Nephrol Dial Transplant (1996) 11: 379-387

Educational Course

NephrologyDialysis

Transplantation

CrystaUuria: a neglected aspect of urinary sediment analysis

G. B. Fogazzi

Divisione di Nefrologia e Dialisi, Ospedale Maggiore, IRCCS, Milan, Italy

Abstract

Crystalluria is a frequent finding in the routine exam-ination of urine sediments. In most instances theprecipitation of crystals of calcium oxalate, uric acid,triple phosphate, calcium phosphate and amorphousphosphates or urates is caused by transient supersat-uration of the urine, ingestion of foods, or by changesof urine temperature and/or pH which occur uponstanding after micturition. In a minority of cases,however, crystalluria is associated with pathologicalconditions such as urolithiasis, acute uric acid nephro-pathy, ethylene glycol poisoning, hypereosinophilicsyndrome. In addition, crystalluria can be due to drugssuch as sulphadiazine, acyclovir, triamterene, piridox-ylate, primidone, which under the influence of variousfactors can crystallize within the tubular lumina andcause renal damage. In all these instances the study ofcrystalluria is diagnostically useful and is also import-ant to follow the course of the disease. However, aproper methodological approach is necessary. Thisincludes the handling of freshly voided urine, theknowledge of the urinary pH, and the use of a contrastphase microscope equipped with polarizing filters.

Introduction

Crystals, seen as 'a heap of rhomboical bricks', werethe first element described when urine was investiga-ted for the first time with a microscope in 1630 bythe French scholar Fabricius Nicolaus De Peiresc(1580-1637) [1], and then were the first element of theurinary sediment to be shown in a figure as containedin Robert Hooke's 'Micrographia', published in 1665(Figure 1) [2]. Crystals were the only known micro-scopic element of the urine for the whole 18th century,during the earlier part of which they attracted theattention of the great Hermann Boerhaave (1668—1734), who carried out experiments to evaluatewhether or not urine of the normal subjects containedcrystals [1]. In the late 1830s, when urine microscopy

Correspondence and offprint requests to: Giovanni B. Fogazzi MD,Divisione di Nefrologia e Dialisi, Ospedale Maggiore, IRCCS, ViaCommenda 15, 20122 Milan, Italy.

was introduced into clinical practice, many of thecrystals known nowadays had already been identified,including those of cystine which were first described in1810 by William H. Wollaston (1766-1828). In 1844,when the first book on urinary deposits was published[3], crystals still represented the main elements of theurine sediment, as demonstrated by the fact that sixchapters of that book were devoted to crystals andonly one to 'non crystalline organic deposits', whoselength was only about one-third of the overall coveragegiven to crystals. Interestingly, polarizing light andchemical reagents added to urine samples on the stageof the microscope were already in use at that time toidentify crystals. By 1880 the classification of urinarycrystals was similar to that which we know currently[4], the crystals of leucine and tyrosine having beendescribed by Theodor F. Frerichs (1819-1885) in 1854,and those of cholesterol by Lionel S. Beale (1828-1906)in 1869.

This paper describes the main types of urinarycrystals as can be identified by conventional proceduresand microscopy, as well as the nephrological disordersin which the study of crystalluria is of importance.

How to identify the urinary crystals

There are several types of urinary crystals (Table 1).Since each type has a wide spectrum of possiblemorphological appearances [5], a proper methodologi-cal approach is necessary to identify them.

First of all, the knowledge of the urinary pH is animportant prerequisite for the identification of crystalsas some crystals tend to precipitate in acidic urine,while others in an alkaline milieu. As shown in Table 1,uric acid crystals and urates are found exclusively inacidic urine (pH< 5.4-5.8), while those of amorphousphosphates, triple phosphate and calcium phosphateare observed in urine with pH of 6.2 > 7.0. Calciumoxalate and cholesterol crystals on the other hand canbe found in a wider pH range (< 5.4-6.7,) althoughthey tend to be more frequent in acidic urine.

Crystals can precipitate while the urine is still in theurinary system or after micturition when changes intemperature and/or pH can occur upon standing. Forinstance, massive precipitation of urates or phosphatescan occur if the urine is stored at 4°C, and triple

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380 G. B. Fogazzi

Fig.

Table 1. Number of positive samples, pH and polarization features of the crystals found in the 200 urine samples from December 1992 toDecember 1994 in the Division of Nephrology and Dialysis of Ospedale Maggiore of Milano

Crystal Number pH features Birefringence

Ca-oxalate dihydrateUric acidAmorphous phosphatesTriple phosphateCa-oxalate monohydrateCholesterolAmorphous uratesCa-phosphate platesCa-phosphate crystals

673627251815732

Range

< 5.4-6.7< 5.4-5.8

6.2->7.06.2->7.0

< 5.4-6.4< 5.4-6.7< 5.4-5.8

6.7->7.07.0

<5.8 (%)

82100——

8973

100——

> 7.0 (%)

—7873

—,——

67100

25100—10010027100

—100

Crystals identified by phase-contrast microscopy and polarized light. pH measured by Dipstix. Urine centrifuged and analysed at roomtemperature.

phosphate crystals can precipitate from a progressiveincrease in pH caused by continuous multiplication ofurea-splitting bacteria after voiding. Thus it is import-ant that the urine is handled as soon as possible andat a temperature similar to that of the body. This isparticularly important for the study of crystalluria instone formers [6], although in this context urine storedat room temperature or at 4°C for several hours isused as well to study the latent phase of supersat-uration [7,8].

The phase-contrast microscope, which represents thestate of the art in urine microscopy at present, is betterthan bright-field microscopy in study of crystals, especi-ally when these are small and colourless. It must beequipped with polarizing filters, which allow differen-tiation of birefringent crystals, which polarize light,from non-birefringent crystals, which do not. Theknowledge of the polarizing features of crystals is

useful to distinguish: (1) crystals that are different incomposition but similar or identical in morphology;for instance, amorphous urates polarize light whilephosphates do not (Table 1); (2) crystals from contam-inants such as starch particles, which under polarizedlight appear as 'pseudo Maltese crosses'; (3) hexagonalcrystals of uric acid from those of cystine. In general,while the former polarize into many nice colours thelatter have a colourless birefringence [9].

Testing the solubility features of crystals is an addi-tional means to identify them in doubtful cases. Thisis done by adding to the sample on the stage of themicroscope, or to the tube containing the sediment,few drops of a chemical reagent which is known todissolve the crystals under investigation. If the crystalsdo not dissolve, they must then belong to anothercategory of crystal. Calcium oxalate is soluble inhydrochloric acid and sodium hydroxide, while uric

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Crystalluria: a neglected aspect of urinary sediment analysis

acid is soluble in alkali (and by heating.) Triple phos-phate and calcium phosphate are soluble in hydro-chloric acid and acetic acid [5].

However, one must be aware of the limitations withthese procedures, as even common crystals at timescannot be identified with certainty due to possibleoccurrences of unusual morphologies. For these casesmore sophisticated techniques are available such aspetrographic microscopy [10], scanning electron-microscopy [11], infrared microscopy [12], or spectro-photometry, which, however, are available only inspecialized laboratories.

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bipyramidal shape, while the latter are more pleiomor-phichic [13], although the ovoid shape is the mostfrequent. Bipyramidal crystals are birefringent onlywhen large or in aggregates, but even then birefringenceis usually not intense. The monohydrates, however,are always strongly birefringent (Table 1). Calciumoxalate may be found in normal subjects, often as aconsequence of ingestion of foods like chocolate, beet-root, peanuts, rhubarb, spinach, etc. [14], in stoneformers (Table 2), in patients with hyperoxaluria, orafter ethylene glycol poisoning (see 'Crystalluria andacute renal failure').

The main types of urinary crystals

The most common urinary crystals are shown inTable 1.

Calcium oxalate crystals (Figure 2)

There are two types of calcium oxalate crystals, thedihydrate (or Wedellite) and the monohydrate (orWhewellite), which are frequently found together inthe same sample. The former have mostly a typical

Uric acid crystals (Figure 2)

These are very pleiomorphic too, but the rhomboidalshape is the most frequent. Distinctive morphologicalfeatures are the amber colour and the constant poly-chromatic birefringence. These crystals can be foundboth in normal subjects as well as in stone formers(Table 2). Moreover, they can be found, alone or withamorphous urates in patients with increased purinemetabolism (see 'Crystalluria and acute renal failure').

Fig. 2. Clockwise from top left: Typical bipyramidal calcium oxalatedihydrate crystals (interference-contrast, 640 x). Ovoid monohydratecalcium oxalate crystals (phase-contrast, 640 x). Rhomboid uricacid crystals (phase-contrast, 400 x). Uric acid crystals under polar-ized light (250 x). (From ref. 5, with permission).

Amorphous phosphates (Figure 3)

These are tiny, colourless or dark granules which canbe either isolated or in clumps. Only the knowledge ofurinary pH and birefringence allow one to differentiatethem from amorphous urates (Table 1). Amorphousphosphates are frequently found in association withcalcium phosphate crystals [11].

Triple phosphate crystals (Figure 3)

The typical shape is that of prisms ('coffin lid'), whichare always strongly birefringent (Table 1). Triple phos-phate crystals are typical of infected urine, especiallythat caused by urea-splitting bacteria. For this reasonthey are frequently found also in patients with in-fected calculi.

Calcium phosphate (Figure 3)

Crystals are pleiomorphic, often appearing as bire-fringent stars or needles, occurring in isolation orin clumps. Plates are granular and non-birefringent.Calcium phosphate crystals were the most frequentcrystals in both normals and stone formers in the studyof Werness et al. [10]; however, this finding was notconfirmed by others (Table 2).

Cholesterol crystals (Figure 4)

These are transparent plates with well-defined edgesand corners, which polarize light inconstantly

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Table 2. Prevalence and

Author [Ref.]

Hallson-Rose[18]Werness el al. [10]*Daudon et al. [7]Habdel-Halim [8]

type of crystalluria in

Crystalluria (%)

N

22269.42

SF

483446

9

normal subjects (N) and

Aggregates (%)

N

2NENE0

SF

7NENE1.4

stone formers (SF) in fresh

Main crystals

N

Ph and OxCa-PhCa-OxCa-Ox

urine

SF

OxCa-PhCa-OxCa-Ox

G.

Uric acid

N

NE62.80

B. Fogazzi

(%)

SF

NE93.13.6

'Figures refer only to the patients defined in the study as 'idiopathic calcium urolithiasis'.NE, not evaluated; Ph, phosphate; Ox, oxalate; Ca-Ph, calcium phosphate; Ca-Ox, calcium oxalate.

Fig. 3. Clockwise from top left: Amorphous phosphates (phase-contrast, 400 x). Triple phosphate crystals (interference-contrast,400 x). A star-like calcium phophate crystal (phase-contrast, 400 x).Calcium phosphate plate (phase-contrast, 400 x). (From ref. 5, withpermission).

(Table 1). They are not found in normal subjects, andcharacteristically occur in patients with lipiduria sec-ondary to nephrotic syndrome, although in our experi-ence they are less frequent than other lipid particles.

Other crystals which can rarely be found in the urineinclude cystine crystals (Figure 4), which precipitateas symmetrical hexagons, mostly aggregated, and areconstantly birefringent. They are typical of patientswith cystinuria, but to find them the urine pH must belowered to 4.0 with glacial acetic acid and storedovernight at 4°C [15,16]. Disappearance of cystinecrystalluria has been observed after the administration

Fig. 4. From top to bottom: A large cholesterol crystal (phase-contrast, 200 x). Hexagonal crystals of cystine (phase-contrast,400 x). Leucine crystal (phase-contrast, 400 x). (From ref. 5, withpermission).

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Crystalluria: a neglected aspect of urinary sediment analysis

of the benzodiazepine chlordiazepoxide and in associ-ation with the appearance of nephrotic syndrome in apatient [16]. The underlying mechanisms are unclear.Leucine crystals (Figure 4) are oily-looking sphereswith concentric striations, which form pseudo-Maltesecrosses under polarized light. Leucine, like tyrosine,which appears as thin needles often aggregated inbundles or rosettes, is typical of patients with hepaticfailure. Other rare crystals, without clinical implica-tions are those of hippuric acid, which appear aselongated hexagons, and calcium carbonate, whichusually appear as clumped granules.

Crystalluria in stone formers

The notion that supersaturation of urine with crystalsis the conditio sine qua non for the formation of stoneshas led several investigators to study the value ofcrystalluria in the identification and follow-up ofpatients with urinary stone disease. Robertson et al.[17] compared the urine of healthy controls and ofpatients with urinary calculi and found that the preval-ence of calcium oxalate or calcium phosphate crystallu-ria was similar in the two groups. The stone formers,however, had larger calcium oxalate crystals (10-12 umin diameter vs 3-4 um), and only their urine containedcrystal aggregates, whose diameter ranged between 20and 300 um, which increased to 500 um after an oraldose of oxalate.

Several other investigators subsequently comparednormal subjects with stone formers, and all of themconfirmed that crystals could actually be found inthe urine of healthy subjects [7,8,10,18] (Table 2).However, crystalluria was less frequent in normalsthan in untreated stone formers, and also some milddifferences were found as far as the predominantcrystals were concerned. The prevalence and the maintypes of crystals in both normal and stone formersvaried considerably in the different studies, however,which may be attributed to different methods employedto study crystals. In fact, while Hallson and Rose [18]studied fresh urines (handled at 37°C) by bright-fieldmicroscopy and a Coulter counter to quantitate crys-tals, Werness et al. [10] used a petrographic microscopeafter recovering crystals by Nucleopore filters. Daudonet al. [7] carried out their study on fresh urine at roomtemperature by polarized microscopy in associationwith X-ray spectroscopy, while Abdel-Hamin [8]investigated fresh samples 'almost at body temperature'by conventional urine microscopy.

Crystalluria has also been evaluated as parameter tomonitor the effects of drugs given to prevent stoneformation. Hallson and Rose [18] halved the incidenceof high crystals volume concentration with thiazide orcellulose phosphate, Werness et al. [10] achieved asignificant reduction of crystalluria in calcium stoneformers treated with orthophosphate or thiazide, whileDaudon et al. [7] found that hydrochlorothiazideat the dosage of 25-50 mg per day did not affectcrystalluria.

383

Finally, crystalluria has also been studied in patientswith primary hyperoxaluria. Werness et al. [10],investigating 182 urine voidings from 12 patients,found crystals in 92% of samples, mostly in moderateto large amounts, and exclusively due to calciumoxalate (monohydrate mainly). Interestingly, specifictreatment significantly reduced the incidence of crys-talluria, a result achieved also by others with ortho-phosphate and pyridoxine [19].

From all this it appears that crystalluria may beuseful in the study of stone formers, but it must beemphasized that (1) such a study requires experiencedpeople and specialized procedures, which are, more-over, not yet standardized [20]; (2) it is difficult toidentify a stone former on the basis of crystalluriaalone [10], as even healthy subjects may have crystalsin the urine.

Crystalluria and acute renal failure

The precipitation of massive amounts of crystals withinthe renal tubules can cause acute renal failure due tointratubular obstruction. This process has been demon-strated in acute uric acid nephropathy, in acute renalfailure caused by ethylene glycol poisoning, in a patientwith hypereosinophilic syndrome, and in a number ofcases after ingestion of drugs (which are describedseparately). In all these conditions the finding of crys-talluria has remarkable diagnostic value.

Acute uric acid nephropathy is a condition seen inpatients with aggressive lymphoproliferative disordersor, less commonly with solid tumours. It is a con-sequence of a massive tumour lysis which may occureither spontaneously or more frequently after chemo-therapy. Tumour lysis results in severe hyperuricaemiasecondary to cell breakdown with purine release, andthe precipitation of uric acid crystals within the luminaof the distal tubules, collecting ducts (where acid-ification and concentration are maximal), and peri tub-ular capillaries [21]. Therefore sustained hydration,urine alkalinization, and the administration of largedoses of the xanthine oxidase inhibitor allopurinol toavoid hyperuricaemia are the recommended preventiveand therapeutic manoeuvres.

Massive amounts of uric acid crystals [22-24], or'amorphous material' [25,26] may be found in theurine. The latter is usually caused by amorphousurates, but in some patients it may be due to crystal-lized xanthine [27,28], whose blood and urinary con-centrations are increased by allopurinol. Xanthine hasa much lower solubility than uric acid (three times lessat pH 5.0, 15 times less at pH 7.0) and hypoxanthine(two times and 11 times less, at a pH of 5.0 and 7.0respectively) and therefore its crystallization canoccur easily.

Although massive crystalluria may be seen inpatients with acute uric acid nephropathy, one mustbe aware that it is not invariably present [26], andthat it may also occur in patients with tumour lysisbut without acute renal failure [28].

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Acute renal failure from ethylene glycol occurs afterthe ingestion (accidental, for suicidal purposes, or as asubstitute of alcohol) of large amounts of this com-pound, which is contained in antifreeze agents.Ethylene glycol is transformed by the liver into glycolic,glyoxalic, and oxalate acids, which are toxic metabol-ites causing a multisystem disease characterized bycerebral (mainly coma and seizures), pulmonary (res-piratory distress), cardiac (mainly arrhythmias), andrenal symptoms [29]. Calcium oxalate crystals arefound in the affected organs, and in the kidneys theyare present in the tubules, both in the cells and in thelumen. The typical laboratory findings are that ofsevere metabolic acidosis, high anion gap, osmolargap, and crystalluria.

Crystalluria in ethylene glycol poisoning is massiveand due to monohydrate calcium oxalate crystals withunusual shape (e.g. short prisms, needles, spindles, orelongated hexagons similar to hippuric acid) andstrong birefringence [30-33] (Figure 5). However,common bipyramidal dihydrate crystals can also befound, especially in the early phases [34]. Crystalluria

G. B. Fogazzi

disappears with the removal of ethylene glycol fromblood by dialysis [35]. Early treatment may preventcrystalluria [36], and occasionally this may be absentin the advanced phases of the poisoning [37].

Crystalluria in acute renal failure caused by hypereo-sinophilic syndrome has been reported in only onepatient so far [38]. Charcot-Leyden crystals, one ofthe hallmarks of hypereosinophilic syndrome, werefound in the renal tubular lumina and in large amountsin the urine. Charcot-Leyden crystals are elongatedbipyramids composed of a single acidic protein with alow molecular weight, and are highly insoluble atneutral pH.

Table 3 summarizes the main information aboutcrystalluria in acute renal failure.

Crystalluria caused by drugs

A variety of drugs may occasionally cause transientcrystalluria, in isolation or in conjunction with otherurinary abnormalities. Overdose, dehydration, orhypoalbuminaemia, which increases the unbound drug•vhich is ultrafiltrated by the glomerulus, are the factors

sually favouring the precipitation of crystals withinle tubular lumina [39,40]. Herein crystalluria due torugs with the most relevant clinical implications isascribed (Table 4).Sulphadiazine, which is the treatment of choice for

>xoplasma encephalitis in patients with AIDS, is theading cause of drug-related crystalluria. Sulphadia-ne is a short acting sulphonamide, rapidly excretedy the kidneys and with a low solubility in the urine,specially at acidic pH. This feature, coupled with highrug dosages, dehydration, and hypoalbuminaemia,

responsible for the precipitation of sulphadiazine•ystals and/or calculi within the urinary system, result-ig in a wide spectrum of renal manifestations, whichiclude asymptomatic crystalluria, haematuria, and;ute renal failure due to obstructive uropathy oritratubular obstruction [41-44]. Crystals and stonesissolve with hydration and alkalinization, and the:nal manifestations usually reverse in a few days.Sulphadiazine crystals appear as strongly birefrin-

;nt 'shocks of wheat' or 'shells' with an amber colour

ible 3. Crystalluria in acute renal failure

taining mainly spindle-like crystals and elongated hexagons, as seenin ethylene glycol poisoning. (Top, phase-contrast, 400 x; bottom,polarized light, 400 x).

jndition

cute uric acidnephropathy

:hylene glycolpoisoning

Hypereosinophilicsyndrome

Crystals

Uric acidAmorphous uratesXanthine

Atypicalcalcium oxalatemonohydrate

Charcot-Leyden

Remarks

Crystalluria not alwayspresent

Crystalluria possiblewithout acute renalfailure

Crystalluria prevented byearly treatment

Crystalluria occasionallyabsent

—

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Crystalluria: a neglected aspect of urinary sediment analysis

Table 4. The main types of crystals due to drugs

Drug

Sulphadiazine

Acyclovir

Triamterene

Piridoxylate

Primidone

Crystal

Birefringent 'stooks ofwheat' or 'shells' withstriation

Birefringent fine needles

Birefringent colouredspheres (brown, green,orange, red)

Asymmetrical hexagonsor rectangles withrounded extremities

Birefringent hexagons

Clinicalmanifestations

Isolated crystalluria,haematuria, ARF,stones

Isolated crystalluria,ARF

ARF, ?stones

Stones

Isolated crystalluria,transient

proteinuriaand haematuria

ARF, acute renal failure.

and a radial striation, for which they are easily distin-guishable from other sulphonamide crystals [45](Figure 6). The search for these crystals in the urine isone of the measures suggested to monitor the patientsunder sulphadiazine therapy [43]. Although their pres-ence alone may not indicate a renal injury, their findingshould encourage hydration and alkalinization, if nota reduction or discontinuation of the drug.

The antiviral agent acyclovir can cause crystalluriaespecially when given intravenously at high dosagesand to dehydrated patients. Crystalluria may either beasymptomatic [46] or associated with acute renal fail-ure, which is usually reversible after discontinuationof the drug [47]. However, intratubular crystals afteracyclovir were found only in animals [48], and a caseof acute tubular necrosis without intratubular crystalsand crystalluria during acyclovir therapy has beendescribed [49]. Therefore the real role of crystalluriain the pathogenesis of acute renal failure in patients

385

receiving acyclovir is not yet defined. For the timebeing, however, it is wise to consider the appearanceof acyclovir crystalluria as a potential insult to thekidney, which should prompt the hydration of thepatient and the reduction or the withdrawal of the drug.

Acyclovir crystals are birefringent and needle-shaped[Figure 7], and when in abundance give to urine asilky and opalescent macroscopic appearance [46].

The diuretic triamterene, can cause a transient andasymptomatic crystalluria in acidic urine [50,51].However, a case of irreversible acute renal failure withintratubular precipitation of triamterene crystals (butwithout crystalluria) has been reported [52]. Thereforetriamterene crystals too should be regarded as a poten-tial cause of severe tubular injury. The role of triamter-ene crystals in favouring the formation of urinary stoneis still matter of debate [53]. Triamterene crystals arespherical and predominantly brown in colour, andunder polarized light they appear as 'Maltese crosses'.In most cases these crystals are associated with browncasts, which are also due to triamterene.

Piridoxylate, an equimolar combination of glyoxylicacid and pyridoxine, used in some European countriesfor the treatment of coronary disease, can cause aunique calcium oxalate trihydrate crystalluria, whichis usually associated with piridoxilate stones [54].Crystals are asymmetrical hexagons, which disappearcompletely from the urine after withdrawal of the drug.

The barbiturate primidone can be a cause of crys-

Fig. 6. A typical 'stook of wheat' crystal of sulphadiazine as itappears under polarized light (256 x) .

V ~-

Fig. 7. Acyclovir crystalluria (bright-field microscope, 1800 x).(From Potter JL and Krill CE. Acyclovir crystalluria. Pediatr InfectDis J 1986; 5: 710-712 with permission).

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talluria following overdose [55,56]. The urinary abnor-malities include isolated crystalluria or crystalluriaassociated with transient haematuria and proteinuria[55]. Crystals are birefringent hexagons which comesingly or in conglomerates. In the latter case they canresemble crystals of cystine [56].

Other drugs such as quinolones, cephalexin, sulpha-methoxazole, aspirin, xylitol, etc. can occasionallycause crystalluria, without relevant clinical implica-tions, however.

Conclusions

Crystalluria is a frequent finding, about 8% of samplesin author's experience. Most of the times it is theconsequence of a transient supersaturation of urinecaused by the ingestion of some foods or by changesof urine temperature and/or pH, which occur uponstanding after micturition. In a minority of cases,however, crystalluria is due to pathological events,some of which can affect the kidneys seriously. In thesecases, crystalluria is diagnostically useful and is alsoimportant to follow the course of the disease. Even inthese circumstances, however, a proper methodologicalapproach is necessary and crystalluria must be matchedwith other laboratory tests and with the clinicalfindings.

Acknowledgement. The author is grateful to Dr See-Odd Leong,Department of Medicine, National University Hospital, Singapore,for valuable help in reviewing the manuscript.

Note added in proof

Since completion of the manuscript it has been shownthat the vasodilator naftidrofuryl oxalate also cancause crystalluria associated with acute renal failure(see Le Meur, Moesch, Rince et al. Nephrol DialTransplant 1995; 10: 1751-1755).

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