"Detection of primary hyperoxaluria in patients with recurrent kidney stones"

Kidney stones or urolithiasis is a frequent occurring problem. Approximately
0.5% of the Dutch population suffers from episodes of urolithiasis (Statistics
Netherlands 2010). A subset of patients with recurrent kidney stones may
develop end-stage renal disease as a consequence of ongoing calcification of
the tubuli. Early recognition of specific causes of urolithiasis may prevent
renal damage. This is observed in patients with a form of primary hyperoxaluria
(type 1 or type 2) (Danpure and Rumsby 2004). These are autosomal recessive
inborn errors of glyoxylate metabolism. Deficiency of either the liver specific
enzyme AGT in primary hyperoxaluria type 1 or the cytosolic enzyme GR/ HPR in
primary hyperoxaluria type 2 leads to elevated endogenous production of
oxalate. The mutated AGXT gene leads to primary hyperoxaluria type 1 and the
mutated GRHPR gene leads to primary hyperoxaluria type 2. The primary
hyperoxalurias are rare metabolic disorders, with 80 patients diagnosed in The
Netherlands so far (van Woerden et al. 2003, and follow-up study, submitted
2011). The primary hyperoxalurias result in the generation of calcium oxalate
depositions in the kidneys, with clinical signs and symptoms of urolithiasis or
nephrocalcinosis (i.e. diffuse deposition of calcium oxalate precipitations in
the renal parenchyma). Kidney function becomes impaired due to ongoing oxalate
deposition in the kidney parenchyma. Irreversible end-stage renal disease may
ensue. Conservative therapy by means of hyperhydration or crystallization
inhibitors, such as citrate prevents renal damage. However, conservative
treatment is only successful when started before decline of renal function.

The two most common forms of primary hyperoxaluria are defined by the so-called
Gly170Arg or Phe152Ile genotype in primary hyperoxaluria type 1. Patients with
these genotypes show decline of oxalate excretion up to normal values upon
treatment with pyridoxine, vitamin B6 (25 mg daily). Pyridoxine serves as the
co-factor of the AGT enzyme, which is partially deficient in these genetic
subgroups. Pyridoxine treatment leads to disappearance of symptoms and
preservation of kidney function (Milliner et al. 1994, van Woerden et al.
2004). This beneficial effect of pyridoxine has been confirmed in all other
primary hyperoxaluria cohort studies thereafter (Monico et al. 2005, Harambat
2010). Following our epidemiologic survey, published in 2003 (van Woerden et
al.. 2003) we observed a large delay between the date of occurrence of symptoms
and date of diagnosis of primary hyperoxaluria. Therefore, we suspected
underdiagnosis of primary hyperoxaluria in The Netherlands. In the Dutch cohort
of patients with primary hyperoxaluria, especially adult patients presented in
end-stage renal disease despite the presence of symptomatic urolithiasis for
years. Late diagnosis, even after kidney transplantation which was performed
because of end-stage renal disease of unknown origin, was also shown in a
recent French cohort study on patients with primary hyperoxaluria (Harambat et
al.. 2010). As early diagnosis and treatment is extremely important to start
treatment timely and preserve renal function, diagnostic screening in patients
with recurrent urolithiasis or unexplained decline of renal function should be
improved. A screening study for patients with hyperoxaluria in the General
Laboratory of Clinical Chemistry in the AMC, Amsterdam, has found a patient
with the pyridoxine sensitive form of primary hyperoxaluria type 1 (van Woerden
et al.. 2007). A recent follow-up study of the Dutch hyperoxaluria cohort was
performed (van der Hoeven et al.. 2011, submitted). It demonstrated end-stage
renal disease in the vast majority of patients diagnosed with primary
hyperoxaluria at adult age, despite the presence of the pyridoxine sensitive
genotype. Diagnosis of primary hyperoxaluria in patients with a history of
recurrent urolithiasis, treated in a urology center, which could have been
prevented by early conservative treatment, motivates us to initiate the current
study. After assembly of the cohort of patients with primary hyperoxaluria in
2003 by investigation of all nephrologists in The Netherlands, the current
proposal targets urology specialists as to focus on patients with recurrent
episodes of urolithiasis.

To date, no other studies have investigated primary hyperoxaluria as an
overlooked cause of recurrent episodes of urolithiasis. In view of the
potential prevention of renal insufficiency, finding patients with primary
hyperoxaluria by our proposed study entitled *Detection of primary
hyperoxaluria in patients with recurrent kidney stones* (short title *the DETOX
study*) would strongly improve conservative management of patients with
urolithiasis. This would lead to a new diagnostic approach, including metabolic
urine screening for patients with recurrent urolithiasis.

Diagnosis of patients with primary hyperoxaluria in a cohort of patients with
recurrent urolithiasis.

Patients will be recruited at the department of urology of the OLVG, Amsterdam.
All patients who underwent a procedure for kidney stone removal by means of
endoscopy or ESWL (extra corporeal shock wave lithotripsy) in 2010 will be
included. The time frame is used to estimate number patients that need to be
screened annually at the department of urology for diagnosis of primary
hyperoxaluria. Exclusion criteria are: secondary hyperoxaluria due to short
bowel disorders, or inflammatory bowel disorders. All other patients will be
approached for diagnostic research for primary hyperoxaluria by means of urine
screening.

Patients will be approached in a two-step approach in accordance with the
procedure that was followed in our screening study in 2007, which was at that
time approved by the Institutional Review Board of the AMC, Amsterdam.
Candidate participants will be sent a request to participate in a study that
investigates urolithiasis. After obtaining a positive answer from them, a
letter with all study information will be sent to candidate participants to
obtain informed consent. After obtaining informed consent of the participants,
they will be asked to deliver a collection of urine in a dry container at the
laboratory for analysis of oxalate, glycolate and L-glycerate for diagnosis of
primary hyperoxaluria. An 8 ml EDTA blood sample will be obtained for DNA
diagnosis to determine genotype of primary hyperoxaluria once urine test
confirms a diagnosis of primary hyperoxaluria.

Minimal risks of phlebotomy for 8 ml blood collection. This is only performed
if primary hyperoxaluria is strongly suspected by urine investigation.