Effects of atorvastatin on kidney function and arterial stiffness in patients with chronic kidney disease

Robert Fassett (2008). Effects of atorvastatin on kidney function and arterial stiffness in patients with chronic kidney disease PhD Thesis, School of Human Movement Studies, The University of Queensland.

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Author Robert Fassett
Thesis Title Effects of atorvastatin on kidney function and arterial stiffness in patients with chronic kidney disease
School, Centre or Institute School of Human Movement Studies
Institution The University of Queensland
Publication date 2008-08
Thesis type PhD Thesis
Supervisor Jeff Coombes
Total pages 327
Total black and white pages 327
Subjects 320000 Medical and Health Sciences
Formatted abstract
Kidney disease, its progression, and the subsequent requirement for dialysis and transplantation are
major public health problems. Treatments that can slow this progression are therefore important.
Experimental studies, small clinical trials and meta-analyses suggest statins may slow the
progression of kidney disease. The LORD trial commenced in 2002 to assess the effect of
atorvastatin on kidney function and potential mechanisms whereby it may act. The LORD study
forms the basis of this PhD.
After an introduction and review of literature, the next three chapters report the study protocol and
baseline data captured as part of the LORD trial. Two chapters that report the outcome data follow
Chapter 3 has been published in the journal BMC Nephrology and contains details of the study
protocol, which was a single center, multi-site, double blind, randomized, placebo controlled trial.
We enrolled 132 patients with a serum creatinine >120 μmol/l. The primary outcome measure was
change in eGFR (MDRD and Cockcroft and Gault) and secondary outcome measures included
changes in creatinine clearance, urinary protein excretion, time to 50% eGFR decline and a measure
of composite serious events.
Chapter 4 reports the relationships at baseline between serum lipids and renal function. This
analysis took into account dietary intake and physical activity levels. These data did not find that
lipids are associated with renal dysfunction in CKD patients not taking lipid-lowering therapy. This
study was published in the International Journal of Clinical Pharmacology and Therapeutics.
Chapter 5 reports the dietary intake of CKD patients before and after filtering for under reporters.
Patients completed a four-day self-reported diet diary and Food Works software was used to
determine the intake of energy, macro and micronutrients. Under reporting was assessed and
nutrient intakes were compared to current guidelines. Energy intake was under-reported in 70.8% ofpatients. Under-reporters were more likely to be female, younger, have a higher BMI and elevated
serum creatinine. When all patients were considered, daily energy, calcium, zinc and dietary fibre
intakes were lower than recommended. However, this was not the case which when valid reporters
alone were analysed. Protein intake was higher than recommended and even higher in valid
reporters. It was concluded that interpreting self-reported diet diary data from CKD patients,
without allowing for under-reporting, might lead to erroneous interpretations. This study was
published in the Journal of Renal Nutrition.
Chapter 6 has been submitted for publication in Medicine Exercise and Sports Science. It contains
data pertaining to levels and predictors of physical activity and self reported health in CKD patients.
These were assessed using the Active Australia and SF-36 questionnaires, respectively. Data were
compared to recommendations and control values. Fifty percent of patients achieved the physical
activity recommendations. Nine percent of patients reported no health enhancing physical activity
in the preceding week. Patients meeting the guidelines were very active, predominantly through
walking. In all patients, physical functioning and self-reported health from the physical component
scale of the SF-36 was significantly lower than control data. Many CKD patients have low levels of
physical activity and self reported health. However, those that are meeting physical activity
guidelines are very active indicating that CKD is not necessarily a limitation to achieving these
The main outcome data is in chapter 7. This is under review by the New England Journal of
Medicine. The rate of decline in eGFR was non-significantly lower in atorvastatin-treated compared
with placebo-treated patients. In patients that had a composite serious event there was a reduction in
the rate of eGFR decline in the atorvastatin-treated compared with placebo-treated patients. There
were no significant differences in the changes in proteinuria or creatinine clearance between groups.
In placebo-treated patients, higher rates of pre-trial (over 12 months) eGFR decline were associated
with a higher risk of composite serious events compared with atorvastatin-treated patients. In
summary, atorvastatin failed to provide renal protection in patients with chronic renal disease.However, atorvastatin may be of benefit to patients who have clinical cardiovascular disease and to
those with declining renal function.
Sixteen patients in the atorvastatin group and eighteen in the placebo were enrolled in an arterial
stiffness sub-study and these data are in chapter 8. Aortic PWV, augmentation index (AIx; a
measure of systemic arterial stiffness) and both central and radial pulse pressure were determined
each nine months over three years. There were no significant differences between aortic PWV, AIx,
and central or brachial pulse pressures at baseline between groups. Aortic PWV increased in both
groups over the 2.5 years of the study. However, atorvastatin-treated patients had a 59% reduced
rate of increase in aortic PWV. There were no significant changes in AIx, central pulse pressure or
radial pulse pressure over time. Aortic stiffness increased over 2.5 years in patients with stages 2-4
CKD. However, the rate of progression of stiffness may be slowed by atorvastatin 10 mg/day in this
patient population.
The results of this thesis provide further information about the relationship between lipid levels and
kidney function, dietary intake and its under-reporting and physical activity levels in stage 2-4 CKD
patients. The main outcome study showed atorvastatin did not slow the progression of CKD except
perhaps in those patients with a composite serious event and declining kidney function on entering
the trial. The progressive increase in arterial stiffness measured by PWV was less evident in
atorvastatin treated patients. In summary, atorvastatin should only be used to treat patients with
CKD and associated clinical cardiovascular disease and perhaps in patients with declining kidney

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Created: Sun, 19 Oct 2008, 21:51:11 EST by Prof Robert Fassett on behalf of The University of Queensland Library