Assessment of endogenous oxalate production and investigation of glyoxylate/oxalate pathways in primary hyperoxaluria patients and healthy subjects

The Primary Hyperoxalurias are a group of rare inborn errors of glyoxylate
metabolism characterized by an increased endogenous oxalate production, which
leads to the development of urolithiasis, nephrocalcinosis and ultimately renal
failure. Once PH patients develop renal failure systemic deposition of oxalate
accelarates resulting in oxalosis, a life threatening condition affecting
multiple organs most notably the skeleton, heart, bone marrow and skin.
To date, the only curative option is liver transplantation. This procedure
however carries a high risk of morbidity and mortality and is limited given the
sparsity of donors. Therefore, less invasive treatments are needed. Promising
drugs based on RNA interference have recently been developed. One aims to
inhibit the enzyme glyoxylate oxidase (GO), responsible for the production of
the precursor of oxalate, the other aims to inhibit lactate dehydrogenasis
(LDH); to reduce the production of oxalate in the liver. Previous studies with
RNAi drugs have shown limited side effects.
In current practice, urinary oxalate excretion is used as the main outcome
measure for studies in PH. However, the variability of urine oxalate excretion
in PH patients is large, limiting its validity as an outcome measure. Within
this study we therefore aim to develop a more solid outcome measure, which is
imperative in order to evaluate therapy efficacy of the new drugs in the
upcoming phase III trials. Simultaneously, our aim is to obtain more insight
into the complex metabolic pathways underlying PH1 and PH2.

Primary: Quantification of oxalate and glycine production in both healthy
subjects and PH patients in order to obtain reference values for clinical
trials.

Secondary: To obtain more insight in the glyoxylate/oxalate pathway, and in
particular the role of hydroxyproline, glycine and glycolate in endogenous
oxalate production.

Experimental study

(continuous primed) infusion with stable isotopes (identical for both groups):
[U-13C]sodium-oxalate, [1-13C] Glycolate and [D5] Glycine

Subjects are asked to visit the AMC for one day (duration of visit is 10
hours). Subjects will have 2 intravenous cannula*s inserted, one for the
administration of the stable isotopes and one for blood sampling. Subjects will
be required to follow a diet low in oxalate for 3 days and start fasting 12
hours prior to the measurements.
A stable isotope is a naturally occurring atom whose nuclei contain the same
number of protons but a different number of neutrons. This alters the mass of
the atom but not its chemical nature. In contrast to radioactive isotopes,
there is no spontaneous decay of stable isotopes (hence the name stable
isotopes). There are no reported risks that can be attributed to the
experimental use of stable isotopes in humans.