Update Stone Preventionand Medical Management

Dean G. Assimos, M.D.Department of Urology

EVALUATION

• Dietary and medical history• Family history• Serum chemistry testing• Urinalysis• Urine culture if indicated• Stone Analysis

All patients with a newly diagnosed stone should undergo a screening evaluation (Clinical Principle)

• Type 1 Distal Renal Tubular Acidosis• Primary hyperparathyroidism• Type II DM• Gout• Obesity• Bowel Disease• Bariatric Surgery• Bone Disease• Immobilization

Medical History

• Low or high calcium intake• Low fluid intake• Excessive intake of animal

protein• Limited fruits and vegetables• High oxalate consumption

Dietary History

EvaluationMedications and Supplements

• Topiramate, acetazolamide, zonisamide• Furosemide• Probenicid• Triamterene• Protease inhibitors• Vitamin C• Calcium supplements

EVALUATIONSerum Chemistries

• Na, K+, Cl, CO2, Ca, BUN, Cr, UA– ↑Ca → 1° HPT or Sarcoidosis– ↓CO2, ↓K+, ↑Cl → Type 1 distal RTA– ↑uric acid → low pH or hyperuricosuria

Serum PTH should be obtained if 1° HPT is suspected (Clinical Principle)

EVALUATION

• Cystine stones → Cystinuria• Uric acid stones → low urine pH• Struvite stones → recurrent UTIs

When a stone is available, a stone analysis should be obtained at least once (Clinical Principle)

EVALUATIONClinicians should obtain metabolic testing in high-risk or interested first-time stone formers and recurrent

stone formers (Standard: Grade B)

24-hr urine testing can be used to inform and monitor treatment regimens

WHO SHOULD WE EVALUATE?

• Recurrent SFs• “High risk” 1st time SFs

– Family history – GI disease/bowel resection– Bariatric surgery– Gout– Type II DM– Obesity– Distal RTA– 1° HPT– Nephrocalcinosis– Cystinuria

• Children or adolescents• Solitary kidney• “Interested” 1st time SFs

SIMPLE METABOLIC EVALUATION

Urine: TV, pH, Ca, Ox, UA, Citrate, Na, K+, Cr,(Optional but helpful: SO4/UUN, Supersaturation)

Metabolic testing should consist of 1 or 2, 24-hr urine collections obtained on a random diet (Expert Opinion)

Fluid TherapyClinicians should recommend to all stone formers a

fluid intake that will achieve a urine volume of at least 2.5L daily (Standard: Grade B)

199 CaOx stone formers

High fluid intake (2 L urine/d)

2621 ml/d yr 5

12% recurrence

No specific recommendations

1014 ml/d yr 5

27% recurrence

Borghi et al, J Urol 155: 839, 1996

Beverages• HPFS, NHS I, NHS II• risk sugar sweetened cola, sugar sweetened

non-cola, sugar sweetened punch. • risk caffeinated and decaffeinated coffee,

tea, red wine, white wine, beer and orange juice.

• Whiskey not risky!

Ferraro et al. Clinical Journal of the American Society of Nephrology, 8:1389, 2013.

Fluid Therapy

• Patients prefer fluid therapy over dietary modifications.

• Fluid App• Smart Bottle• Current NIH study with smart bottle and

financial incentives

McCauley et al. Journal of Urology, 187:1282, 2012.

DIET THERAPY

Clinicians should counsel patients with calcium stones and relatively high urinary calcium to limit sodium intake and

consume 1000-1200 mg/d of dietary calcium (Standard: Grade B)

DIETARY CALCIUMBorghi et al, NEJM 346:77, 2002

120 men w/ recurrent CaOx stones and hypercalciuria

Low Ca diet(n=60)

NL Ca, low protein, low Na diet(n=60)

38% stone recurrence 20% stone recurrence

5 years

Independent effect of calcium, protein and sodium not evaluated

DASH Diet

• Dietary approaches to stop hypertension• Positive points: low-fat dairy, fruits,

vegetables, nuts, legumes• Negative points: meat, sodium, sweetened

drinks.

DASH Score and Stone Risk

0.2

0.4

0.6

0.8

1.0

Q1 Q2 Q3 Q4 Q5

HPFS

NHS I

NHS II

Rel

ativ

eR

isk

DASH Score

P trend < 0.001

17 21 24 27 31J Am Soc Nephrol.(10):2253, 2009

PHARMACOLOGIC THERAPIES

Clinicians should offer thiazide diuretics to patients with high or relatively high urine calcium and recurrent calcium

stones (Standard: Grade B)

• Thiazides act directly at the DRT and indirectly at the PRT to promote Ca reapsorption

• Hypokalemia (potassium chroride, potassium citrate)

THIAZIDE TRIALS: META-ANALYSISPearle, Roehrborn et al, J Endourol 13, 1999

21.3% Risk Reduction(-29 to -13%, 95%CI, p

Guidelines Statement

• Clinicians should should counsel patients with calcium oxalate stones and high urinary oxalate excretion to limit intake of high oxalate containing foods and maintain normal calcium consumption. (Expert opinion)

Treatment of Idiopathic Hyperoxaluria

DietIncreased fluidsLimit oxalate (100 mg)Limit hydroxyproline consumptionNormal calcium consumption Avoid high ascorbic acid intake

Pyridoxine (50-100 mg)Probiotic therapyFish oil

Attalla et al. Urology, 84:555, 2014.

https://regepi.bwh.harvard.edu/health/Oxalate/files

Wide Variability of Food Oxalate Content Reported on line

Treatment Enteric Hyperoxaluria– Correct bowel pathology– Low-fat, low-oxalate diet – Increased fluid intake– Diet alone has limited impact on oxalate

excretion– Calcium citrate– Potassium citrate– Pro-biotic therapy– Natural conjugated bile acids

Pange et al. Urology, 250, 2012.

Primary Hyperoxalurias• Monogenic• Autosomal recessive orders• Defects in enzymes• Extreme hyperoxaluria• Kidneys are initial target

– Stone formation– Nephrocalcinosis

• Potential for renal failure and oxalosis• Refer to a center with expertise in diagnosis and

treatment of these disorders (genetic testing).

PHARMACOLOGIC THERAPIES

Clinicians should offer potassium citrate therapy to patients with recurrent calcium stones and low or relatively

low urinary citrate (Standard: Grade B)

• Potassium citrate provides an alkali load that promotes citrate excretion in the proximal tubule

Months0 6 12 18 24 30 36

Pro

porti

on S

tone

Fre

e

0.0

0.2

0.4

0.6

0.8

1.0

Potassium Citrate

Placebo

Relative Risk= 0.2595% CI = 0.09 - 0.70

EFFECT OF K-CITRATE ON HYPOCITRATURIC STONE FORMERS

Barcelo et al, J Urol 150: 1761, 1993

PHARMACOLOGIC THERAPIES

Clinicians should offer allopurinol to patients with recurrent calcium oxalate stones who have hyperuricosuria

and normal urinary calcium (Standard: Grade B)

ALLOPURINOL RCTs

Rx Selection Durationof study NStns/pt/yr

Remission (%)

p-value

EttingerAllopurinol CaOx

UA Excretion

229 0.12 69

PHARMACOLOGIC THERAPIES

Clinicians should offer thiazide diuretics and/or potassium citrate to patients with recurrent calcium stones in whom

other metabolic abnormalities are absent or have been appropriately addressed and stone formation persists

(Standard: Grade B)

• No trials have directly compared targeted versus empiric medical therapy for stone prevention

• Some RCTs have shown benefit of therapy in patients without regard to metabolic background

24 Hour Urinary Calcium

Curhan and Taylor. Kidney International, 73:489-496, 2008.

Chart1

< 100< 100< 100

100-149100-149100-149

150-199150-199150-199

200-249200-249200-249

250-299250-299250-299

300-349300-349300-349

>350>350>350

NHS I

NHS II

HPFS

mg of Calcium per day

Relative Risk of Stone

1

1

1

1.26

0.89

0.97

1.52

1.58

2.14

1.84

2.73

2.17

1.93

3.28

3.29

2.68

3.6

3.8

4.94

5.86

6.23

Sheet1

< 100100-149150-199200-249250-299300-349>350

NHS I11.261.521.841.932.684.94

NHS II10.891.582.733.283.65.86

HPFS10.972.142.173.293.86.23

24 Hour Urinary Citrate

Curhan and Taylor. Kidney International, 73:489-496, 2008.

Chart1

< 300< 300< 300

300-399300-399300-399

400-499400-499400-499

500-599500-599500-599

600-699600-699600-699

700-799700-799700-799

> 800> 800> 800

NHS I

NHS II

HPFS

mg Citrate

Relative Risk

1

1

1

0.72

0.68

0.59

0.63

0.36

0.49

0.5

0.37

0.59

0.56

0.33

0.42

0.54

0.32

0.35

0.33

0.24

0.3

Sheet1

< 300300-399400-499500-599600-699700-799> 800

NHS I10.720.630.50.560.540.33

NHS II10.680.360.370.330.320.24

HPFS10.590.490.590.420.350.3

PHARMACOLOGIC THERAPIESEttinger et al, J Urol 158: 2069, 1997

64 recurrent, active, primarily CaOx SFs randomized to KMgCit vs Placebo

Proportion of Pts Free of StonesKMgCit

Placebo

Recurrence: 63% for placebo vs 12.8% for KMgCitRelative Risk of treatment failure (K/P) = 0.16

PHARMACOLOGIC THERAPIES

Clinicians should offer potassium citrate to patients with uric acid stones to raise urine pH (6.5-7)Clinicians should not routinely offer allopurinol as first-line

therapy to patients with uric acid stones (Expert Opinion)

From Shekarriz and Stoller, J Urol, 2002

Cystinuria

• Fluid• Sodium, Animal Protein• Urinary pH manipulation (potassium citrate)• Thiol binding drugs (alpha-mercapto-propionyl

glycine)

Identification of Genes Idiopathic CaOx and CaP

• Polygenic• Iceland• Genome-wide association study• 5,419 kidney stone formers (2,172 with

recurrences)• 279,870 controls

Oddson et al. Nature Communications, 2015.

Associated Genes• Sequence variants• ALPL (alkaline phosphatase) OR 1.23• SLC34A1 (Na/Pi co-transporter OR 1.21• CASR (calcium sensing receptor) OR 1.18• CLDN14 (paracellular transport) OR 0.77

Recurrent Kidney Stones• Coding sequence variants• Preferential kidney expression• SLC34A1• TRPV5• Importance of TRPV5 for thiazide response• Up-regulation of TRPV5 by Uromodulin• Requirement of calbindin for thiazide

responseWolf et al. Kidney International, 84:130, 2013.Nie et al. JASN, 27:3447, 2016.Lee et al. American Journal of Physiology, 310:230, 2016.

Rimer et al. Science, 330:337, 2010.

http://www.sciencemag.org/content/330/6002/337/F3.large.jpghttp://www.sciencemag.org/content/330/6002/337/F3.large.jpg

Rimer et al. Science, 330:337, 2010.

http://www.sciencemag.org/content/330/6002/337/F1.large.jpghttp://www.sciencemag.org/content/330/6002/337/F1.large.jpg

http://www.sciencemag.org/content/330/6002/337/F4.large.jpghttp://www.sciencemag.org/content/330/6002/337/F4.large.jpg

Sahota et al. Urology, 84:1249. 2014

Slc3a1 -/-

α- Lipoic Acid

• Nutritional supplement• No reported toxicity• Slc3a1 -/- mouse model• α- mercapto-proprionyl-glycine no inhibition of

stone formation in this model• No impact on urine pH

Zee et al. Nat Med. 23(3):288, 2017.

Oxalate Decarboxylase

• ALLN-177• Obtained from Bacillus subtilis and

expressed in E. Coli• Phase 1, Randomized, Double-Blind,

Placebo Controlled, Cross-Over Design• Healthy adults• 1000 mg oxalate, 400 mg calcium per day

Langman et al. American Journal of Nephrology, 44:150, 2016.

POTENTIAL siRNA LIVER TARGETS

1. Li X, et. Al., Biochim Biophys Acta 1862: 2016

2. Dutta C et. al., Mol Ther 24: 2016 Liebow et. al, JASN 28: 2016

Hydroxyproline Glycolate

Glyoxylate

Oxalate

HYPDH 1 GO 2

LDH

RNA Induced Silencing Complex

Liebow et al. JASN, 28:494, 2017.

Conclusions

• Present management is focused on the phenotype.

• Non-specific• Genomic analysis in the future will allow

more targeted therapy and development of better drugs.

Update Stone Prevention�and Medical Management EVALUATIONSlide Number 3Slide Number 4Evaluation�Medications and SupplementsEVALUATION�Serum ChemistriesEVALUATIONEVALUATIONWHO SHOULD WE EVALUATE?SIMPLE METABOLIC EVALUATIONFluid TherapyBeveragesFluid TherapyDIET THERAPYDIETARY CALCIUM�Borghi et al, NEJM 346:77, 2002DASH DietDASH Score and Stone RiskPHARMACOLOGIC THERAPIESTHIAZIDE TRIALS: META-ANALYSIS�Pearle, Roehrborn et al, J Endourol 13, 1999Guidelines StatementTreatment of Idiopathic HyperoxaluriaSlide Number 22Treatment Enteric HyperoxaluriaPrimary HyperoxaluriasPHARMACOLOGIC THERAPIESEFFECT OF K-CITRATE ON HYPOCITRATURIC STONE FORMERS �Barcelo et al, J Urol 150: 1761, 1993PHARMACOLOGIC THERAPIESALLOPURINOL RCTsPHARMACOLOGIC THERAPIES24 Hour Urinary Calcium24 Hour Urinary CitrateSlide Number 32PHARMACOLOGIC THERAPIESCystinuriaSlide Number 35Identification of Genes �Idiopathic CaOx and CaPAssociated GenesRecurrent Kidney StonesSlide Number 39Slide Number 40Slide Number 41Slide Number 42α- Lipoic AcidSlide Number 44Slide Number 45Oxalate DecarboxylaseSlide Number 47POTENTIAL siRNA LIVER TARGETSSlide Number 49Slide Number 50Slide Number 51Conclusions