Jun 30 2010
The 47th ERA-EDTA/DGfN congress in Munich has been the setting for a wide range of new clinical data. The results of the following clinical trials were presented at "Late-Breaking Clinical Trials Sessions":
ADPKD/sirolimus study
Prof. Rudolf P. Wüthrich and PD Dr. Andreas Serra (Zürich, Switzerland)
This single-center, randomized controlled, open-label trial conducted at University Hospital Zurich assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus in about 100 ADPKD patients. The primary outcome was the inhibition of kidney volume growth measured by blinded magnetic resonance imaging (MRI) volumetry.
Results: In adult ADPKD-patients with CKD stage 1 and 2 and progressive disease, sirolimus did not slow polycystic kidney growth. It had no effect on GFR, and a small increase in albuminuria was observed.
The adherence in the study was excellent and the medication was relatively well tolerated and safe.
ADPKD/everolimus study
Prof. Gerd Walz (Freiburg, Germany)
The primary objective of this placebo-controlled study was to demonstrate that everolimus has superior efficacy compared to placebo in reducing the mean total kidney volume from baseline to 24 month of treatment in patients with ADPKD, and whether the administration of 5 mg/day everolimus is safe and well tolerated. About 400 patients were enrolled. The primary endpoint was the mean total kidney volume as determined by magnetic resonance imaging.
The results: The study showed that cyst growth progressed more slowly under everolimus than under placebo. At month 12 the difference was even significant, but astonishingly the difference did not gain statistical significance at month 24 - probably due to the large number of drop-outs because of side-effects. However, slower cyst growth had no impact on GFR. In the everolimus arm, GFR was even lower than in the placebo group.
ADVANCE-Study
Prof. Paolo Raggi (Gainesville, USA)
The ADVANCE study is a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in subjects with chronic kidney disease receiving hemodialysis.
360 hemodialysis patients were enrolled and randomized (cinacalcet + low-dose vitamin D vs. standard of care without cinacalcet) in the ADVANCE study. The primary endpoint of the study was percentage change in the Agatston CAC score from baseline to week 52. Although the endpoint did not reach statistical significance, a trend towards slower progression of vascular calcification at all evaluated sites was observed among patients randomized to the cinacalcet arm.
4D High-LDL study
Prof. Winfried Maerz (Eppelheim, Germany)
A post-hoc analysis of the 4D study German Diabetes Dialysis Study) was performed to investigate whether LDL cholesterol at baseline is predictive of cardiovascular events and all-cause mortality in these patients with type 2 diabetes mellitus undergoing hemodialysis, and whether the effect of atorvastatin on clinical outcomes depends on LDL at baseline.
Results: High levels of LDL cholesterol showed a tendency to increase the risks of cardiac endpoints and all-cause mortality.
This post hoc analysis also demonstrates that atorvastatin significantly decreases adverse fatal and non-fatal cardiac events and mortality from all causes compared to placebo in patients with a baseline LDL-C greater than 145 mg/dl. No significant effect of atorvastatin was seen when LDL-C was below this threshold. This provides the first indication based on a prospectively designed study that lowering LDL-C in dialysis patients may be of potential clinical value if pre-treatment concentrations are sufficiently high.
IDEAL Trial
Prof. Bruce A. Cooper (St. Leonards, Australia); Prof. David C.H. Harris (Sydney, Australia)
Nephrologists all over the world often complain about the problem of "late referral" and claim that a late start to therapy could worsen the prognosis of the patients. The IDEAL study, a prospective, randomized, multicenter study conducted in Australia and New Zealand, might now lead to a paradigm shift.
828 patients were randomized when commencing dialysis at a glomerular filtration rate of either 10-14 ml/min/1.73m2 ("early start") or 5-7 ml/min/1.73m2 ("late start").
In this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. Furthermore, there was neither a difference in total costs between the two groups nor an improvement of quality of life in the patients who started dialysis earlier.
The investigators conclude that dialysis may be delayed until either kidney function falls below 7%, or until more traditional indicators for dialysis arise.
PLANET Trials
Prof. Dick de Zeeuw (Groningen, The Netherlands)
Proteinuria is a strong predictor of the progression of end-stage renal disease. Reduction of proteinuria in response to a particular medication might support its use in proteinuric CKD patients. There had been some evidence that statin therapy might reduce proteinuria and even improve GFR. The PLANET I and II studies ("Prospective evaluation of proteinuria and renal function in non-diabetic patients with progressive renal disease") compared the effect of two statins, rosuvastatin (RSV in two dosages, 10 mg and 40 mg) and atorvastatin (80 mg) on urinary protein excretion, renal function and lipid parameters in diabetic (PLANET I) and in non-diabetic patients (PLANET II). The randomized, double-blind study showed that Atorvastatin significantly reduces proteinuria, but rosuvastatin did not (with either dosage). GFR decreased significantly more under rosuvastatin than under atorvastatin.
The question now raised is whether atorvastatin has a renoprotective effect, or if rosuvastatin might have a damaging effect on the kidneys. Unfortunately, the ethics commission did not permit a placebo arm in this study, so this question could not be answered.
ALLOPURINOL Trial
Prof. Michelle P. Kao (Dundee, UK)
60 CKD stage 3 patients were enrolled in this randomized, double-blind, placebo-controlled study, which analysed whether xanthine oxidase inhibitors reduce both left ventricular hypertrophy and endothelial dysfunction in cardiovascular patients with renal dysfunction.
LVH is highly prevalent in CKD, and it is known that oxidative stress promotes LVH and endothelial dysfunction. Clinical trials have shown that anti-oxidant vitamins are associated with improved CV outcomes in CKD, and that administration of allopurinol is an alternative way of reducing oxidative stress. The hypothesis underlying this study proved to be true: allopurinol regressed LVH and improved endothelial dysfunction in renal disease.
Novel multi-biomarker approach enhances chronic kidney disease risk assessment