Boards And Beyond Renal

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 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 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 • Forms/degenerates week 4

• Mesonephros • Interim kidney 1st trimester • Contributes to vas deferens in males

Renal Embryology

• Metanephros • Forms permanent kidney • Appears 5th week • Develops into kidney through weeks 32-36

Jason Ryan, MD, MPH

• Bladder develops separately from urogenital sinus

Nephron

Kidney Formation

Metanephric Mesenchyme

Ureteric Bud

• Key Structure #1: Ureteric bud • Outgrowth of mesonephric duct • Gives rise to ureter, pelvis, calyxes, collecting ducts

• Key Structure #2: Metanephric mesenchyme • Interacts with ureteric bud • Interaction forms glomerulus to distal tubule

• Aberrant interaction  kidney malformation

Wilms’ Tumor

Multicystic Dysplastic Kidney

• Most common renal malignancy of young children • Proliferation of metanephric blastema

• Abnormal ureteric bud-mesenchyme interaction • Kidney replaced with cysts • No/little functioning renal tissue

• Embryonic glomerular structures

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Ureteropelvic Junction

Renal Agenesis

• Last connection to form • Common cause obstruction • Often detected in utero • Hydronephrosis

• If single kidney  other kidney compensates • Hypertrophy • Hyperfiltration • Risk of renal failure after decades

• If both kidneys: • Oligohydramnios • Potter’s syndrome

Potter’s Syndrome

Potter’s Syndrome • • • • •

Signs

Fetus exposed to absent or ↓amniotic fluid Amniotic fluid = fetal urine Severe renal malfunction = ↓amniotic fluid Loss of fetal cushioning to external forces External compression of the fetus

• Limb deformities • Flat face • Pulmonary hypoplasia

• Abnormal face/limb formation

• Alteration in lung liquid movement • Abnormal lung formation

Potter’s Syndrome

Horseshoe Kidney

Causes

• Inferior poles fuse • Kidney cannot ascend

• Bilateral renal agenesis • Often detected in utero • Fetal kidneys seen on ultrasound at 10 to 12 weeks

• Pelvis  retroperitoneum

• Posterior urethral valves • • • •

• Trapped by inferior mesenteric artery • Most patients asymptomatic • Associated with Turner syndrome

Occurs in males Tissue (valves) obstruct bladder outflow Ultrasound: dilated bladder, kidneys Can cause oligohydramnios & Potter’s

• Autosomal recessive polycystic kidney disease • Cysts in kidneys/biliary tree • Kidneys don’t form urine

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Urachal Remnants

Urachal Remnants

• Urachus connects dome of bladder to umbilicus • Obliterated at birth  median umbilical ligament • Failed/incomplete obliteration can occur

• Remnant can lead to adenocarcinoma of bladder • Key feature: Cancer at dome of bladder

• Classic case • Adult with painless hematuria • Tumor at dome of bladder • Path showing adenocarcinoma

• Urine can leak from umbilicus • Also can form cyst, sinus, diverticulum • Can lead to infections

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Arterial System Renal Artery Segmental Artery

Renal Anatomy

Interlobar Artery

Jason Ryan, MD, MPH Arcuate Artery Glomerulus

Special Kidney Features

Interlobular Artery

Aortic Dissection

• Right kidney slightly smaller

• Renal arteries come off abdominal aorta • Aortic dissection can cause renal ischemia

• Less development in utero due to liver

• Left kidney has longer renal vein • Often taken for transplant • Dead/dying kidney usually not removed in transplant • New kidney attached to iliac artery/vein

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Fluid Compartments

40% Non-Water

Renal Physiology I

60% Water

Jason Ryan, MD, MPH

Determining Fluid 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

2/3 Intracellular

¾ Interstitial

• A patient is administered 120mg of inulin. An hour later, the patient has excreted 20mg of inulin in the urine. The plasma inulin concentration is 1mg/100ml. What is the extracellular fluid volume for the patient?

Radiolabeled Albumin

1/3 Extracellular 2/3 Intracellular

1/3 Extracellular

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

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 • Low ECV can lead to low blood pressure • Low ECV activates:

Portion of extracellular fluid Contained in arterial system Maintains tissue perfusion Not necessarily correlated with total body water Modified by:

• Sympathetic nervous system • Renin-angiotensin-aldosterone system

• Volume • Cardiac output • Vascular resistance

Evaluating Kidney Function

Evaluating Kidney Function

• Urine output • Glomerular filtration rate

• Renal Blood Flow • How much blood enters kidney

• Filtration Fraction

• How much liquid passes through the filter (i.e. glomerulus)? • Can be determined from blood, urine measurements • GFR falls as kidneys fail

• GFR/RBF

Measuring GFR

Theoretical Determination GFR

• Theoretical determination

• Filtration Driving Forces

• Need to know pressures in capillary, Bowman’s capsule

• Hydrostatic pressure • Oncotic Pressure

• Clinical determination • Need to know plasma concentrations solutes, urine flow

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Glomerular Filtration Rate

Capillary Fluid Exchange • Hydrostatic pressure – fluid PUSHING against walls • High pressure drives fluid TOWARD low pressure

• Oncotic pressure – concentrated solution PULLING fluid in

PGC

∏GC

PBC

∏BC

• High pressure draws fluid AWAY from low pressure

To Raise PGC

Glomerular Filtration Rate

Increase GFR

• Dilate afferent arteriole PGC

∏GC

PBC

∏BC

• • • •

To change GFR: 1. Change PGC 2. Change ∏GC (alter protein levels blood) 3. Change PBC

More blood IN Increase RPF Increase PGC Increase GFR

PGC

∏GC

PBC

∏BC Image courtesy of OpenStax College

To Raise PGC

To Raise ∏GC

Increase GFR

• Constrictefferent arteriole

• Increase protein levels in blood

• Blood backs up behind constricted arteriole • Less blood out • Decreased RPF • Increase PGC • Increase GFR

• Less blood drawn into proximal tubule • Lower GFR • No change RPF

PGC

∏GC

PBC

∏BC Image courtesy of OpenStax College

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PGC

∏GC

PBC

∏BC

Glomerular Flow Dynamics

To Change PBC • Obstruct ureter • Urine backs up behind obstruction • Pressure rises in all portions nephron

• Increase PBC • Less GFR PBC • No effect RPF PGC

∏GC

PBC

∏BC

Autoregulation

Myogenic Mechanism

• Constant GFR/RPF despite changes in BP • #1: Myogenic mechanism

• High BP • Afferent arteriole constricts with high BP • Responds to stretch • Efferent arteriole dilates • Due to decreased renin

• Responds to changes in BP to maintain GFR

• #2: Tubuloglomerular feedback • Responds to changes in [NaCl] to maintain GFR

• Result is maintenance of normal GFR/RPF

• Low BP • Opposite effects as above

Tubuloglomerular Feedback

Severe Volume Loss

• NaCl tubular fluid sensed by macula densa

• • • • •

• Part of JG apparatus

• High GFR  High NaCl  Macula Densa Sensing • Macula Densa  vasoconstriction afferent arteriole

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Profound loss of fluid (vomiting, diarrhea, etc.) RPF will fall significantly Autoregulatory mechanisms activated GFR still falls Cr level can ↑

Renal Function Measurements • Glomerular filtration rate • How much liquid passes through the filter (i.e. glomerulus)?

• Renal plasma flow • How much liquid does the kidney handle?

• Filtration fraction

Renal Physiology II

• Of all substance X entering kidney, what % gets filtered?

• Renal clearance • How much of each blood component gets removed?

Jason Ryan, MD, MPH

Renal Function Measurements

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 Fraction=2/5=40% Urine Flow Fluid out of kidney

Urine Flow Fluid out of kidney

Renal Function Measurements

Renal Function 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 = U x * 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 secretion/resorption • Creatinine = All filtered goes out, small amount secretion

• Using Cr instead of inulin: • Secreted Cr will be counted as filtered • This will slightly overestimate GFR

Cinulin = Uinulin * V = GFR Pinulin

Creatinine • Special formulas to convert Cr to GFR

PCr/GFR Relationship

Cx = Ux * V Px

• Cockcroft-Gault formula • Modification of Diet in Renal Disease (MDRD) formula • Use age, gender, Cr level to estimate GFR

Amount of Cr out in urine Equal to amount produced

• GFR declines with age

CCr = UCr * V = GFR PCr

• Not always accompanied by rise in Cr • Use of formulas is key • Must adjust some medication dosages

Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr)

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Creatinine Clearance

Creatinine

CCr = Constant ≈ GFR PCr

Cr

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  Cr = 0.8 mg/dl • Chronic kidney disease  Cr = 2.0 mg/dl • End stage renal disease (dialysis)  Cr = 4.0mg/dl

RPF Fluid into Glomerulus

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)

• Blood = Plasma + cells/proteins • Renal Blood Flow > Renal Plasma Flow • Separate calculations RBF vs. RPF

CPAH = UPAH * V = RPF PPAH

*PAH clearance underestimates RPF by 10% Not all renal plasma/blood to glomeruli

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Renal Blood Flow (RBF)

Renal Blood Flow (RBF)

• RBF determined from RPF • Blood = Plasma + Cells/Proteins • Cells/Proteins (%) ≈ Hct (%)

• RBF determined from RPF • Blood = Plasma + Cells/Proteins • Cells/Proteins (%) ≈ Hct (%)

RPF = RBF (1-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 = RPF 1- Hct

Renal Function Measurements

Renal Blood Flow (RBF)

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 Variables

Quantifying Kidney Function

• Filtration Fraction

Measured Variables Urine Flow (l/min) Plasma Conc X (mg/l) Urine Conc X (mg/l)

• How much of plasma to kidney gets filtered? • GFR/PBF • Normal = 20%

• Filtration Load X • How much of substance X gets filtered? • Px * GFR • Amount of X delivered to proximal tubule

Determined Variables Renal clearance Renal plasma flow Renal Blood Flow Glomerular filtration rate Filtration fraction

Inulin Clearance = GFR PAH Clearance = RPF

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Prostaglandins and NSAIDs • • • • •

ACE Inhibitors

Prostaglandins dilate afferent arteriole  ↑RBF NSAIDs (ibuprofen) block PG production Afferent arteriole constricts ↓RBF ↓ GFR -- FF Clinical effects:

• • • • • •

• 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 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 • GFRCx  resorption

Example #1: Filtered = 100mg/min Excreted = 120mg/min Additional 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 = 80ml/min Additional 20ml/min “uncleared” by resorption

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Intake and Output

Solutes in Renal Failure • Regulated solutes (Na/K): No concentration change • Unregulated solutes (Urea): Increased plasma level

• Amount of any substance in must equal amount out • When insults occur (renal failure, diarrhea), there is a transient imbalance that alters plasma levels • Steady state returns • Eat 10grams per day salt  excrete 10grams per day

Question 1

Question 2 • 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?

• 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?

= Cinulin

GFR = Uinulin * V Pinulin

Cx = Ux * V = 8 * 200 = 400cc/hr Px 4

V = GFR * Pinulin = 200 * 3 = 100ml/hr Uinulin

Question 4

Question 3 • 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 PPAH RPF = 10 * 200= 5

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400

• A lab animal has an inulin clearance of 100cc/hr. Plasma concentration of substance X is 4mg/mL. It is known that substance X is not reabsorbed, but is secreted at a rate of 25mg/hr. What is the excretion rate of substance X?

RBF = RPF 1- Hct

Amount filtered (X) = GFR * Px Excreted = Filtered – Reabsorbed + Secreted

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 of substance X is 4mg/mL. It is known that substance X is not reabsorbed, but is secreted at a rate of 25mg/hr. What is the excretion rate of substance X?

• If given inulin clearance, that is GFR • GFR can be used to calculate filtered load of other substances • Just need plasma concentration (Px)

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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Nephron H2O NaCl K+ HCO3Glucose Amino Acids

Nephron Physiology Jason Ryan, MD, MPH

Transport

Diffusion

Apical Membrane

Basolateral Membrane

Lumen (Urine)

Interstitium/Blood Na

↑[Na]

Lumen (Urine)

Interstitium/Blood

↑[Na]

↓[Na]

↓[Na] Na

Na

Na

↓[Na]

↑[Na] ATP Na

Segments of Nephron

Osmotic Diffusion Lumen (Urine)

Proximal Tubule

Interstitium/Blood

High Osmolarity 1200mOsm

Low Osmolarity (50mOsm) H2O

Distal Tubule

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

Glucose

ATP K+ K+

Cl-

Glucose

Anions Hydroxide (OH-) Formate Oxalate Sulfate

Lumen (Urine)

Interstitium/Blood

• • • • • • •

Na

Glucose

ATP K+ K+

ClAnions Hydroxide (OH-) Formate Oxalate Sulfate

Glucose

Glucose Clearance

Proximal Tubule Na

Cl

Anions

Cl

Anions Glucose H2O

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Completely reabsorbed proximal tubule Na/Glucose co-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

Na+ Interstitium/Blood

Na

HCO3- +

• No tryptophan transporter in proximal tubule • Amino acids in urine • Skin rash resembling pellagra (plaques, desquamation)

H+

H2CO3 CA

CO2 + H2O

H+ + HCO3-

H2CO 3 CA

CO2 + H2O

CA = Carbonic Anhydrase

Proximal Tubule Bicarb

Fanconi’s Syndrome

Clinical Correlations • Carbonic anhydrase inhibitors

• Impaired ability of proximal tubule to resorb HCO3-, glucose, amino acids, phosphate, and low molecular weight proteins • Polyuria, polydipsia (diuresis from glucose) • Non AG acidosis (loss of HCO3-) • Hypokalemia (↑nephron flow) • Hypophosphatemia (loss of phosphate resorbtion) • Growth failure, dehydration in children

• Weak diuretics • Result in bicarb loss in urine

• Type II Renal Tubular Acidosis • Ion defect • Inability to absorb bicarb • Metabolic acidosis

Proximal Tubule

Fanconi’s Syndrome

Key Points

• Inherited or acquired syndrome (rare) • Inherited form associated with cystinosis

• • • • •

• Lysosomal storage disease • Accumulation of cystine

• Acquired causes: • Lead poisoning • Tenofovir (HIV drug) • Tetracycline

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 • Carbonic anhydrase inhibitors • Type II RTAs

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Proximal Tubule

Thin Descending Loop Henle

Key Points • Most common source renal cell carcinomas • Most common area damaged acute tubular necrosis

• • • • •

Osmolarity of Nephron

H2O H2O H2O H2O H2O

Osmolarity of Nephron • Created by Na, Cl, and Urea • Urea resorption by collecting duct essential to maintain these gradients for water resorption

300mOsm

Cortex

Impermeable to NaCl Concentrates urine Absorbs water Water leaves urine Drawn out by hypertonicity in medulla

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 H2O H2O H2O

600mOsm K

1200 Inner Medulla

1200mOsm

Mg2+ Ca2+

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K Cl-

Thick Ascending Loop Henle

Distal Tubule Lumen (Urine)

Interstitium/Blood

120

Outer Medulla

NaCl NaCl NaCl NaCl NaCl

300

Cortex

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 Na+

K+

ATP

H2O

K+ Cl-

Interstitium/Blood

ATP

K+ Na+

Na+

Na+

Cl-

Intercalated Cell Ca2+

Na Ca2+ ATP H+

Key Points

Collecting Duct Hormones

• Collecting duct functions

• Amount of absorption/secretion heavily dependent on aldosterone and antidiuretic hormone (ADH)

• Resorb Na/H2O • Secrete K+/H+

• Increased Na delivery to CD  increased K excretion • Contributes to hypokalemia with loops/thiazides

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Collecting Duct

Aldosterone

Principal Cell

Lumen (Urine)

• Steroid (mineralocorticoid) hormone • Synthesized/released by zona glomerulosa cells of adrenal cortex • Freely crosses cell membrane (steroid) • Binds to cytosolic protein receptor • Activated receptor modifies gene expression • Increase Na/K-ATPase proteins and Na channels of principal cells • Also promotes K secretion principal cells • Also promotes H secretion intercalated cells

Na+

Interstitium/Blood

Na+ Aldosterone

ATP

K+

K+

Aldosterone

H2O

Intercalated Cell

Aldosterone H+

Aldosterone

Cl-

Nephron Water Permeability

• Overall effect:

Permeable

Impermeable

Variable

• ↑ sodium/water resorption (↑effective circulating volume) • ↑K excretion • ↑H+ excretion

• Release stimulated 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 • 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 • Water channel

• Result is ↑ permeability of cells to water

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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

Intercalated Cell

1200

Inner Medulla

High Water Intake (low ADH) 300

Cortex

• Most diuretics block resorption Na • This sends more Na to collecting duct • ↑osmolarity collecting duct • ↑excretion of Na/H2O

300mOsm

NaCl NaCl

1200mOsm

How Diuretics Work

NaCl

Outer Medulla

600mOsm

H2O

600mOsm

NaCl

Inner Medulla

60

1200mOsm

ADH Urea Resorption

Antidiuretic Hormone (ADH)

• Medullary interstitium very important for producing maximally concentrated urine • High osmolarity portion of kidney

• In setting of high ADH, large osmotic gradient exists to absorb water from urine • As water leaves proximal collecting duct, urea concentration rises • This creates gradient for urea to leave urine in distal collecting duct (medullary portion) • ADH also increases # of urea transporters

H2O H2O

H2O Urea

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Permeable to H20 NOT permeable to Urea

Permeable to H20 AND permeable to Urea

Collecting Duct

Sodium 5%

• Resorption Na/H2O

67%

• Depends on ADH (H2O) and Aldosterone (Na)

• Secretion of K+ and H+ • Depends on Aldosterone

• Urea resorption

3%

25%

1%

Water

Concentration Changes 50/50

Solute

50/50

0% Nephron

67%

Na/Cl

Water 50/50

8-17%

<50/50 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

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Inulin Cr

Renal Hormones • Released by kidney • Renin • Erythropoietin • 1,25 Vitamin D

• Act on kidney

Renal Endocrinology

• • • • •

Jason Ryan, MD, MPH

Juxtaglomerular Apparatus

Angiotensin II Atrial Natriuretic Peptide (ANP) Antidiuretic hormone (ADH) Aldosterone PTH

Stimulation Renin Release

• JG Cells

1. Low blood pressure

• Modified smooth muscle of afferent arteriole

• JG cells

• Macula densa

2. Low NaCl delivery

• Part of distal convoluted tubule

• Macula densa

3. Sympathetic activation

• JG cells secrete renin

• β1 receptors

RAA System Key Elements

Renin-Angiotensin System Angiotensinogen

Sympathetic System

• Renin

Renal Na/Cl resorption

• AII

+ Renin

• Main job is to convert AT to AI AI

+ ACE

A2

• Multiple effects

Arteriolar vasoconstriction JG Cells

• Aldosterone • Collecting duct effects • Resorption of Na • Excretion of K, H+

Adrenal aldosterone secretion

Net Result

↑Salt/Water Retention ↑BP

Pituitary ADH secretion

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Angiotensin II (AII) • • • • •

Angiotensin II

Efferent arteriole constriction Preserves renal function in low-volume state ↑GFR ↑FF ↓RPF

• Increased Na/H2O through several mechanisms • Increased proximal tubule resorption (via capillary effect) • Direct proximal tubule resorption through Na/H+ exchange • Stimulates aldosterone release

Capillary Effect

Proximal Tubule Lumen (Urine)

• Altered by efferent arteriole constriction • ↓hydrostatic pressure from less blood flow • ↑oncotic pressure from more H2O filtered • Net resultis that efferent arteriole constriction by AII leads to increased NaCl resorption

Na+ Interstitium/Blood

Na

HCO3- +

H+

H2CO3 CA

CO2 + H2O

H+ + HCO3-

H2CO 3 CA

CO2 + H2O

CA = Carbonic Anhydrase

Aldosterone

Aldosterone

• Steroid (mineralocorticoid) hormone • Synthesized/released by zona glomerulosa cells of adrenal cortex • Freely crosses cell membrane (steroid) • Binds to cytosolic protein receptor • Activated receptor modifies gene expression

• Increase Na/K-ATPase proteins and Na channels of principal cells • Promotes K secretion principal cells • Promotes H secretion intercalated cells

25

Collecting Duct

Aldosterone

Principal Cell

Lumen (Urine)

• Release stimulated by:

Na+

Interstitium/Blood

Na+

• Angiotensin II • High potassium • ACTH (minor effect)

Aldosterone

K+

Aldosterone

ATP K+

H2O

• Overall effect: • ↑ sodium/water resorption (↑effective circulating volume) • ↑K excretion • ↑H+ excretion

Intercalated Cell

Aldosterone H+

Primary Aldosteronism • • • •

RAA System Drugs

Conn’s syndrome (adenoma) Adrenal hyperplasia Causes resistant hypertension Hallmark is hypertension with ↓K

• ACE-inhibitors • Block conversion AI to AII • Lower blood pressure

• Angiotensin receptor blockers (ARBs) • Block effects of angiotensin II • Lower blood pressure

RAA System Drugs

Atrial Natriuretic Peptide

• Beta Blockers

• • • • • •

• Block sympathetic stim of JG apparatus • Block renin release • Lower blood pressure

• Aldosterone antagonists • • • • • •

Spironolactone, eplerenone Blocks Na resorption Blocks K excretion Blocks H+ excretion Lower blood pressure Will ↑K, ↑H+ (↓pH)

26

Atrial stretch (pressure/volume)  ANP release Vasodilator (↓SVR) Constricts renal efferents/dilates afferents Relax vascular smooth muscle via cGMP ↑GFR, ↓Renin ↑diuresis

Parathyroid Hormone

Parathyroid Hormone Effects • Net Effects:

• Maintains calcium levels • Released by chief cells of parathyroid gland • Secreted in response to:

• ↑[Ca 2+] plasma • ↓ [P043-] plasma • ↑ [P043-] urine

• ↓ [Ca2+] • ↑ plasma [P043-] • ↓ 1 ,25-(0H)2 vitamin D

• Dual effects of Mg • Low Mg  stimulates PTH release • Very low Mg  inhibits PTH release

Parathyroid Hormone Effects

Parathyroid Hormone Lumen (Urine)

• Kidney: • ↑ Ca 2+ resorption (DCT) • ↓ P043- resorption (PCT) • ↑ 1 ,25-(0H)2 vitamin D production

PTH

Interstitium/Blood Na

X

PO4-

3-

• ↑Ca2+ and P04 absorption (via vitamin D)

Proximal Tubule

• Bone: ↑PO4excretion

3-

• ↑Ca2+ and P04 resorption (direct and via vitamin D)

Vitamin D Basics

Parathyroid Hormone Lumen (Urine)

Interstitium/Blood

• Vitamin D2 is ergocalciferol • Vitamin D3 is cholecalciferol • Two sources D3:

Na+ ATP

• Diet • Sunlight (skin synthesizes D3)

K+ Cl-

PTH

Distal Tubule Na Ca2+

ATP K

• GI:

Na+

Na

++

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

• GI: ↑Ca2+ and P043- absorption • Bone: ↑Ca2+ and P043- resorption

Calcium-Phosphate in Renal Failure

Vitamin D and the Kidney • Proximal Tubule converts vitamin D to active form

Sick Kidneys

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)

• Not from CO2 • Derived from amino acids, fatty acids, nucleic acids

Non-volatile 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 by bicarbonate (no change pH) Bicarbonate must be replenished by kidneys

29

Bicarb Reabsorption

Renal Acid-Base Regulation

Proximal Tubule Lumen (Urine)

• #1: Reabsorb/Generate bicarb • #2: Excrete H+

Na+ Interstitium/Blood Na

HCO3- +

H+

H+ + HCO3-

H2CO3

H2CO 3

CA

CA

CO2 + H2O

CO2 + H2O

CA = Carbonic Anhydrase

HCO3- Generation

Bicarb Reabsorption

Collecting Duct

Nephron 6%

Lumen (Urine)

80%

Intercalated Cell CO2 + H2O CA

4%

H2CO3

10%

H+ + HCO3ATP H+

0%

HCO3- Generation

Urinary Buffers

Collecting Duct • • • • •

HCO3-

High H+  low pH  damage to nephron Buffers soak up H+ Protect from low pH Problem: Bicarbonate reabsorbed Need other buffers

• Titratable acids • Ammonia

30

Interstitium/Blood

Titratable Acids

Titratable Acids

• Urinary substances that absorb H+ • Acids • Measured by titration (“titratable”)

• • • •

Mostly phosphate Exists in multiple states HPO4 (one hydrogen) H2PO4 (two hydrogens)

Titratable Acids

Titratable Acids • 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+ + HCO3H2CO3

H2PO4

CA

CO2 + H2O

Ammonia

Terminology

• Limited supply of titratable acids

• Ammonia = NH3 • Ammonium = NH4+

• Varies with dietary intake (especially phosphate)

• Supply of ammonia (NH3) is adaptable • More NH3 generated by kidneys when ↑ H+ • Synthesized from glutamine (amino acid)

Glutamine

31

HCO3 -

H+ excretion HCO3- generation

Ammonia

Renal Acid-Base

↑NH4+ excretion = ↑ H+ excretion

Summary Non-volatile Acids

Interstitium/Blood

Lumen (Urine)

↓ HCO3NH3

H+

NH4+

HCO3-

H+ + HCO3-

↑ HCO3Reabsorption

Buffering Tit. Acids NH4+

H2CO3 CA

CO2 + H2O

Proximal Tubule

H+ excretion HCO3- generation

Net Acid Excretion

Collecting Duct ↑ H+ Excretion ↑ HCO3- Generated

Net Acid Excretion

• Urinary Acid – Urinary Base • Positive value indicates acid being excreted

• Acidosis: Increased net acid excretion • Alkalosis: Decreased net acid excretion

Net Acid = Titratable Acids + NH4+ - HCO3Excretion

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 pH = 6.1 + log

Acid-Base Equilibrium • Normal HCO3- = 22 – 26 mEq/L • Normal pCO2 = 35 – 45 mmHg • Normal pH = 7.35-7.45

[HCO3-] 0.03*pCO2

33

Definitions

Acidosis Symptoms

• Acidosis/alkalosis

• Hyperventilation (Kussmaul breathing) • Depression of myocardial contractility • Cerebral vasodilation

• Disorder altering H+ levels

• Acidemia/alkalemia • Presence of high or low pH in bloodstream

• Increased cerebral blood flow; Increase ICP

• Can have acidosis without acidemia if mixed disorder • i.e. acidosis + alkalosis at same time

CO2 + H2O  HCO3 - + H +

Acidosis Symptoms

Alkalosis Symptoms

• CNS depression (very high CO2 levels) • Hyperkalemia

• Inhibition of respiratory drive • Depression myocardial contractility • Cerebral vasoconstriction

• High H+ shifts into cells in exchange for K+

• Shift in oxyhemoglobin dissociation curve

• Decrease in cerebral blood flow

• Bohr effect • ↓ pH leads to hemoglobin releasing more oxygen

• Hypokalemia • Shift in oxyhemoglobin dissociation curve

Approach to Acid-Base Problems

Acid-Base Problems

3. Determine acid-base disorder

1. Check the pH • pH < 7.35 = acidosis • pH > 7.45 = alkalosis

• • • •

2. Check the HCO3- and pCO2 • •

HCO3 from venipuncture; normal 22-28 mEq/L pCO2 from ABG; normal 35-45mmHg

Acidosis + ↓ HCO3- = metabolic Acidosis + ↑pCO2 = respiratory Alkalosis + ↑HCO3- = metabolic Alkalosis+ ↓ pCO2 = respiratory

acidosis acidosis alkalosis 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 • •

• Step 1: What is acid base disorder? • Metabolic acidosis, respiratory alkalosis, etc.

• Step 2:

Combined respiratory/metabolic Two metabolic disorders

• Is there a second disorder? • Is the compensation appropriate?

Cause vs. Compensation

Compensatory Changes ↓ HCO3- = metabolic acidosis

• •

• • •

Compensation = ↓pCO2

↑ HCO3- = metabolic alkalosis

• •

Compensation = ↑pCO2

Most acid-base disorders, HCO3- and pCO2 abnormal One is “culprit” that is causing disorder Other is compensatory change

↑pCO2 = respiratory acidosis

• •

Compensation = ↑ HCO3-

↓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

Most acid-base disorders, HCO3- and pCO2 abnormal One is “culprit” that is causing disorder Other is compensatory change Example 2 pH = 7.30 (acidosis) HCO3- = high pCO2 = high Respiratory acidosis with metabolic compensation

CO2 + H2O  HCO3 - + H +

CO2 + H2O  HCO3 - + H +

35

Respiratory Compensation

Respiratory Compensation

• Hyper or hypoventilation • Changes pCO2 to compensate for metabolic disorders

• Hyperventilation • • • •

Blows off CO2 Plasma CO2 level falls Less H+ in blood pH rises

• Hypoventilation

CO2 + H2O  HCO 3- + H+

• Retains CO2 • Plasma CO2 level rises • More H+ in blood • pH falls

Renal Compensation

Mixed Disorders

• Acidosis

• Two disorders at same time

• Excess H+ filtered/secreted into nephron • Bicarbonate reabsorbed • Urinary buffers excreted • HPO42- excreted as H2PO4- (phosphate) • NH3 excreted as NH4+ (ammonium) • These bind H+ (buffers) • Prevent severe drops in pH

• • • • •

Metabolic acidosis AND respiratory alkalosis/acidosis Metabolic acidosis AND metabolic alkalosis Two metabolic acidoses Occurs in many pathologic states i.e. vomiting and diarrhea

• To uncover, determine “expected” response • Expected HCO3- for respiratory disorder • Expected CO2 for metabolic disorder • Use renal formulas to determine expected response

• Alkalosis • Reverse of acidosis

• If actual ≠ expected  2nd disorder present

Mixed Disorders

Mixed Disorders

• Cannot “compensate” to normal pH • Classic scenario:

• If actual ≠ expected, determine abnormality • i.e. CO2 higher than expected • i.e. HCO3- lower than expected

• pH = normal; HCO3- and CO2 abnormal • Mixed disorder

• Usual rules then apply for determining 2° disorders: • • • •

36

↑CO2 = acidosis ↓CO2 = alkalosis ↓ HCO3- = acidosis ↑ HCO3- = alkalosis

Metabolic Acidosis Compensation

Compensation Formulas • • • •

Winter’s Formula Metabolic Alkalosis Formula Acute/Chronic Respiratory Equations Delta-Delta

• • • •

Compensatory respiratory alkalosis (↓ pCO2) Hyper ventilation Winter’s Formula: tells you expected pCO2 If actual CO2 ≠ expected, mixed disorder

pCO2 = 1.5 (HCO3-) + 8 +/- 2

Metabolic Acidosis Compensation • • • •

Metabolic Acidosis Compensation

Compensatory respiratory alkalosis (↓pCO2) Hyper ventilation Winter’s Formula: tells you expected pCO2 If actual pCO2 ≠ expected, mixed disorder

• • • •

pCO2 = 1.5 (HCO3-) + 8 +/- 2

Compensatory respiratory alkalosis (↓pCO2) Hyper ventilation Winter’s Formula: tells you expected pCO2 If actual pCO2 ≠ expected, mixed disorder

pCO2 = 1.5 (HCO3-) + 8 +/- 2 Example 2 pH = 7.28 (acidosis) HCO3 = 12 mEq/L (nl = 24) pCO2 = 40mmHg (nl=40) Expected pCO2 = 1.5 (12) + 8 = 26 +/- 2 pCO2>expected Concomitant Respiratory Acidosis

Example 1 pH = 7.20 (acidosis) HCO3 = 9 mEq/L (nl = 24) pCO2 = 22mmHg (nl=40) Expected pCO2 = 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

• • • •

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-])

ΔpCO2 = 0.7 * (Δ[HCO3-])

Example 1 pH = 7.50 (alkalosis) HCO3- = 34 mEq/L (nl = 24) pCO2 = 47mmHg (nl=40) Δ[HCO3-] = (34-24) = 10 Expected ΔpCO2 = 0.7 (10) = 7 Actual ΔpCO2 = 47-40 = 7 No Secondary Disorder

37

Respiratory Acidosis

Respiratory Acidosis

Compensation

Compensation

• Acute compensation • • • •

• Acute compensation

Minutes Intracellular buffers raise [HCO3-] Hemoglobin and other proteins Small ↑pH

• 1 meq/L ↑ [HCO3-] for every 10 mmHg ↑pCO2 • Δ[HCO3-] = ΔpCO2/10

• Chronic compensation • 3.5 meq/L ↑ [HCO3-] for every 10 mmHg ↑pCO2 • Δ[HCO3-] = 3.5* ΔpCO2/10

• Chronic compensation • Days • Renal generation of ↑[HCO3-] • Larger ↑pH (but not back to normal!)

Example 1 pH = 7.15 (acidosis) pCO2 = 80mmHg (nl=40) Acute Δ[HCO3-] = 40/10 = 4 [HCO3-] = 28; pH = 7.17 Chronic Δ[HCO3-] = 3.5* 40/10 = 14 [HCO3-] = 38; pH = 7.30

Respiratory Alkalosis

Respiratory Alkalosis

Compensation

Compensation

• Acute compensation • Chronic compensation

• Acute compensation • 2meq/L ↓ [HCO3-] for every 10 mmHg ↓ pCO2 • Δ[HCO3-] = 2*ΔpCO2/10

• Chronic compensation • 4meq/L ↓[HCO3-] for every 10 mmHg ↓ pCO2 • Δ[HCO3-] = 4 * ΔpCO2/10 Example 1 pH = 7.65 (alkalosis) pCO2 = 20mmHg (nl=40) Acute Δ[HCO3-] = 2* 20/10 = 4 [HCO3-] = 20; pH = 7.63 Chronic Δ[HCO3-] = 4* 20/10 = 8 [HCO3-] = 16; pH = 7.53

Compensation Timeframe

Summary Acidosis

• Respiratory compensation to metabolic disorders • Rapid • Change in respiratory rate • Minutes

Respiratory

Alkalosis

Metabolic

Respiratory

Metabolic

• Metabolic compensation to respiratory disorders • Acute, mild compensation in minutes from cells • Chronic, significant compensation in days from kidneys

38

Compensation Compensation ↑HCO3↓pCO2

Compensation Compensation HCO3↑pCO2

Acute/Chronic Formulas

Acute/Chronic Expected pCO2 Formulas Formula

Winter’s Formula

Acid-Base Disorders 1. 2. 3. 4.

Respiratory Acid Base Disorders

Respiratory alkalosis Respiratory acidosis Metabolic alkalosis Metabolic acidosis

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) After 24-48hrs, kidneys will excrete HCO3pH will fall back toward normal Ventilation rate will decrease Acetazolamide can augment excretion HCO3-

• Two acid-base disorders • Shortly after ingestion: respiratory alkalosis • Salicylates stimulate medulla • Hyperventilation

• Hours after ingestion: AG metabolic acidosis • Salicylates ↓lipolysis, uncouple oxidative phosphorylation • Inhibits citric acid cycle • Accumulation of pyruvate, lactate, ketoacids

39

Aspirin Overdose

Aspirin Overdose

• pH

• Sample case: pH 7.30, PCO2 20, HC03- 14 • Metabolic acidosis • Winter’s formula

• Variable due to mixed disorder • Acidotic, alkalotic, normal

• CO2

• PCO2 = 1.5 (14) + 8 +/- 2 = 29

• Low due to hyperventilation

• PCO2 < Expected • Concomitant respiratory alkalosis

• HCO3• Low due to acidosis

• If patent is acidotic: • Winter’s formula predicts CO2 higher than actual • CO2 lower than expected for compensation

Respiratory Acidosis

Respiratory Acidosis • ↑pCO2 • pH<7.35

• • • •

• • • •

CO2 + H2O  HCO 3- + H+

Hypercapnia • • • •

Cause by hypoventilation Lung disease (COPD, PNA, Asthma) Narcotics Respiratory muscle weakness

Hypercapnia can affect CNS system Most patients with acute ↑CO2 are agitated Some have depressed consciousness (CO2 narcosis) Δ mental status in patient with respiratory disease: • Consider high CO2 • Check ABG • If CO2 high  ventilation

40

Myasthenia gravis Amyotrophic lateral sclerosis Guillain-Barré syndrome Muscular dystrophy

Acid-Base Disorders 1. 2. 3. 4.

Respiratory alkalosis Respiratory acidosis Metabolic alkalosis Metabolic acidosis

Metabolic Alkalosis Jason Ryan, MD, MPH

Metabolic Alkalosis

Metabolic Alkalosis • ↑HCO3• pH>7.45

• • • • • •

Contraction alkalosis Hypokalemia Diuretics Vomiting Hyperaldosteronism Antacid use

CO2 + H2O  HCO3 - + H + Loss of H+ from the body or a gain of HCO3-

Contraction Alkalosis

Proximal Tubule: Bicarb Lumen (Urine)

• ↓ECV  Renin-Angiotensin-Aldosterone activation

Na+ Interstitium/Blood

Na

• ↑H+ secretion proximal tubule (due to AII) • ↑ HCO3- resorption proximal tubule (due to ↑H+ secretion) • ↑H+ secretion collecting duct (due to aldosterone)

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

• 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)

Na+ Aldosterone

ATP

K+

K+

Aldosterone

H2O

Intercalated Cell

HCO3Aldosterone H+

Cl-

Bartter and Gitelman Syndromes

Diuretics • • • •

• Congenital disorders • Bartter

Loop and thiazide diuretics  metabolic alkalosis Volume contraction Hypokalemia ↑Na/H2O delivery to distal nephron ↑K+/H+ secretion

• Dysfunction N-K-2Cl pump ascending limb • Similar to loop diuretic

• Gitelman • Dysfunction of Na-Cl transport in distal tubule • Similar to thiazide diuretic

• Both cause hypokalemia/alkalosis

Vomiting

Urinary Chloride

• Loss of volume  contraction alkalosis • Loss of HCl

• Useful in metabolic alkalosis unknown cause • Low (<10-20) in vomiting

• ↑ production HCl • HCO3- generated during production

• Loss of Cl in gastric secretions

• High (>20) in many other causes alkalosis • Classic scenario:

• Loss of K+ • Urinary chloride is low (<20)

• Young woman with unexplained metabolic alkalosis • Urinary Cl is low • Diagnosis: surreptitious vomiting

42

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

Adrenal overproduction aldosterone Adrenal hyperplasia Adrenal adenoma (Conn’s syndrome) ↑ K+/H+ secretion Hypokalemia Metabolic alkalosis Resistant hypertension

Antacid use

• Often no edema in hyperaldosteronism • Na/Fluid retention  hypertension • Compensatory mechanisms activated

• Milk-alkali syndrome • Excessive intake of: • Calcium • Alkali (base)

• Increased ANP

• Usually calcium carbonate and/or milk • Often taken for dyspepsia

• Increased sodium and free water excretion • Result: diuresis  normal volume status • Urinary chloride will be increased

Metabolic Alkalosis

Antacid use

Keys to Diagnosis

• Hypercalcemia:

• History • Fluid status

• Inhibition Na-K-2Cl in TAL • Blockade (ADH)-dependent water reabsorption collecting duct

• Volume depleted: vomiting or GI losses

• Results in volume contraction • Contraction + alkali = metabolic alkalosis

• Urinary chloride • Low in surreptitious vomiting

43

IV Fluid Administration • Resolves most forms of metabolic alkalosis • • • •

“Fluid responsive” Diuretics Vomiting Contraction alkalosis

• Exceptions are hyperaldosteronism, hypokalemia

44

Non-AG Metabolic Acidosis • • • • • •

Renal Tubular Acidosis

Diarrhea Acetazolamide Spironolactone/Addison’s disease Saline infusion Hyperalimentation Renal tubular 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+

• Distal nephron cells cannot acidify urine • Can’t excrete H+ (acidemia) • Can’t resorb K+ (hypokalemia)

Type I (distal) RTA

Type I (distal) RTA

• Very low HCO3- (often <10meq/L) • Urine pH is high

• Key symptoms: Chronic kidney stones, Rickets • Alkaline urine precipitates stones (sometimes bilateral) • Acidosis  ↑Ca from bones • Acidosis suppresses calcium resorption (↑Ca in urine)

• Distal tubule cannot “acidify” the urine • Urine is alkaline • Diagnosis established if alkaline urine (pH > 5.5) despite a metabolic acidosis (with normal kidneys)

• Growth failure in children

45

Type I (distal) RTA

Urine Anion Gap

• Many etiologies • Genetic forms • Associated with autoimmune diseases

• • • • •

• Sjögren's syndrome • Rheumatoid arthritis

• Medications

In acidosis, lots of NH4 excreted (removes H+) Can’t measure NH4 directly Urinary anion gap (Na + K – Cl) is a surrogate NH4 leaves with Cl UAG becomes negative when acid (H+) being excreted

• Amphotericin B

Urine Anion Gap

Urine Anion Gap

• In GI metabolic acidosis (diarrhea):

• In distal RTA UAG is positive

• UAG becomes negative • Excretion of NH4 with Cl increases • Urine Cl concentration goes up

• Kidneys can’t excrete H+ • NH4 and Cl- don’t increase • UAG (Na + K – Cl) does not become negative as it should in acidosis

• Can also “challenge” patient with NH4Cl • Gives an acid load • Should lower urine pH • In RTA, Urine pH remains >5.3 Negative UAG in acidosis = GI cause Positive UAG in acidosis = RTA

Type I (distal) RTA

Type II (proximal) RTA

• Classic case • • • • • • •

• Defect in proximal tubule HC03- resorption • Urine pH<5.5

Patient with Sjogren’s disease Recurrent bilateral kidney stones Very low bicarb on blood work (<10) Hypokalemia Urine pH is high (>5.5) UAG is positive If given NH4Cl urine remains with high pH

• Initially, pH may be high due to ↑HC03- excretion • Distal tubule excretes H+ as acidosis becomes established • Urine becomes acidic

• Hypokalemia • Loss of HCO3- resorption  diuresis • Volume contraction • ↑aldosterone  ↑K excretion  hypokalemia

• Treatment: Sodium bicarbonate

46

Type II (proximal) RTA

Type II (proximal) RTA

• Milder than type I: [HC03-] 12-20

• Sample Case

• Distal intercalated cells function normally • Secrete acid to compensate

• • • • •

• No kidney stones • Can be seen with Fanconi's syndrome • Generalized failure of proximal tubule • Urine loss of phosphate, glucose, amino acids, urate, protein • Bone wasting from phosphate loss

• Treatment: Sodium bicarbonate

Type IV RTA

Type IV RTA

• Distal tubule failure to respond to aldosterone

• Decreased aldosterone

• Aldosterone deficiency/resistance

• • • •

No symptoms : routine blood work Mild weakness (low K) Mildly reduced HCO3- (10 – 20) Hypokalemia Urine pH is low (<5.3)

• • • •

Decreased excretion K+ Only RTA with HYPERkalemia Urine pH usually remains low (<5.4) Impaired ammonium (NH4+) excretion  acidosis

Diabetic renal disease ACEi or ARB NSAIDs Adrenal insufficiency

• Aldosterone resistance • Potassium sparing diuretics • TMP/SMX

Type IV RTA

Renal Tubular Acidosis

• Classic case: • Diabetic with renal insufficiency • Unexplained hyperkalemia

• Treatment: Fludrocortisone • 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-

BUN

K+

HCO3-

Cr

140

103

15

4.8

26

1.0

• • • • •

Glucose

Positive charged ions – negative charged ions = gap Positive charged = Na (don’t count K+) Negative charged = Cl- + HCO3Anion Gap = Na – (Cl- + HCO3-) Normal <12

100

140

103

15

4.8

26

1.0

100

Anion Gap = 140 – (103 + 26) = 11

The Anion Gap • • • • •

Why the Anion Gap Matters

Results from unmeasured ions Cations: Ca2+, Mg2+, other minerals Anions: proteins (albumin), phosphates, sulfates A low anion gap can be caused by hypoalbuminemia Also caused by multiple myeloma

• Acidosis from primary loss of HCO3• Body compensates with retention of Cl• AG = Na+ – (Cl- + HCO3-) • Normal anion gap

• Acidosis from primary retention of acid • • • • •

• IgG is cationic (+) • Will lower measured (+) ions or increase measured (-) ions

48

i.e. ketoacids, lactic acid HCO3- falls without rise in ClRise in A- to compensate for fall in HCO3AG = Na+ – (Cl- + HCO3-) Result is ↑AG

Two Cases

Why the Anion Gap Matters • • • •

When HCO3- ↓ something negative must ↑ This maintain balance of (-) and (+) charges In normal AG  Cl- rises In high AG  Unmeasured acids rise

AG = 10

134

108

pH 7.31

16

AG = 28

132

93

pH 7.27

11

The Delta-Delta

Winter’s Formula

Delta Ratio

• Acidosis: compensatory respiratory alkalosis (↓ pCO2)

• Anion gap ↑ should be similar to HCO3- ↓ • ΔAG = AG – 12 • Δ HCO3- = 24 – [HCO3-] • Ratio ΔAG/ Δ HCO3- assesses for 2° acid-base disorder

• Hyperventilation

• Winter’s Formula tells you expected ↓pCO2 • If actual CO2 ≠ expected, mixed disorder • Check Winter’s formula for all metabolic acidoses

• Used to check for 2° metabolic acid-base disorder • Winter’s formula assesses for 2° respiratory disorder

Δ Δ = ΔAG

pCO2 = 1.5 (HCO3-) + 8 +/- 2

Δ HCO3-

The Delta-Delta

The Delta-Delta

Delta Ratio

• ΔΔ 1-2 = normal • ΔΔ <1 = 2° non-AG metabolic acidosis

• Consider a patient with pH=7.21 (acidosis) • HCO3- = 12; Na+ = 150, Cl- = 96 • Increased anion gap of 42 • Delta AG = 42-12 = 30 • Delta HCO3- = 24 – 12 = 12 • Delta-Delta = 30/12 = 2.5 • HCO3- is too high • Concurrent metabolic alkalosis or prior resp. acidosis

• HCO3- too low

• ΔΔ >2 = 2° metabolic alkalosis or pre-existing respiratory acidosis • HCO3- too high

Δ Δ = ΔAG Δ HCO3-

49

Non-AG Metabolic Acidosis • Diarrhea • Lose HCO3- in stool

• Acetazolamide • Blocks formation and resorption HCO3-

• Spironolactone/Addison’s disease • Loss of aldosterone effects • Cannot excrete H+ effectively • Body retains H+

Anion Gap Metabolic Acidosis • • • • •

• Saline infusion • ↓renin-angiotensinaldosterone activity • ↓ H+ excretion

• Hyperalimentation • Metabolism  ↑HCl • Lowers pH

• Something with (-) charge that is NOT chloride

• Renal tubular acidosis

Anion Gap Metabolic Acidosis • • • • • • • •

Methanol

Methanol Uremia Diabetic ketoacidosis Propylene glycol Iron tablets or INH Lactic acidosis Ethylene glycol Salicylates

• • • •

Methanol

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. • • • •

Suspected ingestion (accidental, suicide, alcoholic) Confusion (may appear inebriated) Visual symptoms High AG metabolic acidosis

• Treatment: • • • •

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: • • • •

Anion Gap = Na – (Cl- + HC03-) HCO3- will be low (metabolic acidosis) Some other (-) substance must ↑ to balance Other substance is not ClOther substance is “unmeasured anion”

Inhibit alcohol dehydrogenase Blocks bioactivation of parent alcohol to toxic metabolite Fomepizole (Antizol) Ethanol

50

Ethylene Glycol Ethanol

• Classic scenario:

Alcohol Dehydrogenase

Acetaldehyde

• Suspected ingestion (accidental, suicide, alcoholic) • Flank pain, oliguria, anorexia (acute renal failure) • High AG metabolic acidosis

• Treatment: • • • •

Inhibit alcohol dehydrogenase Blocks bioactivation of parent alcohol to toxic metabolite Fomepizole (Antizol) Ethanol

Methanol

Alcohol Dehydrogenase

Ethylene Glycol

Propylene Glycol • • • •

Glycolaldehyde

Isopropyl Alcohol

Antifreeze (lowers freezing point of water) Solvent for IV benzos Metabolized to pyruvic acid, acetic acid, lactic acid Many adverse effects:

• Found in many of the same industrial products as methanol, ethylene glycol • Effects similar to ethanol • Key scenario: ingestion by alcoholic

• Converted by ADH to acetone • Less toxic than methanol or ethylene glycol • Does NOT cause anion gap metabolic acidosis

• Hemolysis • Seizure, coma, and multisystem organ failure

• High AG metabolic acidosis from lactate • Main clinical feature of overdose is CNS depression • No visual symptoms or nephrotoxicity

• Absence of high AG acidosis suggest IA ingestion

• No role for fomepizole or ethanol • Main symptom of ingestion is coma

Uremia

Diabetic Ketoacidosis (DKA)

• Advanced kidney disease • • • •

Formaldehyde

• Usually occurs in type I diabetics • Insulin requirements rise  cannot be met

Early kidney disease can have non-AG acidosis Reduction in H+ excretion (loss of tubule function) Increase in HCO3- excretion Cl- retained to balance charge (normal AG)

• Often triggered by infection

• Fatty acid metabolism  ketone bodies • β-hydroxybutyrate, acetoacetate

• Kidneys cannot excrete organic acids • Retention of phosphates, sulfates, urate, others • Increased anion gap acidosis

51

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:

Low tissue oxygen delivery Pyruvate converted to lactate High levels (>4.0mmol/L)  lactic acidosis AG metabolic acidosis Clinical scenarios: • • • • •

• Insulin (lower glucose) • IV fluids (hydration) • Potassium

Iron

Shock (↓tissue perfusion) Ischemic bowel Metformin therapy (especially with renal failure) Seizures Exercise

Iron

• Acute iron poisoning • Initial GI phase

• AG metabolic acidosis • From ferric irons • Also lactate (hypoperfusion)

• Abdominal pain • Direct toxic effects GI tract

• Later (24 hours) • • • •

Cardiovascular toxicity: shock, tachycardia, hypotension Coagulopathy: iron inhibits thrombin formation/action Hepatic dysfunction: worsening coagulopathy Acute lung injury

• Weeks later: bowel obstruction • Scarring at gastric outlet where iron accumulates

Isoniazid (INH) • • • •

Aspirin Overdose

Tuberculosis antibiotic Acute overdose causes seizures (status epilepticus) Seizures cause lactic acidosis AG metabolic acidosis

• Two acid-base disorders • Shortly after ingestion: respiratory alkalosis • Salicylates stimulate medulla • Hyperventilation

• Hours after ingestion: AG metabolic acidosis • Salicylates ↓lipolysis, uncouple oxidative phosphorylation • Inhibits citric acid cycle • Accumulation of pyruvate, lactate, ketoacids

52

Aspirin Overdose

Aspirin Overdose

• pH

• Sample case: pH 7.30, PCO2 20, HC03- 12 • Metabolic acidosis • Winter’s formula

• Variable due to mixed disorder • Acidotic, alkalotic, normal

• CO2

• PCO2 = 1.5 (12) + 8 +/- 2 = 29

• Low due to hyperventilation

• PCO2 < Expected • Concomitant respiratory alkalosis

• HCO3• Low due to acidosis

• Winter’s formula predicts CO2 higher than actual • CO2 lower than expected for compensation

53

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. An arterial blood gas is drawn showing: pH 7.30, pCO2 33mmHg Electrolytes are: Na 134, K 2.9, Cl 108, HCO3- 16

Acid Base Problems Jason Ryan, MD, MPH

What is the acid-base disorder?

Case 1

134

108

2.9

16

Case 2 An 80-year-old man with a severe cardiomyopathy presents with shortness of breath and edema for the past two days. An arterial blood gas is drawn showing: pH 7.25, pCO2 62mmHg Electrolytes show: HCO3- 27

• Diarrhea non-AG metabolic acidosis • No other clues to suggest a 2nd disorder • pH = 7.30  acidosis • HCO3- = 16 (low)  metabolic acidosis • pCO2 = 33 (low)  respiratory 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

What is the acid-base disorder?

Case 2 • • • • • • • •

Case 3

CHF exacerbation  acute respiratory acidosis pH = 7.25 (acidosis) pCO2 = 62 (high)  respiratory acidosis HCO3- = 27 (high)  metabolic compensation Abnormal same direction  mixed disorder less likely Acute respiratory acidosis ↑ HCO3- 1/10 ↑CO2 Expected ↑HCO3 = 2 (HCO3- of 26) No concurrent disorder

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 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 disorder?

Acute respiratory acidosis

54

Case 3

140

110

3.4

16

• pH 7.25 (acidosis) HCO3- 16 (low)  metabolic acidosis

Case 3 • Must consider RTA given RA history/kidney stones • UAG should be checked

pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (16) + 8 = 32 +/- 2

• • pCO2 32 (low)  respiratory compensation • Expected PCO2 = 32 • AG = 140 – 110 – 16 = 14 • Non-AG metabolic acidosis

• Urine Na + K – Cl • Should be negative due to acidosis • If positive, suggests RTA

• Acid challenge with NH4Cl should be done • Urine pH will remain >5.3 after NH4Cl • Type I RTA cannot acidify urine

Non-AG metabolic acidosis

Case 4

Case 4

140

94

4.0

34

• pH = 7.32 (acidosis)

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

• PCO2 = 69  respiratory acidosis • HCO3- = 34  metabolic compensation • This is chronic • Expected Δ[HCO3-] = 3.5* ΔpCO2/10 • ΔpCO2 = 69 – 40 = 29 • Expected Δ[HCO3-] = 3.5* 29/10 = 10 • Actual Δ[HCO3-] = 34 – 24 = 10

What is the acid-base disorder?

Chronic respiratory acidosis

Case 5

Case 5

A 50-year-old man is found obtunded and poorly responsive. An arterial blood gas is drawn showing: pH 7.52, pCO2 47mmHg Electrolytes show: Na 140, Cl- 96; HCO3- 34

• pH = 7.52 (alkalosis) • HCO3- = 34 (high)  metabolic alkalosis • PCO2 = 47 (high)  respiratory compensation • 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

Case 6

• Cause?

A 59-year-old man with a history of alcoholism and 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: pH 7.30, pCO2 28mmHg Electrolytes show: Na 141, Cl- 102; HCO3- 14

• Contraction alkalosis, hypokalemia, diuretics, vomiting, hyperaldosteronism, antacid use

• Need to know volume status • Reduced in contraction, diuretics, vomiting

• Need to know urinary chloride • Low with GI losses (vomiting)

• This disorder often fluid (saline) responsive

What is the acid-base disorder?

Case 6

141

Case 7

102 14 pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (14) + 8 = 29 +/- 2

• pH = 7.30 (acidosis)

A 50-year-old man with diabetes presents to the emergency room with confusion. His wife says he has been thirsty and urinating frequently. In addition, he takes narcotics for back pain and she believes he has been taking more pills than usual lately for abdominal pain. An arterial blood gas is drawn showing: pH 7.28, pCO2 40mmHg. Electrolytes are:

• HCO3- = 14  metabolic acidosis • pCO2 = 28mmHg  respiratory compensation • Expected PCO2 = 29 +/- 2 • No secondary respiratory disorder • AG = 141 – 102 – 14 = 25 (high) • ΔAG = 25 – 12 = 13; ΔHCO3-=24 – 14 = 10 • ΔΔ = 13/10 = 1.3 • No secondary metabolic disorder

Na 134, K 3.5, Cl 94, HCO3- 12 What is the acid-base disorder?

AG metabolic acidosis

Case 7

134 3.5

Case 7

94 12

• Diabetic, polyuria, polydipsia, abd pain  DKA • Expect AG metabolic acidosis • Narcotic use

134 3.5

94 12

• Winter’s formula pCO2 = 26 • pCO2 higher than expected at 40 • Concomitant respiratory acidosis

• Possible respiratory depression • Respiratory acidosis

• pH = 7.28  acidosis • HCO3- = 12 (low)  metabolic acidosis • pCO2 = 40 (normal)  NO respiratory compensation • Anion gap = 134 – 94 – 12 = 28 (high)

pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (12) + 8 = 26 +/- 2 AG metabolic acidosis with 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. 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

• Winter’s Formula pCO2 = 23 +/ - 2 • Actual pCO2 = 24 • Normal respiratory compensation • ΔAG = 51 – 12 = 39 • ΔHCO3- = 24 – 10 = 14 • ΔΔ = 39/14 = 2.8 • Concurrent metabolic alkalosis

Summary • • • • • • •

pCO2 = 1.5 (HCO3-) + 8 +/- 2 = 1.5 (10) + 8 = 23 +/- 2

Diarrhea non-AG metabolic acidosis Acute respiratory acidosis Renal tubular acidosis - Urine anion gap Chronic respiratory acidosis Metabolic alkalosis -Volume status/urine chloride Methanol toxicity AG metabolic acidosis with respiratory acidosis • Winter’s formula doesn’t match compensation

• AG Metabolic acidosis with metabolic alkalosis • Delta-delta abnormal

AG Metabolic Acidosis with metabolic alkalosis

57

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 • Muscle weakness

QRS Widening

Hyperkalemia

Atrial/ventricular myocytes

Causes • Increased K release from cells

Phase 1 IK+ (out)

• • • • • •

0mv Phase 3 IK+ (out) ERP -85mv

Phase 4

58

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 • Type IV RTA (aldosterone resistance)

• U waves • Flattened T waves

• Arrhythmias • Muscle weakness

Hypokalemia

U waves

Selected Causes T

U

• Increased K entry into cells

Origin unclear May represent repolarization of Purkinje fibers or papillary muscles

T

• Hyperinsulin states • Elevated beta-adrenergic activity • Albuterol, terbutaline, dobutamine • Alkalosis

U

• Increased GI losses

Can be normal

• Vomiting/diarrhea

Hypokalemia

Hypercalcemia

Selected Causes

Symptoms

• Increase renal losses

• Stones (kidney)

• Diuretics • Type I and II RTAs

• Most common effect is polyuria • High Ca in urine can cause stones • Chronic ↑ can cause renal failure

• Hypomagnesemia

• Bones (bone pain) • Groans (abdominal pain)

• Promotes urinary K loss • Cannot correct K until Mg is corrected!!

• Constipation, anorexia, nausea

• Psychiatric overtones • Anxiety, altered mental status

59

Hypercalcemia

Hypocalcemia

Selected Causes

Signs/Symptoms

• Bone resorption

• Tetany

• Hyperparathyroidism • Malignancy

• Trousseau's sign: Hand spasm with BP cuff inflation • Chvostek's sign: Facial contraction with tapping on nerve

• Increase GI absorption

• Seizures

• Hypervitaminosis D • Milk alkali syndrome • High intake calcium carbonate (ulcers) • Triad: Hypercalcemia, metabolic alkalosis, renal failure

Hypocalcemia

Hyperphosphatemia

Selected Causes

Symptoms

• • • •

Hypoparathyroidism Renal failure Pancreatitis (saponification of Mg/Ca in necrotic fat) Hypomagnesemia

• Most patients asymptomatic • Signs and symptoms usually from hypocalcemia • Metastatic calcifications may occur • “Calciphylaxis” • Calcium deposition in media layer of arteries • Painful nodules, skin necrosis

Calcium-Phosphate in Renal Failure

Hyperphosphatemia Selected Causes

Sick Kidneys

• Huge phosphate load • Tumor lysis syndrome • Rhabdomyolysis • Large amount of phosphate laxatives (Fleet’s Phospho-soda)

↑Phosphate

↓1,25-OH2 Vitamin D

• Acute and chronic kidney disease • Hypoparathyroidism ↓Ca from plasma

↓Ca from gut

Hypocalcemia

↑PTH

60

Hypophosphatemia

Hypophosphatemia

Symptoms

Selected Causes

• Main acute symptom is weakness

• Primary hyperparathyroidism • Antacids

• ATP depletion • Often presents are respiratory muscle weakness

• Ammonium hydroxide

• If chronic, can result in bone loss, osteomalacia

• DKA • Glucose induced diuresis  ↑PO4 excretion

• Refeeding syndrome in alcoholics • Low PO4 from poor nutrition • Food intake  metabolism  further ↓PO4

• Urinary wasting • Fanconi Syndrome • Tumor-induced osteomalacia

Hypermagnesemia

Hypermagnesemia

Signs/Symptoms

Selected Causes

• Mg blocks Ca and K channels • Neuromuscular toxicity

• Renal insufficiency

• ↓ DTRs • Paralysis

• Bradycardia, Hypotension, Cardiac arrest • Lethargy • Hypocalcemia (inhibits PTH secretion)

Hypomagnesemia

Hypomagnesemia

Symptoms

Selected Causes

• Neuromuscular excitability

• GI losses (secretions contain Mg)

• Tetany, tremor

• Diarrhea • Pancreatitis (saponification of Mg/Ca in necrotic fat)

• Hypokalemia • Hypocalcemia • Cardiac arrhythmias

• Renal losses • Loop and thiazide diuretics • Alcohol abuse (alcohol-induced tubular dysfunction)

• Drugs • Omeprazole (impaired absorption) • Foscarnet (causes chelation; used for HIV CMV infection)

61

Balance • Water in = water out  “water balance” • Sodium in = sodium out  “sodium balance” • Major regulators:

Sodium and Water Balance

• 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

• Modified by: • Volume • Cardiac output • Vascular resistance

• Major determinant: sodium • Excess sodium  ↑ ECV • Restricted sodium  ↓ ECV

Effective Circulating Volume

Effective Circulating Volume

• Low ECV can lead to low blood pressure • May cause orthostatic hypotension • Dizziness/fainting on standing

• Low ECV activates: • Sympathetic nervous system • Renin-angiotensin-aldosterone system

• Retention of sodium/water

62

Antidiuretic Hormone

Effective Circulating Volume • • • •

ADH; Vasopressin

Some disease states have chronically ↓ ECV Chronic activation of SNS and RAAS Chronic retention of sodium/water by kidneys May or may not lead to increased total body water

• Retention of free water • Major physiologic trigger is plasma osmolality • • • •

Antidiuretic Hormone

Sensed by hypothalamus ADH released by posterior pituitary gland ADH  free water resorption by kidneys Water retention adjusted to maintain normal osmolality

Water Balance

ADH; Vasopressin • Also released with low ECV

• • • • •

• “Non-osmotic release” of ADH • Second trigger in addition to serum osmolality • Only activated with very low ECV

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

Water Balance Restricted Water

↓ Osmolality

↑ Osmolality

↓ ADH

↑ ADH

↓ Water Resorption

↑ Water Resorption

↑ Water Excretion

↓Water Excretion

↓ ADH Total Body Water/ECV

Excess Water

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 ↑ osmolality  water retention  normal sodium Water retention  ↑ ECV Sodium intake expands ECV

Restricted Sodium

Excess Sodium

↓ Osmolality

↑ Osmolality

↓ ADH

↑ ADH

↓ Water Resorption

↑ Water Resorption

↑ Water Excretion

↓Water Excretion

↓ ECV

↑ ECV

Sodium Balance

Sodium Balance

• ECV controlled by SNS and RAAS Total Body Water/ECV

↑ ADH Na In > Na Out [Na] = Normal ↑Posm ADH = Baseline In = Out Na In > Na Out

• Sympathetic nervous system • Renin-angiotensin-aldosterone system

• Activated when ECV is low • Inhibited when ECV is high • Sodium alters ECV  alters SNS/RAAS

ADH = Baseline

Time Sodium Consumption

Sodium Balance • • • •

Sodium Balance

Sodium intake  Expanded ECV Expanded ECV  ↓ SNS and ↓ RAAS Result: Increased sodium excretion Out = In  balance restored

64

Restricted Sodium

Excess Sodium

↓ ECV

↑ ECV

↑ SNS/RAAS

↓ SNS/RAAS

↑ Na Retention

↓ Sodium Retention

↓ Na Excretion

↑ Na Excretion

In = Out

In = Out

Sodium Balance

Sodium Balance Key Points

Total Body Water/ECV

• High sodium intake expands ECV ↑ ADH Na In > Na Out ↑Posm In = Out ADH = Baseline SNS = Baseline RAAS = Baseline

• Weight gain • May cause hypertension

↓SNS/RAAS In = Out [Na] = Normal ADH = Baseline SNS = Decreased RAAS = Decreased

• Low sodium intake contracts ECV • Weight loss • May improve hypertension

Time Sodium Consumption

Out of Balance • Lack of water balance • Alters plasma sodium level • Hypo or hypernatremia

• Lack of sodium balance

GI Losses • Nausea, vomiting, diarrhea • Activation of SNS/RAAS • Volume loss  ↑ ADH release • Non osmotic release of ADH • Driven by volume sensors • No longer controlled by plasma sodium level

• Alters total body volume/ECV • Hypo or hypervolemia

• Water balance control by ADH lost • Free water always retained by kidneys • Plasma sodium determined by relative intake/losses

GI Losses • Hyponatremia often occur • Drinking free water • Not eating (no sodium)

• Hypernatremia can occur • Not taking enough free water

Heart Failure • • • •

65

Chronically ↓ ECV (low cardiac output) Chronic activation of SNS and RAAS Sodium chronically retained Free water also retained to balance sodium

Heart Failure • • • •

Heart Failure

Sodium balance disrupted Sodium excretion always reduced High sodium intake  intake > excretion Hypervolemia often occurs

• ECV does not ↑ normally with fluid retention • Failing heart unable to increase CO • Heart failure patients always have low ECV

• Result: Congestion • Pulmonary edema • Elevated jugular venous pressure • Pitting edema

SIADH

Heart Failure

Syndrome of Inappropriate ADH Secretion • Excessive ADH release • Excess water retention  hyponatremia • Normal total body water

• Water balance disrupted • ↓ ECV  ↑ ADH release • ADH always high • Driven by volume sensors (“non-osmotic”) • No longer controlled by plasma sodium level

• • • •

• Water retention  ↑ ECV  ↓ SNS/RAAS • Sodium excretion  ↓ ECV (back to normal)

Water balance control by ADH lost Free water always retained by kidneys Plasma sodium determined by relative intake/losses Hyponatremia often occurs

• Key findings • Hyponatremia • Normal volume status • Concentrated urine

66

Sodium Disorders • In general, these are disorders of WATER not sodium • Hyponatremia • Too much water

• Hypernatremia • Too little water

Sodium Disorders Jason Ryan, MD, MPH

Hyponatremia

Sodium Symptoms

Symptoms • Malaise, stupor, coma • Nausea

• Hypo and hypernatremia effect brain • Low sodium = low plasma osmotic pressure • Fluid into tissues • Brain swells

• High sodium = high plasma osmotic pressure • Fluid out of tissues • Brain shrinks

Hyponatremia

Plasma Osmolality

Key Diagnostic Tests • Plasma osmolality • Urinary sodium • Urinary osmolality

• • • •

67

Amount of solutes present in plasma Key solute: Sodium Osmolality should be LOW in HYPOnatremia 1st step in hyponatremia is to make sure it’s low

Plasma Osmolality

Plasma Osmolality • Hyponatremia with HIGH osmolality

Serum Osmolality = 2 * [Na] + Glucose + BUN 18 2.8

• • • •

Hyperglycemia or mannitol Glucose or mannitol = osmoles Raise plasma osmolality Water out of cells  hyponatremia

Normal = 285 (275 to 295)

Plasma Osmolality

Plasma Osmolality • 1st step in evaluation of hyponatremia unknown cause

• Hyponatremia with NORMAL osmolality • • • •

Artifact in serum Na measurement Hyperlipidemia Hyperproteinemia (multiple myeloma) “Pseudohyponatremia”

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 • Responds to water intake to maintain sodium levels

• Osmolality sensed by hypothalamus • 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) Plasma free water varies with intake Increased intake  hyponatremia

• Urine should be diluted • More free water than solutes • Low urine osmolality (<100mosm/kg) • Low urinary sodium (<30meq/L)

Hyponatremia

Hyponatremia

General Points

Causes

• If urine is diluted

1. 2. 3. 4.

• Kidneys responding appropriately • ADH level is low (as it should be) • Problem is outside the kidneys

• If urine is not diluted • Kidneys are NOT responding appropriately • Too much ADH • Or drugs/pathology interfering with kidney function

69

Heart failure and Cirrhosis Kidneys ineffective High ADH Psychogenic polydipsia/Dietary

Heart failure and Cirrhosis

Kidneys ineffective

• Perceived hypovolemia  ADH levels high • Urine not diluted (Uosm > 100) • Clinical signs of hypervolemia

• Advanced renal failure • • • • • •

Kidneys cannot excrete free water normally Urine cannot be diluted Minimum Uosm rises even with low ADH Normal <100 Greater than 200 to 250mosmol/kg with renal failure Key point: ↑ Uosm indicates abnormal response to ↓Na

• May occur with euvolemia or hypervolemia

Diuretics

Kidneys ineffective • Diuretics • Cause sodium and water loss • Most commonly thiazides • Can occur with loop diuretics

Cortex

300mOsm

• Highly variable urinary findings • • • •

↑ sodium and water excretion Dehydration  ↑ ADH Water/Na in urine vary by dose, dietary intake Key test: Response to discontinuation of drugs

Outer Medulla

Inner Medulla

Diuretics

High ADH

• Loop diuretics

• Any cause of dehydration  ↑ ADH

• Medullary gradients diminished • Difficult to reabsorb free water (loops = powerful diuretic) • Low likelihood of excess water  hyponatremia

• Vomiting, diarrhea • Sweat

• Sodium level varies with water intake • Free water intake  hyponatremia

• Thiazide diuretics • • • •

Medullary gradients intact Intact ability to absorb free water More sodium out in urine (diuretic effect) Higher likelihood of excess water  hyponatremia

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600mOsm

1200mOsm

SIADH

High ADH

Syndrome of Inappropriate Antidiuretic Hormone Secretion

• Adrenal insufficiency

• • • • •

• Cortisol normally suppresses ADH release • Loss of cortisol (primary/secondary)  ↑ ADH • Loss of aldosterone (primary)  loss of salt/water  ↑ ADH

• Hypothyroidism • SIADH

• • • •

SIADH Drug induced (carbamazepine, cyclophosphamide) Paraneoplastic (small cell lung cancer) CNS Pulmonary disease

• • • • •

SIADH

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

• Diagnostic Criteria • • • • •

Heart failure Cirrhosis Dehydration Thyroid/adrenal disease

Volume Status SIADH

Causes • • • •

Too much ADH released (inappropriate) Causes hyponatremia High urinary Na (>40meq/L) High urinary osmolality (>100 mOsm/kg) No other cause for high ADH

• Common treatment: fluid restriction • Special treatment option:

Hypotonic hyponatremia (↓Posm ↓Na) Normal liver, renal, cardiac function Clinical euvolemia Normal thyroid, adrenal function Urine osmolality > 100 mOsm/kg

• Demeclocycline • Tetracycline antibiotic • ADH antagonist

Demeclocycline

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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 free water

• Water restriction resolves hyponatremia

Tea and toast Beer drinkers (“beer potomania”) Very little sodium ingestion Minimum urine osmolality ~60 mosmol/kg Minimal sodium intake may limit free water excretion Free water intake > output Result: hyponatremia

Special Diets

Special Diets • Salt consumed must equal salt excreted • Imagine highest water to salt ratio is 10:1

• Normal diet • 1000mOsm/day solute • Most dilute urine = 50mOsm/L • Max free water output = 1000/50 = 20L/day

• Special diet • • • •

Normal Diet 3 salt 30 water

250mOsm/day solute Most dilute urine = 50mOsm/L Max free water output = 250/50 = 5L/day Water intake >5L/day  hyponatremia

Restricted Diet 1 salt 10 water

Special Diets

Hyponatremia

• Low urine osmolality (<100mosm/kg)

Hypervolemic Euvolemic Cirrhosis SIADH Hypothyroid CHF Renal failure 2° Adrenal Disease Renal failure Polydipsia Dietary

• Indicates kidneys working • Kidneys trying to eliminate free water

• Free water excretion limited by solute availability

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Hypovolemic Dehydration Diuretics 1°Adrenal Disease

Euvolemic Hyponatremia

Hypovolemic Hyponatremia Hypovolemic

Measure Uosm

Uosm <100 Psychogenic Polydipsia Diet (tea, beer)

Measure UNa

Uosm > 100 SIADH Hypothyroidism Renal Failure

UNa <30 mEq/L Extra-renal cause Vomiting Diarrhea Sweating

↑ ADH and ↑ Uosm

Hypervolemic Cirrhosis CHF Renal failure

(aldosterone)

Euvolemic SIADH Hypothyroid 2° Adrenal Disease Renal failure Polydipsia Dietary

Hypovolemic Dehydration Diuretics 1°Adrenal Disease

Hyponatremia

↓ ADH and ↑ Uosm Euvolemic SIADH Hypothyroid 2° Adrenal Disease Renal failure Polydipsia Dietary

UNa > 30 Renal Cause Diuretics 1°Adrenal Disease

↓ ADH and ↓ Uosm

Hypervolemic Euvolemic Hypovolemic Cirrhosis SIADH Dehydration CHF Hypothyroid Diuretics Renal failure 2° Adrenal Disease 1°Adrenal Disease Renal failure Polydipsia Dietary

Hypervolemic Cirrhosis CHF Renal failure

Dehydration Diuretics 1°Adrenal Disease

Treatment • Fluid restriction • 3% saline • Vaptan drugs (tolvaptan, lixivaptan, and conivaptan)

Hypovolemic Dehydration Diuretics 1°Adrenal Disease

• Block ADH • Main use is in severe hyponatremia of heart failure

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Hypernatremia

Central Pontine Myelinolysis

Symptoms

“Osmotic demyelination syndrome”

• Associated with overly rapid correction ↓Na

• Irritability, stupor, coma

• Usually >10meq per 24 hours

• • • • •

Demyelination of central pontine axons Lesion at base of pons Loss of corticospinal and corticobulbar tracts Quadriplegia Can be similar to locked-in syndrome

Hypernatremia

Acquired Diabetes Insipidus

Causes 1. Water loss • • •

• Hypercalcemia • Hypokalemia • Drugs

Skin and lungs (more H2O than Na) ADH will be high Uosm will high

• Lithium • Amphotericin B

2. Diabetes insipidus • • • •

Loss of ADH activity Central: trauma, tumors Congenital nephrogenic (rare) Acquired (nephrogenic): Many causes

Diabetes Insipidus

Diagnosis Diabetes Insipidus

Symptoms • Polyuria and polydipsia • Similar to diabetes mellitus via different mechanism

• Suspected with polyuria and polydipsia • Often normal [Na] • Water loss stimulates thirst • Hypernatremia occurs if not enough water • Central lesion (central DI) can impair thirst

• Urine osmolality low (50-200mOsm/kg)

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Diagnosis Diabetes Insipidus

Hypernatremia

Diagnosis

Treatment

• Fluid restriction

• Water (ideally PO) • IV Fluids (D5W)

• After 8 hours of no fluid, urine should be concentrated • If urine is dilute  absent/ineffective ADH

• Administration of vasopressin or desmopressin • Should concentrate urine if kidneys work • If no concentration  nephrogenic DI • If concentration  central DI

Diabetes Insipidus Treatments

Diabetes Insipidus Treatments

• Central DI: Desmopressin

• Nephrogenic DI: Thiazides and NSAIDs • Thiazides

• ADH analog • No vasopressor effect (contrast with vasopressin)

• Increase in proximal Na/H2O reabsorption • Less H2O delivery to collecting tubules • Paradoxical antidiuretic effect

• NSAIDs • Inhibit renal synthesis of prostaglandins (ADH antagonists)

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Glomerulus Functions • Allow “ultrafiltrate” into Bowman’s space • Water, electrolytes, glucose, amino acids

• Prevent filtration of most proteins • Prevent filtration of red blood cells • Glomerular pathology

Glomerular Disease Principles

• 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

Capillary Basement Membrane Podocytes (epithelium) Bowman’s Space

Basement Membrane

Podocytes

Negatively charged proteins

• • •

• • • • •

Type IV collagen Heparan sulfate

Repels (-) molecules like albumin Also size barrier

• • •

Only small (~4nm) molecules pass through

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Also called epithelial cells Long “processes” called “foot processes” Wrap capillaries 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

• Breakdown of components of filtration barrier • Things in urine that shouldn’t be there: • Red blood cells • Protein (especially albumin)

Hematuria

Hematuria

• Urinalysis • Dipstick: tests for the presence of heme

• • • • •

• Heme has peroxidase activity  reacts with strip • Heme positive: hemoglobin or myoglobin

• Microscopy: red cells visualized

Many, many causes Gross: abnormal color to urine from blood Microscopic: Incidental finding on urinalysis Can occur after exercise Common causes: • UTI • Kidney stones

• Feared cause: bladder cancer • Glomerular disease is rare cause

Glomerular Bleeding • • • • • •

Proteinuria

Red cell casts Dysmorphic red blood cells Acanthocytes Proteinuria Red, smoky brown or ““coca cola”” Clots generally not seen

• Urine dipstick • • • •

77

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 ratio

• 24-hour urine collection

• “Spot urine” • 1st or 2nd morning urine sample after avoiding exercise • Normal ratio less than 0.2 mg/mg

• • • • •

Glomerular Diseases

Nephrotic Syndrome • Filtration barrier to protein is lost • RBC filtration barrier remains intact • Massive proteinuria

Spectrum Nephritic Syndrome RBC casts Mild proteinuria Renal Failure

Nephrotic Syndrome Massive proteinuria Hyperlipidemia

• 4+ on dipstick • >3.5g/day

• Triggers cascade of pathology

Nephrotic Syndrome ↓ immunoglobulins

↓protein

Infection

↓albumin

↓ ECV ↓GFR

↓ plasma oncotic pressure

↑liver activity

Urine in Nephrotic Syndrome • 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

Proteinuria Frothy urine ↓ ATIII

Thrombosis

RAAS

Na/H2O Retention

Edema

Gold standard for protein evaluation Gives you grams/day or protein excretion Normal is less than 150 mg/day Cumbersome for patients Errors in collection common

Hyperlipidemia

Fatty casts Oval fat bodies

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Nephrotic Syndrome

Nephritic Syndrome

• Classic presentation • • • • • •

• • • •

Frothy urine Swelling of ankles Swelling around eyes (periorbital) Often mistaken for allergic reaction Serum total cholesterol >300mg/dl Proteinuria (>3.5g/day)

Inflammatory process damages entire glomeruli Filtration barrier to RBCs and protein lost 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 Dysmorphic RBCs RBC Casts

↓filtration barrier

Nephritic Syndrome • Classic presentation

Proteinuria

• • • •

↓GFR

↑BUN/Cr

↑Hydrostatic pressure

Hypertension

Oliguria

Edema

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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 • Major determinant of whether a disease process leads to nephritic or nephrotic syndrome is the site of glomerular injury

• Classic presentation • • • •

Dark urine (RBCs) Swelling/edema Fatigue (uremia) Proteinuria (<3.5g/day)

Nephritic/Nephrotic

Nephritic Syndrome

Sites of Glomerular Injury

Major Causes

• Podocyte injury  protein loss only  nephrotic • Endothelial and mesangial cells

1. 2. 3. 4. 5. 6.

• Exposed to blood elements • Injury lead to inflammation (nephritis) • Loss of red blood cells and protein in urine

• Most causes of nephritic syndrome related to endothelial/mesangial injury with influx of inflammatory cells

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Post-streptococcal Berger’s (IgA) nephropathy Diffuse proliferative glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) Alport syndrome Membranoproliferative glomerulonephritis

Post-streptococcal GN

Post-streptococcal GN

• Follows group A β-hemolytic strep infection

• Immune complexes deposit in kidney

• Impetigo (skin) • Pharyngitis

• Circulating antigen-antibodies complexes • In situ formation in kidney

• Nephritogenic strains

• Fix complement • Attract PMNs • Hypocomplementemia (also lupus, MPGN)

• Carry specific subtypes of M protein virulence factor

Post-streptococcal GN

Post-streptococcal GN

• Common in children (can also occur in adults) • Classic case

• Glomeruli: Enlarged, hypercellular

• Child • 2-3 weeks following strep throat infection • Nephritic syndrome

Post-streptococcal GN

Post-streptococcal GN

• Subendothelial antibodies/complexes • Granular IF (IgG, C3)

• Electron microscopy: Subepithelial “humps” • Immune complexes

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Post-streptococcal GN

Post-streptococcal GN

• Good prognosis in children

• No specific therapy (supportive) • Spontaneous resolution

• 95% recover completely

• 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 worldwide • Repeated episodes of hematuria (nephritic) • Over time leads to ESRD and HD (50% patients)

• Overactive immune system • ↑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 • • • •

Recurrent episodes hematuria since childhood Episodes follow URI or diarrheal illness Slowly worsening renal function (BUN/Cr) over time Possible progression to ESRD and HD (20yrs+)

• Don’t confuse with other glomerular disorders • Post-strep GN: weeks after infection • IgA GN: days after infection • Minimal change: nephrotic syndrome after URI

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DPGN

Henoch-Schonlein Purpura • • • • • • •

Diffuse proliferative glomerulonephritis

IgA nephropathy with extra-renal involvement Most common childhood systemic vasculitis Skin: palpable purpura on buttocks/legs GI: abdominal pain, melena Joint pains Diffuse IgA deposition Tissue biopsy: demonstrates IgA

• Systemic lupus erythematosus (SLE) • Most common subtype of SLE renal disease • “Type IV Lupus Nephritis” • Often presents with other SLE features: fever, rash, arthritis

• Immune complex deposition in glomeruli • IC  inflammatory response

DPGN Diffuse proliferative 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

Diffuse proliferative glomerulonephritis

• Subendothelial deposits drive immune response

• Granular IF • “Full house” immunofluorescence

• Anti-dsDNA • Hypocomplementemia (also post-strep, MPGN)

• IgG, IgA, IgM, C3, C1q

• Classic finding: capillary loops thickened • “Wire looping”

83

DPGN

RPGN

Diffuse proliferative glomerulonephritis

Rapidly progressive glomerulonephritis

• Mixed clinical presentation

• Also called “crescentic” glomerulonephritis • Pathologic description: Many causes

• Proteinuria (sometimes nephrotic) • Hematuria • Reduced GFR

• Many diseases lead to this condition

• Severe, often leads to ESRD and HD

RPGN

RPGN

Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis

• Crescents formed by inflammation:

• • • • •

• Monocytes/macrophages • Fibrin

Severe form of glomerulonephritis Progressive loss of renal function Rapid onset Often presents as acute renal failure Generalized symptoms: fatigue, anorexia

RPGN

RPGN

Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis • • • •

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Causes distinguished based on immunofluorescence Type I: Linear IF Type II: Granular IF Type III: Negative IF

RPGN Type I

Goodpasture’s Syndrome

• Anti-glomerular basement membrane antibodies

• Antibody to collagen • Antibodies to alpha-3 chain of type IV collagen

• “Anti-GBM antibodies”

• Antibodies against GBM antigens

• Found in GBM and alveoli

• Unknown stimulus • Type II hypersensitivity

• Hemoptysis and nephritic syndrome • Classic case

• Linear IF

• • • •

• IgG antibodies • Linear pattern

RPGN Type II

Young adult Male Hemoptysis Hematuria

RPGN Type II

• Immune complex deposition

• Post-streptococcal glomerulonephritis

• Type III hypersensitivity

• Can progress to RPGN • Most common cause RPGN

• Granular IF

• Systemic lupus erythematosus (SLE) • Diffuse proliferative glomerulonephritis • Can progress to RPGN

ANCA Diseases

RPGN Type III

Anti-neutrophil cytoplasmic antibodies

• Negative IF

• • • •

• No staining for IgG, IgA, etc.

• “Pauci-immune” • Most patients ANCA positive • c-ANCA or p-ANCA

• Most patients have a vasculitis syndrome

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Wegener's Granulomatosis (c-ANCA) Microscopic Polyangiitis (p-ANCA) Churg-Strauss syndrome (p-ANCA) All can lead to pauci-immune nephritis

RPGN

Alport Syndrome

Rapidly progressive glomerulonephritis

Hereditary Nephritis • Genetic type IV collagen defect • Mutations in alpha-3, alpha-4, or alpha-5 chains • Chains found in basement membranes kidney, eye, ear

• Inherited: X-linked • Classic triad: • Hematuria • Hearing loss • Ocular disturbances

• Look for child with triad and family history

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Nephrotic Syndrome

Nephrotic Syndrome Jason Ryan, MD, MPH

Nephritic/Nephrotic

Nephrotic Syndrome

Sites of Glomerular Injury • Major determinant of whether a disease process leads to nephritic or nephrotic syndrome is the site of glomerular injury • Podocytes

• Classic presentation • • • • •

Frothy urine Swelling of ankles Swelling around eyes (periorbital) Serum total cholesterol >300mg/dl Proteinuria (>3.5g/day)

• Separated from blood by GBM • Injury does not lead to inflammation • Damage  loss of filtration barrier to protein only

• Most causes of nephrotic syndrome related to injury of podocytes or epithelial side of GBM

Nephrotic Syndrome Causes

Glomerular Filtration Barrier

1. 2. 3. 4. 5. 6.

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Minimal change disease Focal segmental glomerulosclerosis (FSGS) Membranous nephropathy Diabetic Amyloidosis Membranoproliferative 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 • Only finding is effacement foot processes EM

• Sometimes has immunological trigger (days before) • 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 • Pink/dense deposition of collagen in glomerulus

• Segmental

• Unique among nephrotic syndrome causes

• Only potion of glomerulus involved

• Focal • Only some glomeruli involved

88

FSGS

FSGS

Pathology

Renal Biopsy

• Sclerotic segments

• Light microscopy: focal, segmental lesions • Electron microscopy: effacement of foot processes • Immunofluorescence

• Collapse of basement membranes • Hyaline deposition (“hyalinosis”)

• Effacement of foot processes

• Usually negative (no immune complexes) • Sometimes IgM, C3, C1 (nonspecific finding)

• Seen on electron microscopy

FSGS

FSGS

Focal segmental glomerulosclerosis

Epidemiology • African Americans

• Caused by podocyte injury • Unknown cause • Often progresses to chronic renal failure

• Most common cause nephrotic syndrome

• 40-60% within 10 to 20 years • Does not respond to steroids • Severe version of minimal change disease

Nephrotic Syndrome Causes

FSGS

FSGS

Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis

• Usually idiopathic (primary) • Many secondary causes

• HIV • Sickle cell patients • Heroin users

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FSGS

Membranous Nephropathy

Other Associations • Massive obesity • Interferon treatment

• Thick glomerular basement membrane • “Membranous”

• Absence of hypercellularity

• Used to treat HCV and HBV • Some leukemias and lymphomas, melanoma

• Loss of nephrons • Single kidney (congenital) • Surgical kidney removal

Membranous Nephropathy

Membranous Nephropathy

Pathophysiology 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 • Light microscopy: capillary/BM thickening • Electron microscopy: subepithelial deposits • Immunofluorescence: granular IgG/C3

• • • •

90

Often idiopathic Autoantibodies 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 Diffuse proliferative glomerulonephritis If nephrotic, this is cause (10-15%)

• Solid tumors • Colon cancer, lung cancer, melanoma

• Infections • Hep B, Hep C

• Drugs • 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

• • • •

Most antibody disorders are nephritic IC  inflammation  nephritis  nephritic syndrome Membranous is nephrotic Subepithelial deposits  nephrotic syndrome

Nephrotic 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 • Apple-green birefringence • Congo red stain

• Kidney is most commonly involved organ

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MPGN Membranoproliferative 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 Glomerulonephritis

Membranoproliferative Glomerulonephritis

• Membrano

• Two major types • Type I much more common • Type II (dense deposit disease) rare

• Thick basement membrane

• Proliferative • Proliferation of mesangial cells, 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

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 by complement IgG usually absent

MPGN Type II

MPGN

Dense Deposit Disease

Membranoproliferative Glomerulonephritis

• Mostly a disease of children • Usually 5 to 15 years old • 50% develop ESRD within ten years

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Tubulointerstitial Disorders • • • •

Tubulointerstitial Disorders

Acute tubular necrosis Interstitial nephritis Papillary necrosis Cortical necrosis

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.

• A kidney attack • Sudden damage to tubular cells • Ischemia (ANY cause severe ↓blood flow) • Drugs • Toxins

Ischemic Causes • • • •

Toxin/Drug Causes

Dehydration Sepsis Cardiogenic shock Massive bleeding

• • • • •

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 • Phase 1: Injury occurs • Phase 2: Maintenance • • • •

Cortex

Rising BUN/Cr Hyperkalemia AG metabolic acidosis May last weeks

• Phase 3: Recovery

Outer Medulla

• Polyuria • Risk of hypokalemia

Toxic ATN Proximal Tubule

Inner Medulla

Prognosis

Acute Interstitial Nephritis

• Typical course is kidney recovery • Tubular cells capable of regeneration

• Inflammation of “interstitium” • Space between cells

• Hypersensitivity (allergic) reaction • Usually triggered by drugs • Sometimes infections or autoimmune disease

• “Tubular re-epithelialization”

• Some patients require temporary dialysis

95

Acute Interstitial Nephritis

Acute Interstitial Nephritis

• Drugs – 75% • • • • •

• Infection – 5-10%

Sulfonamides (TMP-SMX) Rifampin Penicillin Diuretics (furosemide, bumetanide, thiazides) NSAIDs

• Multiple organisms reported • Legionella, Leptospira, CMV, TB

• Systemic diseases – 5-10% • Sarcoidosis • Sjögren's syndrome • SLE

Acute Interstitial Nephritis

Acute Interstitial Nephritis

• Classic findings: • • • •

• Classic presentation

WBC casts (without symptoms of pyelonephritis) “Sterile pyuria” Peripheral eosinophilia Urine eosinophils

• • • • • •

Acute Interstitial Nephritis

Days to weeks after exposure to typical drug Fever, rash or asymptomatic Oliguria Increased BUN/Cr WBC casts Eosinophils in urine

Chronic Interstitial Nephritis

• Usually resolves with stopping offending agent • Rarely progresses to papillary necrosis

• • • •

Can occur with NSAIDs Mild elevation of BUN/Cr Resolves with stoppage of drugs Classic case: • Patient on NSAIDs for chronic pain • Mild increase BUN/Cr • Renal function improves with stoppage of drug

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NSAIDs

Papillary Necrosis

• Chronic interstitial nephritis • Acute tubular necrosis

• • • •

• From ischemia • Block PG vasodilation of afferent arteriole

• Membranous glomerulonephritis

Cell death (necrosis) renal papillae Sloughing of tissue Gross hematuria Often painless

• Nephrotic syndrome

• Papillary necrosis

Papillary Necrosis

Papillary Necrosis

• Triggered by immune stimulus • Classic triggers: • • • •

• Typical presentation • Patient with typical trigger • Gross hematuria

Chronic phenacetin use Diabetes Acute pyelonephritis Sickle cell anemia/trait

Cortical Necrosis • Infarction (ischemia) of cortex • Acute renal failure • Proposed mechanism: • Ischemia and DIC • Massive tissue destruction

• Occurs in very sick patients • Septic shock • Obstetric catastrophes (abruptio placentae, fetal demise)

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Terms • Acute renal failure • Decrease in Cr clearance over days • Often associated with symptoms • Many causes

• Chronic renal failure (chronic kidney disease)

Renal Failure

• Slow, steady deterioration of renal function (years) • Usually due to diabetes, hypertension • Symptoms only in most severe stages

Jason Ryan, MD, MPH

Terms

Uremic Symptoms

• Azotemia

• • • • • •

• 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 • Shock • Heart failure

• Similar to inulin • Freely filtered • Small amount of secretion

2. Obstruction of urine outflow (post-renal)

• Blood urea nitrogen

• Need bilateral obstruction • Kidney stones, BPH, tumors, congenital anomalies

• Freely filtered • Reabsorbed when kidney reabsorbs water

3. Renal dysfunction (intrinsic) • Acute tubular necrosis • Glomerulonephritis

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Key Labs

Real Life Acute Renal Failure

• In acute renal failure both rise (less filtered) • In acute renal failure from dehydration:

• Routine labs on outpatient or inpatient • BUN/Cr elevated • Work up:

• BUN rises more (less filtered, more reabsorbed)

• • • • •

USMLE Acute Renal Failure

Renal Failure Measurements

• Determine cause based on blood, urine testing • • • • • •

Urinalysis (protein, blood, casts) Ultrasound (hydronephrosis) Careful history (meds, co-morbidities, hydration) Physical exam (low blood pressure, dehydration, CHF, etc) Limited use of blood, urine chemistries

• Urinary sodium (UNa) • Varies based on intake of sodium and water • Very low when kidney retaining salt/water • <20 mEq/L is very low

BUN (rises in ARF) Cr (rises in ARF) BUN/Cr ratio (normal ~20:1) 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 BUN resorbed with H2O BUN rises >> Cr rises Result

• • • • • •

• ↑ ↑ BUN • ↑Cr • ↑BUN/Cr ratio

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Lots of H2O resorbed Concentrated urine ↑Uosm Lots of Na resorbed ↓Una ↓Fena

Intrinsic Renal Failure

Pre Renal Failure

BUN/Cr • • • • •

Intrinsic Renal Failure

Intrinsic Renal Failure

Urinary Findings • • • •

Urine: kidney cannot resorb water Uosm low (can’t concentrate urine) UNa high (can’t resorb Na) FeNa high (can’t resorb Na)

Post Renal Failure • • • • •

Kidney cannot filter blood Less BUN/Cr filtered Rising BUN/Cr in blood No extra rise in BUN from ↑resorption Normal ratio (20:1)

Post Renal Failure

Obstruction to outflow Urine backs up High pressure in tubules Kidney cannot filter blood Kidney’s resorptive mechanisms damaged/destroyed

• Diagnosis rarely made by plasma/urinalysis • Key features: • Anuria • Hydronephrosis

• Renal ultrasound is test of choice • Shows enlarged, dilated kidneys

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Post Renal Failure • • • • • • •

Post Renal Failure

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 High pressure in tubules  forces BUN out BUN rises more than Cr ↑BUN/Cr ratio similar to pre-renal

• • • •

Post Renal Failure

Lots of variation in lab values based on tubules Early post renal  tubular function okay Late  high pressure disrupts tubular resorption Urine chemistries variable

Pre, Intrinsic, Post Problems • Diseases often cross boundaries • Pre-renal  ATN

• 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

• Slow, steady fall in creatinine clearance • Blood tests show ↑BUN/Cr

• Eventually progresses to dialysis for many patients • Most common causes diabetes and hypertension

FeNa = P Cr * U Na PNa * UCr

• Hypertensive nephrosclerosis • Diabetes nephropathy

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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) Stage 5  GFR <15 (usually on dialysis)

• • • • •

Dialyzable Substances • • • • •

Acidemia Electrolytes (hyperkalemia) Intoxication (overdose dialyzable substance) Overload of fluid (CHF) Uremic symptoms

Dialysis Methods

Salicylates (aspirin) Lithium Isopropyl alcohol Magnesium laxatives Ethylene glycol

• Hemodialysis • Requires vascular access • Blood pumped from body  filter  back to body • Done in “sessions” of few hours at a time

• Peritoneal dialysis • Fluid cycled through peritoneal cavity • Peritoneum used as dialysis membrane

• Hemofiltration • Constant filtering of blood • Usually done at bedside for critically ill patients

Vascular Access

Complications CKD

• For acute dialysis, central line can be placed • Ideal method is fistula

• Anemia (loss of EPO) • Dyslipidemia

• Connection between artery and vein • Placed surgically, usually in arm • Lowest rates thrombosis, infection

• Mostly triglycerides • Protein loss in urine  stimulation of liver synthesis • Impaired clearance of chylomicrons and VLDL

• Fistula must “mature” for use • Ideally placed several months before dialysis

• Growth failure in children • Renal osteodystrophy

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Calcium-Phosphate in Renal Failure

Calcium-Phosphate in Renal Failure

• Secondary hyperparathyroidism

Sick Kidneys

• Parathyroid stimulation in renal failure

• Tertiary hyperparathyroidism ↑Phosphate

• • • •

↓1,25-OH2 Vitamin D

↓Ca from plasma

↓Ca from gut

Parathyroid becomes autonomous from constant stimulation VERY high PTH levels Calcium becomes elevated Often requires parathyroidectomy

Hypocalcemia

↑PTH

Calcium-Phosphate in Renal Failure

Phosphate Binders

• Untreated parathyroidism leads to renal osteodystrophy

• • • • •

• Bone pain (predominant symptom) • Fracture (weak bones 2° chronic high PTH levels)

• Osteitis fibrosa cystica • Untreated, 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 ACE inhibitors NSAIDs

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Bind phosphate in GI tract Calcium carbonate Calcium acetate (Phoslo) Sevelamer (Renagel) Lanthanum

Urinary Infections • Cystitis • Infection of bladder • “Lower” urinary tract

• Pyelonephritis • Infection of kidneys • “Upper” urinary tract

Urinary Infections Jason Ryan, MD, MPH

Urinary Infections

Etiology

• Most infections “ascend” • Urethra  Cystitis  Pyelonephritis

• Escherichia coli (75-95%) • Proteus mirabilis • Urease producing bacteria • Struvite kidney stones

• Klebsiella pneumoniae • Staphylococcus saprophyticus • Enterococcus faecalis

Symptoms

Symptoms

• Cystitis • • • • • •

• Pyelonephritis

Dysuria (pain with urination) Frequency (going a lot) Urgency (always feel like you have to go) Suprapubic pain No systemic symptoms Usually normal plasma WBC count

• • • • •

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Systemic symptoms (fever, chills) Flank pain CVA tenderness Hematuria WBC casts

Diagnosis

Risk Factors

• Urinalysis

• Women

• Cloudy urine • Leukocyte esterase • 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) • >10WBC/hpf

• 10x more likely than men to get UTIs • Shorter urethra, closer to fecal flora

• • • •

Sexual activity Urinary catheterization Diabetes Pregnancy

• Culture • >100,000 CFUs

Risk Factors

Treatment

• Infants with vesicoureteral reflux

• Fluoroquinolones

• Ureters insert abnormally into bladder • Chronic reflux of urine back into ureters

• Ciprofloxacin, levofloxacin, ofloxacin • Usually 3 day course

• Urinary obstruction

• Nitrofurantoin (Macrobid)

• Anatomic abnormalities in children • Bladder tumors in adults • Enlarged prostate in older males

• Used in pregnancy

• Trimethoprim-sulfamethoxazole (TMP-SMX)

Sterile Pyuria

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

• • • • • • •

Consequence of recurrent pyelonephritis Vesicoureteral reflux in children Recurrent stones in adults Scarring of kidneys Corticomedullary scarring Blunted calyx “Thyroidization of kidney” • Tubules contain eosinophilic material • Looks like thyroid tissue on microscopy

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Cystic Kidney Diseases 1. 2. 3. 4.

Cystic Kidney Disease

Multicystic Dysplastic Kidney Autosomal Recessive Polycystic Kidney Disease Autosomal Dominant Polycystic Kidney Disease Medullary Cystic Kidney Disease

Jason Ryan, MD, MPH

Multicystic Dysplastic Kidney • • • • •

Multicystic Dysplastic Kidney

Abnormal ureteric bud-mesenchyme interaction Kidney replaced with cysts No/little functioning renal tissue Absent ureter Often detected in utero by ultrasound

• If unilateral  remaining kidney hypertrophies • If bilateral  Potter’s syndrome • • • •

Multicystic Dysplastic Kidney

Oligohydramnios Failure of lung maturation Compressed face/limbs Not compatible with life

Polycystic Kidney Disease

• Spontaneous

• Autosomal recessive (infants) • Autosomal dominant (young adults)

• Non-inherited • Different from other cystic disorders • Subsequent pregnancies often okay

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ARPKD • • • • • •

ADPKD

Old name: “juvenile” PKD Occurs in infants Can occur with Potter’s syndrome Renal failure High blood pressure Key associations:

• Occurs in adults • Microscopic cysts present at birth • Too small to visualize with ultrasound • Kidneys appear normal at birth

• Cysts develop over many years • Inherited mutation of APKD1 or APKD2 genes

• Liver disease (fibrosis/cysts) • Can cause portal hypertension (ascites)

ADPKD

ADPKD

• Key associations

• Classic presentation

• Berry aneurysm (subarachnoid hemorrhage) • Liver cysts • Mitral valve prolapse

• • • • •

Medullary Cystic Kidney Disease

Young adult High blood pressure (↑RAAS system) Hematuria Renal failure Family history of sudden death (aneurysm)

Cystic Kidney Diseases

• Autosomal dominant • Cysts in collecting ducts of medulla • Name is misnomer • Most patients DO NOT have cysts

• Kidney fibrosis occurs  small, shrunken kidneys • Contrast with ADPKD (enlarged kidneys)

• Often have early onset (adolescent) gout • Renal failure

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Diuretics Drugs that increase urine output 1. 2. 3. 4. 5.

Diuretics

Carbonic Anhydrase Inhibitors Osmotic Diuretics Loop Diuretics Thiazide Diuretics K+ Sparing Diuretics

Jason Ryan, MD, MPH

Potassium

Sodium • Normal plasma [Na] = 140 meq/L • [Na] tightly regulated

• • • •

• Renin-angiotensin-aldosterone • Antidiuretic hormone (ADH)

• • • •

Sodium intake  H2O retention  [Na] = 140 meq/L Sodium loss  H2O excretion  [Na] = 140 meq/L Any drug that ↑ Na excretion  volume loss Many diuretics work by ↑ Na excretion

Carbonic Anhydrase Inhibitors

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

Carbonic Anhydrase Inhibitors

Carbonic Anhydrase

• Acetazolamide • Weak diuretic effect • Block some Na resorption

HCO3Na

• Causes a non-AG metabolic acidosis • Increased elimination of HCO3-

Acetazolamide

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Carbonic Anhydrase Inhibitors

Carbonic Anhydrase Inhibitors

Clinical Uses

Clinical Uses

• Severe metabolic alkalosis • Glaucoma

• Pseudotumor cerebri • Reduced rate of CSF formation

• Prevention of high altitude sickness

• Blocks formation of aqueous humor

• Low pO2 at high altitude  hyperventilation • Low CO2  respiratory alkalosis • Acetazolamide  acidosis  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

• Drawn out by hypertonicity in medulla

CO2 NADH α-ketoglutarate

Fumarate FADH2 Succinate GTP

Succinyl-CoA

Thin descending limb Concentrates urine Absorbs water Impermeable to NaCl Water leaves urine

CO2 NADH

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H2O H2O H2O H2O H2O

Osmotic Diuretics

Mannitol • • • • • •

300mOsm

Cortex

600mOsm

Outer Medulla

Inner Medulla

1200mOsm

Mannitol • • • •

Sugar alcohol Freely filtered by glomerulus No tubular reabsorption Raises osmolality Reduces water reabsorption Increases urine output

Mannitol

Main use is in cerebral edema, glaucoma Goal is to create a HYPERosmolar state “Osmotherapy” Draws fluid out (brain, eye)

• Cannot use in heart failure patients • Draws fluid out of tissues • Expands intravascular volume • Can cause pulmonary edema

• Can’t use with severe renal disease • High doses cause acute anuric renal failure • Mannitol can cause renal vasoconstriction  anuria

Loop Diuretics

Loop Diuretics Lumen (Urine)

Interstitium/Blood Na+

300mOsm

Cortex

Na+

2Cl

600mOsm K+

Inner Medulla

K+

2Cl-

K

Outer Medulla

ATP

K+

Na

1200mOsm

Mg2+ Ca2+

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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

• Complex mechanism of renal handling • Thiazides, loop diuretics ↑ uric acid reabsorption • Gout promoted by diuretics

• Very high doses or given with other ototoxic agents • Tinnitus, loss of hearing (usually reversible)

• Acute interstitial nephritis • ↑BUN/Cr • White blood cell casts • Urine eosinophils

• Gout

Metabolic Alkalosis

Thiazide Diuretics Lumen (Urine)

• pH>7.45 • ↑HCO3• Diuretics  ↑urine output  ↓ECV • Renin-Angiotensin-Aldosterone activation • ↑H+ secretion  metabolic alkalosis • “Contraction alkalosis” • Seen with loop diuretics and thiazides

Interstitium/Blood Na+ Na+

ATP K+

Cl-

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Cl-

Thiazide Diuretics

Thiazides: Hypercalcemia Lumen (Urine)

Hydrochlorothiazide; chlorthalidone; metolazone

Interstitium/Blood

• Sulfa Drugs (allergy)

Na+ Na+

ATP K+

Chlorthalidone Ca2+

Na HCTZ Ca2+

Metolazone

Thiazide Diuretics

Thiazide Diuretics

Hydrochlorothiazide; chlorthalidone; metolazone

Hydrochlorothiazide; chlorthalidone; metolazone

• Elevates blood levels • • • • •

• Hyponatremia

Glucose Lipids Uric acid Calcium HyperGLUC

• Drugs promote Na loss • H2O resorption intact (normal medullary gradients) • High H2O intake  hyponatremia

• Hypokalemia • Metabolic alkalosis

• Caution: diabetes, ↑lipids, gout, hypercalcemia

Thiazide Diuretics

K-Sparing Diuretics

Hydrochlorothiazide; chlorthalidone; metolazone • Clinical uses • • • •

• Spironolactone/eplerenone

Hypertension Recurrent calcium kidney stones Osteoporosis Diabetes insipidus

• Block aldosterone receptor site

• Triamterene/amiloride • Block aldosterone Na channel

• Good choice for patients with low K • Often from other diuretics

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K Sparing Diuretics

K Sparing Diuretics Principal Cell

Lumen (Urine)

Na+

Spironolactone, Eplerenone, Triamterene, Amiloride

Interstitium/Blood

• All ↑Na/H2O excretion (diuretics) • All “spare” potassium

Na+ Aldosterone

Aldosterone

K+

ATP

• Unlike other diuretics, do not increase K+ excretion

K+

• HYPERkalemia is side effect • Spironolactone  gynecomastia

H2O

• Antiandrogen: Blocks androgen receptor • ↑ estrogen effects/↓ androgen effects

Intercalated Cell

K 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: HCO3- excretion • K sparing: ↓ aldosterone; hyperkalemia (H+/K+ exchanger) • Others cause contraction alkalosis

• Loops and Thiazides have opposite effects on Ca • Loops  hypocalcemia • Thiazides  hypercalcemia

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Diuretics result in volume loss Activates renin-angiotensin-aldosterone system ↑ RAAS  ↑ Na/H2O reabsorption Some adaptation to diuretic effect over time

Kidney Stones Nephrolithiasis 1. 2. 3. 4.

Calcium Struvite Urate 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

• High amount of stone substance in blood • Hypercalcemia • Hyperuricemia

• Low urine volume • Usually from dehydration • Increases concentration of urine substances

• In general, hydration lowers risk of stones

Calcium Stones • • • •

Risk Factors

Calcium oxalate (most common) Calcium phosphate Most common type of kidney stone (80%) Key risk factors

• Most common etiology: idiopathic hypercalciuria • Hypercalcemia (hyperparathyroidism) • High oxalate levels • Crohn’s disease: Fat malabsorption  Fat binds to calcium, leaving oxalate free to be absorbed in the gut • Gastric bypass patients

• Hypercalcemia • High oxalate levels in blood

• Ethylene glycol (antifreeze)

• Radiopaque

• Formation of oxalate • Increases oxalate concentration in urine

• Seen on x-ray and CT scan

• Vitamin C abuse • Oxalate generated from metabolism of vitamin C

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Calcium Stones

Treatment

• Classic case • • • • •

• • • •

Patient drinking less water Flank pain, hematuria Calcium stone on imaging Normal Ca level in plasma Increased calcium level in urine

Most stones pass on their own Large stones that do not pass require surgery Recurrent stone formers may take medication Thiazides • Decrease Ca in urine

• Citrate (Potassium citrate) • Binds with calcium but remains dissolved • Lowers urinary Ca available for stones • Inhibits of stone formation

Struvite Stones

Dietary Sodium ↑ Na ↑ ECV

• • • •

More Na = More Ca Urine High Na diet = Stone formation Low Na diet = Treatment stones

Ammonium-Magnesium-Phosphate stones 2nd most common stone type (15%) Consequence of urinary tract infection Urease-positive bacteria • Proteus, Staphylococcus, Klebsiella • All hydrolyze urea to ammonia • Urine becomes alkaline

↓ RAAS ↓ Na Reabsorption Proximal Tubule

↓ Ca Reabsorption Proximal Tubule

Struvite Stones

Struvite Stones

• Can forms “staghorn calculi”

• Classic presentation

• Stones form a cast of the renal pelvis and calices • Looks like horns of a stag

• • • •

• Won’t pass  surgery required • Untreated  bacterial reservoir

UTI symptoms (dysuria, frequency) Mild flank pain Hematuria Large, branching staghorn stone on imaging

• Treatment:

• Recurrent infection

• Surgery • Antibiotics

• Radiopaque • Seen on x-ray and CT scan

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Uric Acid Stones

Risk Factors

• Cause by high uric acid in urine or acidic urine • H+ + Urate- ↔ Uric acid • Radiolucent stones

• High uric acid levels • Gout • Leukemia, myeloproliferative disease

• Acidic urine (precipitates uric acid)

• Not visible on x-ray • Can see with CT scan

• Chronic diarrhea

• More common in hot, arid climates

• Lowest pH is in the distal tubule/collecting duct

• Low urine volume, acidic urine more common • 5-10% stones in US/Europe • 40% stones in other climates

Treatment

Uric Acid Stones

• Hydration • Alkalization of urine

• Classic case • Flank pain, hematuria • No stone on x-ray

• Potassium bicarbonate

• Choose medical therapy, not surgery

• Rarely allopurinol • Xanthine oxidase inhibitor • Reduces uric acid production

• Medically therapy often effective • Usually does not require surgery

Cystine Stone • • • •

Cystine Stone

Rare type of stone Seen in children with cystinuria Tubular defect  cannot absorb cystine Also form staghorn calculi

• Classic case • Child • No history of UTI (contrast with Struvite) • Large, staghorn stone

• Treatment: • Hydration • Alkalinization of urine

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Renal and Bladder Malignancies 1. 2. 3. 4. 5. 6.

Renal and Bladder Malignancies

Renal Cell Carcinoma Wilms’ Tumor Renal Angiomyolipoma Transitional Cell Carcinoma Squamous Cell Carcinoma Adenocarcinoma

Jason Ryan, MD, MPH

Renal Cell Carcinoma

Renal Cell Carcinoma

Risk Factors

• Most common kidney tumor • Epithelial tumor • Commonly arise from proximal tubule cells

• Males • Age 50-70 • Cigarette smoking • Obesity

Renal Cell Carcinoma

Renal Cell Carcinoma

Symptoms

Symptoms

• Classic triad

• Invades renal vein

• Hematuria • Palpable abdominal mass • Flank pain

• Can block drainage of spermatic vein on left • Left varicocele is classic finding • Not right (right spermatic drains to IVC)

• Many patients have fever, weight loss • Many patients asymptomatic until disease advanced • At presentation ~25% have metastases/advanced disease

• Spreads through venous system • Common sites for metastasis: • Lung • Bone

• Can also spread to retroperitoneal lymph nodes

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Renal Cell Carcinoma

Renal Cell Carcinoma

Paraneoplastic syndromes

Paraneoplastic syndromes

• Many paraneoplastic syndromes • Polycythemia (↑Hct)

• Hypertension • Renin production by tumor

• Cushing’s Syndrome

• Increased EPO production by tumor

• ACTH production by tumor • Look for weight gain, hypertension, hyperglycemia

• Hypercalcemia • Tumor production of PTHrP • Increased Ca from bones

Renal Cell Carcinoma

Renal Cell Carcinoma

Pathology

Genetics

• Most common type is clear cell carcinoma • Cells filled with glycogen and lipids

• Associated with gene deletion chromosome 3 • Von-Hippel-Lindau (VHL) gene • Sporadic mutation • Single tumor • Older patient, usually smoker

• Inherited • Younger patient • Multiple, bilateral tumors

Renal Cell Carcinoma

Von-Hippel-Lindau Disease

Treatment

• Autosomal dominant • Von-Hippel-Lindau (VHL) gene inactivation • Many tumors

• Surgical resection in early disease • Poorly responsive to chemotherapy/radiation • Recombinant cytokines used

• Renal cell carcinomas • Cerebellar hemangioblastoma • Retinal hemangioblastoma

• Aldesleukin (interleukin-2) • Hypotension, fevers, chills are important side effects

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Wilms’ Tumor

Wilms’ Tumor

• Most common renal malignancy of young children • Proliferation of metanephric blastema

• • • • •

• Embryonic glomerular structures

• Classic case • • • •

Young child (~3years old) Huge, palpable flank mass Hematuria Hypertension (renin secretion)

Beckwith Wiedemann Syndrome

WAGR Syndrome

• Pediatric overgrowth disorder • Macrosomia

• Wilms’ tumor • Aniridia

• Height/weight often >97th percentile

• Absence of the iris • Visual problems

• Hemihyperplasia

• Genital anomalies

• Muscles in one limb bigger than other

• Macroglossia • Many embryonal tumors

• Cryptorchidism, ambiguous genitalia

• Mental Retardation • Deletion of WT1 gene chromosome 11

• Wilms’ tumor • Neuroblastoma • Rhabdomyosarcoma

Renal Angiomyolipoma

Transitional Cell Carcinoma

• Benign tumor – young children • Tumors of blood vessels, smooth muscle, fat • Associated with Tuberous Sclerosis • • • • • •

Associated with loss of function mutation WT1 tumor suppressor gene Chromosome 11 May be sporadic Often part of a syndrome

• Most common tumor of urinary tract system • Most common type of bladder cancer • Locations:

Autosomal dominant condition Cortical tubers in brain Subependymal hamartomas in brain Seizures, mental retardation Cardiac rhabdomyomas Leaf-like patches of skin with no pigment (ash-leaf patches)

• Bladder (most common) • Also renal calyces, renal pelvis, ureters

• Often multifocal and recurrent • “Field defect” • Damage to entire urothelium

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Transitional Cell Carcinoma

Transitional Cell Carcinoma

Risk Factors • • • • •

Smoking Cyclophosphamide Phenacetin Aniline dyes (hair coloring) Workplace exposures

• Classic case • • • •

• Test of choice: cystoscopy and biopsy

• Rubber, textiles, leather • Naphthalene (industrial solvent) • Painters, machinists, printers

Transitional Cell Carcinoma

Squamous Cell Carcinoma

Treatment • Surgical resection • Radiation • Chemotherapy

• Rare bladder cancer • Need chronic inflammation of bladder • Several key risk factors

• Combination chemotherapy with platinum-based regimens • Cisplatin, carboplatin

• Recurrent kidney stones or cystitis • UTI with Schistosoma haematobium

Schistosoma haematobium • • • • • • • •

Older, white male Smoker Painless hematuria No casts in urine

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

• Very rare bladder cancer • Glandular proliferation in bladder • Occurs in special circumstances • Urachal remnant • Long history of cystitis • Exstrophy: bladder protrusion through abdominal wall defect

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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 • Intense physical exercise

• Creatine kinase

• Especially if dehydrated

• Elevated levels are hallmark of rhabdomyolysis

• Crush injuries (trauma) • Drugs

• Aldolase, lactate dehydrogenase, AST/ALT

• Statins • Fibrates

Muscle Contents

Muscle Contents

• Potassium and phosphate

• Purines

• Hyperkalemia/hyperphosphatemia in rhabdomyolysis

19 K

• Metabolized to uric acid in liver • Can lead to hyperuricemia

15 P

Adenine

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Guanine

Myoglobin

Myoglobin

• Protein monomer (NOT tetramer like Hgb) • Contains heme (porphyrin plus iron) • Binds oxygen for use by muscle tissue % Saturation

100 75

No allosteric interactions!

50

25 25

50

75

100

pO2 (mmHg)

Myoglobin

Myoglobin

Renal Toxicity

Renal Toxicity

• Obstructs tubules • Toxic to proximal tubular cells • Vasoconstriction

• Made worse by volume depletion in rhabdomyolysis • Intravascular fluid influx into muscle tissue

• Feared outcome rhabdomyolysis: renal failure/death

• Especially in medulla • Leads to renal hypoxia

Rhabdomyolysis

Rhabdomyolysis

Symptoms

Diagnosis

• Muscle pain • Weakness • Dark urine (from myoglobin)

• Creatine kinase • • • •

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Usually very high Normal < 250 IU/L Rhabdomyolysis > 1000 IU/L Sometimes up to 25,000 or more IU/L

Rhabdomyolysis

Rhabdomyolysis

Diagnosis

Diagnosis

• Urinalysis for heme

• Microscopy for red blood cells • Classic finding rhabdomyolysis

• Heme has peroxidase activity • Breaks down peroxide • Changes test strip color

• Dark urine • Positive dipstick for heme • No evidence of red blood cells

• Positive dipstick = hemoglobin or myoglobin

Rhabdomyolysis

Hypocalcemia

Treatment • Volume resuscitation

• Calcium deposits in damaged myocytes • Initial phases rhabdomyolysis: hypocalcemia • Recovery phase: release from myocytes

• IV Fluids (usually isotonic saline) • Titrated to maintain good urine output

• Treatment of electrolyte abnormalities • Dialysis

• Levels return to normal • Can become elevated

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