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The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed., Graphical abstract

Introduction: Cinacalcet (CNL) suppresses the secretion of parathyroid hormone (PTH). Objective: To consider the effect of CNL administration on achievement of K/DOQITM (Kidney Disease Outcomes Quality Initiative) targets in a group of hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). Patients and Methods: Patients undergoing HD who had initiated CNL enrolled in the study. Data were collected at the baseline and after 12 months. This data consisted of serum calcium (Ca), phosphorus (P), intact PTH (iPTH), proportion of calcium in dialysate, administered doses of CNL and proportion of administered phosphate binders and proportion of patients attaining K/DOQITM targets were gathered. Results: Twenty HD patients enrolled in the study. The proportions of individuals attaining K/DOQITM targets at month 12 were 35% for iPTH, 65% for P, 60% for Ca and 80% for Ca×P product, compared with 0%, 45%, 55% and 50% at the baseline respectively. Around 35% of individuals had attained the combined K/DOQITM targets for Ca, P and iPTH compared with 0% at the starting point. Conclusion: CNL ameliorates attainment of K/DOQITM targets in individuals with SHPT. This result is consistent with findings from other studies.

Aim. To examine the relationship between plasma 25-hydroxyvitamin D (25(OH)D) levels and blood hemoglobin A1c (HbA1c) levels in diabetic patients at various stages of chronic kidney disease (CKD).Methods. We screened for data collected between 2003 and 2012. The correlation between 25(OH)D and HbA1c levels was studied in patients categorized according to the severity of CKD and their vitamin D status. A multivariate linear regression model was used to determine whether 25(OH)D and HbA1c levels were independently associated after adjustment for a number of covariates (including erythrocyte metformin levels).Results. We identified 542 reports from 245 patients. The mean HbA1c value was6.7±1.0% in vitamin D sufficiency,7.3±1.5% in insufficiency, and8.4±2.0% in deficiency (P<0.0001). There was a negative correlation between 25(OH)D and HbA1c levels for the population as a whole (r=-0.387,P<0.0001) and in the CKD severity subgroups (r=-0.384,P<0.0001andr=-0.333,P<0.0001for CKD stages 1–3 and 4-5, resp.). In the multivariate analysis, the 25(OH)D level was the only factor associated with HbA1c (P<0.0001).Conclusion. 25(OH)D levels were negatively correlated with HbA1c levels independently of study covariates.

Hyperphosphatemia in chronic kidney disease (CKD) has been associated with elevated cardiovascular morbidity and mortality. Serum phosphate control remains a cornerstone of the clinical management of patients with CKD, in order to both attenuate the progression of secondary hyperparathyroidism or bone disease and (possibly) reduce the risk of vascular calcification. Despite technical improvements in dialysis and the use of dietary restrictions, drug therapy is often required to control phosphate levels in patients with end-stage renal disease (ESRD). Currently available medications for hyperphosphatemia in ESRD are very expensive and not always well tolerated. The discovery and development of new drugs in this indication is therefore a priority for both medical and health-economic reasons. Nicotinamide (an amide derivative of the water-soluble vitamin B3) is a potentially interesting alternative to phosphate binders. In vitro and in vivo data show that nicotinamide reduces hyperphosphatemia by inhibiting sodium-dependent phosphate co-transport in the renal proximal tubule and in the intestine. Accordingly, targeting the sodium-dependent phosphate co-transporter 2b by using nicotinamide as an alternative or adjunct to classical phosphate binders may be a therapeutic option for modulating serum phosphate in CKD. Several recent clinical studies have explored the potential value of nicotinamide in phosphate control (as well as its effects on lipid levels) in dialysis patients. However, we consider that more data on pharmacodynamics, pharmacokinetics and safety are needed before this compound can be recommended as a treatment for hyperphosphatemia in ESRD patients.

International audience; Background: Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. Methods: The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N-methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. Results: After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 +/- 0.4 to 1.8 +/- 0.5 and 2.3 +/- 0.5 to 1.7 +/- 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). Conclusions: Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.

Background and objectives: Cardiovascular disease is the main cause of mortality in chronic kidney disease (CKD) patients. Vitamin D might have beneficial effects on vascular health. The aim of this study was to determine the prevalence of vitamin D deficiency (25-hydroxyvitamin D [25D] ≤ 15 ng/ml) and insufficiency (25D levels between 16 and 30 ng/ml) in a cohort of patients at different CKD stages and the relationships between vitamin D serum levels, vascular calcification and stiffness, and the mortality risk. Design, setting, participants & measurements: One hundred forty CKD patients (85 men, mean age 67 ± 12 yr; CKD stages 2 [8%], 3 [26%], 4 [26%], 5 [7%], and 5D [(33%]) were allocated for a prospective study. Serum levels of 25D and 1,25-dihydroxyvitamin D, aortic calcification score, and pulse wave velocity (PWV) were evaluated. Results: There was a high prevalence of vitamin D deficiency (42%) and insufficiency (34%). Patients with 25D ≤ 16.7 ng/ml (median) had a significantly lower survival rate than patients with 25D >16.7 ng/ml (mean follow-up, 605 ± 217 d; range, 10 to 889; P = 0.05). Multivariate adjustments (included age, gender, diabetes, arterial pressure, CKD stage, phosphate, albumin, hemoglobin, aortic calcification score and PWV) confirmed 25D level as an independent predictor of all-cause mortality. Conclusions: Vitamin D deficiency and insufficiency were highly prevalent in this CKD cohort. Low 25D levels affected mortality independently of vascular calcification and stiffness, suggesting that 25D may influence survival in CKD patients via additional pathways that need to be further explored.

Resume Dans cette revue sur le traitement antihypertenseur optimal chez le patient nephrologique, nous partons de la controverse declenchee par la meta-analyse de Casas et al. pour elargir le debat et discuter une bitherapie optimale non seulement pour la nephroprotection, mais aussi pour la protection cardiovasculaire globale. La frequence de ces dernieres complications est en effet plus grande que celle de l'insuffisance renale terminale chez les malades atteints de nephropathie et leur prevention est autant prioritaire. Nous expliquons l'abondance d'articles contradictoires par les insuffisances methodologiques des etudes voulant prouver le bien-fonde de deux concepts antinomiques sous-jacents a la controverse : 1) « la correction par les antihypertenseurs du risque cardiovasculaire et renal accru des hypertendus est en rapport exclusivement avec la baisse des chiffres tensionnels qu'ils induisent, le seuil optimal de pression (defini par les epidemiologistes) etant de 115/75 mmHg » ; 2) « independamment du niveau de pression, certains antihypertenseurs ont des proprietes intrinseques, protectrices ou deleteres, vis-a-vis de la protection renale et cardiovasculaire, et cette protection peut etre variable suivant l'organe concerne ». Nous pensons que la verite est conciliante et qu'elle reside dans l'acception des deux mecanismes. Des etudes plus rigoureuses restent cependant a faire pour le demontrer. En attendant, nous proposons pour la protection globale cardiovasculaire et renale la bitherapie optimale par diuretiques hypokaliemiants + inhibiteurs du recepteur AT1 de l'angiotensine II, recepteur sense medier tous les effets vasculodeleteres de l'angiotensine II, qu'il s'agisse des inhibiteurs de l'enzyme de conversion (IEC) ou des bloqueurs de ce recepteur (les AT1RB ou sartans). Nous preferons cette bitherapie a celle associant les diuretiques hypokaliemiants + dihydropyridines. Cependant, cette recommandation n'est forte que pour les patients ayant une macroproteinurie. La priorite que nous donnons a la therapeutique diuretique tient au fait que par rapport aux autres classes, elle accorde une meilleure protection a la fois vis-a-vis de l'insuffisance cardiaque et des accidents vasculaires cerebraux. De plus, il s'agit des antihypertenseurs ayant la duree d'action la plus longue (plusieurs semaines). Leur efficacite chez l'insuffisant renal est proportionnelle a la depletion sodee initiale et donc a la dose. Or, le controle de la volemie est incontournable pour obtenir un controle tensionnel optimal chez les insuffisants renaux. Cette therapeutique diuretique sera basee sur les thiazidiques en l'absence d'insuffisance renale severe, mais sera completee par les diuretiques de l'anse (alors meme que ceux-ci, contrairement aux thiazides, n'ont jamais ete valides par une etude randomisee pour la protection cardiovasculaire dans l'hypertension non compliquee). Quant aux diuretiques d'epargne potassique, ils ne seront utilises que pour corriger une hypokaliemie. Quant a l'utilisation des betabloquants, bien qu'ils diminuent l'activation du recepteur AT1, ils ne sont plus recommandables comme antihypertenseurs de premiere intention, car ils sont les antihypertenseurs les plus diabetogenes. Ils gardent en revanche, leurs indications cardiologiques formelles telles que l'angor, l'insuffisance cardiaque et certains troubles du rythme, ou leur indication anesthesiologique de remplacement des IEC et AT1RB. Quant au choix entre IEC ou AT1RB, nous pensons, sur la base de comparaisons indirectes, que les derniers accorderont une cardioprotection comparable, tout en accordant une protection cerebrale superieure. Il faudra attendre 2008 pour le savoir avec les resultats de l'etude ONTARGET. Enfin, nous rappelons la necessite d'individualiser le traitement antihypertenseur, en tenant compte egalement des complications cardiovasculaires deja presentes, de la pathologie associee, de la tolerance (qui peut etre influencee par les saisons et en particulier les canicules) et du cout.

Treatment with erythropoietin and AT1 blockers is protective in experimental acute cerebral ischemia, with promising results in pilot clinical studies in human stroke. This paper examines the effects of using both agents as combination therapy in acute ischemic stroke.We used the single carotid ligation stroke model in the gerbil. Six groups of 50 gerbils were treated either with placebo, erythropoietin (intraperitoneally, 5000 IU/kg, 2 and 48 h after stroke), olmesartan (10 mg/kg per day in drinking water started 36 h after stroke), ramipril (2.5 mg/kg per day in drinking water started 36 h after stroke), erythropoietin + olmesartan, or erythropoietin + ramipril. Long-term (1 month) Kaplan-Meyer survival curves were obtained, and survivors were submitted at day 30 to immediate (object recognition test) and spatial (Morris water maze) memory function tests.Erythropoietin alone and olmesartan alone, but not ramipril, significantly increased survival at day 30 compared with untreated controls (38, 30 and 6% versus 12%, respectively). Combined treatment with erythropoietin and olmesartan further increased the survival rate to 56%, whereas combined therapy with erythropoietin and ramipril decreased 30-day survival to 24% (P0.0001, erythropoietin + olmesartan versus erythropoietin + ramipril). Untreated stroke survivors had markedly altered performances in both the object recognition test (P = 0.0007) and the Morris water maze (P0.0001) tests at day 30 compared with normal gerbils. In erythropoietin-treated animals, ramipril therapy had no beneficial effect whereas olmesartan fully restored normal response to the memory tests.Post-infarct treatment with olmesartan combined with early erythropoietin therapy has a protective effect on survival, and markedly improves long-term memory dysfunction in this experimental model.

Calcimimetics suppress the secretion of parathyroid hormone by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet (Sensipar/Mimpara), Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of secondary hyperparathyroidism in dialysis patients, is, in association with higher dose of a calcium-based oral phosphate binder, a well-tolerated and effective alternative to standard treatments such as vitamin D derivatives in association with a non-calcium-based oral phosphate binder. Here, we present an overview of evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics -- secondary hyperparathyroidism in predialysis chronic kidney disease patients, hypercalcemic hyperparathyroidism in renal transplant recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma -- as well as providing guidance on optimal usage of this drug.

Diuretics are pharmacological agents that increase natriuresis through inhibition of tubular re-absorption of sodium. The mechanisms and site of this inhibition differ with each drug class, accounting for their additive effects on natriuresis increase and their hydroelectrolytic side effects. The response to a given diuretic dose depends on the diuretic concentration on the urine at its action site. This concentration may be decreased by pharmacokinetic factors such as encountered in renal insufficiency or in nephrotic syndrome. These resistance mechanisms of diuretics may be corrected by dose increase, previous diuretic fixation on albumin or warfarin administration. Once these mechanisms are opposed, the diuretic concentration for maximal efficacy is reached at is action site and the natriuresis obtained as the normal maximal plateau. This is not the case when an oedematous systemic disease with effective hypovolemia is present, like in heart failure or cirrhosis, or when chronic use of loop diuretics has induced a hypertrophy of the more distant part of the tubule. In theses cases, a pharmacodynamic resistance exists, resulting in a lower maximal natriuresis plateau in spite of adequate concentration of the diuretic at its action site, even in the absence of pharmacokinetic resistance factors. The main indications of diuretics are systemic oedematous disease and hypertension. In the oedematous diseases, diuretics indication is both straightforward and sufficient only if effective hypervolemia is present. The therapeutic approach is discussed according to the various clinical conditions and pathophysiological background. In uncomplicated hypertension, diuretics are the cornerstone of the therapy. The most suitable diuretic treatment for hypertension is an association of low doses thiazide (12.5-50 mg/day) with potassium sparing diuretics. Rare indications of diuretics are also reviewed.

During the last 20 years, the renin-angiotensin system (RAS) has become an increasingly important focus of basic and clinical cardiovascular research. One main conceptual step forward was made with the discovery of a tissue RAS and the understanging of its critical pathophysiological role in atherogenesis and plaque destabilisation [1]. Major effort to find new strategies for blocking the RAS has produced new classes of drugs which were expected to be clinically important in the management of hypertension and heart failure. As landmark clinical studies have demonstrated that inhibition of the RAS significantly reduces morbidity and mortality from coronary heart disease, myocardial infarction and heart failure, the concept has rapidly emerged that blocking the RAS was the strategy of choice for preventing cardiovascular diseases [2]. More recently, basic research has however continuously extended our understanding of the complexity of the systemic and tissue RASs, that can no longer be viewed as one-way streets in which one single effector, angiotensin II acts solely through its major (AT1) receptor. Meanwhile, clinical trials have challenged the concept that blocking the RAS is the most effective preventive strategy for all patients and all target organs [3]. Consistent with the recent understanding that the RAS encompasses a number of distinct effectors acting through different receptors to promote opposite effects, a growing body of basic and clinical evidence suggests that blunting the RAS is a double-edge sword, with beneficial effects counterbalanced by deleterious ones, resulting in a net effect that critically depends on the experimental conditions, or the clinical characteristics of the study population. Of particular clinical relevance, a number of clinical trials point to the somewhat provocative conclusion that beyond their blood pressure lowering effect antihypertensive drugs that decrease angiotensin II formation are less stroke protective than the ones that increase angiotensin levels [4]. This review focuses on the recent experimental evidence demonstrating that angiotensin II and its derivatives acting through the non-AT1 receptors are involved in protective mechanisms against cerebral ischaemia and discusses in the light of the recent large cardiovascular prevention trials the clinical relevance of this new concept. The perspective of a renewal of therapeutical strategies to optimise the prevention of target organ damage and perhaps even some of the diseases of ageing, such as loss of cognitive function is emphasised.

As suggested by its American brand name (Sensipar), the calcimimetic cinacalcet sensitizes the parathyroid cells to the extracellular calcium signal, suppressing parathyroid hormone (PTH) release and synthesis and preventing parathyroid cell proliferation. This primary PTH suppression decreases the release of calcium and phosphate from bone without increasing intestinal absorption of calcium and phosphate. Therefore cinacalcet decreases the risk of hypercalcemia and hyperphosphatemia in contrast to 1alpha-OH vitamin D derivatives. Compared with calcium-containing oral phosphate binder (OPB), it increases the risk of hypocalcemia and may decrease the PTH-mediated phosphaturia in predialysis patients. This justifies its combined use with calcium-containing OPB in order to prevent hypocalcemia and enhance the hypophosphatemic effect of the latter, while improving PTH suppression. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) has recommended restriction of supplemental elemental calcium to 1.5 g/day, a recommendation that we believe should be revised. No pathophysiologic or randomized trial data have yet evidenced the absolute necessity for systematically using 1alpha-OH vitamin D derivatives and noncalcium-containing OPB rather than higher doses of calcium-containing OPB alone in uremic patients without vitamin D insufficiency. In patients with hyperparathyroidism as severe as in the "Treat to Goal Study," the Durham study showed that a calcium carbonate dose more than three times the K/DOQI limit could decrease PTH into the recommended range, with the advantage of a lower calcium-phosphate product compared with the combination of calcitriol and noncalcium OPB. Besides the efficient PTH suppression associated with lower calcium-phosphate product and a good gastrointestinal tolerance, long-term data suggest that cinacalcet may decrease the risk of parathyroidectomy and fracture, while high bone turnover lesions are improved. However, no long-term data on bone mineral density and cardiovascular calcification and complications are yet available. Such studies, along with those comparing cinacalcet and 1alpha-OH vitamin D-based approaches to hyperparathyroidism, are needed.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P

Based on the Medical Research Council study, Brown and Brown hypothesized in 1986 that angiotensin II could protect against strokes by causing vasoconstriction of the proximal cerebral arteries, thereby preventing Charcot-Bouchard aneurysms from rupturing. In light of this hypothesis, we evaluated the cerebroprotective effects of various drug classes in recent double-blinded, prospective, randomized trials, such as SHEP, PATS, CAPPP, HOPE, PROGRESS, INSIGHT, NORDIL, LIFE, SCOPE, ANBP2, and ALLHAT. Drugs that activate the AT2 receptors, such as diuretics, calcium antagonists, and angiotensin receptor blockers (ARBs), were consistently more beneficial for stroke reduction than drugs devoid of such activation, such as beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, despite an equal fall in arterial pressure (at least in patients with a low incidence of cardiac complications). These clinical and epidemiologic observations are supported by experimental data documenting greater cerebroprotection with ARBs (which increase angiotensin II levels and stimulate the AT2 receptors) than with ACE inhibitors. Stroke is the most devastating consequence of hypertensive cardiovascular disease, and our hypothesis of cerebroprotection by AT2 receptor activation should be tested by a head-to-head comparison of an ARB with an ACE inhibitor.

Experimentally, leptin has a positive effect on bone mass when infused intravenously, but a negative one after intracerebroventricular administration. Renal failure increases its serum level above the concentration beyond which its transport to the brain may be saturated. Thus, we tested, in a chronic haemodialysis population, the hypothesis of a positive relationship between serum leptin and bone mineral density (BMD) when serum levels are above this threshold.Serum leptin (using a two-site RIA), and BMD at the femoral neck, midshaft, and ultradistal radius, as measured by DEXA, were assessed in 17 female and 16 male chronic dialysis patients, with comparable calcium and phosphate metabolism, age and dialysis duration.Polynomial regression analysis showed a U-shaped correlation between BMD Z-score, with an inflexion point, which may correspond to the concentration threshold at which leptin blood-brain carrier is saturated. Linear regression analysis showed no correlation between BMD and serum leptin levels below these points but a significant positive correlation between BMD at the two radius sites and leptin levels above these points. The correlation remained significant after adjustment for BMI, serum PTH and duration of dialysis. Leptin levels were twice as high in female patients and associated with higher BMD Z-scores close to zero.This study suggests a bone-sparing effect of serum leptin in haemodialysis patients only when the serum levels of leptin were higher than the presumed threshold of blood-brain transport saturation. Higher leptin levels in post-menopausal female haemodialysis patients than in male patients may account for their slower bone loss with ageing.

Background. Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO3 alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)3 in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO3 alone vs sevelamer in conjunction with measures to increase calcium balance. Methods. Forty-two patients were randomized: 21 continued their treatment with 4.8 guday CaCO3 and 21 were switched to sevelamer (initial dose: 2.4 guday, increased to 4.4 guday). Each month, when serumcorrected calcium decreased below 2.30 mmolul, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO4 levels. The following parameters were monitored: serum Ca, PO4, bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. Results. Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. Conclusions. Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO3. The transient decrease of serum bicarbonate after discontinuation of CaCO3 in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.

On the basis on a novel metformin assay, Frid et al. published clinical recommendations on use of the drug in patients with type 2 diabetes and varying severity of chronic kidney disease (CKD). The researchers stated that a threshold of 20 μmol/L (2.8 mg/L) was a ‘preliminary upper therapeutic limit’ [1]. However, the latter work can be questioned for several reasons: (i) the patients with an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 were not given the full therapeutic dose (median: 1500 mg/day); (ii) 22% of the patient population had an eGFR

The renin-angiotensin system (RAS) is involved in a complex mechanism that serves to preserve the blood supply to organs so that they can maintain cellular function. Angiotensin II exerts this effect, independently of the blood pressure generated, through two time-related events: a fast opening of the reserve collateral circulation and a much slower response of new vessel formation or angiogenesis. This effect is observed in rats with ligation of the abdominal aorta and in gerbils with abrupt or progressive unilateral carotid artery ligation. Inhibition of the angiotensin-converting enzyme (ACE) or the angiotensin II receptor represses this effect, and it appears that it is mediated through a non-AT1 receptor site of angiotensin II. Many tumors, both benign and malignant, express renin and angiotensin. It seems that the stimulating action of angiotensin II on angiogenesis could also be involved in preserving the blood supply to tumor cells. Administration of converting enzyme inhibitors increases survival and decreases tumor size in tumor-bearing rats. These observations support the hypothesis that the RAS, directly or indirectly, is involved in situations in which the restoration of blood supply is critical for the viability of cells and that it is present not only in normal but also in pathological conditions such as tumors. In view of the ubiquitous presence of renins and angiotensins, it is also likely to be involved in other conditions, such as inflammation, arthritis, diabetic retinopathy, and retrolental fibroplasia, among others in which angiogenesis is prominent. In addition, angiotensin II could be involved, through the counterbalance of the AT1 and AT2 receptors, in the rarefaction of blood vessels as an etiologic component of essential hypertension.

Background. Uraemic bone disease is the result of a number of factors modulating bone formation and resorption in a complex manner. In the present study, the hypothesis tested was that the type of haemodialysis membrane used for renal replacement therapy might also play a role. Methods. We conducted a prospective, open study in 24 chronic haemodialysis patients who were randomized to dialysis treatment with either cellulosic (CELL group, n = 11) or polyacrylonitrile (AN-69 group, n = 13) membrane for 9 months. Repeated determinations of plasma parameters reflecting bone turnover were done in all patients, and a bone biopsy in a subgroup at the start and end of study. Results. At the start, mean plasma intact parathyroid hormone levels were comparable between the two groups and they did not vary significantly at 9 months of treatment. Similarly, plasma bone-specific alkaline phosphatase and osteocalcin (markers of bone formation), and cross-laps (marker of bone resorption) remained unchanged. However, plasma insulin-like growth factor-I (IGF-I) progressively decreased from 169 to 119 ng ml in AN-69 group (P < 0.01), whereas it remained unchanged in CELL group. In addition, the levels of IGF binding protein (IGFBP)-1 and IGFBP-2 were increased while the levels of IGFBP-5 were decreased in AN-69 group. In the five patients of each group who had repeat bone biopsies, histomorphometric analysis showed a decrease in osteoblast surface, osteoclast surface and osteoclast number in AN-69 group at 9 months, compared with baseline values measured at the start of the study. In contrast, all three parameters significantly increased in the CELL group at 9 months (P < 0.001 for the difference between each of the three parameters).Bone formation rate decreased by 31% in the AN-69 group, but increased by 50% in CELL group. However, this latter difference was not statistically significant. Plasma interleukin (IL)-6 and soluble IL-6 receptor levels did not change in the two groups of patients who had undergone bone biopsy. Conclusion. Dialysis with CELL membrane was associated with increased bone turnover whereas the use of AN-69 membrane was associated with decreased bone turnover, suggesting a beneficial effect of the latter on high-turnover uraemic bone disease. However, as the number of patients with repeat bone biopsies was small, these findings need to be confirmed in a larger study. Further studies are also needed to evaluate whether or not the changes in IGF system components play a role in decreased bone cell activity in patients on dialysis using the AN-69 polyacrylonitrile membrane.

Previous studies have shown that angiotensin II (Ang II), by mediating rapid recruitment of collateral circulation, has a protective effect in the setting of acute ischaemia. In an experimental model of acute cerebral ischaemia in the gerbil, Fernandez et al. have reported that the mechanism of the protective effect of Ang II is blood pressure (BP)-independent,1 and that the AT 1-receptor antagonist, losartan, but not the ACE inhibitor (ACE-I), enalapril, decreases mortality following unilateral carotid artery ligation. 2 The aim of this study was to examine the reproducibility of the respective effects of losartan and enalapril, and to verify that these differential effects are drug class-related. Acute cerebral ischaemia was induced in anaesthetised gerbils by unilateral carotid ligation. The effect of pretreatment with two different ACE-I (enalapril and lisinopril), and two different AT 1-receptor antagonists (losartan and candesartan), administered orally or intravenously, on mortality were compared. Kaplan-Meier survival curves at day three were analysed by a log-rank test. Pretreatment with both enalapril and lisinopril significantly decreased survival at day three compared with controls, while the AT1-receptor antagonists losartan and candesartan, despite similarly lowering BP, did not increase mortality. Coadministration of losartan and enalapril increased mortality to the same extent as enalapril alone. This study confirms that Ang II contributes to protective mechanisms against acute cerebral ischaemia through non AT1-receptor-mediated, BP-independent effects.

Contradictions exist in the literature regarding the effect of gastric secretion inhibition on phosphate absorption. In healthy controls, omeprazole would decrease the hyperphosphatemia or the hyperphosphaturia induced by an acute phosphate load, suggesting an inhibition of phosphate absorption. In chronic hemodialysis patients, gastric hypersecretion is associated with hyperphosphatemia, but inhibition of gastric hypersecretion by ranitidine in those receiving calcium carbonate (CaCO3) as a phosphate binder would paradoxically exacerbate their hyperphosphatemia. Because of these conflicting observations, we performed an open crossover study on 16 chronic stable hemodialyzed patients with a daily mean intake of 9.4+/-4 g of CaCO3, and we compared the plasmatic predialysis levels of phosphate, calcium, protides, bicarbonates, intact parathyroid hormone (PTH), urea, and creatininemia during 2 successive periods of 2 months, the first one without omeprazole and the second one with 20 mg omeprazole intake in the morning. Phosphatemia increased with omeprazole but not significantly from 1.80+/-0.38 to 1.89+/-0.42 mM whereas corrected calcemia decreased significantly (p = 0.04) from 2.41+/-0.18 to 2.36+/-0.16 mM as did bicarbonatemia from 26.7+/-3.5 to 25.7+/-3.1 mM (p < 0.05). No change in creatininemia or in blood urea was observed, suggesting the stable efficiency of dialysis as well as the stable intakes of protein and therefore of phosphate during the two study periods. In conclusion, inhibition of gastric secretion by omeprazole increases the plasmatic phosphate predialytic level but in a nonsignificant way. This increase may be explained by a slight but significant concomitant decrease of calcemia and bicarbonatemia. These results do not support the phosphate binding efficiency of CaCO3 being decreased by the inhibition of gastric acid secretion.

Percutaneous recanalization of occlusion of central and proximal veins in chronic hemodialysis. Occlusion of the central and proximal veins in chronic hemodialysis patients results in considerable edema of the arm of the vascular access that is unable to drain normally. This is a formidable problem because it is very often necessary to close the vascular access, which is sometimes the last available one. To avoid resorting to this disastrous solution, recanalization of the occluded vein by percutaneous recanalization followed by endoluminal angioplasty was successfully performed in five patients (4 innominate veins and one axillary vein). Immediate failure occurred in a sixth patient, and delayed failure after two months of patency (innominate vein) in another patient for whom there had been no systematic stent placement. Recanalization was still patent in four other patients at 3, 6, 12 and 26 months. These results are an encouragement to attempt percutaneous recanalization by angioplasty of occluded central veins because, when successful, this technique makes it possible to preserve the vascular access and to avoid onerous surgery. We believe that this technique should therefore become better known.

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This work proposes an improvement of the cascade filtration technique in the treatment of familial hypercholesterolemia. A model of the whole process permitted the definition of the parameters that could influence the selectivity of the fractionation: the pore size, the sieving coefficients of both fractionation and plasmapheresis membrane, and the final retentate flow rate. In vivo studies have shown that the dead–end mode for the secondary filter was not always practical because of severe membrane plugging except when a pulsatile pump was included in the extracorporeal circuit. This pump generated hydrodynamic instabilities which decreased membrane fouling and retarded the build up of the polarization concentration layer. Optimization of these specific operating conditions permitted increase in the selectivity index from 1. 15 to 2. 24. The performances of cascade filtration were then comparable to those of adsorption on dextran sulfate columns.

OBJECTIVE To investigate the role of metformin accumulation in the pathophysiology of metformin-associated lactic acidosis. RESEARCH DESIGN AND METHODS We used high-performance liquid chromatography to measure plasma metformin concentrations in 14 patients who experienced lactic acidosis (pH 5 mmol/l) while receiving chronic metformin treatment. Their treatment was generally based on alkalinization and dialysis therapy. RESULTS Clinical shock and/or evidence of tissue hypoxia was found in all patients with the exception of one who had a nonsteroidal anti-inflammatory drug-induced anuria. Ten patients had significant metformin accumulation (plasma metformin concentrations 4.1-84.9 mg/l, normal value 0.6 ± 0.5 mg/l before drug intake), generally because of failure to withdraw metformin despite intercurrent pathological conditions affecting its renal elimination (serum creatinine concentrations ranging from 269 to 1,091 μmol/l). There was no metformin accumulation (plasma metformin 0.03–0.7 mg/l) in the four other patients, who had less severe renal failure (serum creatinine 140–349 mumol/l). The severity of the patient's general condition did not predict early hospital mortality (death before discharge from the intensive care unit) even in patients in shock. Whereas it was high in those without metformin accumulation (only 1 of 4 patients recovered), early hospital mortality was low in the 10 patients with metformin accumulation and was not related to its extent (3 patients died with end-stage hepatic failure or cardiac failure). Correlation studies showed a positive correlation between serum creatinine and plasma metformin and between plasma metformin and arterial lactate but, for the latter correlation, only in patients with metformin accumulation. CONCLUSION Metformin-associated lactic acidosis is not necessarily due to metformin accumulation; true type B (aerobic) lactic acidosis, i.e., without an apparent associated hypoxic factor, seems exceptional. Neither the severity of the clinical picture nor the degree of metformin accumulation predicted survival; rather, the prognosis was dependent upon the severity of the associated pathological conditions.

Adynamic (or aplastic) bone disease is a bone histologic pattern characterized by decreased bone formation rate, low cellularity, and normal or decreased osteoid thickness. It was first described in symptomatic patients undergoing dialysis who were overloaded with aluminum because of contaminated dialysate or chronic ingestion of aluminic phosphate binders; the evidence of the overload was extensive coloration (more than 25%) with aurin tricarboxylic acid, whereas the Perls stain coloration for iron was negative. We have, however, reported these histologic changes in asymptomatic patients with uremia who were never exposed to aluminum, in two patients before end-stage renal failure and in six patients undergoing dialysis. The main step in the prevention of adynamic bone disease is the absolute exclusion of aluminum exposition even by so-called "safe doses" of aluminum phosphate binders because in the long term they are never actually safe. Because idiopathic adynamic bone disease may nevertheless occur, parathyroid hormone suppressive treatment by oral calcium taken with meals as phosphate binders (+/- 1 alpha-hydroxyvitamin D3 derivatives) should be carefully monitored by measurements of plasma concentrations of not only calcium and phosphate but also of intact parathyroid hormone levels. In order to have normal bone formation rate levels, patient intact parathyroid hormone levels should be between one and three times the upper limit of the normal level. Although adynamic bone disease may not be a true bone disease when not due to aluminum, it is a risk factor for increased incidence of hypercalcemia and hyperphosphatemia and therefore for metastatic calcifications. Therefore, when hypercalcemia occurs with hyperphosphatemia and normal intact parathyroid hormone in patients treated with 1 alpha-hydroxyvitamin D3, it is proposed that the latter drug should be discontinued first, whereas oral calcium is increased to correct hyperphosphatemia, and calcium concentration is decreased in the dialysate to prevent hypercalcemia, even though plasma parathyroid hormone may increase up to three times the upper limit of the normal level. In patients previously exposed to aluminum, a deferoxamine test should be performed and a deferoxamine treatment started if the test is positive.

The aim of the study was to evaluate the role of hypertension in patients hospitalized for serious spontaneous epistaxis. This 6-year retrospective study was based on 219 patients hospitalized in a University Hospital ENT and Head and Neck surgery department for serious spontaneous epistaxis. The following parameters were recorded: length of hospital stay, history of hypertension, blood pressure (BP) recordings (on admission, during hospitalization and on discharge), epistaxis severity criteria, including medical and/or surgical management of epistaxis (blood transfusion depending on blood count, embolization, surgery), medications affecting clotting. Epistaxis was classified into two groups: serious and severe. No significant differences were observed between the two groups in terms of age, sex ratio, history of epistaxis and BP characteristics including history of hypertension, mean BP on admission, mean arterial pressure on discharge and number of patients in whom BP was difficult to control. Patients with more severe epistaxis had a similar exposure to anticoagulant and platelet antiaggregant medications as patients with less severe epistaxis. Overall, on univariate logistic regression analysis, no factors were independently associated with severity of epistaxis. The pathophysiology of serious spontaneous epistaxis remains to be unclear. It concerns elderly patients (>60–70 years old) with a history of hypertension in about 50% of cases. Serious spontaneous epistaxis may also be the presenting sign of underlying true hypertension in about 43% of patients with no history of hypertension. However, hypertension per se does not appear to be a statistically significant causal factor and/or a factor of severity of serious spontaneous epistaxis.

curriculum developed by the author that combines memory exercises and games invented by American and Japanese scholars. Methods: This study evaluates a pilot program of a 10-week memory training program conducted among an elderly population in the community. A total of 30 older adults in two separate groups participated in the program. The study examined many aspects of the elderly before and after they participated in the program, including memory function, social support, quality of life, life satisfaction, and motivation for learning. In addition, observational notes were used to examine changes among the elderly in attitudes and behaviors during the period of the memory training program. Results: The results indicated that the elderly (aged 65 to 78) who had participated in the study had a significant improvement in their learning attitudes, life satisfaction, continual practice using the memory training techniques, and increased attention to memory in their daily lives. In addition, a slight improvement in quality of life and better social support relationships were reported. Conclusions: Although the intervention may be simple in design and has not been tested in conjunction with medical examinations, those who participated in the program indicated stronger wills to be more active in maintaining their memory functions and in continually practicing the memory exercises. The memory training program also can be widely disseminated in the community as a preventive approach to help the elderly population maintain their memory and general well-being.

Ketodiet, physiological calcium intake and native vitamin D improve renal osteodystrophy. The effects of a very low-protein diet (VLPD) supplemented with amino acids and ketoanalogues (KA) and with 1g of calcium carbonate and 1000IU of vitamin D2, were studied in 17 patients with advanced renal failure (GFR ≤ 20ml/min) over a period of one year. The protein intake was 0.3g protein/kg body wt/day. Daily phosphorus and calcium intake were respectively 1,500mg and 300mg. Sequential bone densitometry was performed and bone histomorphometry after double tetracyclin labeling was evaluated, before and after one year of diet. Calcium and phosphate metabolism parameters were monitored every two months. In spite of a significant decrease of GFR, phosphorus, parathyroid hormone (1-84) and osteocalcin plasma levels decreased significantly, while low plasma bicarbonate normalized, and calcitriol and calcium levels remained respectively low and normal. Before the diet, histological study disclosed four cases of mixed osteopathy: osteomalacia associated with osteitis fibrosa (OM/OF), nine pure osteitis fibrosa (OF) and four with normal bone remodeling (NB). After one year of diet, the OM component of OM/OF disappeared, as evidenced by a normalization of the mineral apposition rate and osteoid thickness. In the patients presenting pure OF, a significant decrease in osteoblastic and osteoclastic surfaces, in the number of osteoclasts, and in the bone formation rate (BFR) were found. Vertebral mineral density measured by quantitative computerized tomodensitometry did not change significantly. In conclusion, this study not only confirms the benefical effects of VLPD + KA + calcium on uremic hyperparathyroid bone disease in advanced renal failure assessed using static bone histomorphometry, but also shows a correction of histodynamic bone parameters. These results were achieved without pharmacological doses of vitamin D. Furthermore it suggests that: (1) the suppression of hyperparathyroidism appears largely due to the decrease in plasma phosphate, the correction of acidosis and the increase in 25 OH vitamin D plasma levels, independently of significant permanent changes in plasma concentrations of calcium and calcitriol; and (2) this diet also corrects the osteomalacic component, in spite of the absence of a significant increase in plasma concentration of calcium and calcitriol, probably because of the correction of metabolic acidosis, since the increases in mineral apposition rate and in plasma bicarbonate levels were correlated.

The purpose of this study is to evaluate the place of intravenous 1α-hydroxyvitamin D3 (1α-OH-D3) in the prevention of radiologically obvious hyperparathyroidism (HPT) in patient

International audience; First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia. Third, we review most of the large primary and secondary stroke prevention trials as well as the ACCESS acute stroke trial in which antihypertensive drugs were evaluated. With the exception of the secondary stroke prevention trial PRoFESS, most trials support the hypothesis that angiotensin II-increasing drugs confer specific blood pressure-independent brain ischemia protection when compared with angiotensin II-decreasing drugs or placebo. A careful analysis of the PRoFESS trial, however, reveals study design limitations, the main one being that diastolic BP (

International audience; Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer's disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. beta-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating beta-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Abeta(42) into less toxic Abeta(40). Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Abeta(42) brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on beta-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.

In normal pregnancy, cross-sectional clinical data do not consistently show plasma ANF concentration differences between early pregnancy and the nonpregnant state. Sequential data in the baboon (but not in rat) show a significant decrease in plasma ANF concentration and in cardiac filling pressures in early pregnancy. The latter data support the view that pregnancy is an underfill state secondary to a primary vasodilatation. Cross-sectional and longitudinal studies in normal pregnancy in humans show that plasma ANF levels tend rise to values that are, in the third trimester, higher than in the nonpregnant state. However, late postpartum sequential data (1.5–3 months) in humans do now show a significant drop in plasma ANF concentrations, suggesting that plasma ANF is not actually increased in normal pregnancy. In the baboon (but not in the rat) there is a steady rise in plasma ANF levels to values that are significantly higher in third trimester than before pregnancy. These data suggest that in human pregnancy, in contrast with the baboon, the plasma volume expansion induced by normal pregnancy is not sensed as such by the atria probably because of an isopressive adaptation of plasma volume to an enlarged vascular bed. However, acute decrease or increase of venous return induced by low sodium diet, changing position or infusion of isotonic saline are sensed as such by the atria in normal pregnancy as in the nonpregnant state. In humans and rats, a steady rise in plasma ANF concentration is observed during the first few days after delivery suggesting that at this time the atria sense an effective hypervolemia; the latter occurring through a decrease in the functional size of the intravascular compartment owing to the elimination of the placenta as well as by the autotransfusion carried out by the emptied uterus. The resulting increase in central venous pressure may stimulate ANF release that, together with a decrease in renin and aldosterone secretion, may thus contribute to the diuretic crisis observed after delivery. In pregnancy-induced hypertension, plasma ANF levels are usually increased but may remain normal in mild hypertension. In preeclampsia, plasma ANF concentration is more consistently increased, specially in the severe form. Plasma ANF decreases to normal levels after delivery when hypertension has disappeared. Plasma ANF concentration is directly correlated to blood pressure. A deficiency in ANF secretion can not, therefore, be the primary cause of pregnancy-induced hypertension or preeclampsia. On the contrary, ANF may play a compensatory role preventing further increase of blood pressure. However, because of the suppressive effect of ANF on renin and aldosterone secretion and by promoting a shift of the plasma fluid into the interstitial space, ANF elevation in preeclampsia may actually contribute to worsen the hypovolemia and explain the paradoxical association of hypovolemia with the hypostimulation of the renin–aldosterone system. The mechanism underlying the increased ANF secretion in preeclampsia is not clear since cardiac filling pressures in untreated preeclampsia are decreased and hence increased ANF release through atrial stretch seems unlikely. It is possible that neuroendocrine mechanisms yet to be identified are responsible for this observation.Key words: atrial natriuretic factor, pregnancy, preeclampsia, pregnancy-induced hypertension.

Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers. To elucidate the pathophysiology of dietary calcium independent hypercalciuria, 42 calcium stone formers (Ca SF) were selected because they had on free diet a calciuria greater than 0.1 mmol/kg/day. For four days they were put on a diet restricted in calcium (Ca RD) by exclusion of the dairy products. They collected 24 hour urines on free diet and on day 4 of Ca RD as well as the two-hour fasting urines on the morning of the day 5 and the four-hour urines passed after an oral calcium load of 1 g, for measurement of creatinine, Ca, PO 4 , urea and total hydroxyprolinuria (THP). On day 5 fasting plasma concentrations of Ca, PO 4 , intact PTH, Gla protein, calcidiol and calcitriol were measured. The patients were firstly classified into dietary hypercalciuria (DH, 18 patients) and dietary calcium-independent hypercalciuria (IH, 24 patients) on the basis of the disappearance or not of hypercalciuria on Ca RD. Then the patients with IH were subclassified into absorptive hypercalciuria (AH) because of normal fasting calciuria (8 patients) and into fasting hypercalciuria (16 patients). Fasting hypercalciuric patients were subsequently divided according to the PTH levels into renal hypercalciuria (RH, 1 patient) with elevated fasting PTH becoming normal after the Ca load and undetermined hypercalciuria (UH, 15 patients) with normal PTH levels. Furthermore, their vertebral mineral density (VMD) was measured by quantitative computerized tomography which was normal in DH (91 ± 6% of the normal mean for age and sex) but was decreased in IH to 69 ± 4%. No difference in VMD was observed between AH and UH. Urinary excretions of urea, phosphate and THP was higher in IH than in DH and comparable in AH and UH. Sodium excretion Ca RD was the same in all groups and subgroups as well as the plasma parameters. Plasma calcitriol was increased in IH and DH comparatively to normal in spite of normal plasma calcidiol. Calciuria increase after oral calcium load, an index of Ca absorption, was higher in IH than in controls and comparable in IH and DH as well as in the three subgroups of IH. From these data and correlation studies in IH it is concluded: (1.) VMD is decreased in Ca stone formers with IH but not in those with DH, making the distinction of these two groups of hypercalciuria patients clinically relevant. (2.) The further distinction within IH of AH, RH and UH is not very justified, since RH is exceptional and VMD and other biochemical parameters (with the exception of those taken for subclassification) are not different between AH and UH. (3.) Since in IH, fasting hydroxyprolinuria and fasting calciuria were greater than in control, whereas plasma PTH concentrations were low to normal (with the exception of the case with RH), and fasting calciuria was correlated to fasting hydroxyprolinuria, it is suggested that a primary bone hyperresorption, and not a primary renal leak of calcium or a primary intestinal hyperabsorption, is the main cause of IH. (4.) IH is associated with higher urea excretion on free and Ca R diets than in controls, suggesting a higher protein intake of no dairy origin. This higher intake may favor bone resorption since fasting calciuria and hydroxyprolinuria are correlated to urea excretion. (5.) In IH, the positive correlations of calcitriol with VMD and calciuria increase after Ca oral load, and the negative one between calcitriol and fasting calciuria, suggest that calcitriol attenuates bone resorption by increasing calcium absorption. (6.) In IH, plasma calcitriol is correlated positively to calcidiol and negatively to plasma phosphate which remains in the normal range. Therefore, increased plasma calcitriol in IH may be explained by a hypersensitivity of 25 (OH) vitamin D 1α hydroxylase to PPO 4 , making its synthesis dependent upon 25 (OH) D. (7.) Exclusion of dairy products might be deleterious for the skeleton in Ca stone formers. Restriction of protein intake of non-dairy origin should rather be advised.