Nephrolithiasis Challenging Cases Not So Challenging...

7/20/2015

1

Board Review Course & Update

NephrolithiasisChallenging Cases

Orson W. Moe, M.D.

Department of Internal Medicine

University of Texas Southwestern Medical Center

Dallas, TX, USA

August 2–8, 2014 | Chicago, Illinois

NephrolithiasisChallenging CasesNot So

Do this

If you see this

Do this

If you see this

Do this

If you see this

Do this

Patient presents with this

NephrolithiasisChallenging CasesWhy is it ?

7/20/2015

2

Hypercalciuria Hyperoxaluria Hypocitraturia Alkalinuria Hyperuricosuria

Heterogeneity

Calcium stone

Parameter Desired value to reduce relative stone risk

Calcium <250 mg/day (6.3 mmoles/day)

Oxalate <45 mg/day (0.51 mmoles/day)

Uric Acid <700 mg/day (4 mmoles)

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

pH 5.5 - 7.0

TV > 2 L/day

Na < 200 mEq/day

SO4 < 30 mmol/day (<60 mEq/day)

P < 1100 mg/day (11.6 mmoles/day)

Mg > 60 mg/day (2.5 mmoles/day)

Cl <200 mEq/day

NH4 < 45 mEq /day

Evaluation of urine chemistry

NormalAbnormal Abnormal

Normocalciuria HypercalciuriaHypocalciuria

Sto

ne

Ris

k

Hypocitraturia

My 24 hr Ca

is 249 mg

My 24 hr Ca

is 251 mg

Hypocitraturia

&

Hyperoxaluria

Urinary calcium

Who cares…

Intermediate surrogate Clinical event

7/20/2015

3

• Physiologic basis

• Clinical metabolic studies

• Randomized control trials

Data from the three do not always agree

Evaluating Rx

NephrolithiasisChallenging Cases

Patient #1

37 year old Caucasian veteran

Left sided renal colic with spontaneous passage

More stones visible on plain X Ray


Calcium 278 mg <250 mg/day (6.3 mmoles/day)

Oxalate 32 mg <45 mg/day (0.51 mmoles/day)

Uric Acid 689 mg <700 mg/day (4 mmoles)

Citrate 125 mg >320 mg/day (1.7 mmoles/day)

pH 5.8 5.5 - 7.0

TV 1.98 > 2 L/day

Na 247 mEq < 200 mEq/day

K 30 mEq > 50 mQ/dau

SO4 86 mEq < 30 mmol/day (<60 mEq/day)

P 1220 mg < 1100 mg/day (11.6 mmoles/day)

Mg 65 mg > 60 mg/day (2.5 mmoles/day)

Cl 231 mEq <200 mEq/day

NH4 72 mEq < 45 mEq /day

Creatinine 2050 mg

Healthy otherwise

Served in the gulf war

Physical exam- healthy young male

0.66 mmoles

6.95 mmoles

Patient #1

Why this healthy young man forming stones?

• What are the pathogenic factors?

• What are the etiologic factors?

• Are there intrinsic defects?

Are there any other investigations warranted?

What therapies should be recommended?

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Patient #1






pH 5.8 5.5 - 7.0

TV 1.98 > 2 L/day


K 30 mEq > 50 mEq/day






Creatinine 2050 mg

Patient #1


• What are the pathogenic factor?





Hypercalciuria and hypocitraturia

Dietary salt and protein

Unlikely

Physiologic hypercalciuria and hypocitraturia

Salt

Protein

Ca2+

Ca2+

++

+

+

NH2-R-COOH

SO4-

2H+ + SO42-

2NH4+ + SO4

2-

Non-acid factors

Patient #1


• What are the pathogenic factor?





Hypercalciuria and hypocitraturia

Dietary salt and protein

Unlikely

Dietary modification

Not at the moment

Consider:

Alkali

Thiazides

7/20/2015

5

Patient #1






pH 5.8 5.5 - 7.0

TV 1.98 > 2 L/day








Creatinine 2050 mg

Follow Urine biochemistry

Imaging

Clinical events

40 year old Caucasian female

Recurrent stones: Passage every 2-3 months

Type 2 diabetes : Metformin

Stage 1 hypertension: ACEI

Hypercholesterolemia: Statin

Exam: BMI 30, Otherwise normal

Multiple radioluscent stones






pH 5.0 5.5 - 7.0

TV 2.2 > 2 L/day

Na 135mEq < 200 mEq/day

K 45 mEq >50 mEq

SO4 24 mmoles < 30 mmol/day (<60 mEq/day)




Net acid 85 mEq < 70 mEq

Creatinine 880 mg

Patient #2

100% uric acid

Patient #2

What are the pathogenic factors?

Are there renal or extrarenal defects?

What is the most effective therapy ?

100% uric acid

Patient #2







pH 5.0 5.5 - 7.0

TV 2.2 > 2 L/day








Creatinine 880 mg


Low urine pH

7/20/2015

6

Patient #2



Acid ingestion

Acid production

Defective urinary buffering

Low urine pH

Patient #2



Acid ingestion

Acid production


Low urine pH




pH 5.0 5.5 - 7.0

TV 2.2 > 2 L/day






Net acid/SO4 1.77 ~0.7-1.3

NH4/net acid 0.37 ~0.5-0.8

Creatinine 880 mg

Patient #2



Acid ingestion

Acid production


Low urine pH

Uric acid

H+

NH3

NH4+

Buffer (B-)

HB

OH

N

N

N

NHO

OH

-

H+

NH3

NH4+

Buffer (B-)

HB H+

Patient #2



Acid ingestion

Acid production


Low urine pH

What is the most effective therapy

• Weight reduction?

• Xanthine oxidase inhibitors?

• Potassium citrate?

Adhered to the prescribed alkali Rx

Modest decrease in stone load & passage.

Underwent shockwave therapy

Still forming stones.

What?

7/20/2015

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Parameter Before Rx After Rx

Calcium 143 mg 134 mg

Oxalate 22 mg 24 mg

Uric Acid 690 mg 632 mg

Citrate 310 mg 621 mg

pH 5.0 5.9

TV 2.2 2.1

Na 135mEq 145 mEq

K 45 mEq 96 mEq

SO4 24 mmoles 22 mmoles

P 970 mg 867 mg

Mg 75 mg 64 mg

NH4 32 mEq 8 mEq

Net acid 85 mEq 28 mEq

Creatinine 880 mg 845 mg

What?

60 mEq KCitrate

Maalouf et al. Curr Opin Nephrol Hypertens 2004

-Solubility limit

Time

08 12 16 20 00 04 084.5

5.0

5.5

6.0

6.5

7.0

7.5

Urinary pH

Healthy volunteersUric acid stone formers

Time

08 12 16 20 00 04 08

UndissociatedUric Acid, mg/hr

0

5

10

15

20

25

Cameron et al. KI 2011 Cameron et al. NDT 2009

Time (hrs)

7.5

7.0

6.5

6.0

5.5

5.0

4.5

Uri

ne

pH

8 10 12 14 16 18 20 22 24 2 4 6 8

7.5

7.0

6.5

6.0

5.5

5.0

4.5

Uri

ne

pH

7.5

7.0

6.5

6.0

5.5

5.0

4.5

Uri

ne

pH

K citrate

K citrate

8 10 12 14 16 18 20 22 24 2 4 6 8

8 10 12 14 16 18 20 22 24 2 4 6 8

Patient #3

35 year old Caucasian male

Recurrent kidney stones since age 18

Last 4 years: Escalating frequency

Mixed Ca oxalate – Ca phosphate

Rx: Thiazide 25 mg/day

Last 1 year:

Two shock wave lithotripsies

One ureteroscopic procedure

Negative family history

Negative physical examination

7/20/2015

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Na 138 Ca 10.7 mg/dl (ref 8.5-10.8) Hemoglobin 16 g/dl

K 4.5 Phos 2.4 mg/dl (ref 2.4-4.0) WBC 5,000/mm3

Cl 98 PTH 54 pg/ml (ref 10-55) Platelet 170/mm3

HCO3 28 25 vit D 28 ng/ml (ref 30-70)

Cr 1.3 1,25 vit D 42 pg/ml (ref 20-40)

Patient #3

Urine Parameter

28 months ago Now Desired value to reduce relative stone risk

Calcium 268 mg 374 mg <250 mg/day (6.3 mmoles/day)

Oxalate 28 mg 32 mg <45 mg/day (0.51 mmoles/day)

Uric Acid 500 mg 512 mg <700 mg/day (4 mmoles)

Citrate 346 mg 316 mg >320 mg/day (1.7 mmoles/day)

pH 6.2 6.4 5.5 - 7.0

TV 2.2 2.7 > 2 L/day

Na 135 mEq 167 mEq < 200 mEq/day

SO4 17 mmoles 20 mmoles < 30 mmol/day (<60 mEq/day)

P 1098 mg 1120 mg < 1100 mg/day (11.6 mmoles/day)

Mg 67 mg 72 mg > 60 mg/day (2.5 mmoles/day)

NH4 38 mEq 44 mEq < 45 mEq /day


What can one do?

• Increase dose of thiazide?

• Add potassium citrate?

• Push fluids?

• Dietary changes in salt and protein?

• Nothing. Keep doing surgery

Help

Do something!

FEphos 28%

Na 138 Ca 10.7 mg/dl (ref 8.5-10.7) Hemoglobin 16 g/dl

K 4.5 Phos 2.4 mg/dl (ref 2.4-4.0) WBC 5,000/mm3

Cl 98 PTH 54 pg/ml (ref 10-55) Platelet 170/mm3

HCO3 28 25 vit D 28 ng/ml (ref 30-70)

Cr 1.3 1,25 vit D 42 pg/ml (ref 20-40)

Patient #3

Urine Parameter

28 months ago Now Desired value to reduce relative stone risk

Calcium 268 mg 374 mg <250 mg/day (6.3 mmoles/day)

Oxalate 28 mg 32 mg <45 mg/day (0.51 mmoles/day)

Uric Acid 500 mg 512 mg <700 mg/day (4 mmoles)

Citrate 346 mg 316 mg >320 mg/day (1.7 mmoles/day)

pH 6.2 6.4 5.5 - 7.0

TV 2.2 2.7 > 2 L/day

Na 135 mEq 167 mEq < 200 mEq/day

SO4 17 mmoles 20 mmoles < 30 mmol/day (<60 mEq/day)

P 1098 mg 1120 mg < 1100 mg/day (11.6 mmoles/day)

Mg 67 mg 72 mg > 60 mg/day (2.5 mmoles/day)

NH4 38 mEq 44 mEq < 45 mEq /day


• Increase dose of thiazide?

• Add potassium citrate?

• Push fluids?

• Dietary changes in salt and protein?

• Nothing. Keep doing surgery

Patient #3

24 hr Urine

Pre-PTX Post-PTX


Oxalate 32 mg 34 mg



pH 6.4 6.3

TV 2.7 2.0

Na 167 mEq 120 mEq


P 1120 mg 890 mg

Mg 72 mg 76 mg

NH4 44 mEq 40 mEq


Plasma

Pre-PTX Post-PTX

Calcium (mg/dl) 10.7 9.3

Phosphorus (mg/dl) 2.4 3.8

PTH (pg/ml) 54 19

25 vit D (ng/ml) 32 35

1,25 vit D(pg/ml) 42 32

FE phos (%) 28% 13%

Early Late

Outpatient parathyroidectomy

7/20/2015

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Patient #4






pH 6.0 5.5 - 7.0

TV 1.5 > 2 L/day







Creatinine 880 mg

50 year old male

Morbid obesity, type 2 diabetes, and hypertension

Roux-en-Y gastric bypass

Painful hematuria.

Spontaneous passage, CT scan no stones.

No stone analysis available.

BMI 37 to 28; Glycemia, BP, osteoarthritis improved

Patient #450 year old male



Painful hematuria.




• Why is this patient forming stones?

• Investigations?

• Therapy?





Loose bowel movements

Mild steatorrhea

Well tolerated

Over 24 hours

• Stool volume 167-185 ml

• Stool weight 172-190 gm

• Stool fat 5.0 g

• Stool pH 7.6 Na 8 mEq

Ca2+

Oxalate2-

CaOxalate

Bile salts

Fatty acids

CaMg soaps

CO2

formate

Dietary oxalate

7/20/2015

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Painful hematuria.




• Why is this patient forming stones?

• Investigations?

• Therapy?

Enteric hyperoxaluria. Some contribution from GI Alkali loss

Evaluation of malabsorption and GI alkali loss





Ca2+

Oxalate2-

CaOxalate

Bile salts

Fatty acids

CaMg soaps

CO2

formate

Dietary oxalate

Oxalate restriction

Rx: Malabsorption

Calcium supplement

K Ctrate

Patient #4

Parameter Before After


Oxalate 57 mg 41 mg



pH 6.0 6.8

TV 1.5 2

Na 85 mEq 75 mEq


P 970 mg 1078 mg

Mg 75 mg 78 mg

NH4 58 mEq 40 mEq

Net acid 70 mEq 50 mEq


50 year old male



Painful hematuria.




Rx:

Oxalate restriction

Calcium citrate

Potassium citrate

Patient #518 year old boy

Recurrent bilateral kidney stones x 4 years

Healthy other than short stature BMI 28

Parents from same village. Two healthy siblings ages 12 & 8






pH 6.9 5.5 - 7.0

TV 0.95 > 2 L/day







Creatinine 850 mg

Na 138 Ca 8.5

K 3.4 P 3.5

Cl 107

HCO3 20

BUN 18

Cr 1.2

90% Calcium phosphate 10% calcium oxalate

CT scan bilateral nephrolithiasis and nephrocalcinosis

7/20/2015

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pH 6.9 5.5 - 7.0

TV 0.95 > 2 L/day







Creatinine 850 mg

Na 138 Ca 8.5

K 3.4 P 3.5

Cl 107

HCO3 20

BUN 18

Cr 1.2












pH 6.9 5.5 - 7.0

TV 0.95 > 2 L/day







Creatinine 850 mg



• What is the suspected diagnosis?

• What tests should (can) be done?

• What is the proper therapy (a challenge) to prescribe?

Distal renal tubular acidosis

None to lots

H+ H+HCO3

-

CO2 CO2

NH4Cl loading

tests for ∆pH

U-BpCO2

tests for ∆pCO2

H+

Gradient Flux Patient #518 year old boy









pH 6.9 5.5 - 7.0

TV 0.95 > 2 L/day







Creatinine 850 mg



• What is the suspected diagnosis?

• What tests should (can) be done?

• What is the proper therapy (a challenge) to prescribe?

Distal renal tubular acidosis

None to lots

K Citrate…carefully

7/20/2015

12







Defective acid secretion

Alkaline urine HypocitraturiaHypercalciuria

HPO42- Ca2+H2PO4

-

H+

CaCitrate-

Citrate3-

Rx: K citrate

Pak et al. J Urol 2008

What to do?

K Citrate?

RSR: Relative supersaturation ratio

CPR: Concentration to product ratio

SI: Saturation index

Bru

shit

e

Distal RTA (N=9) MSK treated (N=65)

KCit Dose 60-80 mEq/d20 20-40 mEq/d22

Before After Before After

U pH 6.47 7.05* 6.44 6.91*

U Citrate (mg/d) 221 494* 268 460*

U Calcium (mg/d) 238 164* 378 178*

Stone Rate (/pt/yr) 13 1.0* 0.58 0.10*

Preminger et al. J Urol 1985; Van den Berg et al. Proc Eur Dial Transplant Assoc. 1983

Fabris et al. Clin J Am Soc Nephrol 2010

-3 -2 -1 0 1 2 3

Years

Rx: K Citrate

Patient #6

28 year old female

New onset kidney stones x 2 years

Healthy other than migraine headache


UpH dipstick 7.0

Referred to you to work up RTA

7/20/2015

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Welch et at. AJKD 2006

Sir William Osler

1849-1919

We are here to add what we can to life, not to get what

we can from life.

Live neither in the past nor in the future, but let each

day's work absorb your entire energies, and satisfy your

widest ambition.

Observe, document, tabulate, communicate.

Advice to Medical Students

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