NEPHROLITHIASIS Etiology, stone composition, medical management, and prevention Urology Division, Surgery Department Medical Faculty, University of Sumatera Utara

Epidemiology Prevalence 2-3%, maybe  in mountainous, desert & tropical areas : = 3 : 1, peak age onset 20-40 yrs 25% stone formers have a family history Uric acid and Ca stones more frequent in, infectious stones more common in  The most common kinds of stones are calcium oxalate, uric acid, struvite and cysteine

Composition of renal stones Calcium oxalate 36 – 70% Calcium phosphate (hydroxyapatite) 6 – 20% Mixed Ca oxalate & Ca phosphate 11 – 31% Mg ammonium phosphate (struvite) 6 – 20% Uric acid 6 – 17% Cystine 0.5 – 3% Miscellaneous (xanthine, silicates & drug metabolites) 1 – 4%

Factors influencing stone formation Genetics 1. Idiopathic hypercalciuria 2. Cystinuria 3. Primary hyperoxaluria, type 1 & 2 4. Lesch-Nyhan syndrome is an X-linked disease causing hyperuricemia (def hypoxanthine- guanine fosforibosiltransferase) 5. Familial renal tubular acidosis , Ehlres-Danlos syndrome, Marfan’s syndrome, Wilson’s disease

- >> protein & sodium intake   risk Ca stone Environmental 1. Dietary factors - >> protein & sodium intake   risk Ca stone - >> purine diets   urine pH  hyperuricosuria - B6 deficiency   formation & excretion oxalate - dehydration, inadequate fluid intake, vit C excess, Ca supplements, Ca-containing antacids

2. Geographical factors - higher during summer months - higher in southeast United States and lower in Mid-Atlantic and Northwest regions

Stone formation Crystallization - stone  salts that precipitate out of urine - the point of saturation of a salt in solution is called the solubility product (Ksp) - when the product of the components of a salt (e.g. calcium and oxalate) exceeds Ksp, salt crystals will precipitate out of solution - crystallization is based on Ksp, pH, and the presence of stone inhibitors and promoters

Nucleation - is the process by which stones form around a core, or nucleus - homogeneous stone nuclei form in solution - heterogeneous stone nuclei form around existing structures, such as cellular debris Aggregation - crystals join together to form larger clumps

TYPES OF STONE CALCIUM OXALATE Recommended treatment : - absorptive : Ca restriction, sodium cellulose phosphate, thiazides,  fluid intake - other types : thiazide &  fluid intake

URIC ACID STONES 5-10% of all stone Urine pH < 5.5 Associated with  uric acid in urine, not necessarily associated with hyperuricemia Secondary causes : gout (20%), chemoth/ for myeloproliferative cancer Most common radioluscent

Th/ : dissolve : -  fluids, alkali (citrate th/), allopurinol, protein restriction - aim urine output > 2500 ml/day - potassium citrate or sodium bicarbonate  achieve urine pH 6.5-7.0  avoid pH >7.0  can precipitate ca phosphate - if hyperuricemic or hyperuricosuric  allupurinol

STRUVITE STONES Composed of Mg ammonium phosphate crystals = infection stones or triple phosphate stone Staghorn calculi are typically struvite stone Caused by infection with urease-producing bacteria : - proteus id the most common - urease hydrolized urea to form ammonia  alkalinizes the urine,  pH and allows crystals to form

- AB to prevent infection / stone recurrence Urine pH will be >7.2 Th/ : - surgery - AB to prevent infection / stone recurrence - irrigation with acidic solution  successful but requires lengthy, complicated treatment and  costs  danger : risk of sepsis, hypermagnesemia - acetohydroxamic acid :  inhibit urease;  20-70% severe side effect

CYSTINE STONES 1% of all stones Congenital disorders, autosomal recessive Caused by a defect in cystine reabsorption in the proximal tubule Cystine poorly soluble at normal pH (pKa 8.3) Crystal form  benzene ring on microscopy

Th/ : - low methionine / sodium diet - hydrate to 3 L urine output/day - alkalinize urine : potassium citrate complex cystine - ESWL not effective

CALCIUM PHOSPHATE STONE - urine pH > 5.5 - hypocitraturia - 70% of adults with type 1 RTA have stones - 80% are women - associated with renal cyst

Inhibitors of CaPO4 crystallization : - Mg - pyrophosphate - citrate - nephrocalcin Th / : - potassium bicarbonate or potassium citrate  correct acidosis &  urine citrate -  fluids - thiazides if hypercalciuric

OTHER STONES Dihydroxyadenine  radioluscent Xanthine  radioluscent Matrix  radioluscent Ammonium acid urate Triamterene Indinavir  radioluscent

MEDICAL MANAGEMENT DIETARY PREVENTION - fluids :  urine output   stone formation if possible maintain >2.5 L urine/day - coffee, tea, beer, wine   stone risk - lemon juice   urinary citrate   risk - grapefruit juice   risk PROTEIN -  dietary protein   urine Ca/uric acid/oxalate &  urine citrate  low/moderate protein intake is desirable

- except in case of absorptive hypercalciuria,  Ca intake   stone risk  Ca binds intestinal oxalate  prevent its absorption - unless absorptive hypercalciuria  maintain adequate calcium intake SODIUM - dietary sodium   urinary sodium  has not been proven to  stone risk  sodium in moderation

ASCORBIC ACID (VITAMIN C) - metabolized to oxalate -  vit C intake   urinary oxalate - advice : vitamin C in moderation OXALATE - tea, instant coffee, spinach, chocolate, nuts  oxalate (+)   increase urinary oxalate - high-oxalate foods in moderation for Ca oxalate stone former

PHARMACOLOGICAL PREVENTION THIAZIDES - HCTZ 25-50 mg or chlorthalidone 12.5-25 mg (up to 100mg) - start with small dose, titrate as needed

- Inhibits Ca oxalate crystallization CITRATE - Inhibits Ca oxalate crystallization - effective for hypocitraturic stone disease - potassium citrate 10-20 mEq w/meals - side effects : GI intolerance ALLOPURINOL - inhibits xanthine oxidase &  uric acid prod - use in uric acid & hyperuricosuric Ca oxalate stone - 300 mg/o, max 800 mg -  dose in renal failure

PHOSPHATE (ORTHOPHSOPHATE) -  vit D level   urinary Ca excretion -  urine pyrophosphate & citrate - clinical benefits are uncertain MAGNESIUM -  urinary citrate - clinical benefits uncertain

SODIUM CELLULOSE PHOSPHATE - binds Ca in the gut and inhibits absorption - indicated for use in absorptive hypercalciuria - 5 g with meals ANTIBIOTICS - long-term prophylaxis for struvite stone after surgical treatment - drug should be culture specific

SUMMARY The most common type is calcium oxalate. Uric acid stones form at pH <5.5. Primary treatment and prevention is to alkalinize the urine; surgery is also an option Struvite stone are composed of magnesium ammonium phosphate crystals. They are classically caused by infection with a urease-producing bacterium. Urinary pH is >7.2. treatment is surgery & antibiotics

Cystine stones  caused by a congenital autosomal recessive disorder. Treatment : urinary alkalinization Calcium phosphate stones  associated with type 1 RTA Dietary interventions to prevent stones include  fluid intake,  protein intake and  sodium intake Pharmacological interventions to prevent stones include thiazides, citrate, allopurinol, sodium cellulose phosphate

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