RISK FACTORS AND TREATMENT STRATEGIES FOR URINARY STONES Review of NASA s Evidence Reports on Human Health Risks

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1 Mayo Clinic O Brien Urology Research Center RISK FACTORS AND TREATMENT STRATEGIES FOR URINARY STONES 2017 Review of NASA s Evidence Reports on Human Health Risks John C Lieske, MD July 27, 2017

2 What types of stones are there? All stones submitted to Mayo Medical Labs in 2010 (n=48,446) Number Percent Majority Calcium oxalate 29, % Majority Apatite % Uric Acid % Struvite % Artifact % Brushite % Other % Cystine % Ammonium urate % Drug % Rare 1 } 83.4% Ca

3 Supersaturation RSS <1 1 >1 * DG <0 0 >0 * EQUIL2: computer simulation of supersaturation for calcium oxalate, uric acid, calcium phosphate

4 LABORATORY EVALUATION URINE SUPERSATURATION PROFILE Needed to calculate supersaturation Volume* ph* Calcium* Oxalate* Citrate* Uric Acid* Phosphorous Sodium Potassium Magnesium Sulfate Creatinine Potential treatment targets Complete collection? Many elements also provide valuable dietary clues (sodium, protein, vegetable intake)

5 45 yo airline pilot Case 1 Passed first stone in early 30s; made of calcium Second similar episode a few years later Third stone at age 42: 90% Calcium oxalate monohydrate 10% Hydroxyapatite (form of calcium phosphate)

6 Case 1

7 Fate of preexisting stones Burgher Progression of nephrolithiasis long-term outcomes with observation of asymptomatic calculi J Endourol 18: , 2004

8 24 h urine Ref 25:75% med range Volume 2388 ml ml Osm 417 mosm/kg mo/kg ph Calcium 447 mg mg Oxalate 0.26 mm mm Citrate 810 mg mg Uric acid 740 mg mg Phos 1003 mg mg Sodium 179 meq meq Chloride 160 meq meq Potassium 48 meq meq Sulfate 20 mmol mmol Mag 162 mg mg Creatinine 2045 mg mg Labs- Case 1 Equil SS DG UA Blood Sodium 142 meq/l Pot 4.3 meq/l Chloride Ref med 104 meq/l Bicarb 27 meq/l BUN 13 mg/dl Creat 1.2 mg/dl Calcium 9.7 mg/dl Phos 3.3 mg/dl Uric Acid 7.7 mg/dl 25:75% range CaOx CaP (Ap) CaP (Br)

9 Hypercalciuria Idiopathic (genetic) Primary hyperparathyroidism Immobilization Paget s Disease Vitamin D/ Calcium excess Sarcoidosis Hyperthyroidism/Cushings Renal tubular acidosis

10 Calcium oxalate urolithiasis: overall risk factors Often many Hypercalciuria 39% Hyperuricosuria 39% Hyperoxaluria 16% Low urine citric acid 19% No apparent abnormality 19%

11 Conservative dietary treatment for idiopathic CaOx Stones Drink fluid! Normal dietary calcium 1200 mg/day in dairy Avoid calcium pills Low sodium Moderate animal protein (0.8 mg/kg) (Avoid high oxalate foods Tailored to patient urine and risks)

12 Genetic hypercalciuria: pharmacologic treatments Thiazide diuretics Indapamide or chlorthalidone have longer halflives and can be given once daily Be careful with dosing and close follow-up Potassium Citrate Citrate is a crystallization inhibitor Also can reduce urine calcium (? Effects on bone via neutralizing acid load)? Orthophosphate (K Phos neutral) Indirect effects on vitamin D and urine calcium Also a crystal growth inhibitor Large doses/ GI side effects/ no randomized trial

13 What is oxalate?

14 Hyperoxaluria: What is the relevant concentration? Normal: Ca Ox stone formers: Enteric hyperoxaluria: Primary hyperoxaluria: up to 0.4 mm/day (40 mg/day) up to 0.5 mm/day (50 mg/day) mm/day ( mg/day) mm/day ( mg/day)

15 Calcium phosphate is very insoluble at high ph! Distal Renal Tubular Acidosis Tiseleus HG: A simplified estimate of the ionactivity product of calcium phosphate in urine. Eur Urol 1984: 10: Abnormally high urine ph, even in the presence of systemic acidosis Causes: Autoimmune disease, dysprotienemias, drugs, idiopathic Urinary consequences: hypercalciuria, hypocitraturia, high ph; all favor calcium phosphate formation (Brushite) Rx: Citrate, meq/day Thiazide diuretic But tough! Need to monitor supersaturation closely.

16 Formal Test of distal RTA Ammonium Chloride 100 mg/kg PO night before (10PM) Next morning (6AM) Urine ph < 5.5: normal If urine ph > 5.5 venous ph < 7.3 and bicarb <20: distal RTA Venous ph >7.3 or bicarb > 20: Re-dose ammonium chloride Repeat urine and blood studies in 4 hrs

17 Incomplete distal RTA Run chronically high urine ph with normal serum bicarbonate What is this? Genetic? Acquired?

18 In the absence of RTA, renal excretion of citrate parallels net GI absorption Sakhaee et al: J Bone Miner Res : , 1993

19 Causes of low urine citrate GI losses (diarrhea; ostomy) RTA Acid rich diet (high animal protein) Hypokalemia

20 Uric acid is very insoluble at low ph (pk 5.3) Causes of an abnormally acidic urine Diarrhea states; illeostomy Diet (meat protein excess) Low renal ammoniagenesis (insulin resistance; CKD) RX: Lower protein More volume Citrate

21 Struvite: Infection Cystine: genetic Other Stones

22 Evidence that Nephrolithiasis is Familial Kidney stones develop ~3X more commonly in those with a positive family history 4-12% without 16-37% with Estimates of heritability (h 2 ): 46-63% Familial clustering index for nephrolithiasis vs. 2.0 for DM and HTN Croatian island stone incidence study: Low inbreeding villages = 1.5% Moderate inbreeding villages = 2.3% High inbreeding villages = 5.4%

23 Calcium metabolism in first time stone formers: subtle shift in 1,25 vitamin D levels Number 1,25 Vitamin D (or Serum Ca)

24 JASN 2014

25 Urinary Idiopathic risk Causes Calcium oxalate Diet Rx urolithiasis Medications Hypercalciuria Hyperoxaluria Hypocitraturia Genetic Hyperparathyroid Diet Fat malabsorption Diet GI losses Low salt? Low protein Low oxalate Low fat DASH diet (more vegan) Fruit juices Hyperuricosuria Diet Lower animal protein Low volume/ concentrated urine Habit/ job, environment More fluids, learned new habits Thiazides Potassium citrate Calcium supplements (only EH) Potassium citrate Allopurinol?Vasopressin antagonism

26 Considerations/Gaps Imaging screen for pre existing stones/ new stones after flight CT vs ultrasound Required to be metabolically inactive Preemptive surgery for pre-existing stones If so what size Metabolic screen Stone formers vs Everyone? Circumstances of this screen (diet, etc) Genetic screen for risk factors/predisposition? Report is focused on the environmental factors Precision medicine approach Treatments Generalized vs Individualized Who would be excluded based upon stone risk (if anyone)

27 New treatment targets? Directed at mechanisms of plaque and plug?

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