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Biomedical subjects

T B Drüeke

Publications and source records attributed to T B Drüeke.

At least 19 recordsLinked to original sources
PubMed2006

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.

Chelating Agents↗
PubMed2005

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.

Adult↗
PubMed2001

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.

Arteriosclerosis↗
PubMed2001

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.

Animals↗
PubMed2001

Control of secondary hyperparathyroidism by vitamin D derivatives.

The treatment of the secondary hyperparathyroidism of chronic renal failure patients has greatly improved during the last 2 decades. Significant progress has been made, in particular in the indication of 1alpha-hydroxylated vitamin D derivatives and patient management using these compounds. Treatment and prevention should start early during the development of chronic renal insufficiency. One of the major remaining problems in more advanced stages of renal failure is that control of plasma phosphate often remains extremely difficult. New inert oral phosphate binders are needed. The nephrology community is still waiting for the advent of nonhypercalcemic and nonhyperphosphatemic vitamin D analogs with PTH suppressive activity equal to the parent compound calcitriol or its immediate precursor, alfacalcidol.

Administration, Oral↗
PubMed2001

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.

Calcitriol↗
PubMed2001

Oxidative stress and haemodialysis: role of inflammation and duration of dialysis treatment.

BACKGROUND: Oxidative stress has long been demonstrated in haemodialysis patients. However, the factors influencing their oxidative status have not been characterized extensively in these patients. Therefore, the present study was designed to investigate the influence of a large number of factors known to be associated with oxidative stress. METHODS: In the present cross-sectional study, we determined the plasma levels of lipid and protein oxidation markers in 31 non-smoking haemodialysis patients and 18 non-smoking healthy subjects, together with various components of the antioxidant system at the plasma and erythrocyte level. RESULTS: No influence of age, diabetes or iron overload on oxidative markers and plasma and erythrocyte antioxidant systems was detected in these haemodialysis patients. The lack of an association between iron overload and oxidative status may be related to the lower level of plasma ascorbate in haemodialysis patients, since ascorbate favours the generation of free iron from ferritin-bound iron. Interestingly, plasma C reactive protein (CRP) levels measured by highly sensitive CRP assay were correlated positively with plasma levels of thiobarbituric acid reactive substances (r=0.38, P<0.04) and negatively with plasma alpha-tocopherol levels (r=-0.46, P<0.01). Moreover, significant inverse correlations were observed between duration of dialysis treatment and plasma levels of alpha-tocopherol (r=-0.49, P<0.02) and ubiquinol (r=-0.40, P<0.05). CONCLUSIONS: Our results suggest that inflammatory status and duration of dialysis treatment are the most important factors relating to oxidative stress in haemodialysis patients.

Adult↗
PubMed2001

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.

Acrylic Resins↗
PubMed2000

Caspase-dependent apoptosis in THP-1 cells exposed to oxidized low-density lipoproteins.

Oxidized low-density lipoproteins (oxLDL) play a critical role in atherogenesis. We investigated the apoptotic process in human monocytic THP-1 cell line, exposed to oxLDL generated by treatment of native LDL either with hypochlorous acid (HOCl), mainly affecting the protein moiety, or with copper sulfate (CuSO(4)), mainly affecting the lipid moiety. After incubation with both types of oxLDL, we observed: (i) microscopy signs of apoptosis in THP-1 cells, (ii) a significant increase of apoptotic cells proportional to LDL protein concentration, either by annexin V or by cell cycle phase analysis with propodium iodide flow cytometry, (iii) a reduction of THP-1 cell apoptosis in presence of the caspase inhibitor Z-VAD.fmk, (iv) the resistance of THP-1 cells apoptosis after PMA-elicited differentiation. In conclusion, HOCl-oxLDL are as potent as Cu-oxLDL to induce high rates of apoptosis in monocytes through a caspase-dependent pathway. Moreover, the resistance of differentiated THP-1 cells to oxLDL-induced apoptosis is compatible with the hypothesis that mature macrophages have prolonged survival and thereby enhance the atherogenic process.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Absence of response to human parathyroid hormone in athymic mice grafted with human parathyroid adenoma, hyperplasia or parathyroid cells maintained in culture.

In athymic mice we have developed a model of long-term human PTH hypersecretion, using xenotransplantation of respectively parathyroid gland fragments obtained from patients with primary (primary) or secondary (secondary) uremic hyperparathyroidism (HPT), and parathyroid cells maintained in culture from patients with secondary uremic HPT. Both grafted parathyroid tissue fragments and cultured cells induced prolonged and marked secretion of human intact PTH (iPTH) in nude mice. Despite extremely high plasma iPTH levels, hypercalcemia or hypophosphatemia was not observed. Moreover, PTH secretion was not significantly modified by low-calcium, high-phosphate diet for 3 weeks. Four mice which had a mean plasma human iPTH level of 237+/-152 pg/ml for more than 9 months and 4 age-matched, sham-grafted control mice with undetectable human iPTH levels underwent bone histomorphometry examination. No difference was found between the two groups with respect to active bone resorption surface or number of osteoclasts/mm2. We hypothesize that the characteristic deficit of T cell function and of cytokine and growth factor production may protect nude mice with chronic hypersecretion of human PTH from hypercalcemia and bone lesions. We suggest that this strain of mice could be used for better understanding the relationship between cytokines and bone turnover.

Adenoma↗
PubMed2000

[The salt-free diet].

The debate about the importance of salt in the pathogenesis and treatment of hypertension is still ongoing. The importance of salt is rooted on several factors. First, salt is one of the first factors who has been identified to be of potential importance in blood pressure regulation. Second, during the last decades several other pathogenetic risk factors for essential hypertension have been identified, however, without the identification of one single predominant risk factor. These risk factors include different genetic factors and predispositions as well as modifiable environmental factors. For the development of hypertension usually several of these risk factors have to be present. In miscellaneous disease conditions, such as heart failure, salt induces a sodium and volume retention. Accordingly it is often falsely concluded that salt will lead to a volume retention and hypertension in all subjects and that a salt restriction will lead to a normalization of an elevated blood pressure. Although about 40% of the patients with essential hypertension are salt sensitive, the concept of salt sensitivity is not valid for all subjects of a population. Accordingly one can not conclude that a general salt restriction would be a cure for hypertension. The therapeutic priority in the non-pharmacological prevention and/or therapy of hypertension lies usually in the control of other risk factors than salt intake. These risks include overweight and obesity, alcohol consumption and physical inactivity. These concepts are supported by several recent meta-analysis.

Diet, Sodium-Restricted↗
PubMed2000

Apoptosis in parathyroid hyperplasia of patients with primary or secondary uremic hyperparathyroidism.

BACKGROUND: Chronic oversecretion of parathyroid hormone (PTH) is associated with parathyroid hyperplasia, reflecting a disturbed balance between cell proliferation and apoptosis. This study addressed the unsolved issue of apoptosis in hyperparathyroidism. METHODS: Parathyroid glands from 19 patients with primary (1 degrees ) and 11 patients with secondary (2 degrees ) uremic hyperparathyroidism, as well as 13 normal parathyroid glands, were examined. Apoptosis was evaluated by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end-labeling assay (TUNEL). Because the apoptotic process is regulated by several oncoproteins, the expression of Bcl-2 and Bax was analyzed by immunohistochemistry. RESULTS: The numbers of apoptotic cells in 1 degrees parathyroid adenoma (0.99 +/- 0.03 per 1000 cells, mean +/- SE, P < 0.009) and 2 degrees parathyroid hyperplasia (1.20 +/- 0.54 per 1000 cells, P < 0.005) were significantly higher than in normal parathyroid tissue (0.13 +/- 0. 06 per 1000 cells). Light microscopy examination of hyperplastic parathyroid tissue from a uremic patient showed the presence of nuclei with dense chromatin characteristic of apoptosis. Bcl-2 staining was strong in normal tissues but weak or negative in several sections of 1 degrees and 2 degrees hyperparathyroid tissues, mostly in nodular areas. Bax staining was homogeneous in normal tissue but patchy in several hyperplastic tissues. CONCLUSION: These results suggest that hyperparathyroidism is associated with a compensatory increase in apoptosis, possibly favored by a diminished Bcl-2/Bax ratio. This renders highly improbable the hypothesis that parathyroid hyperplasia is due to a decreased rate of apoptosis.

Apoptosis↗
PubMed2000

Reoperation for secondary uremic hyperparathyroidism: are technical difficulties influenced by initial surgical procedure?

BACKGROUND: Parathyroid surgery in patients with uremia and secondary hyperparathyroidism is performed either by subtotal parathyroidectomy or total parathyroidectomy with immediate reimplantation. The aim of this study was to compare the results of reoperation for persistent or recurrent hyperparathyroidism after parathyroidectomy according to which initial operative procedure was used. PATIENTS AND METHODS: Eighty-nine patients had reoperation for persistent (28 patients) or recurrent (61 patients) hyperparathyroidism after 53 subtotal parathyroidectomies and 36 total parathyroidectomies with immediate reimplantation. Results of the reoperation were assessed in terms of success rate, morbidity, and operative findings. RESULTS: The success rate of reoperation in patients with persistent hyperparathyroidism was 89% and was independent of the initial type of surgery. Success rates of reoperation for recurrent hyperparathyroidism after initial subtotal parathyroidectomy and total parathyroidectomy with immediate reimplantation were 87% and 70%, respectively (P = .02). Hypertrophy of the parathyroid remnant was the main cause of recurrence after subtotal parathyroidectomy. After total parathyroidectomy with immediate reimplantation, recurrence was located in the graft in half the patients, while hyperplastic tissue was found in the neck or the mediastinum in the other half. CONCLUSIONS: Subtotal parathyroidectomy provides the best conditions for successful reoperation in case of recurrent hyperparathyroidism and should become the surgical treatment of choice for secondary hyperparathyroidism.

Adult↗
PubMed2000

Beta2-microglobulin and amyloidosis.

Dialysis-associated amyloidosis is a serious complication in chronic dialysis patients. Its clinical expression in terms of arthralgias, destructive arthopathies and carpal tunnel syndrome is often associated with amyloid deposits, which are mainly composed of beta2-microglobulin (beta2-M) fibrils, but in addition contain a number of other compounds. It is probable that beta2-M-amyloid deposition is related, at least in part, to the elevated plasma beta2-M that is characteristic of chronic renal failure. The latter can decrease with high-performance dialysis techniques but cannot be reduced to the normal range. Almost certainly, several other systemic and local factors are involved, including beta2-M transformed by advanced glycation end products and advanced oxidation protein products, serum P component, ubiquitin, calcium crystals, cytokines, immunoglobulin light chains, proteases and antiproteases, as well as modified collagen and glucosaminoglycans. It is also possible that the beta2-M protein, in its native or modified form, exerts noxious effects on bone and joint tissues, in addition to its mere 'passive' presence as amyloid fibrils. Several retrospective studies and one prospective study suggest that dialysis strategies with highly permeable, synthetic membranes and/or ultrapure dialysate may be partially protective or at least delay the onset of dialysis amyloidosis. Successful kidney transplantation generally halts the disease process and leads to rapid relief of osteoarticular pain although regression of beta2-M-amyloid deposits probably does not occur.

Amyloid↗