5/19/2021

Disclosures

Metabolic Work-up & Prevention of . W. Britt Zimmerman does not have any financial conflicts of interest to disclose as it relates to this presentation. Nephrolithiasis

W. Britt Zimmerman, DO, FACOS Associate Professor & Interim Chairperson Osteopathic Surgical Specialties Michigan State University College of Osteopathic Medicine 5/20/2020

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Objectives . Background

Discuss the metabolic evaluation for urolithiasis . Evaluation Investigate diet therapies for treatment of kidney stones Evaluate pharmacological therapies for management of kidney stones . Dietary therapies Review follow-up for to ensure optimization of patient regarding urolithiasis . Pharmacological therapies

. Follow-up

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Background Evaluation

. 1 in 11 individuals in the US at sometime in their life will suffer from . A clinician should perform a screening evaluation consisting of a kidney stones detailed medical and dietary history, serum chemistries and urinalysis on a patient newly diagnosed with kidney or ureteral stones. . Lifetime recurrence rate is 50%

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Evaluation Evaluation

. High risk patients: . Medical, genetic, or anatomic conditions that increase stone risk . Large stone burden (large stones, multiple stones, bilateral stones . (e.g., gout, Crohn's, cystinuria, hyperparathyroidism, sarcoidosis, polycystic kidney . Patients with recurrent episodes getting stones disease, renal tubular acidosis, medullary sponge kidney, etc.) . Nephrocalcinosis . Pediatric stone formers . Solitary kidney . Uncommon stone composition (e.g., cystine, uric acid, etc.) . Stones arising from urinary infection e.g., struvite . Professions: . Family history of stones . Pilots, bus drivers, truck driver etc. (stone pain while these people are working can cause danger to others)

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. Background Evaluation

. Evaluation . Clinicians should obtain or review available imaging studies to quantify stone burden. . Dietary therapies . Kidney ureters bladder (KUB) X-ray . Renal ultrasound (RUS) . Pharmacological therapies . CT scan of the abdomen & pelvis, preferably without contrast • (Renal stone protocol CT scan)

. Follow-up

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Evaluation Evaluation

. Metabolic testing should consist of one or two 24-hour urine collections . Clinicians should not routinely perform “fast and calcium load” testing . 24-hour urine should include at minimum management of pH, total volume, to distinguish among types of hypercalciuria. calcium, oxalate, citrate, uric acid, sodium, potassium, and creatinine. Other analysis may be obtained at the clinical clinician's discretion.

Normal urinary creatinine excretion per 24 hours (mg/kg/day)

Male 14–26

Female 11–20

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. Background Diet Therapies

. Evaluation . Clinicians should recommend to all stone formers a fluid intake that will achieve a urine volume of at least 2.5 liters daily. . Dietary therapies . Clinicians should counsel patients with calcium stones and relatively . Pharmacological therapies high urinary calcium to limit sodium intake and consume 1,000 mEq or 1,200 mg per day of dietary calcium. . Follow-up

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Diet Therapies Diet Therapies

. Clinicians should counsel patients with calcium oxalate stones and . Clinicians should counsel patients with uric acid stones or calcium relatively high urinary oxalate to limit intake of oxalate-rich foods and stones and relatively high urinary uric acid to limit intake of non-dairy maintain normal calcium consumption. animal protein.

. Clinicians should encourage patients with calcium stones and relatively . Clinicians should counsel patients with cystine stones to limit sodium low urinary citrate to increase their intake of fruits and vegetables and and protein intake. limit non-dairy animal protein.

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. Background Hypercalciuria (urinary calcium greater than 200 mg/day)

. Evaluation Type of Serum calcium PTH Fasting urinary Intestinal Treatment Hypercalciuria calcium calcium absorption . Dietary therapies Absorptive N N or ↓ N ↑ (1) Renal N ↑ (2) ↑ ↑ (2) Low-sodium . Pharmacological therapies diet, thiazides, K-citrate Resorptive ↑ ↑ (1) ↑ ↑ (2) Parathyroidect . Follow-up omy Unclassified N N ↑ ↑ ?

1 = Primary change (i.e., a primary effect of the disease) 2 = Secondary change (i.e., I response to the primary problem) 17 18

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Renal Hypercalciuria Resorptive Hypercalciuria (Primary Hyperparathyroidism)

Renal Calcium Leak: Decrease Hypercalciuria, which causes an increase in PTH and vitamin Increase PTH Increase calcium reabsorption of Calcium in kidney D that keeps serum calcium normal Secretion release from bone Increase filtered calcium load by the kidney Decrease circulating calcium Increase 1,25-OH Increase calcium Vitamin D absorption

Increase calcium release Increase PT secretion from bone Increase filtered calcium load by the Hypercalciuria, but the urinary excretion of Increase calcium kidney calcium is not enough to reduce serum Increase 1,25-OH Vitamin D absorption calcium to normal

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Absorptive Hypercalciuria Absorptive Hypercalciuria Treatment

Increase intestinal Type Hypercalciuria Occurs if Dietary Serum Levels Treatment calcium absorption Calcium intake is

Increase circulating Increase filtered calcium load by calcium kidney None Low High Calcium Phosphorus Parathyroid Hormone Decrease PTH I - + + Normal Normal Normal or Cellulose sodium Secretion Decreased phosphate or thiazide diuretic II - - + Normal Normal Normal or Low calcium diet, low Decreased sodium diet, high fluid Decrease proximal intake tubule calcium Hypercalciuria that maintains a reabsorption in normal serum calcium III - + + Normal Decreased Normal or Oral phosphate kidney Decreased

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Absorptive Hypercalciuria Treatment Absorptive Hypercalciuria Treatment Type Hypercalciuria Occurs if Dietary Serum Levels Treatment Type Hypercalciuria Occurs if Dietary Serum Levels Treatment Calcium intake is Calcium intake is

None Low High Calcium Phosphorus Parathyroid None Low High Calcium Phosphorus Parathyroid Hormone Hormone I - + + Normal Normal Normal or Cellulose sodium I - + + Normal Normal Normal or Cellulose sodium Decreased phosphate or thiazide Decreased phosphate or thiazide diuretic diuretic II - - + Normal Normal Normal or Low calcium diet, low II - - + Normal Normal Normal or Low calcium diet, low Decreased sodium diet, high fluid Decreased sodium diet, high fluid intake intake III - + + Normal Decreased Normal or Oral phosphate III - + + Normal Decreased Normal or Oral phosphate Decreased Decreased Treatment: Treatment: Cellulose sodium phosphate – 5gm po twice daily or 3 times daily • Low calcium diet Thiazide diuretics (hydrochlorothiazide) • Low sodium diet • High fluid intake to keep urine output greater than 2 L/day 23 24

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Absorptive Hypercalciuria Treatment Hypomagnesuria (urine magnesium less than 50 mg/day) Type Hypercalciuria Occurs if Dietary Serum Levels Treatment Calcium intake is . Magnesium increases of the solubility of calcium, phosphate) possibly None Low High Calcium Phosphorus Parathyroid oxalate. Therefore, it inhibits calcium stone formation. Hormone I - + + Normal Normal Normal or Cellulose sodium Decreased phosphate or thiazide diuretic . Hypomagnesuria is associated with hypocitraturia 66% of the time. II - - + Normal Normal Normal or Low calcium diet, low Decreased sodium diet, high fluid intake . Treatment–increase dietary magnesium or use magnesium supplement III - + + Normal Decreased Normal or Oral phosphate Decreased

Treatment: Oral phosphate, e.g., Kphos neural oral 3 to 4 times per day Contraindicated in renal dysfunction

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Xanthinuria Hyperuricosuria urea (urinary uric acid > 600 mg/day)

. Xanthine area may cause xanthine stones (radiolucent). . Characteristics of stone disease associated with hyperuricosuria . Causes of Anuria . High urine uric acid level. . Inherited deficiency and xanthine oxidase. . Hyperuricosuria increases the risk of both calcium oxalate and uric acid stones. . Allopurinol (xanthine oxidase inhibitor). . Urine pH < 5.5 and absence of other causes of acidosis. . Treatment: . low purine diet . Stop allopurinol . Alkalinization is not effective.

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Hyperuricosuria urea (urinary uric acid > 600 mg/day) Hyperuricosuria urea (urinary uric acid > 600 mg/day)

. Causes of the hyperuricosuria . Mechanism of stone formation . Gout . Urine urate crystals form a nidus for formation of calcium or urate stones (a . Lesch-Nyhan disease–defect in Hg PRT enzyme process called nucleation) . Myeloproliferative disorders . Uric acid antagonizes naturally occurring macromolecular inhibitors calcium stone formation . Chemotherapy–results of massive cellular destruction . Glycogen-storage disease . Chronic diarrhea–results in urine acid urine and low urine output . Excessive oral intake of purine rich foods. . Uricosuric medications –salicylate, probenecid

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Hyperuricosuria urea (urinary uric acid > 600 mg/day) Hyperuricosuria urea (urinary uric acid > 600 mg/day)

. Treatment . Treatment continued . Treatment obstructing stones accordingly . Medications used to prevent recurrent stones . Eliminate possible causes, e.g. treat diarrhea • In patients with calcium oxalate stones and hyperuricosuria, start allopurinol (adult dose with normal renal function: allopurinol 300 mg p.o. daily) and/or alkalinize urine to pH ≥ 6.5 with . Diet change potassium citrate. • Moderate sodium restriction • In patients with uric acid stones and hyperuricosuria, first-line therapy is optimization of • Low purine diet–decreased red meat, poultry, and fish urine pH to ≥ 6.5 with potassium citrate. If this fails to alkalize urine or uric acid stones still • Hydration recur, start allopurinol . Allopurinol is often started before chemotherapy to prevent formation of uric acid stones to minimize renal dysfunction associated with a stone.

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Hypocitraturia (Urinary Citrate < 300 mg/day) Hyperoxaluria (urine oxalate> 45 mg/day) . Causes of hypocitraturia . Urinary oxalate has 2 sources • Causes of hyperoxaluria • Dietary intake of oxalate, e.g., beets, spinach, . Acidosis . 80% of serum oxalate is chocolate/cocoa, liver, tea, peanuts, rhubarb, . Hypokalemia–causes and intracellular acidosis. synthesized by the liver strawberries, potatoes, or its precursors (vitamin C). . Urinary tract infection (UTI) . Dietary–20% arises from intake of • Pyridoxine (vitamin B6) deficiency–pyridoxine oxalate or vitamin C is a cofactor for alanine–glyoxylate . Mechanism of stone formation aminotransferase (AGT), liver enzymes that . Citrate complexes with calcium inhibits calcium crystallization. If urinary citrate is metabolize oxalate. • Primary hyperoxaluria: defect in the AGT low, calcium stones are more likely to form. enzyme causes excess oxalate release by the . Acidosis decreases his citrate in the urine and increase his calcium and phosphate liver. • Enteric hyperoxaluria: Crohn's disease, ileal in the urine. These all contribute to stone formation. resection, and jejunal ileal bypass can cause . Hypomagnesuria is associated with hypocitraturia in 66% of cases fat malabsorption. • Chronic diarrhea . Treatment: Potassium citrate to correct both acidosis and hypokalemia and alkalize the urine. 33 34

Hyperoxaluria (urine oxalate> 45 mg/day) Hyperoxaluria (urine oxalate> 45 mg/day)

. Treatment . Treatment (continued) . Primary hyperoxaluria is treated with pyridoxine 20 to 50 mg by BID to QID, low . Oral calcium supplement during meals to saturate oxalate and prevent oxalate oxalate diet, and fluid intake. uptake . Liver transplant (correct the enzyme defect) and renal transplant (for renal . Cholestyramine prevents preventing them from increasing colonic oxalate failure) may be required. permeability. It does not cause sustain reduction in urinary oxalate. . Treat the underlying causes (e.g., dietary access, Crohn's, etc.) . If the patient has diarrhea, hydration is warranted

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Cystinuria (Urinary Cystine > 30 mg/day) Cystinuria (Urinary Cystine > 30 mg/day)

. Cystinuria is an autosomal recessive defect and that impairs renal . Heterozygotes usually have urinary assisting <400 mg/day and usually absorption of 4 amino acids (cystine, ornithine, lysine, arginine). do not form cystine stones. Homozygote usually have urinary cystine > Leading to elevated urinary cystine. In the urine, cystine forms went to 400 mg/day and usually do form cystine stones. cystine molecules join be disulfide bond (cystine is a cystine-cystine . Methionine is a major dietary precursor of cystine. complex) . Cystine stones form in acid urine and may form staghorn stones. . Urolithiasis is the only known pathology of cystinuria . Cystine crystals are hexagon-shaped. . Diagnosis is made by a positive cyanide nitroprusside test. Family members should be screened with cyanide nitroprusside test.

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Cystinuria (Urinary Cystine > 30 mg/day) Cystinuria (Urinary Cystine > 30 mg/day)

. Prevention . Treatment . Oral hydration – this reduces the solubility of cystine . Large obstructing stones should be managed in the usual fashion. Cystine stones . Low-sodium diet – this decreases cystine excretion by the kidney can be resistant to ESWL and pulsed (coumarin dye) laser. Dissolution is typically used as an add adjunct to standard treatment. . Low methionine diet – this decreases cystine production. Minimize intake of animal protein (meat), eggs, wheat, milk, and cheese . Small non-obstructing stones can be dissolved. . In patients who form stones or had urine testing > 300 mg/day, alkalize the urine . Dissolution–calculi of the urine to pH greater than 7.5 preferably with oral to pH > 7.5 with oral potassium citrate potassium citrate.

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Cystinuria (Urinary Cystine > 30 mg/day) Cystinuria (Urinary Cystine > 30 mg/day)

. Thiol therapy–these drugs form disulfide bonds with cysteine (creating a . Captopril – likely not effective. thiol-cysteine complex), which increases the solubility of cysteine. . Every 3 to 6 months during thiol therapy, monitor the following: . Tiopronin (Thiola®) - lower risk of side effects . Liver function test . D-penicillamine . Serum albumin . Tiopronin and d-penicillamine have similar effects . Complete blood count . 24-hour urine for protein and cysteine, urinalysis, and urine pH . Consider checking a KUB every 6 to 12 months.

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High Urine Sodium (Urine Sodium> 200 mEq/day) Renal Tubular Acidosis (RTA) Type I

. High sodium diet increases urine calcium and decreases urinary citrate, . Type I RTA is the only RTA associated with urolithiasis and is the most which increases the risk of urolithiasis common form of RTA. . A high urine sodium suggests a high dietary intake of sodium. . Type I RTA is caused by impaired secretion of hydrogen ions in the distal . Patients on loop diuretics or thiazide diuretics may have a high urine sodium nephron, which results in inability to acidify the urine. In other words, despite low dietary sodium intake. the kidney is unable to adequately secrete acid in the urine.

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Renal Tubular Acidosis (RTA) Type I Renal Tubular Acidosis (RTA) Type I

. Clinical manifestations . Complete RTA–presents with urine pH consistently > 6.0, metabolic . Hyperchloremic metabolic acidosis–usually with serum bicarbonate (carbon acidosis, and hypokalemia oxide) ≤20 mmol/L. The acidosis can cause osteomalacia . Incomplete RTA–presents with urine pH consistently > 6.0, but . Hypokalemia–may cause muscle weakness or paralysis metabolic acidosis and hypokalemia are absent. . Urine pH consistently greater than 6.0 . An oral ammonium chloride loading test is often necessary to diagnose . Urolithiasis incomplete RTA. . Nephrocalcinosis . Renal cyst–usually multiple and bilateral.

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Renal Tubular Acidosis (RTA) Type I Renal Tubular Acidosis (RTA) Type I

. Evaluation for suspected type I RTA . Patients with calcium phosphate stones nephrocalcinosis, bilateral . Obtain a serum creatinine, potassium, chloride, and bicarbonate stones, or multiple/recurrent stones should be evaluated for RTA. . Urinalysis–urine pH should be measured using the second voided morning urine . Acidosis and hypokalemia increase the risk of stone formation by after the patient has fasted overnight causing hypocitraturia, hypercalciuria, and hyperphosphaturia. . If incomplete RTA is suspected, and ammonium chloride loading test can confirm . Treatment–oral potassium citrate or bicarbonate the diagnosis • RTA is present when urine pH is > 5.4 after oral intake of ammonium chloride . Follow the patients with KUB x-ray, serum bicarbonate, and serum potassium.

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Nonidentified Metabolic Abnormality Pharmacologic Therapies - Standard . Clinicians should offer potassium citrate therapy to patients with . Potassium citrate prevents calcium stones in patients with normal urine recurrent calcium stones and low or relatively low urinary citrate. citrate. . Clinicians should offer allopurinol to patients with recurrent calcium . Thiazides prevent calcium stones in patients with normal urine calcium. oxalate stones who have hyperuricosuria and normal urinary calcium. . Patients with recurrent calcium stones despite normal 24-hour urine testing may be treated with potassium citrate with or without a thiazide.

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Pharmacologic Therapies - Standard Pharmacologic Therapies – Expert Opinion

. Clinicians should offer thiazide diuretics and/or potassium citrate to . Clinicians should offer potassium citrate to patients with uric acid and patients with recurrent calcium stones in whom other metabolic cystine stones to raise urinary pH to an optimal level. abnormalities are absent or have been appropriately addressed and . Clinicians should not routinely offer allopurinol as first-line therapy to stone formation persists. patients with uric acid stones. . Clinicians should offer thiazide diuretics to patients with high or . Clinicians should offer cystine-binding thiol drugs, such as tiopronin, to relatively high urine calcium and recurrent calcium stones. patients with cystine stones who are unresponsive to dietary modifications and urinary alkalinization or have large recurrent stone burdens.

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Pharmacologic Therapies - Option . Background

. Clinicians may offer acetohydroxamic acid (Lithostat®) to patients with . Evaluation residual or recurrent struvite stones only after surgical options have been exhausted. . Dietary therapies

. Pharmacological therapies

. Follow-up

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Follow-up Follow-up

. Clinicians should obtain a single 24-hour urine specimen for stone risk . Clinicians should obtain periodic blood testing to assess for adverse factors within six months of the initiation of treatment to assess effects in patients on pharmacological therapy. response to dietary and/or medical therapy. . Clinicians should obtain a repeat stone analysis, when available, . After the initial follow-up, clinicians should obtain a single 24-hour urine especially in patients not responding to treatment. specimen annually or with greater frequency, depending on stone activity, to assess patient adherence and metabolic response.

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Follow-up Conclusions

. Nephrolithiasis is a common problem with multiple causes . Clinicians should monitor patients with struvite stones for reinfection . Prompt evaluation of patients with nephrolithiasis is important to with urease-producing organisms and utilize strategies to prevent such prevent long term complications occurrences. . Modification of dietary consumption is an important treatment modality in the management of nephrolithiasis . Clinicians should periodically obtain follow-up imaging studies to assess . Stone composition should guide pharmacological therapy for stone growth or new stone formation based on stone activity (plain . abdominal imaging, renal ultrasonography or low dose computerized Consistent patient follow-up impacts the quality of patient’s outcomes. tomography).

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