Urine citrate and renal stone disease

Transcription

1 Curren t Review Urine citrate and renal stone disease Howard Goldberg, MD Linda Grass, BSc, RT(C) Rudolf Vogl, BSc, RT(C) Abraham Rapoport, MD, MA, FRCPC, FACP Dimitrios G. Oreopoulos, MD, PhD, FRCPC, FACP Calcium stone disease is attributable to supersaturation of the urine with calcium and other salts, the presence of substances that promote crystallization and a deficiency of inhibitors of crystallization. Citrate is a potent inhibitor of calcium oxalate and calcium phosphate stone formation whose excretion is diminished in some patients with stone disease owing to idiopathic causes or secondary factors such as bowel disease and use of thiazides. The ph within the proximal tubule cells is an important determinant of citrate excretion. Multivariate analysis has shown that the urine concentrations of calcium and citrate are the most important factors in stone formation. In uncontrolled studies potassium citrate, which increases urinary citrate excretion, appears to be promising as a therapeutic agent for patients with stone disease and hypocitraturia refractory to other treatment. On the other hand, there are potential drawbacks to sodium alkali therapy, such as the precipitation of calcium phosphates. La lithiase calcique se produit dans une urine sursaturee en sels calciques et autres, en presence de certains facteurs qui favorisent la cristallisation et en l'absence de certains autres qui l'inhibent. Ainsi l'excretion du citrate, puissant inhibiteur de la formation de calculs d'oxalate et de phosphate de calcium, est abaissee chez certains sujets lithiasiques du fait d'entites morbides, telles certaines enteropathies, ou par des facteurs secondaires comme la prise de thiazi- From the Division of Nephrology and the Metabolic-Renal LabQratory, Toronto Western Hospital Reprint requests to: Dr. Dimitrios G. Oreopoulos, Edith Cavell Wing, 7-044, Toronto Western Hospital, 399 Bathurst St., Toronto, Ont. M5T2S8 des. Le ph interne des cellules du tube contourne de premier ordre joue un role determinant dans cette excretion. L'analyse des variables multiples a montre que la calciurie et la citraturie sont les facteurs les plus importants quant a la formation de calculs. D'apres des essais non comparatifs, le traitement par le citrate de potassium, qui augmente la citraturie, semble prometteur chez les lithiasiques hypocitraturiques qui ont resiste k d'autres thdrapeutiques. Au contraire, l'usage de sels sodiques alcalins pourrait etre desavantageux, en favorisant par exemple la precipitation des phosphates calciques. enal calculi continue to challenge the clinician despite the introduction of several new drugs in the last two decades. Recently there has been a resurgence of interest in citrate as both a cause and a cure for renal stone disease. In this review we summarize current knowledge about the physiologic features of renal citrate excretion and discuss the pathophysiologic role of citrate in stone disease. We emphasize the formation of calcium stones rather than the less common types of stones: uric acid, struvite and cystine. Calcium stones can be traced to one of three abnormalities: supersaturation of the urine with calcium salts, the presence of factors that promote crystallization and deficiency of inhibitors of crystallization.' The urine of stone formers tends to contain more calcium salts (oxalate and phosphate) than that of people who do not form stones, but in both groups the urine is supersaturated with these salts (i.e., the concentration of the salts exceeds their solubility in simple solutions).2 Since these two groups show much overlap in the excretion of calcium salts, supersaturation alone cannot fully explain stone disease.' Thus have evolved the concepts of promoters and inhibitors of crystallization. Promoters, which act CMAJ, VOL. 141, AUGUST 1,

2 as nuclei on which calcium crystals can grow, include uromucoids, uric acid, sodium urate and calcium phosphate.3 Inhibitors prevent crystal growth and aggregation by coating the surface of the growing calcium crystals4 without changing the concentration of calcium oxalate or phosphate. Over the years many methods have been used to assess inhibitory activity, and the results have varied widely. Citrate and glycoproteins of large molecular weight5 have received the most emphasis in recent years. Urine citrate levels and stone formation Over the last 20 years most workers have reported that urinary citrate excretion is reduced in those who form calcium stones as compared with those who do not,6-16 but this distinction is not absolute because of the wide range of normal values and the overlap between the two groups. The early concept that low urinary citrate excretion was associated mainly with renal failure or urinary tract infection has been abandoned.8 Hosking and colleagues16 reported mean urine citrate levels of 2.8 mmol/d in 83 subjects who did not form stones and 1.2 mmol/d in 130 subjects who did; renal failure did not account for the difference. In five other series 15% to 75% (average 30%) of stone formers had citrate excretion values below normal.9-12'15 However, there is no specific correlation between hypocitraturia and the rate of stone formation.16 Several (but not all) groups have reported that citrate excretion is greater in females than in males.7'8'14'15 In contrast, Robertson, Peacock and Nordin6 found no difference in citrate excretion between stone formers and subjects who did not form stones and were matched for age and sex, and Hosking and colleagues16 noted that low citrate excretion occurred mainly in elderly patients with renal stones, whose citrate excretion did not increase with age, as it did in the general population. Schwille and associates1" found statistically significant hypocitraturia only in certain subsets of stone formers (those with normal calcium excretion or elevated uric acid excretion), which emphasizes the lack of uniformity in various investigations of urinary citrate excretion. A review of 176 patient charts in our renal stone dinic showed that 22 patients (12%) had persistently low citrate excretion (less than 1.6 mmol/d) for reasons that were not clear (unpublished observations, 1988). Eight other patients had low citrate excretion concomitant with bowel disease, and one patient had hypocitraturia associated with renal disease. The low citrate levels could not be attributed to urinary tract infection. The patients in our clinic who have very low citrate excretion usually have normal calcium excretion. We have not used oral citrate therapy in these patients long enough to judge its efficacy. In summary, it is hard to make the case that, by itself, low urinary citrate excretion is a decisive 218 CMAJ, VOL. 141, AUGUST 1, 1989 risk factor for renal stone disease in the general population of stone formers, although it may be important in a subgroup of patients who have very low citrate excretion. One cannot assess citrate as a determinant of stone formation in isolation; other risk factors, such as urinary excretion of calcium, oxalate and urate, must be considered. Recently Parks and Coe"5 used multivariate analysis to determine which of these risk factors best separates subjects who form or do not form stones and concluded that the two main independent risk factors were urinary excretion of citrate and calcium. Using equations obtained from this analysis they quantitated their results in terms of a single value, a "diagnostic index" that sums up the contribution of urinary calcium and citrate excretion to the risk of stone disease. Both male and female stone formers had diagnostic indices that were significantly higher than normal values. We obtained a similar separation brtween subjects who form or do not form stones using the simple ratio of urine calcium concentration to urine citrate concentration (unpublished observations, 1988). Physiologic features of citrate excretion Important causes of low urinary citrate excretion associated with renal stone disease include use of acetazolamide,"7 use of thiazides,18 renal tubular acidosis,12 urinary tract infection,8 hypokalemia associated with potassium depletion,812 magnesium depletion,19 bowel disease20 and idiopathic causes.10 These causes can be understood better against the background of the physiologic features of citrate excretion. Citric acid is a tricarboxylic acid whose carboxyl groups have pk values of 3.1, 4.8 and 6.4. At physiologic blood ph (7.4) it exists largely as the salt citrate3.21 In this form it circulates, unbound to protein, and filters freely through the glomerulus. Although we consume Lrulus Fig. 1 - Handling of citrate by tubule. Mitochondria To urine hypothetical renal

3 about 4 g of citric acid per day in our diets, most of the circulating citrate is derived endogenously from oxidative metabolism.10 Fig. 1 shows the renal handling of citrate. The proximal tubule reabsorbs approximately 75% of filtered citrate and thus is the primary determinant of final urinary citrate excretion.2122 Tubule citrate concentrations never exceed resorptive capacity. As well, secretion of citrate from the peritubular capillaries by the proximal tubule is a minor process. Citrate excretion is known to decrease with metabolic acidosis and increase with metabolic alkalosis.22 Oral administration of alkali increases citrate excretion.22 Renal tubular acidosis is associated with profoundly low citrate excretion.12 One explanation of these observations is that metabolic alkalosis produces intracellular alkalosis in the proximal tubule, which leads to decreased mitochondrial citrate uptake, with subsequent intracellular citrate accumulation and therefore reduced citrate uptake by the tubule cells.21 It has also been proposed that the increased intraluminal ph accompanying metabolic alkalosis increases the amount of citrate3- relative to citrate2-. Since the proximal tubule transports citrate2- rather than citrate3- it would take up less citrate in metabolic alkalosis. Thus, oral administration of alkali increases citrate excretion.23 Hypokalemia is thought to produce hypocitraturia by inducing intracellular acidosis.12,22 Thiazides diminish citrate excretion by causing potassium depletion,18 and thus such hypocitraturia is abrogated by potassium supplementation. Diminished renal function results in lower filtration of citrate as well as acidosis;24 both decrease citrate excretion. In urinary tract infection urine citrate values are low because the bacteria metabolize citrate after the urine sample is taken.8'24 The low urine citrate values with magnesium depletion remain unexplained. Hypocitraturia related to bowel disease,2025 particularly inflammatory bowel disease,19'23 can be attributed to potassium and magnesium depletion, acidosis related to stool bicarbonate losses and, possibly, citrate malabsorption, although there is dispute about the last factor.25 Low urine volumes and hyperoxaluria also contribute to stone formation in bowel disease.25 The mechanism behind the reduced citrate excretion in stone formers who show none of these features most likely is increased renal citrate reabsorption,10' 1'26 but the reason for this increased reabsorption is unclear. It has been suggested that some people with low urinary citrate excretion may be consuming too much meat, which has a high acid content27 and theoretically would lead to a subtle decrease in the ph within the proximal tubule cells and reduced citrate excretion. Two groups of investigators have observed stone formers who have low 24-hour urinary citrate excretion with their regular diets and normal citrate excretion after an overnight fast; this implicated a dietary cause for hypocitraturia.1126 Further investigation is needed to determine whether differences in diet can alter acid-base status enough to produce differences in citrate excretion. Citrate in the prevention of stone formation How does citrate prevent stone formation? Its most clearly established effect is to complex urine calcium, thereby directly decreasing the saturation of calcium oxalate.28 Citrate also is an inhibitor of crystallization. Many different methods have been used to measure inhibitor activity, which makes it difficult to compare studies. The usual method is the formation of a solution supersaturated with calcium oxalate or calcium phosphate; calcium oxalate seed crystals are added, and the rate of crystal formation is monitored. Generally it is agreed that compounds of larger molecular weight, such as acidic glycoproteins,1 are the principal inhibitors of calcium oxalate stone formation. However, a few studies have suggested that citrate is also such an inhibitor For example, Pak and Fuller28 showed that citrate increases the "permissible increment" of oxalate, the amount of oxalate that can be added to whole urine before spontaneous precipitation occurs. Kok, Papapoulos and Bijvoet29 did a sophisticated kinetic analysis of crystallization and assessed the rates of crystal growth and aggregation (agglomeration) independently. They described seven stone formers whose sole metabolic abnormality was low urinary citrate excretion accompanied by an abnormally high rate of crystal agglomeration. Replacement of citrate restored agglomeration to normal. In addition, citrate is an important inhibitor of calcium phosphate stone formation.33 The disadvantage of administering citrate in any form of alkali is an increase in the saturation of calcium phosphate. Increased urine ph shifts the equilibrium between HP042- and H2PO4r in favour of the former, thereby tending to precipitate out the less soluble brushite (CaHPO4-2H20).28 For this reason many physicians have been reluctant to use alkali therapy, although the disadvantage is offset, at least in part, by citrate's power to inhibit calcium phosphate crystallization. Pak and coworkers34 studied the clinical effects of orally administered citrate. Since citrate is rapidly metabolized to bicarbonate, the net effect of an oral dose is to provide an alkali load, which increases citrate excretion by decreasing proximal tubule reabsorption.23 Usually oral citrate, 60 (range 30 to 110) mmol (meq)/d, normalizes urinary citrate excretion in patients with hypocitraturia.34 In Canada a popular source of potassium citrate is K-Lyte (Bristol Laboratories of Canada, Ottawa), sold as a 25-mmol effervescent tablet that is dissolved in water before use. It is difficult to secure compliance, because this medication should be ingested two to three times per day, and this dosage may cause gastrointestinal upset, nausea, vomiting or diarrhea. Administration with meals should minimize these side effects. In the United CMAJ, VOL. 141, AUGUST 1,

4 States a slow-release preparation is available that is better tolerated and is required only twice a day; however, the patient must consume a large number of 5-mmol tablets daily. One should seek a urine ph of 6 to 7, because, for reasons noted earlier, excessive alkalinization promotes calcium phosphate stone formation. Oral administration of potassium citrate is contraindicated in hyperkalemia, renal failure, urinary tract infection, the presence of struvite stones and upper gastrointestinal tract disease such as ulcer, gastritis and impaired gastric emptying.35 Does potassium citrate, which is difficult to administer, have any advantage over sodium citrate or sodium bicarbonate, both of which increase urine citrate levels? Theoretically one should avoid sodium alkali salts because renal sodium excretion tends to promote urinary calcium excretion, whereas potassium citrate does not.36 Sodium urate resulting from sodium citrate administration may act as a nucleus for calcium stones3 ("heterogeneous nuclei") and can adsorb macromolecular inhibitory factors, although its precise role in vivo has not been established. Pak, Sakhaee and Fuller37 described five patients whose course during treatment with sodium alkali for uric acid stones was complicated by calcium stone formation. This complication dramatically resolved when potassium citrate was substituted. The report is interesting, but it does not make clear whether compliance and urine ph control were the same before and after citrate therapy. Potassium citrate may be particularly advantageous to patients receiving thiazides, who tend to have potassium depletion as a consequence of therapy with this diuretic. There has been no large prospective controlled study of citrate therapy. In uncontrolled studies in patients with hypocitraturia, calcium stone formers unresponsive to thiazides, stone formers with hyperuricosuria and stone formers with renal tubular acidosis Pak and collaborators showed that citrate treatment drastically reduced the rate of stone formation compared with previous rates in the patients and rates that one might expect in those treated with fluid and diet only.18'28'38'39 For example, they treated 37 patients with recurrent calcium stone formation and hypocitraturia (citrate excretion less than 1.7 mmol/d) with potassium citrate for an average of 2.1 years; during this time the rate of stone formation fell from 2.11 to 0.28 stones per patient per year.28 Urinary citrate excretion increased from 1.2 to 3.2 mmol/d, with only minor side effects. There are several possible criticisms of these impressive results; foremost is the lack of a control group.40 Any group of stone formers (when they are having frequent stones) will show a recurrence rate of only 20% to 30% if they increase their fluid intake and decrease their dietary calcium, oxalate and sodium.41 These phenomena, dubbed the "stone clinic effect",42 probably reflect a combination of the effect of conservative treatment and the tendency for physicians to first see stone formers when the disease is most active. Nevertheless, Pak43 argues that the improvement in his patients is greater than can be explained by the stone clinic effect; he notes that in 10 patients a brief attempt to stop citrate therapy led to a rapid relapse. Generally in these patients follow-up has been relatively short, approximately 2 years. In patients treated with diet modification and fluid, new stones tend to appear only after 3 years.44 Thus, citrate administration may be found to be less effective with longer follow-up. Assessment is further confused by concomitant therapy with thiazides or allopurinol in a large number of patients. The patients of Pak and collaborators seem to differ from the usual clinic patient: they had exceptionally active stone disease (2.1 stones per year v. the more usual 0.4 to 0.6 stones per year),43 and in general they seem to have had a high prevalence of hypocitraturia (55%). All these considerations make caution necessary before citrate therapy is adopted as standard treatment for calcium stone disease. At present we use orally administered potassium citrate (in the form of K-Lyte) in patients with recurrent stone formation and hypocitraturia refractory to other treatments (hydrochlorothiazide or allopurinol) or in patients who have hydrochlorothiazide-induced hypokalemia. Conclusions A great deal has been learned about the rate of urinary citrate excretion in renal stone disease, but more studies are needed to confirm its purported beneficial effects when administered orally. Thus, citrate has not become a first-line therapy for stone disease but may be considered for patients with hypocitraturia refractory to standard therapy, especially if they are receiving thiazides. Citrate excretion, when it is considered relative to calcium excretion, seems to be an important risk factor for renal stone disease. References 1. Coe FL, Favus MJ: Disorders of stone formation. In Brenner BM, Rector FC (eds): The Kidney, Saunders, Philadelphia, 1986: Weber D, Coe FL, Parks JH et al: Urinary saturation measurements in calcium nephrolithiasis. Ann Intern Med 1979; 90: Coe FL: Uric acid and calcium oxalate nephrolithiasis. Kidney Int 1983; 24: Nancellas GM: The kinetics of crystal growth and renal stone formation. In Fleisch M, Robertson WG, Smith LM (eds): Urolithiasis Research, Plenum Pub, New York, 1976: Zerwekh JE, Hwang TIS, Poindexter J et al: Modulation by calcium of the inhibitor activity of naturally occurring urinary inhibitors. Kidney Int 1988; 33: Robertson WG, Peacock M, Nordin BEC: Activity products in stone forming and non-stone forming urine. Clin Sci 1986; 34: CMAJ, VOL. 141, AUGUST 1, 1989

5 7. Elliot JS, Rebeiro ME: The urinary excretion of citric, hippuric, and lactic acid in normal adults and in patients with calcium oxalate urinary calculus disease. Invest Urol 1972; 10: Welshman SG, McGeom MG: Urinary citrate excretion in stone formers and normal controls. BrJ Urol 1978; 48: Pypchuk G, Ehrig U, Wilson DR: Idiopathic calcium nephrolithiasis: 1. Differences in urine crystalloids, urine saturation and brushite and urine inhibitors of calcification between persons with and persons without recurrent kidney stone formation. Can Med Assocj 1979; 120: Rudman D, Kutner MH, Redd SC et al: Hypocitraturia in calcium nephrolithiasis. J Clin Endocrinol Metab 1982; 55: Schwille PO, Scholz D, Schwille K et al: Citrate in urine and serum and associated variables in subgroups of urolithiasis. Nephron 1982; 31: Nicar MJ, Skuria C, Sakhaee K et al: Low urinary citrate excretion in nephrolithiasis. Urology 1983; 21: Menon M, Mahle CJ: Urinary citrate excretion in patients with renal calculi. J Urol 1983; 129: Tiselius HG: Urinary excretions of citrate in normal subjects and patients with urolithiasis. In Smith LH, Robertson WG, Finlayson B et al (eds): Urolithiasis: Clinical and Basic Research, Plenum Pub, New York, 1980: Parks JH, Coe FL: A urinary calcium-citrate index for the evaluation of nephrolithiasis. Kidney Int 1986; 30: Hosking DH, Wilson JWL, Liedtke RR et al: Urinary citrate excretion in normal persons and patients with idiopathic calcium urolithiasis. I Lab Clin Med 1983; 106: Parfitt AM: Acetazolamide and sodium bicarbonate induced nephrocalcinosis and nephrolithiasis. Arch Intern Med 1969; 124: Nicar MJ, Peterson R, Pak CYC: Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol 1984; 131: Adler S: Urinary excretion of citrate - influence of metabolism and acid base condition. In Schwille PO, Smith LH, Robertson WG et al (eds): Urolithiasis and Related Clinical Research, Plenum Pub, New York, 1985: Rudman D, Dedonis JL, Fountain MT et al: Hypocitraturia in patients with gastrointestinal malabsorption. N Engl J Med 1986; 303: Deetjen P: The renal handling of citrate. In Schwille PO, Smith LH, Robertson WG et al (eds): Urolithiasis and Related Clinical Research, Plenum Pub, New York, 1985: Simpson DP: Citrate excretion: a window of renal metabolism. AmJPhysiol 1983; 244: F223-F Butz M, Dulce HJ: Enhancement of urinary citrate in oxalate stone formers by the intake of alkaline salts. In Smith LH, Robertson WG, Finlayson B et al (eds): Urolithiasis: Clinical and Basic Research, Plenum Pub, New York, 1980: Modgkinsen A: Citric excretion in normal adults and patients with renal calculi. Clin Sci 1962; 23: Dobbins JW: Nephrolithiasis associated with intestinal disease. In Schwille PO, Smith LH, Robertson WG et al (eds): Urolithiasis and Related Clinical Research, Plenum Pub, New York, 1985: Uribarri J, Oh MS: Hypocitraturia in renal stone formers [abstrj. Kidney Int 1986; 29: Gamble W, Orten JM, Smith AH: Citric acid cycle in certain alterations of acid-base balance in human subjects. J Appl Physiol 1961; 16: Pak CYC, Fuller C: Idiopathic hypocitraturic calcium-oxalate nephrolithiasis successfully treated with potassium citrate. Ann Intern Med 1986; 104: Kok DJ, Papapoulos SE, Bijvoet OLM: Excessive crystal agglomeration with low citrate excretion in recurrent stone formers. Lancet 1986; 1: Hallson PC, Rose GA, Sulaiman S: Raising urinary citrate lowers calcium oxalate and calcium phosphate crystal formation in whole urine. Urol Int 1983; 38: Ryall RL, Hibberd CM, Marshall VR: A method for studying inhibitory activity in whole urine. Urol Res 1985; 13: Meyer JL, Thomas WC: Trace metal citric acid complexes as inhibitors of calcification and crystal growth. J Urol 1982; 128: Biasz S, Felix R, Newman WF et al: Quantitative determination of inhibitors of calcium phosphate precipitation in whole urine. Miner Electrolyte Metab 1978; 1: Pak CYC, Skurla C, Brinkley L et al: Augmentation of renal citrate excretion by oral potassium citrate administration: time course, dose frequency schedule, and dose response relationship. J Clin Pharmacol 1984; 24: Potassium citrate tablets for nephrolithiasis. Med Lett Drugs Ther 1986; 28: Sakhaee K, Nicar M, Hill K et al: Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone forming salts. Kidney Int 1983; 24: Pak CYC, Sakhaee K, Fuller C: Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 1986; 30: Pak CYC, Peterson R: Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Arch Intern Med 1986; 146: Preminger GM, Sakhaee K, Skurla C et al: Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985; 134: Park GD, Spector R: Hypocitraturic calcium oxalate nephrolithiasis [C]. Ann Intern Med 1986; 104: Ettinger B, Tang A, Citron JT et al: Randomized trial of allopurinol in prevention of calcium oxalate calculi. N Engl JMed 1986; 315: Hosking DH, Erickson SB, Van Den Berg CJ et al: The stone clinic effect in patients with idiopathic calcium urolithiasis. I Urol 1983; 130: Pak CYC: Hypocitraturic calcium-oxalate nephrolithiasis [C]. Ann Intern Med 1986; 104: Coe FL: Clinic stone disease. In Coe FL, Brenner BM, Stein JH (eds): Contemporary Issues in Nephrology, vol 6: Nephrolithiasis, Churchill, New York, 1980: 1-12 The mind A mysterious form of matter secreted by the brain. Its chief activity consists in the endeavor to ascertain its own nature, the futility of the attempt being due to the fact that it has nothing but itself to know itself with. - Ambrose Bierce ( ?) CMAJ, VOL. 141, AUGUST 1,