Showing papers by "Tilman B. Drüeke published in 2009"

Fetuin-A Protects against Atherosclerotic Calcification in CKD

Abstract: Reduced serum levels of the calcification inhibitor fetuin-A associate with increased cardiovascular mortality in dialysis patients. Fetuin-A–deficient mice display calcification of various tissues but notably not of the vasculature. This absence of vascular calcification may result from the protection of an intact endothelium, which becomes severely compromised in the setting of atherosclerosis. To test this hypothesis, we generated fetuin-A/apolipoprotein E (ApoE)-deficient mice and compared them with ApoE-deficient and wild-type mice with regard to atheroma formation and extraosseous calcification. We assigned mice to three treatment groups for 9 wk: (1) Standard diet, (2) high-phosphate diet, or (3) unilateral nephrectomy (causing chronic kidney disease [CKD]) plus high-phosphate diet. Serum urea, phosphate, and parathyroid hormone levels were similar in all genotypes after the interventions. Fetuin-A deficiency did not affect the extent of aortic lipid deposition, neointima formation, and coronary sclerosis observed with ApoE deficiency, but the combination of fetuin-A deficiency, hyperphosphatemia, and CKD led to a 15-fold increase in vascular calcification in this model of atherosclerosis. Fetuin-A deficiency almost exclusively promoted intimal rather than medial calcification of atheromatous lesions. High-phosphate diet and CKD also led to an increase in valvular calcification and aorta-associated apoptosis, with wild-type mice having the least, ApoE-deficient mice intermediate, and fetuin-A/ApoE-deficient mice the most. In addition, the combination of fetuin-A deficiency, high-phosphate diet, and CKD in ApoE-deficient mice greatly enhanced myocardial calcification, whereas the absence of fetuin-A did not affect the incidence of renal calcification. In conclusion, fetuin-A inhibits pathologic calcification in both the soft tissue and vasculature, even in the setting of atherosclerosis.

The role of oxidative stress in chronic kidney disease.

Abstract: New, reliable circulating oxidative stress markers have become available in chronic kidney disease (CKD) patients and have confirmed the long held belief that CKD is a pro-oxidant state. However, several questions related to this state of oxidative stress remain largely unresolved. First, the relative importance of each type of oxidant involved has been insufficiently evaluated. Only two recent studies have addressed this issue, and both suggested that chlorinated stress played a central role. Second, as only few population-based studies are available, the prevalence of oxidative stress among CKD patients remains undetermined. Third, although the link between oxidative stress and inflammation in CKD is emerging as a key process contributing to the genesis of oxidative stress in these patients, its pathogenesis remains poorly defined. Fourth, data favoring the involvement of oxidative stress in uremic toxicity are still limited. Finally, while two recent pilot studies have demonstrated that treatment of CKD patients with antioxidants is able to reduce cardiovascular events, information related to the pharmacokinetic characteristics of antioxidants, as well as their efficacy to prevent oxidative stress, is still limited in this patient group. Thus, although existing data suggest a prominent role of CKD-associated oxidative stress in uremic toxicity, further studies are required to definitively prove this concept.

Left Ventricular Geometry Predicts Cardiovascular Outcomes Associated with Anemia Correction in CKD

Abstract: Partial correction of anemia in patients with chronic kidney disease (CKD) reduces left ventricular hypertrophy (LVH), which is a risk factor for cardiovascular (CV) morbidity, but complete correction of anemia does not improve CV outcomes. Whether LV geometry associates with CV events in patients who are treated to different hemoglobin (Hb) targets is unknown. One of the larger trials to study the effects of complete correction of anemia in stages 3 to 4 CKD was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial. Here, we analyzed echocardiographic data from CREATE to determine the prevalence, dynamics, and prognostic implications of abnormal LV geometry in patients who were treated to different Hb targets. The prevalence of LVH at baseline was 47%, with eccentric LVH more frequent than concentric. During the study, LVH prevalence and mean left ventricular mass index did not change significantly, but LV geometry fluctuated considerably within 2 yr in both groups. CV event-free survival was significantly worse in the presence of concentric LVH and eccentric LVH compared with the absence of LVH (P = 0.0009 and P ≤ 0.0001, respectively). Treatment to the higher Hb target associated with reduced event-free survival in the subgroup with eccentric LVH at baseline (P = 0.034). In conclusion, LVH is common and associates with poor outcomes among patients with stages 3 to 4 CKD, although both progression and regression of abnormal LV geometry occur. Complete anemia correction may aggravate the adverse prognosis of eccentric LVH.

PROGRESS IN UREMIC TOXIN RESEARCH: Beta2‐Microglobulin

Abstract: Among the uremic toxins in the “middle molecule” range, beta2-microglobulin (β2-M) is certainly one of the most frequently studied compounds. Its serum level increases with the progression of chronic kidney disease, to reach very high concentrations in patients with end-stage kidney disease. It is the major protein component of dialysis-related amyloidosis, a dramatic complication which results from high extracellular concentration and posttranslational modification of β2-M and a number of other promoters of amyloid fibril formation and deposition in osteo-articular tissues. Effective removal of β2-M can be achieved with highly effective hemodialysis and hemodiafiltration techniques but predialysis session serum levels cannot be normalized. The prevalence and severity of β2-M amyloidosis appear to have decreased in the last 20 years, although its occurrence may simply be delayed.

Serum pyridinoline as a specific marker of collagen breakdown and bone metabolism in hemodialysis patients

Abstract: Type I collagen represents more than 90% of bone matrix. Quantitative analysis of collagen cross-link molecules such as pyridinoline (PYD) provides valuable information on bone resorption rate. We have studied 37 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Eighteen of them had tetracycline double labeling, allowing to determine dynamic, in addition to static bone parameters. Measurement of serum-free PYD was performed using a new competitive enzyme immunoassay. Serum PYD values were compared with those of three other serum markers of bone metabolism, namely intact PTH (iPTH), bone-specific alkaline phosphatase (bAP), and osteocalcin, for the correlations with bone histomorphometric parameters. Serum PYD levels (mean +/- SD) were significantly higher in dialysis patients than in normal individuals, 90.6 +/- 99.6 nM versus 1.9 +/- 0.4 nM, respectively. Patients with high turnover bone disease had significantly higher serum PYD levels than patients with normal or low bone turnover, 108.8 +/- 108.0 nM versus 34.1 +/- 12.8 nM, respectively. Serum PYD levels were positively correlated with bone resorption parameters including osteoclast surface (r = 0.59, p < 0.0001) and osteoclast number/mm2 (r = 0.61, p < 0.0001), and also with bone formation parameters, osteoblast surface (r = 0.43, p < 0.008), double-labeled surface (r = 0.81, p < 0.001), and BFR (r = 0.91, p < 0.0001). The BFR was better correlated with serum PYD levels than with either serum iPTH or osteocalcin concentrations. However, correlation with serum bAP was comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of secondary hyperparathyroidism in CKD patients with cinacalcet and/or vitamin D derivatives.

Abstract: The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics.

Calcium balance in haemodialysis—do not lower the dialysate calcium concentration too much (con—part)

Abstract: The debate on the most adequate dialysate calcium concentration for intermittent haemodialysis therapy is ongoing. There is probably no one optimal concentration. In general, one would like to maintain a neutral calcium balance in adult haemodialysis patients. However, a slightly negative balance may be preferable to avoid soft-tissue calcium accumulation in face of net calcium loss from the bone with ageing. The problem with measurements of calcium balance is that they are generally imprecise, as are estimations of total body calcium and its distribution in various compartments, unless done with labour-intensive methods and great care. The choice of the dialysate calcium will depend on several factors, including parathyroid and vitamin D status, type and severity of concomitant bone disease, presence or absence of arterial calcification, dietary habits, drug treatment and dialysis modality. Ideally the dialysate calcium would be adapted to each patient's needs. This is not feasible, however, in most dialysis settings and neither is it cost-effective. From a practical point of view, a relatively high dialysate calcium concentration in the range of of 1.50-1.75 mmol/L (3.0-3.5 mEq/L) should probably be preferred in haemodialysis patients with high serum PTH levels who are not prescribed calcium-based phosphate binders or high doses of active vitamin D sterols, and in those who are receiving a calcimimetic. In those who are treated with high doses of calcium-based binders and/or active vitamin D derivatives or who have a very low serum PTH level, the optimal dialysate calcium concentration is probably lower, in the range of 1.25-1.50 mmol/L (2.50-3.0 mEq/L). In the present pro/con debate about the optimal dialysate calcium concentration used for the haemodialysis session, we have accepted to defend the viewpoint that a low calcium concentration may do more harm than benefit in many patients. This viewpoint is opposite to that taken by Gotch [1]. He argues that since calcitriol and other active vitamin D derivatives have become available virtually all haemodialysis patients are in positive calcium balance. We would like to take issue with this statement and warn against the indiscriminate use of a low calcium dialysate in all patients receiving haemodialysis therapy.

Impact of Disturbances of Calcium and Phosphate Metabolism on Vascular Calcification and Clinical Outcomes in Patients with Chronic Kidney Disease

Abstract: Chronic kidney disease (CKD) is frequently complicated by arterial calcification. The latter is part of the associated mineral and bone disorder (CKD-MBD). Hypercalcemia and hyperphosphatemia have long been known to play a major role in the occurrence of vascular and other soft tissue calcification in patients with CKD, together with endocrine disturbances including vitamin D, parathyroid hormone, fibroblast growth factor-23, and klotho. In addition, many other systemic and local promoters, including inflammation and uremic toxins, contribute to the occurrence of vascular calcification, despite a powerful defense system made up of systemic and local inhibitors, as demonstrated in elegant experimental studies done in vitro and in vivo. Most importantly, several reports have shown that both hyperphosphatemia and hypophosphatemia, and to a lesser degree hypercalcemia and hypocalcemia, are associated with an increased relative risk of mortality in patients with CKD. However, all these reports were observational in nature and must therefore be considered as hypothesis generating. It remains to be demonstrated in prospective randomized trials whether normalization of serum phosphorus and/or calcium leads to better patient outcome. In order to improve outcome in patients with CKD-MBD, early medical intervention is of utmost importance.

The Role of EUTox in Uremic Toxin Research

Abstract: In this publication, we review the activities of the European Uremic Toxin Work Group (EUTox) in the field of uremic toxin research. Founded in 1999 under the umbrella of the European Society of Artificial Organs (ESAO), and active since 2000, this group focuses essentially on questions related to solute retention and removal during chronic kidney disease, and on the deleterious impact of those solutes on biological/biochemical systems. As of January 1, 2009, the group had met 28 times; it organized the third meeting, "Uremic Toxins in Cardiovascular Disease," which took place in October 2008 in Amiens, France. The current group is composed of 25 members belonging to 23 European research institutions. As of November 1, 2008, in total 69 papers had been published to which at least two different research groups belonging to EUTox have contributed in a collaborative effort. Of these, 40 papers were on original research and eight were specific EUTox reviews or position statements. A website (http://www.eutox.info) summarizes all relevant information concerning the work group. EUTox also developed an interactive uremic toxin database, where concentrations of known toxins are displayed, to be used by researchers in the field. In the future, EUTox intends to continue its focus on bench to bedside research with specific consideration of proteomics, metabonomics, secretomics, and genomics.

Introduction and definition of CKD-MBD and the development of the guideline statements

Abstract: INTRODUCTION AND DEFINITION OF CKD–MBD Chronic kidney disease (CKD) is an international public health problem affecting 5–10% of the world population. As kidney function declines, there is a progressive deterioration in mineral homeostasis, with a disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in circulating levels of hormones. These include parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and other vitamin D metabolites, fibroblast growth factor-23 (FGF-23), and growth hormone. Beginning in CKD stage 3, the ability of the kidneys to appropriately excrete a phosphate load is diminished, leading to hyperphosphatemia, elevated PTH, and decreased 1,25(OH)2D with associated elevations in the levels of FGF-23. The conversion of 25(OH)D to 1,25(OH)2D is impaired, reducing intestinal calcium absorption and increasing PTH. The kidney fails to respond adequately to PTH, which normally promotes phosphaturia and calcium reabsorption, or to FGF-23, which also enhances phosphate excretion. In addition, there is evidence at the tissue level of a downregulation of vitamin D receptor and of resistance to the actions of PTH. Therapy is generally focused on correcting biochemical and hormonal abnormalities in an effort to limit their consequences. The mineral and endocrine functions disrupted in CKD are critically important in the regulation of both initial bone formation during growth (bone modeling) and bone structure and function during adulthood (bone remodeling). As a result, bone abnormalities are found almost universally in patients with CKD requiring dialysis (stage 5D), and in the majority of patients with CKD stages 3–5. More recently, there has been an increasing concern of extraskeletal calcification that may result from the deranged mineral and bone metabolism of CKD and from the therapies used to correct these abnormalities. Numerous cohort studies have shown associations between disorders of mineral metabolism and fractures, cardiovascular disease, and mortality (see Chapter 3). These observational studies have broadened the focus of CKD-related mineral and bone disorders (MBDs) to include cardiovascular disease (which is the leading cause of death in patients at all stages of CKD). All three of these processes (abnormal mineral metabolism, abnormal bone, and extraskeletal calcification) are closely interrelated and together make a major contribution to the morbidity and mortality of patients with CKD. The traditional definition of renal osteodystrophy did not accurately encompass this more diverse clinical spectrum, based on serum biomarkers, noninvasive imaging, and bone abnormalities. The absence of a generally accepted definition and diagnosis of renal osteodystrophy prompted Kidney Disease: Improving Global Outcomes (KDIGO) to sponsor a controversies conference, entitled ‘Definition, Evaluation, and Classification of Renal Osteodystrophy,’ held on 15–17 September 2005 in Madrid, Spain. The principal conclusion was that the term ‘CKD–Mineral and Bone Disorder (CKD–MBD)’ should be used to describe the broader clinical syndrome encompassing mineral, bone, and calcific cardiovascular abnormalities that develop as a complication of CKD (Table 1). It was also recommended that the term ‘renal osteodystrophy’ be restricted to describing the bone pathology associated with CKD. The evaluation and definitive diagnosis of renal osteodystrophy require a bone biopsy, using an expanded classification system that was developed at the consensus conference based on parameters of bone turnover, mineralization, and volume (TMV).

Effects of uremic toxins on vascular and bone remodeling.

Abstract: Chronic kidney disease (CKD) is associated with both extensive vascular calcification and abnormal bone remodeling, namely renal osteodystrophy. Moreover, there is increasing evidence for a close relationship between bone and vessel function. Pathological vascular calcification has been recently recognized as an active, cell-mediated process with similarities to physiological skeletal mineralization. Accordingly, we described the concept of vascular remodeling, in analogy to bone remodeling. In this review, we discuss the role of uremic toxins in the cross-talk between bone and vessel, and emphasize their potential contribution to the development of both vascular and bone remodeling disorders in patients with CKD.

Evaluation of bone remodeling in hemodialysis patients: serum biochemistry, circulating cytokines and bone histomorphometry.

Abstract: BACKGROUND To optimize the noninvasive evaluation of bone remodeling, we evaluated, besides routine serum markers, serum levels of several cytokines involved in bone turnover. METHODS A transiliac bone biopsy was performed in 47 hemodialysis patients. Serum levels of intact parathyroid hormone (iPTH; 1-84), total alkaline phosphatases (tAP), calcium, phosphate and aluminum (Al) were measured. Circulating levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1Ra) and soluble IL-6 receptor (sIL-6r) were determined using ELISA. Circulating IL-1beta, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-alpha (TNF-alpha) were simultaneously quantified by flow cytometric immunoassay. RESULTS Patients with low/normal bone formation rate (L/N-BFR) had significantly lower serum iPTH (p 300 pg/mL in association with tAP >120 U/L showed low sensitivity (58.8%) and low negative predictive value (44.0%) for the diagnosis of high BFR disease. An iPTH <300 pg/mL in association with normal or low tAP, <120 U/L, was associated with low sensitivity (66.7%) but high specificity (97.1%) for the diagnosis of L/N-BFR. Serum IL-1, IL-6, IL-12p70 and TNF-alpha were positively correlated with BFR, serum IL1-Ra and IL-10 with bone area, and by multiple regression analysis, tAP and IL-6 were independently predictive of BFR. CONCLUSIONS Significant associations were found between several circulating cytokines and bone histomorphometry in dialysis patients. The usefulness of these determinations in the noninvasive evaluation of bone remodeling needs to be confirmed in larger dialysis populations.

La prescription de vitamine D chez le patient dialysé en pratique clinique

Abstract: The vitamin D hormonal system is involved in the regulation of more than 800 genes. Vitamin D deficiency, which is evaluated on the basis of the serum level of 25-hydroxycholecalciferol (25[OH]D), is frequently observed in the general population, particularly in patients with chronic kidney disease (CKD). Vitamin D deficiency is associated with an increased risk of falls and fracture and also with diabetes, malignancies, autoimmune diseases, depression and mortality. Furthermore, CKD is accompanied by a decrease in the renal production of 1,25 dihydroxycholecalciferol (1,25[OH](2)D). Such deficiencies have also been implicated in the pathophysiology of secondary hyperparathyroidism. Currently, vitamin D supplementation is not recommended in stage 5 CKD. However, since there is also significant extra-renal production of 1,25(OH)(2)D this would appear to be in favour of vitamin D treatment. We describe the disturbances of vitamin D metabolism occurring in CKD and discuss the advantages and the potential toxicity risk of vitamin D supplementation as well as the optimal serum 25[OH]D level. We then present the pharmacological properties of the various medicinal forms of vitamin D derivates and suggest therapeutic guidelines for supplementation with 25(OH)D(3) or cholecalciferol. We also examine existing guidelines for the administration of active 1-alpha-hydroxylated vitamin D. Despite the absence of strong scientific support by randomized controlled intervention studies, vitamin D supplementation should be considered in patients with CKD stages 4-5D having vitamin D insufficiency or deficiency, for the prevention of secondary hyperparathyroidism and for other potential benefits owing to its pleiotropic effects.

Conservative treatment of the uremic syndrome.

Abstract: In addition to extracorporeal renal replacement strategies, which in chronic kidney disease (CKD) are largely reserved for the treatment of end-stage kidney failure, conservative measures can be taken to reduce concentration, effects, or both concentration and effects of uremic retention solutes. In this overview, we will focus on those therapies, which are aimed at preventing or delaying cardio-vascular disease, retarding or halting the progression of CKD, or both. We will discuss, consecutively, inhibitors of the renin-angiotensin-aldosterone axis, beta-blockers, calcium-channel antagonists, anti-inflammatory drugs, intestinal sorbents, calcimimetics, and glitazones. Some of these approaches could lead to a therapeutic breakthrough in the future. In addition, comprehensive tables will be provided for more traditional therapeutic approaches, such as lifestyle changes and other pharmaceutical treatments.