The effect of spironolactone on diastolic function in haemodialysis patients.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m2 vs. 1.7 ± 14.1 ml/m2, p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m2 vs. + 2.7 ± 15.9 g/m2; p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.The trial has been registered at clinicaltrials.gov (NCT01691053; first posted Sep. 24, 2012).

Apolipoprotein A-IV concentrations and clinical outcomes in haemodialysis patients with type 2 diabetes mellitus--a post hoc analysis of the 4D Study.

BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and anti-oxidative plasma glycoprotein involved in reverse cholesterol transport. The aim of this study was to examine the association between apoA-IV and all-cause mortality, cardiovascular endpoints and parameters of protein-energy wasting and nutrition in haemodialysis patients. METHODS: This post hoc analysis was performed in the German Diabetes Dialysis Study (4D Study) evaluating atorvastatin in 1255 haemodialysis patients with type 2 diabetes mellitus, followed for a median of 4 years. The association between apoA-IV and relevant outcomes was analysed using Cox proportional hazards regression analyses. Body mass index (BMI) was used as a marker of protein-energy wasting. In addition, a definition of extended wasting was applied, combining median values of BMI, serum albumin, creatinine and sensitive C-reactive protein, to classify patients. RESULTS: Mean (±SD) apoA-IV concentration was 49.8 ± 14.2 mg dL(-1). Age- and gender-adjusted apoA-IV concentrations were strongly associated with the presence of congestive heart failure at baseline [odds ratio = 0.81, 95% confidence interval (CI) 0.74-0.88 per 10 mg dL(-1) increase; P < 0.001). During the prospective follow-up, the strongest association was found for all-cause mortality [hazard ratio (HR) = 0.89, 95% CI 0.85-0.95, P = 0.001), which was mainly because of patients with BMI > 23 kg m(-2) (HR = 0.87, 95% CI 0.82-0.94, P < 0.001) and those in the nonwasting group according to the extended definition (HR = 0.89, 95% CI 0.84-0.96, P = 0.001). This association remained significant after additionally adjusting for parameters associated with apoA-IV at baseline. Further associations were observed for sudden cardiac death. ApoA-IV was less strongly associated with atherogenic events such as myocardial infarction. CONCLUSIONS: Low apoA-IV levels seem to be a risk predictor of all-cause mortality and sudden cardiac death. This association might be modified by nutritional status.

Dyslipidaemia in chronic kidney disease.

Chronic kidney disease (CKD) is associated with a highly atherogenic lipid profile, characterized by elevated triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles. Diverse mechanisms are responsible: uraemia, dialysis, immunosuppressive drugs and concomitant diseases exert their effect on the activity of key enzymes, transfer proteins and receptors involved in lipid metabolism. Post hoc analyses from large scale randomized controlled trials suggest a benefit of statin therapy with respect to cardiovascular and renal endpoints in patients with early CKD comparable to the effect in people without renal disease. Observational studies found a reduction in the risk of contrast media induced nephropathy and a reduction in the risk of hospitalization for sepsis in patients who had CKD and were treated with statins. In contrast, prospective, randomized, controlled statin trials in patients with diabetes on haemodialysis and in renal transplant recipients have not conclusively shown improvements in hard cardiovascular endpoints. This review will focus on lipid disturbances in renal disease, their impact on cardiovascular disease, existing endpoint studies and current treatment guidelines.

[Phenotyping of type 2 diabetes mellitus by "genetic field work": are data sufficient that are based only on a questionnaire?]. / Phänotypisierung durch "genetic field work": Ist die Datenerhebung durch Fragebögen ausreichend?

BACKGROUND AND OBJECTIVE: Genetic studies of complex diseases such as diabetes mellitus (DM) require the recruitment of patients and acquisition of patient data in a time- and cost-effective manner. An effective method to do so may be genetic field work (GFW) that recruits the relatives of index cases, these relatives then replying to appropriate questionnaires. This study investigated the validity of GFW data compared with patient interviews by a physician who had examined those persons. METHODS: 122 relatives were identified through GFW among a cohort of 35 families with DM. Questionnaires with self-reported information on past medical history, cardiovascular risk factors and life style were obtained. In a second step these famiy members were interviewed and examined by a physician in an outpatient setting. RESULTS: Comparison of the two data sets of the 122 individuals yielded clear differences which favored interviews by a physician. The number of persons declaring themselves as having DM was significantly lower by GFW than direct examination (18 vs. 27). Diabetic nephropathy was reported by four individuals by GFW, while examination resulted in the identification of 16 cases. Body weight was also clearly too low when self-reported, so that significantly lower values were recorded for BMI in the questionnaire. Hypertension was reported by 25 vs. 54 participants. The amount of cigarettes smoked was significant lower in the GFW than in physicians' examination. But the numbers recorded for myocardial infarction, peripheral vascular disease and stroke were not significantly different. CONCLUSION: These data show that information obtained by GFW is less accurate than that collected in interview and examination by physicians. The latter are necessary to gain valid data for accurate phenotyping, while GFW is useful in the initial recruitment of relatives.

[Treatment of dyslipoproteinemia in chronic renal failure]. / Die Progression verzögem und das Risiko für die Gefässe senken.

In patients with chronic kidney disease, treatment with statins presumably not only has an influence on cardiovascular endpoints, but also delays the progression of the renal disease. Recommendations for the treatment of lipid metabolism disorders in the general population with normal renal function are based on numerous prospective, randomized and placebo-controlled studies. In contrast, recommendations for patients with pathological renal function can merely be extrapolated from the results of those studies. Post hoc analyses from the large pravastatin studies confirm a significant risk reduction of primary cardiovascular and cerebrovascular end points for the CDK stages 2 and 3. For CKD stages 4 and 5, available data are merely rudimentary, so that the results of ongoing studies will have to be awaited.

Abnormalities in uremic lipoprotein metabolism and its impact on cardiovascular disease.

Patients with end-stage renal disease (ESRD) suffer from a secondary form of complex dyslipidemia consisting of both quantitative and qualitative abnormalities in serum lipoproteins resulting from alterations in lipoprotein metabolism and composition. The prominant features of uremic dyslipidemia are an increase in serum triglyceride levels (due to elevated very low density lipoprotein [VLDL]-remnants and intermediate-density lipoprotein [IDL]) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol often is normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass (sdLDL). The apolipoprotein B (apoB)-containing part of the lipoprotein may undergo modifications (enzymatic- and advanced glycation end-product [AGE]-peptide modification, oxidation, or glycosilation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. While LDL particles undergo a vicious cycle of accumulation and modification, reverse cholesterol transport is also impaired due to low lecithin:cholesterol acyltransferase (LCAT) and paraoxonase activity. Therefore, discoid HDL particles are structurally altered and hepatic cholesterol clearance is limited. The composition of HDL may also be altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is unclear at present. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Nevertheless, patients with renal disease belong to a very high cardiovascular risk group and dyslipidemia should most likely be subjected to sufficient lipid-lowering therapy in most patients. Because it is also still unclear whether we have available therapies with sufficient impact on LDL size, remnant lipoprotein-lowering, and restoration of HDL function, we urgently need the results from large scale intervention trials such as the 4D-trial and the CHORUS study.

Lipid changes and statins in chronic renal insufficiency and dialysis.

Chronic renal failure patients suffer from a secondary form of complex dyslipidemia, similar to the so-called atherogenic dyslipidemia in insulin resistant patients or to diabetic dyslipidemia. The most important abnormalities are an increase in the serum level of triglyceride (elevated VLDL-remnants/IDL), small LDL particles and a low HDL cholesterol. The highly atherogenic LDL subclass, namely LDL-6 or small dense LDL, accumulates in hypertriglyceridemic diabetic hemodialysis patients. All these lipoprotein particles contain apoB, thus much of this complex disorder can be summarized as an elevation of triglyceride-rich apoB containing complex lipoprotein particles. Growing evidence suggests that all of the components of this type of dyslipidemia are independently atherogenic. Further disturbances exist in the dynamics of cholesterol exchange between the various lipoprotein particles and in transport from cells to catabolic sites. The European Joint Task Force and the US National Cholesterol Education Program expert panel have issued guidelines for the general population to lower the cardiovascular risk in hyper- and dyslipidemias. There is preliminary consensus that these guidelines should be applied to dialysis patients. However, the genesis of atherosclerosis in the dialysis population may be different and real benefit from lipid-lowering has not yet been demonstrated in this population. Large-scale, prospective randomized trials (4D-trial, HARP) are underway to determine whether statins reduce cardiovascular complications in diabetic and non-diabetic patients with end-stage renal disease (ESRD) and on hemodialysis treatment.

Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis. Die Deutsche Diabetes Dialyse Studie Investigators.

BACKGROUND: Non-insulin-dependent diabetes mellitus dialysis patients have the highest cardiovascular mortality known in any group of patients. Mixed dyslipidemia with moderately elevated low-density lipoprotein (LDL) cholesterol and high levels of triglyceride-rich lipoproteins is common in this condition. It is not known, however, whether patients with type 2 diabetes on dialysis with this form of dyslipidemia derive benefit from lipid-lowering therapy. Recently, drugs have become available that potently lower triglyceride-rich, apoB-containing lipoproteins and thus permit testing of this issue. This is the first trial to address specifically the issue of whether the excessive cardiovascular mortality of patients with type 2 diabetes on dialysis can be lowered by statins. METHODS: The Die Deutsche Diabetes Dialyse Studie is a prospective randomized placebo-controlled trial that tests the hypothesis that atorvastatin, a hydroxymethyl-glutaryl coenzyme A reductase inhibitor, decreases the rate of cardiovascular mortality and of nonfatal myocardial infarction in patients with type 2 diabetes who have been on hemodialysis treatment for no more than two years. The primary endpoint, cardiovascular mortality, includes fatal myocardial infarction, sudden death, death during coronary intervention, death from heart failure, and other coronary causes. Secondary endpoints comprise overall mortality, nonfatal cardiovascular events, fatal and nonfatal cerebrovascular disease, and the mean percentage change in lipid profile from baseline. The trial enrolls 1200 men and women on hemodialysis for less than two years and with type 2 diabetes at 150 centers throughout Germany. Inclusion criteria are age of 18 to 80 years, low-density cholesterol of 80 to 190 mg/dl (2.1 to 4.9 mmol/liter), and triglyceride levels of less than 1000 mg/dl (11.4 mmol/liter). Patients are randomized to cither inactive (placebo) or active (atorvastatin, 20 mg/day) drug therapy. The average duration of follow-up is more than 2.5 years. To protect against a lower than expected rate of events, the trial will be continued until a predetermined fixed number of endpoints occurs in the entire cohort so that the predefined power of the trial will be guaranteed. CONCLUSIONS: This trial was designed to demonstrate that lipid lowering with atorvastatin will improve life expectancy and quality of life in type 2 diabetics on hemodialysis. The resolution of this question is important because the genesis of vascular lesions in this condition is multifactorial and the precise role of dyslipidemia has not been defined.