Pharmacology of Stone Disease
2008; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês
10.1053/j.ackd.2008.10.004
ISSN1548-5609
Autores Tópico(s)Therapeutic Uses of Natural Elements
ResumoKidney stone disease remains a major health and economic burden on the nation. It has been increasingly recognized that nephrolithiasis can be both a chronic or systemic illness. There have been major limitations in the development of new drugs for the prevention and management of this disease, largely due to our lack of understanding of the complex pathophysiologic mechanisms involving the interaction of three major target organs: the kidney, bone, and intestine. We also do not yet understand the molecular genetic basis of this polygenic disorder. These limitations are coupled with the incorrect perception that kidney stone disease is solely an acute illness, and the lack of reliable tests to assess outcome measures. All of these factors combined have diminished the willingness of the pharmaceutical industry to engage in the development of novel drugs. Kidney stone disease remains a major health and economic burden on the nation. It has been increasingly recognized that nephrolithiasis can be both a chronic or systemic illness. There have been major limitations in the development of new drugs for the prevention and management of this disease, largely due to our lack of understanding of the complex pathophysiologic mechanisms involving the interaction of three major target organs: the kidney, bone, and intestine. We also do not yet understand the molecular genetic basis of this polygenic disorder. These limitations are coupled with the incorrect perception that kidney stone disease is solely an acute illness, and the lack of reliable tests to assess outcome measures. All of these factors combined have diminished the willingness of the pharmaceutical industry to engage in the development of novel drugs. Kidney stone disease continues to have a major impact on the health and economy of the United States. The lifetime risk for nephrolithiasis exceeds 6% to 12% in the general population, and it is also projected that the prevalence of kidney stones will escalate.1Johnson C.M. Wilson D.M. O'Fallon W.M. et al.Renal stone epidemiology: A 25-year study in Rochester, Minnesota.Kidney Int. 1979; 16: 624-631Crossref PubMed Scopus (387) Google Scholar, 2Stamatelou K.K. Francis M.E. Jones C.A. et al.Time trends in reported prevalence of kidney stones in the United States: 1976-1994.Kidney Int. 2003; 63: 1817-1823Crossref PubMed Scopus (1155) Google Scholar One approximation in 2005 estimated the combined inpatient and outpatient costs to be over $2.1 billion.3Pearle M.S. Calhoun E.A. Curhan G.C. Urologic diseases in America project: Urolithiasis.J Urol. 2005; 173: 848-857Abstract Full Text Full Text PDF PubMed Scopus (652) Google Scholar This figure is clearly an underestimate considering the inflation in medical costs over the past 3 years. It has been increasingly recognized that the spectrum of the presentation of nephrolithiasis is wide, and it may be characterized as an acute, localized, chronic, or systemic illness. It has been shown that nephrolithiasis may be associated with an increased risk of end-stage renal disease,4Worcester E. Parks J.H. Josephson M.A. et al.Causes and consequences of kidney loss in patients with nephrolithiasis.Kidney Int. 2003; 64: 2204-2213Crossref PubMed Scopus (89) Google Scholar, 5II. Incidence and prevalence of ESRD.Am J Kidney Dis. 1999; 34: S40-S50PubMed Google Scholar, 6Jungers P. Joly D. Barbey F. et al.ESRD caused by nephrolithiasis: Prevalence, mechanisms, and prevention.Am J Kidney Dis. 2004; 44: 799-805Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar coronary artery disease, the metabolic syndrome, hypertension, and diabetes mellitus.7Sakhaee K. Nephrolithiasis as a systemic disorder.Curr Opin Nephrol Hypertens. 2008; 17: 304-309Crossref PubMed Scopus (124) Google Scholar Therefore, targeted pharmacologic treatments are imperative in the management of this disorder. The developments of such treatments require a comprehensive understanding of the pathophysiologic and molecular genetic basis of this disease. This review highlights some of our current approaches to this complex disorder, the obstacles involved in newer treatment modalities, and future targeted interventions. At the present time, conservative measures such as increased fluid intake to ensure sufficient urinary dilution and conventional treatments including alkali therapy, thiazide diuretics, and allopurinol are the mainstay treatments for various types of nephrolithiasis. As an acute illness, kidney stone disease is associated with significant pain, disability, and loss of productivity.8Lotan Y. Gettman M.T. Roehrborn C.G. et al.Management of ureteral calculi: A cost comparison and decision making analysis.J Urol. 2002; 167: 1621-1629Abstract Full Text Full Text PDF PubMed Google Scholar Up to 50% of patients experiencing acute upper urinary tract stones require surgical intervention because stone dissolution is impractical.9Krepinsky J. Ingram A.J. Churchill D.N. Metabolic investigation of recurrent nephrolithiasis: Compliance with recommendations.Urology. 2000; 56: 915-920Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 10Glowacki L.S. Beecroft M.L. Cook R.J. et al.The natural history of asymptomatic urolithiasis.J Urol. 1992; 147: 319-321PubMed Google Scholar It has recently been shown that medical expulsive treatment facilitates urethral stone passage. There is growing interest in the usage of medical treatment such as calcium-channel blockers and α-adrenergic antagonists to enhance stone passage.11Hollingsworth J.M. Rogers M.A. Kaufman S.R. et al.Medical therapy to facilitate urinary stone passage: a meta-analysis.Lancet. 2006; 368: 1171-1179Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 12Parsons J.K. Hergan L.A. Sakamoto K. et al.Efficacy of alpha-blockers for the treatment of ureteral stones.J Urol. 2007; 177: 983-987Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar A MEDLINE meta-analysis of all scientific data up to 2005, using calcium-channel blockers or α-blockers search criteria, showed that medical treatment with such agents, with or without steroid treatment and regardless of stone size, enhanced the percentage of ureteral stone expulsion11Hollingsworth J.M. Rogers M.A. Kaufman S.R. et al.Medical therapy to facilitate urinary stone passage: a meta-analysis.Lancet. 2006; 368: 1171-1179Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar (Fig 1). Despite such successful results, chemical expulsive treatment has been underused largely because of (1) a lack of widespread physician awareness, (2) the absence of large-scale randomized controlled trials, and (3) limitations in our understanding of the mechanisms of action of these agents. It is crucial to pursue randomized trials because expulsive medical treatment would significantly decrease the cost imposed by shockwave lithotripsy and ureteroscopy.8Lotan Y. Gettman M.T. Roehrborn C.G. et al.Management of ureteral calculi: A cost comparison and decision making analysis.J Urol. 2002; 167: 1621-1629Abstract Full Text Full Text PDF PubMed Google Scholar, 13Bierkens A.F. Hendrikx A.J. De La Rosette J.J. et al.Treatment of mid- and lower ureteric calculi: extracorporeal shock-wave lithotripsy vs laser ureteroscopy. A comparison of costs, morbidity and effectiveness.Br J Urol. 1998; 81: 31-35Crossref PubMed Google Scholar Furthermore, these treatments may vastly improve the quality of life of the patients because they have been shown to reduce episodes of pain,14Resim S. Ekerbicer H. Ciftci A. Effect of tamsulosin on the number and intensity of ureteral colic in patients with lower ureteral calculus.Int J Urol. 2005; 12: 615-620Crossref PubMed Scopus (76) Google Scholar, 15Yilmaz E. Batislam E. Basar M.M. et al.The comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones.J Urol. 2005; 173: 2010-2012Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar lower analgesic requirements,16Porpiglia F. Destefanis P. Fiori C. et al.Effectiveness of nifedipine and deflazacort in the management of distal ureter stones.Urology. 2000; 56: 579-582Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar and reduce the time of stone passage.16Porpiglia F. Destefanis P. Fiori C. et al.Effectiveness of nifedipine and deflazacort in the management of distal ureter stones.Urology. 2000; 56: 579-582Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 17Porpiglia F. Ghignone G. Fiori C. et al.Nifedipine versus tamsulosin for the management of lower ureteral stones.J Urol. 2004; 172: 568-571Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar Nephrolithiasis has been shown to be a chronic disease because its cumulative recurrence rate progressively increases from the onset of acute stone passage and approaches 50% over 10 years.18Uribarri J. Oh M.S. Carroll H.J. The first kidney stone.Ann Intern Med. 1989; 111: 1006-1009Crossref PubMed Scopus (281) Google Scholar Given the chronicity of this illness, long-term pharmacological treatment is necessary to reduce stone recurrence in this population. Most drugs applied in the treatment of kidney stones have been in use for many years. Since the advent of potassium citrate treatment,19Pak C.Y. Peterson R. Sakhaee K. et al.Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis.Am J Med. 1985; 79: 284-288Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 20Barcelo P. Wuhl O. Servitge E. et al.Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis.J Urol. 1993; 150: 1761-1764PubMed Google Scholar no new drug has been developed. Studies using potassium-magnesium citrate have shown its efficacy against recurrent calcium oxalate nephrolithiasis.21Ettinger B. Pak C.Y. Citron J.T. et al.Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis.J Urol. 1997; 158: 2069-2073Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 22Zerwekh J.E. Odvina C.V. Wuermser L.A. et al.Reduction of renal stone risk by potassium-magnesium citrate during 5 weeks of bed rest.J Urol. 2007; 177: 2179-2184Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 23Jaipakdee S. Prasongwatana V. Premgamone A. et al.The effects of potassium and magnesium supplementations on urinary risk factors of renal stone patients.J Med Assoc Thai. 2004; 87: 255-263PubMed Google Scholar However, this drug has not yet been marketed. Three separate randomized trials conducted in the 1990s examining the effect of potassium alkali in recurrent calcium oxalate nephrolithiasis showed a significant decrease in stone recurrence.20Barcelo P. Wuhl O. Servitge E. et al.Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis.J Urol. 1993; 150: 1761-1764PubMed Google Scholar, 21Ettinger B. Pak C.Y. Citron J.T. et al.Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis.J Urol. 1997; 158: 2069-2073Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 24Soygur T. Akbay A. Kupeli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial.J Endourol. 2002; 16: 149-152Crossref PubMed Scopus (138) Google Scholar These studies encompassed a total of 231 subjects with recurrent hypocitraturia calcium nephrolithiasis who were treated with potassium alkali, 30 mEq to 60 mEq/d for a duration ranging between 12 and 36 months. However, a similar fourth study did not show superiority of potassium alkali over the placebo treatment.25Hofbauer J. Hobarth K. Szabo N. et al.Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis—A prospective randomized study.Br J Urol. 1994; 73: 362-365Crossref PubMed Scopus (100) Google Scholar This study was conducted in a total of 50 hypocitraturia calcium nephrolithiasis patients treated with 90 mEq potassium alkali per day over the course of 3 years. The reported lack of efficacy of potassium alkali treatment in this investigation was, in part, attributed to the small size of the study population (Fig 2). Calcium oxalate is the most prevalent type of kidney stone disease in the United States and has been shown to occur in 70% to 80% of the kidney stone population.26Asplin J.R. Hyperoxaluric calcium nephrolithiasis.Endocrinol Metab Clin North Am. 2002; 31: 927-949Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar The effects of thiazide diuretics on recurrent calcium nephrolithiasis have been studied in 6 randomized trials. Four of these studies, conducted in a total of 408 patients over a duration of 26 to 36 months, showed a significant decrease in recurrent kidney stones with thiazides and their analog indapamide27Ettinger B. Citron J.T. Livermore B. et al.Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not.J Urol. 1988; 139: 679-684Abstract Full Text PDF PubMed Scopus (231) Google Scholar, 28Laerum E. Larsen S. Thiazide prophylaxis of urolithiasis. A double-blind study in general practice.Acta Med Scand. 1984; 215: 383-389Crossref PubMed Scopus (163) Google Scholar, 29Ohkawa M. Tokunaga S. Nakashima T. et al.Thiazide treatment for calcium urolithiasis in patients with idiopathic hypercalciuria.Br J Urol. 1992; 69: 571-576Crossref PubMed Scopus (89) Google Scholar, 30Borghi L. Meschi T. Guerra A. et al.Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences.J Cardiovasc Pharmacol. 1993; 22: S78-S86Crossref PubMed Scopus (147) Google Scholar, 31Coe F.L. Evan A. Worcester E. Kidney stone disease.J Clin Invest. 2005; 115: 2598-2608Crossref PubMed Scopus (580) Google Scholar (Fig 2). Conversely, no difference was noted between thiazide treatment and the placebo in 2 of these trials.32Brocks P. Dahl C. Wolf H. et al.Do thiazides prevent recurrent idiopathic renal calcium stones?.Lancet. 1981; 2: 124-125Abstract PubMed Scopus (67) Google Scholar, 33Scholz D. Schwille P.O. Sigel A. Double-blind study with thiazide in recurrent calcium lithiasis.J Urol. 1982; 128: 903-907PubMed Google Scholar Three of these studies alluded to high dietary fluid intake to ensure sufficient urinary volume.27Ettinger B. Citron J.T. Livermore B. et al.Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not.J Urol. 1988; 139: 679-684Abstract Full Text PDF PubMed Scopus (231) Google Scholar, 28Laerum E. Larsen S. Thiazide prophylaxis of urolithiasis. A double-blind study in general practice.Acta Med Scand. 1984; 215: 383-389Crossref PubMed Scopus (163) Google Scholar, 30Borghi L. Meschi T. Guerra A. et al.Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences.J Cardiovasc Pharmacol. 1993; 22: S78-S86Crossref PubMed Scopus (147) Google Scholar However, 2 studies did not indicate whether patients were instructed to maintain a high urinary volume through sufficient fluid intake.29Ohkawa M. Tokunaga S. Nakashima T. et al.Thiazide treatment for calcium urolithiasis in patients with idiopathic hypercalciuria.Br J Urol. 1992; 69: 571-576Crossref PubMed Scopus (89) Google Scholar, 32Brocks P. Dahl C. Wolf H. et al.Do thiazides prevent recurrent idiopathic renal calcium stones?.Lancet. 1981; 2: 124-125Abstract PubMed Scopus (67) Google Scholar In 2 studies, an index of obesity was calculated by dividing weight in pounds by the square of height.27Ettinger B. Citron J.T. Livermore B. et al.Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not.J Urol. 1988; 139: 679-684Abstract Full Text PDF PubMed Scopus (231) Google Scholar, 30Borghi L. Meschi T. Guerra A. et al.Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences.J Cardiovasc Pharmacol. 1993; 22: S78-S86Crossref PubMed Scopus (147) Google Scholar The remaining studies made no indication of the influence of body weight or obesity. In addition, a widely quoted study involving thiazide diuretics in patients with recurrent calcium nephrolithiasis determined chlorthalidone to be significantly superior to both magnesium treatment and placebo.27Ettinger B. Citron J.T. Livermore B. et al.Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not.J Urol. 1988; 139: 679-684Abstract Full Text PDF PubMed Scopus (231) Google Scholar However, only 28.5% of this total study population had hypercalciuria. It appears that the successful response to this treatment also occurred in calcium stone formers without hypercalciuria. Therefore, because this study was performed over 36 months, it is logical to conclude that the reported effectiveness against stone recurrence could not be attributed to regression to the mean or stone clinic effect. In general clinical practice, however, thiazide diuretics are typically only prescribed for those with hypercalciuric calcium nephrolithiasis. In most of the thiazide trials, both symptomatic and clinical stone passage rates were used to determine kidney stone recurrence. Because most of these studies were performed in the 1980s and 1990s, clinical stone passage rate was determined by routine x-ray procedures including kidney-ureter-bladder, intravenous pyelography, and tomography. The appearance of new calculus or the enlargements of preexisting calculi were considered as new stones. In symptomatic patients, new stone passage was verified, and any surgical procedure for stone removal was also considered as a new stone. To exclude stone clinic effect, a grace period of several months was used to mark the washout period. Hyperuricosuria is detected in 15% to 20% of patients with calcium nephrolithiasis.34Coe F.L. Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria, or no metabolic disorder.Ann Intern Med. 1977; 87: 404-410Crossref PubMed Scopus (216) Google Scholar The first double-blind study showing the efficacy of allopurinol was conducted over 20 years ago. In this study, 60 patients with hyperuricosuria and normocalciuria received either the placebo or allopurinol, 100 mg, 3 times a day for 39 months.35Ettinger B. Tang A. Citron J.T. et al.Randomized trial of allopurinol in the prevention of calcium oxalate calculi.N Engl J Med. 1986; 315: 1386-1389Crossref PubMed Scopus (287) Google Scholar Compared with the placebo, allopurinol treatment significantly reduced new calcium oxalate stone incidence and also prolonged the time between new stone recurrences. The findings of this study have not been challenged by new controlled studies. To date, this treatment has largely been safe with the only severe side effect being the possible increased risk of allergic reactions when used in combination with thiazide diuretics36Young Jr., J.L. Boswell R.B. Nies A.S. Severe allopurinol hypersensitivity. Association with thiazides and prior renal compromise.Arch Intern Med. 1974; 134: 553-558Crossref PubMed Scopus (109) Google Scholar (Fig 2). The risk-benefit ratio of pharmacologic interventions with thiazide diuretics and alkali treatment in the kidney stone–forming population has not been fully investigated. However, alkali treatment has been shown to be relatively free of side effects with only minor gastrointestinal complaints. The main concern with this treatment is its overuse, which may increase the propensity for calcium phosphate stone formation. Because thiazide diuretics may have harmful effects extending beyond their efficacy against kidney stone formation, it remains unclear whether its risks may outweigh its benefits. In a recent retrospective meta-analysis of all clinical trials conducted between 1966 and 2004 in thiazide-treated populations, an inverse relationship was shown between changes in serum glucose and potassium concentrations.37Zillich A.J. Garg J. Basu S. et al.Thiazide diuretics, potassium, and the development of diabetes: A quantitative review.Hypertension. 2006; 48: 219-224Crossref PubMed Scopus (368) Google Scholar The result of this study was also supported by The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial in which a 4-year incidence of new-onset diabetes mellitus was shown to be significantly higher with chlorthalidone compared with amlodipine or lisinopril treatments.38Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).JAMA. 2002; 288: 2981-2997Crossref PubMed Scopus (5141) Google Scholar Although the association between thiazide use and glucose intolerance has been known for many years,39Goldner M.G. Zarowitz H. Akgun S. Hyperglycemia and glycosuria due to thiazide derivatives administered in diabetes mellitus.N Engl J Med. 1960; 262: 403-405Crossref PubMed Scopus (103) Google Scholar, 40Sagild U. Andersen V. Andreasen P.B. Glucose tolerance and insulin responsiveness in experimental potassium depletion.Acta Med Scand. 1961; 169: 243-251Crossref PubMed Scopus (78) Google Scholar the exact pathophysiologic mechanism is not well known. One possibility may be that low serum potassium concentrations may cause a decrease in insulin secretion.41Houston M.C. The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics.Am Heart J. 1988; 115: 640-656Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 42Carter B.L. Einhorn P.T. Brands M. et al.Thiazide-induced dysglycemia: Call for research from a working group from the National Heart, Lung, and Blood Institute.Hypertension. 2008; 52: 30-36Crossref PubMed Scopus (81) Google Scholar As of yet, no prospective studies have shown a causal relationship between serum potassium concentrations and the development of diabetes mellitus in the general thiazide-treated population and, more specifically, in thiazide-treated kidney stone patients. This is important because a relationship between type 2 diabetes mellitus and the risk of kidney stone disease has been shown in 3 separate longitudinal studies.43Taylor E.N. Stampfer M.J. Curhan G.C. Diabetes mellitus and the risk of nephrolithiasis.Kidney Int. 2005; 68: 1230-1235Crossref PubMed Scopus (388) Google Scholar It has become more apparent that nephrolithiasis may be a systemic illness. Several prospective epidemiologic studies have shown that obesity and weight gain increase the risk of kidney stone disease.43Taylor E.N. Stampfer M.J. Curhan G.C. Diabetes mellitus and the risk of nephrolithiasis.Kidney Int. 2005; 68: 1230-1235Crossref PubMed Scopus (388) Google Scholar, 44Taylor E.N. Stampfer M.J. Curhan G.C. Obesity, weight gain, and the risk of kidney stones.JAMA. 2005; 293: 455-462Crossref PubMed Scopus (860) Google Scholar In addition, 2 studies conducted in a kidney stone population and in normal subjects showed an inverse relationship between urinary pH and body weight and also a progressive decrease in urinary pH with additional features of the metabolic syndrome.45Maalouf N.M. Sakhaee K. Parks J.H. et al.Association of urinary pH with body weight in nephrolithiasis.Kidney Int. 2004; 65: 1422-1425Crossref PubMed Scopus (331) Google Scholar, 46Maalouf N.M. Cameron M.A. Moe O.W. et al.Low urine pH: A novel feature of the metabolic syndrome.Clin J Am Soc Nephrol. 2007; 2: 883-888Crossref PubMed Scopus (216) Google Scholar However, the pathophysiologic link between obesity, insulin resistance, and calcium stone formation has not yet been established. A direct physiological relationship between insulin sensitivity and urinary pH has been shown in a carefully conducted metabolic study using the hyperinsulinemic euglycemic clamp procedure.47Abate N. Chandalia M. Cabo-Chan Jr., A.V. et al.The metabolic syndrome and uric acid nephrolithiasis: Novel features of renal manifestation of insulin resistance.Kidney Int. 2004; 65: 386-392Crossref PubMed Scopus (443) Google Scholar The result of this study has a major clinical impact on the future development of novel drugs targeting insulin resistance. There are several obstacles to overcome in the development of novel agents for the treatment of nephrolithiasis. These limitations can be divided into 2 different categories: (1) the incorrect perception that kidney stone disease is a self-limiting local disorder without consideration for chronic, recurrent, and systemic illnesses and (2) an incomplete understanding of the pathophysiologic and molecular genetic basis of nephrolithiasis. The misconception that kidney stone disease is a self-limiting disorder hinders nephrologists and urologists in the prevention of recurrent kidney stone disease,48Grampsas S.A. Moore M. Chandhoke P.S. 10-year experience with extracorporeal shockwave lithotripsy in the state of Colorado.J Endourol. 2000; 14: 711-714Crossref PubMed Scopus (28) Google Scholar indirectly impeding the development of new drugs. Additionally, the field is deficient in new agent testing because of the lack of availability of concisely measured outcomes. Although the stone events appear to be ideal for an outcome measure, it is cumbersome because it requires a long-term follow up because the median time for recurrence after the first event is approximately 5 years. This misconception, coupled with poor patient compliance, results in a lack of interest from the pharmaceutical industry in the development of a novel drug because of its perceived low profitability. Moreover, testing new agents requires a surrogate marker other than a stone event. These markers may include the use of spiral computed tomography scans for the detection of small and large stones. To date, computer-based approaches have been used in kidney stone risk assessment but are becoming increasingly recognized as having major flaws. Second, the pathophysiologic mechanisms and molecular genetic basis of nephrolithiasis are diverse and complex. They involve a multifaceted physiologic interaction of 3 major organs participating in calcium homeostasis: the bone, intestine, and kidney. The molecular genetic pathways of nephrolithiasis have not been fully elucidated largely because this illness appears to be a polygenic trait. Moreover, there has been limited success49Bushinsky D.A. Asplin J.R. Grynpas M.D. et al.Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats.Kidney Int. 2002; 61: 975-987Crossref PubMed Scopus (93) Google Scholar, 50Bushinsky D.A. Favus M.J. Mechanism of hypercalciuria in genetic hypercalciuric rats. Inherited defect in intestinal calcium transport.J Clin Invest. 1988; 82: 1585-1591Crossref PubMed Scopus (91) Google Scholar, 51Tsuruoka S. Bushinsky D.A. Schwartz G.J. Defective renal calcium reabsorption in genetic hypercalciuric rats.Kidney Int. 1997; 51: 1540-1547Crossref PubMed Scopus (83) Google Scholar, 52Bushinsky D.A. Grynpas M.D. Nilsson E.L. et al.Stone formation in genetic hypercalciuric rats.Kidney Int. 1995; 48: 1705-1713Crossref PubMed Scopus (80) Google Scholar, 53Krieger N.S. Stathopoulos V.M. Bushinsky D.A. Increased sensitivity to 1,25(OH)2D3 in bone from genetic hypercalciuric rats.Am J Physiol. 1996; 271: C130-C135PubMed Google Scholar in the establishment of accepted animal models that recapitulate the human disease to further explore kidney stone pathophysiology and response to treatment. In the past 10 to 15 years, there have been significant advances in our understanding of the epithelial cell transport of calcium and oxalate,54Jiang Z. Asplin J.R. Evan A.P. et al.Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6.Nat Genet. 2006; 38: 474-478Crossref PubMed Scopus (253) Google Scholar, 55van de Graaf S.F. Hoenderop J.G. Bindels R.J. Regulation of TRPV5 and TRPV6 by associated proteins.Am J Physiol Renal Physiol. 2006; 290: F1295-F1302Crossref PubMed Scopus (87) Google Scholar the role of insulin resistance,45Maalouf N.M. Sakhaee K. Parks J.H. et al.Association of urinary pH with body weight in nephrolithiasis.Kidney Int. 2004; 65: 1422-1425Crossref PubMed Scopus (331) Google Scholar, 46Maalouf N.M. Cameron M.A. Moe O.W. et al.Low urine pH: A novel feature of the metabolic syndrome.Clin J Am Soc Nephrol. 2007; 2: 883-888Crossref PubMed Scopus (216) Google Scholar, 47Abate N. Chandalia M. Cabo-Chan Jr., A.V. et al.The metabolic syndrome and uric acid nephrolithiasis: Novel features of renal manifestation of insulin resistance.Kidney Int. 2004; 65: 386-392Crossref PubMed Scopus (443) Google Scholar, 56Sakhaee K. Adams-Huet B. Moe O.W. et al.Pathophysiologic basis for normouricosuric uric acid nephrolithiasis.Kidney Int. 2002; 62: 971-979Crossref PubMed Scopus (259) Google Scholar, 57Cameron M.A. Maalouf N.M. Adams-Huet B. et al.Urine composition in type 2 diabetes: Predisposition to uric acid nephrolithiasis.J Am Soc Nephrol. 2006; 17: 1422-1428Crossref PubMed Scopus (179) Google Scholar and the link between renal lipotoxicity and the development of uric acid nephrolithiasis. We have also witnessed a major progression in the field by defining the role of interstitial plaque formation as a precursor to calcium oxalate nephrolithiasis.58Evan A.P. Lingeman J.E. Coe F.L. et al.Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle.J Clin Invest. 2003; 111: 607-616Crossref PubMed Scopus (495) Google Scholar, 59Evan A.P. Coe F.L. Lingeman J.E. et al.Renal crystal deposits and histopathology in patients with
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