Multinational, prospective cohort-study in patients with type 2 diabetes for validation of biomarkers

48.4 million Europeans aged 20 and 79 years had diabetes in 2003; by the year
2025 this number will reach 58.6 million. Interestingly a high variability is
observed between countries. By 2025 11.9% of the population will be affected in
Austria. The numbers for Hungary or Poland are expected to be similar (11.2 and
11.0%), but the prevalence will be much lower in the Netherlands and the UK
(5.1 and 4.7% respectively) (www.heartstats.org). One of the most devastating
complications of diabetes is nephropathy and despite diabetes being the main
cause of end stage renal disease in industrialzed nations the incidence also
varies considerably within Europe. In 2008 in Austria 29% of incident dialysis
patients had diabetic nephropathy, a number much different from the one
observed in the Netherlands (14.6%) or Scotland (6.5%). Whereas in Austria the
prevalence of patients with type 1 diabetes on dialysis was 52.9 pmp, the
number for subjects with type 2 disease was 149.3. In the Netherlands the
corresponding figures were 35.9 and 57.9 and in Scotland 80.7 and 25.5
(EDTA-ERA Annual Report 2008). The reasons for these discrepancies are unclear
as no large scale national epidemiological databases are available reporting
the exact incidence and rate of progression of diabetic nephropathy as well as
cardiovascular morbidity and mortality of diabetics with and without
nephropathy. PROVALID will be an indefinite, prospective cohort study in
patients with type II diabetes in five European countries (Austria, Hungary,
Netherlands, Poland and Scotland). The patients will be treated according to
local practice and followed for the incidence of renal and cardiovascular
outcomes as well as mortality.
Diabetic nephropathy occurs in both, type 1 and 2 diabetes mellitus. In type 1
disease approximately 20 to 30 percent of the patients develop microalbuminuria
(MIA, the excretion of 30 to 300 mg of albumin per day) after a mean disease
duration of 15 years (Newman DJ, Mattock, MB, Dawnay AB, Kerry, S, McGuire, A,
Yaqoob, M, Hitman, GA, Hawke, C: Systematic review on urine albumin testing for
early detection of diabetic complications. Health Technol Assess 2005;
9:iii-vi,xiii-163). In contrast to earlier studies currently less than half of
individuals with MIA will progress to overt nephropathy and end stage renal
disease due to better metabolic control, more aggressive blood pressure
reduction and the use of agents that block the renin angiotensin system (Finne
P, Reunanen A, Stenman S, Groop PH, Grönhagen-Riska C: Incidence of end stage
renal disease in patients with type 1 diabetes. JAMA 2005; 294:1782-1787). In
type 2 diabetes the most robust data on the incidence and progression of
nephropathy were derived from the United Kingdom Prospective Diabetes Study.
Among the 5.100 patients with newly diagnosed diabetes enrolled the prevalence
of MIA, macroalbuminuria and either an elevated plasma creatinine concentration
or requirement of renal replacement therapy after 10 years was 25, 5 and 0.8 %
respectively (Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR:
Development and progression of nephropathy in type 2 diabetes: The United
Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63:225-232).
Unfortunately especially in patients with type II diabetes the sensitivity and
specificity of MIA for the progression of renal disease is low even though it
is generally accepted that it confers a decreased cardiovascular prognosis
(Newman DJ, Mattock, MB, Dawnay AB, Kerry, S, McGuire, A, Yaqoob, M, Hitman,
GA, Hawke, C: Systematic review on urine albumin testing for early detection of
diabetic complications. Health Technol Assess 2005; 9:iii-vi,xiii-163). Hence
more specific and / or sensitive biomarkers to identify patients at risk for
renal disease or those whose nephropathy will progress despite state of the art
therapy are urgently needed. Therefore in the PROVALID study blood and urine
will be collected at regular intervals and the specimen will be available for
analysis on a genome, transcriptome, proteome and metabolome level. As
cardiovascular morbidity and mortality will also be registered PROVALID will
also serve as a source of information in the area of cardiovascular research.

PROVALID will have 3 major objectives:

Primary: Determine the cumulative incidence of renal outcomes in patients with
type II diabetes in different European countries.
Renal outcomes are defined as:
* Progression from normoalbuminuria to microalbuminuria (including 30%
increase in albuminuria from baseline)
* Progression from microalbuminuria to macroalbuminuria (including 30%
increase in albuminuria from baseline)
* Progression to doubling of serum creatinine, end stage renal disease (ESRD)
or death

Secondary:
• Annual collection of blood and urine specimen for 5 years to allow validation
of biomarkers potentially of use in renal disease diagnosis, prognosis,
prevention and therapy at the genome, transcriptome, proteome and metabolome
level
• Collection of serum and urine at least once a year allowing centralized
analysis of routine laboratory parameters throughout the entire study

Tertiary: Determine the cumulative incidence of cardiovascular outcomes in
patients with type II diabetes in different European countries.
Cardiovascular outcomes are defined as:
* Cardiovascular death
* Non fatal myocardial infarction or non fatal stroke
* Hospitalization because of heart failure

PROVALID is a prospective cohort study in at least 4.000 individuals with type
II diabetes in five European countries (Austria, Hungary, Netherlands, Poland
and Scotland). The patients will be followed and treated according to local
practice.

The clinical data will be collected in the context of local established
practice and already existing clinical data collection structures. All
necessary procedures to correctly diagnose the progression of albuminuria or
renal disease will be done at the recruiting site. A minimal list of clinical
parameters required for our purpose will be collected. Any other clinical
parameter or outcome parameter that will be collected is advantageous. General
practitioners or colleagues working at other recruitment sites will also
collect annual blood and urine samples from their patients.

There are no risks other than the ones relative to the venapunction.
Patients will not have a direct benefit from the study. However PROVALID will
likely contribute to the discovery of biomarkers potentially of use in renal
disease diagnosis, prognosis, prevention and therapy at the genome,
transcriptome, proteome and metabolome level.