Gérard Friedlander

Latest findings in phosphate homeostasis

The kidney is a key player in phosphate balance. Inappropriate renal phosphate transport may alter serum phosphate concentration and bone mineralization, and increase the risk of renal lithiasis or soft tissue calcifications. The recent identification of fibroblast growth factor 23 (FGF23) as a hormone regulating phosphate and calcitriol metabolism and of klotho has changed the understanding of phosphate homeostasis; and a bone-kidney axis has emerged. In this review, we present recent findings regarding the consequences of mutations affecting several human genes encoding renal phosphate transporters or proteins regulating phosphate transport activity. We also describe the role played by the FGF23-klotho axis in phosphate homeostasis and its involvement in the pathophysiology of phosphate disturbances in chronic kidney disease.

Determination of the best method to estimate glomerular filtration rate from serum creatinine in adult patients with sickle cell disease: a prospective observational cohort study.

BackgroundSickle cell disease (SCD) leads to tissue hypoxia resulting in chronic organ dysfunction including SCD associated nephropathy. The goal of our study was to determine the best equation to estimate glomerular filtration rate (GFR) in SCD adult patients.MethodsWe conducted a prospective observational cohort study. Since 2007, all adult SCD patients in steady state, followed in two medical departments, have had their GFR measured using iohexol plasma clearance (gold standard). The Cockcroft-Gault, MDRD-v4, CKP-EPI and finally, MDRD and CKD-EPI equations without adjustment for ethnicity were tested to estimate GFR from serum creatinine. Estimated GFRs were compared to measured GFRs according to the graphical Bland and Altman method.ResultsSixty-four SCD patients (16 men, median age 27.5u2009years [range 18.0-67.5], 41 with SS-genotype were studied. They were Sub-Saharan Africa and French West Indies natives and predominantly lean (median body mass index: 22u2009kg/m2 [16-33]). Hyperfiltration (defined as measured GFR >110u2009mL/min/1.73u2009m2) was detected in 53.1% of patients. Urinary albumin/creatinine ratio was higher in patients with hyperfiltration than in patients with normal GFR (4.05u2009mg/mmol [0.14-60] versus 0.4u2009mg/mmol [0.7-81], pu2009=u20090.01). The CKD-EPI equation without adjustment for ethnicity had both the lowest bias and the greatest precision. Differences between estimated GFRs using the CKP-EPI equation and measured GFRs decreased with increasing GFR values, whereas it increased with the Cockcroft-Gault and MDRD-v4 equations.ConclusionsWe confirm that SCD patients have a high rate of glomerular hyperfiltration, which is frequently associated with microalbuminuria or macroalbuminuria. In non-Afro-American SCD patients, the best method for estimating GFR from serum creatinine is the CKD-EPI equation without adjustment for ethnicity. This equation is particularly accurate to estimate high GFR values, including glomerular hyperfiltration, and thus should be recommended to screen SCD adult patients at high risk for SCD nephropathy.

Assessment of hydration status in a large population

Both acute and chronic dehydration can have important implications for human behaviour and health. Young children, non-autonomous individuals and the elderly are at a greater risk of dehydration. Mild hypertonic dehydration could be related to less efficient cognitive and physical performance and has been reported to be associated with frequently occurring pathological conditions, especially nephrolithiasis. The assessment of hydration status in a large sample appears to be of interest for conducting epidemiological and large clinical studies aimed at improving preventive and curative care. Especially in large-population studies, methods that are used have to be accurate, cheap, quick and require no technical expertise. Body weight change is widely used to determine acute hydration changes, but seems to be insufficiently accurate in longitudinal studies. Bioimpedance analysis methods enable the assessment of total body water content, but their use is still under debate. Because plasma osmolality directly reflects intracellular osmolality, it constitutes a good marker to assess acute hydration changes, but not chronic hydration status because it changes constantly. Moreover, venepuncture is considered to be invasive and is not suitable for a large-sample study, especially in children. Urinary markers appear to be good alternatives for assessing hydration status in large populations. Collection of urine samples is non-invasive and cheap. High technical expertise is not required to perform urinary marker measurements and these measurements can be carried out quickly. Thus, methods based on urinary markers are very well suited for field studies. Urine colour is probably the least sensitive marker despite its high specificity. Urine osmolality and especially urine specific gravity could be easily used for determining hydration status in large-sample studies.

French Children Start Their School Day with a Hydration Deficit

Background and Aims: Fluid requirements of children vary as a function of gender and age. To our knowledge, there is very little literature on the hydration status of French children. We assessed the morning hydration status in a large sample of 529 French schoolchildren aged 9–11 years. Methods: Recruited children completed a questionnaire on fluid and food intake at breakfast and collected a urine sample the very same day after breakfast. Breakfast food and fluid nutritional composition was analyzed and urine osmolality was measured using a cryoscopic osmometer. Results: More than a third of the children had a urine osmolality between 801 and 1,000 mosm/kg while 22.7% had a urine osmolality over 1,000 mosm/kg. This was more frequent in boys than in girls (p < 0.001). A majority of children (73.5%) drank less than 400 ml at breakfast. Total water intake at breakfast was significantly and inversely correlated with high osmolality values. Conclusions: Almost two thirds of the children in this large cohort had evidence of a hydration deficit when they went to school in the morning, despite breakfast intake. Children’s fluid intake at breakfast does not suffice to maintain an adequate hydration status for the whole morning.

Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list.

High plasma fibroblast growth factor-23 (FGF23) concentration predicts the risk of death and poor outcomes in patients with chronic kidney disease or chronic heart failure. We checked if FGF23 concentration could be modified in patients with end stage liver disease (ESLD) and predict mortality. We measured plasma FGF23 in 200 patients with ESLD registered on a liver transplant waiting list between January 2005 and October 2008. We found that median plasma FGF23 concentration was above normal values in 63% of the patients. Increased FGF23 concentration was not explained by its classical determinants: hyperphosphataemia, increased calcitriol concentration or decreased renal function. FGF23 concentration correlated with the MELD score, serum sodium concentration, and GFR. Forty-six patients died before being transplanted and 135 underwent liver transplantation. We analyzed the prognostic value of FGF23 levels. Mortality was significantly associated with FGF23 levels, the MELD score, serum sodium concentration and glomerular filtration rate. On multivariate analyses only FGF23 concentration was associated with mortality. FGF23 levels were independent of the cause of the liver disease. To determine if the damaged liver can produce FGF23 we measured plasma FGF23 concentration and liver FGF23 mRNA expression in control and diethyl-nitrosamine (DEN)-treated mice. FGF23 plasma levels increased with the apparition of liver lesions in DEN-treated mice and that FGF23 mRNA expression, which was undetectable in the liver of control mice, markedly increased with the development of liver lesions. The correlation between FGF23 plasma concentration and FGF23 mRNA expression in DEN-treated mice suggests that FGF23 production by the liver accounts for the increased plasma FGF23 concentration. In conclusion chronic liver lesions can induce expression of FGF23 mRNA leading to increased FGF23 concentration, which is associated with a higher mortality in patients on a liver-transplant waiting list. In these patients FGF23 concentration was the best predictor of mortality.

Relationship between vitamin D deficiency and bone fragility in sickle cell disease: A cohort study of 56 adults

BACKGROUNDnRecent studies suggest that patients with sickle cell disease (SCD) have profound vitamin D (VD) deficiency. Limited data exist on the effect of VD deficiency on bone fragility in these patients.nnnOBJECTIVESnTo assess the prevalence of VD deficiency in adults with SCD and its consequences on bone metabolism and fragility.nnnMETHODSnThis prospective study included 56 SCD adult patients (mean age 29.8 ± 9.5 years), in a clinically steady state. Clinical and laboratory data were recorded. Bone mineral density (BMD) was measured using dual X-ray absorptiometry. Fracture history, BMD, avascular osteonecrosis, H-shaped vertebra and markers of mineral metabolism were compared between two groups of patients presenting very low (≤ 6 ng/mL, n=26) (group 1) and low (>6 ng/mL, n=26) (group 2) 25(OH)D concentration, respectively.nnnRESULTSnMedian 25(OH)D concentration was 6 ng/mL. VD deficiency (25(OH)D <10 ng/mL) was found in 42 out of 56 patients (75%) and secondary hyperparathyroidism in 40 (71.4%). History of fracture was documented in 17 patients (30.3%), osteopenia and/or osteoporosis in 39.6% of patients. Overall, patients of group 1 were more likely to have sustained a fracture (42.8%) compared to patients of group 2 (17.8%) (p=0.04). These patients had also lower body mass index and significantly higher parathyroid hormone, C-terminal telopeptides of type I-collagen and bone-specific alkaline phosphatase serum levels. There was no difference between group for BMD, avascular osteonecrosis history, H-shaped vertebra, and disease severity markers.nnnCONCLUSIONnThis study suggests that VD deficiency is a key feature in SCD-bone disease. It is highly prevalent and associated with hyperparathyroidism, bone resorption markers, and history of fracture. The optimal supplementation regimen remains to be determined.

Anti‐inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia

Permixon®, the hexanic lipidosterolic extract of saw palmetto Serenoa repens (LSESr), has shown properties that highlight its benefit in the management of benign prostate hyperplasia (BPH). To address its actual anti‐inflammatory potency, we used a unique pro‐inflammatory mouse model of prostate hyperplasia involving prostate‐specific over‐expression of prolactin transgene (Pb‐Prl).

Estimated or Measured GFR in Living Kidney Donors Work-up?

The value of estimated glomerular filtration rate (eGFR) in living kidney donors screening is unclear. A recently published web‐based application derived from large cohorts, but not living donors, calculates the probability of a measured GFR (mGFR) lower than a determined threshold. Our objectives were to validate the clinical utility of this tool in a cohort of living donors and to test two other strategies based on chronic kidney disease epidemiology collaboration (CKD‐EPI) and on MDRD‐eGFR. GFR was measured using 51Cr‐ ethylene‐diamine tetraacetic acid urinary clearance in 311 potential living kidney donors (178 women, mean age 50 ± 11.6 years). The web‐based tool was used to predict those with mGFR < 80 mL/min/1.73 m2. Inputs to the application were sex, age, ethnicity, and plasma creatinine. In our cohort, a web‐based probability of mGFR <90 mL/min/1.73 m2 higher than 2% had 100% sensitivity for detection of actual mGFR <80 mL/min/1.73 m2. The positive predictive value was 0.19. A CKD‐EPI‐eGFR threshold of 104 mL/min/1.73 m2 and an MDRD‐eGFR threshold of 100 mL/min/1.73 m2 had 100% sensitivity to detect donors with actual mGFR <80 mL/min/1.73 m2. We obtained similar results in an external cohort of 354 living donors. We confirm the usefulness of the web‐based application to identify potential donors who should benefit from GFR measurement.

Use of computed tomography assessed kidney length to predict split renal GFR in living kidney donors.

AbstractObjectivesScreening of living kidney donors may require scintigraphy to split glomerular filtration rate (GFR). To determine the usefulness of computed tomography (CT) to split GFR, we compared scintigraphy-split GFR to CT-split GFR. We evaluated CT-split GFR as a screening test to detect scintigraphy-split GFR lower than 40xa0mL/min/1.73xa0m2/kidney.MethodsThis was a monocentric retrospective study on 346 potential living donors who had GFR measurement, renal scintigraphy, and CT. We predicted GFR for each kidney by splitting GFR using the following formula: Volume-split GFR for a given kidneyu2009=u2009measured GFR*[volume of this kidney/(volume of this kidneyu2009+u2009volume of the opposite kidney)]. The same formula was used for length-split GFR. We compared length- and volume-split GFR to scintigraphy-split GFR at donation and with a 4-year follow-up.ResultsA better correlation was observed between length-split GFR and scintigraphy-split GFR (ru2009=u20090.92) than between volume-split GFR and scintigraphy-split GFR (ru2009=u20090.89). A length-split GFR threshold of 45xa0mL/min/1.73xa0m2/kidney had a sensitivity of 100xa0% and a specificity of 75xa0% to detect scintigraphy-split GFR less than 40xa0mL/min/1.73xa0m2/kidney. Both techniques with their respective thresholds detected living donors with similar eGFR evolution during follow-up.ConclusionLength-split GFR can be used to detect patients requiring scintigraphy.Key points• Excellent correlation between kidney length and scintigraphy predicted GFRn • Kidney length screening detects all donors with GFR lower than 40xa0mL/min/1.73xa0m2n • Kidney length screening can replace scintigraphy screening.

Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation

Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355-65. ©2016 AACR.