Nephrolithiasis 7/20/2015. Oldest documented human stone. Acknowledgements and Disclosures

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Carmella Simpson
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Board Review Course & Update July 25-31, 2015 Chicago, Illinois

of Health, American Society of Nephrology Simmons Family Foundation,

industry (past 4 years): Abbvie, Allena, Amgen, Ardelyx, Sanofi,

Magnesium Citrate, Calcium Magnesium Citrate, Synthetic anti-klotho

Department of Internal Medicine University of Texas Southwestern

old post-mortem exam Calcium oxalate 75% Magnesium oxalate 9%

1 Board Review Course & Update July 25-31, 2015 Chicago, Illinois Acknowledgements and Disclosures Research support: National Institutes of Health, American Society of Nephrology Simmons Family Foundation, Charles and Jane Pak Foundation Nephrolithiasis 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 Orson W. Moe, M.D. Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, TX, USA Oldest documented human stone 6700 year old post-mortem exam Calcium oxalate 75% Magnesium oxalate 9% Magnesium ammonium phosphate 6% Carbonate apatite 4% Uric acid 3% Professor S.G. Shattock, 1905 General Concepts 4800 BCE Professor G. Elliot Smith,

Kidney stones A systemic disease Nephrolithiasis Nephrocalcinosis OH HO OH Intratubular

Glomerulonephritis Alport s syndrome Acute cortical necrosis Hemolytic-uremic syndrome

kidney Hypercalcemic states Hyperparathyroidism Distal renal tubular acidosis

toxicity Over-aggressive phosphate therapy, Primary hyperoxaluria.

2 Kidney stones A systemic disease Nephrolithiasis Nephrocalcinosis OH HO OH Intratubular deposits Overlap Interstitial deposits Nephrolithiasis Nephrocalcinosis Cortical Glomerulonephritis Alport s syndrome Acute cortical necrosis Hemolytic-uremic syndrome Tuberculosis Acute transplant rejection Pyelonephritis Medullary 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. General concepts Epidemiology Pathogenesis & Etiology Treatment Agenda General concepts Epidemiology Pathogenesis & Etiology Treatment 2

Magnitude of the problem Epidemiology Annual incidence 0.6-1.

problem Projection: 2000 2050 2095 USA stone belt Annual incidence 0.6-1.

3 Magnitude of the problem Epidemiology Annual incidence % Prevalence 2-7% Lifetime risk 10-20% Geographic variations: Stone belts World stone belt Magnitude of the problem Projection: USA stone belt Annual incidence % Prevalence 2-7% Lifetime risk 10-20% Geographic variations: Stone belts Male > females Caucasians > Hispanics and Asians > Blacks Incidence rising in the USA, EU, and Asia Pearle et al. PNAS2009 3

350- Urolithiasis: Increase in time Magnitude of the problem Per 100,000 Per 100,000 300-200- 100-0- 350-300- 200-100- 0-2005 1995 1990 1985 1980 1975 1971 1965 1 2 3 4 5 6 7 8 9 Decade of life 2005

4 350- Urolithiasis: Increase in time Magnitude of the problem Per 100,000 Per 100, Decade of life Decade of life Annual incidence % Prevalence 2-7% Lifetime risk 10-20% Geographic variations: Stone belts Male > females Caucasians > Hispanics and Asians > Blacks Incidence rising in the USA, EU, and Asia Economic impact $2.1 billion ( and treatment) Romero et al. Rev Urol2010 Annual expenditure 2000 Minnesota study Without nephrolithiaisis (N = 318,956) (N = 322,556) With nephrolithiaisis (N = 3600) All $3,038 $6,532 Age $2,809 $6, $3,278 $7, $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 Fractures 11,909 person-years Stone formers Non-stone formers Saigal et al. Kidney International 2005 Melton et al. Kidney International

5 Human kidney stone composition and relative occurrence Hydroxyapatite (20%) Calcium Oxalate (60%) Uric Acid (9%) Brushite (3%) Struvite (7%) Cystine Ammonium Urate Protease Inhibitors Xanthine Calcareous Non-Calcareous Pathogenesis and Etiology Randall s plaque Crystalluria per se is not a disease 1. Excessive Solutes 3. Calcium phosphate 3. Nidus for anchor deposits 2. Inhibitor-promoter imbalance Naked plaque Plaque with small stones Large stones overlaying plaque Underlying plaque after stone removal Renal Interstitium Renal Tubule Lumen Yasue stain of calcium Transmission EM Andy Evan, Jim Lingeman, and Fred Coe, U Chicago and Indiana University 5

6 1. Excessive Solutes Rx Etiologies Pathophysiology 3. Calcium phosphate 3. Nidus for anchor deposits 2. Inhibitor-promoter imbalance Rx Predisposing conditions Kidney stones Renal Interstitium Renal Tubule Lumen Condition Calcium oxalate Stone type Calcium Uric acid Struvite Cystine Drugs phosphate 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 + 6

Stone analysis 1. Uncover underlying conditions-treatable! 2.

7 Do nothing Recurrence rate 10 years ~ 50-65% 20 years ~ 70-85% Do nothing Do everything Blanket Rx Drink water Decrease salt and protein Alkali Rx Do something 1. Stone analysis 1. Stone analysis 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 3. Blood 2. Imaging 7

8 Stone strainer 1. Stone analysis CaOx Calciumoxalate monohydrate Ca(COO) 2 H 2 O Calcium oxalate dihydrate Ca(COO) 2 2H 2 O CaP Brushite CaHPO 4 2H 2 O Hydroxyapatite Ca 10 (PO 4 ) 6 (OH) 2 Uric Acid Uric acid C 5 H 4 N 4 O 3 Sodium urate NaC 5 H 4 N 4 O 3 Struvite Magnesium ammonium urate NH 4 MgPO 4 6H 2 O Cystine Cystine (SCH 2 CH(NH 2 )CO 2 H) 2 Others Condition Calcium oxalate Stone type Calcium Uric acid Struvite Cystine Drugs phosphate 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 + 1. Stone analysis 3. Blood 2. Imaging 2. Imaging 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 asanalternative to NCCTorIVP Does not deliver ionizing radiation. High cost and limited availability. 8

TG, LDL, HDL 3. Blood Urinalysis UpH 1. Stone analysis 2.

9 3. Blood 3. Blood 1. Stone analysis 2. Imaging Serum Chemistry Na, K, Cl, HCO 2, 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 3. Blood Urinalysis UpH 1. Stone analysis 2. Imaging Uric acid RTA Infection 3. Blood Cigar Envelope Coffin Polygon Amorphous 9

10 Calcium Oxalate Monohydrate Calcium phosphate Calcium Oxalate Dihydrate Tyrosine Melamine Acyclovir Uric Acid Cystine Leucine Sulphonamide 10

24 hrurine 24 hrurine Guideline values Interpretation Metabolic Risk Factors Environmental Calculated Volume >2 L Sodium <200 meq Relative supersaturation ph 5.5-6.

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.

Infection Chloride Calciuria Calcium CaOx and CaP Potassium Alkali intake Relative supersaturation ratio Oxalate CaOx Magnesium CaOx, CaP Phosphate CaP Ammonium Acid excretion Saturation Index Uric

11 24 hrurine 24 hrurine Guideline values Interpretation Metabolic Risk Factors Environmental Calculated Volume >2 L Sodium <200 meq Relative supersaturation ph Chloride <200 meq Calcium <250 mg (6.25 mmoles) Potassium >50 meq Relative supersaturation ratio Oxalate <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) 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 ratio Oxalate 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 Interpretation of urinary biochemical profile Expected Daily Parameter Interpretation Values Total Volume 2.5 L Diminishes with low fluid intake, sweating, and diarrhea. ph <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. > indicates a urinary tract infection as a result of urease-producing bacteria. Creatinine mg/kg Gauges adequacy of collection mg/kg body weight in females and 20-25mg/kg body weight in males. body weight Sodium 100 meq Reflective of dietary sodium intake in the absence of excessive sweating and/or diarrhea. Can cause secondary hypercalciuria. Potassium meq Reflective of dietary potassium intake in the absence of diarrhea. A marker of dietary alkali intake. Calcium mg Direct risk factor and precipitating solute for calcium stones. Possible differences between male and female subjects (higher value in males). mg Low urinary magnesium reflects low magnesium intake, intestinal malabsorption (small bowel disease), and Magnesium 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 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 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. 320 mg Principal inhibitor of calcium stone formation. Hypocitraturia is encountered in states with intracellular acidosis Citrate 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 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:sulfateratio 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 mg Limited urinary solubility at 250mg/L. Treatment 11

Etiologies Rx Dietary and/or Pharmacologic Pathophysiology Predisposing conditions Kidney stones Data Pathophysiologic basis

urine volume Fluid - Hypercalciuria Salt and protein restriction Thiazide, alkali Hyperoxaluria Oxalate restriction - Hypocitraturia

Low urine ph Protein restriction Alkali Low urine volume Fluid - Hyperuricosuria Protein restriction Xanthine oxidase inhibitor

12 Etiologies Rx Dietary and/or Pharmacologic Pathophysiology Predisposing conditions Kidney stones Data Pathophysiologic basis Metabolic studies Randomized clinical trials Overview of therapy 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 12

Dietary Modification Dietary Modification Fluids Sodium Fluids The Panacea Protein-acid Pathophysiologic basis Metabolic studies Randomized

13 Dietary Modification Dietary Modification Fluids Sodium Fluids The Panacea Protein-acid Pathophysiologic basis Metabolic studies Randomized clinical trials Calcium Oxalate Dietary Modification Dietary Modification Fluids Sodium Protein-acid Calcium Oxalate Borghi et al NEJM

Fluids Calcium Dietary Modification Protein-acid Oxalate Sodium Food Fruits Vegetables Nuts Miscellaneous Bread/Starch Moderate Oxalate: Limit Apple,

peas, Lettuce, Lima beans Parsnips, Tomato, Turnips Chicken noodle soup dehydrated Sardines Cornbread Sponge cake, Spaghetti, Beverage/Juices Coffee

Concord grapes, Red currants, Tangerines Citrus peel Beans, Beets Tops, Roots, Greens Celery, Chard, Chive, Collards Dandelion greens, Eggplant,

Pecans Chocolate, cocoa Pepper Soybean curd Fruit cake Grits, white corn Soybean crackers Wheat Germ Beer Juices containing berries Ovaltine Tea, cocoa

14 Fluids Calcium Dietary Modification Protein-acid Oxalate Sodium Food Fruits Vegetables Nuts Miscellaneous Bread/Starch Moderate Oxalate: Limit Apple, Apricots, Peaches, Pears, Pineapple, Plums, Prunes Black currants Cherries, red Orange, edible portion Asparagus Broccoli Carrots, Corn Cucumber Green peas, Lettuce, Lima beans Parsnips, Tomato, Turnips Chicken noodle soup dehydrated Sardines Cornbread Sponge cake, Spaghetti, Beverage/Juices Coffee Cranberry juice Grape juice Orange juice Tomato juice Rich Oxalate: Avoid Blackberries, Blueberries, Raspberries, Strawberries, Dewberries, Gooseberries Concord grapes, Red currants, Tangerines Citrus peel Beans, Beets Tops, Roots, Greens Celery, Chard, Chive, Collards Dandelion greens, Eggplant, Escarole Kale, Leeks, Mustard Greens, Okra Parsley, Peppers, Pokeweed, Potatoes, Rutabagas, Spinach, Summer squash, Watercress Peanuts, Peanut butter Pecans Chocolate, cocoa Pepper Soybean curd Fruit cake Grits, white corn Soybean crackers Wheat Germ Beer Juices containing berries Ovaltine Tea, cocoa Pharmacologic Rx Pharmacologic Rx Calcium Urolithiasis Hypercalciuria Hypocitraturia Hyperuricosuria Urine ph Hypercalciuria Hypocitraturia Hyperuricosuria Urine ph 14

Ca transport Hypercalciuria Thiazide diuretics Calcium Urolithiasis Pharmacologic Rx Drug Dosage(s) Comments Hydrochlorothiazide 50mg/day Single dose is preferred 25mg twice/day Chlorthalidone

15 Ca transport Hypercalciuria Thiazide diuretics Calcium Urolithiasis Pharmacologic Rx Drug Dosage(s) Comments Hydrochlorothiazide 50mg/day Single dose is preferred 25mg twice/day Chlorthalidone Indapamide Amiloride Amiloride/ Hydrochlorothizide 25-50mg/day mg/day 5mg/day 5mg/50mg/day May cause hypokalemia and secondary hypocitraturia. Less side effects than hydrochlorothiazide. Rare occurrence of hypokalemia and hypotension. Potassium sparing. Lowers urinary calcium but to a lesser degree than hydrochlorothiazide. Maintains the hypocalciuric effect of thiazide while averting hypokalemia. Hypercalciuria Hypocitraturia Hyperuricosuria Urine ph RCT: Decrease calciuria and stone events High Solubility CaCitrate - Hypocitraturia Dual role of citrate in urine H 2 PO 4 - H 3 PO 4 3H + CO 2 3HCO 3 - Calcium Urolithiasis Pharmacologic Rx Citrate 3- H + Ca 2+ HPO 4 2- Calcium phosphate complexes Low Solubility Citrate 3- CO 2 Hypercalciuria Hypocitraturia Hyperuricosuria Urine ph Potassium Bicarbonate Potassium Citrate meq base/day RCT: Raises urine citrate and decrease stone events 15

Calcium Oxalate Hyperuricosuria Uric Acid Urolithiasis Pharmacologic Rx Calcium Oxalate

Allopurinol 200-300 mg/day Feboxustat 40-80 mg/day Hyperuricosuric Calcium Urolithiasis

and stone events in isolated hyperuricosuria O H N C H 7 1 C N C O C C N N 3 H H + - O 9

16 Calcium Oxalate Hyperuricosuria Uric Acid Urolithiasis Pharmacologic Rx Calcium Oxalate Soluble complex Calcium Oxalate Insoluble complex Sodium Urate Xanthine oxidase inhibitor Allopurinol mg/day Feboxustat mg/day Hyperuricosuric Calcium Urolithiasis (HUCU) Hypercalciuria Hypocitraturia Hyperuricosuria Urine ph RCT: Reduces hyperuricosuria and stone events in isolated hyperuricosuria O H N C H 7 1 C N C O C C N N 3 H H + - O 9 Uric acid nephrolithiasis: A disease of urinary ph pk~ 5.4 Uric acid Low ph High ph Urate -Solubility limit 16

Urine ph Pharmacologic Rx -Solubility limit Potassium

Urolithiasis Hypercalciuria Hypocitraturia Hyperuricosuria

stone events out in in IL2-3 N EL3-4 C158 N C109 1 2 4 3 5

L-Arginine L-Lysine L-Ornithine L-Cystine L-Leucine

L-Tryptophan Cystine has low solubility CSSC Insoluble x

17 Urine ph Pharmacologic Rx -Solubility limit Potassium Bicarbonate Potassium Citrate meq base/day Cystine Urolithiasis Hypercalciuria Hypocitraturia Hyperuricosuria Urine ph Chelate cystine RCT: Raises urine ph and decrease stone events out in in IL2-3 N EL3-4 C158 N C rbat/4f2 C II b 0,+ AT Urine C Amino acid L-Arginine L-Lysine L-Ornithine L-Cystine L-Leucine L-Phenylalanine L-Histidine L-Methionine L-Alanine L-Tryptophan Cystine has low solubility CSSC Insoluble x Amino Acid x Autosomal recessive pka COOH NH3 Cystine

NH 2 CH 3 H H CH 3 HOOC C C SH H CH 3 HOOC C N C C SH H = O CH 3 Cystine

D: Drug C: Cystine Penicillamine DSSD + CS CSSC + DSSD α-mercaptopropionylglycine

Cysteine or Cysteine-drug complex Agenda and take-home points General concepts

Epidemiology Common. Disabling. Expensive.

18 NH 2 CH 3 H H CH 3 HOOC C C SH H CH 3 HOOC C N C C SH H = O CH 3 Cystine solubility (mg/ml) Risk of CaP! D: Drug C: Cystine Penicillamine DSSD + CS CSSC + DSSD α-mercaptopropionylglycine (Tiopronin) DS + CSSD 2CSSD CSSC + DS CS + CSSD ph Insoluble Cysteine or Cysteine-drug complex Agenda and take-home points General concepts Epidemiology Pathogenesis & Etiology Treatment General concepts A systemic disease. Epidemiology Common. Disabling. Expensive. Pathogenesis & Etiology Diverse causes converging on abnormal urine chemistry. Urine. Stone. Imaging. Blood. Treatment Medically treatable. Dietary. Pharmacologic. 18

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