Francesca Pivari

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.

The Cardiovascular Burden in End-Stage Renal Disease

It is well documented that chronic kidney disease patients have an extremely high risk of developing cardiovascular (CV) disease (CVD) compared to the general population. Declining renal function itself represents a continuum of CV risk, and in those individuals who survive to reach end-stage renal disease, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Several pathophysiological pathways have been suggested to account for this, including endothelial dysfunction, dyslipidemia, inflammation, left ventricular hypertrophy, troponins, phosphate, vitamin D, fibroblast growth factor-23, and NT-proBNP. All these conditions and biomarkers may have clear associations with current and subsequent CVD.

High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity

Bone health impairment is a common finding in HIV-infected patients on antiretroviral treatment. High serum parathyroid hormone (PTH) concentration in patients on antiretroviral treatment containing tenofovir disoproxil fumarate (TDF) has been reported. Hyperparathyroidism was not always sustained by a reduction in vitamin D concentration. We thus hypothesized a direct inhibitory effect of TDF on the Calcium-sensing receptor (CaSR), leading to hyperparathyroidism. Human embryonic kidney cells were transfected with CASR wild-type gene or mutated in different sites (N124K, T1051G, C788T, T888M). Cells were grown in standard conditions and the activity of CaSR was assessed after stimulation with CaCl2 with and without TDF (100 nM-1 μM). We evaluated by western blot phospho-p44/42 ERK expression levels as a marker of CaSR activity. In silico structure models were obtained for wild-type and N124K mutant. Molecular docking with TDF was also evaluated. The stimulation by CaCl2 and TDF 100 nM led to a decrease of 55% of CaSR activity (P < 0.001), whereas the stimulation by CaCl2 and TDF 1 μM reduced the activity by 68% (P < 0.001). The decreased CaSR activity was comparable to that observed from known CASR gene inactivating mutations (T1051G, C788T), which inhibit the receptor activity by 56% and 78%, respectively. The TDF inhibits the CaSR activity carrying a gain of function mutation in the intracellular domain (T888M), but it does not influence the activity of the receptor carrying the N124K activating mutation. Our data show that TDF is able to inhibit the activity of CaSR in a dose-dependent manner. Hyperparathyroidism observed in TDF-treated patients may be therefore promoted by the direct effect of the drug on CaSR.

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

Calcifediol to treat secondary hyperparathyroidism in patients with chronic kidney disease

ABSTRACT Introduction: Deranged vitamin D metabolism represents an active trigger of secondary hyperparathyroidism (SHPT) in CKD. Correction of 25(OH)D deficiency by nutritional Vitamin D administration is suggested by KDIGO guidelines, to prevent and treat SHPT in CKD stage G3-G5 and G1T-G5T patients, although with a still inconsistent background. Nutritional vitamin D is available as cholecalciferol, ergocalciferol, or calcifediol. Superiority of calcifediol in increasing 25(OH)D levels has been suggested due to its better bioavailability. The safer pharmacokinetic of the recent modified-release (MR) formulation of calcifediol was effective in replenishing 25(OH)D levels with minimal impact on vitamin D catabolism and fibroblast-growth factor-23 (FGF-23) activation. Areas covered: the review discusses utility of calcifediol for treating SHPT in different CKD stages under physiology driven approach, focusing on vitamin D metabolism, guidelines suggestions and comparison between clinical effects on SHPT elicited by calcifediol, cholecalciferol and ergocalciferol. Expert commentary: although optimal targets of 25(OH)D and parathormone remain uncertain, calcifediol, especially in its newer MR formulation, may represent an intriguing option to combine an efficacious correction of 25(OH)D deficit and SHPT, with a limited impact on vitamin D catabolism and FGF-23 activation. Newer data are required to better explore the role of MR calcifediol in treating SHPT.