Boards and Beyond: Renal A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 2-1-2017
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Table of Contents Renal Embryology Renal Anatomy Renal Physiology I Renal Physiology II Nephron Physiology Renal Endocrinology Acid Excretion Acid Base Principles Respiratory Respirator y Acid Base Disorders Metabolic Alkalosis Renal Tubular Acidosis Metabolic Acidosis Acid Base Problems Electrolyte Disorders
Sodium and Water Balance Sodium Disorders Glomerular Disease Principles Nephritic Syndrome Nephrotic Syndrome MPGN Tubulointerstitial Tubulointerstitial Disease Renal Failure Urinary Tract Infections Cystic Kidney Disease Diuretics Kidney Stones Renal and Bladder Malignancy Rhabdomyolysis
1 4 5 9 16 24 29 33 39 41 45 48 54 58
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62 67 76 80 87 92 94 98 104 106 108 114 117 121
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Kidney Development •
Pronephros
•
Mesonephros
•
Renal Embryology
•
Jason Ryan, MD, MPH •
•
•
•
Interim kidney 1 st trimester
•
Contributes to vas deferens in males
Metanephros •
Forms permanent kidney
•
Appears 5 th week
•
Develops into kidney through weeks 32-36
Bladder develops separately from urogenital sinus
Nephron
Kidney Formation •
Forms/degenerates week 4
Metanephric Mesenchyme
Ureteric Bud
Key Structure #1: Ureteric bud •
Outgrowth of mesonephric duct
•
Gives rise to ureter, ureter, pelvis, calyxes, collecting ducts
Key Structure #2: Metanephric mesenchyme •
Interacts with ureteric ureteric bud
•
Interaction forms glomerulus glomerulus to distal tubule
Aberrantinteraction kidney malformation
Multicystic Dysplastic Kidney
Wilms’ Tumor •
Most common renal malignancy of young children
•
Abnormalureteric bud-mesenchyme bud-mesenchyme interaction
•
Proliferation of metanephric metanephric blastema
•
Kidney replaced with cysts
•
No/little functioning renal tissue
•
Embryonic glomerular structures
1
Ureteropelvic Junction •
•
•
•
Renal Agenesis
Last connection to form Common cause obstruction Oftendetected in utero Hydronephrosis
•
•
•
•
•
•
•
Severe renal malfunction malfunction = ↓amniotic fluid Loss of fetal cushioning to external forces External compression of the fetus
•
Alteration in lung liquid movement
•
•
•
•
•
Risk of renal failure failure after decades
If both kidneys: •
Oligohydramnios
•
Potter’s syndrome
Limbdeformities Flat face Pulmonaryhypoplasia
Abnormal lung formation
Horseshoe Kidney
Causes
•
Hyperfiltration
Abnormal face/limb face/limb formation
Potter’s Syndrome •
Hypertrophy
•
Signs
Fetus exposed to absent or ↓amniotic fluid Amnioticfluid = fetal urine
•
•
Potter’s Syndrome
Potter’s Syndrome •
If single kidney other kidney compensates
Bilateral renal agenesis •
Often detected in utero
•
Fetal kidneys seen on ultrasound at 10 to 12 weeks Occurs in males
•
Tissue (valves) obstruct bladder outflow
•
Ultrasound: dilated bladder, bladder, kidneys
•
Can cause oligohydramnios oligohydramnios & Potter’s Cysts in kidneys/biliary tree
•
Kidneys don’t form urine
Kidney cannot ascend
•
•
•
Autosomal recessive polycystic kidney disease •
Inferior poles fuse
•
•
Posteriorurethralvalves •
•
2
Pelvis retroperitoneum
Trapped by inferior mesenteric artery Most patients asymptomatic Associated with Turner syndrome
Urachal Remnants •
•
•
Urachal Remnants
Urachus 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
Adult with painless hematuria
•
Urine can leak from umbilicus
•
•
Also can form cyst, sinus, diverticulum
•
Tumor at dome of bladder
•
Can lead to infections
•
Path showing adenocarcinoma
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Arterial System Renal Artery
Segmental Artery
Renal Anatomy
Interlobar Artery
Jason Ryan, MD, MPH Arcuate Artery
Glomerulus
Special Kidney Features •
•
Aortic Dissection
Right kidney slightlysmaller •
•
Less development in utero utero due to liver
•
Left kidney has longer renal vein •
Often taken for transplant
•
Dead/dying kidney usually usually not removed in transplant
•
New kidney attached to iliac artery/vein
Interlobular Artery
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Renal arteries come off abdominal aorta aorta Aortic dissection can cause renal ischemia
Fluid Compartments
40% Non-Water
Renal Physiology I
60% Water
Jason Ryan, MD, MPH
Determining Fluid Volume Volume
1/4 Plasma 1/3 Extracellular ¾ Interstitial
2/3 Intracellular
Fluid Compartments Inulin 40% Non-Water
1gram
1Liter Fluid
1gram
Unknown Volume
60% Water
1g/L
1/4 Plasma
•
Radiolabeled Albumin
1/3 Extracellular 2/3 Intracellular
1/3 Extracellular 2/3 Intracellular
¾ Interstitial
Sample Question
Inulin
60% Water
Radiolabeled Albumin
X grams Inulin infused Equilibrium concentration = Y g/L ECF = X/Y (Liters)
1g/L
Fluid Compartments 40% Non-Water
1/4 Plasma
A patient is administered 120mg of inulin. An hour later, later, the patient has excreted 20mg of inulin in the urine. The plasma inulin concentration is 1mg/100ml. 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
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Effective Circulating Volume •
•
•
•
•
Effective Circulating Volume
Portion of extracellular fluid Contained in arterial system
•
•
Volume
•
Cardiac output
•
Vascular resistance
•
Sympathetic nervous system
•
Renin-angiotensin-aldosterone system
Evaluating Kidney Function
Urine output Glomerularfiltrationrate •
Can be determined determined from blood, urine urine measurements
•
GFR falls as kidneys f ail
•
Filtration Fraction
How much blood blood enters kidney
GFR/RBF
Theoretical Theoretic al Determination Determinatio n GFR •
Need to know pressures in capillary, Bowman’s capsule
Clinicalde termination termination •
Renal Blood Flow
•
Theoretical determination •
•
•
How much liquid passes through through the filter (i.e. glomerulus)?
Measuring GFR
•
Low ECV activates: activates:
Modified by:
•
•
Low ECV can lead to low blood pressure
•
Maintains tissue perfusion Not necessarily correlated with total body water
Evaluating Kidney Function •
•
Need to know plasma concentrations concentrations solutes, urine flow
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FiltrationDrivingForces •
Hydrostatic pressure
•
Oncotic Pressure
Glomerular Filtration Rate
Capillary Fluid Exchange •
Hydrostatic pressure – fluid PUSHING PUSHING against walls
•
Oncotic pressure – concentrated concentrated solution PULLING fluid in
•
•
High pressure drives fluid TOWARD low pressure GC
GC
High pressure draws fluid AWAY from low pressure
BC
To Raise PGC
Glomerular Filtration Rate
Increase GFR •
GC
GC
Dilate afferent arteriole •
More blood IN
•
Increase RPF
•
•
PBC
BC
∏BC
Increase P GC Increase GFR
To change GFR: 1. Change PGC 2. Change ∏GC (alter protein levels blood) 3. Change PBC
GC
GC
BC
BC
Image courtesy of OpenStax College
To Raise PGC
To Raise ∏GC
Increase GFR •
Constrict efferent arteriole •
•
Less blood out
•
Decreased RPF
•
•
•
Blood backs up behind constricted arteriole
Increase protein levels in blood •
Less blood drawn into proximal tubule
•
Lower GFR
•
No change RPF
Increase PGC Increase GFR PGC
∏GC
GC
GC
PBC
∏BC
BC
BC
Image courtesy of OpenStax College
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Glomerular Flow Dynamics
To Change PBC •
•
•
•
Obstructureter •
Urine backs up behind obstruction
•
Pressure rises in all portions nephron
Increase PBC Less GFR PBC No effect RPF
GC
GC
BC
BC
Autoregulation •
•
Constant GFR/RPF despite changes in BP #1: Myogenic mechanism •
•
Myogenic Mechanism •
•
Afferent arteriole constricts with high BP
•
Efferent arteriole dilates dilates
•
Result is maintenance of normal GFR/RPF
•
Responds to changes changes in BP to maintain GFR
#2:Tubuloglomerularfeedback •
High BP
•
Responds to changes in [NaCl] to maintain GFR •
•
Opposite effects as above
Severe Volume Loss
NaCl tubular fluid sensed by macula densa •
Due to decreased decreased renin
Low BP •
Tubuloglomerular Feedback
Responds to stretch
Part of JG apparatus
•
Profound loss of fluid (vomiting, diarrhea, etc.)
•
RPF will fall significantly significantly
•
High GFR High NaCl Macula Densa Sensing
•
•
Macula Densa vasoconstriction vasoconstriction afferentarteriole
•
•
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Autoregulatory mechanisms activated GFR still falls Cr level can ↑
Renal Function Measurements •
Glomerularfiltrationrate
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Renal plasma flow
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Filtrationfraction
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Renalclearance
•
•
Renal Physiology II
•
•
Jason Ryan, MD, MPH
Renal Function Measurements
How much liquid passes through the filter (i.e. glomerulus)?
How much liquid does the kidney kidney handle? Of all substance X entering kidney, what what % gets filtered? How much of each blood component gets removed?
Renal Function Measurements
GFR Fluid across Glomerulus
GFR Fluid across Glomerulus
RPF Fluid into Glomerulus
RPF Fluid into Glomerulus RPF = 5L/min GFR = 2L/min Filtration Fr action=2/5=40% action=2/5=40% Urine Flow Fluid out of kidney
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
RPF Fluid into Glomerulus Urine Flow = 100cc/hr Urine [K] = 10meq/cc Excretion K = 100 * 10 = 1000meq/hr
Urine Flow Fluid out of kidney
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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 Number in liters/min (volume flow)
Cx = Ux * V Px
Use these measured variables to get RPF, GFR, etc.
Creatinine
Determining GFR •
•
•
•
•
Inulin clearance used to determine GFR Inulin = neither secreted or resorbed
•
•
All inulin filtered goes out Amount blood “cleared” of inulin is amount of blood filtered by glomerulus Clearance of inulin (liters/min) = GFR
•
Breakdown product muscle metabolism Closest naturally occurring substance to inulin •
Inulin = All filtered goes out, no no secretion/resorption
•
Creatinine = All filtered goes out, small amount secretion
Using Cr instead of of inulin: •
Secreted Cr will be counted as filtered
•
This will slightly overestimate GFR
Cinulin = Uinulin * V = GFR Pinulin
Creatinine
PCr/GFR Relationship
Cx = Ux * V Px
•
•
Special formulas to convert Cr to GFR •
Cockcroft-Gault formula
•
Modification of Diet in Renal Renal Disease (MDRD) formula
•
Use age, gender, gender, Cr level to estimate GFR
Amount of Cr out in urine Equal to amount produced
GFR declines with age age •
Not always accompanied accompanied by rise in Cr
•
Use of formulas is key
•
Must adjust some medication dosages
CCr = UCr * V = GFR PCr
Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr)
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Creatinine Clearance
Creatinine
CCr = Constant ≈ GFR
Cr
PCr Double PCr (1.0 to 2.0)
Half the GFR
GFR
Renal Function Measurements
Creatinine •
•
GFR Fluid across Glomerulus
Worsening renal function = high blood Cr level Some sample values:
•
Normal kidney function
•
Chronic kidney disease
•
End stage renal disease (dialysis)
Cr = 0.8 mg/dl
Cr = 2.0 mg/dl
RPF Fluid into Glomerulus
Cr = 4.0mg/dl
Urine Flow Fluid out of kidney
Plasma versus Blood
Renal Plasma Flow (RPF) •
•
•
•
Use Para-aminohippuric acid (PAH) to estimate RPF PAH is filtered and secreted 100% of PAH that enters kidney leaves blood in urine Clearance PAH (l/min) = Blood flow to kidney (l/min)
CPAH = UPAH * V = RPF PPAH
*PAH clearance underestimates RPF by 10% Not all renal plasma/blood to glomeruli
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•
Blood = Plasma + cells/proteins
•
Renal Blood Flow > Renal Plasma Flow
•
Separate calculations RBF vs. RPF
Renal Blood Flow (RBF) •
•
•
Renal Blood Flow (RBF)
RBF determined from RPF Blood = Plasma + Cells/Proteins
•
•
Cells/Proteins (%) ≈ Hct (%)
•
RPF = RBF (1-Hct)
RBF = RPF 1- Hct
Renal Function Measurements
Renal Blood Flow (RBF) •
Cells/Proteins (%) ≈ Hct (%)
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
•
RBF determined from RPF Blood = Plasma + Cells/Proteins
GFR Fluid across Glomerulus
1 liter/min = RPF Hct = 40% RPF Fluid into Glomerulus
RBF = 1 1- Hct
=
1 = 1.6 l/min 0.6 Urine Flow Fluid out of kidney
Other Renal Function Function Variables •
Filtration Fraction •
•
Quantifying Kidney Function Measured Variables Urine Flow (l/min) Plasma Conc X (mg/l)
How much of plasma to kidney kidney gets filtered?
•
GFR/PBF
•
Normal = 20%
Urine Conc X (mg/l)
Filtration Load X •
How much of substance X gets filtered?
•
Px * GFR
•
Amount of X delivered to proximal proximal tubule
Determined Variables Renal clearance Renal plasma flow Renal Blood Flow Glomerular filtration rate Filtrationfraction
Inulin Clearance = GFR PAH Clearance = RPF
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Prostaglandins and NSAIDs •
•
•
•
•
ACE Inhibitors
Prostaglandins Prostaglandins dilate afferent arteriole ↑RBF NSAIDs (ibuprofen) block PG production
•
•
Afferent arteriole constricts ↓RBF ↓ GFR -- FF Clinicaleffects: •
Acute renal failure
•
Acute heart failure
•
•
•
•
Secretion and Absorption
AII constricts most blood vessels This could ↓RBF ↓ GFR But AII constricts efferent arteriole preferentially This maintains maintains GFR ACE inhibitors blunt AII effects ↓ GFR ↑ RBF ↓FF
Secretion and Absorption
GFR Fluid across Glomerulus GFR*Px = Filtered Load
•
•
•
Excreted = Filtered – Reabsorbed + Secreted Amount filtered (X) = GFR * Px Amount excreted (X) = V * Ux
Example: 10mgX/min filtered, 20mgX/min excreted Additional 10mgX/min must be secreted
What if Filtered Load ≠ Excretion Urine Flow Fluid out of kidney V*Ux = Excretion
Secretion and Absorption •
•
•
Secretion and Absorption
Filtered = Excreted if no secretion/resorption
•
Filtered < Excreted if some secreted Filtered > Excreted if some resorbed
•
•
If clearance (x) = GFR no secretion/resorption secretion/resorption GFRCx resorption
Example #1: Filtered = 100mg/min Excreted = 120mg/min Additional 20mg/min 20mg/min must be secreted
Example #1: GFR = 100ml/min Cx = 120ml/min Additional 20ml/min “cleared” by secretion
Example #2: Filtered = 100mg/min Excreted = 80mg/min 20mg/min must be resorbed
Example #2: GFR = 100ml/min Cx = 8 0ml/min Additional 20ml/min “uncleared” by resorption
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Intake and Output •
•
•
•
Solutes in Renal Failure
Amount of any substance in must equal amount out When insults occur (renal failure, diarrhea), there is a transient imbalance imbalance that alters plasma levels Steady state returns
Regulated solutes (Na/K): No concentration change
•
Unregulated solutes (Urea): Increased plasma level
Eat 10grams per day salt excrete 10grams per day
Question 1 •
•
Question 2 •
A patient has a urine output of 4800cc/day (200cc/hr). Plasma concentration of substance X is 4mg/dL. Urine concentration of X is 8mg/dL. What is the clearance of substance X?
=
GFR = Uinulin * V Pinulin
Cx = Ux * V = 8 * 200 = 400cc/hr Px
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? inulin
4 V = GFR * Pinulin = 200 * 3 = Uinulin
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 = RPF
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•
A lab animal has an inulin clearance of 100cc/hr. Plasma concentration of substance 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?
RBF = RPF
PPAH
RPF = 10 * 200=
6
Question 4
Question 3 •
100ml/hr
1- Hct Amount filtered (X) = GFR * Px Excreted = Filtered – Reabsorbed + Secreted
400
RBF = 400 = 800ml/hr 1- 0.5
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Question 4 •
Key Points
A lab animal has an inulin clearance of 100cc/hr. Plasma concentration 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?
•
•
•
Amount filtered (X) = GFR * Px = 100 * 4 = 400mg/hr Excreted = Filtered – Reabsorbed + Secreted Excreted = 400 - 0 + 25 425mg/hr
Key Points •
•
•
•
Amount filtered = GFR * Px Amount excreted = V * Ux Excreted = Filtered + Secreted - Resorbed For Inulin Filtered = Excreted
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If given inulin clearance, that is GFR GFR can be used to calculate filtered load of other substances Just need plasma concentration concentration (Px)
Nephron
H2O NaCl K+ HCO3Glucose Amino Acids
Nephron Physiology Jason Ryan, MD, MPH
Transport
Diffusion
Apical Membrane
Basolateral Membrane
Lumen (Urine)
Interstitium/Blood Interstitium/Blood
Lumen (Urine)
Interstitium/Blood
Na
↑[Na]
↑[Na]
↓[Na]
↓[Na] Na
Na
Na
↓[Na]
↑[Na] ATP Na
Segments of Nephron
Osmotic Diffusion
Proximal Tubule
Lumen (Urine)
Distal Tubule
Interstitium/Blood
High Osmolarity 1200mOsm
Low Osmolarity (50mOsm) H2O
Collecting Duct
H2O
Descending Limb
H2O
Ascending Limb
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Proximal Tubule
Proximal Tubule Lumen (Urine)
100% Glucose Amino Acids
Interstitium/Blood Na+ ATP
67% Water Bicarb NaCl Potassium Phosphate
K
Proximal Tubule
Proximal Tubule
Lumen (Urine)
Lumen (Urine)
Interstitium/Blood
Interstitium/Blood
Na+ Na+
Na Na+
ATP K+
Glucose
ATP
Glucose
K+ K+
Cl-
Glucose
Anions Hydroxide (OH-) Formate Oxalate Sulfate
Lumen (Urine)
Interstitium/Blood
•
Na
•
Glucose
ATP
•
K+ K+
ClCl
Anions Hydroxide (OH-) Formate Oxalate Sulfate
Glucose
Glucose Clearance
Proximal Tubule Na
Cl Anions
Anions Glucose H2O
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Completely reabsorbed proximal tubule Na/Glucoseco-transport At glucose ~160mg/dl glucose appears in urine
•
Glucose ~350mg/dl all transporters saturated
•
Diabetes mellitus = “sweet” diabetes
•
In pregnancy, ↓glucose reabsorption
•
Some glucosuria normal
Proximal Tubule: Bicarb
Amino Acid Clearance •
•
Lumen (Urine)
Na/AA transporters in proximal tubule reabsorb all amino acids Hartnup disease •
No tryptophan transporter transporter in proximal tubule
•
Amino acids in urine
•
Skin rash resembling pellagra (plaques, (plaques, desquamation)
Na+ Interstitium/Blood Na
HCO3- +
H+
H+ + HCO 3-
H2CO3
H2CO 3
CA
CO2 + H2O
CA
CO2 + H2O
CA = Carbonic Anhydrase
Proximal Tubule Bicarb
Fanconi’s Syndrome
Clinical Correlations •
•
Carbonicanhydrase inhibitors •
Weak diuretics
•
Result in bicarb bicarb loss in urine
•
Type II Renal Tubular Acidosis •
Ion defect
•
Inability to absorb bicarb
•
Metabolic acidosis
•
•
•
•
Hypophosphatemia Hypophosphatemia (loss of phosphate re sorbtion)
•
Growth failure, dehydration in children
Key Points
•
Inherited or acquired syndrome (rare)
•
•
Inherited form associated with cystinosis
•
•
Lysosomal storage disease
•
Accumulation of cystine
•
Acquiredcauses: •
Lead poisoning
•
Tenofovir (HIV drug)
•
Non AG acidosis (loss of HCO3-) Hypokalemia (↑nephron flow)
Proximal Tubule
Fanconi’s Syndrome
•
Impaired ability of proximal tubule to resorb HCO3-, glucose, amino acids, phosphate, and low molecular weightproteins Polyuria, polydipsia (diuresis from glucose)
Tetracycline
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Workhorse of the nephron Absorbs most water, Na, K, and other molecules Loss of amino acids Hartnup disease
•
Glucose in urine diabetes
•
Loss of bicarb in urine urine •
Carbonic anhydrase inhibitors
•
Type II RTAs
Proximal Tubule
Thin Descending Loop Henle
Key Points •
Most common source renal cell carcinomas
•
•
Most common area damaged acute tubular necrosis
•
•
•
•
Osmolarity of Nephron
Concentratesurine Absorbswater Water leaves urine Drawn out by hypertonicity in medulla
H2O H2O H2O H2O H2O
Osmolarity of Nephron •
•
300mOsm
Cortex
Impermeable to NaCl
Created by Na, Cl, and Urea Urea resorption by collecting duct e ssential to maintain these gradients for water resorption
600mOsm
Outer Medulla
Inner Medulla
1200mOsm
Thin Descending Loop Henle
Thick Ascending Loop Henle Lumen (Urine)
Interstitium/Blood Na+
300
Cortex
300mOsm
Na+
ATP
K+
K+
2Cl-
Outer Medulla
H2O H2O
600mOsm K
H2O H2O H2O
1200 Inner Medulla
K Cl-
1200mOsm
M
19
2+ Ca2+
Thick Ascending Loop Henle
Distal Tubule Lumen (Urine)
Interstitium/Blood
120 NaCl NaCl NaCl NaCl NaCl
300
Cortex
Outer Medulla
Na+ Na+
300mOsm
ATP K+
Cl-
H2O H2O H2O H2O H2O
Cl-
600mOsm
1200 Inner Medulla
1200mOsm
Collecting Duct
Distal Tubule
Principal Cell
Lumen (Urine) Lumen (Urine)
Interstitium/Blood
Interstitium/Blood
Na+
Na+
ATP
K+
Na+
Na+
K+
ATP H2O
K+ -
Cl
Cl-
Intercalated Cell Ca2+
Na Ca2+ ATP H+
Key Points •
•
Collecting Duct Hormones
Collecting duct functions •
Resorb Na/H2O
•
Secrete K +/H+
•
Increased Na delivery to CD increased K excretion •
Contributes to hypokalemia with loops/thiazides
20
Amount of absorption/secretion heavily dependent on aldosterone and antidiuretic hormone (ADH)
Collecting Duct
Aldosterone
Principal Cell
Lumen (Urine) •
•
•
•
•
•
•
•
Steroid( mineralocorticoid) mineralocorticoid)hormone Synthesized/released Synthesized/released by zona glomerulosa cells of adrenalcortex Freely crosses cell membrane (steroid) Binds to cytosolic protein receptor
ATP K+
K+
Intercalated Cell
Also promotes K secretion principal cells Also promotes H secretion intercalated cells
Aldosterone
Aldosterone
•
•
↑K excretion
•
↑H+ excretion
Cl-
Nephron Water Permeability
Overalleffect: ↑ sodium/water resorption (↑effective circulating volume)
Aldosterone
H2O
Activated receptor modifies gene expression Increase Na/K-ATPas Na/K-ATPase e proteins and Na channels of principal cells
•
Interstitium/Blood
Na+ Aldosterone
H+
•
Na+
Permeable
Impermeable
Variable
Release stimulated by: by: •
Angiotensin II
•
High potassium
•
ACTH (minor effect)
Antidiuretic Hormone (ADH)
ADH Water Resorption
Vasopressin •
Promotes free water retention (inhibits secretion)
•
•
Two receptors: V1, V2
•
•
V1: Vasoconstriction
•
V2: Antidiuretic response
•
Secretion stimulated by hyperosmolarity hyperosmolarity
•
Released by posterior pituitary
•
V2 receptors on principal cells collecting duct G-protein, cAMP second messenger system Results is endosome insertion into cell membrane
•
Endosomes contain aquaporin 2
•
Result is ↑ permeability of cells to water
•
21
Water channel
Collecting Duct Lumen (Urine)
Water Deprivation (High ADH)
Principal Cell
Interstitium/Blood
AQP-3
H2O
H2O
AQP-4
300
Cortex
ADH
V2
AQP-2 Channel
300mOsm H2O
H2O
H2O
Outer Medulla
H2O H2O
Intercalated Cell
1200
Inner Medulla
High Water Intake (low ADH)
•
Cortex
300mOsm NaCl
•
NaCl NaCl
1200mOsm
How Diuretics Work •
Outer Medulla
600mOsm
•
600mOsm
Most diuretics block resorption Na This sends more Na to collecting duct ↑osmolarity collecting duct
↑excretion of Na/H2O
NaCl
Inner Medulla
60 1200mOsm
ADH Urea Resorption •
Medullary interstitium very important for producing maximallyconcentratedurine •
•
•
•
•
Antidiuretic Hormone (ADH)
High osmolarity portion portion of kidney
In setting of high ADH, large osmotic gradient exists to absorb water from urine As water leaves proximal collecting duct, urea concentrationrises This creates gradient for urea to leave urine in distal collecting duct (medullary portion)
H2O
Permeable to H20 NOT permeable to Urea
H2O
H2O Urea
ADH also increases # of urea transporters
22
Permeable to H20 AND permeable to Urea
Collecting Duct •
ResorptionNa/H2O
•
Secretion of K+ and H+
•
Urearesorption
•
•
Sodium 5%
67%
Depends on ADH (H2O) and and Aldosterone (Na)
Depends on Aldosterone 3%
25%
1%
Water
Concentration Changes 50/50
Solute
50/50
0% Nephron
67%
Na/Cl
Water 50/50
<50/50
8-17% Nephron
Glucose Bicarb
15% 50/50
>50/50 Nephron
Variable
Concentration Changes 3.0 PAH
Inulin/Cr
2.0 Cl/Urea Na/K
[Tubule] 1.0 [Plasma] 0.5
0
Glucose/ Amino Acids/ HCO3Distance Along Proximal Tubule
23
Inulin Cr
Renal Hormones •
•
Renal Endocrinology Jason Ryan, MD, MPH
Juxtaglomerular Apparatus •
Renin
•
Erythropoietin
•
1,25 Vitamin D
Act on kidney •
Angiotensin II
•
Atrial Natriuretic Peptide Peptide (ANP)
•
Antidiuretic hormone (ADH)
•
Aldosterone
•
PTH
1. Low blood pressure
Modified smooth muscle of afferent afferent arteriole
•
Macula densa
•
JG cells secrete renin
•
•
Stimulation Renin Release
JG Cells •
Released by kidney
•
Part of distal convoluted convoluted tubule
•
Angiotensinogen Sympathetic System
•
+ Renin
Renin •
Renal Na/Cl resorption
•
A2
•
JG Cells Adrenal aldosterone secretion
Net Result
Pituitary ADH secretion
24
Main job is to convert AT AT to AI
AII •
Arteriolar vasoconstriction
↑Salt/Water Retention ↑BP
β1 receptors
RAA System Key Elements
Renin-Angiotensin System
+ ACE
Macula densa
3. Sympathetic activation •
AI
JG cells
2. Low NaCl delivery
Multiple effects
Aldosterone •
Collecting duct effects
•
Resorption of Na
•
Excretion of K, H+
Angiotensin II (AII) •
•
•
•
•
Angiotensin II
Efferent arteriole constriction Preserves renal function in low-volume low-volume state
•
↑GFR ↑FF ↓RPF
Capillary Effect •
•
•
•
Increased Na/H2O through several mechanisms •
Increased prox imal tubule resorption (via capillary effect)
•
Direct proximal tubule resorption through Na/H+ Na/H+ exchange
•
Stimulates aldosterone release
Proximal Tubule Lumen (Urine)
Altered by efferent arteriole constriction constriction
Na+ Interstitium/Blood Na
↓hydrostatic pressure from less bloodflow ↑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
H2CO 3
CA
CO2 + H2O
CA
CO2 + H2O
CA = Carbonic Anhydrase
Aldosterone •
•
•
•
•
Aldosterone
Steroid( mineralocorticoid) mineralocorticoid)hormone
•
Synthesized/released Synthesized/released by zona glomerulosa cells of adrenalcortex
•
Freely crosses cell membrane (steroid) Binds to cytosolic protein receptor
•
Activated receptor modifies gene expression
25
Increase Na/K-ATPase proteins and Na channels of principal cells Promotes K secretion principal cells Promotes H secretion intercalated cells
Collecting Duct
Aldosterone
Principal Cell
Lumen (Urine) •
•
Release stimulated by: by: •
Angiotensin II
•
High potassium
•
ACTH (minor effect)
↑ sodium/water resorption (↑effective circulating volume)
•
↑K excretion
•
↑H+ excretion
Interstitium/Blood
Na+ Aldosterone
K+
Aldosterone
ATP K+
H2O
Overalleffect: •
Na+
Intercalated Cell
Aldosterone H+
Primary Aldosteronism •
•
RAA System Drugs
Conn’s syndrome (adenoma) Adrenalhyperplasia
•
Causesresistanthypertension
•
Hallmark is hypertension with ↓K
•
•
RAA System Drugs •
•
Block sympathetic stim stim of JG apparatus
•
Block renin release
•
Lower blood pressure
•
•
•
•
Aldosteroneantagonists •
Spironolactone, eplerenone
•
Blocks Na resorption
•
Blocks K excretion
•
Blocks H+ excretion
•
Lower blood pressure
•
Will ↑K, ↑H+ (↓pH)
•
Block conversion AI to AII
•
Lower blood pressure
Angiotensin receptor blockers (ARBs) •
Block effects of angiotensin II
•
Lower blood pressure
Atrial Natriuretic Peptide
Beta Blockers •
ACE-inhibitors
26
Atrial stretch (pressure/volume) ANP release Vasodilator (↓SVR) Constrictsrenalefferents/dilates afferents Relax vascular smooth muscle via cGMP
•
↑GFR, ↓Renin
•
↑diuresis
Parathyroid Hormone
Parathyroid Hormone Effects
•
Maintains calcium levels
•
Released by chief cells of parathyroid gland
•
Secreted in response to: •
•
•
•
•
•
•
•
↓ [P043-] plasma
•
↑ [P043-] urine
↓ 1 ,25-(0H)2 vitamin D
Dual effects of Mg •
Low Mg stimulates PTH release
•
Very low Mg inhibits PTH release
Parathyroid Hormone Lumen (Urine)
Kidney: 2+
•
↑ Ca
•
↓ P043- resorption (PCT)
•
↑ 1 ,25 -(0H)2 vitamin D production
resorption (DCT)
PTH
Interstitium/Blood Interstitium/Blood Na
X
PO4-
3-
↑Ca2+ and P04 absorption (via vitamin D)
Proximal Tubule
Bone: •
Na ATP K
GI: •
•
↑[Ca 2+] plasma
↓ [Ca2+] ↑ plasma [P043-]
Parathyroid Hormone Effects •
Net Effects:
↑Ca2+ and P04 3- resorption (direct and via vitamin D)
↑PO4excretion
Vitamin D Basics
Parathyroid Hormone Lumen (Urine)
Interstitium/Blood Interstitium/Blood
•
Na+ Na+
•
•
ATP
Vitamin D2 is ergocalciferol Vitamin D3 is cholecalciferol cholecalciferol Two sources D3: •
Diet
•
Sunlight (skin synthesizes D3)
K+ -
Cl
PTH
Distal Tubule Na Ca2+
++
Ca2+
↑Ca Resorption
27
Vitamin D Activation •
•
•
•
•
Vitamin D Function
Vitamin D3 from sun/food inert (no biologic activity) Liver: Converts to 25-OH Vitamin D (calcidiol)
•
•
Kidney: Converts to 1,25-OH2 Vitamin D (calcitriol) 1,25-OH2 Vitamin D = active form Serum [25-OH VitD] best indicator vitamin D status
Calcium-Phosphate in Renal Failure
Vitamin D and the Kidney •
GI: ↑Ca2+ and P043- absorption Bone: ↑Ca2+ and P043- resorption
Sick Kidneys
Proximal Tubule converts vitamin D to active form PTH
25-OH Vitamin D
+ 1α - hydroxylase
↑Phosphate
1,25-OH2 Vitamin D
↓1,25-OH2 Vitamin D
↓Ca from plasma
↓Ca from gut
Hypocalcemia
↑PTH
EPO •
•
•
•
EPO Injections
Made by interstitial cells peritubular capillary
•
Released in response to hypoxia Decreased production in renal failure
•
•
Normocytic anemia
28
Darbepoetin alfa (Aranesp) Epoetin alfa (Epogen) Used to treat anemia of chronic kidney disease
•
FDA Black Box warning
•
Generally reserved for patients with severe anemia
Types of Acids •
Two types of acids produced via metabolism •
Volatile acids
•
Non-volatile acids
Acid Excretion Jason Ryan, MD, MPH
Volatile Acids •
•
•
Non-volatile Acids
CO2 Combines with water to form carbonic acid and H+
•
•
Eliminated by lungs (not kidneys)
Non-volatile Acids •
Not from CO2 Derived from amino acids, fatty acids, nucleic acids
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
29
Bicarb Reabsorption
Renal Acid-Base Regulation •
•
Proximal Tubule Lumen (Urine)
#1:Reabsorb/Generatebicarb #2: Excrete H+
Na+ Interstitium/Blood Na
HCO3- +
H+
H+ + HCO 3-
H2CO3
H2CO 3
CA
CA
CO2 + H2O
CO2 + H2O
CA = Carbonic Anhydrase
HCO3- Generation
Bicarb Reabsorption Reabsorption
Collecting Duct
Nephron 6%
Lumen (Urine)
Interstitium/Blood
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 up H+ Protect from low pH
•
Problem:Bicarbonatereabsorbed Need other buffers
30
Titratable acids Ammonia
-
Titratable Acids •
•
•
Titratable Acids
Urinary substances that absorb H+ Acids
•
•
Measured by titration (“titratable”)
•
•
•
•
HPO4 (one hydrogen) H2PO4 (twohydrogens)
Titratable Acids
Titratable Acids •
Mostlyphosphate Exists in multiple states
HPO4 filtered by glomerulus Form H2PO4 with addition of H + H2PO4 excreted in urine = excretion of H+
Interstitium/Blood
Lumen (Urine) HPO4
H+
↑H2PO4 excretion = ↑ H+ excretion
H+ + HCO3-
H2CO3
H2PO4
CA
CO2 + H2O
Ammonia •
•
•
•
•
Terminology
Limited supply of titratable acids
•
Varies with dietary intake intake (especially phosphate)
•
Supply of ammonia (NH3) is adaptable More NH3 generated by kidneys when ↑ H+ Synthesized fromglutamine from glutamine(amino (amino acid)
Glutamine
31
Ammonia = NH3 Ammonium = NH4+
HCO3 -
H+ excretion HCO3- generation
Ammonia
Renal Acid-Base
↑NH4+ excretion = ↑ H+ excretion
Summary Non-volatileAcids
Interstitium/Blood
Lumen (Urine)
↓ HCO3NH3
H+
NH4+
HCO3-
H+ + HCO 3-
↑ HCO3Reabsorption
Buffering Tit. Acids NH4+
H2CO3 CA
CO2 + H2O
H+ excretion HCO3- generation
Net Acid Excretion •
•
Proximal Tubule
Collecting Duct
↑ H+ Excretion ↑ HCO3- Generated
Net Acid Excretion
Urinary Acid – Urinary Base Positive value indicates acid being excreted
•
•
Net Acid = Titratable Acids + NH4 + - HCO3Excretion
Acidosis: Increased net acid excretion Alkalosis: Decreased net acid excretion
Net Acid = Titratable Acids + NH4 + - HCO3Excretion
32
Acid-Base Equilibrium
Acid Base Principles
CO2 + H2O HCO3- + H +
Jason Ryan, MD, MPH
Determines pH
Acid-Base Equilibrium
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
33
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(Kussmaulbreathing) Depressionof myocardial myocardial contractility contractility Cerebralvasodilation •
Increased cerebral blood flow; Increase ICP
Can have acidosis without acidemia if mixed disorder •
i.e. acidosis + alkalosis at same same time
CO2 + H2O HCO3- + H +
Acidosis Symptoms •
•
CNS depression (very high CO2 levels) Hyperkalemia •
•
Alkalosis Symptoms •
•
High H + shifts into cells in exchange for K +
•
Shift in oxyhemoglobin oxyhemoglobin dissociation curve •
Bohr effect
•
↓ pH leads to hemoglobin releasing more oxygen
Inhibition of respiratory drive Depressionmyocardialcontractility Cerebralvasoconstriction vasoconstriction •
•
•
Approach to Acid-Base Problems
Acid-Base Problems
3. Determineacid-basedisorder
1. Check the pH •
pH < 7.35 = acidosis
•
•
pH > 7.45 = alkalosis
•
2. Check the HCO3- and pCO2 •
HCO3 from venipuncture; venipuncture; normal 22-28 mEq/L
•
pCO2 from ABG; normal 35-45mmHg
Decrease in cerebral cerebral blood flow
Hypokalemia Shift in oxyhemoglobin oxyhemoglobin dissociation curve
•
•
metabolic acidosis Acidosis + ↓ HCO 3- = metabolic respiratory acidosis Acidosis + ↑pCO 2 = respiratory Alkalosis + ↑HCO3- = metabolic alkalosis
Alkalosis+ ↓ pCO 2 = respiratory alkalosis
CO2 + H2O HCO3- + H +
34
Approach to Acid-Base Problems
Approach to Acid-Base Problems
4. For metabolic acidosis only: Calculate anion gap 5. Use special formulas to check for mixed disorder •
Combined respiratory/metabolic
•
Two metabolic disorders
•
Step 2:
•
Compensation = ↓pCO2
•
↑ HCO3- = metabolic alkalosis •
•
Metabolic acidosis, acidosis, respiratory alkalosis, etc.
•
Is there a second second disorder?
•
Is the compensation compensation appropriate?
Cause vs. Compensation
↓ HCO3- = metabolic acidosis
•
Step 1: What is acid base disorder? •
Compensatory Changes •
•
•
Most acid-base disorders, HCO3- and pCO2 abnormal One is “culprit” that is causing disorder Other is compensatory change
Compensation = ↑pCO2
acidosis ↑pCO2 = respiratory acidosis
•
•
Compensation = ↑ HCO3-
alkalosis ↓pCO2 = respiratory alkalosis
•
•
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 with respiratory compensation
-
CO2 + H2O HCO3 + H
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 metabolic compensation
+
-
CO2 + H2O HCO3 + H
35
+
Respiratory Compensation •
•
Respiratory Compensation
Hyper or hypoventilation hypoventilation Changes pCO2 to compensate for metabolic disorders
•
Hyperventilation •
•
•
•
Less H+ in blood
•
pH rises
Hypoventilation •
•
•
•
Renal Compensation •
CO2 + H2O HCO 3- + H+
Retains CO 2 Plasma CO2 level rises More H+ in blood pH falls
Mixed Disorders
Acidosis
•
Two disorders at same time
•
Excess H+ filtered/secreted i nto nephron
•
Metabolic acidosis acidosis AND respiratory alkalosis/acidosis
•
Bicarbonate reabsorbed
•
Metabolic acidosis acidosis AND metabolic alkalosis
•
Urinary buffers excreted
•
Two metabolic acidoses
•
Occurs in many pathologic pathologic states
•
i.e. vomiting and and diarrhea
•
•
•
•
•
Blows off CO2 Plasma CO2 level falls
HPO42- excreted as H 2PO4- (phosphate) NH3 excreted as NH 4+ (ammonium) These bind H+ 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
To uncover, uncover, determine “expected” response •
Expected HCO3- for respiratory disorder
•
Expected CO 2 for metabolic disorder
•
Use renal formulas to determine determine expected expected response
If actual ≠ expected 2nd disorder present
Mixed Disorders •
If actual ≠ expected, determine abnormality •
•
abnormal •
Usual rules then apply for determining 2° disorders: •
•
•
•
36
i.e. CO2 higher than expected i.e. HCO3- lower than expected
↑CO2 = acidosis ↓CO2 = alkalosis ↓ HCO3- = acidosis ↑ HCO3- = alkalosis
Metabolic Acidosis Compensation
Compensation Formulas •
•
•
•
Winter’s Formula Metabolic Alkalosis Formula Acute/ChronicRespiratory Equations Delta-Delta
•
•
•
•
Compensatoryrespiratory alkalosis(↓ pCO2) Hyperventilation
Winter’s Formula: tells you expected pCO2 If actual CO2 ≠ expected, mixed disorder
pCO2 = 1.5 (HCO 3-) + 8 +/- 2
Metabolic Acidosis Compensation •
•
•
•
Metabolic Acidosis Compensation
Compensatoryrespiratory alkalosis(↓pCO2) Hyperventilation
•
•
Winter’s Formula: tells you expected pCO2 If actual pCO2 ≠ expected, mixed disorder
•
•
pCO2 = 1.5 (HCO 3-) + 8 +/- 2
Compensatoryrespiratory alkalosis(↓pCO2) Hyperventilation
Winter’s Formula: tells you expected pCO2 If actual pCO2 ≠ expected, mixed disorder
pCO2 = 1.5 (HCO 3-) + 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
•
•
•
•
Compensatory respiratory acidosis (↑pCO2) Hypoventilation
•
•
↑pCO2 0.7 mmHg per 1.0meq/L ↑ [HCO3-] If actual pCO2 ≠ expected, mixed disorder
ΔpCO2 = 0.7 *
•
•
Compensatory respiratory acidosis (↑pCO2) Hypoventilation
↑pCO2 0.7 mmHg per 1.0meq/L ↑ [HCO3-] If actual pCO2 ≠ expected, mixed disorder
ΔpCO2 = 0.7 * (Δ[HCO3-])
(Δ[HCO3-])
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
37
Respiratory Acidosis
Respiratory Acidosis
Compensation
Compensation
•
Acutecompensation •
•
•
Minutes
Acute compensation •
[HCO3-]
•
Intracellular buffers raise
•
Hemoglobin and other proteins
•
Small ↑pH
•
•
•
Days
•
Renal generation of ↑[HCO3-]
•
Larger ↑pH (but not back to normal!)
Chroniccompensation •
Chronic compensation
1 meq/L ↑ [HCO 3-] for every 10 mmHg ↑pCO2 Δ[HCO3-] = ΔpCO 2/10
•
3.5 meq/L ↑ [HCO 3-] for every 10 mmHg ↑pCO2 Δ[HCO3-] = 3.5* ΔpCO 2/10 Example 1 pH = 7.15 (acidosis) pCO2 = 80mmHg (nl=40) Acute Δ[HCO 3-] = 40/10 = 4 [HCO 3-] = 28; pH = 7.17 Chronic Δ[HCO 3-] = 3.5* 40/10 = 14 [HCO3-] = 38; pH = 7.30
Respiratory Alkalosis
Respiratory Alkalosis
Compensation
Compensation
•
Acutecompensation
•
Chronic compensation
•
Acute compensation •
•
•
2meq/L ↓ [HCO 3-] for every 10 mmHg ↓ pCO2 Δ[HCO3-] = 2*ΔpCO 2/10
Chroniccompensation •
•
4meq/L ↓[HCO 3-] for every 10 mmHg ↓ pCO2 Δ[HCO3-] = 4 * ΔpCO 2/10 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 [HCO 3-] = 16; pH = 7.53
Compensation Timeframe •
•
Summary Acidosis
Respiratory compensation to metabolic disorders •
Rapid
•
Change in respiratory respiratory rate
•
Minutes
Respiratory
Alkalosis
Metabolic
Respiratory
Metabolic
Metabolic compensation to respiratory disorders •
Acute, mild compensation compensation in minutes from cells
•
Chronic, significant compensation in days from kidneys
Compensation Compensation ↑HCO 3↓pCO 2
Acute/Chronic Formulas
38
Winter’s Formula
Compensation Compensation HCO3↑pCO 2
Acute/Chronic Expected pCO 2 ormulas Formula
Acid-Base Disorders 1. Respiratoryalkalosis 2. Respiratory acidosis 3. Metabolic alkalosis 4. Metabolic acidosis
Respiratory Acid Base Disorders Jason Ryan, MD, MPH
Respiratory Alkalosis
Respiratory Alkalosis •
•
↓pCO2 pH>7.45
•
Caused by hyperventilation •
Pain
•
Early high altitude exposure
•
Early aspirin overdose
CO2 + H2O HCO3- + H +
High Altitude •
•
•
•
•
•
Aspirin Overdose
Lower atmospheric pressure Lower pO2 Hypoxia hyperventilation ↓pCO2 respiratory alkalosis (pH rises)
Ventilation rate will decrease
•
Acetazolamide Acetazolamide can augment excretion HCO3-
Two acid-base acid-base disorders
•
Shortly after ingestion: respiratory alkalosis
•
After 24-48hrs, kidneys will excrete HCO3pH will fall back toward normal
•
•
39
•
Salicylates stimulate medulla
•
Hyperventilation
Hours after ingestion: AG metabolic metabolic acidosis •
Salicylates ↓lipolysis, uncouple oxidative phosphorylation
•
Inhibits citric acid acid cycle
•
Accumulation of pyruvate, lactate, ketoacids
Aspirin Overdose •
•
pH Variable due to mixed disorder
•
Acidotic, alkalotic, normal
•
•
Winter’s formula
•
PCO2 < Expected
•
Concomitantrespiratory alkalosis
•
Low due to hyperventilation
HCO3If patent is acidotic: acidotic: •
Winter’s formula predicts CO 2 higher than actual
•
CO2 lower than expected for compensation
Respiratory Acidosis
↑pCO2 pH<7.35
•
•
•
•
CO2 + H2O HCO 3 - + H+
Hypercapnia •
Hypercapnia can affect CNS system
•
Most patients with acute ↑CO2 are agitated
•
•
PCO2 = 1.5 (14) + 8 +/- 2 = 29
Low due to acidosis
Respiratory Acidosis •
Sample case: pH 7.30, PCO 2 20, HC03- 14 Metabolic acidosis
•
CO2
•
•
•
•
•
•
Aspirin Overdose
Some have depressed consciousness consciousness (CO2 narcosis) Δ mental status in patient with respiratory disease: •
Consider high CO2
•
Check ABG
•
If CO2 high ventilation
40
Cause by hypoventilation hypoventilation Lung disease (COPD, PNA, Asthma) Narcotics Respiratorymuscleweakness •
Myasthenia gravis
•
Amyotrophic lateral sclerosis sclerosis
•
Guillain-Barré syndrome
•
Muscular dystrophy
Acid-Base Disorders 1. Respiratoryalkalosis 2. Respiratory acidosis 3. Metabolic alkalosis 4. Metabolic acidosis
Metabolic Alkalosis Jason Ryan, MD, MPH
Metabolic Alkalosis
Metabolic Alkalosis •
•
↑HCO3pH>7.45
•
•
•
•
•
•
Contractionalkalosis Hypokalemia Diuretics Vomiting Hyperaldosteronism Antacid use
CO2 + H2O HCO3 - + H + Loss of H + from the body or a gain of HCO 3-
Contraction Alkalosis •
Proximal Tubule: Bicarb Lumen (Urine)
Renin-Angiotensin-Aldosteroneactivation ↓ECV Renin-Angiotensin-Aldosterone •
•
•
Na+ Interstitium/Blood Na
↑H+ secretion proximal tubule (due to AII) ↑ HCO 3- resorption proximal tubule (due to ↑H + secretion) (due to aldosterone) ↑H+ secretion collecting duct (due
HCO3- +
H+
H2CO3 CA
CO2 + H2O
H+ + HCO 3-
H2CO 3 CA
CO2 + H2O
CA = Carbonic Anhydrase
41
Collecting Duct
Hypokalemia
Principle Cell
Lumen (Urine)
Na+
Interstitium/Blood •
+
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
Intercalated Cell
HCO3Aldosterone H+
Cl-
Bartter and Gitelman Syndromes
Diuretics •
•
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 transport in distal tubule
•
Similar to thiazide diuretic
Both cause hypokalemia/alkalosis
Urinary Chloride
•
Loss of volume contraction alkalosis
•
Useful in metabolic alkalosis unknown cause
•
Loss of HCl
•
Low (<10-20) in v omiting
•
↑ production HCl
•
HCO3- generated during production
•
Loss of K+
•
Urinary chloride is low (<20)
•
•
•
42
Loss of Cl in gastric secretions
High (>20) in many other causes alkalosis Classicscenario: •
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 •
•
•
•
•
•
•
•
Compensatorymechanismsactivated Increased ANP
Increased sodium and free water excretion Result: diuresis normal volume status
•
•
Hypokalemia Metabolic alkalosis Resistant hypertension
Milk-alkali Milk-alkali syndrome Excessive intake 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
Antacid use
Often no edema in hyperaldosteronism hyperaldosteronism Na/Fluidretention hypertension •
Adrenaloverproduction aldosterone Adrenalhyperplasia
Keys to Diagnosis
Hypercalcemia: •
Inhibition Na-K-2Cl in TAL TAL
•
Blockade (ADH)-dependent (ADH)-dependent water reabsorption collecting duct
•
Results in volume contraction contraction
•
Contraction + alkali = metabolic alkalosis
•
History
•
Fluid status
•
Urinary chloride
•
•
43
Volume depleted: depleted: vomiting or GI losses
Low in surreptitious surreptitious vomiting
IV Fluid Administration •
•
Resolves most forms of metabolic alkalosis alkalosis •
“Fluid responsive”
•
Diuretics
•
Vomiting
•
Contraction alkalosis
Exceptionsare hyperaldosteronism, hyperaldosteronism, hypokalemia hypokalemia
44
Non-AG Metabolic Acidosis •
•
Renal Tubular Acidosis
•
•
Diarrhea Acetazolamide
Spironolactone/Addison’s disease Saline infusion
•
Hyperalimentation
•
Renal tubular acidosis acidosis
Jason Ryan, MD, MPH
Renal Tubular Acidosis •
•
•
Type I (distal) RTA
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 nephron cells cannot acidify urine excrete H+ (acidemia) Can’t excrete
Can’t resorbK+ (hypokalemia)
Type I (distal) RTA •
Key symptoms: Chronic kidney stones, Rickets •
•
Distal tubule cannot cannot “acidify” the urine
•
•
Urine is alkaline
•
•
Diagnosis established if alkaline urine (pH > 5.5) despite a metabolic acidosis acidosis (with normal normal kidneys)
•
45
Alkaline urine precipitates stones (sometimes bilateral) Acidosis ↑Ca from bones
Acidosis suppresses 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 •
In acidosis, lots of NH4 excreted (removes H+) Can’t measureNH4 directly Urinary anion gap (Na + K – Cl) is a surrogate NH4 leaves with Cl UAG becomes negative when acid (H+) being excreted
Urine Anion Gap
In GI metabolic acidosis (diarrhea): •
•
•
•
UAG becomes negative
In distal RTAUAG is positive •
Excretion of NH4 with Cl increases Urine Cl concentration concentration goes up
•
•
•
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 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 Urine pH<5.5
•
Patient with Sjogren’s Sjogren’s disease
•
Recurrent bilateral 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 remains with high pH
•
•
•
Treatment: Sodium bicarbonate
46
Initially, pH may be high due to ↑HC0 3- excretion Distal tubule excretes excretes H+ as acidosis acidosis becomes established Urine becomes acidic
Hypokalemia
•
Loss of HCO3- resorption
•
Volume contraction
diuresis
•
↑aldosterone ↑K excretion hypokalemia
Type II (proximal) RTA •
•
•
Type II (proximal) RTA
Milder than type I: [HC03-] 12-20
•
Distal intercalated intercalated cells function normally
•
No symptoms : routine 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, glucose, amino acids, acids, urate, protein
•
Bone wasting from phosphate loss
•
Type IV RTA •
•
•
•
•
Aldosterone deficiency/resistance
Decreased excretion K+ Only RTA with HYPERkalemia Urine pH usually remains low (<5.4) Impaired ammonium (NH4+) excretion acidosis
•
Type IV RTA •
•
Diabetic with renal insufficiency
•
Unexplained hyperkalemia
Treatment: Fludrocortisone •
Mildly reduced HCO3- (10 – 20)
•
Hypokalemia
•
Urine pH is low (<5.3)
Treatment: Sodium bicarbonate
Decreased aldosterone •
Diabetic renal disease
•
ACEi or ARB
•
NSAIDs
•
Adrenal insufficiency
Aldosterone Aldosterone resistance resistance •
Potassium sparing diuretics
•
TMP/SMX
Renal Tubular Acidosis
Classic case: •
•
Type IV RTA
Distal tubule failure to respond to aldosterone •
•
Sample Case
•
Mineralocorticoid
47
Metabolic Acidosis •
•
Most complex set of acid-base disorders Etiology determined by anion gap
Metabolic Acidosis Jason Ryan, MD, MPH
The “Chem 7”
The Anion Gap
Fishbone
•
Na+
Cl-
K+
HCO3-
BUN
•
Glucose
•
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
15
140
100 4.8
26
103
15 100
1.0
4.8
26
1.0
Anion Gap = 140 – (103 + 26) = 11
The Anion Gap •
•
•
•
•
Why the Anion Gap Matters
Results from unmeasured ions Ca 2+,
•
Mg2+,
Cations: 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 increase increase measured (-) ions
Acidosis from primary loss of HCO3•
Body compensates compensates with retention retention of Cl -
•
AG = Na + – (Cl- + HCO3-)
•
Normal anion gap
Acidosis from primary retention of acid •
48
i.e. ketoacids, lactic lactic acid
•
HCO3- falls without rise in Cl-
•
Rise in A - to compensate for fall in HCO3 -
•
AG = Na + – (Cl- + HCO3-)
•
Result is ↑AG
Two Cases
Why the Anion Gap Matters •
•
•
•
When HCO3- ↓ something negative must ↑ This maintain balance of (-) and (+) charges
AG = 10
134
108 pH
In normal AG Cl- rises In high AG Unmeasured acids rise
7.31
16
132
93
AG = 28
pH
7.27
11
The Delta-Delta
Winter’s Formula •
Acidosis: compensatory respiratory alkalosis (↓ pCO pCO2) •
•
•
•
Delta Ratio •
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 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 (HCO3-) + 8 +/- 2
Δ HCO HCO3
The Delta-Delta •
ΔΔ 1-2 = normal ΔΔ <1 = 2° non-AG metabolic acidosis •
•
•
•
HCO3- too low
•
ΔΔ >2 = 2° metabolic alkalosis or pre-existing respiratory acidosis •
•
•
HCO3- too high
•
•
ΔΔ
= ΔAG Δ HCO3
-
The Delta-Delta
Delta Ratio •
= ΔAG
•
-
49
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 30/12 = 2.5 HCO3- is too high Concurrent metabolic alkalosis or prior resp. acidosis
Non-AG Metabolic Acidosis •
Diarrhea •
•
Saline infusion
-
Lose HCO3 in stool
•
Acetazolamide •
•
•
Blocks formation and resorption HCO 3-
•
•
Loss of aldosterone 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
•
•
•
•
•
•
•
•
•
Iron tablets or INH Lacticacidosis
•
Salicylates
Methanol •
•
•
Suspected ingestion (accidental, suicide, alcoholic)
•
Confusion (may appear inebriated)
•
Visual symptoms
•
High AG metabolic metabolic acidosis
•
•
•
•
Treatment:
•
Inhibit alcohol dehydrogenase dehydrogenase
•
Blocks bioactivation of parent alcohol to toxic 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:
•
Something with (-) charge that is NOT chloride
Methanol
Diabetic ketoacidosis Propylene glycol
Ethyleneglycol
Other substance is “unmeasuredanion” “unmeasured anion”
Renal tubular acidosis acidosis
Methanol Uremia
•
Some other (-) substance must ↑ to balance Other substance is not Cl Cl•
Anion Gap Metabolic Acidosis •
Anion Gap = Na – (Cl- + HC03-) HCO3- will be low (metabolic acidosis) acidosis)
50
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 •
•
Ethanol
Classic scenario: •
Suspected ingestion (accidental, suicide, alcoholic)
•
Flank pain, oliguria, anorexia (acute renal failure)
•
High AG metabolic metabolic acidosis
Treatment: •
Inhibit alcohol dehydrogenase dehydrogenase
•
Blocks bioactivation of parent alcohol to toxic toxic metabolite
•
Fomepizole (Antizol)
•
Ethanol
Methanol
Alcohol Dehydrogenase
Alcohol Dehydrogenase
EthyleneGlycol
Propylene Glycol •
•
•
•
•
•
•
•
•
Metabolized to pyruvic acid, acetic acid, lactic acid Many adverse effects: Hemolysis
•
Seizure, coma, and and multisystem organ failure
•
High AG metabolic acidosis from lactate Main clinical feature of overdose is CNS depression
•
Uremia
•
•
•
•
Reduction in H + excretion (loss of tubule function)
•
Increase in HCO3 - excretion
•
Cl- retained to balance balance charge (normal AG)
Does NOT cause anion gap metabolic acidosis Absence of high AG acidosis suggest suggest IA ingestion
No role for fomepizole or ethanol Main symptom of ingestion is coma
Diabetic Ketoacidosis (DKA)
Advanced kidney disease Early kidney disease can can have non-AG acidosis
Key scenario: ingestion ingestion by alcoholic
Converted by ADH to acetone Less toxic than methanol or e thylene glycol •
•
No visual symptoms or nephrotoxicity nephrotoxicity
•
Glycolaldehyde
Found in many of the same industrial products as methanol, ethylene glycol Effects similar similar to ethanol •
•
•
•
Formaldehyde
Isopropyl Alcohol
Antifreeze (lowers freezing point of water) Solvent for IV benzos
•
Acetaldehyde
•
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
51
Often triggered by infection
β-hydroxybutyrate, acetoacetate
Diabetic Ketoacidosis (DKA) •
•
•
Lactic Acidosis
Polyuria,polydipsia (↑glucose diuresis) Abdominal pain, nausea, vomiting
•
•
Kussmaul respirations •
Deep, rapid breathing
•
From acidosis
•
High AG metabolic acidosis from ketones
•
Treatment:
•
•
•
•
•
•
•
Shock (↓tissue perfusion) perfusion)
•
Ischemic bowel
Insulin (lower glucose)
•
Metformin therapy (especially (especially with renal failure)
•
Seizures
•
Potassium
•
Exercise
Iron
Acute iron poisoning Initial GI phase •
Abdominal pain
•
Direct toxic effects GI tract
•
AG metabolic acidosis •
From ferric irons
•
Also lactate (hypoperfusion) (hypoperfusion)
Later (24 hours) Cardiovascular toxicity: shock, shock, tachycardia, tachycardia, hypotension
•
Coagulopathy: iron inhibits thrombin formation/action
•
Hepatic dysfunction: dysfunction: worsening coagulopathy
•
Acute lung injury
Weeks later: bowel obstruction Scarring at gastric outlet where iron accumulates
Isoniazid (INH) •
•
IV fluids (hydration)
•
•
Clinicalscenarios:
•
•
•
High levels (>4.0mmol/L) lactic acidosis AG metabolic acidosis
•
Iron •
Low tissue oxygen delivery Pyruvate converted to lactate
Aspirin Overdose
Tuberculosis antibiotic Acute overdose causes seizures (status epilepticus) Seizures cause lactic acidosis
•
Two acid-base acid-base disorders
•
Shortly after ingestion: respiratory alkalosis
AG metabolic acidosis •
52
•
Salicylates stimulate medulla
•
Hyperventilation
Hours after ingestion: AG metabolic metabolic acidosis •
Salicylates ↓lipolysis, uncouple oxidative phosphorylation
•
Inhibits citric acid 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
•
PCO2 < Expected
•
Concomitantrespiratory alkalosis
•
Low due to hyperventilation
HCO3•
•
•
CO2 •
•
Aspirin Overdose
Low due to acidosis
Winter’s formula predicts CO2 higher than actual CO2 lower than expected for compensation compensation
53
PCO2 = 1.5 (12) + 8 +/- 2 = 29
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: pH 7.30, pCO2 33mmHg Electrolytes are: Na 134, K 2.9, Cl 108, HCO3- 16
Jason Ryan, MD, MPH
What is the acid-base acid-base disorder?
Case 1 •
•
•
•
•
•
•
•
134
108
2.9
16
Case 2
Diarrhea non-AGmetabolicacidosis No other clues to suggest a 2nd disorder
An 80-year-old man with a severe cardiomyopathy cardiomyopathy presents with shortness of breath and edema for the
pH = 7.30 acidosis HCO3- = 16 (low) metabolic acidosis pCO2 = 33 (low) respiratory compensation compensation Abnormal same direction mixed disorder less likely 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
past two days. An arterial blood gas is drawn showing: pH 7.25, pCO2 62mmHg Electrolytes show: HCO3- 27 What is the acid-base acid-base disorder?
Case 2
Case 3
•
CHF exacerbation acute respiratory acidosis
•
pH = 7.25 (acidosis) (acidosis)
•
•
•
•
•
•
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
pCO2 = 62 (high) respiratoryacidosis HCO3- = 27 (high) metaboliccompensation 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 acidosis
54
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 Expected PCO2 = 32 AG = 140 – 110 – 16 = 14 Non-AG metabolic acidosis
•
Must consider RTA given RA history/kidney stones UAG should be checked •
•
Urine Na + K – Cl
•
Should be negative due due to acidosis
•
If positive, suggests RTA
Acid challenge with NH4Cl should be done •
•
Urine pH will remain >5.3 after NH 4Cl Type I RTA cannot acidify urine
Non-AG metabolic acidosis
Case 4
Case 4
75-year-old man has a long-standing history of severe COPD for which he requires chronic oxygen therapy.
•
•
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?
•
140
94
4.0
34
pH = 7.32 (acidosis) (acidosis) PCO2 = 69 respiratoryacidosis HCO3- = 34 metaboliccompensation 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; HCO 3- 34
•
•
•
•
pH = 7.52 (alkalosis) (alkalosis) HCO3- = 34 (high) metabolic alkalosis PCO2 = 47 (high) respiratorycompensation
ΔpCO2 = 0.7 * (Δ[HCO3 -]) Δ PCO2 = 47- 40 = 7 Δ[HCO3-] = 34 – 24 = 10 Expected Δ PCO2 = 0.7 * (10) = 7
What is the acid-base disorder? Pure metabolic alkalosis
55
Case 5 •
Cause? •
•
depression presents with altered mental status. He was found by his ex-wife sleeping in his tool shed. He reports blurry vision and black spots. An arterial blood gas is drawn showing:
Reduced in contraction, diuretics, vomiting
Need to know urinary chloride •
•
A 59-year-old man with a history of alcoholism and
Contraction alkalosis, hypokalemia, diuretics, vomiting, hyperaldosteronism, antacid use
Need to know volume status •
•
Case 6
pH 7.30, pCO2 28mmHg Electrolytes show: Na 141, Cl- 102; HCO3- 14
Low with GI losses losses (vomiting)
This disorder often fluid (saline) responsive
What is the acid-base acid-base disorder?
141
Case 6
102
•
pH = 7.30 (acidosis) (acidosis)
•
HCO3- = 14 metabolic acidosis
•
•
•
•
•
•
•
Case 7
14 pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (14) + 8 = 29 +/- 2
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
pCO2 = 28mmHg respiratory compensation compensation Expected PCO2 = 29 +/- 2
takes narcotics for back pain and she believes he has been taking more pills than usual lately for abdominal
No secondary respiratory disorder AG = 141 – 102 – 14 = 25 (high)
ΔHCO3-=24 – 14
ΔAG = 25 – 12 = 13; ΔΔ = 13/10 = 1.3 No secondary metabolic disorder
pain. An arterial blood gas is drawn showing: pH 7.28, pCO2 40mmHg. Electrolytes are:
= 10
Na 134, K 3.5, Cl 94, HCO3- 12 What is the acid-base disorder? 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 acidosis
•
•
•
pH = 7.28 acidosis
134 3.5
94 12
Winter’s formula pCO2 = 26 pCO2 higher than expected at 40 Concomitantrespiratory acidosis
pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (12) + 8 = 26 +/- 2
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
56
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. 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 pCO2 = 24 (low) respiratory compensation Abnormal same direction mixed disorder less likely Anion gap = 140 – 79 – 10 = 51 (high)
What is the acid-base disorder?
Case 8 •
•
•
•
•
•
•
140
79
3.2
10
Summary
Winter’s Formula pCO2 = 23 +/ - 2 Actual pCO2 = 24 Normalrespiratory compensation ΔAG = 51 – 12 = 39
•
•
pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (10) + 8 = 23 +/- 2
•
•
ΔHCO3- = 24 – 10 = 14 ΔΔ = 39/14 = 2.8 Concurrent metabolic alkalosis
•
•
Diarrhea non-AG metabolic acidosis Acuterespiratory acidosis Renal tubular acidosis - Urine anion gap Chronicrespiratory acidosis Metabolic alkalosis -Volume status/urine chloride Methanoltoxicity
•
AG metabolic acidosis with respiratory acidosis
•
AG Metabolic acidosis with metabolic alkalosis
•
•
AG Metabolic Metabolic Acidosis Acidosis with with metabolic metabolic alkalosis
57
Winter’s formula doesn’t match compensation Delta-delta abnormal
Potassium •
•
Need potassium for HEART and SKELETAL MUSCLES Hypo, hyper effects: •
EKG changes
•
Arrhythmias
•
Weakness
Electrolytes Jason Ryan, MD, MPH
Hyperkalemia
Peak T waves
Signs/Symptoms •
EKG changes •
QRS widening
•
Peaked T waves
•
Arrhythmias
•
Muscleweakness
QRS Widening
Hyperkalemia
Atrial/ventricular Atrial/ventricular myocytes
Causes
Phase 1 IK+ (out)
•
0mv Phase 3 IK+ (out) ERP -85mv Phase 4
58
Increased K release from cells •
Acidosis
•
Insulin deficiency
•
Beta blockers
•
Digoxin
•
Lysis of cells
•
Hyperosmolarity
Hyperkalemia
Hypokalemia
Causes
Signs/Symptoms
•
Decreased K excretion in urine
•
EKG changes
•
Acute and chronic kidney disease
•
U waves
•
Type IV RTA (aldosterone resistance)
•
Flattened T waves
•
•
Hypokalemia
U waves
Selected Causes T
U
•
Origin unclear May represent repolarization of Purkinje fibers or papillary muscles
Arrhythmias Muscleweakness
Increased K entry into cells •
Hyperinsulin states
•
Elevated beta-adrenergic beta-adrenergic activity
•
Alkalosis
•
T
U
•
Can be normal
Albuterol, terbutaline, dobutamine
Increased GI losses •
Vomiting/diarrhea
Hypokalemia
Hypercalcemia
Selected Causes
Symptoms
•
•
Increase renal losses
•
Stones (kidney)
•
Diuretics
•
Most common effect effect is polyuria
•
Type I and II RTAs
•
High Ca in urine can cause cause stones
•
Chronic ↑ can cause cause renal failure
Hypomagnesemia •
Promotes urinary K loss
•
•
Cannot correct K until Mg is corrected!!
•
Bones (bone pain) Groans (abdominal pain) pain) •
•
•
59
Constipation, anorexia, nausea
Psychiatric overtones Anxiety, altered mental status
Hypercalcemia
Hypocalcemia
Selected Causes
Signs/Symptoms
•
•
Bone resorption
•
Tetany
•
Hyperparathyroidism
•
Trousseau's sign: Hand Hand spasm with BP cuff inflation
•
Malignancy
•
Chvostek's sign: Facial Facial contraction with tapping on nerve
Increase GI absorption •
Hypervitaminosis D
•
Milk alkali syndrome •
High intake calcium carbonate (ulcers)
•
Triad: Hypercalcemia, metabolic alkalosis, renal failure
•
Seizures
Hypocalcemia
Hyperphosphatemia
Selected Causes
Symptoms
•
•
Hypoparathyroidism Renalfailure
•
Pancreatitis Pancreatitis (saponification of Mg/Ca in necrotic fat)
•
Hypomagnesemia
•
•
•
Selected Causes
Tumor lysis syndrome
•
Rhabdomyolysis
•
Large amount of phosphate laxatives (Fleet’s (Fleet’s Phospho-soda)
•
Acute and chronic kidney disease
•
Hypoparathyroidism
•
“Calciphylaxis”
•
Calcium deposition in media layer of arteries
•
Painful nodules, skin necrosis
Sick Kidneys
Huge phosphate load •
Metastatic calcifications may occur
Calcium-Phosphate in Renal Failure
Hyperphosphatemia •
Most patients asymptomatic Signs and symptoms usually from hypocalcemia
↑Phosphate
↓1,25-OH2 Vitamin D
↓Ca from plasma
↓Ca from gut
Hypocalcemia
↑PTH
60
Hypophosphatemia
Hypophosphatemia
Symptoms
Selected Causes
•
•
Main acute symptom is weakness •
ATP depletion
•
Often presents are respiratory muscle weakness
•
Primary hyperparathyroidism
•
Antacids
•
DKA
•
Refeeding syndrome in alcoholics
•
If chronic, can result in bone loss, osteomalacia osteomalacia
•
•
Ammonium hydroxide Glucose induced diuresis
↑PO4 excretion
•
Low PO4 from poor poor nutrition
•
Food intake metabolism further ↓PO4
Urinarywasting •
Fanconi Syndrome
•
Tumor-induced osteomalacia
Hypermagnesemia
Hypermagnesemia
Signs/Symptoms
Selected Causes
•
Mg blocks Ca and K channels
•
Neuromuscular toxicity
•
•
•
•
↓ DTRs
•
Paralysis
•
Renalinsufficiency
Bradycardia, Hypotension, Cardiac arrest Lethargy Hypocalcemia Hypocalcemia (inhibits PTH secretion)
Hypomagnesemia
Hypomagnesemia
Symptoms
Selected Causes
•
Neuromuscular excitability •
•
•
•
•
Tetany, tremor
Hypokalemia Hypocalcemia
•
Cardiacarrhythmias •
61
GI losses ( secretions contain Mg) •
Diarrhea
•
Pancreatitis (saponification of Mg/Ca in necrotic fat)
Renal losses •
Loop and thiazide thiazide diuretics
•
Alcohol abuse (alcohol-induced tubular dysfunction)
Drugs •
Omeprazole (impaired absorption)
•
Foscarnet (causes (causes chelation; used used for HIV CMV infection)
Balance •
•
Sodium and Water Balance
•
Water in = water out “water balance” Sodium in = sodium out “sodiumbalance” “sodium balance” Majorregulators: •
Antidiuretic hormone (ADH)
•
Sympathetic nervous system (SNS)
•
Renin-angiotensin-aldosterone system (RAAS)
Jason Ryan, MD, MPH
Effective Circulating Volume •
•
Effective Circulating Volume
Portion of extracellular fluid Contained in arterial system
•
Maintains tissue perfusion
•
Not necessarily correlated with total body water
•
•
Effective Circulating Volume •
Low ECV can lead to low blood pressure
•
May cause orthostatic hypotension
•
Modified by: •
Volume
•
Cardiac output
•
Vascular resistance
Majordeterminant: sodium •
Excess sodium ↑ ECV
•
Restricted sodium
↓ ECV
Effective Circulating Volume •
Dizziness/fainting Dizziness/faintingon standing •
62
Low ECV activates: activates: •
Sympathetic nervous system
•
Renin-angiotensin-aldosterone system
Retentionof sodium/water sodium/water
Antidiuretic Hormone
Effective Circulating Volume •
•
•
•
ADH; Vasopressin
Some disease states have chronically ↓ ECV Chronic activation activation of SNS and RAAS Chronic retention of sodium/water by kidneys May or may not lead to increased total body water
Antidiuretic Hormone Also released with low ECV •
Retention of free water
•
Major physiologic trigger is plasmaosmolality
•
ADH “Non-osmotic release” of of ADH
•
•
Second trigger in addition to serum serum osmolality
•
Only activated with very low ECV
•
Sensed by hypothalamus
•
ADH released by posterior pituitary gland
•
ADH free water resorption by kidneys
•
Water retention adjusted adjusted to maintain maintain normal osmolality
Water Balance
ADH; Vasopressin •
•
•
•
•
Water Balance
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 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
63
Sodium Balance
Sodium Balance •
•
•
•
•
Plasma sodium maintained at ~ 140meq/L Excess sodium ↑ osmolality
Excess Sodium
↓ Osmolality
↑ Osmolality
↓ ADH
↑ ADH
↓ Water Resorption
↑ Water Resorption
↑ Water Excretion
↓Water Excretion
↓ ECV
↑ ECV
↑ osmolality water retention normal sodium Water retention ↑ ECV Sodium intake expands ECV
Sodium Balance
Sodium Balance
•
V C E / r e t a W y d o B l a t o T
Restricted Sodium
↑ ADH Na In > Na Out [Na] = Normal ↑Posm ADH = Baseline In = Out Na In > Na Out
•
•
ADH = Baseline
•
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: Increased sodium e xcretion
Restricted Sodium
Excess Sodium
↓ ECV
↑ ECV
↑ SNS/RAAS
↓ SNS/RAAS
↑ Na Retention
↓ Sodium Retention
↓ Na Excretion
↑ Na Excretion
In = Out
In = Out
Out = In balance restored
64
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 •
Weight loss
•
May improve hypertension
Time Sodium Consumption
Out of Balance •
•
Lack of water balance balance •
Alters plasma sodium level
•
Hypo or hypernatremia
GI Losses •
•
•
Lack of sodium balance •
Alters total body volume/ECV
•
Hypo or hypervolemia
•
•
•
•
Hyponatremia often occur •
Drinking free water
•
Not eating (no sodium)
Hypernatremia can occur •
Volume loss •
•
GI Losses
Nausea, vomiting, diarrhea Activation of SNS/RAAS
↑ ADH release
Non osmotic release release 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 enough free water
65
Chronically ↓ ECV (low cardiac output) Chronic activation of SNS and RAAS Sodiumchronicallyretained Free water also retained to balance sodium
Heart Failure •
•
•
•
Heart Failure
Sodium balance disrupted Sodiumexcretionalwaysreduced
•
High sodium intake intake > excretion Hypervolemia often occurs
•
ECV does not ↑ normally with fluid retention •
Failing heart unable to increase CO
•
Heart failure patients patients always have low ECV
Result:Congestion Result: Congestion •
•
•
•
•
•
ADH always high
•
Driven by volume sensors (“non-osmotic”)
•
No longer controlled controlled by plasma sodium level
Pitting edema
Syndrome of Inappropriate ADH Secretion
Water balance disrupted ↓ ECV ↑ ADH release •
Elevated jugular venous pressure
•
SIADH
Heart Failure •
Pulmonary edema
•
•
•
•
Water balance control by ADH lost Free water always retained by kidneys
•
Excessive ADH release Excess water retention hyponatremia Normal total body water •
Water retention ↑ ECV ↓ SNS/RAAS
•
Sodium excretion ↓ ECV (back to normal)
Key findings •
Plasma sodium determined by relative intake/losses Hyponatremia often occurs
66
Hyponatremia
•
Normal volume status
•
Concentrated urine
Sodium Disorders •
•
In general, these are disorders ofWATER of WATERnot not sodium Hyponatremia •
•
Too much water
Hypernatremia •
Too little water
Sodium Disorders Jason Ryan, MD, MPH
Hyponatremia
Sodium Symptoms •
•
•
Symptoms
Hypo and hypernatremia effectbrain effect brain Low sodium = low plasma osmotic pressure •
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 •
•
Plasma osmolality
•
Urinary sodium Urinary osmolality
•
•
•
67
Amount of solutes present in plasma Key solute:Sodium solute: Sodium Osmolality should be LOW in HYPOnatremia HYPOnatremia 1st step in hyponatremia is to make sure it’s low
Plasma Osmolality
Plasma Osmolality •
Serum Osmolality = 2 * [Na] + Glucose Glucose + BUN 18
2.8
Hyponatremia with HIGH osmolality •
Hyperglycemia or mannitol
•
Glucose or mannitol mannitol = osmoles
•
Raise plasma osmolality
•
Water out of cells
hyponatremia
Normal = 285 (275 to 295)
Plasma Osmolality •
Plasma Osmolality
Hyponatremia Hyponatremia with NORMAL osmolality •
Artifact in serum Na measurement
•
Hyperlipidemia
•
Hyperproteinemia (multiple myeloma)
•
“Pseudohyponatremia”
•
1st step in evaluation of hyponatremia unknown cause Plasma Osmolality
Low
Normal Lipids Protein
High Glucose Mannitol
Further Workup
Urinary Sodium
Urinary Osmolality
•
Usually > 20meq/L
•
•
Varies with dietary sodium and free water in urine
•
•
Low value: low sodium intake or excess free water
•
•
68
Concentrations of all osmoles in urine (Na, Cl, K, 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)
Antidiuretic Hormone
Antidiuretic Hormone
ADH; Vasopressin
ADH; Vasopressin
•
•
•
Osmolality sensed by hypothalamus
•
Responds to water intake to maintain sodium levels
ADH released by posterior pituitary gland ADH free water resorption by kidneys
Excess Water
Restricted Water
↓ Osmolality
↑ Osmolality
↓ ADH
↑ ADH
↓ Water Resorption
↑ Water Resorption
↑ Water Excretion
↓Water Excretion
↓ Uosm
↑ Uosm
Antidiuretic Hormone
Hyponatremia
ADH; Vasopressin
General Points
•
•
•
•
Any cause of high ADH can cause hyponatremia Sodium no longer controlled by ADH (always high)
•
Urine should be diluted •
Plasma free water varies with intake Increased intake hyponatremia
More free water than than solutes
•
Low urine osmolality (<100mosm/kg)
•
Low urinary sodium sodium (<30meq/L)
Hyponatremia
Hyponatremia
General Points
Causes
•
If urine is diluted •
•
1. Heart failure and Cirrhosis Cirrhosis 2. Kidneys ineffective 3. High ADH
Kidneys responding appropriately
•
ADH level is low (as it should should be)
•
Problem is outside the kidneys
4. Psychogenic polydipsia/Dietary
If urine is not diluted •
Kidneys are NOT responding appropriately
•
Too much ADH
•
Or drugs/pathology drugs/pathology interfering with kidney function
69
Heart failure and Cirrhosis •
•
•
Kidneys ineffective
Perceivedhypovolemia ADH levels high Urine not diluted (Uosm > 100)
•
Clinical signs of hypervolemia
•
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
May occur with euvolemia or hypervolemia
Diuretics •
•
•
Diuretics
Kidneys ineffective •
Advancedrenal Advanced renalfailure
Cause sodium and and water loss
•
Most commonly thiazides
•
Can occur with loop diuretics
Cortex
Highly variable urinary findings •
↑ sodium and water excretion
•
Dehydration ↑ ADH
•
Water/Na in urine vary by dose, dietary dietary intake
•
Key test: Response to 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 = powerful diuretic)
•
Sweat
•
Low likelihood of excess water
hyponatremia
Thiazidediuretics •
Medullary gradients intact
•
Intact ability to absorb free water
•
More sodium out out in urine (diuretic (diuretic effect)
•
Higher likelihood of excess water
hyponatremia
70
•
Sodium level varies with water intake
•
Free water intake hyponatremia
600mOsm
1200mOsm
SIADH
High ADH •
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Adrenal insufficiency insufficiency
•
•
Cortisol normally suppresses ADH release
•
Loss of cortisol (primary/secondary)
•
Loss of aldosterone (primary)
•
Hypothyroidism
•
SIADH
•
↑ ADH
•
loss of salt/water ↑ ADH
•
•
Druginduced (carbamazepine, (carbamazepine,cyclophosphamide) Paraneoplastic Paraneoplastic (small cell lung cancer)
•
•
•
CNS
•
•
Pulmonarydisease
•
•
SIADH •
•
Hypotonic hyponatremia hyponatremia (↓Posm ↓Na) Normal liver, liver, renal, cardiac function
•
Clinical euvolemia
•
Normal thyroid, adrenal adrenal function
•
Urine osmolality > 100 mOsm/kg
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 volume status
SIADH
DiagnosticCriteria •
Heart failure
•
Volume Status SIADH
Causes
•
No other cause for high ADH •
SIADH •
Too much ADH released (inappropriate) Causeshyponatremia High urinary Na ( >40meq/L) High urinary osmolality (>100 mOsm/kg)
•
Common treatment: fluid restriction
•
Special treatment option: •
Demeclocycline
•
Tetracycline antibiotic
•
ADH antagonist
Demeclocycline
71
Psychogenic Polydipsia •
•
•
•
•
Special Diets
Need to drink >18L/day to get hyponatremia Occurs in psychiatric patients (compulsive)
•
•
Hyponatremia Low urine osmolality (<100mosm/kg) •
Indicates kidneys working
•
Kidneys trying to eliminate eliminate free water
•
•
•
•
Water restriction resolves hyponatremia
•
•
Salt consumed must equal salt excreted Imagine highest water to salt ratio is 10:1
•
•
Normal Diet 3 salt 30 water
•
Minimal sodium intake may limit free water excretion Free water intake > output Result: hyponatremia
Normal diet •
1000mOsm/day solute
•
Most dilute urine = 50mOsm/L
•
Max free water output = 1000/50 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 •
Very little sodium ingestion Minimum urine osmolality ~60 mosmol/kg
Special Diets
Special Diets •
Tea and toast Beer drinkers (“beer potomania”)
Hyponatremia
Low urine osmolality (<100mosm/kg) •
Indicates kidneys working
•
Kidneys trying to eliminate eliminate free water
Hypervolemic Cirrhosis CHF Renal failure
Free water excretion limited by solute availability
Euvolemic SIADH Hypothyroid
Hypovolemic Dehydration Diuretics
2° Adrenal Disease Renal failure
1°AdrenalDisease
Polydipsia Dietary
72
Euvolemic Hyponatremia
Hypovolemic Hyponatremia Hypovolemic
Measure Uosm
Uosm <100 PsychogenicPolydipsia Diet (tea, beer)
Measure UNa
Uosm > 100 SIADH Hypothyroidism Renal Failure
UNa <30 mEq/L Extra-renalcause Vomiting Diarrhea Sweating
↑ ADH and ↑ Uosm Hypervolemic Cirrhosis CHF
Euvolemic SIADH Hypothyroid
UNa > 30 Renal Cause Diuretics 1°AdrenalDisease (aldosterone)
Hypovolemic Dehydration
Hypervolemic Cirrhosis
Euvolemic SIADH
Hypovolemic Dehydration
Diuretics
CHF Renal failure
Hypothyroid 2° Adrenal Disease
Diuretics 1°AdrenalDisease
Renal failure Polydipsia Dietary
Hyponatremia
↓ ADH and ↑ Uosm
CHF Renalfailure
Diuretics 1°Adrenal Disease
↓ ADH and ↓ Uosm
Renal failure 2° Adrenal Disease 1°Adrenal Disease Renal failure Polydipsia Dietary
Hypervolemic Cirrhosis
Dehydration
Treatment
Euvolemic SIADH Hypothyroid
Hypovolemic Dehydration Diuretics
2° Adrenal Disease Renal failure
1°AdrenalDisease
•
•
•
Polydipsia Dietary
73
Fluid restriction 3% saline Vaptan drugs (tolvaptan, lixivaptan, lixivaptan, and conivaptan) 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 •
•
•
•
•
•
•
Irritabili ty, stupor, stupor, coma
Usually >10meq per 24 hours
Demyelination of central pontine axons Lesion at base of pons Loss of corticospinal corticospinal and corticobulbar corticobulbar tracts Quadriplegia Can be similar to locked-in syndrome
Hypernatremia
Acquired Diabetes Insipidus
Causes 1. Water loss •
Skin and lungs (more (more H2O than Na)
•
ADH will be high
•
Uosm will high
•
•
•
Drugs •
2. Diabetesinsipidus •
Hypercalcemia Hypokalemia
•
Lithium Amphotericin B
Loss of ADH activity
•
Central: trauma, tumors
•
Congenital nephrogenic nephrogenic (rare)
•
Acquired (nephrogenic): Many causes
Diabetes Insipidus
Diagnosis Diabetes Insipidus
Symptoms •
Polyuriaandpolydipsia
•
Suspected with polyuria and polydipsia
•
Similar to diabetes mellitus via different mechanism
•
Often normal [Na]
•
74
•
Water loss stimulates thirst
•
Hypernatremia occurs if not enough enough water
•
Central lesion (central (central DI) can impair thirst
Urine osmolality low (50-200mOsm/kg)
Diagnosis Diabetes Insipidus
Hypernatremia
Diagnosis
Treatment
•
•
Fluidrestriction •
After 8 hours of no fluid, urine urine should be concentrated
•
If urine is dilute absent/ineffective ADH
Water (ideally PO)
•
IV Fluids (D5W)
Administration Administration of vasopressin or desmopressin •
Should concentrate concentrate urine if kidneys work
•
If no concentration
•
If concentration
nephrogenic DI
central DI
Diabetes Insipidus Treatments •
•
Diabetes Insipidus Treatments
Central DI: Desmopressin •
ADH analog
•
No vasopressor vasopressor effect (contrast (contrast with vasopressin)
•
•
•
Nephrogenic DI: Thiazides and NSAIDs Thiazides •
Increase in proximal Na/H2O reabsorption
•
Less H2O delivery delivery to collecting tubules
•
Paradoxical antidiuretic effect
NSAIDs •
75
Inhibit renal synthesis synthesis of prostaglandins (ADH antagonists)
Glomerulus Functions •
Allow “ultrafiltrate” into Bowman’s space
•
Prevent filtration of most proteins
•
Glomerular Disease Principles
•
•
Water, Water, electrolytes, glucose, amino acids
Prevent filtration of red blood cells Glomerularpathology •
Proteinuria
•
Hematuria
Jason Ryan, MD, MPH
Glomerular Filtration Barrier
Capillary Endothelium •
•
Capillary Endothelium
Fenestrated (i.e. has openings) Only small (~40nm) molecules pass through
•
Repels red cells, white cells, platelets
•
First barrier to filtration 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 through
76
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) Can fit through all size barriers
•
•
Negatively charged Repelled by GBM charge barrier
Hematuria •
•
•
•
•
•
•
Red blood cells
•
Protein (especially (especially albumin)
Hematuria
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 •
Breakdown of components of filtration barrier Things in urine that shouldn’t be be there:
Proteinuria
•
Clots generally not seen
Common causes: •
UTI
•
Kidney stones
•
Feared cause: bladder cancer
•
Glomerular disease is rare cause
•
Dysmorphic red blood cells Acanthocytes Red, smoky brown or ““coca cola””
Microscopic: Incidental finding on urinalysis Can occur after exercise
Proteinuria
Red cell casts
•
Many, many causes Gross: abnormal color to urine from blood
77
Urinedipstick •
Color change indicates amount of protein
•
Primarily detects albumin (good for glomerular disease!)
•
1+, 2+, 3+, 4+
•
Affected by urine concentration
Proteinuria •
Proteinuria
Urine protein-to-creatinine protein-to-creatinineratio
•
24-hour urine collection Gold standard for protein evaluation
•
“Spot urine” “Spot urine”
•
•
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 than 150 mg/day
•
Cumbersome for patients
•
Errors in collection common
Glomerular Diseases
Nephrotic Syndrome •
Spectrum
•
•
Nephritic Syndrome RBC casts Mild proteinuria Renal Failure
Nephrotic Syndrome Massive proteinuria Hyperlipidemia •
Nephrotic Syndrome ↓ immunoglobulins
•
↓protein
↓albumin
Proteinuria Frothy urine
•
↓ ATIII •
↓ ECV ↓GFR
↓ plasma oncotic pressure
↑liver activity
Thrombosis
RAAS
Na/H2O Retention
Edema
Hyperlipidemia
Massive proteinuria •
4+ on dipstick
•
>3.5g/day
Triggers cascade of pathology
Urine in Nephrotic Syndrome
•
Infection
Filtration barrier to protein is lost RBC filtration barrier remains intact
Fatty casts Oval fat bodies
78
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 Maltese cross
Nephrotic Syndrome •
Nephritic Syndrome
Classic presentation
•
•
Frothy urine
•
Swelling of ankles
•
Swelling around eyes eyes (periorbital)
•
•
•
Often mistaken for allergic reaction
•
Serum total cholesterol cholesterol >300mg/dl
•
Proteinuria (>3.5g/day)
•
•
Nephritic Syndrome Dysmorphic RBCs RBC Casts
↓filtration barrier
Glomerular damage: ↓GFR RBC in urine •
Dysmorphic
•
RBC Casts
Protein in urine •
Less than nephrotic syndrome due to lower GFR
•
<3.5g/day
Nephritic Syndrome •
Proteinuria
Classicpresentation •
↓GFR
↑BUN/Cr
Inflammatory process damages entire glomeruli Filtration barrier to RBCs and protein lost
↑Hydrostatic pressure
Hypertension
Oliguria
Edema
79
Dark urine (RBCs)
•
Swelling
•
Fatigue (uremia)
•
Proteinuria (<3.5g/day)
Nephritic Syndrome
Nephritic Syndrome Jason Ryan, MD, MPH
Nephritic/Nephrotic
Nephritic Syndrome •
Sites of Glomerular Injury
Classic presentation •
Dark urine (RBCs)
•
Swelling/edema
•
Fatigue (uremia)
•
Proteinuria (<3.5g/day)
•
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 and mesangial cells
•
•
Exposed to blood blood elements
•
Injury lead to inflammation (nephritis)
•
Loss of red blood cells and and protein in urine
1. Post-streptococcal 2. Berger’s (IgA) nephropathy 3. Diffuseproliferative glomerulonephritis glomerulonephritis 4. Rapidlyprogressiveglomerulonephritis(RPGN) 5. Alport syndrome
Most causes of nephritic syndrome related to endothelial/mesangial injury with influx of inflammatory inflammatory cells
6. Membranoproliferative
80
glomerulonephritis
Post-streptococcal Post-streptococcal GN •
•
Post-streptococcal Post-streptococcal GN
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
•
Child
•
2-3 weeks following strep throat infection
•
Nephritic syndrome
•
Post-streptococcal Post-streptococcal GN •
Subendothelial
•
Granular IF (IgG, C3) C3)
Hypocomplementemia (also lupus, MPGN)
Post-streptococcal Post-streptococcal GN
Common in children (can also occur in adults) Classic case •
Fix complement Attract PMNs
Glomeruli:Enlarged,hypercellular
Post-streptococcal Post-streptococcal GN
antibodies/complexes
•
Electron microscopy: microscopy: Subepithelial “humps” •
81
Immune complexes
Post-streptococcal Post-streptococcal GN •
Good prognosis in children •
•
Post-streptococcal Post-streptococcal GN •
95% recover completely
•
No specific therapy (supportive) Spontaneousresolution
Adults have worse prognosis •
About 60% recover
•
Many develop renal insufficiency
•
Can be late: 10 to 40 years after initial illness
•
Can develop RPGN
IgA Nephropathy
IgA Nephropathy
Berger’s Disease
Berger’s Disease
•
•
•
Most common form glomerulonephritis 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
•
Granular IF
•
Stained for IgA
•
Classic case •
•
82
Recurrent episodes episodes hematuria since childhood
•
Episodes fol low URI or diarrheal illness
•
Slowly worsening renal renal function (BUN/Cr) over time
•
Possible progression to ESRD and HD (20yrs+)
confuse with other glomerular disorders Don’t confuse •
Post-strep GN: weeks after infection
•
IgA GN: days after after infection
•
Minimal change: nephrotic syndrome after URI
DPGN
Henoch-Schonlein Henoch-Schonlein Purpura •
•
•
•
•
•
•
Diffuse proliferative glomerulonephritis glomerulonephritis
IgA nephropathy with e xtra-renal involvement Most common childhoodsystemic childhood systemicvasculitis
•
Systemic lupus erythematosus (SLE) •
Skin: palpable purpura on buttocks/legs GI: abdominal pain, melena •
Joint pains
Most common subtype subtype of SLE renal renal disease
•
“Type IV Lupus Lupus Nephritis”
•
Often presents with other SLE features: features: fever, fever, rash, arthritis
Immune complex deposition in glomeruli •
Diffuse IgA deposition Tissue biopsy: demonstrates IgA
IC inflammatory response
DPGN Diffuse proliferative glomerulonephritis glomerulonephritis •
•
Diffuse: More than 50% glomeruli affected Proliferative: •
Increase in cellularity of glomeruli
•
Mesangial cells
•
Endothelial cells
•
Monocyte/neutrophil infiltration
DPGN
DPGN
Diffuse proliferative glomerulonephritis glomerulonephritis
Diffuse proliferative glomerulonephritis glomerulonephritis
•
•
Subendothelial deposits drive immune response •
Anti-dsDNA
•
Hypocomplementemia (also post-strep, MPGN)
•
•
•
Classic finding: capillary loops thickened •
Granular IF immunofluorescence “Full house” immunofluorescence
“Wire looping”
83
IgG, IgA, IgM, C3, C1q
DPGN
RPGN
Diffuse proliferative glomerulonephritis glomerulonephritis
Rapidly progressive glomerulonephritis glomerulonephritis
•
•
Mixed clinical presentation presentation •
Proteinuria (sometimes nephrotic)
•
Hematuria
•
Reduced GFR
•
Also called “crescentic” glomerulonephritis glomerulonephritis
•
Pathologic description: Many causes •
Many diseases lead lead to this condition
Severe, often leads to ESRD and HD
RPGN
RPGN
Rapidly progressive glomerulonephritis glomerulonephritis
Rapidly progressive glomerulonephritis glomerulonephritis
•
Crescents formed byinflammation by inflammation:: •
Monocytes/macrophages
•
Fibrin
•
•
•
•
•
Severe form of glomerulonephritis 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 •
•
•
•
84
Causes distinguished based on immunofluorescence immunofluorescence Type I: Linear IF Type II: Granular IF Type III: Negative IF
Goodpasture’s Syndrome
RPGN Type I •
Anti-glomerular Anti-glomerular basementmembrane antibodies •
•
•
•
“Anti-GBM antibodies”
•
Antibodies against GBM antigens •
Unknown stimulus
•
Type II hypersensitivity
•
•
•
Linear IF •
IgG antibodies
•
Linear pattern
•
•
Type III hypersensitivity
Granular IF •
•
•
•
•
No staining for IgG, IgA, etc.
•
“Pauci-immune” Most patients ANCA patients ANCA positive •
Hemoptysis
•
Hematuria
Post-streptococcal glomerulonephritis •
Can progress to RPGN
•
Most common cause RPGN
Systemic lupus erythematosus (SLE) •
Diffuse proliferative glomerulonephritis
•
Can progress to RPGN
Anti-neutrophil cytoplasmic antibodies
NegativeIF •
Male
•
ANCA Diseases
RPGN Type III •
Young adult
•
RPGN Type II
Immune complex deposition deposition •
Found in GBM and alveoli
Hemoptysis and nephritic syndrome Classic case •
RPGN Type II •
Antibody to collagen Antibodies to alpha-3 chain of type IV collagen
•
•
c-ANCA or p-ANCA
Most patients have a vasculitis syndrome
85
Wegener's Granulomatosis Granulomatosis(c-ANCA) MicroscopicPolyangiitis(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 •
•
•
•
86
Genetic type IV collagen defect •
Mutations in alpha-3, alpha-4, or alpha-5 chains
•
Chains found in basement membranes membranes kidney, eye, ear
Inherited:X-linked Classic triad: •
Hematuria
•
Hearing loss
•
Ocular disturbances
Look for child with triad and family history
Nephrotic Syndrome
Nephrotic Syndrome Jason Ryan, MD, MPH
Nephritic/Nephrotic
Nephrotic Syndrome •
Sites of Glomerular Injury
Classic presentation •
Frothy urine
•
Swelling of ankles
•
Swelling around eyes eyes (periorbital)
•
Serum total cholesterol cholesterol >300mg/dl
•
Proteinuria (>3.5g/day)
•
•
•
Major determinant of whether a disease process leads to nephritic or nephrotic syndrome is the site of glomerular injury Podocytes •
Separated from blood by GBM
•
Injury does not lead to inflammation
•
Damage loss of filtration barrier to protein protein only
Most causes of nephrotic syndrome related to injury of podocytes or epithelial side of GBM
Nephrotic Syndrome Causes
Glomerular Filtration Barrier
1. Minimal change disease 2. Focal segmental glomerulosclerosis (FSGS) 3. Membranous nephropathy 4. Diabetic 5. Amyloidosis 6. Membranoproliferative
87
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 Associated with Hodgkin Lymphoma
Effacement (flattening) Foot Processes
Minimal Change Disease
Minimal Change Disease
Renal Biopsy
Other Features
•
•
•
Normal light microscopy No important findings IF 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 to steroids •
•
Glomerulosclerosis •
Unique among among nephrotic syndrome causes
•
Segmental •
•
Only potion of glomerulus involved
Focal •
88
Pink/dense deposition of collagen in glomerulus
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
Light microscopy: focal, segmental lesions Electron microscopy: effacement of foot processes Immunofluorescence •
Usually negative (no immune complexes)
•
Sometimes IgM, C3, C1 (nonspecific (nonspecific finding)
FSGS
FSGS
Focal segmental glomerulosclerosis glomerulosclerosis
Epidemiology
•
•
•
Caused by podocyte injury Unknown cause
•
African Americans •
Most common cause 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 change disease
Nephrotic Syndrome Causes Causes
FSGS
FSGS
Focal segmental glomerulosclerosis glomerulosclerosis
Focal segmental glomerulosclerosis
•
Usually idiopathic(primary) (primary)
•
•
Many secondary causes
•
•
89
HIV Sickle cell patients Heroin users
FSGS
Membranous Nephropathy
Other Associations Associations •
Massiveobesity
•
Interferon treatment
•
•
Used to treat HCV HCV and HBV
•
Some leukemias and lymphomas, melanoma
Thick glomerular basement membrane
•
Absence of hy percellularity
•
“Membranous”
Loss of nephrons •
Single kidney (congenital)
•
Surgical kidney removal
Membranous Nephropathy
Membranous Nephropathy •
•
Pathophysiology Subepithelial Subepithelial Immune Complex Deposition “granular”
Membrane thick from immune complex deposition •
IF microscopy very useful
•
“Granular” deposits of IgG and C3 staining
Basement Membrane Deposition “Spike and Dome”
Membranous Nephropathy
Membranous Nephropathy
Renal Biopsy •
•
•
Lightmicroscopy:capillary/BM thickening
•
Electronmicroscopy:subepithelialdeposits Immunofluorescence: Immunofluorescence: granularIgG/C3
•
•
•
90
Often idiopathic Autoantibodies Autoantibodies Antigen:phospholipase Antigen: phospholipase A2 receptor (PLA2R) Expressed on podocytes
Membranous Nephropathy
Membranous Nephropathy
Secondary Causes
Secondary Causes
•
•
•
•
Systemic lupus erythematosus (SLE) Most lupus renal disease in nephritic Diffuseproliferative glomerulonephritis glomerulonephritis If nephrotic, this is cause (10-15%)
•
Solid tumors
•
Infections
•
Drugs
•
•
Colon cancer, lung cancer, mel anoma Hep B, Hep C
•
Penicillamine, gold, NSAIDs
•
All used to treat rheumatoid arthritis
Tumor Hepatiti s Rheumatoid Arthritis
Membranous Nephropathy
Autoantibodies
Other Features •
•
•
Most common cause nephrotic syndrome in adults
•
Excellent prognosis in children Some adults develop ESRD ESRD
•
Most antibody disorders are nephritic IC inflammation nephritis nephritic syndrome
•
Membranous is nephrotic
•
Subepithelialdeposits nephroticsyndrome
Nephrotic Syndrome Syndrome Causes
Diabetic Nephropathy •
•
•
Amyloidosis
Non-enzymatic glycosylation Basement membranes: leakage of protein Long term effect: sclerosis of glomerulus
•
Proteinuria
•
Can develop nephrotic syndrome
•
Extracellular buildup of amyloid proteins
•
Classic biopsy findings
•
91
•
Apple-green birefringence
•
Congo red stain
Kidney is most c ommonly involved involved organ
MPGN Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis •
•
•
•
MPGN
Rare glomerular disorders Can cause nephritic or nephrotic syndrome Varying degrees of renal dysfunction Renal failure (↑BUN/Cr)
•
Hematuria
•
Proteinuria (+/- nephrotic range)
Jason Ryan, MD, MPH
MPGN
MPGN
Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis
Membranoproliferative Membranoproliferative Glomerulonephritis Glomerulonephritis
•
Membrano •
•
•
Thick basement membrane
•
Proliferative •
•
Two major types Type I much more common Type II ( dense deposit disease) rare
Proliferation of mesangial mesangial cells, mesangial mesangial matrix
MPGN Type I
MPGN Type I
IC deposits trigger mesangial ingrowth Splits basement membrane “Tram track” appearance on light microscopy Common (80%) in Type I
Type I Subendothelial immune complex deposition IgG complement activation activation
92
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
MPGN Type II
C3 Nephritic Factor
Dense Deposit Disease
C3 Covertase Stabilizing Antibody •
•
•
•
•
Found in >80% patients with MPGN II C3 convertase activates alternative pathway Stabilized by C3 nephritic factor Over activation of complement system Hypocomplementemia(↓C3)
Type II Basement Membrane “Electron dense” deposits Mediated bycomplement 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
93
Tubulointerstitial Disorders •
•
Tubulointerstitial Disorders
•
•
Acute tubular necrosis necrosis Interstitialnephritis Papillarynecrosis Corticalnecrosis
Jason Ryan, MD, MPH
Acute Tubular Necrosis •
Acute Tubular Necrosis
A 50-year-old man develops pneumonia followed by septic shock. He is taken to the ICU for management with antibiotics and vasopressors. Hospital day #2, his BUN increases to 40 mg/dl and his Cr rises to 2.0 mg/dl. Urinalysis shows muddy brown casts.
•
•
Ischemic Causes •
•
•
•
A kidney attack Sudden damage to tubular cells •
Ischemia (ANY cause severe ↓blood flow)
•
Drugs
•
Toxins
Toxin/Drug Causes
Dehydration
•
Sepsis Cardiogenic shock
•
•
Massivebleeding
94
Aminoglycosides Contrast dye Uric acid, especially tumor lysis syndrome
•
Myoglobin (rhabdomyolysis)
•
Ethylene glycol (antifreeze)
Acute Tubular Necrosis •
•
•
Acute Tubular Necrosis
Tubular epithelial cells die, slough off into urine Obstructs urine flow •
↓GFR
•
↑BUN and Cr
Cortex
Epithelial cells form casts in tubules •
Granular casts
•
“Muddy brown”
Outer Medulla Ischemic ATN Proximal Tubule Medullary TAL
Inner Medulla
Acute Tubular Necrosis
ATN Phases •
•
Cortex
•
Outer Medulla Toxic ATN Proximal Tubule
Phase 1: Injury occurs occurs Phase 2: Maintenance •
Rising BUN/Cr
•
Hyperkalemia
•
AG metabolic acidosis
•
May last weeks
Phase 3: Recovery •
Polyuria
•
Risk of hypokalemia
Inner Medulla
Prognosis •
Typical course is kidney recovery
•
Tubular cells capable of regeneration
•
Some patients require temporary dialysis
•
Acute Interstitial Nephritis •
Inflammationof “interstitium” •
“Tubular r e-epithelialization”
95
Space between cells
•
Hypersensitivity(allergic)reaction
•
Usually triggered by drugs
•
Sometimes infections or autoimmune disease
Acute Interstitial Nephritis •
Acute Interstitial Nephritis
Drugs – 75%
•
Sulfonamides (TMP-SMX)
•
Multiple organisms organisms reported
•
Rifampin
•
Legionella, Leptospira, CMV, TB
•
Penicillin
•
Diuretics (furosemide, bumetanide, thiazides)
•
NSAIDs
•
Acute Interstitial Nephritis •
Infection – 5-10%
•
Systemic diseases – 5-10% •
Sarcoidosis
•
Sjögren's syndrome
•
SLE
Acute Interstitial Nephritis
Classicfindings:
•
Classicpresentation
•
WBC casts (without (without symptoms of pyelonephritis)
•
•
“Sterile pyuria”
•
Fever, rash or asymptomatic
•
Peripheral eosinophilia
•
Oliguria
•
Urine eosinophils
•
Increased BUN/Cr
Acute Interstitial Nephritis
Days to weeks after after exposure to typical typical drug
•
WBC casts
•
Eosinophils i n urine
Chronic Interstitial Nephritis
•
Usually resolves with stopping offending agent
•
•
Rarely progresses to papillary necrosis
•
•
•
Can occur with NSAIDs NSAIDs Mild elevation of BUN/Cr Resolves with stoppage of drugs Classic case: •
96
Patient on NSAIDs for chronic pain
•
Mild increase BUN/Cr
•
Renal function improves improves with stoppage of drug
NSAIDs •
•
Papillary Necrosis
Chronicinterstitialnephritis Acute tubular necrosis •
From ischemia
•
Block PG vasodilation vasodilation of afferent arteriole
•
Membranousglomerulonephritis glomerulonephritis
•
Papillarynecrosis
•
•
•
•
•
•
Papillary Necrosis
Triggered by immune stimulus Classictriggers: •
•
Chronic phenacetin phenacetin use
•
Diabetes
•
Acute pyelonephritis
•
Sickle cell anemia/trait
Cortical Necrosis •
•
•
•
Gross hematuria Often painless
Nephrotic syndrome
Papillary Necrosis •
Cell death (necrosis) renal papillae Sloughing of tissue
Infarction (ischemia) of cortex Acute renal failure Proposed mechanism: •
Ischemia and DIC
•
Massive tissue destruction
Occurs in very sick patients •
Septic shock
•
Obstetric catastrophes catastrophes (abruptio placentae, fetal demise)
97
Typical presentation •
Patient with typical trigger
•
Gross hematuria
Terms •
Acute renal failure •
•
Renal Failure
Decrease in Cr clearance over days
•
Often associated associated with symptoms
•
Many causes
Chronic renal failure (chronic kidney disease) •
Slow, steady deterioration deterioration of renal function function (years)
•
Usually due to diabetes, hypertension
•
Symptoms only in most most severe stages
Jason Ryan, MD, MPH
Terms •
Azotemia •
•
Uremic Symptoms •
Insufficient filtering of blood by kidneys
•
Uremia •
•
Azotemia + “uremic” symptoms
•
•
•
Acute Renal Failure
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
2. Obstruction of urine outflow (post-renal)
•
Blood urea nitrogen
•
Need bilateral obstruction
•
Freely filtered
•
Kidney stones, stones, BPH, tumors, congenital anomalies
•
Reabsorbed when kidney reabsorbs water
3. Renal dysfunction (intrinsic) •
Acute tubular necrosis
•
Glomerulonephritis
98
Key Labs •
•
Real Life Acute Acute Renal Failure
In acute renal failure both rise (less filtered) In acute renal failure from dehydration: •
•
•
BUN rises more (less filtered, more reabsorbed)
•
Routine labs on outpatient or inpatient BUN/Crelevated Work up: •
USMLE Acute Renal Failure •
Urinalysis (protein, blood, casts)
•
Ultrasound (hydronephrosis)
•
Careful history (meds, (meds, co-morbidities, hydration)
•
Physical exam (low blood pressure, pressure, dehydration, CHF, CHF, etc)
•
Limited use of blood, urine chemistries
Renal Failure Measurements
Determine cause based on blood, urine testing
•
Urinary sodium (UNa) Varies based on intake of sodium and water
•
BUN (rises in ARF)
•
•
Cr (rises in ARF)
•
Very low when kidney retaining salt/water
•
BUN/Cr ratio (normal ~20:1)
•
<20 mEq/L is very low
•
•
•
UNa
•
FeNa Uosm
Fractional excretion of Na (FeNa) •
•
Amount of filtered Na that is excreted
•
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 Rising BUN/Cr in blood
•
•
More resorption H2O H2O
•
•
BUN resorbed with H2O
•
•
BUN rises >> Cr rises rises
•
•
Result
•
•
↑ ↑ BUN
•
↑Cr
•
↑BUN/Cr ratio
99
Lots of H2O resorbed resorbed Concentratedurine ↑Uosm Lots of Na resorbed
↓Una ↓Fena
Intrinsic Renal Failure
Pre Renal Failure
BUN/Cr •
•
•
•
•
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 •
•
•
Normal ratio (20:1)
Intrinsic Renal Failure
Urinary Findings •
Kidney cannot filter blood Less BUN/Cr filtered filtered Rising BUN/Cr in blood No extra rise in BUN from ↑resorption
Post Renal Failure
Obstruction to outflow Urine backs up High pressure in tubules
•
Kidney cannot filter blood
•
mechanismsdamaged/destroyed Kidney’s resorptive mechanisms
100
•
Diagnosis rarely made by plasma/urinalysis
•
Key features: •
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 High pressure in tubules prevents filtration
•
•
Only exception is BUN/Cr ratio BUN may rise like pre-renal
•
•
Lots of variation in lab values based on tubules Early post renal tubular function okay Late high pressure disrupts tubular re sorption Urine chemistries variable variable
High pressure in tubules forces BUN out BUN rises more than Cr Cr ↑BUN/Cr ratio similar to pre-renal
Post Renal Failure
Pre, Intrinsic, Post Problems •
Diseases often cross boundaries
•
Diuretics obscure urine findings
•
Pre-existing chronic renal disease
•
Chronic Kidney Disease
Fractional Excretion Na •
Pre-renal •
•
•
FeNa <1% UNa <20
Intrinsic renal •
FeNa >1%
•
UNa >40
Pre-renal ATN
•
Slow, steady fall in creatinine clearance •
FeNa = P Cr * U Na PNa * UCr
101
Blood tests show ↑BUN/Cr
•
Eventually progresses to dialysis for many patients
•
Most common causes diabetes and hypertension •
Hypertensive nephrosclerosis
•
Diabetes nephropathy
Stages of Kidney Disease •
•
•
•
•
Indications for Dialysis
Stage 1 GFR >90 Stage 2 GFR 60-89
•
•
Stage 3 GFR 30-59 Stage 4 GFR 15-29 (approaching dialysis dialysis))
•
•
Stage 5 GFR <15 (usually on dialysis)
•
Dialyzable Substances •
•
•
•
•
Acidemia Electrolytes (hyperkalemia) Intoxication(overdosedialyzablesubstance) Overload of fluid (CHF) (CHF) Uremicsymptoms
Dialysis Methods
Salicylates(aspirin) Lithium
•
Isopropylalcohol Magnesium laxatives •
Ethyleneglycol
•
Vascular Access
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 through peritoneal cavity
•
Peritoneum used as dialysis membrane
Hemofiltration •
Constant filtering of blood
•
Usually done at at bedside for critically ill patients
Complications CKD
•
For acute dialysis, central line can be placed
•
Anemia (loss of EPO)
•
Ideal method is 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 and VLDL
stimulation of liver synthesis
•
Fistula must “mature” for use
•
Growth failure in children
•
Ideally placed several months before dialysis
•
Renal osteodystrophy
102
Calcium-Phosphate 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 from constant stimulation
•
VERY high PTH levels
•
Calcium becomes elevated
•
Often requires parathyroidectomy
Hypocalcemia
↑PTH
Calcium-Phosphate Calcium-Phosphate in Renal Failure •
•
Phosphate Binders
Untreated parathyroidism leads to renal osteodystrophy •
Bone pain (predominant (predominant symptom)
•
Fracture (weak bones 2° chronic high PTH levels)
•
•
•
•
Osteitisfibrosacystica •
Untreated, severe severe high PTH levels
•
Bone cysts
•
Brown tumors ( osteoclasts w/fibrous tissue)
•
Drugs and Renal Function •
•
•
Many drugs worsen renal function Decrease GFR Associated with ↑BUN/Cr
•
Loop, Thiazide, and K sparing diuretics
•
ACEinhibitors
•
NSAIDs
103
Bind phosphate in GI tract Calcium carbonate Calcium acetate (Phoslo) Sevelamer(Renagel) Lanthanum
Urinary Infections •
•
Urinary Infections
Cystitis •
Infection of bladder bladder
•
“Lower” urinary tract
Pyelonephritis •
Infection of kidneys
•
“Upper” urinary tract
Jason Ryan, MD, MPH
Urinary Infections •
•
Etiology
Most infections “ascend” Urethra Cystitis Pyelonephritis
•
•
•
•
•
Symptoms •
Escherichia coli (75-95%) Proteusmirabilis •
Urease producing producing bacteria
•
Struvite kidney stones
Klebsiellapneumoniae 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 plasma WBC count
104
Diagnosis •
Urinalysis
•
Cloudy urine
•
10x more likely than than men to get get UTIs
•
Leukocyte esterase
•
Shorter urethra, closer closer to fecal flora
•
•
Produced by WBCs in urine
•
Nitrites •
90% UTI bugs convert nitrates to nitrites
•
Some that don’t: enterococcus, staph saprophyticus
•
Best for detecting aerobic gram-negative rods (E. Coli)
•
•
•
>100,000 CFUs
Treatment
Infants with vesicoureteral reflux
•
•
•
Fluoroquinolones
•
Ureters insert abnormally into bladder
•
Ciprofloxacin, levofloxacin, ofloxacin
•
Chronic reflux of urine urine back into ureters
•
Usually 3 day course
Urinary obstruction •
Anatomic abnormalities abnormalities in children
•
Bladder tumors in adults
•
Enlarged prostate in older males
•
Nitrofurantoin (Macrobid) •
•
Sterile Pyuria •
Pregnancy
>10WBC/hpf
Risk Factors
•
Sexualactivity Urinary catheterization catheterization Diabetes
Culture •
•
Women
•
•
•
Risk Factors
Used in pregnancy
Trimethoprim-sulfamethoxazole
(TMP-SMX)
Chronic Pyelonephritis
Some women with chlamydia/gonorrhea complain of urinary tract symptoms Urinalysis shows pyuria but no bacterial growth
•
•
•
Majority women are asymptomatic with chlamydia or gonorrhea
Vesicoureteral reflux in children Recurrent stones in adults
•
Scarring of kidneys
•
Corticomedullary Corticomedullary scarring
•
•
105
Consequence of recurrent pyelonephritis
Blunted calyx of kidney” “Thyroidization of •
Tubules contain contain eosinophilic material
•
Looks like thyroid tissue on microscopy
Cystic Kidney Diseases Diseases 1. MulticysticDysplasticKidney 2. Autosomal Recessive Polycystic Kidney Disease 3. Autosomal Dominant Polycystic Kidney Disease 4. Medullary Cystic Kidney Disease
Cystic Kidney Disease Jason Ryan, MD, MPH
Multicystic Dysplastic Kidney •
•
•
•
•
Multicystic Dysplastic Kidney
Abnormalureteric bud-mesenchyme bud-mesenchymeinteraction 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 other cystic disorders
•
Subsequent pregnancies often okay
•
Oligohydramnios
•
Failure of lung maturation
•
Compressed face/limbs
•
Not compatible with life
Polycystic Kidney Disease
Spontaneous •
If unilateral remaining kidney hypertrophies If bilateral Potter’s syndrome
106
•
Autosomalrecessive(infants)
•
Autosomal dominant (young adults)
ARPKD •
•
•
•
•
•
ADPKD
Old name: “juvenile” PKD Occurs in infants
•
•
Can occur with Potter’s syndrome Renalfailure High blood pressure Key associations: associations: •
Liver disease (fibrosis/cysts)
•
Can cause portal hypertension (ascites)
ADPKD •
•
Too small to visualize with ultrasound
•
Kidneys appear appear normal at bi rth
•
Cysts develop over many years
•
Inherited mutation of APKD1 or APKD2 genes
ADPKD
Key associations associations
•
Classicpresentation
•
Berry aneurysm (subarachnoid hemorrhage)
•
•
Liver cysts
•
High blood pressure (↑RAAS system)
•
Mitral valve prolapse
•
Hematuria
•
Renal failure
•
Family history of sudden sudden death (aneurysm)
Medullary Cystic Kidney Disease •
Autosomal dominant
•
Cysts in collecting ducts of medulla
•
Occurs in adults Microscopic cysts present at birth
•
Name is misnomer
•
Most patients DO NOT have cysts
Cystic Kidney Diseases Diseases
Kidney fibrosis occurs small, shrunken kidneys •
Contrast with ADPKD (enlarged kidneys)
•
Often have early onset (adolescent) gout
•
Renalfailure
Young adult
107
Diuretics Drugs that increase urine output 1. CarbonicAnhydraseInhibitors 2. Osmotic Diuretics 3. LoopDiuretics 4. ThiazideDiuretics 5. K+ Sparing Diuretics Diuretics
Diuretics Jason Ryan, MD, MPH
Potassium
Sodium •
•
•
•
•
•
Normal plasma [Na] = 140 meq/L [Na] tightly regulated regulated •
Renin-angiotensin-aldosterone
•
Antidiuretic hormone (ADH)
•
•
•
•
Sodium intake H2O retention [Na] = 140 meq/L Sodium loss H2O excretion [Na] = 140 meq/L
Secreted 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
Any drug that ↑ Na excretion volume loss Many diuretics work by ↑ Na excretion
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Anhydrase
•
Acetazolamide Acetazolamide
•
Weak diuretic effect
•
Causes a non-AG metabolic acidosis
•
HCO3Na
•
Block some Na resorption Increased elim ination of HCO3-
Acetazolamide
108
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors
Clinical Uses
Clinical Uses
•
Severe metabolic metabolic alkalosis
•
Glaucoma •
•
Pseudotumorcerebri
•
Prevention of high altitude sickness
•
Blocks formation of aqueous humor
Reduced rate of CSF formation
•
Low pO2 at high altitude
•
Low CO2 respiratory alkalosis
•
Acetazolamide
acidosis
hyperventilation
reverses alkalosis
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors
Side Effects
Side Effects
•
•
•
Metabolic acidosis
•
Paresthesias (“tingling” in extremities) Sulfa allergy
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
109
Thin descending limb Concentratesurine Absorbswater 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
•
•
•
Freely filtered by glomerulus No tubular reabsorption reabsorption Raisesosmolality
•
Reduces water reabsorption
•
Increases urine output
1200mOsm
Mannitol •
Sugar alcohol
Mannitol
Main use is in cerebral edema, glaucoma Goal is to create a HYPERosmolar state
•
Cannot use in heart failure patients •
“Osmotherapy” Draws fluid out (brain, eye)
•
Loop Diuretics
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+
Na
2Cl
600mOsm K+
Inner Medulla
K+
2Cl-
K
Outer Medulla
ATP
K+
1200mOsm
M
110
2+ Ca2+
K+
Cl-
Loop Diuretics
Loop Diuretics
Furosemide, bumetanide, torsemide, ethacrynic acid
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 Exception: Ethacrynic acid (used in allergic patients)
Na K 2Cl
Ethacrynic Acid
Furosemide
Loop Diuretics
Uric Acid
Furosemide, bumetanide, torsemide, ethacrynic acid •
•
•
Ototoxicity •
Very high doses or given with other other ototoxic agents
•
Tinnitus, loss of hearing hearing (usually reversible)
•
•
•
Acute interstitial nephritis nephritis •
↑BUN/Cr
•
White blood cell cell casts
•
Urine eosinophils
•
•
•
•
•
•
Gout promoted by diuretics
Gout
Metabolic Alkalosis •
Complex mechanism of renal handling Thiazides, loop diuretics ↑ uric acid reabsorption
Thiazide Diuretics Lumen (Urine)
pH>7.45
Interstitium/Blood Na+
↑HCO3Diuretics ↑urine output ↓ECV Renin-Angiotensin-Aldosterone activation
Na+
ATP K+
↑H+ secretion metabolic alkalosis “Contractionalkalosis” “Contractionalkalosis” Seen with loop diuretics and thiazides
Cl-
111
Cl-
Thiazide Diuretics
Thiazides: Hypercalcemia Lumen (Urine)
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone
Interstitium/Blood
•
Sulfa Drugs (allergy)
Na+ Na+
ATP K+
Chlorthalidone Ca2+
Na HCTZ Ca2+
Metolazone
Thiazide Diuretics
Thiazide Diuretics
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone
•
•
Elevates blood levels
•
Glucose
•
•
Lipids
•
H2O resorption intact (normal medullary medullary gradients)
•
Uric acid
•
High H2O intake
•
Calcium
•
HyperGLUC
Clinical uses Hypertension
•
Recurrent calcium kidney stones
•
Osteoporosis
•
Diabetes insipidus
hyponatremia
Hypokalemia
•
Metabolic alkalosis
K-Sparing Diuretics
Hydrochlorothiazide; Hydrochlorothiazide; chlorthalidone; chlorthalidone; metolazone
•
Drugs promote Na loss
•
Caution: diabetes, ↑lipids, gout, hypercalcemia
Thiazide Diuretics •
Hyponatremia
•
•
Spironolactone/eplerenone •
•
Triamterene/amiloride •
•
Block aldosterone Na channel
Good choice for patients with low K •
112
Block aldosterone receptor site
Often from other diuretics
K Sparing Diuretics
K Sparing Diuretics Principal Cell
Lumen (Urine)
Na+
Spironolactone, Eplerenone, Triamterene, Amiloride
Interstitium/Blood
•
Na+ Aldosterone
Aldosterone
K+
ATP
•
K+
•
•
H2O
•
Intercalated Cell
K
All ↑Na/H2O excretion (diuretics) All “spare” potassium Unlike other diuretics, do not increase K + excretion
HYPERkalemia HYPERkalemia is side effect Spironolactone gynecomastia •
Antiandrogen: Blocks androgen receptor
•
↑ estrogen effects/↓ androgen effects
H+ HCO3Aldosterone
ATP H+
Cl-
RAA System
Renal Failure •
•
•
Renin-Angiotensin-Aldosterone
All diuretics can cause renal failure ↓ECV ↓GFR BUN/Cr may rise in the plasma
Rules of Thumb •
All diuretics except K sparing: ↑ K excretion
•
CA inhibitors and K sparing cause acidosis (↓pH) •
•
CA Inhibitors: HCO 3- excretion
•
K sparing: ↓ aldosterone; hyperkalemia (H +/K+ exchanger)
•
Others cause cause contraction alkalosis
Loops and Thiazides have opposite effects on Ca •
Loops hypocalcemia
•
Thiazides
hypercalcemia
113
•
Diuretics result in volume loss
•
Activates renin-angiotensin-aldo renin-angiotensin-aldosterone sterone system
•
↑ RAAS ↑ Na/H2O reabsorption
•
Some adaptation to diuretic effect over time
Kidney Stones Nephrolithiasis 1. Calcium 2. Struvite 3. Urate 4. Cystine
Kidney Stones Jason Ryan, MD, MPH
Symptoms •
•
•
Risk Factors
Flank pain (side between the ribs and the hip) Colicky (waxes and wanes in severity)
•
Hematuria •
•
Calcium Stones •
•
•
•
•
Calcium oxalate (most common)
•
•
•
Key risk factors factors Hypercalcemia
•
High oxalate levels in blood
Hypercalcemia
•
Hyperuricemia
Low urine volume •
Usually from dehydration
•
Increases concentration concentration of urine substances
In general, hydration lowers risk of stones
Most common etiology: idiopathic hypercalciuria Hypercalcemia (hyperparathyroidism) High oxalate levels •
•
•
Radiopaque •
•
Risk Factors
Calciumphosphate Most common type of kidney stone (80%) •
High amount of stone substance in blood
Seen on x-ray and CT scan •
Gastric bypass patients
Ethylene glycol (antifreeze) •
Formation of oxalate
•
Increases oxalate concentration in urine
Vitamin C abuse •
114
Crohn’s disease: Fat malabsorption Fat binds to calcium, leaving oxalate free to be absorbed in the gut
Oxalate generated generated from metabolism metabolism of vitamin C
Calcium Stones •
Treatment
Classic case •
•
Patient drinking less water
•
Flank pain, hematuria
•
Calcium stone on imaging
•
•
•
•
Normal Ca level in plasma
•
Increased calcium calcium level in urine
Recurrent stone formers may take medication Thiazides •
•
Decrease Ca in urine
Citrate(Potassiumcitrate) •
Binds with calcium but remains dissolved
•
Lowers urinary Ca available available for stones
•
Inhibits of stone formation
Struvite Stones
Dietary Sodium ↑ Na
↑ ECV
Most stones pass on their own Large stones that do not pass require surgery
•
More Na = More Ca Urine High Na diet = Stone formation Low Na diet = Treatment Treatment stones
•
•
•
↓ RAAS
↓ Na Reabsorption Proximal Tubule
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
115
Treatment: •
Surgery
•
Antibiotics
Uric Acid Stones •
•
•
•
Risk Factors
Cause by high uric acid in urine or acidic urine H+ + Urate- ↔ Uric acid
•
Radiolucentstones •
Not visible on x-ray
•
Can see with CT scan
•
High uric acid levels •
Gout
•
Leukemia, myeloproliferative myeloproliferative disease
Acidic urine (precipitates uric acid) •
Lowest pH is in the distal tubule/collecting tubule/collecting duct
•
•
Treatment •
•
•
•
Potassium bicarbonate
Rarely allopurinol •
Xanthine oxidase inhibitor
•
Reduces uric acid production
•
Medically therapy often effective
•
Usually does not require surgery
•
Cystine Stone •
•
•
•
Low urine volume, acidic urine more common
•
5-10% stones in US/Europe
•
40% stones in other climates
Uric Acid Stones
Hydration Alkalization Alkalization of urine •
Chronic diarrhea
More common in hot, arid climates
Classic case •
Flank pain, hematuria
•
No stone on x-ray
Choose medical therapy, not surgery
Cystine Stone
Rare type of stone stone
•
Seen in children with cystinuria Tubular defect cannot absorb cystine Also form staghorn calculi
•
116
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 2. Wilms’ Tumor 3. Renal Angiomyolipoma 4. TransitionalCell Carcinoma Carcinoma
Renal and Bladder Malignancies
5. Squamous Cell Carcinoma 6. Adenocarcinoma
Jason Ryan, MD, MPH
Renal Cell Carcinoma
Renal Cell Carcinoma •
•
•
Risk Factors
Most common kidney tumor 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 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
•
•
•
117
Can block drainage of spermatic vein on left
Spreads through venous system Common sites for metastasis: •
Lung
•
Bone
Can also spread to retroperitoneal lymph nodes
Renal Cell Carcinoma
Renal Cell Carcinoma
Paraneoplastic Paraneoplastic syndromes
Paraneoplastic Paraneoplastic syndromes
•
Manyparaneoplasticsyndromes
•
Polycythemia (↑Hct) •
•
•
Hypertension
•
Cushing’s Syndrome
•
Increased EPO production by tumor
Hypercalcemia •
Tumor production production of PTHrP
•
Increased Ca from bones
Renin production by tumor
•
ACTH production by tumor
•
Look for weight gain, hypertension, hyperglycemia
Renal Cell Carcinoma
Renal Cell Carcinoma
Pathology
Genetics
•
Most common type is clear cell carcinoma carcinoma
•
•
Cells filled with glycogen and lipids
•
•
•
•
•
Sporadicmutation •
Single tumor
•
Older patient, usually smoker
Inherited •
Younger patient
•
Multiple, bi lateral tumors tumors
Renal Cell Carcinoma
Von-Hippel-Lindau Disease •
Associated with gene deletion chromosome chromosome 3 Von-Hippel-Lindau Von-Hippel-Lindau( VHL)gene
Treatment
Autosomal dominant
•
Von-Hippel-Lindau Von-Hippel-Lindau (VHL) gene inactivation Many tumors
•
•
Surgical resection in early disease Poorlyresponsive tochemotherapy/radiation chemotherapy/radiation Recombinantcytokinesused
•
Renal cell carcinomas
•
Aldesleukin (interleukin-2)
•
Cerebellar hemangioblastoma
•
Hypotension, fevers, chills are important side effects
•
Retinal hemangioblastoma
118
Wilms’ Tumor •
•
Most common renal malignancy of young children Proliferation of metanephric metanephric blastema •
•
Wilms’ Tumor •
•
Embryonic glomerular structures
•
Classic case •
Young child (~3years old)
•
Huge, palpable palpable flank mass
•
Hematuria
•
Hypertension (renin secretion)
•
•
•
•
Wilms’ tumor Aniridia •
Absence of the iris
•
Visual problems
•
•
•
•
•
•
Pediatricovergrowthdisorder Macrosomia •
MentalRetardation Deletion of WT1 gene chromosome 11
Height/weight often >97th percentile
Hemihyperplasia
•
Macroglossia
•
Many embryonal tumors
•
Cryptorchidism, ambiguous genitalia
Renal Angiomyolipoma •
Often part of a syndrome
•
Genital anomalies •
Chromosome Chromosome 11 May be sporadic
Beckwith Wiedemann Syndrome
WAGR Syndrome •
Associated with loss of function mutation mutation WT1 tumor suppressor gene
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 Associated with Tuberous Sclerosis
•
•
Most common tumor of urinary tract system Most common type of bladder cancer Locations:
•
Autosomal dominant condition
•
Bladder (most common) common)
•
Cortical tubers in brain
•
Also renal calyces, calyces, renal pelvis, ureters
•
Subependymal hamartomas in brain
•
Seizures, mental retardation
•
Cardiac rhabdomyomas
•
Leaf-like patches patches of skin with no pigment (ash-leaf (ash-leaf patches)
•
119
Often multifocal and recurrent •
“Field defect”
•
Damage to entire entire urothelium
Transitional Cell Carcinoma
Transitional Cell Carcinoma
Risk Factors •
•
•
•
•
Smoking
•
Cyclophosphamide Phenacetin Aniline dyes (hair coloring)
•
Workplace exposures •
•
Rubber, textiles, leather
•
Naphthalene (industrial solvent)
•
Painters, machinists, machinists, printers
Transitional Cell Carcinoma •
•
Surgicalresection Radiation
•
•
Chemotherapy
•
•
•
•
•
•
•
Smoker
•
Painless hematuria
•
No casts in urine
Test of choice: cystoscopy and biopsy
•
Rare bladder cancer cancer Need chronic inflammation of bladder Several key risk factors
•
Combination chemotherapy with platinum-based regimens
•
Recurrent kidney stones stones or cystitis
•
Cisplatin, carboplatin
•
UTI with Schistosomahaematobium
Schistosoma haematobi h aematobium um •
Older, white male
•
Squamous Cell Carcinoma
Treatment •
Classic case
Adenocarcinoma
Trematode
•
Found in Africa and Middle East (Egypt) Acquired from freshwater containing larvae
•
•
Penetrate the skin Migrate to liver and mature to adults Infects bladder Usually causes hematuria Can result in bladder cancer
120
Very rare bladder cancer Glandular proliferation in bladder Occurs in special circumstances •
Urachal remnant
•
Long history of cystitis
•
Exstrophy: bladder protrusion protrusion through abdominal wall defect
Rhabdomyolysis •
•
Syndrome caused by muscle necrosis Can lead to renal failure and death
Rhabdomyolysis Jason Ryan, MD, MPH
Rhabdomyolysis
Muscle Contents
Causes of Muscle Damage •
Intensephysical Intensephysical exercise •
•
•
•
Statins
•
Fibrates
•
Aldolase, lactate dehydrogenase, AST/ALT
Elevated levels are hallmark of rhabdomyolysis
Muscle Contents
Potassium and phosphate •
Creatinekinase •
Crush injuries(trauma) injuries (trauma) Drugs
Muscle Contents •
•
Especially if dehydrated
•
Hyperkalemia/hyperphosphatemia in rhabdomyolysis
19
15
K
P
Purines •
Metabolized to uric acid in liver
•
Can lead to hyperuricemia
Adenine
121
Guanine
Myoglobin •
•
•
Myoglobin
Protein monomer (NOT tetramer like Hgb) Containsheme Contains heme (porphyrin plus iron)
100
Binds oxygen for use by muscle tissue
n 75 o i t a r u t a 50 S %
No allostericinteractions!
25 25
50
75
100
pO2 (mmHg)
Myoglobin
Myoglobin
Renal Toxicity
Renal Toxicity
•
•
•
Obstructstubules Toxic to proximal tubularcells tubular cells Vasoconstriction •
Especially in medulla
•
Leads to renal hypoxia
•
Made worse by volume depletion in rhabdomyolysis rhabdomyolysis
•
Fearedoutcome rhabdomyolysis: rhabdomyolysis:renal renal failure/death
•
Intravascular fluid influx into muscle muscle tissue
Rhabdomyolysis
Rhabdomyolysis
Symptoms
Diagnosis
•
•
•
Muscle pain
•
Weakness Dark urine (from myoglobin)
Creatinekinase •
122
Usually very high
•
Normal < 250 IU/L
•
Rhabdomyolysis > 1000 1000 IU/L
•
Sometimes up to 25,000 or more more IU/L
Rhabdomyolysis
Rhabdomyolysis
Diagnosis
Diagnosis
•
Urinalysis forheme forheme •
•
Heme has peroxidase activity
•
Breaks down peroxide
•
Changes test test strip color
Microscopy for red blood cells
•
Classicfinding rhabdomyolysis rhabdomyolysis •
Positive dipstick = hemoglobin or myoglobin
Rhabdomyolysis Volume resuscitation •
IV Fluids (usually isotonic saline)
•
Titrated to maintain good urine output
•
Treatment of electrolyte abnormalities abnormalities
•
Dialysis
Dark urine
•
Positive dipstick for heme
•
No evidence of of red blood cells
Hypocalcemia
Treatment •
•
•
•
•
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Calcium deposits in damaged myocytes Initialphases rhabdomyolysis: rhabdomyolysis:hypocalcemia hypocalcemia Recovery phase: release from myocytes •
Levels return to normal
•
Can become elevated