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Biomedical subjects

Z A Massy

Publications and source records attributed to Z A Massy.

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↗
PubMed2004

Impact of inflammation and oxidative stress on vascular calcifications in chronic kidney disease.

Vascular and/or valvular calcifications in patients with chronic kidney disease (CKD) appear to indicate a poor prognosis in terms of overall survival and cardiovascular morbidity and mortality. Inflammation and oxidative stress represent new features of the arterial and/or valvular calcification process. However, only limited observational and epidemiological data are available in these areas. Therefore, the link between inflammation, oxidation and vascular and/or valvular calcifications deserves careful consideration in CKD patients, since they may become targets for the development of new therapeutic strategies.

Calcinosis↗
PubMed2004

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.

Adult↗
PubMed2003

[Management of micro-inflammation in uremia].

Chronic micro-inflammation is commonly observed in patients with chronic renal failure. However, the causes of this micro-inflammation remain mainly indeterminated. Therefore, the appropriate therapeutic management of uremic microinflammation is not yet established. Meanwhile, it appears to be reasonable to use current non-specific anti-inflammatory therapies (e.g. ACEI, statins) in order to reduce uremic micro-inflammation. However, it is clear that such an approach is not sufficient, and further strategies (e.g. vitamin E) are warranted to optimize uremic micro-inflammation prevention.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Hyperlipidemia and cardiovascular disease after organ transplantation.

Hyperlipidemia, a frequent and persistent complication after solid organ transplantation, contributes to cardiovascular morbidity and mortality and may influence the development of allograft vasculopathy. The pathogenesis of posttransplantation hyperlipidemia is not fully understood, although several epidemiological factors are strongly implicated including age, weight, pretransplantation lipid levels, and immunosuppressive therapy. Management strategies to reduce hyperlipidemia and modify cardiovascular risk include dietary restrictions and the use of lipid-lowering agents. The selective use of immunosuppressants, such as tacrolimus, that have neutral or fewer adverse effects on lipid metabolism may also provide a useful option. A combination of lipid-lowering therapies and optimization of immunosuppressive regimens compatible with prolonged allograft survival is probably necessary to significantly reduce posttransplantation hyperlipidemia and its potentially harmful consequences.

Graft Rejection↗
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

Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients.

BACKGROUND: Hyperhomocysteinemia, 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-methyltetrahydrofolate (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. METHODS: First, 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. RESULTS: The 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 micromol/L (18.8 to 21.2); and FA, 19.5 micromol/L (18.3 to 20.7). Moreover, neither treatment resulted in "normalization" of tHcy levels (that is, final on-treatment values <12 micromol/L) among a significantly different or clinically meaningful number of patients [MTHF, 2 out of 25 (8%); FA, 0 out of 25 (0%); Fisher's exact test of between groups difference, P = 0.490]. Second, we compared the relative responsiveness of (N = 10) RTRs and (N = 39) HD patients with equivalent baseline tHcy levels (RTR range of 14.2 to 23.6 micromol/L, and HD range of 14.4 to 24.9 micromol/L) to 12 weeks of tHcy-lowering treatment. The RTRs received 2.4 mg/day of FA, 50.0 mg/day of vitamin B6, and 0.4 mg/day of vitamin B12, while the HD patients received 15 mg/day of FA or an equimolar amount (17 mg/day) of the reduced folate, MTHF, in addition to 50.0 mg/day of vitamin B6 and 1.0 mg/day of vitamin B12. The mean percentage (%) reductions (+/- 95% confidence interval) in tHcy were as follows: RTR 28.1% (16.2 to 40.0%); HD 12.1% (6.6 to 17.7%, P = 0.027 for comparison of between groups differences by analysis of covariance adjusted for baseline tHcy levels). Moreover, 5 out of 10 (50.0%) of the RTR versus only 2 out of 39 (5.1%) of the HD patients had final on-treatment tHcy levels <12 micromol/L (P = 0.002 for comparison of between groups differences by Fisher's exact test). CONCLUSIONS: First, in comparison to high-dose FA, high-dose oral MTHF-based supplementation does not afford improved tHcy-lowering efficacy among HD patients. The preponderance of HD patients (that is,> 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absorption 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 supraphysiological 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.

Adult↗
PubMed2001

Longer duration of predialysis nephrological care is associated with improved long-term survival of dialysis patients.

BACKGROUND: Late nephrological referral of chronic renal failure patients has been shown to be associated with high morbidity and short-term mortality on dialysis. However, the impact of predialysis nephrological care duration (PNCD) on the long-term survival of dialysis patients had not been evaluated. METHODS: We studied data from all 1057 consecutive patients who started dialysis treatment at the Necker Hospital from 1989 to 1998 (mean age at start of dialysis 53.8+/-17.2 years (range 18-91 years), excluding from analysis patients who presented with acute renal failure (n=60) or advanced malignancy (n=35). We evaluated the effects of PNCD and clinical risk factors on all-cause mortality after long-term follow-up on dialysis. RESULTS: Among the 1057 patients analysed (13.2% diabetics), PNCD was <6 months in 258 patients, 6-35 months in 267 patients, 36-71 months in 227 patients and >or=72 months in 307 patients. Cardiovascular (CV) morbidity, namely a history of myocardial or cerebral infarction, peripheral arteriopathy, and/or cardiac failure, before starting dialysis was 39.6% and 37.4%, respectively, in patients followed for <6 months or 6-35 months, compared with 24.4% in those followed for 36-71 months and 19.9% in those followed for >or=72 months (P<0.001). Five-year survival was significantly lower in patients with a PNCD of <6 months (59+/-4.1%) than for 36-71 months or >or=72 months (77.1+/-3.7 and 73.3+/-3.6%, respectively, P<0.001), but similar to those followed for 6-35 months (65.3+/-3.9%, NS). By Cox proportional hazard analysis, PNCD <6 months, age, diabetes and prior CV disease were independent predictive factors of all-cause death on dialysis. CONCLUSIONS: This study provides suggestive evidence that longer duration of regular nephrological care in the predialysis period, at least for several years prior to the start of dialysis, is associated with a better long-term survival on dialysis. Such data strongly support the argument for early referral and regular nephrological care of chronic renal failure patients.

Adult↗
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

Cardiovascular risk factors in kidney transplantation.

Classical and non-classical cardiovascular risk factors are common after renal transplantation, and they are effectively associated with the development of cardiovascular disease. Despite the absence of large, controlled clinical trials examining the effect of prevention strategies, therapies should not be withheld from renal transplant recipients with significant risk factors, because their risk of developing cardiovascular disease is at least as high as that of the general population.

Cardiovascular Diseases↗
PubMed2001

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.

Adult↗
PubMed2001

Uremic toxicity: present state of the art.

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.

Cardiovascular Diseases↗
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

Controlled comparison of L-5-methyltetrahydrofolate versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients.

BACKGROUND: The hyperhomocysteinemia regularly found in hemodialysis patients is largely refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high-dose L-5-methyltetrahydrofolate-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients. METHODS AND RESULTS: We block-randomized 50 chronic, stable hemodialysis patients on the basis of their screening predialysis tHcy levels, sex, and dialysis center into 2 groups of 25 subjects treated for 12 weeks with oral folic acid at 15 mg/d (FA group) or an equimolar amount (17 mg/d) of oral L-5-methyltetrahydrofolate (MTHF group). All 50 subjects also received 50 mg/d of oral vitamin B(6) and 1.0 mg/d of oral vitamin B(12). The mean percent reductions (+/-95% CIs) 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 ANCOVA adjusted for pretreatment tHcy. Final on-treatment values (mean with 95% CI) were MTHF, 20.0 micromol/L (18.8 to 21.2 micromol/L); FA, 19.5 micromol/L (18.3 to 20.7 micromol/L). Moreover, neither treatment resulted in "normalization" of tHcy levels (ie, final on-treatment values <12 micromol/L) among a significantly different or clinically meaningful number of patients: MTHF, 2 of 25 (8%); FA, 0 of 25 (0%); Fisher's exact test of between-groups difference, P=0.490. CONCLUSIONS: Relative to high-dose folic acid, high-dose oral L-5-methyltetrahydrofolate-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (ie, >90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution.

Administration, Oral↗