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Reconsideration of the 1988 NIH Consensus Statement on Prevention and Treatment of Kidney Stones: Are the Recommendations Out of Date?

Treatment Update

TREATMENT UPDATE Reconsideration of the 1988 NIH Consensus Statement on Prevention and Treatment of Kidney Stones: Are the Recommendations Out of Date? David S. Goldfarb, MD New York Harbor Department of Veterans Affairs Medical Center and New York University School of Medicine, New York, NY In 1988, a consensus conference was held at the National Institutes of Health to develop guidelines for prevention and treatment of kidney stones. The recommendations regarding the medical evaluation of stone formers and treatment directed at stone prevention are reviewed. The relevance of those 1988 guidelines is evaluated for continued pertinence. Most of the recommendations promulgated in the consensus statement remain useful today. One significant change is the current consensus that dietary calcium restriction is no longer considered appropriate therapy, as there is no evidence that it actually prevents stones and has as a consequence the potential to worsen bone demineralization. [Rev Urol. 2002;4(2):53–60] Published 2002 by MedReviews, LLC Key words: Urolithiasis • Oxalates • Citrates • Kidney calculi/diet therapy • Kidney calculi/drug therapy T This article is a U.S. Government work and, as such, is in the public domain in the United States. he evaluation of causative metabolic abnormalities in patients with kidney stones has been expected to lead to effective strategies for stone prevention in such individuals. If one were to visit the National Institutes of Health (NIH) web site in search of recommendations for stone evaluation and prevention, one could read the consensus statement that summarized the discussion of a learned group of researchers and clinicians that took place in March 1988.1 It is interesting that the Internet surfer today is met with this proviso: “This statement is outdated and is no longer viewed by NIH as guidance for medical practice." The NIH has not provided another set of guidelines to replace the previous set. (Recommendations regarding evaluation are briefly summarized in Table 1; recommendations regarding prevention are summarized in Table 2). In fact, though several reviews on this subject appear annually,2,3 no similar consensus VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 53 Prevention and Treatment of Kidney Stones continued meeting has been held, and no consensus document written. But before calling for another such gathering, one might ask what recommendations, if any, from the 1988 guidelines are out of date. The NIH consensus conference asked two questions that will be briefly reviewed here: 1) What are the clinical and laboratory approaches for the evaluation of patients with stones?; and 2) What are the methods of medical prevention, and how successful are they? The clinical and laboratory approaches for the evaluation of patients are summarized in Table 1. I will not deal here with the prevention of cystine and struvite stones. The consensus conference also outlined directions for future research. Though it would be a fascinating exercise to gauge the scientific progress that has been made in understanding the pathophysiology of stone disease since 1988, I will not attempt that task at this time. Finally, the consensus statement asked the question: What is the role of lithotripsy, and can it replace medical prevention? The answer then, when the technique was relatively new, and now is that lithotripsy cannot replace medical prevention. It is relatively expensive, has unproven long-term safety,4 and is not always effective.5 Lithotripsy may also be associated with lower stone-free rates and higher rates of stone recurrence in some settings.6 These issues, as well as the rise of more flexible ureteroscopes and improvements in percutaneous nephrostolithotomy, have led to an overall decline in the use of extracorporeal lithotripsy. The balance of this review will deal with medical prevention and treatment. Surprisingly, we find little today of a controversial nature in the recommendations regarding the clinical and laboratory approaches to stone formers as they were conceived in 1988. The emphasis on history-taking is finding modifiable factors in diet, fluid intake, and urine output. A family history of stones should be elicited and can be important in suggesting relatively infrequent causes, such as renal tubular acidosis (RTA), polycystic kidney disease, or multiple endocrine neoplasia syndromes (with hyperparathyroidism). However, up to 40% of patients in emergency rooms with renal colic have a positive family history7; men with a positive family history have a relative risk of an incident stone of 2.6 as compared with those without a family history.8 A large proportion of these family histories is probably accounted for by Table 1 NIH Consensus Statement: Recommendations on the Evaluation of Stone Formers (Suggested Revisions in Italics) Evaluation of Patient with First Stone Episode History: medications, occupation, family history of stones or other kidney disease, inflammatory bowel disease (eg, Crohn’s disease). Diet: intake of protein, purines, sodium, fluids, oxalate, and calcium Laboratory tests: electrolytes, blood urea nitrogen, creatinine, calcium, phosphate and uric acid levels, urinalysis, urine culture if indicated, stone analysis if available (if not, consider qualitative cystine screening) Radiology: plain radiographs, ultrasonography, and/or intravenous pyelography to find more stones, radiolucent stones, or anatomic abnormalities. Helical CT scanning may now be the preferred imaging study. Diagnosis: 1. Consider renal tubular acidosis (suggested by a low serum bicarbonate concentration). 2. Hyperparathyroidism and sarcoidosis (if hypercalcemia is present). Consider measuring PTH in patients with high-normal or marginally elevated serum calcium levels. Evaluation of Patient with Recurrent Stone Formation or Growth (and All Children) Twenty-four hour urine collection: Volume, pH, levels of calcium, phosphorus, sodium, uric acid, oxalate, citrate, creatinine, supersaturation of calcium oxalate, calcium phosphate, and uric acid. Repeat as necessary: 24-hour urine collection and analysis to monitor response to dietary changes and effectiveness of treatment. Specialized testing: Not indicated for most patients. Includes provocative acid-loading tests, oral calcium deprivation and loading studies, determination of urinary inhibitor concentrations, measures of urinary supersaturation (although supersaturation is now easily computed by laboratories specializing in assessment of stone risk). 54 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY Prevention and Treatment of Kidney Stones the hereditary nature of idiopathic hypercalciuria, one of the more common metabolic abnormalities in the general population with stones. The genetic origin of most heredityinfluenced stone disease, or its interaction with environmental influences such as diet, in the general population has not been established in the ensuing years. Therefore the family history for most patients has no current etiologic significance. Candidate genes such as chloride channels, mutations of which cause hypercalciuria,9 have not been shown to be significant in the broader population of stone formers.10 Occupational history is of interest to the extent that some stone formers work in hot environments (eg, lifeguards), have strenuous activities (eg, athletes), or are discouraged from drinking by inadequate bathroom facilities (eg, police). Medications that may be relevant to stone formation have always included the poorly soluble sulfonamides such as sulfamethoxazole and triamterene. In recent years, patients with HIV infection have had more than occasional stone episodes from the poorly soluble protease inhibitor indinavir.11 Diet remains a subject of much interest in stone disease due to the epidemiologic and pathophysiologic data relating dietary intake to urinary lithogenicity. Recently, prospective data demonstrating that alteration of diet actually prevents stones have been presented (see below). Therefore, eliciting dietary histories high in animal protein or oxalate, or low in calcium-rich dairy intake can lead to modifications that in theory should affect stone formation.12 In recent years the popularity of the high-protein/high-fat Atkins diet has led to concern about increased risk of stones. Perhaps for short periods the effects of this diet can be overcome by increased fluid intake, but for longer periods, it is probably lithogenic. Since the NIH consensus statement was published, studies by Curhan and colleagues have led to a reversal of beliefs about dietary calcium con- related to stone incidence. As a result, the previous popular advice to restrict calcium intake has been supplanted by a recommendation for at Prospective data demonstrating alteration of diet to an extent that actually prevents stones are lacking. tent.13,14 These prospective epidemiologic studies demonstrated that dietary calcium intake is inversely least 800 mg of dietary elemental calcium per day. Low calcium intake is thought to allow unbound solubi- Table 2 NIH Consensus Statement: Recommendations on Prevention of Recurrent Stones (Suggested Revisions in Italics) A. Nonspecific Therapy Increase in fluid intake to achieve a doubling of the urinary output or a 24-hour urinary output of greater than 2 liters. B. Specific Therapy Calcium oxalate stones: 1. Hypercalciuria a. Dietary excess: 1. Restrict sodium intake 2. (No longer appropriate: calcium restriction; calcium intake of 800 mg per day should instead be encouraged) b. Drugs: 1. Thiazides 2. (Not felt to be of proven efficacy: cellulose phosphate and orthophosphate) 2. Hyperuricosuria a. Dietary excess: restrict purines and animal protein intake b. Drugs: allopurinol 3. Hypocitraturia a. Drugs: citrate supplements 4. Hyperoxaluria a. Dietary excess: restrict oxalate intake b. Drugs: restrict intake of vitamin C? Urate stones: a. Dietary excess: restrict purine intake b. Drugs: bicarbonate or citrate supplements for urinary alkalinization; allopurinol for patients with recalcitrant stones VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 55 Prevention and Treatment of Kidney Stones continued lized oxalate in intestinal contents to be absorbed into the blood and then excreted by the kidneys. Oral calcium may therefore serve as an oxalate binder, diminishing its absorption and ensuring its excretion in the limitation of animal protein, oxalate, and sodium, not based on detailed analysis of an individual’s urinary chemistry is unlikely to lead to persistent modification of diet: it may seem too vague and too drastic. And Oral calcium may serve as an oxalate binder, diminishing its absorption and ensuring its excretion in the feces. feces. Besides increasing stone formation, calcium restriction may exacerbate the osteopenia that is often seen in stone formers.15 Serum tests relevant to stone disease have changed little in the ensuing years. As before, one needs to know baseline renal function, and serum concentrations of bicarbonate, potassium, uric acid, calcium, and phosphorus. The diagnosis of hyperparathyroidism should be sought in patients with calcium concentrations in the high normal range (>10.0 mg/dL), as well as in the high range. Patients with hyperparathyroidism in fact can present with normal serum parathormone values, because elevations in serum calcium concentration should be accompanied by suppression of parathyroid hormone values into the low range. Analysis of stone risk factors in 24-hour urine collections is reserved for patients with recurrent stone disease or stone growth, a principle that has not changed since 1988.16,17 Although the rate of recurrence after a single first stone episode is relatively high, it is not universal. It is likely that many people, particularly the young, are ultimately not willing to make specific dietary modifications or take daily medications to prevent an acute episode of renal colic, particularly if the episode was followed by spontaneous stone passage not requiring urologic intervention. Generic dietary advice, such as 56 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY although the drugs used for stone prevention are well tolerated (see below), most individuals are too wary of pharmaceuticals to be willing to take them for what may be perceived as a brief and transient phenomenon. It seems appropriate to reserve urine collections for recurrent or large stone formers. How the 24-hour urine collections are performed has been an important question in the ensuing years. It is interesting that the consensus statement did not at the time firmly endorse in its recommendations the detailed testing studied and advocated by Pak to classify hypercalciuria.18 The goal of such studies was to divide hypercalciuria into states of severely and mildly increased intestinal calcium absorption, or decreased renal calcium reabsorption. The therapeutic implications of such a classification have not been proven. The problem was that calcium restriction of patients with increased calcium absorption fails to eliminate hypercalciuria in many of those affected, implying that bone calcium loss would ensue19 and that increased bone turnover was in fact the etiology of a proportion of hypercalciuria. Further, epidemiologic studies showed that lower calcium intake was associated with an increased risk of stones.13,20 Finally, thiazides were demonstrated to be effective stone preventatives in unclassified patients with hypercalciuria.21 Pak himself advocated a simplified approach in non-research settings, in which the collections are done while patients eat their usual diets and again after dietary advice is given.22 As for radiologic evaluation, ultrasound and intravenous pyelography (IVP) are still reasonable options after the acute episode has resolved. The point of imaging at that point is to screen for conditions such as polycystic kidney disease or asymptomatic stones. These tests are steadily being replaced by imaging of the kidneys with helical computed tomographic (CT) scanning. Helical CT scanning is faster and more sensitive than IVP, and it does not require the use of intravenous contrast material. It is more expensive than IVP, but the cost is continually decreasing because no radiocontrast is required and technician time required is less.23 Prevention Drug therapy At the time of the consensus statement, there was no controlled clinical study to examine the effectiveness of an increase in fluid intake for stone prevention. Nonetheless, historical data were felt to “strongly suggest that hydration is effective," and a doubling of the urinary output or a 24-hour urinary output of greater than 2 liters was recommended. Since then, one randomized trial has demonstrated a 45% reduction in stone incidence with an increase in fluid intake alone at 5 years.24 This recommendation therefore remains a mainstay of initial, “nonspecific" therapy and particularly valuable advice after a first stone, because most first-stone formers would not be eligible for more “specific" therapy, not having performed 24-hour urine collections. For specific therapies, the options discussed included drugs and dietary Prevention and Treatment of Kidney Stones restrictions. Thiazides were considered the only drug in 1988 that had been shown most probably to prevent stones in randomized trials.25 A recent meta-analysis confirms their stone prevention of magnesium salts other than citrate. The benefit of citrate supplementation was not demonstrated in one prospective randomized trial. This trial included some patients with One randomized trial of potassium citrate supplementation in patients with hypocitraturia demonstrated an absolute risk reduction in stone recurrence of 92% compared to placebo. importance today.21 The probable efficacy of allopurinol for prevention of calcium oxalate stones has long been known, but the original data have not been enlarged upon.26 The effect is important in patients with isolated hyperuricosuria and not with other metabolic abnormalities, such as hypercalciuria. The data in favor of citrate supplementation, based on the known effects of citrate to lower supersaturation of calcium salts and inhibit crystal growth and aggregation, remain quite favorable. One randomized trial of potassium citrate supplementation in patients with hypocitraturia demonstrated an absolute risk reduction in stone recurrence of 92% compared to placebo.27 In a second trial, 64 patients were randomly assigned to receive placebo or potassium-magnesium citrate (42 mEq potassium, 21 mEq magnesium, and 63 mEq citrate) daily for up to 3 years in a doubleblind design.28 New calculi formed in 63.6% of subjects receiving placebo and in 12.9% of subjects receiving potassium-magnesium citrate. This preparation might have fewer gastrointestinal side effects than potassium citrate alone but is not yet available for prescription. In addition to these randomized trials there is a wealth of nonrandomized trials suggesting benefit of citrate supplementation. Although magnesium may affect calcium oxalate crystal growth, there are no data demonstrating efficacious normal citrate excretion, and some patients were given sodium citrate.29 Sodium supplementation would be expected to increase calcium excretion. Two other possibly effective drug treatments were mentioned in the consensus statement but had not been evaluated in double-blind and prospective studies. Cellulose phosphate, which binds calcium in the intestine, reduces intestinal calcium absorption but may thereby cause increased oxalate absorption and cause negative calcium balance with bone demineralization. Currently available preparations of neutral orthophosphate are not well tolerated Drug therapy of hyperoxaluria, not discussed at the consensus conference, remains unexplored with respect to stone prevention in cases of relatively mild, nongenetic hyperoxaluria, which in many cases is likely to be diet-related. The shortterm benefits of preparations showing reductions in urinary oxalate have been most often studied in the special case of enteric hyperoxaluria, a disorder most often attributed to fat malabsorption with calcium binding and effects of bile acids on colonic oxalate absorption. Cholestyramine and Ox-Absorb®, a calcium-charged hydrocolloid,33 both appear to reduce urinary oxalate excretion but have not been shown to prevent stones. A short-term study recently demonstrated a reduction in urinary oxalate excretion after oral intake of a preparation of lactic-acid bacteria, which appeared to reduce oxalate content in vitro.34 There is also a prospect of metabolizing intestinal oxalate by oral intake of oxalatedegrading enzymes derived from Oxalobacter formigenes.35 One recent study showed no increase in the relative risk of stones in patients taking oral vitamin C supplements. and have no proven efficacy. A new preparation of neutral potassium phosphate, which increases urinary excretion of citrate and pyrophosphate, inhibiting calcium oxalate crystal growth and agglomeration, may have advantages.30 It appears to reduce urinary calcium excretion more than intestinal calcium absorption, causing positive calcium balance. In one randomized double-blind study, it reduced urinary calcium excretion at 3 months.31 In a 4-year study, it did not lead to a reduction in bone mineral density.32 It is not yet commercially available. The possible risk of oral vitamin C being converted to oxalate and causing hyperoxaluria was mentioned in the consensus statement. The actual clinical significance of this phenomenon in patients with normal renal function remains uncertain and controversial. One recent study showed no increase in the relative risk of stones in patients taking oral vitamin C supplements.36 Dietary therapy The consensus statement recommended dietary restriction of sodium, calcium, oxalate, and purines and VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 57 Prevention and Treatment of Kidney Stones continued acknowledged that prospective trials of such dietary manipulations were lacking. This lack of data is still troubling today.37 The most significant change since 1988 is the elimination of calcium restriction as a part of the standard advice for calcium stone formers (see above). In fact, increases in calcium intake appear to prevent stones, because increases in urinary calcium are accompanied by decreases in urinary oxalate excretion.12 Sodium restriction remains important, as sodium excretion leads to increased calcium excretion, aggravates osteoporosis,38 and worsens the hypokalemia and hypocitraturia caused by thiazides.39 Assessment of the utility of oxalate restriction is made difficult by a number of issues, including methodologic problems in measuring food oxalate content and assessing true intake; questions about oxalate bioavailability and effects of other dietary constituents; and possible genetic aspects of intestinal oxalate absorption.12,40 Intake of some beverages said to increase urinary oxalate, such as tea, is not associated with increases in stones,41 while grapefruit juice is consistently associated with more stone disease with less oxalate content.42,43 Restriction of oxalate intake should be coupled with an increase in dietary calcium intake, particularly when ingesting oxalatecontaining foods. These studies have also shown a decrease, not an increase, in stone formation with increased intake of coffee and beer. Both have mild diuretic properties due to the respective effects of caffeine and alcohol, but these effects may be protective, not injurious. Restriction of dietary animal protein and purine intake in patients with calcium or urate stones has a sound pathophysiologic basis. Protein restriction leads to increased urinary citrate excretion and decreases in urinary calcium, oxalate, and urate excretion.44 Despite these acute effects, one randomized trial of 99 patients who were either given no instruction regarding protein intake or assigned to a low-protein group (56–64 g daily) actually showed a significant increase in stone formation in the intervention group.45 Methodologic questions about this limited study leave no consensus at this time about the long-term usefulness of dietary protein restriction. The combination of all of these dietary changes does appear to be effective in preventing stones in patients with hypercalciuria. In a recent randomized controlled trial, Borghi and colleagues randomized 120 patients with recurrence of calcium stones and hypercalciuria to two Main Points • A family history of stones can be important in suggesting relatively infrequent causes, such as renal tubular acidosis, polycystic kidney disease, or multiple endocrine neoplasia syndromes (with hyperparathyroidism). • Up to 40% of patients in emergency rooms with renal colic have a positive family history; men with a positive family history have a relative risk of an incident stone of 2.6 as compared with those without a family history. • Some stone formers work in hot environments (eg, lifeguards), have strenuous activities (eg, athletes), or are discouraged from drinking by inadequate bathroom facilities (eg, police). • Patients with HIV infection have had more than occasional stone episodes from the poorly soluble protease inhibitor indinavir. • Intake of some beverages said to increase urinary oxalate, such as tea, is not associated with increases in stones, while grapefruit juice is consistently associated with more stone disease with less oxalate content. • Prospective epidemiologic studies have demonstrated that dietary calcium intake is inversely related to stone incidence; low calcium intake is thought to allow unbound solubilized oxalate in intestinal contents to be absorbed into the blood and then excreted by the kidneys. • Thiazides were demonstrated to be effective stone preventatives in unclassified patients with hypercalciuria. • Citrate lowers supersaturation of calcium salts and inhibits crystal growth and aggregation; studies suggest that potassium-magnesium citrate may have fewer gastrointestinal side effects than potassium citrate alone, but it is not yet available for prescription. • Neutral potassium phosphate increases urinary excretion of citrate and pyrophosphate, inhibiting calcium oxalate crystal growth and agglomeration; it is not yet commercially available. • A reduction in urinary oxalate excretion was demonstrated after oral intake of a preparation of lactic-acid bacteria, which appeared to reduce oxalate content in vitro; intestinal oxalate may be metabolized by oral intake of oxalate-degrading enzymes derived from Oxalobacter formigenes. • A diet restricted in calcium intake was associated with more stone recurrences in patients with hypercalciuria than a diet with unrestricted calcium intake and restrictions in sodium, oxalate, and animal protein. 58 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY Prevention and Treatment of Kidney Stones different diets: a diet with restricted calcium and oxalate intake, and a diet with unrestricted calcium intake, as well as restrictions of dietary oxalate, salt and animal protein. At 5 years, the patients on the unrestricted calcium diet had significantly fewer stone recurrences. The diet was most effective for patients with a relatively low risk of recurrence as defined by relatively fewer recent or total episodes of stones. Though the importance of any one of the dietary manipulations that led to successful stone prevention is unproven, both groups had reductions in urinary calcium excretion; in one due to the reduction in calcium intake, and in the other presumably due to the successful restriction of sodium. The difference was that the group with calcium restriction had little change in urinary oxalate despite the restriction in oxalate intake, whereas the group with no calcium restriction had a significant decline in urinary oxalate. This finding confirms the epidemiologic data suggesting that calcium restriction leads to an adverse result. Whether this diet would be similarly efficacious in patients with calcium stones but without hypercalciuria is uncertain; it is likely that it would be appropriate.46 Conclusion The recommendations of the 1988 NIH consensus statement remain largely intact and surprisingly current. New insights into the genetic basis of disease will no doubt be important in nephrolithiasis in the near future, but evaluation of stone formers has, if anything, been simplified since 1988. As for therapy, the major change in the ensuing years is that dietary calcium restriction is no longer considered safe or effective. Other individual dietary manipulations remain inadequately evaluated in randomized controlled trials, but the combination of restriction of salt, oxalate, and animal protein, with unrestricted calcium intake appears to be effective in stone prevention. 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