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Urine and stone analysis for the investigation of the renal stone former: a consensus conference

Urine and stone analysis for the investigation of the renal stone former: a consensus conference The Consensus Group deliberated on a number of questions concerning urine and stone analysis over a period of months, and then met to develop consensus. The Group concluded that analyses of urine and stones should be routine in the diagnosis and treatment of urinary stone diseases. At present, the 24-h urine is the most useful type of urine collection, and accepted methods for analysis are described. Patient education is also important for obtaining a proper urine sample. Graphical methods for reporting urine analysis results can be helpful both for the physician and for educating the patient as to proper dietary changes that could be beneficial. Proper analysis of stones is also essential for diagnosis and management of patients. The Consensus Group also agreed that research has shown that evaluation of urinary crystals could be very valuable, but the Group also recognizes that existing methods for assessment of crystalluria do not allow this to be part of stone treatment in many places. Keywords Nephrolithiasis · Urine analysis · Stone analysis · Crystalluria Introduction urine testing that would have been relevant to managing their urinary stone disease [5]. A possible interpretation of this The use of urine analysis as a guide to the diagnosis and low utilization of urine data is that physicians in the US are treatment of kidney stones is recommended for at least some unconvinced that urine testing is valuable and cost-effective stone formers in all of the published international guidelines [6–8]. [1–4] (see Supplemental Table 1), but data suggest it is not In the UK, most health authorities have abandoned the generally utilized as widely as has been recommended. For routine biochemical screening of stone patients to save example, a recent study of a large cohort within the United money in favour of managing kidney stone patients solely States (US) Veterans Affairs Health Care System found that through the urological removal or disintegration of their fewer than 1-in-6 stone forming patients had undergone 24-h stones. This approach, in itself, does not “cure” the patients’ underlying risk of forming further stones. Furthermore, in general, no preventative treatment is instituted and so most A Consensus Conference, held as part of the 4th International Meeting of the Menarini Foundation on Nephrolithiasis Renal patients return with further stones at a later date. It has been Stones in Practice: An Advanced Course: 20−22 June 2019, shown that this strategy actually costs more than would be Verona, IT. the case if proper biochemical screening were to be insti- tuted thereby resulting in a reduction in stone recurrence [9]. Electronic supplementary material The online version of this In contrast, within specialist stone centres for the treat- article (https ://doi.org/10.1007/s0024 0-020-01217 -3) contains supplementary material, which is available to authorized users. ment of stone patients in Europe, the use of urine analysis for patient management is relatively uniform, with a recent * James C. Williams Jr. survey showing that 96% of stone centres perform 24-h [email protected] urine analyses as part of both initial and follow-up visits for Extended author information available on the last page of the article Vol.:(0123456789) 1 3 2 Urolithiasis (2021) 49:1–16 patients [10]. However, these specialist stone centres did not The Group initially performed its work by means of elec- agree on the best methods for collection and analysis of a tronic communication over a period of 5 months prior to 24-h urine specimen, and only 3 of the 24 stone centres that Meeting in June 2019 in Verona, where it sought to reach a were surveyed commented that they used any calculation consensus. This document provides a summary of the con- of the supersaturation levels of urinary salts and acids to clusions of the Group. assess their patients’ risks of forming further stones. Thus, even in health centres that specialize in the management of References used stone patients, there exists some uncertainty about how urine analyses should be performed and how the data should be This document does not provide an exhaustive listing of all interpreted. relevant research papers in the field. Instead, the works cited A lack of uniformity also exists regarding methods of here have been selected as being the most appropriate for stone analysis, which is essential to the interpretation of achieving consensus. All provide useful entry points into urine analyses [11]. In the recent survey of European stone each subject area. However, an effort was made to ensure centres, 21% of the centres reported using only wet chemi- that no significant paper was ignored in the deliberations of cal, rather than spectroscopic methods for stone analysis the Consensus Group. This effort included solicitation of [10], even though the use of chemical analysis has repeatedly important papers from each of the members of the Group, been shown to result in serious errors that can lead to incor- followed by an appropriately extensive subject search using rect clinical conclusions [12, 13]. Finally, the identification PubMed. Some key papers were also searched forward to of crystals in urine has not gained much traction as an aid look for citing articles using Web of Science (Clarivate). to diagnosing and managing the stone forming patient, even though some researchers suggest that the disappearance of crystalluria is the best evidence that clinical management Q1. What is the value of collecting urine has been effective in reducing the risk of stone recurrence samples from patients with kidney stones? [14, 15]. th The purpose of the convocation of the 4 International The process of crystallization in urine is complex, but urine Meeting of the Menarini Foundation on Nephrolithiasis was analysis allows identification of the potential key chemi- to address these issues and to seek the consensus of an inter- cal factors which are thought to lead to the precipitation of national Group of experts who specialize in various aspects minerals that form stones. Armed with such information, of the use of urine, stone, and crystalluria analyses for treat- physicians can institute appropriate interventions to alter ing stone patients. The Group worked to develop consensus these factors with a view to reducing the risk of further stone on general topics (such as the value of urine analysis for formation. treating stone forming patients) and on specific issues (such Treatment regimens such as specific dietary recommen- as how a specimen should be collected and analysed). The dations (for example, to manage hypercalciuria and mild Group also sought to identify areas of study that would be hyperoxaluria [16]), or administration of medications such especially fruitful for improving the scientific grounding of as citrate (to increase pH and citrate in urine), thiazides (to these practices. decrease hypercalciuria), or allopurinol (to decrease hyperu- ricosuria) are generally not implemented without prior urine analysis to identify the underlying pathological conditions Brief of the Consensus Group concerned. Moreover, most physicians who prescribe such medications want to follow up their patients with repeat The brief which was assigned to the Group by the Meeting’s urine analysis to ensure that the patient is complying with organizers was: (1) to assess the current evidence for the treatment and that the medication is having the desired use of urine analysis in the treatment of nephrolithiasis and effect. Urine analysis is, therefore, crucial for directing the to recommend best practice thereof; (2) to specify practi- clinician towards suitable treatment and for following up the cal recommendations for the optimum collection of urine patient over time. specimens and what variables should be measured in the Although it might be possible for a physician to prescribe specimens; (3) to identify the most suitable methods for medications such as citrate, thiazides, or allopurinol in an measuring urine properties and constituents, what can be empiric manner, and without urine analysis results [7], this measured at home, what supersaturation and risk indices is not common practice. A recent study of 130,489 stone should be calculated, and how the results should be commu- patients in the US veterans system showed that only a minor- nicated to the referring physician and to the patient, and (4) ity of patients (13%) underwent a 24-h urine workup, but to recommend optimum methods for the analysis of stones that this minority was more likely to be prescribed citrate, and crystals passed in urine. thiazide, or allopurinol than were the stone formers who 1 3 Urolithiasis (2021) 49:1–16 3 were not requested to collect a 24-h urine [17]. Importantly, risk factors for stone-formation are more frequently abnor- their data also showed that prescription of these medica- mal in stone forming patients than in normal controls [7, tions followed logically from the results of the patients’ 19–21]. Reports also show that 24-h abnormalities provide 24-h urines. Thus, physicians treating these stone patients useful information to help understand the underlying cause were more likely to prescribe medication when the urine of stones in a given patient as well as for targeting changes analysis data pointed to a specific need in the patient (e.g., in urine composition that should reduce his/her risk of to reduce hypercalciuria). Our consensus is that this is a stone recurrence. Both the American Urological Associa- rational approach, and that most physicians would not want tion (AUA) and the European Association of Urology (EAU) to commit a patient to a medication without prior evidence in their guidelines recommend 24-h urine samples as the from urine analysis. Indeed, a recent paper has shown that a standard procedure for evaluation at least for calcium stone decline in supersaturation values for calcium oxalate (CaOx) formers [1, 2]. In general, 24-h urine supersaturation levels and in 24-h urine excretion of citrate, potassium and mag- may be used to predict the likelihood that a person is a stone nesium with treatment were associated with longer periods former [22, 23]. without recurrence [18]. The Consensus Group recognized Yet, as mentioned in the Introduction, remarkably few that more studies, such as this one, would be helpful in stone patients in the US are evaluated using 24-h urine data. establishing the value of therapy driven by urine analysis A recent study of a very large cohort showed that patients in stone patients. who did not complete a 24-h urine study (87% of 130,489 Urine analysis also forms part of the work-up of a stone- patients, all of whom were within a system that would pay forming patient for the identification of diseases predispos- for their 24-h urine testing) were less likely to receive medi- ing to or associated with nephrolithiasis. These conditions cations that are thought to reduce the risk for stone recur- include primary hyperparathyroidism, primary hyperoxalu- rence such as thiazides, alkali, citrate or allopurinol. Those ria, enteric hyperoxaluria, cystinuria, and distal renal tubular who did collect a 24-h urine were prescribed medication that acidosis. The percentage of stone formers who have one of was clearly linked to the results of their 24-h urine analyses these conditions is not large, but recognizing these diseases [17]. This points to the practical value of 24-h urine testing is essential for proper treatment, and urine analysis is cer- in providing the physician with data to prompt and guide tainly part of that process. the prescription of appropriate dietary advice or medication. The assessment of a patient’s diet to identify potential Most of the participating experts expressed their belief predisposing factors is another extremely important benefit that 24-h urine analysis is essential for diagnosing and fol- which clinicians can derive from analysis of urine. This lowing up patients with calcium-containing stones, for the aspect is discussed in several sections which appear later appropriate prescription of medication to reduce stone recur- in this document. rence, for advising patients on dietary adjustments, and for It was recognized by the Consensus Group that in most verifying (and encouraging) patient compliance. Even in countries, detailed analysis of urine samples from stone those few cases in which spot urine could suffice for the formers tends to be limited to specialist laboratories and diagnosis (i.e., cystinuria or primary hyperoxaluria) 24-h practices. The Group agreed that transfer of basic skills to urine collections are essential for monitoring not only the general practitioners could benefit huge numbers of patients effects of treatment on urine composition, but also on com- worldwide. pliance to the recommendation to increase water intake. However, the efficacy of monitoring 24-h urine analysis Consensus on Q1 during follow up with concomitant modification of dietary advice and drug treatment culminating in a decrease in stone The consensus in the Group was that analysis of urine sam- recurrence is not established. Ferraro et al. [18] have investi- ples is essential for the meaningful management of stone gated this issue using a post-hoc analysis of the Borghi trial formers. The Group recommends that urine analysis needs [24]. Due to the experimental design only very short-term to be performed in conjunction with metabolic studies, stone variations (1 week) were considered. A prospective, rand- analysis and dietary assessment. omized trial has been conducted to compare recurrence in patients whose dietary recommendations were made with Q2. What type of urine collection is best and without tests that included 24-h urine analysis [25], and for assessing a patient’s risk of forming stones: the results of this trial support the value of 24-h urine test- a 24‑h urine, or some other type of collection? ing in reducing stone recurrence. However, more long-term, randomized control trials involving large numbers of stone Numerous reports in the literature on patients with urolithi- patients are needed to establish the actual value of 24-h urine asis refer to results of analysis of 24-h urine composition. testing in preventing stone recurrence. An overwhelming number have shown that 24-h urinary 1 3 4 Urolithiasis (2021) 49:1–16 The Group agreed that spot urines (including morning Patient education is also important for proper urine col- fasting urines) or other urine collections over part of a day lection, both to motivate the patient to complete the collec- can be valuable, too, but there are too few studies to iden- tions properly and to ensure that the collections represent the tify best practice for urine analysis outside of the standard patient’s normal lifestyle practices. For the two 24-h urine 24-h collection. In view of the well-known diurnal varia- samples at initial evaluation, it is wise to coach the patient tion of urine composition in calcium stone forming patients that one collection should be done on a day at work and one [26–29], it seems certain that analysis of urine at specific performed on a non-working day. Left to their own choice, times of day could be even more informative than the com- a patient is likely to want to collect both specimens at home, prehensive 24-h urine. This is important, because in some yet most people spend more days at work than at home and patients (such as children) obtaining a 24-h urine speci- the environmental and nutritional differences may be critical men is impractical. A recent paper has suggested that an in determining their stone risk. Most importantly, 24-h urine afternoon collection of urine in children may substitute in collections should only be carried out when the patients are some ways for a 24-h urine specimen [30]. In adults, there consuming their free, everyday diets—never as in-patients, is evidence of variation among individuals in their diurnal since the foods and drinks served in hospital may be very patterns of urine composition [29], which complicates this different from those normally consumed by the patients at approach. However, a recent proof-of-concept study on home. healthy volunteers has suggested that it might be rational to The frequency of follow-up analyses should be deter- investigate specific timed urine collections according to the mined by the kind of treatment that has been prescribed, stone type (e.g., 8 pm to 8 am for calcium oxalate, 2–4 pm but in most cases an initial follow-up at 3–6 months is war- for uric acid, or any 2-h timed urine collection during day- ranted [36, 37]. If no changes are made in treatment, then time for calcium phosphate [31]. More studies in this direc- annual checks thereafter are probably sufficient for tracking. tion are likely to be helpful. Consensus on Q3 Consensus on Q2 The Consensus Group recommends two 24-h urine analyses The Consensus Group agreed that 24-h urine analysis is for initial evaluation of stone patients. One collection should essential for diagnosing and following stone patients and be made on a workday and the other should be made during a should be the main modality utilized in most practices. non-workday. It is important that the patients should collect However, the Group recognizes the significant value of other their 24-h urines when they are consuming their free, eve- urine collection modalities and encourages further research ryday diets. Follow-up at 3–6 months is recommended. The in this area. Consensus Group emphasizes that patient education on how and when to collect their 24-h urine samples is important. Q3. How many urine collections should be made from a given patient Q4. Is urine composition a reliable indicator and how frequently should follow‑up of the patient’s diet? urine samples be collected to monitor the patient’s progress? It is well known that dietary habits affect the risk of kidney stone formation. There are a number of ways to assess a Studies have shown that a single urine collection often does patient’s diet: (1) diet diary; (2) 24-h diet recall; (3) food not provide a complete picture of the abnormalities in a frequency assessment; and (4) 24-h urine chemistries. These stone patient, and that collection of two urine samples for approaches have strengths and weaknesses, but the use of analysis is generally better [32–34]. One practical aspect 24-h urine composition in conjunction with one of the diet of having at least two analyses is that variations in dietary history approaches may provide the most comprehensive factors can sometimes be easily identified (such as when way to assess the role of diet and its effect on stone risk. oxalate excretion varies dramatically between two days) and Urine data provide an objective measure that does not identification of relevant conditions such as hypercalciuria depend on patient recall (with its possible bias), and the data can be more accurately established [32]. relevant to diet can be interpreted quickly and easily. The It is also recognised that the diagnostic accuracy of dietary data derived from the 24-h urine analysis also allow 24 h-urine testing not only increases with the number of assessment of the possible metabolic interaction between urines collected, but also with time passing before urine col- certain dietary factors that may have an effect on urinary risk lections after a stone event, most likely due to a vanishing factors for stones; for example, if the patient has a high urine ‘stone clinic effect’ [35]. calcium it is important to know if markers of sodium and 1 3 Urolithiasis (2021) 49:1–16 5 protein intake are high for the same day [38, 39]. Multiple In addition to providing a primary therapeutic endpoint 24-h urine collections also provide an estimate of dietary for solutes, passing a sufficiently large urine volume is variance [34, 40]. critical for reducing solute supersaturation levels in stone Dietary sodium intake is notoriously difficult to estimate formers. To increase urine volume, fluid intake greater than by history or food frequency questionnaire. Salt added dur- average may not by itself overcome the effects of living or ing food preparation is often unquantified as is salt added at working in a high ambient temperature, physical activity or mealtime. Urine sodium excretion is considered the most chronic diarrhoea [46, 47]. Thus, the patient should achieve reliable method to assess sodium intake [41]. Confounding a goal of urine output rather than a set fluid intake [42] factors include excessive sweating, diarrheal diseases, and and in this regard, the 24-h urine volume is a very useful sodium retention (such as during menstruation), all of which measure. can lead to discrepancy between sodium intake and urine Urine pH, citrate, calcium and oxalate are dependent on sodium excretion, but in general urinary sodium excretion factors in addition to diet and, therefore, cannot be used as is a sufficiently accurate measure of dietary sodium intake reliable indicators of dietary intake. Citrate and pH depend to be a useful clinical tool [42, 43]. on the balance of alkali intake and intake of dietary acid Urine potassium can be used as a marker of dietary potas- precursors, as well as loss of alkali from the gastrointesti- sium intake. Approximately 85 to 90% of diet potassium is nal tract and physiologic abnormalities such as metabolic absorbed assuming normal gut function [42]. In steady state, syndrome. Only a fraction of dietary calcium is absorbed, urine potassium excretion will approximate intestinal potas- and that fraction varies from person to person. Urine cal- sium absorption. Because potassium is predominantly an cium may also derive from bone mineral; furthermore, it is intracellular cation there is considerable capacity to accept influenced by sodium and protein intake [ 48]. All in all, this the dietary load, leading to some offset in time from inges- makes calcium intake difficult to assess from urinary excre- tion to excretion of a potassium load. However, there is still tion alone. Oxalate has variable intestinal absorption and good agreement of intake to excretion [43]. Urine potassium 50% or more of urine oxalate derives from endogenous oxa- excretion can be particularly useful in monitoring adherence late production. Moreover, the calcium content of the diet to prescribed potassium alkali. itself influences the intestinal absorption of oxalate, prob- Urine urea can be used as a marker of total protein intake ably because the formation of insoluble calcium oxalate in [42], while sulphate is as a marker of animal protein intake, the food mixture reduces the oxalate available for intestinal as sulphur amino acids are oxidized to sulfuric acids, which absorption [49–51]. Indeed, a recent paper has demonstrated is excreted as sulphate [42, 44]. These two markers are that high calcium ingested simultaneously with food intake highly correlated, and either can be used to monitor protein reduces oxaluria and significantly also urinary CaOx super - intake. As sulphate is probably not measured routinely in all saturation in idiopathic calcium oxalate stone formers [52]. stone clinics, it should be mentioned that uric acid is also a reliable marker of animal (non-dairy) protein, because—in Consensus on Q4 comparison with other urinary protein markers such as phos- phate and sulphate—only uric acid increases significantly on The Consensus Group recognizes that although urine chem- certain acid-rich diets [45]. istry has limitations as an indicator of dietary intake, it nev- Despite these strengths, there are weaknesses in using ertheless provides important information about diet that 24-h urine data alone to assess diet. This method will yield cannot be easily obtained by other means, and which can data only for a single day’s diet and will not provide a meas- be valuable for managing treatment of the individual stone ure of fat or carbohydrate intake. Moreover, the urine data former. alone will not allow an assessment of calcium or oxalate intake. A further limitation of using the 24-h collection for Q5. How should urine collections be made—(a) dietary assessment is that it is possible that some patients in a container which does not contain a preservative may temporarily increase their compliance with their die- of any kind, (b) in a container to which preservative tary advice in an attempt to “improve” the composition of has been added before collection, (c) in a container to which preservative is added after collection or (d) their urine collection, which they can accomplish easily for a single day. This applies particularly to the intake of fluid some other method of collection? and its effect on urine volume. It is recognised that patients often try to “please” their doctor by drinking more on the The addition of stabilizers and the conditions under which day before and during the day of their urine collection. The urine is collected and stored represent important aspects Internet may also play a significant role in directing patients to consider in the determination of 24-h urinary constitu- (rightly or wrongly) as to what to eat and drink to self-treat ents. In most situations, a 24-h urine specimen cannot be their stone problem. analysed immediately, and so an additive that will inhibit 1 3 6 Urolithiasis (2021) 49:1–16 the growth of microorganisms in the specimen is necessary Q7. What analytes should be measured in urine [53, 54]. One approach for this has been to add thymol as and why? Should we distinguish between samples a preservative to the container before collection (at about collected for the routine screening of patients 1 g thymol per litre capacity of the container [54], and this and samples collected for specific studies? method appears to preserve all important urine constituents to be measured [55, 56]. Other preservatives (such as chlo- The constituents to be measured in a 24-h urine specimen rhexidine) have also been used [57]. Another approach has are defined by the needs of diagnosing disorders and for been to add acid (typically boric acid [1]) to the container planning treatment with recurrent stone formers. The volume before collection, as is commonly done for urine collected of the 24-h urine specimen is an important measurement, for microbiological analysis [58]. However, if acid is added and counselling stone formers to increase urine volume is a as a preservative, the pH of the urine may need to be meas- common and effective form of treatment [65]. For analytes, ured in an additional independent specimen, and it should pH is essential for the calculation of the relative supersatura- be recognized that the pH of a spot urine is unlikely to cor- tion of urine with respect to all potential stone constituents, respond with that of a 24-h specimen [28]. but particularly calcium phosphate and uric acid. It can also be an indicator of stone type when its value lies within cer- Consensus on Q5 tain well-defined ranges. Other urinary constituents which the Consensus Group recommends for routine screening are The Consensus Group agreed that a 24-h urine specimen calcium, oxalate, citrate and uric acid as they are potential should be collected in the presence of a preservative, and indicators of hypercalciuria, mild and hereditary hyperoxalu- that use of a non-acidic preservative simplifies the meas- ria, hypocitraturia and hyperuricosuria, respectively, all of urement of all parameters needed for supersaturation which are well established risk factors for stone formation. calculations. Urinary sodium should be measured to assess dietary salt intake, as described in question 4 above, and for its potential link with hypercalciuria. Additional constituents need to be Q6. How should collected urine be handled measured particularly for accurate calculation of supersatu- before aliquoting for different analyses? ration values [66]. These include potassium, magnesium, phosphate, chloride, sulphate and ammonium. The latter two When a 24-h urine specimen is received (that is preserved constituents are also recommended as important markers of with a non-acidic agent), its pH should be first measured dietary composition. Creatinine is useful for assessing the using a pH meter (NOT by dipstick), and then the speci- completeness of a given patient’s 24-h collection, particu- men thoroughly mixed. Some reports indicate that urine larly if the patient is being followed up over a period of time. can then be aliquoted for various analyses without any fur- Urea is useful for assessing total protein intake, as men- ther processing [59, 60]. However, studies specifically with tioned earlier in this report. Finally, it is recommended that urine from stone formers have shown that acidification of cystine screening be performed at least once in each patient an aliquot is important for proper dissolution of crystals for to rule out this genetic cause of stones, an easy diagnosis the measurement of calcium and oxalate [61–63], and that which is too often neglected [67]. alkalinisation of another aliquot is important for dissolution of uric acid crystals when they are present [63, 64]. Consensus on Q7 Consensus on Q6 The consensus is that relatively few urinary constituents are needed for the routine clinical workup of patients (volume, The Consensus Group recommends that when a urine speci- pH, calcium, sodium, oxalate, citrate, uric acid, urea, cre- men arrives in the laboratory, its pH should be measured atinine) to provide initial insights about possible pathogenic immediately using a pH meter. After vigorous agitation, one conditions and to enable more complete dietary recommen- aliquot should be acidified (to pH of < 2) and another alka- dations, but that several more are required to enhance the linised (to 6.5 or higher) for dissolution of crystals that may accuracy of supersaturation calculations (potassium, magne- be present in the specimen. sium, phosphate, chloride, sulphate and ammonium). 1 3 Urolithiasis (2021) 49:1–16 7 test strip or dipstick), calcium, potassium, sodium, mag- Q8. What inhibitors and/or promoters nesium, phosphate, creatinine, urea, chloride. For oxalate, of crystallization should be measured either enzymatic or chromatographic methods have been in urine—if any? shown to work well with urine, but oxalate analysis can be especially sensitive to interference by other compounds, The only substances with relative inhibitory capacity that are so laboratories must vet their procedures with care [61, at present routinely determined in urine are citrate and mag- 74]. It should be noted that to ensure complete dissolution nesium, and it is likely that the actual effect of these two ions of crystals of calcium oxalate in urine, it is essential to is primarily through reduction of supersaturation of calcium acidify the aliquot to < pH 2, particularly if the urine has oxalate and calcium phosphate, rather than through direct both a raised oxalate AND calcium content [57]. However, effects on crystallization [68]. Citrate shows some ability to this may raise a problem with the subsequent analysis of inhibit the crystallization of calcium salts, but probably its oxalate in the acidified sample if one of the enzymatic most important role is related to its ability to form soluble methods is used for measuring oxalate. The enzymes con- complexes with calcium, which results in a decrease in the cerned work optimally at pH levels approximately between supersaturation levels of insoluble calcium salts [69]. Mag- 3.5 and 5.5. This requires addition of significant amounts nesium, which can also exert a certain capacity to inhibit of alkali to be added to neutralize the added acid with the formation of calcium salts, plays its most important role a resultant marked increase in the ionic strength of the in the formation of a soluble species with the oxalate ion, mixture. In turn, this may inhibit the full functioning of which leads to a decrease in the level of supersaturation of the enzyme and lead to an underestimate of the oxalate urine with respect to calcium oxalate and calcium phosphate content of the urine [75]. Measurement of oxalate is best [68]. carried out by HPLC [76] or by ion-chromatography [77], It seems certain that macromolecules in urine play an but attention should be paid to the possibility of high pH in important role in the in vitro inhibition and promotion of the eluent leading to conversion of ascorbic acid to oxalate crystallization [70], but there is little understanding of [78]. Citrate can be measured by enzymatic or chromato- which, if any, of these molecules are useful for planning graphic methods [79]. Uric acid is commonly measured treatment in stone formers. Both osteopontin and Tamm- in automated systems using an enzymatic method [80]. Horsfall glycoprotein have been shown in laboratory settings Both ammonium and sulphate (or S) determinations to inhibit crystallization [71], and excretion of both have are uncommon. Urinary ammonium can be measured by been found to be lower in stone-formers [72, 73]. However, enzymatic methods using automated systems [81, 82], and data on how such measurements might be used in governing the potential exists to use electronic methods [83, 84]. the treatment of stone formers are lacking. For sulphate, either precipitation with barium chloride or chromatographic methods is successful [85]. Consensus on Q8 For cystine determination, the colorimetric nitroprus- side technique works well [86], as do some chromato- The Group agreed that more research is needed into the graphic methods [87]. However, analysts should note that action of inhibitors and promoters of crystallization in urine, assays may not distinguish cystine from soluble thiol drug- and how their concentrations can be clinically managed, cysteine complexes. This would be important in patients before measurement of any of these becomes a regular part who are taking tiopronin or D-penicillamine, which form of the screening and treatment of stone formers. thio-cysteine bonds to increase cysteine solubility in urine. However, thiol-cysteine bonds can be broken during sam- ple preparation, releasing cysteine which recombines with Q9. What are the best methods for analysing itself to form cystine. The result is inaccurate measure- urine for the analytes specified in Q7? ment in patients taking thiol drugs and inability to judge drug efficacy. An approach in managing cystine patients Most of the constituents to be analysed in urine can be meas- and judging the effectiveness of medication has been to ured using the methods already established in clinical labo- measure the cystine capacity of the urine, a separate analy- ratories but each laboratory should confirm that the preser - sis that uses a solid phase method [88, 89]. Newer technol- vation method used (e.g., thymol, boric acid, etc.) does not ogy may also allow improvements in treatment of cystine interfere with any of the assays performed on the sample. stones [90]. Because assays vary in subtle details between manufacturers, this issue must be addressed by each individual laboratory. Standard methods are in place in any clinical laboratory for the measurement of volume, pH (by meter, and not by 1 3 8 Urolithiasis (2021) 49:1–16 Consensus on Q9 Q11. Is there is value in calculating relative supersaturation in 24‑h urines? The Consensus Group concluded that analysis of most analytes needed for proper assessment of 24-h urine col- Urine is said to be supersaturated with respect to a given lections is standard in most countries. The group agreed salt or acid when its activity product (a chemical measure that more research is needed into the development of an of how much of a particular salt or acid is contained in a easy and fast method for the separate detection in urine solution) exceeds its solubility product at which point the of soluble and insoluble cystine to monitor treatment in urine is said to be completely saturated with the salt or acid patients with cystinuria. concerned. When urine is at the solubility product of that salt or acid it is defined as having a relative supersaturation value of 1. In the case of calcium oxalate, urine from normal Q10. Are there any specific tests available adults may have relative supersaturation levels between 4 that patients can usefully perform at home and 10 [96] but in the urine of untreated stone-formers this to assess their risk of forming stones? may reach values of 20 or more [22]. For comparison, the relative supersaturation of normal urine with respect to cal- Increasing urine volume is a common form of treatment for cium phosphate is in the range 0.4–2.3 [96] but in untreated stone patients, and a simple qualitative monitoring of urine stone-formers may reach values of 10 or more [22]. For uric colour [91] or urine conductivity [92] have been reported acid, the relative supersaturation of normal urine is in the as being useful to patients who are seeking to maintain an range 0.4–1.9 [96] but in untreated stone-formers may reach appropriate intake of fluids. For some kinds of stones, the values up to 3.5 [22]. value of the urine pH is an important indicator of treatment In general, an increase in the relative supersaturation level success [93] and tracking this through each day using a of any of these salts or uric acid is consistent with the min- dipstick has been recommended for cystinuric patients [1]. eral deposited in stones [97], and so it makes sense to insti- New devices that can provide more accurate measurement tute treatment modalities that are designed to decrease urine of urine pH by the patient at home are becoming commer- supersaturation levels in stone-formers. Indeed, reduction in cially available [94, 95]. Potentially such devices could also the relative supersaturation of urine with respect to calcium provide other measures of urine composition. oxalate correlates with a lower risk for calcium oxalate stone If such measures are to be employed, it is important to recurrence [18]. counsel the patient on how to carry out the analyses at home Measurement of urinary supersaturation of stone-forming with proper technique, and for many patients, overcoming salts and uric acid has been regarded as the gold standard their reluctance to do anything with their own urine can be a for determining the risk of stone formation for over 50 years. challenge. However, research is needed in this area, as there Although supersaturation can be determined empirically, is little known about how successful home monitoring of sophisticated computer programs have been widely used to urine can be in reducing the rate of stone recurrence. calculate this important urinary property. Examples include SUPERSAT [29], EQUIL2 [98], JESS [99], and LithoRisk [100]. These programs generate similar but non-identical Consensus on Q10 values for supersaturation depending on the number and type of urinary constituents that are used in the various calcula- The Consensus Group accepts that there are tests that tions. Lowering mineral supersaturation values by means patients can perform on their own urine at home that may of dietary adjustment or relevant medication has been and be of (minor) utility, but proper counselling of patients is continues to be the goal of most treatment regimens as it pro- essential. However, it is recognized that these tests will vides a numerical indication of potential efficacy in reducing merely serve as an indicator of progress to the patients them- the likelihood of stone recurrence. Several members of the selves rather than being of clinical value to the prescribing Consensus Group stated that they seek to reduce calcium physician. Home monitoring of the urine pH is an impor- oxalate urine supersaturation levels in the urines of calcium tant measure to self-adjust bicarbonate/citrate treatment in oxalate stone formers to half of their initial value, but con- cystinuric patients. sensus was not agreed on a definitive target value for this objective. 1 3 Urolithiasis (2021) 49:1–16 9 Consensus on Q11 Consensus on Q12 The Group agreed that calculated relative supersaturation The Consensus Group recognizes that several urine-based values provide a better indication of the propensity for crys- risk indices have been proposed, but that as yet none has tals to form than will the measure of any single analyte in the support of clinical trials to establish any of them as a urine, and that these can be useful in directing treatment standard predictor of stone recurrence in patients. The Group of stone formers and in assessing the efficacy of treatment. recommends that research in this area would be of great value to the stone treatment community. Q12. Is there any value in using indices Q13. How should the results of screening tests be of stone risk that seek to predict stone reported to the urologist or nephrologist treating recurrence? the patient and how should the results be conveyed to the patient in a patient‑friendly format? As discussed above, values for urine supersaturation can be useful in identifying urine properties to be targeted for The results of 24-h urine measurements can appear as a long therapy (low volume, high calcium, etc.) and for assessing list of numbers that will be difficult to interpret for the inex- the success of therapy (indicated by a reduction in urine perienced physician, and incomprehensible to the patient. supersaturation). But other efforts have been made to use Thus, a simplified graphical format for presenting these data urine analyses (or other data) to provide prediction of the can go a long way toward making them broadly useful within probability of stone recurrence in a given patient, in part to the stone treatment community. It may also be a valuable reduce the number of analyses necessary for the calculation means to convey in a simple visual way the results of urine of relative supersaturation using sophisticated computer pro- analysis to the patients concerned. grams. These indices also can have the value of integrating Two examples of how reports might be presented are data in ways that avoid any controversy about cut-off values shown in Fig. 1. The upper panel shows part of a 24-h urine for what would be ‘normal’ in analysis results [16]. analysis report in which the colour of each box in the table The two Tiselius Activity Product (AP) Indices for cal- and the size of typeface draw the eye to values that increase culating the risk of forming calcium oxalate and calcium the chances of stone formation. If one reads the report from phosphate stones are both relatively simple quotients involv- bottom-to-top, one sees the progress of the patient over time. ing urine constituents that together require only six measure- The lower panel shows another approach, in which risk indi- ments in urine: pH, calcium, oxalate, citrate, magnesium, ces calculated from urine data are displayed in the form of a and volume [21]. High values of these Indices have been coloured Target Diagram, where values distant from the cen- shown to correlate with stone recurrence [101]. The Robert- tre (i.e., in the red zone of the target) indicate a higher risk son set of risk indices (P ) is another alternative for assess- for stone recurrence and the values that the patient should SF ing stone risk [102]. Altogether these indices require seven be targeting to be safe from stone recurrence are shown in urinary measurements for assessing the biochemical risk the central, green bull’s-eye. of forming calcium oxalate and calcium phosphate stones, These are just two examples, and within our Consensus but they also calculate the risk of forming uric acid stones. Group, a number of laboratories presently utilize a variety These indices correlate with actual stone recurrence [66]. of such graphical approaches to enhance readability by the The BONN-Risk Index relies on a laboratory estimation of physician and to provide effective ways to convey results the resistance of a urine sample to support the crystallization to a patient. Note that both examples in Fig.  1 allow the of calcium oxalate [103]. This is a specialized test procedure physician to show the patient what changes have occurred that includes an implicit assessment of the levels of promot- with alterations in diet or medication. This kind of graphical ers and inhibitors of crystallization in the urine and has been information is likely to improve patient motivation and help claimed to discriminate between a population that was prone advance the physician–patient relationship over the course to form stones and one that was not [104]. of monitoring stone disease within a given individual. None of these measures has become widely adopted by physicians treating stone patients, and none has been Consensus on Q13 assessed in trials to evaluate how well they can predict stone recurrence in a given patient. Yet, each shows promise to be The Group strongly recommends that results of 24-h urine able to identify patients who are at risk of stone recurrence. analyses should be communicated in a manner that enhances understanding in both physician and patient, and that physi- cians should consider using any of the graphical methods which are available. 1 3 10 Urolithiasis (2021) 49:1–16 Fig. 1 Examples of urine analysis reports that include graphical fea- value for calcium phosphate (SS CaP). b Part of the graphical report tures to aid in interpretation. a Part of the LithoLink report (Labora- for urine results from the LITHOSCREEN system for assessing stone tory Corporation of America, Burlington, NC, USA) for 24-h urine patients [29]. Note that targeted values (least likely to lead to a stone results. Note that measures that are out of the normal range are high- recurrence) are at the centre of the diagram, in the green bull’s eye. lighted both by a change in background colour and an increase in the PSF indicates the Robertson biochemical risk of forming stones as size and boldness of the typeface. The history of the patient is also described above under Q12. The initial untreated PSF values for the shown, with the most recent results on the top line. Note that in this patient are shown in the purple lines and shape, and the values after case, the patient has significantly increased the urine volume, and treatment are shown in light blue. Before treatment, this patient was thereby reduced the supersaturation value for calcium oxalate (SS at risk of forming both uric acid and calcium oxalate stones or a mix- CaOx). However, this was done along with a dramatic increase in die- ture of the two. Following suitable dietary treatment, the PSF values tary salt (Na 24), which likely led to the increase in urine calcium (Ca of the patient all fell into the green bull’s eye. Similar target diagrams 24), which was part of what drove an increase in the supersaturation are also available for both 24-h urine and dietary composition [29] 1 3 Urolithiasis (2021) 49:1–16 11 Q14. Is there value in studying crystalluria? Q15. How should crystalluria best be assessed? The presence of crystals in urine is prima facie evidence that the balance between solute supersaturation and promoters In most laboratories presently assessing crystalluria, it is on one hand and inhibitors of crystallization on the other has thought that examination of the first morning urine yields tipped toward precipitation. As such, crystalluria can provide the most crystals, reflecting the propensity of minerals to evidence of the propensity of the urine to form stones [105]. precipitate in the urine when it is most concentrated. How- However, it is recognized that this is not a conclusive diagnos- ever, unless the patient lives in close proximity to the analy- tic as some non-stone formers form crystals in their urine [106, sis laboratory, this is unlikely to be practical. Thus, typical 107], although these crystals, at least for calcium oxalate, are analyses are done using the second morning urine, which is reported to be smaller and less aggregated than those found in collected midstream, while on premises at the laboratory, the fresh urine samples from recurrent stone-formers [108]. and immediately submitted for analysis [111, 112]. Urine Studies of repeated urine specimens for crystalluria have is kept at room temperature and processed quickly (ideally shown that this kind of crystalluria (large crystals, aggre- within 20 min, but certainly within 2 h). Urine pH should gated crystals) to be strongly correlated with stone recur- be measured by meter. An aliquot of the urine is centrifuged rence [22, 108]. Furthermore, a more recent study of 188 to concentrate the specimen 20-fold, and then 50 µl pipetted patients over 3 years with multiple urine specimens showed onto a slide and topped with a coverslip. that having 50% or more urine samples with crystals was These laboratories generally record crystal counts as predictive of stone recurrence with a sensitivity of 88% number per high-power field, and crystal types are iden- and a specificity of 84% [14]. This study is very suggestive tified using a combination of bright-field and polarization that persistent crystalluria accurately reflects a propensity microscopy [105, 110]. With this method, crystalluria can for stone formation. Similar results were seen in cystine be expressed as mild (1–5 crystals per high power field), patients, in which the volume of cystine crystals was also moderate (6–10), severe (11–20), and very severe (> 20). seen as highly predictive of those patients who would form Alternatively, it is possible to quantify crystal content of a new cystine stone [109]. urine using machine measures [108, 113], an approach that Additionally, examination of urine crystals can reveal may be more likely to be automated in a way that assess- rarer types of stone disease. For example, the crystals of cys- ment of crystalluria could be made more widely available. tine and 2,8-dihydroxyadenine in urine are very distinctive, As mentioned above under Q14, the development of auto- easy to identify under the microscope, and pathognomonic mated evaluation methods for assessing crystalluria would of these two genetic diseases [105, 110]. be useful, as would be the standardization of criteria for Unfortunately, obtaining the proper urine specimens to measurement and reporting of urinary crystals. Research in determine crystalluria requires patients to submit specimens these areas is needed. early in the morning, and for the specimens to be examined promptly (see comments in Q15 below). In addition, labora- Consensus on Q15 tory personnel must be skilled in assessing urinary crystals by microscopic examination. All these issues currently make For present practice, the Consensus Group recommends that assessment of crystalluria rare. crystalluria should be determined by microscopy in morn- ing urines by a skilled observer. The Group also recognizes Consensus on Q14 that research into new methods, standardization of reporting criteria, and further research into how to apply test results Crystalluria provides a natural indication of the propensity for patient diagnosis and treatment will all be important for for stone formation, and thus would be valuable in assess- making crystalluria determination more widespread in the ing the probability of stone recurrence and in indicating if treatment of stone diseases. treatment is efficacious. Availability of crystalluria deter - mination in more laboratories would likely benefit patients who are motivated to reduce their risk of stones. However, Q16. How should kidney stones best be the Consensus Group recognizes that research in this area analysed? is needed for standardization of results and for the develop- ment of easy-to-perform evaluation methods (and possibly All published guidelines on treatment of stone form- automatization) so that the use of crystalluria in diagnosis ers include stone analysis as a first step in classifying the and treatment can become a routine part of care for stone patient. Indeed, assessment of the results from the analysis formers. 1 3 12 Urolithiasis (2021) 49:1–16 of urine is impossible to do properly without knowing the Sometimes the general morphological class of the stone can kind of stone produced. also still be identified [117]. A general principle for stone Stone analysis begins with examination of the stone under analysis is that the more complete the specimen, the better a stereomicroscope to assess which part (or parts) of the will be the quality of the analysis [121], so submission of stone should be taken for molecular analysis. Most stones collections of fragments for analysis will generally be better contain more than one mineral [114], and identification of than sending just a few. visually distinct parts of the stone for dissection is important for correct analysis of minor constituents [115]. Stone por- Consensus on Q17 tions taken should then be analysed by a molecular method, typically by either infrared spectroscopy or X-ray diffraction The Consensus Group recommends the analysis of frag- to identify mineral types [116]. Whatever method is used, ments, because knowledge of a stone’s mineral composition it is important that it be able to distinguish, for example, (albeit only partial) is an integral part of interpreting 24-h brushite from other forms of calcium phosphate, and cal- urine results and in planning treatment. cium oxalate dihydrate from monohydrate. It is relatively simple to identify the morphological types of stones. This can significantly support clinically relevant Conclusions information [117, 118]. This is done during the initial exami- nation by stereomicroscope and typically also includes vis- The Consensus Group concludes that analyses of urine ual examination of the interior of the stone. It is easy, for and stones should be routine in the diagnosis and treat- example, to distinguish a calcium oxalate stone that formed ment of urinary stone diseases. At present, the 24-h urine initially as the dihydrate, which is indicative of the pres- is the most useful type of urine collection, and methods ence of hypercalciuria [119], even when its composition will for analysis and standards for interpretation are widely have transformed over time to the monohydrate form of the available. Patient education is also important for obtaining mineral. a proper urine sample. Graphical methods for reporting As discussed for the measurement of crystalluria, above, urine analysis results can be helpful both for the physician it is recognized that the development of methods of stone and for educating the patient as to proper dietary changes analysis that do not require a skilled observer would be valu- that could be beneficial. Proper analysis of stones is also able in enabling analysis of stone morphology and composi- essential for diagnosis and management of patients. The tion to be carried out more widely across the globe. Consensus Group also agrees that research has shown that evaluation of urinary crystals could be very valuable, but Consensus on Q16 the Group also recognizes that existing methods for assess- ment of crystalluria do not allow this to be part of stone The Consensus Group strongly recommends that stone anal- treatment in many places. ysis be performed if possible as part of the workup of stone Acknowledgements This article is based on the results of a Consensus patients. The analysis should be conducted using infrared Conference held during the “4th INTERNATIONAL MEETING OF spectroscopy or X-ray powder diffraction. Visual identifica- THE MENARINI FOUNDATION ON NEPHROLITHIASIS”, Verona, tion of stone morphology is also valuable. June 20-22, 2019 generously supported by the International Foundation Menarini, Milan, Italy with an unrestricted educational Grant. Q17. Is there any value in analysing stone Compliance with ethical standard fragments? Conflict of interest J. Asplin is an employee of Labcorp/Litholink; and D.S. Goldfarb is owner and patent holder with Dr. Arnie’s, Inc., and is Analysis of whole stones yields information on morphol- a consultant/researcher with Alnylam, Retrophin, Synlogic, and Dic- ogy and composition, but also allows discovery of the man- erna. All other authors declare no conflict of interest. ner in which the stone was retained during early growth. Open Access This article is licensed under a Creative Commons Attri- Specifically, the identification of stones that have grown on bution 4.0 International License, which permits use, sharing, adapta- Randall’s plaque is easy to perform [120]. However, many tion, distribution and reproduction in any medium or format, as long methods of stone removal (e.g., shock wave lithotripsy, laser as you give appropriate credit to the original author(s) and the source, lithotripsy) result in the fragmentation of stones. provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are Though information of how a stone might have been included in the article’s Creative Commons licence, unless indicated formed (such as the presence of Randall’s plaque) is lost otherwise in a credit line to the material. If material is not included in when stones are fragmented, analysis of the fragments the article’s Creative Commons licence and your intended use is not still allows for the mineral composition to be determined. 1 3 Urolithiasis (2021) 49:1–16 13 permitted by statutory regulation or exceeds the permitted use, you will 17. 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Bazin D, Leroy C, Tielens F, Bonhomme C, Bonhomme-Coury luria. Clin Chim Acta 26:105–110 L, Damay F, Le Denmat D, Sadoine J, Rode J, Frochot V, 114. Daudon M, Donsimoni R, Hennequin C, Fellahi S, Le Moel G, Letavernier E, Haymann J-P, Daudon M (2016) Hyperoxalu- Paris M, Troupel S, Lacour B (1995) Sex and age-related com- ria is related to whewellite and hypercalciuria to weddellite: position of 10617 calculi analyzed by infrared-spectroscopy. Urol what happens when crystalline conversion occurs? C R Chim Res 23:319–326 19:1492–1503 115. Krambeck AE, Khan NF, Jackson ME, Lingeman JE, McAteer 120. Letavernier E, Vandermeersch S, Traxer O, Tligui M, Baud L, JA, Williams JC Jr (2010) Inaccurate reporting of mineral com- Ronco P, Haymann JP, Daudon M (2015) Demographics and position by commercial stone analysis laboratories: implications characterization of 10,282 Randall plaque-related kidney stones: for infection and metabolic stones. J Urol 184:1543–1549 a new epidemic? Medicine (Baltimore) 94:e566 116. Daudon M, Williams JC Jr (2020) Characteristics of human kid- 121. Krambeck AE, Lingeman JE, McAteer JA, Williams JC Jr (2010) ney stones. In: Coe F, Worcester EM, Lingeman JE, Evan AP Analysis of mixed stones is prone to error: a study with U.S. (eds) Kidney stones. Jaypee Medical Publishers, New Delhi, pp laboratories using micro CT for verification of sample content. 77–97 Urol Res 38:469–475 117. Daudon M, Dessombz A, Frochot V, Letavernier E, Haymann J-P, Jungers P, Bazin D (2016) Comprehensive morpho-constitutional Publisher’s Note Springer Nature remains neutral with regard to analysis of urinary stones improves etiological diagnosis and jurisdictional claims in published maps and institutional affiliations. therapeutic strategy of nephrolithiasis. C R Chim 19:1470–1491 Affiliations 1 2 3 4 5 James C. Williams Jr.  · Giovanni Gambaro  · Allen Rodgers  · John Asplin  · Olivier Bonny  · 6 7 8 9 10 Antonia Costa‑Bauzá  · Pietro Manuel Ferraro  · Giovanni Fogazzi  · Daniel G. Fuster  · David S. Goldfarb  · 6 11 12 13 14 15 Félix Grases  · Ita P. Heilberg  · Dik Kok  · Emmanuel Letavernier  · Giuseppe Lippi  · Martino Marangella  · 16 17 18 19 20 Antonio Nouvenne  · Michele Petrarulo  · Roswitha Siener  · Hans‑Göran Tiselius  · Olivier Traxer  · 21 22 23 Alberto Trinchieri  · Emanuele Croppi  · William G. Robertson 1 12 Department of Anatomy, Cell Biology & Physiology, SAELO, Oegstgeest, The Netherlands Indiana University School of Medicine, Indianapolis, Service des Explorations Fonctionnelles Multidisciplinaires, IN 46260, USA Hôpital Tenon, Paris, France Division of Nephrology and Dialysis, Department Laboratory of Clinical Chemistry and Hematology, of Medicine, University of Verona, Verona, Italy University Hospital of Verona, Verona, Italy Department of Chemistry, University of Cape Town, Fondazione Scientifica Mauriziana ONLUS, Turin, Italy Cape Town, South Africa Internal Medicine and Subacute Long Term Unit, Azienda Litholink, Laboratory Corporation of America Holdings, Ospedaliero-Universitaria di Parma, Parma, Italy Itasca, IL, USA Ospedale Ordine Mauriziano di Torino, Turin, Italy Service of Nephrology, Department of Medicine, Lausanne University Hospital and Department of Biomedical Sciences, University Stone Center, Department of Urology, University University of Lausanne, Lausanne, Switzerland Hospital Bonn, Bonn, Germany 6 19 IUNICS-Idisba, University of Balearic Islands, Department of Clinical Science, Intervention and Technology Palma de Mallorca, Spain (CLINTEC), Karolinska Institutet, Stockholm, Sweden 7 20 UOC Nefrologia, Fondazione Policlinico Universitario Service d’Urologie, Hôpital Tenon, Paris, France A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore, School of Urology, University of Milan, Milan, Italy Rome, Italy USL Toscana Centro, Florence, Italy Policlinico di Milano, Milan, Italy Nuffield Department of Surgical Sciences, University Inselspital, Bern University Hospital, University of Bern, of Oxford, Oxford, UK Bern, Switzerland NYU Langone Health, NYU Grossman School of Medicine and the New York Harbor VA Healthcare System, New York, NY, USA Universidade Federal de São Paulo, São Paulo, SP, Brazil 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Urological Research Springer Journals

Urine and stone analysis for the investigation of the renal stone former: a consensus conference

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10.1007/s00240-020-01217-3
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Abstract

The Consensus Group deliberated on a number of questions concerning urine and stone analysis over a period of months, and then met to develop consensus. The Group concluded that analyses of urine and stones should be routine in the diagnosis and treatment of urinary stone diseases. At present, the 24-h urine is the most useful type of urine collection, and accepted methods for analysis are described. Patient education is also important for obtaining a proper urine sample. Graphical methods for reporting urine analysis results can be helpful both for the physician and for educating the patient as to proper dietary changes that could be beneficial. Proper analysis of stones is also essential for diagnosis and management of patients. The Consensus Group also agreed that research has shown that evaluation of urinary crystals could be very valuable, but the Group also recognizes that existing methods for assessment of crystalluria do not allow this to be part of stone treatment in many places. Keywords Nephrolithiasis · Urine analysis · Stone analysis · Crystalluria Introduction urine testing that would have been relevant to managing their urinary stone disease [5]. A possible interpretation of this The use of urine analysis as a guide to the diagnosis and low utilization of urine data is that physicians in the US are treatment of kidney stones is recommended for at least some unconvinced that urine testing is valuable and cost-effective stone formers in all of the published international guidelines [6–8]. [1–4] (see Supplemental Table 1), but data suggest it is not In the UK, most health authorities have abandoned the generally utilized as widely as has been recommended. For routine biochemical screening of stone patients to save example, a recent study of a large cohort within the United money in favour of managing kidney stone patients solely States (US) Veterans Affairs Health Care System found that through the urological removal or disintegration of their fewer than 1-in-6 stone forming patients had undergone 24-h stones. This approach, in itself, does not “cure” the patients’ underlying risk of forming further stones. Furthermore, in general, no preventative treatment is instituted and so most A Consensus Conference, held as part of the 4th International Meeting of the Menarini Foundation on Nephrolithiasis Renal patients return with further stones at a later date. It has been Stones in Practice: An Advanced Course: 20−22 June 2019, shown that this strategy actually costs more than would be Verona, IT. the case if proper biochemical screening were to be insti- tuted thereby resulting in a reduction in stone recurrence [9]. Electronic supplementary material The online version of this In contrast, within specialist stone centres for the treat- article (https ://doi.org/10.1007/s0024 0-020-01217 -3) contains supplementary material, which is available to authorized users. ment of stone patients in Europe, the use of urine analysis for patient management is relatively uniform, with a recent * James C. Williams Jr. survey showing that 96% of stone centres perform 24-h [email protected] urine analyses as part of both initial and follow-up visits for Extended author information available on the last page of the article Vol.:(0123456789) 1 3 2 Urolithiasis (2021) 49:1–16 patients [10]. However, these specialist stone centres did not The Group initially performed its work by means of elec- agree on the best methods for collection and analysis of a tronic communication over a period of 5 months prior to 24-h urine specimen, and only 3 of the 24 stone centres that Meeting in June 2019 in Verona, where it sought to reach a were surveyed commented that they used any calculation consensus. This document provides a summary of the con- of the supersaturation levels of urinary salts and acids to clusions of the Group. assess their patients’ risks of forming further stones. Thus, even in health centres that specialize in the management of References used stone patients, there exists some uncertainty about how urine analyses should be performed and how the data should be This document does not provide an exhaustive listing of all interpreted. relevant research papers in the field. Instead, the works cited A lack of uniformity also exists regarding methods of here have been selected as being the most appropriate for stone analysis, which is essential to the interpretation of achieving consensus. All provide useful entry points into urine analyses [11]. In the recent survey of European stone each subject area. However, an effort was made to ensure centres, 21% of the centres reported using only wet chemi- that no significant paper was ignored in the deliberations of cal, rather than spectroscopic methods for stone analysis the Consensus Group. This effort included solicitation of [10], even though the use of chemical analysis has repeatedly important papers from each of the members of the Group, been shown to result in serious errors that can lead to incor- followed by an appropriately extensive subject search using rect clinical conclusions [12, 13]. Finally, the identification PubMed. Some key papers were also searched forward to of crystals in urine has not gained much traction as an aid look for citing articles using Web of Science (Clarivate). to diagnosing and managing the stone forming patient, even though some researchers suggest that the disappearance of crystalluria is the best evidence that clinical management Q1. What is the value of collecting urine has been effective in reducing the risk of stone recurrence samples from patients with kidney stones? [14, 15]. th The purpose of the convocation of the 4 International The process of crystallization in urine is complex, but urine Meeting of the Menarini Foundation on Nephrolithiasis was analysis allows identification of the potential key chemi- to address these issues and to seek the consensus of an inter- cal factors which are thought to lead to the precipitation of national Group of experts who specialize in various aspects minerals that form stones. Armed with such information, of the use of urine, stone, and crystalluria analyses for treat- physicians can institute appropriate interventions to alter ing stone patients. The Group worked to develop consensus these factors with a view to reducing the risk of further stone on general topics (such as the value of urine analysis for formation. treating stone forming patients) and on specific issues (such Treatment regimens such as specific dietary recommen- as how a specimen should be collected and analysed). The dations (for example, to manage hypercalciuria and mild Group also sought to identify areas of study that would be hyperoxaluria [16]), or administration of medications such especially fruitful for improving the scientific grounding of as citrate (to increase pH and citrate in urine), thiazides (to these practices. decrease hypercalciuria), or allopurinol (to decrease hyperu- ricosuria) are generally not implemented without prior urine analysis to identify the underlying pathological conditions Brief of the Consensus Group concerned. Moreover, most physicians who prescribe such medications want to follow up their patients with repeat The brief which was assigned to the Group by the Meeting’s urine analysis to ensure that the patient is complying with organizers was: (1) to assess the current evidence for the treatment and that the medication is having the desired use of urine analysis in the treatment of nephrolithiasis and effect. Urine analysis is, therefore, crucial for directing the to recommend best practice thereof; (2) to specify practi- clinician towards suitable treatment and for following up the cal recommendations for the optimum collection of urine patient over time. specimens and what variables should be measured in the Although it might be possible for a physician to prescribe specimens; (3) to identify the most suitable methods for medications such as citrate, thiazides, or allopurinol in an measuring urine properties and constituents, what can be empiric manner, and without urine analysis results [7], this measured at home, what supersaturation and risk indices is not common practice. A recent study of 130,489 stone should be calculated, and how the results should be commu- patients in the US veterans system showed that only a minor- nicated to the referring physician and to the patient, and (4) ity of patients (13%) underwent a 24-h urine workup, but to recommend optimum methods for the analysis of stones that this minority was more likely to be prescribed citrate, and crystals passed in urine. thiazide, or allopurinol than were the stone formers who 1 3 Urolithiasis (2021) 49:1–16 3 were not requested to collect a 24-h urine [17]. Importantly, risk factors for stone-formation are more frequently abnor- their data also showed that prescription of these medica- mal in stone forming patients than in normal controls [7, tions followed logically from the results of the patients’ 19–21]. Reports also show that 24-h abnormalities provide 24-h urines. Thus, physicians treating these stone patients useful information to help understand the underlying cause were more likely to prescribe medication when the urine of stones in a given patient as well as for targeting changes analysis data pointed to a specific need in the patient (e.g., in urine composition that should reduce his/her risk of to reduce hypercalciuria). Our consensus is that this is a stone recurrence. Both the American Urological Associa- rational approach, and that most physicians would not want tion (AUA) and the European Association of Urology (EAU) to commit a patient to a medication without prior evidence in their guidelines recommend 24-h urine samples as the from urine analysis. Indeed, a recent paper has shown that a standard procedure for evaluation at least for calcium stone decline in supersaturation values for calcium oxalate (CaOx) formers [1, 2]. In general, 24-h urine supersaturation levels and in 24-h urine excretion of citrate, potassium and mag- may be used to predict the likelihood that a person is a stone nesium with treatment were associated with longer periods former [22, 23]. without recurrence [18]. The Consensus Group recognized Yet, as mentioned in the Introduction, remarkably few that more studies, such as this one, would be helpful in stone patients in the US are evaluated using 24-h urine data. establishing the value of therapy driven by urine analysis A recent study of a very large cohort showed that patients in stone patients. who did not complete a 24-h urine study (87% of 130,489 Urine analysis also forms part of the work-up of a stone- patients, all of whom were within a system that would pay forming patient for the identification of diseases predispos- for their 24-h urine testing) were less likely to receive medi- ing to or associated with nephrolithiasis. These conditions cations that are thought to reduce the risk for stone recur- include primary hyperparathyroidism, primary hyperoxalu- rence such as thiazides, alkali, citrate or allopurinol. Those ria, enteric hyperoxaluria, cystinuria, and distal renal tubular who did collect a 24-h urine were prescribed medication that acidosis. The percentage of stone formers who have one of was clearly linked to the results of their 24-h urine analyses these conditions is not large, but recognizing these diseases [17]. This points to the practical value of 24-h urine testing is essential for proper treatment, and urine analysis is cer- in providing the physician with data to prompt and guide tainly part of that process. the prescription of appropriate dietary advice or medication. The assessment of a patient’s diet to identify potential Most of the participating experts expressed their belief predisposing factors is another extremely important benefit that 24-h urine analysis is essential for diagnosing and fol- which clinicians can derive from analysis of urine. This lowing up patients with calcium-containing stones, for the aspect is discussed in several sections which appear later appropriate prescription of medication to reduce stone recur- in this document. rence, for advising patients on dietary adjustments, and for It was recognized by the Consensus Group that in most verifying (and encouraging) patient compliance. Even in countries, detailed analysis of urine samples from stone those few cases in which spot urine could suffice for the formers tends to be limited to specialist laboratories and diagnosis (i.e., cystinuria or primary hyperoxaluria) 24-h practices. The Group agreed that transfer of basic skills to urine collections are essential for monitoring not only the general practitioners could benefit huge numbers of patients effects of treatment on urine composition, but also on com- worldwide. pliance to the recommendation to increase water intake. However, the efficacy of monitoring 24-h urine analysis Consensus on Q1 during follow up with concomitant modification of dietary advice and drug treatment culminating in a decrease in stone The consensus in the Group was that analysis of urine sam- recurrence is not established. Ferraro et al. [18] have investi- ples is essential for the meaningful management of stone gated this issue using a post-hoc analysis of the Borghi trial formers. The Group recommends that urine analysis needs [24]. Due to the experimental design only very short-term to be performed in conjunction with metabolic studies, stone variations (1 week) were considered. A prospective, rand- analysis and dietary assessment. omized trial has been conducted to compare recurrence in patients whose dietary recommendations were made with Q2. What type of urine collection is best and without tests that included 24-h urine analysis [25], and for assessing a patient’s risk of forming stones: the results of this trial support the value of 24-h urine test- a 24‑h urine, or some other type of collection? ing in reducing stone recurrence. However, more long-term, randomized control trials involving large numbers of stone Numerous reports in the literature on patients with urolithi- patients are needed to establish the actual value of 24-h urine asis refer to results of analysis of 24-h urine composition. testing in preventing stone recurrence. An overwhelming number have shown that 24-h urinary 1 3 4 Urolithiasis (2021) 49:1–16 The Group agreed that spot urines (including morning Patient education is also important for proper urine col- fasting urines) or other urine collections over part of a day lection, both to motivate the patient to complete the collec- can be valuable, too, but there are too few studies to iden- tions properly and to ensure that the collections represent the tify best practice for urine analysis outside of the standard patient’s normal lifestyle practices. For the two 24-h urine 24-h collection. In view of the well-known diurnal varia- samples at initial evaluation, it is wise to coach the patient tion of urine composition in calcium stone forming patients that one collection should be done on a day at work and one [26–29], it seems certain that analysis of urine at specific performed on a non-working day. Left to their own choice, times of day could be even more informative than the com- a patient is likely to want to collect both specimens at home, prehensive 24-h urine. This is important, because in some yet most people spend more days at work than at home and patients (such as children) obtaining a 24-h urine speci- the environmental and nutritional differences may be critical men is impractical. A recent paper has suggested that an in determining their stone risk. Most importantly, 24-h urine afternoon collection of urine in children may substitute in collections should only be carried out when the patients are some ways for a 24-h urine specimen [30]. In adults, there consuming their free, everyday diets—never as in-patients, is evidence of variation among individuals in their diurnal since the foods and drinks served in hospital may be very patterns of urine composition [29], which complicates this different from those normally consumed by the patients at approach. However, a recent proof-of-concept study on home. healthy volunteers has suggested that it might be rational to The frequency of follow-up analyses should be deter- investigate specific timed urine collections according to the mined by the kind of treatment that has been prescribed, stone type (e.g., 8 pm to 8 am for calcium oxalate, 2–4 pm but in most cases an initial follow-up at 3–6 months is war- for uric acid, or any 2-h timed urine collection during day- ranted [36, 37]. If no changes are made in treatment, then time for calcium phosphate [31]. More studies in this direc- annual checks thereafter are probably sufficient for tracking. tion are likely to be helpful. Consensus on Q3 Consensus on Q2 The Consensus Group recommends two 24-h urine analyses The Consensus Group agreed that 24-h urine analysis is for initial evaluation of stone patients. One collection should essential for diagnosing and following stone patients and be made on a workday and the other should be made during a should be the main modality utilized in most practices. non-workday. It is important that the patients should collect However, the Group recognizes the significant value of other their 24-h urines when they are consuming their free, eve- urine collection modalities and encourages further research ryday diets. Follow-up at 3–6 months is recommended. The in this area. Consensus Group emphasizes that patient education on how and when to collect their 24-h urine samples is important. Q3. How many urine collections should be made from a given patient Q4. Is urine composition a reliable indicator and how frequently should follow‑up of the patient’s diet? urine samples be collected to monitor the patient’s progress? It is well known that dietary habits affect the risk of kidney stone formation. There are a number of ways to assess a Studies have shown that a single urine collection often does patient’s diet: (1) diet diary; (2) 24-h diet recall; (3) food not provide a complete picture of the abnormalities in a frequency assessment; and (4) 24-h urine chemistries. These stone patient, and that collection of two urine samples for approaches have strengths and weaknesses, but the use of analysis is generally better [32–34]. One practical aspect 24-h urine composition in conjunction with one of the diet of having at least two analyses is that variations in dietary history approaches may provide the most comprehensive factors can sometimes be easily identified (such as when way to assess the role of diet and its effect on stone risk. oxalate excretion varies dramatically between two days) and Urine data provide an objective measure that does not identification of relevant conditions such as hypercalciuria depend on patient recall (with its possible bias), and the data can be more accurately established [32]. relevant to diet can be interpreted quickly and easily. The It is also recognised that the diagnostic accuracy of dietary data derived from the 24-h urine analysis also allow 24 h-urine testing not only increases with the number of assessment of the possible metabolic interaction between urines collected, but also with time passing before urine col- certain dietary factors that may have an effect on urinary risk lections after a stone event, most likely due to a vanishing factors for stones; for example, if the patient has a high urine ‘stone clinic effect’ [35]. calcium it is important to know if markers of sodium and 1 3 Urolithiasis (2021) 49:1–16 5 protein intake are high for the same day [38, 39]. Multiple In addition to providing a primary therapeutic endpoint 24-h urine collections also provide an estimate of dietary for solutes, passing a sufficiently large urine volume is variance [34, 40]. critical for reducing solute supersaturation levels in stone Dietary sodium intake is notoriously difficult to estimate formers. To increase urine volume, fluid intake greater than by history or food frequency questionnaire. Salt added dur- average may not by itself overcome the effects of living or ing food preparation is often unquantified as is salt added at working in a high ambient temperature, physical activity or mealtime. Urine sodium excretion is considered the most chronic diarrhoea [46, 47]. Thus, the patient should achieve reliable method to assess sodium intake [41]. Confounding a goal of urine output rather than a set fluid intake [42] factors include excessive sweating, diarrheal diseases, and and in this regard, the 24-h urine volume is a very useful sodium retention (such as during menstruation), all of which measure. can lead to discrepancy between sodium intake and urine Urine pH, citrate, calcium and oxalate are dependent on sodium excretion, but in general urinary sodium excretion factors in addition to diet and, therefore, cannot be used as is a sufficiently accurate measure of dietary sodium intake reliable indicators of dietary intake. Citrate and pH depend to be a useful clinical tool [42, 43]. on the balance of alkali intake and intake of dietary acid Urine potassium can be used as a marker of dietary potas- precursors, as well as loss of alkali from the gastrointesti- sium intake. Approximately 85 to 90% of diet potassium is nal tract and physiologic abnormalities such as metabolic absorbed assuming normal gut function [42]. In steady state, syndrome. Only a fraction of dietary calcium is absorbed, urine potassium excretion will approximate intestinal potas- and that fraction varies from person to person. Urine cal- sium absorption. Because potassium is predominantly an cium may also derive from bone mineral; furthermore, it is intracellular cation there is considerable capacity to accept influenced by sodium and protein intake [ 48]. All in all, this the dietary load, leading to some offset in time from inges- makes calcium intake difficult to assess from urinary excre- tion to excretion of a potassium load. However, there is still tion alone. Oxalate has variable intestinal absorption and good agreement of intake to excretion [43]. Urine potassium 50% or more of urine oxalate derives from endogenous oxa- excretion can be particularly useful in monitoring adherence late production. Moreover, the calcium content of the diet to prescribed potassium alkali. itself influences the intestinal absorption of oxalate, prob- Urine urea can be used as a marker of total protein intake ably because the formation of insoluble calcium oxalate in [42], while sulphate is as a marker of animal protein intake, the food mixture reduces the oxalate available for intestinal as sulphur amino acids are oxidized to sulfuric acids, which absorption [49–51]. Indeed, a recent paper has demonstrated is excreted as sulphate [42, 44]. These two markers are that high calcium ingested simultaneously with food intake highly correlated, and either can be used to monitor protein reduces oxaluria and significantly also urinary CaOx super - intake. As sulphate is probably not measured routinely in all saturation in idiopathic calcium oxalate stone formers [52]. stone clinics, it should be mentioned that uric acid is also a reliable marker of animal (non-dairy) protein, because—in Consensus on Q4 comparison with other urinary protein markers such as phos- phate and sulphate—only uric acid increases significantly on The Consensus Group recognizes that although urine chem- certain acid-rich diets [45]. istry has limitations as an indicator of dietary intake, it nev- Despite these strengths, there are weaknesses in using ertheless provides important information about diet that 24-h urine data alone to assess diet. This method will yield cannot be easily obtained by other means, and which can data only for a single day’s diet and will not provide a meas- be valuable for managing treatment of the individual stone ure of fat or carbohydrate intake. Moreover, the urine data former. alone will not allow an assessment of calcium or oxalate intake. A further limitation of using the 24-h collection for Q5. How should urine collections be made—(a) dietary assessment is that it is possible that some patients in a container which does not contain a preservative may temporarily increase their compliance with their die- of any kind, (b) in a container to which preservative tary advice in an attempt to “improve” the composition of has been added before collection, (c) in a container to which preservative is added after collection or (d) their urine collection, which they can accomplish easily for a single day. This applies particularly to the intake of fluid some other method of collection? and its effect on urine volume. It is recognised that patients often try to “please” their doctor by drinking more on the The addition of stabilizers and the conditions under which day before and during the day of their urine collection. The urine is collected and stored represent important aspects Internet may also play a significant role in directing patients to consider in the determination of 24-h urinary constitu- (rightly or wrongly) as to what to eat and drink to self-treat ents. In most situations, a 24-h urine specimen cannot be their stone problem. analysed immediately, and so an additive that will inhibit 1 3 6 Urolithiasis (2021) 49:1–16 the growth of microorganisms in the specimen is necessary Q7. What analytes should be measured in urine [53, 54]. One approach for this has been to add thymol as and why? Should we distinguish between samples a preservative to the container before collection (at about collected for the routine screening of patients 1 g thymol per litre capacity of the container [54], and this and samples collected for specific studies? method appears to preserve all important urine constituents to be measured [55, 56]. Other preservatives (such as chlo- The constituents to be measured in a 24-h urine specimen rhexidine) have also been used [57]. Another approach has are defined by the needs of diagnosing disorders and for been to add acid (typically boric acid [1]) to the container planning treatment with recurrent stone formers. The volume before collection, as is commonly done for urine collected of the 24-h urine specimen is an important measurement, for microbiological analysis [58]. However, if acid is added and counselling stone formers to increase urine volume is a as a preservative, the pH of the urine may need to be meas- common and effective form of treatment [65]. For analytes, ured in an additional independent specimen, and it should pH is essential for the calculation of the relative supersatura- be recognized that the pH of a spot urine is unlikely to cor- tion of urine with respect to all potential stone constituents, respond with that of a 24-h specimen [28]. but particularly calcium phosphate and uric acid. It can also be an indicator of stone type when its value lies within cer- Consensus on Q5 tain well-defined ranges. Other urinary constituents which the Consensus Group recommends for routine screening are The Consensus Group agreed that a 24-h urine specimen calcium, oxalate, citrate and uric acid as they are potential should be collected in the presence of a preservative, and indicators of hypercalciuria, mild and hereditary hyperoxalu- that use of a non-acidic preservative simplifies the meas- ria, hypocitraturia and hyperuricosuria, respectively, all of urement of all parameters needed for supersaturation which are well established risk factors for stone formation. calculations. Urinary sodium should be measured to assess dietary salt intake, as described in question 4 above, and for its potential link with hypercalciuria. Additional constituents need to be Q6. How should collected urine be handled measured particularly for accurate calculation of supersatu- before aliquoting for different analyses? ration values [66]. These include potassium, magnesium, phosphate, chloride, sulphate and ammonium. The latter two When a 24-h urine specimen is received (that is preserved constituents are also recommended as important markers of with a non-acidic agent), its pH should be first measured dietary composition. Creatinine is useful for assessing the using a pH meter (NOT by dipstick), and then the speci- completeness of a given patient’s 24-h collection, particu- men thoroughly mixed. Some reports indicate that urine larly if the patient is being followed up over a period of time. can then be aliquoted for various analyses without any fur- Urea is useful for assessing total protein intake, as men- ther processing [59, 60]. However, studies specifically with tioned earlier in this report. Finally, it is recommended that urine from stone formers have shown that acidification of cystine screening be performed at least once in each patient an aliquot is important for proper dissolution of crystals for to rule out this genetic cause of stones, an easy diagnosis the measurement of calcium and oxalate [61–63], and that which is too often neglected [67]. alkalinisation of another aliquot is important for dissolution of uric acid crystals when they are present [63, 64]. Consensus on Q7 Consensus on Q6 The consensus is that relatively few urinary constituents are needed for the routine clinical workup of patients (volume, The Consensus Group recommends that when a urine speci- pH, calcium, sodium, oxalate, citrate, uric acid, urea, cre- men arrives in the laboratory, its pH should be measured atinine) to provide initial insights about possible pathogenic immediately using a pH meter. After vigorous agitation, one conditions and to enable more complete dietary recommen- aliquot should be acidified (to pH of < 2) and another alka- dations, but that several more are required to enhance the linised (to 6.5 or higher) for dissolution of crystals that may accuracy of supersaturation calculations (potassium, magne- be present in the specimen. sium, phosphate, chloride, sulphate and ammonium). 1 3 Urolithiasis (2021) 49:1–16 7 test strip or dipstick), calcium, potassium, sodium, mag- Q8. What inhibitors and/or promoters nesium, phosphate, creatinine, urea, chloride. For oxalate, of crystallization should be measured either enzymatic or chromatographic methods have been in urine—if any? shown to work well with urine, but oxalate analysis can be especially sensitive to interference by other compounds, The only substances with relative inhibitory capacity that are so laboratories must vet their procedures with care [61, at present routinely determined in urine are citrate and mag- 74]. It should be noted that to ensure complete dissolution nesium, and it is likely that the actual effect of these two ions of crystals of calcium oxalate in urine, it is essential to is primarily through reduction of supersaturation of calcium acidify the aliquot to < pH 2, particularly if the urine has oxalate and calcium phosphate, rather than through direct both a raised oxalate AND calcium content [57]. However, effects on crystallization [68]. Citrate shows some ability to this may raise a problem with the subsequent analysis of inhibit the crystallization of calcium salts, but probably its oxalate in the acidified sample if one of the enzymatic most important role is related to its ability to form soluble methods is used for measuring oxalate. The enzymes con- complexes with calcium, which results in a decrease in the cerned work optimally at pH levels approximately between supersaturation levels of insoluble calcium salts [69]. Mag- 3.5 and 5.5. This requires addition of significant amounts nesium, which can also exert a certain capacity to inhibit of alkali to be added to neutralize the added acid with the formation of calcium salts, plays its most important role a resultant marked increase in the ionic strength of the in the formation of a soluble species with the oxalate ion, mixture. In turn, this may inhibit the full functioning of which leads to a decrease in the level of supersaturation of the enzyme and lead to an underestimate of the oxalate urine with respect to calcium oxalate and calcium phosphate content of the urine [75]. Measurement of oxalate is best [68]. carried out by HPLC [76] or by ion-chromatography [77], It seems certain that macromolecules in urine play an but attention should be paid to the possibility of high pH in important role in the in vitro inhibition and promotion of the eluent leading to conversion of ascorbic acid to oxalate crystallization [70], but there is little understanding of [78]. Citrate can be measured by enzymatic or chromato- which, if any, of these molecules are useful for planning graphic methods [79]. Uric acid is commonly measured treatment in stone formers. Both osteopontin and Tamm- in automated systems using an enzymatic method [80]. Horsfall glycoprotein have been shown in laboratory settings Both ammonium and sulphate (or S) determinations to inhibit crystallization [71], and excretion of both have are uncommon. Urinary ammonium can be measured by been found to be lower in stone-formers [72, 73]. However, enzymatic methods using automated systems [81, 82], and data on how such measurements might be used in governing the potential exists to use electronic methods [83, 84]. the treatment of stone formers are lacking. For sulphate, either precipitation with barium chloride or chromatographic methods is successful [85]. Consensus on Q8 For cystine determination, the colorimetric nitroprus- side technique works well [86], as do some chromato- The Group agreed that more research is needed into the graphic methods [87]. However, analysts should note that action of inhibitors and promoters of crystallization in urine, assays may not distinguish cystine from soluble thiol drug- and how their concentrations can be clinically managed, cysteine complexes. This would be important in patients before measurement of any of these becomes a regular part who are taking tiopronin or D-penicillamine, which form of the screening and treatment of stone formers. thio-cysteine bonds to increase cysteine solubility in urine. However, thiol-cysteine bonds can be broken during sam- ple preparation, releasing cysteine which recombines with Q9. What are the best methods for analysing itself to form cystine. The result is inaccurate measure- urine for the analytes specified in Q7? ment in patients taking thiol drugs and inability to judge drug efficacy. An approach in managing cystine patients Most of the constituents to be analysed in urine can be meas- and judging the effectiveness of medication has been to ured using the methods already established in clinical labo- measure the cystine capacity of the urine, a separate analy- ratories but each laboratory should confirm that the preser - sis that uses a solid phase method [88, 89]. Newer technol- vation method used (e.g., thymol, boric acid, etc.) does not ogy may also allow improvements in treatment of cystine interfere with any of the assays performed on the sample. stones [90]. Because assays vary in subtle details between manufacturers, this issue must be addressed by each individual laboratory. Standard methods are in place in any clinical laboratory for the measurement of volume, pH (by meter, and not by 1 3 8 Urolithiasis (2021) 49:1–16 Consensus on Q9 Q11. Is there is value in calculating relative supersaturation in 24‑h urines? The Consensus Group concluded that analysis of most analytes needed for proper assessment of 24-h urine col- Urine is said to be supersaturated with respect to a given lections is standard in most countries. The group agreed salt or acid when its activity product (a chemical measure that more research is needed into the development of an of how much of a particular salt or acid is contained in a easy and fast method for the separate detection in urine solution) exceeds its solubility product at which point the of soluble and insoluble cystine to monitor treatment in urine is said to be completely saturated with the salt or acid patients with cystinuria. concerned. When urine is at the solubility product of that salt or acid it is defined as having a relative supersaturation value of 1. In the case of calcium oxalate, urine from normal Q10. Are there any specific tests available adults may have relative supersaturation levels between 4 that patients can usefully perform at home and 10 [96] but in the urine of untreated stone-formers this to assess their risk of forming stones? may reach values of 20 or more [22]. For comparison, the relative supersaturation of normal urine with respect to cal- Increasing urine volume is a common form of treatment for cium phosphate is in the range 0.4–2.3 [96] but in untreated stone patients, and a simple qualitative monitoring of urine stone-formers may reach values of 10 or more [22]. For uric colour [91] or urine conductivity [92] have been reported acid, the relative supersaturation of normal urine is in the as being useful to patients who are seeking to maintain an range 0.4–1.9 [96] but in untreated stone-formers may reach appropriate intake of fluids. For some kinds of stones, the values up to 3.5 [22]. value of the urine pH is an important indicator of treatment In general, an increase in the relative supersaturation level success [93] and tracking this through each day using a of any of these salts or uric acid is consistent with the min- dipstick has been recommended for cystinuric patients [1]. eral deposited in stones [97], and so it makes sense to insti- New devices that can provide more accurate measurement tute treatment modalities that are designed to decrease urine of urine pH by the patient at home are becoming commer- supersaturation levels in stone-formers. Indeed, reduction in cially available [94, 95]. Potentially such devices could also the relative supersaturation of urine with respect to calcium provide other measures of urine composition. oxalate correlates with a lower risk for calcium oxalate stone If such measures are to be employed, it is important to recurrence [18]. counsel the patient on how to carry out the analyses at home Measurement of urinary supersaturation of stone-forming with proper technique, and for many patients, overcoming salts and uric acid has been regarded as the gold standard their reluctance to do anything with their own urine can be a for determining the risk of stone formation for over 50 years. challenge. However, research is needed in this area, as there Although supersaturation can be determined empirically, is little known about how successful home monitoring of sophisticated computer programs have been widely used to urine can be in reducing the rate of stone recurrence. calculate this important urinary property. Examples include SUPERSAT [29], EQUIL2 [98], JESS [99], and LithoRisk [100]. These programs generate similar but non-identical Consensus on Q10 values for supersaturation depending on the number and type of urinary constituents that are used in the various calcula- The Consensus Group accepts that there are tests that tions. Lowering mineral supersaturation values by means patients can perform on their own urine at home that may of dietary adjustment or relevant medication has been and be of (minor) utility, but proper counselling of patients is continues to be the goal of most treatment regimens as it pro- essential. However, it is recognized that these tests will vides a numerical indication of potential efficacy in reducing merely serve as an indicator of progress to the patients them- the likelihood of stone recurrence. Several members of the selves rather than being of clinical value to the prescribing Consensus Group stated that they seek to reduce calcium physician. Home monitoring of the urine pH is an impor- oxalate urine supersaturation levels in the urines of calcium tant measure to self-adjust bicarbonate/citrate treatment in oxalate stone formers to half of their initial value, but con- cystinuric patients. sensus was not agreed on a definitive target value for this objective. 1 3 Urolithiasis (2021) 49:1–16 9 Consensus on Q11 Consensus on Q12 The Group agreed that calculated relative supersaturation The Consensus Group recognizes that several urine-based values provide a better indication of the propensity for crys- risk indices have been proposed, but that as yet none has tals to form than will the measure of any single analyte in the support of clinical trials to establish any of them as a urine, and that these can be useful in directing treatment standard predictor of stone recurrence in patients. The Group of stone formers and in assessing the efficacy of treatment. recommends that research in this area would be of great value to the stone treatment community. Q12. Is there any value in using indices Q13. How should the results of screening tests be of stone risk that seek to predict stone reported to the urologist or nephrologist treating recurrence? the patient and how should the results be conveyed to the patient in a patient‑friendly format? As discussed above, values for urine supersaturation can be useful in identifying urine properties to be targeted for The results of 24-h urine measurements can appear as a long therapy (low volume, high calcium, etc.) and for assessing list of numbers that will be difficult to interpret for the inex- the success of therapy (indicated by a reduction in urine perienced physician, and incomprehensible to the patient. supersaturation). But other efforts have been made to use Thus, a simplified graphical format for presenting these data urine analyses (or other data) to provide prediction of the can go a long way toward making them broadly useful within probability of stone recurrence in a given patient, in part to the stone treatment community. It may also be a valuable reduce the number of analyses necessary for the calculation means to convey in a simple visual way the results of urine of relative supersaturation using sophisticated computer pro- analysis to the patients concerned. grams. These indices also can have the value of integrating Two examples of how reports might be presented are data in ways that avoid any controversy about cut-off values shown in Fig. 1. The upper panel shows part of a 24-h urine for what would be ‘normal’ in analysis results [16]. analysis report in which the colour of each box in the table The two Tiselius Activity Product (AP) Indices for cal- and the size of typeface draw the eye to values that increase culating the risk of forming calcium oxalate and calcium the chances of stone formation. If one reads the report from phosphate stones are both relatively simple quotients involv- bottom-to-top, one sees the progress of the patient over time. ing urine constituents that together require only six measure- The lower panel shows another approach, in which risk indi- ments in urine: pH, calcium, oxalate, citrate, magnesium, ces calculated from urine data are displayed in the form of a and volume [21]. High values of these Indices have been coloured Target Diagram, where values distant from the cen- shown to correlate with stone recurrence [101]. The Robert- tre (i.e., in the red zone of the target) indicate a higher risk son set of risk indices (P ) is another alternative for assess- for stone recurrence and the values that the patient should SF ing stone risk [102]. Altogether these indices require seven be targeting to be safe from stone recurrence are shown in urinary measurements for assessing the biochemical risk the central, green bull’s-eye. of forming calcium oxalate and calcium phosphate stones, These are just two examples, and within our Consensus but they also calculate the risk of forming uric acid stones. Group, a number of laboratories presently utilize a variety These indices correlate with actual stone recurrence [66]. of such graphical approaches to enhance readability by the The BONN-Risk Index relies on a laboratory estimation of physician and to provide effective ways to convey results the resistance of a urine sample to support the crystallization to a patient. Note that both examples in Fig.  1 allow the of calcium oxalate [103]. This is a specialized test procedure physician to show the patient what changes have occurred that includes an implicit assessment of the levels of promot- with alterations in diet or medication. This kind of graphical ers and inhibitors of crystallization in the urine and has been information is likely to improve patient motivation and help claimed to discriminate between a population that was prone advance the physician–patient relationship over the course to form stones and one that was not [104]. of monitoring stone disease within a given individual. None of these measures has become widely adopted by physicians treating stone patients, and none has been Consensus on Q13 assessed in trials to evaluate how well they can predict stone recurrence in a given patient. Yet, each shows promise to be The Group strongly recommends that results of 24-h urine able to identify patients who are at risk of stone recurrence. analyses should be communicated in a manner that enhances understanding in both physician and patient, and that physi- cians should consider using any of the graphical methods which are available. 1 3 10 Urolithiasis (2021) 49:1–16 Fig. 1 Examples of urine analysis reports that include graphical fea- value for calcium phosphate (SS CaP). b Part of the graphical report tures to aid in interpretation. a Part of the LithoLink report (Labora- for urine results from the LITHOSCREEN system for assessing stone tory Corporation of America, Burlington, NC, USA) for 24-h urine patients [29]. Note that targeted values (least likely to lead to a stone results. Note that measures that are out of the normal range are high- recurrence) are at the centre of the diagram, in the green bull’s eye. lighted both by a change in background colour and an increase in the PSF indicates the Robertson biochemical risk of forming stones as size and boldness of the typeface. The history of the patient is also described above under Q12. The initial untreated PSF values for the shown, with the most recent results on the top line. Note that in this patient are shown in the purple lines and shape, and the values after case, the patient has significantly increased the urine volume, and treatment are shown in light blue. Before treatment, this patient was thereby reduced the supersaturation value for calcium oxalate (SS at risk of forming both uric acid and calcium oxalate stones or a mix- CaOx). However, this was done along with a dramatic increase in die- ture of the two. Following suitable dietary treatment, the PSF values tary salt (Na 24), which likely led to the increase in urine calcium (Ca of the patient all fell into the green bull’s eye. Similar target diagrams 24), which was part of what drove an increase in the supersaturation are also available for both 24-h urine and dietary composition [29] 1 3 Urolithiasis (2021) 49:1–16 11 Q14. Is there value in studying crystalluria? Q15. How should crystalluria best be assessed? The presence of crystals in urine is prima facie evidence that the balance between solute supersaturation and promoters In most laboratories presently assessing crystalluria, it is on one hand and inhibitors of crystallization on the other has thought that examination of the first morning urine yields tipped toward precipitation. As such, crystalluria can provide the most crystals, reflecting the propensity of minerals to evidence of the propensity of the urine to form stones [105]. precipitate in the urine when it is most concentrated. How- However, it is recognized that this is not a conclusive diagnos- ever, unless the patient lives in close proximity to the analy- tic as some non-stone formers form crystals in their urine [106, sis laboratory, this is unlikely to be practical. Thus, typical 107], although these crystals, at least for calcium oxalate, are analyses are done using the second morning urine, which is reported to be smaller and less aggregated than those found in collected midstream, while on premises at the laboratory, the fresh urine samples from recurrent stone-formers [108]. and immediately submitted for analysis [111, 112]. Urine Studies of repeated urine specimens for crystalluria have is kept at room temperature and processed quickly (ideally shown that this kind of crystalluria (large crystals, aggre- within 20 min, but certainly within 2 h). Urine pH should gated crystals) to be strongly correlated with stone recur- be measured by meter. An aliquot of the urine is centrifuged rence [22, 108]. Furthermore, a more recent study of 188 to concentrate the specimen 20-fold, and then 50 µl pipetted patients over 3 years with multiple urine specimens showed onto a slide and topped with a coverslip. that having 50% or more urine samples with crystals was These laboratories generally record crystal counts as predictive of stone recurrence with a sensitivity of 88% number per high-power field, and crystal types are iden- and a specificity of 84% [14]. This study is very suggestive tified using a combination of bright-field and polarization that persistent crystalluria accurately reflects a propensity microscopy [105, 110]. With this method, crystalluria can for stone formation. Similar results were seen in cystine be expressed as mild (1–5 crystals per high power field), patients, in which the volume of cystine crystals was also moderate (6–10), severe (11–20), and very severe (> 20). seen as highly predictive of those patients who would form Alternatively, it is possible to quantify crystal content of a new cystine stone [109]. urine using machine measures [108, 113], an approach that Additionally, examination of urine crystals can reveal may be more likely to be automated in a way that assess- rarer types of stone disease. For example, the crystals of cys- ment of crystalluria could be made more widely available. tine and 2,8-dihydroxyadenine in urine are very distinctive, As mentioned above under Q14, the development of auto- easy to identify under the microscope, and pathognomonic mated evaluation methods for assessing crystalluria would of these two genetic diseases [105, 110]. be useful, as would be the standardization of criteria for Unfortunately, obtaining the proper urine specimens to measurement and reporting of urinary crystals. Research in determine crystalluria requires patients to submit specimens these areas is needed. early in the morning, and for the specimens to be examined promptly (see comments in Q15 below). In addition, labora- Consensus on Q15 tory personnel must be skilled in assessing urinary crystals by microscopic examination. All these issues currently make For present practice, the Consensus Group recommends that assessment of crystalluria rare. crystalluria should be determined by microscopy in morn- ing urines by a skilled observer. The Group also recognizes Consensus on Q14 that research into new methods, standardization of reporting criteria, and further research into how to apply test results Crystalluria provides a natural indication of the propensity for patient diagnosis and treatment will all be important for for stone formation, and thus would be valuable in assess- making crystalluria determination more widespread in the ing the probability of stone recurrence and in indicating if treatment of stone diseases. treatment is efficacious. Availability of crystalluria deter - mination in more laboratories would likely benefit patients who are motivated to reduce their risk of stones. However, Q16. How should kidney stones best be the Consensus Group recognizes that research in this area analysed? is needed for standardization of results and for the develop- ment of easy-to-perform evaluation methods (and possibly All published guidelines on treatment of stone form- automatization) so that the use of crystalluria in diagnosis ers include stone analysis as a first step in classifying the and treatment can become a routine part of care for stone patient. Indeed, assessment of the results from the analysis formers. 1 3 12 Urolithiasis (2021) 49:1–16 of urine is impossible to do properly without knowing the Sometimes the general morphological class of the stone can kind of stone produced. also still be identified [117]. A general principle for stone Stone analysis begins with examination of the stone under analysis is that the more complete the specimen, the better a stereomicroscope to assess which part (or parts) of the will be the quality of the analysis [121], so submission of stone should be taken for molecular analysis. Most stones collections of fragments for analysis will generally be better contain more than one mineral [114], and identification of than sending just a few. visually distinct parts of the stone for dissection is important for correct analysis of minor constituents [115]. Stone por- Consensus on Q17 tions taken should then be analysed by a molecular method, typically by either infrared spectroscopy or X-ray diffraction The Consensus Group recommends the analysis of frag- to identify mineral types [116]. Whatever method is used, ments, because knowledge of a stone’s mineral composition it is important that it be able to distinguish, for example, (albeit only partial) is an integral part of interpreting 24-h brushite from other forms of calcium phosphate, and cal- urine results and in planning treatment. cium oxalate dihydrate from monohydrate. It is relatively simple to identify the morphological types of stones. This can significantly support clinically relevant Conclusions information [117, 118]. This is done during the initial exami- nation by stereomicroscope and typically also includes vis- The Consensus Group concludes that analyses of urine ual examination of the interior of the stone. It is easy, for and stones should be routine in the diagnosis and treat- example, to distinguish a calcium oxalate stone that formed ment of urinary stone diseases. At present, the 24-h urine initially as the dihydrate, which is indicative of the pres- is the most useful type of urine collection, and methods ence of hypercalciuria [119], even when its composition will for analysis and standards for interpretation are widely have transformed over time to the monohydrate form of the available. Patient education is also important for obtaining mineral. a proper urine sample. Graphical methods for reporting As discussed for the measurement of crystalluria, above, urine analysis results can be helpful both for the physician it is recognized that the development of methods of stone and for educating the patient as to proper dietary changes analysis that do not require a skilled observer would be valu- that could be beneficial. Proper analysis of stones is also able in enabling analysis of stone morphology and composi- essential for diagnosis and management of patients. The tion to be carried out more widely across the globe. Consensus Group also agrees that research has shown that evaluation of urinary crystals could be very valuable, but Consensus on Q16 the Group also recognizes that existing methods for assess- ment of crystalluria do not allow this to be part of stone The Consensus Group strongly recommends that stone anal- treatment in many places. ysis be performed if possible as part of the workup of stone Acknowledgements This article is based on the results of a Consensus patients. The analysis should be conducted using infrared Conference held during the “4th INTERNATIONAL MEETING OF spectroscopy or X-ray powder diffraction. Visual identifica- THE MENARINI FOUNDATION ON NEPHROLITHIASIS”, Verona, tion of stone morphology is also valuable. June 20-22, 2019 generously supported by the International Foundation Menarini, Milan, Italy with an unrestricted educational Grant. Q17. Is there any value in analysing stone Compliance with ethical standard fragments? Conflict of interest J. Asplin is an employee of Labcorp/Litholink; and D.S. Goldfarb is owner and patent holder with Dr. Arnie’s, Inc., and is Analysis of whole stones yields information on morphol- a consultant/researcher with Alnylam, Retrophin, Synlogic, and Dic- ogy and composition, but also allows discovery of the man- erna. All other authors declare no conflict of interest. ner in which the stone was retained during early growth. Open Access This article is licensed under a Creative Commons Attri- Specifically, the identification of stones that have grown on bution 4.0 International License, which permits use, sharing, adapta- Randall’s plaque is easy to perform [120]. However, many tion, distribution and reproduction in any medium or format, as long methods of stone removal (e.g., shock wave lithotripsy, laser as you give appropriate credit to the original author(s) and the source, lithotripsy) result in the fragmentation of stones. provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are Though information of how a stone might have been included in the article’s Creative Commons licence, unless indicated formed (such as the presence of Randall’s plaque) is lost otherwise in a credit line to the material. If material is not included in when stones are fragmented, analysis of the fragments the article’s Creative Commons licence and your intended use is not still allows for the mineral composition to be determined. 1 3 Urolithiasis (2021) 49:1–16 13 permitted by statutory regulation or exceeds the permitted use, you will 17. 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C R Chim 19:1470–1491 Affiliations 1 2 3 4 5 James C. Williams Jr.  · Giovanni Gambaro  · Allen Rodgers  · John Asplin  · Olivier Bonny  · 6 7 8 9 10 Antonia Costa‑Bauzá  · Pietro Manuel Ferraro  · Giovanni Fogazzi  · Daniel G. Fuster  · David S. Goldfarb  · 6 11 12 13 14 15 Félix Grases  · Ita P. Heilberg  · Dik Kok  · Emmanuel Letavernier  · Giuseppe Lippi  · Martino Marangella  · 16 17 18 19 20 Antonio Nouvenne  · Michele Petrarulo  · Roswitha Siener  · Hans‑Göran Tiselius  · Olivier Traxer  · 21 22 23 Alberto Trinchieri  · Emanuele Croppi  · William G. Robertson 1 12 Department of Anatomy, Cell Biology & Physiology, SAELO, Oegstgeest, The Netherlands Indiana University School of Medicine, Indianapolis, Service des Explorations Fonctionnelles Multidisciplinaires, IN 46260, USA Hôpital Tenon, Paris, France Division of Nephrology and Dialysis, Department Laboratory of Clinical Chemistry and Hematology, of Medicine, University of Verona, Verona, Italy University Hospital of Verona, Verona, Italy Department of Chemistry, University of Cape Town, Fondazione Scientifica Mauriziana ONLUS, Turin, Italy Cape Town, South Africa Internal Medicine and Subacute Long Term Unit, Azienda Litholink, Laboratory Corporation of America Holdings, Ospedaliero-Universitaria di Parma, Parma, Italy Itasca, IL, USA Ospedale Ordine Mauriziano di Torino, Turin, Italy Service of Nephrology, Department of Medicine, Lausanne University Hospital and Department of Biomedical Sciences, University Stone Center, Department of Urology, University University of Lausanne, Lausanne, Switzerland Hospital Bonn, Bonn, Germany 6 19 IUNICS-Idisba, University of Balearic Islands, Department of Clinical Science, Intervention and Technology Palma de Mallorca, Spain (CLINTEC), Karolinska Institutet, Stockholm, Sweden 7 20 UOC Nefrologia, Fondazione Policlinico Universitario Service d’Urologie, Hôpital Tenon, Paris, France A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore, School of Urology, University of Milan, Milan, Italy Rome, Italy USL Toscana Centro, Florence, Italy Policlinico di Milano, Milan, Italy Nuffield Department of Surgical Sciences, University Inselspital, Bern University Hospital, University of Bern, of Oxford, Oxford, UK Bern, Switzerland NYU Langone Health, NYU Grossman School of Medicine and the New York Harbor VA Healthcare System, New York, NY, USA Universidade Federal de São Paulo, São Paulo, SP, Brazil 1 3

Journal

Urological Research – Springer Journals

Published: Oct 13, 2020

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