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23. Metabolic Evaluation and Medical Management of Stone Disease
Keywords
Metabolic evaluationMedical managementUrolithiasisEpidemiology
Nephrolithiasis has a high worldwide prevalence with rates which range from 7 to 13% in North America, 5 to 9% in Europe, and 1 to 5% in Asia according to recent reports [1]. This prevalence appears to be increasing, with recent data from the National Health and Nutrition Examination Survey (NHANES) in the United States showing a 63% relative increase from 6.3% in 1988–1994 to 10.3% in 2007–2010 [2]. Also changing is the gender gap in the prevalence of stone disease. While historically nephrolithiasis has been considered to be a male-predominant disease, a re-analysis of the NHANES over the time period 2007–2012 showed no difference in stone prevalence between men and women under 50 years of age [3]. Similarly disproportionate increases affecting demographic groups historically considered to be at lower risk for nephrolithiasis, including children, African Americans, and Hispanics, have been documented recently as well [2, 4].
These increases in overall and gender-specific prevalence of nephrolithiasis have been linked to systemic conditions such as obesity, diabetes, and metabolic syndrome. Moreover, the magnitude of increased kidney stone risk conferred by obesity appears to disproportionately affect women [5]. Based in part on the high degree of geographic variability of stone disease prevalence in the United States as well as internationally, studies have hypothesized and subsequently demonstrated that weather related variables such as increasing ambient temperature and sunlight exposure constitute risk factors for nephrolithiasis as well [6]. These findings have led to concerns that progression of global warming in the coming decades could further contribute to increasing stone disease prevalence [7, 8].
The economic burden of nephrolithiasis is tremendous. As of 2000, the estimated annual cost attributed to urolithiasis in the United States was $2.1 billion dollars, representing a 50% increase since 1994 [9]. More contemporary estimates are as high as $10 billion dollars annually [10]. As a consequence of an increasing stone prevalence, it is predicted that the overall expenses related to nephrolithiasis will continue to increase over time [7].
Stone Types and Associated Metabolic Conditions
Non-calcium stones are less commonly encountered and include struvite (magnesium ammonium phosphate, 5–10%), uric acid (5–10%), cystine (1–2%), urate (ammonium acid urate, sodium urate, <1%), xanthine (<1%), and medication-related stones (indinavir, ephedrine, triamterene, silicates, ciprofloxacin, sulfa medications) [13].
Calcium-Based Urolithiasis
Calcium Oxalate Stones
While calcium oxalate is the most common stone type, the formation of calcium oxalate stones has been associated with a large number of different metabolic defects [14], and therefore stone analysis alone in these patients may not be specifically revealing into the potential underlying disorder [15]. Metabolic defects which have been associated with calcium oxalate stone formation include hypercalciuria (absorptive and renal), hypocitraturia, hyperuricosuria, hyperoxaluria, gouty diathesis (low urine pH), and low urine volume. On comprehensive metabolic evaluation over 97% of patients will have an identifiable metabolic derangement, and many patients will be discovered to have multiple of these risk factors in combination.
Calcium Phosphate Stones
Calcium phosphate stone formation, in contrast to calcium oxalate, is more likely to be associated with a specific metabolic disorder such as distal renal tubular acidosis (RTA 1) or primary hyperparathyroidism [14, 15].
Uric Acid Urolithiasis
At a urine pH of less than 5.35, uric acid exists predominantly in its free form which has exceedingly poor solubility in urine and therefore crystallizes to form uric acid stones [16]. Low urine volume and only occasionally hyperuricosuria can contribute to the development of uric acid stones, but these factors play a secondary role to low urine pH [17]. Low urine pH, defined as a pH lower than 5.5 and also known as “gouty diathesis,” has been associated with systemic insulin resistance [18, 19] and increased body weight [20] through a postulated mechanism of impaired ammoniagenesis in the renal tubules. The most common cause of hyperuricosuria is dietary purine excess. Other medical conditions which may cause hyperuricosuria include gout, certain myeloproliferative and hematologic disorders with rapid cell turnover, and rarely hereditary errors in purine metabolism or urate transport. In the setting of hyperuricosuria without pH <5.5, formation of microscopic uric acid crystals in the urine has been demonstrated to form a nidus that can seed heterogeneous nucleation of calcium oxalate stones and lead to hyperuricosuric calcium urolithiasis (HUCU) [21, 22].
Infectious Urolithiasis
Infectious stones are composed of magnesium ammonium phosphate, more commonly referred to as struvite, which may be present purely or in mixed composition with other stone types, often carbonate apatite and hydroxyapatite [23]. These calculi occur secondary to urinary tract infection by urease-splitting bacteria [24]. Common uropathogenic organisms associated with urease production include Proteus, Klebsiella, Providencia, Morganella, Corynebacterium, and Ureaplasma species [25]. Staphylococcus and Pseudomonas species may occasionally produce urease, however E. coli does so only exceedingly rarely. Bacterial urease catalyzes the conversion of urea to ammonia and carbon dioxide, which promotes the formation of alkaline urine (pH > 7.2) and creates a milieu conducive to the formation of struvite or mixed struvite stone [23]. Struvite growth may be enhanced in the setting of concurrent chronic infection and obstruction [26]. Women are twice as likely to have struvite stones than men due to their higher incidence of urinary tract infections [27].
In the past it was believed that struvite stones composed the majority of staghorn calculi. More recent series, however, suggest that stones with staghorn configurations more commonly have a metabolic etiology, specifically calcium phosphate [28].
Cystine Urolithiasis
Cystinuria is a hereditary condition, usually with an autosomal recessive inheritance pattern, which is characterized by defective resorption of the dibasic amino acids cystine, ornithine, lysine, and arginine within the proximal renal tubule [29]. While urinary concentrations of all four of these amino acids are elevated, only cystine forms renal stones due to its very poor solubility in urine at physiologic temperature, pH, and concentration [30]. Notably, even though cystine stone formers all have definitive genetic derangements, they often also demonstrate other metabolic abnormalities such as hypocitraturia, hyperuricosuria, and hypercalciuria [31].
Other Non-Calcium Urolithiasis
Ammonium Acid Urate Stones
Ammonium acid urate (AAU) stones are rarely encountered in industrialized nations, with an incidence of less than 1% in North America [32]. Risk factors for the development of these stones, in order of prevalence, include morbid obesity (40.6%), recurrent UTIs (36.4%), inflammatory bowel disease (25%) with or without ileostomy diversion (22.7%), recurrent uric acid stones (20.5%), and a history of laxative abuse (13.6%) [33].
AAU stones are more classically encountered endemically in the composition of pediatric bladder stones in the developing world, where they are thought to occur in areas where diets are poor in phosphorus content, rich in purine-containing cereal grains, restricted in access to abundant clean water, with a high incidence of diarrheal illness [34].
The proposed mechanism for formation of AAU stones in the setting of the above-listed risk factors involves dehydration from chronic GI fluid and sodium loss leading to intracellular acidosis and concomitant increased urinary ammonium and decreased urinary sodium. These changes, coupled with low urinary pH and hyperuricosuria, create an environment in which AAU stones may form.
Medication-Induced Stones (Table 23.3)
Direct Promotion of Stone Formation
Several drugs are known to directly promote stone formation via concentration and direct precipitation in the urine [13]. These medications include but are not limited to indinavir (as well as newer generation protease inhibitors used to treat HIV [35]), ciprofloxacin, triamterene, silicates, guaifenesin/ephedrine, and sulfa medications. The diagnosis and treatment of these stone types can be very difficult as many of them are quite radiolucent, even on CT.
Indirect Promotion of Stone Formation
Several other medication classes promote stone formation indirectly by altering urine parameters that increase stone risk. Loop diuretics (e.g. furosemide) and corticosteroids cause hypercalciuria. Carbonic anhydrase inhibitors (e.g. acetazolamide), certain anti-convulsants (topiramate and zonisamide), and thiazides can produce intracellular acidosis, hypocitraturia, and overly-alkaline urine in the long term which increases risk for calcium phosphate stones. As previously mentioned, laxative abuse has been associated with ammonium acid urate stone formation. Vitamin C supplementation, in excess, has been linked to hyperoxaluria and increased stone formation rates [36, 37].
Metabolic Evaluation of Stone Disease
Goals
Prospective studies have shown that first time stone formers are estimated to have a 27–50% risk for stone recurrence within 5 years of their initial stone episode [38, 39]. Because urinary stone disease carries significant morbidity, discomfort, and cost, patients and physicians alike are motivated to reduce recurrence as much as possible. The goal of the metabolic evaluation therefore is to identify any specific metabolic derangements which may contribute to the formation of new stones or the growth of existing stones.
Specific dietary therapy made on the basis of a comprehensive metabolic evaluation has been shown to be superior to generalized dietary recommendations in preventing stone recurrence [40]. Additionally, targeted medical therapy based on the findings of a comprehensive medical evaluation has been shown to reduce stone growth and new stone formation compared to empiric treatment [41, 42].
Who Needs Metabolic Evaluation?
Recent recommendations from the American Urological Association Nephrolithiasis Guidelines Panel suggest that metabolic testing should be performed in recurrent stone formers and in high risk or interested first time stone formers [43]. Patient populations considered to be at high risk for stone recurrence include those with a family history of stone disease, inflammatory or other malabsorptive bowel disease, recurrent urinary tract infections, obesity, renal tubular acidosis type 1, primary hyperparathyroidism, osteoporosis, gout, or diabetes mellitus type 2 [44].
There is controversy regarding whether non-high risk first-time stone formers should undergo metabolic evaluation or be treated empirically. There is ample evidence that stone recurrence is greatly reduced in first-time calcium-based nephrolithiasis patients by increasing fluid intake with or without general dietary modification, suggesting that the recurrence risk for these patients can be reduced without undergoing the cost and inconvenience of metabolic testing [38, 45]. However, there is also evidence that recurrent stone formers and first-time stone formers have similar types and frequencies of metabolic abnormalities on 24-h urine testing [46], and since we know from several randomized controlled trials that directed medical therapy for specific urinary abnormalities can reduce stone recurrence [47], this finding suggests that first-time stone formers may in fact benefit from comprehensive metabolic evaluation and selective medical treatment.
Stone formers with stone types that are associated with increased likelihood of metabolic derangements should undergo metabolic evaluation. Uric acid and cystine stone formation have been demonstrated to coincide with gouty diathesis and cystinuria metabolic derangements, respectively, in nearly all cases [15], and therefore metabolic evaluation in these patients is justified. For many years, pure struvite stones were believed to have a low likelihood of being associated with specific intervenable metabolic derangements and therefore metabolic evaluation was not routinely recommended for these patients [48]. However, more contemporary reports have identified metabolic abnormalities in pure struvite stone formers to be more common than previously believed and suggest that these patients would benefit from comprehensive evaluation and directed medical therapy [49].
There is controversy regarding whether or not all children with urolithiasis require a comprehensive metabolic evaluation following a stone episode. While the overall incidence of pediatric nephrolithiasis has rapidly increased over the past few decades in the United States [50], this increase appears to be occurring disproportionally in school-aged children older than age 8 and is hypothesized to be related to increases in the prevalence of pediatric and adolescent obesity during the same time period [51]. Augmenting this epidemiologic data, a recent retrospective multi-institutional study of pediatric 24 h urine studies demonstrated that children older than age 10 are significantly less likely than younger children to have an identifiable metabolic abnormality on evaluation and their most common abnormalities were low urine volumes and hypocitraturia [52]. Conversely, children aged 10 or younger were significantly more likely to have metabolic disorders, specifically hyperoxaluria, hypercalciuria, and elevated calcium phosphate supersaturation. Taken together, these findings suggest that perhaps older children may be evaluated and treated with or without comprehensive metabolic evaluation in a manner similar to adult first-time stone formers, whereas younger children should be treated as high risk patients and encouraged to complete a full evaluation.
What Are the Components of the Metabolic Evaluation?
Medical History and Physical Examination
Risk factors for urolithiasis from medical history
Risk factors for urolithiasis from patient history | |
|---|---|
Medical history | Primary hyperparathyroidism |
Renal Tubular Acidosis (RTA) Type 1 | |
Gout | |
Metabolic syndrome/diabetes mellitus Type 2 | |
Obesity | |
Inflammatory bowel disease | |
Chronic diarrhea/malabsorptive gastrointestinal disorder | |
Osteoporosis | |
Spina Bifida or Other Neurologic Disorder | |
Personal or family history of nephrolithiasis | |
Recurrent urinary tract infections | |
Surgical history | Bariatric surgery |
Gastrointestinal reconstruction | |
Urinary diversion | |
Prior urologic surgery | |
Dietary history | Low fluid intake |
High salt intake | |
High animal protein intake | |
Low fruit and vegetable intake | |
Very high or very low calcium intake | |
High oxalate intake | |
Special Diets (i.e. Low Carbohydrate/High Protein) | |
Stone-inducing medications
Stone-inducing medications | ||
|---|---|---|
Medications | Direct stone promotion | Indinivir (and other antiretroviral protease inhibitors) |
Ciprofloxacin | ||
Triamterene | ||
Silicates | ||
Guaifenesin/Ephedrine | ||
Sulfa Medications | ||
Indirect stone promotion | Carbonic anhydrase inhibitors (Acetazolamide, Topiramate, Zonisamide) | |
Long term loop diuretics | ||
Chronic corticosteroid use | ||
Vitamin D and Calcium Supplements | ||
Vitamin C Supplements | ||
Chemotherapy | ||
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