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Board Review Course & Update

Nephrolithiasis

Orson W. Moe, M.D.

Department of Internal Medicine

University of Texas Southwestern Medical Center

Dallas, TX, USA

July 25 - 31, 2015 | Chicago, IllinoisAcknowledgements and Disclosures

•Research support: National Institutes of Health, American Society of Nephrology

Simmons Family Foundation, Charles and Jane Pak Foundation

•Paid consultations for industry (past 4 years):Abbvie, Allena, Amgen, Ardelyx, Sanofi, Takeda

•Co-inventor of patent (Meta Pharm products):Potassium Magnesium Citrate, Calcium Magnesium Citrate, Synthetic anti-Klotho antibody

Professor G. Elliot Smith, 1901

Calcium oxalate 75%

Magnesium oxalate 9%

Magnesium ammonium phosphate 6%

Carbonate apatite 4%

Uric acid 3%

4800 BCE

Professor S.G. Shattock, 1905

Oldest documented human stone

6700 year old

post-mortem exam

General ConceptsGeneral Concepts

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A systemic disease

Kidney stones

OH

OHHO

Nephrolithiasis Nephrocalcinosis≠

Intratubular deposits Interstitial depositsOverlap

Nephrolithiasis Nephrocalcinosis≠Cortical

Medullary

Glomerulonephritis

Alport’s syndrome

Acute cortical necrosis

Hemolytic-uremic syndrome

Tuberculosis

Acute transplant rejection

Pyelonephritis

Medullary sponge kidney

Hypercalcemic states

Hyperparathyroidism

Distal renal tubular acidosis

Furosemide therapy in infants

Bartter syndrome

Ethylene glycol toxicity

Vitamin D toxicity

Over-aggressive phosphate therapy

Primary hyperoxaluria

Medullary sponge kidney

Hypercalcemic states

Hyperparathyroidism

Distal renal tubular acidosis

Furosemide therapy in infants

Bartter syndrome

Ethylene glycol toxicity

Vitamin D toxicity

Over-aggressive phosphate therapy,

Primary hyperoxaluria.

Agenda

• General concepts

• Epidemiology

• Pathogenesis & Etiology

• Evaluation

• Treatment

General concepts

Epidemiology

Pathogenesis & Etiology

Evaluation

Treatment

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Epidemiology

Magnitude of the problem

• Annual incidence

• Lifetime risk 10-20%

2-7%• Prevalence

0.6-1.5%

• Geographic variations: Stone belts

World stone belt

USA stone belt

2000Projection:

Pearle et al. PNAS 2009

2050

2095

Magnitude of the problem

• Annual incidence

• Lifetime risk 10-20%

2-7%• Prevalence

0.6-1.5%

• Geographic variations: Stone belts

• Caucasians > Hispanics and Asians > Blacks

•Male > females

• Incidence rising in the USA, EU, and Asia

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20051995199019851980197519711965

1 2 3 4 5 6 7 8 9 Decade of life

350-

300-

200-

100-

0-

350-

300-

200-

100-

0-

20051995199019851980197519711965

1 2 3 4 5 6 7 8 9 Decade of life

Romero et al. Rev Urol 2010

Urolithiasis: Increase in time

Pe

r 1

00

,00

0P

er

10

0,0

00

Magnitude of the problem

• Annual incidence

• Lifetime risk 10-20%

2-7%• Prevalence

0.6-1.5%

• Economic impact $2.1 billion(Evaluation and treatment)

• Geographic variations: Stone belts

• Caucasians > Hispanics and Asians > Blacks

•Male > females

• Incidence rising in the USA, EU, and Asia

(N = 322,556)

Without nephrolithiaisis(N = 318,956)

With nephrolithiaisis(N = 3600)

All $3,038 $6,532Age

18-44 $2,809 $6,114

45-54 $3,278 $7,093

55-64 $3,123 $6,525

Gender

Male $2,808 $6,302

Female $3,331 $6,825

Region

Northeast $2,948 $6,442

Midwest $2,962 $6,456

South $3,152 $6,647

West $2,978 $6,472

Saigal et al. Kidney International 2005

Annual expenditure 2000

Melton et al. Kidney International 1998

Stone formers

Non-stone formers

Fractures 11,909 person-years1950-1974

Minnesota study

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Human kidney stone composition and relative occurrence

Calcareous

Non-CalcareousHydroxyapatite

(20%) Uric Acid

(60%)

(9%)

(7%)

Ammonium Urate

Protease Inhibitors

Xanthine

Brushite (3%)

Calcium Oxalate

Struvite

Cystine

Pathogenesis and Etiology

2. Inhibitor-promoter

imbalance

Renal Tubule LumenRenal Interstitium

3. Calcium

phosphate

deposits

Excessive Solutes1.

3. Nidus for anchor

Crystalluria per se is not a disease

Randall’s plaque

Naked plaque Plaque with small

stones

Large stones

overlaying plaqueUnderlying plaque

after stone removal

Andy Evan, Jim Lingeman, and Fred Coe, U Chicago and Indiana University

Yasue stain of calcium Transmission EM

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2. Inhibitor-promoter

imbalance

Renal Tubule LumenRenal Interstitium

3. Calcium

phosphate

deposits

Excessive Solutes1.

3. Nidus for anchor

Rx

Rx

Kidney stones

Pathophysiology

Etiologies

Predisposing

conditions

Condition Stone typeCalcium

oxalate

Calcium

phosphate

Uric acid Struvite Cystine Drugs

Environmental/Dietary

Low urine volume + + + + + +

High protein diet + +

High salt diet +

Metabolic

Primary hyperparathyroidism + +

Granulomatous diseases +

Metabolic acidosis + +

Metabolic syndrome/gout/type 2

diabetes

+

Hyperuricosuric conditions + +

Intestinal diseases +

Chronic diarrheal states + +

Fat malabsorption +

Post Bariatric surgery + +

Idiopathic

Hypercalciuria + +

Hyperoxaluria +

Congenital syndromes

Renal tubular acidosis +

Cystinuria +

Primary hyperoxaluria +

Urinary tract infection +

Medications

Drugs that alter urine chemistry + + +

Insoluble drug +

Evaluation

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Do nothing Do everything

EvaluationDo nothing

Recurrence rate

• 10 years ~ 50-65%

• 20 years ~ 70-85%

Blanket Rx

• Drink water

• Decrease salt and protein

• Alkali Rx

Do something

1. Uncover underlying conditions- treatable !

2. Associated conditions that need attention e.g. low bone density

3. Guide prescription- Tailored therapy

4. Follow efficacy of therapy

Evaluation

3. Blood4. Urine

2. Imaging

1. Stone analysis

1. Stone analysis

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Evaluation

1. Stone analysis

Stone strainer

CaOx Calcium oxalate monohydrate Ca (COO)2·H2O

Calcium oxalate dihydrate Ca (COO)2·2H2O

CaP Brushite CaHPO4·2H2O

Hydroxyapatite Ca10(PO4)6(OH)2

Uric Acid Uric acid C5H4N4O3

Sodium urate NaC5H4N4O3

Struvite Magnesium ammonium urate NH4MgPO4·6H2O

Cystine Cystine (SCH2CH(NH2)CO2H)2

Others

Condition Stone typeCalcium

oxalate

Calcium

phosphate

Uric acid Struvite Cystine Drugs

Environmental/Dietary

Low urine volume + + + + + +

High protein diet + +

High salt diet +

Metabolic

Primary hyperparathyroidism + +

Granulomatous diseases +

Metabolic acidosis + +

Metabolic syndrome/gout/type 2

diabetes

+

Hyperuricosuric conditions + +

Intestinal diseases +

Chronic diarrheal states + +

Fat malabsorption +

Post Bariatric surgery + +

Idiopathic

Hypercalciuria + +

Hyperoxaluria +

Congenital syndromes

Renal tubular acidosis +

Cystinuria +

Primary hyperoxaluria +

Urinary tract infection +

Medications

Drugs that alter urine chemistry + + +

Insoluble drug +

Evaluation

2. Imaging

3. Blood4. Urine

1. Stone analysis

2. Imaging

Evaluation

2. Imaging

Kidneys Ureters and Bladder X-ray (KUB)

Limited sensitivity and specificity (60-77%). Cannot see UA, xanthine,

and 2,8-dihyroxyadenine (2,8-DHA) stones. Simple. Follow up

Ultrasound

See radio-opaque and radio-luscent stones

Non-invasive. No radiation: children, pregnant women

False positive and negative diagnosis of obstruction.

Computerized tomography

All stones except indinavir stones, visualized by non contrast CT.

High sensitivity and specificity. As small as 1mm.

Significant radiation exposure

Intravenous pyelogram

Use has diminished.

Guide in percutaneous or endoureteral procedures.

Magnetic resonance imaging

Explored as an alternative to NCCT or IVP

Does not deliver ionizing radiation. High cost and limited availability.

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Evaluation

3. Blood4. Urine

2. Imaging

1. Stone analysis

3. Blood

Evaluation

3. Blood

Serum Chemistry • Na, K, Cl, HCO2, BUN, Cr, Glucose

• Ca, P, Uric Acid, Mg, Protein

• ALP, ALT, AST, Bilirubin, LDH, CK

CBC • Hb, WBC, Plt

Endocrine • PTH, 25-OH-Vitamin D

Lipid profile • Chol, TG, LDL, HDL

Evaluation

4. Urine3. Blood

2. Imaging

1. Stone analysis

4. Urine

Evaluation

4. Urine

UpH

5.0 5.5 6.0 6.5 7.0

Uric acid RTA Infection

Urinalysis

Cigar

Envelope

Coffin

Polygon

Amorphous

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Calcium Oxalate

Monohydrate

Calcium Oxalate

Dihydrate

Evaluation

4. Urine

Evaluation

4. Urine

Calcium phosphate

Evaluation

4. Urine

Uric Acid Cystine

Evaluation

4. Urine

Melamine

Acyclovir

Tyrosine

Sulphonamide

Leucine

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Evaluation

4. Urine24 hr urine

Guideline values

Metabolic Risk Factors Environmental Calculated

Volume >2 L Sodium <200 mEq Relative supersaturation

pH 5.5-6.5 Chloride <200 mEq

Calcium <250 mg (6.25 mmoles) Potassium >50 mEq Relative supersaturation

ratioOxalate <45 mg (0.5 mmoles) Magnesium >60 mg

Phosphate <1100 mg (>35 mmoles) Ammonium <45 mEq Saturation Index

Uric acid <700 mg (4.2 mmoles) Sulfate <30 mmoles

Citrate >320 mg (1.7 mmoles) Citrate >320 mg

Cystine <60 mg (0.25 mmoles)

Evaluation

4. Urine

Metabolic Risk Factors Environmental Calculated

Volume Universal. Intake & loss Sodium Calciuria Relative supersaturation

pH UA. CaOx. RTA. Infection Chloride Calciuria

Calcium CaOx and CaP Potassium Alkali intake Relative supersaturation

ratioOxalate CaOx Magnesium CaOx, CaP

Phosphate CaP Ammonium Acid excretion Saturation Index

Uric acid CaOx and UA Sulfate Acid intake

Citrate CaOx. CaP Citrate Acid-base

Cystine Cystine

24 hr urine

Interpretation

ParameterExpected Daily

ValuesInterpretation

Total Volume ≥ 2.5 L Diminishes with low fluid intake, sweating, and diarrhea.

pH 5.8-6.2 <5.5 increases risk of uric acid precipitation commonly found in uric acid stone patients, subjects with intestinal

disease and diarrhea, and in those with intestinal bypass surgery.

>6.7 increases risk of calcium phosphate precipitation seen in patients with dRTA, primary hyperparathyroidism,

alkali overtreatment, repeated shock wave lithotripsy.

>7.0-7.5 indicates a urinary tract infection as a result of urease-producing bacteria.

Creatinine 15-25 mg/kg

body weight

Gauges adequacy of collection. 15-20mg/kg body weight in females and 20-25mg/kg body weight in males.

Sodium 100 mEq Reflective of dietary sodium intake in the absence of excessive sweating and/or diarrhea. Can cause secondary

hypercalciuria.

Potassium 40-60 mEq Reflective of dietary potassium intake in the absence of diarrhea. A marker of dietary alkali intake.

Calcium ≤ 250-300 mg Direct risk factor and precipitating solute for calcium stones. Possible differences between male and female

subjects (higher value in males).

Magnesium ≥ mg Low urinary magnesium reflects low magnesium intake, intestinal malabsorption (small bowel disease), and

following bariatric surgery. Role as inhibitor is controversial.

Oxalate ≤ 45 mg Direct risk factor and precipitating solute for calcium oxalate stones. Seen in intestinal fat malabsorption and

sometimes following bariatric surgery. Values higher than 100 mg/day is suspicious of primary hyperoxaluria.

Phosphorus ≤1100 mg Indicative of dietary phosphorus intake and absorption. High excretion rate may increase the risk of calcium

phosphate stone. Conditions of renal phosphate leak can also lead to secondary hypercalciuria.

Uric Acid 600-800 mg Can contribute to uric acid stones when urine pH is low. Can also increase risk of calcium oxalate stones.

Encountered with the overindulgence of purine-rich foods. Values > 1000 mg may indicate rare enzyme

deficiencies.

Sulfate ≤ 25-30 mmol Sulfate is a marker of the acid content in the diet. Dietary acid intake is important to guide interpretation of urine

pH, citrate, ammonium excretion.

Citrate ≥ 320 mg Principal inhibitor of calcium stone formation. Hypocitraturia is encountered in states with intracellular acidosis

such as metabolic acidosis, dRTA, chronic diarrhea, excessive protein ingestion, frequent strenuous physical

exercise, potassium deficiency, carbonic anhydrase inhibitors and rarely with ACE-inhibitors.

Ammonium 30-40 mEq Ammonia is a major buffer which carries protons in the form of ammonium. Its excretion usually corresponds

with dietary acid load (marked by urinary sulfate). High ammonium:sulfate ratio indicates non-dietary acid load

such as GI alkali loss or high endogenous acid production.

Chloride 100 mEq Usually correspond with sodium intake and excretion. Renal sodium bicarbonate loss may lead to discrepancies

in urine sodium and chloride

Cystine ≤ 30-60 mg Limited urinary solubility at 250mg/L.

Interpretation of urinary biochemical profile

Treatment

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Kidney stones

Pathophysiology

Etiologies

Predisposing

conditions

RxDietary Pharmacologicand/or

• Pathophysiologic basis

• Metabolic studies

• Randomized clinical trials

Data

Type Risk Diet therapy Pharmacologic therapy

Calcium stones Low urine volume Fluid -

Hypercalciuria Salt and protein restriction Thiazide, alkali

Hyperoxaluria Oxalate restriction -

Hypocitraturia Protein restriction Alkali

Hyperuricosuria Protein/purine restriction Xanthine oxidase inhibitor

High urine pH * -

Uric acid stones Low urine pH Protein restriction Alkali

Low urine volume Fluid -

Hyperuricosuria Protein restriction Xanthine oxidase inhibitor

Cystine stones Low urine volume Fluid

Cystinuria Methionine and salt

restriction

Tiopronin

D-penicillamine

Low urine pH Protein restriction Alkali

Overview of therapy

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Dietary Modification

Fluids

Calcium

Sodium

Protein-acid

Oxalate

Dietary Modification

Fluids

• Pathophysiologic basis

• Metabolic studies

• Randomized clinical trials

The PanaceaThe PanaceaThe PanaceaThe Panacea

Dietary Modification

Calcium

Sodium

Protein-acid

Fluids

Oxalate

Dietary Modification

Borghi et al NEJM 2002

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Dietary Modification

Calcium

Sodium

Protein-acid

Fluids

Oxalate

Food Moderate Oxalate:Limit

Rich Oxalate:Avoid

Fruits Apple, Apricots, Peaches, Pears, Pineapple, Plums, PrunesBlack currantsCherries, redOrange, edible portion

Blackberries, Blueberries, Raspberries, Strawberries, Dewberries, GooseberriesConcord grapes, Red currants, TangerinesCitrus peel

Vegetables AsparagusBroccoliCarrots, CornCucumberGreen peas, Lettuce, Lima beansParsnips, Tomato, Turnips

Beans, BeetsTops, Roots, Greens Celery , Chard, Chive, CollardsDandelion greens, Eggplant, EscaroleKale, Leeks, Mustard Greens, OkraParsley, Peppers, Pokeweed, Potatoes, Rutabagas, Spinach, Summer squash, Watercress

Nuts Peanuts, Peanut butterPecans

Miscellaneous Chicken noodle soup dehydratedSardines

Chocolate, cocoaPepperSoybean curd

Bread/Starch CornbreadSponge cake, Spaghetti,

Fruit cakeGrits, white cornSoybean crackersWheat Germ

Beverage/Juices CoffeeCranberry juice Grape juice Orange juice Tomato juice

BeerJuices containing berries OvaltineTea, cocoa

•Hypercalciuria

•Hypocitraturia

•Hyperuricosuria

•Urine pH

Pharmacologic Rx

•Hypercalciuria

•Hypocitraturia

•Hyperuricosuria

•Urine pH

Calcium Urolithiasis

Pharmacologic Rx

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Hypercalciuria

Thiazide diuretics

Drug Dosage(s) Comments

Hydrochlorothiazide50mg/day

25mg twice/daySingle dose is preferred

Chlorthalidone 25-50mg/dayMay cause hypokalemia and secondary

hypocitraturia.

Indapamide 1.2-2.5mg/dayLess side effects than hydrochlorothiazide. Rare

occurrence of hypokalemia and hypotension.

Amiloride 5mg/dayPotassium sparing. Lowers urinary calcium but to

a lesser degree than hydrochlorothiazide.

Amiloride/

Hydrochlorothizide5mg/50mg/day

Maintains the hypocalciuric effect of thiazide

while averting hypokalemia.

RCT: Decrease calciuria and stone events

↑ Ca transport

•Hypercalciuria

•Hypocitraturia

•Hyperuricosuria

•Urine pH

Calcium Urolithiasis

Pharmacologic Rx

Hypocitraturia

Citrate3- H+

Calcium phosphate complexes

Low Solubility

Ca2+ HPO42-

H2PO4- H3PO4CaCitrate-

High Solubility

Citrate3-

CO2

3H+

CO2

3HCO3-

Potassium Bicarbonate

Potassium Citrate

RCT: Raises urine citrate and decrease stone events

Dual role of citrate in urine

30-60 mEq base/day

•Hypercalciuria

•Hypocitraturia

•Hyperuricosuria

•Urine pH

Calcium Urolithiasis

Pharmacologic Rx

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Hyperuricosuria

Xanthine oxidase inhibitorAllopurinol 200-300 mg/day

Feboxustat 40-80 mg/day

Calcium Oxalate

Calcium OxalateSoluble complex

Calcium OxalateInsoluble complex

Sodium Urate

RCT: Reduces hyperuricosuria and stone events in isolated hyperuricosuria

Hyperuricosuric Calcium Urolithiasis (HUCU)

•Hypercalciuria

•Hypocitraturia

•Hyperuricosuria

•Urine pH

Uric Acid Urolithiasis

Pharmacologic Rx

O

NC

H

NC

C

C N

H

H

NC

O

O9

3

17

H+ -

pK ~ 5.4

Uric acid UrateLow pH

High pH

O

NC

H

NC

C

C N

H

H

NC

O

O9

3

17

H

-Solubility limit

Uric acid nephrolithiasis: A disease of urinary pH

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Urine pH

Potassium Bicarbonate

Potassium Citrate

30-60 mEq base/day

RCT: Raises urine pH and decrease stone events

-Solubility limit

•Hypercalciuria

•Hypocitraturia

•Hyperuricosuria

•Urine pH

Cystine Urolithiasis

Pharmacologic Rx

•Chelate cystine

Cystine has low solubilityAmino acid

L-Arginine

L-Lysine

L-Ornithine

L-Cystine

L-Leucine

L-Phenylalanine

L-Histidine

L-Methionine

L-Alanine

L-Tryptophan

N

C158

out

in

II

in

C

C

N

C109C109

IL2-3

EL3-4

1 2 43 5 6 7 8 9 10 11 12

rBAT/4F2 b 0,+ AT

Urine

Amino Acid

xx Autosomal recessive

CSSCInsoluble

pKa COOH NH3

Cystine 1.65 7.85

2.26 9.85

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Cys

tin

eso

lub

ilit

y

(mg

/ml)

4 5 6 7 8 9

1200

1000

800

600

400

200

0

Risk of CaP !

pHCysteine or

Cysteine-drug complex

HOOC – C – C – SH

NH2 CH3

CH3

– –

– –

H

HOOC – C – N – C – C – SH

H H– –

–

H

=

O

CH3

CH3

––

Penicillamine α-mercaptopropionylglycine

(Tiopronin)

DSSD + CS DS + CSSD

CSSC + DSSD 2CSSD

CSSC + DS CS + CSSD

D: Drug

C: Cystine

Insoluble

Agenda and take-home points

• General concepts

• Epidemiology

• Pathogenesis & Etiology

• Evaluation

• Treatment

General concepts

Epidemiology

Pathogenesis & Etiology

Evaluation

Treatment

A systemic disease.

Diverse causes converging on abnormal urine chemistry.

Common. Disabling. Expensive.

Urine. Stone. Imaging. Blood.

Medically treatable. Dietary. Pharmacologic.