Towards HOMe-based Albuminuria Screening: an implementation study testing two approaches

Chronic Kidney Disease is a worldwide major public health problem that is
associated with an increased incidence of kidney failure resulting in dialysis
and/or transplantation, and also an increased risk of cardiovascular events,
both accompanied by high costs for society. Symptoms of Chronic Kidney Disease
become present only when kidney function drops to below 30%. At that time
preventive measures will have only limited efficacy. However, protein excretion
in the urine has increasingly been recognized as early marker kidney damage,
but it is also associated with the presence of a high blood pressure, diabetes,
and/or high cholesterol levels, which are all important risk factors for kidney
and cardiovascular disease. Importantly, the prevalence of undiagnosed
cardiovascular and kidney risk factors in the Dutch general population is
higher than the prevalence of known risk factors. Population screening for
urinary protein loss could therefore detect a considerable number of subjects
with yet unknown risk factors for progressive kidney and cardiovascular disease
who can benefit of early intervention. However, it unclear whether the Dutch
population is willing to participate a population screening, which method is
suitable for large-scale screening and whether such a screening is
cost-effective.

Primary Objective:
To investigate whether population screening for increased albuminuria among the
Dutch population can contribute to the early detection of yet undiagnosed risk
factors for renal and cardiovascular diseases in an early stage. For this, we
will investigate:
1. The participation rate of the screening;
2. The yield of albuminuria screening (number of subjects with elevated
albuminuria [ACR >30 mg/g] and with newly diagnosed risk factors including
hypertension, diabetes, hypercholesterolemia, and impaired kidney function),
and;
3. To evaluate the cost-effectiveness of albuminuria screening and compare this
to standard of care.

Secondary Objectives:
1.To assess differences in participation rate, yield, and cost-effectiveness
between the two different screening methods (PeeSpot test vs. ACR | EU test).
2.To asses the characteristics of the participants, including differences in
age, sex, educational level, estimated social economic status, medication use,
and history and presence of disease (obtained by a questionnaire);
3.To asses the characteristics of the non-responders, including differences in
age, sex, and estimated social economic status (the latter is based on data of
Statistics Netherlands, providing estimated social economic status based on
postal codes);
4.To examine differences in characteristics of the responders and
non-responders of the two different screening methods (PeeSpot vs. ACR | EU).
5.To assess the usability of the two different screening methods (PeeSpot vs.
ACR | EU).
6. To examine the differences in rate of previously undiagnosed risk factors
(hypertension, diabetes, hypercholesterolemia, and impaired kidney function)
that were found at the elaborate screening between subjects who have
albuminuria and subjects without albuminuria.

Observational study (with an invasive measurement in a small part of the
participants)

Subjects will be 1:1 randomized using a computer generated algorithm into group
A or group B. Participants randomized to group A will receive the PeeSpot urine
collection device (Hessels+Grob B.V., Deventer, The Netherlands; Hessels et al.
2011) (see Appendix D). This device consists of a holder containing a urine
collection pad, which is an absorption felt containing a dried hygroscopic
polymer. When subjects urinate on the pad (midstream urine), it can absorb 1.2
ml urine. The holder can be placed back into the tube and can be easily send to
the laboratory by mail for measurement of albuminuria. Because of the dried
preservative in the urine absorption felt, the urine has a preservation
capacity of 4 days at room temperature. In the laboratory, the urine collecting
device can be centrifuged to separate the urine from the pad, and albumin and
creatinine can be measured. The results of the test will be sent to the
participant by letter. If the test result is positive (which indicates elevated
albuminuria), participants will be sent two extra tests for confirmation. When
elevated albuminuria is confirmed (at least 1 out of the 2 confirmatory test in
accordance with prevailing guidelines), the person in question will be referred
for further screening for Chronic Kidney and CardioVascular Disease risk
factors (hypertension, diabetes, hypercholesterolemia, impaired kidney
function) to the central screening facility.
Participants randomized to group B will receive the ACR | EU kit (see
Appendix E), which consists of a urine test strip, a custom designed urine cup,
a color calibrator, and instructions to download the Healthy.io application on
their smartphone. For the test, subjects have to collect urine in the cup
(midstream urine) and immerse and remove the urine test strip of which the
chemical pads will change in color in response to the presence of albuminuria
and creatinine. The stick is placed on the color calibrator and scanned with
the application with the use of the flash light. Participants then enter the
unique participant ID, printed on each kit into the app for anonymous
identification. Healthy.io*s system automatically analyzes the
semi-quantitative albumin and creatinine levels indicated on the stick and
returns an albumin creatinine ratio and level (normal, abnormal, high
abnormal). In case the test is positive (abnormal or high abnormal, which
indicates elevated albuminuria), participants will be sent two extra tests for
confirmation. When elevated albuminuria is confirmed (at least 1 out of the 2
confirmatory test in accordance with prevailing guidelines), the person in
question will be invited for further screening for Chronic Kidney and
CardioVascular Disease risk factors (hypertension, diabetes,
hypercholesterolemia, impaired kidney function) to the central screening
facility. When the participant does not perform the confirmatory tests, the
participant will receive a push notification via the app as a reminder.

This is a study comparing two non-invasive screening techniques (PeeSpot and
ACR | EU tests). The participants receive the test via mail and the test (both
the Peespot and ACR | EU test) can be carried out at home. Clear instructions
regarding the test will be included. When the participant tests positive for
albuminuria, this should be confirmed with a confirmation test. The researcher
will send an extra tests via the mail to the participant (the same test as the
initial test). If this second test result is negative, a third test will be
send for deciding the definitieve result. When at least one of these extra
tests is also positive, so in total at least two out of two or three test, the
participant will be invited to participate a one-time elaborate screening in
the Amphia Hospital in Breda. Based on literature, we estimate that
approximately 600 participants will be invited for this screening. In this
screening, anthropometric measurements will be performed (height and weight),
blood pressure will be measured, and blood will be drawn (venipuncture, 7 mL)
for assessing traditional risk factors for cardiovascular and renal disease
(including HbA1c, glucose, total cholesterol, high-density lipoprotein (HDL)
cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, and
creatinine).

Furthermore, a subset of the participants will, at the end of the study receive
a questionnaire including questions on demographics, educational level, disease
history, medication use, quality of life, and usability of the screening test.
This subset of participants include: 1) all subjects with an overall positive
test for albuminuria (at least 2 out of 3 ACR tests positive) invited to the
elaborate screening 2) a subset of subjects with an initial negative ACR test
who will be asked to perform a second and third test to examine the
false-negative rates (N=500 for both arms) and 3) a subset of the
false-negative subset with a second negative test that will be invited for the
elaborate screening (N=200 for both arms). The questionnaire will contain
questions regarding demographic variables (age, sex, ethnic background,
educational level), history of disease (including the presence of albuminuria,
hypertension, diabetes, hypercholesterolemia, and decreased renal function),
and use of medication. The EuroQol 5D-5L, a standardized questionnaire that
provides a score at five health levels (mobility, self-care, daily activities,
pain/discomfort and anxiety/depression), whereby a weighted health index can be
derived for an individual, will also be included in this questionnaire.
Moreover, some questions will be asked about the usability of the urine test.
Finally, data about the participants* GP and pharmacy will be asked (together
with permission to contact the GP/pharmacy in context of the study in an
additional informed consent).

A short questionnaire will be sent to non-responders (of the first 1250 invited
participants from both groups). This questionnaire contains some questions
about the reasons why people did not participate in the study.

Risks in this study are limited. There are several limitations to screening
programs in general, including: 1) confrontation with an unfavorable result, 2)
unnecessary anxiety in case of false-positive test results, and 3) unwarranted
reassurance in case of false-negative results. We will try to limit these risks
as much as possible, by for example the need for confirmation in case of any
abnormal finding before action is taken. In case albuminuria is increased in
the initial test, it has to be confirmed in at least one out of the two
follow-up urine samples that are tested (for ACR | EU as well as for the
PeeSpot method) which is in agreement with prevailing guidelines. Only in case
there is confirmed increased albuminuria, subjects will be invited to have
blood pressure, cholesterol, glucose, and kidney function measured at a
screening facility. In case this screening shows any further abnormalities next
to the increased albuminuria, patients will be referred to their general
practitioner with an advice for confirmation (and potential treatment). In this
way the percentage of subjects with false positive findings will be minimized.
Moreover, treatment that is advised will be fully based on prevailing general
practitioner guidelines (NHG Standaarden CardioVascular Risk Management and
Chronic Kidney Disease) to avoid unnecessary treatment.