Lorenza Macrina

Idiopathic calcium nephrolithiasis: A review of pathogenic mechanisms in the light of genetic studies

Background: Calcium nephrolithiasis is a multifactorial disease with a polygenic milieu. Association studies identified genetic polymorphisms potentially implicated in the pathogenesis of calcium nephrolithiasis. The present article reviews the mechanisms of calcium stone formation and the potential contribution of gene polymorphisms to lithogenic mechanisms. Summary: Endoscopy observations suggested that precipitation of calcium-oxalate on the Randalls plaque at the papilla surface may cause idiopathic calcium-oxalate stones. The Randalls plaque is a hydroxyapatite deposit in the interstitium of the kidney medulla, which resembles a soft tissue calcification. Conversely, calcium-phosphate stones may develop from crystalline deposits located at the tip of the Bellini duct. Polymorphisms of eleven genes have been associated with stones in genome-wide association studies and replicated candidate-gene association studies: VDR, SLC34A1, SLC34A4, CLDN14, and CaSR genes coding for proteins regulating tubular phosphate and calcium reabsorption; CaSR, MGP, OPN, PLAU, and UMOD genes coding for proteins preventing calcium salt precipitation; AQP1 gene coding for a water channel in the proximal tubule. The renal activity of the last gene, DGKH, is unknown. Polymorphisms in these genes may predispose to calcium-oxalate and -phosphate stones by increasing the risk of calcium-phosphate precipitation in the tubular fluid. Key Messages: Genetic findings suggest that tubular fluid supersaturation with respect to calcium and phosphate predisposes to calcium-oxalate stones by triggering cellular mechanisms that lead to the Randalls plaque formation.

Dietary style and acid load in an Italian population of calcium kidney stone formers

BACKGROUND AND AIMS Animal protein intake may cause an acid load that predisposes individuals to stones by influencing calcium and citrate excretion. These associations were not confirmed in recent studies. Therefore the present study was aimed to compare acid load of diet in stone formers and controls. METHODS AND RESULTS Participants to the study were 157 consecutive calcium stone formers and 144 controls. Diet was analyzed in these subjects using a software that evaluated nutrient intake from a three-day food intake diary. This software also estimated the potential renal acid load (PRAL, mEq/day). Twenty-four-hour urine excretion of ions and citrate was measured in stone formers. Stone former diet had lower intake of glucose, fructose, potassium and fiber and higher PRAL in comparison with controls. The multinomial logistic regression analysis showed that stone risk decreased in association with the middle and the highest tertiles of fiber intake and increased in association with the highest tertile of PRAL. The linear multiple regression analysis showed that calcium excretion was associated with the sodium excretion and that citrate excretion was associated with the PRAL and animal protein intake in stone formers. CONCLUSION Our findings suggest that stone formers may undergo a greater dietary acid load sustained by a low vegetable intake and base provision. Dietary acid load does not appear as the main determinant of calcium excretion, but may promote stone risk by decreasing citrate excretion. Sodium intake may predispose to stones by stimulating calcium excretion.

Position Statement from ADA/AACE/EASD/TES in Response to a Recently Published Letter to the Editor in The Lancet and an Editorial Addressing the Israeli-Palestinian Fighting in Gaza

Derek LeRoith, MD, PhD, Editor in Chief, Endocrine Practice R. Mack Harrell , MD, President, American Association of Clinical Endocrinologists George Grunberger, MD, President Elect, American Association of Clinical Endocrinologists Leonard Wartofsky, MD, Editor in Chief, The Journal of Clinical Endocrinology and Metabolism Andrea C. Gore, PhD, Editor in Chief, Endocrinology Margaret Wierman, MD, Acting Editor in Chief, Endocrine Reviews Stephen R. Hammes, MD, PhD, Editor in Chief, Molecular Endocrinology Carol A. Lange, PhD, Editor in Chief, Hormones and Cancer Richard J. Santen, MD, President, Endocrine Society George L. Bakris, MD, Editor in Chief, American Journal of Nephrology

Litiasi renale: prevenzione e terapia:

Recent guidelines have identified two steps in the prevention of recurrent urinary stones. The first includes general measures that may be recommended in all patients, irrespective of stone composition. These recommendations are substantially nutritional and include a diet with balanced intake of nutrients and abundant fluid ingestion, low in salt and normal in caloric intake, rich in vegetables and including dairy products. The second step includes specific measures based on the clinical activity of the kidney stone disease and the presence of acquired or hereditary conditions favouring recurrent stone formation. In this setting clinicians may prescribe drugs according to the composition of the stones and the urinary or metabolic abnormalities associated with the stones; surgical treatment may be coupled with medical therapy when there is malformation of the urinary tract or infected stones. Therefore, the role of clinicians in the treatment of stone formers is complex and requires the ability to characterize patients from a clinical, metabolic and nutritional point of view in order to provide the most personalized treatment possible.

Intestinal Calcium Absorption among Hypercalciuric Patients with or without Calcium Kidney Stones

BACKGROUND AND OBJECTIVES Idiopathic hypercalciuria is a frequent defect in calcium kidney stone formers that is associated with high intestinal calcium absorption and osteopenia. Characteristics distinguishing hypercalciuric stone formers from hypercalciuric patients without kidney stone history (HNSFs) are unknown and were explored in our study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared 172 hypercalciuric stone formers with 36 HNSFs retrospectively selected from patients referred to outpatient clinics of the San Raffaele Hospital in Milan from 1998 to 2003. Calcium metabolism and lumbar bone mineral density were analyzed in these patients. A strontium oral load test was performed: strontium was measured in 240-minute urine and serum 30, 60, and 240 minutes after strontium ingestion; serum strontium concentration-time curve and renal strontium clearance were evaluated to estimate absorption and excretion of divalent cations. RESULTS Serum strontium concentration-time curve (P<0.001) and strontium clearance (4.9±1.3 versus 3.5±2.7 ml/min; P<0.001) were higher in hypercalciuric stone formers than HNSFs, respectively. The serum strontium-time curve was also higher in hypercalciuric stone formers with low bone mineral density (n=42) than in hypercalciuric stone formers with normal bone mineral density (n=130; P=0.03) and HNSFs with low (n=22; P=0.01) or normal bone mineral density (n=14; P=0.02). Strontium clearance was greater in hypercalciuric stone formers with normal bone mineral density (5.3±3.4 ml/min) than in hypercalciuric stone formers and HNSFs with low bone mineral density (3.6±2.5 and 3.1±2.5 ml/min, respectively; P=0.03). Multivariate regression analyses displayed that strontium absorption at 30 minutes was positively associated calcium excretion (P=0.03) and negatively associated with lumbar bone mineral density z score (P=0.001) in hypercalciuric stone formers; furthermore, hypercalciuric patients in the highest quartile of strontium absorption had increased stone production risk (odds ratio, 5.06; 95% confidence interval, 1.2 to 20.9; P=0.03). CONCLUSIONS High calcium absorption in duodenum and jejunum may expose hypercalciuric patients to the risk of stones because of increased postprandial calcium concentrations in urine and tubular fluid. High calcium absorption may identify patients at risk of bone loss among stone formers.

Calcium-Sensing Receptor

Extracellular calcium is essential to assure metabolic functions in different cells. Cellular response to its changes is achieved through the calcium-sensing receptor (CaSR) localized on the plasma membrane. Its presence in parathyroid glands and kidney tubules is recognized as a key factor for the homeostasis of calcium, because it enables these cells to regulate parathyroid hormone secretion and tubular calcium reabsorption. CaSR is also crucial for bone cell activity in skeleton development and bone remodeling. Activating or inactivating CaSR mutations cause hypercalcemic or hypocalcemic disorders, whereas CaSR polymorphic variants may contribute to individual variability of serum calcium concentrations.

Cytocrome P450 and its interaction with drugs

Cytocrome P450 is a family of enzymes involved in the metabolism of several drugs. Their role in drug metabolism may cause interactions that may result in either drug toxicity or lack of efficacy. Antiepileptic drugs, like carbamazepine, activate the expression of the cytocrome P450 CYP24A1, which may cause vitamin D deficiency by accelerating the catabolism of its active metabolites. Other drugs may modify the activity of different enzymes of the cytocrome P450 family; among these drugs, omeprazole inhibits CYP3A4 and increases the activity of calcium channel blockers, statin, cyclosporine, and tacrolimus. By contrast, carbamazepin increases CYP3A4 activity. Therefore, nephrologists, who often need to prescribe complex therapies, have to take into account these drug interactions.

Update on the calcium-sensing receptor

The cells of the human body have a receptor that is sensitive to extracellular calcium [calcium-sensing receptor (CaSR)] and whose tissue expression is decreased in patients with chronic kidney disease. The CaSR plays a key role both in the regulation of PTH secretion by parathyroid cells, as well as in calcium tubular reabsorption by renal tubular cells. Recent biochemical and cellular studies found that this receptor has peculiar functional characteristics. Furthermore, pharmacological research has brought to the marker agonists for CaSR (calcimimetics) that today are used for treating secondary hyperparathyroidism and may have an effect on cardiovascular and bone diseases in patients with chronic kidney disease. With regard to the latter, the EVOLVE and ADVANCE trials were dedicated to understanding the role of cinacalcet, a calcimimetic drug, in the prevention of vascular calcification and cardiovascular events in patients with chronic kidney disease. Research in this field has thus opened promising perspectives for the treatment of chronic kidney disease.