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Urinary stone disease has afflicted mankind for millennia. The oldest renal stone on record was described by Shattock in 1905 and was found in an Egyptian mummy in a tomb dating to approx 4400 bc . This 1.5-cm calciferous calculi lay beside the first lumbar vertebra. The description of urinary stones has been a process of intense scientific investigation culminating in a burst of activity in the 19th century, when essentially all urinary stones seen commonly today were described and named. The first part of this chapter addresses some history that underlies the current names we use for urinary calculi.

Urinary stones are polycrystalline aggregates consisting of varying amounts of crystal and organic matrix components. Although urolithiasis is inclusive of renal, ureteral, and bladder stones, the following discussion will pertain only to symptomatic renal and ureteral stones, as they are the most common. The most common urinary stone types are calcium oxalate, calcium phosphate, uric acid, struvite (magnesium ammonium phosphate), and cystine. In an analysis of 14,557 renal and ureteral stones, 52% were purely calcium oxalate, 13% purely calcium phosphate, 15% a mixture of calcium oxalate and phosphate, 4% struvite, 8% uric acid, and 8% other compounds . As the majority of stones are of the calcium variety, it is likely that most epidemiological studies of nephrolithiasis pertain to this compositional form. Of the less common stone varieties, struvite stones are commonly associated with urinary tract infections, most notably secondary to urease splitting organisms such as and . Uric acid stones, associated with hyperuricosuric patients, are found in patients with gout, dehydration, and excessive purine intake. Finally, cystine stones are a rare form associated with inborn errors of metabolism resulting in abnormal absorption of dibasic amino acids in the small bowel and proximal renal tubule.

The lifetime risk of stone formation is estimated at 5–10%; hence, stone disease represents one of the most frequent causes of hospitalization in the United States . Various intrinsic and extrinsic factors are associated with risk for stone formation. Among intrinsic factors are race, sex, and genetics . Over the past decade significant advances have occurred in our understanding of the underlying genetic lesions that are associated with many forms of stone disease. However, it is interesting to note that most advances in the identification of genetic defects have been made in the rarer forms of stone disease. Progress toward understanding the genetic contribution in the more common forms of calcium oxalate stone disease has been impeded by the fact that many forms of this disease are complex, associated with phenotypic variability, and further compounded by multifactorial inheritance. A recent review of the literature indicates that 27 individual chromosomal loci have been associated with various forms of urolithiasis . All modes of inheritance are represented among the various genetic stone diseases.

Water is a pivotal element in digestion, circulation, elimination, and regulation of body temperature. A critical function of the urinary system is the maintenance of normal composition and volume of body fluid; this is accomplished by glomerular filtration, tubular reabsorption, and tubular secretion of soluble and filterable plasma components. By such means, urine contains water, electrolytes, minerals, hydrogen ions, end products of protein metabolism, and other compounds not useful to the metabolism, energy requirements, or structure of the body. Under normal circumstances, urine will not contain solid particles (stones).

It is well established that human urine is supersaturated with respect to ions and molecules, which can crystallize as clinical crystalluria with a potential for stone development. Regardless of the specific site of crystallization within the nephron, crystals can either pass from the kidney into the bladder and be excreted or attach to cells in the late collecting duct and grow into mature kidney stones. The crystalline composition of a stone reflects the urine chemistry and abnormalities in tubular physiology during the process of stone development. Accurate knowledge of the composition of the stone is critical to elucidating the underlying etiology of the patient’s clinical disorder(s) that precipitated the stone disease.

An understanding of extracellular calcium handling in the body is helpful for those who treat stone disease. Calcium is a component in the majority of urinary stones. Researchers and clinicians seek to broaden their knowledge of calcium handling and of derangements in calcium metabolism in an effort to uncover the etiology of a patient’s stone disease and to prevent further recurrence.

Oxalate excretion is a prerequisite for the formation of calcium oxalate stones and the development of hyperoxaluric states. In this chapter, we review the aspects of oxalate physiology germane to these conditions, the clinical manifestations of these entities, as well as therapy.

Renal stone disease is frequently associated with abnormal urinary acid-base balance. Renal tubular defects may influence urinary pH and alter urinary excretion of various substances, predisposing to stone formation. This chapter provides a background for the understanding of acid-base disorders, mainly from a renal perspective. Most of the concepts of pulmonary and renal acid-base regulation are well established. The concepts of renal tubular acidosis, however, are still being refined. In the past several years, the developments of microbiological and genetic research have added new insights to the pathophysiology of renal tubular disorders. The topics in this section will touch on basic renal and nonrenal acid-base regulation, systemic and urinary buffering, and focus on regulation of urinary pH, and renal tubular acidosis.

It is intriguing that despite marked abnormal urinary factors, most humans will not form stones. Alternatively, some patients develop stones despite normal urinary composition. The key element, therefore, appears to be inhibition of the steps in calculogenesis (nucleation, crystal growth, aggregation, and crystal/stone retention). Urolithiasis will not develop if any one of these steps is blocked. Despite this simple fact, it is unclear exactly why many people form stones. Numerous molecules have been identified that inhibit crystallization in vitro but many stone formers have normal levels of these substances; others will continue to develop stones despite replacement of these known inhibitors. The formation of urinary calculi requires a complex combination of factors, both promoting and inhibiting stone formation. Fortunately, there are many patients who can be helped because of our existing knowledge about two specific urinary inhibitors: citrate and magnesium. This chapter will discuss the in vitro and in vivo evidence regarding citrate and magnesium as inhibitors of urinary stone disease.

As a direct consequence of the renal function of water preservation urine becomes supersaturated with slightly soluble salts like calcium oxalates and calcium phosphates . When the supersaturation is high enough and lasts long enough, crystals will form. Crystallization involves crystal nucleation, growth, and aggregation . Most crystals are, however, discharged during urination without causing any discomfort . But in some individuals, a number of crystals remain in the urinary space either by adhering to the urothelium or by accreting mass through aggregation . Under appropriate conditions, retained crystals evolve into stone nidi thus establishing a base for stone growth . Apparently there are mechanisms to ensure crystals can be passed harmlessly. It has become clear that defense mechanisms act at all levels, from supersaturation to nucleation, crystal growth, crystal aggregation, crystal structure, crystal habit, crystal surface properties, and crystal interactions with the epithelial lining of the renal tubules and urinary tract. In fact there also appears to be a mechanism for removal of material that passed the previous defenses. Crystals that are retained in the renal tubules can enter the renal interstitium where they are attacked by macrophages that are attracted by the chemokines such as MCP-1 produced by renal epithelial cells as well as the crystal-associated compounds like osteopontin .