Uric acid nephrolithiasis

Uric Acid Nephrolithiasis* ALEXANDER

B. GUTMAN, M.D. nnd TS’AI-FAN New

U

York, New

(2,6,%trioxypurine) represents the intact purine structure in its most fully oxidized state and is the major end product of purine metabolism in man. Other than serving as a spent nitrogen metabolite, uric acid has no physiologic function. Its chief characteristic is its sparing solubility in water and body fluids which, as will be explained, is a virtue in some animals but a vice in man. The quantity of uric acid formed and eliminated depends in part on the amount of preformed purines ingested in the diet but chiefly on the rate of de nouo purine biosynthesis. This involves a stepwise sequence of complex enzymatic reactions [ 71 in the course of which glutamine amide nitrogen is utilized to contribute N-9 and N-3 of the purine ring (Fig. l), glycine to form C-4, C-5 and N-7, aspartate amino nitrogen contributes N-l, the beta-carbon of serine is utilized by way of intermediates to form C-2 and C-8, and C-6 is derived from bicarbonate. The over-all reaction of the sequence may be written :

M.D.

York

gen as uric acid. In the uricotelic reptiles and birds this is the major pathway of waste nitrogen elimination, and an advantageous one because the insolubility of uric acid makes disposal of waste nitrogen possible with minimal loss of water and electrolytes; the uric acid is discharged as a semisolid mass by way of a cloaca so capacious that there is no hazard of obstruction. In ureotelic mammals this role of de novo purine biosynthesis in maintaining “nitrogen balance” is of lesser importance but still significant. In most mammals such urate as is formed and filtered at the glomerulus is promptly reabsorbed in the proximal convolution to be recycled to the liver for conversion by hepatic uricase to freely water-soluble allantoin. The allantoin then readily passes through the slender, long conduits of the kidney and urinary tract, which are admirably designed for conservation of water and electrolytes in ureotelic mammals but not for elimination of difficultly soluble compounds in quantities that may form occlusive deposits. Further details of the evolutionary role of uric acid as waste nitrogen are given elsewhere [3]. By a quirk of evolutionary development man is, of all ureotelic creatures (with the possible

RIG ACID

2NH4+

Yti,

+ 2HCOO+ HCOI+ glycine + aspartate + ribose-5-phosphate + inosinic acid + fumaric acid + 9HzO

The first purine to be elaborated is thus inosinic acid, which is then enzymatically converted to a variety of biologically vital purine nucleotides, which in turn are ultimately catabolized to uric acid. The surplus inosinic acid formed but not so utilized appears to be shunted off for more direct degradation to uric acid by way of hypoxanthine and xanthine. These various enzymatic reactions were recently reviewed by Wyngaarden [Z]. De novo biosynthesis of purines from amino acids serves not only to furnish necessary purine nucleotides but also as a means of maintaining “nitrogen balance” by eliminating waste nitro-

1;1-

,;<

Asporlic

aad+

NH

I

,,~lyclne

5c

r/

Formole

eco I

II

FIG. 1. Uric acid, indicating numbering of purine ring and source of each atom in de nouo purine biosynthesis.

* From the Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029. This work was supported in part by grant-in-aid A-162, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health.

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Uric

Acid

Nephrolithiasis-Gutman, TABLE

PER

CENT

I nvvstigator

URIC

Year,

ACID

1926, 1947, 1952, 1955,

New York Boston area St. Louis Winston-Salem

Melick, Henneman Hughes et al. [72] Nicholas [ 131 Leonard [ 141

1958, 1960, 1961, 1961,

Boston Durham Houston Pensacola

I

OF ALL

Place

Beer 1; P&n, Frondel [X] Carroll, Brennan 19. Boyce Ct al. [ 701 [ 7 71

STONES

STONES

10 (loyo) 7.6y0, of which

207 287 2,500 772

1963, Boston area and all over U.S.A. 1965, Chicago

24,000

* The Dalmatian coach hound likewise is predisposed to uric acid urolithiasis because of a genetic mutation, but of different nature. Uricase is present in the liver, indeed in normal quantity, but uric acid nevertheless is converted to allantoin incompletely and very sluggishly [4]. This impaired degradation of uric acid, together with the well known defect in tubular reabsorption of filtered urate, combine to cause hyperuricosuria. VOL.

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Prr Cent, Uric .Jcid Stones

100 500

Prien

exception of the Dalmatian coach hound*), the most vulnerable to uric acid urolithiasis. This is because of a genetic mutation that took place at some point before the branching off of the anthropoids and resulted in disappearance of uricase from human tissues. As a consequence of loss of the main pathway of degradation of uric acid the levels of uric acid in the plasma and urine of normal man, an omnivore, are some tenfold or more those in most other mammals, normally occurring in such high concentrations that uric acid is held only precariously in solution. The stage is thus set for the formation of uric acid precipitates when superimposed abnormalities further jeopardize maintenance of uric acid in solution. The surprising thing is not that uric acid urolithiasis occasionally occurs in man but that it does not happen more often. Uric acid may precipitate out of the urine in nonaggregates varying in quantity from crystalluria demonstrable only microscopically in the centrifuged sediment to massive deposits of crystals sufficient to clog the ureters and cause acute obstructive nephropathy. Small aggregates of uric acid crystals may appear as a recurrent discharge of brownish or reddish microliths designated sand or gravel according to

i

‘l.\bout 10%” 37(6.1%), of which 30 “pure.”

10,000

Fried [ 771

(lJ.S.4.

136 600

1962, stones from all over U.S.A.

Vermeulen,

EXAMINED

Total No. Stones Examined

HerrinK [ 751

r 161

7.57

Yii

300

7 “tnixed”

3.47, “pure,” 4.2”; “mixed” 20 (9.7%) 5 (1.8%) 89 (3.6%) 33 (4.3%) of which 12 contained oxalate, 3 had phosphate 944 (9.4%) of which 740 were relatively “pure” uric acid About 8%, of which 18% contained oxalate 17.2% “uric acid type”

fineness or coarseness. “Pure” uric acid stones originating in the upper urinary tract ordinarily smooth, rounded and are relatively small, colored pale yellow to deep brown, brownish red or reddish black. On section they are usually found to be laminated, an indication of oriented crystal overgrowth. They are composed of anhydrous free uric acid, sometimes with uric acid dihydrate in varying proportions, the color being imparted by urochromes of uncertain Characteristically radiolucent, some nature. uric acid calculi may contain enough admixture of calcium salts to cast a shadow. Larger uric acid stones of the upper urinary tract, which sometimes reach the size of typical staghorn calculi, are usually of mixed composition, containing free uric acid layered with deposits of oxalates and/or phosphates, the latter marking periods of heavy urinary tract infection or overzealous administration of alkali. Good descriptions of the physical properties (among other aspects) of “pure” and “mixed” uric acid stones will be found in the comprehensive monograph by Atsmon, de Vries and Frank [3]. A very readable account of the results of recent x-ray diffraction studies is given by Lonsdale [S]. PREVALENCE

In most parts of the world stones composed chiefly of uric acid constitute only a small fraction of the calculi occurring in the upper urinary tract of the population at large [5,6]. In the U.S.A. the estimates usually given approximate 10 per cent of all stones found (Table I), with a

Uric Acid Nephrolithiasis-Gutman,

758

, , 4.0 4.4 48

, , .

. ,

5.2 5.6 6.0 6.4 6.8 7.2 75 PH

,] 8.0

FIG. 2. Dissociation of uric acid in relation to pH, calculated from the Henderson-Hasselbalch equation and a pKa of 5.75 for uric acid.

lower proportion in the “stone belts” of some southern states [12-141 and a higher incidence (17.2 per cent of “uric acid type”) reported from Chicago [77]. In Toronto, Rapoport et al. [ 781 found about 15 per cent of an unstated number of kidney stones to be composed of uric acid. Albuquerque et al. [79], reporting their experience in Rio de Janeiro, noted uric acid stones in forty-nine of 275 of their more recent cases of urolithiasis (17.8 per cent) ; they also record the results of analysis of 542 calculi, of which 11.1 per cent were made up of “pure” uric acid, 3.8 per cent of uric acid and calcium oxalate, 1.0 per cent of calcium phosphate and uric acid, and 0.3 per cent of uric acid and triple phosphates. From Australia, Wardlaw [ZO] reported that eleven of 196 upper urinary tract stones (5.6 per cent) were composed of “urate.” In Great Britain and most other European countries from which data have been recorded the relative proportion of uric acid stones originating in the upper urinary tract is some 5 per cent [5,6], but figures of 13 per cent are cited for Germany [27], 14.8 per cent for Czechoslovakia [zz], and in France Cottet and Weber [23] recorded 23.3 per cent of uric acid calculi in 179 cases of urolithiasis. The highest ratios come from Israel, where de Vries and his associates [5] found uric acid stones in 39.5 per cent of 544 patients with urolithiasis. The prevalence of uric acid nephrolithiasis in the population of the U.S.A. at large is estimated to be of the order of 0.01 per cent, based on a survey of admissions to general hospitals

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by Boyce et al. [24] who found that a diagnosis of urinary calculus was made in 9.47 persons per 10,000 population, and on the assumption that about 10 per cent of these calculi were composed of uric acid. In certain segments of the population, however, uric acid nephrolithiasis is far more prevalent. For example, in primary gout 10 to 25 per cent of patients give a history of stone, gravel or sand, ordinarily composed of uric acid. In our series of 1,394 patients with primary gout, 305 (22 per cent) had passed concrements of various sizes; analysis of 120 of these revealed 100 of them (84 per cent) to be made up of uric acid, five of uric acid and oxalate (4 per cent), ten of calcium oxalate and five of calcium phosphate [25]. In myeloproliferative and neoplastic disorders, notably after vigorous cytolytic therapy, the prevalence of uric acid precipitates in the urinary tract also is strikingly high [26,27]. In earlier times lower urinary tract stones composed of ammonium acid urate, uric acid and oxalate were common, notably in juveniles. Such bladder stones are still prevalent in certain areas of Thailand, Turkey and India, but for obscure reasons they have since virtually disappeared elsewhere in both the nongouty and gouty populations [6]. PATHOGENESIS

According to Bergmann and Dikstein [28] ionization at N-9 (Fig. 1) accounts for the weakly acidic properties of uric acid, which has a pKal of 5.75; that is, in solution at pH 5.75 uric acid is half ionized, half unionized. At the alkaline pH of the plasma, uric acid is virtually completely dissociated whereas in distinctly acid urine it is very largely undissociated (Fig. 2): at pH 5.4, 69 per cent is undissociated free acid; at pH 5.2, 78 per cent; at pH 5.0, 85 per cent; at pH 4.75, 91 per cent. Thus with a urinary excretion of 500 mg. of uric acid per day the quantity of free uric acid to be passed would be about 425 mg. per day at urine pH 5.0 whereas it would be only 180 mg. per day at pH 6.0. When there is hyperuricosuria with a urinary uric acid excretion of 1,000 mg. per day, the free uric acid would constitute 850 mg. per day at pH 5.0 and only 360 mg. per day at pH 6.0, the latter figure actually less than the free uric acid in urine containing 500 mg. per day when the urine pH is 5.0. There is a corresponding effect of urine pH on the concentration of AMERICAN

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Uric Acid Nephrolithiasis--C~u/mn. free uric acid in the urine when the urine volume is reduced. The significance of these figures for uric acid stot~e formation lies in the circumstance that free uric acid is more sparingly soluble than its to the estimates of sodiurtr salt. According Peters and Van Slyke [29], with which subsequent studies substantially agree, the free uric acid concentration in a saturated solution of uric acid in urine would be about 60 mg. per L. at pH 5.0 and 37”c., about 220 mg. per L. at pH 6.0, and some 1,580 mg. per L. at pH 7.0. Since the urine of normal men contains, on the average, some 400 mg. of uric acid per L. (calculated on the basis of a mean twenty-four hour urinary uric acid output of 600 mg. in 1.5 L. on an ordinary American diet), the urine must be supersaturated with respect to uric acid in periods. In many persons over appreciable considering the pathogenesis of uric acid nephrolithiasis one should therefore examine the factors that lead to supersaturation of the urine with respect to undissociuted (free) uric acid, namely, undue acidity of the urine and increased concentration of uric acid in the urine, and the factors that lead to separation of solid phase uric acid from its supersaturated solution in the urine. I7ndue Acidity of Urine. The importance of urine pH in this connection is expressed in an old adage that states that uric acid stones develop only in acid urine. For reasons already indicated the formation of uric acid calculi is facilitated when the urine is unduly acid, and especially when it remains so throughout the day- as a result of disturbances in the normal circadian rhythm of the urine pH. The urine is acidified in the course of renal secretion of metabolically produced hydrogen ions, normally totaling 45 to 60 or more mEq. per twenty-four hours, which are generated, as Relman and his associates have shown quantitatively [30], by oxidation of sulfur-containing amino acids, formation of intermediary acids in incomplete oxidation of carbohydrate and lipid, and hydrolysis of certain phosphoester linkages. Acidification of the urine occurs by net exchange of hydrogen ions for sodium ions [37-351. This process begins in the proximal tubule and is continued along the nephron into the distal tubule and collecting duct, where the major fall in pH in distinctly acid urine occurs. The pH of the final urine reflects complex interactions of many factors [31-351 and is subject VOL.

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to wide diurnal fluctuations: norrnally~ the, urirre is distinctly acid at night and in the early trrorning hours, but the pH rises sharply- in the 111orning and postprandial “alkaline tides” to 1~~1s usually in excess of 6.0 for much of the day /,j//j. As will be documented later, in IIMIIV cases of uric acid nephrolithiasis this circadian rhy thrrr is absent or aborti\re and the urine pH renrains persistently acid. There is no present indication that primary abnormalities in the metabolic generation of hydrogen ions (spontaneous or iatrogenit systemic acidosis) or in the tubular secretion of hydrogen ions (potassium depletion, disturbed adrenal regulation and more obscure causes) are commonly responsible for the unduly acid urine usually associated with uric acid nephrolithiasis. Current interest revolves chiefly around the possibility of irregularities in the excretion of protons. This occurs by way of reabsorption of filtered bicarbonate, by buffering as titratable acid and by the formation of ammonium ions. In the acid urine pH range in question (<5.6) reabsorption of filtered bicarbonate is complete, leaving the burden of buffering additional hydrogen ions secreted into the urine to titratable acid (chiefly filtered disodium phosphate) and ammonia, normally in ammonium ion : titratable acid ratios in the range 1.25 to 1.5. As will be pointed out later, much of the current lively discussion regarding undue acidity of the urine associated with uric acid nephrolithiasis revolves around the question whether or not urinary ammonium excretion is deficient, relative to the degree of acidity of the urine, and if so how this is to be interpreted. The ammonia generated by the kidneys derives preponderantly from glutamine [37j, most of which is formed by glutamine synthetase in the liver, then in part transported in high plasma concentration to the kidneys, where more is extracted than any other amino acid by far [38]. In the kidneys glutamine is deamidated by glutaminase 1 and deaminated by glutamate dehydrogenase and by transamination. The ammonia thus set free in the cells of the tubules passively diffuses down a concentration gradient into the more acid tubular fluid, where it combines with hydrogen ion to form relatively nondiffusible ammonium ions that are not reabsorbed, hence are excreted. In this role ammonia acts as a buffer, like phosphate [31]. As hydrogen ions are taken up by ammonia the pH of the tubular fluid tends to rise until replaced by

Uric

Acid

Nephrolithiasis-Gutman,

ions secreted into it [32]. If the supply of ammonia is deficient the pH of the urine would therefore be expected to be unduly acid. The most likely causes of such a deficiency in supply of ammonia would appear to be an insufficiency of glutamine presented to or extracted by the kidneys or an enzymatic error in the liberation of ammonia from glutamine in the kidneys. Hyperuricosuria. The mean daily endogenous production of uric acid in normal man on a low limited protein intake approximates purine, 700 mg. [2], of which somewhat less than 500 mg. is eliminated in the urine [39] and the remainder by way of the gut [40]. The daily urinary output of uric acid is subject, however, to wide variation depending on the intake of dietary uric acid precursors (preformed purines and proteins), the presence of disorders that enhance uric acid production and the state of the kidneys. The importance of diet in this connection is indicated by the large excess of uric acid, 200 to 400 mg. or more per day, that is cleared rapidly by the kidneys after ingestion of meals rich in purines and proteins; this hyperuricosuria may be accompanied by comparatively little sustained rise in plasma urate. Conversely, rigid restriction of the purines and proteins of the diet reduces urinary uric acid excretion appreciably, usually with comparatively little decline in plasma urate. In disorders characterized by overproduction of uric acid there is assumed to be acceleration of the committed, rate-regulating reaction of de nouo purine biosynthesis, previously discussed : fresh hydrogen

Glutamine + 5-phosphoribosylpyrophosphate + Hz0 + phosphoribosylamine -Iglutamate + PPi The reason for acceleration of this reaction in primary gout is not known. We have suggested [41,42 ] that availability of an excess of glutamine substrate may stimulate the rate. Wyngaarden [Z 1, Seegmiller [43] and others favor the view that the reaction is accelerated because of inadequate restraints on the specific amidotransferase involved, due to a b’reakdown of feedback inhibition by nucleotides. Seegmiller et al. [&I recently demonstrated absence of hypoxanthine guanine phosphoribosyltransferase (an enzyme that regenerates inosinic and

Yii

guanylic acids from the purine bases hypoxanthine and guanine) in the Lesch-Nyhan syndrome, an inborn neurologic disorder associated with overproduction of uric acid and pronounced hyperuricemia and hyperuricosuria, and occasional uric acid nephrolithiasis. The diminution in regeneration of these nucleotides is presumed to result in inadequate feedback inhibition of the specific amidotransferase in question. A similar mechanism has been suggested for primary gout by Seegmiller and his associates [45] who showed that a partial deficiency of hypoxanthine guanine phosphoribosyltransferase occurs also in some cases of primary gout, notably in marked overproducers of uric acid. However initiated, the surplus of inosinic acid generated by augmented de nouo purine biosynthesis in primary gout appears to be converted to uric acid chiefly by way of the shunt previously mentioned, since isotope studies indicate rapid incorporation of precursors into uric acid (reviewed by Wyngaarden [2]). It is not altogether clear either how the rateregulating reaction of de nouo purine biosynthesis is accelerated to produce the overproduction of uric acid and hyperuricemia in polycythemia vera and other myeloproliferative disorders, granulocytic leukemias, lymphomas and the like, except that this presumably is initiated by the increased requirements for cellular purine nucleotides. Isotope studies in these disorders indicate more delayed incorporation of precursors into uric acid, consistent with the rate of augmented turnover of cells. The quantity of uric acid appearing ultimately in the urine is the resultant of the rates of three renal regulating processes: filtration of the plasma urate at the glomerulus, “active” tubular reabsorption of the filtered urate and “active” tubular secretion of urate [46,47]. Normally, the plasma urate is filtered at a mean rate of 6.7 mg. per minute under the conditions of clearance measurements [39]. This rate accelerates if the plasma urate (or glomerular filtration) increases, decelerates if the glomerular filtration rate or plasma urate level falls. A filtered urate load of such proportions, if not largely reabsorbed, would make uric acid urolithiasis a common complaint indeed, since even after prompt exhaustion of the body urate pool (normally averaging some 1.2 gm.) renal excretion of uric acid presumably would conAMERICAN

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Uric Acid Nephrolithiasis-Gutmnn, tinur iit about the rate of uric acid production. Happil\. the mean normal urinary output of iuric acid is only 0.5 mg. per minute as measured b!- rlearancc methods [39]. It is likely that tubular reabsorption of the filtcrrd mate, even when substantially augnicntecl by overproduction of uric acid, is niore complete than is implied by these figures, since the apparent maximal tubular capacity for reabsorption of urate (estimated to be about 15 mg. per minute per 1.73 Xl’. ]#Jj is more than sufficient for the purpose. The reabsorbed urate is recycled, in part for modulated secretion by the tubules, in lesser part for elimination by way of the gut, where the uric acid is degraded by bacterial enzymes. By these devices the urinary output of uric acid is maintained within the wide limits of normal variation even in most cases of primary gout with hyperuricemia due to overproduction of uric acid. There are situations, however, in which some filtered urate may escape reabsorption and spill over into the urine. This may occur when filtered urate loads are inordinately high due to marked overproduction or intravenous injection of uric acid [49], or consumption of purines is in great excess, and also when tubular reabsorption of urate is defective, whether innately (as in the Dalmatian coach hound [50]), as a result of tubular damage by disease (Fanconi’s syndrome, Wilson’s disease, etc.) [.51] or following suppression of tubular reabsorption of urate by uricosuric drugs [52]. Under the usual circumstances of virtually complete reabsorption of filtered urate the elimination of uric acid in the urine is effected by tubular secretion of urate, for when tubular secretion of urate is sufficiently suppressed by pyrazinamide the urine is almost free of uric acid [53,54]. Steele and Rieselbach [54,55] demonstrated a direct relationship between the rate of tubular secretion of urate per nephron and the plasma urate level, a relationship that is maintained in the face of renal damage until uremia is advanced. If hyperuricemia is sufficientlv pronounced the rate of tubular secretion of uric acid increases to produce hyperuricosuria [50 J. We have been implying that (in contrast to tophaceous deposits in the joints) it is the concentration of uric acid in the urine, not in the plasma, that directly contributes to the genesis of uric acid nephrolithiasis. There are paralVOL.

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lelisms here, however, since the degree IA l”)~“ruricosuria ordinarily depends in largts ~neasure on the degree of hyperuriccmia, and the tlistinction may be difficult to make. For exaniple, in an analysis of our data on 888 patients with primary gout [25], 215 with stone, yra\-c, ,I or sand, this calculus formation occurred in 11 per cent of the patients with a urinary uric- acid excretion of less than 300 mg. per twent\--four hours, 21 per cent with a urinary uric acid excretion of 300 to 499 or 500 to 699 mg. per twenty-four hours, about 35 per cent with hyperuricosuria of 700 to 1,100 mg. per twentyfour hours and 50 per cent with more marked hyperuricosuria. Similarly, in respect to plasma urate levels, there was a 12 per cent incidence of nephrolithiasis in patients with 6.1 to 7.0 mg. per cent plasma urate, an essentially equal prevalence of stone averaging about 20 per cent when the plasma urate was within the range of 7.1 to 12.0 mg. per cent, and a higher incidence approximating 50 per cent when hyperuricemia exceeded 12.0 mg. per cent. The untreated patients with marked hyperuricosuria also had marked hyperuricemia, although in most of those with moderate hyperuricemia the urinary uric acid excretion was within or only moderately beyond the upper limits of normal variation. However, in 16 per cent of the total number of gouty patients with stone, calculus developed after the administration of liberal doses of uricosuric drugs, which produced hyperuricosuria with lowered plasma urate levels. In contrast allopurinol, which decreases the uric acid in the urine as well as in the plasma, markedly reduced the incidence of nephrolithiasis in the gouty subjects prone to it. Moreover, in conditions in which hyperuriremia is accompanied by reduced urinary excretion of uric acid, as in chronic renal insufficiencv, states of lactic and /?-hydroxybutyric acidosis, and following therapeutic administration of pyrazinamide or chlorothiazide, uric acid stone formation is rare. These various observations indicate that hyperuricosuria, rather than hyperuricemia, is the primary factor, hyperuricemia being of importance only secondarily when it results in hyperuricosuria. This conclusion is in accord with the site of uric acid deposits found in the kidney substance. They occur Iimch more often in the medulla and medullary-cortical junction, where the tubular fluid is concentrated and acidified, than in the cortex,

762

Uric Acid Nephrolithiasis-Gutman,

where some ten to twenty times more plasma urate is filtered and reabsorbed than is secreted by the tubules more distally. Hyperuricosuria plays an important role in uric acid nephrolithiasis only when it leads to increased concentration of uric acid in the urine, elimination of uric i.e., when the augmented acid in the urine is not accompanied by proportionate expansion in urine volume. It should also be made clear that increased concentration of undissociated uric acid in the urine, which as previously pointed out is the critical factor in production of supersaturated solutions of uric acid, may readily occur without hyperuricosuria or may not occur despite hyperuricosuria, depending upon the urine pH. Thus in idiopathic uric acid lithiasis, the disorder in which uric acid nephrolithiasis appears to be most common in the population at large, unduly acid urine pH, not hyperuricosuria, is characteristic. It is therefore relevant that increased concentration of uric acid in the urine, in those prone to uric acid stone formation, often goes hand in hand with undue acidity of the urine. This occurs in primary gout for example. Moreover, when the rate of urine flow is sufficiently reduced by dehydration the urine pH tends to fall, so marked reduction in urine volume is likely to be accompanied by low urine pH. Similarly, when there is substantial extrarenal loss of water, sodium and potassium in ulcerative colitis, notably with ileostomy and severe depletion by this route, the urine is often both excessively concentrated and unduly acid [56,57]. However, if overproduction of uric acid is inordinate, and the capacity of the urinary tract to eliminate it is overwhelmed, acute obstructive nephropathy by uric acid precipitates may ensue even when the urine is not too acid. Separation of Solid Phase Uric Acid From Supersaturated Solution in the Urine. The principle that it is the concentration of undissociated uric acid, not of uric acid per se, that is critical for supersaturation in the urine is borne out by experiment. Fried and Vermeulen [58] found that the urine of twenty of fifty normal human subjects investigated, especially urine samples of low pH, was indeed supersaturated with respect to uric acid as shown when solid uric acid was added to the urine. Sperling and de Vries [59,60] concluded from similar experiments that urine, if of pH below 5.5 or 5.7, invariably is supersaturated with respect to uric acid. Certain it is that uric acid readily precipitates out spontaneously when urine is allowed to stand

Yii

a characteristic after passage, often forming lateritious sediment colored by urochromes. The degree of supersaturation of the urine with respect to uric acid is sometimes remarkable and there has been much speculation as to the physicochemical forces that maintain uric acid in metastable solution. Perhaps the time sequences of urine formation in the kidney sufficiently account for this phenomenon. On the other hand it has been suggested that urinary mucoproteins (such as the Tamm-Horsfall mucoprotein) or other substances might act as “solubilizers” ; this possibility is discussed by de Vries and his associates [5,67] and elsewhere in this Symposium. If such substances did play an important role in maintaining uric acid in metastable solution one would suppose that they would be deficient in the urine of uric acid stone formers but this appears not to be the case [67]; the urine of patients with idiopathic uric acid lithiasis seems to have the same capacity for supersaturation with uric acid as normal urine [59]. The nature of the nidus that catalyzes crystal overgrowth in uric acid stones also has been much discussed although there is no compelling reason why it should not be initiating uric acid crystals in most cases, namely, those in which the stones are composed of “pure” uric acid or rrmixed” stones with a uric acid core. When not initiating uric acid crystals, the most likely candidate for nucleation of uric acid concretions would appear to be calcium oxalates. Oxalates are universally found to be a rather common contaminant and accompaniment of uric acid stones; in his large series Prien [76] states that he noted significant amounts of calcium oxalate monohydrate in about 18 per cent of uric acid calculi. This would be expected in view of the difficult solubility of calcium oxalate throughout the range of variation in urine pH, including the acidity favored by uric acid stone formation. Lonsdale [S] has recently called attention to the close epitaxial relationship in respect to the dimensions of common faces of crystals of uric acid and crystals of calcium oxalates, a circumstance that would facilitate the oriented overgrowth of uric acid calculi upon a nucleation center of calcium oxalates. Thus the orthogonal network dimensions (A) of face 100 of uric acid crystals are 6.21 by 7.40, of face 001 of calcium oxalate monohydrate (whewellite) 6.28 by 14.57, and of face 101 of calcium oxalate dihydrate (weddellite) a simple multiple, 12.30 by 14.32. It may well be, as Lonsdale suggests [6], AMERICAN

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Uric Acid Nephrolithiasis-Gutnun. that one of the determinants of uric acid stone formation is the availability of seeds of calcium oxalates, formed as a result of contraction of the urine volume or excessive renal elimination of oxalate of exogenous (dietary) or endogenous (metabolic) origin. Although an organic matrix of abnormal mucoproteins or related substances may well play a role in the formation of many concreIttents [ /0,62,63], there is little evidence for this in uric acid stones, even though some protein, as well as pigment, may be adsorbed diffusely onto the surfaces of uric acid crystals as they aggregate. Fried and Vermeulen [58] have shown that sizable concretions of uric acid can be generated artifically in vitro from solutions supersaturated with respect to uric acid but devoid of any organic materials. Unknown Factors in Uric Acid Stone Formation. Many uncertainties in the pathogenesis of uric acid nephrolithiasis remain. The fact is that the foregoing conditions predisposing to uric acid calculus formation seem to prevail in some subjccts in whom uric acid urolithiasis never develops, and certainly in many who have had but one or two sporadic episodes of stone in their lifetime. This raises the question whether the immediately precipitating causes are exacerbations of the known factors described or unrecognized influences that are interposed. Sometimes accentuation of one of the established predisposing factors can be demonstrated or conjectured, tnore often not. Attempts to do so are often futile because they are of necessity retrospective and it is impossible to determine precisely the time and circumstances of initiation and growth of uric acid stones. All one can say is that, as anticipated from the solubility properties of free uric acid, uric acid nephrolithiasis is far more prevalent under the conditions mentioned than in their absence. Dietary (including vitamin or other defisocial, occupational (nociency), infectious, tably sedentary) and a variety of other causes ha\-e been implicated in the pathogenesis of uric acid nephrolithiasis. At present these are only interesting speculations, as recounted elsewhere [.5,6,63]. CLASSIFICATION

The etiologic classification of uric acid nephrolithiasis is in a rather unsatisfactory state. The diagnosis of idiopathic uric acid lithiasis, the largest category in the experience of most stone clinics, is made by exclusion, and should exclude VOL.

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hyperuricemia and hyperuricosuria of whatever cause. The difficulties begin with defining the lower limits of hyperuricemia and hyprruricosuria. No general agreement has been reached as to the upper limit of normal variation in serum even by statistical analurate concentration, ysis of the results of differential spectrophotometry using highly purified uricase, a reliable and widely employed method for measuring uric acid. In our studies on gout we arbitrarily assign an upper limit of about 6.5 mg. per rent for men and 5.5 mg. per cent for women. Seegmiller et al. [43] prefer 7.0 mg. per cent for men, a figure 2 standard deviations above the mean (5.1 mg. per cent) found in 940 nongouty men; this figure overlapped in 9 per cent of gouty men and 5 per cent of normal men. Some population surveys suggest that the upper limit of normal may be 7.5 mg. per cent. Certain it is that a disconcertingly large number of completely asymptomatic men are found to have what would generally be regarded as unequivocal hyperuricemia; whether or not they have larval gout or other disease associated with hyperuricemia cannot be determined without prolonged follow up, and often not even then. Similar problems crop up in setting the precise upper limit of normal variation in the daily urinary output of uric acid. On a low purine, limited protein (about 60 gm. per day) diet, which often is not reliably followed except in a metabolic ward, the daily urinary excretion of uric acid should not much exceed 550 lng. The nitrogen intake can be checked by urinary total nitrogen measurements in twenty-four hour collections. On a free diet the results vary widely with the quantity of purines and proteins ingested. Unless the twenty-four hour urinary total nitrogen excretion is excessive (>18 or 20 gm.) the daily elimination of uric acid should not go beyond 700 to 800 mg. per twentyfour hours, which may be taken as the lower limit of hyperuricosuria under these circumstances. The greatest obstacle in classification, however, centers around ambiguities in the diagnosis of primary gout. To avoid even greater confusion, this diagnosis is usually limited to patients with hyperuricemia who have already suffered at least one attack of typical acute arthritis responsive to colchicine therapy. Such seizures, however, ordinarily do not occur until well along in the course of the disorder whereas, at least in male subjects, hyperuricemia is present from puberty. To compound the difficulties

Uric Acid Nephrolithiasis-Gutman, TABLE II ETIOLOGIC CLASSIFICATION OF URIC ACID NEPHROLITHIASIS Idiopathic

uric acid nephrolithiasis

1. Sporadic 2. Genetically

1.

2. 3. Uric 1. 2. Uric 1. 2. 3.

uric

acid

nephrolithiasis

first clinical gout,

indeed,

Our of

the

infrequently

of later

occasionally to judge

incidence.

resentative

not

manifestation

manifestation ial

transmitted

acid nephrolithiasis associated with hyperuricemia due to Inborn errors of metabolism a. Primary gout b. Lesch-Nyhan syndrome c. Glycogen storage diseases Myeloproliferative and other neoplastic diseases Undetermined causes acid nephrolithiasis associated with dehydration due to excessive extrarenal loss of water By way of the skin By way of the gastrointestinal tract acid nephrolithiasis associated with hyperuricosuria without significant hyperuricemia, due to Uricosuric drugs Overindulgence in purines and proteins Inherent or acquired defect in tubular reabsorption of uric acid

Uric

overt

it may by

be

association

is the primary its

only

of famil-

experience

[25]

general

experience

is fairly in

repthis

In 305 patients with primary gout who gave a history of stone, the mean age at onset of acute arthritis was forty-two years, that at onset of stone forty-four years, but in 40 per cent of the cases lithiasis preceded arthritis, sometimes by an appreciable interval, more than a decade in 14 per cent in our series. Before age thirty, onset with stone was more frequent than onset with acute arthritis (twenty cases versus eight). There does not seem to be any easy way out of this diagnostic dilemma. In the classification that follows (Table II) we separately list uric acid nephrolithiasis associated with primary gout (meaning patients who have had at least one attack of overt gouty arthritis) and uric acid nephrolithiasis associated with hyperuricemia of unknown cause, even though most of the latter in our series, for reasons to be given, probably have primary gout too. We also think it justifiable to list separately uric acid nephrolithiasis associated with hyperuricosuria, without significant hyperuricemia, under circumstances to be indicated. Idiopathic lyric Acid Nephrolithiasis. As already stated this diagnosis should properly be made respect

(reviewed

by Atsmon

et al.

[5]).

Yii

only when significant hyperuricemia and hyperuricosuria are absent. There are few distinctive clinical features of the disorder [5,64]. Idiopathic uric acid nephrolithiasis affects women almost as frequently as men, and is alleged to be more common in Jews and Italians. Stone, gravel or sand appears most often in middle age, with or without renal colic, but is not uncommon earlier in life. Attacks of colic and passage of stone usually are recurrent. The proportion of larger sized “mixed” stones, often associated with chronic urinary tract infection in women, seems to be higher than in gout, and surgical intervention is more often required. An hereditary form of idiopathic uric acid nephrolithiasis, unrelated to primary gout, has been described by de Vries and his associates [5,65]. It is transmitted as an autosomal dominant trait and is characterized by early onset of renal colic and uric acid lithiasis, marked and recurrent morbidity due to uric acid stone formation, a high incidence of urinary tract obstruction and infection with renal damage, and relatively early death in uremia in a large proportion of cases. The one physiologic abnormality found consistently in idiopathic uric acid nephrolithiasis, as here defined, is a low urine pH. This to be sure is to be anticipated in any patient with uric acid stone but the acidity is often unusually pronounced (pH < 5.2) and moreover apt to persist because of failure of the normal morning and postprandial “alkaline tides” to appear ([5,7 7, 78,36,63-681 and others). The undue acidity of the urine was ascribed by Henneman, Wallach and Dempsey [69] to reduced renal formation of ammonia noted by them in two cases of idiopathic uric acid nephrolithiasis. These results were confirmed by Woeber et al. [70] and in a well documented study by Rapoport et al. [78] who found in sixteen patients with uric acid calculi (nine of them hyperuricemic however) a mean urinary ammonium excretion of 33.9 mEq. per twenty-four hours as compared to 42.1 mEq. per twenty-four hours in sixteen patients with calcium oxalate stone and 62.8 mEq. per twenty-four hours in eleven normal subjects. The mean ammonium ion: titratable acid ratios in these three groups were 0.80, 1.55 and 1.45, respectively. On the other hand a careful analysis of twenty-four hour urine collections in twelve patients with uric acid nephrolithiasis (four of them overtly gouty) by Wrong and his associates [68] failed to reveal any reduction in AMERICAN

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Uric Acid Nephrolithiasis-Gu2man, urinary ammonium excretion, in relation to urine pH, exrept when associated with advanced renal darnagc; an excess of titratable acid and thus inexplicably of total hydrogen ion excretion was reported in this series. Barzel et al. [SS] found in twrnty-four hour urine samples a mean urinary armnonium excretion of 20 PEq. per minute in se\‘en patients with idiopathic uric acid lithiasis, 15.5 PEq. per minute in five control subjects of the same (older) age group and 26 &q. per minute in three younger control subjrrts. The>- stressed the importance of aging as a factor in renal production of ammonia. The results of these various studies are thus conflicting as to fact and interpretation, and the issue remains in doubt. One of the uncertainties is whether the reported diminution in urinary ammonium excretion in patients with uric acid stone can be ascribed to minor renal damage, not discernible by conventional renal function tests? consequent to nephrolithiasis. This is possible but unlikely since, contrary to widespread belief, renal production of ammonia is not significantly reduced in kidney disease until there is apprerlable loss of renal mass as evidenced by a substantial decline in glomcrular filtration [71-7.31. Moreover, Rapoport et. al. [78] found the urinary ammonium excretion to be significantly lower in patients with uric acid stones than in those with calcium oxalate stones. As to the effects of aging on renal production of ammonia, this factor really cannot be truly assessed until more data are available. There is no information as to the cause of the reputed deficiency in urinary ammonium excretion in idiopathic uric acid nephrolithiasis uncomplicated by severe renal damage. Of the possible explanations, one to be considered is a deficiency in the supply or utilization of glutamine for renal production of ammonia, a pathogenesis that will be discussed in relation to the similar questions in primary gout. In that event the distinction between idiopathic uric acid nephrolithiasis and primary gout would be even more difficult and tenuous than it is, and one must ask why hyperuricemia and hyperuricosuria do not occur in idiopathic uric acid nephrolithiasis. All that can be said at present is that patients with hyperuricemia are excluded by definition, and hyperuricosuria has been noted in some patients classified, rightly or wrongly, as having idiopathic uric acid nephrolithiasis [5]. Uric dcid Nephrolithiasis in Primary Gout. It was pointed out earlier that the prevalence of VOL.

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uric acid stone, gravel and sand in prilnarb- qout (10 to 25 per cent) is of the order l.l~~N rilncs that in the population of the U.S.:\. ar large, which seems to be about 0.01 per cent. \l-e ha\.e elsewhere [25] discussed the role of’ ullduc: acidity of the urine and hyperuricosuria as predisposing factors in the 280 of our 1.258 patients with primary gout who had uric acid nephrolithiasis. The significance in this connecCon of highly concentrated urine is implied 111the report of Atsmon et al. [5] that in Israel 75 per cent of the gouty subjects have uric arid nrphrolithiasis. Of those of our gouty subjects affected \vith stone 90 per cent were men, reflecting the preponderance of men in the series as a whole. _tge distribution in relation to onset of acure arthritis has already been mentioned. In 53 per cent of patients the attacks of renal colic or passage of uric acid concretions were recurrent, at intervals sometimes very frequent in the case of sand, within a year or two in most instances, but sometimes not for periods of five or more ).ears. Most stones were small enough for spontaneous passage and about 80 per cent \verc discharged without need for cystoscopic manipulation or surgical intervention. As prr\-iously indicated 84 per cent of 120 stones recovered were: composed chiefly of uric acid. Associated infections of the urinary tract were not infrequent, especially with impacted larger stones, and refractory chronic pyeloncphritis \+.as noted in sixteen cases. We have already called attention to the higher incidence of stone (up to 50 per cent) in gouty subjects who are florid overproducers and overexcretors of uric acid, but in some 70 per cent of patients with primary gout the quantities of uric acid excreted in the urine are within the wide limits of normal variation or moderately above (up to 800 mg. per twenty-four hours), yet in 22 per cent of them in our series ncphrolithiasis developed. When the urine pH was examined it was found, in conformit)- byit the findings of others [5,23,67,68,7&77], usually to be unduly and persistently acid, with aborti\-r or no “alkaline tides,” both in gout)- patients without stone and more particularhin those in whom calculus had developed. ‘Thus in preprandial morning urine samples. c-ollectcd at a mean flow of 1.2 ml. per minute in 325 gouty and eighty normal subjects, the urine pH was <4.8 to 5.0 in 48 per cent of gouty patients with stone, 36 per cent in gouty patients without

Uric

Acid

Nephrolithiasis-Gutman,

stone and 15 per cent in control subjects; at pH 5.1 to 5.6 the respective figures were 44, 54 and 60 per cent; and at pH 5.7 to >5.9 they were 8, 9 and 26 per cent. In such early morning urine samples comparison of the urinary ammonium excretion in sixty-two normal and 126 gouty subjects, selected for study because they had no detectable renal impairment by standard renal function tests, revealed a mean deficit of 25 to 30 per cent in urinary ammonium excretion, in relation to urine pH at levels <5.7, in the patients with primary gout (p < 0.001). There was no significant difference in mean titratable acid excretion in the gouty and nongouty subjects in these early morning samples but the apparent deficit in elimination of total metabolic acid in gouty subjects disappeared in twenty-four hour collections due to a compensatory increase in titratable acid presumably in response to meals [78]. After taking ammonium chloride there was a marked increase in urinary ammonium output in both gouty and nongouty subjects, but significantly less in gouty subjects; excretion of titratable acid increased about the same in both groups [78]. In the selected cases of the study on urinary ammonium excretion just described, renal damage could have been at most minimal [25,78]. Moreover, aging could be excluded as the cause of the deficiency in urinary ammonium excretion by appropriate cross comparisons of similar age groups. The major difficulties encountered in such studies, including our own, arise from the exceedingly marked dispersion of values for urinary ammonium excretion, even at the same distinctly acid urine pH, in both normal and gouty man, and the appreciable overlap in the two groups [78]. As in the case of idiopathic uric acid nephrolithiasis, there is conflicting opinion both as to fact and interpretation in regard to urinary ammonium excretion in primary gout [5,78,66, 68,77,76-801. The views of Rapoport et al. [78] and of Wrong et al. [68,77] have already been cited. Pak Poy [76], in a study of nine patients with primary gout, none with stone but most with some degree of renal damage, found no distinct decline in urinary ammonium excretion in relation to urine pH except when renal function was definitely impaired. Pollak and Mattenheimer [79] concluded from their investigation of four gouty subjects that such reduction in urinary ammonium elimination as was observed was attributable to aging and occult renal

Yii

damage. Sperling et al. [80] studied fifteen gouty and nine normal subjects and found, in twenty-four hour urine collections said to be matched at a mean diurnal pH of 5.9, an average urinary ammonium excretion of 16.9 PEq. per minute in the gouty and 20.6 ,uEq. per minute in the nongouty subjects; this difference was ascribed to aging. Plante et al. [77] noted urinary amsignificantly less than norma monium excretion, in relation to urine pH, in ten gouty subjects with well preserved renal function, and a less pronounced response to ammonium chloride loading, but these abnormalities were observed only when the patients were taking a high purine diet and not on a low purine intake. We have suggested [47,42] that the putative defect in renal production of ammonia in primary gout reflects an abnormality in the metabolism of glutamine, the major source of urinary ammonium. This glutamine hypothesis was first proposed when it was found [47,87] that patients with primary gout given glytine-16N excreted 15NH4+ in the urine in only one to two thirds of the normal proportion of the isotope dose, and that uric acid-15N was abnormally heavily labeled at positions N-9 and N-3 (Fig. l), both derived from the amide nitrogen of glutamine. These findings were interpreted as indicating that the heavily labeled glutamine not fully utilized by the kidney for production of ammonia was recycled to the liver for elimination of the surplus nitrogen as extra urea and uric acid. The glutamine hypothesis would thus conveniently account not only for the deficiency of urinary ammonium and consequent undue acidity of the urine, which is an important factor in the predisposition to uric acid nephrolithiasis, but also for overproduction of uric acid, with hyperuricemia (and its clinical sequels) and in more pronounced cases of hyperuricosuria, also an important factor in uric acid stone formation. The hypothesis would appear to be consonant with the biologic role both of glutamine and of de novo purine biosynthesis in disposal of waste nitrogen, mentioned earlier. Recent as yet unpublished studies in our laboratory offer supportive evidence by demonstrating in patients with primary gout apparently compensatory excessive tubular reabsorption of filtered glutamine and selective overutilization of administered glutamine for uric acid production. The regulation of glutamine utilization for AMERICAN

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Uric Acid Nephrolithiasis---Gz&m, fortii;itioii of anunonia in normal and acidotic man is a complex operation not well understood, and the precise nature of the putative defect in pr-iniary gout is still speculative. The simplest explanation, perhaps, would be a deficiency in glutarninase I 1411 but this is not borne out in the only assays yet recorded in the gouty kidney [7.9]. Pollak and Slattenheimer [79] obtained values of 192 to 248 units for glutaminase I in four gouty kidneys but in six normal kidneys the figures varied from 85 to 440 units, about half of them above and half below those found in gout. In view of this spread, a reflection of the technical problems confronted in the assay, the question must remain in abeyance until more data are recorded. liir Acid h’ephrolithiasis in the Lesch-Nyhan Syndrome and in Glycogen Storage Diseases. These are relatively rare inborn errors occasionally complicated by uric acid stones. The LeschNyhan syndrome [82] is a neurologic disorder of childhood characterized by mental retardation, choreoathetosis, an extraordinary compulsion for self-mutilation and marked overproduction of uric acid with hyperuricemia and hyperuricosuria, the last presumably responsible for uric acid stone formation [83]. As already mentioned, guanine hypoxanthine phosphoribosyltransferase is lacking in this syndrome [&I. Type I glycogen storage disease (glucose 6-phosphatase deficiency) often is associated with hyperuricemia and typical gouty manifestations, which may include uric acid nephrolithiasis [84]. Although the hyperlacticacidosis of this disorder brings about a reduction in urinary uric acid excretion, the renal clearance of uric acid nevertheless is increased in an appreciable proportion of cases [85]. In several such instances concomitant overproduction of uric acid has been demonstrated, perhaps due to availability of excessive 5-phosphoribosylpyrophosphate substrate for the committed reaction of de nova purine biosynthesis [86]. 1:1-ic Acid Nephrolithiasis in Myeloproliferatice and Other h’eoplastic Diseases. In some disorders of augmented hemopoiesis, and other neoplastic diseases characterized by increased formation and destruction of cells, notably lymphoma and lymphosarcoma, uric acid production exceeds the normal and indeed often that in primary gout. Isotope studies of the kinetics of overproduction of uric acid in the myeloproliferative syndrome [87,88] and in chronic granulocytic leukemia [89] reveal peak labeling of uric VOL.

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1968

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767

acid ten to fourteen days after administration of precursors, a rate consistent with the rate of cell turnover. In these disorders hypcruricemia is ]1’7,h’!/]; frequent and may be pronounced when overproduction of uric acid is grcatl). accelerated by vigorous cytolytic therapy scruin urate levels of 20 mg. per cent may be rcachcd [90], and occasionally the levels are much higher (in primary gout, in contrast, serum uratc levels rarely exceed or even reach 14 mg. per cent). Hyperuricosuria frequently ensues [27,89,97, 921. In chronic granulocytic leukemia Krakoff cites a mean urinary uric acid excretion of 1.07 gm. per day [89], increasing in this disease and in lymphosarcoma to 2 or 3 gm. per day or more after cytolytic therapy [9U]. It is not surprising, in view of the potent cancer chemotherapeutic agents now available, that the capacity of the tubules to reabsorb filtered urate should occasionally be quite overwhelmed, and that some filtered urate should spill over into the urine, further increasing the renal elimination of uric acid effected by enhanced tubular secretion of urate. This is the implication of relevant renal clearance studies by Watkin and Weinstein [93] and in two of the leukemic cases cited by Rieselbach et al. [ZS] in which Curie acid:GFR ratios were very close to 1.0. In any event, such high concentrations of undissociatcd (free) uric acid in the distal reaches of the nephron, where the final concentration and acidifira tion of the urine is achieved, promote precipitation of uric acid [26]. The result is acute obstructive uric acid nephropathy, due to clogging of the nephrons and ureters by a myriad of uric acid crystals [26, 89,94-1021, as amply demonstrated by pathologic examination [95-97,99, IOO]. When hyperuricosuria is less pronounced, and onset less abrupt, the formation of organized uric acid calculi is favored [98,101-1031. Weisberger and Persky [98] reported uric acid stones in about 5 per cent of their patients with leukemia, about one third of whom had not received radiation or other forms of cytolytic treatment. Presumably the urine is sufficiently acid in such cases of uric acid nephrolithiasis but there is little information on the range of urine pH in these disorders, and that little is difficult to assess because of the frequency of urinary tract infection and gross impairment of renal function. The term “secondary gout” [ 1051 is applied when acute and/or chronic arthritic manifestations of gout do not arise de novo on a genetic

Uric Acid Nephrolithiasis-Gutman, basis but as complications of another disorder, usually of augmented hemopoiesis, associated with overproduction of uric acid. In our experience [25,27] the disease by far most frequently complicated by secondary gout is the myeloproliferative syndrome, often beginning as polycythemia Vera, with transitional myelofibrosis and myeloid metaplasia. Less common is secondary gout complicating chronic granulomatous leukemia, secondary polycythemia and the chronic hemolytic anemias. Other associations are noted by Talbott [106]. In our series of fifty-nine cases of secondary gout, mostly- compiled before the advent of allopurinol, uric acid nephrolithiasis developed in twenty-five (42 per cent) [25], a prevalence almost twice that in our patients with primary gout; this high incidence doubtless is chiefly due to the circumstance that the hyperuricemia and hyperuricosuria of secondary gout, notably after cytolytic therapy, are often more marked than in primary gout [25,27]. Male subjects predominated (84 per cent) in the cases with stone. The mean age at the first episode of renal stone was fifty-seven years; in nine cases (36 per cent) uric acid calculi appeared before the initial attack of acute gouty arthritis. Renal colic and discharge of calculi, which are almost invariably composed of “pure” uric acid, were recurrent in three fourths of these patients. In nine instances (36 per cent) surgical intervention was necessary to relieve obstruction. Chronic pyelonephritis, often refractory to treatment, was demonstrated in one fourth of the patients, a reflection of the impaired resistance to infection in the underlying disease before and particularly after cancer chemotherapy. Renal insufficiency with azotemia was frequent, with terminal renal failure in three cases. Uric ilcid ,Vephrolithiasis Associated with Hyperuricemia of Undetermined Cause. Our experience with sixty-three cases in this category corresponds very closely with that described in our patients with overt gout [25], and most of them doubtless carry the gouty trait. In fact in some of the patients first classified in this group typical acute gouty arthritis subsequently developed and they were reclassified as having primary gout; moreover, fourteen gave a family history of gouty arthritis and five of both gouty arthritis and stone. (Thirteen gave a family history of calculus alone.) All but three of the sixty-three patients were male. The mean age at the initial attack of renal

Yii

colic or passage of stone, gravel or sand was thirty-eight years (spread, twelve to sixty-two years) and in nineteen (31 per cent) the onset was before age thirty. Calculi were recurrent in 75 per cent. The stones in thirty-one of the forty-one cases in which they were analyzed were composed of “pure” uric acid; the remainder were “mixed” uric acid stones containing appreciable admixture of oxalate or phosphate. Most stones were passed spontaneously. Complications of nephrolithiasis were very much as in the patient with overt primary gout. The mean serum urate concentration in these sixty-three patients (8.5 mg. per cent) was somewhat lower than that of our patients with overt primary gout and stone (9.4 mg. per cent) but the proportion of those with hyperuricosuria (urinary uric acid excretion >700 mg. per day on a moderately restricted diet) was higher, 65 versus 36 per cent, in the forty-six patients in which this was measured. In nineteen patients in whom the pH of early morning urine samples was tested it was found to be 4.8 to 5.0; in eighteen it was 5.1 to 5.3; in seven it was 5.4 to 5.6; and tended to be higher in those with “mixed” uric acid calculi. The mean urinary ammonium excretion in thirty-one subjects with urine pH <5.6 was 23.8 f 5.9 mEq. per minute, corresponding with that found in our patients with overt primary gout but significantly less than normal in that pH range. The mean urinary excretion of titratable acid was within normal limits. Uric Acid Nephrolithiasis Associated with Dehydration Due to Excessive Extrarenal Loss of Water. There can be little doubt that by increasing the urinary concentration of difficultly soluble solutes, insidious loss of water in excess by extrarenal routes is an important factor in precipitating stone formation in those predisposed to nephrolithiasis. When such dehydration is accompanied by increased acidity of the urine, as commonly occurs, the urinary concentration of undissociated uric acid is considerably increased and the development of uric acid nephrolithiasis is favored. As already mentioned, there is a significant incidence of uric acid calculus in association with excessive loss of water, sodium and potassium by way of the gastrointestinal tract in chronic diarrheas of granulomatous, infectious or iatrogenic origin, notably in ulcerative colitis especially when ileostomies are unduly productive [ I7,56,57]. AMERICAN

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Uric

Acid

Nephrolithiasis-Gu/rnun,

A ltlorc frcqucnl rausr of uric acid nephrolithiasis. hou-ever. is cxressivc loss of water by way of the skin. Urolithiasis may occur in the course of protracted fevers, but usually as a result of climactic, conditions, in the hot months of tht, “stone SCaSon” [ 141. Marked contraction of the In-inc \-olurne is a special hazard in torrid areas of the world, as documented in Israel by de Vrics and his associates [5] who remark that in the desert regions a fluid intake of 10 to 15 L. a day may be required to maintain a daily urine volume of 1 L. lJTrJTric Acid 2Vephrolithiasis Associated with Hyperuricosuria, Withcut Hyperuricemia. In this cate“without hyperuricemia” gory the qualification is intended to exclude the more common instances of hyperuricosuria due to endogenous overproduction of uric acid. This would rule out the approximately 30 per cent of patients with primary gout who are habitual overexcretors of uric acid, hyperuricosuria in hyperuricemic cases of myeloproliferative or other neoplastic with hyperuricemia of undisease, patients determined cause who may have hyperuricosuria, etc. There remains a polyglot group of hyperuricosuric subjects with uric acid nephrolithiasis who arc likely to be categorized as idiopathic unless the urinary uric acid excretion is determined. Atsmon et al. [Sr] record a number of such patients, without hyperuricemia, who were classified as having idiopathic uric acid lithiasis but were subsequently discovered to eliminate uric acid in the urine in quantities up to 2.2 gm. per day. -4s these investigators imply, it is not possible to maintain such high renal excretions and clearances of uric acid without a defect in tubular reabsorption and/or overproduction of uric acid. When the urinary uric acid exeretion habitually exceeds the normal daily production of uric acid, which averages some 700 mg. on a limited purine, protein dietar!- intake, o\-erproduction of uric acid must be assumed. If there is no accompanying hyperuricemia, an additional defect in tubular reabsorption of urate may be present. Perhaps the Inost frequent cause of hyperuricosuria in this setting is habitual or occasional gluttoll). with overconsumption of purines and proteins; as already explained, the surplus uric acid formed in these circumstances is likely to be so rapidly cleared by the kidneys, with hyperuricosuria, that transient hyperuricemia may be missed. The history given by the patient may VOL..

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1968

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-769

be unreliable in this rrspecl, as in t\\o of our own patients who w-ere thought 10 1lal.t idiopathic uric acid lithiasis until a urillar\. uric acid excretion in excess of 800 ~nq. per da)- was discovered, with a daily urinal-\- total nirror(rn elimination of about 20 gni. Paiicnts \t-it11(I\-CI‘t gout not infrequently turn up aftc,r fvsri\.c: occasions not only with acute arthriris l,llt ~OIIKYtimes also with uric acid nephrolithiasis. In the unwary gouty patient 12-1~0lakes potent uricosuric drugs, such as probcllcc-id. X11fi npyrazone or sahcylate in high dosage,. \vithout increasing fluid consumption uric acic! nephrolithiasis may develop; as alread!- sratrd this category accounted for 16 per CCI~Lof rhc total number of stone cases (305) in our patients kvith primary gout. With greater alrarencss of this hazard in recent years, and especiall!- since the introduction of allopurinol, the incidence of iatrogenic uric acid calculus has declined markedly, but such cases still tnrll up occasionally. This cause of uric acid ncphrolithiasis may be overlooked if a history of uricosnric drux ingestion is not elicited, since the scrunl urate level usually is no longer ele\.ared. When a person who is not an o\-erprucluc,cr of uric acid is given a uricosuric drug. transitor) hyperuricosuria for a da); or two CIEIXS~ until there is hypouricemia due to depletion of the body pool of urate, normally a\-eraKing about 1.2 gm. The hypouricemia and incrrased renal clearance of uric acid persist so ions as the druy is taken but the rate of urinary uric arid cxcrction soon declines to approximate tlre rate of uric acid production. Since this is normal. the daily urinary uric acid excretion then falls to within the broad limits of normal \.arintion, 300 to 700 mg. per day when the dietar). inlake of purines and proteins is not excessive: \vhile thus not hyperuricosuric, the renal excretion of uric acid may nevertheless be greater than otherwise because the rate of elimination b>- 12-a\.of the gut, which appears to be dependent upon the serum urate level, presumabl\. declines. If the diet is rich in purines and pi.oteins, ilrlpaired tubular reabsorption of urate results in a larger and faster outpuring of uric acid in the urine, for reasons already mentioned, and therein lirs the greater danger of uric acid stone formation. Finally, there is the possibilit!of h>-peruricosuria due to inherent impairnlent of tubular reabsorption of filtered urate. This ma\. occur as part of a generalized defect in tubular reahsorption, as in the Fanconi syndrome. \Vilson’s

Uric

Acid

Nephrolithiasis-Gutman,

disease, and the like, but in these disorders uric acid nephrolithiasis is not encountered because the urine is apt to be too alkaline as a result of accompanying more or less pronounced renal tubular acidosis. The defect in tubular reabsorption of uric acid may, however, be innate and unique, as in the classic case described by Praetorius and Kirk [707] in an apparently healthy young man who did not reabsorb filtered urate at all, as an isolated defect-the human equivalent of the Dalmatian coach hound. It would appear that lesser degrees of this reabsorptive deficiency may occur in man, a possibility in accord with the rather wide variation in the apparent reabsorptive Tm for urate observed in different human subjects [48]. As already indicated, it is likely that the hazard of uric acid nephrolithiasis is enhanced under these circumstances, especially if the urine pH is also unduly acid and the dietary intake of purines and proteins is excessive. MEDICAL

MANAGEMENT

The efficacy of adequate hydration, use of alkalinizing agents, regulation of the diet and control of urinary tract infection in most cases of uric acid nephrolithiasis has been established by long and universal experience ([5,7 7,26,63, 708-7 701 and many others), and need not be belabored here. We wish, therefore, only to comment on some points, aimed particularly at more precise control of the critical concentration of undissociated uric acid in the urine, and to summarize our experience with a newer agent, allopurinol, in 108 cases of uric acid nephrolithiasis. Surely the simplest and safest, perhaps also the most efficacious prophylactic measure is a fluid intake sufficient to maintain an adequate urine volume, generally put at about 2 L. per twenty-four hours or somewhat above. It is more customary to control the fluid intake than to measure the daily urinary output directly, which is satisfactory provided there is no excessive extrarenal water loss, an assumption which may not be tenable when there is exposure to hot, dry weather and in other situations already mentioned. Fruit juices afford a convenient source of fluid, tending to alkalinize as well as to dilute the urine. In cases of frequently recurrent or impacted calculi, fluid should probably be taken also in the late evening or night, even at the cost of some nocturia, because of the sparse, concentrated and acid urine produced by the

Yii

kidneys during the night. Overhydration should be avoided because of possible adverse effects. Maintaining copious urine flow also serves to counteract the low urine pH of sluggish urine flow but usually not enough to avoid undue acidity of the urine. Alkalinizing agents then are given, with the objective of making the urine less acid, but not alkaline. To achieve urine pH levels of 7.0 or above when initially very low is often difficult, may be hazardous, and is usually unnecessary. The older patient with uric acid stone who may also have hypertension, cardiovascular and/or renal disease obviously should not be exposed to overloading with alkalinizing sodium salts and unlimited fluid intake; even if tolerated, overalkalinization favors the precipitation of phosphate in stone-prone patients. Moreover, as a glance at Figure 2 will show, the theoretic advantages in preventing uric acid precipitates by inducing a urine pH much beyond 6.5 are miniscule. The fact is that uric acid stones rarely form in urine at pH above 6.0. We consider, in agreement with Loeper and Cottet [708] and others, that maintenance of a urine pH of 6.0 to 6.5 is a proper objective in patients predisposed to uric acid nephrolithiasis; probably closer to pH 6.0 will prove to be sufficient in most cases. This range of urine pH can usually be maintained readily by appropriate dosage, divided over the day, of such alkalinizing agents as sodium bicarbonate, potassium citrate, citrate mixture or acetazolamide (this last reduces urinary citrate excretion, which may be disadvantageous in this setting [777]), or by various more palatable tradename alkalinizing mixtures. The urine pH should be checked periodically by the patient at home, for which purpose Nitrazine paper is convenient. We think it prudent in many cases of uric acid nephrolithiasis, particularly in hyperuricosuric patients, to avoid purine-rich foods and to limit the protein intake to not more than about 90 gm. per day (ample to maintain nitrogen balance) [772], although this admittedly is less important since the advent of allopurinol. The substantial increase in urinary excretion of uric acid after a meal rich in purines and proteins has already been pointed out. The diet is especially significant in the patient with primary gout and uric acid calculus because proportionately more amino acid nitrogen is diverted to de novo purine biosynthesis, as shown by glycine-lSN incorporation studies on a high protein diet [773] and by abnormally high urinary uric acid nitrogen : total nitrogen ratios AMERICAN

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Uric Acid Nephrolithias.s-Gutman.

771

Yii

L

NT%-N I

II

9’&”

Oxldose HCGC-N N

N

Xonthine

C-N %I

“0-A

I!i

i-N/ +N’

Xonthme -----f Owdose

,:

HN

A

&

g-NJ/ ‘N’

I n

Hypolanlhine

Xonthine

H c-l:

Uric

.C=D

r: acid

OH

t N?

”

\,C-: II )N

Xanthine

I H-C6 eC zN ,\?/ \I 1 N N

Osidose

I

H 4 -

Hydroxypyrozols

(3,4-d

I pyrlmldlne

4,6-Dlhydrorypyrozolo

( 3,4-dlpyrimidine

Top, catalysis by xanthine oxidase of the sequential oxidation of hypoxanthine to xanthine and of xanthine to uric acid. By inhibiting xanthine oxidase activity, allopurinol and oxipurinol interrupt this sequence. Bottom, conversion of allopurinol, an analog of hypoxanthine, to oxipurinol by the action of xanthine oxidase.

FIG. 3.

in gouty subjects, usually > 1.8 per cent in gouty subjects, <1.6 per cent in nongouty subjectswhen the dietary protein intake is 100 f 20 gm. per day [174]. Application of the general principles of adequate hydration, use of alkalinizing agents and regulation of the diet to the care of patients with uric acid nephrolithiasis need not be as haphazard as often in the past. It is possible to individualize treatment by calculating the concentration of undissociated uric acid in the urine under any given set of conditions (Fig. 2) and then to adjust the conditions to avoid excessive supersaturation of uric aicd, thus minimizing the hazard of uric acid calculus. For example, if as recommended the daily urine volume is 2 L. and the urine pH is maintained at 6.0, and the daily urinary elimination of uric acid is a reaof undissonable 600 mg., the concentration sociated uric acid in the urine would approximate 110 mg. per L., a very satisfactory result in view of the estimates [29] that 220 mg. uric acid per L. is required to saturate the urine at pH 6.0. On the other hand, if the daily urinary elimination of uric acid is the same but the urine volume is only 1 L. per day and the urine pH is allowed to persist at 5.0, the concentration of undissociated uric acid in the urine would approximate 510 mg. per L. whereas saturation of the urine with respect to uric acid occurs at about 60 mg per L. when the pH is 5.0. Precipitation of uric acid need not and probably would not ensue under these conditions, unless voi..

45,

NOVEMBER

1968

perhaps abruptly induced, because of the large capacity of the urine for supersaturation with uric acid but supersaturation is a prerequisite for uric acid nephrolithiasis and appropriate corrections should be made. Use of Allopurinol in Uric Acid Nephrolithiasis. The conventional measures thus far discussed suffice in 75 or 80 per cent of the cases of uric acid nephrolithiasis. In difficult or refractory cases, notably those with inordinate hyperuricosuria, it is often helpful to add allopurinol to the regimen. This drug (4-hydroxypyrazolo[3,4-D]p+midine), an antimetabolite analog of hypoxanthine, is a potent but usually well tolerated inhibitor of xanthine oxidase, the enzyme that catalyzes conversion of hypoxanthine to xanthine and of xanthine to uric acid (Fig. 3) ; by thus inhibiting the formation of uric acid, allopurinol (unlike uricosuric drugs) diminishes the concentration of uric acid in the urine as well as in the plasma. In the process allopurinol is converted by xanthine oxidase to its oxidation product oxipurinol (4,6-dihydroxypyrazolo[3,4-~lpyrimidine) (Fig. 3), which also inhibits xanthine oxidase. In fact much of the suppression of uric acid production ascribed to allopurinol appears to be effected by oxipurinol, which has a much longer biologic half-life in man (eighteen to thirty hours, due largely to tubular reabsorption of filtered oxipurinol) than allopurinol (about one and a half hours) [ 1751. Allopurinol was introduced in 1963 by Rundles et al. [716] for use in the treatment of

Uric

772

Acid

Nephrolithiasis-Gutman,

TABLE III CLINIC.AL

STATUS

NEPHROLITHIASIS

OF

108

BEFORE

PATIENTS

WITH

ALLOPURINOL

URIC

THERAPY

Clinical Status Renal colic and/or discharge of stone, gravel or sand, recurrent Obstructive uric acid uropathy Unilateral nephrectomy Pyelolithotomy or nephrostomy Appreciable proteinuria Azotemia Family history of Overt gout Lithiasis Gout and lithiasis

ACID

No.

88 47 16 15 29 26 27 13 15

the hyperuricemia of leukemia and primary gout. In testing this new drug we were particularly impressed with its potential in the management of difficult cases of uric acid nephrolithiasis as observed in nineteen such patients with primary gout and three with secondary gout: by reducing the urinary elimination of uric acid, the passage of stone, gravel or sand ceased fairly promptly ev-en when previously frequently recurrent [777]. Since our initial report our observations on allopurinol therapy for uric acid nephrolithiasis have been expanded to include 108 patients (of 400 patients with uric acid stone culled from a composite of 1,523 cases of primary gout, secondary gout and nongouty nephrolithiasis) of whom eighty-four had primary gout, eight myeloproliferative or other neoplastic disorder and sixteen hyperuricemia and/or hyperuricosuria of undefined cause. Only patients refractor)- to conventional measures were selected for treatment with allopurinol hence there was a high proportion of frequently recurrent lithiasis, obstructive uropathy and other complications in this series (Table III). The urine pH in these cases was distinctly acid, in the pattern already described, except in the instances of impacted “mixed” stones with urinar)- tract infection. The serum urate, which exceeded 10.0 mg. per cent in 70 per cent of the cases, fell to less than 7 mg. per cent in 90 per cent of the patients after treatment with allopurinol. The urinary uric acid excretion before allopurinol was in excess of 800 mg. per day in approximately half of the cases and over 1 gm. per day in about one third of them; after treatment with allopurinol it decreased to less than 600 mg. per day in about 90 per cent of the cases. Recurrence of renal colic and passage of stone,

Yii

sand or gravel soon ceased in all but ten patients, five of them with large “mixed” uric acid calculi and secondary infection, in the remainder as a result inadequate dosage usually due to inability to continue the use of allopurinol because of drug intolerance. In several instances there was a single delayed recurrence of stone, which was found to be composed of uric acid, not xanthine. That uric acid calculi may diminish in size in response to allopurinol therapy is suggested by the disappearance of radiolucent areas in serial pyelograms in two cases. Allopurinol was administered in divided dosage of 200 to 400 mg. per day (600 mg. in a few cases for short periods), depending upon response. About half of these patients have taken allopurinol for not less than two years, and ten for more than four years. In patients taking the drug regularly for several years the daily requirement sometimes seemed to diminish and the dosage could be reduced, in a few instances to half the initial amount, with adequate response. I n patients with renal insufficiency lower doses (100 to 200 mg. per day) were given because allopurinol not converted to oxipurinol is rapidly eliminated in the urine, oxipurinol more slowly [ 7751, and renal retention results in high plasma drug levels much more likely to elicit side reactions. Of side effects encountered in this series the more frequent were skin rash, often with drug fever, in five instances (our over-all experience with allopurinol is 6 per cent) and activation of acute arthritis in five cases of primary gout (our over-all incidence is 10 per cent). Unless administration of the drug is discontinued promptly the skin rash may be extensive, hemorrhagic and, in one of our cases, exfoliating. Since pruritus appears before the rash, this complaint should signal cessation of allopurinol therapy. Attempts to “desensitize” by beginning with very small doses after an interval were successful in two instances, unsuccessful in four; substitution of oxipurinol in one case elicited a prompt cross reaction. With respect to activation of acute arthritis in patients with gout, this occurred despite continued colchicine prophylaxis routinely given in doses of 1 mg. per day or more. Usually the tendency to acute attacks subsides in time, but the outbreaks were so severe and protracted in two patients that they refused to continue the allopurinol. Five patients complained of diarrhea and abdominal cramps, in one jaundice developed, none in this series was found to have a significant leukopenic AMERICAN

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Uric Acid Nephrolithiasis-Gutman, reaction (this occurred in two of our treated patients who did not have stone). Our results conform to the general favorable experience with allopurinol [ 118-1281 as a supplementary measure in preventing recurrence of renal colic and passage of stone, gravel and sand. It is useful for prophylaxis in those predisposed to uric acid nephrolithiasis, notably in patients with gout and in patients with leukemia and other neoplasia receiving cytolytic therapy,. It is indicated in the treatment of patients with obstructive uric acid nephropathy, acute or protracted. There is no convincing evidence? however, that allopurinol will reverse the insufficiency of chronic renal disease associated with retention hyperuricemia. SUMMARY

Available estimates indicate that about 10 per cent of all renal calculi encountered in the U.S.A. as a whole are composed of uric acid and that the prevalence of uric acid nephrolithiasis in the population at large is of the order of 0.01 per cent. In pathogenesis the critical factors are those that lead to supersaturation of the urine with respect to undissociated (free) uric acid, which is more sparingly soluble than urates, and the factors that lead to separation of solid phase uric acid from its saturated solution in the urine, with organized crystal overgrowth. In regard to the first, the importance of persistent undue acidity of the urine, hyperuricosuria and contraction of the urine volume is stressed; the controversial role of deficient urinary ammonium excretion in undue acidity of the urine is discussed. In regard to the second, it is concluded that initiating uric acid crystals probably form the nidus in most cases, seeds of calcium oxalates in some. An etiologic classification of uric acid nephrolithiasis is proposed and the various categories discussed : idiopathic uric acid nephrolithiasis; uric acid stones associated with inborn errors of metabolism, neoplastic disorders and hyperuricemia of undetermined cause; with dehydration; and with hyperuricosuria without hyperuricemia. Conventional medical management is reviewed. The beneficial effects of supplementary treatment with allopurinol in 108 difficult cases of uric acid nephrolithiasis are summarized, with illustrative case reports. ILLUSTRATIVE

CASE REPORTS

CASE 1. A fifty-one year old man (J.C.), had had recurrent attacks of renal colic with passage of sand VOL.

45,

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1968

Yii

--_(

3

every few weeks for four years. There was no hi>rur) of acute gouty arthritis in the patient or his famil\-; one brother had a calcium stone. When first seen hv us in 1965 the only noteworthy findings on physical examination were the presence on both ear lobes of several distinct tophi, said to have been prrsent for two years, and moderate clubbing of the fingers. The latter was attributed to bronchiectasis of the lo\\er lobe of the left lung first noted in 1941 hiit not c\-ident in chest roentgenograms taken in 1966. ‘l-here was no polycythemia. Pulmonary function studir< rcvealed only equivocal oxygen unsaturation. The serum urate was 9.4 mg. per cent. the urinary uric acid excretion was 600 mg. per day with a total nitrogen of 11 .O gm. The urine pH varied from 4.6 to 5.0, there was no proteinuria. the serum nonprotein nitrogen was 34 mg. per cent, serum creatinine 1.4 mg. per cent. Since starting allopurinol therapy, 300 mg. per day, serum urate has been maintained at about 5.3 mg. per cent, urinary uric acid excretion at about 360 mg. per day, and neither colic nor passage of sand has recurred. Comment: This case illustrates the fairly prompt and persistent response to allopurinol typical of most patients in this series. A4most unusual aspect of what is presumed to br primary gout was the development of tophi before onset of acute gouty arthritis; the evidence for secondary gout related to secondary polycythemia was unsubstantial. CASE 2. (Previously reported by Alexander and Brendler [728].) This patient (J.B.), a well developed and well nourished sixteen year old boy, had had yearly recurrence of renal colic and, or hematuria since the age of twelve. There was no history of joint pains. In October 1964 he was admitted to the hlount Sinai Hospital because of acute obstructive uropathy following another such episode, characterized by left renal colic, chills, fever and gross hematuria. Phvsical examination was otherwise within normal limits. Blood pressure was 180/100 mm. Hg. The urine \vas scanty on admission, contained many red cells and a few white cells. The blood urea nitrogen Lraried from 96 to 169 mg. per cent, serum creatinine 7.2 mg. per cent, inorganic phosphate 7.6 mg. per cent, bicarbonate 20.5 mEq. per L. The serum urate was 1’.8 mg. per cent, the twenty-four hour urinary uric acid excretion was persistently excessive, varying benveen 1 .O and 1.2 gm. with a total nitrogen content of 7 to 8 gm. Crine culture grew out enterococcus. Cystoscopy prior to admission had shown no efflux from either ureteral orifice; catheters were readily passed to both renal pelves, retrograde pyelograms had demonstrated normal collecting systems and ureters on both sides. Intravenous urography shortly after admission failed to visualize either collecting system. No calculi were seen. Alkalinization of the urine had no effect on the clinical course or on the serum or urine uric acid

774

Uric

Acid

Nephrolithiasis-Gutnlan,

levels but administration of allopurinol, 200 mg. per day, reduced the serum urate to 8.2 mg. per cent and the urinary uric acid excretion somewhat to 900 mg. per day within a week. Concomitantly the blood urea nitrogen level fell to 33 mg. per cent, the serum creatinine to 1.7 mg. per cent, the blood pressure to 140/90 mm. Hg, with rapid clinical improvement. An intravenous urogram revealed essentially normal kidneys. Following discharge the patient continued to take allopurinol, 200 mg. per day, for six months, then voluntarily discontinued taking the drug. Three weeks later left renal colic recurred, serum urate was 17.8 mg. per cent, urinary uric acid excretion 585 mg. per day (from one functioning kidney), blood urea nitrogen 20 mg. per cent; an intravenous urogram showed a normal right kidney, but the left was not visualized. Allopurinol therapy, 300 mg. per day, was reinstituted. Two days later the left ureteral obstruction cleared spontaneously, whereupon the urinary uric acid excretion was found to exceed 1 gm. per twentyfour hours. In a few days the serum urate was reduced to 6.1 mg. per cent, the urinary uric acid excretion to 420 mg. per twenty-four hours, and an intravenous urogram a week later showed normal visuahzation on both sides. The patient continued to take allopurinol regularly, and has remained free of symptoms. The serum urate has stabilized at about 7.0 mg. per cent; there are no indications of renal damage. This patient has a remarkable family history of renal lithiasis and gout. His father’s two aunts had renal lithiasis necessitating nephrectomy because of obstruction and infection. The maternal grandfather had tophaceous gout. Two of the four maternal uncles had recurrent urolithiasis, another had both urolithiasis and gout. One uncle (SD.) gave a history of bilateral renal lithiasis with anuria for thirty hours at age forty; he has had recurrences of lithiasis since then. His serum uric acid level was 9.8 mg. per cent and urinary uric acid excretion was excessive, 1,580 mg. per day. Another uncle (J.D.) has had recurrent lithiasis since the age of thirty-one, but passed the calculi spontaneously. His serum uric acid was 8.7 mg. per cent, the twenty-four hour urinary uric acid excretion 1,510 mg. Another uncle (J.E.D.), aged forty-one, and a maternal aunt (H.D.), aged fortyfive, are both normouricemic (5.9 and 4.9 mg. per cent, respectively) and asymptomatic. Both parents have been entirely asymptomatic but the father has a serum urate of 7.3 mg. per cent, the mother’s is 5.9 mg. per cent. One sister, aged twenty-four, has a serum urate of 5.7 mg. per cent. One uncle (H.D.), who is now fifty-five, has had frequently recurrent passage of gravel since age twenty, with blocking of both ureters by proved uric acid stones at age fifty-four. The serum urate then was 14 mg. per cent, the urinary uric acid excretion 1,060 mg. per twenty-four hours with a total nitrogen excretion of only 7.3 gm. His first attack of acute gouty arthritis was at age forty-one, and he soon

Yii

became tophaceous. Since taking allopurinol, 300 mg. per day, eighteen months ago his serum urate level has been maintained at about 4.9 mg. per cent, urinary uric acid excretion at about 345 mg. per day and there has been no recurrence of uric acid lithiasis,

Comment: Burdened with such a genetic background and so early victim to acute obstructive uric acid nephropathy, the prospect at best in this patient would be a fulminating course of primary gout with rapid development of renal insufficiency. The favorable response to allopurinol offers a more hopeful prognosis. CASE 3. When first seen by us in 1965, this patient (H.M.) was sixty-six years of age and gave a history of having had regional ileitis since 1952 and polycythemia vera diagnosed in 1957 when he was found to have a red cell count of 7.3 million per cu. mm., a hemoglobin of 20 gm. per cent and splenomegaly. In 1957 also he suffered the first of subsequently recurrent and protracted attacks of acute gouty arthritis. A year later renal colic and discharge of calculi began, and for about four years passage of uric acid gravel had been frequent. There was no familial history of gout or lithiasis. The polycythemia vera progressed, despite treatment, into the stage of myeloid metaplasia and by 1965 the liver and spleen almost filled the entire abdomen. There was cardiac enlargement with moderate dependent edema. Extensive tophaceous deposits appeared in and around the joints. The serum urate was 14.8 mg. per cent, urinary uric acid excretion 705 mg. per twenty-four hours with a total nitrogen excretion of only 8.6 gm., and the fresh urine contained gross uric acid precipitates. The urine pH was low, proteinuria was present. The serum nonprotein nitrogen was 40 mg. per cent, serum creatinine 2.4 mg. per cent. The red cell count was 3.81 million per cu. mm., hemoglobin 10.6 gm. per cent, white blood cell count 18,050 per cu. mm. with many immature cells of the myeloid series and characteristic abnormalities of the peripheral red cells. Administration of allopurinol, 300 mg. per day, decreased the serum urate to 10.3 mg. per cent, the urinary uric acid excretion to 555 mg. per day with disappearance of the uric acid precipitates. The dosage of allopurinol was increased, ultimately to 600 mg. per day, when his serum urate level fell to 6.2 mg. per cent, the urinary uric acid excretion to 438 mg. per day. There was no recurrence of renal colic or passage of uric acid gravel over the fifteen months to his death of acute intestinal hemorrhage as a complication of his underlying diseases.

Comment: There was prompt and sustained relief of renal colic and frequently recurrent passage of uric acid gravel and sand in this patient with gout, presumed to be secondary on the assumption that the polycythemia vera had been present for years before its discovery in the AMERICAN

JOURNAL

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MEDICINE

Uric sa111c )c’ar arthritis.

as his first

attack

Acid

Nephrolithiasis-Gr/man,

of acute

gouty

(1~s): 4. This sixty year old woman (Mrs. G. G.) gave a history of recurrent renal lithiasis since age thirty--one and right nephrectomy at age thirty-six. ‘l.en years later a transureteral ureterostomy anastomosing the left upper ureter to the stump of the right ureter was performed to relieve a left ureteral obstruction which had occurred after ureterolithotomy. In October 1965 hematuria developed. Retrograde pyelogram showed a fairly large radiolucent stone occupying the two lower calyces of the left kidney and extending into the renal pelvis. The urine contained a trace of protein, the serum nonprotein nitrogen was 42 mg. per cent, serum creatinine 1.5 mg. per cent. The serum urate was 12.7 mg. per cent, the urinary uric acid excretion 310 mg. per day. Alkazanr and allopurinol, 300 mg. per day, were started. The serum urate level fell to 5.4 mg. per cent, the urinary uric acid excretion to 200 mg. per day. The urine pH, previously very acid, was maintained at 6.5. In June 1966 and again in June 1967 no calculus could be demonstrated on retrograde pyelogram.

Comment: solution

This

of a large

case is cited uric

acid

to illustrate calculus

when

disthe

to 6.5 and allopurinol reduced the concentration of uric acid in the urine. urine

pH was brought

CASE 5. A thirty year old man (S.T.), had had ulcerative colitis for eighteen months when in September 1966 subtotal colectomy, with ileostomy, was performed. In December 1966 he began to complain of bilateral renal colic with passage of uric acid gravel almost every day. The urine volume was much reduced, the serum urate level rose to 14 mg. per cent. These complications were associated with malfunction of the ileostomy. When this was corrected, hydration resumed, and following administration of allopurinol, 300 mg. per day, his colicky pains disappeared, the appearance of uric acid gravel in the urine ceased and his serum urate levei fell to 5.4 mg. per cent.

Comment: This is an example of urinary discharge of uric acid gravel following dehydration as a result of malfunctioning ileostomy. The to conventional measures, suppleresponsr rnented with allopurinol, was striking. CASE 6. This fifty-seven year old man (A.M.) had had recurrent acute gouty arthritis for seventeen years, finally controlled with daily prophylactic colchicine. In the past ten years he had had three attacks of renal colic with hematuria. In 1957 an intravenous pyelogram was negative, but when repeated in 1962 revealed a small lucent calculus in the left kidney and three opaque ones in the right kidney. In 1957 and 1962 the patient had two bouts of substernal chest pain apparently due to diaphragmatic VOL.

45.

NOVEMBER

1968

infarction,

Yii which

left liim with

77’ I

angina1

pain.

r,

i’llc,re

was no family history of gout or renal lithiasis. When first seen in 1963 there were moderate tophaceous deposits at the left elbo\v. and minimal swellings at both first metatarsal phalaneral regions. The blood pressure was 170/l 10 mm. Hg. ()tller physical findings were unremarkable. The serum urate was 13.9 mg. per cent. twcntyfour hour urinary uric acid excretion 1.14.5 mg. \vith a total nitrogen content of 13.5 gm. The urine pH was 4.7, the urine contained a trace of all)umin, a few red cells and some white cells. Yrinc culture was positive for enterococcus. Various antibiotics failed to sterilize the urine. The administration of allopurinol. .300 mg. per day, reduced the serum urate to 6.5 mg. per cent and the urinary uric acid excretion to 450 mg. per day. While taking allopurinol, the patient had two attacks of renal colic and hematuria. Repeat intravenous pyelograms in 1965 failed to demonstrate the small lucent calculus in the left kidney but showed a large radiopaque calculus in the right kidnev for which pyelo- and nephrolithotomy bias performed. At the time of the operation three calculi were removed, and a portion of a calcuhn was subjected to chemical analysis. The outer layer contained 69 per cent calcium oxalate and 18 per cent uric acid. the middle portion contained 80 per cent uric acid and the innermost core was 85 per cent uric acid. No xanthine, hypoxanthine. allopurinol or oxipurinol was detectable. Subsequent to pyelolithotomy bleeding occurred, and the right kidney had to be removed. Examination of the kidney showed focal acute netrotizing pyelitis and a small area of recent infarction with acute inflammation. but no abscesses. Scattered hemorrhagic necrosis of renal parenchyma was present at the operative site. At the time of this writing, two years and eight months postoperatively. the patient is well. The urine is clear, the urine culture is negative, the serum urate level is maintained at 6.2 mg. per cent with allopurinol. 200 mg-. per (la)-.

In this instance an infect4 kidirey was the site of a “mixed” uric acid stone, the outer coat of which was layered with calcium oxalate and was resistant to allopurinol. On the left side, a “pure” uric arid stone apparently diminished in size enough to 1~ passed spontaneously and uneventfully. Comment:

on the right

CASE 7. A fifty-five year old man (M.E.) had liad right-sided renal colic about once a year for fifteen years until, in 1964, traumatic rupture of the right kidney led to its removal together with an enclosed staghorn “mixed” uric acid calculus weighing 32 gm. He also gave a history of yearly attacks of acute gouty arthritis for ten years, responsive to colchicine. When seen in 1964 postoperatively his serum m-ate, which had been 7.2 mg. per cent. was 12.7 mg. per cent, urinary uric acid excretion 530 mg. per clay serum nonprotein nitrogen 59 and serum creatinine

Uric

776

Acid

Nephrolithiasis-Gutman,

3.8 mg. per cent. The urine contained 4+ protein with hyaline and granular casts, and a few red and white blood cells. Urine culture grew nonhemolytic streptococci. Given allopurinol, 300 mg. per day, serum urate decreased to 6.7 mg. per cent and urinary uric acid excretion to 160 mg. per day; these levels were maintained. Nevertheless his renal status deteriorated, the serum nonprotein nitrogen and creatinine levels rose slowly but steadily, and he died in uremia after several months.

17.

18.

19.

20.

Comment: Despite a good response of the serum urate and urinary uric acid excretion to allopurinol, renal insufficiency presumably due to chronic pyelonephritis in the one remaining kidney progressed relentlessly, with death in uremia. REFERENCES 1. BUCHANAN, J. M. Enzymatic synthesis of purine nucleotides. Harvey Lect., 54: 104, 1958-59. 2. \VYNGAARDEN, J. B. Gout. In: The Metabolic

Basis of Inherited Disease, 2nd ed. Edited by Stanbury, J. B., Wyngaarden, J. B. and Fredrickson, D. S. New York, 1966. McGraw-Hill Book co.

3. GUTMAN, A. B. The biological significance of uric acid. Harvey Lect., 60: 35, 1964-65. 4. Yti, T. F., BERGER,L. and GUTMAN, A. B. Defective

5.

6. 7.

8.

9. 10.

11.

12.

13.

14. 15. 16.

conversion of uric acid to allantoin in the Dalmatian dog. Arthritis @ Rheumat., 9: 552, 1966. .ITSMON, A., DE VRIES, A. and FRANK, M. Uric Acid Lithiasis. Amsterdam, 1963. Elsevier Publishing Co. LONSDALE, K. Human stones. Science, 159: 1199, 1968. BEER, E. Uric acid and uratic stones in the kidneyuric acid showers and their diagnosis. Surg. Gynec. t?? Obst., 43: 436, 1926. PRIEN, E. L. and FRONDEL,C. Studies in urolithiasis. 1. The composition of urinary calculi. J. L’rol. 57: 949, 1947. CARROLL, G. and BRENNAN,R. V. The role of infection in nephrolithiasis. J. Ural., 68: 88, 1952. BOYCX, W. H., GARVEY, F. K. and NORFLEET, C. M., JR. The metal chelate compounds of urine. Their relation to the initiation and growth of calculi. Am. J. Med., 19: 87, 1955. MELICK, R. A. and HENNEMAN,P. H. Clinical and laboratory studies of 207 consecutive patients in a kidney-stone clinic. New England J. Med., 259: 307, 1958. HUGHES, J., COPPRIDCE, W. M., ROBERTS, L. C. and MANN, V. I. Oxalate urinary tract stones. J.A.M.A., 172: 774, 1960. NICHOLAS, H. 0. Urinary calculi. III. Further observations on calculi from patients in the Southeast Texas area. Clin. Chem., 7: 175, 1961. LEONARD,R. H. Quantitative composition of kidney stones. Clin. Chem., 7: 546, 1961. HERRING, L. C. Observations in the analysis of ten thousand urinary calculi. J. Ural., 88: 545, 1962. PRIEN, E. L. Crystallographic analysis of urinary

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31. 32.

33.

34.

35.

Yii

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OF

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Uric Acid Nephrolithiasism-Gufvmn, %I. ~~l.r.ro'i~, .I.S., %IAKP, K. F. and LEWIS, L. Urinary

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.50.

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.52.

53.

54. VOL.

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56.

57.

58.

59.

60.

61.

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67. 68.

69.

70.

71.

72.

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89.

90.

91.

92. 93.

94.

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97.

98.

99. 100.

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104.

105. 106. 107.

108. 109.

110. 111. 112.

113.

114.

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Yii

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JOURNAL

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1968

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4-hydroxypyrazolo(3,4-d)pyrimidine) on serum .rn(l urinary uric acid in primary and sccondaryv,out. .I/,/. ./. .U/d., 37 : 885, 1964. 11%. l
VOL.

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DECONTI, Li. C. a~ld CAI.ABKOSI. P. I-w (,f allopurinol for prrvention and control of hypcruricemia in patients with ncoplastic tlisraw .\.Pu I~~&artd J. .Ued., 274: 481. 1900. 124. Ll’.%rrs, K. \V. E.. \~'.ITKINS~ t'..l.,MAI IIIIAS. J. Q. and GIBBS, D. .\. .Allopurinol and acute uric acid nephropathy. &it. .\f. J., 1: 205. 1960. 125. KERSLEY, G. D. Pharmaceutical treatiiwnt of gout. Ann. I%yj. Med., 8: 199, 1966. 126. ANDERSON, E. E., I