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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