The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages.

SUMMARY: The hormone fibroblast growth factor 23 (FGF23) is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. In a cohort of 142 patients with CKD stages 2-5D, plasma FGF23 was independently associated with aortic calcification but not with pulse wave velocity or bone mineral density. INTRODUCTION: FGF23 is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. Previous studies related to FGF23 and vascular and bone outcomes have been restricted to dialysis patients. The aim of the present study was to establish whether or not plasma FGF23 is associated with aortic and coronary calcification, arterial stiffness, and bone mineral density in patients with early as well as late stages of CKD. METHODS: In a cohort of 142 patients with CKD stages 2-5D, we made routine biochemistry and intact FGF23 determinations, and assessed aortic and coronary calcification, bone mineral density (BMD), and arterial stiffness by multislice spiral computed tomography and automated pulse wave velocity (PWV). RESULTS: Plasma intact FGF23 levels were elevated in CKD patients; the elevation preceded that of serum phosphate in early-stage CKD. Patients with elevated FGF23 levels had higher aortic and coronary calcification scores than patients with lower FGF23 levels. Multivariate linear regression analysis indicated that only age (p < 0.001) and FGF23 (p = 0.008) were independently associated with aortic calcification score. Plasma FGF23 was neither associated with PWV nor with BMD. CONCLUSION: Our data suggest that plasma FGF23 is an independent biomarker of vascular calcification in patients with various CKD stages including early stages. The association between vascular calcification and FGF23 levels appears to be independent of BMD. It remains to be seen whether this association is independent of bone turnover and bone mass.

Is parathyroid hormone measurement useful for the diagnosis of renal bone disease?

The non-invasive diagnosis of bone turnover in patients with chronic kidney disease (CKD) remains difficult compared with bone histomorphometry as the gold standard. Most clinicians rely on surrogate markers, mainly serum parathyroid hormone and total alkaline phosphatases, in association with serum calcium and phosphorus. Although very high serum PTH levels generally allow the diagnosis of high bone turnover, slight elevations, normal, or low values cannot allow a reliable distinction between normal or low turnover.

Pleiotropic effects of the non-calcium phosphate binder sevelamer.

The number of chronic kidney disease (CKD) patients and related adverse outcomes has dramatically increased worldwide in the past decade. Therefore, numerous experimental and clinical studies have recently addressed the underlying mechanisms, in particular the marked increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients with advanced stage of CKD. Its control by calcium-containing phosphate binders is effective, but at the price of potentially noxious calcium overload. Sevelamer hydrochloride is a phosphate binder that offers an effective control of hyperphosphatemia as calcium-rich binders but without increase of calcium load. Beyond the control of phosphate, sevelamer seems to exert pleiotropic effects which include the correction of lipid abnormalities and the clearance of some uremic toxins.

Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).

Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and are an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified based on bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) sponsored a Controversies Conference on Renal Osteodystrophy to (1) develop a clear, clinically relevant, and internationally acceptable definition and classification system, (2) develop a consensus for bone biopsy evaluation and classification, and (3) evaluate laboratory and imaging markers for the clinical assessment of patients with CKD. It is recommended that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD, which can be further assessed by histomorphometry, and the results reported based on a unified classification system that includes parameters of turnover, mineralization, and volume, and (2) the term CKD-Mineral and Bone Disorder (CKD-MBD) be used to describe a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism and/or extra-skeletal calcification. The international adoption of these recommendations will greatly enhance communication, facilitate clinical decision-making, and promote the evolution of evidence-based clinical practice guidelines worldwide.

Pathophysiological aspects of vascular calcification in chronic renal failure.

The nephrology community has progressively recognized that vascular calcification in patients with chronic renal failure is a major problem in terms of morbidity and mortality. This type of soft tissue calcification is not only passive, as thought previously, but implies active processes as well. It results from disturbances of the normal balance between calcification inhibitors and promoters, acting both at the systemic and the local level, and from the phenotypic change of smooth muscle cells towards osteoblast-like calcifying cells in the vessel wall. The recognition of the main factors involved will allow in the future a more appropriate prophylactic and therapeutic approach of this clinically important complication of chronic renal failure.

Pathophysiological aspects of vascular calcification in chronic renal failure

La comunidad nefrológica ha aprendido progresivamente que las calcificacionesvasculares son un problema importante para la mortalidad y la morbilidad de lospacientes con insuficiencia renal crónica. Este tipo de calcificaciones de tejidosblandos no es solo pasiva como se ha pensado hasta ahora, sino que tambiénestán implicados en ella procesos activos. Es el resultado de la ruptura del balanceentre inhibidores y promotores de la calcificación que actúan tanto a nivelsistémico como local y del cambio en el fenotipo de las células musculares lisasque se transforman en células parecidas a los osteoblastos con propiedades decalcificar. El conocer los principales factores implicados nos permitirá en el futurotratar mejor y de forma profiláctica esta importante complicación de la insuficienciarenal crónica

The nephrology community has progressively recognized that vascular calcificationin patients with chronic renal failure is a major problem in terms of morbidityand mortality. This type of soft tissue calcification is not only passive, asthought previously, but implies active processes as well. It results from disturbancesof the normal balance between calcification inhibitors and promoters, actingboth at the systemic and the local level, and from the phenotypic change of smoothmuscle cells towards osteoblast-like calcifying cells in the vessel wall. The recognitionof the main factors involved will allow in the future a more appropriateprophylactic and therapeutic approach of this clinically important complicationof chronic renal failure

Short-term effect of folic acid supplementation in renal transplant recipients and chronic kidney disease patients with comparable renal function impairment.

Recent evidence suggested that the efficacy of folic acid supplementation in reducing plasma total homocysteine (Hcy) concentration might be similar in renal transplant recipients (RTR) and chronic kidney disease (CKD) patients with a comparable degree of reduction of renal function. However, a direct comparison of the response to high dose folic acid supplementation between renal transplant recipients and CKD patients has never been made. Therefore, the goal of this study was to evaluate the response to folic acid (5 mg/day) supplementation in 15 stable renal transplant recipients with evidence of chronic allograft nephropathy, and in 15 CKD (stage 3) patients matched for age, sex and renal function living in the area of Skopje, Macedonia. After 12 weeks of folic acid supplementation, plasma total Hcy concentrations were significantly reduced in the two groups. Percent reduction of plasma total Hcy levels was nearly identical in the two groups (25.7% vs 24.5%, p = NS). These results confirm previous findings regarding the efficacy of folic acid therapy given separately to either renal transplant recipients or CKD patients, and extend them to a direct confirmation of identical efficacy.

Hyporesponsiveness to recombinant human erythropoietin.

The introduction of recombinant human erythropoietin (rh-Epo, epoetin) as a treatment for the anaemia of renal failure has transformed the management of this condition. Nevertheless, a significant number of patients fail to respond. There are many different possible causes of inadequate response to epoetin. Iron deficiency, whether absolute or functional, is considered to be the most important, and it is widely accepted that maintaining adequate iron levels reduces rh-Epo dosage requirement and improves efficacy in haemodialysis patients. Infection and inflammation have been shown to influence responsiveness to rh-Epo by disrupting iron metabolism and eliciting the release of cytokines that inhibit erythropoiesis. Another factor for consideration is severe hyperparathyroidism, which can lead to a reduced number of responsive erythroid progenitor cells. Inadequate dialysis can also negatively impact on rh-Epo therapy, and aluminium overload interferes with iron metabolism and reduces the efficacy of rh-Epo. Deficiencies in vitamin B(12), folic acid and potentially vitamin C can all reduce the efficacy of treatment with rh-Epo. Optimizing patient response to rh-Epo therapy, therefore, requires consideration of many factors, some well established and others that are more controversial, and the list continues to grow with the identification of new factors.

Genetic aspects of secondary hyperparathyroidism in uremia.

In addition to the well-known uremia-related factors calcium, phosphate, and vitamin D, genetic polymorphisms and gene mutations appear to have a role as well in modulating parathyroid function. Allelic polymorphisms of the vitamin D receptor gene have been most often examined but to date their precise place is not yet certain in patients with chronic renal failure. The frequent transformation of parathyroid cell proliferation from polyclonal to monoclonal growth in patients with severe secondary hyperparathyroidism must be attributed to mutations or deletions of various tumor-suppressor genes, and probably more rarely also to an activation of tumor-enhancer genes.

Inhibition of nitric oxide synthesis attenuates insulin-mediated sympathetic activation in rats.

BACKGROUND AND OBJECTIVES: Infusion of insulin produces sympathoexcitation, nitric oxide (NO) generation and NO-mediated vasodilation. Because central nervous system NO may inhibit sympathetic outflow, the present study was designed to determine whether NO synthase blockade would enhance insulin-mediated sympathetic activation. We additionally aimed to determine whether augmented sympathoexcitation and reduced NO-mediated vasodilation, during combined NO synthase blockade and hyperinsulinemia, would result in a blood pressure increase. DESIGN AND METHODS: We infused vehicle (Control; n = 7) or insulin (10 mU/min) in anaesthetized rats receiving either no pretreatment (Insulin; n = 7) or after pretreatment with the NO blocker, NG-monomethyl-L-arginine (L-NMMA-insulin; 0.25 mg/kg per min; n = 7), while measuring mean arterial pressure (MAP), heart rate and lumbar sympathetic nerve activity (SNA) during euglycemic clamp. An additional control group received L-NMMA (L-NMMA; n = 7). RESULTS: Insulin rats had large SNA increases (190 +/- 22% from 100% baseline), contrasting with small increases in the Control (136 +/- 10%) and L-NMMA (135 +/- 20%) groups. Unexpectedly, NO blockade abolished insulin-induced SNA increases in the L-NMMA-insulin group (96 +/- 12%). In agreement with the SNA findings, Insulin rats had heart rate increases while no heart rate changes were observed in the L-NMMA-insulin, Control, or L-NMMA groups. In addition, there was an unexpected was a lack of MAP increase in L-NMMA-insulin rats. MAP also did not change in the Control, L-NMMA or Insulin groups. CONCLUSIONS: These findings suggest that NO is necessary for insulin to exert its sympathoexcitatory effects, and that insulin-induced NO release may play a role in activating increases in lumbar SNA.

Human parathyroid cell proliferation in response to calcium, NPS R-467, calcitriol and phosphate.

It remains uncertain how calcium, phosphate and calcitriol regulate parathyroid cell growth. The present study was aimed at examining possible direct effects of these modulators and of the calcimimetic NPS R-467 on parathyroid cell growth in vitro. Cell proliferation was determined by [3H]thymidine incorporation and cell cycle antigen Ki 67 expression in a parathyroid cell culture model derived from uraemic patients. The effect of NPS R-467 on parathyroid hormone (PTH) secretion and intracellular [Ca2+]i response was also examined. Increasing the [Ca2+] in the medium from 0.5 to 1.7 mM increased DNA synthesis (P < 0.005) and the number of Ki 67-positive cells (P < 0.005). However, NPS R-467 (0.01-1 microM) inhibited 3[H]thymidine incorporation by 35% in the presence of 0.5 mM [Ca2+]e. Exposure of cells to Ca2+ or NPS R-467 led to a rapid increase of intracellular Ca2+, although the pattern of increase differed. Addition of calcitriol (10-10-10-7 M) to the culture medium suppressed [3H]thymidine incorporation dose-dependently. Finally, high levels of phosphate (3.5 mM) in the medium led to a significant (P < 0.05) increase in [3H]thymidine incorporation. The observed stimulatory effect of Ca2+ in the medium in vitro appears to be at variance with the inhibitory effect of calcimimetic NPS R-467 in vitro. In an attempt to solve these apparent discrepancies, and based on the notion of a reduced calcium-sensing receptor (CaR) expression in parathyroid tissues of uraemic patients, we hypothesize that Ca2+ may regulate parathyroid cell proliferation via two different pathways, with predominant growth inhibition in cases of high CaR expression or activation, but prevailing stimulation of proliferation in cases of low CaR expression.

Dialysis-induced oxidative stress: biological aspects, clinical consequences, and therapy.

Oxidative stress, which results from a rupture in the natural balance between pro- and antioxidant systems, is considered as a major factor in dialysis-associated morbidity and mortality. Emerging pharmacologic and dialytic antioxidant therapeutic and dialysis strategies should enable us to reduce the harmful consequences of oxidative stress in dialysis patients. Moreover, since there is increasing evidence of oxidative stress long before the initiation of maintenance dialysis, antioxidant therapeutic strategies should probably be developed very early in the course of renal failure.

Effect of type of dialysis membrane on bone in haemodialysis patients.

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.

High serum apolipoprotein AIV levels in renal transplant recipients.

BACKGROUND: Human apolipoprotein (apo) AIV might play a role in post-transplant reverse cholesterol transport, which appears to be comparable to that seen in healthy subjects. However, there may be subtle differences between healthy individuals and renal transplant recipients, given the other abnormalities of lipoprotein metabolism in the latter. Therefore, the aim of the present study was to investigate possible changes of serum apo AIV levels in renal transplant recipients, and to evaluate potential factors influencing these levels. PATIENTS AND METHODS: Total and free serum apo AIV was determined in 36 clinically stable renal transplant recipients and in 20 sex- and age-matched healthy control subjects. RESULTS: Mean total serum apo IV concentrations (+/- SD) were significantly higher in renal transplant recipients than in control subjects (202 +/- 102 vs 79 +/- 45 mg/l, p < 0.01). The percentage of lipoprotein-free fractions of apo AIV was comparable in both groups. The elevated total serum concentrations of apo AIV were mainly related to creatinine clearance and partially to serum triglyceride levels in renal transplant recipients. CONCLUSION: Our data suggest that the observed elevation of serum apo AIV concentrations in renal transplant recipients is essentially related to the presence of impaired renal function.

[Refractory ascites in hemodialysis: treatment by paracentesis- reinjection during dialysis]. / Ascite réfractaire en hémodialyse: traitement par ponction-réinjection en cours de dialyse.

Two hemodialysis patients, one male and one female, aged 46 and 54 years, were treated with preceed respectively for refractory ascites secondary to hepatic cirrhosis and for large polycystic liver. Preceed was decided because of the rapid reappearance of effusion following repeated puncture and albumin infusion, the poor tolerance to ultrafiltration (UF) and the poor nutritional status of the patients, with severe hypoalbuminemia. Abdominal paracentesis was performed on initiation of the dialysis session. Reinjection of the ascites fluid was made into the arterial line, allowing its UF and control of its flow. The procedure was performed whenever necessary, i.e., when inter-dialysis weight gain and ascites volume were high. In both cases, improvement was quickly obtained, with less rapid and less severe reappearance of the effusion and correction of albuminemia. Dialysis sessions with UF were better tolerated. No notable side effect was observed. The first patient was treated for 2 months, when he died of an unrelated cause. The other patient was treated for 6 months and then could be transferred to a dialysis center near her home. Twenty five months after start of dialysis treatment, kidney and liver transplantation were performed in this same patient. After transplantation, reappearance of moderate ascites and oedema is attributed to e degradation of renal function, without liver dysfunction. Five weeks after transplantation, improvement of renal function and ascites regression were noted. Preceed is an effective method of treating refractory ascites in the hemodialysis patient. Compared to classical paracentesis, it has the advantage of good tolerance, patient comfort and moderate cost.