Urine Luck!

(Part II)Renal slides

byDan Cushman

Donations accepted and strongly encouraged

Presidential Election 2008…

You have a choice.

Kupin for President!

Test ValueSerum [Na+] 140 mEq/LSerum [Cl-] 103 mEq/LSerum [K+] 4.5 mEq/L

pCO2 40 mmHgSerum [HCO3

-] 24 mEq/LSerum [Ca2+] 9.4 mEq/dLAnion Gap 13Hematocrit ~0.45Serum [Hb] 15 g/dL

Normal values

Test ValueBUN 16 mg/dL

Serum [Cr] 0.7 – 1.4 mg/dLSerum [uric acid] 5 mg/dL

BUN/Cr 16Urine specific gravity 1.002 – 1.030

Plasma specific gravity 1.010Urine pH 5-7

Urine protein TraceSerum glucose 100

Normal values (continued)

Laboratory Evaluation of ARF

Pre- renal Azotemia

Glomerulonephritis ATN

RBCs ------ Dysmorphic -----

WBCs ------ +++ -----

RBC cast ------ ++++ -----

Granular cast ------ ++++ +++

Raise or lower plasma creatinine level

Condition Increase/DecreaseCirrhosis Decrease

Male gender IncreasePregnancy Decrease

Rhabdomyolysis IncreaseOld age Decrease

Increased muscle mass IncreaseTrimethoprim, Tagamet Increase

Statins IncreaseChildren Decrease

Raise or lower BUN levelCondition Increase/Decrease

Catabolism Increase↓ protein intake Decrease

GI bleeding IncreaseCorticosteroids Increase

Condition ATN PRARecovery 2-3 weeks Rapid

Cell death? Yes NoUrine sodium High (>40) Low (<20)

FENa High (>3%) Low (<1%)Ur. Spec. Grav. Iso (1.010) High (>1.015)Ur. Osmolality Normal (280) High (>500)RBCs in urine Absent AbsentPlasma [K+] High High

Granular casts Present No, sir

ATN vs. Pre-renal Azotemia

Raise or lower BUN:Cr ratioCondition Increase/Decrease

Trimethoprim DecreaseVolume depletion Increase

Cimetidine DecreaseRhabdomyolysis Decrease

Renal failure NormalStatins Decrease

ATN NormalPre-renal azotemia Increase

Cocaine Decrease

How?Impairs Creatinine secretion

How?

How?

Cockroft and Gault formulaWhich variables go on each side of the equation?

Cr [Na+]SexGFRAge[K+]

(140- )* / (72 * ) =

Wgt

(Adjust by 0.85 with )

Condition Increase/DecreaseCO Increase

Systemic Resistance DecreaseLevels of Renin/catechol. Increase

RBF DecreaseSerum Na+ Decrease

BP DecreaseFENa Decrease

Treat with vasodilators? No!

HRS

Drugs inducing ATN (4)

1. Aminoglycosides2. Amphotericin3. IV contrast4. Cisplatinum

1. Proximal tubule2. Distal tubule3. Proximal tubule4. Distal & proximal

Which parts of the kidney do these affect?

Match the Correct Response and Substance

PGE AT II Constriction Dilation

Midodrine

ADH

Octreotide

NE

Match the drug with its actionα1-agonists

Glucagon antagonism

V1 agonists

Somatostatin Ornipressin

What do all of these drugs do?

Splanchnic vasoconstriction

Which region is most likely to be affected by

ARF?Outer Medulla

HyperkalemiaWhat happens to the T-wave?

Peaked

The P wave?

Decreased amplitude

How does trimethoprim cause

hyperkalemia?Impairs distal tubule K+

secretion

And NSAIDs?Decreased PGE decreased aldosterone decreased K+

secretion

(same with ACEIs and ARBs)

Hyperkalemia is treated with? Insulin/glucose, β2-agonists,

Calcium chloride, kayexalate

Condition Acute ChronicRenal Size (cm) >10cm <9cm

[Ca2+] No correlation No correlationEchogenicity Normal Increased

Osteodystrophy Absent PresentAcidosis No correlation No correlation

Casts Bland, Granular WaxyAnemia No correlation No correlation

[K+] Increased No correlation?[phosphorous] No correlation No correlation

Acute vs. Chronic Kidney Disease

TIPSWhat’s the point of TIPS?

Reduce portal hypertension, as HRS is a reversible phenomena of a functional nature, not

structural damage

What veins are involved?

*Little known fact: Due to the large proportion of alcoholic cirrhotic patients undergoing TIPS, Dr. Eugene Esmerald coined the phrase “tipsy,” referring to his future patients.

* Totally made that all up.

Phases of Acute Renal Failure

1. Initiating – exposure 2. Oliguric – 10-14 days, <400cc/day3. Diuretic – no change in renal function4. Recovery – 3-12 months

Chinese Herb NephropathyWhat herb is associated with it?

Fangchi

If you said Fang Ji, you need to work on your Herbology;

that’s remedial.Fangchi contains which toxic agent?

Aristolic acidWhich does what physiologically? Inhibits protein reabsorption in

the proximal tubules and covalently binds to DNA

This causes what?Weight loss!

(And cortical interstitial fibrosis)

(And transitional cell cancer)

Herbal nephropathy

Name the four pathophysiologic effects of Sheng Fu Chui (also known as Willowroot, Tonguebait, Snifflewood, or Tree tamer’s juice)

I made all that up.

(Sounds real, though, doesn’t it?)

St. John’s WortWhat is SJW used for?

Depression

Does it work?Shut up. I hate you.

How can SJW be harmful if taken as a complementary

medicine?It induces the CYP450 and intestinal

P-glycoprotein/MDR1 enzymes

Will the plasma concentration of penicillin be increased or decreased

when given with St. John’s Wort? Neither, penicillin doesn’t use the CYP450 excretion pathway.

What about if you took an oral contraceptive (that had the same

CYP450 excretion) with SJW? (And you thought you were depressed before…)

Grapefruit juiceWhy shouldn’t you drink it if you’re taking medications?

It inhibits the CYP450 pathway, which increases plasma levels

of the other medications

Why should you drink it if you’re not taking medications?

It’s refreshing

StarfruitWhat component of starfruit is dangerous to the kidney?

High levels of oxalate

How is this bad?

Kidney stones

What should you do to your “pickled sour juice” to make it

safer?

Dilute it. I have no idea what pickled sour juice is, I’m just reading off the

slide.

EphedraEphedra is also known as what (the Chinese name)?

Minh Hoang

What renal issues can it cause?

Ephedra stones, hypertension

I mean Ma Huang

LicoriceSpell the active ingredient in licorice (hint: the second word is “Gabra”)

ZLA

Y

RI

H

G

CY

R

LicoriceWhat does glycyrrhizic acid bind directly to?

11 β-hydroxysteroid dehydrogenase

What is the normal job of 11 β-hydroxysteroid dehydrogenase? Degrade cortisol

Why? Cortisol binds to aldosterone receptors

Where is this important?

Principal cells

What condition comes from this? Apparent Mineralocorticoid Excess

(AME)

Heavy MetalsHow do heavy metals get reabsorbed in the kidney?

Through the DMT1 channel in the proximal tubule

What happens?

↓ reabsorption of other divalent cations, ↑ serum levels of toxic metals

What does lead lead to? (The first “lead” is Pb)

CKD, plus the triad: hypertension, renal failure, gout

What about Cadmium?

Irreversible damage, including osteoporosis and hypertension

Heavy MetalsLead Cadmium

HTN

CKD

Fanconi’s Syndrome

Gout

Nephrolithiasis

Osteoporosis

Treatment – Chelation Therapy

Autoregulation CurveWhat are the labels on the axes?

RB

F o

r G

FR

Systolic blood pressure

What happens to the curve upon administration of NSAIDs?

It shifts to the right!

(The same blood pressure doesn’t allow for a large enough GFR)

Condition Increase/DecreaseSize of the kidney Increase (by 1-1.5cm)

RBF Increase – peaks at 4wksGFR Increase – peaks end 1st tri

Ureter size Increase (hydroureter)Systemic vasc. Resistance Decrease

CO IncreaseBlood pressure Decrease

Heart rate IncreaseHematocrit Decrease

Kidney in pregnancy

?

?

?

Condition Increase/DecreaseBlood volume Increase

Plasma volume IncreaseSerum creatinine Decrease

Urine protein IncreaseUric acid reabsorption Decrease

Na reabsorption IncreaseAldosterone Increase

Renin Increase

Kidney in pregnancy (cont)

Marker Increase/DecreaseUric Acid Increase (>5.5 mg/dL)

Urine protein Increase (>300 mg/day)Serum creatinine Increase (>0.8, <1.5mg/dL)

Urine calcium Decrease (<150 mg/day)Hematocrit Increase (>0.36)

Platelets Decrease (<100,000)GFR Decrease

Renin Decrease

Preeclampsia

?

?

?

?

?

?

Marker Increase/DecreaseBlood pressure Increase ( >160/110)Urine protein Increase (>5g/day)Urine output Decrease (<500mL/day)

Seizure (yes/no) No (that’s eclampsia)Serum transaminase Increase (>2x normal)

Platelets Decrease (<100,000)Liver capsule Distension

Severe preeclampsia

?

?

?

?

?

Use this drug? Yes/NoACEI NoCCB YesARB No

NSAID NoHydralazine Yes

Beta-blockers YesDiuretics No

Morphine Sweet, sweet morphine… I don’t know

Preeclampsia

Pregnancy sucksWhat causes gestational diabetes insipidus?

Vasopressinases in placenta ↓ ADH

Why are pregnant patients often hyponatremic?

The osmostat is decreased, resulting in a reduced [Na+] by 5mEq/L

Are they acidotic or alkalotic?

Generally alkalotic

Due to what? What is the resultant [HCO3

-] level in the serum?

Progesterone → Hyperventilation → respiratory alkalosis; Low [HCO3

-] in the serum

*Little known fact: Babies can suck the life out of you. At least according to a Swedish survey from 1997 (JASA, Hortenz et. al, 1997)

* Totally made that all up.

What am I?

Preeclampsia

Type Systolic BP Diastolic BP Other factor

Gestational >140 >90 NO Proteinuria, after week 20

Preeclampsia >140 >90 Proteinuria >300mg/d, new-onset

Chronic HTN >140 >90 Onset before week 20 possible

Hypertension in pregnancy

What is the pathophysiology of preeclampsia?

The cytotrophoblastic tissue of the fetus does not invade into the maternal placenta, thus not allowing for dilation of the spiral arteries and results in placental ischemia. That’s bad.

Should the blood pressure be lowered?

Yes (for the mother’s sake), though it won’t cure preeclampsia

Drugs (not the fun kind)What is the equation for bioavailability? Bioavailability (AUC)o

(AUC)iv

=

Do IV drugs experience the first-pass effect?

No

If you were administering an IV drug, will you need to administer more or less of the equivalent oral drug?

More

Name the three sites of first-pass metabolism1. CYP450 enzymes in the small intestine2. CYP450 enzymes in the liver3. P-Glycoprotein in the small intestine

Drugs (not the fun kind)Drug’s effect

on body

Pharmacokinetics

Pharmacodynamics

Body’s effect on drug

Which is smaller – the lag time (tlag) or the time at Cmax (tmax) ?

tlag will always be smaller

Name the four factors that will reduce bioavailability of an oral drug1. Destruction in gut2. Lack of absorption3. Destruction by gut wall4. Destruction by liver

Match

Drugs (not the fun kind)If patient D has diabetes mellitus and patient N is normal, who will more likely require a higher dose of a dose-dependent drug?

Patient D, because he/she may have diabetic gastroparesis

Which patient will take more time to have effects of the drug?

Patient D

What will happen to the tlag and Cmax of patient D?

Increased tlag and decreased Cmax

What’s the importance of phosphate binders?

They are antacids that reduce the absorption of some drugs (fluoroquinolones)

What does CKD do to CYP450 metabolism? I have no idea how, but CKD

itself reduces the potency of CYP450 and P-glycoprotein

*Little known fact: The DARE program has saved a grand total of 3 children from a life of drugs. In 1998, police officer Greg Partroy accidentally backed over a group of schoolchildren in rural Indiana with his DARE van. Thus, they never did drugs after that. The War on Drugs is a winning proposition!

* Totally made that all up.

Volume of DistributionWhat is the equation for Volume of Distribution? Vd = Dose / [drug]plasma

What would CKD do specifically that could affect Vd (4 things)?

1. Decreased albumin levels2. Decreased protein binding3. Decreased tissue binding4. Volume overload

How does CKD lower albumin binding?

Uremic toxins displace drug from albumin

How much phenytoin (dilantin) is protein bound? With and without CKD.

90% without, 75% with CKD

Which of the two are measured in serum drug concentrations?

Bound

UnboundBoth!

KineticsWhat order am I?

Is this what the body usually does?

First-order

Yup

Where is the majority of kidney drug metabolism localized? The proximal tubule

What ways does the kidney remove drugs (4)?

Filtration, secretion, absorb & destroy, pH

How much insulin is removed by the kidney?

30% – kidney failure can result in higher-than-normal levels of insulin

What will dialysis remove?Small, unbound drug

Osmolarity[Na] in hyponatremia <135 mEq/L

[Na] in severe hyponatremia <120 mEq/L

ADH decreases with pain? No – it increases

Site of hypothalamic volume control Supraoptic nucleus

Site of hypothalamic tonicity control Paraventricular nucleus

↑ plasma osmolarity = ? ADH Increase

More powerful – volume or tonicity Volume

More sensitive – volume or tonicity Tonicity (2% vs. 10%)

Body protects volume or tonicity more? Volume

Idiogenic molecule for osmotic force Myoinositol

Is BUN part of osmolarity calculation? Yes

Urine [Na+] in CHF <20 mEq/L (due to ↑ renin)

↑/↓ water excretion in CHF? Decreased (due to ADH)

↑/↓ ADH levels from pain/surgery? Increased

Osmolarity (continued)

I don’t have a good title for thisOsmolarity

Number of particles that exist in a fluid environment

Number of particles existing in a fluid environment that have the potential to exert

water movement

TonicityMatch

Which of the following two conditions causes most clinical complications?

Hypertonic hyponatremia

Hypotonic hyponatremia

Equation 1: Tonicity = ? Equation 2: Osmolarity = ?

T = 2[Na] + [Glu] / 18 O = 2[Na] + [Glu] / 18 + BUN / 3

Calculate

Hyperglycemia Uremia

Glucose 900 90

Na 130 130

BUN 30 120

Osmolality (2*130)+(900/18)+(30/3)320

(2*130)+(90/18)+(120/3)305

Tonicity (2*130)+(900/18)310

(2*130)+(90/18) 265

Diagnosis Hypertonic Hypotonic

Cause Serum osmolality Volume statusHyperglycemia Hypertonic Hypovolemic?

GI Loss Hypotonic HypovolemicPseudohyponatremia Isotonic ?

CHF Hypotonic HypervolemicSIADH Hypotonic Isovolemic

Renal losses – diuretics Hypotonic HypovolemicCirrhosis Hypotonic HypervolemicK+ losses Hypotonic Isovolemic

Kidney failure Hypotonic HypervolemicReset osmostat Hypotonic Isovolemic

Third-space losses Hypotonic HypovolemicImpaired adrenal function Hypotonic Isovolemic

Hypertonic infusion Hypertonic ?

Hyponatremia

SIADHWhat does it stand for? Syndrome of Inappropriate

Antidiuretic Hormone

Good kidney function? Sure

What’s the urine concentration like?

>100 mosm/L, typically >300 mosm/L

And the urine [Na+]? Also high, >30 mEq/L (without Na restriction)

Is the plasma hypo- or hyperosmolar?

Hypoosmolar

Is the plasma hypo- or hypertonic?

Hypotonic

What malignancy is it associated with?

Small-cell carcinoma

Evaluation of hyponatremiaProves existence of

hypotonic hyponatremia

Increased value suggests SIADH

Match

Free water clearance affected by [ADH]

Proves existence of pseudohyponatremia

Decreased value suggests hypovol. hyponatremia

Identifies polydypsia

Urine osmolality

Plasma osmolality

Urine Sodium

HyponatremiaWhat types of cells are particularly sensitive to rapid volume changes?

Oligodendrocytes

What occurs when they are re-salted quickly during treatment for hyponatremia?

Osmotic Demyelinating Syndrome

How long does it take for this become clinically apparent?

2-6 days

What correction rate should be used for hyponatremic patients to avoid ODS?

1-2 mEq/L/hr, not exceeding 12 mEq/L increase per 24h

Or… what should be a safe level to increase the [Na] to?

[Na] = 120mEq/L

Or, just use aquaretics

PolyuriaGreater than 3L per day

What urine osmolality separates water diuresis from osmotic diuresis? 300 mosm/L

What is the diagnosis if there is a polyuric patient with a low serum [Na]?

Primary polydypsiaAnd if it’s a high serum [Na]?

Diabetes insipidus or osmotic diuresis

Diabetes InsipidusCentral – tell me about it

Deficient secretion of ADH; treat with exogenous ADH

And nephrogenic?Renal resistance to the action of ADH, no response to exogenous ADH

What drug is notorious for causing nephrogenic DI?

Lithium

That’s a really good Nirvana song. What are the first lyrics?

I’m so happy/cuz today I found my friends/in my head…

Anyway, what else is associated with nephrogenic DI (2)?

Hypercalcemia, hypokalemia (inhibition of TALH Na-K ATPase)

More common in heat or cold? Heat

Two most common types of stone? Calcium Oxalate > Struvite

More common in men or women? Men

More commonly bilateral? No – unilateral

Location of stone formation That rhymed. Tip of renal papillae.

Most common etiology of CaOx stones Hypercalciuria

… which is exactly what level? > 4mg/kg/day

Kidney Stones

Most common causes of hypercalciuria? Renal leak, increased absorption

Does hypercalciuria = stones? No, most clinically silent

Intake of what electrolyte → stones? Na

What type of stones from ↑ PTH? CaPO >> CaOx

Main source of dietary oxalate Vitamin C

Relationship between urate and CaOx crystals ↑ urinary Urate → ↑ CaOx crystals

What is epitaxy? Increased growth of one type of a crystal due to presence of another type

Kidney Stones

Preferred pH of CaOx stones (↑/↓)? ↓Dietary source of urine urate Animal protein

What else does that contribute to (3)? Hypercalciuria, hypocitraturia, ↓pHurine

3 stone inhibitors Citrate, Mg, Phosphorous

2 influences on citrate levels Age (↓), acidity (↓)

Does ↑ water intake = ↓ stones? Yes – take that, Dr. Barrett.

Does ↓ Ca intake = ↓ stones? No, the opposite is true

Kidney Stones

Why? It binds to oxalate, decreasing its absorption in the intestine

StonesWhat contributes to hypercalciuria (8)? 1. Renal Leak

2. Increased absorption (Vit D receptor)

3. Idiopathic

4. Increased sodium

5. Hyperparathyroidism

6. Too much animal protein

7. Reduced calcium intake

8. Loop diuretics (thiazides actually help increase Ca reabsorption)

Cystinuria treament?Alkalanize urine, D-penicillinamine, diamox, captopril

Triple-Phosphate StonesWhat are the three cations that phosphate binds to in a triple-phosphate stone?

Ammonia, Magnesium, Calcium

How do UTI’s predispose someone to these stones?

There is a production of urease by bacteria → more ammonium

More common in men or women?

Women. Ha ha.

What specific population is more likely to develop one of these?

Spinal cord injury patients

What is the pH of the urine like? >7.2

Type X-ray pH

Calcium oxalate Opaque Acidic

Ephedra Translucent ?

Uric Acid Translucent Acidic

Triple Phosphate Opaque Basic

Cystine Opaque Acidic

Calcium Phosphate Opaque Basic

Kidney Stones

Notice that all the high-pH stones have “phosphate” in their

name!

Notice that all the radio-opaque stones contain calcium or

cystine

Match the stones!Calcium oxalate Triple Phosphate Cystine

Rolling Uric acid

Match the stones!Calcium oxalate Triple Phosphate Cystine

Past tense Uric acid

Acid-BaseDiabetic/alcoholic ketoacidosisRenal Tubule AcidosisMethanol ingestionDiureticsDiarrheaLactic (& D-lactic) acidosisEthylene glycol ingestionVomitingPrimary hyperaldosteronismEarly renal failureMassive IV fluidsGittleman’s/Bartter’s syndromes

High-AG metabolic acidosisMetabolic acidosis

High-AG metabolic acidosisMetabolic alkalosisMetabolic acidosis

High-AG metabolic acidosisHigh-AG metabolic acidosis

Metabolic alkalosisMetabolic alkalosisMetabolic acidosisMetabolic acidosisMetabolic alkalosis

Renal Tubular AcidosisWhere does type I occur?

The distal tubuleWhat is the pathogenesis?

DT can not secrete protons sufficiently

Does this result in an acidosis or alkalosis?

Read the name of the disorder, Einstein.

Where does type II occur The proximal tubule

What is the pathogenesis?

Is the urine in type II more or less acidic than type I?

PT can not reabsorb HCO3-

sufficiently

The urine is more acidic because the DT is working normally

Is there an associated hypo- or hyperkalemia?

Hypokalemia

Glomerulus

?

?

Which is which?Endothelium Epithelium

*Little known fact: The Scanning Electron Microscope once saved an obviously guilty physicist who had been arrested for lewd behavior. The physicist’s defense was that his PhD was in SEM, meaning that his sado-masochistic fantasies were merely research.

* Totally made that all up.

ProteinuriaMax normal protein excretionMajor normal protein type in urine% of urine that is albuminTrace amount of albumin on dipstickMicroalbuminuria (amt in urine)Macroalb. shows on dipstick?Microalb. shows in urine protein?What dipstick level is pathologic?Protein/Cr ratio = ?Protein/Cr ratio of 1.0 = ?Fatty casts signify…?RBC casts signify…?

150mg/dayTamm-Horsfall (50%)

15%10-20mg/dL (not mg/day)

<300 mg/dayYes

Not necessarily2+ (1 could be due to conc. urine)

24hr urine proteinuria1.0g/day

Nephrotic syndromeGlomerulonephritis

Note: proteinuria itself is a risk factor for CKD with increased BP – what should be the goal BP of a patient with proteinuria?

Less than 125/175!What about

severely restricting protein intake?

Doesn’t do much – moderate protein restriction is the general recommendation

What other condition (beside proteinuria) should require a more aggressive blood pressure reduction strategy?

Diabetic nephropathy

ACE InhibitorsAre they good for prevention of renal disease?

Yes! And their benefit seems to stem from more than just a decrease in systemic blood pressure

What do ACE inhibitors do to mesangial deposition of macromolecules? …to the release of TGF-β?

Decreases both

Do ACE inhibitors increase or decrease procollagen formation?

Decrease

If a patient is taking an ACE inhibitor, what should you monitor in the blood?

Check for hyperkalemia

ProteinuriaWhy is specific gravity important when measuring proteinuria?

A concentrated urine can show a falsely high urine albumin level

What about if there’s an infection? Inflammation plasma

exudation ↑ albumin

Hematuria?Red cells pull in albumin as well; dipstick value will never be higher than the true value

What are the 4 clinical findings involved in Nephrotic Syndrome?

Hypoalbuminuria, hypercholesterolemia, edema, >3.5g protein/day

What neoplasms can be associated with NS?

Membranous nephropathy = adenocarcinoma, minimal change = lymphoma

ProteinuriaDysmorphic RBCs signify…?Leukocytes, PMNs signify…?Eosinophils, leukocytes…?Oval fat bodies…?Most common adult cause of NSMost common childhood cause of NSProteinuria level for diagnosis of NSDiabetes + nephrotic proteinuria = ?

GlomerulonephritisInfection. Duh.

Interstitial nephritisNephrotic syndrome (NS)

Focal SclerosisMinimal Change Disease

>3.5 g/protein/dayAdvanced renal disease

Combined Hematuria and ProteinuriaImportance of RBC Morphology

DysmorphicRBCs

Non-Dysmorphic

RBCs

Proteinuria

Glomerular

Glomerular

Glomerular /Urologic

Glomerular /Urologic

1.? 2.?

4.?

3.?

ProteinuriaHow do you diagnose orthostatic proteinuria?

Daytime specimen vs. nighttime specimen

What makes you suspect transient proteinuria? Fever, CHF, strenuous exercise

Normal Tubular Overflow Orthostatic Glomerular

Proteinuria (mg or g)

150 mg 0.5 – 2 g 0.5 to > 3 g 0.5 – 2 g > 3.5 g

Type of proteinuria

Tamm Horsfall

B-2 microglobulin, Albumin

Light chains(Kappa

/Lambda)

Albumin Albumin

HTN ------- ---------- ---------- ----------- + + + +

Renal Failure -------- + + + ----------- + +

Hematuria -------- ---------- ---------- ----------- + +

Proteinuria

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Use SSA test to look for non-albumin proteins

What am I and what am I associated with?

Oval fat bodies – nephrotic syndrome

Cholesterol crystals – nephrotic syndrome

What am I and what am I associated with?

Normal red blood cells – vampires

Dysmorphic RBCs – glomerular filtration

problem

AG Metabolic Acidosis

• M• U• D• P• I• L• E• S

ethanol

remia

iabetic/alcoholic ketoacidosis

araldehyderon actic acidosis thylene glycol alicylate overdose (aspirin)

Non-AG Metabolic Acidosis

• R• E• D• D

enal tubular acidosis (RTA) arly renal failure

iarrhea

ilution

Metabolic Alkalosis

• H• D• T• V

yperaldosteronism (primary or secondary) iuretics

he unimportant syndromes

omiting What are those?

Gitelman syndrome

Bartter syndromeWhat drugs do they mimic?

Thiazides

Loop-actingWill they present with HTN?

No (aldo is normal)

ECFVCharacteristic ↑ or ↓

Edema ↑Rales ↑

Orthostatic hypotension ↓BUN/Cr > 20 ↓

[Na+] > 40 Doesn’t matter↑ weight ↑

High urine osm ↓JVD ↑

Poor skin turgor ↓

Proteinuria

1 2

3 4 5

Immune complexes

Description TypeCirculating III

In Situ IIInduction of abnormal host

responseIV

HIVANWhat is the histologic presentation of HIVAN? (Collapsing) Focal

segmental glomerulosclerosisWhat is the microscopic

pathogenesis of this? HIV infects podoctyes, resulting in hypertrophy and hyperplasia, with tubuloreticular inclusion bodies

What happens to the tubules? They undergo microcystic

dilationWho does it affect? What’s their blood pressure like?

What’s a tubuloreticular inclusion body? Aggregation of proteins

from IFN production

Predominantly AA males; BP is normotensive due to cytokine responseHow do you treat it?

HAART – for the rest of the patient’s life

What am I?

(Normal)HIVAN (Collapsing FSGS)

What am I?

HIVAN

Hepatitis CWhat is the main disease associated with Hep C? Cryoglobulinemic GN

What is the microscopic appearance of this? Membranoproliferative GN

What two Ig’s are involved in this cryoglobulinemia?

IgM is directed against IgG [to be exact, anti-HCV (e2) IgG]

How often does a HepC patient present with cryoglobulinemia?

50% of the time, but 2-3% are symptomatic

What cells does HepC infect?

Liver and B-cells

How does Hep C enter the cell?

LDLR (E1) and CD81 (E2)

Why are B cell infections important? ↓ threshold for B-cell activation

→cryoglobulinemia, B-cell lymphoma

HRS HCV + CG + MPGN

FENA < 1% < 1%

Proteinuria Normal (<150 mg/day) Nephrotic or Non-Nephrotic range

Urine Analysis Bland Microhematuria, red cell casts

Blood pressure Low High

C4, C3 level Normal Low

Extra-renal signs None Purpura / ulcers, arthralgias, polyneuropathy

Hepatitis C vs. HRS

Hepatitis BDo most people survive HepB?

Yes – immune response is sufficient for most people

What kind of virus is it?Hepadna

What are its main antigens?

eAg, sAg, cAg

What is the main type of histologic presentation with HepB?

Membranoproliferative GN (I & III)

What immune complexes (ICs) can be formed?

IgG – HepB eAg

Which type of ICs – circulating, in-situ, or direct-effect?

Circulating

More boy or girl instances of hepB? Boys (80%) – no preference in adults

Where do the ICs “land” in the kidney?

They have single deposits on the basement membrane

Incidence of Acute Interstitial Nephritis

?

What three hormones are associated with the interstitium?

EPO, Prostaglandins, Vit D hydroxylation

What are the two main cells located in the interstitium?

Monocytes and fibroblasts…and the molecular

composition?Glycoproteins, glycosaminoglycans, and collagen

Acute Interstitial Nephritis

What am I?What are the two main cells types that infiltrate the interstitium?

T-cells and eosinophils (not PMNs!)What are the two types of AIN?Infectious and allergic

What is the clinical presentation of someone with an acute allergic interstitial nephritis?Triad: rash, fever,

eosinophilia; plus proteinuria <2g

How long does it take to develop? 2-3 weeks, except for NSAIDs

(6mo)What’s the pathogenesis? Drug has Ag site similar to body’s HLA; T-cell-mediated response → podocyte change (minimal change disease)

Common Drugs NSAIDs

Time of onset 7-10 days 3-6 months

Fever 80% 0%

Rash 70% 25%

Eosinophilia 50% 25%

Proteinuria < 2g Nephrotic > 3g

Recovery Period 1-2 Weeks 3-12 Months

Allergic Interstitial Nephritis

What quantity of eosinophilia must be present to diagnose AIN?

5%

AIN GN

Kidney size Normal / Large Normal

Metabolic Acidosis

HyperchloremicNon-anion gap

Anion gap

Potassium Severe Hyperkalemia or Hypokalemia

Mild / Moderate Hyperkalemia

Blood Pressure Normal /mildly Elevated

Moderate to High Elevation

Anemia Severe Mild-moderate

Edema Minimal Marked

Proteinuria Tubular < 2 gm Nephrotic > 3 gm

Acute Interstitial Nephritis vs. GN

Acute pyelonephritis

What am I?What is the main infiltrate in pyelonephritis?

PMNs

Do you get granular casts?Yes

WBC casts?Yes

Eosinophiluria? NopeRBCs? Yes

Chronic Interstitial Nephritis

What am I?How can it develop (3)?

AIN → CIN, Directly, or part of a primary glomerular disease

What is the most effective treatment?

No treatment available

What kind of casts are present?Waxy

What kind of infiltrate is present? There actually isn’t much of an infiltrateWhat happens to the tubules? They atrophy and dilateWhat drug can directly cause this? Daily combination of acetaminophen

and other analgesics, plus caffeine or nicotine (for many years)

Acute Interstitial Nephritis

Chronic Interstitial Nephritis

Specific Gravity £1.010 1.010

RBCs Yes No

WBCs Yes No

RBC casts rare No

WBC casts Yes No

Granular Casts Yes No

Waxy Casts No Yes

FENA High > 3% High > 3%

Eosinophiluria Yes No

AIN vs. CIN

What do the two types of interstitial nephritis look like in ultrasound?

AIN = normal/largeCIN = small

Minutiae break!!!!!!

When was complement first discovered? Who cares!!

Phosphatidylserine has a key role in what?

Who cares!!

Ag:Ab complexesWhat happens when you’re stuck at this

point?

High levels of Ag:Ab complexes → GN

Is IgG high-level/high-affinity or

low-level/low-affinity?

High-level/high-affinity

Stuff you’ll forget

↑What am I?↑

What pathway do I lead to?

Where in the glomerulus can these Ag:Ab complexes

end up?

Mesangium → inflammation → GN

Histones are an example of what kind of IC formation?

In situ

Which complement protein is a molecular adjuvant?

C3d

ComplementThe complement cascade is

similar to which other cascade? Coagulation cascade

How are they linked? Complement activation often simultaneously activates the

coagulations cascade; activates platelets; modifies mast cells & basophils; initiates Tissue Factor

coagulation pathway

Is that local or systemic? Local

Whew. I know.

Be more specific, how are the two linked…? (hint: one

coagulation molecule joins with one complement molecule)

C5 + thrombin → C5a + C5b

ComplementWhich complement pathway

requires a microbial surface to start the cascade?

All of them

What is important about C3a? It’s an anaphylatoxin

Which pathway(s) includes C3? All of them

What is important about C3d? It’s an adjuvant, and therefore a link between the humoral and

innate immune systems

*Little known fact: the character C3PO in the “Star Wars” science fiction movie trilogy was originally named C3d because director George Lucas’s neighbor did research at nearby UCSF on opsonization. Because the neighbor was so flamboyantly homosexual, Lucas cast C3d as a gay robot in his friend’s honor. The movie’s financial backer (Peter Ordwell) actually turned out to be homophobic, and a closet homosexual, so he gave Lucas the choice of increasing the manliness of the robot or changing the name to C3PO, after his own initials. Lucas went with the gay robot.

* Totally made that all up.

What is the relationship between complement and RBCs?

RBCs have C3b receptors, allowing complement-bound Ag:Ab complexes to bind to them, allowing them to be

phagocytized

Four Secondary GN diseases with low complement levels

1. Post-infectious GN2. Membranoproliferative GN (Hep C)3. Cryoglobulinemia4. Lupus Nephritis

Immune complexesWhere do ICs generally deposit

(4)?1. Joints

2. Glomeruli3. Choroid plexus

4. Small vessels of the skin

What would a granular IHC pattern represent?

Ag:Ab complex-mediated disease

And a linear deposition?Anti-basement membrane Ab-

mediated disease

Scant deposition Pauci-immune disease

How would you treat IC diseases?

Corticosteroids, immunosuppressants,

plasmapheresis

CryoglobulinsWhat’s the big deal with

cryoglobulins?They can activate complement →

systemic inflammation

What are the three types? Monoclonal and Mixed

Ig of 1 single isotype and 1 single light-chain

class (e.g. IgG-κ)

2 or 3 Ig isotypes (usually IgM) with

mono- or polyclonal components

Which one is associated with RhF?

Type I Type II/III

Which one is more common?

Which one is found in multiple myeloma?

…and Hep C?

Type II

Cryoglobulins

IgG

IgM

Is this a type I, II, or III?

Type II or III

How would you differentiate between the two?

Type II is a monoclonal Ab (against polyclonal Ig), while type

III is a polyclonal Ab (against polyclonal Ig)

What would Type I look like?

Or(Light chain)

Complement

(High/low for each)

(High/low for each)

(High/low for each)

(High/low for each)

ComplementWhat does a high complement

level indicate? An acute response

Decreased levels? That there are excess IC’s in the serum (production has been exceeded by consumption)

What are the three most commonly measured

complement proteins?C3, C4, and CH50

CH50 – what’s that?A marker that measures all

components of complement (C1-C9)

Which pathways use C4? Classical, Lectin

Which pathways use C3? All of them

Which pathways use C1? Classical

Tubular/Interstitial PathologyWhich process is reversible?

Tubulointerstitial nephritis

Which process results in polyuria and nocturia? ATN

Which process results in a metabolic acidosis?

Which process usually results from ischemia?

What is the most common cause of pyelonephritis? Ascending infection

By which bacteria? E. coliWhat could cause a vesicoureteral

reflux?Short ureter, spinal cord injury

* Totally made that all up.

*Little known fact: Fortunately, the word structure still fits, but vesicoureteral reflux was originally coined by Dr. Frank Barrows in 1882. Dr. Barrows was known for his urology center in downtown Philadelphia, and his theory of medicine involved the “Quick Draw” as he called it. Historians differ on the exact maneuver, but Dr. Barrows made his patients create a “vesicoureteral reflex.” This routinely caused damage to the vesicular portion of the ureter, not allowing compression during voiding. Later physicians changed his “reflex” to “reflux” based on the ensuing patient condition.

What am I?

Acute Pyelonephritis

What cells are present?

PMNs

What am I?

Acute Pyelonephritis

Is this associated with diabetes? Yes - ↑ susceptibility to infection

Sudden or insidious onset? Sudden

Clinical presentation CVA tenderness, fever, dysuria, pyuria

What’s in the urine? WBC casts

What am I?

Chronic Pyelonephritis

What cells are present?

Leukocytes

(Note normal glomeruli!)

What am I?

Chronic Pyelonephritis

Is this associated with hypertension?

Yes

What are the two types? Reflux nephropathy, chronic obstructive pyelonephritis

Clinical presentation?

Insidious or repeated acute bouts of pyelonephritis

What’s in the urine?

Waxy casts

What am I?

Acute Tubular Necrosis

What am I?

Acute Tubular Necrosis

What happens to urine output? It decreases (<400mL/day)

What is the most common etiology?

Ischemia > toxic injury

What happens to tubular epithelial cells?

Because they are susceptible to ischemia, they lose cell polarity

Which leads to…? Abnormal ion transport → ↑ Na delivery to distal tubule → vasoconstriction → ↓ GFR

What happens to detached injured tubular cells?

They create an obsruction

The point of all this? DECREASED GFR

Oh – how bad is the inflammation?

Virtually absent?

Question Answer

Pathogenesis Drugs act as haptens during secretion by tubules

Hypersensitivity Reaction types Type I (IgE) and IV (cell-mediated)

Clinical signs (2wks post-drug) Fever, rash, eosinophilia

↑/↓ Crserum ↑

(Analgesic)

Lcation of necrosis Renal papillae

Pathogenesis Acetominophen covalently binds to tubular cells

Acute drug-induced interstitial nephritis

What am I the result of?

Obstructive Uropathy

What am I?

Hydronephrosis

What am I?

Uterovesicular obstruction

Note the bilateral hydronephrosis and hydroureters

What am I?

Minimal Change Disease

Affects which population?

Children

Nephrotic or Nephritic Syndrome?

Nephrotic

Responsive to steroids?

Yes

Immune complex-mediated?

No

What am I?

Focal Segmental Glomerulosclerosis

Affects which population?

African-American adults

Nephrotic or Nephritic Syndrome?

Nephrotic, usually (or nephrotic-range proteinuria)

Immune complex-mediated?

No

What am I?

Diabetic Nephropathy

How the hell can you tell that?

Nodular appearance

How should this be screened (2)?

GFR, microalbuminuria

Treatment?

No cure, but BP and glycemic control greatly reduce risk of acquiring it in the first place

What am I?

Crescentic GN

What is this indicative of?

Rapidly-Progressive GN

What makes the crescent?

Proliferating cells push in the rest of the glomerulus

Does this result in polyuria or oliguria?Oliguria

(Umbrella term)

What am I?

IgA Nephropathy

Affects which populations?

Asian, Hispanic

Clinical presentation

Hematuria (intermittent gross or micro-)

What usually exists in history?

Respiratory illness 5 days prior

How long does hematuria last?

Recurrent/persistent for years

What am I?

Post-strep GN

When did infection occur?

Respiratory – 10 days prior

Nephrotic or Nephritic Syndrome?

Nephritic

What happens with complement levels?

↓ acutely, ↑ as disease resolves

Where do the IC’s deposit?

Subepithelial

Note humps in SEM

* Totally made that all up.

*Little known fact: Famed televangelist Pat Robertson once called the Streptococcus genus “the evil genus” and suggested that his followers help him “Step on Strep” in a two-hour tirade. The blasphemy, he stated, partially came from the “humps” in the Scanning Electron Microscope view of post-streptococcal glomerulonephritis. The main reason for the source of evil, Robertson claimed, was that the actual name of the genus involved “coccus.” Inside sources claimed that he also did not approve of enterococcus.

What am I?

Goodpasture’s Syndrome

What is the pathophysiology?

Ab’s directed against BM

What is a related disease?Anti-GBM disease (no lung

involvement)

Rapid or progressive development?

Rapid

How is it treated?Plasmapheresis, corticosteroids,

immunosuppressants

What else do you need to remember?

Transplant patients with Alport Syndrome may develop Ab’s

against new collagen

What am I?

Amyloidosis

What is primary amyloidosis?

Light chains (mostly from multiple myeloma) – AL

Secondary?

Serum amyloid or other abnormal protein – AA

Nephritic or Nephrotic?Nephrotic

What stain do you use?

(Congo Red)

+(hint)

What am I?

Membranoproliferative GN

What is the pathophysiology?

Two words: Hep CWhat is the major microscopic

pathologic finding?

Cryoglobulins!

What clinical sign is easily visible?

Palpable purpura, possibly Nephrotic or Nephritic Synd.

And what happens with complement?

It stays persistently low

Are there sub-endothelial or sub-epithelial deposits?

Sub-endothelial

What am I?

HIV-Associated Nephropathy

What am I?

Membranous GN

Affects which population?

Caucasians over 40

Nephrotic or Nephritic Syndrome?

Nephrotic

What is the pathophysiology?

Immune-complex-mediated

Where do the IC’s deposit?

Subepithelial

Responsive to steroids?

No

What am I?

Pheochromocytoma

Hemorrhages present?

Yes, why else would I have asked that question?

* Totally made that all up.

*Little known fact: Pheochromocytomas derive their name from the character Pheo Huxtable (played by Malcolm-Jamal Warner), who played the son of actor Bill Cosby in the 80’s TV show “The Cosby Show.”

What am I?

Fanconi Syndrome

What type of light chain causes this?

Kappa (kills)

What’s special about these κ-LC?

They’re resistant to lysosomal degradation

What is the clinical presentation?

• B• U• T• G• A• P

icarbonaturia ricosuria

ubular proteinuria lucosuria minoaciduria hosphaturia

What type of RF can these create?

ATN

What am I?

Cast nephropathy

What type of light chain causes this?

Kappa (kills)

What’s special about these κ-LC?It has a special attraction to

Tamm-Horsfall proteins

↑ or ↓ cast nephropathy?

Characteristic ↑ or ↓

High pH ↓

High flow rate ↓

↑ tubular Ca2+ ↑

Infection ↑

NSAIDs ↑

??

??

????

??

What can this lead to?Tubular pressure → interstitial nephritis

Treatment?

Increase urine output, alkalize urine, and chemotherapy

What am I?

Amyloidosis

What form of amyloid will show from multiple myeloma?

Amyloid L

What is its special property?It is thermodynamically unstable

and unfolds easily

What are some of the special presentations for MM-related amyloidosis?

Hard liver, no retinopathy

How would you diagnose it?

Superficial abdominal fat bad biopsy, UPEP

What 2⁰ structure do the proteins create?

Β-pleated sheet

What is amyloid A?

A liver protein produced in response to inflammatory cytokines – it is

associated with chronic inflammation

…And amyloid Aβ2M?

A normally-present protein that accumulates in dialysis patients (in

joints, usually)

How do you treat it?

It’s tough… mostly treat the underlying symptoms; dialysis

What am I?

Multiple Myeloma

What cells proliferate?

B cells

What is needed for diagnosis?

Bone marrow generation of clonal plasma cells (10% BM), monoclonal protein in serum

What’s the clinical presentation?

CRAB – hyperCalcemia, Renal insufficiency, Anemia, Bone pain

Is monoclonal IgG always present in serum?

No, 10-20% only make light chains

Note that this can’t be detected by SPAP – a urine electrophoresis test

is required

What are the symptoms of this?Lethargy, confusion, polyuria, renal insufficiency

What am I?

Monoclonal Deposition Disease (MCDD)

What is the special property of this LC?

It induces change in other cells

What does this resemble?Diabetic nephropathy

Where are the deposits?Outer aspect of the basement

membrane of the tubules

What am I?

A kidney

What happens with the cortex?It is decreased in size

With benign nephrosclerosis

How often does it occur with HTN?

15% of the time

What happens to the arteries?

Hyaline arteriosclerosis or fibromuscular hyperplasia

What about the tubules and interstitium?

Tubules → atrophy, interstitial fibrosis

What am I?

Fibromuscular hyperplasia

What is that?

A proliferation of myointimal cells and deposition of collagen &

glycosaminoglycans

What am I?

Malignant hypertension

What is that?

A proliferation of myointimal cells leading to lumenal narrowing

What is present histologically in the kidney?

Necrotizing arteriolitis and fibrinoid necrosis

Necrotizing arteriolitis

Fibrinoid Necrosis

What does the kidney look like grossly?

It has pinpoint petechial hemorrhages due to ruptured

capillaries

Disease Light SEM IHCMinimal Change None Diffuse effacement of the

foot processes None

FSGS Not all glomeruli, focal mesangial hypercellularity

Diffuse effacement of the foot processes Mild IgM

Membranous GN Thickening of BM without hypercellularity

Subepithelial deposition of immune complexes

Granular Ig + complement present along BM

Membranoproliferative GN Lobular appearance, BM thickened, cellular prolif. Subendothelial deposits Granular deposition of IgG

and C3 along membranes

Post-streptococcal GN Crescentic glomerulitis with cellular proliferation

Humps, large subepithelial deposits Granular deposits along BM

Goodpasture’s Crescents, hypercellular glomeruli Breaks in BM Linear deposition on BM

Pauci-Immune GN Crescents, hypercellular glomeruli

Swollen endothelia, fibrin thrombi None

Chronic RF Advanced scarring, glomerular balls Dense collagen deposition N/A

Amyloidosis Congo red stains apple green Amyloid fibers N/A

Under the microscope

?? ?? ??

?? ?? ??

?? ?? ??

?? ?? ??

?? ?? ??

?? ?? ??

?? ?? ??

?? ?? ??

?? ?? ??

???? ??

??

??

????

Minimal Change Disease(Normal)

??

Membranous GN

Membranoproliferative GN

Match the definitionsPulmonary-renal vasculitic

syndrome

CRF

Rapidly-progressive GN

Asymptomatic proteinuriaAsymptomatic hematuriaIntermittent gross

hematuria

Microhematuria with the same characteristics as in the Nephritic Syndrome, but patient lacks the other features

Macrohematuria with the same characteristics as in the Nephritic Syndrome, but patient lacks the other features

Proteinuria without the additional features of the nephrotic syndrome

Relentless loss of renal function within weeks or months (creatinine doubles in < 3 months), may have either of the features 1 - 5

Vasculitis with involvement of the lungs and the kidney. Usually presents with hematuria.

Chronic kidney problems

Three immune mechanisms of glomerular Injury

1. Antibody-mediated injury2. Cell-mediated injury3. Activation of alternate complement pathway

Match the definitions

Diffuse

Focal

Global

SegmentalSubepithelialSubendothelial

Located between basement membrane and foot processes

Located between basement membrane and endothelial cell

Involving a portion of one glomerulus

Involving the entire glomerulusInvolving all of the glomeruliInvolving some of the glomeruli

Glomerulopathies – primary or secondary?

Disease 1⁰ 2⁰Polyarteritis

Goodpasture’sMembranous GN

Membranoproliferative GNDiabetes Mellitus

SLEFSGS

IgA NephropathyMinimal Change

Amyloidosis

What am I?

Waxy Cast

Present in Nephrotic or Nephritic Syndrome?

Nephrotic

Glomerulopathies – Nephrotic Syndrome (NoS) or Nephritic Syndrome (NiS)?

Disease NoS NiSMembranoproliferative

CrescenticMinimal Change

FSGSAcute Diffuse Proliferative

ProliferativeMembranous

Diabetic glomerulosclerosisAmyloidosis

(Can also be NiS)

(Can also be NoS)

(Can also be NiS)

Clinical Presentations – Nephrotic Syndrome (NoS) or Nephritic Syndrome (NiS)?

Sign/Symptom NoS NiSHematuria

HyperlipidemiaHyperalbumenemia

OliguriaEdema

HypoalbuminemiaPyuria

ProteinuriaAzotemia

Neither

How much? >3.5g/day

How much? <3gms/100mL

Lupus NephritisMain lab finding? ANA-positive

Mostly affects which population? Young womenWhat is the renal presentation? Can look like any glomerular

clinicopathologic syndromeWhat does it look like under the

light microscope?

What about IMF? “Full house” – all of them

Treatment? ACEI/ARB, Corticosteroids, immunosuppressants

Systemic VasculitesWhat do these have to do with

the kidney? They can result in a crescentic, pauci-immune GN

Name 3 of these diseases (there are actually 4) Wegener’s granulomatosis

Churg-StraussMicroscopic polyangitisIsolated pauci-immune GN

What size of vessels are affected? Small

What type of antibodies are present?

ANCA

What do ANCAs do? Activate neutrophils → vasculitis

Treatment? ACEI/ARB, Corticosteroids, immunosuppressants

ANCAWhat type of Ig is it? Usually IgG

What are the two types? Perinuclear ANCACytoplasmic ANCA

What does p-ANCA target? Myeloperoxidase, mainly

…and c-ANCA? Proteinase 3 (PR3)

Name three diseases and their associated ANCA 1. Wegener’s – c-ANCA

2. Microscopic polyangitis – p-ANCA3. Glomerulonephritis – p-ANCA

(Note: the diseases that contain the letter “p” have p-ANCA)

Are ANCAs pathogenic?

Yes

Wegener’s GranulomatosisWho’s it named after? Joe P. Granulomatosis

What’re the main clinical presentations? Chronic sinusitis

Oral/nasal mucosal ulcerationsArthralgiasNephritic syndrome

Main lab finding? ANCA-positive

What other vasculitis is similar? Microscopic polyangitis (the same thing, without granulomas)

– Kidding

What other vasculitis is similar? Isolated pauci-immune GN (same thing, just limited to kidney)

Henoch-Schönlen PurpuraWhat does it resemble? IgA Nephropathy

How is it different? ANCA–negativeSystemic vasculitis

Plasma CellsDo they make more heavy

chains or light chains? An excess of light chains

How can they lead to renal dysfunction (2)? Size

Special properties of AA sequence

Which is larger – IgG or Albumin? IgG

Are there light chains in the urine? Yes, someHow do they get cleared? They’re transported into the

tubules where they are degraded by lysosomes

Does a dipstick show light chains? No, its “protein” value only refers to albuminThen how do you verify their

presence? Urine electrophoresis

Small vessel vasculitis

ANCA-positive:

Granuloma present?

Yes No

Asthma and eosinophilia present?

Microscopic polyangiitis

Yes No

Churg-Strauss Syndrome

Wegener’s Granulomatosis

ANCA-negative

IgA-dominant immune deposit?

Yes No

Cryoglobulin present?

Yes No

Cryoglobulinemia Others, e.g., inflammatory bowel disease-asscoiated

vasculitis

Henoch-Schönleinpurpura

Primary AldosteronismWhat causes it? Nobody knows

What are the two types? Solitary adenomaBilateral hyperplasia

What are the three main findings? HTN, hypokalemia, metabolic alkalosis

What is the PAC/PRA ratio (↑/↓)? High (PAC ↑, PRA↓)

How do you confirm the diagnosis after obtaining a high ratio? Challenge ‘em with NaCl –

aldosterone should normally decrease in a high-salt diet

How would you treat the bilateral hyperplasia?

Spironolactone or eplerenone

PheochromocytomaWhich portion of the adrenal

gland is affected? The adrenal medulla

Where else can they appear? Sympathetic ganglia

What are the clinical symptoms? Triad: Sweating, headache, tachycardia (all episodic)

Is the HTN paroxysmal or sustained?

Yes – it depends on the patient

How is it diagnosed? Check the plasma metanephrines

What can throw off metanephrine levels? Drugs, alcohol, physical stress

SBP mmHg DBP mmHg

<120 and <80

120-139 or 80-89

140-159 or 90-99

≥ 160 or ≥100

NormalNormal

PrehypertensionPrehypertension

Stage 1 HTNStage 1 HTN

Stage 2 HTNStage 2 HTN

Blood Pressure ClassificationWhat happens to systolic BP

with age? To diastolic?Systolic increases, diastolic decreases

How does each one respond to vascular stiffness and

resistance?↑R, ↑Stiffness = ↑SBP↑R, ↓Stiffness = ↑DBP

What does a hypertensive headache feel like?

There is no proven link between HTN and headaches

Renovascular HTNWhat is the cause of renovascular HTN?

Renal artery stenosis → renal ischemia

What are the 2 clinical presentations?

Atherosclerosis (men), fibromuscular dysplasia (women)

Which portions of the renal artery are affected for each?

Athero. = proximal 2cm, FMD = distal /branches

Which group is younger? FMD (younger women)

Does this cause an acute or insidious rise in BP?

Acute

What’s the treatment?Anti-hypertensives or percutaneous angioplasty (not ACEI/ARB)

HypertensionHow can CKD lead to hypertension?

↓ GFR → ↑ Na retention; ↑ peripheral resistance

What is the recommended treatment?

ACEI or ARB, of course (not if patient has renal stenosis, though)

What is GRA (glucocorticoid-remediable aldosteronism)?

Familial hyperaldosterism type I (a rare AD disorder)

What age patient gets it? Younger (<21 usually)

What’s the treatment? Glucocorticoids

What’s the pathophysiology?Genetic mutation causes ACTH-dependent formation of aldo in the zona fasciculata

Apparent Mineralocorticoid Excess Syndromes

Which age group is generally affected?

Juvenile (it’s an AR disorder)

What is the pathophysiology?

Deficiency in 11-β hydroxysteroid dehydrogenase type II

What happens to the serum potassium level?

It decreases, also giving a metabolic alkalosis

And the plasma aldosterone? Low

What about the urinary free cortisol to cortisone ratio?

Very high (10x normal)

What’s the therapy?Mineralocorticoid blockade, Na-channel block, dexamethasone

Adrenal gland Which region produces

aldosterone?

What about people with GRA?

Which region produces cortisol?

How is ATII related to all this?

ATII stimulates aldosterone

synthase in ZG

What enzyme creates cortisol?

11-β-hydroxylase

Would renin be ↑ or ↓?

Decreased

How is it diagnosed?

Test the effects of Dexamethasone

(which suppresses ACTH)

Hypertension – label the lines

Control

ACE Inhibition

Angiotensin II

What are the three ways ATII raises BP?

1. Smooth muscle cell proliferation

2. Aldosterone release, sodium reabsorption

3. Direct vasoconstriction

What is the effect of ATII on NO (2)?

1. ATII → AT2R → ↑NO2. ATII → ↑O2

- → ↓NO

ACE Inhibitors

Thiazides

Hypertension Drugs

Hypo- or hyperkalemia? HypokalemiaHypo- or hyperuricemia? HyperuricemiaHypo- or hypernatremia? Hyponatremia↑ or ↓ Ca2+ reabsorption? Increased

Hypo- or hyperkalemia? HyperkalemiaContraindications? Pregnancy, renal stenosisMech. of action? Blocks (ATI → ATII) enzyme↑ or ↓ GFR? Decreased

Angiotensin-Receptor Blockers

Aldosterone-receptor blockers

Hypertension Drugs

Hypo- or hyperkalemia? Hyperkalemia↑ or ↓ triglycerides? HypertriglyceridemiaHypo- or hypernatremia? HyponatremiaTwo main drugs Spironolactone

Eplerenone

Hypo- or hyperkalemia? HyperkalemiaContraindications? Pregnancy, renal stenosisMech. of action? Blocks AT1 receptor↑ or ↓ GFR? Decreased

HypertensionIf you had normal BP at 55, how likely is it that will you have normal BP the rest of your life?

10% chance (!)

What percentage of adults in the US have hypertension?

46% (well, 22% pre-hypertensive + 24% hypertensive)

What percentage of adults with HTN are actually treated?

60%

And what percentage are controlled? 33%

What is the pathologic hallmark of uncontrolled HTN?

Accelerated atherosclerosis

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

With Compelling Indications

Lifestyle Modifications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist.

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, or combination.

Without Compelling Indications

?? ?? ??

Algorithm for Treatment of Hypertension

Churg-Strauss SyndromeNephritic or Nephrotic? Nephritic

What’re the main clinical presentations? Worsening asthma

RashPeripheral nephropathyGastroenteritis

Main lab finding? ANCA-positive

What special finding is visible on biopsy?

Eosinophilia

What am I?

+ O +A cryogoblin, obviously

(nerd)

Hypersensitivities• Type I

– Delayed or immediate?– Mediated by what Ig?

• Example ?

• Type II– What is it?

• Example?• Type III

– Involves what two factors?

• Type IV– Delayed or immediate?– Involves what cells?

– Example?

• Type I – Immediate– IgE

– Pollen binds to IgE on mast cells and immediately releases histamine/inflammatory mediators leading to rhinitis / asthma

• Type II– Ab directed to Ag’s on your own cells

• Anti-GBM• Type III

– Immune complex deposition and complement activation

• Type IV– Delayed– T cells stimulated by antigen release

cytokines due to prior exposure• Interstitial nephritis

Type Benign or malignant?Wilms tumor Malignant

Angiomyolypoma BenignReninoma Benign

Oncocytoma BenignRCC Malignant

Adenoma BenignTransitional carcinoma Malignant

Lymphoma MalignantHemangioma Benign

Tumors of the kidney

What am I?How do you know (3)?

Simple cyst1. Anechoic (black)2. Smooth-walled

3. Posterior enhancement

What’s the treatment?Just observation

What am I?

Type Characteristics

TYPE 2 Thickwalled / Border forming calcification

TYPE 4 Solid and cystic areas

TYPE 3 Sepatations/ non border forming calcifications

TYPE 1 Simple cyst

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Cysts

Benign tumorsRenal adenoma

Epithelial

Oncocytoma

Angiomyolipoma

Tissue type?

Treatment? Observe if <3cm, otherwise excise or ablate

Defining feature in CT? Stellate central scar

Looks similar to…? Renal Cell Carcinoma

Well-defined or diffuse edges? Well-defined

Treatment Excision

Made of…? Fat, muscle, vascular tissue

Associated with…? Tubular sclerosis

Stereotypical patient? Female with massive hematuria and bilateral solid masses

What am I?

Renal Cell Carcinoma

More common in men or women?

Men (2:1), usually ~40-50 years old

Can it be familial?Yes, and don’t smoke.

What are the main originating cells?Clear cells of the proximal CT

What are the top 4 presentations?Hematuria, constitutional, anemia,

flank pain

Staging Characteristics

T1b Tumor of 5cm (between 4 and 7cm)

T3a Tumor invading the renal vein

T2 Tumor of 12cm (more than 7cm)

T1a Tumor of 1cm (less than 4cm)

T3c Tumor invading the right atrium

T3b Tumor invading the IVC at the renal vein

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Renal Cell CarcinomaParaneoplastic conditions

Hypercalcemia (specific)1. PTH →

2. Renin → Hypertension (specific)

3. EPO → Anemia (non-specific), erythrocytosis (specific)

Also…? Diabetes (specific)

Cushings (specific)

ESR, Hepatic dysfunction, fever, neuropathy (non-specific)

Treatment? Radical/partial nephrectomy

Most common locations of metastasis?

Lungs, liver, adrenal glands, brain

Treatment of metastases? Surgical excision, immunotherapy

Urinary system anatomyWhat separates the upper

urinary tract from the lower?

The vesicoureteral junction

Who has a higher resistance to flow – men or women? Men

Does the PS or symp. nerv. system innervate the lower UT?

Both

What type of muscle is in the internal sphincter? Smooth muscle

What does the detrusor muscle do?

Empties the bladder

What level of the spinal cord does the pudendal come from?

S2 – S4

What about the pelvic nerve? S2 – S4

What nerve is responsible for voluntary urine control? Pudendal

What type of receptors are responsible for bladder contraction? M2, M3

What type of receptors are responsible for pelvic floor contraction?

nAChR

Will an α-agonist promote urinary retention or voiding?

Retention

Would a β2-blocker promote urinary retention or voiding?

Voiding

What do the pelvic nerves innervate? The bladder

Voiding Dysfunction – describe3. Static/dynamic retention – often due to BPH

1. Stress incontinence – due to weak pelvic floor muscles

2. Urge incontinence – due spastic/overactive bladder muscles

4. Inactive bladder muscles – often due to nerve damage (S2 – S4)What types of therapies can help?

Kiegel exercises, α-agonists

Anti-muscarinic agents (oxybutynin, tolterodine), Botox

Cytoscopy, urinalysis, α-blockers, prostate therapy (α1-antagonists, 5-α-reductase inhibitors)

Repair damage if possible, otherwise intermittent catheterization

Urodynamics – name the condition

Pressure

Flow

1. Urge incontinence

2. Stress incontinence

3. Obstruction

4. Non-functioning bladder

Pressure

Volume

Pressure

Volume

Leak

Abdominal Strain

Is there a correlation between absolute levels of BUN & Cr and

the development of uremic symptoms?

No

BPHWhat is the most common

region for BPH?The transition zone

What about prostate cancer?The peripheral zone

What’s the difference between clinical and histological BPH?

Clinical BPH has LUTS & BOO in addition to

enlargement of the prostate

*LUTS = Lower Urinary Tract Symptoms; BOO = Bladder Outlet Obstruction

Will prostate removal relieve irritative symptoms?

(Reference to Kazakhstan BPH autopsy study)

Probably not; the long-standing bladder

dysfunction → OAB regardless of BOO

What else will prostate surgery do?

Retrograde ejaculation 80% of the time

What’s the point of an AUA questionnaire?

It helps to quantify the amount of LUTS

Sorry – I can’t stop thinking about how horrible retrograde

ejaculation must be

BPHWhat’s flomax?An α1a-specific antagonist

What happens to the prostate with age?

It steadily increases in size

What does a 5-α-reductase inhibitor do?

Decreases the conversion of testosterone → DHT, reducing

prostate enlargement

What’s the quickest accurate way to measure prostate size?

(Reference to Kazakhstan BPH autopsy study)

Ultrasound is preferred

What’s terazosin?An α1-specific antagonist

Why wouldn’t you use a 5-α-R inhibitor with an α-blocker?

Cuz you’re an idiot. I would use a combination therapy like that if it was required.

PTH

1

2 3

Off-topic… does anemia occur early or late in renal disease?

Early!

Does Vitamin D increase or decrease serum [Ca2+]?

Increases it

Name three functions of Vitamin D with respect to calcium (hint: bones, small intestine, kidney)

Bone: increases Ca (and PO) releaseSI: Increases Ca absorptionKidney: Decreases Ca excretion

Which rises with CKD – serum phosphate or serum Ca?

Phosphate – keep in mind that increased serum phosphate corresponds with increased mortality

How does the body respond to an elevated serum phosphate level?

It increases its release of PTH

How can an elevated PTH affect the bones? What disease does it lead to?

Osteitis Fibrosa Cystica

How can that be prevented?

Decrease serum phosphorous – dietary restriction, Vitamin D supplementation, and phosphate binders

Overactive Bladder Symptoms

One or more symptoms:– Frequency (>8 micturitions/24 hours; Nocturia >2

times)– Urgency (Strong desire to void at low bladder

volumes)– Urge incontinence (Strong desire to void plus

involuntary urine loss)

How many people with OAB have incontinence?– 57%

Erectile Dysfunction

What is the prevalence of sexual dysfunction?

52% of males, 43% of females

What’re the most common male/female

complaint?

Premature ejaculation (men), no interest

(women)What’re the three key points in the definition of erectile dysfunction?

Sufficient rigidity & duration for satisfactory

sexual relationsIs the tunica albuginia deep or shallow to the

deep dorsal vein?

Deep – remember the emissary veins run

through the t.a.

How does the penis stay rigid during an

erection?

Blood cannot leave due to the compression of

the emissary veins

How does NO play a role in erections?

NO activates GC which converts GTP → cGMP → smooth muscle relax

How does sildenafil (Viagra) work?

It inhibits PDE5, which normally degrades

cGMP

What person is most likely to have ED?

An old, diabetic, hypertensive, hypercholesterolemic, depressed, low-testosterone smoker on a ton

of medications for his heart diseaseIf a patient has ED,

what can it signify?

Vascular disease, malignancy, diabetes,

depressionWhat percent of

patients with ED have low testosterone?

Only 6%

What symptoms would suggest a psychogenic erectile dysfunction?

Sudden onset, specific situation, normal nocturnal erections,

relationship problems, sexual development problems

What drug is contraindicated with

PDE5 inhibitors?

Nitroglycerine!

Prostate Where are most of the glands?Where does BPH occur?

What is felt in a digital rectal exam?

How many men will be diagnosed with

prostate cancer?1/6

Prostate cancerWhere is PSA usually found? It is secreted by the prostate

into the semen

What is it? Prostate-Specific Antigen; a serine protease

Is it more specific or sensitive of a test?

More sensitive, less specific

What are your chances of having prostate cancer with a PSA of 15?

>50%

What else could you measure? Percent Free PSA

Who should be screened (3)? Men > 50, AA Men > 40, family history >40

How is the diagnosis performed? Rectal biopsy of prostate

How is prostate cancer staged (3)? Gleason score, PSA, digital exam

To where does it like to spread? LN, bone, local extension

Prostate cancerWhat happens when it metastasizes to bone?

It produces osteoblastic activity in the bone

What’s the prognosis for a T2 tumor?

Potentially curable

What about a T3? Probably uncurable

What are the 3 treatment options? Radical prostatectomy, radiation therapy, watchful waiting

How would metastatic PC be treated? Androgen deprivation therapy – not a cure

What does castration accomplish? Decreases testosterone formation → ↓ proliferation of some cancer cells

What is the main side effect? Hot flashes

Prostate cancerIs there a genetic component? Yes – 10% of cases 1q24-25

Monoclonal or polyclonal? Polyclonal

Where is the first spread of the cancer, usually? Hematogenous → bone

How many layers in the glands of an adenocarcinoma? One

Which Gleason grade is highly-differentiated? Low score (~1)

Which Gleason score is the cutoff for a good prognosis and a bad? 6 (>6 = bad, ≤6 = good)

What are two microscopic features of malignancy?

Perineural and capsular invasion

What test would verify the presence of a malignant lymphoma? CD20 IHC

Type Cell origin Assoc. gene

Conventional RCC Proximal CT VHL

Papillary RCC Distal part of PCT c-MET

Chromophobe RCC Intercalated cells

Collecting Duct Carc Collecting duct

Medullary Carc Collecting duct

Oncocytoma Intercalated cells

Renal Cell Neoplasms1. More common – familial or sporadic?2. Appearance of cytoplasm?3. Papillary or non-papillary in appearance?4. Associated with what disease?5. VHL gene performs what function?6. Treatment?

1. Sporadic2. Granular or clear3. Non-papillary4. Von-Hippel Lindau Syn.5. Suppressor gene6. Tyrosine Kinase Inhibitors

1. What is the center of the pap. structure?2. Function of c-MET?3. Treatment?

1. Fibromuscular core2. Oncogene3. Tyrosine Kinase Inhibitors

1. Prognosis?2. Looks similar to what other neoplasm?

1. Excellent2. Oncocytoma

1. What marker is associated with this?2. Slow-growing or aggressive?3. Similar to what other carcinoma?

1. LMW and HMW keratin2. Aggressive3. Urothelial carcinoma

1. Associated with what disease?2. Slow-growing or aggressive?

1. Sickle cell trait2. Aggressive

1. Arises from what tissue type?2. Main macroscopic feature?3. Comprises what percent of all renal

neoplasms?

1. Epithelial2. Stellate central scar3. 5%

ProstatitisMost common cause of acute? E. coli

PMNs or lymphocytes? PMNs = acute

Most common cause of chronic?

Abacterial > E. coli

BPHWhich portions undergo hyperplasia? All of them

Physically, what is the first symptom? Compression of the urethra

How many layers are present in the glands? Two

What is the main gross feature?

Nodules

Bladder cancerMore frequent in men or women? Men

Associated with what disease? Schistosomiasis

Is there a genetic component? Yes, in some cases

Associated with smoking? Of course

What do transitional cell carcinomas look like macroscopically? Papillary or flat

What is the prognosis for a grade I urothelial carcinoma? Very good – it’s seldom invasive

What do they look like microscopically?

Pretty much the same as normal transitional epithelium

Where do high-grade carcinomas metastasize to?

Lymph nodes

Which type of bladder cancer is associated with schistosomiasis?

Squamous cell carcinoma of the bladder

Which is more common – urothelial carcinoma or adenocarcinoma of the bladder?

Urothelial carcinoma

What am I?

AD Polycystic Kidney Disease

What is the pathophysiology?

Two-hit hypothesis → fluid movement, cell prolif, BM

What are the main associated renal findings (4)?

HTN, infection, hematuria, ESRD

Who is the stereotypical patient?

AA man with HTN & hematuria before 35yo

What are the main associated extra-renal findings (3)?

Liver cysts, MV prolapse, Berry aneurysms

Which tubules are affected?

All of themWhat imaging technique is

used for diagnosis?

Ultrasound, CT

How many cysts are required for diagnosis?

15-29 yo: 2 cysts in one/both kidneys30-59 yo: 2 cysts in each kidneys

> 60yo: 4 cysts in each kidney

Uni- or bilateral?Always bilateral

Develop early or late in life?Later in life

What is the most commonly responsible gene? PKD1 (16p13.3)

Main cause of deathCVD > Other/infection

What am I?

AR Polycystic Kidney Disease

What is the pathophysiology?

In utero: fusiform dilation of tubules

Are the kidneys large or small?

Large

Is this a systemic disease?No

What do the cysts look like?Elongated and radially distributed

(perpendicular to the cortex)

What happens to the liver?

Which tubules are affected?

Just the collecting ducts

How do the infants die?Pulmonary hypoplasia →

respiratory failure

Portal fibrosis

What shape do the kidneys develop into ?

(They’re the normal bean shape)

Cystic kidney diseasesWhat is the incidence of MSK? 1:200 (common!)

Usual presentation of MSK Asympt > hematuria, RTA, stones

Prognosis of MCD? Will progress to ESRD

Presentation of MCD? Uremia in 2nd/3rd decade, gout, sodium wasting

What’s the genetic basis of AS? X-linked > AR, AD

Pathophysiology of AS? Disorder of collagen IV (BM type)Renal consequences of AS? Microhematuria → proteinuria

& HTN → ESRD

Non-renal consequences of AS? Deafness, ocular defects, leiomyocytosis of esophagus

MSK = Medullary Sponge Kidney MCD = Medullary Cystic DiseaseAS = Alport Syndrome

How do you diagnose AS? Biopsy → IHC for collagen type IV α chains (NEGATIVE)

What is the treatment for AS?

Transplantation

But…

You can develop AGBM disease from the new collagen

What am I?

Wilms’ Tumor

Off-topic: What is the most common benign renal tumor?

Congenital mesoblastic nephromaWhat is the histologic precursor

to Wilms’ Tumor?Nephrogenic rests

How old are patients diagnosed?Between 2 and 5yo

Arises from what tissue?

Primitive blastema

Unilateral or bilateral?

Both (bilateral 5-10%)

Whats a stage I? Stage V?I = intact capsule (epithelial) ; V

= bilateral

Treatment?

Chemotherapy

What’s an anaplastic Wilms’ tumor?

A highly responsive version with underlying p53 mutations

Which three syndromes are associated with WT?

WAGR, Denys-Drash, and Beckwith-Wiedemann

Type Age of onset Uni- or bilateral?Wilms tumor 2-5 Uni > Bi

AD PKD Later in life BiAR PKD Birth – juvenile Bi

Renal agenesis In utero BiRenal hypoplasia In utero Uni > BiCystic Renal Dysp In utero Both

Congenital Tumors of the kidney