Albert Fournier

Role of Metformin Accumulation in Metformin-Associated Lactic Acidosis

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 <7.35 and lactate concentration >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 patients 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.

Fenofibrate Increases Creatininemia by Increasing Metabolic Production of Creatinine

Fenofibrate is a potent hypolipemic agent, widely used in patients with renal insufficiency in whom dyslipidemia is frequent. A moderate reversible increase in creatinine plasma levels is an established side effect of fenofibrate therapy, which mechanism remains unknown. We have previously reported that in 13 patients with normal renal function or moderate renal insufficiency, two weeks of fenofibrate therapy increased creatininemia without any changes in renal plasma flow and glomerular filtration rate [1]. In 13 additional patients, muscular enzymes (AST, GPT, CPK, LDH) and myoglobin were measured before and after 2 weeks on fenofibrate, and the values of creatininemia obtained by the Jaffé technique and HPLC were compared. CPK and AST activity and plasma myoglobin increased in 2 patients with fenofibrate, but muscular enzymes remained unchanged in the population as a whole, and were not correlated to the changes in creatininemia. The changes in creatininemia induced by fenofibrate measured by the Jaffé technique were strongly correlated to those measured by HPLC (r2 = 0.675, p = 0.0006). Analysis of the pooled data of the two arms of the study showed in 26 patients that two weeks of fenofibrate therapy efficiently reduced total cholesterol and triglycerides plasma levels, and raised creatininemia from 139 ± 8 to 160 ± 10 µmol/l (p < 0.0001), but confirmed that creatininuria also increased to the extent that creatinine clearance remained unchanged (68 ± 6 vs. 67 ± 6 ml/min, n.s.). It is concluded that the increase in creatininemia induced by fenofibrate in renal patients does not reflect an impairment of renal function, nor an alteration of tubular creatinine secretion, and is not falsely increased by a dosage interference. Fenofibrate-induced increase of daily creatinine production is neither readily explained by accelerated muscular cell lysis. It is proposed that fenofibrate increases the metabolic production rate of creatinine.

Vitamin D Affects Survival Independently of Vascular Calcification in Chronic Kidney Disease

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] <or= 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 <or= 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.

Protection against ischemia: a physiological function of the renin-angiotensin system.

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.

Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil.

Objectives 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. Methods 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. Results 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% (P < 0.0001, 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 (P < 0.0001) 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. Conclusion 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.

Non-AT1-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil

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.

Invasive versus non-invasive diagnosis of renal bone disease.

&NA; At present, bone histomorphometry remains the gold standard for the diagnosis of the various types of renal bone disease. In the search for a non‐invasive method of diagnosis, biochemical serum markers of bone remodelling, in addition to serum intact parathyroid hormone and aluminium determinations, have been proposed as the most reliable tools and are at present widely used in clinical practice. Their respective diagnostic values, as separate items and in combined analysis, are thoroughly discussed in the present review.

Viewpoint: How Do Calcimimetics Fit Into the Management of Parathyroid Hormone, Calcium, and Phosphate Disturbances in Dialysis Patients?

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 1α‐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 1α‐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 1α‐OH vitamin D‐based approaches to hyperparathyroidism, are needed.

PATHOPHYSIOLOGY AND TREATMENT OF IDIOPATHIC HYPERCALCIURIA

Nearly 50 years after its initial description by Dr. F. Albright, the term idiopathic hypercalciuria (IH) is still in use. The exact mechanism of hypercalciuria is still unknown despite extensive pathophysiologic investigations; recent advances represent the focus of this review. A precise definition of true IH is proposed, taking into account the various nutritional conditions influencing calcium excretion. The potential pathogenic mechanisms are discussed, and the limits of the classical Paks pathophysiological classification are recalled. The evidence supporting the role of an increased intestinal calcium absorption, a defect in renal tubular calcium reabsorption, or an increased bone loss as a primary mechanism in IH are successively examined. Since overall available human data indicates that all three mechanisms may be found in IH, the hypothesis that a broader disorder encompassing all these various abnormalities may be involved in IH is discussed. Three global hypotheses to account for IH physiopathology are examined: a diffuse defect in fatty acid content of cell membranes, an increased expression of the vitamin D receptor of the 25(OH) vitamin D 1 alpha-hydroxylase, or of the calcium sensor receptor and a monocyte disease. Finally, the available clinical data justifying the therapeutic approaches are reviewed, and guidelines for dietary recommendations regarding calcium and also animal protein, sodium chloride, alcohol, carbohydrate, phosphate, and potassium intakes are proposed, and drug therapy indications are discussed.

OASIS-HT: design of a pharmacogenomic dose-finding study

Experimental evidence and observations in humans strongly support an interactive role of mutated alpha-adducin, sodium (Na(+))/potassium (K(+))-adenosine triphosphatase (ATPase) activity and endogenous ouabain in Na(+) homeostasis and the pathogenesis of hypertension. The Ouabain and Adducin for Specific Intervention on Sodium in HyperTension (OASIS-HT) trial is an early Phase II dose-finding study, which will be conducted across 39 European centers. Following a run-in period of 4 weeks without treatment, eligible patients will be randomized to one of five oral doses of rostafuroxin consisting of 0.05, 0.15, 0.5, 1.5, or 5.0 mg/day. Each dose will be compared to a placebo in a double-blind crossover experiment with balanced randomization. Treatment will be initiated with the active drug and continued with placebo or vice versa. Each double-blind period will last 5 weeks. The primary end point is the reduction in systolic blood pressure defined as the average of three clinic readings with the patient in the sitting position. Secondary end points include the reduction in diastolic blood pressure on clinic measurement, the decrease in the 24-h blood pressure, and the incidence of end points related to safety. Secondary objectives are to investigate the dependence of the blood pressure-lowering activity on the plasma concentration of endogenous ouabain and the genetic variation of the enzymes involved in the metabolism of this hormone, and the adducin cytoskeleton proteins. Eligible patients will have Grade I or II systolic hypertension without associated conditions and no more than two additional risk factors. In conclusion, OASIS-HT is a combination of five concurrent crossover studies, one for each dose of rostafuroxin to be studied. To our knowledge, OASIS-HT is the first Phase II dose-finding study in which a genetic hypothesis is driving primary and secondary end points.