Kidney Stones
(Metabolic-Diagnosis & Treatment)

The kidney stone problem in the United States can be divided into medical and surgical. The surgical dissolution and extraction of kidney stones will be the subject of a separate discussion. This will include expectant therapy (waiting for the stone to pass naturally), shockwave lithotripsy (ESWL/ crushing a stone with a shockwave generator), and open surgical stone removal (invasive procedures). Kidney stones account for one in a thousand hospitalizations, are frequent in the South, occur more commonly in middle-age white Americans, and tend to recur with an attack rate of 30-50% in those patients who are not managed medically. The average age of occurrence of a kidney stone in our Columbia hospital (Medical City Dallas Hospital) population is approximately 42 years of age. Men are three times as likely to develop stones as women.

Risk factors are multiple including fluid intake per day, region of the United States residing (worse in hot climates), previous history of kidney stone, family history of kidney stone, age, infection in the urine, and diet with particular respect to high calcium foods (dairy products) and high oxalate foods (colas, chocolate, spinach, peanuts and tea).

Most kidney stones produce severe pain, often coming in waves, beginning in the lower back and moving into the side or groin. Other symptoms include bloody urine, nausea, fever, and burning with urination.

A simplified explanation of kidney stones includes the supersaturation of certain salts in the urine such as calcium phosphate and brush*te which can then form nucleation of calcium oxalate monohydrate and calcium oxalate dihydrate stones. An analysis of the kidney stone, if available, is an initial starting point for understanding stone formation. Calcium stones comprise more than half of the kidney stones seen in an adult population in kidney stone centers. Calcium stones come in five varieties:

1. calcium oxalate monohydrate (whewellite) CaC204
2. calcium oxalate dihydrate (weddellite) CaC204-2H2O
3. calcium phosphate, carbonate form (carbonate apatite) CA10(PO4-CO3OH)6(OH)2
4. calcium phosphate, hydroxyl form (hydroxylapatite) CA10(PO4)6(OH)2
5. calcium hydrogen phosphate dihydrate (brush*te) CaHPO4-2H2O.

Of these calcium stones, calcium oxalate monohydrate alone, or calcium oxalate dihydrate alone or in combination with calcium oxalate monohydrate are by far the most common calcium stones. The calcium oxalate monohydrate stone is one of the most difficult stones to break with shockwave lithotripsy because of its hardness.

A study of the 24 hour urine calcium, both on a low calcium diet and so-called random diet (diet which the patient ordinarily takes) is a beginning point for studying risk factors for stone prevention. A 24 hour urine calcium is generally considered to be elevated if urine calcium is present in an amount greater than 4 mg/kg/day. This usually translates to 250-300 mg excreted in a 24 hour urine sample. These samples are often collected on a weekend when the patient can easily obtain a 24 hour urine sample and store this sample in the refrigerator.

Patients who have high urinary calcium (hypercalciuria) are further divided into three categories:

1. resorptive hypercalciuria (hyperparathyroidism)
2. renal hypercalciuria or renal leak
3. absorptive hypercalciuria

Primary hyperparathyroidism is diagnosed when the finding of hypercalcemia (elevated serum calcium), hypophosphotemia (low serum phosphate), hypercalciuria (>4 mg/kg/day), combined with inappropriately high serum immunoreactive parathyroid hormone. Hypercalcemic symptoms such as peptic ulcer or bone disease (due to reabsorption of bone) may be present. However, the majority of patients with hyperparathyroidism are diagnosed when elevated serum calcium is identified in an SMA screening panel. Most of these patients are asymptomatic when diagnosed unless they present with a kidney stone. This diagnosis is often overlooked by the urologist because they are often concerned with extraction or dissolution of the stone and not the underlying metabolic causation for stone formation. This disease is treated by neck exploration after appropriate identification of the overactive parathyroid adenoma (benign tumor) usually present in one of the four parathyroid glands, which results in hyperexcretion of parathyroid hormone.

Absorptive hypercalciuria is a condition in which the intestines absorb too much calcium from the diet. This condition is diagnosed by normal fasting calcium:creatinine ratio (to be described further) with an abnormal load test > 0.2. The condition is further divided into type I, II and III. Type II absorptive hypercalciuria is a less exaggerated form of type I, which totally corrects on a low calcium diet as defined by a 400 mg calcium, 100 meq sodium diet daily. Type III hypercalciuria involves a low serum phosphate which is a trigger for increased parathyroid hormone production which results in secondary bone resorption and increased intestinal absorption mediated by 125 Vitamin D3. This condition can be reversed by supplying the patient with orthophosphates. Treatment of type I absorptive hypercalciuria includes the use of thiazide diuretics (Esidrex or hydrochlorothiazide at a dose of 50 mg b.i.d. with appropriate potassium supplementation or Trichlormethiazide at a dose of 4 mg q.d.). Sodium cellulose phosphate can also be administered as an alternative to thiazides. Sodium cellulose phosphate is a resin which binds calcium in the intestine and is taken before each meal in order to lower the calcium absorption and subsequent excretion in the urine. All types of absorptive hypercalciuria, however, must be treated with a low calcium diet. All treatments can be overridden by patients who refuse to adhere to a low calcium (low dairy product-milk, cheese & ice-cream) diet.

Renal hypercalciuria is a disorder of the kidney where calcium is filtered but not reabsorbed as it should in the kidney tubule. Again, patients excrete > 250-300 mg/day of calcium or > 4 mg/kg/day of calcium in the urine. These patients have an abnormally high fasting calcium and creatinine ratio and also respond in exaggerated fashion to a 1 gm oral calcium load (fasting load test resulting in a ratio of > 0.2 of calcium:creatinine after a 4 hr. load test). Renal hypercalciuria can be reversed with thiazide diuretics. Esidrex can be administered at a dosage of 50 mg b.i.d. or Trichlormethiazide at a dose of 4 mg q.d. Serum potassium needs to be monitored and supplemented (40-60 meq/d) if made low by thiazide treatment.

Normocalciuria (< 250 mg in a 24 hour urine or < 4 mg/kg/day in adults) has also been identified in patients with calcium oxalate stones. Risk factors include a high urinary oxalate excretion of > 44 mg/day. This can occur with different forms of bowel disease such as ulcerative colitis and regional enteritis. It can also occur from excess dietary oxalate intake (leafy vegetables, spinach, rhubarb) or may be a primary abnormality of the intestine.

Another etiology for normocalciuric calcium oxalate stones include a high urinary uric acid excretion (> 600 mg/day) which can act as a nidus for calcium oxalate stones. Also, a lack of inhibitors in the urine which inhibit stone formation such as citrate (< 320 mg/day) or magnesium (< 50 mg/day) can result in promotion of calcium oxalate stone formation. Patients who are found to have low urinary citrate or low urinary magnesium can be supplemented or given citrate or magnesium in their diet to prevent stone formation. Hyperexcretion of uric acid can also be treated in the urine based upon underlying pathophysiology.

Infection stones - magnesium hydrogen phosphate trihydrate (Newberyite) MGHPO4-3H2O. This particular stone found on stone analysis, is suggestive of urinary tract infection. A variant of the infection stone is known as struvite or magnesium ammonium phosphate stones. They are often associated with pyuria, positive urine culture for urea splitting organisms such as Proteus and certain species of Pseudomonas, Klebsiella and staphylococcus. Urinary pH is often high > 7.0. Treatment is directed at eliminating underlying infection.

Uric acid lithiasis - C5H4N403. In this condition urinary pH is usually low (< 5.5), serum uric acid is normal or high. Urinary uric acid is usually elevated > 600 mg/day. Microscopic examination of urinary sediments may reveal the presence of uric acid crystals. Treatment is directed at lowering urinary uric acid by lowering purines in the diet and instituting 300 mg of Allopurinol (trade name Zyloprim) q.d. to lower urinary uric acid production. Urinary pH may be raised to a level of 7 in order to further increase solubility of uric acid in the urine. These stones are radiolucent (not seen on x-ray) and thus, present a challenge to the urologist. Uric acid, contrary to common opinion, can be broken relatively easy with shockwave lithotripsy, assuming the stone can be imaged. It also is one of the few stones that may be dissolved with medical therapy (Allopurinol plus alkali).

Cystinuria - SCH2CH(NH2)-C00H)2: This is an inborn error in metabolism, characterized by disturbance in kidney and intestinal handling of dicarboxylic acids including cystine. Stone formation results from excessive excretion of cystine and low solubility of dicarbolic acid in the normal acid pH urine. Mainstays of treatment include alkalization, particularly at night, hydration to the point of nighttime voiding, thiol or penicillimine binders to lower cystine excretion in the urine. Because these stones have a sulfur moiety, they can be seen on plain x-rays and are not radiolucent as uric acid stones.

Renal tubular acidosis: This is a condition characterized by elevated chlorine in the serum, high urinary pH (> 6.8) in the absence of infection. Low potassium may also be present in the serum. Calcification of the kidney occurs more commonly in this condition, but kidney stones can occur as well. There is an incomplete form of renal tubular acidosis characterized by normal pH and bicarbonate, but impaired ability of the urine to acidify. This disorder can be diagnosed by ammonium chloride loading test.

Fasting and calcium load test: Patients, after having been on a low calcium, low sodium (< 400 mg calcium, & < 100 meq sodium) diet for one week, fast overnight, come to the office at 7 o'clock where a 7-9 o'clock urine is obtained in the fasting state. Oral calcium (1 gm) is then administered by mouth. The patient is hydrated and urine is collected for the next four hours. The ratio of calcium:creatinine is calculated in the urine with the normal fasting ratio being < 0.11 and the normal calcium:creatinine ratio following the 1 gm oral calcium load being < 0.20. This test is generally performed in hypercalciuric patients in order to separate patients appropriately into the three common classes of hypercalciuria for treatment.

In summary, metabolic tests including blood screens, 24 hour urine samples, provocative calcium loading tests, and stone analysis are all used in the diagnostic metabolic work up of patients with stone disease. Appropriate treatment of underlying metabolic disorder for stone disease has been shown to dramatically lower the incidence and cost of recurrent stone treatment. The old-time advice to drink a lot of water and come back and see the urologist when one forms another stone is no longer acceptable medical management for recurrent stone formers.

For physicians reading this page, table 1 and table 2 review the metabolic work up performed at our office in an outpatient setting in patients with recurrent stone disease. Table 3 reviews normal serum and urinary values. Figure 1 reviews general classifications for patients with stone disease. Figure 2 reviews the therapeutic algorithm used for treatment of patients with stone disease.

Table 1. Outline of Ambulatory Protocol

Visit 1:	History and physical examinations; 24-hour urine collection on random diet
Visit 1:	History and physical examinations; 24-hour urine collection on random diet
Visit 1:	24-hour urine collection on restricted diet of 400 mg of calcium and 100 mEq of sodium per day; "fast and load" study

Table 2. Laboratory Tests

BLOOD

URINE

CYSTINE (QUALITATIVE ANALYSIS)

CBC

SMA

iPTH

Ca

UA

Cr

Na

Ph

Total Volume

Ox

cAMP

Visit 1

X

X

X

X

X

X

X

X

X

Visit 2

X

X

X

X

X

X

X

Visit 3

X

X

X

X

X

X

X

X

X

X

FAST

X

X

X

LOAD

X

X

X

Table 3. Normal Serum and Urinary Values

PARAMETERS		VALUES
Serum:
	Calcium (mg/dl)	<10.5
	Phosphorus (mg/dl)	>2.5
	Uric Acid (mg/dl)	<9.0 (male)
		<7.7 (female)
	Bicarbonate (mEq/liter)	22-32
	Chloride (mEq/liter)	97-108
	Serum immunoreactive parathyroid hormone (ul-eq/ml)	<36
24-Hour Urine:
	Volume (ml/24 hr)	>2000
	pH	Variable
	Calcium (mg/24 hr)	<4 mg/kg (random)
		<200 mg/24 hr (restricted)
	Sodium (mEq/24 hr)	Variable
	Uric Acid (mg/24 hr)	<600
	Oxalate (mg/24 hr)	<44
	Cyclic AMP (nmol/100 ml glomerular filtrate)	<5.40
Qualitative Urinary Cystine:		Negative
	Fast:
	Calcium/Glomerular Filtrate (mg/100 ml glomerular filtrate)	<0.11
	Cyclic AMP (nmol/100 ml glomerular filtrate)	<6.85
	Load:
	Calcium/Creatinine (mg/mg)	<0.20
	Cyclic AMP (nmol/100 ml glomerular filtrate)	<4.60

© Dallas Urology and Associates

Edited by DrFetner - 09 Apr 2007 at 10:17am