Guntram Schernthaner

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. Methods. The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. Results. Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62–2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17–1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19–2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04–1.37) and high calcium (HR = 1.74, 95% CI 1.30–2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01–1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13–1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. Conclusion. Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus.

Aims: To assess the safety and tolerability of the dipeptidyl peptidase‐4 inhibitor linagliptin in patients with type 2 diabetes.

Medical Antihyperglycaemic Treatment of Type 2 Diabetes Mellitus * Update of the evidence-based guideline of the German Diabetes Association

Correspondence Prof. Stephan Matthaei Spokesperson for the Panel of Experts Quakenbr ü ck Diabetes Centre, DDG clinical diabetes centre Department of Diabetology, Metabolism and Endocrinology at the Christliches Krankenhaus Academic Teaching Hospital of the Hannover Medical University Danziger Stra ß e10 49610 Quakenbr ü ck Tel.: + + 49 / 5431 / 15 2830 Fax: + + 49 / 5431 / 15 2831 S.Matthaei@ckq-gmbh.de

Hemoglobin Variability Does Not Predict Mortality in European Hemodialysis Patients

Patients with CKD exhibit significant within-patient hemoglobin (Hb) level variability, especially with the use of erythropoiesis stimulating agents (ESAs) and iron. Analyses of dialysis cohorts in the United States produced conflicting results regarding the association of Hb variability with patient outcomes. Here, we determined Hb variability in 5037 European hemodialysis (HD) patients treated over 2 years to identify predictors of high variability and to evaluate its association with all-cause and cardiovascular disease (CVD) mortality. We assessed Hb variability with various methods using SD, residual SD, time-in-target (11.0 to 12.5 g/dl), fluctuation across thresholds, and area under the curve (AUC). Hb variability was significantly greater among incident patients than prevalent patients. Compared with previously described cohorts in the United States, residual SD was similar but fluctuations above target were less frequent. Using logistic regression, age, body mass index, CVD history, dialysis vintage, serum albumin, Hb, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use, ESA use, dialysis access type, dialysis access change, and hospitalizations were significant predictors of high variability. Multivariable adjusted Cox regression showed that SD, residual SD, time-in-target, and AUC did not predict all-cause or CVD mortality during a median follow-up of 12.4 months (IQR: 7.7 to 17.4). However, patients with consistently low levels of Hb (<11 g/dl) and those who fluctuated between the target range and <11 g/dl had increased risks for death (RR 2.34; 95% CI: 1.24 to 4.41 and RR 1.74; 95% CI: 1.00 to 3.04, respectively). In conclusion, although Hb variability is common in European HD patients, it does not independently predict mortality.

Cardiovascular risk and thiazolidinediones-what do meta-analyses really tell us?

Meta‐analyses of clinical trials suggest that the use of the thiazolidinedione (TZD), rosiglitazone, in patients with type 2 diabetes mellitus may increase the risk of myocardial ischaemic events by 30–40%. Although these controversial data must be interpreted with caution, in the absence of definitive prospective cardiovascular (CV) outcomes data, they represent a prominent source of evidence concerning the CV safety of rosiglitazone. The results of meta‐analyses and a large randomized‐controlled CV outcomes trial provide strong evidence that pioglitazone does not increase the risk of coronary events. This article clarifies the clinical significance of these meta‐analytical findings alongside other sources of evidence and assesses their impact on evolving treatment guidelines and recommendations for the use of TZDs in patients with type 2 diabetes.

Kidney disease in diabetology: lessons from 2008

Diabetic nephropathy (DNP) is a devasting disorder and is now worldwide the leading cause of end-stage renal failure. This diabetic complication is a complex disease, whereby various genetic and environmental factors determine susceptibility and progression to end-stage renal disease (ESRD). DNP seems to occur as a result of an interaction between metabolic and haemodynamic factors, which activate common pathways that lead to renal damage. In addition, the renin–angiotensin system (RAS) is also an important target for both metabolic and haemodynamic derangements in DNP. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products, activation of the RAS and protein kinase C and stimulation of the polyol pathway, elicits vascular inflammation and alters gene expression of growth. Despite the rapid research progress, ideal predictors to assess prospectively, and with high precision, the risk for DNP in individuals with diabetes are still lacking. Unfortunately, currently available therapies are usually initiated at more advanced stages of DNP characterized by clinically overt manifestations, including increased urinary albumin excretion and decreased glomerular filtration. Although these interventions have proven efficacy in slowing the progression of DNP, they cannot prevent ESRD. It is hoped that new insights into the molecular mechanisms that underlie the origin and progression of DNP are emerging from largescale genetic and molecular studies in experimental models and humans, and will finally improve the therapeutic options for DNP. Until that, the available treatment strategies have to be used in a more aggressive way, in order to improve the prognosis of patients with DNP as outlined in the review of some papers published in 2007.

Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: The randomized MARLINA-T2D trial

The MARLINA‐T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard‐of‐care in individuals with type 2 diabetes and albuminuria.

Safety and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin in elderly patients with type 2 diabetes: a comprehensive analysis of data from 1331 individuals aged ≥ 65 years

To investigate individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin across a range of glucose‐lowering regimens in a large elderly population with type 2 diabetes mellitus (T2DM).

Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA–T2D™ trial

Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA–T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA–T2D™ is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.

An Epidemiological Study of Hemodialysis Patients Based on the European Fresenius Medical Care Hemodialysis Network: Results of the ARO Study

Background/Aims: ARO, an observational study of hemodialysis (HD) patients in Europe, aims to enhance our understanding of patient characteristics and practice patterns to improve patient outcome. Methods: HD patients (n = 8,963) from 134 Fresenius Medical Care facilities treated between 2005 and 2006 were randomly selected from 9 European countries (Czech Republic, France, Hungary, Italy, Poland, Portugal, Spain, Slovak Republic and Slovenia) and Turkey. Information was captured on demographics, comorbidities, medications, laboratory and dialysis parameters, and outcome. Results: Patients were followed for 1.4 ± 0.7 years. Wide variation by country was observed for age, sex and diabetes as a cause of chronic kidney disease. Cardiovascular disease was present in 73% of patients. Dialysis parameters were homogeneous across countries. Arteriovenous fistulas were frequently used (73%). More incident patients had hemoglobin <11 g/dl than prevalent patients (50 vs. 33%, respectively). Phosphatemia and intact parathyroid hormone were similar between incident and prevalent patients (4.7 ± 1.2 mg/dl and 190 vs. 213 ng/l, respectively). Medication use varied widely by country. In total, 5% of patients underwent renal transplantation. Overall death rate was 124/1,000 patient-years. Conclusion: ARO revealed differences in HD practice patterns and patient characteristics in the 10 participating countries. Future ARO studies will fill gaps in the knowledge about the care of European HD patients.