Biochemical Determinants of Severe Lithogenic Activity in Patients With Idiopathic Calcium Nephrolithiasis

doi:10.1016/j.urology.2011.07.1382

Urology

Volume 79, Issue 1, January 2012, Pages 48-54

https://doi.org/10.1016/j.urology.2011.07.1382 Get rights and content

Objective

To analyze the biochemical alterations in plasma and the urine determinants of severe lithogenic activity in patients with idiopathic calcium nephrolithiasis.

Methods

We performed a cross-sectional study of 120 patients divided into 2 groups: group 1, 60 patients without nephrolithiasis; and group 2, 60 patients with severe and/or recurrent calcium nephrolithiasis. In all patients, a study of renal function, calcium metabolism, and bone remodeling markers, and a study of the lithogenic factors were performed in urine after fasting and in 24-hour urine samples.

Results

We observed greater values for phosphorus in group 1 than in group 2 (P = .03). Also, we found greater values for intact parathyroid hormone (P = .01), osteocalcin (P = .000), and β-crosslaps (P = .000) in group 2 than in group 1. In the 24-hour urine samples, significant differences were found between groups 1 and 2 in calciuria (11.7 vs 17.4 mg/dL; P = .000), citraturia (50.6 vs 33.5 mg/dL; P = .002), calcium/creatinine quotient (0.14 vs 0.20; P = .001), calcium/citrate quotient (0.05 vs 0.13; P = .04), and calcium/creatinine quotient after fasting (0.09 vs 0.16; P = .000).

Conclusion

We consider the determinants of severe and/or recurrent calcium lithiasis to be hypercalciuria and hypocitraturia and a calcium/citrate quotient >0.06. As risk markers we can consider phosphatemia <2.9 mg/dL, phosphate/chlorine quotient >35, alkaline phosphatase >80 U/L, intact parathyroid hormone >60 pg/mL, osteocalcin >16 ng/mL, β-crosslaps >0.400 ng/mL, and β-crosslaps/osteocalcin quotient >0.028.

Section snippets

Study Subjects

We performed a cross-sectional study of 120 patients who had been included in a unique cohort from East Andalucia to study the relationship between urine and plasma markers and severe or recurrent calcium nephrolithiasis. These patients were divided into 2 groups. Group 1 included 60 patients aged 25-60 years without lithiasis, and group 2, included 60 patients aged 25-60 years with severe and/or recurrent calcium nephrolithiasis.

We considered severe lithogenic activity to include multiple

Results

The mean age of the subjects in group 1 was 49.5 years and was 46 years in group 2. The difference was not statistically significant (P = .15).

In the plasma levels of the analyzed variables, we found statistically significant differences for phosphorus, iPTH, osteocalcin, β-crosslaps. The phosphorus value was 3.2 mg/dL in group 1 and 2.29 mg/dL in group 2 (P = .03), The iPTH was 45.2 pg/dL in group 1 and 55.5 pg/dL in group 2 (P = .01), and osteocacin was 14.1 ng/dL in group 1 and 17 ng/dL in

Comment

Urolithiasis has a high and increasing incidence over time, and about 50% of the patients will develop another episode within 5 years. We can control recurrence with adequate medical care.⁹ Metabolic and clinical assessments have allowed us to control lifestyle habits, diet, and lithogenic drug use and to diagnosis severe disease¹⁰ early (eg, endocrine, metabolic, degenerative, neoplasia). A metabolic assessment is recommended when the patient is free of calculi or after removal, to avoid bias

Conclusions

We believe the determinants for severe and/or recurrent calcium lithiasis are hypercalciuria and hypocitraturia, and a calcium/citrate quotient of >0.06. The levels of calciuria >12.5 mg/dL or 200 mg/24 hours were detected in 60%-70% of the patients, and 72.6% of the patients presented with fasting hypercalciuria (calcium/creatinine quotient in the night urine sample after fasting >0.11). We believe the risk markers include phosphatemia <2.9 mg/dL, chlorine/phosphate quotient >35, alkaline

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Bone resorption in dogs with calcium oxalate urolithiasis and idiopathic hypercalciuria
2019, Research in Veterinary Science
Citation Excerpt :
Markers of bone turnover, including bone degradation proteins (e.g. β-crosslaps), bone formation proteins (e.g. osteocalcin), and cytokines that regulate bone resorption (e.g. IL-1, IL-6, and TNF-alpha), are altered in patients with calcium-containing nephrolithiasis and IH (Arrabal-Polo et al., 2011; Arrabal-Polo et al., 2012; Arrabal-Polo et al., 2013; Arrabal-Polo et al., 2014; Tasca et al., 2009). Measurement of serum, plasma, or urine β-crosslaps is a major method of documenting increased bone resorption, and β-crosslaps has been repeatedly documented to be increased in human patients with nephrolithiasis and IH (Arrabal-Polo et al., 2011; Arrabal-Polo et al., 2012; Arrabal-Polo et al., 2013; Arrabal-Polo et al., 2014). This biomarker is a product of type I collagen breakdown by osteoclasts.
People with calcium oxalate (CaOx) urolithiasis and idiopathic hypercalciuria (IH) often have evidence of increased bone resorption, but bone turnover has not previously been investigated in dogs with these conditions. The aim of this study was to determine whether a marker of bone resorption, β-crosslaps, differs between dogs with CaOx urolithiasis and IH compared to controls. This retrospective, cross-sectional study used a canine specific ELISA to measure β-crosslaps concentrations in stored frozen serum samples from 20 dogs with CaOx urolithiasis and IH and 20 breed-, sex-, and age-matched stone-free controls (18 Miniature Schnauzers, 14 Bichons Frise, and 8 Shih Tzus). Dogs with CaOx urolithiasis and IH had lower β-crosslaps concentrations relative to controls (P = .0043), and β-crosslaps had a moderate negative correlation with urinary calcium-to-creatinine ratios (r = −0.44, P = .0044). Miniature Schnauzers had lower β-crosslaps concentrations than the other two breeds (P = .0035). The ELISA had acceptable intra-assay precision, but concentrations decreased when samples were repeatedly assayed over time. Assay recovery rates were also below acceptance criteria. In conclusion, Miniature Schnauzers, Bichons Frise, and Shih Tzus with CaOx urolithiasis and IH have evidence of decreased bone resorption compared to stone-free controls. This suggests that other causes of IH, such as intestinal hyperabsorption of calcium, underlie risk for CaOx urolithiasis in these breeds. Results should be confirmed in larger populations and with other β-crosslaps assays and additional biomarkers of bone turnover. The stability of canine serum β-crosslaps after freeze-thaw cycles and storage at various temperatures requires investigation.
Retrospective Review of Serum and Urinary Lithogenic Risk Factors in Patients with Osteoporosis and Osteopenia
2015, Urology
Citation Excerpt :
Patients with relapsing calcium lithiasis present altered bone remodeling marker levels13 and a higher incidence of loss of bone mineral density, which is more frequent and severe in patients with fasting hypercalciuria.14 Up to 70% of patients with renal lithiasis present loss of bone mineral density,9 which is expressed in the form of increased bone remodeling factor levels, especially bone resorption markers in blood and urine.10,15,16 The bone markers most usually used are osteocalcin (bone formation) and β-crosslaps (bone resorption), which were more elevated in group 3 than in the other groups.
To analyze differences in bone remodeling markers, lithogenic factors and bone densitometry among the 3 groups of patients (controls, patients with relapsing calcium renal lithiasis, and patients with loss of bone mineral density without lithiasis).
This is a cross-sectional study including 203 patients who were divided in 3 groups: group 1 (controls), group 2 (patients with relapsing calcium renal lithiasis), and group 3 (patients with osteopenia and/or osteoporosis in the lumbar spine or hip). Bone densitometry, calcium-phosphorous and bone metabolism analysis, and analysis of lithogenic risk factors in fasting urine samples and 24-hour urine samples were performed. Statistical analysis was performed with SPSS 17.0. A P ≤.05 was considered statistically significant.
Patients in group 2 presented greater calcium excretion and a lower citrate excretion in 24-hour urine samples as compared with the other 2 groups. The proportion of hypercalciuria and hypocitraturia was higher in group 2. In addition, patients in group 2 presented a lower loss of bone mineral density as well as altered bone remodeling markers as compared with those in group 1. Patients in group 3 also presented alterations in urine calcium and citrate excretion with respect to the control group, with elevated fasting calcium and citrate levels and calcium-to-citrateratio.
Lithogenic risk factors are altered in patients with osteopenia and/or osteoporosis without renal lithiasis although to a lesser extent than patients with calcium renal lithiasis.
Distinct metabolic characteristics and risk of stone recurrence in patients with multiple stones at the first-time presentation
2014, Urology
Citation Excerpt :
The most impressive finding was that stone multiplicity was an independent predictor of recurrent stone formation, adjusted for well-known clinical and metabolic risk factors for stone formation (eg, age, gender, BMI, familial stone history, and urinary parameters). In agreement with other studies, the patients with stones excreted higher levels of calcium and uric acid and lower levels of urinary citrate than the control subjects.23-25 Although the patients with stones also excreted higher levels of phosphate than the control subjects, there is currently no consensus on the association between phosphate excretion and lithogenic risk.26
To characterize the clinical and metabolic abnormalities of patients presenting with multiple stones and determine their risk of new stone formation.
This retrospective case-controlled study consisted of 911 patients who had ureter stones for the first time and 107 age- and sex-matched patients without stones. The patients were classified into 2 groups: those with a single ureter stone (n = 690) and those with 1 or more additional stones somewhere in the ureter or kidney (n = 221). All patients underwent 24-hour urinary metabolic evaluation. The 240 patients (26.3%) who were followed for >12 months (median follow-up, 35.0 months) were included in recurrence analyses. Stone recurrence was defined as “new stone formation,” namely, the radiographic appearance of stones that had not been present in previous examinations.
The multiple-stone group had significantly lower urinary citrate excretion than the single-stone (P = .011) and control (P = .003) groups. Compared with the single-stone group, it also had a higher incidence of hypocitraturia (P = .011) and stone recurrence (27 of 84 [32.1%] vs 29 of 156 [18.6%] patients; P = .025). Multivariate Cox regression analyses revealed that stone multiplicity (hazard ratio, 2.343; 95% confidence interval, 1.302-4.220; P = .005) was an independent predictor of recurrent stone formation. Kaplan-Meier curves showed identical results.
The patients with multiple stones had distinct metabolic characteristics, particularly hypocitraturia and a significantly higher risk of recurrence than patients with 1 stone. Patients with multiple stones, even if it is their first stone episode, should undergo metabolic evaluation and possibly also potassium citrate therapy to prevent future stones.
Association of severe calcium lithogenic activity and bone remodeling markers
2013, Urology
Citation Excerpt :
An improvement in bone quality has been observed in patients treated with citrate.19 In these patients, not only does the excretion of calcium in the 24-hour urine increase and citrate in the 24-hour urine decrease, but an important increase is also produced in the postfasting urine calcium/creatinine ratio6 and in the markers for bone remodeling, both for bone resorption (dipyridoline and β-crosslaps) and for bone formation (osteocalcin and alkaline phosphatase).3,20 We have demonstrated in this study that patients with calcium lithiasis and severe lithogenic activity show greater loss of bone mineral density than patients without lithiasis or with calcium lithiasis and light lithogenic activity, as measured by bone densitometry and through markers of bone remodeling, whether the markers are for bone resorption (β-crosslaps) or bone formation (osteocalcin).
To establish cutoff points for markers of bone remodeling that allow for screening of patients at risk for serious lithogenic activity.
We conducted a cross-sectional study with 182 patients (aged between 25 and 60 years) divided into 3 groups: group 1, 56 patients without lithiasis; group 2, 67 patients with light calcium lithiasis; and group 3, 59 patients with severe calcium lithiasis. The criteria for inclusion in and exclusion from the study were established, and light and severe lithogenic activity were defined. Metabolic variables in blood and urine, along with bone densitometry, were studied for the groups. Statistical analysis of the results and preparation of receiver operating characteristic curves to establish optimal cutoff points were performed.
The patients in group 3 showed the greatest bone mineral density loss and the highest values for markers of bone remodeling, together with increased 24-hour calciuria. Using the receiver operating characteristic curves developed and based on statistical significance (P = .0001), the following cutoff points for severe lithogenic activity, with a sensitivity between 75% and 85%, were established: β-crosslaps >0.331 ng/mL; osteocalcin >13.2 ng/mL; β-crosslaps/osteocalcin >0.024; 24-hour calciuria >306.6 mg; and fasting urine calcium/creatinine >0.105.
Patients with calcium lithiasis and elevated values for osteocalcin, β-crosslaps, β-crosslaps/osteocalcin, 24-hour calciuria, and fasting urine calcium/creatinine may present a high risk of severe lithogenic activity.
Calcium renal lithiasis and bone mineral density. Importance of bone metabolism in urinary lithiasis
2013, Actas Urologicas Espanolas
La litiasis renal cálcica es una enfermedad multifactorial, en la que intervienen en su fisiopatología diferentes factores minerales y metabólicos que pueden encontrarse alterados, entre ellos el metabolismo óseo y fosfocálcico.
Establecer la evidencia científica y demostrar la relación existente entre litiasis renal cálcica y pérdida de densidad mineral ósea, mediante el uso de marcadores de remodelado óseo y metabolitos urinarios y séricos.
Se realiza una revisión bibliográfica en PubMed utilizando diferentes MeSHTerms como Nephrolithiasis, Bone mineral density, Urinary stones, Calcium, Bone resorption y Bone formation, usando diferentes combinaciones. Se seleccionan únicamente los trabajos con resúmenes en inglés o español y se descartan casos clínicos y trabajos con estudio estadístico inapropiado. Se seleccionan un total de 40 publicaciones.
En los diferentes estudios analizados se observa que los pacientes con hipercalciuria presentan una mayor pérdida de densidad mineral ósea con respecto a los normocalciúricos. Entre los pacientes con litiasis cálcica, tanto los que tienen normocalciuria como los que tienen hipercalciuria presentan pérdida de densidad mineral ósea, siendo más evidente en estos últimos. Esta pérdida de densidad mineral está acentuada y es importante en los pacientes con litiasis recidivante. El aumento de los marcadores calcio/creatinina en ayunas y β-crosslaps son los más determinantes de litiasis y pérdida de densidad mineral en estos pacientes.
Se recomienda solicitar marcadores de remodelado óseo y calcio/creatinina en ayunas en pacientes con litiasis cálcica recidivante por la importante presencia de pérdida de densidad mineral ósea, con un nivel de evidencia iii.
Calcium Nephrolithiasis is a multifactorial disease; in its pathophysiology is involved various minerals and metabolic factors that may be altered, including bone and phosphor-calcium metabolism.
To establish the scientific evidence and demonstrate the relationship between calcium nephrolithiasis and bone mineral density loss, through the use of bone turnover markers, serum and urinary metabolites.
We performed a PubMed literature review using different MeSH Terms like «Nephrolithiasis» «Bone mineral density»,«Urinary stones», «Calcium», «Bone resorption» and «Bone formation», with different combinations. We only selected articles with abstracts in English or Spanish and discarded clinical cases and articles with inappropriate statistical study. A total of 40 articles were selected.
In different studies reviewed have been observed that patients with hypercalciuria have a higher bone mineral density loss with respect to normocalciuric. Among patients with calcium stones (normocalciuric or hypercalciuric), there is loss of bone mineral density, being more evident in patients with stones and hypercalciuria. This mineral density loss is marked and important in patients with recurrent calcium stones. Increased markers like fasting calcium/creatinine and β-CrossLaps are determinant of nephrolithiasis and mineral density loss in these patients.
We recommend perform markers of bone turnover and fasting calcium/creatinine in patients with recurrent calcium stones by the significant presence of bone mineral density loss, with a level of evidence III.
How useful is an oral calcium load test for diagnosing recurrent calcium stone formers?
2022, Urolithiasis

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Endourology and StoneBiochemical Determinants of Severe Lithogenic Activity in Patients With Idiopathic Calcium Nephrolithiasis

Objective

Methods

Results

Conclusion

Section snippets

Study Subjects

Results

Comment

Conclusions

Endocrinol Metab Clin North Am

Endocrinol Metab Clin North Am

Urol Clin North Am

Endocrinol Metab Clin North Am

Am J Kidney Dis

Estudio de factores fisico-químicos en pacientes com litiasis renal

Arch Esp Urol

Tipos de cálculos renales: relación con la bioquímica urinaria

Arch Esp Urol

Mineral density and bone remodelling markers in patients with calcium lithiasis

BJU Int.

Bone alterations in children with idiopathic hypercalciuria at the time of diagnosis

Pediatr Nephrol

Endocrine changes and urinary citrate excretion

Scand J Urol Nephrol

Tratamiento de la litiasis renal con bifosfonatos

Arch Esp Urol

Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum

J Bone Miner Res

Influence of urinary stones on the composition of a 24-hour urine sample

Clin Chem

Analysis of hypophosphatemia in calcium nephrolithiasis

Mol Urol

The diagnostic value of the phosphate levels in serum and 24-hour urine samples in patients with recurrent renal stone disease

Scand J Urol Nephrol

Endourology and Stone
Biochemical Determinants of Severe Lithogenic Activity in Patients With Idiopathic Calcium Nephrolithiasis