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Vascular calcification associated with chronic kidney disease (CKD) is an active, regulated process. Apoptosis of vascular smooth muscle cells has long been known to play a major role in its pathogenesis, with apoptotic bodies derived from these cells acting as nucleating structures for calcium crystal formation and deposition. Ye et al. now show in experimental models in vitro and in vivo that ferroptosis can also contribute to the development of vascular calcification in CKD.

Lung congestion is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis, and its estimation by ultrasound may be useful to guide ultrafiltration and drug therapy in this population. In an international, multi-center randomized controlled trial (NCT02310061) we investigated whether a lung ultrasound-guided treatment strategy improved a composite end point (all-cause death, non-fatal myocardial infarction, decompensated heart failure) vs usual care in patients receiving chronic hemodialysis with high cardiovascular risk. Patient-Reported Outcomes (Depression and the Standard Form 36 Quality of Life Questionnaire, SF36) were assessed as secondary outcomes. A total of 367 patients were enrolled: 183 in the active arm and 180 in the control arm. In the active arm, the pre-dialysis lung scan was used to titrate ultrafiltration during dialysis and drug treatment. Three hundred and seven patients completed the study: 152 in the active arm and 155 in the control arm. During a mean follow-up of 1.49 years, lung congestion was significantly more frequently relieved in the active (78%) than in the control (56%) arm and the intervention was safe. The primary composite end point did not significantly differ between the two study arms (Hazard Ratio 0.88; 95% Confidence Interval: 0.63-1.24). The risk for all-cause and cardiovascular hospitalization and the changes of left ventricular mass and function did not differ among the two groups. A post hoc analysis for recurrent episodes of decompensated heart failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 0.41-0.97) showed a risk reduction for these outcomes in the active arm. There were no differences in patient-reported outcomes between groups. Thus, in patients on chronic hemodialysis with high cardiovascular risk, a treatment strategy guided by lung ultrasound effectively relieved lung congestion but was not more effective than usual care in improving the primary or secondary end points of the trial.

Cardiovascular disease is highly prevalent in patients with chronic kidney disease. Hyperphosphatemia is associated with subclinical atheromatosis in chronic kidney disease. Phosphate-induced endothelial dysfunction and vascular calcification are thought to be key inducers of atherosclerosis in this condition. Zhou et al. now demonstrate that phosphate promotes de novo cholesterol synthesis in vascular smooth muscle and macrophages through increased 3-hydroxy-3-methylglutaryl coenzyme A reductase activation. This observation may change current concepts of atherosclerosis development and management in chronic kidney disease.

The most important contributors to the anemia of patients with chronic kidney disease are insufficient erythropoietin production and erythropoietin hyporesponsiveness, decreased red blood cell half-life, iron deficiency, and inflammation. However, in contrast to the role of kidney failure, that of proteinuria and nephrotic syndrome is less clear. Bissinger et al. now provide evidence in mouse models and patients with chronic kidney disease that heavy proteinuria alters erythrocyte metabolism and increases erythrocyte death.

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.

Contains fulltext : 215593.pdf (Publisher’s version ) (Closed access) Although blood pressure control is a major goal in chronic kidney disease, no worldwide overview of either its achievement or antihypertensive prescriptions is currently available. To evaluate this we compared crude prevalence of uncontrolled blood pressure among 17 cohort studies, including 34 602 individuals with estimated glomerular filtration rate under 60 ml/min/1.73 m(2) and treated hypertension across four continents, and estimated observed to expected prevalence ratios, adjusted for potential confounders. Crude prevalence of blood pressure of 140/90 mm Hg or more varied from 28% to 61% and of blood pressure of 130/80 or more from 54% to 84%. Adjusted prevalence ratios indicated poorer hypertension control than expected in cohorts from European countries, India, and Uruguay, and better control in patients from North American and high-income Asian countries. Four antihypertensive drug classes or more were prescribed to more than 30% of participants in North American and some European cohorts, but this practice was less common elsewhere. Renin angiotensin-aldosterone system inhibitors were the most common antihypertensive drugs, prescribed for 54% to 91% of cohort participants. Differences for other drug classes were much stronger, ranging from 11% to 79% for diuretics, 22% to 70% for beta-blockers, and 27% to 75% for calcium-channel blockers. The confounders studied explain only a part of the international variation in blood pressure control among individuals with chronic kidney disease. Thus, considerable heterogeneity in prescription patterns worldwide calls for further investigation into the impact of different approaches on patient outcomes.

The aim of this study was to investigate 28-day mortality after COVID-19 diagnosis in the European kidney replacement therapy population. In addition, we determined the role of patient characteristics, treatment factors, and country on mortality risk using ERA-EDTA Registry data on patients receiving kidney replacement therapy in Europe between February 1, 2020 and April 30, 2020. Additional data on all patients with a diagnosis of COVID-19 were collected from seven European countries encompassing 4298 patients. COVID-19 attributable mortality was calculated using propensity-score matched historic controls and after 28 days of follow-up was 20.0% (95% confidence interval 18.7%-21.4%) in 3285 patients receiving dialysis, and 19.9% (17.5%-22.5%) in 1013 recipients of a transplant. We identified differences in COVID-19 mortality across countries, and an increased mortality risk in older patients receiving kidney replacement therapy and male patients receiving dialysis. In recipients of kidney transplants older than 75 years of age 44.3% (35.7%-53.9%) did not survive COVID-19. Mortality risk was 1.28 (1.02-1.60) times higher in transplant recipients compared with matched dialysis patients. Thus, the pandemic has had a substantial effect on mortality in patients receiving kidney replacement therapy; a highly vulnerable population due to underlying chronic kidney disease and high prevalence of multimorbidity., Graphical abstract

The aims of this study were to determine the frequency of dialysis and kidney transplantation and to estimate the regularity of comprehensive conservative management (CCM) for patients with kidney failure in Europe. This study uses data from the ERA-EDTA Registry. Additionally, our study included supplemental data from Armenia, Germany, Hungary, Ireland, Kosovo, Luxembourg, Malta, Moldova, Montenegro, Slovenia and additional data from Israel, Italy, Slovakia using other information sources. Through an online survey, responding nephrologists estimated the frequency of CCM (i.e. planned holistic care instead of kidney replacement therapy) in 33 countries. In 2016, the overall incidence of replacement therapy for kidney failure was 132 per million population (pmp), varying from 29 (Ukraine) to 251 pmp (Greece). On 31 December 2016, the overall prevalence of kidney replacement therapy was 985 pmp, ranging from 188 (Ukraine) to 1906 pmp (Portugal). The prevalence of peritoneal dialysis (114 pmp) and home hemodialysis (28 pmp) was highest in Cyprus and Denmark respectively. The kidney transplantation rate was nearly zero in some countries and highest in Spain (64 pmp). In 28 countries with five or more responding nephrologists, the median percentage of candidates for kidney replacement therapy who were offered CCM in 2018 varied between none (Slovakia and Slovenia) and 20% (Finland) whereas the median prevalence of CCM varied between none (Slovenia) and 15% (Hungary). Thus, the substantial differences across Europe in the frequency of kidney replacement therapy and CCM indicate the need for improvement in access to various treatment options for patients with kidney failure. European UnionEuropean Commission [PP-01-2016]; ERAEDTA This study was funded by the European Union (grant PP-01-2016) and ERAEDTA.

International audience; In chronic kidney disease (CKD), calcium-sensing receptor (CaSR) expression and function have been extensively studied in parathyroid tissue and vascular tissues. To examine whether similar changes occurred in other tissues, we measured total and surface CaSR expression in monocytes of patients with various stages of CKD and healthy volunteers respectively in cross-sectional studies. We further explored in vitro the impact of uremic serum on CaSR expression in monocytes (U937 and THP-1 cell lines), and whether human peripheral blood mononuclear cells or U937 and THP-1 monocytes might modify vascular calcium deposition in rat carotid arteries in vitro. CKD was associated with a decrease in peripheral blood mononuclear cell CaSR expression both in total and at the monocyte surface alone (43% and 34%, respectively in CKD stages 4-5). This decrease was associated with a reduction in the ability of monocytes to inhibit vascular calcification in vitro. Pretreatment with the calcimimetic NPSR568 of peripheral blood mononuclear cells isolated from patients with CKD significantly improved monocyte capacity to reduce carotid calcification in vitro. The fewer peripheral blood mononuclear cells expressing cell surface CaSR, the more calcimimetic treatment enhanced the decrease of carotid calcium content. Thus, we demonstrate that monocyte CaSR expression is decreased in patients with CKD and provide in vitro evidence for a potential role of this decrease in the promotion of vascular calcification. Hence, targeting this alteration or following monocyte CaSR expression as an accessible marker might represent a promising therapeutic strategy in CKD-associated arterial calcification.

Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB+ microbiota enabled PTH to expand intestinal TNF+ T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF+ T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut–bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism., T cells are involved in the bone loss induced by parathyroid hormone (PTH), but their origin is unknown. Here, the authors show that the intestinal microbiota is required for PTH to induce bone loss and describes mechanisms for microbiota-mediated gut–bone crosstalk in mouse models of hyperparathyroidism.

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

Vascular calcification and kidney fibrosis are 2 important features of chronic kidney disease. Bone morphogenetic proteins/growth differentiation factors and their receptors are implicated in the pathogenesis of both processes. Modulation of the bone morphogenetic protein/growth differentiation factor pathways by a soluble chimeric protein that contains the activin receptor IIA (ActRIIA) domain and acts as an ActRIIA ligand trap for activin and other ligands could become a new therapeutic strategy for vascular calcification and kidney fibrosis in chronic kidney disease.

In the majority of patients with chronic kidney disease (CKD) the total and low-density lipoprotein (LDL) cholesterol are usually normal, with the exception of patients with nephrotic-range proteinuria and in peritoneal dialysis patients. Moreover, epidemiological evidence shows that the link between serum total cholesterol or LDL cholesterol and cardiovascular disease (CVD) in CKD is not as straightforward as in the general population. In addition, atherosclerosis-related events are responsible for only similar to 30% of CVD in these patients. Nevertheless, intervention trials, particularly the Study of Heart and Renal Protection, and meta-analyses showed a proportional reduction of cardiovascular risk associated with the absolute reduction in LDL cholesterol in patients with CKD similar to the general population, with apparent attenuation of this relationship in end-stage kidney disease. Therefore, the use of cholesterol-lowering agents appears to be indicated in early CKD stages to prevent atherosclerosis-related risk. However, uncertainty persists as to the optimal management of this risk in end-stage kidney disease patients. In the present review, we discuss these issues and end up with a practical plan aimed to help the nephrologist in managing atherosclerosis-related risk using cholesterol-lowering therapies in CKD patients.

Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.

The recent research findings concerning syndromes of muscle wasting, malnutrition, and inflammation in individuals with chronic kidney disease (CKD) or acute kidney injury (AKI) have led to a need for new terminology. To address this need, the International Society of Renal Nutrition and Metabolism (ISRNM) convened an expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI. The ISRNM expert panel recommends the term ‘protein–energy wasting’ for loss of body protein mass and fuel reserves. ‘Kidney disease wasting’ refers to the occurrence of protein–energy wasting in CKD or AKI regardless of the cause. Cachexia is a severe form of protein–energy wasting that occurs infrequently in kidney disease. Protein–energy wasting is diagnosed if three characteristics are present (low serum levels of albumin, transthyretin, or cholesterol), reduced body mass (low or reduced body or fat mass or weight loss with reduced intake of protein and energy), and reduced muscle mass (muscle wasting or sarcopenia, reduced mid-arm muscle circumference). The kidney disease wasting is divided into two main categories of CKD- and AKI-associated protein–energy wasting. Measures of chronic inflammation or other developing tests can be useful clues for the existence of protein–energy wasting but do not define protein–energy wasting. Clinical staging and potential treatment strategies for protein–energy wasting are to be developed in the future.

It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/β-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen.

Klotho is a protein that exerts paracrine and endocrine functions. In chronic kidney disease (CKD), its expression is decreased in several tissues. This decrease probably plays important roles in various complications associated with CKD, in both a fibroblast growth factor-23 (FGF23)-dependent and an FGF23-independent manner. The clinical diagnosis of Klotho deficiency is not easy. The relevance of circulating Klotho levels, if any, needs to be adequately defined. Serum Klotho may not reflect tissue Klotho concentration.

Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients.BackgroundHyperhomocysteinemia, a putative atherothrombotic risk factor, is observed in at least 85% of patients undergoing maintenance hemodialysis (HD), as well as 65 to 70% of renal transplant recipients (RTRs). The hyperhomocysteinemia regularly found in HD patients is largely refractory to combined oral vitamin B supplementation featuring supraphysiological doses of folic acid (FA). Relative to their HD counterparts, the hyperhomocysteinemia of RTRs appears to be considerably less refractory to treatment with high-dose FA-based vitamin B supplementation regimens, although controlled comparison data are lacking. We evaluated whether improved total homocysteine (tHcy)-lowering efficacy could be achieved in chronic HD patients with a high-dose L-5-methyl-tetrahydrofolate (MTHF)-based regimen, as suggested by recent uncontrolled findings, and compared the relative responsiveness of RTRs and HD patients with equivalent baseline tHcy levels, to 12 weeks of tHcy lowering with combined folate-based vitamin B treatment.MethodsFirst, we blocked randomized 50 chronic, stable HD patients based on their screening predialysis tHcy levels, sex, and dialysis center into two groups of 25 subjects treated for 12 weeks with oral FA at 15 mg/day, or an equimolar amount (17 mg/day) of oral MTHF. All 50 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12.ResultsThe mean percentage (%) reductions (± 95% confidence intervals) in predialysis tHcy were not significantly different [MTHF 17.0% (12.0 to 22.0%), FA 14.8% (9.6 to 20.1%),P = 0.444 by matched analysis of covariance adjusted for pretreatment tHcy]. Final on-treatment values (mean with 95% confidence interval) were: MTHF, 20.0 μmol/L (18.8 to 21.2); and FA, 19.5 μmol/L (18.3 to 20.7). Moreover, neither treatment resulted in “normalization” of tHcy levels (that is, final on-treatment values 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absoprption or circulating plasma and tissue distribution. Second, relative to RTR with comparable baseline tHcy levels, the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering vitamin B treatment regimens featuring suprahysiological amounts of FA or the reduced folate MTHF. Accordingly, RTRs are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering vitamin B intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease.

Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis Background Farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP) are isoprenoid products of the intracellular mevalonate pathway used for prenylation of several low molecular weight G proteins, including Ras. It is likely that platelet-derived growth factor (PDGF) stimulation of mesangial cell proliferation requires prenylated, low molecular weight G proteins. The purpose of this study was to investigate the dependence of platelet-derived growth factor-stimulated mesangial cell DNA synthesis and cell membrane Ras incorporation on FPP and GGPP. Methods Quiescent human mesangial cells were exposed to PDGF (25 ng/ml) to stimulate DNA synthesis. Some cells were also treated with the HMG-CoA reductase inhibitor lovastatin (2.5 to 10.0 μM), which inhibits isoprenoid synthesis, in the presence or absence of exogenous FPP or GGPP. DNA synthesis was assessed by thymidine incorporation, and Western blot analysis was used to measure total cell membrane Ras. Results Stimulation of mesangial cells with PDGF did not increase total cell membrane Ras. Lovastatin reduced cell membrane Ras, and this was prevented by simultaneous exposure of mesangial cells to exogenous FPP (2.5 to 10.0 μM) or GGPP (1 to 5 μM). Lovastatin also reduced PDGF-stimulated mesangial cell DNA synthesis by 90%, and this was completely prevented by simultaneous exposure of cells to exogenous GGPP (1 μM), but not to FPP. Conclusions The results of this study suggest that both FPP and GGPP can provide for mesangial cell membrane Ras localization and that PDGF-stimulated mesangial cell DNA synthesis requires the isoprenoid GGPP.

Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors. The pathogenesis of chronic renal allograft rejection is unknown. It is also unclear why cyclosporine has failed to prevent chronic rejection. We examined possible risk factors for graft loss to chronic rejection among 706 renal transplants using the Cox proportional hazards model with fixed and time-dependent covariates. Both the number and the severity of acute rejection episodes were independent risk factors for chronic rejection [relative risk (95% confidence interval) 2.31 (2.04 to 2.60) and 1.53 (1.27 to 1.84), respectively]. Cyclosporine and cyclosporine withdrawal had no effect on chronic rejection. Acute rejections occurring within the first three months after transplantation, when cyclosporine most effectively prevented acute rejection, also had no effect on chronic rejection. Risk factors that were independent of acute rejection and not clearly attributable to immune mechanisms included serum albumin [0.20 (0.10 to 0.38) for each g/dl], proteinuria [1.42 (1.29 to 1.57) for each g/24 hr], and serum triglycerides [1.09 (1.03 to 1.16) for each 100 mg/dl]. These results suggest that the reduction in acute rejection episodes from cyclosporine has failed to reduce graft failure from chronic rejection, possibly because the early (within the first 3 months) and mild acute rejection episodes that are most effectively prevented by cyclosporine do not cause chronic rejection. In addition, the results suggest that there may be a number of nonimmunologic risk factors for chronic rejection.

Lipid-lowering therapy in patients with renal disease. A growing number of clinical trials have examined the effects of different lipid lowering strategies in patients with renal disease. We carried out a meta-analysis to compare and contrast the relative efficacy of various antilipemic therapies in different renal disease settings. Studies that investigated one or more therapies designed to lower serum lipids were combined using weighted multiple linear regression. The analysis adjusted treatment effects for differences in baseline lipid levels and possible placebo effects. The results showed that antilipemic therapies generally had similar effects on lipids in different renal disease settings. In nephrotic syndrome the greatest and most consistent reductions in low density lipoprotein cholesterol (LDL) were seen with 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (regression coefficient with 95% confidence interval in mg/dl = -63, -79 to -46). Similar results were seen for LDL in renal transplant (-51, -57 to -45), renal insufficiency (-62, -82 to -42), hemodialysis (-65, -80 to -50) and continuous ambulatory peritoneal dialysis (CAPD) patients (-84, -104 to -64). Fibric acid analogues had less effect on LDL, but caused greater reductions in triglycerides: -132, -178 to -87, in nephrotic syndrome; -69, -93 to -45 in transplant; -107, -169 to -45 in renal insufficiency; -72, -120 to -24 in hemodialysis; and -96, -162 to -30 in CAPD. In general, the effects of diet and other therapies were less consistent. Despite possible limitations of this meta-analysis, the results provide a useful framework for choosing antilipemic therapy, and point to areas for future long-term studies examining the safety and efficacy of lipid lowering strategies in patients with renal disease.

Potential strategies to normalize the levels of homocysteine in chronic renal failure patients. Recently published evidence suggests that, either than folate therapy, the enhancement of homocysteine remethylation in tissues by correcting the multiple abnormalities of the remethylation pathway in chronic renal failure that extend beyond folate-related disturbances, or else the improved removal of uremic toxins and/or Hcy through intensified dialysis procedures may represent two strategies to normalize total homocysteine in uremic patients.

Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease (CVD) in patients with chronic renal failure (CRF). The phosphate-binder sevelamer has been shown to decrease both phosphate and FGF23, but limited data indicate that sevelamer improves CRF-related CVD, such as diastolic dysfunction, left ventricular hypertrophy (LVH), and aortic stiffness. To gain additional information, we measured the effects of sevelamer on CVD in a murine model of CRF. Groups of CRF and sham-operated mice received regular chow or 3% sevelamer–HCl in the chow for 14 weeks, starting 6 weeks after the initiation of CRF or sham operation. After the first 8 weeks of sevelamer treatment, CRF mice had decreased serum phosphate levels and an improved aortic systolic expansion rate, pulse-wave velocity, and diastolic function, although LVH remained unchanged. Following an additional 6-week course of sevelamer, LVH had not progressed. The FGF23 serum level was not reduced by sevelamer until after 14 weeks of treatment. In multiple regression analysis, serum phosphate, but not FGF23, was independently correlated with LV diastolic function and mass. Thus, sevelamer first improved aortic stiffness and diastolic dysfunction and secondarily prevented LVH in mice with CRF. The phosphate-lowering, rather than FGF23-lowering, effect appears to be responsible for the observed cardiovascular improvement.

To the Editor: The recent in vitro studies of the Slatopolsky group1 have shown that the 'non active' 25-OH-vitamin D metabolite was actually efficient (even though less potent) at physiological concentration for suppressing parathyroid hormone synthesis by direct stimulation of the vitamin D receptor, and that this direct stimulation was even preponderant over that induced by 1,25(OH) vitamin D3 produced in situ. This is consistent with our earlier reports evidencing (1) in predialysis patients,2 a good long-term control of hyperparathyroid bone disease by just normocalcemic dose of 25-OH-vitamin D in association with up to 2.4 g/day of CaCO3 and (2) in dialysis patients,3 an independent inverse link between parathyroid hormone and 25-OH-vitamin D serum concentrations independently of serum concentrations of calcitriol, calcium, and phosphate.

Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy.BackgroundFolic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients.MethodsIn a cohort of 37 patients on intermittent HD treatment, plasma tHcy concentrations were determined before and during i.v. supplementation of folinic acid (50mg once per week), together with i.v. pyridoxine (250mg 3 times per week), to prevent vitamin deficiency, particularly in those treated by recombinant erythropoietin.ResultsFolinic acid and pyridoxine i.v. supplementation was given for 11.2 ± 2.45 months (range 7.5 to 17 months). The mean plasma tHcy levels decreased significantly from 37.3 ± 5.8 μM at baseline to 12.3 ± 5.4 μM on folinic acid treatment (P < 0.001). Moreover, 29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up (that is

The central role of nuclear factor-kB in mesangial cell activation Background Nuclear factor-kBB (NF-kB) is a family of transcription factors that is recognized by the kB enhancer element. Numerous proinflammatory genes have binding sites for NF-kBB, and the products of these genes are an integral part of cellular activation and inflammatory response systems. Because there is a close relationship between NF-kB and mediators of cell activation, it is possible that a disruption of NF-kB–activating pathways may effectively influence mesangial cell activation. Methods We reviewed available studies related to both NF-kB and mesangial cells in order to provide evidence for the role of NF-kB in mesangial cell activation. Results Studies reported by this laboratory and others showed that various experimental maneuvers that modulate NF-kB activation result in a parallel modulation of proinflammatory molecule production in cultured mesangial cells. Likewise, the ability of the inhibitors of NF-kB activation to down-regulate the inflammatory response in animal models of renal disease has been recently demonstrated. Conclusions These data suggest a pivotal role of NF-kB in mesangial cell activation and designate it as an obvious target for the modulation of this activation. Studies are necessary to characterize the role of NF-kB in human renal injury.

Role of oxidized low-density lipoprotein in the atherosclerosis of uremia. Lipoprotein oxidation is involved in the genesis of atherosclerosis. In chronic renal failure (CRF), oxidative stress is enhanced because of an imbalance between pro-oxidant and antioxidant systems. Oxidative modifications of low-density lipoproteins (LDLs) occur not only at the level of lipid moiety, but also of protein moiety. We have shown that oxidation of LDL by hypochlorous acid (HOCl) in vitro, reflecting increased myeloperoxidase activity in vivo, leads to modifications of apoliproteins such that the latter in turn are capable of triggering macrophage nicotinamide adenine dinucleotide phosphate-oxidase activation. These oxidative changes of LDL protein moiety, if shown to occur to a significant extent in uremic patients in vivo, may represent an important alternative pathway in the pathogenesis of atheromatous lesions.

Chronic inflammation associated with chronic kidney disease predicts all-cause and cardiovascular mortality in hemodialysis patients. Here we sought to evaluate the association between plasma levels of the inflammatory mediator interleukin-6 (IL-6) and mortality and aortic calcification/stiffness in 125 patients at different stages (2-5D) of chronic kidney disease. Using multivariate linear regression, we found that plasma IL-6 was independently associated with C-reactive protein, albumin and the stage of chronic kidney disease, but not the aortic calcification score or pulse wave velocity. During follow-up studies (median of 829 days), 38 patients died, 22 from cardiovascular events. Plasma IL-6 significantly predicted overall and cardiovascular mortality; this association persisted after multiple adjustments or restricting the analysis to pre-dialysis patients. Moreover, IL-6 was a significantly better predictor of mortality than C-reactive protein, albumin or tumor necrosis factor-α. Hence, plasma IL-6 independently predicted overall and cardiovascular mortality in patients at different stages of chronic kidney disease; however, whether lowering plasma IL-6 will affect the outcome of chronic kidney disease will require more direct evaluation.

Homocyst(e)ine, oxidative stress, and endothelium function in uremic patients. Moderate hyperhomocyst(e)inemia and impaired endothelium-dependent vasodilatation are present in uremic patients. However, the precise mechanism(s) underlying the link between moderate hyperhomocyst(e)inemia and endothelium dysfunction in uremic patients remains to be determined. Experimental and clinical evidence have led to the suggestion that moderate hyperhomocyst(e)inemia may predispose to endothelium dysfunction through a mechanism that involves generation of reactive oxygen species and a decrease in nitric oxide bioavailability. Recent preliminary findings in uremic patients provide support for some aspects of this suggestion. These data must be confirmed in additional studies. Moreover, the relative importance of homocysteine-induced oxidant stress versus other potential mechanisms of endothelium dysfunction in these patients remains to be determined.

To the Editor: In the CHOICE dialysis cohort, Melamed et al. found in their lagged analysis that intact PTH levels o76 pg/ml were associated with a 35% lower mortality compared to levels of 160–308 pg/ml. In order to appropriately discuss this observation in relation with National Kidney Foundation-Kidney Disease Outcomes Quality Initiative optimal intact parathyroid hormone (PTH) of 150–300 pg/ml, we think that these figures have to be first corrected by the 50% lower median bias induced by the Diasorin intact PTH assay when compared with the Nicholls Allegro assay to which Kidney Disease Outcomes Quality Initiative is referring. This means that Allegro PTH o150 pg/ml would be associated with a better survival than PTH of 300–620 pg/ml. This certainly challenges the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative recommendation of preventing a PTH o150 pg/ml. This is not too surprising as this recommendation was just based on claims of a few authors (cited by Melamed) who pointed out a link between low bone turnover and mortality. Furthermore, this recommendation disregarded the results of the bone histomorphometric study meta-analysis suggesting that Allegro PTH o60 pg/ml best predicted low bone turnover. It should be, however, noted that the observation by Melamed et al. is in agreement with the most recent prognostic evaluation of PTH by Block et al., which, owing to better adjustment with other comorbidities (specially malnutrition), did not find anymore a higher mortality with Allegro PTH o150 pg/ml, but found a higher mortality when PTH was 4600 pg/ml.