The Journal of Urology
Volume 180, Issue 3 , Pages 813-819, September 2008

Medical Stone Management: 35 Years of Advances

  • Charles Y.C. Pak

      Affiliations

    • Corresponding Author InformationCorrespondence: Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-8885.

Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas

Received 14 April 2008 published online 17 July 2008.

Article Outline

Purpose

The urological community has had a vital role in the author's 35 years of research on the medical management of urolithiasis. The goal of this article is to review the progress made from the perspective of collaborating urologists and urological journals in which the findings were reported.

Materials and Methods

The author's work appeared in 94 articles in urological journals, including 63 in The Journal of Urology®, and in 28 other journals with collaborating urologists. Progress on various aspects of medical management of stone disease was reviewed based on these articles.

Results

Pathophysiological exploration was performed by elucidating metabolic-dietary etiologies of hypocitraturia, separating hypercalciuria into 3 types, and linking gouty diathesis (uric acid stones) with obesity and insulin resistance. Physicochemical consequences of hypocitraturia were delineated and semi-empirical methods were developed to assess calcium salt saturation. Potassium-rich fruit juices differed from potassium-poor fruit juices and excessive salt intake increased the stone forming risk. Vital to diagnostic separation was a comprehensive analysis of urine for stone risk factors. As an example of selective treatment, potassium citrate was shown to be useful for controlling uric acid stones by urinary alkalinization as well as calcareous stones by hypercitraturia.

Conclusions

During the last 35 years much progress has been made on the pathophysiology of stone formation, crystallization of stone forming salts, diagnostic separation and prevention of stone recurrence. The author's contribution in this effort would not have been possible without the active participation and support of the urological community.

Key Words: urolithiasis, history, 21st century, crystallization, citric acid, lectures

Abbreviations and Acronyms: FDA, Food and Drug Administration, NIH, National Institutes of Health, PTH, parathyroid hormone, UT, University of Texas

 

When I was asked to give the 2008 Lattimer Lecture, I was intrigued and challenged. This presentation allows me to reflect on my own research during the last 35 years at UT Southwestern. It also gives me an opportunity to acknowledge past and current members of the American Urological Association, who were indispensable in the successful performance of my research by offering their friendship, support and collaboration. This lecture will be a personal, historical perspective on my exploration of the medical management of stone disease, achieved by working closely with the members of the urological community.

In performing my research I have always recognized the need to engage urologists. A total of 27 urologists have reciprocated by being my collaborators. The active involvement of the urological community in my research is amply illustrated by 94 publications in urological journals (63 in The Journal of Urology) and 28 publications in other journals with collaborating urologists.

Some of my collaborating urologists were foremost figures in urology, including Paul Peters, Birdwell Finlayson and Martin Resnick. A few were my former postdoctoral fellows who later distinguished themselves, including Glenn Preminger, Tadaichi Kitamura and Thomas Hwang. Many were established academicians in urology, including Donald Griffith, John Gregory and Margaret Pearle. To those who might be offended, my sincere apologies for concentrating on my own research and inadvertently neglecting their contributions.

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Overall Theme of Research 

The overall goal of my research from the outset has been to formulate a selective medical approach composed of an elucidation of the causes of stone formation and the prevention of stone recurrence. Figure 1 shows the elements of the selective approach.

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  • Fig. 1. 

    Elements of selective approach. Diagnostic separation into different causes is made using knowledge gained from pathophysiological exploration, physicochemical elucidation and dietary aberrations. Tailor-made treatment is then chosen for each cause.

The mechanisms of stone formation were sought by a 3-pronged effort. Under pathophysiological exploration various metabolic-physiological disturbances that predispose certain persons to form stones were identified. The physicochemical factors that lead to crystallization of stone forming salts were examined. A search was made for dietary aberrations that cause or contribute to stone formation. From the knowledge so obtained a diagnostic scheme for the medical causes of stones was developed. Lastly, treatments that are tailor-made to correct the underlying metabolic-dietary disturbances or abnormal urinary biochemistry-physicochemistry were sought.

In each of these endeavors much progress has been made during the last 35 years. I shall describe my own role in this progress from the perspective of contributions made by key collaborating urologists or publications in urological journals.

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The Beginning 

The Mentorship of Bartter and Seldin 

My journey began in 1972 when I decided to leave the National Institutes of Health for the UT Southwestern Medical School. My mentors, Fredric C. Bartter at NIH and Donald W. Seldin at UT Southwestern, urged me to concentrate on stone disease. I was ready to meet this task since I had acquired earlier the essential training in solution chemistry1 and metabolic balance techniques,2 and was exposed to patients with idiopathic hypercalciuria at Bartter's clinic.3 In Dallas Seldin helped me organize my own mineral metabolism group as well as establish the General Clinical Research Center.

Embraced by Paul Peters 

To jump-start the research program in 1972 I needed to recruit a large number of patients with stones. Paul Peters, Chief of Urology at UT Southwestern, embraced me. “Heck, do not worry,” Peters said. “I can get you all the patients you need for your studies.”

Thereupon Peters organized the practicing urological community in Dallas to refer patients to me. This group included C. Caramela, C. Fetner, M. Fine, A. Freeman, G. Hurt, M. Kadesky and D. Reisman. From a thorough evaluation of patients I was able to formulate an ambulatory diagnostic protocol, differentiating stone disease into various causes.4, 5, 6

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Pathophysiological Exploration 

Joined by Glenn Preminger 

I had been engaged in detailed metabolic studies from the beginning but my efforts toward pathophysiological exploration received a major boost when Glenn Preminger joined me in 1983. “Why do you want to do a fellowship in my group?” I asked. “I want to combine medical-metabolic with urological approaches,” Glenn replied.

During the succeeding 12 years of association as a fellow and later as a faculty member in Peter's urology group, Preminger fulfilled his promise. He participated in pivotal metabolic studies, as described.

Pathophysiology of Hypocitraturia 

Hypocitraturia is due to or is associated with strenuous physical exercise, salt abuse,7 overindulgence in animal proteins (meat products), distal renal tubular acidosis,8 potassium deficiency9, 10 and chronic diarrhea.11 The common denominator is intracellular acidosis. The ensuing decrease in pH in proximal tubular cells alters the metabolism and reabsorption of citrate, resulting in hypocitraturia.

Pathophysiology of Hypercalciuria 

I have long held a view that hypercalciuria of urolithiasis is heterogeneous in origin (fig. 2). In absorptive hypercalciuria a primary enhancement of intestinal calcium absorption leads to hypercalciuria by increasing the renal filtered load of calcium. The suppressed parathyroid function contributes to hypercalciuria by inhibiting renal calcium reabsorption. In renal hypercalciuria, hypercalciuria ensues from a primary renal calcium leak. Intestinal calcium absorption is secondarily increased from the stimulated synthesis of 1,25-dihydroxyvitamin D (calcitriol or active vitamin D) from secondary hyperparathyroidism. Resorptive hypercalciuria is typified by primary hyperparathyroidism. Hypercalciuria is due to high bone resorption and a secondary increase in intestinal calcium absorption from stimulated calcitriol synthesis.

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  • Fig. 2. 

    Three forms of hypercalciuria. Absorptive hypercalciuria is believed to be due mainly to intestinal calcium hyperabsorption. Renal hypercalciuria results primarily from renal leak of calcium and secondarily from stimulation of 1,25-dihydroxyvitamin D (1,25-(OH)2D) synthesis. Resorptive hypercalciuria is characterized by primary hyperparathyroidism (PHPT).

The contribution of the urological community in this effort was considerable. Peters and his colleagues helped emphasize the diversity of hypercalciuria by recognizing hypercalciuric variants in our ambulatory medical evaluation of urolithiasis.4, 5 The evidence that absorptive hypercalciuria is familial was published in The Journal of Urology.12 Preminger and I provided evidence for the uniqueness of absorptive hypercalciuria by noting persistent hyperabsorption of calcium and eventual attenuation of the hypocalciuric response to thiazide treatment.13

Pathophysiology of Gouty Diathesis 

Gouty diathesis describes uric acid stone formation in the absence of secondary causes, such as chronic diarrheal states, strenuous physical exercise, dehydration and over ingestion of animal proteins. As the term implies, the principal disturbance for undue urinary acidity is believed to be or is associated with primary or secondary gout. Recent studies from our group have implicated gouty diathesis as a part of the metabolic syndrome of obesity and insulin resistance.14, 15

Figure 3 shows our group's working scheme for gouty diathesis. There may be an exaggerated acid load delivered to the kidneys from dietary acid excess or absorption and enhanced endogenous acid production in the liver and muscle, believed to be due to fat deposition and insulin resistance. In the kidneys fat infiltration and insulin resistance impair ammoniagenesis, decreasing ammonium (buffer) excretion. These extrarenal and intrarenal actions lead to unusually acid urine, in which uric acid is sparingly soluble. The growth of precipitated uric acid into a stone may depend on decreased inhibitor and increased promoter activity.

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  • Fig. 3. 

    Working scheme for gouty diathesis. Low urinary pH develops from excessive dietary and endogenous acid (H+ A−) load to kidneys, and from decreased renal synthesis of ammonia (NH4+ A−) and urinary excretion of ammonium (NH4+) due to renal fat infiltration and insulin resistance. Ensuing precipitation of uric acid may lead to formation of uric acid stones when there is inhibitor deficiency or promoter excess.

In The Journal of Urology in 1988 we presented our early description of gouty diathesis16 and in 1995 we reported the association of gouty diathesis with obesity, dyslipemia, hyperuricemia and gouty arthritis.17 In 2003 Preminger helped affirm this scheme by observing a high prevalence of uric acid stones and unusually acid urine in stone forming patients with type II diabetes.18

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Physicochemical Elucidation 

Brotherly Hand of Birdwell Finlayson 

Our work on the factors governing the crystallization of stone forming salts received a major impetus from the brotherly hand of Birdwell Finlayson. Finlayson and I shared common bonds since we had graduated from the University of Chicago, and he and my brother obtained a Ph.D. in biophysics at the same institution.

Finlayson and I were members of the NIH Committee on Research Needs in Urolithiasis in the late 1970s. The report of this committee led the NIH to begin a large funding program, Specialized Centers of Research in Urolithiasis. In 1977 we reported that activity products obtained by various computer programs overestimated the urinary saturation of calcium oxalate and brushite, and yielded widely varying results, while a semi-empirical approach based on the ratio of activity products before and after incubation with synthetic salts gave a saturation value that was independent of the computer programs used.19 In 1989 he collaborated with me on a nonstone research project to show that calcium citrate forms a soluble calcium citrate complex, rendering it more soluble and absorbable than calcium carbonate.20

Physicochemical Sequelae of Hypocitraturia 

In 1983 we reported in Urology® that hypocitraturia is common.21 Since citrate is a well-known inhibitor, hypocitraturia provides a setting for the facilitated crystallization of calcium oxalate and calcium phosphate (fig. 4). 1) The complexation of calcium by citrate20 is reduced in hypocitraturia, thereby increasing the amount of ionized calcium and, hence, the saturation of calcium salts.8, 11 2) The aggregation of preformed calcium oxalate crystals and spontaneous nucleation of calcium oxalate are exaggerated.22 3) To be reported in The Journal of Urology, the crystal growth of calcium phosphate (brushite) is facilitated in hypocitraturia.23

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  • Fig. 4. 

    Physicochemical effects of hypocitraturia. Hypocitraturia increases urinary saturation of calcium oxalate (CaOx) by impairing formation of calcium citrate complex (CaCit−). Hypocitraturia also promotes aggregation and nucleation of calcium oxalate, and crystal growth of calcium phosphate (CaP).

Other Physicochemical Studies 

Other physicochemical explorations were reported in urological journals or performed with collaborating urologists. In these efforts we pioneered semi-empirical methods for assessing the urinary saturation of calcium oxalate,19 brushite23 and cystine.24 In collaboration with Margaret Pearle we reported that urinary calcium is as important as urinary oxalate for determining the urinary saturation of calcium oxalate.25

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Dietary Aberrations 

Enrichment by Margaret Pearle 

Since Margaret Pearle arrived to replace Glenn Preminger at the UT Southwestern urology group, she has enriched the clinical stone research in Dallas, especially on the dietary role in stone formation. With her postdoctoral fellow Traxer et al she convincingly reported that vitamin C consumption enhances urinary oxalate excretion.26 With Matsumoto et al she reported that a high calcium diet imposed without a change in other mineral constituents increases the urinary saturation of calcium oxalate.27 In a detailed retrospective study she noted that a broad dietary modification with restricted intake of calcium, oxalate, sodium and animal proteins, and high fluid intake significantly decreases urinary calcium in patients with hypercalciuria but not in those with normocalciuria, without increasing urinary oxalate in either group.28 Through her work she emphasized that the so-called calcium-oxalate interaction (binding of oxalate by calcium in the bowel and complexation of oxalate by calcium in urine) depends on the dietary intake of calcium and oxalate, and on the state of intestinal calcium absorption.

Variable Metabolic Effects Among Fruit Juices 

Noteworthy is the work of Pearle with Gettman et al of the effect of cranberry juice on stone forming risk.29 Combined with studies by others from our group30, 31 the following scheme on the metabolic effects of fruit juices can be constructed.

Of potassium-poor fruit juices lemonade hardly alters urinary pH30 and cranberry juice slightly reduces it,29 probably from unidentified, nonmetabolizable organic anions (fig. 5, top). In contrast, potassium-rich orange juice substantially increases urinary pH.30, 31 Concurrently potassium-poor lemonade and cranberry juices exert a negligible effect on urinary citrate29, 30 despite their high citrate content but potassium-rich orange juice enhances urinary citrate excretion markedly (fig. 5, bottom).30, 31

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  • Fig. 5. 

    Change (Δ) in urinary pH and citrate produced by potassium-poor lemonade and cranberry juices, and by potassium-rich orange juice. Two bars for orange juice indicate 2 studies.

Citrus fruit juices vary considerably in their potassium content.32 Lemon and cranberry are virtually free of potassium. Apple and pineapple juices are moderate with a potassium content of about 30 mEq/l. Potassium-rich fruit juices comprise orange and grapefruit juices with a potassium content of about 50 and 40 mEq/l, respectively. Potassium is almost entirely absorbed from the bowel and it is excreted in urine unaltered, whereas absorbed citrate is almost completely oxidized in the liver. The unopposed potassium accounts for the alkali load. The citraturic action of fruit juices is largely due to the renal effects of alkali. Thus, the ability of fruit juices to enhance urinary pH and citrate depends almost entirely on their potassium content.

Dietary Sodium 

In The Journal of Urology my group reported that sodium load increases urinary calcium and decreases urinary citrate, probably by producing a mild metabolic acidosis from bicarbonaturia.7 In the same journal Preminger et al reported that potassium alkali reduces urinary calcium but sodium alkali does not,8 affirming the differing physiological effects of sodium and potassium cations. Thus, excess dietary sodium is a risk for stone formation.

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Diagnostic Separation 

Ambulatory Evaluation in 1980 

Our approach to the diagnostic separation of stone disease was empirical. From the preceding explorations we hypothesized that kidney stones develop from various metabolic and dietary disturbances rendering the physicochemical environment of urine conducive to the crystallization of stone forming salts. We then evaluated a large number of patients with stones as thoroughly as possible using all available tools. After data were acquired the patients were categorized into different medical causes according to predetermined criteria.

Our first report, coauthored with Peters, appeared in 1980 after evaluating 241 consecutive patients referred to us mostly by urologists in Dallas.5 Ten causes were identified (see Appendix). From the response to the fast and calcium load test hypercalciuria was separated into absorptive (types I and II based on severity), renal and resorptive (primary hyperparathyroidism) variants. We had begun to measure urinary uric acid routinely in the mid 1970s, stimulated by the report of the formation of calcium stones in patients with hyperuricosuria.33 Thus, hyperuricosuric calcium urolithiasis was listed as an entity. However, we had not obtained urinary citrate since the importance of hypocitraturia in stone formation was not fully appreciated. Therefore, we omitted hypocitraturia as an entity.

Ambulatory Evaluation 1988 

I reported an update on the results of our ambulatory evaluation in 1988 in The Journal of Urology6 based on my presentation at the 1987 annual meeting of the American Urological Association. Additional causes were recognized and some entities were regrouped, reflective of new tests and further progress in pathophysiology (see Appendix). Thus, hypercalciuria was further categorized into renal phosphate leak (absorptive hypercalciuria type III) and fasting hypercalciuria. Primary and dietary hyperoxaluria was added to hyperoxaluric calcium oxalate urolithiasis. A new entity, hypocitraturic calcium urolithiasis, was introduced, under which were included distal renal tubular acidosis, chronic diarrheal syndrome and idiopathic hypocitraturia. Gouty diathesis replaced uric acid stones and cystinuria was added as a cause.

This detailed classification required a comprehensive analysis of 24-hour urine samples on random and restricted diets for stone risk factors, serum for systematic multichannel analysis and PTH, and the fast and calcium load test.5, 6 Our group in Dallas still uses this protocol, believing that careful metabolic assessment would not only facilitate the selection of existing or experimental drugs, but also help elucidate the pathophysiology of stone formation and mechanism of drug action. I believe that a comprehensive evaluation should be adopted at specialized stone centers and it is indicated in patients with moderate-severe stone disease.

Simplified Classification 1996 

I soon realized that a comprehensive evaluation is difficult or impractical in a routine setting. Even when it can be performed, the limited availability of drugs does not allow a substantial improvement in treatment selection. Thus, in 1996 I collaborated with experts from the urological community, including Martin Resnick, Donald Griffith, Mani Menon and Glenn Preminger, to devise a simplified diagnostic protocol.34 In this approach designed especially for the private practice setting various causes of urolithiasis were determined primarily from the main urinary abnormalities, such as hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, low urinary pH, high urinary pH and cystinuria (see Appendix). It required 1 to 3, 24-hour urine samples collected on a random diet for stone risk factors. When desired, serum calcium and PTH were measured to differentiate subtypes of hypercalciuria.

Stone Risk Profile 

In 1985 we reported in The Journal of Urology a method for displaying the results of urinary composition from a 24-hour urine collection.35 Metabolic risk factors included calcium, oxalate, uric acid, citrate and pH. Environmental factors comprised total volume, sodium, sulfate, phosphorus and magnesium. Using the 2 groups of factors the urinary saturation of stone forming salts (calcium oxalate, brushite, monosodium urate, uric acid and struvite) was calculated as physicochemical factors. These measurements from a single urine collection are now offered at commercial clinical laboratories, facilitating the adoption of the mentioned simplified protocol.

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Tailor-Made Treatment 

Friendship and Unyielding Support of Martin Resnick 

As a strong advocate of medical prevention of stone disease, Martin Resnick offered me invaluable support and encouragement. During 3 decades of our close relationship he and I coauthored 10 publications, including a classic book on kidney stones.36 He was a key member of the urological community who joined me in developing a simplified approach for the medical management of stone disease.34 Along with Donald Griffith, Resnick willingly participated in the multicenter trial for potassium citrate as a co-investigator, although no financial support was available. He said, “I want what's good for my patients.”

Potassium Citrate 

The urological community had a vital role in our elucidation of the physiological and physicochemical action of potassium citrate. As an alkali, potassium citrate alkalizes urine and enhances citrate excretion, offering protection against uric acid and calcium containing stones, respectively. In The Journal of Urology we reported that potassium citrate not only averts hypokalemia, but also increases urinary citrate in patients with hypercalciuria maintained on thiazide.10 Preminger et al reported that potassium citrate is more effective than sodium citrate in the management of distal renal tubular acidosis due to the hypocalciuric action of potassium alkali.8 In 1985 the results of our long-term trial with potassium citrate were published in The Journal of Urology.11 Potassium citrate was shown to decrease the urinary saturation of calcium salts and virtually eliminate new stone formation in distal renal tubular acidosis, chronic diarrheal syndrome, gouty diathesis with uric acid stones alone or with calcium oxalate, stone relapse on other treatment and combined treatment with thiazide and/or allopurinol. In 1985 the FDA approved potassium citrate for stone prevention despite the absence of a randomized trial, citing the extensive supporting evidence in physiology and physicochemistry.

In 1993 the randomized trial was finally completed and its results were published in The Journal of Urology.37 Of patients with hypocitraturic calcium urolithiasis the fraction of those remaining free of stones during the 3 years of the trial was considerably higher among those on potassium citrate than on placebo (fig. 6). The relative risk was 0.25, indicative of a 75% decrease in the stone formation rate produced by treatment.

Thiola 

In 1982 I was asked by the FDA to organize a multicenter trial testing the efficacy of tiopronin for the management of cystine stones. A product of a Japanese company, tiopronin was believed to be safer than penicillamine. In 1986 we reported in The Journal of Urology the results of the multicenter trial, showing the safety and effectiveness of tiopronin for preventing cystine stones.24 The FDA approved tiopronin as an orphan drug in 1988.

A Potentially Useful, Simplified Approach to Management 

I have always pursued the notion that the safe and effective management of stone disease can best be delivered by a tailor-made treatment, in which drugs are selected to overcome underlying metabolic disturbances. While sound, the adoption of this approach is constrained by the need for a detailed evaluation and the limited number of available drugs. I would like to impart a new simplified approach, developed with the input of urological community, which may be worthy of consideration.

Dietary modification 

In 2005 Pearle helped me perform a retrospective analysis of data collected from 951 patients undergoing our ambulatory evaluation.28 This evaluation required 24-hour urine collections on random and restricted diets. By comparing urinary biochemistry between the 2 diets we were able to discern the effect on urinary stone risk factors of broad dietary modification (restricted intake of calcium to 400 mg a day, oxalate, sodium and animal proteins, and high fluid intake). Patients were separated into 3 groups according to their 24-hour urinary calcium on a random diet. Thus, urinary calcium was greater than 275 mg per day in moderate-severe hypercalciuria, 200 to 275 mg per day in mild hypercalciuria and less than 200 mg per day in normocalciuria. On the restricted diet urinary oxalate did not change in any group, indicating that a secondary increase in oxalate excretion can be prevented by dietary oxalate restriction.38 On dietary modification with restricted calcium intake urinary calcium and the saturation of calcium oxalate did not change in normocalciuria and they slightly decreased in mild hypercalciuria.28 However, dietary modification significantly and substantially reduced urinary calcium and the saturation of calcium oxalate in patients with moderate-severe hypercalciuria, of whom most had absorptive hypercalciuria. Thus, dietary calcium restriction has no value for normocalciuria and limited value for mild hypercalciuria but it may be useful in protecting against stone formation in moderate-severe hypercalciuria.

A nonrandomized trial with combined dietary modification and pharmacological intervention 

Despite its potential value for stone prevention dietary calcium restriction may cause or exaggerate bone loss. However, most stone forming patients with moderate-severe hypercalciuria require a hypocalciuric agent (thiazide or indapamide), often combined with potassium citrate. There is some evidence that hypocalciuric agents and potassium alkali directly confer protection against bone loss. In 2003 Pearle and I reported in The Journal of Urology that bone mineral density of the spine, femur and radius remains unchanged or slightly increases during long-term treatment with thiazide (or indapamide) and potassium citrate in patients with moderate-severe hypercalciuria kept on a low calcium diet (400 mg per day).39 Thus, I believe that calcium restriction does not pose a threat to bone loss in patients with hypercalciuria when treated with thiazide (or indapamide) and potassium citrate. We also reported in The Journal of Urology that potassium citrate alone with liberal calcium intake prevented spinal bone loss in patients with normocalciuria or mild hypercalciuria.40

A potentially useful, simplified approach 

Based on the preceding discussion I offer the following, potentially useful scheme as a simplified approach to the medical management of calcium urolithiasis. Separate moderate-severe hypercalciuria from mild hypercalciuria and normocalciuria using 24-hour urinary calcium obtained on a random diet. The simplified diagnostic protocol described permits this step. In the former group provide thiazide (or indapamide) with potassium citrate along with broad dietary modification (restricted intake of calcium, oxalate, sodium and animal proteins, and high fluid intake). In mild hypercalciuria or normocalciuria offer liberal calcium intake together with other dietary adjustments. In the presence of hypocitraturia or active stone disease consider providing potassium citrate. This scheme needs validation by a detailed metabolic assessment and prospective long-term followup.

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Conclusions 

During my 35 years of research in urolithiasis much progress has been made on the pathophysiology of stone formation, crystallization of stone forming salts, diagnostic separation and prevention of stone recurrence. In this effort I purposely sought the friendship and active input of the urological community, which has responded in kind.

Martin Resnick once told me, “You're an internist masquerading as a urologist.” I would have responded to him, “I am a urologist in heart and spirit, masquerading as a mineralogist.”

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Acknowledgments 

Special thanks to Orson Moe, Director of the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research at UT Southwestern.

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Appendix 

Appendix. Classification of Urolithiasis
198019881996
Absorptive hypercalciuria
Type ISameHypercalciuria
Type IISame
Renal hypercalciuriaSame
Primary hyperparathyroidismSameSame
Renal phosphate leak
Fasting hypercalciuria
Hyperuricosuric Ca urolithiasisSameHyperuricosuria
Enteric hyperoxaluriaHyperoxaluric Ca urolithiasisHyperoxaluria
Enteric
Primary
Dietary
Uric acid lithiasisGouty diathesisLow pH
Infection lithiasisSameHigh pH and NH4
Renal tubular acidosisHypocitraturic Ca urolithiasisHypocitraturia
Renal tubular acidosis
Chronic diarrhea
Idiopathic
CystinuriaSame
No metabolic abnormalitySameDietary disturbances

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References 

  1. Pak CYC. Physicochemical basis for the formation of renal stones of calcium phosphate origin: calculation of the degree of saturation of urine with respect to brushite. J Clin Invest. 1969;48:1914
  2. Pak CYC, Zisman E, Jowsey J, Delea C, Bartter FC. Treatment of osteoporosis with calcium infusion. Am J Med. 1969;47:7
  3. Pak CYC, East D, Sanzenbacher LJ, Delea CS, Bartter FC. Gastrointestinal calcium absorption in nephrolithiasis. J Clin Endocrinol Metab. 1972;35:261
  4. Pak CYC, Fetner C, Townsend J, Brinkley L, Northcutt C, Barilla DE, et al. Evaluation of calcium urolithiasis in ambulatory patients: comparison of results with those of inpatients evaluation. Am J Med. 1978;64:979
  5. Pak CYC, Britton F, Peterson R, Ward DL, Northcutt C, Breslau NA, et al. Ambulatory evaluation of nephrolithiasis: classification, clinical presentation and diagnostic criteria. Am J Med. 1980;69:19
  6. Pak CYC. Medical management of nephrolithiasis in Dallas: update. J Urol. 1988;140:461
  7. Sakhaee K, Harvey JA, Padalino PK, Whitson P, Pak CYC. Potential role of salt abuse on the risk for kidney stone formation. J Urol. 1991;150:310
  8. Preminger GM, Sakhaee K, Pak CYC. Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate. J Urol. 1988;139:240
  9. Pak CYC, Peterson R, Sakhaee K, Fuller CJ, Preminger GM, Reisch J. Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis. Am J Med. 1985;79:284
  10. Nicar MJ, Peterson R, Pak CYC. Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol. 1984;131:430
  11. Pak CYC, Fuller CJ, Sakhaee K, Preminger GM, Britton F. Long-term treatment of calcium nephrolithiasis with potassium citrate. J Urol. 1985;134:11
  12. Pak CYC, McGuire JL, Peterson R, Britton F, Harrod MJ. Familial absorptive hypercalciuria in a large kindred. J Urol. 1981;126:717
  13. Preminger GM, Pak CYC. Eventual attenuation of hypocalciuric response to hydrochlorothiazide in absorptive hypercalciuria. J Urol. 1987;137:1104
  14. Sakhaee K, Adams-Huet B, Moe OW, Pak CYC. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int. 2002;62:971
  15. Abate N, Chandalia M, Cabo-Chan AV, Moe OW, Sakhaee K. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004;65:386
  16. Harvey JA, Pak CYC. Gouty diathesis and sarcoidosis in a patient with recurrent calcium nephrolithiasis. J Urol. 1988;139:1287
  17. Khatchadourian J, Preminger GM, Whitson P, Adams-Huet B, Pak CYC. Clinical and biochemical presentation of gouty diathesis: comparison of uric acid versus pure calcium stone formation. J Urol. 1995;54:1665
  18. Pak CYC, Sakhaee K, Moe OW, Preminger GM, Poindexter J, Peterson R, et al. Biochemical profile on stone-forming patients with diabetes mellitus. Urology. 2003;61:523
  19. Pak CYC, Hayashi Y, Finlayson B, Chu S. Estimation of the state of saturation of brushite and calcium oxalate in urine: a comparison of three methods. J Lab Clin Med. 1977;89:891
  20. Pak CYC, Poindexter J, Finlayson B. A model system for assessing physicochemical factors affecting calcium absorbability from the intestinal tract. J Bone Miner Res. 1989;4:119
  21. Nicar MJ, Skurla C, Sakhaee K, Pak CYC. Low urinary citrate excretion in nephrolithiasis. Urology. 1983;21:8
  22. Nicar MJ, Hill K, Pak CYC. Inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro. J Bone Miner Res. 1987;2:215
  23. Pak CYC, Rodgers K, Poindexter JR and Sakhaee K: New methods for assessing crystal growth and saturation of brushite in whole urine: effect of pH, calcium and citrate. Unpublished data.
  24. Pak CYC, Fuller CJ, Sakhaee K, Zerwekh J, Adams BV. Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine. J Urol. 1986;136:1003
  25. Pak CYC, Adams-Huet B, Poindexter J, Pearle MS, Peterson R. Relative effect of urinary calcium and oxalate on saturation of calcium oxalate. Kidney Int. 2004;66:2032
  26. Traxer O, Huet B, Pak CYC, Pearle MS. Effect of ascorbic acid consumption on urinary stone risk factors. J Urol. 2003;170:397
  27. Matsumoto ED, Heller HJ, Adams-Huet B, Brinkley LJ, Pak CYC, Pearle MS. Effect of a high and low calcium diet on stone-forming risk during liberal oxalate intake. J Urol. 2006;176:132
  28. Pak CYC, Poindexter JR, Pearle M, Sakhaee K, Peterson RD. Effect of dietary modification on stone risk factors. Kidney Int. 2005;68:2264
  29. Gettman MT, Ogan K, Brinkley LJ, Adams-Huet B, Pak CYC, Pearle MS. Effect of cranberry juice consumption on urinary stone risk factors. J Urol. 2005;174:590
  30. Odvina CV. Comparative value of orange juice versus lemonade in reducing stone-forming risk. Clin J Am Soc Nephrol. 2006;1:1269
  31. Wabner CL, Pak CYC. Effect of orange juice consumption on urinary stone risk factors. J Urol. 1993;149:1405
  32. Pak CYC. General guidelines in medical evaluation. In:  Resnick MI,  Pak CYC editor. Urolithiasis: A Medical and Surgical Reference. Philadelphia: WB Saunders; 1990;p. 153–172
  33. Coe FL, Raisen L. Allopurinol treatment of uric-acid disorders in calcium stone formers. Lancet. 1973;1:129
  34. Pak CYC, Griffith DP, Menon M, Preminger GM, Resnick M. Urolithiasis. In:  Bone RC,  Glassock R editor. Current Practice of Medicine. 4:Philadelphia: Current Medicine; 1996;p. 13.3
  35. Pak CYC, Skurla C, Harvey JA. Graphic display of urinary risk factors for renal stone formation. J Urol. 1985;134:867
  36. Resnick MI, Pak CYC. Urolithiasis: A Medical and Surgical Reference. Philadelphia: WB Saunders; 1990;
  37. 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
  38. Pak CYC, Peterson R, Poindexter J. Adequacy of a single stone risk analysis in the medical evaluation of urolithiasis. J Urol. 2000;165:378
  39. Pak CYC, Heller H, Pearle MS, Odvina CV, Poindexter J, Peterson R. Prevention of stone formation and bone loss in absorptive hypercalciuria by combined dietary and pharmacological interventions. J Urol. 2003;169:465
  40. Pak CYC, Peterson R, Poindexter J. Prevention of spinal bone loss by potassium citrate in calcium urolithiasis. J Urol. 2001;168:31

 Supported by National Institutes of Health continuing research grant support since 1972 and Program Project Grant P01-DK20543.

PII: S0022-5347(08)01284-6

doi:10.1016/j.juro.2008.05.048

The Journal of Urology
Volume 180, Issue 3 , Pages 813-819, September 2008

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