Chapter 8 Justin Ziemba, MD; Phillip Mucksavage, MD 2. The prevalence of nephrolithiasis has increased from 5.2% in 1994 to 8.8% in 2010. 3. The overall prevalence of nephrolithiasis in the United States is 8.8%. 4. Approximately 1 in 11 individuals has reported a history of nephrolithiasis in the United States. 5. The prevalence is 10.6% in males and 7.1% in females; the incidence is 105 cases per 100,000 males and 68 cases per 100,000 females. 6. Females have two-thirds the risk of developing nephrolithiasis as compared to males. 7. Non-Hispanic white individuals have the highest prevalence of nephrolithiasis, followed by non-Hispanic black and then Hispanic individuals. 8. In screening populations, approximately 8% of individuals will have incidental asymptomatic kidney stones detected with CT. 9. Of these asymptomatic stones, 15% to 20% will spontaneously pass, 15% to 30% will become symptomatic, 30% to 45% will increase in size, and 5% to 25% will require intervention. 1. Calcium oxalate (dihydrate and monohydrate): 70%. 2. Calcium phosphate (hydroxyapatite): 20%. 3. Mixed calcium oxalate and calcium phosphate: 11% to 31%. 4. Uric acid: 8%. 5. Magnesium ammonium phosphate (struvite): 6%. 6. Cystine: 2%. 7. Miscellaneous: xanthine, silicates, and drug metabolites, such as indinavir (radiolucent on x-ray and CT scan). b. Calcium salt stones c. Rare nephrocalcinosis d. Rare risk of end-stage renal disease 2. Primary hyperoxaluria types 1, 2, and 3 b. Pure monohydrate calcium oxalate stones (whewellite) c. Nephrocalcinosis d. Risk of end-stage renal disease 3. Distal renal tubular acidosis (RTA) a. Autosomal recessive or dominant b. Apatite stones c. Nephrocalcinosis d. Risk of end-stage renal disease 4. Cystinuria a. Autosomal recessive associated with a defect on chromosome 2 b. Cystine stones c. No nephrocalcinosis d. Risk of end-stage renal disease 5. Lesch-Nyhan syndrome (HGPRT deficiency) b. Uric acid stones c. No nephrocalcinosis d. Risk of end-stage renal disease b. Increased calcium and vitamin D supplementation may increase the risk of calcium stones. c. Increased dietary sodium intake is associated with an increased risk of calcium and sodium urinary excretion, which leads to increased calcium stones. d. Increased dietary animal protein intake may lead to increased uric acid and calcium stones. e. Increased water intake is associated with a reduced risk of all types of kidney stones. 2. Obesity a. Obesity and weight gain are associated with an increased risk of developing kidney stones. 3. Diabetes a. Diabetes is a risk factor for the development of kidney stones. b. Insulin resistance may lead to altered acidification of the urine and increased urinary calcium excretion. 4. Geographical factors b. Stone incidence peaks approximately 1 to 2 months after highest annual temperature. a. Necessary for a phase change from a solution to a solid b. Supersaturation depends on the pH, temperature, and ionic species of the solution. c. Thermodynamic solubility product is the concentration at which saturation is reached and crystallization is possible. d. The formation product is the concentration at which spontaneous crystallization is inevitable. e. The metastable zone refers to the area between the thermodynamic solubility product and the formation product where no spontaneous crystallization occurs, but existing crystals can grow and new crystallization can occur on a seed. 2. Crystal formation a. Nucleation is the first step in crystal formation and can be either homogenous or heterogeneous. 1) Homogenous nucleation occurs only in pure solutions (i.e., not urine). 2) Heterogeneous nucleation, which requires a lower supersaturation value than homogenous nucleation, occurs in urine, and crystallization can begin on cellular components and other crystals. b. Epitaxy refers to the ability of one crystalline structure to facilitate the nucleation of another crystalline structure. c. Once nucleation has occurred, crystals grow via aggregation or agglomeration. d. Crystal retention occurs in the renal tubules and is thought to be required for stone formation via two mechanisms, either the free particle or fixed particle hypothesis. 2) The fixed particle hypothesis requires the adherence of the crystals to nearby structures, such as the renal epithelium, which facilitates crystal growth and stone formation. 3. Inhibitors and promoters b. Inhibitors can prevent crystal aggregation. 1) Common inhibitors include citrate, magnesium, Tamm-Horsfall protein, and glycosaminoglycans. c. Promoters can enhance crystal aggregation. 1) Common promoters include cellular matrix, oxalate, low urine volume, and epitaxy. 4. Pathogenesis of stone formation a. Crystal-induced renal injury 2) Deposition of oxalate leads to oxidative stress and formation of reactive oxygen species, which injure the renal epithelium. 3) Stone formation then preferentially develops through crystal adherence to the injured renal epithelium. b. Randall plaques 2) The calcium phosphate deposits enlarge throughout the interstitium and ultimately erode through the epithelium at the tips of the renal papilla. 3) This deposit of calcium phosphate serves as a nucleus for secondary calcium oxalate stone formation. c. Low urinary inhibitors 2) Urinary citrate is an inhibitor of calcium stone formation by binding to calcium to reduce supersaturation and prevent nucleation. d. Stasis 2) Hypothesis that stasis prevents urinary washout of crystals. a. Approximately 70% to 80% of incident stones are calcium oxalate. b. Initial event is precipitation of calcium phosphate on the renal papilla as Randall plaques, which serve as a nucleus for calcium oxalate precipitation and stone formation. c. Calcium oxalate stones preferentially develop in acidic urine (pH less than 6.0). d. Development depends on supersaturation of both calcium and oxalate within the urine. 2. Idiopathic hypercalciuria a. Identified in 30% to 60% of calcium oxalate stone formers and in 5% to 10% of nonstone formers b. The upper limit of normal for urinary calcium excretion is 250 mg/day for women and 300 mg/day for men. c. Need to exclude hypercalcemia, vitamin D excess, hyperthyroidism, sarcoidosis, and neoplasm. d. Diagnosed via exclusion in patients with a normal serum calcium but elevated urinary calcium on a random diet. 3. Absorptive hypercalciuria b. Divided into type I, II and III, depending on whether urinary calcium levels can be affected by calcium in the diet (type I and II) or renal phosphate leak leading to increased calcium absorption (type III). c. Increased calcium absorption leads to a higher filtered load of calcium delivered to the renal tubule. d. The treatment for each subtype is generally the same, so determining which type (often requiring inpatient evaluation) is no longer necessary. e. Normal serum calcium 4. Renal hypercalciuria a. Impaired proximal tubular reabsorption of calcium leads to renal calcium wasting. b. Normal serum calcium; hypercalciuria persists despite a calcium restricted diet. c. Distinguished from primary hyperparathyroidism by normal serum calcium levels and secondary hyperparathyroidism. 5. Resorptive hypercalciuria a. Primary hyperparathyroidism is the underlying mechanism. b. Increased PTH levels cause bone resorption and intestinal calcium absorption, which leads to elevated serum calcium that exceeds the reabsorptive capacity of the renal tubule. c. Normal to slightly elevated serum calcium 6. Hypercalcemic hypercalciuria 7. Hyperoxaluria a. The upper limit of normal for urinary oxalate excretion is 45 mg/d in women and 55 mg/d in men. b. Acts as a potent inhibitor of stone formation by complexing with calcium c. Dietary hyperoxaluria is related to increased consumption of oxalate-rich foods, and/or a low-calcium diet, which by reducing the availability of intestinal calcium to complex to oxalate, allows an increased rate of free oxalate absorption by the gut. d. Enteric hyperoxaluria can be caused by small bowel disease or loss, exocrine pancreatic insufficiency, or diarrhea, all of which reduce small bowel fat absorption, leading to an increase in fat complexing with calcium, and thereby facilitating free oxalate absorption by the colon. e. Primary hyperoxaluria is a genetic disorder in one of two genes, which results in increased production or urinary excretion of oxalate. In type I, which is an autosomal recessive trait, AGXT (alanine-glyoxylate aminotransferase) is deficient in the liver. This results in increased production of oxalate. These patients develop early oxalosis, stone formation, and ultimate renal failure. In type II, there is a deficiency in D-glycerate dehydrogenase and glyoxylate reductase, which leads to increased urinary oxalate excretion; this type is extremely rare with only 21 reported cases. 8. Hypocitraturia a. The lower limit of normal is less than 500 mg/d for women and 350 mg/d for men. b. Acts as an inhibitor of stone formation by complexing with calcium. c. Citrate is regulated by tubular reabsorption, and reabsorption varies with urinary pH. In acidic conditions, tubular reabsorption is enhanced, which lowers urinary citrate levels. d. Diseases that cause acidosis, such as chronic diarrhea or distal RTA, cause lower urinary citrate levels. Thiazide therapy can also reduce citrate levels via potassium depletion. e.
Nephrolithiasis
Epidemiology
Composition of renal stones
Pathogenesis and physiochemical properties
Genetics
Environmental
Physical and biochemical properties of stone formation
Pathophysiology of stone formation
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