CrystaUuria: a neglected aspect of urinary sediment analysis

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1 Nephrol Dial Transplant (1996) 11: Educational Course Nephrology Dialysis Transplantation CrystaUuria: a neglected aspect of urinary sediment analysis Divisione di Nefrologia e Dialisi, Ospedale Maggiore, IRCCS, Milan, Italy Abstract Crystalluria is a frequent finding in the routine examination of urine sediments. In most instances the precipitation of crystals of calcium oxalate, uric acid, triple phosphate, calcium phosphate and amorphous phosphates or urates is caused by transient supersaturation of the urine, ingestion of foods, or by changes of urine temperature and/or ph which occur upon standing after micturition. In a minority of cases, however, crystalluria is associated with pathological conditions such as urolithiasis, acute uric acid nephropathy, ethylene glycol poisoning, hypereosinophilic syndrome. In addition, crystalluria can be due to drugs such as sulphadiazine, acyclovir, triamterene, piridoxylate, primidone, which under the influence of various factors can crystallize within the tubular lumina and cause renal damage. In all these instances the study of crystalluria is diagnostically useful and is also important to follow the course of the disease. However, a proper methodological approach is necessary. This includes the handling of freshly voided urine, the knowledge of the urinary ph, and the use of a contrast phase microscope equipped with polarizing filters. Introduction Crystals, seen as 'a heap of rhomboical bricks', were the first element described when urine was investigated for the first time with a microscope in 1630 by the French scholar Fabricius Nicolaus De Peiresc ( ) [1], and then were the first element of the urinary sediment to be shown in a figure as contained in Robert Hooke's 'Micrographia', published in 1665 (Figure 1) [2]. Crystals were the only known microscopic element of the urine for the whole 18th century, during the earlier part of which they attracted the attention of the great Hermann Boerhaave ( ), who carried out experiments to evaluate whether or not urine of the normal subjects contained crystals [1]. In the late 1830s, when urine microscopy was introduced into clinical practice, many of the crystals known nowadays had already been identified, including those of cystine which were first described in 1810 by William H. Wollaston ( ). In 1844, when the first book on urinary deposits was published [3], crystals still represented the main elements of the urine sediment, as demonstrated by the fact that six chapters of that book were devoted to crystals and only one to 'non crystalline organic deposits', whose length was only about one-third of the overall coverage given to crystals. Interestingly, polarizing light and chemical reagents added to urine samples on the stage of the microscope were already in use at that time to identify crystals. By 1880 the classification of urinary crystals was similar to that which we know currently [4], the crystals of leucine and tyrosine having been described by Theodor F. Frerichs ( ) in 1854, and those of cholesterol by Lionel S. Beale ( ) in This paper describes the main types of urinary crystals as can be identified by conventional procedures and microscopy, as well as the nephrological disorders in 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 possible morphological appearances [5], a proper methodological approach is necessary to identify them. First of all, the knowledge of the urinary ph is an important prerequisite for the identification of crystals as 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 in acidic urine (ph< ), while those of amorphous phosphates, triple phosphate and calcium phosphate are observed in urine with ph of 6.2 > 7.0. Calcium oxalate and cholesterol crystals on the other hand can be found in a wider ph range (< ,) although they tend to be more frequent in acidic urine. Crystals can precipitate while the urine is still in the urinary system or after micturition when changes in temperature and/or ph can occur upon standing. For Correspondence and offprint requests to: Giovanni B. Fogazzi MD, Divisione di Nefrologia e Dialisi, Ospedale Maggiore, IRCCS, Via instance, massive precipitation of urates or phosphates Commenda 15, Milan, Italy. can occur if the urine is stored at 4 C, and triple 1996 European Dialysis and Transplant Association-European Renal Association

2 380 Fig. Table 1. Number of positive samples, ph and polarization features of the crystals found in the 200 urine samples from December 1992 to December 1994 in the Division of Nephrology and Dialysis of Ospedale Maggiore of Milano Crystal Ca-oxalate dihydrate Uric acid Amorphous phosphates Triple phosphate Ca-oxalate monohydrate Cholesterol Amorphous urates Ca-phosphate plates Ca-phosphate crystals Number Birefringence ph features Range <5.8 (%) > 7.0 (%) < < > >7.0 < < < > , Crystals identified by phase-contrast microscopy and polarized light. ph measured by Dipstix. Urine centrifuged and analysed at room temperature. phosphate crystals can precipitate from a progressive increase in ph caused by continuous multiplication of urea-splitting bacteria after voiding. Thus it is important that the urine is handled as soon as possible and at a temperature similar to that of the body. This is particularly important for the study of crystalluria in stone formers [6], although in this context urine stored at room temperature or at 4 C for several hours is used as well to study the latent phase of supersaturation [7,8]. The phase-contrast microscope, which represents the state of the art in urine microscopy at present, is better than bright-field microscopy in study of crystals, especially when these are small and colourless. It must be equipped with polarizing filters, which allow differentiation of birefringent crystals, which polarize light, from non-birefringent crystals, which do not. The knowledge of the polarizing features of crystals is useful to distinguish: (1) crystals that are different in composition but similar or identical in morphology; for instance, amorphous urates polarize light while phosphates do not (Table 1); (2) crystals from contaminants such as starch particles, which under polarized light appear as 'pseudo Maltese crosses'; (3) hexagonal crystals of uric acid from those of cystine. In general, while the former polarize into many nice colours the latter have a colourless birefringence [9]. Testing the solubility features of crystals is an additional means to identify them in doubtful cases. This is done by adding to the sample on the stage of the microscope, or to the tube containing the sediment, few drops of a chemical reagent which is known to dissolve the crystals under investigation. If the crystals do not dissolve, they must then belong to another category of crystal. Calcium oxalate is soluble in hydrochloric acid and sodium hydroxide, while uric

3 Crystalluria: a neglected aspect of urinary sediment analysis acid is soluble in alkali (and by heating.) Triple phosphate and calcium phosphate are soluble in hydrochloric acid and acetic acid [5]. However, one must be aware of the limitations with these procedures, as even common crystals at times cannot be identified with certainty due to possible occurrences of unusual morphologies. For these cases more sophisticated techniques are available such as petrographic microscopy [10], scanning electronmicroscopy [11], infrared microscopy [12], or spectrophotometry, which, however, are available only in specialized laboratories. The main types of urinary crystals The most common urinary crystals are shown in Table 1. Calcium oxalate crystals (Figure 2) There are two types of calcium oxalate crystals, the dihydrate (or Wedellite) and the monohydrate (or Whewellite), which are frequently found together in the same sample. The former have mostly a typical 381 bipyramidal shape, while the latter are more pleiomorphichic [13], although the ovoid shape is the most frequent. Bipyramidal crystals are birefringent only when large or in aggregates, but even then birefringence is usually not intense. The monohydrates, however, are always strongly birefringent (Table 1). Calcium oxalate may be found in normal subjects, often as a consequence of ingestion of foods like chocolate, beetroot, peanuts, rhubarb, spinach, etc. [14], in stone formers (Table 2), in patients with hyperoxaluria, or after ethylene glycol poisoning (see 'Crystalluria and acute renal failure'). Uric acid crystals (Figure 2) These are very pleiomorphic too, but the rhomboidal shape is the most frequent. Distinctive morphological features are the amber colour and the constant polychromatic birefringence. These crystals can be found both in normal subjects as well as in stone formers (Table 2). Moreover, they can be found, alone or with amorphous urates in patients with increased purine metabolism (see 'Crystalluria and acute renal failure'). Amorphous phosphates (Figure 3) These are tiny, colourless or dark granules which can be either isolated or in clumps. Only the knowledge of urinary ph and birefringence allow one to differentiate them from amorphous urates (Table 1). Amorphous phosphates are frequently found in association with calcium phosphate crystals [11]. Triple phosphate crystals (Figure 3) The typical shape is that of prisms ('coffin lid'), which are always strongly birefringent (Table 1). Triple phosphate crystals are typical of infected urine, especially that caused by urea-splitting bacteria. For this reason they are frequently found also in patients with infected calculi. Calcium phosphate (Figure 3) Crystals are pleiomorphic, often appearing as birefringent stars or needles, occurring in isolation or in clumps. Plates are granular and non-birefringent. Calcium phosphate crystals were the most frequent crystals in both normals and stone formers in the study of Werness et al. [10]; however, this finding was not confirmed by others (Table 2). Fig. 2. Clockwise from top left: Typical bipyramidal calcium oxalate dihydrate crystals (interference-contrast, 640 x). Ovoid monohydrate calcium oxalate crystals (phase-contrast, 640 x). Rhomboid uric acid crystals (phase-contrast, 400 x). Uric acid crystals under polarized light (250 x). (From ref. 5, with permission). Cholesterol crystals (Figure 4) These are transparent plates with well-defined edges and corners, which polarize light inconstantly

4 382 Table 2. Prevalence and type of crystalluria in normal subjects (N) and stone formers (SF) in fresh urine Author [Ref.] Hallson-Rose[18] Werness el al. [10]* Daudon et al. [7] Habdel-Halim [8] Crystalluria (%) Aggregates (%) Uric acid (%) Main crystals N SF N SF N SF N SF Ph and Ox Ca-Ph Ca-Ox Ca-Ox Ox Ca-Ph Ca-Ox Ca-Ox 'Figures refer only to the patients defined in the study as 'idiopathic calcium urolithiasis'., not evaluated; Ph, phosphate; Ox, oxalate; Ca-Ph, calcium phosphate; Ca-Ox, calcium oxalate. Fig. 3. Clockwise from top left: Amorphous phosphates (phasecontrast, 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, with permission). (Table 1). They are not found in normal subjects, and characteristically occur in patients with lipiduria secondary to nephrotic syndrome, although in our experience they are less frequent than other lipid particles. Other crystals which can rarely be found in the urine include cystine crystals (Figure 4), which precipitate as symmetrical hexagons, mostly aggregated, and are constantly birefringent. They are typical of patients with cystinuria, but to find them the urine ph must be lowered to 4.0 with glacial acetic acid and stored overnight at 4 C [15,16]. Disappearance of cystine crystalluria has been observed after the administration Fig. 4. From top to bottom: A large cholesterol crystal (phasecontrast, 200 x). Hexagonal crystals of cystine (phase-contrast, 400 x). Leucine crystal (phase-contrast, 400 x). (From ref. 5, with permission).

5 Crystalluria: a neglected aspect of urinary sediment analysis of the benzodiazepine chlordiazepoxide and in association with the appearance of nephrotic syndrome in a patient [16]. The underlying mechanisms are unclear. Leucine crystals (Figure 4) are oily-looking spheres with concentric striations, which form pseudo-maltese crosses under polarized light. Leucine, like tyrosine, which appears as thin needles often aggregated in bundles or rosettes, is typical of patients with hepatic failure. Other rare crystals, without clinical implications are those of hippuric acid, which appear as elongated hexagons, and calcium carbonate, which usually appear as clumped granules. Crystalluria in stone formers The notion that supersaturation of urine with crystals is the conditio sine qua non for the formation of stones has led several investigators to study the value of crystalluria in the identification and follow-up of patients with urinary stone disease. Robertson et al. [17] compared the urine of healthy controls and of patients with urinary calculi and found that the prevalence of calcium oxalate or calcium phosphate crystalluria was similar in the two groups. The stone formers, however, had larger calcium oxalate crystals (10-12 um in diameter vs 3-4 um), and only their urine contained crystal aggregates, whose diameter ranged between 20 and 300 um, which increased to 500 um after an oral dose of oxalate. Several other investigators subsequently compared normal subjects with stone formers, and all of them confirmed that crystals could actually be found in the urine of healthy subjects [7,8,10,18] (Table 2). However, crystalluria was less frequent in normals than in untreated stone formers, and also some mild differences were found as far as the predominant crystals were concerned. The prevalence and the main types of crystals in both normal and stone formers varied considerably in the different studies, however, which may be attributed to different methods employed to study crystals. In fact, while Hallson and Rose [18] studied fresh urines (handled at 37 C) by bright-field microscopy and a Coulter counter to quantitate crystals, Werness et al. [10] used a petrographic microscope after recovering crystals by Nucleopore filters. Daudon et al. [7] carried out their study on fresh urine at room temperature by polarized microscopy in association with 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 to monitor the effects of drugs given to prevent stone formation. Hallson and Rose [18] halved the incidence of high crystals volume concentration with thiazide or cellulose phosphate, Werness et al. [10] achieved a significant reduction of crystalluria in calcium stone formers treated with orthophosphate or thiazide, while Daudon et al. [7] found that hydrochlorothiazide at the dosage of mg per day did not affect crystalluria. Finally, crystalluria has also been studied in patients with primary hyperoxaluria. Werness et al. [10], investigating 182 urine voidings from 12 patients, found crystals in 92% of samples, mostly in moderate to large amounts, and exclusively due to calcium oxalate (monohydrate mainly). Interestingly, specific treatment significantly reduced the incidence of crystalluria, a result achieved also by others with orthophosphate and pyridoxine [19]. From all this it appears that crystalluria may be useful in the study of stone formers, but it must be emphasized that (1) such a study requires experienced people and specialized procedures, which are, moreover, not yet standardized [20]; (2) it is difficult to identify a stone former on the basis of crystalluria alone [10], as even healthy subjects may have crystals in the urine. Crystalluria and acute renal failure The precipitation of massive amounts of crystals within the renal tubules can cause acute renal failure due to intratubular obstruction. This process has been demonstrated in acute uric acid nephropathy, in acute renal failure caused by ethylene glycol poisoning, in a patient with hypereosinophilic syndrome, and in a number of cases after ingestion of drugs (which are described separately). In all these conditions the finding of crystalluria has remarkable diagnostic value. Acute uric acid nephropathy is a condition seen in patients with aggressive lymphoproliferative disorders or, less commonly with solid tumours. It is a consequence of a massive tumour lysis which may occur either spontaneously or more frequently after chemotherapy. Tumour lysis results in severe hyperuricaemia secondary to cell breakdown with purine release, and the precipitation of uric acid crystals within the lumina of the distal tubules, collecting ducts (where acidification and concentration are maximal), and peri tubular capillaries [21]. Therefore sustained hydration, urine alkalinization, and the administration of large doses of the xanthine oxidase inhibitor allopurinol to avoid hyperuricaemia are the recommended preventive and therapeutic manoeuvres. Massive amounts of uric acid crystals [22-24], or 'amorphous material' [25,26] may be found in the urine. The latter is usually caused by amorphous urates, but in some patients it may be due to crystallized xanthine [27,28], whose blood and urinary concentrations are increased by allopurinol. Xanthine has a much lower solubility than uric acid (three times less at 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 7.0 respectively) and therefore its crystallization can occur easily. Although massive crystalluria may be seen in patients with acute uric acid nephropathy, one must be aware that it is not invariably present [26], and that it may also occur in patients with tumour lysis but without acute renal failure [28]. 383

6 184 Acute renal failure from ethylene glycol occurs after the ingestion (accidental, for suicidal purposes, or as a substitute of alcohol) of large amounts of this compound, which is contained in antifreeze agents. Ethylene glycol is transformed by the liver into glycolic, glyoxalic, and oxalate acids, which are toxic metabolites causing a multisystem disease characterized by cerebral (mainly coma and seizures), pulmonary (respiratory distress), cardiac (mainly arrhythmias), and renal symptoms [29]. Calcium oxalate crystals are found in the affected organs, and in the kidneys they are present in the tubules, both in the cells and in the lumen. The typical laboratory findings are that of severe metabolic acidosis, high anion gap, osmolar gap, and crystalluria. Crystalluria in ethylene glycol poisoning is massive and due to monohydrate calcium oxalate crystals with unusual shape (e.g. short prisms, needles, spindles, or elongated hexagons similar to hippuric acid) and strong birefringence [30-33] (Figure 5). However, common bipyramidal dihydrate crystals can also be found, especially in the early phases [34]. Crystalluria disappears with the removal of ethylene glycol from blood by dialysis [35]. Early treatment may prevent crystalluria [36], and occasionally this may be absent in the advanced phases of the poisoning [37]. Crystalluria in acute renal failure caused by hypereosinophilic syndrome has been reported in only one patient so far [38]. Charcot-Leyden crystals, one of the hallmarks of hypereosinophilic syndrome, were found in the renal tubular lumina and in large amounts in the urine. Charcot-Leyden crystals are elongated bipyramids composed of a single acidic protein with a low molecular weight, and are highly insoluble at neutral ph. Table 3 summarizes the main information about crystalluria in acute renal failure. Crystalluria caused by drugs A variety of drugs may occasionally cause transient crystalluria, in isolation or in conjunction with other urinary abnormalities. Overdose, dehydration, or hypoalbuminaemia, which increases the unbound drug vhich is ultrafiltrated by the glomerulus, are the factors sually favouring the precipitation of crystals within le tubular lumina [39,40]. Herein crystalluria due to rugs with the most relevant clinical implications is ascribed (Table 4). Sulphadiazine, which is the treatment of choice for >xoplasma encephalitis in patients with AIDS, is the ading cause of drug-related crystalluria. Sulphadiane is a short acting sulphonamide, rapidly excreted y the kidneys and with a low solubility in the urine, specially at acidic ph. This feature, coupled with high rug dosages, dehydration, and hypoalbuminaemia, responsible for the precipitation of sulphadiazine ystals and/or calculi within the urinary system, resultig in a wide spectrum of renal manifestations, which iclude asymptomatic crystalluria, haematuria, and ;ute renal failure due to obstructive uropathy or itratubular obstruction [41-44]. Crystals and stones issolve 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 seen in ethylene glycol poisoning. (Top, phase-contrast, 400 x; bottom, polarized light, 400 x). jndition Crystals Remarks cute uric acid nephropathy Uric acid Amorphous urates Xanthine :hylene glycol poisoning Atypical calcium oxalate monohydrate Crystalluria not always present Crystalluria possible without acute renal failure Crystalluria prevented by early treatment Crystalluria occasionally absent Hypereosinophilic syndrome Charcot-Leyden

7 385 Crystalluria: a neglected aspect of urinary sediment analysis receiving acyclovir is not yet defined. For the time being, however, it is wise to consider the appearance Clinical Drug Crystal of acyclovir crystalluria as a potential insult to the manifestations kidney, which should prompt the hydration of the patient and the reduction or the withdrawal of the drug. Isolated crystalluria, Sulphadiazine Birefringent 'stooks of Acyclovir crystals are birefringent and needle-shaped wheat' or 'shells' with haematuria, ARF, [Figure 7], and when in abundance give to urine a striation stones silky and opalescent macroscopic appearance [46]. Acyclovir Birefringent fine needles Isolated crystalluria, The diuretic triamterene, can cause a transient and ARF Triamterene Birefringent coloured ARF,?stones asymptomatic crystalluria in acidic urine [50,51]. spheres (brown, green, However, a case of irreversible acute renal failure with orange, red) intratubular precipitation of triamterene crystals (but Piridoxylate Asymmetrical hexagons Stones without crystalluria) has been reported [52]. Therefore or rectangles with triamterene crystals too should be regarded as a potenrounded extremities Primidone Birefringent hexagons Isolated crystalluria, tial cause of severe tubular injury. The role of triamtertransient ene crystals in favouring the formation of urinary stone proteinuria is still matter of debate [53]. Triamterene crystals are and haematuria spherical and predominantly brown in colour, and under polarized light they appear as 'Maltese crosses'. ARF, acute renal failure. In most cases these crystals are associated with brown casts, which are also due to triamterene. and a radial striation, for which they are easily distinpiridoxylate, an equimolar combination of glyoxylic guishable from other sulphonamide crystals [45] acid and pyridoxine, used in some European countries (Figure 6). The search for these crystals in the urine is for the treatment of coronary disease, can cause a one of the measures suggested to monitor the patients unique calcium oxalate trihydrate crystalluria, which under sulphadiazine therapy [43]. Although their pres- is usually associated with piridoxilate stones [54]. ence alone may not indicate a renal injury, their finding Crystals are asymmetrical hexagons, which disappear should encourage hydration and alkalinization, if not completely from the urine after withdrawal of the drug. a reduction or discontinuation of the drug. The barbiturate primidone can be a cause of crysthe antiviral agent acyclovir can cause crystalluria especially when given intravenously at high dosages and to dehydrated patients. Crystalluria may either be asymptomatic [46] or associated with acute renal failure, which is usually reversible after discontinuation of the drug [47]. However, intratubular crystals after acyclovir were found only in animals [48], and a case of acute tubular necrosis without intratubular crystals and crystalluria during acyclovir therapy has been described [49]. Therefore the real role of crystalluria in the pathogenesis of acute renal failure in patients Table 4. The main types of crystals due to drugs V ~Fig. 6. A typical 'stook of wheat' crystal of sulphadiazine as it appears under polarized light (256 x ). Fig. 7. Acyclovir crystalluria (bright-field microscope, 1800 x). (From Potter JL and Krill CE. Acyclovir crystalluria. Pediatr Infect Dis J 1986; 5: with permission).

8 386 talluria following overdose [55,56]. The urinary abnormalities include isolated crystalluria or crystalluria associated with transient haematuria and proteinuria [55]. Crystals are birefringent hexagons which come singly or in conglomerates. In the latter case they can resemble crystals of cystine [56]. Other drugs such as quinolones, cephalexin, sulphamethoxazole, aspirin, xylitol, etc. can occasionally cause crystalluria, without relevant clinical implications, however. Conclusions Crystalluria is a frequent finding, about 8% of samples in author's experience. Most of the times it is the consequence of a transient supersaturation of urine caused by the ingestion of some foods or by changes of urine temperature and/or ph, which occur upon standing after micturition. In a minority of cases, however, crystalluria is due to pathological events, some of which can affect the kidneys seriously. In these cases, crystalluria is diagnostically useful and is also important to follow the course of the disease. Even in these circumstances, however, a proper methodological approach is necessary and crystalluria must be matched with other laboratory tests and with the clinical findings. 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 shown that the vasodilator naftidrofuryl oxalate also can cause crystalluria associated with acute renal failure (see Le Meur, Moesch, Rince et al. Nephrol Dial Transplant 1995; 10: ). References 1. Fogazzi GB, Cameron JS, Ritz E el al. The history of urinary microscopy to the end of the 19th century. Am J Nephrol 1994; 14: Hooke R. 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