The main objective of the study is to investigate the effect of a heparan sulphate glycosaminoglycan deficiency on the glomerular filtration barrier in humans. This main objective is approached through the secondary objectives of assessing whether a…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are the differences in proportion of subjects with
micro-albuminuria, urinary albumin/creatinine ratio, and the difference in
perfused boundary region between patients and controls.
Secondary outcome
N/A
Background summary
Heparan sulphate (HS) glycosaminoglycans (GAG) have long been considered
essential in glomerular filtration.(1) In the glomerular filtration barrier
(GFB), they are present in both the glomerular basement membrane as the
glomerular endothelial glycocalyx. In various proteinuric renal diseases, a
decrease in HS-GAG expression was observed in the glomerular filtration
barrier.(2) Also, in vitro experiments showed that removal of HS-GAG from the
glycocalyx results in increased permeability to albumin.(3) Several animal
models have been used to address the question whether loss of HS-GAG results in
loss of glomerular permselectivity. Both mouse(4-7) and zebrafish (own results,
in preparation for submission) do not exhibit loss of glomerular
permselectivity. This study aims to investigate the effect of a HS-GAG
deficiency in humans on the glomerular filtration barrier by studying the
occurrence of micro-albuminuria and structural changes to the microvascular
endothelium.
Reference List
(1) Kanwar YS, Linker A, Farquhar MG. Increased permeability of the
glomerular basement membrane to ferritin after removal of glycosaminoglycans
(heparan sulfate) by enzyme digestion. J Cell Biol 1980 Aug;86(2):688-93.
(2) van den Born J, van den Heuvel LP, Bakker MA, Veerkamp JH, Assmann
KJ, Weening JJ, et al. Distribution of GBM heparan sulfate proteoglycan core
protein and side chains in human glomerular diseases. Kidney Int 1993
Feb;43(2):454-63.
(3) Singh A, Satchell SC, Neal CR, McKenzie EA, Tooke JE, Mathieson
PW. Glomerular endothelial glycocalyx constitutes a barrier to protein
permeability. J Am Soc Nephrol 2007 Nov;18(11):2885-93.
(4) Chen S, Wassenhove-McCarthy DJ, Yamaguchi Y, Holzman LB, van
Kuppevelt TH, Jenniskens GJ, et al. Loss of heparan sulfate glycosaminoglycan
assembly in podocytes does not lead to proteinuria. Kidney Int 2008
Aug;74(3):289-99.
(5) Sugar T, Wassenhove-McCarthy DJ, Esko JD, van Kuppevelt TH,
Holzman L, McCarthy KJ. Podocyte-specific deletion of NDST1, a key enzyme in
the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in
podocyte organization in vivo. Kidney Int 2014 Feb;85(2):307-18.
(6) Harvey SJ, Jarad G, Cunningham J, Rops AL, van d, V, Berden JH, et
al. Disruption of glomerular basement membrane charge through podocyte-specific
mutation of agrin does not alter glomerular permselectivity. Am J Pathol 2007
Jul;171(1):139-52.
(7) Goldberg S, Harvey SJ, Cunningham J, Tryggvason K, Miner JH.
Glomerular filtration is normal in the absence of both agrin and
perlecan-heparan sulfate from the glomerular basement membrane. Nephrol Dial
Transplant 2009 Jul;24(7):2044-51.
Study objective
The main objective of the study is to investigate the effect of a heparan
sulphate glycosaminoglycan deficiency on the glomerular filtration barrier in
humans. This main objective is approached through the secondary objectives of
assessing whether a HS-GAG deficiency results in micro-albuminuria and/or a
reduced thickness of the microvascular glycocalyx.
Study design
The study is designed as a cross sectional, observational study.
Study burden and risks
Volunteers are requested to visit the Leiden University Medical Center once.
Before visiting, they are asked to fill out one questionnaire. Participating
HME-MO patients are asked for permission to view their mutation status. During
the visit, volunteers are asked to deliver two urine samples. Also, a
non-invasive technique is used to assess the microcirculation by placing a
small camera under the tongue. This procedure is painless and takes 5-10
minutes. To perform this analysis, participants are asked to fast for at least
two hours prior to the site visit. It is further described in the 'Methods'
section of the research protocol. The overall risk of participating in this
study is negligible. The main burden of participation consists of the site
visit and the two hour fasting period. A travel reimbursement and token of
gratitude (VVV bon) is given to participants. Other than these incentives, no
benefit is obtained through participating in this study.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
Subjects should be over 18 years of age and capacitated.
Exclusion criteria
No confirmed mutation status in either the EXT1 or EXT2 gene
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL53340.058.15 |