How to manage urolithiasis

Key Points

Stone disease has afflicted humans since antiquity. Kidney stones have been found in a 7,000-year-old Egyptian mummy.¹ The total cost of urolithiasis in the United States is estimated at $2.1 billion per year,² and given the 37% increase in prevalence over 18 years (1976-1980 to 1988-1994), it is clear that urolithiasis remains an important public health concern with substantial economic and quality-of-life impacts.³ Unfortunately, not only is stone disease becoming more common, but it is increasing at a faster rate in women than in men. One recent study documented that the male-to-female ratio of urolithiasis incidence decreased from 1.4 in 1992 to 1.0 in 2008.⁴

Although the cause of these trends is unclear, several hypotheses may explain the absolute and relative increase in urolithiasis in women. One hypothesis attributes the increase to societal and lifestyle factors, including gender equality in the workforce; increased athletic activity with the risk of dehydration; dietary changes such as high-fat, high-protein diets, increased intake of soft drinks, and increased sodium intake from processed, preserved, and fast food consumption; and increasing rates of obesity and metabolic syndrome.^5-7 Other researchers suggest environmental and geographic factors, theorizing that global warming and higher population density in hot, sunny, arid areas account for the increase in incidence.^8,9 Others cite the aging population, changing attitudes toward healthcare, and increased diagnosis and treatment of asymptomatic stones because of the rising use of cross-sectional imaging.³ It is most likely that the etiology of urolithiasis is multifactorial.

Given the rising risk of urolithiasis in women and the unique considerations of treatment of stones in pregnancy, ob/gyns should have at least a basic understanding of the management of this condition. This article discusses the pathophysiology, management, and prevention of urolithiasis.

Role of calcium

Calcium stones, formed from either calcium oxalate or calcium phosphate, account for 70% of cases.¹⁰ Hypercalciuria is the most common finding on 24-hour urine collection in individuals prone to calcium stone formation.¹¹ This finding can be due to hyperparathyroidism, increased intestinal absorption, and impaired renal reabsorption.

Women with urolithiasis are almost five times more likely than men to have hyperparathyroidism.¹² Calcium homeostasis is maintained by parathyroid hormone (PTH), the release of which is stimulated by low serum calcium levels. PTH increases conversion of 25-hydroxyvitamin D₃ [25(OH)D₃] to 1,25-dihydroxyvitamin D₃ [1,25(OH)₂ D₃] in the kidney. The active vitamin D, 1,25(OH)₂ D₃, then stimulates absorption of calcium and phosphate from the intestinal tract. In addition, PTH stimulates osteoclasts to absorb bone, thereby increasing serum calcium and phosphate concentrations. In the kidney, PTH stimulates reabsorption of calcium and decreases reabsorption of phosphate, thus increasing serum calcium while decreasing serum phosphate.¹¹

Although the risk of urolithiasis is not increased during pregnancy, hypercalciuria is present because of an increased glomerular filtration rate (GFR) of calcium in addition to placental production of 1,25(OH)₂ D₃. Moreover, pregnant women have increased levels of urinary uric acid and sodium because of physiologically increased GFR, making heterogeneous nucleation more likely. These changes favoring stone formation are offset by increased production of inhibitors such as citrate, magnesium, and glycoproteins, thereby maintaining the same risk as in nonpregnant women.^11,13

Hypercalcemia can occur in nonpregnant individuals as a result of malignancy, sarcoidosis, thyrotoxicosis, vitamin D toxicity, and primary hyperparathyroidism. Lung and breast cancers are responsible for approximately 60% of malignancy-associated hypercalcemia because of PTH-related protein.¹¹ A study of 38 patients with hypercalcemia of cancer showed that 30 patients had elevated plasma concentrations of a PTH-related protein.¹⁴ Typically, hypercalcemia accompanying these pathologic changes increases the risk of urolithiasis.

Role of hormones

It has been hypothesized that estrogen provides a protective effect for women by inhibiting bone reabsorption and decreasing calciuria by enhancing renal calcium reabsorption. A retrospective study noted decreased 24-hour urine calcium levels with postmenopausal estrogen therapy¹⁵ ; however, a large, multi-institutional, randomized trial (a review of data from the Women's Health Initiative) showed a 20% increased risk of nephrolithiasis in women receiving postmenopausal estrogen therapy.¹⁶ Estrogen plus progesterone was not shown to have an impact on decreasing stone risk in this study; however, these hormones may facilitate stone passage.

Progesterone causes relaxation of ureteral smooth muscle that, in conjuction with the distal compression caused by the gravid uterus, creates the hydroureter commonly seen in pregnant women.¹³ There is some evidence that this hydroureter facilitates stone passage; a spontaneous passage rate of 81% is seen in pregnant women compared with only 47% in nonpregnant women.^13,17,18 It is prudent to note that although urolithiasis does not affect perinatal outcomes, urolithiasis in pregnant women has been associated with elevated rates of complications including recurrent abortion, hypertension, gestational diabetes, and cesarean delivery.¹³

Role of oxalate

Increased oxalate in the urine can be seen with primary hyperoxaluria, caused by disorders of biosynthetic pathways; or enteric hyperoxaluria, which occurs in patients with inflammatory bowel disease or after bowel resection. Impaired fatty acid absorption leads to saponification of fatty acids with calcium and magnesium. Less calcium and magnesium are therefore available to bind oxalate in the gut, leading to increased intestinal oxalate absorption and subsequent hyperoxaluria.¹¹ Women who undergo Roux-en-Y gastric bypass surgery have an increased risk of stone formation at 3 months because of low urine volume (100%)¹⁹ and a long-term risk of de novo hyperoxaluria (52%) and hypocitraturia (38%) at 2 years.²⁰ Another mechanism of increased urinary oxalate is excessive vitamin C intake, resulting in metabolism of ascorbic acid (vitamin C) into oxalic acid.¹¹

Other causes of urolithiasis

Cystinuria is caused by a genetic defect that impairs intestinal and renal tubular transport of dibasic amino acids.¹¹ Cysteine is a dibasic amino acid that is poorly soluble, and even small elevations lead to intractable cysteine stones.

Gouty diathesis is characterized by idiopathic low urine pH, which predisposes the patient to uric acid and calcium stone formation. At a pH of less than 5, even modest amounts of uric acid are insoluble, and both uric acid and calcium stones form on the nidus created by uric acid crystallization. Hyperuricosuria can be caused by dietary purine excess or uric acid overproduction.¹¹

Urinary pH above 6.5 predisposes to calcium phosphate calculi.^11,21 An important cause of high urine pH is renal tubular acidosis type 1, which can be associated with kidney stones (most commonly calcium phosphate stones) in up to 70% of people. Women in particular are predisposed to renal tubular acidosis, representing 80% of all cases.²¹ Acid-base status also is the most important determinant of urinary citrate excretion, an important inhibitor of stone formation.¹¹

Findings similar to renal tubular acidosis type 1 are seen in patients taking topiramate or zonisamide, two medications commonly prescribed for migraines, chronic pain, and seizure disorders.^11,22 Patients taking topiramate have a 2- to 4-fold increased risk of calculus because of a significant, dose-dependent decrease in urinary citrate excretion, which increases the risk of stone formation because of carbonic anhydrase inhibition, causing metabolic acidosis, high urine pH, and low urine citrate levels.²²

Women may have an elevated risk of medullary sponge kidney, a renal malformation associated with nephrocalcinosis, recurrent calcium urolithiasis, and distal renal tubular acidosis. In one study, women represented the majority (70%) of 97 patients with medullary sponge kidney who had additional stone risk factors.²³

In addition to metabolic risk factors, women are twice as likely as men to have infection-related stones because of an increased risk of recurrent urinary tract infection. Infection-related stones, which are composed of either struvite (ie, magnesium ammonium phosphate) or carbonate apatite, represent 5% to 15% of all stones and are associated with urease-splitting bacteria such as Proteus, Pseudomonas, and Klebsiella.¹¹