Nephrolithiasis
1. Define hypercalciuria, kidney (renal) stones, renal calculi, nephrolithiasis, urolithiasis, renal lithiasis, and nephrocalcinosis.
Hypercalciuria is urinary calcium excretion greater than 300 mg/day in men and greater than 250 mg/day in women. A more accurate definition is urinary calcium excretion greater than 4 mg per kg of ideal body weight per day in either sex. A good estimate of the 24-hour urine calcium excretion is 1.1 times the calcium-to-creatinine ratio (Ca/Cr) on a random urine specimen. For example, if urine calcium is 20 mg/dL and urine creatinine is 70 mg/dL, then the Ca/Cr would be 20:70 or 0.286 g (286 mg/day). The estimated 24-hour urinary calcium excretion would be 1.1 × 286 = 315 mg/day. Kidney stones, renal calculi, nephrolithiasis, urolithiasis, and renal lithiasis are synonymous terms that define the clinical syndrome of formation and movement of stones in the urinary collecting system. Renal calculi are abnormally hard, crystalline, insoluble substances that form in the renal collecting system. Nephrocalcinosis is deposition of calcium salts in the renal parenchyma.
2. Who is at risk for the development of kidney stones?
The average prevalence of kidney stones in the United States is approximately 5%, with the lifetime risk for a stone being 13% in men and 7% in women. The yearly cost of kidney stone disease in the United States is more than $5 billion. Fifty percent of patients with kidney stones have a recurrence within 5 to 10 years. Stones occur most often between ages 20 and 60 years and occur in Caucasians more than other ethnicities. Women have had more stones in recent years, possibly because of increased calcium and protein intake and greater exercise with the potential for dehydration. Review of nephrolithiasis in the Women’s Health Initiative suggests that hormone replacement therapy is a risk for renal stones. Other risks for stones include a family history of stones, obesity, diabetes mellitus, hypertension, autosomal dominant polycystic kidney disease, medullary sponge kidney, renal tubular acidosis, urine volume less than 2 L/day, dietary sodium greater than 2 g/day, low water intake, and high protein intake (see question 4).
3. What are the compositions and approximate frequencies of kidney stones in the United States?
There are six major types of stones, as outlined in Figure 17-1, which also shows the approximate frequency of occurrence of each type of stone.
Figure 17-1. Frequency of the kinds of kidney stones.
4. What are the main causes of nephrolithiasis?
The most common causes of nephrolithiasis are the various types of idiopathic hypercalciuria (IH): absorptive hypercalciuria (AH) types AH-I to AH-III (renal phosphate leak) and renal hypercalciuria (RH). Other causes are primary hyperparathyroidism, hyperoxaluria, hyperuricosuria, hyperphosphaturia, hypocitraturia, hypomagnesuria, infection stones, gouty diathesis, renal tubular acidosis, cystinuria, and, possibly, nanobacteria. Rarely, kidney stones may form from xanthine, triamterene, monosodium urate, ephedrine, guaifenesin, and indinavir (protease inhibitor). Patients with idiopathic nephrolithiasis make up 10% to 20% of “stone formers” in whom routine workup yields no identifiable cause.
5. Describe the conditions associated with both renal stone disease and hypercalciuria.
Calcium stones account for 80% of all kidney stones. Approximately 40% to 50% of calcium stone formers have hypercalciuria. Of those with hypercalciuria, 40% have IH, 5% have primary hyperparathyroidism, and 3% have renal tubular acidosis. Other causes of hypercalciuria include excessive dietary vitamin D, excessive calcium and alkali intake, sarcoidosis, Cushing’s syndrome, hyperthyroidism, Paget’s disease of bone, and immobilization. Nephrolithiasis is also associated with infection, acute and chronic kidney injury, coronary artery disease, type 2 diabetes mellitus, hypertension, and the metabolic syndrome.
6. What are the most important causes of normocalciuric calcium nephrolithiasis?
The most important and most common causes of normocalciuric calcium nephrolithiasis are hypocitraturia (50%), hyperuricosuria (25%), hyperoxaluria (10%), and urinary stasis (5%).
7. Describe the process of renal stone formation.
Initially, urinary crystallization or precipitation of sparingly soluble salts and acids occurs. Nucleation follows as the initial crystals and urinary matrix ions form a stable framework for crystal enlargement through growth and aggregation. After they are sufficiently large, crystals become trapped in a narrow portion of the urinary collecting system (often at the end of collecting ducts), forming a nidus for further stone growth. Alternatively, crystals form in the medullary interstitium, are extruded, and adhere to the renal papilla and form a Randall’s plaque nidus for further crystal accumulation and stone growth. Once stone growth occurs, the stone may detach from the renal papilla, move distally, and cause obstruction. Common sites for obstruction are the ureteropelvic junction, midureter, and ureterovesical junction.
8. Discuss the pathophysiologic factors that influence the formation of renal stones.
Renal stones result from hereditary or acquired disorders causing supersaturation of stone precursors, deficiency of stone inhibitors, and possibly excess promoters. Supersaturation causes crystallization with mineral precursors, such as calcium and oxalate. Calcium oxalate crystals bind to anionic, sialic acid–containing glycoproteins on the apical surfaces of renal tubular epithelial cells, allowing further growth. Other factors that increase stone formation include urinary stasis (medullary sponge kidney), decreased flow (obstruction), increased urine ammonium (infection), dehydration (concentrated urine), and increased urinary alkalinity (renal tubular acidosis [RTA]). Type I RTA promotes stone formation through the increased release of calcium and phosphorus from bone to buffer the acidemia, with resulting hypercalciuria and hyperphosphaturia. The acidemia enhances proximal tubule reabsorption of citrate with resulting hypocitraturia. The alkaline urine of RTA promotes precipitation of calcium phosphate stones. Acidemia with a positive urine anion gap (UNa + UK − UCl) is a clue to the presence of RTA.
9. What are the main chemical precursors of renal stones?
Relatively high concentrations of salt and acid solutes are the main determinants of crystalluria and stone formation. Calcium oxalate is most common and is supersaturated to four to five times its solubility in normal urine. Other precursors are calcium phosphate (hydroxyapatite) and calcium phosphate monohydrate (brushite). Uric acid, cystine, struvite (magnesium ammonium phosphate), and mucoprotein are undersaturated stone precursors. Drugs such as ascorbic acid (conversion to oxalate) and triamterene (nidus for stone formation) also may promote renal stone formation.
10. What are the main inhibitors of renal stone formation? How do they work?
Inhibitors include urinary citrate, pyrophosphate, magnesium, nephrocalcin, uropontin, glycosaminoglycans, and Tamm-Horsfall protein. Most of them bind crystal precursors; for example, citrate binds calcium, making it less available to bind to oxalate. Inhibitors improve solubility and impair precipitation, nucleation, crystal growth, or aggregation. They also compete with stone precursor minerals, such as calcium oxalate, for binding to the apical surfaces of epithelial cells and inhibit epithelial cell adhesion and internalization of calcium oxalate crystals. Finally, inhibitors impair stone precursor transformation to a focus for crystallization and stone growth.
11. What is nephrocalcin? What role does it play in the formation of renal stones?
Nephrocalcin is an anionic protein produced by the proximal renal tubule and the loop of Henle. It normally inhibits the nucleation, crystal growth, and aggregation phases of stone formation. However, nephrocalcin isolated from some stone formers has defective structure and function and is found in the matrix of many calcium stones. Thus nephrocalcin may have a dual role in stone formation. When normal, it acts as an inhibitor of stone formation. When abnormal, it may act as a promoter by binding calcium and forming a nidus for crystallization.
12. What are the promoters of renal stone formation?
Promoters of renal stone formation are poorly characterized but are believed to be primarily urinary mucoproteins and glycosaminoglycans. Under certain conditions, promoters enhance the formation of renal stones.
13. How does the kidney handle calcium?
Approximately 60% of the serum calcium is ionized or complexed and freely filtered by the glomerulus. The kidney reabsorbs 98% of the filtered calcium passively throughout the nephron. Sixty percent of the reabsorption occurs in the proximal convoluted tubule, 30% in the loop of Henle, and 10% in the distal tubule. Furosemide impairs calcium reabsorption in the loop of Henle and increases urinary calcium excretion. Thiazide diuretics impair distal tubule reabsorption of sodium, thereby increasing intracellular negativity and calcium reabsorption. PTH increases distal tubular calcium reabsorption by enhancing calcium channel activity.
14. Calculate the normal filtered and excreted load of calcium per day.
The serum calcium concentration is normally 10 mg/dL. The kidney filters complexed and free calcium, which makes up 60% of the total, or 6 mg/dL. The normal glomerular filtration rate (GFR) is 120 mL/min. Thus the filtered load of calcium is 6 mg/100 mL × 120 mL/min × 1440 min/day = 10,368 mg/day. Because the kidney reabsorbs 98% of the filtered calcium, only 2% is excreted. Thus normally the kidney excretes about 200 mg of calcium/day (10,368 mg/day × 0.02 = 207 mg/day). If the excreted calcium level increases to 5%, the urinary calcium level increases to 500 mg/day.
KEY POINTS 1: INCIDENCE AND ETIOLOGY OF NEPHROLITHIASIS
1. Kidney stones are increasingly more common, possibly because of excessive dietary protein and calcium, exercise without adequate hydration, and rising rates of obesity.
2. Approximately 10% of the U.S. population has a lifetime risk for at least one kidney stone.
3. Stones form because of super saturation of urinary stone precursors (such as calcium and oxalate), insufficient stone inhibitors (such as citrate), abnormal urine pH, or insufficient urine volume.
4. Stones are most commonly calcium based and result from hypercalciuria caused by excess absorption of dietary calcium, resorption of bone calcium, and unusually decreased renal calcium reabsorption.
5. Restricting dietary calcium without restricting dietary oxalate increases oxalate absorption and the risk for calcium oxalate stones.
15. How do the serum calcium level and dietary sodium intake affect hypercalciuria?
To help prevent hypercalcemia, nonrenal elevation in serum calcium causes increase in both filtered calcium and urinary calcium. Increased sodium delivery to the loop of Henle and the distal tubule also raises urinary calcium. In non–stone formers, urinary calcium excretion increases about 40 mg for each 100 mEq of sodium excretion. In hypercalciuric stone formers, calcium excretion increases up to 80 mg per each 100 mEq of sodium. Because urinary sodium excretion equilibrates to dietary sodium intake, restricting dietary sodium reduces urinary calcium excretion. In patients with stones, recommended daily dietary sodium is no more than 100 mEq (2300 mg).
16. Describe the etiology and pathophysiology of IH.
IH affects 10% of the general population and 40% of stone formers. The four types of IH are AH-I to AH-III and RH. AH-I and AH-II result from increased intestinal sensitivity to calcitriol with intestinal calcium hyperabsorption and higher numbers of vitamin D receptors in osteoblasts, causing greater bone resorption and resorptive hypercalciuria. The latter accounts for decreased bone mass seen in many patients with AH-I and some of those with AH-II. AH-III, an unusual disorder, is due to a renal phosphate leak with urinary loss of phosphate, decreased serum phosphate, and increases in renal calcitriol production and intestinal calcium absorption. The level of the phosphaturic factor, fibroblast growth factor-23, is increased in some patients with calcium nephrolithiasis, hypophosphatemia, and renal phosphate leak. RH is characterized by impaired tubular reabsorption of calcium, which causes a decrease in serum calcium, elevations in parathyroid hormone (PTH) and calcitriol, and increases in bone resorption and intestinal calcium absorption.
17. Distinguish among the various forms of IH.
18. When is it necessary to distinguish among the various forms of IH?
Only complicated nephrolithiasis unresponsive to usual therapy requires differentiation (see Website reference on hypercalciuria review at the end of the chapter).
19. Explain the differences in serum levels of phosphorus and PTH in AH-III and RH.
