Clinical practice companion


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Clinical practice companion

  2. 2. We are pleased to present you with a collection of recent articles relevant to today’s practicing physician. NEJM is committed to helping physicians improve patient care by providing the best current information in an understandable and clinically useful format . These regular features, Clinical Practice, Clinical Therapeutics, and Current Concepts, demonstrate how to diagnose and manage diseases, keep you up to date with the latest in clinical care, and highlight the best treatments and management options. This collection will only be available for a limited time, with free access available by clicking through from the Special Collections tab in My NEJM. Limited Time Free Clinical Practice Companion
  3. 3. CLINICAL PRACTICE CLINICAL PRACTICE Gout T. Neogi February 3, 2011 CLINICAL PRACTICE Calcium Kidney Stones E.M. Worcester and F.L. Coe September 2, 2010 CLINICAL PRACTICE Emergency Treatment of Asthma S.C. Lazarus August 19, 2010 CLINICAL PRACTICE Early Alzheimer’s Disease R. Mayeux June 10, 2010 CLINICAL PRACTICE Helicobacter pylori Infection K.E.L. McCol April 29, 2010 CLINICAL THERAPEUTICS CLINICAL THERAPEUTICS Iron-Chelating Therapy for Transfusional Iron Overload G.M. Brittenham January 13, 2011 CLINICAL THERAPEUTICS Bisphosphonates for Osteoporosis M.J. Favus November 18, 2010 CLINICAL THERAPEUTICS Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration J.C. Folk and E.M. Stone October 21, 2010 CLINICAL THERAPEUTICS Dietary Therapy in Hypertension F.M. Sacks and H. Campos June 3, 2010 CLINICAL THERAPEUTICS Mitral-Valve Repair for Mitral-Valve Prolapse S. Verma and T.G. Mesana December 3, 2009 CURRENT CONCEPTS REVIEW ARTICLE Point-of-Care Ultrasonography C.L. Moore and J.A. Copel February 24, 2011 REVIEW ARTICLE Myocardial Infarction Due to Percutaneous Coronary Intervention A. Prasad and J. Herrmann February 3, 2011 REVIEW ARTICLE MDR Tuberculosis — Critical Steps for Prevention and Control E. Nathanson and others September 9, 2010 OTHER CLINICAL RESOURCES VIDEOS IN CLINICAL MEDICINE Clinical Evaluation of the Knee T.L. Schraeder and others July 22, 2010 INTERACTIVE MEDICAL CASE Lying Low J.J. Ross and others February 10, 2011 5 4 52 51 101 100 132 131 137 63 110 12272 80 91 15 25 35 43 Table of Contents Table of Contents BACK to TOC
  4. 4. 4 Clinical Practice Clinical Practice articles begin with the presentation of a single case and continue to provide a complete description of diagnostic and treatment strategies, therapeutic options, areas of uncertainty, treatment guidelines — everything you need to know about the current state of knowledge about a common condition. These articles are also available in audio format, so you can listen at your computer or download articles for transfer to any iPod or MP3 player. BACK to TOC
  5. 5. 5 clinical practice The new engl and jour nal of medicine n engl j med 364;5 february 3, 2011 443 This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. An audio version of this article is available at Gout Tuhina Neogi, M.D., Ph.D. From the Section of Clinical Epidemiolo- gy Research and Training Unit, Boston University School of Medicine; and the Department of Epidemiology, Boston University School of Public Health — both in Boston. Address reprint requests to Dr. Neogi at the Clinical Epidemiology Unit, Boston University School of Medi- cine, 650 Albany St., Suite X-200, Boston, MA 02118, or at N Engl J Med 2011;364:443-52. Copyright © 2011 Massachusetts Medical Society. A 54-year-old man with crystal-proven gout has a history of four attacks during the previous year. Despite receiving 300 mg of allopurinol daily, his serum urate level is 7.2 mg per deciliter (428 μmol per liter). He is moderately obese and has hypertension, for which he receives hydrochlorothiazide, and his serum creatinine level is 1.0 mg per deciliter (88 μmol per liter). How should his case be managed? The Clinical Problem Symptoms and Prevalence Gout is a type of inflammatory arthritis induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. It is associated with hyperurice- mia, which is defined as a serum urate level of 6.8 mg per deciliter (404 μmol per liter) or more, the limit of urate solubility at physiologic temperature and pH.1 Hu- mans lack uricase and thus cannot convert urate to soluble allantoin as the end prod- uct of purine metabolism. Hyperuricemia that is caused by the overproduction of urate or, more commonly, by renal urate underexcretion is necessary but not suffi- cient to cause gout. In one cohort study, gout developed in only 22% of subjects with urate levels of more than 9.0 mg per deciliter (535 μmol per liter) during a 5-year period.2 Gout has two clinical phases. The first phase is characterized by intermittent acute attacks that spontaneously resolve, typically over a period of 7 to 10 days, with asymptomatic periods between attacks. With inadequately treated hyperuricemia, transition to the second phase can occur, manifested as chronic tophaceous gout, which often involves polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. Although the prevalence of tophaceous gout varies among populations, in one study, tophi were detected in three quarters of patients who had had untreated gout for 20 years or more.3 Recurrent attacks are common. In one study, approximately two thirds of patients with at least one gout attack in the previous year had recurrent attacks.4 An estimated 6.1 million adults in the United States have had gout.5 The preva- lence increases with age and is higher among men than among women, with a ratio of 3 or 4 to 1 overall.5-7 However, this sex disparity decreases at older ages, at least in part because of declining levels of estrogen, which has uricosuric effects in women. The rising incidence and prevalence of gout are probably related to the aging of the population, increasing levels of obesity, and dietary changes.6,7 Risk Factors The use of thiazide diuretics, cyclosporine, and low-dose aspirin (<1 g per day) can cause hyperuricemia, whereas high-dose aspirin (≥3 g per day) is uricosuric. Factors Click here to access audio version. BACK to TOC
  6. 6. 6 The new engl and jour nal of medicine n engl j med 364;5 february 3, 2011444 that are associated with hyperuricemia and gout include insulin resistance, the metabolic syndrome, obesity, renal insufficiency, hypertension, conges- tive heart failure, and organ transplantation.8,9 The uricosuric effects of glycosuria in diabetes may re- duce the risk of gout.10 Rare X-linked inborn errors of metabolism can cause gout.8 Genomewide as- sociation studies have identified common poly- morphisms in several genes involved in renal urate transport that are associated with gout, includ- ing SLC2A9, ABCG2, SLC17A3, and SLC22A12.11,12 The risk of incident gout is increased in persons with an increased intake of dietary purines (par- ticularly meat and seafood), ethanol (particularly beer and spirits), soft drinks, and fructose13-16 and is decreased in those with an increased intake of coffee, dairy products, and vitamin C (which lower urate levels).15,17,18 Triggers for recurrent flares include recent di- uretic use, alcohol intake, hospitalization, and surgery.19,20 Urate-lowering therapy, which reduces the risk of gout attacks in the long term, can trigger attacks in the early period after its initia- tion, presumably as a result of mobilization of bodily urate stores.21,22 Str ategies and Evidence The diagnostic standard remains synovial fluid or tophus aspiration with identification of nega- tively birefringent monosodium urate crystals under polarizing microscopy. Crystals are detect- able during attacks and also potentially between attacks, primarily in previously inflamed joints in patients with hyperuricemia.23 However, crys- tal evaluation is not performed routinely in clini- cal practice.15 Hyperuricemia may not be present during acute gout attacks and therefore may not be a helpful criterion for diagnosis. A typical pre- sentation that is strongly suggestive of the diag- nosis includes rapid development of severe pain (i.e., within 24 hours), erythema, and swelling in a characteristic joint distribution — for example, in the first metatarsophalangeal joint (podagra). In a population with a 0.5% prevalence of gout overall, a patient with hyperuricemia and this pre- sentation has an 82% chance of having gout.23 The differential diagnosis of acute gout in- cludes other crystal-induced arthritides (e.g., cal- cium pyrophosphate dihydrate) and a septic joint. Joint aspiration with Gram’s staining and culture must be performed if a septic joint is suspected, even if monosodium urate crystals are identified. Older adults, particularly women, may present with polyarticular involvement, which may be mis- taken for rheumatoid arthritis; a tophus may be mistaken for a rheumatoid nodule. Tophaceous deposits that are not clinically apparent may be visualized by plain radiography or another imag- ing method. A diagnosis of gout should prompt evaluation for potentially modifiable risk factors (e.g., dietary habits) and associated coexisting ill- nesses (e.g., hypertension and hyperlipidemia) that may require intervention. Treatment Options Acute Gout The main aim of therapy for acute gout is rapid relief of pain and disability caused by intense in- flammation. Options for managing acute attacks include the use of nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, glucocorticoids, and possibly corticotropin.24 The choice of agent, dose, and duration of therapy is guided by consideration of coexisting illnesses that preclude the safe use of a particular regimen, as well as the severity of the gout. Adjunctive measures include applying ice to and resting the affected joint.25 NSAIDs and colchicine are first-line agents for acute attacks (Table 1).24 Oral colchicine has long been used, although it has only recently (in 2009) been approved by the Food and Drug Ad- ministration (FDA) for use in patients with acute gout. In a randomized trial, colchicine (at a dose of 1.2 mg at the onset of a flare, followed by 0.6 mg 1 hour later) was significantly more likely than placebo to result in a reduction in pain of 50% or more 24 hours later (rates, 37.8% and 15.5%, respectively).26 This regimen had efficacy similar to that of a high-dose regimen (1.2 mg, then 0.6 mg per hour for 6 hours), with fewer gastrointestinal side effects. This study did not address treatment after the first 24 hours. The relative efficacy of colchicine as compared with NSAIDs is unknown. In head-to-head studies, various NSAIDs have had similar benefits for acute gout, and a controlled trial showed the efficacy of tenoxicam over placebo.24,27 When the use of NSAIDs or colchicine is poor- ly tolerated or contraindicated, glucocorticoids or corticotropin may be used, although evidence for the use of intraarticular and intramuscular glu- cocorticoids and corticotropin is limited by a lack BACK to TOC
  7. 7. 7 clinical practice n engl j med 364;5 february 3, 2011 445 Table1.PharmacologicManagementOptionsforAcuteGoutAttacks. Drug ExamplesofRegimensfrom RandomizedClinicalTrials AlternativeRegimensfor CompleteAttackResolution*Precautions Nonsteroidalantiinflammatory drug† Avoidinpatientswithrenalorhepaticinsufficiency,bleedingdis- order,congestiveheartfailure,orallergy;associatedwithan increasedriskofadversethromboticandgastrointestinal events;maybeadministeredwithaproton-pumpinhibitor inpatientsatriskforgastrointestinalevents. Naproxen500mgorallytwicedailyfor5days375–500mgorallytwicedailyfor3days, then250–375mgorallytwicedaily for4–7daysoruntilattackresolves Indomethacin50mgorallythreetimesdailyfor2days, then25mgorallythreetimesdaily for3days 50mgorallythreetimesdailyfor3days, then25mgorallythreetimesdaily for4–7daysoruntilattackresolves Colchicine1.2mgorallyatfirstsignofgoutflare, followedby0.6mgorally1hrlater Consideradditionalacutegoutregimen tocontinuemanagingattack 12–24hraftercolchicineregimen (e.g.,0.6mgofcolchicinetwicedaily, anonsteroidalantiinflammatory drugregimen,oranoralglucocorti- coidregimenuntilattackresolves) Avoid(oruselowerdose)inolderadultsandthosewithrenal insufficiency,hepaticdysfunction,orknowngastrointestinal symptoms;adjustdose(andavoidinpatientswithrenal orhepaticimpairment)ifusedinconjunctionwith P-glycoproteinorCYP3A4inhibitors(e.g.,cyclosporine,clar- ithromycin,certainantiretroviralagents,certainantifungal agents,certaincalcium-channelblockers,andgrapefruit juice);avoidforgout-flaretherapyinpatientswithrenalorhe- paticimpairmentwhoarealreadyreceivingcolchicinepro- phylaxis;monitorforgastrointestinalsymptoms,myotoxicity, andblooddyscrasias( Oralglucocorticoids (prednisoneor prednisolone)‡ Prednisolone,30–35mgdailyfor5daysPrednisone,30–60mgdailyfor2days (dependingonseverityofattack), thenreduceby5–10mgevery2days (dependingonstartingdose)in 10-daytaper Usecautioninpatientswithhyperglycemiaorcongestiveheart failure;maybeusedinpatientswithmoderate-to-severerenal impairment. *Longerdurationsoftherapymaybenecessaryforpatientswithlong-standingdiseaseandsevereflares. †Therearenopublishedtrialsestablishingtheefficacyofcelecoxib,theonlyselectivecyclooxygenase-2inhibitoravailableintheUnitedStates,foruseinacutegout. ‡Althoughthereareinsufficientdatatorecommendtheuseofintraarticularglucocorticoidinjection,itmaybeausefulalternativeforattacksthatarelimitedtooneortwojointsand amenabletoaspirationandintheabsenceofjointsepsis. BACK to TOC
  8. 8. 8 The new engl and jour nal of medicine n engl j med 364;5 february 3, 2011446 of data from blinded, randomized, placebo- controlled trials24,27-29 (Table 1). Monoarticular attacks are often managed with the use of intra- articular glucocorticoids. In two randomized, placebo-controlled trials of a 5-day course of oral prednisolone (one evaluating a dose of 30 mg daily and the other a dose of 35 mg daily), the efficacy of prednisolone was equivalent to that of standard regimens of indomethacin (vs. the 30-mg dose of prednisolone) and naproxen (vs. the 35-mg dose).30,31 The dose and duration of therapy for acute gout should be sufficient to eradicate the profound inflammatory response. Although randomized tri- als have generally studied the effects of short courses of treatment on pain reduction, clinical experience suggests that 7 to 10 days of treatment may be necessary to ensure the resolution of symptoms. Increased doses of antiinflammatory drugs are typically prescribed for the first few days, with a reduction in the dose once symptoms begin to improve.32 Flares should be treated without interruption of urate-lowering therapy. A “medications in the pocket” strategy should be considered for patients with established gout so that therapy can be started promptly at the onset of symptoms that are consistent with typical at- tacks. There is evidence that attacks of gout are caused by the activation of the NLRP3 inflamma- some by urate crystals, leading to the release of interleukin-1β33 (Fig. 1). For this reason, inter- leukin-1 antagonists are being studied as poten- tial options for patients in whom other treatments are not feasible.34 In a randomized trial, the fully human monoclonal antibody canakinumab sig- nificantly reduced pain from acute gout, as com- pared with 40 mg of intramuscular triamcino- lone acetonide, 72 hours after administration of the study drug.35 Anakinra and rilonacept im- proved acute and chronic gout symptoms, respec- tively, in two small, uncontrolled pilot studies; however, rilonacept did not significantly reduce pain, as compared with indomethacin, in a ran- domized trial.34,36,37 More data are needed to as- sess the potential role of these agents. Hyperuricemia Pharmacologic Approaches The purpose of lowering serum urate levels is to prevent acute flares and development of tophi. However, gout does not develop in all patients with hyperuricemia, and antihyperuricemic therapies are not without risk. Recommendations that are based on both consensus and evidence support the consideration of urate-lowering therapy in pa- tients with hyperuricemia who have at least two gout attacks per year or tophi (as determined by either clinical or radiographic methods).38 How- ever, the severity and frequency of flares, the pres- ence of coexisting illnesses (including nephroli- thiasis), and patient preference are additional considerations.24 Urate-lowering therapy should not be initiated during acute attacks but rather started 2 to 4 weeks after flare resolution, with a low initial dose that is increased as needed over a period of weeks to months, and with close mon- itoring of urate levels, renal function, and adverse effects. The dose should be adjusted as necessary to maintain a serum urate level below 6 mg per deciliter (357 μmol per liter), which is associated with a reduced risk of recurrent attacks and to- phi.22,39,40 It is uncertain whether a more stringent target of less than 5 mg per deciliter (297 μmol per liter) results in greater disease control.41,42 Ther- apy is generally continued indefinitely. Three classes of drugs are approved for low- ering urate levels: xanthine oxidase inhibitors, uricosuric agents, and uricase agents (Table 2 and Fig. 2). Xanthine oxidase inhibitors block the synthesis of uric acid and can be used regardless of whether there is overproduction of urate. In this class of drugs, the one most commonly pre- scribed to lower urate levels is allopurinol, which is effective in decreasing flares and tophi, particu- larly among patients in whom target urate levels are achieved.22,39 Although allopurinol has an ac- ceptable side-effect profile in most patients, a mild rash develops in approximately 2%.22,39,43 Severe allopurinol hypersensitivity is much less common but can be life-threatening. Allopurinol desensi- tization can be attempted in patients with mild cutaneous reactions, but its safety in those with more serious reactions is unknown.44 The major- ity of patients receive 300 mg of allopurinol daily, but this dose is often inadequate to achieve target urate levels. Daily doses up to 800 mg may be used in patients with normal renal function. The dose is typically reduced in patients with renal impair- ment, owing to concerns about an increased risk of hypersensitivity in such patients. However, stud- ies have not shown an association between dose and risk of hypersensitivity, and a reduced dose may contribute to suboptimal gout control.43 BACK to TOC
  9. 9. 9 clinical practice n engl j med 364;5 february 3, 2011 447 In 2009, another xanthine oxidase inhibitor, febuxostat, was approved by the FDA for the treatment of hyperuricemia in patients with gout. As compared with a daily dose of 300 mg of allopurinol, febuxostat at daily doses of 80 mg and 120 mg was 2.5 and 3 times as likely, re- spectively, to achieve serum urate levels of less than 6 mg per deciliter in a 52-week trial.22 Dur- ing the initial 8 weeks of the study, the fre- quency of gout attacks was higher among pa- tients receiving 120 mg of febuxostat than among those receiving either 80 mg of febuxo- stat or 300 mg of allopurinol, but there was no significant difference among the three groups for the remainder of the trial. In another study involving patients with renal impairment (de- fined as a creatinine clearance of 30 to 89 ml per minute), daily doses of 80 mg and 40 mg of febuxostat were superior to 300 mg of allopuri- nol (or 200 mg in patients with moderate renal impairment) for lowering serum urate to a level below 6 mg per deciliter.39 There was no in- crease in cardiovascular risk or hypersensitivity associated with the use of either dose of febuxo- stat, as compared with allopurinol, although the trial was not powered for such comparisons. Postmarketing surveillance is needed to better understand the risks and benefits of febuxostat. Its efficacy as compared with increased doses of al- lopurinol is not known, nor is its safety in per- sons with allopurinol hypersensitivity. Uricosuric drugs (including probenecid, sulfin- pyrazone, and benzbromarone) block renal tubu- lar urate reabsorption. Although these drugs can be used in patients with underexcretion of urate (accounting for up to 90% of patients with gout), they are used less frequently than xanthine oxi- dase inhibitors and are contraindicated in pa- tients with a history of nephrolithiasis. Benzbro- marone (not available in the United States) may be used in patients with mild-to-moderate renal insufficiency but is potentially hepatotoxic, where- as the other two drugs are generally ineffective in patients with renal impairment. In two open- label, randomized trials, benzbromarone was equivalent to allopurinol (the latter at a daily dose of as much as 600 mg) and superior to probenecid (among patients in whom target urate levels were not achieved with 300 mg of allopurinol) in lower- ing serum urate to 5 mg per deciliter or less.41,45 Uricase converts uric acid into soluble allan- toin. Pegloticase, a polyethylene glycolated (peg- ylated) modified porcine recombinant uricase, was approved by the FDA in 2010 for chronic gout that is refractory to conventional treatments. The approval was based on data from two double- blind, randomized, placebo-controlled, 6-month trials showing the drug’s urate-lowering and to- phus-reducing effects. However, pegloticase must be administered intravenously, and infusion reac- tions were common.46 Rasburicase, which is ap- proved for use in preventing the tumor lysis syn- Resident macrophage lineage cells Pro–interleukin-1β NLRP3 inflammasome Interleukin-1 receptor Adhesion molecules, chemokines C5b-9 Interleukin-1β Monosodium urate crystals Endothelial or synovial cell Neutrophil recruitment, activation, and release of additional inflammatory mediators + + Other mediators (e.g., TNF-α, interleukin-6 and 8, leukotrienes, alarmins) Figure 1. Mechanisms of Inflammation in Gout. In acute gout, monosodium urate crystals that have undergone phagocyto- sis activate the NLRP3 inflammasome, leading to secretion of interleukin- 1β. In turn, this secretion can induce further production of interleukin-1β and other inflammatory mediators and further the activation of synovial lin- ing cells and phagocytes. Monosodium urate crystals also induce many other inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α], inter- leukin-6 and 8, leukotrienes, and alarmins) by mechanisms that are both dependent on and independent of interleukin-1. Experimental models of gout have demonstrated a role for the activation of the terminal comple- ment pathway (C5b-9 membrane attack complex) induced by monosodium urate crystals. Binding of interleukin-1β to the interleukin-1 receptor results in signal transduction, leading to altered expression of adhesion molecules and chemokines, which together with the other inflammatory events re- sults in the neutrophil recruitment that is a major driver of the intense in- flammation in gout. In chronic gout, with low-grade synovitis and frequent- ly recurring or nonresolving flares, these inflammatory processes are probably ongoing with potentially continued release of inflammatory medi- ators, including interleukin-1β, in the presence of persistent monosodium urate crystals. BACK to TOC
  10. 10. 10 The new engl and jour nal of medicine n engl j med 364;5 february 3, 2011448 Table2.PharmacologicOptionsforHyperuricemiaTherapyinGout.* DrugExampleofRegimenConsiderationsorPrecautions Urate-loweringtherapyAimtomaintainserumuratelevelsbelow6mgperdeciliter,whichrequiresregu- larmonitoringandmayrequiredoseadjustments.Accompanytheinitiation oftherapywithflareprophylaxis. XanthineoxidaseinhibitorUseinpatientswithurateoverproductionorunderexcretion.Avoiduse(ormoni- torclosely)inpatientsreceivingazathioprineor6-mercaptopurinebecause thesedrugsaremetabolizedbyxanthineoxidase. AllopurinolStartingdose:50–100mgorallydaily;increasedoseevery2–4wk toachieveserumuratetarget,withdosebasedoncreatinine clearance;averagedailydose,300mg,althoughmanypatients requirehigherdoses Usewithcautioninpatientswithrenalinsufficiency(basedoncreatinineclear- ance).Themaximaldosemaybeashighas800mgdaily,buttherearelimited datafordosesabove300mgdaily.Amildrashoccursinapproximately2%of patients,andtheriskispotentiallyincreasedbycoadministrationofampicillin, amoxicillin,thiazidediuretics,orACEinhibitors.Allopurinolhypersensitivityis rare,occurringinapproximately0.1%ofpatients,butcanbefatal(rateof death,20%).Ifthetargetserumuratelevelisnotachieved,considerdosees- calationbeyondthelevelsuggestedbyguidelinesinpatientswithrenalimpair- ment(withclosemonitoring)orconsidertheuseofanalternativetherapy (e.g.,febuxostat).Allopurinolcanincreasetheanticoagulanteffectofwarfarin. FebuxostatStartingdose:40mgorallydaily;increaseto80mgorallydaily after2–4wktoachieveserumuratetarget,ifnecessary† Useasasecond-lineagentforpatientswhohavecontraindicationsoraninade- quateresponsetoallopurinoloruricosurictherapy.Althoughnodoseadjust- mentisrequiredforpatientswithmild-to-moderaterenalorhepaticinsuffi- ciency,thereareinsufficientdataforuseinpatientswithacreatinineclearance of<30mlperminuteorseverehepaticimpairment.Currentlycontraindicated forusewiththeophylline.Febuxostathasahighercostthanallopurinol. Uricosuricagent(probenecid)‡Startingdose:250mgorallydaily;increaseby500mgpermotoa maximaldoseof2–3gperday(2divideddoses)inpatients withnormalrenalfunctiontoachieveserumuratetarget Avoidinpatientswithahistoryofnephrolithiasisandacreatinineclearanceof <30mlperminute.Adequatehydrationisrequiredtoreduceriskofnephroli- thiasis.Theuseofthisdrugcanincreaseserumpenicillinlevels.Evaluatefor renaluricacidexcretioninpatientswithafamilyhistoryofearlyonsetofgout, onsetofgoutat<25yr,orahistoryofnephrolithiasis,sincethismayidentify patientswithanoverproductionofurateinwhomuricosurictherapyshouldbe avoidedbecauseoftheriskofnephrolithiasis. BACK to TOC
  11. 11. 11 clinical practice n engl j med 364;5 february 3, 2011 449 drome, is not appropriate for use in patients with gout because of its immunogenicity and short half-life. Lifestyle, Nutrition, and Adjunctive Therapies Observational data indicate that nonpharmaco- logic approaches, such as avoiding alcohol or mod- ifying one’s diet, can reduce serum urate levels but may not be sufficient to control established gout.24 In one randomized trial involving persons without gout, 500 mg of vitamin C per day for 2 months resulted in serum urate levels that were 0.5 mg per deciliter (30 μmol per liter) lower than in those receiving placebo.47 The intake of dairy milk reduced serum urate levels by approximately 10% during a 3-hour period in a small, random- ized, crossover trial involving healthy volunteers.48 Whether these approaches would have similar ef- fects in persons with gout, or with a longer dura- tion of therapy, is not known. Losartan and feno- fibrate, which have uricosuric effects, may be considered in patients with gout who have hyper- tension or hypertriglyceridemia, respectively,49 al- though it is not known whether their use reduces the frequency of gout attacks. Flare Prophylaxis during Initiation of Urate-Lowering Therapy Because rapid lowering of urate levels is associat- ed with gout flares, with an increased risk asso- ciated with therapies that more effectively lower urate levels,22,46 prophylaxis against acute flares is advised during the initiation of urate-lowering therapy (Table 2).24 In a study of patients with nor- mal renal function who were starting allopurinol therapy, oral colchicine (at a dose of 0.6 mg twice daily for an average of 5.2 months) significantly reduced the likelihood of gout attacks and less- ened the severity of flares that did occur, as com- pared with placebo.21 Diarrhea was common, resulting in a once-daily regimen of colchicine for many patients. Thus, the general recommenda- tion for flare prophylaxis is to use colchicine at a dose of 0.6 mg once or twice daily, with dose ad- justments as needed for renal impairment, poten- tial drug interactions, or intolerance. Although NSAIDs are also used for prophylaxis, there are few studies that support their use.24 For patients without tophi, prophylaxis should be continued for 6 months. The optimal duration for those with tophi is uncertain; ongoing prophylaxis until to- phus resolution may be necessary. Uricase(pegloticase)Intravenousinfusionof8mgevery2wk;requirespremedication withantihistaminesandglucocorticoids;startgout-flarepro- phylaxis≥7daysbeforeinitiatingtreatment Useforchronicgoutinadultswhosediseaseisrefractorytoconventionaltherapy (e.g.,lackofnormalizationofserumurate,inadequatecontrolofsignsand symptomswiththeuseofaxanthineoxidaseinhibitoratmaximummedically appropriatedose,orothercontraindication).Thereisariskofinfusionreac- tions(26%,vs.5%inplacebogroup)evenwithpremedication,particularlyin patientswithoutatherapeuticresponse(inwhomserumuratelevelsincrease toabove6mgperdeciliter,particularlyontwoconsecutiveoccasions)orwith antibodiesagainstpegloticase.Anaphylaxisoccursin5%ofpatients(vs.0%in placebogroup).Nodataareavailableregardingretreatmentafterstopping treatmentforlongerthan4weeks.DonotuseinpatientswithG6PDdeficiency, andusecautioninpatientswithcongestiveheartfailure(insufficientsafetydata; someexacerbationsinclinicaltrials).Costishigherthanforothertherapies. Flareprophylaxisduringinitiation ofurate-loweringtherapy Aimtoreducetheriskofflareduringinitialdecreaseinuratelevels,presumably relatedtorapidmobilizationofbodilyuratestores.Thedurationoftherapy isnotwelldefinedbuttreatmentforatleast6mooruntiltophiresolveis recommended. Colchicine0.6mgorallyonceortwicedailyastoleratedSeeTable1forprecautions,particularlytakingintoaccountpotentialforincreased toxiceffectswithprolongedtherapy. NSAIDNaproxen,250mgtwicedailySeeTable1forprecautions,particularlytakingintoaccountpotentialforincreased toxiceffectswithprolongedtherapy.Thisdrughasnotbeenformallytested buthasbeenusedforprophylaxisintrialsofurate-loweringtherapies. *ACEdenotesangiotensin-convertingenzyme,andNSAIDnonsteroidalantiinflammatorydrug. †Febuxostatatadoseof120mgisavailableinEurope. ‡BenzbromaroneandsulfinpyrazoneareavailableinalimitednumberofcountriesbutnotintheUnitedStates. BACK to TOC
  12. 12. 12 The new engl and jour nal of medicine n engl j med 364;5 february 3, 2011450 Areas of Uncertainty Data are limited regarding the safety and effica- cy of combination therapies for the treatment of gout (e.g., the use of a xanthine oxidase inhibitor and a uricosuric agent for hyperuricemia or the use of multiple drugs for acute gout attacks). The safety and cost-effectiveness of new agents for gout, including inhibitors of urate transporter 1 and purine nucleoside phosphorylase, which are under development, and interleukin-1 antagonists, require further study. Preliminary data have sug- gested the potential efficacy of the interleukin-1 antagonists canakinumab and rilonacept for flare prophylaxis.34 Risk factors for recurrent gout flares may differ from those that predispose patients to the initial attack. Whether factors that lower serum urate levels over the long term in persons without gout would have similar effects with short-term or episodic exposure in persons with gout requires clarification. It is not known to what level urate can be safely lowered. Observational data have suggested associations between low urate levels and an in- creased risk of Parkinson’s disease,50 but it is unclear whether the low levels are a cause or consequence of disease. The optimal duration of urate-lowering therapy is also uncertain, and such therapy is recommended indefinitely at this time. In one study, the withdrawal of urate-lowering therapy was associated with prolonged symptom- free intervals (3 to 4 years) in a cohort of 89 pa- tients after long-term control of urate levels (<7 mg per deciliter), flares, and tophi resolution,51 but further study is needed. Finally, the concept of asymptomatic hyperuri- cemia as a benign condition is being challenged. Experimental data suggest that urate may con- tribute to vascular remodeling and hypertension, although it remains uncertain whether urate plays a causal role in cardiovascular disease.9 Guidelines The American College of Rheumatology is cur- rently developing guidelines for the management of gout. The European League against Rheumatism and the British Society for Rheumatology have published guidelines for the evaluation and man- agement of gout on the basis of trial data (when available) and expert consensus.23,24,42 The pres- ent recommendations are largely consistent with these guidelines. Conclusions and Recommendations In patients presenting with suspected gout, the diagnosis should be confirmed by examination of synovial fluid or tophus aspirate for monosodium urate crystals. Management should be tailored to the stage of disease and coexisting illnesses. The patient who is described in the vignette has crystal- proven gout, with multiple attacks and a serum urate level of more than 6 mg per deciliter despite receipt of allopurinol at a dose of 300 mg per day. Exogenous purines Xanthine oxidase inhibitors Dietary restriction Recombinant uricase Renal insufficiency or failure Uricosuric agents Endogenous purines Body urate pool Renal tubules Figure 2. Management Strategies in Patients with Hyperuricemia. Hyperuricemia can be targeted at many levels. Restric- tion of exogenous purine intake through dietary modi- fications or the use of xanthine oxidase inhibitors to block uric acid synthesis from endogenous purine me- tabolism can reduce the amount of urate that contrib- utes to the total-body urate pool. Modified uricase agents reduce the total-body urate pool by converting uric acid into soluble allantoin. In patients with normal renal function, uricosuric agents can promote renal elimination of urate, thereby reducing total-body urate pools. However, decreased renal urate excretion in pa- tients with renal impairment leads to increased total- body urate stores. BACK to TOC
  13. 13. 13 clinical practice n engl j med 364;5 february 3, 2011 451 Since his renal function is normal, the allopuri- nol dose should be increased (e.g., 100-mg incre- ments every 2 to 4 weeks until the target urate level is reached), with monitoring of renal function and serum urate levels and assessment for potential adverse reactions. Colchicine prophylaxis (0.6 mg once or twice daily) is reasonable while the dose of allopurinol is escalated. If target serum urate levels cannot be achieved or if the patient has seri- ous side effects at higher allopurinol doses, the use of either febuxostat or a uricosuric agent is another option, given his normal renal function. The patient should understand that the intake of alcohol and an excessive amount of meat or seafood and sugar-sweetened drinks may contrib- ute to elevated urate levels and should be mini- mized. He should be advised to keep well hydrated and to lose weight. Associated cardiovascular risk factors should be identified and treated. Although the use of hydrochlorothiazide may contribute to the increased urate level, I would not necessarily change that medication if it is effectively con- trolling his blood pressure, and I would advise him to take the diuretic consistently, since inter- mittent use may precipitate flares. The addition of losartan for the hypertension might be considered. He should be advised to maintain his urate-low- ering regimen during flares, which can be man- aged with colchicine. Follow-up is necessary to ensure that appropriate serum urate levels are achieved and maintained and to monitor the pa- tient for adverse effects. Dr. Neogi reports serving as a core expert panel leader for the American College of Rheumatology Gout Treatment Guidelines. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at I thank Drs. Saralynn Allaire, Hyon Choi, and Yuqing Zhang for their review of the first draft of the manuscript and Dr. Rob- ert Terkeltaub for his review of an earlier version of Figure 1. References 1. Loeb JN. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum 1972;15:189-92. 2. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study. Am J Med 1987;82:421-6. 3. Gutman AB. The past four decades of progress in the knowledge of gout, with an assessment of the present status. Ar- thritis Rheum 1973;16:431-45. 4. Neogi T, Hunter DJ, Chaisson CE, Al- lensworth-Davies D, Zhang YQ. Frequency and predictors of inappropriate manage- ment of recurrent gout attacks in a longi- tudinal study. J Rheumatol 2006;33:104-9. 5. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part II. Arthritis Rheum 2008;58:26-35. 6. Arromdee E, Michet CJ, Crowson CS, O’Fallon WM, Gabriel SE. Epidemiology of gout: is the incidence rising? J Rheuma- tol 2002;29:2403-6. 7. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004;31:1582-7. 8. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516. 9. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21. [Erratum, N Engl J Med 2010;362:2235.] 10. Rodríguez G, Soriano LC, Choi HK. Impact of diabetes against the future risk of developing gout. Ann Rheum Dis 2010;69:2090-4. 11. Dehghan A, Kottgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a ge- nome-wide association study. Lancet 2008; 372:1953-61. 12. Taniguchi A, Urano W, Yamanaka M, et al. A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis Rheum 2005;52:2576-7. 13. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004;363:1277-81. 14. Choi HK, Willett W, Curhan G. Fruc- tose-rich beverages and risk of gout in women. JAMA 2010;304:2270-8. 15. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093- 103. 16. Choi HK, Curhan G. Soft drinks, fruc- tose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008; 336:309-12. 17. Choi HK, Gao X, Curhan G. Vitamin C intake and the risk of gout in men: a pro- spective study. Arch Intern Med 2009; 169:502-7. 18. Choi HK, Willett W, Curhan G. Coffee consumption and risk of incident gout in men: a prospective study. Arthritis Rheum 2007;56:2049-55. 19. Hunter DJ, York M, Chaisson CE, Woods R, Niu J, Zhang Y. Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study. J Rheumatol 2006;33:1341-5. [Erratum, J Rheumatol 2006;33:1714.] 20. Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a trigger of re- current gout attacks. Am J Med 2006; 119(9):800.e13-800.e18. 21. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Col- chicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31: 2429-32. 22. Becker MA, Schumacher HR Jr, Wort- mann RL, et al. Febuxostat compared with allopurinol in patients with hyperurice- mia and gout. N Engl J Med 2005;353: 2450-61. 23. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the EULAR Standing Com- mittee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1301-11. 24. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Com- mittee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312-24. 25. Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 2002; 29:331-4. 26. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for BACK to TOC
  14. 14. 14 n engl j med 364;5 february 3, 2011452 clinical practice early acute gout flare: twenty-four-hour out- come of the first multicenter, randomized, double-blind, placebo-controlled, parallel- group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-8. 27. Sutaria S, Katbamna R, Underwood M. Effectiveness of interventions for the treatment of acute and prevention of re- current gout — a systematic review. Rheu- matology (Oxford) 2006;45:1422-31. 28. Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum 1988;31: 803-5. 29. Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. System- ic corticosteroids for acute gout. Cochrane Database Syst Rev 2008;2:CD005521. 30. Janssens HJ, Janssen M, van de Lis- donk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double- blind, randomised equivalence trial. Lan- cet 2008;371:1854-60. 31. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral predniso- lone/paracetamol and oral indomethacin/ paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled tri- al. Ann Emerg Med 2007;49:670-7. 32. Mandell BF, Edwards NL, Sundy JS, Simkin PA, Pile JC. Preventing and treat- ing acute gout attacks across the clinical spectrum: a roundtable discussion. Cleve Clin J Med 2010;77:Suppl 2:S2-S25. 33. Martinon F, Pétrilli V, Mayor A, Tardi- vel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflamma- some. Nature 2006;440:237-41. 34. Neogi T. Interleukin-1 antagonism in acute gout: is targeting a single cytokine the answer? Arthritis Rheum 2010;62: 2845-9. 35. So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty ar- thritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum 2010; 62:3064-76. 36. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakin- ra in acute gout. Arthritis Res Ther 2007;9:R28. 37. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009;68:1613-7. 38. Mikuls TR, MacLean CH, Olivieri J, et al. Quality of care indicators for gout man- agement. Arthritis Rheum 2004;50:937-43. 39. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63. 40. Perez-Ruiz F, Lioté F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 2007;57:1324-8. 41. Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escala- tion of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout. Ann Rheum Dis 2009;68:892-7. 42. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheuma- tology guideline for the management of gout. Rheumatology (Oxford) 2007;46: 1372-4. 43. Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in pa- tients with gout. J Rheumatol 2006;33: 1646-50. 44. Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desensitization to allopurinol following cutaneous reac- tions. Arthritis Rheum 2001;44:231-8. 45. Reinders MK, van Roon EN, Jansen TL, et al. Efficacy and tolerability of urate- lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis 2009;68:51-6. 46. Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloti- case (polyethylene glycol-conjugated uri- case) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008;58:2882-91. 47. Huang HY, Appel LJ, Choi MJ, et al. The effects of vitamin C supplementation on serum concentrations of uric acid: re- sults of a randomized controlled trial. Arthritis Rheum 2005;52:1843-7. 48. Dalbeth N, Wong S, Gamble GD, et al. Acute effect of milk on serum urate con- centrations: a randomised controlled cross- over trial. Ann Rheum Dis 2010;69:1677- 82. 49. Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyper- uricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis 2003;62:572-5. 50. Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Phar- macol Exp Ther 2008;324:1-7. 51. Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla JM. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long- term urate-lowering therapy: a prospective study. Arthritis Rheum 2006;55:786-90. Copyright © 2011 Massachusetts Medical Society. CLINICAL TRIAL REGISTRATION The Journal requires investigators to register their clinical trials in a public trials registry. The members of the International Committee of Medical Journal Editors (ICMJE) will consider most reports of clinical trials for publication only if the trials have been registered. Current information on requirements and appropriate registries is available at BACK to TOC
  15. 15. 15 clinical practice The new engl and jour nal of medicine This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations. n engl j med 363;10 september 2, 2010954 An audio version of this article is available at Calcium Kidney Stones Elaine M. Worcester, M.D., and Fredric L. Coe, M.D. From the Nephrology Section, Depart- ment of Medicine, University of Chicago, Chicago. Address reprint requests to Dr. Worcester at the Nephrology Section, MC 5100, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, or at N Engl J Med 2010;363:954-63. Copyright © 2010 Massachusetts Medical Society. A 43-year-old man presents for evaluation of recurrent kidney stones. He passed his first stone 9 years earlier and has had two additional symptomatic stones. Analysis of the first and the last stones showed that they contained 80% calcium oxalate and 20% calcium phosphate. Analysis of a 24-hour urine collection while the patient was not receivingmedications revealed a calcium level of 408 mg (10.2 mmol), an oxalate level of33mg(367μmol),andavolumeof1.54liters;theurinepHwas5.6.Thepatienthad been treated with 20 to 40 mmol of potassium citrate daily since he passed his first stone. How should he be further evaluated and treated? The Clinical Problem In the United States, the prevalence of kidney stones has risen over the past 30 years.1 By 70 years of age, 11.0% of men and 5.6% of women will have a symptom- atic kidney stone. The risk among white persons is approximately three times that among black persons. About 80% of stones are composed of calcium oxalate with variable amounts of calcium phosphate. Diagnosis of a calcium stone requires analysis after passage or removal of the stone. After passage of a first stone, the risk of recurrence is 40% at 5 years and 75% at 20 years. Among patients with recurrent calcium stones who have served as control subjects in randomized, controlled trials of interventions, new stones formed in 43 to 80% of subjects within 3 years.2-9 Hospitalizations, surgery, and lost work time that are associated with kidney stones cost more than $5 billion annually in the United States.10 Stone formation is associ- ated with increased rates of chronic kidney disease and hypertension,11,12 increases that are not completely explained by obesity, which is a risk factor for each of these conditions.13 Although many inherited and systemic diseases are associated with calcium kidney stones,14 most such stones are idiopathic. The majority of patients with idiopathic stones have at least one metabolic abnormality, as identified by 24-hour urine testing. Prevention requires evaluation to identify systemic disease and modi- fiable factors. Pathogenesis Physicochemical Factors Supersaturation, often expressed as the ratio of urinary calcium oxalate or calcium phosphate concentration to its solubility, is the driving force in stone formation. At levels of supersaturation below 1, crystals dissolve, whereas at supersaturation levels above 1, crystals can nucleate and grow, promoting stone formation. Supersatura- tion is generally higher in patients with recurrent kidney stones than in those without the condition, and the type of stone that is formed correlates with urinary Click here to access audio version. BACK to TOC
  16. 16. 16 clinical practice n engl j med 363;10 september 2, 2010 955 supersaturation. Calcium oxalate supersaturation is independent of urine pH, but calcium phosphate supersaturation increases rapidly as urine pH rises from 6 to 7. Since calcium oxalate stones form over an initial calcium phosphate layer,15 treat- ment optimally should lower the supersaturation of both types. Most 24-hour analyses of kidney- stone risk that are performed at specialized labo- ratories include calculated supersaturation values. Urine also contains substances that can ac- celerate or retard urinary crystallization.16 The only such substance that can be modified in practice at this time is citrate, which can slow the growth of calcium crystals.17 Anatomic abnormalities, in particular those that result in urinary stasis (such as ureteropelvic junction obstruction, horseshoe kidney, or poly- cystic kidney), may precipitate or worsen stone formation.18 Patients with a single functioning kidney are at particular risk, since stone passage with ureteral obstruction can result in acute kid- ney failure. Metabolic Factors Imbalances between excretions of calcium, oxa- late, and water create supersaturation. Hypercal- ciuria, the most common metabolic abnormality found in patients with recurrent calcium stones, is most often familial and idiopathic19 and is strongly influenced by diet. Gut calcium absorp- tion is increased in persons with idiopathic hyper- calciuria, but serum calcium values remain un- changed, since absorbed calcium is promptly excreted.20 On a low-calcium diet, such persons often excrete more calcium than they eat,21 and urinary calcium excretion also rises markedly af- ter the intake of calcium-free nutrients such as simple oral glucose; in such cases, the only source possible is bone. Although hypercalciuria is some- times divided into subtypes (absorptive, resorptive, and renal leak), this classification is not helpful in guiding treatment. However, measurement of serum calcium is indicated to identify patients with primary hyperparathyroidism. The level of oxalate excretion is modestly higher among patients with recurrent calcium stones than among those without the condition, possibly because of increased oxalate absorption in the gut.22 The intake of ascorbic acid and a high level of protein may increase oxalate pro- duction.23 Because calcium binds with oxalate in the gut and hinders its absorption, oxalate is more readily absorbed when dietary calcium is low.23 This may be why a low-calcium diet does not successfully prevent stone recurrence.24 Citrate chelates calcium in the urine, decreas- ing supersaturation and reducing the growth of crystals17; hypocitraturia is a risk factor for stone formation. Distal renal tubular acidosis, hypo- kalemia, and the use of carbonic anhydrase in- hibitors (e.g., topiramate) lead to hypocitraturia, but the cause of this condition in most patients with recurrent kidney stones is unknown.25 Hyperuricosuria, often from high dietary intake of purines, is thought to promote the formation of calcium stones by reducing the solubility of calcium oxalate.26 Histopathology Intraoperative papillary biopsy specimens ob- tained from patients with recurrent kidney stones show that the pattern of crystal deposition differs according to the type of stone. Idiopathic calci- um oxalate stones form over regions of intersti- tial calcium phosphate deposits (Randall’s plaque) on the papillary surface,27 whereas idiopathic calcium phosphate stones are associated with crystal deposits in inner medullary collecting ducts that contain mainly apatite,28,29 sometimes mixed with other crystals. (For additional details, see the Supplementary Appendix, available with the full text of this article at Str ategies and Evidence Patients with recurrent calcium stones should be evaluated to rule out systemic disease and guide preventive therapy. Evaluation includes history taking directed at detecting potential causes of stones (Table 1). All stones should be analyzed to classify the type and to detect conversion from one stone type to another — for example, from calcium oxalate to struvite in the presence of in- fection or to calcium phosphate if the urinary pH rises in response to treatment.30 Computed tomography (CT) without the use of contrast material provides information regard- ing the presence, size, and location of stones, as well as ruling out anatomic abnormalities and providing a baseline for assessing whether sub- sequent stones that are passed are old or new (with the latter indicating a need for improved preventive treatment). Given the expense and radiation exposure of CT, renal ultrasonography BACK to TOC
  17. 17. 17 The new engl and jour nal of medicine n engl j med 363;10 september 2, 2010956 or abdominal plain radiography may be used in follow-up imaging of known stones, although these methods are less sensitive than CT. Metabolic testing should be done after the resolution of the acute episode of stone passage, when patients have resumed their usual diet and activity. Evaluation includes a blood test to screen for hypercalcemia, chronic kidney disease, and renal tubular acidosis. Analysis of a 24-hour urine collection to detect metabolic abnormali- ties should preferably be performed twice, since mineral excretions may vary from day to day.31 Tables 2 and 3 provide a suggested framework for testing and interpretation. Whether to evalu- ate patients after a single kidney-stone episode is controversial, although it seems prudent to rule out systemic disease, especially in patients with a first stone before adulthood. Treatment Management of Symptomatic Stones Stones that have formed in kidneys do not re- quire removal or fragmentation unless they cause obstruction, infection, serious bleeding, or persis- tent pain. Ureteral stones of less than 10 mm in Table 1. Key Coexisting Medical Conditions, Medication Use, Diet, and Other Factors Associated with Calcium Kidney Stones. Variable Features Type of Kidney Stone Calcium Oxalate Calcium Phosphate Medical or surgical history Bowel disease Chronic diarrhea, malabsorption Yes Intestinal surgery Small-bowel resection, ileostomy Yes Bariatric surgery Duodenal switch, Roux-en-Y gastric bypass Yes Sarcoidosis Yes Yes Gout Yes Renal tubular acidosis Yes Bone disease or fracture Primary hyperparathyroidism, idiopathic hypercalciuria, myeloma Yes Yes Immobilization Trauma, prolonged illness Yes Yes Hyperthyroidism Untreated, iatrogenic Yes Yes Renal anomaly Urinary stasis Yes Yes Medications Topiramate Seizures, migraine Yes Calcium supplements Antacids, dietary supplement Yes Yes Carbonic anhydrase inhibitor Glaucoma Yes Alkali Bicarbonate, citrate Yes Vitamin D Yes Yes Occupational or recreational factor Dehydration Hot environment, inability to drink Yes Yes Dietary factor Oxalate loads Nuts, spinach, ascorbic acid Yes Excess salt Prepared foods, snack foods Yes Yes Eating disorders Vomiting, use of laxatives Yes Yes Strange diets* Protein powder, sugar loads Yes Yes Family history History of kidney stones in a first- degree relative Idiopathic hypercalciuria, primary hyperoxaluria Yes Yes * Strange diets include very restrictive choices of food or the use of a large number or amount of supplements. BACK to TOC
  18. 18. 18 clinical practice n engl j med 363;10 september 2, 2010 957 Table 2. Diagnostic Testing for Patients with Recurrent Kidney Stones.* Measurement Normal Value or Range for Adults Purpose Blood testing Calcium 8.8–10.3 mg/dl Detection of primary hyperparathyroidism, excessive vitamin D intake, sarcoidosis Phosphate 2.5–5.0 mg/dl Detection of primary hyperparathyroidism Creatinine 0.6–1.2 mg/dl Detection of chronic kidney disease Bicarbonate 20–28 mmol/liter Detection of renal tubular acidosis Chloride 95–105 mmol/liter Detection of renal tubular acidosis Potassium 3.5–4.8 mmol/liter Detection of renal tubular acidosis, eating disorders, gastro- intestinal disease Urine collection over 24-hour period Volume >1.5 liter/day Detection of low volume as cause of stones Calcium <300 mg/day for men, <250 mg/day for women; <140 mg/g creatinine/day Detection of hypercalciuria Oxalate <40 mg/day Detection of hyperoxaluria pH 5.8–6.2 Calculation of calcium phosphate and uric acid supersatura- tion, diagnosis of renal tubular acidosis Phosphate 500–1500 mg/day Calculation of calcium phosphate supersaturation Citrate >450 mg/day for men, >550 mg/day for women Detection of low citrate level and diagnosis of renal tubular aci- dosis; calculation of calcium phosphate supersaturation Uric acid <800 mg/day for men, <750 mg/day for women Detection of hyperuricosuria as cause of stones; calculation of uric acid supersaturation Sodium 50–150 mmol/day Diet counseling; calculation of supersaturation Potassium 20–100 mmol/day Use of potassium salts; calculation of supersaturation Magnesium 50–150 mg/day Detection of malabsorption; calculation of supersaturation Sulfate 20–80 mmol/day Calculation of supersaturation; measure of net acid production Ammonium 15–60 mmol/day Calculation of supersaturation Creatinine 20–24 mg/kg/day for men, 15–19 mg/kg/day for women Comparison of actual with predicted creatinine to assess the completeness of the urine collection Protein catabolic rate† 0.8–1.0 g/kg/day Estimation of protein intake Calculated supersaturation‡ Calcium oxalate 6–10 Guidance of treatment Calcium phosphate 0.5–2 Guidance of treatment Other screening tests Urinary cystine screening§ Negative Detection of cystinuria Stone analysis Basic classification of condition * Blood testing for renal tubular acidosis, chronic kidney disease, and hypercalcemia, along with urinary cystine screening and kidney-stone analysis, are appropriate for all patients with recurrent kidney stones. Collection of urine over a 24-hour period is appropriate if medical prevention of kidney-stone formation is planned. To convert the values for calcium to millimoles per day, multiply by 0.025. To convert the values for phosphate to millimoles per day, multiply by 0.0323. To convert the values for creatinine to micromoles per day multiply by 0.00884. To convert the values for urinary oxalate to micromoles per day, multiply by 11.11. To convert the values for urinary citrate to mmol per day, multiply by 0.0052. To convert the values for urinary uric acid to millimoles per day, multiply by 0.00595. To convert the values for urinary magnesium to mmol per day, multiply by 0.0411. To convert the values for urinary urea nitrogen to moles per day, multiply by 0.0357. † The protein catabolic rate is calculated by multiplying the urea nitrogen excretion in grams per day by 6.25 and dividing by body weight in kilograms. ‡ Supersaturation is expressed as the ratio of urinary calcium oxalate or calcium phosphate concentration to its solubility. § Urinary cystine was tested with the use of the cyanide nitroprusside test. A negative test means that the cystine concentration is less than 75 mg per liter. BACK to TOC
  19. 19. 19 The new engl and jour nal of medicine n engl j med 363;10 september 2, 2010958 diameter may be followed with conservative treat- ment in the absence of fever, infection, or renal failure, if pain is controlled. Opioid analgesics and nonsteroidal antiinflammatory agents are both effective for pain control in acute colic. Therapy with drugs that block α1-adrenergic re- ceptors or calcium-channel blockers may facili- tate passage of ureteral stones.32 In general, stones larger than 10 mm in diameter will not pass, and those smaller than 5 mm will; stones from 5 mm to 10 mm have variable outcomes. Stones in the distal ureter are more likely to pass than those located more proximally. If stones do not pass, there are several surgi- cal options for removal.33 Data to guide surgical recommendations are derived largely from meta- analyses of small trials. For ureteral stones, the treatment of choice is either shock-wave litho- tripsy or ureteroscopy with laser lithotripsy. Stone- free rates are better with ureteroscopy, but com- plication rates are higher, including sepsis and ureteral injury. For stones lodged in the kidney, the size, location, and presumed composition play a role in determining treatment. Not all stone types fragment equally well; for example, calcium oxalate monohydrate and brushite stones are more resistant to fragmentation than calci- um oxalate dihydrate or apatite stones. Shock- wave lithotripsy and ureteroscopy are frequently used for smaller stones. Percutaneous nephro- lithotomy may be used for single large stones (above 2 cm) or a large or obstructing stone bur- den. This procedure requires general anesthesia and hospitalization and carries more risk of com- plications, including bleeding and infection, than other techniques but can result in a stone-free kidney.34 Open or laparoscopic procedures are occasionally used for stone removal in challeng- ing cases. Prevention of Idiopathic Calcium Oxalate Stones Prevention of recurrent stones requires decreas- ing urinary supersaturation, which is generally achieved by raising urine volume and lowering calcium and oxalate excretion. It should be rec- ognized that urinary abnormalities are graded risk factors, and thresholds for the definition of normal urinary function are not absolute cut- offs.35 Table 4 summarizes treatment strategies. Table 3. Primary Causes of Calcium Kidney Stones and Their Treatments.* Cause Key Abnormality Serum Calcium Serum Parathyroid Hormone Urine Calcium Urine pH Urine Citrate Urine Oxalate Idiopathic calcium oxalate Normal Normal Normal or increased Normal Normal or decreased Normal or increased Idiopathic calcium phosphate Normal Normal Normal or increased Increased Normal or decreased Normal Primary hyperparathyroidism Increased Increased Increased Increased Normal Normal Sarcoidosis Increased Decreased Increased Normal Normal Normal Lithium use Increased Increased Increased Increased Normal Normal Oral supplementation with calcium or vitamin D Normal or increased Normal Increased Normal Normal Normal Ileostomy Normal or decreased Normal Decreased Decreased Decreased Normal Short-bowel syndrome Normal or decreased Normal Decreased Decreased Decreased Increased Bariatric surgery Normal or decreased Normal Decreased Normal Decreased Increased Renal tubular acidosis Normal Normal Normal or increased Increased Decreased Normal * NA denotes not available because histologic analyses have not been reported for patients with the listed conditions. BACK to TOC
  20. 20. 20 clinical practice n engl j med 363;10 september 2, 2010 959 (For additional details regarding treatment trials, see Table 1 in the Supplementary Appendix.) A randomized trial of increased fluid intake that was targeted to maintain a daily urine vol- ume of more than 2 liters showed a significant reduction in recurrent stone passage among pa- tients with first-time kidney stones.36 A target urine volume of 2 to 2.5 liters is reasonable and can be achieved by an increased intake of fluids, especially water, although most low-sodium, low- carbohydrate fluids are acceptable in moderation for this purpose. In a randomized, controlled trial involving Italian men with hypercalciuria,24 a diet that was low in animal protein (52 g per day), sodium (50 mmol per day), and oxalate (200 mg per day) with normal calcium intake (1200 mg per day) was associated with a reduction in stone forma- tion of almost 50% over a period of 5 years, as compared with a diet that was low in calcium (400 mg per day) and oxalate. In contrast, in a U.S. trial, a low-protein diet did not reduce stone recurrence during a 4.5-year period, but compli- ance with the diet was poor and dietary sodium was not restricted.37 A low-sodium diet can sig- nificantly decrease excretion of both calcium and oxalate,38 but data on the effect of a sodium- restricted diet alone on stone recurrence are lacking. Calcium restriction should be avoided in patients with hypercalciuria, since it may result in a reduction in bone mineral density39 and an increased rate of fracture.40 Thiazide-type diuretics decrease urine calcium excretion, and in randomized, controlled trials, these medications significantly reduced recur- rence rates of calcium stones by more than 50% during a 3-year period, as compared with place- bo.2,4,6,9 Long-acting agents like chlorthalidone and indapamide are effective with once-daily doses, whereas twice-daily doses are recom- mended for hydrochlorothiazide. Hyperoxaluria may occur when dietary calci- um is low or oxalate intake is unusually high or (less commonly) when oxalate is overproduced. Dietary oxalate restriction to less than 100 mg per day and the avoidance of an intake of ascor- bic acid above 100 mg per day are prudent if hy- peroxaluria is present. Foods that are very high in oxalate include spinach, rhubarb, wheat bran, chocolate, beets, miso, tahini, and most nuts. (A list of the oxalate content of various foods is available at under Resources.) Marked Supersaturation Tissue Changes Treatment Urine Uric Acid Urine Volume Calcium Oxalate Calcium Phosphate Uric Acid Interstitial Plaque Collecting-Duct Plugging Normal or increased Normal or decreased High Normal or high Normal or high Increased Not present � � Thiazide for idiopathic hypercalciuria; potassium citrate for calcium oxalate Normal Normal High High Normal Normal Increased � � � � � (and perhaps calcium phosphate) stones; allopurinol for hyperuricosu- ria; sodium restriction and possible protein or oxalate restriction; in- creased fluid intake Normal Normal High High Low Increased Increased Parathyroid surgery Normal Normal High High Normal NA NA Glucocorticoids, possible ketoconazole Normal Normal High High Normal NA NA Discontinuation of lithium Normal Normal High High Low NA NA Discontinuation of supplements Normal Decreased High Low High Increased Increased � � Normal Decreased High Low High Normal Increased � � � Fluids, alkali; supplements to reduce urine oxalate excretion for the short- bowel syndrome and bariatric surgery Normal Normal High Normal Normal Normal Increased � � Normal Increased Normal High Low Normal Increased Alkali, possible thiazides BACK to TOC
  21. 21. 21 The new engl and jour nal of medicine n engl j med 363;10 september 2, 2010960 hyperoxaluria should prompt consideration of malabsorption or one of the primary hyperox- aluria syndromes.41 Two randomized trials have shown substan- tial reductions in stone recurrence among patients with hypocitraturia who were treated with po- tassium alkali three times daily.3,7 One trial of sodium–potassium citrate had negative results.8 Potassium alkali may be safely combined with thiazide9,42 when indicated, but no trials have com- pared the combination against either agent alone for the prevention of stone recurrence. Hyperuricosuria can decrease the solubility of calcium oxalate and increase the incidence of calcium oxalate stones. Allopurinol (at a dose of 300 mg daily) decreased stone recurrence in a randomized trial involving patients with idio- pathic calcium oxalate stones who had hyperuri- cosuria.5 A reduction in the intake of protein (and therefore purine) is also prudent but has not been explicitly tested among patients with hyperuricosuria and recurrent kidney stones. In long-term clinical follow-up, preventive treatment resulted in persistent reductions in stone recurrence during a period of 20 years or more.43 However, compliance tended to wane over time, with rates of nonadherence approach- ing 20% per year.44 Prevention of Calcium Phosphate Stones Most calcium stones consist of more than 90% calcium oxalate with trace amounts of calcium phosphate, but the proportion of calcium phos- phate in stones has increased over time.45,46 Idio- pathic calcium phosphate stones (more than 50% calcium phosphate) are more common among women and are associated with alkaline urine pH, a condition whose cause is not well under- stood. Mild abnormalities in urine acidification may be present, although metabolic acidosis is uncommon.46,47 Some patients convert from the formation of calcium oxalate stones to the forma- tion of calcium phosphate stones. In one study, such patients had a urine pH that was more alka- line (>6.2) at baseline than those who continued to produce calcium oxalate stones.30 Calcium phosphate stones are associated with poorer stone-free rates after percutaneous nephrolitho- tomy and with more shock-wave lithotripsy treat- ments than are calcium oxalate stones.46,48 Among patients with calcium phosphate stones, treatment is similar to that of patients with cal- cium oxalate stones except that potassium al- Table4.TreatmentRecommendationsforthePreventionofIdiopathicCalciumKidneyStonesinAdults. TreatmentMechanismofActionDoseSelectionCriteriaPotentialComplications FluidsLowerssupersaturationbydilution ofsolutes Adequatetomaintainurinevolume >2litersdaily Usefulforallpatients;possiblesole treatmentforpatientswithasingle stoneepisode Needtoavoidfluidscontainingexcess saltorcarbohydrates DietLowerssupersaturationbydecreasing calciumandoxalateexcretion; maintainsbonemineral,prevents hyperoxaluria Sodium,<100mmol/day;protein, <0.8–1gofanimalprotein/kg/day; oxalate,<100mg/day;calcium, 800–1000mg/day Recommendationsforsodiumand proteinespeciallyusefulin patientswithhypercalciuriaor hyperuricosuria;foroxalatein patientswithhyperoxaluria;and forcalciuminallpatientswith calciumstones Difficultyinmaintainingdiet;should obtaincalciumfromdietarysources andavoidsupplements Thiazide-type diuretic Lowerssupersaturationbydecreasing calciumexcretion Chlorthalidone,12.5–50mg/day; indapamide,1.25–2.5mg/day; hydrochlorothiazide,12.5–25mg twicedaily Patientswithhypercalciuria;may beusefulforsomewithnormo- calciuria Hypokalemia,reducedbloodpressure (maybedesirable);allergyandsun sensitivity PotassiumalkaliLowerssupersaturationbychelating calcium;inhibitsgrowthofcalcium crystals Potassiumcitrate,10–20mmoltwo orthreetimesdaily PatientswithhypocitraturiaNeedtomonitorurinepHandcalcium phosphatesupersaturation;avoid supersaturationof>1 AllopurinolLowersurinaryuricacidconcentra- tion,whichmayimprovesolubility ofcalciumsalts 100–300mg/day(maybetakenonce daily) Patientswithhyperuricosuriaand calciumstones Allergy(maybesevere) BACK to TOC
  22. 22. 22 clinical practice n engl j med 363;10 september 2, 2010 961 kali should be used cautiously because it raises urine pH, potentially worsening calcium phos- phate supersaturation. Levels of urine pH and citrate and the degree of supersaturation should be assessed after starting therapy. If the citrate level does not rise and the degree of supersatura- tion worsens, the medication is unlikely to be of benefit. Areas of Uncertainty Treatment trials for calcium stones have not looked specifically at outcomes in patients with calcium phosphate stones. Dietary recommenda- tions to increase fluids, lower salt and protein intake, and maintain a normal intake of calcium are supported by an Italian randomized trial,24 but no women were included in this study, and it is unclear whether many Americans can comply with the necessary dietary pattern sufficiently to successfully prevent stones. The Dietary Ap- proaches to Stop Hypertension (DASH)–Sodium diet, when modified to remove high-oxalate foods, replicates many of the features of the study diet and may provide a model to follow, but its effects on stone recurrence have not been explicitly stud- ied.49 Stone formation is associated with an in- creased risk of bone disease, chronic kidney disease, and hypertension, but it is not known whether effective stone prevention decreases these risks. Guidelines Guidelines of the American Urological Associa- tion ( recommend that patients who require surgery for ureteral stones should be informed about benefits and risks of all current treatment approaches. Shock-wave lithotripsy and ureteroscopy with laser lithotripsy are both con- sidered acceptable first-line treatments, although ureteroscopy achieves greater stone-free rates. Percutaneous access and open or laparoscopic surgery are used as needed for selected cases. The guidelines do not address evaluation or treat- ment to prevent recurrent stones. Conclusions and Recommendations Preventive treatment to decrease stone recur- rence is indicated for patients with recurrent cal- cium stones, such as the patient in the vignette. If systemic disease is not present, treatment should focus on metabolic abnormalities uncov- ered during the workup, such as hypercalciuria, hypocitraturia, hyperuricosuria, or hyperoxalu- ria. Although data comparing specific supersatu- ration targets are lacking, a logical strategy is to lower calcium oxalate and calcium phosphate supersaturation to the low end of the normal range. Patients should be advised to increase fluid intake to at least 2 liters daily and reduce sodi- um intake to 2300 mg and protein intake to 0.8 to 1 g per kilogram of body weight per day, since these dietary interventions have reduced stone recurrence in randomized trials. Calcium intake should not be reduced below the recommended intake for sex and age and should be supplied by food rather than by supplements, which may in- crease the risk of stone formation. In many pa- tients, medication is also needed; the choice of medication is influenced by the metabolic ab- normalities identified, the type of stone, and the preference of patients. The stones of the patient in the vignette con- tain 20% phosphate, despite a low urine pH while the patient was not receiving medications; the increased phosphate level may reflect his previous treatment with citrate. Both hypocitra- turia and hypercalciuria may contribute to his stone formation. In addition to the recommen- dations above, we would initiate therapy with a thiazide-type diuretic (e.g., 25 mg of chlorthali- done daily) to lower the urinary calcium level. A reduction in sodium intake will also reduce a thiazide-induced loss of potassium. A follow-up 24-hour urine collection and se- rum chemical analysis should be performed in 4 to 6 weeks to assess the efficacy of treatment and possible side effects, particularly hypokale- mia, which can worsen hypocitraturia. If potas- sium supplementation is needed, it may be added as potassium alkali, but the urine pH level and the level of calcium phosphate supersaturation should be monitored. If the level of calcium phosphate supersaturation rises and is consistent- ly above 1, potassium chloride should be substi- tuted. Primary treatment with potassium alkali would be an alternative to a thiazide but may not lower the level of urinary calcium phosphate supersaturation as effectively. Ongoing attention is warranted at follow-up visits to monitor wheth- er the patient is adhering to preventive recom- mendations. BACK to TOC
  23. 23. 23 The new engl and jour nal of medicine n engl j med 363;10 september 2, 2010962 Drs. Worcester and Coe report receiving consulting fees from LabCorp. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at We thank Andrew Evan, Ph.D., for providing original versions of the figures in the Supplementary Appendix and guidance in the preparation of the manuscript. References 1. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int 2003;63:1817-23. 2. Borghi L, Meschi T, Guerra A, No- varini A. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol 1993;22:Suppl 6: S78-S86. 3. Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A. Potassium- magnesium citrate is an effective prophy- laxis against recurrent calcium oxalate nephrolithiasis. J Urol 1997;158:2069-73. 4. Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calci- um oxalate calculous recurrence but mag- nesium hydroxide does not. J Urol 1988; 139:679-84. 5. Ettinger B, Tang A, Citron JT, Liver- more B, Williams T. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986;315: 1386-9. 6. Laerum E, Larsen S. Thiazide prophy- laxis of urolithiasis: a double-blind study in general practice. Acta Med Scand 1984; 215:383-9. 7. Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CYC. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993;150:1761-4. 8. Hofbauer J, Höbarth K, Szabo N, Mar- berger M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate uro- lithiasis — a prospective randomized study. Br J Urol 1994;73:362-5. 9. Fernández-Rodríguez A, Arrabal-Mar- tín M, García-Ruiz MJ, Arrabal-Polo MA, Pichardo-Pichardo S, Zuluaga-Gómez A. Papel de las tiazidas en la profilaxis de la litiasis calcica recidivante. Actas Urol Esp 2006;30:305-9. 10. Saigal CS, Joyce G, Timilsina AR. Di- rect and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005; 68:1808-14. 11. Rule AD, Bergstralh EJ, Melton LJ III, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 2009;4:804-11. 12. Madore F, Stampfer MJ, Rimm EB, Curhan GC. Nephrolithiasis and risk of hypertension. Am J Hypertens 1998;11: 46-53. 13. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kid- ney stones. JAMA 2005;293:455-62. 14. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest 2005;115:2598- 608. 15. Evan AP, Coe FL, Lingeman JE, et al. Mechanism of formation of human cal- cium oxalate renal stones on Randall’s plaque. Anat Rec (Hoboken) 2007;290: 1315-23. 16. De Yoreo JJ, Qiu SR, Hoyer JR. Molec- ular modulation of calcium oxalate crys- tallization. Am J Physiol Renal Physiol 2006;291:F1123-F1131. 17. Tiselius HG, Berg C, Fornander AM, Nilsson MA. Effects of citrate on the dif- ferent phases of calcium oxalate crystal- lization. Scanning Microsc 1993;7:381-9. 18. Gambaro G, Fabris A, Puliatta D, Lupo A. Lithiasis in cystic kidney disease and malformations of the urinary tract. Urol Res 2006;34:102-7. 19. Worcester EM, Coe FL. New insights into the pathogenesis of idiopathic hyper- calciuria. Semin Nephrol 2008;28:120-32. 20. Worcester EM, Gillen DL, Evan AP, et al. Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis. Am J Physiol Renal Phys- iol 2007;292:F66-F75. 21. Coe FL, Favus MJ, Crockett T, et al. Effects of low-calcium diet on urine cal- cium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in nor- mal subjects. Am J Med 1982;72:25-32. 22. Voss S, Hesse A, Zimmermann DJ, Sauerbruch T, von Unruh GE. Intestinal oxalate absorption is higher in idiopathic calcium oxalate stone formers than in healthy controls: measurements with the [(13)C2]oxalate absorption test. J Urol 2006;175:1711-5. 23. Taylor EN, Curhan GC. Determinants of 24-hour urinary oxalate excretion. Clin J Am Soc Nephrol 2008;3:1453-60. 24. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the preven- tion of recurrent stones in idiopathic hy- percalciuria. N Engl J Med 2002;346:77- 84. 25. Hamm LL, Hering-Smith KS. Patho- physiology of hypocitraturic nephrolithia- sis. Endocrinol Metab Clin North Am 2002; 31:885-93. 26. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with cal- cium nephrolithiasis. N Engl J Med 1974; 291:1344-50. 27. Miller NL, Gillen DL, Williams JC Jr, et al. A formal test of the hypothesis that idiopathic calcium oxalate stones grow onRandall’splaque.BJUInt2009;103:966- 71. 28. Evan AP, Lingeman JE, Coe FL, et al. Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int 2005;67:576-91. 29. Evan AE, Lingeman JE, Coe FL, et al. Histopathology and surgical anatomy of patients with primary hyperparathyroid- ism and calcium phosphate stones. Kid- ney Int 2008;74:223-9. 30. Parks JH, Coe FL, Evan AP, Worcester EM. Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time. Nephrol Dial Transplant 2009;24:130-6. 31. Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inadequate for the medical evaluation of nephrolithiasis. J Urol 2002;167:1607-12. 32. Hollingsworth JM, Rogers MA, Kauf- man SR, et al. Medical therapy to facili- tate urinary stone passage: a meta-analy- sis. Lancet 2006;368:1171-9. 33. Wignall GR, Canales BK, Denstedt JD, Monga M. Minimally invasive approaches to upper urinary tract urolithiasis. Urol Clin North Am 2008;35:441-54. 34. Keeley FX Jr, Assimos DG. Clinical tri- als of the surgical management of uro- lithiasis: current status and future needs. Adv Chronic Kidney Dis 2009;16:65-9. 35. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int 2001; 59:2290-8. 36. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary vol- ume, water and recurrences of idiopathic calcium nephrolithiasis: a 5-year random- ized prospective study. J Urol 1996;155: 839-43. 37. Hiatt RA, Ettinger B, Caan B, Quesen- berry CP Jr, Duncan D, Citron JT. Ran- domized controlled trial of low animal protein, high fiber diet in the prevention of recurrent calcium oxalate kidney stones. Am J Epidemiol 1996;144:25-33. 38. Nouvenne A, Meschi T, Prati B, et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am J Clin Nutr 2010;91:565-70. 39. Heilberg IP, Weisinger JR. Bone dis- ease in idiopathic hypercalciuria. Curr Opin Nephrol Hypertens 2006;15:394-402. BACK to TOC
  24. 24. 24 clinical practice n engl j med 363;10 september 2, 2010 963 40. Lauderdale DS, Thisted RA, Wen M, Favus MJ. Bone mineral density and frac- ture among prevalent kidney stone cases in the Third National Health and Nutri- tion Examination Survey. J Bone Miner Res 2001;16:1893-8. 41. Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009; 75:1264-71. 42. Odvina CV, Preminger GM, Lindberg JS, Moe OW, Pak CY. Long-term combined treatment with thiazide and potassium citrate in nephrolithiasis does not lead to hypokalemia or hypochloremic metabolic alkalosis. Kidney Int 2003;63:240-7. 43. Parks JH, Coe FL. Evidence for durable kidney stone prevention over several de- cades. BJU Int 2009;103:1238-46. 44. Parks JH, Asplin JR, Coe FL. Patient adherence to long-term medical treatment of kidney stones. J Urol 2001;166:2057- 60. 45. Mandel N, Mandel I, Fryjoff K, Rej- niak T, Mandel G. Conversion of calcium oxalate to calcium phosphate with recur- rent stone episodes. J Urol 2003;169:2026- 9. 46. Parks JH, Worcester EM, Coe FL, Evan AP, Lingeman JE. Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int 2004; 66:777-85. 47. Gault MH, Parfrey PS, Robertson WG. Idiopathic calcium phosphate nephro- lithiasis. Nephron 1988;48:265-73. 48. Kacker R, Meeks JJ, Zhao L, Nadler RB. Decreased stone-free rates after per- cutaneous nephrolithotomy for high cal- ciumphosphatecompositionkidneystones. J Urol 2008;180:958-60. 49. Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol 2009;20:2253-9. Copyright © 2010 Massachusetts Medical Society. Fox Robert Raichelson, M.D. BACK to TOC
  25. 25. 25 clinical practice The new engl and jour nal of medicine n engl j med 363;8 august 19, 2010 755 This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. An audio version of this article is available at Emergency Treatment of Asthma Stephen C. Lazarus, M.D. From the Division of Pulmonary and Crit- ical Care Medicine and the Cardiovascu- lar Research Institute, University of Cali- fornia, San Francisco, San Francisco. Address reprint requests to Dr. Lazarus at the University of California, San Fran- cisco, 505 Parnassus Ave., San Francisco, CA 94143-0111, or at N Engl J Med 2010;363:755-64. Copyright © 2010 Massachusetts Medical Society. A46-year-oldwomanwhohashadtwoadmissionstotheintensivecareunit(ICU)for asthma during the past year presents with a 4-day history of upper respiratory illness and a 6-hour history of shortness of breath and wheezing. An inhaled corticosteroid has been prescribed, but she takes it only when she has symptoms, which is rarely. Shegenerallyusesalbuteroltwiceperdaybuthasincreaseditsusetosixtoeighttimes per day for the past 3 days. How should this case be managed in the emergency de- partment? The Clinical Problem Asthma is one of the most common diseases in developed countries and has a worldwide prevalence of 7 to 10%.1 It is also a common reason for urgent care and emergency department visits. From 2001 through 2003 in the United States, asthma accounted for an average 4210 deaths annually and an average annual total of ap- proximately 504,000 hospitalizations and 1.8 million emergency department visits.2 The average annual rate of emergency department visits for asthma was 8.8 per 100 persons with current asthma. Rates were higher among children than among adults (11.2 vs. 7.8 visits per 100 persons), among blacks than among whites (21 vs. 7 visits per 100 persons), and among Hispanics than among non-Hispanics (12.4 vs. 8.4 visits per 100 persons). Women made twice the number of emergency depart- ment visits as men.2 Approximately 10% of visits result in hospitalization.1 Asthma is a heterogeneous disease, with varied triggers, manifestations, and responsiveness to treatment. Some patients with acute severe asthma presenting to the emergency department have asthma that responds rapidly to aggressive therapy, and they can be discharged quickly; others require admission to the hospital for more prolonged treatment. The reasons for this difference in responsiveness to treatment include the degree of airway inflammation, presence or absence of mucus plugging, and individual responsiveness to β2-adrenergic and corticosteroid medi- cations. The major challenge in the emergency department is determining which patients can be discharged quickly and which need to be hospitalized. Str ategies and Evidence Initial Assessment in the Emergency Department Patients presenting to the emergency department with asthma should be evaluated and triaged quickly to assess the severity of the exacerbation and the need for urgent intervention (Fig. 1). A brief history should be obtained, and a limited physical ex- amination performed. This assessment should not delay treatment; it can be per- formed while patients receive initial treatment. Clinicians should search for signs Click here to access audio version. BACK to TOC
  26. 26. 26 The new engl and jour nal of medicine n engl j med 363;8 august 19, 2010756 of life-threatening asthma (e.g., altered mental status, paradoxical chest or abdominal movement, or absence of wheezing), which necessitate ad- mission. Attention should be paid to factors that are associated with an increased risk of death from asthma, such as previous intubation or ad- mission to an ICU, two or more hospitalizations for asthma during the past year, low socioeco- nomic status, and various coexisting illnesses.3 The measurement of lung function (e.g., forced expiratory volume in 1 second [FEV1] or peak ex- piratory flow [PEF]) can be helpful for assessing Initiate treatment with oxygen to achieve SaO2 ≥90% Reassess history, symptoms, vital signs, results of physical examination, PEF, and SaO2 after 60–90 min of treatment Triage patient immediately Take brief history to ascertain risk factors Previous intubation or ICU admission ≥2 Hospitalizations or ≥3 emergency department visits in past yr >2 Canisters of short-acting β2-adrenergic agonist per mo Coexisting conditions Assess vital signs and perform brief physical examination Observe for breathlessness Measure respiratory rate and heart rate, check for pulsus paradoxus Note whether accessory muscles of respiration used Perform chest examination Assess for mild-to-moderate exacerbation FEV1 or PEF ≥40% Patient talks in sentences Pulse ≤120 beats/min Minimal or no pulsus paradoxus SaO2 ≥90% Assess for severe exacerbation FEV1 or PEF <40% Patient talks in words or phrases but not sentences Pulse >120 beats/min, respiratory rate >30 breaths per min Pulsus paradoxus (decrease in systolic arterial pressure by >25 mm Hg on inspiration) Loud wheezes or silent chest SaO2 <90% or PaO2 <60 mm Hg Initiate treatment Short-acting β2-adrenergic agonist administered by means of a metered- dose inhaler with valved holding chamber or a nebulizer, up to 3 doses in first hr Oral corticosteroids if no immediate response or if patient recently received systemic corticosteroids Initiate treatment High-dose short-acting β2-adrenergic agonist plus ipratropium bromide administered by means of a metered- dose inhaler with valved holding chamber or a nebulizer every 20 min or continuously for 1 hr Oral corticosteroids Figure 1. Initial Assessment of a Patient Presenting to the Emergency Department with Asthma. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3.3 FEV1 denotes forced expiratory volume in 1 second, ICU intensive care unit, PaCO2 partial pressure of arterial carbon dioxide, PaO2 partial pressure of arterial oxygen, PEF peak expiratory flow, and SaO2 arterial oxygen saturation. BACK to TOC
  27. 27. 27 clinical practice n engl j med 363;8 august 19, 2010 757 the severity of an exacerbation and the response to treatment but should not delay the initiation of treatment. Laboratory and imaging studies should be performed selectively, to assess patients for impending respiratory failure (e.g., by measuring the partial pressure of arterial carbon dioxide [PaCO2]), suspected pneumonia (e.g., by obtaining a complete blood count or a chest radiograph), or certain coexisting conditions such as heart dis- ease (e.g., by obtaining an electrocardiogram). Treatment in the Emergency Department All patients should be treated initially with sup- plementary oxygen to achieve an arterial oxygen saturation of 90% or greater, inhaled short-acting β2-adrenergic agonists, and systemic corticoste- roids (Fig. 1). The dose and timing of these agents and the use of additional pharmacologic therapy depend on the severity of the exacerbation. β2-Adrenergic Agonists Inhaled short-acting β2-adrenergic agonists should be administered immediately on presentation, and administration can be repeated up to three times within the first hour after presentation. The use of a metered-dose inhaler with a valved holding chamber is as effective as the use of a pressurized nebulizer in randomized trials,4,5 but proper technique is often difficult to ensure in ill patients. Most guidelines recommend the use of nebulizers for patients with severe exacerba- tions; metered-dose inhalers with holding cham- bers can be used for patients with mild-to-mod- erate exacerbations, ideally with supervision from trained respiratory therapists or nursing person- nel (see the Supplementary Appendix and a Video, both available at, for descrip- tions of how to use inhalers with and inhalers without a holding chamber, respectively). The dose administered by means of metered-dose in- halers for exacerbations is substantially greater than that used for routine relief: four to eight puffs of albuterol can be administered every 20 minutes for up to 4 hours and then every 1 to 4 hours as needed (Table 1). Albuterol can be delivered by means of a nebulizer either inter- mittently or continuously. A meta-analysis of re- sults from six randomized trials indicated that intermittent administration and continuous ad- ministration have similar effects on both lung function and the overall rate of hospitalization,6 whereas a Cochrane review of findings from eight trials suggested that continuous adminis- tration resulted in greater improvement in PEF and FEV1 and a greater reduction in hospital ad- missions, particularly among patients with severe asthma.7 Albuterol is the inhaled β2-adrenergic agonist most widely used for emergency management. Levalbuterol, the R-enantiomer of albuterol, has been shown to be effective at half the dose of albuterol, but randomized trials conducted in the emergency department have not consistently shown a clinical advantage of levalbuterol over racemic albuterol.8,9 Pirbuterol and bitolterol are effective for mild or moderate exacerbations, but a higher dose is required than with albuterol or levalbuterol, and their use for severe exacerba- tions has not been studied. Oral or parenteral administration of β2- adrenergic agonists is not recommended, since neither has been shown to be more effective than inhaled β2-adrenergic agonists, and both are associated with an increased frequency of side effects. The long-acting inhaled β2-adrenergic salmeterol has not been studied for the treat- ment of exacerbations, though trials with formot- erol ( numbers, NCT00819637 and NCT00900874) are under way. Anticholinergic Agents Because of its relatively slow onset of action, in- haled ipratropium is not recommended as mono- therapy in the emergency department but can be added to a short-acting β2-adrenergic agonist for a greater and longer-lasting bronchodilator ef- fect.10,11 In patients with severe airflow obstruc- tion, the use of ipratropium together with a β2- adrenergic agonist in the emergency department, as compared with a β2-adrenergic agonist alone, has been shown to reduce rates of hospitaliza- tion by approximately 25%,12,13 although there is no apparent benefit of continuing ipratropium after hospitalization. Systemic Corticosteroids In most patients with exacerbations that neces- sitate treatment in the emergency department, systemic corticosteroids are warranted. The ex- ception is the patient who has a rapid response to initial therapy with an inhaled β2-adrenergic agonist. Although most randomized, controlled BACK to TOC
  28. 28. 28 The new engl and jour nal of medicine n engl j med 363;8 august 19, 2010758 Table1.MedicationsforTreatmentofAsthmaExacerbationintheEmergencyDepartment.* DrugandAvailableFormulationDoseComments Short-actingβ2-adrenergicagonistsAdverseeffectsincludetachycardia,palpitations,tremor,andhypo- kalemia. Albuterol Metered-doseinhaler(90μg/puff)4–8puffsevery20minupto4hr,thenevery1–4hrasneeded Nebulizersolution(0.63mg/3ml,1.25 mg/3ml,2.5mg/3ml,or5.0mg/ml) 2.5–5mgevery20minoverthefirsthr,then2.5–10mgevery 1–4hrasneededor10–15mg/hrcontinuously Foroptimaldelivery,dilutesolutiontoaminimumof3mlatagasflow of6–8liters/min.Uselarge-volumenebulizersforcontinuousadmin- istration. Levalbuterol† Metered-doseinhaler(45μg/puff)Sameasforalbuterol,metered-doseinhaler;levalbuterol administeredinhalfthemilligramdoseofalbuterolhas similarefficacyandsafety Nebulizersolution(0.63mg/3ml,1.25 mg/0.5ml,or1.25mg/3ml) 1.25–2.5mgevery20minoverthefirsthr,then1.25–5mg every1–4hrasneeded;levalbuteroladministeredathalf themilligramdoseofalbuterolhassimilarefficacyand safety;continuousnebulizationhasnotbeenevaluated BitolterolHasnotbeenstudiedinpatientswithsevereasthmaexacerbations.Not availableintheUnitedStates. Metered-doseinhaler(370μg/puff)Sameasforalbuterol,metered-doseinhaler;bitolterolthought tobehalfaspotentasalbuterolonamilligrambasis Nebulizersolution(2mg/ml)Sameasforalbuterol,nebulizersolution;bitolterolthought tobehalfaspotentasalbuterolonamilligrambasis Pirbuterol,metered-doseinhaler(200μg/puff)Sameasforalbuterol,metered-doseinhaler;pirbuterol thoughttobehalfaspotentasalbuterolonamilligram basis Hasnotbeenstudiedinpatientswithsevereasthmaexacerbations. AnticholinergicagentsAdverseeffectsincludedrymouth,cough,andblurredvision. IpratropiumbromideShouldnotbeusedasfirst-linetherapy;shouldbeaddedtoshort-acting β2-adrenergicagonisttherapyforsevereexacerbations.Theaddition ofipratropiumtoashort-actingβ2-adrenergicagonisthasnotbeen showntoprovidefurtherbenefitoncethepatientishospitalized. Metered-doseinhaler(18μg/puff)8puffsevery20minasneeded,forupto3hr Nebulizersolution(0.25mg/ml)0.5mgevery20minfor1hr(threedoses),thenasneeded; canbeusedwithalbuterolinonenebulizer BACK to TOC