Objective: Recurrence of urolithiasis is frequent. There are no reliable markers able to indicate recurrent stone former patients. Fetuin-A inhibits hydroxyapatite crystals formation and expansion. This study aims at evaluating whether serum fetuin-A may predict recurrent urolithiasis in young adults. Materials and methods: This is a multicentre study. Young adults patients with recurrent urolithiasis attending 3 urology clinics were enrolled from July 2011 to December 2012. Inclusion criteria were: age 18-40 years, presence of more than one kidney stone. Exclusion criteria were: diabetes mellitus, metabolic disorders, obesity, hypertension, cardiovascular disease, infection diseases. Controls were participants without history of urolithiasis and currently undetected stones. Routine biochemistry, serum concentration of oxalate, fetuin-A, and parathyroid hormone (PTH) were assessed; 24/h urinary excretion of creatinine, uric acid, calcium, sodium, phosphorus, potassium, magnesium, glucose, oxalate, amylase, and protein was measured. Kidney ultrasonography and plain X-ray examination was performed. Results: The total cohort was represented by 120 young adults participants (90 patients, and 30 controls). Clinical characteristics were not different between patients and controls. No significant differences were found in serum concentrations as well as in 24/h urinary excretion of recorded variables. No significant difference was found in serum concentration of fetuin-A (median 35.1 ± 18.62 SD Vs 35.12 ± 14.12, μg/ml; p = 0,908). Conclusions: The data of present study do not substantiate the hypothesis that serum fetuin-A may be a reliable predictor of recurrent urolithiasis in young adults

Alberto Saita

Carla Micheli

Dario Bruzzese

Domenico Prezioso

Domenico Russo

Ester Illiano

Mario Motta

Massimo Porena

Paolo Ferrari

Tullio Lotti

Vincenzo Bisesti

English

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Archivio Italiano di Urologia e Andrologia 2013; 85, 4180INTRODUCTIONUrolithiasis represents a process of unwanted calcifica-tion and the recurrence is the rule (1). The underlyingmechanisms of stone formation are not clearly known. Inaddition, there are no markers able to distinguishbetween patients who will have stone recurrence fromthose who will not. Therefore, it is clinically important toidentify potential factor(s) that may help clinicians inmaking decision.ORIGINAL PAPERSerum fetuin-A and recurrent urolithiasis in young adultsDomenico Prezioso 1, Alberto Saita 2, Mario Motta 2, Massimo Porena 3, Carla Micheli 3, Ester Illiano 1, Dario Bruzzese 4, Vincenzo Bisesti 5, Paolo Ferrari 6,Tullio Lotti 7, Domenico Russo 51 Department of Gynecology, Obstetric and Urology, University Federico II, Naples, Italy;2 Department of Urology, “Ospedale Vittorio Emanuele”, University of Catania, Catania, Italy;3 Department of Urology and Andrology, Ospedale Santa Maria della Misericordia, University of Perugia,  Perugia, Italy;4 Department of Preventive Medical Sciences, University Federico II, Naples, Italy; 5 Department of Nephrology, University Federico II, Naples Italy;6 Department of Urology, Ospedale Hesperia, Modena, Italy;7 University Federico II, Naples, Italy.Objective: Recurrence of urolithiasis is frequent. There are no reliable markers able toindicate recurrent stone former patients. Fetuin-A inhibits hydroxyapatite crystals for-mation and expansion. This study aims at evaluating whether serum fetuin-A may pre-dict recurrent urolithiasis in young adults.Materials and methods: This is a multicentre study. Young adults patients with recur-rent urolithiasis attending 3 urology clinics were enrolled from July 2011 to December 2012.Inclusion criteria were: age 18-40 years, presence of more than one kidney stone. Exclusion cri-teria were: diabetes mellitus, metabolic disorders, obesity, hypertension, cardiovascular disease,infection diseases. Controls were participants without history of urolithiasis and currently unde-tected stones. Routine biochemistry, serum concentration of oxalate, fetuin-A, and parathyroidhormone (PTH) were assessed; 24/h urinary excretion of creatinine, uric acid, calcium, sodium,phosphorus, potassium, magnesium, glucose, oxalate, amylase, and protein was measured.Kidney ultrasonography and plain X-ray examination was performed.Results: The total cohort was represented by 120 young adults participants (90 patients, and 30controls). Clinical characteristics were not different between patients and controls. No significantdifferences were found in serum concentrations as well as in 24/h urinary excretion of recordedvariables. No significant difference was found in serum concentration of fetuin-A (median 35.1 ±18.62 SD Vs 35.12 ± 14.12, µg/ml; p = 0,908). Conclusions: The data of present study do not substantiate the hypothesis that serum fetuin-Amay be a reliable predictor of recurrent urolithiasis in young adults.KEY WORDS: Calcification; Inhibition; Extra osseous calcification; Fetuin-A; Recurrent urolithiasis.Submitted 14 April 2013; Accepted 30 April 2013 No conflict of interest declaredSummaryAlong with the multiple traditional pathogenic factorsinvolved in stone formation (1-3), great relevance hasbeen recently given to inhibitors of ectopic calcification(4, 5). Inhibitors raise the concentrations of calcium andoxalate required for spontaneous formation of new crys-tals and decrease crystal growth, aggregation, and bind-ing to renal cells.Fetuin-A plays a crucial role in the extra osseous calcifi-DOI: 10.4081/aiua.2013.4.180Prezioso_Stesura Seveso  18/12/13  10:42  Pagina 180181Archivio Italiano di Urologia e Andrologia 2013; 85, 4Serum fetuin-A and recurrent urolithiasis in young adultscation process by inhibiting the formation and expansionof hydroxyapatite crystals (6-8). Unfortunately there isscarce information on fetuin-A in patients with recurrenturolithiasis. One sole study evaluated urine fetuin con-centration in patients with urolithiasis (9). Since urinaryexcretion of fetuin-A may result inaccurate as ascertainedin several renal injury models (10, 11), in the presentstudy serum fetuin-A was assessed in patients with recur-rent multiple urolithiasis and compared with that of nor-mal subjects. So far there is no data on this issue.MATERIALS AND METHODSThis is a multicentre study performed in outpatientsattending 3 urology clinics from July 2011 to December2012. The study protocol was approved by the institu-tional review board of Catania. Procedures were carriedout according to the declaration of Helsinki. Beforeenrollment all patients signed informed consent.Inclusion criteria were: age 18-40 years, recurrenturolithiasis, current presence of kidney stones. Exclusioncriteria were: diabetes mellitus, metabolic disorders, con-genital or acquired dyslipidemia, obesity, hypertension,cardiovascular disease, infection diseases.Serum concentration of glucose, creatinine, sodium,potassium, uric acid, calcium, phosphorus, magnesium,total cholesterol, triglycerides, oxalate, fetuin-A, andparathyroid hormone (PTH) was assayed. Urinary excretion of creatinine, uric acid, calcium, sodi-um, phosphorus, potassium, magnesium, glucose,oxalate, amylase, protein was assessed on 24-hour col-lections. Kidney ultrasonography and plain X-ray exam-ination was performed.Serum fetuin-A was measured by Human Fetuin-A ELISA(Biovendor Laboratory Medicine). The intra- and inter-assay variations were evaluated by measuring three dif-ferent samples in 33 replicates (intra-assay coefficient ofvariation < 5,2%, inter-assay coefficient of variation< 3,8%, limit of detection 0.35mg/L).                             The body mass index (BMI) of patients and controls wascalculated. Mann-Whitney test (abnormal data distribution), non-paired t-test (normal data distribution), chi square, andFisher exact test were used to compare data of subjectswith and without urolithiasis; P < 0.05 was considered assignificant. RESULTSWe enrolled 90 young adults patients (30 patients in eachcentre; 58 men, 32 women) with documented recurrentformation of urinary stones, and 30 individuals (10 ineach centre; 14 men, 16 women) without urolithiasis. Clinical characteristics and laboratory variables of patientswith and without urolithiasis are reported in Tables 1, 2and 3. Both groups were homogeneous for age, and BMI.There were no significant differences in serum concentra-tion except for serum calcium and phosphorus; both ionsControls Patients pMean ± SD Median (range) Mean ± SD Median (range)Age 28.47 ± 5.75 27.5 [19-40] 31.21 ± 7.18 32 [18-42] 0.068BMI 23.47 ± 3.06 24 [18-31] 23.03 ± 2.73 23 [18-30] 0.413Table 1.Clinical characteristics of controls and patients with urolithiasis.Controls PatientsVariables Mean ± SD Mean ± SD pFetuin-A (µg/ml)               35.1 ± 18.6 (35.1 ± 18.6 µg/ml ) 35.1 ± 14.1 (35.1 ± 14.1µg/ml) 0.908Oxalate (µmol/L) 97 ± 22 (8.7 ± 1.9 mg/L) 124 ± 73 (11.1 ± 6.6 mg/L) 0.612PTH (ng/L) 46 ± 20 (46 ± 20 pg/mL) 47 ± 18 (47 ± 18 pg/mL) 0.701Sodium (mmol/L) 144 ± 3.4 (144 ± 3.4 mEq/L) 142 ± 2.2 (142 ± 2.2 mEq/L) 0.177Potassium (mmol/L) 4.6 ± 0.9 (4.6 ± 0.9 mEq/L) 4.7 ± 0.4 (4.7 ± 0.4 mEq/L) 0.028Calcium (mmol/L) 2.3 ± 0.10 (9.22 ± 0.42 mg/dL) 2.4 ± 0.10 (9.56 ± 0.42 mg/dL) 0.041Phosphorus (mmol/L) 1.29 ± 0.20 (4.0 ± 0.62 mg/dL) 1.15 ± 0.29 (3.57 ± 0.89 mg/dL 0.028Total cholesterol (mmol/L) 4.65 ± 0.75 (181 ± 29 mg/dL) 4.78 ± 1.16 (187 ± 45 mg/dL) 0.331Triglycerides (mmol/L) 0.85 ± 0.21 (75 ± 19 mg/dL) 1.06 ± 0.55 (94 ± 49) 0.396Table 2.Baseline serum concentration of variables measured in controls and patients with urolithiasis.BMI: body mass index.PTH: parathyroid hormone.Prezioso_Stesura Seveso  18/12/13  10:42  Pagina 181Archivio Italiano di Urologia e Andrologia 2013; 85, 4D. Prezioso, A. Saita, M. Motta, M. Porena, C. Micheli, E. Illiano, D. Bruzzese, V. Bisesti, P. Ferrari, T. Lotti, D. Russo182were significantly different between patients with andwithout urolithiasis (serum calcium: mean 9.22 mg/dL ±0.42 SD vs 9.56 mg/dL ± 0.42 SD; p 0.041; serum phos-phorus: mean 4.0 mg/dL ± 0.62 SD vs 3.57 mg/dL ± 0.89SD; p 0.028). There were no significant differences in 24/hurinary excretion of measured variables. Serum concen-tration of fetuin was similar in patients and controls (mean35.1 ± 18.62 SD vs 35.12 ± 14.12 µg/ml; p = 0.908).DISCUSSIONIn this study a potential association was investigatedbetween serum concentration of fetuin-A and recurrenturolithiasis in young adults.Formation of stones within the urinary tract is a complexprocess driven by multiple factors. Although normalurine is frequently supersaturated with respect to calci-um and oxalate, most individuals do not form stones.Typically, any crystals formed are rapidly passed beforeachieving a size sufficient for retention. Increased quan-tities of calcium and/or oxalate are excreted by manystone former. Therefore, increased supersaturation alonedoes not account for urinary stone; as a consequence,other factors may influence their formation and growth.Therefore, it is clinically relevant to identify new poten-tial factor(s) that may help clinicians in making decision. Fetuin-A inhibits the precipitation of hydroxyapatite fromsupersaturated solutions of calcium and phosphate byforming fetuin-mineral complex, a high molecular masscomplex (6-8, 12). This inhibitory action is at least in partfacilitated by the transient formation of soluble, colloidalspheres, so-called calciprotein particles, containing fetuin-A, calcium, and phosphate. The action of fetuin-A is mostprominent in organs involved in the secretion or transportof mineral-rich fluids or in the generation of local pHchanges such as the kidney. Fetuin-A deficient rats havecalcification in the pelvis but not in the medulla or the cor-tex compared to wild type; in this experimental model,calcification was primarily a consequence of the lack offetuin-A and not of renal damage. Interestingly, animalshad calcium and phosphate concentrations within thenormal range; this finding rules out hypocalcaemia orhyperphosphatemia as a cause of the ectopic calcification.Therefore, the underlying mechanism may involve a directinteraction of fetuin-A with the mineral phase and the pre-vention of large crystal formation.Owing to the crucial role of fetuin-A in the process leadingto extra osseous calcification, it was stimulating to evaluateits potential role in patients with recurrent urolithiasis.Ascertaining a role of serum fetuin A in recurrenturolithiasis should be of clinical interest considering thatthe recurrence of urolithiasis is the rule in all forming-stone patients and that there are no laboratory markersable to distinguish between patients who will have stonerecurrence from those who will not.There is at present scarce information on urine fetuin-A inpatients with recurrent urolithiasis. In one sole study,urine fetuin concentration was found lower in 38 patientswith urolithiasis who were compared to 22 controls (9).The lower urine fetuin-A levels were not due to other con-ventional promoters and inhibitors of urine crystallization.On the basis of these data, measurement of urinary fetuin-A was suggested as more reliable risk predictor than thetraditional markers of recurrent urolithiasis (9).This interesting suggestion, however, should be viewedwith caution taking in account the data attained by pro-teonomics that have shown that urinary excretion offetuin-A is altered in several renal injury models (11).Urinary exosomal fetuin-A is elevated in patients withacute kidney injury in intensive care unit (11). Recently,urinary exosomal fetuin-A levels was found significantlyincreased after cisplatin-induced tubule damage (11).Thus, urinary fetuin-A excretion may be strongly affect-ed in presence of structural renal injury.The data of the present study do not confirm the hypoth-esized relationships between serum fetuin-A concentra-tion and recurrent urolithiasis. In fact, there was no sig-nificant difference in serum fetuin-A concentrationbetween patients and controls. Similarly, there were nosignificant differences in traditional variables. These dataconfirm that there are no markers able to distinguishbetween patients who will have stone recurrence fromControls PatientsPhosphate (mmol/24 h) 368 ± 68 (1141± 211 mg) 334 ± 108 (1037 ± 335 mg) 0.451Uric acid (μmol/24 h 39792 ± 10290 (669 ± 173 mg) 38365 ± 14454 (644.97 ± 242.67 mg) 0.634Calcium (mmol/24 h) 37.4 ± 9.2 (150 ± 37 mg) 59.6 ± 34.9 (239 ± 140 mg) 0.095Amylase (U/24 h) 236 ± 171.42 247.77 ± 100.5 0.158Sodium (mmol/24 h) 164.14 ± 36.06 179.33 ± 61.58 0.315Potassium (mmol/24 h) 73.67 ± 22.36 57.29 ± 21.6 0.058Chlorine (mmol/24 h) 182.7 ± 46.6 186 ± 69.97 0.747Proteinuria (mg/24 h) 142± 42 188 ± 134 0.508Magnesium (mmol/24 h) 58 ± 25.1 (141 ± 61 mg) 44.4 ± 17.8 (108 ± 43 mg) 0.148Glycosuria (mmol/24 h) 4.8 ± 1.5 (87 ± 27 mg) 4.7 ± 1.9 (85 ± 35 mg) 0.771Table 3.24/h urinary excretion of variables measured in controls and patients with urolithiasis.Prezioso_Stesura Seveso  18/12/13  10:42  Pagina 182183Archivio Italiano di Urologia e Andrologia 2013; 85, 4Serum fetuin-A and recurrent urolithiasis in young adultsthose who will not. In addition, neither serum concen-tration nor urinary excretion of fetuin-A may be regard-ed as reliable predictors of recurrent urolithiasis.Hopefully, studies performed with proteonomics mayfind true predictor(s) of recurrent urolithiasis.CONCLUSIONSThe data of present study do not substantiate thehypothesis that serum fetuin-A may be a reliable predic-tor of recurrent urolithiasis in young adults.REFERENCES1. Coe FL, Favus MJ, Asplin JR. Nephrolithiasis. In Brenner BM, ed.The Kidney. 7th ed, Philadelphia:Saunders. 2004; 1819-1866.2. De Yoreo JJ, Qiu SR, Hoyer JR. Molecular modulation of calciumoxalate crystallization. Am J Physiol Renal Physiol. 2006; 291:F1123-F1132, 3. Asplin JR, Parks JH, Coe FL. Dependence of upper limit ofmetastability on supersaturation in nephrolithiasis. Kidney Int.1997; 52:1602-1608, 4. Schinke T, Amendt C, Trindl A, et al. The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and inmineralizing calvaria cells. A possible role in mineralization andcalcium homeostasis. J Biol Chem. 1996; 271:20789-20796.5. Schafer C, Heiss A, Schwarz A, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein⁄fetuin-A is a systemically actinginhibitor of ectopic calcification. J Clin Invest. 2003; 112:357-366, 6. Heiss A, DuChesne A, Denecke B, et al. Structural basis of calci-fication inhibition by alpha 2-HS glycoprotein⁄fetuin-A. Formationof colloidal calciprotein particles. J Biol Chem. 2003; 278:13333-13341. 7. Westenfeld R, Schafer C, Kruger T, et al. Fetuin-A Protectsagainst Atherosclerotic Calcification in CKD. J Am Soc Nephrol2009; 20:1264-74. 8. Schlieper G, Westenfeld R, Brandenburg V, Ketteler M. Inhibitorsof calcification in blood and urine. Semin Dial. 2007; 20:113-21.9. Stejskal D, Karpisek M, Vrtal R. et al. Urine fetuin-A values inrelation to the presence of urolithiasis BJU International. 2008;101:1151-1154.10. Heiss A, Pipich V, Jahnen-Dechent W, Schwahn D. Fetuin-A is amineral carrier protein: small angle neutron scattering provides newinsight on Fetuin-A controlled calcification inhibition. Biophys J.2010; 99:3986-95.11. Zhou H, Pisitkun T, Aponte A, et al. Exosomal Fetuin-A identi-fied by proteomics: A novel urinary biomarker for detecting acutekidney injury. Kidney Int. 2006; 70:1847-1857.12.Price PA, Lim JE. The inhibition of calcium phosphate precipita-tion by Fetuin Is accompanied by the formation of a Fetuin-Mineralcomplex J Biol Chem. 2003; 278:22144-22152.CorrespondenceEster Illiano, MD (Corresponding Author)ester.illiano@inwind.itDomenico Prezioso, MDdprezioso@libero.it Department of Gynecology, Obstetric and Urology,University Federico II, Naples, ItalyAlberto Saita, MDalsaurol@hotmail.comMario Motta, MD mmotta@unict.it; mmotta@mbox.unict.itDepartment of Urology “Ospedale Vittorio Emanuele”,University of Catania, Catania, ItalyMassimo Porena, MDuropg@rdn.itCarla Micheli, MDcarla.micheli@libero.itDepartment of Urology and Andrology, Ospedale Santa Maria della Misericordia, University of Perugia, Perugia, ItalyDario Bruzzese, MDdbruzzes@unina.itDepartment of Preventive Medical Sciences, University Federico II, Naples, ItalyVincenzo Bisesti, MD vincenzo.bisesti@libero.itDomenico Russo, MDdomenicorusso51@hotmail.comDepartment of Nephrology, University Federico II, Naples, ItalyPaolo Ferrari, MD  pferrari@hesperia.itDepartment of Urology, Ospedale Hesperia, Modena, ItalyTullio Lotti, MD pferrari@hesperia.itUniversity Federico II, Naples, ItalyPrezioso_Stesura Seveso  18/12/13  10:42  Pagina 183

Serum fetuin-A and recurrent urolithiasis in young adults

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Archivio Italiano di Urologia e Andrologia

Objective: Recurrence of urolithiasis is frequent. There are no reliable markers able to indicate recurrent stone former patients. Fetuin-A inhibits hydroxyapatite crystals formation and expansion. This study aims at evaluating whether serum fetuin-A may predict recurrent urolithiasis in young adults. Materials and methods: This is a multicentre study. Young adults patients with recurrent urolithiasis attending 3 urology clinics were enrolled from July 2011 to December 2012. Inclusion criteria were: age 18-40 years, presence of more than one kidney stone. Exclusion criteria were: diabetes mellitus, metabolic disorders, obesity, hypertension, cardiovascular disease, infection diseases. Controls were participants without history of urolithiasis and currently undetected stones. Routine biochemistry, serum concentration of oxalate, fetuin-A, and parathyroid hormone (PTH) were assessed; 24/h urinary excretion of creatinine, uric acid, calcium, sodium, phosphorus, potassium, magnesium, glucose, oxalate, amylase, and protein was measured. Kidney ultrasonography and plain X-ray examination was performed. Results: The total cohort was represented by 120 young adults participants (90 patients, and 30 controls). Clinical characteristics were not different between patients and controls. No significant differences were found in serum concentrations as well as in 24/h urinary excretion of recorded variables. No significant difference was found in serum concentration of fetuin-A (median 35.1 ± 18.62 SD Vs 35.12 ± 14.12, μg/ml; p = 0,908). Conclusions: The data of present study do not substantiate the hypothesis that serum fetuin-A may be a reliable predictor of recurrent urolithiasis in young adults.</jats:p

Crossref

Objective: Recurrence of urolithiasis is frequent. There are no reliable markers able to
indicate recurrent stone former patients. Fetuin-A inhibits hydroxyapatite crystals formation
and expansion. This study aims at evaluating whether serum fetuin-A may predict
recurrent urolithiasis in young adults.
Materials and methods: This is a multicentre study. Young adults patients with recurrent
urolithiasis attending 3 urology clinics were enrolled from July 2011 to December 2012.
Inclusion criteria were: age 18-40 years, presence of more than one kidney stone. Exclusion criteria
were: diabetes mellitus, metabolic disorders, obesity, hypertension, cardiovascular disease,
infection diseases. Controls were participants without history of urolithiasis and currently undetected
stones. Routine biochemistry, serum concentration of oxalate, fetuin-A, and parathyroid
hormone (PTH) were assessed; 24/h urinary excretion of creatinine, uric acid, calcium, sodium,
phosphorus, potassium, magnesium, glucose, oxalate, amylase, and protein was measured.
Kidney ultrasonography and plain X-ray examination was performed.
Results: The total cohort was represented by 120 young adults participants (90 patients, and 30
controls). Clinical characteristics were not different between patients and controls. No significant
differences were found in serum concentrations as well as in 24/h urinary excretion of recorded
variables. No significant difference was found in serum concentration of fetuin-A (median 35.1 ±
18.62 SD Vs 35.12 ± 14.12, μg/ml; p = 0,908).
Conclusions: The data of present study do not substantiate the hypothesis that serum fetuin-A
may be a reliable predictor of recurrent urolithiasis in young adults

RUSSO, DOMENICO

Archivio della ricerca - Università degli studi di Napoli Federico II

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Serum fetuin-A and recurrent urolithiasis in young adults

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Archivio della ricerca - Università degli studi di Napoli Federico II