A Comparison between Clinical and Metabolic Features of Renal Calyceal Microlithiasis and Overt Urolithiasis in Different Pediatric Age Groups.

INTRODUCTION: This study assesses the differences in the presentations, complications and metabolic abnormalities of children with renal calyceal microlithiasis (RCM) and overt urolithiasis in different pediatric ages. MATERIALS AND METHODS: A total of 465 children with urolithiasis were investigated retrospectively. Patients were categorized based on their ages to infancy, early childhood, middle childhood and adolescence. When the hyperechogenic spots on ultrasound imaging were <3 mm, they were considered RCM, and if they were ≥3 mm, they were considered overt urolithiasis. RESULTS: Metabolic abnormalities were detected in 71%; hyperuricosuria in infants, hyperoxaluria in younger children and hypocitraturia in older children were the most common metabolic abnormalities. Hypercalciuria was the only metabolic abnormality that was significantly associated with overt urolithiasis in all pediatric ages (OR 2.25, 95% CI 1.21-4.19). The clinical presentations were not significantly different between RCM and overt urolithiasis; however, complications such as urinary tract infection was significantly higher with overt urolithiasis in infancy (p = 0.01), early childhood (p = 0.02), middle childhood (p = 0.007) and adolescence (p = 0.01). Also, growth retardation was significantly higher with overt urolithiasis in infancy and early childhood (p = 0.02). CONCLUSIONS: Most children with urolithiasis have underlying urinary metabolic abnormalities that differ according to the child's age. Despite these differences, hypercalciuria is significantly associated with overt urolithiasis in all pediatric ages. Clinical and laboratory features cannot differentiate RCM and overt urolithiasis; however, complications are significantly higher with overt urolithiasis.

Renal papillary calcification and the development of calcium oxalate monohydrate papillary renal calculi: a case series study.

BACKGROUND: The objective of this study is to determine in a case series (four patients) how calcified deposits in renal papillae are associated with the development of calcium oxalate monohydrate (COM) papillary calculi. METHODS: From the recently collected papillary calculi, we evaluated retrospectively patients, subjected to retrograde ureteroscopy, with COM papillary lithiasis. RESULTS: The COM papillary calculi were found to result from subepithelial injury. Many of these lesions underwent calcification by hydroxyapatite (HAP), with calculus morphology and the amount of HAP in the concave zone dependent on the location of the calcified injury. Most of these HAP deposits grew, eroding the epithelium covering the renal papillae, coming into contact with urine and starting the development of COM calculi. Subepithelial HAP plaques may alter the epithelium covering the papillae, resulting in the deposit of COM crystals directly onto the epithelium. Tissue calcification depends on a pre-existing injury, the continuation of this process is due to modulators and/or crystallization inhibitors deficiency. CONCLUSIONS: Since calculus morphology and the amount of detected HAP are dependent on the location and widespread of calcified injury, all types of papillary COM calculi can be found in the same patient. All patients had subepithelial calcifications, with fewer papillary calculi, demonstrating that some subepithelial calcifications did not further evolve and were reabsorbed. A high number of subepithelial calcifications increases the likelihood that some will be transformed into COM papillary calculi.

A low fractional excretion of Phosphate/Fgf23 ratio is associated with severe abdominal Aortic calcification in stage 3 and 4 kidney disease patients.

BACKGROUND: Vascular calcification (VC) contributes to high mortality rates in chronic kidney disease (CKD). High serum phosphate and FGF23 levels and impaired phosphaturic response to FGF23 may affect VC. Therefore, their relative contribution to abdominal aortic calcification (AAC) was examined in patients CKD stages 3-4. METHODS: Potential risk factors for AAC, measured by the Kauppila Index (KI), were studied in 178 patients. RESULTS: In multivariate linear analysis, AAC associated positively with age, male gender, CKD-stage, presence of carotid plaques (CP) and also with FGF23, but negatively with fractional excretion of phosphate (FEP). Intriguingly, FEP increased with similar slopes with elevations in PTH, with reductions in GFR, and also with elevations in FGF23 but the latter only in patients with none (KI = 0) or mild (KI = 1-5) AAC. Lack of a FEP-FGF23 correlation in patients with severe AAC (KI > 5) suggested a role for an impaired phosphaturic response to FGF23 but not to PTH in AAC. Logistic and zero-inflated analysis confirmed the independent association of age, CKD stage, male gender and CP with AAC, and also identified a threshold FEP/FGF23 ratio of 1/3.9, below which the chances for a patient of presenting severe AAC increased by 3-fold. Accordingly, KI remained unchanged as FEP/FGF23 ratios decreased from 1/1 to 1/3.9 but markedly increased in parallel with further reductions in FEP/FGF23 < 1/3.9. CONCLUSIONS: In CKD 3-4, an impaired phosphaturic response to FGF23 with FEP/FGF23 < 1/3.9 associates with severe AAC independently of age, gender or CP.

Urine Cotinine level with smoking history predicts a risk of coronary artery calcification.

We investigated whether urine cotinine level, alone or combined with smoking status and cumulative smoking amount, could predict coronary calcium (CAC) score increase over time. The study population included 10,980 subjects. We analysed an association between CAC score increase over time and single or combined smoking-related factors. Urine cotinine level of ≥100 ng/mL, current or ex-smokers, and cumulative smoking amount of ≥1 pack-years (PY) showed significantly higher odds ratios (ORs) for CAC score increase over time. A combination of current smokers with >10 PY and urine cotinine level of ≥100 ng/mL showed the highest OR. Irrespective of smoking status and cumulative smoking amount, all combinations with urine cotinine of ≥100 ng/mL showed higher ORs than other combinations with urine cotinine level of <100 ng/mL. Urine cotinine levels can be useful to predict coronary artery calcification and encourage smokers to quit smoking.

Relationship between Urinary Level of Phytate and Valvular Calcification in an Elderly Population: A Cross-Sectional Study.

Pathological calcification generally consists of the formation of solid deposits of hydroxyapatite (calcium phosphate) in soft tissues. Supersaturation is the thermodynamic driving force for crystallization, so it is believed that higher blood levels of calcium and phosphate increase the risk of cardiovascular calcification. However several factors can promote or inhibit the natural process of pathological calcification. This cross-sectional study evaluated the relationship between physiological levels of urinary phytate and heart valve calcification in a population of elderly out subjects. A population of 188 elderly subjects (mean age: 68 years) was studied. Valve calcification was measured by echocardiography. Phytate determination was performed from a urine sample and data on blood chemistry, end-systolic volume, concomitant diseases, cardiovascular risk factors, medication usage and food were obtained. The study population was classified in three tertiles according to level of urinary phytate: low (<0.610 µM), intermediate (0.61-1.21 µM), and high (>1.21 µM). Subjects with higher levels of urinary phytate had less mitral annulus calcification and were less likely to have diabetes and hypercholesterolemia. In the multivariate analysis, age, serum phosphorous, leukocytes total count and urinary phytate excretion appeared as independent factors predictive of presence of mitral annulus calcification. There was an inverse correlation between urinary phytate content and mitral annulus calcification in our population of elderly out subjects. These results suggest that consumption of phytate-rich foods may help to prevent cardiovascular calcification evolution.

Renal calcification incidence in very low birth weight infants.

Serial ultrasound examinations were performed on 31 neonates with birth weights of less than 1,500 g for the detection of renal calcifications. Renal calcifications occurred in 20 (64%) of the infants at a mean age of 39.3 +/- 26.7 days of life. Infants with renal calcifications had shorter gestations (28.2 +/- 1.8 v 31 +/- 1.4 weeks, P less than .004) and lighter birth weights (924 +/- 195 v 1,338 +/- 100 g, P less than .004) than those infants without renal calcifications (n = 11). Furosemide administration was more common in the infants with renal calcifications (65% v 9.1%, P less than .001). The mean total dose of furosemide administered before renal calcifications were noted was 9.59 +/- 7.25 mg/kg. The 20 neonates with renal calcifications had a mean urine calcium level of 12.0 +/- 6.8 mg/kg/24 hours, mean urine calcium to creatinine ratio of 1.32 +/- 1.03 (range 0.3 to 4.45), and a mean alkaline phosphatase concentration of 961 +/- 327 IU. Initial parathyroid hormone levels were not different between the two groups, and subsequent determinations in infants with renal calcifications did not differ significantly from initial values. Renal calcifications are fairly common among very low birth weight infants, particularly in those receiving supplemental calcium and furosemide therapy. Although long-term implications of such findings are not known, close monitoring of renal function by serial determinations of urine calcium and urine calcium to creatinine ratios may identify those infants at risk for renal calcifications.

Calcification and uptake of Tc-99m diphosphonates in neuroblastomas: concise communication.

Sixty-six percent of 54 patients with neuroblastoma demonstrated uptake of bone-seeking radioagents by the primary tumor. This is a higher incidence than previously reported. Uptake was slightly more common in abdominal than thoracic tumors. There was a significant correlation between the size of the tumor and tracer uptake. Calcification was demonstrated in the primary tumor in almost 90% of the 54 patients. This is a much higher incidence of calcification than previously reported. Microscopy shows that the calcification is not always due to tumor necrosis; it also occurs in areas of viable tumor cells. Tracer uptake is believed to be related to calcium metabolism. The rate of metabolic activity rather than the total amount of calcium present within the tumor may be the most important factor in determining the amount of uptake. No significant relationship was found between tracer uptake and tumor stage or homovanillic acid and vanillylmandelic acid metabolic activity.

Abolished phosphaturic response to parathormone in adult patients with Fahr disease and its restoration after propranolol administration.

The similar localization of intracranial calcification in hypoparathyroidism and in Fahr disease without parathyroid gland disorder suggests that in these two disorders the pathomechanism of calcium phosphate deposition in the brain may be similar. It may be that in Fahr disease some factors, such as chronic respiratory alkalosis, could lead to hypoparathyroidism-like changes in the brain tissue. Abolition of the phosphaturic response to parathormone (PTH) was recently demonstrated in acute experimental hypocapnia. In three adult patients with Fahr disease, a tendency towards compensatory respiratory alkalosis and arterial hypocapnia was found. The parathormone test revealed a marked decrease in phosphaturia response to PTH, but normal cAMP response. In one patient, the parathormone test was repeated during propranolol administration and showed a considerable improvement in the phosphaturic response to parathormone. It is postulated that chronic hyperventilation and hypocapnia as well as phosphaturic resistance to PTH, intracellular increase of phosphate concentration and development of hypoparathyroidism-like intracranial calcification in patients with Fahr disease could all be caused by disturbance of adrenergic receptors and their relationship to PTH receptors.

High dietary phosphate intake induces development of ectopic calcifications in a murine model of familial tumoral calcinosis.

Familial tumoral calcinosis is characterized by ectopic calcifications due to persistent hyperphosphatemia. The most common genetic cause of the disease is mutations in GALNT3, encoding a glycosyltransferase involved in a posttranslational modification of fibroblast growth factor 23 (FGF23). The Galnt3 knockout mouse we developed was hyperphosphatemic due to low intact Fgf23 levels, but did not develop any apparent calcifications on a standard rodent diet. We therefore tested the hypothesis that a further challenge with a high phosphate diet could induce ectopic calcifications in Galnt3 knockout mice. Mice were fed either normal (0.6%) or high (1.65%) phosphate diet for 20 weeks beginning from weaning at 3 weeks. The high phosphate diet did not affect serum phosphorus concentration. However, regardless of the dietary phosphate contents, serum phosphorus levels were consistently elevated in Galnt3 knockout mice. The mice on the high phosphate diet had slightly low serum calcium, but significantly high alkaline phosphatase, parathyroid hormone (PTH), and calcium in the kidney. Although none of Galnt3 knockout mice on the normal phosphate diet developed calcifications, calcifications appeared in approximately one-half of the mice on the high phosphate diet by 12 weeks. Calcified masses were most often found around the neck and on the back and as large as 9.9 mm in length. These data indicate that dietary phosphate load has major impact on the development of ectopic calcifications in tumoral calcinosis.

Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA).

OBJECTIVES: This study sought to investigate associations of phosphate metabolism biomarkers with aortic valve calcification (AVC). BACKGROUND: Calcific aortic valve disease (CAVD) is a common progressive condition that involves inflammatory and calcification mediators. Currently there are no effective medical treatments, but mineral metabolism pathways may be important in the development and progression of disease. METHODS: We examined associations of phosphate metabolism biomarkers, including serum phosphate, urine phosphate, parathyroid hormone (PTH) and serum fibroblast growth factor (FGF)-23, with CT-assessed AVC at study baseline and in short-term follow-up in 6814 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). RESULTS: At baseline, AVC prevalence was 13.2%. Higher serum phosphate levels were associated with significantly greater AVC prevalence (relative risk 1.3 per 1 mg/dL increment, 95% confidence incidence: 1.1 to 1.5, p<0.001). Serum FGF-23, serum PTH, and urine phosphate were not associated with prevalent AVC. Average follow-up CT evaluation was 2.4 years (range 0.9-4.9 years) with an AVC incidence of 4.1%. Overall, phosphate metabolism biomarkers were not associated with incident AVC except in the top FGF-23 quartile. CONCLUSIONS: Serum phosphate levels are significantly associated with AVC prevalence. Further study of phosphate metabolism as a modifiable risk factor for AVC is warranted.

Fahr's syndrome: literature review of current evidence.

Fahr's disease or Fahr's syndrome is a rare, neurological disorder characterized by abnormal calcified deposits in basal ganglia and cerebral cortex. Calcified deposits are made up of calcium carbonate and calcium phosphate, and are commonly located in the Basal Ganglia, Thalamus, Hippocampus, Cerebral cortex, Cerebellar Subcortical white matter and Dentate Nucleus. Molecular genetics of this disease haven't been studied extensively; hence evidence at the molecular and genetic level is limited. Fahr's disease commonly affects young to middle aged adults. Etiology of this syndrome does not identify a specific agent but associations with a number of conditions have been noted; most common of which are endocrine disorders, mitochondrial myopathies, dermatological abnormalities and infectious diseases. Clinical manifestations of this disease incorporate a wide variety of symptoms, ranging from neurological symptoms of extrapyramidal system to neuropsychiatric abnormalities of memory and concentration to movement disorders including Parkinsonism, chorea and tremors amongst others. Diagnostic criteria for this disease has been formulated after modifications from previous evidence and can be stated briefly, it consist of bilateral calcification of basal ganglia, progressive neurologic dysfunction, absence of biochemical abnormalities, absence of an infectious, traumatic or toxic cause and a significant family history. Imaging modalities for the diagnosis include CT, MRI, and plain radiography of skull. Other investigations include blood and urine testing for hematologic and biochemical indices. Disease is as yet incurable but management and treatment strategies mainly focus on symptomatic relief and eradication of causative factors; however certain evidence is present to suggest that early diagnosis and treatment can reverse the calcification process leading to complete recovery of mental functions. Families with a known history of Fahr's disease should be counseled prior to conception so that the birth of affected babies can be prevented. This review was written with the aim to remark on the current substantial evidence surrounding this disease.

Effect of dietary mineral sources and oil content on calcium utilization and kidney calcification in female Fischer rats fed low-protein diets.

We studied the effects of dietary mineral source and oil intake on kidney calcification in 4-wk-old female Fischer rats after consuming the AIN-76 purified diet (AIN-76). A modified AIN-76 mineral mixture was used, although the original calcium (Ca)/phosphorus (P) molar ratio remained unchanged. Rats were fed the modified diets for a period of 40 d before their kidneys were removed on the last day. Ca balance tests were performed on days 31 to 36 and biochemical analysis of urine was also studied. Kidney Ca, P, and magnesium (Mg) in the standard diet group (20% protein and 5% oil) were not affected by the mineral source. Kidney Ca, P, and Mg in the low-protein (10% protein) diet group, were found to be influenced by the dietary oil content and mineral source. In particular, the different mineral sources differentially increased kidney mineral accumulation. Pathological examination of the kidney showed that the degree of kidney calcification was proportional to the dietary oil content in the 10% dietary protein group, reflecting the calcium content of the kidney. The information gathered on mineral sources in this study will help future researchers studying the influence of dietary Ca/P molar ratios, and histological changes in the kidney.

Fetuin, matrix-Gla protein and osteopontin in calcification of renal allografts.

BACKGROUND: Calcification of renal allografts is common in the first year after transplantation and is related to hyperparathyroidism. It is associated with an impaired long-term function of the graft (Am J Transplant 5∶1934-41, 2005). Aim of this study is to examine the role of the anti-calcifying/calcifying factors in the pathophysiology of renal allograft calcification. METHODS: We analyzed protocol allograft biopsies, blood and urine samples of 31 patients with and 27 patients without allograft calcification taken at 6 weeks, 3 and 6 months after transplantation. Patient demographical data, cold ischemia time, initial graft function and donor characteristics were comparable between the two groups. Biopsies were stained for osteopontin, fetuin, and matrix-gla-protein. Serum and urine electrolytes, matrix-gla-protein, fetuin, Vitamin D and intact parathyroid hormone in serum and osteopontin (OPN) in urine were examined. RESULTS: Serum levels of fetuin and matrix-Gla protein as well as urinary levels of OPN showed specific time dependent changes (6 weeks vs. 3 months vs. 6 months; all p<0.0001). In patients with calcifications, urinary levels of OPN were decreased by 55% at 6 weeks and increased thereafter, showing 54% higher levels at 6 months compared to patients without calcification (6 weeks: p<0.01, 6 months: p<0.05). Local protein expression of fetuin-A, matrix-Gla protein and OPN in the graft was specifically increased around calcified plaques, without differences in the mRNA tissue expression. CONCLUSION: Anticalcifying factors show significant changes in the early phase after renal transplantation, which may be important for the prevention of allograft calcification. The differences in OPN indicate an involvement of this factor in the regulation of calcification.

Interaction between oxidative stress and high-density lipoprotein cholesterol is associated with severity of coronary artery calcification in rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that oxidative stress is increased in patients with rheumatoid arthritis (RA) due to increased inflammation and contributes to the pathogenesis of atherosclerosis. METHODS: The independent association between urinary F2-isoprostane excretion, a measure of oxidative stress, and RA was tested using multiple linear regression models in 169 patients with RA and 92 control subjects, frequency matched for age, race, and sex. The relationship between F2-isoprostane excretion and coronary calcium, a marker of atherosclerosis, was examined in multivariable proportional odds logistic regression models that also assessed the interactions between oxidative stress and low-density lipoprotein and high-density lipoprotein (HDL) cholesterol. RESULTS: F2-isoprostane excretion was significantly higher in patients with RA (median 2.75 [interquartile range (IQR) 1.60-4.06] ng/mg creatinine) than in control subjects (median 1.86 [IQR 1.25-2.62] ng/mg creatinine; adjusted P = 0.006). In patients with RA, F2-isoprostanes were positively correlated with body mass index (P < 0.001), but not with disease activity or mediators of inflammation such as the Disease Activity Score in 28 joints or serum tumor necrosis factor α, interleukin-6, and C-reactive protein concentrations in adjusted multivariable models (P > 0.05 for all). In patients with RA, F2-isoprostanes significantly modified the effect of HDL cholesterol on coronary calcification (P = 0.02 for interaction) after adjustment for age, sex, and race. As F2-isoprostane levels increased, HDL lost its protective effect against coronary calcification. CONCLUSION: Oxidative stress measured as F2-isoprostane excretion was higher in patients with RA than in control subjects. Among patients with RA, higher F2-isoprostane excretion and HDL cholesterol concentrations interacted significantly and were positively associated with the severity of coronary calcification.

Inhibitors of calcification in blood and urine.

In bone and teeth formation, coordinated calcification is a highly desirable biological process. However, heterotopic calcification at unwanted tissue sites leads to dysfunction, disease and, potentially, to death and therefore requires prevention and treatment. With the recent discovery of calcification inhibitors we now know that biological calcification is not passive but a complex, active and highly regulated process. Calcification at vascular sites is the most threatening localization and manifests as part of atherosclerosis or arteriosclerosis. Atherosclerosis is often accompanied by intimal plaque calcification, whereas arteriosclerosis is characterized by calcification of the media. The severity of calcification of cerebral or coronary atherosclerotic plaques is associated with an increased incidence of events such as stroke or myocardial infarction. Medial calcification is the major cause of arterial stiffness, which contributes to left ventricular dysfunction and heart failure. Patients with chronic kidney disease are at especially increased risk for both intimal and medial calcification. In this context, it is currently thought that calcium-regulatory factors including fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates act in a local or systemic manner to prevent calcifications of the vasculature, and that dys-regulations of such calcification inhibitors may contribute to progressive calcifications. Nephrolithiasis represents another process of unwanted calcification responsible for significant morbidity. More than 80% of renal stones contain calcium. Urinary factors inhibiting calcification are citrate, glycosaminoglycans, Tamm-Horsfall protein, and osteopontin. This review summarizes current experimental and clinical data underlining the biological importance of these calcification inhibitors.

Hypercalcemia during the resolution of calcinosis universalis in juvenile dermatomyositis.

Dystrophic calcification is seen in more than 50% of children with juvenile dermatomyositis and tends to resolve spontaneously in some patients. Calcinosis universalis is the least common type of calcification seen and rarely regresses. We describe a boy with juvenile dermatomyositis and calcinosis universalis who developed hypercalcemia during spontaneous regression of dystrophic calcification. The treatment and possible mechanisms of this complication are discussed.

The role of calcium deposition in the ligamentum flavum causing a cauda equina syndrome and lumbar radiculopathy.

Our report concerns five patients who underwent lumbar decompressive surgery for cauda equina syndrome and radiculopathy secondary to degenerative stenosis associated with calcium deposition in the ligamentum flavum. The resected ligamentum flavum showed diffuse to massive calcium crystal deposition with a histologically marked degeneration in the elastic fibres. Energy dispensive radiographic microanalysis confirmed the crystal to be calcium pyrophosphate dihydrate in all patients, hydroxyapatite mixed in three and calcium orthophosphate mixed in one. The deposition appeared to be a change that is associated with the degenerative process in the ligament and, in some cases having marked deposition in a localised event, it causes or aggravates the neurological symptoms.

Excretion of inhibitors of calcification in urine. Part I. Findings in control subjects and patients with renal stones.

The total excretion of inhibitors of in vitro calcification was measured (in inhibiting units per day) in 24-hour urine samples of 11 control subjects and 20 patients with renal calculi. A semiquantitative method incorporating the rachitic rat cartilage technique was used. In both groups there was a significant positive correlation between the number of inhibiting units per day and the daily urine volume. The mean number of inhibiting units per day was significantly (P smaller than 0.05) higher in the stone patients than in the controls. However, the stone-formers had significantly larger (P smaller than 0.01) 24-hour urine volumes. When corrections were made for urine volume there was no significant difference between the two groups. These data suggest that the underlying abnormality responsible for renal stone formation is not a persistent decrease in the total concentration of urinary inhibitors of calcification.