Fibroblast growth factor 23 as a risk factor for cardiovascular events and mortality in patients in the EVOLVE trial.

INTRODUCTION: High mortality rates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) receiving maintenance hemodialysis are largely due to cardiovascular (CV) events. METHODS: We evaluated associations between MBD parameters, fibroblast growth factor 23 (FGF23) concentrations, and clinically adjudicated CV events from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. Patients enrolled in EVOLVE, who had not experienced any study endpoints between randomization and week 20 with evaluable baseline and week 20 values for key laboratory parameters (parathyroid hormone, calcium, phosphate, and FGF23), were assessed. We used adjusted Cox proportional hazards regression models to estimate relative risk of outcomes (primary composite, all-cause mortality, and CV events) based on FGF23 and MBD parameters. Laboratory values were modeled with linear terms and using natural cubic splines with two degrees of freedom. FINDINGS: For the primary endpoint, patients assessed (N = 2309) were followed up over a mean duration of 3.1 years, during which 1037 CV events (497 deaths, 540 nonfatal events) occurred. Adjusted models showed an association between FGF23 and the risk of CV events. Hazard ratio per log unit of FGF23 at week 20 was 1.09 [95% CI: 1.03-1.16], and the hazard ratio per log unit change in FGF23 from week 0 to week 20 was 1.09 [95% CI: 1.00-1.17]. DISCUSSION: Our data highlight FGF23 as an independent CV risk factor and potential biomarker and therapeutic target for patients with CKD-MBD receiving maintenance hemodialysis.

Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis.

BACKGROUND: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. METHODS: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. RESULTS: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P < 0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. CONCLUSION: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.

Cinacalcet-induced hypocalcemia in a cohort of European haemodialysis patients: predictors, therapeutic approaches and outcomes.

BACKGROUND: Calcimimetic treatment of secondary hyperparathyroidism in chronic dialysis patients is often followed by hypocalcemia. METHODS: We investigated the frequency, predictors, consequences and therapeutic responses following cinacalcet-induced hypocalcemia in an incident European hemodialysis cohort of 1068 patients with a cinacalcet prescription. RESULTS: Of 905 normocalcemic patients initiating cinacalcet, 67% developed hypocalcemia within 12 months: 68% mild, 23% moderate, 9% severe. Compared to persistently normocalcemic patients, those with severe hypocalcemia were more often diabetic, overweight, had cardiovascular disease, shorter dialysis vintage, used a catheter dialysis access, had fewer active vitamin-D sterols, and exhibited higher CRP and iPTH and lower calcium levels. Multivariate predictors of hypocalcemia included a catheter for vascular access, low albumin and high iPTH. Generally, no therapeutic intervention to prevent hypocalcemia was taken prior to cinacalcet initiation. After the hypocalcemic event, the most common clinical response was no change of the dialysis or medical regimen. Following the hypocalcemic event, iPTH remained low even in those with severe hypocalcemia. The number of deaths and cardiovascular events did not differ between patients with and without hypocalcemia within six months following cinacalcet initiation. CONCLUSION: Two-thirds of cinacalcet initiated patients experienced hypocalcaemia with 9% being severe. Hypocalcemia was mostly asymptomatic, transient (with and without targeted intervention to correct it) and not associated with an increase in cardiovascular events or deaths.

Predictors of cinacalcet discontinuation and reinitiation in hemodialysis patients: results from 7 European countries.

BACKGROUND: The putative benefits of cinacalcet therapy for management of secondary hyperparathyroidism (SHPT) are thought to be most manifested when patients are taking it consistently and as prescribed. Real-world descriptions of cinacalcet prescription discontinuation and reinitiation in European hemodialysis patients are lacking. To address this knowledge gap, we used Dialysis Outcomes and Practice Patterns Study (DOPPS) data, based on dialysis facility medical records, from seven European countries to estimate rates and predictors of cinacalcet prescription discontinuation and reinitiation in hemodialysis patients and to describe the trajectories of CKD-MBD laboratory values after discontinuation. METHODS: Cox regression analyses were used to predict (1) cinacalcet discontinuation among 613 patients with ≥3 consecutive months without cinacalcet prescription immediately prior to a new cinacalcet prescription and (2) cinacalcet reinitiation among 415 patients with a newly discontinued cinacalcet prescription immediately after ≥3 consecutive months of prescribed use. RESULTS: Cinacalcet was discontinued in 21 and 35% of new users after 6 and 12 months, respectively. Cinacalcet was reinitiated in 38 and 49% of newly-discontinued users after 6 and 12 months, respectively. Predictors of discontinuation included lower parathyroid hormone (PTH) in the previous month (< 150 pg/ml vs. 150-299, HR = 2.57 [95% CI: 1.52-4.33]) and lower serum calcium in the previous month (< 8.4 mg/dl vs. 8.4-10.19, HR = 1.67 [95% CI: 1.08-2.59]). Predictors of reinitiation included higher PTH in the previous month (300-599 pg/ml vs. 150-299, HR = 1.88 [95% CI = 1.19-2.97]; 600+ pg/ml, HR = 3.02 [95% CI = 1.92-4.76]). After cinacalcet discontinuation, mean serum PTH increased from 408 to 510 pg/ml, mean serum calcium briefly rose from 9.12 to 9.22 mg/dl before declining to 9.06 mg/dl, and mean serum phosphorus showed little change. CONCLUSIONS: Nephrologist discontinuation of cinacalcet therapy is common in European countries. Additional research is needed to identify optimal cinacalcet treatment strategies for SHPT management, including comparisons of intermittent cinacalcet therapy versus sustained treatment with reduced dose or frequency.

Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis.

Etelcalcetide, a d-amino acid peptide, is an intravenous calcimimetic approved for the treatment of secondary hyperparathyroidism. Etelcalcetide binds the calcium-sensing receptor and increases its sensitivity to extracellular calcium, thereby decreasing secretion of parathyroid hormone (PTH) by chief cells. Etelcalcetide and its low-molecular-weight transformation products are rapidly cleared by renal excretion in healthy subjects, but clearance is substantially reduced and dependent on hemodialysis in end-stage renal disease. The effective half-life is 3-5 days in patients undergoing hemodialysis 3 times a week. A clinical study using a single microtracer intravenous dose of [14 C]etelcalcetide indicated that 60% of the administered dose was eliminated in dialysate. Etelcalcetide undergoes reversible disulfide exchange with serum albumin to form a serum albumin peptide conjugate that is too large (67 kDa) to be dialyzed, until a subsequent exchange forms etelcalcetide or a low-molecular-weight transformation product. This exchange from albumin is apparent after hemodialysis, when it partially restores etelcalcetide concentrations in plasma. Etelcalcetide has no known risks for drug-drug interactions. In phase 3 studies, 74%-75% of hemodialysis patients with secondary hyperparathyroidism who received etelcalcetide achieved a >30% PTH reduction from baseline versus 8%-10% of patients who received placebo. The pharmacokinetics and pharmacodynamics of etelcalcetide in hemodialysis patients supports a 5-mg starting dose administered after hemodialysis and uptitration in 2.5- or 5-mg increments every 4 weeks to a maximum dose of 15 mg 3 times a week.

[Cinacalcet impact on calcium homeostasis and bone remodeling in 13 renal transplanted patients with hyperparathyroidism and hypercalcaemia]. / Effet du cinacalcet sur l'homéostasie calcique et le remodelage osseux chez 13 transplantés rénaux présentant une hyperparathyroïdie avec hypercalcémie.

The purpose of the study is to assess the impact of cinacalcet on calcium and bone remodeling, in post-renal transplanted patients with persistent hypercalcaemia secondary to hyperparathyroidism. Thirteen renal-transplanted adult recipients with a glomerular filtration rate over 30 ml/min/1.73 m(2), a total serum calcium>2.60 mmol/l with ionized calcium>1.31 mmol/l and a parathyroid hormone serum level over 70 pg/ml, were treated with cinacalcet for 4 months followed by a 15-day wash out. The results show that cinacalcet lowers significantly total and ionized calcium respectively from 2,73 (2,67-2,86) to 2,31 (2,26-2,37) mmol/l (P<0.05) and from 1,39 (1,37-1,47) to 1,21 (1,15-1,22) mmol/l (P<0.05) with no alteration of the 24-hour urine calcium/creatinine ratio and no significant expected PTH serum level suppression (153 [115-214,9] and 166 [122-174] pg/ml). On the other hand, fasting urine calcium was significantly decreased from 0,61 (0,27-1,02) to 0,22 (0,15-0,37) (P<0.05) and bone-specific alkaline phosphatases increased from 20,5 (13-46,6) to 33,8 (12-58,9) ng/ml, upon cinacalcet treatment. After its discontinuation, all these effects were reversible. In conclusion, cinacalcet normalizes total and ionized calcium in renal-transplanted recipients with hypercalcemia secondary to hyperparathyroidism through a mechanism that could be independent of PTH serum level suppression. The increase in bone-specific alkaline phosphatases, biochemical markers of bone accretion and the significant decrease in fasting urine calcium suggest the possibility of a beneficial impact of cinacalcet on bone remodeling.

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population.

BACKGROUND: A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. METHODS: The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. RESULTS: Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62-2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17-1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19-2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04-1.37) and high calcium (HR = 1.74, 95% CI 1.30-2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01-1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13-1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. CONCLUSION: Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

An epidemiological study of hemodialysis patients based on the European Fresenius Medical Care hemodialysis network: results of the ARO study.

BACKGROUND/AIMS: ARO, an observational study of hemodialysis (HD) patients in Europe, aims to enhance our understanding of patient characteristics and practice patterns to improve patient outcome. METHODS: HD patients (n = 8,963) from 134 Fresenius Medical Care facilities treated between 2005 and 2006 were randomly selected from 9 European countries (Czech Republic, France, Hungary, Italy, Poland, Portugal, Spain, Slovak Republic and Slovenia) and Turkey. Information was captured on demographics, comorbidities, medications, laboratory and dialysis parameters, and outcome. RESULTS: Patients were followed for 1.4 ± 0.7 years. Wide variation by country was observed for age, sex and diabetes as a cause of chronic kidney disease. Cardiovascular disease was present in 73% of patients. Dialysis parameters were homogeneous across countries. Arteriovenous fistulas were frequently used (73%). More incident patients had hemoglobin <11 g/dl than prevalent patients (50 vs. 33%, respectively). Phosphatemia and intact parathyroid hormone were similar between incident and prevalent patients (4.7 ± 1.2 mg/dl and 190 vs. 213 ng/l, respectively). Medication use varied widely by country. In total, 5% of patients underwent renal transplantation. Overall death rate was 124/1,000 patient-years. CONCLUSION: ARO revealed differences in HD practice patterns and patient characteristics in the 10 participating countries. Future ARO studies will fill gaps in the knowledge about the care of European HD patients.

Hemoglobin variability does not predict mortality in European hemodialysis patients.

Patients with CKD exhibit significant within-patient hemoglobin (Hb) level variability, especially with the use of erythropoiesis stimulating agents (ESAs) and iron. Analyses of dialysis cohorts in the United States produced conflicting results regarding the association of Hb variability with patient outcomes. Here, we determined Hb variability in 5037 European hemodialysis (HD) patients treated over 2 years to identify predictors of high variability and to evaluate its association with all-cause and cardiovascular disease (CVD) mortality. We assessed Hb variability with various methods using SD, residual SD, time-in-target (11.0 to 12.5 g/dl), fluctuation across thresholds, and area under the curve (AUC). Hb variability was significantly greater among incident patients than prevalent patients. Compared with previously described cohorts in the United States, residual SD was similar but fluctuations above target were less frequent. Using logistic regression, age, body mass index, CVD history, dialysis vintage, serum albumin, Hb, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use, ESA use, dialysis access type, dialysis access change, and hospitalizations were significant predictors of high variability. Multivariable adjusted Cox regression showed that SD, residual SD, time-in-target, and AUC did not predict all-cause or CVD mortality during a median follow-up of 12.4 months (IQR: 7.7 to 17.4). However, patients with consistently low levels of Hb (<11 g/dl) and those who fluctuated between the target range and <11 g/dl had increased risks for death (RR 2.34; 95% CI: 1.24 to 4.41 and RR 1.74; 95% CI: 1.00 to 3.04, respectively). In conclusion, although Hb variability is common in European HD patients, it does not independently predict mortality.

Timing of onset of CKD-related metabolic complications.

Chronic kidney disease (CKD) guidelines recommend evaluating patients with GFR <60 ml/min per 1.73 m(2) for complications, but little evidence supports the use of a single GFR threshold for all metabolic disorders. We used data from the NephroTest cohort, including 1038 adult patients who had stages 2 through 5 CKD and were not on dialysis, to study the occurrence of metabolic complications. GFR was measured using renal clearance of (51)Cr-EDTA (mGFR) and estimated using two equations derived from the Modification of Diet in Renal Disease study. As mGFR decreased from 60 to 90 to <20 ml/min per 1.73 m(2), the prevalence of hyperparathyroidism increased from 17 to 85%, anemia from 8 to 41%, hyperphosphatemia from 1 to 30%, metabolic acidosis from 2 to 39%, and hyperkalemia from 2 to 42%. Factors most strongly associated with metabolic complications, independent of mGFR, were younger age for acidosis and hyperphosphatemia, presence of diabetes for acidosis, diabetic kidney disease for anemia, and both male gender and the use of inhibitors of the renin-angiotensin system for hyperkalemia. mGFR thresholds for detecting complications with 90% sensitivity were 50, 44, 40, 39, and 37 ml/min per 1.73 m(2) for hyperparathyroidism, anemia, acidosis, hyperkalemia, and hyperphosphatemia, respectively. Analysis using estimated GFR produced similar results. In summary, this study describes the onset of CKD-related complications at different levels of GFR; anemia and hyperparathyroidism occur earlier than acidosis, hyperkalemia, and hyperphosphatemia.

Pitfalls of measuring total blood calcium in patients with CKD.

Disorders of mineral and bone metabolism are prevalent in patients with chronic kidney disease (CKD). The recent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend that blood calcium (Ca) be regularly measured in patients with stages 3 to 5 CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) position states that the measurement of ionized Ca (iCa) is preferred and that if total Ca (tCa) concentration is used instead, then it should be adjusted in the setting of hypoalbuminemia. In 691 consecutive patients with stages 3 to 5 CKD, we compared the ability of noncorrected and albumin-corrected tCa concentration to identify low, normal, or high iCa concentration. The agreement between noncorrected or albumin-corrected tCa and iCa was only fair. The risk for underestimating ionized calcium was independently increased by a low total CO(2) concentration when either noncorrected or albumin-corrected Ca was used and by a low albumin concentration only when noncorrected tCa was used. The risk for overestimating iCa was increased by a low albumin concentration only when albumin-corrected Ca was used. In conclusion, albumin-corrected tCa does not predict iCa better than noncorrected tCa. Moreover, both noncorrected and albumin-corrected tCa concentrations poorly predict hypo- or hypercalcemia in patients with CKD.

Partial fanconi syndrome induced by imatinib therapy: a novel cause of urinary phosphate loss.

Imatinib mesylate (Gleevec, Glivec; Novartis, Basel, Switzerland) is a specific tyrosine kinase inhibitor that has become the gold-standard treatment for patients with chronic myeloid leukemia. Several tyrosine kinases inhibited by imatinib are expressed in the kidney, and although the drug is usually well tolerated, several cases of acute renal failure were reported. We describe for the first time a case of a patient treated by imatinib for chronic myeloid leukemia who developed partial Fanconi syndrome with mild renal failure, which leads to a discussion of the pathophysiological characteristics of imatinib-induced renal toxicity. Patients on long-term imatinib treatment should be monitored for renal failure, as well as proximal tubule dysfunction, including hypophosphatemia.

Effect of early correction of anemia on the progression of CKD.

BACKGROUND: This study is designed to assess the effect of early and complete correction of anemia by using recombinant human erythropoietin (epoetin) alfa on the progression of chronic kidney disease (CKD). METHODS: Patients were randomly assigned to achieve high (13 to 15 g/dL [130 to 150 g/L]) or low (11 to 12 g/dL [110 to 120 g/L]) hemoglobin-level targets during 4 months of stabilization, followed by 36 months of maintenance. Glomerular filtration rate (GFR) decrease was measured by using iohexol clearance. Quality of life, nutrition, and safety also were monitored. RESULTS: Because of labeling changes for subcutaneous administration of epoetin alfa (Eprex; Johnson and Johnson, Schaffhausen, Switzerland), the study was terminated prematurely. There were 195 patients enrolled in each group; 108 high-hemoglobin and 133 low-hemoglobin patients entered the maintenance phase. Mean maintenance duration was 7.4 months for the high-hemoglobin group and 8.3 months for the low-hemoglobin group. GFR decrease was numerically, but not statistically significantly, lower with the high-hemoglobin group (0.058 versus 0.081 mL/min/1.73 m2/mo [< 0.01 mL/s/1.73 m2/mo]). Physical quality-of-life measures showed trends (Role-Physical, P = 0.055; Physical Function, P = 0.083) or statistically significant improvement (Vitality, P = 0.042) with high hemoglobin levels at the end of the stabilization phase. Adverse events were similar between groups. Cardiovascular adverse events occurred in 25% of the high-hemoglobin and 18% of the low-hemoglobin patients (P = 0.137). Neither epoetin dosage nor hemoglobin level was associated with cardiovascular adverse events or death. CONCLUSION: These data suggest that normalization of hemoglobin levels in patients with CKD is safe. Longer duration studies are needed to clarify efficacy benefits with high hemoglobin levels.

[Contribution of stem cells to renal repair after ischemia/reperfusion]. / Place des cellules souches dans la réparation rénale après ischémie-reperfusion.

Repair of inflammatory and/or ischemic renal injury involves endothelial, mesangial and epithelial regeneration. These structures may be rebuilt by resident progenitor cells and bone marrow-derived stem cells. Resident progenitor cells in adult kidney have not yet been conclusively identified. They are likely to be slowly cycling cells located mainly in the outer medulla and renal papilla. In glomerulonephritis with mesangiolysis, mesangial regenera- tion involves progenitor cells migrating from the juxtaglomerular apparatus and also bone marrow-derived cells. In acute ischemic renal failure, epithelial regeneration of proximal tubules results from the migration, proliferation and differentiation of resident progenitor cells; bone marrow-derived cells may play an accessory role. Molecular mechanisms underlying these repair processes could be targets for new therapeutic approaches.

Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure.

Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPARbeta/delta+/- and PPARbeta/delta-/- mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPARbeta/delta as a remarkable new target for preconditioning strategies.

15-deoxy-Delta12,14-prostaglandin J2 inhibits glucocorticoid binding and signaling in macrophages through a peroxisome proliferator-activated receptor gamma-independent process.

15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is involved in the control of inflammatory reaction. We tested the hypothesis that 15d-PGJ(2) would exert this control in part by modulating the sensitivity of inflammatory cells to glucocorticoids. Human U937cells and mouse RAW 264.7 cells were exposed to 15d-PGJ(2), and binding experiments were performed with [(3)H]dexamethasone as a glucocorticoid receptor (GR) ligand. 15d-PGJ(2) caused a transient and concentration-dependent decrease in [(3)H]dexamethasone-specific binding to either cells through a decrease in the number of GR per cell without significant modification of the K(d) value. These changes were related to functional alteration of the GR rather than to a decrease in GR protein. They did not require the engagement of peroxisome proliferator-activated receptor gamma (PPARgamma), because the response to 15d-PGJ(2) was neither mimicked by the PPARgamma agonist ciglitazone nor prevented by the PPARgamma antagonist bisphenol A diglycidyl ether. 15d-PGJ(2) altered GR possibly through the interaction of its cyclopentenone ring with GR cysteine residues because the cyclopentenone ring per se could mimic the effect of 15d-PGJ(2), and modification of GR cysteine residues with methyl methanethiosulfonate suppressed the response to 15d-PGJ(2). Finally, 15d-PGJ(2)-induced decreases in glucocorticoid binding to GR resulted in parallel decreases in the ability of GR to activate the transcription of a glucocorticoid-inducible reporter gene and to reduce the expression of monocyte chemoattractant protein-1. Together these data suggest that 15d-PGJ(2) limits glucocorticoid binding and signaling in monocytes/macrophages through a PPARgamma-independent and cyclopentenone-dependent mechanism. It provides a way in which 15d-PGJ(2) would exert proinflammatory activities in addition to its known anti-inflammatory activities.

[Calpains participate in inflammatory reaction development]. / Les calpaïnes participent au développement de la réaction inflammatoire.

Calpains are cysteine proteases first identified 50 years ago. Because they are present in the cytosol of mammalian cells and because they are activated in response to Ca2+ mobilization, they are thought to be involved mainly in cell signalling pathways. They could participate in cellular responses such as apoptosis, proliferation, extracellular matrix adhesion and motility, that have relevance to pathophysiological issues in ischemia, inflammation, repair and tumor progression. Here we consider calpain functions in inflammatory reaction. We report the recent observation that calpain inhibitors reduce the development of acute and chronic inflammation. This has opened the door for understanding how these enzymes are effective in inflammation. We present data suggesting that calpains are primarily responsible for the activation of nuclear factor-kappa B, a transcription factor with a pivotal role in inflammation. They are involved in inflammatory cell adhesion and migration, pro-inflammatory mediator release and anti-inflammatory hormone resistance as well. In addition, we emphasize the intriguing possibility that calpains are externalized during inflammatory process and that they play a role in the microenvironment of inflammatory cells. Thus, both intracellular and extracellular calpains would offer novel therapeutic targets in inflammation.

Anemia management and the delay of chronic renal failure progression.

Interstitial fibrosis plays a key role in the progression of chronic kidney diseases. Analysis of the biologic effects of erythropoietin and of the pathophysiology of interstitial fibrosis suggest that treatment with epoetin may slow the progression of chronic kidney disease, both by decreasing interstitial fibrosis and by protecting against its consequences. The results of two small prospective studies and of a retrospective one also suggest that treatment with epoetin may have such protective effects.