For 30 Days
Severe, often leads to ESRD and HD
RPGN
Also called “crescentic”glomerulonephritis glomerulonephritis Pathologicdescription:Manycauses
•
•
•
•
•
Severe form of glomerulonephritis Progressive loss of renal function Rapid onset Often presents as acute renal failure Generalizedsymptoms:fatigue,anorexia
RPGN
RPGN
Rapidly progressive glomerulonephritis glomerulonephritis
Rapidly progressive glomerulonephritis glomerulonephritis •
•
•
•
88
Causes distinguished based on immunofluorescence Type I: Linear IF IF Type II: Granular IF Type III: Negative IF
Goodpasture’s Syndrome
RPGN Type I •
Anti-glomerular basement membrane antibodies •
•
•
“Anti-GBM antibodies”
•
Unknown stimulus
Antibodies to alpha-3 chain of type IV collagen
•
Type II hypersensitivity
•
•
•
Linear IF •
IgG antibodies
•
Linear pattern
DISCOVER NEW BOOKS
•
Type III hypersensitivity
Granular IF
•
•
•
Hemoptysis
•
Hematuria
Post-streptococcal
BUILD YOUR DIGITAL READING LISTS
glomerulonephritis
•
Can progress to RPGN
•
Most common cause RPGN
Systemic lupus erythematosus (SLE) •
Diffuse proliferative glomerulonephritis
•
Can progress to RPGN
Anti-neutrophil cytoplasmic antibodies antibodies
NegativeIF
•
No staining for IgG, IgA, etc.
•
“Pauci-immune” Most patients ANCA patients ANCApositive positive •
Male
•
ANCA Diseases
RPGN Type III •
Young adult
•
READ EVERYWHERE RPGN Type II
•
•
Found in GBM and alveoli
Hemoptysis and nephritic syndrome Read Free For 30 Days Classic case •
Immunecomplex deposition •
•
Antibody to collagen
•
Antibodies against GBM antigens
RPGN Type II •
•
•
•
c-ANCA or p-ANCA
Most patients have a vasculitis syndrome
89
Wegener's Granulomatosis (c-ANCA) Microscopic Polyangiitis (p-ANCA) Churg-Strauss Churg-Strauss syndrome(p-ANCA) All can lead to pauci-immune nephritis
RPGN
Alport Syndrome
Rapidly progressive glomerulonephritis glomerulonephritis
Hereditary Nephritis •
•
•
Genetic type IV collagen defect •
Mutations in alpha-3, alpha-4, or alpha-5 chains
•
Chains found in basement basement membranes kidney, kidney, eye, ear
Inherited: X-linked Classic triad: Read •
•
DISCOVER NEW BOOKS
90
Hematuria
Free For 30 Days
•
Hearing loss
•
Ocular disturbances
Look for child with triad and family history
READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Nephrotic Syndrome
Read Free For 30 Days
Nephrotic Syndrome Jason Ryan, MD, MPH
Nephrotic Syndrome •
DISCOVER NEW BOOKS
Sites of Glomerular Injury
Classicpresentation •
Frothy urine
•
Swelling of ankles
•
Swelling around eyes (periorbital)
•
Serum total cholesterol >300mg/dl
•
Proteinuria (>3.5g/day)
Nephritic/Nephrotic READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS •
•
Major determinant of whether a disease process leads to nephritic or nephrotic syndrome is the site of glomerular injury Podocytes •
•
Glomerular Filtration Barrier
Separated from blood by GBM
•
Injury does not lead to inflammation
•
Damage loss of filtration barrier to to protein only
Most causes of nephrotic syndrome related to injury of podocytes or epithelial side of GBM
Nephrotic Syndrome Causes 1. Minimal change disease 2. Focalsegmental glomerulosclerosis glomerulosclerosis(FSGS) 3. Membranous nephropathy 4. Diabetic 5. Amyloidosis 6. Membranoproliferative
91
glomerulonephritis
Minimal Change Disease
Minimal Change Disease
Pathology •
•
•
•
•
Caused by effacement of foot processes Loss of anion (-) charge barrier GBM Triggered by cytokines damage to podocytes Usually idiopathic
Read For 30 Days Associated with Free Hodgkin Lymphoma
Effacement (flattening) Foot Processes
Minimal Change Disease
DISCOVER NEW BOOKS
Renal Biopsy •
•
•
Minimal Change Disease READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Other Features
Normal light microscopy No important findings IF
•
Sometimes has immunological trigger (days before) •
Only finding is effacement foot processes EM •
•
Viral infection (URI)
•
Allergic reaction (bee sting)
•
Recent immunization
“Selective”
proteinuria
•
Only albumin in urine (not immunoglobulin)
•
Contrast with other glomerular disease “non-selective”
Most common cause nephrotic syndrome in children •
Classic presentation is a child with recent URI
Minimal Change Disease
FSGS
Prognosis and Treatment
Focal segmental glomerulosclerosis
•
•
Favorable prognosis Responds very well tosteroids to steroids •
•
Glomerulosclerosis
•
Segmental
•
Focal
•
Unique among nephrotic syndrome causes
•
•
92
Pink/dense deposition of collagen in glomerulus Only potion of glomerulus involved Only some glomeruli involved
FSGS
FSGS
Pathology
Renal Biopsy
•
•
Scleroticsegments •
Collapse of basement membranes
•
Hyaline deposition (“hyalinosis”)
•
•
•
Effacement of foot processes •
Seen on electron microscopy
FSGS
DISCOVER NEW BOOKS
•
•
Immunofluorescence •
Usually negative (no immune complexes)
•
Sometimes IgM, C3, C1 (nonspecific (nonspecific finding)
Read Free For 30 Days
FSGS READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Epidemiology
Focal segmental glomerulosclerosis glomerulosclerosis •
Light microscopy: focal, segmental lesions Electron microscopy: effacement of foot processes
Caused by podocyte injury Unknown cause
•
African Americans •
Most common cause nephrotic syndrome
Often progresses to chronic renal failure •
40-60% within 10 to 20 years
•
Does not respond to steroids
•
Severe version of minimal changedisease
Nephrotic Syndrome Causes Causes
FSGS
FSGS
Focal segmental glomerulosclerosis glomerulosclerosis
Focal segmental glomerulosclerosis
•
•
Usually idiopathic(primary) (primary) Many secondary causes
•
•
•
93
HIV Sickle cell patients Heroin users
FSGS
Membranous Nephropathy
Other Associations •
•
•
Massiveobesity Interferon treatment •
Used to treat HCV and and HBV
•
Some leukemias and lymphomas, lymphomas, melanoma
Thick glomerular basement membrane
•
Absence of hypercellularity
•
“Membranous”
Read Free For 30 Days
Loss of nephrons •
Single kidney (congenital)
•
Surgical kidney removal
Membranous Nephropathy •
•
DISCOVER NEW BOOKS
Subepithelial Subepithelial Immune Complex Deposition “granular”
Membrane thick fromimmune from immune complex deposition •
IF microscopy very useful useful
•
“Granular” deposits of IgG and C3 staining
Membranous Nephropathy READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Pathophysiology
Basement Membrane Deposition “Spike and Dome”
Membranous Nephropathy
Membranous Nephropathy
Renal Biopsy •
•
•
Lightmicroscopy: capillary/BMthickening Electronmicroscopy:subepithelialdeposits
•
•
Immunofluorescence: granular IgG/C3
•
•
94
Often idiopathic Autoantibodies Autoantibodies Antigen:phospholipase Antigen:phospholipase A2 receptor (PLA2R) Expressedon podocytes
Membranous Nephropathy
Membranous Nephropathy
Secondary Causes
Secondary Causes
•
•
•
•
Systemic lupus erythematosus (SLE) Most lupus renal disease in nephritic
•
Solidtumors
•
Infections
•
Drugs
•
Diffuse proliferative glomerulonephritis If nephrotic, this is cause (10-15%)
•
Colon cancer, lung cancer, cancer, melanoma Hep B, Hep C
Read Free For 30 Days
•
Penicillamine, gold, NSAIDs
•
All used to treat rheumatoid arthritis
Tumor Hepatitis Rheumatoid Arthritis
Membranous Nephropathy
DISCOVER NEW BOOKS
Other Features •
•
•
Most common cause nephrotic syndrome in adults
READ EVERYWHERE Autoantibodies •
Excellent prognosis in children Some adults develop ESRD
•
•
•
BUILD YOUR DIGITAL READING LISTS
Most antibody disorders are nephritic IC inflammation nephritis nephriticsyndrome Membranousisnephrotic Subepithelialdeposits nephroticsyndrome
Nephrotic Syndrome Causes Causes
Diabetic Nephropathy •
•
•
•
•
Amyloidosis
Non-enzymatic glycosylation Basement membranes: leakage of protein Long term effect: sclerosis of glomerulus Proteinuria
•
Extracellular buildup of amyloid proteins
•
Classic biopsy findings
•
Can develop nephrotic syndrome
95
•
Apple-green Apple-green birefringence
•
Congo red stain
Kidney is most comm only involved organ
MPGN Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis •
•
•
•
•
MPGN
•
Rareglomerulardisorders Can cause nephritic or nephrotic syndrome Varying degrees of renal dysfunction Renal failure (↑BUN/Cr)
Read Free For 30 Days Hematuria Proteinuria (+/- nephrotic range)
Jason Ryan, MD, MPH
MPGN
DISCOVER NEW BOOKS
Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis •
Membrano •
•
•
Thick basement membrane
•
Proliferative •
MPGN READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis
•
Two major types Type I much more common Type II (dense deposit disease) rare
Proliferation of mesangial cells, mesangial mesangial matrix
MPGN Type I
MPGN Type I
IC deposits trigger mesangial ingrowth Splits basement membrane “Tramtrack” “Tram track” appearance on light microscopy Common (80%) in Type I
Type I complex deposition Subendothelialimmune complexdeposition IgG complement activation
96
MPGN Type I •
•
MPGN Type I
Subendothelial antibodies/complexes Granular IF for IgG and C3
•
May be idiopathic
•
Associated with hepatitis B and C infection
Read Free For 30 Days
MPGN Type II
DISCOVER NEW BOOKS
Dense Deposit Disease
C3Nephritic Factor READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
C3 Covertase Stabilizing Antibody •
•
•
•
•
Found in >80% patients with MPGN II C3convertaseactivatesalternative activates alternative pathway Stabilized by C3 nephritic factor Over activation of complement system Hypocomplementemia(↓C3)
Type II Basement Membrane “Electron dense” deposits Mediated by complement IgG usually absent
MPGN Type II
MPGN
Dense Deposit Disease
Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis
•
•
•
Mostly a disease of children Usually 5 to 15 years old 50% develop ESRD within ten years
97
Acute Renal Injury
Tubulointerstitial Disorders
•
Acute fall in GFR GFR
•
Rise in serum BUN and Creatinine
•
•
Common problem in hospitalized hospitalized patients Read Free For 30 Days Two major causes: •
Poor renal perfusion
•
Acute tubular necrosis
Jason Ryan, MD, MPH
Acute Tubular Necrosis •
DISCOVER NEW BOOKS
Sudden damage to tubular epithelial cells •
Ischemia (ANY cause severe ↓ blood flow)
•
Drugs
•
Toxins
READ EVERYWHERE Ischemic ATN
BUILD YOUR DIGITAL READING LISTS
•
Ischemia vasoconstriction ↓ GFR
•
Loss of tubular cell polarity
•
•
•
Na-K-ATPase moves to luminal side More sodium in urine Macula densa vasoconstriction Interstitium/Blood
Lumen (Urine)
Na+
Tubular Epithelial Cell
Ischemic Causes •
•
•
•
ATP
Toxin/Drug Causes
Hypovolemia
•
Cardiogenic shock Massive bleeding Any cause of decreased pe rfusion
•
•
•
•
•
•
98
Aminoglycosides Contrast dye Uric acid (tumor lysis syndrome) Myoglobin (rhabdomyolysis) Lead Cisplatin Ethyleneglycol(antifreeze)
K
Acute Tubular Necrosis
Acute Tubular Necrosis
Pathology
•
Tubular epithelial cells die, slough off into urine
•
•
Obstructs urine flow intrinsic intrinsic renal failure
•
•
•
↓ GFR
•
↑ BUN and Cr
•
•
Epithelial cells form casts in tubules •
Granular casts
•
“Muddy brown”
•
Patchy, focal necrosis of nephron Large skip areas of normal nephron Occlusion of tubular lumen by casts Ischemicinjury Proximal tubule
•
Thick ascending limb
Toxic injury •
Acute Tubular Necrosis
DISCOVER NEW BOOKS
Read Free For 30 Days
•
Proximal tubule
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Acute Tubular Necrosis
Cortex
Cortex
Inner Medulla
Ischemic ATN Proximal Tubule Medullary TAL
Inner Medulla
Toxic ATN Proximal Tubule Outer Medulla
Outer Medulla
ATN Phases •
Phase 1: Injury occurs occurs •
•
•
Prognosis
Slight decline urine output output
•
Typical course is kidney recovery
•
Tubular cells capable of regeneration
•
Some patients require temporary dialysis
Phase 2: Maintenance •
Oliguria
•
Rising BUN/Cr
•
Hyperkalemia
•
AG metabolic acidosis
•
May last weeks
•
Phase 3: Recovery •
Polyuria
•
Risk of hypokalemia
99
“Tubular re-epithelialization”
Acute Interstitial Nephritis
Acute Interstitial Nephritis
Tubulointerstitial Tubulointerstitial Nephritis
Tubulointerstitial Tubulointerstitial Nephritis
•
Inflammation of renal tubules and “interstitium” •
•
•
•
•
Hypersensitivity(allergic)reaction •
•
•
Space between cells cells
•
Read Free For 30 Days
Usually triggered by drugs Sometimes infections or autoimmune autoimmune disease Usually resolves with stopping offending agent
Acute Interstitial Nephritis
•
DISCOVER NEW BOOKS
Acute Interstitial READ EVERYWHERE Nephritis BUILD YOUR DIGITAL READING LISTS Tubulointerstitial Tubulointerstitial Nephritis
Drugs – 75% of cases
•
Infection – 5-10% of cases
•
Sulfonamides (TMP-SMX)
•
Multiple organisms reported reported
•
Rifampin
•
Legionella, Leptospira, CMV, TB
•
Penicillin
•
Diuretics (furosemide, bumetanide, thiazides)
•
NSAIDs
•
Drugs often act as haptens •
Haptens = illicit immune response when bound
•
Attach to basement membrane/epithelial membrane/epithelial cells
•
Illicit immune response
Acute Interstitial Nephritis Classicfindings: •
Exposure to a trigger
•
Fever, rash, malaise
•
Acute renal failure (↑ BUN/Cr)
•
WBC casts (without (without symptoms of cystitis)
•
“Sterile pyuria”
•
Peripheral eosinophilia
•
Urine eosinophils
Systemic diseases – 5-10% of cases •
Sarcoidosis
•
Sjögren's syndrome
•
SLE
Acute Interstitial Nephritis
Tubulointerstitial Tubulointerstitial Nephritis •
Considered a glomerular disease when occur together together
Mediated by eosinophils and neutrophils
Tubulointerstitial Tubulointerstitial Nephritis •
Main clinical feature is renal failure Absenceof nephritic/nephrotic nephritic/nephroticsyndrome
100
•
Usually resolves with stopping offending agent
•
Rarely progresses topapillary to papillary necrosis
Chronic Interstitial Nephritis •
•
•
•
•
•
Mononuclear cell infiltration Fibrosis and atrophy of tubules Seen with longstanding use of NSAIDs Mild elevation of BUN/Cr Resolves with stoppage of drugs Classic case: •
•
•
•
•
•
Acute interstitial nephritis (fever, renal failure)
•
Chronic interstitial nephritis (renal failure)
•
Acute tubular necrosis
•
Mild increase BUN/Cr
•
Renal function improves improves with stoppage of drug
•
Ischemia
•
Block PG vasodilation of afferent arteriole
DISCOVER NEW BOOKS
Read Free For 30 Days
•
Membranous glomerulonephritis
•
Papillary necrosis
•
Nephrotic syndrome
Papillary Necrosis READ EVERYWHERE
BUILD YOUR DIGITAL READING LISTS
Classic Causes
Coagulative Coagulative necrosis of renal papillae Sloughing of tissue
•
•
Gross hematuria Often painless
•
•
Chronic phenacetin use Diabetes Acute pyelonephritis Sickle cell anemia
In isolation •
No intrinsic renal failure
•
No WBC casts
May obstruct urine flow
Papillary Necrosis •
•
Patient on NSAIDs for chronic pain
Papillary Necrosis •
NSAIDs
Cortical Necrosis
Typical presentation •
Patient with typical trigger
•
Gross hematuria
•
Painless
•
Normal renal function function
•
•
•
101
Caused by ischemia of renal cortex Acute onset severe renal failure Seen in very sick patients •
Septic shock
•
Obstetric catastrophes (abruptio placentae, fetal demise)
•
Acute renal failure
•
Oliguria anuria
Terms •
•
Renal Failure
Acute renal failure •
Decrease in Cr clearance clearance over days
•
Often associated with symptoms
•
Many causes
ChronicRead renal failure (chronic kidney disease) Free For 30 Days •
Slow, steady deterioration of renal function (years)
•
Usually due to diabetes, hypertension
•
Symptoms only in most severe stages
Jason Ryan, MD, MPH
Terms •
Azotemia •
•
DISCOVER NEW BOOKS
•
Insufficient filtering of blood by kidneys
•
Uremia •
READ EVERYWHERE Uremic Symptoms
•
Azotemia + “uremic” symptoms
•
Acute Renal Failure
BUILD YOUR DIGITAL READING LISTS
Anorexia Nausea,vomiting Platelet dysfunction (bleeding) Pericarditis
•
Asterixis
•
Encephalopathy
Key Labs
1. Insufficient blood flow to kidneys (pre-renal)
•
Creatinine
•
Dehydration
•
Similar to inulin
•
Shock
•
Freely filtered
•
Heart failure
•
Small amount of secretion secretion
2. Obstruction of urine outflow (post-renal)
•
Blood urea nitrogen
•
Need bil ateral obstruction obstruction
•
Freely filtered
•
Kidney stones, BPH, tumors, congenital anomalies
•
Reabsorbed when kidney reabsorbs water
3. Renaldysfunction(intrinsic) •
Acute tubular necrosis
•
Glomerulonephritis
102
Key Labs
Real Life Acute Acute Renal Failure
•
In acute renal failure both rise (less filtered)
•
Routine labs on outpatient or inpatient
•
In acute renal failure from dehydration:
•
BUN/Cr elevated
•
Work up:
•
BUN rises more (less filtered, more reabsorbed)
•
Urinalysis (protein, blood, casts)
•
Ultrasound (hydronephrosis)
•
Careful history (meds, co-morbidities, hydration)
•
Physical exam (low blood pressure, dehydration, CHF, CHF, etc) etc)
•
Limited use of blood, urine chemistries
Read Free For 30 Days
DISCOVER NEW BOOKS Renal READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS USMLE Acute Renal Failure Failure Measurements •
Determine cause based on blood, urine testing
•
Urinary sodium (UNa)
•
BUN (rises in ARF) ARF)
sodium and water • Varies based on intake of sodium
•
Cr (rises in ARF)
salt/water • Very low when kidney retaining salt/water
•
BUN/Cr ratio (normal ~20:1)
•
•
•
• <20 mEq/L is very low
UNa FeNa
•
Fractional excretion of Na (FeNa) • Amount of filtered Na that is excreted
Uosm
• Very low when kidney retaining salt/water • <1% is low •
Urinary osmolarity (Uosm) • Measure of concentrating ability of kidney • Very high when kidney retaining water • >550 mOsm/kg is high
Pre-Renal Failure
Pre-Renal Failure
BUN/Cr
Urinary Findings
•
•
•
•
•
•
•
Decreased blood flow to kidneys Less BUN/Cr filtered filtered Rising BUN/Cr in blood More resorption H2O H2O
•
•
•
•
BUN resorbed with H2O BUN rises >> Cr rises Result •
•
•
↑ ↑ BUN
•
↑Cr
•
↑BUN/Cr ratio
103
Lots of H2O resorbed resorbed Concentrated urine ↑Uosm Lots of Na resorbed resorbed
↓Una ↓Fena
Intrinsic Renal Failure
Pre Renal Failure
BUN/Cr •
•
•
•
•
Intrinsic Renal Failure
DISCOVER NEW BOOKS
Urinary Findings •
•
•
•
•
•
•
•
Rising BUN/Cr in blood No extra rise in BUN from ↑resorption
Free NormalRead ratio (20:1)
For 30 Days
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Intrinsic Renal Failure
Urine: kidney cannot resorb water Uosm low (can’t concentrate concentrate urine) UNa high (can’t resorb Na) FeNa high (can’t resorb resorb Na)
Post Renal Failure •
Kidney cannot filter blood Less BUN/Cr filtered filtered
Post Renal Failure
Obstruction to outflow Urine backs up High pressure in tubules Kidney cannot filter blood
•
Diagnosis rarely made by plasma/urinalysis plasma/urinalysis
•
Key features:
•
Kidney’s resorptive mechanisms damaged/destroyed
•
104
•
Anuria
•
Hydronephrosis
Renal ultrasound is test of choice Shows enlarged, dilated kidneys
Post Renal Failure
Post Renal Failure
•
Plasma/urine Plasma/urine findings similar to intrinsic renal
•
Lots of variation in lab values based on tubules
•
High pressure in tubules prevents filtration
•
Early post renal tubular function okay
•
•
•
•
•
Only exception is BUN/Cr ratio BUN may rise like pre-renal
•
•
Late high pressure disrupts tubular resorption Urinechemistriesvariable
Read Free For 30 Days
High pressure in tubules forces BUN out BUN rises more than Cr
↑BUN/Cr ratio similar to pre-renal
DISCOVER NEW BOOKS
Post Renal Failure
READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Pre, Intrinsic, PostProblems •
Diseases often cross boundaries
•
Diuretics obscure urine findings
•
Pre-existing chronic renal disease
•
Fractional Excretion Na •
•
FeNa <1%
•
UNa <20
Intrinsicrenal •
FeNa >1%
•
UNa >40
ATN
Chronic Kidney Disease
Pre-renal •
Pre-renal
•
Slow, steady fall in creatinine clearance •
•
FeNa = PCr * UNa
•
PNa * UCr
105
Blood tests show show ↑BUN/Cr
Eventually progresses to dialysis for many patients Most common causes diabetes and hypertension •
Hypertensive nephrosclerosis
•
Diabetes nephropathy
Stages of Kidney Kidney Disease
Indications for Dialysis
•
Stage 1 GFR >90
•
Acidemia
•
Stage 2 GFR 60-89
•
Electrolytes (hyperkalemia)
•
•
•
Stage 3 GFR 30-59 Stage 4 GFR 15-29 (approaching (approaching dialysis)
•
•
•
•
•
Stage 5 GFR <15 (usually on dialysis)
Dialyzable Substances •
•
•
DISCOVER NEW BOOKS
Salicylates (aspirin) Lithium Isopropyl alcohol Magnesium laxatives
•
•
Vascular Access
Free UremicRead symptoms
For 30 Days
READ EVERYWHERE Dialysis Methods •
Ethyleneglycol
Intoxication(overdosedialyzablesubstance) Overload of fluid (CHF)
BUILD YOUR DIGITAL READING LISTS
Hemodialysis •
Requires vascular access
•
Blood pumped from body
•
Done in “sessions” of few hours at a time
filter
back to body
Peritoneal dialysis •
Fluid cycled through peritoneal peritoneal cavity
•
Peritoneum used as dialysis dialysis membrane
Hemofiltration •
Constant filtering of blood
•
Usually done at bedside bedside for critically ill patients
Complications CKD
•
For acute dialysis, central line can be placed
•
Anemia(loss of EPO)
•
Ideal method is fistula fistula
•
Dyslipidemia
•
Connection between artery and vein
•
Mostly triglycerides
•
Placed surgically, usually in arm
•
Protein loss in urine
•
Lowest rates thrombosis, infection
•
Impaired clearance of chylomicrons chylomicrons and VLDL
stimulation of liver synthesis
•
Fistula must “mature” for use
•
Growth failure in children
•
Ideally placed several months before dialysis
•
Renal osteodystrophy
106
Calcium-Phosphate in Renal Failure
Calcium-Phosphate in Renal Failure
Sick Kidneys
•
Secondary hyperparathyroidism
•
Tertiary hyperparathyroidism
•
↑Phosphate
↓1,25-OH2 Vitamin D
↓Ca from plasma
↓Ca from gut
Parathyroid stimulation in renal failure
•
Parathyroid becomes autonomous autonomous from constant stimulation stimulation
•
VERY high PTH levels
•
Calcium becomes elevated elevated
•
Often requires parathyroidectomy
Read Free For 30 Days
Hypocalcemia
↑PTH
Calcium-Phosphate in Renal Failure •
•
DISCOVER NEW BOOKS
Untreated parathyroidism leads to renal osteodystrophy •
Bone pain (predominant (predominant symptom)
•
Fracture (weak bones 2° chronic chronic high PTH levels)
•
•
•
•
Osteitisfibrosacystica •
Untreated, severe high PTH levels
•
Bone cysts
•
Brown tumors ( osteoclasts w/fibrous tissue)
•
Drugs and Renal Function •
•
•
•
•
•
READ EVERYWHERE Phosphate Binders
Many drugs worsen renal function Decrease GFR Associatedwith ↑BUN/Cr Loop, Thiazide, and K sparing diuretics ACEinhibitors NSAIDs
107
Bind phosphate in GI tract Calcium carbonate Calcium acetate (Phoslo) Sevelamer (Renagel) Lanthanum
BUILD YOUR DIGITAL READING LISTS
Urinary Infections •
•
Urinary Infections
Cystitis •
Infection of bladder bladder
•
“Lower” urinary tract
Pyelonephritis
Read Free For 30 Days
•
Infection of kidneys
•
“Upper” urinary tract
Jason Ryan, MD, MPH
Urinary Infections •
•
DISCOVER NEW BOOKS
Mostinfections “ascend” Urethra Cystitis Pyelonephritis
READ EVERYWHERE Etiology •
Escherichiacoli(75-95%)
•
Proteus mirabilis
•
•
•
Symptoms •
•
Urease producing bacteria
•
Struvite kidney stones
Klebsiella pneumoniae Staphylococcus saprophyticus Enterococcus faecalis
Symptoms
Cystitis
•
Pyelonephritis
•
Dysuria (pain with urination)
•
Systemic symptoms (fever, (fever, chills)
•
Frequency (going a lot)
•
Flank pain
•
Urgency (always feel like you have have to go)
•
CVA tenderness
•
Suprapubic pain
•
Hematuria
•
No systemic symptoms
•
WBC casts
•
Usually normal plasma WBC count
108
BUILD YOUR DIGITAL READING LISTS
Diagnosis •
Urinalysis
•
10x more likely than men to get UTIs
•
Leukocyte esterase
•
Shorter urethra, closer to fecal flora
•
Produced by WBCs in urine
•
Nitrites •
•
90% UTI bugs convert nitrates nitrates to nitrites •
•
saprophyticus Some that don’t: enterococcus, staph saprophyticus
•
Best for detecting aerobic gram-negative gram-negative rods (E. Coli)
•
•
30 Days
>100,000 CFUs
DISCOVER NEW BOOKS
Infants with vesicoureteral reflux
READ EVERYWHERE Treatment •
Ureters insert abnormally into bladder
•
Ciprofloxacin, levofloxacin, ofloxacin
•
Chronic reflux of urine back into ureters
•
Usually 3 day course
Urinary obstruction •
Anatomic abnormalities in children
•
Bladder tumors in adults
•
Enlarged prostate in older males
•
Nitrofurantoin (Macrobid) •
•
BUILD YOUR DIGITAL READING LISTS
Fluoroquinolones
•
Sterile Pyuria
•
UrinaryRead catheterization catheterizat ionFor Free
Diabetes Pregnancy
>10WBC/hpf
Risk Factors
•
Sexual activity
Culture •
•
Women
Cloudy urine
•
•
•
•
•
•
Risk Factors
Used in pregnancy
Trimethoprim-sulfamethoxazole
(TMP-SMX)
Chronic Pyelonephritis
Some women with chlamydia/gonorrhea complain of urinarytractsymptoms
•
•
Urinalysis shows pyuria but no bacterial growth
•
Majority women are asymptomatic with chlamydia or gonorrhea
•
•
•
•
109
Consequence of recurrent pyelonephritis Vesicoureteral reflux in children Recurrent stones in adults Scarring of kidneys Corticomedullary Corticomedullary scarring Blunted calyx “Thyroidizationof kidney” •
Tubules contain eosinophilic material
•
Looks like thyroid tissue on micr oscopy
Cystic Kidney Diseases 1. MulticysticDysplasticKidney 2. Autosomal Recessive Polycystic Kidney Disease
Cystic Kidney Disease
4. Medullary Cystic Kidney Disease
Read Free For 30 Days
Jason Ryan, MD, MPH
DISCOVER NEW BOOKS Multicystic READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Multicystic Dysplastic Kidney Dysplastic Kidney •
•
•
•
•
Abnormal ureteric bud-mesenchyme interaction Kidney replaced with cysts
•
•
No/little functioning renal tissue Absent ureter Often detected in utero by ultrasound
Multicystic Dysplastic Kidney •
Non-inherited
•
Different from other cystic cystic disorders
•
Subsequent pregnancies pregnancies often okay
•
Oligohydramnios
•
Failure of lung maturation
•
Compressed face/limbs
•
Not compatible w ith life
Polycystic Kidney Disease
Spontaneous •
If unilateral remainingkidneyhypertrophies If bilateral Potter’s syndrome
110
•
Autosomalrecessive(infants)
•
Autosomal dominant (young adults)
ARPKD
ADPKD
•
Old name: “juvenile” PKD
•
Occurs in adults
•
Occurs in infants
•
Microscopic Microscopic cysts present at birth
•
•
•
•
Can occur with Potter’s syndrome Renalfailure High blood pressure Key associations: •
Liver disease (fibrosis/cysts)
•
Can cause portal hypertension (ascites)
ADPKD •
•
•
DISCOVER NEW BOOKS
Key associations
Too small to visualize with ultrasound
•
Kidneys appear normal at at birth
Cysts develop many years Readover Free For 30 Days Inherited mutation of APKD1 or APKD2 genes
READ EVERYWHERE ADPKD •
BUILD YOUR DIGITAL READING LISTS
Classicpresentation
•
Berry aneurysm (subarachnoid hemorrhage)
•
•
Liver cysts
•
High blood pressure (↑RAAS system)
•
Mitral valve prolapse
•
Hematuria
•
Renal failure
•
Family history of sudden death (aneurysm)
Medullary Cystic Kidney Disease •
Autosomal dominant
•
Cysts in collecting ducts of medulla
•
•
•
Name is misnomer
•
Most patients DO NOT have cysts
Cystic Kidney Diseases
Kidney fibrosis occurs small, shrunken kidneys •
Contrast with ADPKD (enlarged kidneys) kidneys)
•
Often have early onset (adolescent) gout
•
Renalfailure
Young adult
111
Diuretics Drugs that increase urine output 1. Carbonic Anhydrase Inhibitors 2. OsmoticDiuretics 3. Loop Diuretics 4. ThiazideDiuretics Read Free 5. K+ Sparing Diuretics Diuretics
Diuretics
For 30 Days
Jason Ryan, MD, MPH
Sodium •
•
•
•
DISCOVER NEW BOOKS
Normal plasma [Na] = 140 meq/L [Na] tightlyregulated •
Renin-angiotensin-aldosterone
•
Antidiuretic hormone (ADH) (ADH)
READ EVERYWHERE Potassium •
•
•
•
BUILD YOUR DIGITAL READING LISTS
Secreted bydistal by distal tubule and collecting duct Varies with Na/H2O delivery to distal nephron More urine flow more secretion of potassium Most diuretics lead to hypokalemia
Sodium intake H2O retention [Na] = 140 meq/L Sodium loss H2O excretion [Na] = 140 meq/L
•
Any drug that ↑ Na excretion volume loss
•
Many diuretics work by ↑ Na excretion
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Anhydrase Inhibitors
Carbonic Anhydrase
•
•
Acetazolamide Acetazolamide Weak diuretic effect •
HCO3Na
•
Block some Na resorption
Causes a non-AG metabolicacidosis •
Increased elimi nation of HCO HCO 3-
Acetazolamide
112
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors
Clinical Uses
Clinical Uses
•
•
Severe metabolicalkalosis Glaucoma •
•
Pseudotumorcerebri
•
Prevention of high altitude sickness
•
Blocks formation of aqueous humor humor
Reduced rate of CSF formation
•
Low pO2 at high altitude
•
Low CO2 respiratory alkalosis
hyperventilation
•
Acetazolamide acidosis reverses alkalosis
Read Free For 30 Days
Carbonic Anhydrase Anhydrase Inhibitors Anhydrase Anhydrase DISCOVER NEW BOOKS Carbonic READ EVERYWHERE Inhibitors BUILD YOUR DIGITAL READING LISTS Side Effects •
•
•
Side Effects
Metabolic acidosis
•
Paresthesias (“tingling” in extremities) Sulfaallergy
Cause kidney stones •
Reduce urinary citrate excretion
•
Citrate inhibits calcium stone formation
Citrate (Citric Acid) Acetazolamide
TCA Cycle
Osmotic Diuretics
Acetyl-CoA
•
NADH
•
Oxaloacetate
Citrate
•
•
Malate
•
Isocitrate
•
CO2 NADH α-ketoglutarate
Fumarate FADH2 Succinate GTP
Succinyl-CoA
CO2 NADH
113
Thin descending limb Concentratesurine Absorbs water Impermeable to NaCl Water leaves urine Drawn out by hypertonicity in medulla
H2O H2O H2O H2O H2O
Osmotic Diuretics
Mannitol •
•
•
300mOsm
Cortex
•
•
600mOsm
Outer Medulla
Inner Medulla
•
•
•
Raisesosmolality
Read Free For Reduces water reabsorption Increases urine output
30 Days
1200mOsm
DISCOVER NEW BOOKS
Mannitol •
•
Sugar alcohol Freely filtered by glomerulus No tubular reabsorption reabsorption
Main use is in cerebral edema, glaucoma Goal is to create a HYPERosmolar HYPERosmolar state
READ EVERYWHERE Mannitol •
“Osmotherapy” Draws fluid out (brain, eye)
•
Loop Diuretics
BUILD YOUR DIGITAL READING LISTS
Cannot use in heart failure patients •
Draws fluid out of tissues
•
Expands intravascular volume
•
Can cause pulmonary edema
use with severe renal disease Can’t use •
High doses cause acute anuric renal failure
•
Mannitol can cause renal vasoconstriction
anuria
Loop Diuretics Lumen (Urine)
Interstitium/Blood Na+
300mOsm
Cortex
Na+
ATP
K+
K+
Na
2Cl-
K
Outer Medulla
2Cl
600mOsm K+
Inner Medulla
1200mOsm
Mg2+ Ca2+
114
K+ Cl-
Loop Diuretics
Loop Diuretics
Furosemide,bumetanide,torsemide,ethacrynicacid
Furosemide, bumetanide, torsemide, ethacrynic acid
•
Inhibit Na-K-2Cl pump
•
•
Strong diuretic effect
•
•
Two mechanisms that promote diuresis
•
•
•
↑ Na excretion
•
↓ medullary osmotic gradients
Used for edematous states •
Heart failure, cirrhosis
•
•
Hypokalemia Hypocalcemia Hypomagnesemia Most are sulfa drugs drugs Read Freeacid For 30inDays Exception: Ethacrynic (used allergic patients)
Na K 2Cl
Ethacrynic Acid
Furosemide
Loop Diuretics
DISCOVER NEW BOOKS
Furosemide, bumetanide, torsemide, ethacrynic acid •
•
Ototoxicity •
Very high doses or given with other ototoxic ototoxic agents
•
Tinnitus, loss of hearing (usually reversible)
•
•
•
•
Acute interstitial nephritis nephritis •
White blood cell casts
•
Urine eosinophils
pH>7.45
•
↑HCO3-
•
•
•
Complex mechanism of renal handling Thiazides, loop diuretics ↑ uric acid reabsorption Gout promoted by diuretics
Gout
•
•
BUILD YOUR DIGITAL READING LISTS
↑BUN/Cr
•
Metabolic Alkalosis
•
READ EVERYWHERE Uric Acid
Thiazide Diuretics Lumen (Urine)
Interstitium/Blood Na+
Diuretics ↑urine output ↓ECV Renin-Angiotensin-Aldosterone activation ↑H+ secretion metabolic alkalosis
Na+
ATP K+
Cl-
“Contraction alkalosis” Seen with loop diuretics and thiazides
115
Cl-
Thiazide Diuretics
Thiazides: Hypercalcemia Hypercalcemia Lumen (Urine)
Hydrochlorothiazide; Hydrochlorothiazide;chlorthalidone; metolazone
Interstitium/Blood
•
Sulfa Drugs (allergy)
Na+ Na+
ATP
Read Free For 30 Days
K+
Chlorthalidone Ca2+
Na HCTZ Ca2+
Metolazone
Thiazide Diuretics
DISCOVER NEW BOOKS
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone •
•
BUILD YOUR DIGITAL READING LISTS
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone
Elevates blood levels
•
Hyponatremia
•
Glucose
•
Drugs promote Na loss
•
Lipids
•
H2O resorption intact intact (normal medullary gradients)
•
Uric acid
•
High H2O intake
•
Calcium
•
HyperGLUC
Hypokalemia
•
Metabolic alkalosis
K-Sparing K-Sparing Diuretics
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone Clinicaluses •
Hypertension
•
Recurrent calcium kidney stones
•
Osteoporosis
•
Diabetes insipidus
hyponatremia
•
Caution:diabetes, ↑lipids, gout, hypercalcemia
Thiazide Diuretics •
Thiazide Diuretics READ EVERYWHERE
•
Spironolactone/eplerenone
•
Triamterene/amiloride
•
Good choice for patients with low K
•
•
•
116
Block aldosterone receptor receptor site Block aldosterone Na channel Often from other diuretics
K Sparing Diuretics
K Sparing Diuretics Principal Cell
Lumen (Urine)
Spironolactone, Spironolactone, Eplerenone, Triamterene, Amiloride
Interstitium/Blood Na+
•
Na+ Aldosterone
Aldosterone K+
ATP
•
K+
All ↑Na/H2O excretion (diuretics) All “spare” potassium •
•
H2O
Unlike other diuretics, do not increase K + excretion
HYPERkalemia HYPERkalemia is side effect
Read Free For 30 Days
Intercalated Cell
K H+
HCO3Aldosterone
ATP H+
Cl-
Spironolactone •
•
DISCOVER NEW BOOKS
Similar structure to testosterone •
Blocks testosterone effects
•
Gynecomastia in men
•
Eplerenone: No gynecomastia gynecomastia
•
•
•
•
Activates progesterone receptors
Testosterone
Progesterone
RAA System
Rules of Thumb
Renin-Angiotensin-Aldosterone
•
•
All diuretics can cause renal failure ↓ECV ↓GFR BUN/Cr may rise in the plasma
Amenorrhea in women
Spironolactone
•
BUILD YOUR DIGITAL READING LISTS
Derivativeofprogesterone •
•
READ EVERYWHERE Renal Failure
Diuretics result in volume loss Activates renin-angioten sin-aldoste rone system ↑ RAAS ↑ Na/H2O reabsorption Some adaptation to diuretic effect over time
•
All diuretics except K sparing:↑ K excretion
•
CA inhibitors and K sparing cause acidosis (↓pH)
•
117
•
CA Inhibitors: HCO 3- excretion
•
K sparing: ↓ aldosterone; hyperkalemia (H +/K+ exchanger)
•
Others cause contraction alkalosis
Loops and Thiazides have opposite effects on Ca hypocalcemia
•
Loops
•
Thiazides
hypercalcemia
Kidney Stones Nephrolithiasis 1. Calcium 2. Struvite 3. Urate 4. Cystine
Read Free For 30 Days
Kidney Stones Jason Ryan, MD, MPH
Symptoms •
•
•
DISCOVER NEW BOOKS
Flank pain (side between the ribs and the hip) Colicky (waxes and wanes in severity)
READ EVERYWHERE Risk Factors •
Hematuria •
•
Calcium Stones •
•
•
•
•
Calcium oxalate (most common)
Hypercalcemia
•
High oxalate levels in blood
•
•
•
•
Hypercalcemia
•
Hyperuricemia
Low urine volume •
Usually from dehydration
•
Increases concentration of urine substances
In general, hydration lowers risk of stones
Most common etiology: idiopathic hypercalciuria Hypercalcemia (hyperparathyroidism) High oxalate levels •
•
•
Radiopaque •
High amount of stone substance in blood
Risk Factors
Calciumphosphate Most common type of kidney stone (80%) Key risk factors •
BUILD YOUR DIGITAL READING LISTS
Seen on x-ray and CT scan •
Gastric bypass patients
Ethyleneglycol(antifreeze) •
Formation of oxalate
•
Increases oxalate concentration in urine
Vitamin C abuse •
118
Crohn’s disease: Fat malabsorption Fat binds to calcium, leaving oxalate free to be absorbed absorbed in the gut
Oxalate generated from metabolism metabolism of vitamin C
Calcium Stones •
Treatment
Classic case •
Patient drinking less water
•
Flank pain, hematuria
•
Calcium stone on imaging imaging
•
Most stones pass on their own
•
Large stones that do not pass require surgery
•
•
•
Normal Ca level in plasma
•
Increased calcium level in urine
•
•
DISCOVER NEW BOOKS
Dietary Sodium ↑ Na
↑ ECV
Recurrent stone formers may take medication Thiazides
•
Binds with calcium but remains dissolved
•
Lowers urinary Ca available for stones
•
Inhibits of stone formation
READ EVERYWHERE Struvite Stones •
More Na = More Ca Urine High Na diet = Stone formation Low Na diet = T reatment stones
Read Free For 30 Days
Decrease Ca in urine urine
Citrate(Potassiumcitrate)
•
•
•
↓ RAAS
↓ Na Reabsorption Proximal Tubule
BUILD YOUR DIGITAL READING LISTS
Ammonium-Magnesium-Phosphate stones 2nd most common stone type (15%) Consequence of urinary tract infection Urease-positive bacteria •
Proteus, Staphylococcus, Staphylococcus, Klebsiella
•
All hydrolyze urea to ammonia
•
Urine becomes alkaline
↓ Ca Reabsorption Proximal Tubule
Struvite Stones •
•
•
Can forms “staghorncalculi” “staghorn calculi”
•
Classicpresentation
•
Stones form a cast of the renal pelvis and calices
•
UTI symptoms (dysuria, frequency)
•
Looks like horns of a stag
•
Mild flank pain
•
Hematuria
•
Large, branching staghorn stone on imaging
pass surgery required Won’t pass Untreated bacterialreservoir •
•
Struvite Stones
•
Recurrent infection
Radiopaque •
Seen on x-ray and CT scan
119
Treatment: •
Surgery
•
Antibiotics
Uric Acid Stones •
Cause by high uric acid in urine or acidic urine
•
H+ + Urate- ↔ Uric acid
•
•
•
•
Not visible on x-ray
•
Can see with CT CT scan
•
•
DISCOVER NEW BOOKS
Hydration Alkalization of urine
•
Reduces uric acid production
•
•
•
Leukemia, myeloproliferative disease
•
More common in hot, arid climates
Read Free For 30 Days
Chronic diarrhea
•
Low urine volume, acidic urine more common
•
5-10% stones in US/Europe
•
40% stones in other climates
READ EVERYWHERE Uric Acid Stones
•
BUILD YOUR DIGITAL READING LISTS
Classic case •
Flank pain, hematuria
•
No stone on x-ray
Choose medical therapy, not surgery
Medicallytherapyofteneffective Usually does not require surgery
Cystine Stone •
Gout
•
Acidic urine (precipitates uric acid)
•
Rarely allopurinol Xanthine oxidase inhibitor
•
•
Potassium bicarbonate
•
High uric acid levels
•
Lowest pH is in the distal tubule/collecting duct
•
•
•
Radiolucent stones
Treatment •
Risk Factors
Cystine Stone
Raretype of stone
•
Seen in children with cystinuria Tubular defect cannot absorb cystine Also form staghorn calculi •
120
Classic case •
Child
•
No history of UTI (contrast with Struvite)
•
Large, staghorn stone
Treatment: •
Hydration
•
Alkalinization of urine
Renal and Bladder Malignancies 1. Renal Cell Carcinoma Carcinoma 2. Wilms’ Tumor
Renal and Bladder Malignancies
4. Transitional Cell Carcinoma Read For 30 5. Squamous CellFree Carcinoma 6. Adenocarcinoma
Days
Jason Ryan, MD, MPH
Renal Cell Carcinoma •
•
•
DISCOVER NEW BOOKS
Renal Carcinoma READCell EVERYWHERE BUILD YOUR DIGITAL READING LISTS Risk Factors
Most common kidney tumor
•
Epithelial tumor Commonly arise from proximal tubule cells
•
•
•
Males Age 50-70 Cigarettesmoking Obesity
Renal Cell Carcinoma
Renal Cell Carcinoma
Symptoms
Symptoms
•
•
•
•
Classic triad
•
Invades renal vein
•
Hematuria
•
•
Palpable abdominal mass
•
Left varicocele is classic finding
•
Flank pain
•
Not right (right spermatic spermatic drains to IVC)
Many patients have fever, weight loss Many patients asymptomatic until disease advanced
•
•
At presentation ~25% have metastases/advanced disease •
121
Can block drainage of spermatic vein on left
Spreads through venous system Common sites for metastasis: •
Lung
•
Bone
Can also spread to re troperitoneal lymph nodes
Renal Cell Carcinoma
Renal Cell Carcinoma
Paraneoplastic Paraneoplastic syndromes
Paraneoplastic Paraneoplastic syndromes
•
•
Manyparaneoplasticsyndromes Polycythemia (↑Hct) •
•
•
Cushing’s Syndrome
Hypercalcemia •
Tumor production of PTHrP
•
Increased Ca from bones
DISCOVER NEW BOOKS
Pathology
•
Hypertension •
Increased EPO production by tumor
Renal Cell Carcinoma •
•
Most common type is clear cell carcinoma Cells filled with glycogen and lipids
•
•
Look for weight gain, hypertension, hyperglycemia hyperglycemia
Read Free For 30 Days
Associated with gene deletion chromosome chromosome 3 Von-Hippel-Lindau Von-Hippel-Lindau(VHL) gene Sporadic mutation •
Single tumor
•
Older patient, usually smoker
Inherited •
Younger patient
•
Multiple, bilateral tumors
Renal Cell Carcinoma
Von-Hippel-Lindau Disease
•
ACTH production by tumor tumor
•
Genetics
•
•
•
Renal Carcinoma READCell EVERYWHERE BUILD YOUR DIGITAL READING LISTS
•
•
Renin production by tumor
Treatment
Autosomal dominant
•
Von-Hippel-Lindau Von-Hippel-Lindau (VHL) gene inactivation Many tumors
•
•
Surgical resection in early disease Poorly responsive to chemotherapy/radiation Recombinantcytokinesused
•
Renal cell carcinomas
•
Aldesleukin (interleukin-2)
•
Cerebellar hemangioblastoma
•
Hypotension, fevers, chills are important side effects
•
Retinal hemangioblastoma
122
Wilms’ Tumor
Wilms’ Tumor
•
Most common renal malignancy of young children
•
Associated with loss of function mutation
•
Proliferation of metanephric blastema
•
WT1 tumor suppressor gene
•
•
Embryonic glomerular structures
•
Young child (~3years old)
•
Huge, palpable flank mass
•
Hematuria
•
Hypertension (renin secretion)
WAGR Syndrome •
•
•
•
•
•
DISCOVER NEW BOOKS
Wilms’ tumor Aniridia •
Absence of the iris
•
Visual problems
•
•
•
•
Read Free For Often part of a syndrome
Mental Retardation Deletion of WT1 gene chromosome chromosome 11
Height/weight often >97th percentile
•
Hemihyperplasia
•
Macroglossia
•
Many embryonal tumors
•
Cryptorchidism, ambiguous genitalia
30 Days
Pediatricovergrowthdisorder Macrosomia •
Renal Angiomyolipoma •
Chromosome 11 May be sporadic
Beckwith Wiedemann READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Syndrome
Genitalanomalies •
•
•
Classic case
Muscles in one limb bigger than other
•
Wilms’ tumor
•
Neuroblastoma
•
Rhabdomyosarcoma
Transitional Cell Carcinoma
Benign tumor – young children
•
Tumors of blood vessels, smooth muscle, fat AssociatedwithTuberous Sclerosis
•
•
Most common tumor of urinary tract system Most common type of bladder cancer Locations:
•
Autosomal dominant condition
•
Bladder (most common)
•
Cortical tubers in brain
•
Also renal calyces, renal renal pelvis, ureters
•
Subependymal hamartomas in brain
•
Seizures, mental retardation
•
Cardiac rhabdomyomas
•
Leaf-like patches of skin with no pigment (ash-leaf patches)
•
123
Often multifocal and recurrent •
“Field defect”
•
Damage to entire urothelium urothelium
Transitional Cell Carcinoma
Transitional Transitio nal Cell Carcinoma
Risk Factors •
•
•
•
•
Smoking Cyclophosphamide
•
•
Phenacetin Aniline dyes (hair coloring) Workplace exposures •
Rubber, Rubber, textiles, leather
•
Naphthalene (industrial solvent)
•
Painters, machinists, printers
Classic case
•
Older, whit e male
•
Smoker
•
Painless hematuria
•
No casts in urine
Read Free For 30 Days
Test of choice: cystoscopy and biopsy
Transitional Cell Carcinoma DISCOVER NEW BOOKS Squamous READ EVERYWHERE BUILD YOUR DIGITAL READING LISTS Cell Carcinoma Treatment •
•
•
Surgical resection Radiation
•
•
Chemotherapy
•
•
•
•
•
•
•
•
Several key risk factors
•
Combination chemotherapy with platinum-based regimens regimens
•
Recurrent kidney stones or cystitis
•
Cisplatin, carboplatin
•
UTI with Schistosoma haematobium
Schistosoma haematobi h aematobium um •
Rare bladder cancer Need chronic inflammation of bladder
Adenocarcinoma
Trematode
•
Found in Africa and Middle East (Egypt) Acquiredfromfreshwatercontaininglarvae Penetrate the skin
•
•
Very rare bladder cancer Glandular proliferation in bladder Occurs in special circumstances •
Migrate to liver and mature to adults Infects bladder Usually causes hematuria hematuria Can result in bladder cancer
124
Urachal remnant
•
Long history of cystitis cystitis
•
Exstrophy: bladder protrusion through abdominal wall defect
Rhabdomyolysis •
Syndrome caused by muscle necrosis
•
Can lead to renal failure and death
Read Free For 30 Days
Rhabdomyolysis Jason Ryan, MD, MPH
Rhabdomyolysis
DISCOVER NEW BOOKS
Causes of Muscle Damage •
Intense physical exercise •
Crush injuries (trauma)
•
Drugs •
Statins
•
Fibrates
•
Aldolase , lactate dehydrogenase , AST/ALT AST/ALT
•
Hyperkalemia/hyperphosphatemia in rhabdomyolysis
19 K
Elevated levels are hallmark hallmark of rhabdomyolysis
Muscle Contents
Potassium andphosphate and phosphate •
Creatine kinase •
Muscle Contents
BUILD YOUR DIGITAL READING LISTS
•
Especially if dehydrated
•
•
READ Contents EVERYWHERE Muscle
15 P
Purines •
Metabolized to uric acid in liver
•
Can lead to hyperuricemia
Adenine
125
Guanine
Myoglobin
Myoglobin •
Protein monomer (NOT tetramer like Hgb)
•
Containsheme Contains heme (porphyrin plus iron)
•
Binds oxygen for use by muscle tissue
100
n 75 o i t a r u t a 50 S %
Read Free ForNo 30allosteric Days interactions!
25 25
50
75
100
pO2 (mmHg)
Myoglobin Renal Toxicity •
•
•
Obstructs tubules Toxic to proximal tubular cells Vasoconstriction •
Especially in medulla
•
Leads to renal hypoxia
DISCOVER NEW BOOKS
Myoglobin READ EVERYWHERE •
Made worse by volume depletion in rhabdomyolysis rhabdomyolysis
•
Fearedoutcome rhabdomyolysis: rhabdomyolysis:renal renal failure/death
•
Intravascular fluid influx into muscle tissue
Rhabdomyolysis
Rhabdomyolysis
Symptoms
Diagnosis
•
•
•
Musclepain Weakness
BUILD YOUR DIGITAL READING LISTS
Renal Toxicity
•
Dark urine (from myoglobin)
126
Creatine kinase •
Usually very high
•
Normal < 250 IU/L
•
Rhabdomyolysis > 1000 IU/L
•
Sometimes up to 25,000 or or more IU/L
Rhabdomyolysis
Rhabdomyolysis
Diagnosis
Diagnosis
•
Urinalysis forheme forheme •
•
•
Heme has peroxidase activity
•
Breaks down peroxide
•
Changes test strip color
•
Positive dipstick = hemoglobin or myoglobin
Rhabdomyolysis
DISCOVER NEW BOOKS
Treatment •
•
•
Volume resuscitation •
IV Fluids (usually isotonic saline)
•
Titrated to maintain good urine output
•
•
127
•
Dark urine
•
Positive dipstick f or heme
•
No evidence of red blood cells
Read Free For 30 Days
READ EVERYWHERE Hypocalcemia •
Treatmentofe lectrolyteabnormalities Dialysis
Microscopy for red blood cells Classicfinding rhabdomyolysis rhabdomyolysis
BUILD YOUR DIGITAL READING LISTS
Calcium deposits in damaged myocytes Initialphases rhabdomyolysis: rhabdomyolysis:hypocalcemia hypocalcemia Recovery phase: release from myocytes •
Levels return to normal
•
Can become elevated