Renal calculi

Renal Calculi T. D. R. H O C K A D A Y

LLOYD It. SMITH, JR.

TABLE

INCIDENCE

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SYMPTOMS AND SIGNS

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Symptoms .

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Signs

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Composition and Structure of Stones

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Concentration of Urinary CrystalIolds .

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PATIIOGENESIS OF STONES

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O t h e r Urinary Factors

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Site of Stone Formation .

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INVESTIGATION

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Presence and Effects of a Stone .

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Nature and Origin of Stones .

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TREATMENT

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Surgical T r c a t m e n t

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Medical T r e a t m e n t

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PROC,I'r

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58

Su.~t.xtARV

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60

is a Lecturer in Medicine in the Department of the Regius Professor of Medicine, The Radcliffe Infirmary, Oxford, England, to which he returned recently after a )'ear in the Endocrine Unit, Massachusetts General Hospital, as a Rockefeller Traveling Fellow. Dr. Ifockaday received his medical education at Brasenose College, Oxford University, a n d at the Middlesex tIospltal, London, where he held appointments in the Departments of Cardiology and Neurology. His chief interests lie in the investigation of metabollc disturbances.

is Chief of the Endocrine Unit, Massachusetts General IIospltal and Assistant Professor of Medicine at Ilarvard Medical School, from which institution he received his M.D. degree in 1948. Dr. Smith is on leave of absence during 1963-1964 as Visiting Investigator, Department of Biochemistry, Oxford University. His interests are inborn errors of metabolism, metabolic diseases and endocrine disorders.

"No stretch of chemical or physical imagination will permit so heterogenous a group of compounds [as renal stones] to be ascribed to a common origin, or their disposition in kidney, ureter, or bladder to be uniformly charged to an identical cause."--How~a~n KrLnv.

K I D N E Y S T O N E S were early known and early treated. At first, treatment was mainly surgical, and it was essentially simple in its aim to take stones out of the kidneys with as little renal damage as possible. Operation, however, often damaged or removed renal tissue; and, in severely afflicted patients, it did not prevent recurrence of stones. Surgery, therefore, was no more than palliative for these patients. Can stones, once formed, be dissolved? O r can stone formation be prevented? Medical treatment has aimed to do these things; but dissolution of stones (large enough to be detected by x-ray) has occurred rarely and, therefore, hope has centered on stone

prevention. So far, prevention has been successful only in certain Small groups of patients in whom a cause for the formation of stones was understood (e.g., hyperparathyroldlsm, cystinuria); no preventive treatment for the majority of patients has yet become established. To understand any such treatment, whether it be discovered by accident or design, one must know what stones are made of, what leads to their formation and how they form when they do occur. The pathogenesls of stones, therefore, is considered here, in addition to the more obviously necessary topics of the incidence of stones, the symptoms and signs that they cause, what investigations may help in clinical diagnosis and possible treatments for stone. The Greek physicians were well aware of urinax3' calculi, and especially of their frequent occurrence in boys. Surgery, confined to a perlneal approach, was common; but Hippocrates advised a plentiful fluid intake, and his followers swore to forgo "cutting for the stone?' The first recorded operation for renal stone was performed in 1474 on a man condemned to death because he had stolen from a church (1). This criminal, the Archer of Meudon, was known to suffer from urinary calculus, and surgeons petitioned the king to allow them to perform a renal operation on the Archer. Their plea was granted and the operation performed, but there is no record of whether a stone was removed. The patient recovered from the operation and was well 10 days later. It is not clear how long a "follow-up" medieval law allowed. More conventionally, Marchettis carried out successful nephrollthotomy in 1633, again in France, but a fistula persisted for 10 )'ears (1). In this monograph, no distinction (in general) will be made between renal stones and those found elsewhere in the urinary passages. In America and western Europe today, only about 5% of urinary tract calculi originate outside the kidney and its pelvis. In following the style of DISEASE-A-MONTH reviews, references will be given only to review articles and reports of particular note. INCIDENCE

The true incidence of kidney stones in the United States is not known. Several studies have been carried out in attempts to ar-

rive at reliable estimates. Data from a survey by questionnaire of hospitals (about a quarter of which made a satisfactory return) indicate that approximately 0.9 person per 1,000 of the population enter a hospital each year because of renal stones (8). There is considerable variation in incidence within the country, with

SURVEY OF THE $ YEARS 1945-1952 FIVE YEARS 1945-1952 Genital Hasp. Adm~st~ons--Tola| . . . . . . $1,266,42| General Hasp. Adm~ss;ons--$uryeyed..~17,463,335 Per Cent of Gen. Hcsp. Adm. Surveyed.._21.$ Total Adrn. for calculi . . . . . . . . . . . . . . . . . . . . . . . 124,353 Adm. far cQlcul; per 1000 G. H. Adm.__..7.1 Estimated |otaJ G. H. Adm. for colcul; ..... 576,99Z

(~ ONE YEAR 1952 17,760,057 4,046,006 2Z.$ 29,924 7.4 131,42.1

[]

Adm. Io Gen. Hasp. per 10~0 pop. |1950) Adm. for Calculi per ICr G. H. Adm. Av. per year for 5 years, 1945-52

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Area of highest |nc~dence

Fro. 1.--Incldence of cases of urinary calculi among patients admitted to general hospitals during 1918-52, inclusive. (Reproduced, with permission, from Boyce, W. H., Garret-, F. K., and Strawcutter, H. E.: J.A.M.A. 161 : 1437, 1956.) the highest rate in the Southeast (Fig. 1). During 1952 there were 1.9 hospital admissions for urinary tract calculi per 1,000 people in South Carolina, contrasted with 0.6 in New Mexico. This suggestion of a relatively high incidence of stones in the South and Southeast was also noted in examinations for military sen,ice in World War I and in a survey directed to members of the American Urological Association (9). Apart from errors 7

inherent in survey technic, figures derived from hospital admissions must underestimate the total occurrence of kidney stones. Most patients with urinary calculi have a single small stone which may be passed spontaneously or with the aid of cystoscopie manipulation alone. In addition, renal stones may not be diagnosed, either because they never cause sufficient symptoms to prompt examination or because the necessary investigations are not made. In a survey of 25,000 autopsies of hospital patients in Philadelphia, the incidence of kidney stone was 1.12% (5). In 0.38~b, urolithiasis was thought to be an important contributory cause of death. In England in the middle of the last century, nearly half the patients with urinary calculi were children and a relatively high proportion of stones were vesieal. In Europe and North America, children are now rarely affected (especially if the rare genetic disorders specifically conducive to stones are excluded) ; whereas in India, Southeast Asia and China, urinary stone continues to be a children's disease. In the United States, symptomatic kidney stones most frequently occur between the ages of 30 and 50 years, with males predominating from 1.15 : 1 to 1.41:1 over females. An epldemie of urolithiasls occurred in central Europe after World War I and persisted for at least 20 years (17). The apparent incidence of stones increased about tenfold. Although no cause was established, several investigators stressed the increased consumption of certain vegetables. There may be a familial diathesls for urinary stone. In a minority of patlents--such as those with cystinuria, gout, primary hyperoxalurla or xanthinurla--the stones are manifestations of inherited recognizable metabolic faults. (These conditions will be considered individually later.) But more common types of stone also seem to have an increased familial occurrence. A Norwegian physician listed 15 cases of urolithlasis from five generations of his own family. In a recent survey in Ireland, the incidence of renal and gallbladder stones in the parents, siblings and children of noncystinurle patients attending a kidney stone clinic was compared with the incidence in a control group matched for family size and age (29). Sixteen parents of 174 patients with urinary stone had had renal stones, compared with only 1 parent of a control patient. For siblings, the numbers were 15 and 4, respec-

tively--again, a highl)" significant difference. The difference was not explicable by hypercalciuria. Tile two groups had an equal incidence of gallstones among their relatives. Such a study does not exclude the effect of environment or dietary habits, as opposed to a genetically transmitted diathesls for stone formation. No environmental factor has been found constantly related to stone formation. No clear-cut geologic difference distinguishes the "stone belt" of tile Southeast from its surroundings; nor do the districts around the world in which urinary stone is common have a constant geologic feature. Climate has been thought important, through low rainfall, low fluid intake and, so, low urine volume. However, stone is said to be almost unknown in the Sudan, where the rainfall is very small and thirst is general. Perhaps a racial factor is involved ( 1). In summary, kidney stones occur frequently, and they are important in the production of disability and death. Perhaps 150,000-200,000 patients enter hospitals annually in the United States because of renal stones (8). From one autopsy series (5), it can be estimated that approximately 19,000 patients die annually with stones, and that, in 6,300, death would be attributable to the complications of urolithiasis. For comparison, the national mortality statistics record 1,200 deaths from urinary stone throughout the United States in 1959. SYMPTOMS AND SIGNS

The cardinal symptom of renal calculus is pain. Less frequently, either gross hematuria or symptoms caused by urinary infection, or even tile passage of a small stone or "gravel" in the urine, may be the main evidence of the presence of a stone. Paradoxically, large stones long resident in the kidney often cause few symptoms, while small stones that have already left the kidney give rise to severe pain as they traverse or lodge in the ureter. SY~IPTO~IS PAIN.--Pain from a renal stone may be felt while the stone is hn the kidney, the ureter, the bladder or the urethra. The most typical pain is that often called "renal colic," which consists of

periods of severe pain, usually lasting from 5 to 30 minutes. During this time the pain increases in severity, often with short intervals of partial relief, only for the pain to return more severely than before. Shortly after the pain finally reaches its maximal severity, it begins to ease, usually waning over the same length of time that it waxed, but sometimes much more rapidly. The severe pain is as though deep tissues were being gripped and twisted or torn. It is usually felt in the "renal angle" (between the twelfth rib and the erector splnae), but it may be experienced anywhere along a line that runs caudally and ventrally round the flank above the superior anterior iliae spine to the illac fossa, groin and external genltalia--ln the distributions of the eleventh thoracic to the second lumbar dermatomes. The pain is usually so severe that the patient cannot bear to be still and constantly writhes about the bed. The pain of renal colic probably is related to a rise in pressure in the renal pelvis and ureter above an obstruction, rather than to excessive peristaltic activity in these regions (39). Pressure recordings and x-ray studies have demonstrated either no change or a decrease in peristalsis above an experimental ureteral block. Except where it runs obliquely through the bladder wall, the lower ureter is remarkably less sensitive to local distention than is the upper ureter. For example, a pressure of 150-190 mm. Hg was not usually felt in the lower half, while the average pressure necessary to elicit pain in the upper half was 33 mm. Hg. This is a little less than the maximal renal filtration pressure. The typical pain of renal colic can be reproduced by intraureteral balloon inflation, during which pain starts in the corresponding costovertebral angle. Inflation of a balloon within the intramural part of the ureter produces a sharp burning sensation, felt deeply just above the pubis or in the urethra. Pain from renal colic does not move downward from the renal angle as a stone descends the ureter but, while persisting there, spreads into the more caudal of the seg'ments ( T l l - L 1 ) that correspond to the innervatlon of the upper urinary tract (39). A true shift of the focus of the pain occurs only with entry of the stone into the intramural ureter, when a burning sensation is felt in the groin or just above the pubis, together with a desire to urinate. Until the stone enters the bladder cavity, there may be l0

increase of pressure above it, and continuing renal pain may mask these vesieal symptoms. Rarely, pain may be referred farther and be felt in the thigh, sole of the foot or even in the area of the contralateral kidney (1). Renal colic is always accompanied by anorexia and frequently by nausea and vomiting. Small bladder stones rarely cause pain, but large ones may cause suprapubic pain or urgency of mlcturltion. When a stone passes along the urethra, there is often severe pain in the penis, especially at its tip. A persistent mild ache in the renal angle may accompany a stationary intrarenal calculus over months or years, with exacerbations produced by sudden movements or change in posture. H~.~raTURra.--Vislble hematuria may occur at any time in association with kidney stones, but it more often follows than precedes pain. It may occur without pain. Bleeding from the renal pelvis may lead to formation of a small clot whose passage down tile ureter may give all tile s}anptoms of renal colic. The blood is usually evenly mixed with the urine, as distinct from urethral bleeding, in which most of the discoloration appears at tile beginning of the stream. INvEcTIo,~.--Urinary tract infection is frequently present in patients with kidney stone, althoug}~ it is much more common when stones have been recognized for a long time titan when the diagnosis of stone is first made. Urinary frequency, urgency, dysuria, nocturla (or return of enuresis in the young) and, in acute cases, manifestations of systemic infection may occur in the absence of colic or hematurla or may complicate ureteral obstrnetlon. With neglect, p)'onephrosls may result. URE~nA.--The complex of symptoms and signs associated with uremia may occur with bilateral loss of renal function secondary to hydronephrosis, pyelonephrltls, associated nephrocalclnosis or direct renal injut3, from large stones.

SIGNS Physical examination of a patient whh renal calculus is of no help in making a positive diagnosis. However, it has two important aspects. First, from it the physician gains a clearer idea of the focus and radiation of tile patient's pain than from any conversation with the bedclothes pulled up. Second, from the 11

physical findings, other causes of acute abdominal pain may be excluded. Very rarely, sig'ns outside the trunk may suggest a metabolic background for stone formation--such as tophi in gout, or an epulis or other palpable bone cyst in hyperparathyroidism. PATHOGENESIS OF STONES

All kidney stones cannot have a common pathogenesis, because they vary so much in composition. In general, kidney stones occur either when there is an increased concentration of constituent crystalloid in the urine or when some other change has occurred in the urine or in the urinary tract epithelium conducive to stone formation at normal crystallold concentrations. A review of the pathogenesis of kidney stones should consider the structure and composition of stones, the concentrations of urinary crystallolds and how they may vary and, finally, other noncrystalloid changes in urine and urinary tract that possibly are important in protecting against, or in disposing toward, stone formation. CO]~fPOSITION AND STRUCTURE OF STONES

All stones contain complex organic substances, of such molecular size that they form colloidal solutions when pure. Conversely stated, kidney stones are not composed solely of agglutinated masses of inorganic or organic crystals. The protein content (largely mucoprotein) comprises, on the average, 2 . 5 ~ of the dry weight of a stone. Despite this relatively smMl amount, there has been much debate over the role of protein in stone formation. These colloid elements, just like the crystalloid, usually have an organized distribution within a stone, including the areas close to the stone's center (center of origin, not geometric center, since stones often grow eccentrically). Do the crystallolds come out of solution because of local effects in the neighborhood of certain types of colloid, and so does a stone originate around colloid? O r arc the colloids deposited at regular intervals upon the surface of a growing crystallold mass? Or is there a true "symbiosis," precipitation of either favoring deposition of the other? Again, one answer is not to bc expected for all stones. 12

S T O N E C R Y S T A L L O I D S . - - T l l e relative frequency of stone composition (reported) varies with geographic area, age of the population, incidence of infection, economic status, date of the study (i.e., the calcium oxalate "epidemic" in central Europe of a generation ago) and the accuracy of the analytic procedures employed. The two largest and most reliable series for the United States, both derived mainly from New England, are in reasonably close agreement (33, 37) (Table 1). TABLE

1.--CRYSTALLOID COMPOSITION OF STONES r TOTALNo. OF STONES Collection Stones AnabTed of I,t'D0 from 155 Stones* Pat~ents'~

Calcium oxalate Calcium phosphate--hydroxyapatit e hydrogen phosphate dihydrate Calcium oxalate and calcium phosphate Magnesium ammonium phosphate with either calcium oxalate or calcium phosphate Uric acid (including stones with calcium oxalate) Cystine

33 3 2 34

23 17

19

13 11 2

6

3

26

* Ref. 37 as source. f Ref. 33. In the original reference, 52 cases were not analyzed.

In addition to these major types, stones containing xanthlne and alkapton piganent have rarely been reported in xanthlnuria and alkaptonurla, respectively, while silicate has also been found occasionally as a major constituent of stones from patients ingesting large amounts of silicate, usually the magnesium salt as an antacid. All kidney stones obtained should be analyzed, and every effort should be made to obtain stones [or analysis. Usually this is done chemically, according to well-tried technics (28, 30). It may be emphasized that this is essentially a qualitative procedure rather than an accurate quantitative analysis. The defects of chemical analysis have been cogently stated (37). An inclusive answer is obtained for a body that is not homogeneous and may vary considerably in composition from part to part; no idea of the relationships of the parts is obtained; and the presence of compounds that are not present may be deduced. Thus, a chemical report of calcium, magnesium, ammo13

nium and phosphate omits tile frequent finding that the magnesium ammonium phosphate is present only in the outer layers of the stone and therefore has had little to do with formation of tile original calcium phosphate nucleus. Also, a stone consisting predominantly of calcium oxalate may have a small central nucleus of uric acid. Calcium carbonate does not occur in renal calculi, although its presence is deduced from chemical analysis. In fact, the carbonate ions form part of the crystal lattice of apatlte, the mineral form in which calcium phosphate usually occurs in stones. Most often crystallization occurs in the hydroxyl form Calo (P04)c (OH)o, but sometimes with carbonate instead of the hydroxyls. The possible alternative to chemical analysis is use of the polarizing microscope. This involves the initial expense of purchase and need for considerable experience in using the instrument but then has the advantages of speed and sensitivity over chemical analysis, as well as the theoretical advantages previously mentioned. Another possibility is x-ray diffraction analysis; but this is more expensive, tedious and insensitive than polarogmphy, although in the past it has been valuable in verifying identification by optical crystallography. An experienced physician can tell much about tile composition of a stone by study of its surface, both intact and on section, both naked-eye and with a hand lens. Calcium oxalate.---The substance most commonly found in calculi is calcium oxalate, and a large number of calculi have its monohydrate as the sole crystallold. The dihydrate, never found alone, often forms the outer portion of a stone with the monohydrate centrally located. It seems likely that the more insoluble dihydrate precipitates first and later changes to the monohydrate. The stones are commonly mammillated like a mulberry, or covered with spiky projections or small irregular crystals. Also, because they have scarified tile epithelium, these stones are usually stained brown with blood plg-ment. Occasionally, if small, the stones are smooth and look like pebbles from a river bed. Relatively few of these stones, if sectioned, show very definite organization with both radial striations and concentric laminations. These 14

stones are always opaque to x-ray (even if not invariably seen on x-ray of the patient) (Fig. 2, A). In urine sediment, calcium oxalate crystals are characteristically colorless, glistening and octahedral, giving the "envelope" appearance of a square crossed diagonally by two intersecting lines (these are the dihydrate crystals) (Fig. 2, B). Rarely, dumbbells, spheres or other variants are seen. The crystals are insoluble in sodium hydroxide but will dissolve in strong hydrochloric acid. They can occur in alkaline, as well as in acid, urine. Calcium phosphate.--Pure apatite stones with an organized crystalline structure may be an untarnished white. The more common stones, in which the calcium phosphate is deposited amorphously and is often mixed with either calcium oxalate or magnesium ammonium phosphate, are dirty white with an irregular, granular outer surface and often an unorganized cut surface. If the triple phosphate predominates, as it often does in the outer part of a stone, the surface is bluish gray, smooth and hard. These stones, inasmuch as they contain calcium, are also opaque to x-rays, but less densely so than calcium oxalate or cystine stones (Fig. 3, A) ; also, they appear less homogeneous by x-ray than do those two types. A concentrle lamellar structure may be apparent. In the sediment, amorphous phosphates are found most frequently, either as single small granules or clusters of them (Fig. 3, B). Calcium phosphate has two, more distinct, crystalline forms in urine. The basic phosphate (of which apatite is a derivative) is known as "stellar phosphate" because its colorless prisms may be arranged in stars and rosettes. The individual prisms are slender, with one beveled end, but they may be needle-like. More common is the acid salt, which forms thin, irregular, usually granular, colorless plates of typical appearance, except that small plates may be mistaken for squamous epithelial cells. The acid salt may be incorporated into stones as its dihydrate, but it occurs in only 1% of calculi. These phosphate crystals all dissolve readily in acetic acid and are found in alkaline urine. Magnesium ammonium phosphate.--Magnesium ammonium phosphate (triple phosphate) occurs mixed with calcium phosphate in stones. Once it has appeared during stone growth as a predominant element, the nature of further deposits will not 15

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FIo. 2. A, x-ray of bilateral calcium oxalate stones. B, ealclum oxalate cx3-stals in urinary sediment. (Fig. 2, A [and subsequent x-rays] from collection of x-rays by Dr. Fuller Albrlght. Fig. 2, B reproduced, with permission, from Maurice, P. F., and Henneman, P. H.: Medicine 40:315, 1961.)

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Fxo. 3.--A, x-ray of bilateral calcium phosphate staghorn calculi in a patient with renal tubular aeldosls. B, amorphous phosphate crystals and calcium phosphate cast in urinary sediment. (7, triple-phosphate crystals, of magnesium-ammonium-calcium phosphate, in urinary sediments. (B and C from Maurlce, P. F., and Henneman, P. H.: Medicine 40:315, 1961.)

17

change (e.g., all outer layer of calcium oxalate will not develop), perhaps because the responsible infection is never eradicated. The opacity to x-rays depends on the degree of admL,:ture with calcium phosphate. These mixed stones are often large. Triple-phosphate crystals are colorless, and in shape they are modified prisms, colloquially called "coffin llds" (Fig. 3, C). If their long axis shortens, tile)" closely resemble calcium oxalate crystals but do not have the same luster, and, also, they readily dissoh'e in acid. They occur in alkaline urine and usually point to

B..

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e 25"Fxo. 4.--A, x-ray of stone with a urle acid center, made visible by surrounding calcium oxalate. B, pleomorphie uric acid crystals in urinary sediment. (B from Maurice, P. F., and Henneman, P. H. : Medicine 40 : 315, 1961.) infection with an ammonia-producing organism (Bacterium proteus, Staphylococcus, Escherichia coli). Uric acid.--Uric acid stones usually have uric acid as the sole crystalloid, but about a fifth of them also contain calcium oxalate. They are yellow or reddish brown with a hard, highly polished surface, smooth or slightly mammillated. Uric acid calculi are not opaque to x-rays and so can only be shown in the urinary tract by contrast with opaque media. Occasionally a urate center may be visible, in contrast to a surrounding opaque stone concretion (Fig. 4, A).

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When uric acid is plentiful in urine, red grains may be seen, with the naked eye, adhering to the sides of the container. These most pleomorphic of crystals lnav appear as rosette-like clusters of prisms and whetstones, red or yellow from adsorbed urinary pigments, or even as rhombic plates (Fig. 4, B). Occasionally there are colorless hexagonal plates that resemble cystine crystals. Uric acid crystals are easily dissolved by sodium hydroxide and are found in the more acid urines. Cystine.--Cystlne stones are smooth, polished, translucent and waxy, yellow or green in color, and have radial striations on their cut surface. They are radiopaque and have the most uniform appearance of any stone (Fig. 5, A). Cystine crystals, which are colorless, highly refractive, thick hexagonal plates with well-defined edges, occur either singly or in irregular columns (Fig. 5, B). The)" dissolve readily in hydrochloric acid and so may be distinguished from uric acid. Their growth may be encouraged by acidifying urine with glacial acetic acid to between pH 4 and 5 and placing the specimen in a refrigerator for a few hours. STONE

PROTEIN

AND

ITS

RELATION

TO

CRYSTALLOIDS.---Thc

stone proteins make up what is usually called "the matrix," but this implies a "container" and so a theory of stone formation not yet established. As noted, all stones contain protein in a relatively constant amount, averaging 2.5% of their dry weight. The proteins in calculi are not the same as those in the ground substance of bone, nor are they a selection of the total protein of urine. Their major constituent is similar to, but not identical with, the uromucoid group of proteins present in urine. Recently King and Boyce found a protein in stones which is identical immunologically with a protein often found in the urine of patients with stones but absent from normal urine (26). Investigation of these relatively insoluble proteins is difficult and far from complete, but is being pursued by modern inethods of protein chemistry. The relationship between the ct)'stalloid and protein elements of a stone may vary widely, from a regtdar, highly organized interwoven pattern to a disordered intermixture without discernible pattern. Two typical arrangements can be contrasted (10), but, naturally, many intermediate fon'ns occur. Stones whose 19

B FIG. 5. A. x-ray of cystine calculi. B, cystine crystals from urinary scdimcnt. (B, from Maurice, P. F., and tlcnneman, P. H.: Medicine 40:315, 1961.) -

0

Q t

20

0

main feature is a radial striation of the surfaces exposed by fracture have been called "concretionary"; the striation may be so prominent that it can be seen with the naked eye. Concentric laminations are always present in areas of radial striation and, indeed, may overshadow the latter. Radial striations occur only in areas where there is a single crystalloid. Such stones are hard, and there is usually a nodularity to their outer surface. They formed 42% of 500 consecutive stones examined (10a). This strncture is more common in calcium oxalate or uric acid than in apatite stones. T h e basis of the structure is thought to be the alignment of colloids around crystals to form a gel in whose interstices further crystallization occurs, according to the pattern imposed by the structure of the gel. The colloid gel serves to shield crystallization from disturbance by convection currents or other irregularities. The colloid matrix determines tile structure of the stone, but its strength depends on the continuity of the crystalline element which has formed in the aqueous phase of the gel. These stones, if freshly recovered, always have a closely adherent muclnous layer which is in position to align tile next phase of crystallization and to be incorporated, itself, into the organic matrix. In contrast with these radially striated, "concretionary" growths are "crystalline" or "sedimentary" stones, in which the shape depends on the crystalline element but the strength depends on an abundant but amorphous organic component. These stones are most commonly made of well-formed calcium oxalate crystals in disordered aggregates in whose interstices there are crystals of calcium phosphate as apatite. Individual crystals may be 1 ram. or more in size. The organic mucoid phase maintains the structural integrity, for, if such a stone, with basic calcium phosphate as its main constituent, is placed in normal hydrochloric acid, the phosphate crystals dissolve but a coherent mucoid mass remains. In contrast, in hot 4N sodium hydroxide solution (in which calcium phosphate is insoluble) the stone disperses into a fine white cloud. In the growth of these stones, the association between crystals and mucopolysaccharide is less precise, and it is not dependent on the geometry of the crystals, so that the colloids condense into 21

a coherent mass about which more crystals, often of different types, grow without constant orientation, their size and direction ultimately determining the shape of the stone. This mode of formation is possibly illustrated by the observation that in a recumbent patient the first evidence of stone may be a hazy, but large, "staghorn" shadow on x-ray which subsequently develops much more in density than in size. Again~ a calculus which appears clearly defined on x-ray may, at operation, prove to be a thick putty-like sludge, which on drying assumes the ordinary appearance of a phosphatic calculus (10b). In these examples a "sedimentary" type of growth is postulated~ but one in which the density of cr)'stal deposition relative to colloid accretion has been slight. Extreme instances of such growth are given by the radiotranslucent masses in the renal pelvis observed in 6 patients from whom calcium phosphate stones had previously been removed by open operation and who had then been placed on a Iow-calclum, sodium phytate regimen, with a decline Of the urinary calcium to under $6 rag./24 hours. On analysis, the stones were found to contain inorganic ash, largely calcium phosphate, in amounts up to only 28--46~ of their dr}" weight and othenvise contained complex organic compounds similar to those found in any decalcified calculus. Concentric lamination, but not radial striation, was present. Such a preponderance of the colloid element in these stones has been used to support the belief that the colloid element is primary in stone formation (7). Stones are not sharply divided between those with concretionary and those with sedimentary structnre. A stone may have a center of one type and outer layers of the other structure, or the stone may be a mixture of the two forms. But the distinction may have importance for understanding stone formation, for hypercalciufia is more common in patients with stones of sedimentary structure ( 4 3 ~ ) than in those whose stones are either completely concretlonary or have radial striation in their outer parts (15% with hypercalclurla) (3). In summary, in this section the crystalloid and colloid constituents of stones have been described. The various crystallolds may be identified from characteristic properties of the crystals, which 92

float free in urine, while stones of varying compositions can sometimes be identified by direct inspection. Exact analysis requires chemical or polarographic methods. The colloids are mainly glycoproteins and are beginning to be identified by electrophoretic and immunologic methods. The two elements are intermingled in formed calculi, sometimes according to a precise pattern (concretionary stones) and sometimes less formally (sedimentary).

CONCENTRATION OF URINARY CRYSTALLOIDS An increased concentration of urinary crysta]loids may be the most important factor in inlt]ating or furthering stone growth. Such an increase may occur because of rcduction of urinary water, secondaryto dehydrationor, more commonly,through an increase in the excretion of tile crystalloid. There is little evidence to suggest that increased urinary excretion of orthophosphate promotes stone formation; but increase in tile excretion of calcium, oxalate, urate, cystine, xanthine or ammonia has been thought to cause stone formation. CALcIu,x~.--Approximately 90~ of kidney stones in the United States contain calcium. Most of the calcium filtered b y the glomerulus is reabsorbed by tile renal tubule. The renal excretion of calcium is a complex function, and it is difficult to control tlle many variables involved in studies on calcium clearance. These variables include: tile plasma concentration of calcium; its protein binding (and therefore its filtration); complex formation with anions; the rate of sodium excretion, at least at high urine flow rates (44); and tile action of parathyroid hormone. Recently, parathyroid hormone has been shown to increase the tubular reabsorption of calclum (46) ; this effect is often overshadowed by the attending hypercalcemla with excessive glomerular filtration of calcium. Whatever its orlgln--excessive filtration (i.e., hypercalcemla) or diminished tubular reabsorptlon--the urinary calcium may be an important determinant of stone formation. On an ordinary diet, urinary calcium does not usually exceed 150-900 mg./24 hours. The level of urinary calcium alters little with alterations in calcium ingestion because of limited net absorption from the

23

intestine. Over the past two decades a number of investigators have described an increased frequency of hypercalciuria in stone patients, varying from 66% (15) to 33% (33) to 20% (3) of the patients studied. Some of the variation is due to the level of urinary calcium chosen as normal and the degree of dietary control. The kidney stone which develops in an uninfected hyperealciuric patient may be made of calcium oxalate, calcium phosphate or varying mixtures of the two. Many disorders are associated with persistently increased renal excretion of calcium and, therefore, with an increased tendency to stone formation. The most important of these are: primary hyperparathyroidism, acute osteoporosis, sarcoldosls and berylliosis, vitamin-D intoxication, renal tubular acidosis, neoplastic bone destruction and excessive calcium ingestion. When this group of disorders has been excluded, there remain those patients uneasily diagnosed as having idiopathic hypercalciuria. These conditions will be considered briefly in relation to stone formation. Primary hyperparathyroldism.--As noted previously, hyperparathyroidlsm increases urine calcium because it raises serum calcium despite its action of increasing renal tubular reabsorptlon of calcium. I-Iypercalciurla does not invariably accompany hyperparathyroldlsm, even in the presence of hypercalcemla and normal renal function. It is generally agreed that the renal manifestations of primary hyperparathyoldism are those most frequently encountered, with detectable bone involvement (as judged by x-ray or reflected in serum alkaline phosphatase) occurring in a minority of cases (perhaps 25%). The percentage of patients who have exhibited kidney stones at the time of diagnosis of hyperparathyroidism varies from 49 (2) to 78 (21) in large series. Of patients seen with nephrolithlasis within a hospital setting, approximately 5-10% (21, 33) are found to have hyperparathyroidism on subsequent investigation. Hyperparathyroldism can no longer be considered an extremely rare disorder. Approximately 1% of patients with peptic ulcer may have hyperparathyroidism (47), and a frequency of 1 case per 1,000 hospital admissions has been reported (30). The large and controversial subject of diagnostic tests for hyperparathyroidism has been reviewed recently and will not be considered 24

in detail here. We believe that the levels of serum phosphorus, alkaline phosphatase or ionized calcium, the presence or absence of hypercalciuria, the various calcium infusion tests as presently employed and tile mechanisms for expressing renal tubular transport of phosphorus are rarely of aid in the diagnosis of primary hyperparathyroidism. Tile most valuable positive findings are unexplained hypercalcemia and, more rarely, characteristic x-ray evidence of osseous invoh'ement, partlcularly subperiosteal bone resorption. Accuracy in the repeated measurement of serum calcium is more elusive than widely realized (30). The most promising new development in the diagnosis of parathyroid disease is the recent preliminary report of a specific radioimmunoassay for circulating parathyroid hormone (6). Coupled with calcium infusion, this may allow a direct demonstration of parathyroid autonomy. Acute osteoporosis.--Ninety-nine per cent of the body's calcium is in bone. Neoplastic destruction of bone or any imbalance in the normal processes of born. a'emodellng will release this calcium in excess. There is current controversy as to whether osteoporosls, which may be crudely defined as decreased mass of bone of normal composition, is caused by failure of osteoid synthesis or increased bone destruction. In the elderly patient with senile or postmenopausal osteoporosis, this imbalance, whatever its mechanism, usually occurs over a long time, and there may be a major loss (30-50%) of bone calcium without significant daily hypercalciuria. No increased incidence of kidney stones has been observed in this group. In a minority of patients, osteoporosis occurs more acutely, with severe hypercalciuria and stone formation. This happens most frequently on immobilization of the young after injury, but also with paralytic immobilization at any age, with immobilization of patients with the high bone-turnover rate of Paget's disease, in Cushing's syndrome and in thyrotoxicosis. The high incidence of renal and vesical calculi in paraplegics has been well documented. In one series, 21 of 44 patients with severe paralytic poliomyelitis developed kidney stones (13). Here there may be additional factors, such as overventilation by an artificial respirator with compensatory alkalinization of the urine and 25

urinary retention, with its predispostion to infection by the organisms likely to be introduced at every catheterization. In Cushing's syndrome, whether iatrogenlc or spontaneous, hypercalciuria is common and 20-309b of patients with spontaneous Cushing's syndrome have nephrolithiasis. I-Iypercalciuria frequently occurs in thyrotoxlcosis; the abnormality of bone is perhaps a combination of acute osteoporosls and osteitis fibrosa. Many have observed, however, that this hypercalciuria is rarely associated with stone formation. This also seems true of the osteoporosis and hypercalcluria of acromegaly. Sarcoidosis and berylliosis.--Sarcoidosis and the sarcoid-like granulomatosis associated with beryllium intoxication may be associated with hypercalcemia and hypercalciuria. The incidence of hypercalcemla reported in a large series of patients with sarcoidosis was 17v~ (:32). Hypercalciuria may be complicated by stone formation, nephrocalcinosis and irreparable renal damage. Tile disorders of calcium metabolism in sarcoidosis include excessive absorption of calcium from the intestine, simulating hypervitamlnosls D. There is no current satisfactory explanation as to why this occurs in some patients with sarcoid. The hypercalcemia and'hypercalciurla can be reversed by glucocorticoid therapy. Usually, the diagnosis can be strongly suspected from extrarenal manifestations of the disease, including hyperglobulinemia, and can be established by biopsy. Rarely, the hypercalcemlc symptoms and complications dominate the clinical picture, closely simulating primary hyperparathyroidism. Vitamin-D intoxicatlon.--Excesslve intake of vitamin D may result in hypercalcemla, hypercalclurla, metastatic calcification, nephrocalcinosis, kidney stones and renal failure. Generally, the serum phosphorus is normal or elevated in contrast to the tendency toward hypophosphatemia of primary hyperparathyroidism. The diagnosis is primarily based on a history of vitamin-D intake. Fortunately, this disorder is becoming rarer with the decline in the use of the vitamin in the therapy of arthritis. Normocalcemic hypercalciuria commonly occurs during the treatment of hypoparathyroidism with vitamin D. As in the case of sarcoid, the hypercalcemia of vitamin-D intoxication usually responds promptly to glucocortlcold therapy. 26

Renal tubular addosis.--Renal tubular acidosis, familial or acquired, is characterized by an inability to attain a high gradient in hydrogen ion concentration between tubular urine and the renal tubular cell. This failure to excrete a urine of normal titratable acidity is associated with systemic acidosis (hyperchloremic acidosis) and a tendency toward renal wasting of potassium, sodium and calcium (2). Tile syndrome may be complicated by hypokalemic paralysis or osteomalacla, but more commonly it presents with kidney stones and nephrocalclnosis. The cause of hypercalcluria is not clear; and, indeed, when the patient is studied, the urine ealclum is often found to be normal or even low. The diagnosis of renal tubular acidosis is established by tile demonstration of hyperchloremlc acidosis with inability to attain greater urine acidity than pH 6.5-6.0. Provocative tests with aeld loads may help to expose tile defective renal acldifieation mechanism. Neoplastic bone destruction.---Destruction of bone by metastatic tumor or by multiple myeloma is probably the most common cause of hypercalcluria. Kidney stones rarely result, probably because of the limited duration of the disorders. Certain tumors, particularly carcinoma of the lung and kidney, may be associated with hypercalcemia and hypophosphatemia in the absence of direct invasion of bone by neoplastic tissues. It is assumed that such tumors release a parathyroid-like substance that produces tile changes in calcium metabolism. Stone formation has not been a frequent finding in this group of patients---once again, probably because of the limited duration. Excessive calcium ingestion.--The average daily c~ilcltimintake for an adult in the United States is approximately 1.2 Gm. Although some cheeses are rich in calcium, in practice rnilk~ which contains approximately 1 mg~ of calcium per milliliter, is tile only source of any large increase in dietary intake. Calcium is so poorly absorbed from tile intestine that the urine calcium rises by only 100-200 rag. after drinking 2 quarts of milk (ca. 2 Gm. calcium). Such modest hypercalciuria secondary to habitual excessive milk ingestion is probably of importance in increasing the likelihood of stone formation, but this has not been established. After prolonged ingestion of milk and absorbable alkali in the 97

treatment of peptic ulcer, there may be impaired renal function, with azotemla, hypercalcemla, systemic alkalosls and metastatic calcification. At this stage of the milk-alkali syndrome, renal insufficiency prevents hypercalcluria, although stone formation may occur and nephrocalcinosls is frequent. A large series of patients with acute reversible hypercalcemia associated with the treatment of peptic ulcer has been described (45). Previous impairment of kidney function was suggested to be common to the minority of patients so treated who exhibited this complication. Ingestion of alkali is not known to increase calcium absorption from the intestine or to affect directly its renal clearance. Systemic alkalosis may promote metastatic calcification, including nephrocalclnosls, but occurrence of the latter in renal tubular acidosis does not support this. ldlopathic hypercalciuria.----Whenthe known causes of hypercalciurla have been excluded, there remains a group of patients who have persistent normocalcemlc hypercalciuria in the absence of demonstrable bone disease. These patients are usually sccn first in middle life and are commonly male. Some tend toward hypophosphatemia, but serum calcium and alkaline phosphatase levels are normal (33). The pathogenesls of this syndrome or group of syndromes, is not clear. Primary hyperparathyroidism has been excluded in a number of these patients by neck exploration and identification and biopsy of all four glands. Absorption of calcium from the intestine appears to be increased, as in sarcoidosis; but, in contrast, the hypercalclurla is not reduced by glucocorticoid therapy. On the other hand, it has been reported that trapping calcium in the intestine with ingested phytate can reduce urinary calcium (30). Improved methods for measuring calcium absorption, clearance and bone dynamics, together with a specific assay for parathyroid function, may allow future clarification of this category-of-convenlence. OxanATz.--Oxalate is an important crystalloid constituent in perhaps one half to two thirds of stones in the United States. It is of even higher relative incidence in the stone areas of Southeast Asia. Although calcium oxalate cr)'stals have long been identified in urine, reliable quantitative methods for measuring oxalate excretion have become available only in the past decade. 28

On a diet of nonnal oxalate content, the 24-hour cxcretlon of oxalate in the adult averages 31 rag. (range 10-50 rag.) ; in the child, 33 mg./1.73 m -~ (range 10--60 mg.) (16). ~Iost of the urinary oxalate is formed within the body, since oxalate is poorly absorbed from the intestine (only 2-5~b of that ingested appears in the urine). Studies with isotopic oxalate show it to be a metabolic end-product, not further metabolized in man. The pathways by which oxalate may be formed are illustrated in Figure 6. Current evidence suggests that approximately 40~b of oxalate is HO I

SERINE

"

L

9

HYDROXYPROLINE

II

HOC-COH l

H Glycolote

IT

H 0 I

II

~i~

|1

J

II

HC-C0H

HzN-C-COH H

/ : Hydroxyg lulomale

Glyoxylole

Glulomole

- CO z + HCOOH Formale

1.-f

71 .i

Glycine

1

J f. 1"

ASCORBIC ACID--

0 0

? -

-

-

-

II

-

-

n

-~ HOC -COH Oxalate

Fzo. 6.--Pathwa)'s in oxalate synthesis. derived from the glycine pool and that an equal amount is formed from tile first two carbon atoms of ascorbic acld. It may also be formed from glycolic acid and, more remotely, from tile catabolism of hydroxyproline, the amino-acld characteristic of collagen. The only known immediate precursor of oxalate is glyoxylate, ahhough it has not yet been established whether ascorbic acid goes through this two-carbon intermediate prior to oxalate formation. Current methods do not allow accurate measurement of plasma oxalate concentration, so that no reliable value for its renal clear29

ance is available in nmn. Tile clearance of isotopic oxalate in the dog approximates glomerular filtration rate; i.e., there is no net tubular reabsorptlon. If a similar clearance rate pertains in man, and if all plasma oxalate is uhrafilterable, the plasma concentration cannot exceed 0.02 rag./100 ml. Most patients with oxalate kidney stones do not excrete excessive urinary oxalate. Their stones form in a urine of normal oxalate content because of hypercalciuria or because of other changes in the urine itself (pp. 38--44). Hyperoxaluria may occur after excessive ingestion of oxalate or its precursors, during p)'rldoxine deficiency and in tile genetic disorder, primary hyperoxaluria. Many vegetables are high in oxalate content (notably broccoli, rhubarb, spinach and tomato). As with calcium, most of the oxalate ingested is not absorbed; but a significant increase of urinary oxalate follows excessive ingestion of oxalate, and this may increase the long-term tendency toward stone formation. Some increase in urinary oxalate may occur after ingestion of large amounts of such precursors as ascorbic acid and glycine, but the doses required exceed those approachable with natural diets. Ethylene glycol intoxication is also characterized by acute hyperoxaluria, but death or recover), occurs before stone formation. Pyridoxine deficiency leads to hyperoxalurla and metastatic deposition of calcium oxalate in experimental animals, presumably because of a block in tile transamlnase reaction between glyoxylate and glycine (Fig. 6). In man, pyridoxine deficiency has not been established as a cause of hyperoxaluria and stone formation, although this deficiency has been considered to underlie the high incidence of calcium oxalate stones among children in Southeast Asia. Slight elevations of urinary oxalate have been described in a few patients with hepatic cirrhosis. The most important disorder in which excessive urinary excretion of oxalate clearly leads to stone formation is primary hyperoxaluria. Primary hyperoxaluria is a rare genetic disease characterized by persistent excessive urinary excretion of oxalate. Approxlmately 50 well-authenticated cases have been described in the past decade, with equal distribution in males and females. The disease is probably much more frequent than this, as may well appear with accurate measurement of urinary oxalate in patients 30

with recurrent calcium oxalate nephrolithiasis or with nephrocalcinosis. In most cases of primary hyperoxaluria, symptoms have appeared in early childhood with rapid progression to death in uremia within a few years. ~'Iore recently, a few cases have been found in adults with recurrent stones. Renal damage results from hydronephrosis, pyelonephritis and calcium-oxalate nephrocalcinosis. At postmortem there is oxalosis, a widespread deposition of calcium oxalate. The exact mode of inheritance of primary hyperoxaluria is unproved; but the equal sex incidence, occurrence in two or more siblings in eleven families, consanguinity in three families, and absence of stone diathesis or of hyperoxaluria in parents are all consistent with transmission as an autosomal recessive trait. The diagnosis of primary hyperoxalurla depends on persistent excessive excretion of oxalate, usually more than 100 reg./day. Diagnosis may be established by the demonstration of oxalosis. In the absence of evidence of decreased excretion, of decreased destruction (normally oxalate is not metabolized) or of increased absorption, the accumulation of oxalate is thought to be secondary to an increased rate of formation. The only immediate precursor of oxalate so far identified in mammalian systems is glyoxylate. Recent studies have demonstrated a block in the metabolism of isotopic glyoxylate in patients with primary hyperoxaluria, with increased conversion of the compound into urinary oxalate and glycolate (Fig. 6) (16). Excessive excretion of glycolate was found to be as characteristic of the disease as excretion of oxalate; but, since glycolate is readily soluble, this alone would not cause kidney stones. The exact enz)zne involved in this abnormality of two-carbon acid metabolism has not been identified despite study of liver biopsies from patients. Presumably, a genetic block in one of the metabolic pathways of glyoxylate has led to its accumulation with a secondary diversion into oxalate and glycolate. C),stine.--Cystine is a normal constituent of urine, and 20--60 rag. are excreted daily. The plasma concentration of cystine is approximately 0.8 rag./100 nil., and clearance studies have demonstrated that, normally, about 96-98% of the cystlne t h a t is filtered is reabsorbed by the renal tubules. In this active reabsorp31

tion, there is competition with other diamino acids (ornithine, lysine and arginine) for a common mechanism. A small percentage of the cystine measured in urine is excreted as cysteine, but this is spontaneously oxidized to cystine. Urinary cystine is partly derived from ingested cysteine and cystine, but most of it comes from methionine along the pathway shown in Figure 7. Cystine kidney stones constitute about 1 - 2 ~ of tile stones found in most large series, although the percentage in childhood is higher (27). Although some excess of urinary cystine occurs in all of the generalized aminoacidurias, the excess is large enough to form stones only in the genetic disorder cystinurlz/. In fact, S--CH 3

SH

I

I

CH2

~

CH2

HOCH2

[ -[--

CHNH2

~

S - -

CH2

]

I

CH2

CHNHz

I

I

I

I

CH2

CH2

COOH

CH2

]

I

I

CHNH2

CHNH2

CHNH2

I

I

I

COOH

COOH

COOH

Methionine

Homocysteine

Serine

HS- CHz

I ~

CHNH2

I

I

COOH

COOH

Cystathionine

Cysleine

Fro. 7.--Formation of cysteine from methioninc.

cystine owes its name to its discovery as the major constituent of a bladder stone. Cystinuria is transmitted as an autosomal recessive trait, but with differing degrees of penetrance in heterozygotes. In some families, heterozygotes excrete a sig-nificant excess of cystine and lysine; in others, no chemical abnormality can be demonstrated. The incidence of heterozygous cystinuria is estimated at 1 in 250500 persons; of homozygous cystinuria, 1 in 80,000-900,000 persons. Cystinuria presents clinically only with recurrent stone formation, usually beginning in childhood. It is really a disorder in the transport of four amino acids---cystine, lysine, arginine and ornithine--which have a superficial chemical resemblance and share a common transport mechanism (Fig. 8). The excretion of 32

lysine usually exceeds that of cystine, but none of tile other three amino acids are as insoluble as cystine. Stone formation is likely when the excretion of cystine exceeds 250-300 rag. daily. Excretion of a mixed disulfide of cysteine and homocysteine has been reported. Recently evidence has been obtained that there is imAMINOAClDURIA OF CYSTINURIA (Harris) C OOH l H-C-NHz H'C'H S

N -""~TOm~J

H H-C-NHz H-C-H D:

o: ,55

H-C-NHz COOH

H-C-NH2 COOH

6/sh'ne

Zys/ne

1055

.HN=C-NH2

q-H

H-(~-H

N-- ~ 25rng

H- C,-H H-C-NHz COOH

D= 739

.-C,-H

Argia/ae

H-C- NHz

tJ: 0

H-C-H H-r COOH

D= 3BO

.-,C-H

O/aitMae

8.--Structural formulas of the four dibasic amino acids involved in the transport defect of cystinuria. Figures are given for normal (N) 24-hour urinary excretion levels and the average values in some patients with cystinurla (D). Fio.

paired transport of the same four dibasic amino acids across the intestinal mucosa in patients with cystinuria (35). This is the probable explanation of the older observations that oral cystine fails to exacerbate cystinurla and of the presence of increased bacterial degradation products from the colon (putrescine, cadaverine) in the urine. This impaired intestinal absorption has no known clinical significance in cystinuria. Attempts to demonstrate a similar 33

genetic transport defect across other cell membranes in cystinuric subjects have so far been unsuccessful. Although competitive inhibitlon of transport for tile dibasic amino acids (with the exception of cystine) can be demonstrated in vitro, using kidney slices, the enz)wnatie mechanisms involved have not been rigorously defined. Cystinuria has been described in certain animal species, including the blotched genet, the mink and a breed of Irish terrlers. The diagnosis of cystinuria is established by analysis of a stone or by the measurement of excess urinary cystine, preferably with the chromatographic finding of the four dibasic amino acids in excess. The reaction to the nonspecific nitroprusside test is usually positive in the presence of excess disulfide. Generally, cystine "benzene-ring" crystals are demonstrable in concentrated acidified (acetic acid) urine specimens (Fig. 5, B). Therapy will be considered in a later section. URIC ACID.---Uric acid is the major constituent of about 5 ~ of kidney stones in the United States. In man, uric acid is the end-product of purine metabolism and is formed by pathways outlined in Figure 9. Isotope incorporation data (using glycine or 5 (4)-amino-4 (5)-imidazolecarboxamide) have suggested a "uricotelic shunt" with direct formation of uric acid without prior incorporation of the purine precursors in tissue nucleic acids (40). This evidence, based largely on the time of appearance of isotopic precursors in urinaI 3' urate, may equally well be explained by a more rapid turnover of one cell population with early release of its nucleic acids, or the effect of rapid turnover within cells of certain nucleic acids, such as messenger ribonucleic acid (RNA). Uric acid is formed from ingested purlnes as well as from those synthesized in the body. In the adult, the synthesis of uric acid on a low-purlne diet is approximately 500-1,100 reg./day. Approximately one quarter to one third of the uric acid formed is destroyed by bacteria after its secretion into the intestine. Although man does not have uricase to convert uric acid to allantoln, uric acid can also be destroyed by certain other enzymes, such as the verdoperoxidase of leukocytes. Most uric acid is not destroyed but is excreted by the kidney. The serum level of urate in men, measured by a specific spec34

.-T C

~ ~ rv~

g

T

z

~

X

=d

~

C',l

'w

m

''-'9

1~1~

w ~-

~

35

oo

trophotometric uricase technic, is 5.1 -4-S.D. 0.93 mg./100 ml. (40). Plasma urate is completely uhrafilterable. Its net clearance is approximately 8 ~ with a normal 24-hour urinary urate of 270600 rag. on a low-purlne diet. There is now good evidence, summarlzed elsewhere (18), that uric acid is both reabsorbed and actively secreted by the renal tubule; the clearance technic measures the net result. The known causes of uric acid stone are excessive excretion of uric acid and excessive urine aeldity. In some patients, neither of these factors is present. Urle acid stones occur in 20-30% of patients with primary gout and in 30--40% of those with gout secondary to proliferative disorders, such as myeloid metaplasla, polycythemla vera, leukemia and lymphoma. Excessive renal excretion of uric acid is present in only about 20-25% of patients with primary gout but in most of those with secondary gout, although inereased serum uric acid is an almost universal feature in both groups. The hyperurieemia associated with proliferative disorders seems clearly the result of increased turnover of nucleic acids and possibly purine nucleotides. No single pathogenesls has been established for the hyperuricemla of primal')" gout (40). Overproduction of uric acid has been found in only two thirds of patients by available methods; the remainder show a decreased renal clearance for the level of hyperuricemla. The decreased urate excretion may be indirectly produced, as is that which accompanies the hyperlactacldemla of glycogen storage disease. The excretion of urate may also be reduced by the progressive renal damage associated with gout (characterized by interstitial urate deposits, infection and obstructlon secondau" to stones) and with the alleged increased incidence of nephrosclerosls. Treatment with antineoplastic drugs or irradiation may temporarily exaggerate the increased urinary urate in patients with proliferative diseases. A similar effect occurs in patients with primary gout early in their treatment with urlcosuric drugs. Most patients with uric acid stones do not have gout and do not excrete excessive amounts of urinary uric acid. The solubility of uric acid in urine is strikingly less than that of its sodium or potassium salt. Urine pH, which determines the ratio of urate ion to free uric acid, therefore directly determines urate solubility. 36

At pH 5.0, only 8 rag. of urate is soluble per 100 ml. of urine, so that urine must be supersaturated in order to excrete the usual uric acid load in a normal urine volume. At pH 7.0, the solubility of urate rises to 158 mg./100 ml. urine. The urine pH is, therefore, the major determinant of urate solubility. Henneman found excessive urinary acidity without systemic acidosis in a group of patients with uric acid stone diathesis (22). He has suggested that the primary defect is in renal tubular formation of ammonia, so that a urine of greater acidity is needed to excrete excess hydrogen ion. A similar persistently acid urine may occur in some patients with diarrhea and fecal loss of cations. Because of the direct effect of pH on urate solubility, the treatment of uric acid stones is primarily that of alkallnlzatlon. A~iMomA.--Urinary ammonia has two sources: (a) renal tubular cells, which make it from glutamlne in response to excess hydrogen ion, and (b) bacteria in the urine. Tubular secretion of ammonia is important in stone formation only when deficient, as in some patients with uric acid stone dlathesis. Excessive urinary ammonia, ahvays of bacterial origin, is important because it produces both increase of ammonium ion concentration and patholo~e alkalinization of the urine, which favors precipitation of calcium phosphate and magnesium ammonium phosphate. Ammonia is produced from urea by the enzyme urease, found in a number of bacteria, including Bact. proteus and Staphylococcus. The importance of infection in stone formation is difficult to assess. Undoubtedly, many calcium oxalate and phosphate stones form in urine which is sterile. In one survey (9), infection was thought to be of importance in 47% of the stones formed; while in the Boston series, only 3 out of 207 cases of stones were thought to be based primarily on infection (33). The importance of secondary infection, however, was emphasized by the fact that 31 of these 207 patients were judged to have stones caused by infection secondary to the original calculus. In 22 of these 31 cases, magnesium ammonium phosphate was a stone constituent. Hellstrom analyzed 750 cases of renal and ureteral stones from a large Swedish hospital and estimated 22% to be infective in origin (20). In this group with infection as the cause of stones, the infective agent was the Staphylococcus (usually Staph. albus) 37

in 75~Io of tile cases. These low-grade pathogens cause little destruction of renal substance, ahhough they produce well-marked inflammatory changes in the pelvic epithelium. Sometimes a primary oxalate stone is found, around which a typical triple-phosphate stone has grown. Bacterial infection may promote stone formation in other ways, some of which will be discussed in tlae next section. XnNTrlINE.--Xanthine cannot easily be measured separately from hypoxanthine (the corresponding 2-deoxy compound). The concentration of these two purlnes together in plasma is from 0.1 to 0.3 rag./100 ml., and hypoxanthine is thought to be the major component. The net tubular reabsorption, again of the two compounds summed, is from 68 to 88~b of that filtered. Xanthine stones are rare, and in only 1 of the 34 cases recently reviewed (48) had urinary xanthine been measured. Its concentration was raised, as was the plasma concentration; but this patient may be unusual, for both serum and urinary uric acid concentrations were low. In other patients with xanthlne stones, serum and urinary" acid have been normal o r increased in amount. Of the foregoing 34 patients, 6 were under 15 years of age. In no instance was stone formation familial. In two thirds of the patients, the stones were pure xanthinc; but in the others, stones were composed of a mixture, with uric acid.

OTHER URINARY FACTORS All stones arise because the urine contains more of a substance than it can hold in solution. The changes that may occur in the concentrations of urinary crystalloids which are constituents of stones and how these changes may lead to stone formation have just been described. In over half of all stones, however (if those formed in infected urine are excluded), there is no abnormality in the urinary concentration of the crystalloid that forms the stone. In these cases, changes in a variety of factors have been suggested to be the cause of stone formation. These factors include the "saltlng-ln effect," the concentration of substances which antagonize stone formation, the amount and type o f urinary proteins and the effect of stasls and infection. 38

"SALTING-IN-EFFEGTS."~One phenomenon, the supcrsaturation of liquids, has caused some confusion because the phrase has been used in different ways. A liquid is supersaturated with a crystalline solid only when it contains more of the substance in solution than the liquid can hold in suspension. The inevitability of crystallization is inherent in the definition and does not depend upon encounter with some unevenness of the fluid's boundaries. Supersaturation is much less likely to occur in the presence of irregular surfaces, because these provide foci about which crystallization can occur. The important variable with supersaturated solutions is the length of time before crystallization occurs, and this depends largely on the substance concerned. Presumably, during this interval molecules are becoming orientated into submicroscopic particles, and it is the speed of this micellar formation that determines the duration of supersaturation. Crystallization of calcium oxalate from solutions of relatively simple chemicals mixed so as to mimic urine in their concentrations occurs, if at all, within 15 minutes, while calcium phosphate may require as long as 24 hours. Substances are often more soluble in aqueous solutions of simple compounds than they are in water itself. A compound may be present without supersaturation in urine at a concentration above that which could remain dissolved in water because simple substances, both electrolytes and nonelectrolytes, present in urine increase its solubility. Thus, sodium, added to water either as its chloride or dihydrogen phosphate in a concentration similar to that at which it occurs in urine, increases the solubility of calcium oxalate threefold (19). Potassium has a similar effect, and magnesium is especially potent. Nonelectrolytes are also effective; thus, the addition of 3 Gm. of urea per 100 ml. doubles the solubility of calcium oxalate. Presumably, this "salting-in" effect, shown as a nonspecific property by many simple ions and molecules, results from their suppression of the chemical activity of the ions and molecules likely to precipitate. PROTECTIVE SUnSTANCES.--If a mock urine is prepared by adding simple substances of known composition to water in approximately the concentrations at which they occur in urine, calcium oxalate is as soluble in this artificial urine as in natural urine 39

(34). Natural urine, however; has a greater capacity to maintain calcium phosphate in solution than has mock urine, although the artificial urine holds ahnost as much calcium phosphate in solution for 15 minutes after mixing as does natural urine. One or 2 hours after mixing, the superiority of natural urine is clearly evident (see Table 2), but this difference has decreased again at 4 and 24 hours. Such findings have stimulated a search for the substances in urine responsible for this capacity, which is over and above the nonspecific "salting-ln effect" found sufficient to explain the difference between urine and water for calcium oxalate. T A B L E 2 . - - V A R I A T I O N OF DISSOLVED CALCIUI~I P H O S P t I A T E 1,V'ITII T I ~ I E * AVER_~OE FILTRATE CALCIU.~! IN MO./IO0 ML. Hr. 1 Iir. 2 fir. 4 tlr. 24 lit.

Natural urine Artificial (mock) urine

36 30

33 18

26 14

19 14

17 12

~ Ref. 43.

Magnesium and citrate were tlle first to be recognized as ions that are particularly effective in increasing the solubility in mock urine of both calcium oxalate and calcium phosphate. Magnesium ion at a concentration of 32 rag./100 ml. more than doubled the solubility of calcium oxalate in water, an effect almost as great as that of 2 Gm.[100 ml. of sodium. Citrate is even more effective, and 100 rag.J100 ml. of sodium citrate increases the solubility of calcium oxalate sevenfold. Extra magnesium or citrate added to mock urine increases the time during which the urine can remain supersaturated. T h e action of citrate can be explained by its formation with calcium of a nonionized complex; and because of this property, variation in urinary citrate has been suggested to be important in stone formation. Most observers of urinary citrate, however, have not recorded the urine pH, with which the concentration of citrate changes. When patients with infected urine are excluded, patients with stones are found to have normal citrate excretion. Another compound that increases calcium solubility is pyrophosphate; addition of this to the first preparations of mock urine lessened their difference from natural urine by about 15%. A recent report has suggested that pyrophosphate may be reduced in 40

the urine of habitual stone formers (14). Also, an unidentified substance that passes through the semipermeable membrane on dialysis of normal urine increases the capacity of mock urine to maintain a supersaturated solution longer and may be similar to the active fraction identified by studies with rat cartilage. Stone formation has been likened to the calcification of cartilage. Some urines (called "good") do not bring about calcification of rachitic rat cartilage suspended in them, while other urine specimens (called "evil") cause calcification (24). Interestingly, patients with calculi pass many more specimens of "evil" urine than do people without calculi. The "good" or "evil" nature of urine is unchanged by boiling, by changing the pH to 1 or to 12, by passage through activated charcoal, by incubation with papain or hyaluronldase or by dialysis and subsequent concentration of the dlalysate back to the original specific gravity of the urine. Although all these experiments point to a small and stable molecule as the determinant, comparison of "good" and "evil" urines has shown no consistent difference in the concentrations of calcium, sodium, potassium, chloride, metaphosphate, organic acids and magnesium, although interesting effects in relation to magnesium have been found. By adding enough magnesium, any urine can be made "good" in the cartilage test; and by removing magnesium, any urine can be converted to "evil." From experiments on the removal and replacement of the divalent cations, it has seemed that "evil" urine has an increased capacity to divert magnesium from its action of preventing calcification (36). Passage through a Dowex cation-exchange resin does not remove the substance(s) in urine which are largely responsible for maintaining calcium in solution in the presence of excess phosphate, but a weak anlon-exchange resin removes them. Attempts to isolate this substance(s) continue; there is some evidence that it is a highly acidic peptide (24). URINARY PROTr~INs.--Protein is an integral part of all stones and must be derived either from the surrounding urine or from the kidney. The urinary proteins, therefore, have recently been studied both in patients with stones and in normals. About 250 rag. of nondial)Table substances are normally passed in the urine each day; these are mostly proteins, and mainly glycoprotelns 41

with tile carbohydrate moiety constituting as much as 409~. No lipoproteins have been found among these substances. One third of the proteins in urine are serum proteins with all the electrophoretic fractions represented, ahhough in altered proportions. Thus, tile albumin:globulin ratio is about 0.5. Other proteins have recognized functions--e.g., chorionic gonadotropin. By electrophoretic and immunologic methods, certain other proteins have been identified--e.g., the Tamm-Horsfall protein, which has been shown to coat crystals growing in a solution containing it (31). Another protein or group of proteins similar to TammHorsfall protein in some respects is uromucoid; this probably forms most of the noncrystalloid fraction of calculi. Proteins can affect the solubility of crystalloids in water, and it has been suggested that urinary colloids may either favor or prevent stone formation. But, as Randall wrote in 1937, "these fascinating suppositions lack only tile two essentials of tangible fact and unquestionable troth" (38). Patients with stones have a urinary protein content 10-15 times the normal. This increase includes many of the proteins of normal urine, although not all to the same extent. It is possible that in patients with stones the kidney handles many proteins abnormally. Increases in the total nondialyzable solids, as measured by the Boyce technic, are also observed in noncalculous renal disease. In a recent review of urinary colloids, it was concluded that "every single colloid component demonstrated by free or immunoelectrophoresis with antl-human serum to be present in normal urine has also been found in calculous urine and conversely" (31). One possible exception was noted, an r protein which Boyce found only in urine from patients with stones. More recently, Boyce has identified immunologically a protein which is present in all calcium-containing stones and often in the urine of patients with stones but is absent from urine from normal persons or from patients with renal disease but no stones. It has not been found in human serum. It has recently been reported that this "matrix substance A" can be extracted from kidneys from stone patients but not from normal persons (26). If the presence and distribution of this protein is confirmed, it would be of great importance in relating urine proteins to stone 42

formation. But before the urinmT proteins (even the apparently specific ones demonstrated by Boyce) can be accepted as a major cause of stone formation, their presence in the urine of people without calculi must be shown to be a reliable indicator of future stone formation. INFECTION AND STASlS.--Clinlcally, tWO factors have been clearly recognized to promote stone formation: (a) infection and (b) stasis, or sluggish flow, of urine. The presence of foreign bodies has also been noted as a rare cause of stones. Infection with certain organisms markedly increases the urinary concentration of ammonia with rise of pH. Although bacteria have been rec%maized within, and even cultured from calculi, examination of centers of stones has not shown bacteria to be of any importance physically in the initiation of stone formation, and immunologic study has not found bacterial protein an important component of stone protein. The influence of infection on stone formation has varied widely in frequency with different series-from 4 7 ~ for all stones (9) to 2 ~ in formation of a first stone (33). Infection may alter the urinary epithelium so that its surface is more favorable to stone formation. This has never been established, although metaplasia of urinary epithelium has been thought the important factor in the purely experimental formation of stones in animals deficient in vitamin A. Stones impair drainage of urine, and so does the damage done to the kidneys both by stones and by the manipulations necessary for their removal. Stasis of urine is also caused by congenital defects; or by acquired obstructions of the ureter, or, more commonly, the urethra; or within vesical diverticula. Stasis gives time for stones to grow, for precipitation from supersaturated solutions, and perhaps for the structure of proteins to become ahered. Obstruction to drainage may have its main action in encouraging infection, for infection is common with stasis, while stones are not particularly common in patients with obstruction but without infection. The presence of a foreign body as a nldus for stone formation sometimes has been thought important; and, both clinically and experimentally, stones have been observed to grow around foreign 43

bodies introduced into the bladder. Neither bacteria nor celhdar fragments are found at the center of most stones on analysis. The beginnings of stone formation must depend either on the condensation of dead or stagnant substances within the kidney or on the aggregation within urine of either crystalloid or colloid molecules to form a body large enough to provide a focus for further deposition. In those rare instances when sizable cellular fragments are present in urine, stone formation is common. In 103 patients with renal papillary necrosis, 27 had renal calculi, and all these calculi had a nucleus of renal tubular tissue (25). SITE OF STONE FORMATION

Do stones arise free in the urine of the renal pelvis as submicroscopic aggregates which then grow by deposition of colloids and crystalloids? O r does stone formation begin on altered areas of the epithelium lining the urinary tract? Or do stones originate within the kidney substance? Caulk, in 1912, first described a lesion of the renal papilla whose importance Randall was to emphasize greatly in his review of current hypotheses of stone formation in 1937 (38). In searching for an "initiating lesion," Randall examined 429 pairs of kidneys collected at autopsies irrespective of the cause of death, and found.a papillary lesion in as many as 17%. These lesions were small but were recogaaizable, with a hand lens, as cream-colored areas due to an abnormality just below the epithelium, often close to or at the papillary tip but sometimes well away from it. These areas were plaques of calcium in the interstitial tissue. Calcium seemed to be deposited first in the basement membrane of cells of the terminal tubules, from which it spread into the intertubular spaces, while the tubules were compressed by surrounding fibrous tissue. T h e epithelium overlying these plaques degenerated, and even desquamated, to bare the plaque to calyeeal urine; and on this exposed surface, salts different from those of the original plaque might be deposited. Microscopy also showed small homogeneous areas of dense connective tissue and a few degenerated nuclei. It was thought that these areas might be the sites of calcium deposition and the formation of subendothellal plaques. 44

Tile hypothesis that these plaques, on ulceration to the surface, are sites of initiation for stone formation was supported by finding, on many small stones, a smooth area with a small depression, thought to be presumptive evidence of previous mural attachment. As further support, some plaques were seen to be free at their edges, and it could easily be imagined that they could break away entirely. These important observations left the site of stone formation unsolved, since the lesions were found so much more frequently than were renal stones. No connection was reported between the frequency of the lesions and that of grown stones. In 18 kidneys, there were 29 calculi connected to a renal papilla; but no connection between these stones and a subendothelial plaque could be established, perhaps bceause of difficulties in decalcifying the sections. Further studies have confirmed the frequency of intrarenal calcification, particularly in the pyramids, despite the relatively rare occurrence of stone. An examination of sections of the renal pyramids from 168 kidneys (grossly normal or exhibiting varied path010003,) revealed small deposits of calcium, visible under the low power of the microscope, in ever}" kidney (4). These deposits seemed to arise by coalescence and necrosis of mononuclear phagocytes, which elsewhere were close to, or enclosed, tiny flecks of calcium. At first the coalesced phagocytes retained a "droplet" appearance, but this was absent where they formed an amorphous mass. These tiny calculi occurred throughout the renal parenchyma. Some lay just under the epithelium near the tip of a papilla and so were ideally placed to form a classic Randall's plaque. Microscopic calculi were seen in every case, even though only 1 in 3,333 parts of the total pyramidal region had been examined. Radlologic examination of kidneys in intact people, of kidneys exposed at operation and of thin slices cut from kidneys removed at operation or autopsy showed that all kidneys contain small radiopacities (11). There were usually only one or two opacities in each kidney, but occasionally there were as many as twelve. The concretions occurred in definite areas: first, and most commonly, just outside the fornices of the calyces or in line with the 45

intralobular vessels that run along the sides of the calyces or between the pyramids; secondly, in the corticomedullary zone; and thlrdl)5 irmnediately beneath the renal capsule. Except for this third location the concretions were ahvays close to, although outside, blood vessels. Some were irregular, but most were spherical and about 0.2 mm. in diameter. They often occurred in small groups, and then usually in line rather than in a huddle. If such a concretion was picked out with forceps, a cavity with a smooth shining wall remained. When a calculus was present in the lumen of a calyx, concretions were usually unduly numerous in the corresponding renal segment. Radiographs showed plaques of calcium on the papillary surface which often suggested aggregations of many concretions. Many of these structural relationships of intrarenal calcifications are illustrated in Figure 10. These findings are consistent with the surgical observations that, in many patients with recurrent calculi, all the calculi come from the same calyx. It has been suggested that the distribution and origin of these small concretions, which have the same composition and structure on x-ray diffraction as true calculi, relate to the anatomy of the renal l)anphatics which occur primarily as two plexuses. The first plexus, in the pyramids, arises just beneath the mucosa near the tip of a papilla and runs between the collecting tubules to join cortlcomedullary vessels, which drain into hilar lymphatics. The other is a very extensive network in the cortex related especially to the larger venous sinuses and communicating with subeapsular and perinephric plexuses. Concretions identical with those in the renal substance have been isolated from perihilar adipose tissue, where they are thought to have laln whhin lymphatic vessels (11). The lymphatics are the natural vessels for removal of calciumladen phagocytes. When there is faulty lymphatic drainage, such removal might be impaired with the aggregation of phagocytes within lymphatic channels to form concretions. When superficially placed, whether along a papillary surface or at the apex of a calyceal fornix, such an aggregation of calclum-contalning phagocytes may give rise to typical Randall's plaques and so be potential precursors of stones. Concretions which break free without first enlarging could easily pass down the urinary passages 46

r

Ran~alVz p/aq~;e.

Stone in C2fr'l pouch.

Fro. 10.--A microradiograph showing early stone formation. (Courtesy of R. J. Cart.) (Permission of Dr. Hamilton Stewart and publishers of Brit. J. Urol.)

47

and be voided, or they might grow while free in the urine, depending on the concentration of salts and colloids. At the usual rate of urine flow, little growth could be expected; so stag-nation of urine or fixture of the concretion to the epithelium may be important. In summary, small calcium-containing deposits are common in all kidneys, but they occur more frequently in renal seg-ments associated with stone formation. Their composition is very similar to that of renal calculi. They may occur just under the epithelial surface of calyces or pyramids and may even ulcerate through this surface to provide a favorable site for stone formation. Those within the kidney lie within smooth-walled cavities; and this, together with their distribution, has led to the suggestion that they form within renal lymphatics. Their possible role in stone formation has been discussed. INVESTIGATION

Investigation of a patient may seek, first, to determine whether lie has a urinary calculus and, if so, where it is in the urinary tract and what alterations of structure and function it has caused. Secondl}5 when a stone has been detected, its nature and origin must be determined, as far as possible.

PRESENCE AND EFFECTS OF A STONE

History taking and examination have already been considered. The first, and usually the most important, investigation is examination of a fresh specimen of urine. In patients with acute pain, the urine is often scanty in amount. It usually contains a small amount of albumin and nearly always some blood, although the red cells may be visible only on microscopy. Commonly, a small excess of white cells is also present, and these will be plentiful if there is infection, in which case bacteria may also be seen, either on a straight examination or by Gram stain. Some excess of white cells may be seen when an inflamed abdominal organ (e.g., the appendix) lies close to the ureter, and red cells have also even been reported in such cases. Renal carbuncle or 48

perinephric abscess can also cause such urinary abnormalities, although, again, red cells are rare. In these last conditions, however, there will be much greater tenderness in the renal area on palpation than with stone (except perhaps during an acute attack of colic), and there may well be guarding or rigidity of the posterior abdominal muscles. Fever is usually more pronounced. Renal or ureterlc neoplasm is a cause of hematurla that must ahvays be remembered in differential diagnosis, especially since such neoplasms may be responsible for clot colic or, with ureteric growths, obstruction from the tumor itself. The only way to distinguish hematurla from hemoglobinuria is by microscopic identification of red cells, even when their presence has been suggested by the settling of a faint smoky haze on urine which has been standing. Red discoloration of the urine may also occur from beets, ingested dyes or certain drugs, such as antipyrine or the anticoagulant phenindione. Every urinary specimen must be examined for "sand" or larger calculous debris, and this or any stone that is passed must be analyzed. Any infected urine must be cultured to determine the infecting organisms, and their sensitivity in vitro to antibiotics should be tested. Occasionally, and perhaps only when a stone has completely obstructed a ureter, the urine is completely normal. With complete obstruction of one ureter, there may rarely be marked oliguria because of mechanical block on one side and inhibition of function contralaterally. The mechanism of this ollg-uria is not clear and may be largely the result of vomiting, dehydration and resulting electrolyte abnormalities. Anuria for more than 24 hours should never be ascribed to reflex inhibition. Simultaneous bilateral calculous obstruction is also rare. Further investigations are best made between attacks of colic. Plain x-ray of the abdomen is by far the most helpful investigation, since about 80fb of renal calculi are visible on x-ray. Apart from the quality of the x-ray photograph, visibility depends on the eomposltion of the stone, as already described (Figs. 2, A and 5, A). The opacity usually lies opposite the second lumbar vertebra at the margin of the psoas shadow; or along the course of the ureter, although this may have been displaced (by kinking from ,t9

adhesions developed in connection with previous attacks) from its usual position along the line of the lateral tips of the transverse processes of the vertebrae. In particular, the lateral curve before the ureter enters the bladder may be exaggerated. Any opacity must be distinguished from a gallstone, which is best done by means of a lateral view, which should routinely accompany an anteroposterior film if stone is suspected; from calcified l)anph nodes (usually following tuberculosis), which show an irregular mottled density instead of the usually uniform density of a stone; from phlebollths, which are usually multiple; from calcification in costal cartilage, usually streaky and aligned with the length of the cartilage and, again, excluded on the lateral view; from calcified plaques of arteriosclerosis in abdominal arteries (this may be difficuh, but there is usually a view in which these, seen edge on, appear much smaller than the more rounded stone) ; from spinal exostoses; and from a stercolith, which should be movable by enema. Once a stone has entered the ureter, it is likely to move lower from one examination to the next. Plain film may be of help in the differential diagnosis of abdominal pain; for instance, there may be air under the diaphragan from a perforated viscus or horizontal fluid levels with bowel obstruction. During an attack of renal colic, plain films are often the only x-ray examination necessary unless there is suspicion of a radiolucent stone or of impaired function of a kidney. Then an intravenous pyelogram (I\rP) is indicated, for excretion of the dye by the kidneys gives a measure of their function while a radiolucent stone may be seen by contrast with the opaque dye. Complete ureteral obstruction will be demonstrated only if it is of recent onset; otherwise, back pressure will have stopped urine formation and so the dye will never reach the obstruction. A retrograde pyelogram may then be necessary to define the obstruction, but it is always advisable to avoid instrumentation of the urinary tract if possible. Diag'nostlcally, cystoscopy is best confined to a prompt investigation of cases with frank hematurla and no evidence of stone on x-ray. Then it may be of great help by determining the affected side, on which blood may spurt from the ureteral orifice. Cystoscopy is also important in cases of stones growing in the 50

bladder~ but otherwise it is best avoided diagnostically because of the risk of introducing infection into the renal tract. Alterations in tile kidney caused by a stone are either anatomical or functional. An IVP will show if a stone, perhaps causing few symptoms, is associated with hydronephrosis or calyceal distortions suggestive of pyelonephritis, and it will give an idea of the ability of the kidney to excrete the radlopaque dye. An IVP should not be done if the blood urea nitrogen exceeds 50 rag./ 100 ml., since useful pictures will rarely be obtained. Renal function can also be assessed from the serum creatinine values and the creatinine clearance. Examination of the blood does not help directly to detect a renal stone, but it may be helpful in differential diagnosis. In renal colic the white cell count (total and differential) is little altered in the absence of infection unless the blood is drawn shortly after colic, when there may be a mild polyrnorphonuelear excess, perhaps the same in origin as the excess found after exercise. Occult bleeding caused by a stone is virtually never severe enough to lower the hemoglobin, and a fall in hemoglobin is much more likely due to accompanying uremia from severe bilateral disease. Red-cell examination may suggest sickle-cell anemia as the cause of abdominal pain. A positive reaction to a blood Hinton test will suggest the possibility of a tabetic crisis. Serum amylase is elevated in acute pancreatitis. Urine (or blood) examination for sugar and urine test with Ehrlich's aldehyde reagent for porphobilinogen will help to exclude tile abdominal symptoms of uncontrolled diabetes or of acute intermittent porphyrla, respectively. NATURE AND ORIGIN OF STONES

Once a stone has been detected and its effects on the urinary tract assessed so that any necessary symptomatic treatment can be given, the nature of the stone and why it occurred must be investigated. The x-ray and examination of the urinary sediment for crystals may give valuable information about their structure. The urinary crystals cannot be relied on absolutely, however, to disclose the composition of the stone, because the urine, when examined, may have little relation to the circumstances that were 51

present when tile stone was foianed. An early morning specimen should be used, because urine passed during the day may be too dilute for crystals to form. Thus, even in primary hyperoxaluria, when the urinary oxalate is chemically well above normal, there may be no oxalate crystals. Much better is the analysis of stones previously passed or removed by surgery. A stone is more useful to the man who made it when it is in a laboratory instead of his trouser pocket. The importance of an oxalate nucleus in a stone whose outer layers are of triple phosphate, or a uric acid nucleus with an oxalate covering, has been noted. To investigate why a stone formed, the patient must be asked about his family histor3", his fluid intake and urine output (especially through the night), his consumption of milk, alkalies and vitamin D (and any treatment that may contain this unknown to him) and any possible symptoms of hyperparathyroidism or gout. Since measurements of serum calcium have become more accurate and more frequent, hyperparathyroldlsm is diagnosed correctly in patients whose histories may tell only of lassitude, constipation, thirst and polyuria, irritability or depression, headache, previous peptic ulcer or pancreatitls, or backache as the only skeletal s~anptom. Other important historical features and possible findings on physical examination have been described trader the discussion of the individual components of stones. Invcstigation of either blood or urine may be helpful. With the urine, correct recording of volume may itself give an important clue by demonstrating chronic excretion of concentrated urine. A pH chart, plotting the reaction of ever), specimen passed during 3--4 days, may also give valuable information almost equally simply. The extent of change in pH may be important after loading with acid both in patients with renal tubular acidosis (little change) and in some patients with uric acid stones (unduly large change). The urinary excretion over a 24-hour period is the basic measure in the demonstration of increased excretlon of a cl3"stallold and may be needed for the determination of the values for calcium (on a standard diet containing about 200--250 rag. Ca/24 hours), oxalate (again on a standard diet, low in oxalate), cystine and xanthine. With blood, the determination of sen~m calcium, phosphate and alkaline phosphatase; 52

serum uric acid; and serum bicarbonate (renal tubular acidosis) may be helpful. Biopsy may be diagnostic in sarcoidosis, in tile oxalosls of hyperoxaluria (but this should already have been diagnosed from the urinary oxalate) and in neoplastic disease. TREATMENT

T h e treatment of kidney stones may be medical or surgical, specific or nonspecific. Rational medical therapy requires knowledge of any change in crystalloid content or other alteration in the urine conducive to stone formation.

SURGICALTREATMENT The special problems relating to the surgical treatment of kidney stones cannot be covered in a brief, general review. Demonstration of a kidney stone is not in itself an indication for surgery. The best outcome in any case of calculus is the spontaneous passage of the stone without residual damage to the urinary tract. If movement of a stone is indicated by the patient's symptoms (more marked urinary frequency and a sensation of burning on micturition indicate that the stone is in or near to the bladder) or by x-ray, relief of pain and encouragement of fluid intake are all that is necessary, together with treatment of any infection present. T h e conflicting dangers are: (a) too zealous investigation and treatment, with the introduction of infection into a urlnary tract from which the stone would have passed unaided; and (b) neglect, with ureterie obstruction and serious renal damage. In acute cases, the latter complication is most unlikely to occur without continuous and severe pain in the renal angle. There is no infallible rule about the period of time during which complete ureteral obstruction may persist without irreparable damage to a normal kidney. Although remarkably little has been written about the natural history of kidney stones, it is clear that stones may remain unchanged in size and not cause renal damage or significant symptoms for many years. Operative removal is reserved for those stones which obstruct the flow of urine, cause continuing pain 53

or show other evidence of damage to the kidney or urinary tract 9 (excessive bleeding, compression of the renal cortex, recurrent infection). Although surgery is usually directed toward the immediate problem of stone removal (either cystoscoplc or operative), occasionally it may be of value in preventing stone recurrence~ for example, when a source of obstruction to urine flow can be removed. ~EDICAL TREAT~XIENT Strictly speaking, medical therapy is directed toward the stone diathesls rather than the stone itself, with the hope of preventing growth or recurrence. Rarely, some reduction in size of an existing stone is attained. The types of medical treatment available will be discussed below, under the specific disorders leading to stone formation. H~'PERCALCltmlA.--The treatment of hypercalciuria may be determined when its origin has been established--surgery for hyperparathyroldism, corticosterolds for vitamln-D intoxication and sometimes for sarcoidosis, and nonabsorbable antacids and lowcalcium diet for the milk-alkali syndrome. Absorbable alkali, sodium and/or potassium citrate, however, is the treatment of renal tubular acidosis. Excessive urinary calcium must come from the skeleton or from the intestine. Calcium loss from the skeleton in acute osteoporosis may be reduced by minimizing, as much as possible, immobilization of patients with Paget's disease, orthopedic disorders (especially in the young) and neurologic impairment. If the patient is completely paralyzed, his bed should be rocked (head to foot). To reduce calcium absorption from tile intestine, the patient is fed a low-calcium diet, which means, in practice, the elimination of milk to drink and cheese. In the absence of pathologically increased absorption, urinai'y calcium varies little with changes in calcium ingestion. Calcium absorption can be actively reduced. A suspension of sodium phytate (hexaphosphoinosltol [Rencal], 3 Gin. three times daily), may reduce calcium absorption; this drug has beeh reported to be of value in idiopathic hypercalciurla (30). Phytate, in addition to trapping calcium in 54

the intestine as an insoluble salt, is partly hydrolyzed with absorption of the freed phosphate. Part of the success of phytate may be due to this effect, as noted below. As with any kidney stone, calcium oxalate or calcium phosphate stones associated with hypercalcluria should be treated with a forced fluid reglmen, as will be described later. OXALATE.--Calcium oxalate stones may be secondary to hypercalciuria of whatever origin or may occur without any cause for stone formation detectable by current technics. Precipitation of calcium oxalate is not significantly influenced by pH changes over tile physiologic range in urine, so that there is little to gain by altering urine pH. In primary hyperoxaluria, excessive excretion of oxalate in the urine is clearly the immediate cause of stone. Because pyridoxine deficiency is productive of hyperoxaluria and calcium oxalate nephrocalcinosis in experimental animals, pyridoxine has been used in the treatment of a number of patients with primary hyperoxaluria. The results have been unconvincing in reducing either stone formation or urinary oxalate. Attempts to lower oxalate formation by reducing glycine intake (lowprotein diet) or by trapping precursor glycine as hippurate with ingested benzoate have been similarly disappointing. Foods rlch in oxalate should be eliminated from the diet. In summary, no method has yet been devised to reduce oxalate excretion significantly in primary hyperoxaluria or in the more frequent case of stone formation in the presence of normal urinary oxalate. ~Iore precise definition of the presumed enzyme defect of primary hyperoxaluria may allow more logical therapy. At present, the treatment of oxalate stones in the presence of normal or elevated urinary oxalate is based on measures to reduce urine calcium and the use of nonspecific treatments--e.g., forced fluids and possibly hlgh-phosphate intake. C,,'STmV..---As previously noted, the presence of a cystine stone in man is diagnostic of the genetic disorder, cystlnuria. Cystine is partly derived from that ingested but is largely synthesized from methlonine (Fig. 7). Attempts to treat cystinuria by Iow-proteln diet have usually been disappointing, although favorable results have been reported. The solubility of cystine is increased in an alkaline urine; but, 55

unfortunately, major effect occurs only above pH 7.5, an alkalinity difficult to maintain and carrying with it an increased hazard of phosphate stone formation. It is, however, worth while to achieve this alkalinity in the severe case of cystinuria; and the urine pH is best controlled by the patient's own charting, using nitrazine or other indicator paper. Induced polyurla has been the major defense against cystine stone formation, since cystine stones rarely form at cystine concentrations less than 250-300 mg./L. The importance of maintaining a nocturnal water diuresis has been particularly emphasized by Dent and his colleagues. Very recently a promising new appi~oach to the treatment of cystinuria has been introduced with the use of D-penicillamine (fl,fl-dimethylcysteine) orally to form a mixed disulfide with cystelne (12). The resulting disulfide is much more soluble than the cystine it replaces, and it is excreted in the urine. With large doses of mpenicillamine (3-4 Gm. daily), urinary cystine can be reduced virtually to zero. This new method of treatment has not been widely used as yet, so that its indications are not established. Because of the expense and rare side effects of the drug, this method of treatment will probably be reserved for the more severe cases not controllable by forced fluids and alkalinization. URIC ncio.--The uric acid stone diathesis is the condition most easily and effectively treated. The marked enhancement of urate solubility with increasing alkalinization of the urine, well within the physiologic range, has been described above. Maintaining urine pH at 6.5 or above is sufficient treatment for virtually all patients. Treatment does not stop with prescription of alkali but must be checked by actual urine pH charts filled in by the patient, just as a diabetic records his tests for urine sugar. AM3IONIUM-CONTAINING STONES.--It is a medical dictum that it is impossiblc to eradicate a chronic urinary tract infection in the presence of kidney stones. In fact, careful follow-up shows that permanent cure of any chronic urinary tract infection is attained in a minority of cases, perhaps not more than 10-20~. Long-term suppressive therapy may be useful even when cure is impossible. A number of excellent reviews on the treatment and prognosis of chronic pyelonephritis are available, and so a r6sum6 of this subject will not be attempted. An attractive principle of 56

treatment, not yet established in practice, is suggested bv the effect of the diuretic chlormerodrin in inhibiting bacterial urease in such a way that the inhibition is transmitted to progeny of the affected bacteria (41). Unfortunately, the sensitivity of the bacteria to particular antibiotics may be altered--and not ahvays in a direction beneficial to treatment. In addition to the specific measures described in the treatment of particular types of stones, many patients may be helped in three other ways. These are: first, change of pH; second, increase of urine volume; and third, alteration of the "protective substances" which perhaps determine how likely stone formation is in urine of a particular crystalloid composition. The success of pH alteration depends on the crystalloid composition of tile stone and has been described above. The simplest and most basic medical measure in the treatment of any type of stone diathesis is to insure a large fluid intake. The importance of urine volume in determining crystalloid concentration at a given excretion level is self-evident. If relative lack of substances inimical to stone formation is a factor, tile question might be raised whether treatment by dilution of urine is beneficial. In partial answer, it can be shown that 10 ml. of urine diluted with 10 ml. of water will dissolve a greater total amount of calcium phosphate than did the ori~nal urine, although less per unit volume. The importance of maintaining a large urine volume has been particularly well documented for cystinuria, and the evidence suggests that partial reabsorption of cystlne stones may be effected by water diuresis alone. It is particularly important that the usual nocturnal oliguria be avoided; so extra fluid should be taken before retiring. As a rule of thumb, fluid intake during the evening should be sufficient to produce nocturia. In theory, a fruitful approach to the treatment of kidney stones would be to increase the "protective substances" in urine, the evidence for which has been discussed in the section on pathogenesis. The most promising of these attempts is the use of a hlgh-phosphate program. This treatment stemmed initially from Bovce's observations that the patients with recurrent calculi who benefited from oral phytate were those in whom there was a marked 57

rise in urinary phosphate. Howard found that a dietary supplementation of 1 to 3 Gin. of phosphorus (given in three divided doses after meals as a balanced sodium and potassium preparation at physiologic pH) is capable of converting the urine of a stone-formlng patient from "evil" (one which calcified rachitic cartilage) to "good" (as defined by the same test). This conversion of the biologic test system does not occur if the phosphate is added directly to urine. Presumabl),, the ingestion of phosphate stimulates the formation of protective substance or substances in the urine. Although its mechanism of action is not clear, early experience with this program has been very encouraging. This treatment is gradually becoming more widely used, and favorable initial reports continue. There are other treatments which have been advocated and even widely used but which, in our opinion, have never been clearly shown to be beneficial. These include: oral sallcylates, the low phosphate-alumlnum hydroxide regimen, intramuscular hyaluronldase and direct irrigation of stones. While the latter is, perhaps, of value with a nephrostomy tube in position, usually its discomforts and the danger of renal damage outweigh its immediate, and usually temporary, benefits. PROGNOSIS

Stones are not the same; nor are those who form them; nor are those who treat patients who have them. To judge the results of treatment, the natural history of patients with stone must be known; but it is of little use to have figures that include stones of different composition and structure, which have occurred in patients with large variations in daily volume of urine, which may or may not be infected. Now that some of ttle various causes of stone are recognized, it is to be hoped that figures will be collected for the prognosis of patients who have a particular type of stone (at least primarily) with a particular etlolo~' and who receive the same treatment. Stones are common enough for such figures to be obtained for many of the subgroups within a reasonable length of time. Because most reported series deal with a mixed group of patients, 58

it seems valueless to do more than sketch a picture of the natural history of stone formers. Many have only one stone during their whole life and pass this after a short but painful illness. In others, a single stone remains in a kidney and causes no, or only mild, symptoms until the patient dies of an unrelated disease. But in a third group, stone formation is a chronic illness and llfelong treatment may be as necessary as in a diabetic. Some of these patients die of renal failure, but in others the illness iS so indolent that they die of another disease before their kidneys fail. Chronlcity has two causes: a long period of time during which a single stone may persist, and the tendency for stones to recur. The latter may be due either to the fact that an excessive urinary concentration of a erystalloid constituent of the stones is undiagnosed or cannot be treated successfully because some other factor predisposing to stone is present in the urine, or to the eontlnued presence of abnormal structure of the urinary tract. Two examples of such abnormal stnlcture are: (1) a congenital malformation that causes obstruction and predisposes to infection, and (2) a diseased segment of a kidney. Despite the lack of knowledge of the prognosis of patients with stones catalogued according to subgroups, there seems little doubt that a patient with a stone today is more fortunate than one who lived 30 years ago. Understanding of likely contributory causes is more advanced in perhaps a quarter of eases, and this often brings better management. Infection can be suppressed (if not eradicated) more successfully. One finding may be quoted as an example of this improvement: between 1930 and 1950, there was a recurrence rate of 47% after operation in one series of patients with stone; in 1960, a series of 219 operations was reported with a recurrence rate of only 6%, and only 2% recurrence after the last 99 operations (42). This result, of cdurse, cannot be used to compare the changes in any one factor in treatment, because the improvement is presumably compounded of alterations in diagnostlc methods, understanding of some factors that contribute to stone formation, the treatment of infection, the type of operation and general surgical and anesthetic technics. 59

SUMMARY

Renal calculi are common causes of disability and death in patients of all ages. F a r from representing a single disease entity, they constitute the end-result of a spectrum of disorders having as a common feature the formation of insoluble crystallold-protein aggregates within the kidney or urinary passages. T h e pathogenesis of stone formation may be clear from the increased urinary excretion of the stone's constituent crystalloid or from the presence of infection. Often, no such slmple explanation of stone formation is apparent. Much research is cfirrently directed toward understanding the importance of factors other than crystalloid concentration in stone formation. Surgical treatment is aimed at removing a stone already likely to damage the urinary tract. On the other hand, medical therapy has as its major aim the prevention of stone growth or recurrence. Rational medical treatment of a stone can be undertaken only if all the factors important in its formation are known.

REFERENGES

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