DETAILED METABOLIC WORKUP & MEDICAL

MANAGEMENT IN UROLITHIASIS

Gaurav NaharDNB

Urology(Std.)MMHRC

GOALS OF M.E.

Why?• The main goal of metabolic evaluation

isto prevent recurrent stone formation

in high-risk stone producers,to prevent further growth of any

existing stones, &to prevent extrarenal complications in

associated systemic disorders.

CHARACTERISTICS

It should be• simple to perform,• economically viable,• provide information that can be

applied toward a selective, rational therapy of stone disease.

Selection of Patientsfor Metabolic Evaluation

• First-time “stone formers”-50% risk of recurrence within subsequent 10 years.

• Stone clinic effect: “single stone formers” placed on a conservative program of high fluid intake alone or combined with avoidance of dietary excess revealed a low incidence of recurrent stone disease.

• Decision to thoroughly investigate a first-time stone former should ideally be shared by the physician and the patient.

Contd...

• Formation of a first stone may be the harbinger of a more severe underlying systemic disorder such as renal tubular acidosis, bone disease, or hypercalcemia due to hyperparathyroidism.

• In such patients, metabolic evaluation is justified solely to make the correct diagnosis in order to prevent extrarenal complications.

TIMING

When?• At least 1 month after stone passage

or stone removal, allowing the patient to return to their normal routine.

Indications for a Metabolic Stone Evaluation

Who ?• Recurrent stone formers• Strong family history of stones• Intestinal disease (particularly chronic diarrhea)• Pathologic skeletal fractures• Osteoporosis• History of urinary tract infection with calculi• Personal history of gout• Infirm health (unable to tolerate repeat stone episodes)• Solitary kidney• Anatomic abnormalities• Renal insufficiency• Stones composed of cystine, uric acid, struvite• Children

Abbreviated Protocol for Low-Risk,Single Stone Formers

History• Underlying predisposing conditions• Medications(calcium, vitamin C, vitamin D, acetazolamide, steroids)• Dietary excesses, inadequate fluid intake or excessive fluid lossMultichannel blood screen• Basic metabolic panel (sodium, potassium, chloride, carbon dioxide, blood

urea nitrogen, creatinine)• Calcium• Intact parathyroid hormone• Uric acidUrine• Urinalysis pH > 7.5: infection lithiasis pH < 5.5: uric acid lithiasis Sediment for crystalluria• Urine culture Urea-splitting organisms: suggestive of infection lithiasis• Qualitative cystine

Contd...

Radiography• Radiopaque stones: calcium oxalate, calcium

phosphate, magnesium ammonium phosphate (struvite), cystine

• Radiolucent stones: uric acid, xanthine, triamterene

Intravenous pyelography: radiolucent stones, anatomic abnormalities

Stone analysis

CRYSTAL MORPHOLOGY

Scanning electron micrographs of various urinary crystals.

• A, Apatite(Amorphous)• B, Struvite

(Rectangular,Coffin-lid)• C, Ca oxalate dihydrate

(Envelope,tetrahedral)• D, Ca oxalate

monohydrate(Hourglass)• E, Cystine(Hexagonal)• F, Ammonium acid urate.• G, Brushite(Needle-shaped)

Extensive Diagnostic Evaluation

• Should be performed in patients with recurrent nephrolithiasis, and stone formers at increased risk for further stone formation.

• To identify underlying physiologic derangements.

• Pt. to discontinue any medication that interferes with metabolism of calcium, uric acid, or oxalate. (vitamin D, calcium supplements, antacids, diuretics, acetazolamide, & vitamin C) & any current medication for stone treatment (thiazides, phosphate, allopurinol, or magnesium).

Contd...

• It involves two outpatient visits.Three 24-hour urine samples are collected.

• First two 24-hour specimens: on random diet, reflective of their usual dietary intake.

• Third 24-hour sample: after 1 week, on a calcium-, sodium-, & oxalate-restricted diet.

Fast and Calcium Load Test:• discriminate b/w various forms of hypercalciuria.• no longer performed by most clinicians.• essential if plan to place a patient with absorptive

hypercalciuria on a calcium binding resin. Normal fasting urinary calcium < 0.11 mg/dL GF Normal postload urinary calcium < 0.2 mg

calcium/mg creatinine

Simplified Metabolic Evaluation

• All patients: basic metabolic screening, searching for systemic disorders.

• High-risk stone patients: more extensive metabolic evaluation based on two 24-hour urine samples.

• Cornerstone of these simplified protocols- development of a urine preservation method that allows collection of urine without refrigeration.

• Urinary constituents most commonly assayed: calcium, oxalate, citrate, total volume, sodium, magnesium, potassium, pH, uric acid, and sulfate.

• commercially available urine analysis packages.

STONE ANALYSIS TO DETERMINE METABOLIC

ABNORMALITIES• Most stones are a mixture of more than one

component, relative ratios or predominance of any particular molecule has predictive value.

• Ca apatite & mixed Ca oxalate-Ca apatite stones: RTA & 1° hyperparathyroidism

• Pure & Mixed Uric acid stones: Gouty diathesis• Brushite stones: RTA• Infection stones: Infection• Cystine stones: Cystinuria• Pure uric acid, pure infection & pure cystine

stones- start treatment; no further testing required.

IMAGING IN DETERMINING STONE COMPOSITION

• Hounsfield unit (HU)measurement to determine stone composition- significant variation for diff.stone types.

• DECT technology: to distinguish b/w uric acid, Ca phosphate & Ca oxalate calculi.

HU ratiosDECT Slope algorithmDECT attenuation values.

Classification of Nephrolithiasis

1. Absorptive hypercalciuria (i)Type I (ii)Type II

2. Renal hypercalciuria

3. Primary hyperparathyroidism

4. Unclassified calcium nephrolithiasis

5. Hyperoxaluric calcium nephrolithiasis (i)Enteric hyperoxaluria (ii)Primary hyperoxaluria (iii)Dietary hyperoxaluria

6. Hypocitraturic calcium nephrolithiasis (i)Distal renal tubular acidosis (ii)Chronic diarrheal syndrome (iii)Thiazide-induced (iv)Idiopathic

7. Hypomagnesiuric calcium nephrolithiasis

8. Gouty diathesis

9. Cystinuria

10. Infection stones

11.Low urine volume

12.No disturbance and miscellaneous

Diagnostic criteria

CONSERVATIVE MEDICAL M/M

1.Fluid recommendations

2.Dietary recommendations

3.Obesity

1. Fluid recommendations

VOLUME:• Forced increase in fluid intake to

achieve a urine output of 2L.• Two effects: 1.Mechanical diuresis that ensues

may prevent urinary stagnation & formation of symptomatic calculi.

2.Creation of dilute urine alters supersaturation of stone components.

Contd...

WATER HARDNESS:• Although water hardness can alter

urinary parameters, it does not play a significant role in recurrence risk.

Contd...

CARBONATED BEVERAGES:• Carbonated water offers increased

protection against recurrent stone formation, by increasing urinary citrate levels.

• Soda flavored with phosphoric acid may increase stone risk, whereas those with citric acid may decrease risk.

• Caffeine intake may increase the risk of stone recurrence in calcium stone formers by increasing the excretion of calcium.

Contd...

CITRUS JUICES:• Citrus juices (particularly lemonlemon and

orange juices) may be a useful adjunct to stone prevention.

2. Dietary Recommendations

PROTEIN RESTRICTION:• Incidence of renal stones is higher with

increased animal protein intake.• Protein intake increases urinary calcium,

oxalate, & uric acid excretion and probability of stone formation even in normal subjects.

• Diets high in fruits and vegetables impart a significantly reduced risk of stone formation than diets high in animal protein.

Contd...

SODIUM RESTRICTION:• An important element of dietary prevention of

recurrent nephrolithiasis.• A high sodium intake increases calcium

excretion, urinary pH and decreases citrate excretion. Net effect- increased propensity for crystallization of calcium salts in urine.

• Animal protein restriction, moderate calcium ingestion, & a reduced-sodium diet decreases stone episodes by roughly 50%.

• Calcium stone formers who ingest large quantities of daily salt are more likely to suffer from decreased bone mineral density

Contd...

DIETARY CALCIUM:• Evidence supports maintenance of a

moderate calcium intake in calcareous nephrolithiasis.

• Dietary calcium restriction may subsequently increase oxalate absorption, thereby raising Ca oxalate supersaturation.

• "Safe" Calcium supplementation: Time & Type

Time- to be taken with meals.Ca citrate- "Stone friendly" Ca supplement.

OXALATE AVOIDANCE:• Avoidance of excess dietary oxalate is

reasonable & intuitive.• Vitamin C in large doses(By conversion to

oxalate) may increase the risk of stone recurrence. Doses should be limited to 2 g/day.

Contd...

3. Obesity

• Increased BMI, larger waist size, & weight gain correlate with an increased risk of stone episodes.

• More pronounced for women.

Contd...

METABOLIC SYNDROME:• Hypertension, Hypertriglyceridemia,

Glucose intolerance & Central obesity.

• Obesity & Insulin resistance → impaired ammonium excretion→ Low urinary pH→ Increased incidence of uric acid stone formation.

Contd...

IMPACT OF WEIGHT-LOSS DIETS:• a low-carbohydrate, high-protien diet

delivers a marked acid load to kidney, increases risk for stone formation & bone loss.

Contd...

IMPACT OF BARIATRIC SURGERY:• Bariatric surgery may significantly

increase the overall risk of stone formation.

• Jejunoileal bypass(before) & Roux-en-Y gastric bypass(now) both increase oxalate nephropathy & nephrolithiasis.

SELECTIVE MEDICAL M/M

• Selective treatment program would be more effective and safe than “random” therapy.

Rx ALGORITHM FOR UROLITHIASIS

Medications

I.Calcium-Based Calculi

HYPERCALCIURIA(>200mg/day):

• Absorptive Hypercalciuria(AH): an increased amount of Ca absorbed by intestinal tract.

AH type1- increased urinary excretion of calcium on both fasting & loading specimens.

AH type2- elevated urinary Ca on regular diet, normalises on fasting.

a low iPTH due to suppression from a constant abundance of available serum Ca.

Rx: Absorptive Hypercalciuria

AH type1:

• Thiazides(1st choice)+Pot.citrate +dietary restriction.(drug holiday in long-term therapy)

• Thiazides do not treat underlying cause of AH but reduce urinary calcium & manage its symptoms.

• MoA: Thiazides directly stimulate calcium resorption in distal nephron while promoting sodium excretion.

• S/E: Potassium wasting, muscle cramps, hyperuricosuria, intracellular acidosis, hypocitraturia

Contd...

• Sodium cellulose phosphate (SCP) effectively decreases absorption of intestinal Ca but abandoned due to GI intolerance & side effects.

• S/E: GI distress, hypomagnesemia, hyperoxaluria, PTH stimulation.

Contd...

• Thiazides- limited long-term effectiveness in AH type1.

Other hypocalciuric agents:• Hydrochlorthiazide,Indapamide(OD dose)• Amiloride + thiazide(K.Cit not needed)• Triamterene(Risk of triamterene stones)

Contd...

AH type2:• No specific drug Rx needed.• Moderate Ca intake(400 to 600

mg/day) & high fluid intake(sufficient to achieve a minimum urine output of >2 L/day).

• Avoidance of excessive sodium intake further decrease hypercalciuria.

Contd...

Orthophosphate:

• MoA- inhibit 1,25-(OH)2vitamin D synthesis; reduces urinary Ca by binding Ca in intestinal tract.

• Has a role when other methods are ineffective.

• S/E: GI upset,soft tissue calcification.• UroPhos-K: a slow-release, neutral

potassium phosphate prepared in wax matrix limits GI upset.

Contd...

Dietary Bran:• Rice bran binds intestinal Ca &

increases urinary pyrophosphate.• Thiazide + bran superior to bran

alone.

Contd...

• Renal Hypercalciuria: due to a wasting of calcium by functioning nephron.

• constant loss of Ca from distal tubules.• hypercalciuria during all phases of

fasting, loading, or restriction of dietary calcium.

• mild elevation of iPTH.

Rx:Renal Hypercalciuria

• Thiazides(Rx of choice) + Pot.citrate(correct hypokalemia, increase urinary citrate)

• Thiazides correct renal leak of Ca by augmenting calcium reabsorption in distal tubule and by causing ECV depletion and stimulating proximal tubular reabsorption of Ca.

• Correction of 2° hyperparathyroidism restores normal serum 1,25-dihydroxyvitamin D concentration & intestinal Ca absorption.

• Sustained correction for upto 10 yrs.

Contd...

• Resorptive Hyperclaciuria (1°hyperparathyroidism): overproduction of PTH from dominant adenoma or diffuse hyperplasia.

• Hypercalcemia,hypercalciuria in all phases, & raised iPTH.

Rx: 1°hyperparathyroidism

• Parathyroidectomy: resection of dominant adenoma or all four glands.

• No established medical Rx.

• Orthophosphates used only when Sx cannot be undertaken.

Contd...

• HYPERURICOSURIC CA OXALATE NEPHROLITHIASIS (HUCN): (>800mg/day) Heterogeneous nucleation/Epitaxy.

• Hyperuricosuria + pH> 5.5.• Causes: increased dietary purine

intake, Gout, MPD/LPD,MM, neoplastic states, pernicious anemia, 2°polycythemia, Hbpathies, thalassemia etc.

Rx: HUCN

• Decreased dietary protein intake.• Allopurinol decreases uric acid

production by inhibiting Xanthine oxidase( which converts xanthine to uric acid).

• Potassium citrate alters the urinary milieu in hyperuricosuria by decreasing supersaturation of uric acid & calcium oxalate.

Contd...

HYPEROXALURIA: (>40mg/day)

• Enteric Hyperoxaluria: fat malabsorption results in saponification of fatty acids with divalent cations such as Ca and Mg, thereby reducing Ca oxalate complexation and increasing the pool of available oxalate for reabsorption.

• Diarrhoea,dehydration,HCO3- losses.

• A/w chronic diarrheal syndrome, small bowel resection, jejunoilleal bypass, intrinsic disease.

Rx: Enteric Hyperoxaluria • Oxalate-restricted diet.• High fluid intake (to ensure adequate urine

volume).• Anti-diarrhoeal agent.• Probiotics & gut flora correction

(O.formigenes).• Pot.Citrate (correct hypokalemia, metabolic

acidosis, increase urinary citrate).• Oral Ca citrate or Mg gluconate(ileal disease)• Cholestyramine(binds bile salts in bowel

lumen).• Replace dietary fat with MCT(correct

malabsorption).

• Primary Hyperoxaluria: rare AR disorder of glyoxylate metabolism, normal glyoxylate to glycine conversion is prevented, preferential oxidative conversion to oxalate.

• Two types; PH1 & PH2.

Contd...

Rx: Primary Hyperoxaluria

• Present during childhood with early stone formation, tissue deposition of oxalate (oxalosis), & renal failure due to nephrocalcinosis.

• Death before age 20 in untreated patients

• Early Dx & Combined liver-kidney transplant.

Contd...

• Dietary Hyperoxaluria:1.Oxalate rich foods.2.Increased animal protein.3.Severe Ca restriction4.Ascorbic acid supplementation5.Reduced levels/absent colonisation

of O.formigenes.6.Cystic fibrosis pts.(prolonged

antibiotics; absent O.formigenes.)

Contd...

HYPOCITRATURIC CA OXALATE NEPHROLITHIASIS: (<550mg/day in F; <450mg/day in M)

• Distal RTA(Type1): Hypokalemic,hyperchloremic,non-AG metabolic acidosis.

• Abnormal collecting duct function; inability to acidify urine in systemic acidosis.(pH>5.5).

• Ca phosphate stones m.c.• Two-thirds pts.adults-nephrolithiasis, nephrocalcinosis.• Infants- Vomiting or diarrhoea, FTT & growth

retardation.• Children- Renal stones & metabolic bone disease.

Rx: Distal RTA Hypocitraturia

• Potassium citrate correct the metabolic acidosis & hypokalemia in distal RTA.

• Large doses(up to 120 mEq/day) may be required in severe acidotic states.

• Target dose in children: 3-4mEq/kg/day in divided doses.

Contd...

• Chronic Diarrhoeal states: Lab findings like enteric hyperoxaluria; except for bowel inflammation.

• moderate decreases in urinary citrate excretion with associated low urine volumes.

• Rx: Pot.Citrate(60-120mEq in 3-4 doses; liquid prepn preferred due to rapid intestinal transit time).

Contd...

• Thiazide-Induced & Idiopathic Hypocitraturia:

• Rx: Pot.citrate therapy.

Contd...

HYPOMAGNESURIC CALCIUM NEPHROLITHIASIS: (<80mg/day)

• Low urinary Mg, hypocitraturia, & low urine volume.

1.Chronic thiazide therapy.2.IBD causing malabsorption.3.Laxative abuse.

Rx: Hypomagnesuria

• Magnesium supplementation beneficial in stone reduction.

• Use of magnesium limited by risk of diarrhea (Mg oxide, hydroxide).

• Potassium-magnesium citrate(new)may restore urinary magnesium and citrate levels with minimal GI side effects.

II.Uric acid Calculi

• Uric acid: end product of purine metabolism.• pKa- 5.35. At more acidic pH, undissociated

uric acid predominates & precipitates; at higher pH 6.5, >90% uric acid is ionised & soluble.

• 3 main determinants: low urine pH, low urine volume & hyperuricosuria.

• "Gouty diathesis” refers to a stone-forming propensity characterized by low urine pH of unknown etiology with or without associated gouty arthritis.

Rx: Gouty Diathesis

• Major goal: to increase urinary pH>5.5, preferably b/w 6.0 & 6.5.

• Alkalinisation to a pH>7.0 should be avoided (increased risk of Ca phosphate stone formation).

• Pot.citrate therapy.• Allopurinol, if hyperuricemia or

hyperuricosuria present.

III. Cystinuria

• AR error of transepithelial transport involving intestine & kidneys.

• Inability to reabsorb dibasic amino acids cystine, ornithine, lysine, and arginine (COLA).

• Resultant accumulation of cystine causes crystallization when concentrations rise above the saturation point (roughly 250mg/L of urine)

• Young age presentation.

Contd...

Object: to reduce urinary concentration of cystine to below its solubility limit(200 to 300 mg/L).

• High fluid intake to produce 2.5-3L/day of urine.

• Urinary alkalinisation by Pot.citrate.• Restricted salt/sodium diet.• Use of cystine binding agents (increase

cystine solubility in urine via formation of a more soluble mixed-disulfide bond).

Contd...

1.α-mercaptopropionylglycine (Thiola, Tiopronin)- m.c.used.

S/E: asthenia, GI distress, rash, joint aches, and mental status changes.

2. D-penicillamine (Cuprimine)S/E: Nephrotic syndrome, dermatitis,

pancytopenia3. CaptoprilS/E: rash,cough,hypotension.

IV. INFECTION CALCULI(STRUVITE)

• Form in alkaline(pH>7.2), infected urine with urease producing bacteria in an ammonia-rich environment.

• Women produce more infection calculi than men.

• Infection calculi most likely produce staghorn stones.

• Symptoms of UTI may be present.

Rx: Struvite stones

• PCNL first-line therapy for managing complex, renal staghorn calculi.

• Complete elimination of all infected stone material essential for prevention of recurrent struvite stone formation.

• Antibiotic prophylaxis.• Hemiacridin irrigation for residual

fragment dissolution.

Contd...

• Acetohydroxamic acid, a urease inhibitor, reduce urinary saturation of struvite, & retard stone formation.

• Prevent recurrence of new stones.• Inhibit the growth of stones in patients

with chronic urea-splitting infections.• S/E: Thromboembolic phenomena, tremor

headache, palpitations, edema, GI distress, loss of taste, rash, alopecia, anemia, abdominal pain

MEDICATION RELATED STONES

MISCELLANEOUS

MEDICAL M/M OF BLADDER CALCULI:• Stone dissolution using Suby G or M

solution: beneficial in irrigating indwelling suprapubic or urethral catheters to decrease and prevent encrustation and occlusion.

• Twice-or thrice-daily irrigation with 0.25%-0.5% acetic acid solution beneficial prophylaxis against recurrent struvite calculi when catheters must be left indwelling for long periods.

• Uric acid calculi may be dissolved by irrigation with alkaline solutions

Contd...

MEDICAL M/M OF CALCULI DURING PREGNANCY:• Due to temporary physiologic changes, a metabolic

evaluation is not undertaken to determine the cause of the stone disease until delivery & return to baseline health status.

• Majority of ureteral calculi during pregnancy pass spontaneously.

• Dx during pregnancy- USG or limited IVP.• Rx- Hydration, analgesics & antibiotics. Stents, if

required exchange every 4-6 weeks.• URSL with Holmium laser lithotripsy is safe.

Thank You !!!