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Demographics and Characterization of 10,282 Randall Plaque-Related Kidney Stones

Demographics and Characterization of 10,282 Randall Plaque-Related Kidney Stones Demographics and Characterization of 10,282 Randall Plaque-Related Kidney Stones A New Epidemic? Emmanuel Letavernier, MD, PhD, Sophie Vandermeersch, BSc, Olivier Traxer, MD, PhD, Mohamed Tligui, MD, Laurent Baud, MD, PhD, Pierre Ronco, MD, PhD, Jean-Philippe Haymann, MD, PhD, and Michel Daudon, PharmD, PhD 26 vs 34 years, P ¼ 0.02), had increased ionized serum calcium levels Abstract: Renal stone incidence has progressively increased in indus- (P ¼ 0.04), and increased serum osteocalcin (P ¼ 0.001) but similar trialized countries, but the implication of Randall plaque in this epi- 25-hydroxyvitamin D levels. The logistic regression analysis showed demic remains unknown. Our objectives were to determine whether the that age (odds ratio [OR] 0.96, confidence interval [CI] 0.926 – 0.994, prevalence of Randall plaque-related stones increased during the past P ¼ 0.02), weight (OR 0.97, CI 0.934 – 0.997, P ¼ 0.03), and osteocalcin decades after having analyzed 30,149 intact stones containing mainly serum levels (OR 1.12, CI 1.020 – 1.234, P ¼ 0.02) were independently calcium oxalate since 1989 (cross-sectional study), and to identify associated with Randall plaque. The prevalence of the FokI f vitamin D determinants associated with Randall plaque-related stones in patients receptor polymorphism was higher in patients with plaque (P ¼ 0.047). (case – control study). In conclusion, these findings point to an epidemic of Randall plaque- The proportion of Randall plaque-related stones was assessed over associated renal stones in young patients, and suggest a possible 3 time periods: 1989 – 1991, 1999 – 2001, and 2009 – 2011. Moreover, we implication of altered vitamin D response. analyzed clinical and biochemical parameters of 105 patients affected (Medicine 94(10):e566) by calcium oxalate stones, with or without plaque. Of 30,149 calcium oxalate stones, 10,282 harbored Randall plaque Abbreviations: CI = confidence interval, COD = calcium oxalate residues (34.1%). The prevalence of Randall plaque-related stones dihydrate, COM = calcium oxalate monohydrate, FTIR = Fourier increased dramatically during the past years. In young women, 17% transform infrared spectroscopy, OR = odds ratio, VDR = vitamin of calcium oxalate stones were associated with Randall plaque during D receptor. the 1989 – 1991 period, but the proportion rose to 59% 20 years later (P< 0.001). Patients with plaques experienced their first stone-related event earlier in life as compared with those without plaque (median age INTRODUCTION here is strong evidence that renal stone incidence increased Editor: Pavlos Malindretos. T during the past decades in industrialized countries, now Received: December 1, 2014; revised: January 25, 2015; accepted: January affecting >10% of the population and constituting a major 28, 2015. 1–3 public health challenge. Calcium oxalate stones are now From the Sorbonne universite ´s-UPMC Univ Paris 06 (EL, SV, OT, LB, PR, J-PH, MD); INSERM UMR S 1155 (EL, SV, LB, PR, J-PH, MD); AP-HP identified as the main type of urinary calculi in western (EL, LB, J-PH, MD), Ho ˆ pital Tenon, Explorations fonctionnelles multi- countries and account for at least 70% of all kidney stones. disciplinaires and Cristal Laboratory; AP-HP (OT, MT), Ho ˆ pital Tenon, Longitudinal epidemiological studies performed in USA, Service d’Urologie; and AP-HP (PR), Ho ˆ pital Tenon, Service de Europe, or Japan evidenced that the progression in calcium Nephrologie, Paris, France. Correspondence: Emmanuel Letavernier; Michel Daudon, Service des oxalate and uric acid stones was responsible for the increase in 1,4 – 7 Explorations Fonctionnelles Multidisciplinaires, Ho ˆ pital TENON, 4 the prevalence of urolithiasis. Calcium oxalate stone Rue de la Chine, 75020 Paris, France (e-mail: emmanuel.letavernier growth results from urine supersaturation due to low diuresis @tnn.aphp.fr; [email protected]). and intermittent biological disorders such as hypercalciuria, EL and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data hyperoxaluria, and/or hypocitraturia. However, the starting analysis. Study concept and design: MD and EL. Acquisition, analysis, point of calcium oxalate stones received little attention until and interpretation of data: all authors. Drafting of the article: EL, MD, recently. LB, and PR. Critical revision of the article for important intellectual Since Alexander Randall made the hypothesis that the content: all authors. Statistical analysis: EL and MD. Study supervision: EL and MD. origin of renal calculi was calcium phosphate plaque at the This work was partially funded by the Agence Nationale de la Recherche tip of renal papillae, relatively few studies were dedicated to the (ANR-13-JSV1-0010-01) and the Socie´te´ de Ne´phrologie-Fondation du 8– 10 Randall plaque. A major contribution to this field was made Rein (Genzyme grant). The sponsors had no role in the design and by Evan et al who reported that Randall plaque of patients conduct of the study; collection, management, analysis, and interpret- ation of the data; preparation, review, or approval of the article; decision with nephrolithiasis begins in basement membranes of thin to submit the article for publication. loops of Henle. The same group highlighted the relationship The authors have no conflicts of interest to disclose. 12 between calcium excretion and plaque formation. The recent Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. increased interest for Randall plaque is likely to originate from This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is the development of renoureteroscopy, which enables plaque permissible to download, share and reproduce the work in any medium, visualization, and also from an increased incidence of stones provided it is properly cited. The work cannot be changed in any way or 10 due to heterogeneous nucleation processes from plaques. used commercially. However, the implication of Randall plaque in kidney stone ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000566 epidemic is not documented. Medicine Volume 94, Number 10, March 2015 www.md-journal.com 1 Letavernier et al Medicine Volume 94, Number 10, March 2015 We conducted a study to assess the evolution of Randall DNA Analysis plaque-related stone incidence during the last decades in France Buffy coats were collected from patients who provided and characterize the specific clinical and biological profile of informed written consent, according to French legislation, in the patients developing plaque-related stones to identify Randall view of further genetic analyses. The cohort is registered plaque risk factors. (Commission nationale de l’informatique et des liberte´s Declaration Number 1709404v0). The regions containing single nucleotide polymorphisms of the vitamin D receptor (VDR) METHODS gene were amplified using the appropriate primer set, by 17 18 Morphoconstitutional Analysis of Renal Stones methods adapted from Seo et al and Mossetti et al. The Morphologic examination and classification of renal stone forward primer for ApaI and TaqI polymorphism was 5 -AGCA- surface and section were combined with Fourier transform GAGCAGAGTTCCAAGCAGA-3 . The reverse primer for infrared spectroscopy (FTIR) to classify renal stones and ApaI and TaqI polymorphism was 5 -ATCTTGGCATAGAGC- 13,14 0 identify the different crystalline phases. Starting from a AGGTGGCT-3 . The forward primer for BsmI polymorphism 0 0 database of 71,000 urinary stones collected between 1989 and was 5 -CAACCAAGACTACAAGTACCGCGTCAGTGA-3 . 2013, intact calcium oxalate stones (30,149, which passed The reverse primer for BsmI polymorphism was 5 -AACCAG- spontaneously or removed intact) were selected for further CGGAAGAGGTCAAGGG-3 . The forward primer for FokI 0 0 analysis, whereas fragmented stones resulting from urological polymorphism was 5 -ACTGACTCTGGCTCTGACCGT-3 . procedures were excluded because of the frequent loss of The reverse primer for FokI polymorphism was 5 -TGGGTT- Randall plaque. The composition and structure of stones with- GGTGTAGGAGGCTGT-3 . Each polmerase chain reaction out Randall plaque were compared with those of stones devel- product was digested with the appropriate restriction endonu- oped at the surface of Randall plaques identified by the typical clease (FastDigest for BsmI, ApaI, TaqI, and FokI) as recom- 13–15 renal papilla imprint and plaque residues at stone surface. mended by the manufacturer instruction (Thermo Scientific, The proportions of the main stone components were assessed, as Illkirch, France). The presence of BsmI, ApaI, TaqI, and FokI well as the internal structure of the stone according to FTIR and restriction enzyme sites was designated as lowercase b, a, t, and 13–15 morphoconstitutional stone classification. All stones have f, respectively, whereas absence was designated as uppercase B, been analyzed by a single investigator (M.D.). The term ‘‘core’’ A, T, and F, respectively. refers to the most internal part of the stone (developing on the Randall plaque when it is). Statistical Analyses Chi-square test was used for stone composition and epi- Evolution of Plaque-Related Stone Incidence demiological data; Student t test was used to compare the mean Over the Past Decades proportion of calcium oxalate phases. Fisher exact test and In order to assess the longitudinal changes in the pro- Mann–Whitney U test were used to compare other categorical portions of stones initiated from a Randall plaque, we compared or quantitative variables, respectively (clinical, biological, and the incidence of Randall plaque in men and women over 3 equal genetic determinants of Randall plaque). Reported values periods of time: 1989–1991, 1999–2001, and 2009–2011. We represent number (percentage), mean  standard deviation, or considered the number and the percentage of stones, grown median (p25 and p75). Variables potentially associated with from plaques or not, among all the stones mainly composed of Randall plaque (P< 0.10) were entered in a multivariable calcium oxalate (>85% of the stone according to FTIR) logistic regression. These variables were age, weight, ionized recorded in our database, and which passed spontaneously or calcium, phosphate reabsorption rate, 25-hydroxyvitamin D, were removed intact. and osteocalcin. A P value <0.05 was considered significant. Statistics were performed independently by 2 authors using both Clinical and Biological Data of Renal Stone number cruncher statistical system (NCSS) 6.0 (NCSS 6.0, Formers NCSS statistical software, Kaysville, UT, USA) and StatView More than 1000 renal stone formers were referred for 5.0 software (SAS Institute Inc., Cary, NC, USA). metabolic investigation to our Physiology unit between 2000 and 2012 (Tenon Hospital, Paris). Patients provided a 24-hour urine collection under a free diet. They all were referred for an RESULTS oral calcium load test, the results of which were similar in both Morphoconstitutional Analysis of Randall groups (not shown). Serum and urine parameters were assessed Plaque-Related Stones as previously described. Because identification of Randall plaque may be underrecognized in fragmented stones, we Of 30,149 intact stones containing mainly calcium oxalate selected only patients who had both complete biological data analyzed between 1989 and 2013, 10,282 stones harbored Ran- and also intact renal stones analyzed exclusively in the Cristal dall plaque residues (34.1%). The predominant crystalline phase laboratory (Paris). In addition, we selected stones containing determined by FTIR was either calcium oxalate monohydrate >85% calcium oxalate according to FTIR analysis. Exclusion (COM or whewellite) or calcium oxalate dihydrate (COD or criteria were primary hyperparathyroidism, renal tubular acido- weddellite); only 84 Randall plaque-related stones had a different sis, renal failure (assessed by measured creatinine renal clear- composition (mainly uric acid associated with COM). The exist- ance lower than 60 mL/min/1.73 m ), genetic or enteric ence of Randall plaque was not influenced by sex because 23.8% hyperoxaluria, and treatments interfering with calcium homeo- of stones with plaque and 24.6% of stones without plaques stasis: bisphosphonates and diuretics. Overall, 105 patients met originated from women. The morphoconstitutional analysis evi- these criteria. To our knowledge, none of the 22 women denced that Randall plaque-related stones were predominantly included in the study have been diagnosed with osteoporosis made of COM, and their core, in contact with the plaque, or received hormone replacement therapy. was a typical radial and concentric COM-type ‘‘Ia’’ structure 2 www.md-journal.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Medicine Volume 94, Number 10, March 2015 Epidemics of Randall Plaque AB CD EF GH FIGURE 1. Representative calcium oxalate stones from the database. (A) Typical COM (subtype Ia) stone with a Randall plaque (arrow) made of carbapatite. (B) Calcium oxalate stone composed of COM (dark area) around the Randall plaque (arrow) and secondary covered by COD crystals (light part on the left side). (C) Typical subtype Ia cross-section of a COM stone initiated from a Randall plaque. Note the crystallization of COM is organized from the light carbapatite deposit, which corresponds to the Randall plaque (arrow). (D) Calcium oxalate stone mainly composed of COD. The stone was initiated from a Randall plaque. Note the depressed surface that corresponds to the umbilication, that is, the imprint of the papilla. The white deposit is the part of the Randall plaque located at the surface of the papilla (arrow). Of interest, the first layers of calcium oxalate around the Randall plaque are made of COM (dark area). (E) Example of subtype Ia stone developed in free caliceal cavities (without Randall plaque). (F) Cross-section of the same stone exhibiting a well-organized and compact structure made of very thin concentric layers with radial organization. (G) Typical subtype IIa COD stone developed in free caliceal cavities (without Randall plaque). (H) Typical subtype IIa COD stone section characterized by a loose and poorly organized structure (without Randall plaque). Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com 3 Letavernier et al Medicine Volume 94, Number 10, March 2015 Nucleation of CaOx stones on plaques (all) Clinical and Biological Determinants of Randall 50 Plaque In order to identify clinical or biological parameters specifi- cally associated with Randall plaque, we collected data from 105 patients who had both extensive metabolic evaluations in our physiology unit, and intact calcium oxalate stones analyzed in the Cristal laboratory, with or without Randall plaque residues at stone surface (42 and 63 patients, respectively, Table 1). In the latter group, no phosphate was detected in stone cores, ruling out the hypothesis of calcium oxalate stones released from the papilla with a plaque covered up by subsequent growth of calcium 1990 2000 2010 oxalate. Patients with Randall plaque were younger than those Period without plaque (P ¼ 0.005, Table 1), and experienced their first Nucleation of CaOx stones on plaques (males) stone-related event earlier in life (median age 26 vs 34 years, P ¼ 0.02). Twenty four-hour urine collection under free diet did 1989–1991 not reveal any difference in 24-hour urine volume, calcium 1999–2001 excretion or salt and protein consumption because sodium and 2009–2011 urea daily excretions were similar in both groups of patients. Ionized calcium serum levels and renal phosphate reabsorption rate were significantly higher in the Randall plaque group (P ¼ 0.04 and P ¼ 0.03, respectively). There was no significant difference in 25-hydroxyvitamin D status or parathyroid hormone levels, and 1,25-dihydroxyvitamin D serum levels were similar in both groups. By contrast, osteocalcin, a bone remodeling marker, 10–<20 20–<30 30–<40 40–<50 50–<60 60–<70 ≥≥ 70 was markedly increased in patients with plaques (P ¼ 0.001) unlike bone alkaline phosphatase and urinary deoxypyridinoline. Age, y The logistic regression analysis showed that age (odds ratio [OR] Nucleation of CaOx stones on plaques (females) 0.96, confidence interval [CI] 0.926 – 0.994, P ¼ 0.02), weight (OR 0.97, CI 0.934 – 0.997, P ¼ 0.03), and osteocalcin serum 1989–1991 levels (OR 1.12, CI 1.020 – 1.234, P ¼ 0.02) were independently 1999–2001 associated with Randall plaque. 2009–2011 Vitamin D Receptor Polymorphisms A written consent for DNA collection was obtained in 69 among the 105 participants. We retrospectively analyzed VDR polymorphisms once biological determinants of Randall plaque have been assessed. All patients but 1 were white. Table 2 shows the prevalence of BsmI, ApaI, TaqI, and FokI VDR genotypes in 10–<20 20–<30 30–<40 40–<50 50–<60 60–<70 ≥70 patients with and without Randall plaque. The prevalence of Age, y FokI f allele was significantly higher in patients with Randall FIGURE 2. Epidemic of Randall plaque-related stones in men and plaque (P ¼ 0.047). No statistical difference was observed in the women over 3 periods. The analysis of 1780 intact calcium oxalate distribution of ApaI, BsmI, and TaqI polymorphisms between stones during the 1989–1991 period (period I), 4310 during the the 2 groups. 1999–2001 period (period II), and 3830 during the 2009–2011 period (period III) revealed a dramatic increase in the proportion of Randall plaque-related stones (period II and period III vs period I: DISCUSSION P< 0.001 in men and women). CaOx ¼ calcium oxalate, Our laboratory has been collecting stones sent for identifi- RP ¼ Randall plaque. cation and classification from >200 hospitals in France. We thus accumulated material from >70,000 stones, of which >30,000 converging on the plaque (Figure 1, and supplementary Figures were intact calcium oxalate stones available for further analysis. S1, and S2, http://links.lww.com/MD/A210). Our data show that Randall plaque-related stones represented 34% of stones containing mainly calcium oxalate during the past decades; there is a dramatic and steady increase in the incidence An Epidemic of Randall Plaque-Related Stones of Randall plaque-related stones particularly in the younger During the past 2 decades, the incidence of stones derived population (<30 years) defining a new epidemic; osteocalcin from plaques increased dramatically in France, especially in serum levels are independently associated with Randall plaque. young men and women (Figure 2). We observed over the last These data together with higher prevalence of the VDR f FokI 2 periods, a dramatic increase of Randall plaque-related stones allele suggest as a working hypothesis that the recent propensity in children and young adults (Figure 2). For instance, in female to supplement children with vitamin D may be one of the factors patients between 20 and 30 years, 17.2% of calcium oxalate responsible for the dramatic increase of Randall plaque-related stones were due to Randall plaque during the 1989 – 1991 stones in genetically predisposed subjects. period, but the proportion rose to 59.2% 20 years later Over the past years, evidence has been accumulated that (P< 0.001). In parallel, the male/female ratio decreased from Randall plaque growth was related to increased calcium con- 3.26 to 2.59 (P< 0.001) during these 2 decades. centration in distal tubular fluid. This led to consider a 2-step 4 www.md-journal.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Percentage of RP Percentage of RP Percentage of RP Medicine Volume 94, Number 10, March 2015 Epidemics of Randall Plaque TABLE 1. Clinical and Biological Characteristics of Renal Stone Formers Parameter No Plaque Randall Plaque P Value n63 42 Male patients, % 50 (79) 33 (79) 1.00 Age, y 50.0 (40.5, 57.0) 44 (28.2, 48.7) 0.005 Age at first stone, y 34.0 (25.0, 44.0) 26.0 (20.2, 37.7) 0.02 Recurrence, % 48 (76) 35 (83) 0.47 White and North African, % 62 (98) 41 (98) 1.00 Weight, kg 77.0 (70.0, 88.0) 72.0 (64.0, 79.0) 0.01 Height, cm 173 (164, 178) 175 (168, 180) 0.27 Blood Creatinine, mg/dL 0.88 (0.75, 1.01) 0.90 (0.81, 0.97) 0.97 Cr clearance, mL/min 125 (103, 156) 122 (103, 141) 0.43 Calcium, mg/dL 9.04 (8.76, 9.20) 9.08 (8.88, 9.52) 0.12 Calcium ionized, mg/dL 4.68 (4.56, 4.8) 4.76 (4.64, 4.84) 0.04 Phosphorus, mg/dL 2.82 (2.51, 3.03) 2.76 (2.45, 3.13) 0.69 Phosphate reabsorption rate 0.89 (0.85, 0.91) 0.91 (0.86, 0.93) 0.03 Magnesium, mg/dL 2.07 (1.90, 2.19) 2.02 (1.95, 2.14) 0.86 Uric acid, mg/dL 5.91 (4.75, 6.82) 5.80 (5.14, 6.86) 0.66 PTH, pg/mL [N:8 – 76] 42 (33.7, 51.0) 33 (27.0, 52.0) 0.29 25(OH)D, ng/mL 16.7 (11.3, 24.5) 23.4 (15.2, 32.7) 0.08 1,25(OH)2D, pg/mL 57.8 (40.7, 82.5) 62 (51.0, 78.4) 0.38 Osteocalcin, ng/mL 12.5 (10.0, 14.4) 15.0 (12.8, 19.2) 0.001 BAP, ng/mL 12.0 (9.3, 14.9) 13.2 (10.5, 14.9) 0.37 Urine Volume, mL/d 2040 (1522, 2575) 1911 (1528, 2096) 0.13 Calcium, mg/d 266 (171, 364) 238 (163, 299) 0.35 Oxalate, mg/d 29.7 (20.7, 35.2) 28.8 (22.5, 36.0) 0.84 Citrate, mg/d 409 (232, 614) 526 (284, 695) 0.32 Urea, g/d 11.79 (9.02, 14.17) 11.76 (10.11, 14.06) 0.60 Creatinine, mg/d 1630 (1111, 2076) 1531 (1271, 2016) 0.62 Phosphate, mg/d 861 (607, 1127) 935 (777, 1046) 0.16 Uric acid, mg/d 613 (497, 772) 643 (494, 865) 0.71 Magnesium, mg/d 100.0 (73.7, 132.4) 116.8 (84.9, 142.1) 0.10 Sodium, g/d 3.33 (2.39, 4.62) 3.31 (2.35, 4.44) 0.67 deoxypyridinoline/Cr, nMol/mMol 4.12 (3.49, 5.60) 4.45 (4.02, 5.77) 0.34 Ammonia, mg/d 634 (498, 800) 771 (519, 992) 0.18 Fasting pH 5.86 (5.43, 6.40) 6.04 (5.59, 6.51) 0.32 Clinical and biological characteristics of calcium oxalate stone formers with intact stones submitted for analysis, with or without Randall plaque. Reported values represent number (percentage) or median (p25, p75). 1,25(OH)2D ¼ 1,25-dihydroxyvitamin D, 25(OH)D ¼ 25-hydroxyvitamin D, BAP ¼ bone alkaline phosphatase, Cr ¼ creatinine, n ¼ number of observations, PTH ¼ parathyroid hormone. process: first, a calcium-dependent growth of the plaque within intensive public health interventions. In addition, we observed papilla interstitium, resulting in plaque outbreak through no difference in sodium and urea daily excretion between the urothelium and, secondarily, calcium oxalate crystallization 2 groups of patients. Thus, our data suggest that other recent due to increased urine supersaturation. In the United States, dietary changes would explain the modifications of Randall endoscopic evidence of papillary Randall plaques was found in plaque-related stone incidence. It seems unlikely that the 74% to 99% patients having ureteroscopic or percutaneous change in prevalence of stones with Randall plaque could be 10,20 stone removal. Our study shows that Randall plaque was attributed to the changes in nature of urological intervention a minor determinant of stone formation in France 20 years ago, over the past 20 years as we analyzed plaque prevalence among but some recent changes resulted in an epidemic of Randall calcium oxalate stones only, and observed a similar increase of plaque-related stones, especially in young adults. Salt and fragmented stones referred to our laboratory among various protein intakes are well known as major dietary determinants stone species, due to the development of renoureteroscopy of calcium urinary excretion. It was thus tempting to speculate (unpublished data). that increased salt and protein consumption by children and Several lines of evidence argue for a potential role of vitamin 24 – 26 young adults during the past 20 or 30 years may explain our D metabolites and VDR in stone formation. Recently, an observations. However, a decrease in meat consumption has increased biological response to 1,25-dihydroxyvitamin D has 22 27 been observed in children during the past decades in France. been reported in genetic hypercalciuric stone-forming rats. Moreover, salt intake increased gradually during the past Breslau et al previously showed that hypercalciuria might be century but decreased during the past years in France, after driven by an increased sensitivity to vitamin D in some patients Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com 5 Letavernier et al Medicine Volume 94, Number 10, March 2015 17,18,34 vary according to populations. Interestingly, we observed a TABLE 2. Prevalence of FokI, ApaI, BsmI, and TaqI VDR Poly- relatively high prevalence of BsmI b, ApaI a, and TaqI T VDR morphisms polymorphisms (baT haplotype) in both groups, similar to the distribution observed in 62 European renal stone formers affected No Randall P by fasting idiopathic hypercalciuria. We identified the FokI f Plaque Plaque Value allelic polymorphism as significantly overrepresented in the Randall plaque group. This polymorphism has been related to FokI increased osteocalcin circulating levels. However, no signifi- FF (%) 21 (56.8) 12 (37.5) cant relationship could be identified between f allele and osteo- Ff (%) 13 (35.1) 13 (40.6) calcin in our small series: osteocalcin median serum levels were ff (%) 3 (8.1) 7 (21.9) 12.9 (10.3, 16.0) ng/mL and 13.7 (12.1, 18.2) ng/mL in FF Allelic prevalence (F/f) 74.3/25.7 57.8/42.2 0.047 homozygous patients and f allele carriers, respectively. It seems ApaI likely that other unidentified VDR polymorphisms or VDR AA (%) 11 (29.7) 9 (28.1) coactivators may promote sensitivity to vitamin D and control Aa (%) 18 (48.6) 13 (40.6) serum osteocalcin levels in patients with Randall plaque. aa (%) 8 (21.6) 10 (31.3) At last, the timescale of stone formation should be con- Allelic prevalence (A/a) 54.1/45.9 48.4/51.6 0.61 sidered. It has been shown that calcium phosphate crystal- BsmI lization begins in basement membranes of thin loops of BB (%) 5 (13.5) 6 (18.7) Henle and then spreads toward the tip of the papilla. Surface Bb (%) 17 (45.9) 10 (31.3) expression of Randall plaque would precede stone formation. bb (%) 15 (40.6) 16 (50.0) Indeed, Randall plaques have been observed in patients in the Allelic prevalence (B/b) 36.5/63.5 34.4/65.6 0.86 absence of renal stones. In addition, the concentric and radial TaqI structure of type Ia calcium oxalate stone evidences that stone TT (%) 18 (48.6) 16 (50.0) grows from the Randall plaque (Figure 1C). However, the delay Tt (%) 15 (40.6) 9 (28.1) required for Randall plaque formation is unknown. The striking tt (%) 4 (10.8) 7 (21.9) point of our epidemiologic data is the younger age of the Allelic prevalence (T/t) 68.9/31.1 64.1/35.9 0.59 population that develops calcium oxalate stones from Randall Prevalence of VDR polymorphisms in calcium oxalate stone formers plaques, with the age peak of such stones ranging now between with intact stones submitted for analysis, with or without Randall 20 and 30 years. This suggests the plaque is developed before 20 plaque. VDR ¼ vitamin D receptor. years of age and probably in children and teenagers. Since recent reports failed to evidence a beneficial effect of vitamin D supplementation on disease occurrence, our results raise con- 37,38 with normal 1,25-dihydroxyvitamin D serum levels. Large inter- cerns about the systematic use of vitamin D in children. ventional studies aimed for bone protection by vitamin D and Our study has several limitations. First, it was not designed calcium reported an increase in renal stone incidence in treated to assess past vitamin D intakes of patients. Although there was patients. Many dairy products are now enriched with vitamin D, a nonsignificant trend toward higher 25-hydroxyvitamin D and children receive frequent supplementation. Of notice, vita- serum levels in patients affected by Randall plaque, these levels min D intakes in USA have probably been higher than in Europe were in the normal range and reflect only recent vitamin D intake during the past decades, due to dietary enrichment, especially and production in adulthood, not the exposure to vitamin D during infant nutrient supplementation. infancy. We hope that the correlation we observed between By using data from a fully phenotyped population, we biological activity markers of vitamin D and Randall plaque found significantly increased ionized calcium and osteocalcin may lead to large epidemiological studies in children. Second, serum levels, and modestly increased phosphate reabsorption 71000 stones have been referred from >200 hospitals during rate in the Randall plaque group. These results are highly decades, giving us an opportunity to draw a representative view of suggestive of an increased response to vitamin D in these urolithiasis in Western Europe. Since calcium oxalate stone patients as levels of 1,25-dihydroxyvitamin D, the active form incidence grows in France and North America, it seems likely of vitamin D, were similar in both groups. Of notice, 39 patients that Randall plaque may explain for a part the overall increase of had high 1,25-dihydroxyvitamin D serum levels (>67 pg/mL), a calcium oxalate stone frequency observed during the past dec- common setting in renal stone formers, whereas few patients ades. However, the design of our study provides data about stone had elevated levels of 25-hydroxyvitamin D. proportions but not stone incidence. At last, as stated above, VDR The most interesting finding was the observation that the polymorphisms have been assessed in small groups, and FokI f bone remodeling marker, osteocalcin, unlike bone alkaline phos- polymorphism is unable to explain alone patient phenotype, phatase, was independently associated with Randall plaque. The particularly osteocalcin levels. Moreover, unlike TaqI and ApaI, osteocalcin gene has a classical VDR response element in FokI polymorphism has not been related to increased risk of promoter region, and is considered as a hallmark feature of urolithiasis. Further, genetic studies are needed in larger popu- 31,32 VDR activation. Taken together, our results suggest that lations of various ethnicities to confirm these preliminary results patients prone to develop plaques have an increased biological and identify other polymorphisms that would explain sensitivity response to 1,25-dihydroxyvitamin D implying VDR. In turn, to vitamin D. VDR activation increases calcium absorption by intestinal epi- In conclusion, our large-scale study draws attention on 26,28 thelial cells and eventually calcium renal excretion. In important aspects of Randall plaque-related stones. On the basis addition, VDR activation in osteoclasts has been shown recently of the analysis of 30,149 intact stones, we observed a high 27,33 to promote bone resorption, increasing thereby calciuria. proportion of calcium oxalate stones grown on Randall plaque. A few VDR polymorphisms (mainly ApaI and TaqI) have We describe an epidemic of Randall plaque-related stones, been related to an increased risk of urolithiasis, but the results may especially in young adults, whereas renal stone prevalence 6 www.md-journal.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Medicine Volume 94, Number 10, March 2015 Epidemics of Randall Plaque increases worldwide making urolithiasis a public health pro- forming patients. Am J Physiol Renal Physiol. 2008;295:F1286– F1294. blem. We postulate that vitamin D intakes during childhood may promote Randall plaque formation, in genetically predis- 20. Linnes MP, Krambeck AE, Cornell L, et al. Phenotypic characteriza- posed patients, possibly resulting in an increased risk of renal tion of kidney stone formers by endoscopic and histological quantifica- stones. tion of intrarenal calcification. Kidney Int. 2013;84:818–825. 21. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for REFERENCES the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346:77–84. 1. Stamatelou KK, Francis ME, Jones CA, et al. Time trends in 22. Lioret S, Dubuisson C, Dufour A, et al. Trends in food intake in reported prevalence of kidney stones in the United States: 1976- French children from 1999 to 2007: results from the INCA (e ´tude 1994. Kidney Int. 2003;63:1817–1823. Individuelle Nationale des Consommations Alimentaires) dietary 2. Daudon M. Epidemiology of nephrolithiasis in France. Ann Urol surveys. Br J Nutr. 2010;103:585–601. (Paris). 2005;39:209–231. 23. http://www.anses.fr/fr/documents/NUT2012sa0052.pdf. 3. Pearle MS, Calhoun EA, Curhan GC. Urologic Diseases of America 24. Hoopes RR Jr, Reid R, Sen S, et al. Quantitative trait loci for Project. Urologic diseases in America project: urolithiasis. J Urol. hypercalciuria in a rat model of kidney stone disease. J Am Soc 2005;173:848–857. Nephrol. 2003;14:1844–1850. 4. Denstedt JD, Fuller A. Epidemiology of stone disease in North 25. Favus MJ, Karnauskas AJ, Parks JH, et al. Peripheral blood monocyte America. In: Talati JJ, Tiselius HG, Albala DM, eds. Urolithiasis: vitamin D receptor levels are elevated in patients with idiopathic Basic Science and Clinical Practice. et al, eds. Urolithiasis: Basic hypercalciuria. J Clin Endocrinol Metab. 2004;89:4937–4943. Science and Clinical Practice. London: Springer Verlag; 2012:13–20. 26. Worcester EM, Coe FL. 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Jackson RD, LaCroix AZ, Gass M, et al., Women’s Health Initiative and Clinical Practice. London: Springer Verlag; 2012:89–96. Investigators. Calcium plus vitamin D supplementation and the risk 8. Randall A. The origin and growth of renal calculi. Ann Surg. of fractures. N Engl J Med. 2006;354:669–683. 1937;105:1009–1027. 30. Curtis DM. Infant nutrient supplementation. J Pediatr. 1990;117 9. Ohman S, Larsson L. Evidence for Randall’s plaques to be the (2 pt 2):S110–118. origin of primary renal stones. Med Hypotheses. 1992;39:360–363. 31. Morrison NA, Shine J, Fragonas JC, et al. 1,25-dihydroxyvitamin D- 10. Low RK, Stoller ML. Endoscopic mapping of renal papillae for responsive element and glucocorticoid repression in the osteocalcin Randall’s plaques in patients with urinary stone disease. J Urol. gene. Science. 1989;246:1158–1161. 1997;158:2062–2064. 32. Ja ¨a ¨skela ¨ inen T, Ryha ¨nen S, Ma ¨enpa ¨a ¨ PH. 9-cis retinoic acid 11. Evan AP, Lingeman JE, Coe FL, et al. 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Demographics and Characterization of 10,282 Randall Plaque-Related Kidney Stones

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Abstract

Demographics and Characterization of 10,282 Randall Plaque-Related Kidney Stones A New Epidemic? Emmanuel Letavernier, MD, PhD, Sophie Vandermeersch, BSc, Olivier Traxer, MD, PhD, Mohamed Tligui, MD, Laurent Baud, MD, PhD, Pierre Ronco, MD, PhD, Jean-Philippe Haymann, MD, PhD, and Michel Daudon, PharmD, PhD 26 vs 34 years, P ¼ 0.02), had increased ionized serum calcium levels Abstract: Renal stone incidence has progressively increased in indus- (P ¼ 0.04), and increased serum osteocalcin (P ¼ 0.001) but similar trialized countries, but the implication of Randall plaque in this epi- 25-hydroxyvitamin D levels. The logistic regression analysis showed demic remains unknown. Our objectives were to determine whether the that age (odds ratio [OR] 0.96, confidence interval [CI] 0.926 – 0.994, prevalence of Randall plaque-related stones increased during the past P ¼ 0.02), weight (OR 0.97, CI 0.934 – 0.997, P ¼ 0.03), and osteocalcin decades after having analyzed 30,149 intact stones containing mainly serum levels (OR 1.12, CI 1.020 – 1.234, P ¼ 0.02) were independently calcium oxalate since 1989 (cross-sectional study), and to identify associated with Randall plaque. The prevalence of the FokI f vitamin D determinants associated with Randall plaque-related stones in patients receptor polymorphism was higher in patients with plaque (P ¼ 0.047). (case – control study). In conclusion, these findings point to an epidemic of Randall plaque- The proportion of Randall plaque-related stones was assessed over associated renal stones in young patients, and suggest a possible 3 time periods: 1989 – 1991, 1999 – 2001, and 2009 – 2011. Moreover, we implication of altered vitamin D response. analyzed clinical and biochemical parameters of 105 patients affected (Medicine 94(10):e566) by calcium oxalate stones, with or without plaque. Of 30,149 calcium oxalate stones, 10,282 harbored Randall plaque Abbreviations: CI = confidence interval, COD = calcium oxalate residues (34.1%). The prevalence of Randall plaque-related stones dihydrate, COM = calcium oxalate monohydrate, FTIR = Fourier increased dramatically during the past years. In young women, 17% transform infrared spectroscopy, OR = odds ratio, VDR = vitamin of calcium oxalate stones were associated with Randall plaque during D receptor. the 1989 – 1991 period, but the proportion rose to 59% 20 years later (P< 0.001). Patients with plaques experienced their first stone-related event earlier in life as compared with those without plaque (median age INTRODUCTION here is strong evidence that renal stone incidence increased Editor: Pavlos Malindretos. T during the past decades in industrialized countries, now Received: December 1, 2014; revised: January 25, 2015; accepted: January affecting >10% of the population and constituting a major 28, 2015. 1–3 public health challenge. Calcium oxalate stones are now From the Sorbonne universite ´s-UPMC Univ Paris 06 (EL, SV, OT, LB, PR, J-PH, MD); INSERM UMR S 1155 (EL, SV, LB, PR, J-PH, MD); AP-HP identified as the main type of urinary calculi in western (EL, LB, J-PH, MD), Ho ˆ pital Tenon, Explorations fonctionnelles multi- countries and account for at least 70% of all kidney stones. disciplinaires and Cristal Laboratory; AP-HP (OT, MT), Ho ˆ pital Tenon, Longitudinal epidemiological studies performed in USA, Service d’Urologie; and AP-HP (PR), Ho ˆ pital Tenon, Service de Europe, or Japan evidenced that the progression in calcium Nephrologie, Paris, France. Correspondence: Emmanuel Letavernier; Michel Daudon, Service des oxalate and uric acid stones was responsible for the increase in 1,4 – 7 Explorations Fonctionnelles Multidisciplinaires, Ho ˆ pital TENON, 4 the prevalence of urolithiasis. Calcium oxalate stone Rue de la Chine, 75020 Paris, France (e-mail: emmanuel.letavernier growth results from urine supersaturation due to low diuresis @tnn.aphp.fr; [email protected]). and intermittent biological disorders such as hypercalciuria, EL and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data hyperoxaluria, and/or hypocitraturia. However, the starting analysis. Study concept and design: MD and EL. Acquisition, analysis, point of calcium oxalate stones received little attention until and interpretation of data: all authors. Drafting of the article: EL, MD, recently. LB, and PR. Critical revision of the article for important intellectual Since Alexander Randall made the hypothesis that the content: all authors. Statistical analysis: EL and MD. Study supervision: EL and MD. origin of renal calculi was calcium phosphate plaque at the This work was partially funded by the Agence Nationale de la Recherche tip of renal papillae, relatively few studies were dedicated to the (ANR-13-JSV1-0010-01) and the Socie´te´ de Ne´phrologie-Fondation du 8– 10 Randall plaque. A major contribution to this field was made Rein (Genzyme grant). The sponsors had no role in the design and by Evan et al who reported that Randall plaque of patients conduct of the study; collection, management, analysis, and interpret- ation of the data; preparation, review, or approval of the article; decision with nephrolithiasis begins in basement membranes of thin to submit the article for publication. loops of Henle. The same group highlighted the relationship The authors have no conflicts of interest to disclose. 12 between calcium excretion and plaque formation. The recent Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. increased interest for Randall plaque is likely to originate from This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is the development of renoureteroscopy, which enables plaque permissible to download, share and reproduce the work in any medium, visualization, and also from an increased incidence of stones provided it is properly cited. The work cannot be changed in any way or 10 due to heterogeneous nucleation processes from plaques. used commercially. However, the implication of Randall plaque in kidney stone ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000566 epidemic is not documented. Medicine Volume 94, Number 10, March 2015 www.md-journal.com 1 Letavernier et al Medicine Volume 94, Number 10, March 2015 We conducted a study to assess the evolution of Randall DNA Analysis plaque-related stone incidence during the last decades in France Buffy coats were collected from patients who provided and characterize the specific clinical and biological profile of informed written consent, according to French legislation, in the patients developing plaque-related stones to identify Randall view of further genetic analyses. The cohort is registered plaque risk factors. (Commission nationale de l’informatique et des liberte´s Declaration Number 1709404v0). The regions containing single nucleotide polymorphisms of the vitamin D receptor (VDR) METHODS gene were amplified using the appropriate primer set, by 17 18 Morphoconstitutional Analysis of Renal Stones methods adapted from Seo et al and Mossetti et al. The Morphologic examination and classification of renal stone forward primer for ApaI and TaqI polymorphism was 5 -AGCA- surface and section were combined with Fourier transform GAGCAGAGTTCCAAGCAGA-3 . The reverse primer for infrared spectroscopy (FTIR) to classify renal stones and ApaI and TaqI polymorphism was 5 -ATCTTGGCATAGAGC- 13,14 0 identify the different crystalline phases. Starting from a AGGTGGCT-3 . The forward primer for BsmI polymorphism 0 0 database of 71,000 urinary stones collected between 1989 and was 5 -CAACCAAGACTACAAGTACCGCGTCAGTGA-3 . 2013, intact calcium oxalate stones (30,149, which passed The reverse primer for BsmI polymorphism was 5 -AACCAG- spontaneously or removed intact) were selected for further CGGAAGAGGTCAAGGG-3 . The forward primer for FokI 0 0 analysis, whereas fragmented stones resulting from urological polymorphism was 5 -ACTGACTCTGGCTCTGACCGT-3 . procedures were excluded because of the frequent loss of The reverse primer for FokI polymorphism was 5 -TGGGTT- Randall plaque. The composition and structure of stones with- GGTGTAGGAGGCTGT-3 . Each polmerase chain reaction out Randall plaque were compared with those of stones devel- product was digested with the appropriate restriction endonu- oped at the surface of Randall plaques identified by the typical clease (FastDigest for BsmI, ApaI, TaqI, and FokI) as recom- 13–15 renal papilla imprint and plaque residues at stone surface. mended by the manufacturer instruction (Thermo Scientific, The proportions of the main stone components were assessed, as Illkirch, France). The presence of BsmI, ApaI, TaqI, and FokI well as the internal structure of the stone according to FTIR and restriction enzyme sites was designated as lowercase b, a, t, and 13–15 morphoconstitutional stone classification. All stones have f, respectively, whereas absence was designated as uppercase B, been analyzed by a single investigator (M.D.). The term ‘‘core’’ A, T, and F, respectively. refers to the most internal part of the stone (developing on the Randall plaque when it is). Statistical Analyses Chi-square test was used for stone composition and epi- Evolution of Plaque-Related Stone Incidence demiological data; Student t test was used to compare the mean Over the Past Decades proportion of calcium oxalate phases. Fisher exact test and In order to assess the longitudinal changes in the pro- Mann–Whitney U test were used to compare other categorical portions of stones initiated from a Randall plaque, we compared or quantitative variables, respectively (clinical, biological, and the incidence of Randall plaque in men and women over 3 equal genetic determinants of Randall plaque). Reported values periods of time: 1989–1991, 1999–2001, and 2009–2011. We represent number (percentage), mean  standard deviation, or considered the number and the percentage of stones, grown median (p25 and p75). Variables potentially associated with from plaques or not, among all the stones mainly composed of Randall plaque (P< 0.10) were entered in a multivariable calcium oxalate (>85% of the stone according to FTIR) logistic regression. These variables were age, weight, ionized recorded in our database, and which passed spontaneously or calcium, phosphate reabsorption rate, 25-hydroxyvitamin D, were removed intact. and osteocalcin. A P value <0.05 was considered significant. Statistics were performed independently by 2 authors using both Clinical and Biological Data of Renal Stone number cruncher statistical system (NCSS) 6.0 (NCSS 6.0, Formers NCSS statistical software, Kaysville, UT, USA) and StatView More than 1000 renal stone formers were referred for 5.0 software (SAS Institute Inc., Cary, NC, USA). metabolic investigation to our Physiology unit between 2000 and 2012 (Tenon Hospital, Paris). Patients provided a 24-hour urine collection under a free diet. They all were referred for an RESULTS oral calcium load test, the results of which were similar in both Morphoconstitutional Analysis of Randall groups (not shown). Serum and urine parameters were assessed Plaque-Related Stones as previously described. Because identification of Randall plaque may be underrecognized in fragmented stones, we Of 30,149 intact stones containing mainly calcium oxalate selected only patients who had both complete biological data analyzed between 1989 and 2013, 10,282 stones harbored Ran- and also intact renal stones analyzed exclusively in the Cristal dall plaque residues (34.1%). The predominant crystalline phase laboratory (Paris). In addition, we selected stones containing determined by FTIR was either calcium oxalate monohydrate >85% calcium oxalate according to FTIR analysis. Exclusion (COM or whewellite) or calcium oxalate dihydrate (COD or criteria were primary hyperparathyroidism, renal tubular acido- weddellite); only 84 Randall plaque-related stones had a different sis, renal failure (assessed by measured creatinine renal clear- composition (mainly uric acid associated with COM). The exist- ance lower than 60 mL/min/1.73 m ), genetic or enteric ence of Randall plaque was not influenced by sex because 23.8% hyperoxaluria, and treatments interfering with calcium homeo- of stones with plaque and 24.6% of stones without plaques stasis: bisphosphonates and diuretics. Overall, 105 patients met originated from women. The morphoconstitutional analysis evi- these criteria. To our knowledge, none of the 22 women denced that Randall plaque-related stones were predominantly included in the study have been diagnosed with osteoporosis made of COM, and their core, in contact with the plaque, or received hormone replacement therapy. was a typical radial and concentric COM-type ‘‘Ia’’ structure 2 www.md-journal.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Medicine Volume 94, Number 10, March 2015 Epidemics of Randall Plaque AB CD EF GH FIGURE 1. Representative calcium oxalate stones from the database. (A) Typical COM (subtype Ia) stone with a Randall plaque (arrow) made of carbapatite. (B) Calcium oxalate stone composed of COM (dark area) around the Randall plaque (arrow) and secondary covered by COD crystals (light part on the left side). (C) Typical subtype Ia cross-section of a COM stone initiated from a Randall plaque. Note the crystallization of COM is organized from the light carbapatite deposit, which corresponds to the Randall plaque (arrow). (D) Calcium oxalate stone mainly composed of COD. The stone was initiated from a Randall plaque. Note the depressed surface that corresponds to the umbilication, that is, the imprint of the papilla. The white deposit is the part of the Randall plaque located at the surface of the papilla (arrow). Of interest, the first layers of calcium oxalate around the Randall plaque are made of COM (dark area). (E) Example of subtype Ia stone developed in free caliceal cavities (without Randall plaque). (F) Cross-section of the same stone exhibiting a well-organized and compact structure made of very thin concentric layers with radial organization. (G) Typical subtype IIa COD stone developed in free caliceal cavities (without Randall plaque). (H) Typical subtype IIa COD stone section characterized by a loose and poorly organized structure (without Randall plaque). Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com 3 Letavernier et al Medicine Volume 94, Number 10, March 2015 Nucleation of CaOx stones on plaques (all) Clinical and Biological Determinants of Randall 50 Plaque In order to identify clinical or biological parameters specifi- cally associated with Randall plaque, we collected data from 105 patients who had both extensive metabolic evaluations in our physiology unit, and intact calcium oxalate stones analyzed in the Cristal laboratory, with or without Randall plaque residues at stone surface (42 and 63 patients, respectively, Table 1). In the latter group, no phosphate was detected in stone cores, ruling out the hypothesis of calcium oxalate stones released from the papilla with a plaque covered up by subsequent growth of calcium 1990 2000 2010 oxalate. Patients with Randall plaque were younger than those Period without plaque (P ¼ 0.005, Table 1), and experienced their first Nucleation of CaOx stones on plaques (males) stone-related event earlier in life (median age 26 vs 34 years, P ¼ 0.02). Twenty four-hour urine collection under free diet did 1989–1991 not reveal any difference in 24-hour urine volume, calcium 1999–2001 excretion or salt and protein consumption because sodium and 2009–2011 urea daily excretions were similar in both groups of patients. Ionized calcium serum levels and renal phosphate reabsorption rate were significantly higher in the Randall plaque group (P ¼ 0.04 and P ¼ 0.03, respectively). There was no significant difference in 25-hydroxyvitamin D status or parathyroid hormone levels, and 1,25-dihydroxyvitamin D serum levels were similar in both groups. By contrast, osteocalcin, a bone remodeling marker, 10–<20 20–<30 30–<40 40–<50 50–<60 60–<70 ≥≥ 70 was markedly increased in patients with plaques (P ¼ 0.001) unlike bone alkaline phosphatase and urinary deoxypyridinoline. Age, y The logistic regression analysis showed that age (odds ratio [OR] Nucleation of CaOx stones on plaques (females) 0.96, confidence interval [CI] 0.926 – 0.994, P ¼ 0.02), weight (OR 0.97, CI 0.934 – 0.997, P ¼ 0.03), and osteocalcin serum 1989–1991 levels (OR 1.12, CI 1.020 – 1.234, P ¼ 0.02) were independently 1999–2001 associated with Randall plaque. 2009–2011 Vitamin D Receptor Polymorphisms A written consent for DNA collection was obtained in 69 among the 105 participants. We retrospectively analyzed VDR polymorphisms once biological determinants of Randall plaque have been assessed. All patients but 1 were white. Table 2 shows the prevalence of BsmI, ApaI, TaqI, and FokI VDR genotypes in 10–<20 20–<30 30–<40 40–<50 50–<60 60–<70 ≥70 patients with and without Randall plaque. The prevalence of Age, y FokI f allele was significantly higher in patients with Randall FIGURE 2. Epidemic of Randall plaque-related stones in men and plaque (P ¼ 0.047). No statistical difference was observed in the women over 3 periods. The analysis of 1780 intact calcium oxalate distribution of ApaI, BsmI, and TaqI polymorphisms between stones during the 1989–1991 period (period I), 4310 during the the 2 groups. 1999–2001 period (period II), and 3830 during the 2009–2011 period (period III) revealed a dramatic increase in the proportion of Randall plaque-related stones (period II and period III vs period I: DISCUSSION P< 0.001 in men and women). CaOx ¼ calcium oxalate, Our laboratory has been collecting stones sent for identifi- RP ¼ Randall plaque. cation and classification from >200 hospitals in France. We thus accumulated material from >70,000 stones, of which >30,000 converging on the plaque (Figure 1, and supplementary Figures were intact calcium oxalate stones available for further analysis. S1, and S2, http://links.lww.com/MD/A210). Our data show that Randall plaque-related stones represented 34% of stones containing mainly calcium oxalate during the past decades; there is a dramatic and steady increase in the incidence An Epidemic of Randall Plaque-Related Stones of Randall plaque-related stones particularly in the younger During the past 2 decades, the incidence of stones derived population (<30 years) defining a new epidemic; osteocalcin from plaques increased dramatically in France, especially in serum levels are independently associated with Randall plaque. young men and women (Figure 2). We observed over the last These data together with higher prevalence of the VDR f FokI 2 periods, a dramatic increase of Randall plaque-related stones allele suggest as a working hypothesis that the recent propensity in children and young adults (Figure 2). For instance, in female to supplement children with vitamin D may be one of the factors patients between 20 and 30 years, 17.2% of calcium oxalate responsible for the dramatic increase of Randall plaque-related stones were due to Randall plaque during the 1989 – 1991 stones in genetically predisposed subjects. period, but the proportion rose to 59.2% 20 years later Over the past years, evidence has been accumulated that (P< 0.001). In parallel, the male/female ratio decreased from Randall plaque growth was related to increased calcium con- 3.26 to 2.59 (P< 0.001) during these 2 decades. centration in distal tubular fluid. This led to consider a 2-step 4 www.md-journal.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Percentage of RP Percentage of RP Percentage of RP Medicine Volume 94, Number 10, March 2015 Epidemics of Randall Plaque TABLE 1. Clinical and Biological Characteristics of Renal Stone Formers Parameter No Plaque Randall Plaque P Value n63 42 Male patients, % 50 (79) 33 (79) 1.00 Age, y 50.0 (40.5, 57.0) 44 (28.2, 48.7) 0.005 Age at first stone, y 34.0 (25.0, 44.0) 26.0 (20.2, 37.7) 0.02 Recurrence, % 48 (76) 35 (83) 0.47 White and North African, % 62 (98) 41 (98) 1.00 Weight, kg 77.0 (70.0, 88.0) 72.0 (64.0, 79.0) 0.01 Height, cm 173 (164, 178) 175 (168, 180) 0.27 Blood Creatinine, mg/dL 0.88 (0.75, 1.01) 0.90 (0.81, 0.97) 0.97 Cr clearance, mL/min 125 (103, 156) 122 (103, 141) 0.43 Calcium, mg/dL 9.04 (8.76, 9.20) 9.08 (8.88, 9.52) 0.12 Calcium ionized, mg/dL 4.68 (4.56, 4.8) 4.76 (4.64, 4.84) 0.04 Phosphorus, mg/dL 2.82 (2.51, 3.03) 2.76 (2.45, 3.13) 0.69 Phosphate reabsorption rate 0.89 (0.85, 0.91) 0.91 (0.86, 0.93) 0.03 Magnesium, mg/dL 2.07 (1.90, 2.19) 2.02 (1.95, 2.14) 0.86 Uric acid, mg/dL 5.91 (4.75, 6.82) 5.80 (5.14, 6.86) 0.66 PTH, pg/mL [N:8 – 76] 42 (33.7, 51.0) 33 (27.0, 52.0) 0.29 25(OH)D, ng/mL 16.7 (11.3, 24.5) 23.4 (15.2, 32.7) 0.08 1,25(OH)2D, pg/mL 57.8 (40.7, 82.5) 62 (51.0, 78.4) 0.38 Osteocalcin, ng/mL 12.5 (10.0, 14.4) 15.0 (12.8, 19.2) 0.001 BAP, ng/mL 12.0 (9.3, 14.9) 13.2 (10.5, 14.9) 0.37 Urine Volume, mL/d 2040 (1522, 2575) 1911 (1528, 2096) 0.13 Calcium, mg/d 266 (171, 364) 238 (163, 299) 0.35 Oxalate, mg/d 29.7 (20.7, 35.2) 28.8 (22.5, 36.0) 0.84 Citrate, mg/d 409 (232, 614) 526 (284, 695) 0.32 Urea, g/d 11.79 (9.02, 14.17) 11.76 (10.11, 14.06) 0.60 Creatinine, mg/d 1630 (1111, 2076) 1531 (1271, 2016) 0.62 Phosphate, mg/d 861 (607, 1127) 935 (777, 1046) 0.16 Uric acid, mg/d 613 (497, 772) 643 (494, 865) 0.71 Magnesium, mg/d 100.0 (73.7, 132.4) 116.8 (84.9, 142.1) 0.10 Sodium, g/d 3.33 (2.39, 4.62) 3.31 (2.35, 4.44) 0.67 deoxypyridinoline/Cr, nMol/mMol 4.12 (3.49, 5.60) 4.45 (4.02, 5.77) 0.34 Ammonia, mg/d 634 (498, 800) 771 (519, 992) 0.18 Fasting pH 5.86 (5.43, 6.40) 6.04 (5.59, 6.51) 0.32 Clinical and biological characteristics of calcium oxalate stone formers with intact stones submitted for analysis, with or without Randall plaque. Reported values represent number (percentage) or median (p25, p75). 1,25(OH)2D ¼ 1,25-dihydroxyvitamin D, 25(OH)D ¼ 25-hydroxyvitamin D, BAP ¼ bone alkaline phosphatase, Cr ¼ creatinine, n ¼ number of observations, PTH ¼ parathyroid hormone. process: first, a calcium-dependent growth of the plaque within intensive public health interventions. In addition, we observed papilla interstitium, resulting in plaque outbreak through no difference in sodium and urea daily excretion between the urothelium and, secondarily, calcium oxalate crystallization 2 groups of patients. Thus, our data suggest that other recent due to increased urine supersaturation. In the United States, dietary changes would explain the modifications of Randall endoscopic evidence of papillary Randall plaques was found in plaque-related stone incidence. It seems unlikely that the 74% to 99% patients having ureteroscopic or percutaneous change in prevalence of stones with Randall plaque could be 10,20 stone removal. Our study shows that Randall plaque was attributed to the changes in nature of urological intervention a minor determinant of stone formation in France 20 years ago, over the past 20 years as we analyzed plaque prevalence among but some recent changes resulted in an epidemic of Randall calcium oxalate stones only, and observed a similar increase of plaque-related stones, especially in young adults. Salt and fragmented stones referred to our laboratory among various protein intakes are well known as major dietary determinants stone species, due to the development of renoureteroscopy of calcium urinary excretion. It was thus tempting to speculate (unpublished data). that increased salt and protein consumption by children and Several lines of evidence argue for a potential role of vitamin 24 – 26 young adults during the past 20 or 30 years may explain our D metabolites and VDR in stone formation. Recently, an observations. However, a decrease in meat consumption has increased biological response to 1,25-dihydroxyvitamin D has 22 27 been observed in children during the past decades in France. been reported in genetic hypercalciuric stone-forming rats. Moreover, salt intake increased gradually during the past Breslau et al previously showed that hypercalciuria might be century but decreased during the past years in France, after driven by an increased sensitivity to vitamin D in some patients Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com 5 Letavernier et al Medicine Volume 94, Number 10, March 2015 17,18,34 vary according to populations. Interestingly, we observed a TABLE 2. Prevalence of FokI, ApaI, BsmI, and TaqI VDR Poly- relatively high prevalence of BsmI b, ApaI a, and TaqI T VDR morphisms polymorphisms (baT haplotype) in both groups, similar to the distribution observed in 62 European renal stone formers affected No Randall P by fasting idiopathic hypercalciuria. We identified the FokI f Plaque Plaque Value allelic polymorphism as significantly overrepresented in the Randall plaque group. This polymorphism has been related to FokI increased osteocalcin circulating levels. However, no signifi- FF (%) 21 (56.8) 12 (37.5) cant relationship could be identified between f allele and osteo- Ff (%) 13 (35.1) 13 (40.6) calcin in our small series: osteocalcin median serum levels were ff (%) 3 (8.1) 7 (21.9) 12.9 (10.3, 16.0) ng/mL and 13.7 (12.1, 18.2) ng/mL in FF Allelic prevalence (F/f) 74.3/25.7 57.8/42.2 0.047 homozygous patients and f allele carriers, respectively. It seems ApaI likely that other unidentified VDR polymorphisms or VDR AA (%) 11 (29.7) 9 (28.1) coactivators may promote sensitivity to vitamin D and control Aa (%) 18 (48.6) 13 (40.6) serum osteocalcin levels in patients with Randall plaque. aa (%) 8 (21.6) 10 (31.3) At last, the timescale of stone formation should be con- Allelic prevalence (A/a) 54.1/45.9 48.4/51.6 0.61 sidered. It has been shown that calcium phosphate crystal- BsmI lization begins in basement membranes of thin loops of BB (%) 5 (13.5) 6 (18.7) Henle and then spreads toward the tip of the papilla. Surface Bb (%) 17 (45.9) 10 (31.3) expression of Randall plaque would precede stone formation. bb (%) 15 (40.6) 16 (50.0) Indeed, Randall plaques have been observed in patients in the Allelic prevalence (B/b) 36.5/63.5 34.4/65.6 0.86 absence of renal stones. In addition, the concentric and radial TaqI structure of type Ia calcium oxalate stone evidences that stone TT (%) 18 (48.6) 16 (50.0) grows from the Randall plaque (Figure 1C). However, the delay Tt (%) 15 (40.6) 9 (28.1) required for Randall plaque formation is unknown. The striking tt (%) 4 (10.8) 7 (21.9) point of our epidemiologic data is the younger age of the Allelic prevalence (T/t) 68.9/31.1 64.1/35.9 0.59 population that develops calcium oxalate stones from Randall Prevalence of VDR polymorphisms in calcium oxalate stone formers plaques, with the age peak of such stones ranging now between with intact stones submitted for analysis, with or without Randall 20 and 30 years. This suggests the plaque is developed before 20 plaque. VDR ¼ vitamin D receptor. years of age and probably in children and teenagers. Since recent reports failed to evidence a beneficial effect of vitamin D supplementation on disease occurrence, our results raise con- 37,38 with normal 1,25-dihydroxyvitamin D serum levels. Large inter- cerns about the systematic use of vitamin D in children. ventional studies aimed for bone protection by vitamin D and Our study has several limitations. First, it was not designed calcium reported an increase in renal stone incidence in treated to assess past vitamin D intakes of patients. Although there was patients. Many dairy products are now enriched with vitamin D, a nonsignificant trend toward higher 25-hydroxyvitamin D and children receive frequent supplementation. Of notice, vita- serum levels in patients affected by Randall plaque, these levels min D intakes in USA have probably been higher than in Europe were in the normal range and reflect only recent vitamin D intake during the past decades, due to dietary enrichment, especially and production in adulthood, not the exposure to vitamin D during infant nutrient supplementation. infancy. We hope that the correlation we observed between By using data from a fully phenotyped population, we biological activity markers of vitamin D and Randall plaque found significantly increased ionized calcium and osteocalcin may lead to large epidemiological studies in children. Second, serum levels, and modestly increased phosphate reabsorption 71000 stones have been referred from >200 hospitals during rate in the Randall plaque group. These results are highly decades, giving us an opportunity to draw a representative view of suggestive of an increased response to vitamin D in these urolithiasis in Western Europe. Since calcium oxalate stone patients as levels of 1,25-dihydroxyvitamin D, the active form incidence grows in France and North America, it seems likely of vitamin D, were similar in both groups. Of notice, 39 patients that Randall plaque may explain for a part the overall increase of had high 1,25-dihydroxyvitamin D serum levels (>67 pg/mL), a calcium oxalate stone frequency observed during the past dec- common setting in renal stone formers, whereas few patients ades. However, the design of our study provides data about stone had elevated levels of 25-hydroxyvitamin D. proportions but not stone incidence. At last, as stated above, VDR The most interesting finding was the observation that the polymorphisms have been assessed in small groups, and FokI f bone remodeling marker, osteocalcin, unlike bone alkaline phos- polymorphism is unable to explain alone patient phenotype, phatase, was independently associated with Randall plaque. The particularly osteocalcin levels. Moreover, unlike TaqI and ApaI, osteocalcin gene has a classical VDR response element in FokI polymorphism has not been related to increased risk of promoter region, and is considered as a hallmark feature of urolithiasis. Further, genetic studies are needed in larger popu- 31,32 VDR activation. Taken together, our results suggest that lations of various ethnicities to confirm these preliminary results patients prone to develop plaques have an increased biological and identify other polymorphisms that would explain sensitivity response to 1,25-dihydroxyvitamin D implying VDR. In turn, to vitamin D. VDR activation increases calcium absorption by intestinal epi- In conclusion, our large-scale study draws attention on 26,28 thelial cells and eventually calcium renal excretion. In important aspects of Randall plaque-related stones. On the basis addition, VDR activation in osteoclasts has been shown recently of the analysis of 30,149 intact stones, we observed a high 27,33 to promote bone resorption, increasing thereby calciuria. proportion of calcium oxalate stones grown on Randall plaque. A few VDR polymorphisms (mainly ApaI and TaqI) have We describe an epidemic of Randall plaque-related stones, been related to an increased risk of urolithiasis, but the results may especially in young adults, whereas renal stone prevalence 6 www.md-journal.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. Medicine Volume 94, Number 10, March 2015 Epidemics of Randall Plaque increases worldwide making urolithiasis a public health pro- forming patients. 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