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Published in final edited form as: Urolithiasis. 2020 May 12;48(4):337–344. doi: 10.1007/s00240-020-01187-6

Are conventional stone analysis techniques reliable for the identification of 2,8-dihydroxyadenine kidney stones? A case series

Hrafnhildur L Runolfsdottir 1,2, Tzu-Ling Lin 3, David S Goldfarb 4, John A Sayer 5,6,7, Mini Michael 8, David Ketteridge 9, Peter R Rich 10, Vidar O Edvardsson 1,11, Runolfur Palsson 1,12
PMCID: PMC7395965  NIHMSID: NIHMS1610308  PMID: 32399606

Abstract

We have recently encountered patients incorrectly diagnosed with adenine phosphoribosyltransferase (APRT) deficiency due to misidentification of kidney stones as 2,8-dihydroxyadenine (DHA) stones. The objective of this study was to examine the accuracy of stone analysis for identification of DHA. Medical records of patients referred to the APRT Deficiency Research Program of the Rare Kidney Stone Consortium in 2010–2018 with a diagnosis of APRT deficiency based on kidney stone analysis were reviewed. The diagnosis was verified by measurement of APRT enzyme activity or genetic testing. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of pure crystalline DHA and a kidney stone obtained from one of the confirmed APRT deficiency cases were generated. The ATR-FTIR spectrum of the kidney stone matched the crystalline DHA spectrum and was used for comparison with available infrared spectra of stone samples from the patients. Of 17 patients referred, 14 had sufficient data available to be included in the study. In all 14 cases, the stone analysis had been performed by FTIR spectroscopy. The diagnosis of APRT deficiency was confirmed in seven cases and rejected in the remaining seven cases. Comparison of the ATR-FTIR spectrum of the DHA stone with the FTIR spectra from three patients who did not have APRT deficiency showed no indication of DHA as a stone component. Misidentification of DHA as a kidney stone component by clinical laboratories appears common among patients referred to our program. Since current clinical protocols used to interpret infrared spectra for stone analysis cannot be considered reliable for the identification of DHA stones, the diagnosis of APRT deficiency must be confirmed by other methods.

Keywords: APRT deficiency, Infrared spectroscopy, Kidney stone composition, Misdiagnosis, Nephrolithiasis

Introduction

Adenine phosphoribosyltransferase (APRT) deficiency (OMIM 102600) is a rare inherited disorder of purine metabolism that leads to excessive renal excretion of 2,8-dihydroxyadenine (DHA), resulting in kidney stones and crystal nephropathy. End-stage kidney disease occurs in 15–20% of patients [1, 2]. In some cases, APRT deficiency is not diagnosed until after kidney transplantation, often in the setting of allograft failure due to disease recurrence [3, 4].

Radiolucent DHA kidney stones are the most common feature of APRT deficiency, reported in up to 60% of those affected [1, 5], and as many as one-third of patients experience recurrent stones. Treatment with the oxidoreductase (XOR; xanthine dehydrogenase/oxidase) inhibitors, allopurinol and febuxostat, has been shown to prevent stone formation and halt the progression of chronic kidney disease (CKD) in patients with APRT deficiency [2, 5]. Early diagnosis of the disorder is a prerequisite for timely institution of pharmacotherapy.

The diagnosis of APRT deficiency is confirmed by identification of biallelic pathogenic variants in the APRT gene or abolished enzyme function in red blood cell lysates [6, 7]. Analysis of urine crystal or kidney stone material has also been considered diagnostic of the disorder, using the recommended techniques of X-ray diffraction crystallography or infrared spectroscopy [6, 8, 9]. Fourier transform infrared (FTIR) spectroscopy is currently the most commonly used method in clinical stone analysis laboratories [10, 11].

We have recently encountered cases where kidney stones were misidentified as DHA stones by infrared spectroscopy. The objective of this study was to examine the accuracy of stone analysis for identification of DHA as a kidney stone component.

Methods

Ethical approval

The study was approved by the National Bioethics Committee of Iceland (NBC 09–072) and the Icelandic Data Protection Authority. The clinical and research activities reported are consistent with the Principles of the Declaration of Helsinki.

Study population

This was a retrospective study of all patients referred to the APRT Deficiency Research Program of the Rare Kidney Stone Consortium (RKSC,https://www.rarekidneystones.org/) at Landspitali–The National University Hospital in Reykjavik, Iceland, from 2010 to 2018, with a presumptive diagnosis of the disorder based on kidney stone analysis.

Clinical data and diagnostic testing

Clinical information was obtained from the APRT Deficiency Registry that was established in 2010 to collect observational data from patients with the disease worldwide. Registry variables include age at presentation, first kidney stone event and number of clinical kidney stone episodes; results of laboratory studies, including serum creatinine (SCr) measurements, urine microscopy, renal imaging studies and kidney stone analysis; and XOR inhibitor treatment. Urinary DHA excretion was measured using an ultra-high performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) assay as previously described [12]. APRT enzyme activity measurement or mutation analysis of the APRT gene was performed to confirm or rule out the diagnosis of APRT deficiency.

Evaluation of kidney stone spectra

To facilitate the study of individual patient stone analysis results, attenuated total reflection-Fourier transform infrared (ATR-FTIR) reference spectra were generated in the Glynn Laboratory of Bioenergetics at University College London by one of the authors (PRR). First, a reference spectrum of pure crystalline DHA, supplied by Santa Cruz Biotechnology (cat. no. sc-498575), was produced. To ensure its crystalline state and purity, the DHA was solubilised in alkali and recrystallised after neutralisation. ATR-FTIR reference spectra were also generated for solid urea, sodium hydrogen urate, uric acid, hydroxyapatite (Sigma H-0252; calcium hydroxide phosphate, dried at pH 6.8 with 1 mM phosphate) and ammonium acid urate. All these chemicals were purchased from Sigma Aldrich Chemical Company except ammonium acid urate which was synthesised by addition of 0.6 mL of 0.2 M ammonium sulphate to 1 mL of 11 mM sodium hydrogen urate at pH 6.5–7.0 and 80 °C. Ammonium acid urate precipitated on cooling to 4 °C and was washed with water and dried. The ATR-FTIR spectra were recorded with a Bruker IFS 66/S spectrometer, fitted with a liquid nitrogen-cooled MCT-A detector and a silicon ATR microprism (3 mm diameter; 3 reflections; DuraSampIIR II, SensIR/Smith Detection). The frequencies quoted have an accuracy to ± 1 cm−1. Sample spectra were recorded versus a background spectrum of the clean prism surface. Reference materials were either loaded onto the prism surface as a suspension in several μL of distilled water, followed by thorough drying with a gentle stream of dry argon gas, or placed on the prism as solids and pressed to maximise surface contact. In addition, an ATR-FTIR spectrum of a stone sample obtained from one of the patients with confirmed APRT deficiency (case 13; Table 1) was recorded. This spectrum closely matched the ATR-FTIR spectrum of pure crystalline DHA and was used as a reference to assess the original infrared spectra of kidney stone specimens from three patients (cases 4, 5 and 8; Table 1) that were available for examination. These spectra had been recorded in clinical laboratories and were supplied as transmittance spectra with little useful information outside the fingerprint region (from ~ 2000 to 750 cm−1). The spectra were compared to the reference DHA stone spectrum in the same transmittance form and wavenumber range.

Table 1.

Characteristics of patients with kidney stones reported to contain 2,8-dihydroxyadenine

Case Sex Country Age at stone analysis (years) Stone events (number) SCr at last follow-up (μmol/L) Stone analysis method Proportion of DHA in stone material Urine DHA-to-Cr ratio (mg/mmol) Genetic testing APRT enzyme analysis
1 Female USA 34 1 NA FTIR 100% BLQ NA Normal
2 Male USA 58 4 88 FTIR 100% NA Normal NA
3 Female UK 45 1 95 FTIR 64% BLQ Benign variant NA
4 Male UK 28 1 70 FTIR 12% BLQ NA Normal
5 Male S-Africa 22 1 88 FTIR 60% BLQ Normal Normal
6 Male S-Africa 26 1 80 FTIR 30% BLQ Normal Normal
7 Female Australia 11 NA NA FTIR Trace BLQ Normal Normal
8 Male USA 37 5 153 FTIR 100% NA Pathogenic biallelic mutations No enzyme function
9 Female USA 22 7 106 FTIR 100% 14.9 Pathogenic biallelic mutations NA
10 Female USA 47 6 72 FTIR 100% NA Pathogenic biallelic mutations No enzyme function
11 Male USA 30 2 71 FTIR 100% BLQ* NA No enzyme function
12 Female índia 2 2 35 FTIR 100% 26.3 Pathogenic biallelic mutations No enzyme function
13 Male Italy 2 2 49 FTIR 100% 2.5* Pathogenic biallelic mutations No enzyme function
14 Female UK 55 4 69 FTIR 100% 37.2 Pathogenic biallelic mutations NA
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BLQ below limit of quantitation, DHA 2,8-dihydroxyadenine, FTIR Fourier transform infrared spectroscopy, SCr serum creatinine, NA not available

*

On treatment with an XOR inhibitor

Statistical analysis

Descriptive statistics were carried out using SPSS (IBM SPSS Statistics, version 21.0; 2012). Data are presented as number, percentage, and median (range).

Results

Seventeen patients were referred to the APRT Deficiency Research Program with the presumptive diagnosis of APRT deficiency based on analysis of kidney stone composition demonstrating DHA. Information on the stone analysis method used in two patients who subsequently had the diagnosis of APRT deficiency confirmed was not available. In one case, stone analysis carried out by X-ray diffraction indicated DHA as a stone component, but the diagnosis of APRT deficiency was excluded by genetic testing and measurement of APRT activity. The details of stone analysis results were not available. These three cases were excluded from further analysis because of incomplete data. In the remaining 14 cases, kidney stone analysis had been carried out using FTIR spectroscopy. The characteristics of the 14 patients are shown in Table 1. Their median age was 29 years (range, 2–58 years) and 7 were females. The diagnosis of APRT deficiency was confirmed by analysis of APRT enzyme activity and/or genetic testing in 7 out of 14 patients, all of whom had kidney stones composed of 100% DHA. Urine samples were available for five of the seven patients, three of whom had a high urine DHA-to-Cr ratio, ranging from 14.9 to 37.2 mg/mmol, while two individuals on allopurinol therapy had levels that were low (2.5 mg/mmol) or below the limit of quantitation. The stone analysis spectra could not be acquired for any of these seven cases. However, analysis of a kidney stone sample obtained from case 13 (Table 1) revealed an FTIR spectrum which corresponded closely to that of the pure crystalline DHA, indicating that it was indeed an essentially pure (100%) DHA stone (Fig. 1). This stone spectrum was used as a reference in the evaluation of available infrared spectra.

Fig. 1.

Fig. 1

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Comparison of the fingerprint region of attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of a 2,8-dihydroxyadenine (DHA) stone (obtained from case 13) and pure crystalline DHA. Spectra were recorded in ATR mode and are plotted as transmittance spectra. All have been scaled to roughly the same signal intensities for ease of comparison. Wavenumbers of the stone spectrum that closely match those of crystalline DHA are labelled

In seven cases, the diagnosis of APRT deficiency made by stone analysis was rejected by confirmatory testing. The first case was a 37-year-old female from the United States who experienced her second kidney stone episode with infrared spectroscopy-based stone analysis revealing 100% DHA. Treatment with allopurinol was initiated. No DHA crystals were observed on urine microscopy and analysis of a 24-h urine sample showed a DHA level below the limit of quantitation. The diagnosis of APRT deficiency was excluded by demonstration of normal APRT enzyme function. Subsequently, allopurinol was discontinued.

The second case was referred by the same physician as the first case for evaluation of suspected APRT deficiency based on stone composition by FTIR analysis reported as 100% DHA. This 58-year-old male with a family history of gout had passed three kidney stones during a 16-month period, the last of which was sent for analysis. Metabolic evaluation showed a low urine pH and high urinary uric acid excretion, which is strongly inconsistent with APRT deficiency. Sequencing of the APRT gene did not disclose pathogenic variants. Repeat stone analysis revealed calcium oxalate as the principal stone constituent.

Two patients were referred from the United Kingdom. The first patient (case 3) was a 45-year-old female with a history of recurrent kidney stones and high serum uric acid levels who passed an 8 mm stone that was reported to be composed of 64% DHA, 26% calcium oxalate and 10% uric acid, determined using infrared spectroscopy. However, replotting of the fingerprint region of the supplied FTIR transmittance spectrum with the equivalent spectrum of the confirmed DHA stone did not disclose characteristics consistent with DHA (Fig. 2). The majority of dominant features of the spectrum appeared to most closely resemble urea, suggesting that significant soluble contaminants were present in the analysed sample. The second patient (case 4) was a 28-year-old male with a first kidney stone reported to contain 12% DHA, 69% calcium phosphate and 18% calcium oxalate by FTIR analysis. Again, replotting of the fingerprint region of the supplied FTIR transmittance spectrum with the equivalent spectrum of the validated DHA stone failed to reveal any features consistent with DHA, and the majority of the stone composition could instead be assigned to a hydroxyapatite (calcium phosphate hydroxide)-like material plus residual water (Fig. 3). Urine DHA was not detected in either of these patients, while the female patient reportedly had elevated 24-h urinary uric acid excretion. Both patients had normal APRT activity and genetic testing did not disclose a pathogenic variant in the APRT gene. The results of the stone analysis for the female patient were re-evaluated by the original laboratory, again using FTIR spectroscopy, revealing a purine component that was not DHA.

Fig. 2.

Fig. 2

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Comparison of the fingerprint region of the Fourier transform infrared spectrum from case 3 with reference spectra. The 2,8-dihydroxyadenine (DHA) stone and crystalline urea reference spectra were recorded in attenuated total reflection mode and are plotted as transmittance spectra. All have been scaled to roughly the same signal intensities for ease of comparison. The spectrum from case 3 shows no features consistent with DHA

Fig. 3.

Fig. 3

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Comparison of the fingerprint region of the Fourier transform infrared (FTIR) spectrum from case 4 with reference spectra. The 2,8-dihydroxyadenine (DHA) stone, hydroxyapatite (calcium phosphate hydroxide) and liquid water reference spectra were recorded in attenuated total reflection mode and are plotted as transmittance spectra. All have been scaled to roughly the same signal intensities for ease of comparison. The supplied FTIR spectrum from case 4 does not correspond to DHA. The majority of the stone composition is compatible with hydroxyapatite (calcium phosphate hydroxide)-like material plus residual water

Two brothers from South Africa (cases 5 and 6), 22 and 26 years of age, were referred to our program after infrared analysis of stone material was reported as 60% and 30% DHA, respectively. Both had urine DHA below the limit of quantitation and the APRT enzyme function was normal. Genetic analysis did not reveal pathogenic variants in the APRT gene.

The final patient (case 7) was a female from Australia who presented with hematuria and multiple bilateral kidney stones at age 11 years. Kidney stone composition, analysed using infrared spectroscopy, was reported as calcium phosphate with trace amounts of DHA. The patient was placed on treatment with allopurinol and increased fluid intake was recommended. However, the fingerprint region of the supplied FTIR transmission spectrum again showed no correspondence to the spectrum of the DHA stone (Fig. 4). Instead, a close match was found to the infrared spectrum of ammonium acid urate [13, 14]. APRT enzyme activity proved to be normal on two separate occasions. Urine testing was negative for DHA, but metabolic screening performed at the referring institution showed slightly elevated urinary cystine levels, possibly consistent with heterozygous mutation in SLC7A9. Treatment with allopurinol was subsequently discontinued.

Fig. 4.

Fig. 4

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Comparison of the fingerprint region of the Fourier transform infrared spectrum from case 7 with reference spectra. The 2,8-dihydroxyadenine (DHA) stone, ammonium acid urate, sodium hydrogen urate and uric acid reference spectra were recorded in attenuated total reflection mode and are plotted as transmittance spectra. All have been scaled to roughly the same signal intensities for ease of comparison. The supplied FTIR transmission spectrum shows no correspondence to the spectrum of the DHA stone

Discussion

This study shows that 7 out of 14 patients who had analysis of kidney stone composition performed, using infrared spectroscopy, were erroneously diagnosed with APRT deficiency. This finding highlights shortcomings of the clinical infrared protocols used for stone analysis in reliably identifying DHA as a stone constituent and emphasizes the need for confirming the diagnosis of APRT deficiency, either by demonstrating absence of APRT enzyme activity or a pathogenic variant in both alleles of the APRT gene. In addition, measurement of urinary DHA excretion appears to be a reliable method for diagnosing APRT deficiency.

Analysis of stone composition is an essential component of the clinical evaluation of nephrolithiasis, providing clues regarding the pathophysiology and facilitating the selection of targeted treatment for prevention of recurrent stone episodes [15, 16]. Wet chemical methods, which were commonly used for analysis of stone composition in the past, are inaccurate and often lead to a wrong diagnosis [10]. Furthermore, these methods fail to identify rare purine stones resulting from genetic disorders, including DHA stones which are confused with uric acid stones [17, 18]. Consequently, only physical methods such as X-ray diffraction crystallography and FTIR spectroscopy are currently considered acceptable for the analysis of kidney stone composition [16].

First introduced as a stone analysis procedure in 1955 [19], FTIR spectroscopy is currently preferred in most laboratories worldwide as the analysis time is short and the cost of the equipment is significantly less than for X-ray crystallography [17, 20]. Morphologic examination coupled to FTIR analysis is considered important in the diagnosis of rare types of kidney stones, including DHA calculi [9]. The same technique is useful for analysis of crystal composition when no stones are available, including in kidney biopsies when crystal nephropathy is present.

In FTIR spectroscopy, the sample is irradiated with a broadband infrared beam. Absorption occurs at frequencies associated with specific infrared-active molecular vibrational normal modes, which increase in parallel with the number of atoms. Hence, most molecules composed of more than a few atoms have characteristic absorption spectra with multiple bands. Infrared absorption spectra of the stone samples can be analysed by comparison to reference spectra of pure substances to determine the chemical composition of the stone [10, 11]. However, infrared spectra in the ‘fingerprint’ region, below 1800 cm−1, tend to be complex and mixtures of components may have overlapping bands from the different constituents. In general, published reports on stone analysis employing infrared spectroscopy have not included details of the reference infrared spectra that were used, so the robustness of the deconvolution methods cannot be independently verified. A number of additional factors can complicate the analysis. Pure compounds may exist in different ionic, crystalline or hydration states which can result in significant differences in their infrared signatures. Moreover, the relative intensities of bands of a pure substance are different when the spectra are recorded in transmission versus ATR mode and this must be considered when comparing spectra measured in these modes. In the case of ATR-FTIR spectra, caution is needed to ensure that material representative of the whole sample is present in the very thin (several microns) infrared-active volume. In many instances, spectra are presented in transmittance form and although useful for highlighting minor bands, transmittance (as opposed to absorbance) band intensities of a pure compound will not remain at a constant ratio to each other when bands are strongly absorbing. When fitting reference spectra to stone spectra, care must also be taken to account for possible artefacts caused by broad baseline drifts by beamline water vapour interference. All these factors will complicate the accurate deconvolution of component mixtures in dried stone samples, making automated analysis of spectra difficult without additional expert scrutiny of data. Indeed, several reports have highlighted the inaccuracies of current automated methods of infrared stone analysis [10, 17, 20], as was clearly the case in the three examples reported here. However, the quality of FTIR spectra recorded in ATR mode can be extremely high when optimally performed (Fig. 1), which is particularly simple in terms of sample handling. Furthermore, the wavenumber range is extendable both above and below the typical fingerprint region, providing additional bands that can be diagnostic for DHA [21]. Accurate recording of ATR-FTIR spectra in combination with a more global analysis of the full spectral range in comparison to reference compounds could provide a far more robust method for DHA detection and quantitation.

The misidentification of kidney stone components as DHA in our study is striking. Although FTIR spectroscopy is currently the most widely used stone analysis method, it is limited by the quality of the reference libraries available and the choice of computer algorithm chosen for matching sample spectral data with the reference library [10, 11, 20]. Indeed, incorrect results are known to occur and are more common when stones contain a mixture of constituents [10, 22]. It is noteworthy that the majority of misidentified stone specimens from the patients included in the current study reportedly contained less than 70% DHA. Stones from patients with APRT deficiency are typically composed of pure DHA [23–25], though occasional mixed stones containing calcium salts have been reported [26, 27]. Thus, stone analysis reports of mixed stones containing DHA should raise a suspicion of erroneous interpretation.

The misdiagnosis of the cases reported herein resulted from incorrect assignment of the infrared spectra in most cases. Although the infrared spectrum of DHA is very specific and the identification of DHA can be definitive when performed by trained laboratory personnel [9], untrained operators can incorrectly attribute spectra of other materials such as uric acid and its salts to DHA. Stringent quality control measures in clinical laboratories are considered essential for improving the accuracy of kidney stone analysis [11].

Clinicians caring for patients with rare kidney stone disorders must be familiar with the potential misidentification of DHA stones from infrared spectra and should invariably confirm the diagnosis of APRT deficiency using APRT enzyme function analysis or sequencing of the APRT gene to search for pathogenic mutations affecting both alleles. Indeed, due to increasing availability and markedly reduced cost, genetic testing is becoming a favoured diagnostic method for APRT deficiency. The APRT gene should be included in high-throughput next-generation sequencing panels for rare types of CKD and kidney stone disease [28]. Finally, our recently described UPLC-MS/MS assay for measurement of urine DHA is a promising alternative method for the diagnosis of APRT deficiency [12].

Misdiagnosis of the patients in this case series as having APRT deficiency could have led to lifelong XOR inhibitor therapy. These medications, particularly allopurinol, are associated with adverse effects. Erroneous stone analysis results could also lead to missed cases of APRT deficiency, thereby precluding the institution of appropriate therapy. Incorrect analysis or failure to identify a stone constituent may also result in inadequate therapy of other stone types.

In conclusion, misidentification of DHA as a kidney stone component by clinical laboratories appears common among patients referred to our program. The determination of kidney stone composition is often based on automated analysis of FTIR spectra of varying quality and thus is subject to error. The diagnosis of APRT deficiency should always be confirmed by enzyme activity measurement, genetic testing or detection of DHA in urine samples.

Acknowledgements

Part of this work was presented as an abstract at the American Society of Nephrology Kidney Week, November 15–20, 2016, Chicago, IL. We are grateful to Unnur A. Thorsteinsdottir, Ph.D. student, and Margret Thorsteinsdottir, Ph.D., at ArcticMass, Reykjavik, Iceland, for performing the urinary 2,8-dihydroxyadenine measurements.

Funding This study was supported by the Rare Kidney Stone Consortium (U54DK083908), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research. The Rare Kidney Stone Consortium is funded through collaboration between NCATS and National Institute of Diabetes and Digestive and Kidney Diseases. PRR was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC awards BB/K001094/1).

Footnotes

Compliance with ethical standards

Conflict of interest None of the authors declare financial or other conflicting interests.

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affliations.

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