Basics of urinary stone disease
One out of 13 women will become symptomatic with a kidney stone in her lifetime; that incidence is rising in the United States resulting from the increasing prevalence of obesity and diabetes. Often, the symptoms are acute and painful, and require a visit to the emergency room. Unfortunately, half of patients who pass a kidney stone will have a recurrence within 5 years. This section will provide a brief review of urinary tract stone disease and recommendations for prevention in women with known stone disease, as well as when to refer a patient with an asymptomatic stone found on an evaluation for microscopic or gross hematuria.
The incidence of asymptomatic stones is 8% to 10% of the population. In a study of over 5000 patients undergoing a screening computed tomography colonography, asymptomatic stones were found in 9.7% of men and 6.3% of women. The average number of stones found was 2.1, with a mean stone size of 3 mm ( ). Survey studies are used to assess the prevalence of symptomatic stones. The National Health and Nutrition Examination Survey (NHANES) conducted in 2007 to 2010 ( n = 12,100) included questions about a history of kidney stones. The prevalence was found to be 8.8% overall, at 10.6% in men and 7.1% in women ( ). This was a marked increase from the NHANES III cohort (1976–1994), in which the prevalence was 6.3% among men and 4.1% among women ( ). found that kidney stones were more prevalent among obese individuals compared with normal-weight individuals (11.2% vs. 6.1%). Black, non-Hispanic and Hispanic individuals were less likely to report a history of stone disease than White, non-Hispanic individuals. Obesity and diabetes were strongly associated with a history of kidney stones in multivariate analysis.
The pathophysiology of stone formation is complex; however, there are a few concepts that are important in understanding renal stone formation. Urinary supersaturation is the driving force for the phase change of minerals from a dissolved salt to a solid. Although supersaturation is essential, by itself it does not result in the formation of a stone. The solid precipitates out of the urine and forms crystals in the urine that are often identified by a clinical laboratory with urine microscopy. The process of stone formation requires nucleation, crystal growth, crystal aggregation, and crystal retention. Once formed, the crystals may flow in the urine or become retained in the urinary tract at sites that promote growth, leading to stone formation.
The majority of stones seen in the United States contain calcium, most commonly calcium oxalate (60%), followed by hydroxyapatite (20%) and brushite (2%). Of the non–calcium-containing stones, uric acid (7%) and struvite stones (7%) are the most common. Along with low urine volume and low urine pH, urinary calcium and oxalate are important and equal contributors to calcium oxalate stone formation. Inhibitors of stone formation include high urinary volume, higher urinary pH, citrate, and magnesium.
Radiologic imaging for the presence of stones
Noncontrast computed tomography (CT stone protocol) is the gold standard for imaging urinary tract stones because of its lower radiation exposure (85% decrease) as compared with three-phase CT. It is also beneficial because it can assess renal anatomy and other associated findings such as hydronephrosis and perinephric stranding. An alternative imaging modality includes the use of renal ultrasound in combination with a plain film of the kidneys, ureters, and bladder (KUB). KUB imaging is typically required with ultrasound imaging because ultrasound measurements of renal stone size are not as accurate and are less able to visualize stones in the ureter.
There is not much evidence on how or when to treat asymptomatic stones. Stones that are asymptomatic in the kidney can become symptomatic while passing through the ureter. Ureteral stones usually become impacted at three distinct ureteral sites: at the ureteropelvic junction, crossing the iliac vessels, and at the ureterovesical junction. Stone passage rates are dependent on the size of the stone and will be discussed in detail later. Stones that are 2 mm or less have excellent passage rates and require intervention less than 5% of the time. That said, the average time to passage could be a week. Renal stones 2 mm or greater should be referred to a urologist, who can clearly state the risk and benefits of a stone removal from the kidney. Kidney stones larger than 1 cm are less likely to traverse the ureteropelvic junction and result in acute pain. Although asymptomatic, they should be addressed, because the stone will continue to enlarge. Stones less than 2 cm may be amenable to more conservative surgical treatments, such as extracorporeal shock wave lithotripsy and ureteroscopic interventions. Stones greater than 2 cm require percutaneous nephrolithotomy or open/laparoscopic stone removal, which are more morbid procedures.
Upper urinary tract stones can be the cause of pain, infection, obstruction, active stone growth, or hematuria. In a study of 180 women presenting to the emergency room with a symptomatic upper tract stone, one-third had kidney stones, and two-thirds had ureteral stones ( ). Of those with a kidney stone on presentation, the average stone size was 7.9 mm. The majority (45%) required no intervention other than medications and a urology referral, whereas 33% required ureteroscopy, 10% required a stent, and 12% required percutaneous nephrolithotomy. Ureteral stones had an average size of 4.3 mm. The majority (86%) of the stones were located in the distal ureter, 11% were in the proximal ureter, and 3% were located in the midureter. The majority of the women (77%) were managed without surgical intervention. Of the individuals for whom follow-up information was obtained (41%), the average size of the stones that passed spontaneously was 3.3 mm.
Spontaneous passage rates of stones in the ureter are dependent on the stone size and location. In a study of 850 male and female patients with acute flank pain, 172 (13.5%) were found to have ureteral stones ( ). The majority of stones (67%) passed spontaneously, and the rest required intervention. The spontaneous passage rate for stones 1 mm in diameter was 87%; for stones 2 to 4 mm, 76%; for stones 5 to 7 mm, 60%; for stones 7 to 9 mm, 48%; and for stones larger than 9 mm, 25%. Spontaneous passage rates as a function of the stone location were 48% in the proximal ureter, 60% for midureteral stones, 75% for distal stones, and 79% for ureterovesical junctional stones. Limited studies have demonstrated that 84% of pregnant women with ureteral colic spontaneously pass renal calculi when treated conservatively with hydration, analgesics and, if infected, antibiotics. If stents are required, they can be done cystoscopically using ultrasound or minimal radiographic imaging ( ).
Time to passage of stones is also dependent on stone size. In a study of 75 men and women who were prospectively followed for stone passage, stones smaller than 2 mm passed in 8.2 days, with 4.8% requiring intervention, whereas stones between 2 and 4 mm took an average of 12 days and up to 40 days to pass, with 17% requiring intervention ( ). Stones that were larger than 4 mm took 22 days to pass, and 11% needed an intervention, whereas intervention was required for 50% of patients with ureteral calculi greater than 5 mm. Factors that predicted a spontaneous stone passage were right-sided stones, distal location in the ureter, and smaller size.
The recurrence rate for patients who have passed their first stone is approximately 50%. Risk factors for stone recurrence are anatomic upper tract abnormalities (pelvic kidney), a family history of renal stones, intestinal diseases that result in chronic diarrhea, osteoporosis, urinary tract infections, and gout. There is some debate if a complete metabolic work-up for stone disease should be undertaken after passage of the first stone. Many experts advocate fluid and dietary recommendations until patients suffer a recurrence. A metabolic work-up may be required if a woman has the previously listed risk factors, is premenopausal, has a solitary or transplanted kidney, or has stones that were composed of cystine, uric acid, or struvite. Blood tests such as a basic metabolic panel, serum calcium, serum uric, and intact parathyroid hormone are relatively inexpensive and can be performed in first-time stone formers as a simple screen for underlying metabolic issues.
Dietary recommendations for individuals with stones
The following dietary recommendations should be reviewed with women who have a history of kidney stones:
Increase fluid intake to achieve a urine output of 2 L or more a day. Carbonated water is preferred to still water because it has been found to increase urinary citrate levels, which inhibit stone formation.
Increase the dietary intake of citrate to increase urinary citrate levels, which inhibit stone formation. Natural juices that are highest in citrate are grapefruit, lemon, and orange juice. Of the commercially available citrus-based beverages, Crystal Light (Kraft Foods) has the highest concentration of citrate.
Abstain from high protein diets, because protein increases urinary calcium, oxalate, and uric acid excretion and can increase the probability of stone formation even in normal subjects.
Reduce dietary sodium, because dietary sodium and not dietary calcium restriction has been found to prevent recurrent nephrolithiasis.
Reduce dietary oxalate by limiting foods that are rich in oxalate, such as spinach, beets, chocolate, nuts, and tea. There is debate about the conversion of ascorbic acid to urinary oxalate; however, most experts agree that daily vitamin C intake should be limited to less than 2 grams.
Women have 5% of the bladder stones seen in adults, and these stones are typically associated with foreign bodies (sutures, synthetic meshes) or urinary stasis ( ). Bladder stones can be asymptomatic or can be the source of recurrent urinary tract infections, hematuria, and irritable symptoms. Bladder stones typically result from an underlying issue, such as urinary retention or foreign body in the bladder; therefore, the treatment must address the stone and the underlying issue. In cases of urinary retention caused by pelvic organ prolapse, the placement of a pessary or surgical intervention should be considered at the same time as bladder stone removal.
The stone can usually be fragmented manually with the use of a mechanical stone-crushing forceps bridge, requiring the use of a 26-/28-French resectoscope sheath and 30-degree lens. Care should be taken when using a crushing forceps; the stone is picked up and positioned away from the bladder mucosa when the jaws of the crushing forceps are engaged, because they can cause significant damage. When the stone is attached to mesh, it may be impossible to elevate the stone sufficiently; however, holding the forceps horizontally and parallel to the bladder mucosa will allow for the stones to be crushed safely into fragments. Typically, stones attached to a foreign body are soft and easily crushed.
Although there are numerous reports discussing the use of cystoscopic removal of stone and underlying foreign body, most experts recognize that the stone will recur unless the offending material is completely removed from the bladder wall. The most difficult cases of stone/foreign body removal from the bladder typically involve a mesh sling arm on the anterior lateral bladder wall, which often requires a combined transvaginal and retropubic approach. Cystoscopic access to the lateral anterior bladder wall is limited, and endoscopic transvesical procedures are usually best approached through the anterior bladder wall or bladder dome.
Bladder cancer is the most common malignancy of the urinary tract and ranks as the seventeenth most common cancer in women based on worldwide cancer data ( ). There are approximately 19,000 newly diagnosed cases of bladder cancer in women annually, and the incidence in men outnumbers that in women by a ratio of 3.2:1 owing to the higher rates of cigarette use and occupational exposures in men ( ). Bladder cancer is 1.5 times more common in White women than in Black women. Despite women having higher health care utilization than men, by the time bladder cancer is diagnosed, women have more distant metastasis and, as a result, a higher mortality rate ( ). Delay in bladder cancer diagnosis in women may be attributed to delay in the evaluation of associated symptoms that mimic common lower urinary tract symptoms ( ).
In the United States and Western Europe, the most common histological type (>90%) is urothelial carcinoma, whereas in other parts of the world squamous cell carcinoma is more prevalent, because of schistosomiasis. This distinction is important, because squamous carcinoma is more aggressive and has a mortality rate that is significantly higher than that of urothelial carcinoma. There is also a non–schistosomiasis-associated squamous cell carcinoma that has been reported in patients with spinal cord injury, particularly following long-term use of an indwelling catheter. These patients are generally diagnosed at a late stage and present with poor prognosis ( ).
Bladder cancer risks increase with age. Nine out of ten individuals diagnosed are over the age of 55 years; the average age at diagnosis is 73 years ( ). External risk factors include tobacco use in the form of cigarettes, which accounts for 30% of urothelial cancers in women and 46% of all bladder cancer deaths in high-income countries ( ; ; ). The risk of bladder cancer decreases 15 years after quitting, but the risk remains and is dependent on the number of years smoked and the number of cigarettes smoked per day ( ; ). The risk of secondhand smoke in promoting bladder cancer formation is considered to be negligible but has not been well studied.
Occupational carcinogens, such as aromatic amines, diesel engine exhaust, paints, dyes, chlorinated hydrocarbons, metals, and industrial oils that affect the lung and skin, are associated with approximately 30% of bladder cancers. Occupations associated with environmental risks include aluminum process painters, machinists and other metal workers, leather workers, shoemakers, printers, hairdressers, dry cleaners, and transport workers ( ). Although dietary factors such as artificial sweeteners have been associated with the development of bladder cancers in animals, there has been no evidence in humans. Medical interventions associated with bladder cancer include pelvic radiation exposure and cyclophosphamide chemotherapy. The latency period for bladder cancer development is often 15 to 30 years after the exposure.
Few studies have looked at lower urinary tract symptoms at the time of evaluation for hematuria. As a result, the literature regarding urinary symptoms, degree of hematuria, and diagnosis of bladder cancer is often based on the retrospective analysis of patients referred to a urology clinic. The limitations of these studies are based on the reality that compliance with guidelines for referral is low. In a survey of primary care physicians, 64% of microscopic hematuria findings were not routinely referred for urologic evaluation ( ).
Hematuria is the most common presenting symptom of patients with bladder cancer, noted in approximately 85% of those who are subsequently diagnosed. Men and women may also present with common lower urinary tract symptoms such as dysuria, urgency, and nocturia before the first-time diagnosis of bladder cancer ( ). A prospective study looking at gender disparities regarding clinical symptoms and referral patterns before a diagnosis of bladder cancer found that, although clinical symptoms did not differ between the sexes, there might be a difference in referral patterns ( ). Even when presenting with gross hematuria, one study showed that men are 65% more likely to receive a urologic referral than women ( ). Women were more likely to receive symptomatic treatment for alleged urinary tract infections without further investigation or referral, resulting in diagnostic delay.
Gross hematuria is the most prognostic clinical sign of underlying urologic disease; up to 23% of patients with gross hematuria have a malignancy, and another 44% might have other urological conditions ( ). In patients 40 to 59 years of age, gross hematuria carries a positive predictive value for urologic cancer that is higher for women than for men (6.4% vs. 3.6%; ). Microscopic hematuria is less commonly associated with malignancy than gross hematuria; however, hematuria can occur in apparently normal individuals and is, most often, the result of benign causes. In a prospective study of 736 women with a mean age of 59 years who presented to a hematuria clinic, 252 (34%) had gross hematuria, with a cancer detected in 40 (15.9%), compared with a 3.5% cancer detection rate in women with microscopic hematuria (≥3 red blood cells [RBC]/high power field [HPF]). report that 115 (15.6%) had the finding of urinary tract infection, and that 34% had irritative voiding symptoms. There were no pathological findings in 68% and 52% of the patients evaluated for microscopic and gross hematuria, respectively.
Asymptomatic microscopic hematuria guidelines in women
Asymptomatic microscopic hematuria (AMH) is commonly encountered, although the risk of associated malignancy is low. In a retrospective cohort study using a large, integrated health care system database of 3,742,348 urinalyses performed on 2,705,696 women over a 6-year span, 20% of the urinalyses had microscopic hematuria, including those of patients with an identified benign cause of microscopic hematuria, such as urinary tract infection ( ). The overall rate of urologic cancer in this cohort was 1.3%.
Screening of healthy asymptomatic patients with urinalysis for cancer detection is not currently recommended by any major health organization. The US Preventative Services Task Force concludes that the evidence is “insufficient to determine the balance of benefits and harms of screening for bladder cancer in asymptomatic adults” ( ). Despite the lack of evidence for screening, annual urinalysis screening by primary care practitioners (including obstetrics/gynecologists) who care for women continues, and, as a result, urogynecologists and urologists receive referrals for women with AMH. Until recently, the only published guidelines directing the work-up for microscopic hematuria were the 2016 American Urological Association (AUA) Guidelines for AMH. These 2016 guidelines outlined the principles and recommendations for AMH and gross hematuria in men and women. The guidelines were not gender-specific and recommended that AMH (≥3 RBC/HPF) in a single specimen in a patient over the age of 35 years warrants a cystoscopy and CT urography, whereas persistent or recurrent AMH should have a repeat evaluation within 3 to 5 years. Contrary to common practice, urine cytology was not recommended as part of the microscopic hematuria work-up.
Recent studies in women suggest that the 2016 AUA guidelines may result in unnecessary evaluations. In 2011, Gleason et al. published a study of 210,000 women with AMH (≥3 RBC/HPF) and gross hematuria (>100 RBC/HPF) on microscopic analysis who were enrolled in an institutional health plan and followed for 3 years after their diagnosis of AMH. The authors found low rates of urologic cancers (0.02%) in women younger than 40 years, independent of the degree of hematuria. The rates of urologic cancers in women older than 40 years were dependent on the degree of hematuria (from 0.16% in women with 0–2 RBC/HPF to 1.77% in those with 100+ RBC/HPF [representing gross hematuria]). The authors proposed that an alternative approach to the AUA guidelines is to perform hematuria evaluation in women over the age of 40 years with one urinalysis that demonstrates greater than 25 RBC/HPF.
In light of this study and others, the American College of Obstetricians and Gynecologists (ACOG) and the American Urogynecological Society (AUGS) published AMH guidelines for women in 2017 based on studies that only included women. The guidelines state the following conclusions:
In low-risk, never-smoking women younger than 50 years without gross hematuria and with fewer than 25 RBC/HPF, the risk of urinary tract malignancy is less than or equal to 0.5%.
Asymptomatic, low-risk, never-smoking women aged 35 to 50 years should undergo evaluation only if they have more than 25 RBC/HPF.
Age over 60 years, history of smoking, and gross hematuria are the strongest predictors of urologic cancer.
ACOG and AUGS encourage organizations producing future guidelines on the evaluation of microscopic hematuria to perform sex-specific analysis of the data and produce practical sex-specific recommendations.
In 2020, the AUA, in conjunction with the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction, updated their guidelines to use a risk-stratified approach for evaluation of AMH based upon a patient’s risk factors for urinary tract cancer ( ). Based on these updated guidelines, once diagnosed, clinicians should categorize patients as low-, intermediate-, or high-risk for genitourinary malignancy, which will determine next steps: See Fig. 40.1 for the algorithm. The AUA guideline panel suggests that physicians and patients engage in a shared decision-making process to select the best option for each individual patient. The new clinical guidelines include the following principles:
When diagnosing, clinicians should not define microhematuria by a positive dipstick test alone. Rather, the dipstick test should prompt formal microscopic evaluation of the urine to determine microhematuria.
During the initial evaluation of microhematuria, clinicians should consider such factors as genitourinary malignancy, medical renal disease, and gynecologic or nonmalignant genitourinary disease as potential causes of microhematuria.
After evaluation, clinicians should categorize patients based on risk to determine next steps, including repeating urinalysis, cystoscopy, renal ultrasound, or axial imaging (e.g., CT urogram).