Correlation research demonstrates that an inflammatory diet is a risk factor for calcium oxalate renal stone formation.

BACKGROUND AND AIMS: Previous studies have demonstrated associations between the Dietary Inflammatory Index (DII®), an analytical tool which evaluates the inflammatory potential of the diet according to the pro- and anti-inflammatory properties of its components, and renal stone formation. However, these have not comprehensively addressed important parameters such as stone type, gender, DII scores in stone formers (SFs) and healthy controls (Cs) and associations of DII with urine and blood chemistries. These were adopted as the survey parameters for the present study, the purpose of which was to test whether the contributory role of an inflammatory diet on stone formation could be further confirmed. METHODS: 97 calcium oxalate (CaOx) SFs and 63 Cs, matched for age and gender each completed a semi-quantitative food frequency questionnaire from which nutrient composition was computed. These data were used to calculate the DII® score. To control the effect of energy intake, energy-adjusted DII scores were calculated per 1000 kcal consumed (E-DII™). A single blood sample and two consecutive overnight (8h) urine samples were collected from a subset (n = 59 SFs and n = 54 Cs) of the overall number of particpants (n = 160). These were analysed for renal stone risk factors. Data were analysed using regression models fit in R software. RESULTS: E-DII scores were found to fit the data better than DII, so they were used throughout. E-DII scores were significantly more positive (more pro-inflammatory) in SFs than in controls in the combined gender group (-0.34 vs. -1.73, p < 0.0001) and separately in males (-0.43 vs. -1.78, p = 0.01) and females (-0.26 vs. - 1.61, p = 0.05). In blood, a significant negative correlation was seen between E-DII and HDL cholesterol. In urine significant positive correlations were seen between E-DII and each of calcium (ρ = 0.25, p = 0.02), phosphate (ρ = 0.48, p < 0.001), magnesium (ρ = 0.33, p < 0.0001) and uric acid (ρ = 0.27, p = 0.004) concentrations. A significant negative correlation was seen between E-DII and urinary volume ρ = -0.27, p = 0.003). There was no correlation between E-DII scores and the relative supersaturations of urinary CaOx, calcium phosphate (brushite) and uric acid. CONCLUSIONS: Our findings provide hitherto unreported quantitative evidence in support of the notion that the diet of calcium oxalate renal stone patients is significantly more pro-inflammatory than that of healthy controls.

Conflicts of interest and the risk of bias are inevitable in urolithiasis research.

This review examines data from stone conferences and research journals to assess whether justifiable concerns exist about possible bias in urolithiasis research and if so, how they can be minimized. Conflict of interest (COI) policies of two major urological congresses and three symposia dedicated to stone research were reviewed. Disclosure slides were viewed in webcasts and were evaluated for robustness and speaker compliance with respect to policy. Additionally, disclosure and COI policies of ten Science Citation Index (SCI)-approved journals were assessed and compared with actual declarations in published papers on urolithiasis. It was observed that disclosure and conflict declarations are frequently conflated in congresses and journals. Differences between the two ideologies appear to be ignored or unappreciated. Disclosures in the major urological meetings revealed a high percentage of financial relationships with industry. In dedicated stone conferences, more than two-thirds of speakers failed to display a declaration slide. Both scenarios generate questions about objectivity. Disclosure and COI statements in journals varied widely in format, detail and content. It is concluded that there exists a misinformed and incorrect perception in urolithiasis research that disclosure of potential COIs somehow validates a study as being objective and unbiased. Current policies and practices at conferences and in published papers create a setting in which concerns of bias prevail. Changes, including the establishment of a universal policy, insistence of independent and explicit declarations of disclosures and conflicts, implementation of sanctions for transgression and the introduction of intensive scrutiny by reviewers are required to minimize doubts.

Comparison of Supersaturation Outputs from Different Programs and Their Application in Testing Correspondence with Kidney Stone Composition.

Introduction: Relative supersaturation (SS) for calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid (UA) has been used for assessing urinary crystallization and estimated by programs, including EQUIL, Joint Expert Speciation System (JESS), and Lithorisk. We compared outputs from these programs and their correspondence with stone composition. Materials and Methods: SS of CaOx, CaP, and UA, using EQUIL, JESS, and Lithorisk were calculated from stone-forming patients. Pearson correlation coefficients were used to ascertain the correspondence between the outputs. Fractional regression models evaluated the relationship between SS and the percentage of each compound in the stones. Results: Two hundred eleven patients were included. Pearson correlation coefficients for CaOx (r ≥ 0.96), CaP (r ≥ 0.99), and UA SS (r ≥ 0.99) showed a high correspondence between all programs. We observed a significant correspondence between CaOx SS and the percentage of CaOx dihydrate in the stone (p < 0.001), as well as between the percentage of brushite and apatite and CaP SS. UA SS showed the strongest correspondence with the percentage of UA in the stones (p < 0.001). Conclusions: Good correlation between EQUIL, JESS, and Lithorisk was observed and good correspondence with stone composition. The magnitude of the association demonstrated by fractional regression models supports evidence for applying SS in clinical practice.

The Efficacy of Polyunsaturated Fatty Acids as Protectors against Calcium Oxalate Renal Stone Formation: A Review.

In the pathogenesis of hypercalciuria and hyperoxaluria, n-6 polyunsaturated fatty acids (PUFAs) have been implicated by virtue of their metabolic links with arachidonic acid (AA) and prostaglandin PGE2. Studies have also shown that n-3 PUFAs, particularly those in fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-can serve as competitive substrates for AA in the n-6 series and can be incorporated into cell membrane phospholipids in the latter's place, thereby reducing urinary excretions of calcium and oxalate. The present review interrogates several different types of study which address the question of the potential roles played by dietary PUFAs in modulating stone formation. Included among these are human trials that have investigated the effects of dietary PUFA interventions. We identified 16 such trials. Besides fish oil (EPA+DHA), other supplements such as evening primrose oil containing n-6 FAs linoleic acid (LA) and γ-linolenic acid (GLA) were tested. Urinary excretion of calcium or oxalate or both decreased in most trials. However, these decreases were most prominent in the fish oil trials. We recommend the administration of fish oil containing EPA and DHA in the management of calcium oxalate urolithiasis.

Successful urinary discrimination between calcium oxalate kidney stone patients and healthy subjects using 1 H NMR spectroscopy: Suggestion of a possible link to protein content.

Stone formation in the urinary tract is a multifactorial world-wide disease afflicting between 8 and 20% of population groups in different geographical locations. Discrimination between stone formers and healthy persons on the basis of urine composition remains a crucial goal among researchers. Since 1 H NMR is able to monitor the metabolic function of the kidney we applied it to the urine of 60 stone formers (34 females, 26 males) and 38 healthy persons (14 females, 24 males). Spectra were normalized relative to an internal standard and integrated over 37 consecutive regions. The resulting data were subjected to principal component and canonical discriminant analysis. Excellent discrimination between patient and controls for both genders was achieved, with all the data falling within the 95% confidence interval. The most important variables allowing for this inter-group separation correspond to those associated with protein signals. We therefore speculate that the discrimination between patients and controls may be due to the presence or absence of macromolecular stone promoters and/or inhibitors. This supports numerous in vitro studies demonstrating that urinary macromolecules play significant roles in stone formation and prevention. Our finding that 1 H NMR analysis of urine differentiates between stone formers and healthy persons represents an important breakthrough for rapid screening of individuals who are at risk for this disease.

Correction to: Different effects of γ-linolenic acid (GLA) supplementation on plasma and red blood cell phospholipid fatty acid composition and calcium oxalate kidney stone risk factors in healthy subjects from two race groups with different risk profiles pose questions about the GLA-arachidonic acid-oxaluria metabolic pathway: pilot study.

The authors would like to add the following paragraph in the acknowledgement section of the original version of the paper.

Correction to: Testing the dogma that total phospholipid fatty acid composition of blood plays a role in kidney stone pathogenesis, using a high-low risk human model: results from a pilot study.

The authors would like to add the following paragraph in the acknowledgement section of the original version of the paper.

Testing the dogma that total phospholipid fatty acid composition of blood plays a role in kidney stone pathogenesis, using a high-low risk human model: results from a pilot study.

Previous studies have suggested that ω-3 and ω-6 polyunsaturated fatty acid (PUFA) composition in plasma and red blood cell (RBC) total phospholipids plays a role in urolithiasis. Our aim was to test the robustness of this dogma by retrospectively comparing baseline profiles of these parameters in subjects from high- and low-stone-risk groups. The documented difference in stone occurrence in white (relatively common) (W) and black (rare) (B) subjects prompted us to select these groups as the high-low risk model for the study. Blood and urine samples were obtained from ten subjects in each group and were analysed for PUFAs and stone risk factors, respectively. Concentrations of linoleic acid (LA), eicosadienoic acid (EDA) and arachidonic acid (AA) in plasma and or/RBC total phospholipids were significantly higher in B. Differences in other PUFA profiles were also observed. There was no inter-group difference in AA/LA ratios. Urinary oxalate was significantly higher while urinary phosphate was significantly lower in B. We speculate that elevated AA in B might arise because of a possibly enhanced elongation of LA to EDA, as well as an enhanced ∆-8-desaturation of EDA to dihomo-gamma-linolenic acid (DGLA), which is the immediate precursor of AA. Alternatively, we speculate that the ∆-5-desaturation step of DGLA to AA might be more highly activated in this group. Irrespective of the mechanism, our observed inter-group differences in phospholipid PUFA composition are in conflict with previously published dogma which relates PUFA characteristics to high- and low-stone risk.

Different effects of γ-linolenic acid (GLA) supplementation on plasma and red blood cell phospholipid fatty acid composition and calcium oxalate kidney stone risk factors in healthy subjects from two race groups with different risk profiles pose questions about the GLA-arachidonic acid-oxaluria metabolic pathway: pilot study.

Fatty acid (FA) composition of phospholipids in plasma and red blood cells (RBC) can influence calciuria, oxaluria and renal stone formation. In this regard, the ratio of arachidonic acid (AA) and its precursor linoleic acid (LA) appears to be important. Administration of γ-linolenic acid (GLA) has been shown to increase the concentration of dihomo-gamma linoleic acid (DGLA) relative to AA indicating that it may attenuate biosynthesis of the latter. Such effects have not been investigated in race groups having difference stone occurrence rates. Black (B) and white (W) healthy males ingested capsules containing linoleic acid (LA) and GLA, for 30 days. Plasma and RBC total phospholipid (TPL) FA profiles, serum and 24 h urine biomarkers of hypercalciuria and urinary stone risk factors were determined on days 0 and 30. Data were tested for statistical significance using GraphPadInstat version 3.02. Concentration and percentage content of DGLA in plasma TPL increased in W but not in B. Arachidonic acid (AA) did not change in either group. There was no change in calcium excretion in either group but oxalate and citrate excretion increased in W. We suggest that elongation of GLA to DGLA may occur more rapidly than desaturation of DGLA to AA in W and that depressed activity of the enzyme elongase may occur in B. Calciuric and citraturic effects may be dependent on the quantity of LA or on the mass ratio of LA/GLA in the FA supplement. Questions about the mooted DGLA-AA-oxaluria pathway arise. We speculate that there exists a potential for using GLA as a conservative treatment for hypocitraturia. The observation of different responses in B and W indicates that such differences may play a role in stone formation and prevention.

Physicochemical mechanisms of stone formation.

In this article, the term "physicochemical mechanism" is defined as a sequential series of steps culminating in the formation of a renal stone. Distinctions are drawn between physicochemical prerequisites for urinary supersaturation, crystallization, and stone formation. In particular, attention is focussed on the transition from crystal to stone. Emphasis is laid on crystal retention being the fundamental mechanism by which stones are formed, and mention is made of the different ways in which it can be achieved. The processes which dictate crystal-size enlargement, either during free particle flow or during fixed particle entrapment, are described. Modulators of these processes are classified in terms of their mode of action on particular steps in the mechanism rather than on their molecular weight or size. Three different approaches for describing stone formation mechanisms are summarized. These involve mathematical models, qualitative step-by-step pathways, and qualitative non-schematic descriptions. It is suggested that although physicochemical mechanisms are crucially involved in stone formation, they do so in concert with numerous other mechanistic processes, all of which are dictated by their own specific conditions.

Acceptance of mixed scientific and clinical activities in a sub-speciality urology meeting.

Basic urolithiasis research into the causes for stone formation has been stagnating for a long time. Emergence of effective stone treatment modalities has shifted the public and clinicians' focus away from basic research towards symptomatic treatment solutions. This has occurred in spite of urolithiasis being a highly recurrent disease with an enormous socio-economic impact warranting a prophylactic and recurrence-preventing approach. An integrated, multidisciplinary translational platform has been developed in the form of urolithiasis meetings bringing together urologists, radiologists, nephrologists, basic scientists, dieticians and other stake holders interested in stone disease, for an exchange of knowledge, mutual education and understanding, and professional networking. Traditionally, such combined meetings are split into sessions addressing the specific interests of clinicians and scientists. At the recent Experts in Stone Disease Symposium we devised and implemented a program which mixed clinical and basic science activities throughout. We interviewed delegates between sessions regarding their acceptance of this novel concept using a standardized questionnaire. Sessions were well-attended, alleviating our initial anxiety that delegates would not appreciate a "no-choice" program. Of the 74 delegates who were interviewed, 60 (81%) were urologists, and 14 (19%) were non-urologists such as nephrologists, dieticians, and students. This is representative of the overall distribution of delegates at the conference. 71% felt that a closer co-operation and understanding between clinicians and scientists will ultimately benefit both groups, as well as patients; 95% found the mixed session approach beneficial, with half appreciating it as very good and innovative; 94% believed that they had derived useful learnings from the "other side"; 94% found that such mixed sessions are useful for their future work and understanding of the urolithiasis field as a whole; 94% agreed that mixed meetings of this type are useful in enhancing networking between the different stake holders in urolithiasis treatment and research. Finally, 85% would like to visit future mixed session meetings, and 89% would encourage their juniors to attend, too. Not only was a platform created to facilitate multidisciplinary exchange and networking, but delegates from several different backgrounds were encouraged to attend presentations in disciplines other than their own. The results of our survey confirm an overwhelmingly positive acceptance of this integrated multidisciplinary concept for stone meetings. As such, we are encouraged to continue with this concept in future conferences.

Folium pyrrosiae ingestion has no effect on the thermodynamic or kinetic urinary risk factors for calcium oxalate urolithiasis in healthy subjects: a poor prognosis for alternative treatment in this type of stone former.

Kidney stone disease occurs throughout the world. Conservative treatments involving herbal preparations have been used in traditional Chinese medicine. In vitro studies have suggested that Folium pyrrosiae (FP) has therapeutic potential in this context. The present study was undertaken to investigate the effects of ingested FP on urinary thermodynamic and kinetic risk factors for calcium oxalate (CaOx) stone formation in subjects from two different population groups. Healthy white (n = 9) and black (n = 9) males ingested 1.5 g FP each day for 7 days. 24 h urines (baseline and day 7) and blood samples (baseline and day 3) were collected. Urines were analyzed for lithogenic risk factors and were subjected to CaOx crystallization experiments in which the metastable limit (MSL), particle size-volume distribution and crystal deposition kinetics were determined. Urine composition values were used to calculate the relative supersaturation (RS) of CaOx and other urinary salts. Blood samples were analyzed for liver enzymes to monitor the safety of the protocol. Food diaries were recorded on days 0 and 7. Data were analyzed statistically using standard software. Nutrient intakes and the concentration of liver enzymes did not change during the study. No side effects were reported. There were no statistically significant differences in any of the thermodynamic (RS, MSL) or kinetic (particle volume-size distribution, crystal deposition rate) risk factors for CaOx stone formation in either of the groups following ingestion of FP relative to baseline values. FP does not have potential as a therapeutic agent in the management of CaOx kidney stone disease.

Enteric hyperoxaluria secondary to small bowel resection: use of computer simulation to characterize urinary risk factors for stone formation and assess potential treatment protocols.

BACKGROUND AND PURPOSE: We used computer modeling to investigate the influence of physicochemical stone risk factors on urinary supersaturation (SS) of calcium oxalate (CaOx) in patients with severe hyperoxaluria, relative hypocalciuria, hypocitraturia, and CaOx nephrolithiasis after extensive small bowel resection, usually performed for Crohn's disease. We also simulated different treatment strategies, including oral calcium supplements and citrate, in such patients. MATERIALS AND METHODS: A baseline urine model was derived by consolidating data acquired by ourselves with those from another patient cohort. Calcium and oxalate excretions in this model were altered to obtain an extreme case. For comparison, additional models were based on published urine data from normal subjects (N) and idiopathic CaOx stone formers (SF). The Joint Expert Speciation System was used to simulate different urine situations based on reported compositional values. RESULTS: [Ca(2+)][Ox(2-)] ionic concentration products and SS(CaOx) are substantially higher in enteric hyperoxaluric patients than in N and SF, despite their relatively lower calcium excretions. Molar Ca:Ox ratios are substantially lower in enteric hyperoxalurics than in N and SF. Oral calcium supplements can reduce SS(CaOx), but monitoring is required to avoid exceeding a safe dosing threshold. A simple calculation can alert the clinician that this threshold is being approached or even exceeded. Increasing urinary pH and citrate decreases SS(CaOx) but not to the same extent as decreasing Ox excretion. CONCLUSIONS: Calcium supplements can help reduce stone risk in patients with severe enteric hyperoxaluria, but initial efforts should be directed toward reducing urinary oxalate by reducing dietary oxalate. Citrate therapy that increases both urine pH and urinary citrate provides an additional therapeutic benefit.

Herbal preparations affect the kinetic factors of calcium oxalate crystallization in synthetic urine: implications for kidney stone therapy.

Herbal remedies are increasingly being considered as suitable long-term treatments for renal dysfunction. The objective of the present study was to investigate the effect of some herbal extracts, all previously identified in published studies as influencing kidney stone formation, on the crystallization characteristics of calcium oxalate (CaOx) in synthetic urine (SU). Five herbal extracts were selected for the study: Folium pyrrosiae, Desmodium styracifolium, Phyllanthus niruri, Orthosiphon stamineus and Cystone(®). Concentrated stock solutions of each herbal extract were prepared and were tested at their recommended dosages in in vitro crystallization studies in SU. CaOx crystallization experiments were performed in which the metastable limit (MSL), average particle size, and nucleation and growth rates were determined. The CaOx MSL of SU was unaltered by the five herbal extracts. Three of the herbs (Desmodium styracifolium, Orthosiphon stamineus and Cystone(®)) significantly reduced the average particle size of precipitated crystals relative to undosed SU. All of the extracts increased the rate of nucleation and decreased the rate of growth significantly in SU. Cystone(®) showed the greatest effect on the measured risk factors. It is concluded that all of the herbs have the potential to serve as inhibitors of calcium oxalate stone formation and warrant investigation in clinical trials.

Variability in kidney stone incidence between black and white South Africans: AGT Pro11Leu polymorphism is not a factor.

BACKGROUND AND PURPOSE: Kidney stone disease is rare in the South African black (B) population and more prevalent in the white (W) population. Genetic studies have not previously examined this anomaly. The AGT Pro11Leu polymorphism in the alanine:glyoxylate aminotransferase (AGT) enzyme has been suggested as possibly playing a role in the pathogenesis of idiopathic calcium oxalate kidney stones. The present study was undertaken to investigate whether differences occur in the frequency of this polymorphism in subjects of both race groups. MATERIALS AND METHODS: Healthy B (n=60) and W (n=60) male subjects each provided early morning spot urine, blood, and buccal cell samples. The AGT Pro11Leu locus was amplified using the polymerase chain reaction and polymorphism was genotyped using a restriction fragment length polymorphism. RESULTS: There was no difference in the frequency of the AGT Pro11Leu polymorphism, and the major allele (C) was present at a frequency of 0.82 in B and 0.83 in W. Thus, the most common genotype homozygous normal CC genotype was observed at similar frequencies in both groups (0.68 and 0.65 in B and W, respectively), as were the heterozygous CT genotype (CT) and the homozygous variant TT genotype (TT) genotypes (0.33 & 0.02 and 0.28 & 0.03 in B and W, respectively). Neither urinary oxalate nor any other component in the two groups was correlated with the frequency of the AGT Pro11Leu polymorphism. CONCLUSIONS: Our data imply that the AGT Pro11Leu polymorphism is not directly responsible for the low incidence of stone formation in B. We conclude that other factors must be instrumental in protecting the B population from urolithiasis.

Urinary saturation: casual or causal risk factor in urolithiasis?

OBJECTIVE: To assess (i) the extent to which urinary supersaturation (SS) has successfully discriminated between stone formers and healthy individuals (N), (ii) whether absolute SS has diagnostic worth and (iii) whether high SS is the fundamental cause of stone formation per se. MATERIALS AND METHODS: Google Scholar was used to identify studies in which urinary compositional data had been determined. In those cases where SS values were not given, or where other risk indices had been reported, they were (re-)calculated. Collected data were termed 'global' but were then 'filtered' according to stone type and protocols used for SS calculations. SS distribution plots for calcium oxalate, brushite and uric acid were constructed. Data were statistically analysed using the unpaired t-test and Mann-Whitney test. RESULTS: In all, 47 studies yielded 123 SS values for healthy individuals and 122 values for stone formers. The mean and median SS values were significantly greater in stone formers compared with healthy individuals in all but one of the comparisons. Wide variations in SS occurred for healthy individuals and stone formers. The two groups could not be separated. CONCLUSIONS: Absolute SS has no diagnostic worth. It is impossible to quantify the meaning of a 'high' SS value. Urines cannot be identified as originating from healthy individuals or stone formers based on their SS. SS should be determined in clinical and research settings for relative comparisons during the assessment of treatment efficacies. This study provides a compelling argument for SS being a casual factor rather than a causal one.

Malic acid supplementation increases urinary citrate excretion and urinary pH: implications for the potential treatment of calcium oxalate stone disease.

BACKGROUND AND PURPOSE: Raising urinary pH and citrate excretion with alkali citrate therapy has been a widely used treatment in calcium nephrolithiasis. Citrate lowers ionized Ca(+2) concentrations and inhibits calcium salt precipitation. Conservative alternatives containing citrate such as fruit juices have been investigated and recommended. Any compound that induces systemic alkalosis will increase citraturia. Malate, a polycarboxylic anion like citrate, is a potential candidate for chelating Ca(+2) and for inducing systemic alkalinization. We undertook to investigate these possibilities. MATERIALS AND METHODS: Theoretical modeling of malic acid's effects on urinary Ca(+2) concentration and supersaturation (SS) of calcium salts was achieved using the speciation program JESS. Malic acid (1200 mg/day) was ingested for 7 days by eight healthy subjects. Urines (24 hours) were collected at baseline and on day 7. They were analyzed for routine lithogenic components, including pH and citrate. Chemical speciation and SS were calculated in both urines. RESULTS: Modeling showed that complexation between calcium and malate at physiological concentrations of the latter would have no effect on SS. Administration of the supplement induced statistically significant increases in pH and citraturia. The calculated concentration of Ca(+2) and concomitant SS calcium oxalate (CaOx) decreased after supplementation, but these were not statistically significant. SS for the calcium phosphate salts hydroxyapatite and tricalcium phosphate increased significantly as a consequence of the elevation in pH, but values for brushite and octacalcium phosphate did not change significantly. CONCLUSIONS: We speculate that consumption of malic acid induced systemic alkalinization leading to reduced renal tubular reabsorption and metabolism of citrate, and an increase in excretion of the latter. The decrease in SS(CaOx) was caused by enhanced complexation of Ca(+2) by citrate. We conclude that malic acid supplementation may be useful for conservative treatment of calcium renal stone disease by virtue of its capacity to induce these effects.

Citrate occurs widely in healthy and pathological apatitic biomineral: mineralized articular cartilage, and intimal atherosclerotic plaque and apatitic kidney stones.

There is continuing debate about whether abundant citrate plays an active role in biomineralization of bone. Using solid state NMR dipolar dephasing, we examined another normally mineralized hard tissue, mineralized articular cartilage, as well as biocalcifications arising in pathological conditions, mineralized intimal atherosclerotic vascular plaque, and apatitic uroliths (urinary stones). Residual nondephasing ¹³C NMR signal at 76 ppm in the spectra of mineralized cartilage and vascular plaque indicates that a quaternary carbon atom resonates at this frequency, consistent with the presence of citrate. The presence, and as yet unproven possible mechanistic involvement, of citrate in tissue mineralization extends the compositional, structural, biogenetic, and cytological similarities between these tissues and bone itself. Out of 10 apatitic kidney stones, five contained NMR-detectable citrate. Finding citrate in a high proportion of uroliths may be significant in view of the use of citrate in urolithiasis therapy and prophylaxis. Citrate may be essential for normal biomineralization (e.g., of cartilage), play a modulatory role in vascular calcification which could be a target for therapeutic intervention, and drive the formation of apatitic rather than other calcific uroliths, including more therapeutically intractable forms of calcium phosphate.