INTRODUCTION

Kidney stones are a common problem facing nephrologists, urologists, and general internists in the United States. A study of nephrolithiasis rates from Rochester, Minnesota showed that in the period from 1970 to 2000 the incidence of new onset symptomatic kidney stones declined in men from 15.5 to 10.5 cases per 10,000, but increased in women from 4.3 to 6.8 cases per 10,000. The male-to-female ratio declined from 3:1 to 1.3:1 over this time. The prevalence of stone disease in the United States increased 37% between National Health and Nutrition Examination Survey (NHANES) II (1976-1980) and NHANES III (1988-1994). In the United Kingdom, hospitalizations for stone disease have increased 63% in the last decade. The prevalence of stone disease in the United States appears to be increasing in women, perhaps as a result of the obesity epidemic. Individuals with increased body mass index (BMI) are known to excrete more sodium, oxalate, uric acid, and phosphate in the urine. In addition, as BMI increases, urine pH decreases, which may increase the risk of uric acid stones. The peak incidence for the initial episode of renal colic occurs early in life between the ages 20 and 35 years. In women there is a second peak at age 55 years. By age 70 years, 11% of men and 5.6% of women will have had a symptomatic kidney stone. The recurrence rate is 40% to 50% after 5 years, 50% to 60% at 10 years, and 75% at 20 years. Nephrolithiasis is a major cause of morbidity from pain (renal colic) and renal parenchymal damage from urinary tract obstruction and infection, and results in about $5 billion of economic costs in the United States annually.

Calcium-containing stones make up 80% or more of all stones in the United States and contain calcium oxalate alone, a combination of calcium oxalate and calcium phosphate, or calcium phosphate alone. The remainder is composed of uric acid or struvite. Cystine stones are rare in adults. In more arid climates, such as the Middle East, uric acid stones are more common than calcium-containing stones. Studies based on samples received by stone analysis laboratories suggest that 10% to 20% of all stones are made up of struvite, but this is because of an overrepresentation of stones from surgical specimens.

A kidney stone is an organized mass of crystals that grows on the surface of a renal papilla. They result whenever the excretory burden of a poorly soluble salt exceeds the volume of urine available to dissolve it. Supersaturation of urine with respect to a stone-forming salt is necessary but not sufficient for stone formation. Interestingly, urine in normal patients is often supersaturated with respect to calcium oxalate, calcium phosphate, and uric acid, yet stone formation does not occur. Other factors such as inhibitors of crystallization play an important role in the pathogenesis of stone formation. Normal urine contains several inorganic and organic inhibitors of crystallization. Citrate, magnesium, and pyrophosphate are the most important of these inhibitors of crystallization.

Recent studies of intraoperative papillary biopsies have shed further insight into the pathogenesis of calcium oxalate and calcium phosphate stone formation. The initial site of crystal formation is on the basolateral surface of the thin limb of the loop of Henle in patients with idiopathic hypercalciuria that form calcium oxalate stones. Stones consist of a core of calcium phosphate (apatite) surrounded by alternating layers of matrix and calcium oxalate. The crystal nidus erodes through the surface of the renal papilla into the renal pelvis. Stones form over regions of calcium deposition on the surface of the renal papilla known as Randall’s plaques. Why calcium phosphate precipitates in this region of the nephron has been the subject of studies by Worcester and Coe. They found that in patients with idiopathic hypercalciuria, urinary calcium excretion increases after meals as a result of reduced proximal tubular calcium reabsorption, leading to increased calcium delivery to the thin limb. These patients consistently have supersaturated urine with respect to calcium phosphate.

Calcium phosphate stones consist of greater than 50% calcium phosphate. They are seen more commonly in women and are associated with higher urinary pHs. Papillary biopsies in these patients reveal dilated ducts of Bellini that are plugged with apatite, which project out into the papillary space. These plugs are associated with a focal papillary tubulointerstitial nephritis secondary to crystal-induced injury.

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THE PATIENT WITH RENAL COLIC

Stones form on the surface of a renal papilla; if they remain there, they do not produce symptoms. If the stone dislodges it can impact anywhere between the ureteropelvic and ureterovesicular junction, resulting in renal colic. Renal colic presents as severe flank pain that begins suddenly, peaks within 30 minutes, and remains constant and unbearable. It requires narcotics for relief and is associated with nausea and vomiting. The pattern of pain radiation may provide a clue as to where in the urinary tract the stone is lodged. Pain radiating around the flank and into the groin is common for a stone trapped at the ureteropelvic junction. Signs of bladder irritation such as dysuria, frequency, and urgency are associated with stones lodged at the ureterovesicular junction (the narrowest portion of the ureter). Pain may radiate to the testicles or vulva. Struvite stones are often incidentally discovered on plain abdominal radiograph because they are generally too large to move into the ureter. The abdominal, rectal, and pelvic examinations are directed at ruling out other potential etiologies of abdominal pain. Physical examination is remarkable for costovertebral angle tenderness and muscle spasm.

A complete blood count, serum chemistries, and urinalysis are required to evaluate patients. The white blood cell (WBC) count may be mildly elevated as a result of the stress of the acute event. A WBC count greater than 15,000/mm³ suggests either another intraabdominal cause for the pain or pyelonephritis behind an obstructing calculus. Elevations of the serum blood urea nitrogen (BUN) and creatinine concentrations are not common, and if present, are usually secondary to prerenal azotemia from volume depletion. Obstruction of a solitary functioning kidney, as is the case after a renal transplantation, will result in acute kidney injury. Any patient with abdominal pain should have a careful urinalysis performed. Approximately 90% of patients with renal colic will have microscopic hematuria.

If nephrolithiasis is suspected after the initial evaluation, one must next establish a definitive diagnosis. A radiograph of the abdomen can identify radiopaque stones larger than or equal to 2 mm in size (calcium oxalate and phosphate, struvite, and cystine stones). Radiolucent stones (uric acid) and stones that overlie the bony pelvis are often missed. Unfortunately, two-thirds of kidney stones trapped in the ureter will overlie the bony pelvis. As a result, an abdominal radiograph is most valuable to rule out other intraabdominal processes. It is not sensitive enough to exclude nephrolithiasis with certainty. An ultrasound examination readily identifies stones in the renal pelvis, but is much less accurate for detecting ureteral stones. The intravenous pyelogram (IVP) was formerly the gold standard for the diagnosis of renal colic. It identifies the site of the obstruction, although the stone itself may not be visualized. Structural or anatomic abnormalities and renal or ureteral complications can be detected. Major disadvantages of the IVP include the need for intravenous contrast and the prolonged waiting time required to adequately visualize the collecting system in the presence of obstruction. As a result, spiral computerized tomography (CT) is the test of choice in the majority of emergency departments. Spiral CT is highly sensitive, rapid, and does not require contrast. It may also identify the site of obstruction. Figure 13.1 is an example of a kidney stone detected on spiral CT scanning. If the patient does not have a stone, the spiral CT may also identify other causes of abdominal pain, such as appendicitis and ischemic bowel.

After a stone is identified in the ureter by spiral CT, subsequent management involves an assessment of the likelihood of spontaneous passage, the degree of pain present, and whether there is suspected urinary tract infection (UTI). The probability of spontaneous passage is related to the stone size and its location in the ureter at the time of initial presentation (Table 13.1). In general, the smaller the stone and the more distal in the ureter it is located, the higher the likelihood of spontaneous passage. In general, about half of all stones larger than 5 mm will require urologic intervention. The patient with pain who cannot be managed with oral medication cannot take fluids and who has a solitary kidney or evidence of pyelonephritis, requires hospital admission. Stones unlikely to pass spontaneously require further urologic intervention.

α₁-Receptor antagonists and calcium channel blockers have been successfully used to aid in stone passage (medical expulsive therapy). Corticosteroids, when added, are of modest benefit. Medical expulsive therapy is more likely to be beneficial in patients with pain that is well controlled when the stone is located in the distal ureter or the stone is smaller than 10 mm.

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RISK FACTORS FOR CALCIUM-CONTAINING STONES

Calcium-containing stones make up the majority of stones in the United States and are generally composed of a mixture of calcium oxalate and calcium phosphate. In mixed stones, calcium oxalate predominates, and pure calcium oxalate stones are more common than pure calcium phosphate stones. Calcium phosphate precipitates in alkaline urine, whereas calcium oxalate precipitation does not vary with pH. Because urine is acidic in most patients on a standard Western diet, calcium oxalate stones are more common. Hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria, low urine volume, and medullary sponge kidney are the major risk factors for calcium-containing stone formation. Patients may form calcium-containing stones with a single or any combination of risk factors. Some patients form calcium-containing stones with no risk factors indicating that our knowledge of the stone-forming process is incomplete. Table 13.2 shows the upper limits of normal in a 24-hour urine for some of these risk factors in men and women.

Hypercalciuria is present in as many as two-thirds of patients with calcium-containing stones. It results from an increased filtered load, decreased proximal tubular reabsorption, or decreased distal tubular reabsorption. Proximal tubular calcium reabsorption is similar to sodium. Whenever proximal sodium reabsorption is decreased there is a parallel decrease in proximal calcium reabsorption and vice versa. Distal nephron calcium reabsorption is stimulated by parathyroid hormone (PTH), diuretics (thiazides and amiloride), and alkaline pH, and inhibited by acidic pH and phosphate depletion.

The most common cause of hypercalciuria (90%) is idiopathic. In 3 families, the absorptive hypercalciuria phenotype was localized to a region of chromosome 1 (1q23.3-q24). Although the precise mechanism is unknown, these patients have increased 1,25(OH)₂ vitamin D₃ (calcitriol) concentration, low PTH concentration, and reduced bone mineral density. Three potential pathophysiologic mechanisms were proposed: increased intestinal calcium absorption; enhanced bone demineralization; and decreased renal calcium or phosphorus reabsorption. Patients with idiopathic hypercalciuria can be subdivided on the basis of a fast and calcium load study into absorptive hypercalciuria types I, II, and III and renal leak hypercalciuria. This is based on the assumption that if the physiologic mechanism is identified this information will guide specific therapy. In practice, however, this is often unnecessary. Randomized controlled trials of pharmacologic intervention did not subdivide patients in this fashion.

Other important causes of hypercalciuria include primary hyperparathyroidism, renal tubular acidosis (RTA), sarcoidosis, immobilization, Paget’s disease, hyperthyroidism, milk–alkali syndrome, and vitamin D intoxication. Filtered calcium load is increased in primary hyperparathyroidism as a result of bone calcium release and increased intestinal calcium absorption mediated by calcitriol. In the subset of patients with hypercalciuria increased filtered load overcomes distal PTH action to increase calcium reabsorption. In RTA, an increased filtered calcium load results from bone calcium release in response to buffering of systemic acidosis. Acidosis also directly inhibits distal tubular calcium reabsorption. In sarcoidosis macrophages produce calcitriol via activation of 1α-hydroxylase leading to increased intestinal calcium absorption with a resultant increase in filtered load. Immobilization, Paget’s disease, and hyperthyroidism result in calcium release from bone and increase the filtered load.

Citrate is an important inhibitor of calcium oxalate precipitation in urine. It complexes calcium in the tubular lumen and as a result there is less calcium available to associate with oxalate. Citrate deposits on the surface of calcium oxalate crystals and prevents them from growing and aggregating. This latter effect may be more important. Chronic metabolic acidosis as occurs with chronic diarrhea or distal RTA and an acid-loading diet high in protein enhance proximal tubular citrate reabsorption and reduce urinary citrate concentration. Hypokalemia also causes hypocitraturia. Sodium-citrate cotransporter expression in the apical membrane of proximal tubule is upregulated with hypokalemia.

Hyperuricosuria is an important risk factor for calcium-containing stone formation. Uric acid and monosodium urate decrease calcium oxalate and calcium phosphate solubility, a phenomenon known as “salting out.” Uric acid can bind to macromolecular inhibitors and decrease their activity.

Oxalate in urine is derived from 2 sources. The majority (80% to 90%) comes from endogenous production in liver. The remainder is derived from dietary oxalate and ascorbic acid. The most common causes of hyperoxaluria include; enteric hyperoxaluria from inflammatory bowel disease, small bowel resection, or jejunoileal bypass; dietary excess; and the very uncommon inherited disorder primary hyperoxaluria. In enteric hyperoxaluria, intestinal hyperabsorption of oxalate occurs via 2 mechanisms. Free fatty acids bind calcium and decrease the amount available to complex oxalate increasing free oxalate, which can then be absorbed. In addition, bile salts and fatty acids increase colonic oxalate permeability. Intestinal fluid losses also decrease urine volume, and bicarbonate and potassium losses can lead to hypocitraturia.

Low urine volume is a very common risk factor for calcium-containing stone formation. The risk of stone formation in the United States is largest in areas where temperature is highest and humidity lowest (the stone belt of the Southeast and Southwest). Studies show that 3% to 12% of patients with calcium-containing stones have medullary sponge kidney. One should have a high index of suspicion for medullary sponge kidney in those who do not have any of the previously discussed risk factors for calcium-containing stone formation. It occurs in 1 in 5000 patients and involves men and women with equal frequency. The medullary and inner papillary collecting ducts are irregularly enlarged resulting in urinary stasis that promotes precipitation and attachment of crystals to the tubular epithelium. An IVP establishes the diagnosis revealing linear papillary striations or collections of contrast media in dilated collecting ducts. Patients present in the fourth or fifth decade with kidney stones or recurrent UTI that may be associated with a distal RTA.

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