USMLE Step 1 Review

James Paparello, M.D.

Department of Nephrology

Northwestern University

Email: JPaparello@nmff.org

Renal Physiology and Tubular function

Body Water50-60 % of body weight

Total Body Water

Intracellular Water Extracellular Water (2/3 total body water) (1/3 total body water)

Intravascular(1/4) Extravascular (3/4) (Plasma)

Body Water Calculation

Body Weight = 70 kg (154 lbs)

Total Body Water (TBW) = 60 % of Weight = 42 Kg• Intracellular Water = 2/3 of TBW = 28 Kg• Extracellular Water (ECV) = 1/3 of TBW = 14 Kg

– Extravascular water = ¾ of ECV = 10.5 Kg– Intravascular water = ¼ of ECV = 3.5 Kg = Plasma water

Blood Volume = Plasma Water/(1 – Hct) = 6.4 Kg (assign Hct of .45)

First Aid:

• TBW = ICF + ECF• 60 – 40 – 20 rule (% of Total body

weight)

Inulin

• ECF = Plasma volume + Interstitial volume¼ ¾

Albumin

Edema

Two requirements:• Alteration in capillary hemodynamics favoring movement of fluid out of

vascular space (into interstitium)

• Renal retention of Na+ and water

Starling’s Law:

LpS[(Pcap – Pif) – σ(πcap – πif)]

Lp = porosity, S = surface area, σ = reflection coefficient of proteins

Differences are between hydrostatic and oncotic pressures (capillary and interstitial)

Capillary Fluid Exchange

Filtration pressure = LpS[(Pcap – Pif) – σ(πcap – πif)]

Increased Pcap: Heart failure

Decreased πcap: Nephrotic syndrome, liver failure

Increased Capillary permeability (Kf = LpS): infections, toxins, burns

Increased πif : Lymphatic blockage

Remember:

• The glomerulus is a specialized capillary network:

• GFR = Kf [(Pgcap – Pbowman) – σ(πgcap – πbowman)]

Remember:

• The glomerulus is a specialized capillary network:

• GFR = Kf [(Pgcap – Pbowman) – σ(πgcap – πbowman)]

• GFR = Amount excreted = Urine concentration x V

Plasma conc. Plasma conc.

GFR calculation

GFR = Uinulin x V/Pinulin = Cinulin

We use creatinine instead of inulin (only a small amount of creatinine is secreted)

Normal GFR ~ 120 cc/min

Clearance Calculations

Px * Cx = Ux * V

Cx = (Ux * V)/Px

If Cx < GFR, then tubular reabsorption of x

If Cx > GFR, then tubular secretion of x

If Cx = GFR (e.g. inulin), there is not net absorption or secretion

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You develop a drug that blocks tubular reuptake of urea. What happens to urea clearance ?

1 2 3

0% 0%0%

1. It increases

2. It decreases

3. No change, as the GFR does not change

Glucose Clearance

• At plasma glucose of > 200-300 mg/dl, tubular reabsorption is saturated, and glycosuria occurs.– Tm = maximal transport (for glucose, reabsorption) of a

solute.

– If glycosuria, blood sugar concentration > 200, so patient may have diabetes.

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Plamsa Glucose: 95 mg/dL

Filtered glucose = 95

Reabsorbed Glucose = 95

Glucose in urine = 0

Plamsa Glucose: 375 mg/dL

Filtered glucose = 375

If max tubular absorption is 200 mg/dL:

Reabsorbed Glucose = 200

Glucose in urine = 175

Clearance of Free Water

• CH2O = V – Cosm

• V = urine flow rate

• Cosm = (Uosm * V)/Posm

– So if CH2O is positive, the kidney is excreting free water (dilute urine)

– If CH2O is negative, the kidney is retaining free H2O (excreting concentrated urine)

Renal Plasma Flow

Renal plasma flow = Plasma flow glomerulus + plasma flow tubules

PAH is actively secreted by the tubules, so PAH in the blood that does not go through the glomerulus (1 – FF = 0.8) is cleared by tubular excretion. Therefore, PAH clearance accounts for both blood through the glomerulus (FF) and the blood through the tubules.

Therefore: Effective renal plasma flow = (UPAH * V)/PPAH

Renal Blood Flow = Renal Plasma Flow/(1 – HCT)

Filtration Fraction

Fraction of the material that enters the kidney and is filtered (normally 0.20)

FF = GFR/RPF = 120/600 = 0.2

Netter, Atlas of Human Anatomy, 1989, Plate 322

Renal Hemodynamics

Glomerular Filtration Barrier

Three components:

1) Fenestrated Capillary Endothelium (size barrier)

2) Fused basement membrane with heparan sulfate (negative charge barrier)

3) Epithelial layer consisting of podocyte foot processes

Afferent/Efferent Hemodynamics

Glomerulus with capillary loops surrounded by Bowman’s space

Afferent Arteriole Efferent Arteriole

Blood Flow

Proximal Tubule (continuation of urinary space)

Afferent/Efferent Hemodynamics:Dilation of Afferent Artery

Glomerulus with capillary loops surrounded by Bowman’s space

Afferent Arteriole Efferent Arteriole

Blood Flow

Proximal Tubule (continuation of urinary space)

Renal Hemodynamics

Renal Hemodynamics

Dilation of Afferent Artery

• Caused by:– Prostaglandins

• Physiologic Changes Glomerular capillary pressure Nephron Plasma Flow, GFR

Filtration fraction:Afferent Artery Dilation

GFR So min. change in FF.

RPF

Afferent/Efferent Hemodynamics: Constriction of Afferent Artery

Glomerulus with capillary loops surrounded by Bowman’s space

Afferent Arteriole Efferent Arteriole

Blood Flow

Proximal Tubule (continuation of urinary space)

Renal Hemodynamics

Renal Hemodynamics

Constriction of Afferent Artery

• Caused by – NSAIDs (decrease prostaglandin production)

• Physiologic results: Glomerular capillary pressure Nephron plasma flow, GFR

N.B. Afferent arteriolar changes happen before the glomerulus, so no change in filtration fraction.

Filtration fraction:Afferent Arteriole Constriction

GFR So no change in FF

RPF

Afferent/Efferent Hemodynamics:Efferent Arteriole Dilation

Glomerulus with capillary loops surrounded by Bowman’s space

Afferent Arteriole Efferent Arteriole

Blood Flow

Proximal Tubule (continuation of urinary space)

Renal Hemodynamics

Renal Hemodynamics

Efferent Arteriole Dilation

• Caused by:– ACE-I, ARB

• Physiologic results: Glomerular capillary pressure Nephron Plasma flow, but GFR ( **N.B.

Decreases filtration fraction)

Filtration fraction:

GFR So filtration fraction decreases.

RPF

Afferent/Efferent Hemodynamics:Efferent Arteriole Constriction

Glomerulus with capillary loops surrounded by Bowman’s space

Afferent Arteriole Efferent Arteriole

Blood Flow

Proximal Tubule (continuation of urinary space)

Renal Hemodynamics

Renal Hemodynamics

Efferent Arteriole Constriction

• Caused by:– Angiotensin II

• Physiologic results: Glomerular capillary pressure Nephron Plasma flow, but GFR ( **N.B.

Increases filtration fraction)

Filtration fraction:

GFR so increased FF

RPF

N.B. efferent arteriole changes cause opposite effects on GFR and RPF

Which of the following would be expected to result in an increase in GFR soon after administration ?

1 2 3 4

0% 0%0%0%

1. ACE-Inhibitors

2. Angiotensin receptor blockers

3. Non-steroidal anti-inflammatory medications

4. Prostaglandins

Other Changes in Renal Function

GFR FF(GFR/RPF)

Increased Plasma Protein (πgcap)

Decreased Plasma Protein (πgcap)

Ureteral Blockage

Note: None of the above change RPF, hence FF goes in the direction of the GFR

Remember:

• The glomerulus is a specialized capillary network:

• GFR = Kf [(Pgcap – Pbowman) – σ(πgcap – πbowman)]

• GFR = Amount excreted = Urine concentration x V

Plasma conc. Plasma conc.

Tubular Function

Renal Sodium Handling

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Proximal Tubule Cell(Figure from Up to Date, ed. B.D. Rose)

Renal Sodium Handling

Proximal Tubule Cell

Proximal Tubule Diuretic

• Acetazolamide inhibits carbonic anhydrase

• Carbonic Anhydrase promotes the absorption of sodium with bicarbonate

• Inhibiting carbonic anhydrase causes less sodium reabsorption and less bicarbonate reabsorption/H+ secretion

Proximal Tubule Cell

Acetazolamide

• Causes less Bicarbonate absorption (less H+ excretion)

• Less Sodium absorption (sodium absorbed by H+/Na+ antiport)

Acetazolamide

• Although works in the proximal tubule, it is a weak diuretic (the rest of the nephron can compensate for the sodium being lost)

• Can cause a non-gap acidosis– The A in DURHAM

• Used to treat metabolic alkalosis, particularly if volume overloaded

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Thick Ascending Limb Cell(Figure from Up to Date, ed. B.D. Rose)

Renal Sodium Handling

Thick Ascending Limb Cell(Figure from Up to Date, ed. B.D. Rose)

Diuretics: Loop

• Agents: Furosemide (Lasix), Torsemide (Demadex), Bumetanide (Bumex)

• Inhibit the Na+-K+-2Cl- symporter in the thick ascending limb of the loop of Henle.

• Side effects: Fluid and electrolyte imbalances, volume depletion, ototoxicity, hyperuricemia, hyperglycemia, increased LDL and triglycerides

• Used for volume overload (rapid diuresis). Used for HTN particularly in chronic kidney disease. Can also be used with normal saline to treat hypercalcemia.

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Distal Convoluted Tubule Cell(Figure from Up to Date, ed. B.D. Rose)

Renal Sodium Handling

Distal Convoluted Tubule Cell(Figure from Up to Date, ed. B.D. Rose)

Distal Convoluted Tubule Cell(Figure from Up to Date, ed. B.D. Rose)

Diuretics: Distal Convoluted Tubule

• Class often called Thiazides because hydrochlorothiazide is the most well known and recognized– Hydrochlorothiazide (HCTZ), Chlorthalidone, Metolazone

• Inhibit the Na – Cl symporter in the distal convoluted tubule.

• Side effects: Impotence, fluid and electrolyte imbalances, impaired glucose tolerance, and increased cholesterol

• Used to treat hypertension. Also can be used to reduce the risk of kidney stones in patients with hypercalciuria

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Principal Cell (Collecting tubule)(Figure from Up to Date, ed. B.D. Rose)

Renal Sodium Handling

Principal Cell (Collecting tubule)(Figure from Up to Date, ed. B.D. Rose)

This cell also has luminal water channels mediated by a basal V2 receptor (ADH receptor)

Note, the more sodium delivered here, the more K+ excretion

Principal Cell : Effect of Aldosterone

(Figure from Up to Date, ed. B.D. Rose)

Principal Cell: Spironolactone(Figure from Up to Date, ed. B.D. Rose)

Principal Cell: Spironolactone(Figure from Up to Date, ed. B.D. Rose)

Principal Cell: Amiloride(Figure from Up to Date, ed. B.D. Rose)

Principal Cell: Amiloride(Figure from Up to Date, ed. B.D. Rose)

Diuretics: K+ Sparing

• Agents: Triamterene, Amiloride, Spironolactone, Eplerenone

• Mechanism:– Triamterene and Amiloride inhibit renal epithelial Na+ channels in

the late distal tubule and collecting duct. – Spironolactone and Eplerenone antagonize the mineralocorticoid

receptor on epithelial calls in the late distal tubule and cortical collecting duct.

• Side effects: – Amiloride and Triamterene: Hyperkalemia, nausea, vomiting– Spironolactone: Hyperkalemia, gynecomastia

• Adjunctive treatments with diuretics to avoid hypokalemia. Use caution if at risk for hyperkalemia.

Which diuretic causes the most sodium loss after one dose ?

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0% 0%0%0%

1. Acetazolamide

2. Thiazide

3. Loop (e.g. furosemide)

4. Potassium sparing (e.g. amiloride)

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Juxtaglomerular Appartus(Figure Taken from Up to Date, ed. By B.D. Rose)

Renin Angiotensin System (RAS)

Angiotensinogen

Renin

Angiotensin I

Angiotensin Converting Enzyme

Angiotensin II

Via Aldosterone

Sympathetic Activation Na/H2O Retention

Smooth Muscle Vasoconstriction Decreased Bradykinin

Adapted from Lippincott’s Illustrated Reviews: Pharmacology, 1992. P. 382.

RAS (Med Study)

1. Potent Vasoconstriction (A-II)

2. Aldosterone release

3. ADH release from posterior pituitary

4. Increased thirst (dipsogenic)

Renal Syndromes and Path

Light E.M.(From Up to Date)

Renal Path:Segmental and Global

No lesion Segemental lesions Global

Renal Path:Focal and Diffuse

Normal Focal Diffuse

< 50 % > 50 %

Crescent

Light E.M.(From Up to Date)

Renal Syndromes

Glomerular Tubular Uncertain Interstitial Diseases Asymptomatic U/A Findings

Nephrotic: Nephritic:Minimal Change Disease Immune complex mediatedFSGS Anti-GBM DiseaseMembranous Pauci-Immune(Diabetes, SLE)

Always look for underlying systemic disease (e.g. diabetes, paraproteinemia, vasculitis)Realize the disease can be acute (RPGN) or chronic

Nephritis

Nephritic Syndrome: Hematuria (glomerular), usually mild proteinuria, and hypertension

Classification of Glomerulonephritis

Immune Complex Pauci-Immune

IgA ANCA

SLE Wegner’s

PIGN Anti-GBM MPA

Churg-Straus

A 25 yo Japanese male comes to the office noticing his urine is darker, with a “rust” color. He has had a recent upper respiratory

infrection. He notes this has happened to him before. His urinalysis is notable for blood and protein in his urine.

1 2 3 4 5

0% 0% 0%0%0%

1. Lupus

2. PIGN

3. IgA nephropathy

4. Focal Segmental Glomerulosclerosis

5. Membranous GN

Renal Syndromes

Glomerular Tubular Uncertain Interstitial Diseases Asymptomatic U/A Findings

Nephrotic: Nephritic:Minimal Change Disease Immune complex mediatedFSGS Anti-GBM DiseaseMembranous Pauci-Immune(Diabetes, SLE)

Always look for underlying systemic disease (e.g. diabetes, paraproteinemia, vasculitis)Realize the disease can be acute (RPGN) or chronic

Nephrotic Syndrome

• > 3.5 gm protein/day

• Severe edema

• Hypoalbuminemia

• Hyperlipidemia

• Lipiduria

Nephrotic Syndrome

• Minimal Change Disease

• FSGS

• Membranous

• Amyloidosis

• Diabetes

0

20

40

60

80

100

120

0 5 16 35 55 100

MCDz

AMYLOID

DIABETES

MPGN

Other GN

FSGS

MEM

Approximate Frequency of Causes for Nephrotic Syndrome

Age

Acute Renal Failure/Oliguria

“ … a deterioration of renal function over a period of hours to days, resulting in the failure of the kidney to excrete nitrogenous waste products and to maintain fluid and electrolyte homeostasis.”

Rise in Serum Creatinine > 0.5 mg/dl over baseline

Etiology of Acute Renal Failure/Oliguria

Acute Renal Failure

Prerenal Intrinsic Postrenal

~ 70 % ~ 25 % ~ 5 %

Intrinsic Renal Failure

Intrinsic Causes

Tubular Interstitial Acute Necrosis Nephritis GN (10 %) (5 %)

Ischemia Toxins (50 %) (35 %)

NEJM Vol. 334, # 22 p. 1449 Fig. 1

Urinary Indices

Condition Prerenal ATN AGN Obs

U Osm > 500 <350 300-500+ 300-500*

U Na < 20 > 40 < 40 > 40

FE Na < 1 > 1 < 1 > 1

Cast formationCornell Website

Acid/Base

1. Determine pH status (alkalemia or acidemia)-Blood pH < 7.36 is acidemia, blood pH > 7.44 is alkalemia

2. Determine if primary process is respiratory or metabolic (or both)-Alkalosis: Respiratory if pCO2 is < 40, metabolic if HCO3 is > 25-Acidosis: Respiratory if pCO2 > 40, metabolic if HCO3 is < 25

3. Calculate Anion Gap [Na – (Cl +HCO3)]4. Check degree of compensation

Metabolic Acidosis: Decrease in pCO2 = 1.3 x decrease in bicarbonateMetabolic Alkalosis: Increase in pCO2 = 0.6 x increase in bicarbonateRespiratory Acidosis, Acute: Increase in 10 mmHG pCO2, increase HCO3 by 1Respiratory Acidosis, Chronic: Increase in 10 mmHG pCO2, increase HCO3 by 4Respiratory Alkalosis, Acute: Decrease in PCO2 of 10, decrease in HCO3 by 2Respiratory Alkalosis, chronic: Decrease in pCO2 of 10, decrease in HCO3 by 4

Acid/Base

5. Determine whether there is a 1:1 relationship between anions in the blood (delta – delta)

Increased Anion Gap metabolic acidosis: every 1 point increase in anion gap should be accompanied by a 1 mEq/L decrease in bicarbonate

Normal anion gap metabolic acidosis: every 1 mEq/L increase in chloride should be accompanied by a 1 mEq/L decrease in bicarbonate

Metabolic Acidosis

• Gap:– Methanol

– Uremia

– DKA

– Paraldehyde

– Infection/Ischemia

– Lactic

– Ethanol/Ethylene Glycol

– Salicylate

• Non-Gap– Diarrhea

– Ureteral Diversions

– RTA

– Hypocapnia

– Acetazolamide, Ampho B

– Mineralocorticoid deficiency

Metabolic Acidosis

• Primary disturbance is low serum bicarb., and pH is low

• PCO2 will decrease (Compensatory resp. alkalosis)

• DKA, Diarrhea, lactic acidosis

Metabolic Alkalosis

• Saline Responsive (U Cl < 10)– GI loss

• Upper – Vomiting, NG suction

• Lower – Diarrhea (with Cl-), adenoma

– Post hypercapnia

– Diuretics

• Saline resistant (U CL > 20)– Alkali Ingestion

– Adrenal Excess• Hyperaldosteronism

• Cushing’s Disease

• Meds. (steroids)

– Bartter’s syndrome

– Gitelman’s syndrome

– Liddle’s syndrome

– Licorice

– “Refeeding” alkalosis

Metabolic Alkalosis

• Primary disturbance is high serum bicarbonate, and pH is high

• PCO2 increases (compensatory resp. acidosis)

• Vomiting

Respiratory Acidosis

• Pulmonary Disease

• Laryngospasm

• Pleural Disease

• Impaired Respiratory Mechanics(sedation, weakness)

Respiratory Acidosis

• Primary disturbance is high pCO2, and pH is low

• Serum bicarb. Increases – compensatory metabolic alkalosis

• COPD, airway obstruction

Respiratory Alkalosis

• Sepsis

• Severe liver disease

• CNS injury (CVA, infection)

• Medications (CNS stimulant, ASA)

• Hyperthyroidism

• Pulmonary causes (hypoxia, ventilators)

Respiratory Alkalosis

• Primary disturbance is decrease in PCO2, and pH is high

• Serum HCO3 decreases, compensatory metabolic acidosis

• Hyperventilation, high altitude

What is the following acid base abnormality ? Na: 141, K: 3.3, Cl: 86, HCO3: 25.

pH: 7.40 pCO2: 41

1 2 3 4

0% 0%0%0%

1. No disturbance

2. Metabolic acidosis

3. Metabolic acidosis and Respiratory alkalosis

4. Metabolic acidosis and metabolic alkalosis

Acid/Base

1. Determine pH status (alkalemia or acidemia)-Blood pH < 7.36 is acidemia, blood pH > 7.44 is alkalemia

2. Determine if primary process is respiratory or metabolic (or both)-Alkalosis: Respiratory if pCO2 is < 40, metabolic if HCO3 is > 25-Acidosis: Respiratory if pCO2 > 40, metabolic if HCO3 is < 25

3. Calculate Anion Gap [Na – (Cl +HCO3)]4. Check degree of compensation

Metabolic Acidosis: Decrease in pCO2 = 1.3 x decrease in bicarbonateMetabolic Alkalosis: Increase in pCO2 = 0.6 x increase in bicarbonateRespiratory Acidosis, Acute: Increase in 10 mmHG pCO2, increase HCO3 by 1Respiratory Acidosis, Chronic: Increase in 10 mmHG pCO2, increase HCO3 by 4Respiratory Alkalosis, Acute: Decrease in PCO2 of 10, decrease in HCO3 by 2Respiratory Alkalosis, chronic: Decrease in pCO2 of 10, decrease in HCO3 by 4

Acid/Base

5. Determine whether there is a 1:1 relationship between anions in the blood (delta – delta)

Increased Anion Gap metabolic acidosis: every 1 point increase in anion gap should be accompanied by a 1 mEq/L decrease in bicarbonate

Normal anion gap metabolic acidosis: every 1 mEq/L increase in chloride should be accompanied by a 1 mEq/L decrease in bicarbonate

• Good luck

• The fact that you’re here (at NW) = high likelihood of success

• P = M.D.

“Success is peace of mind attained only through self-satisfaction in knowing you’ve made the effort to the best of which you’re capable.

People ask me: Have you lived up to your pyramid ?

My answer is always the same: No, but I have tried.”

- John Wooden