Bone - MRI in Renal Insufficiency

Metabolic bone disease in pediatric end stage renal disease
Children with end stage renal disease (ESRD) usually also suffer from
extrarenal manifestations of their disease. One of those extrarenal
manifestations is metabolic bone disease (MBD), frequently referred to as Renal
Osteodystrophy (ROD). In 2004 ROD was defined by the (American) National
Kidney Foundation as a constellation of bone disorders, present in or
exacerbated by renal failure which leads to bone fragility and fractures,
abnormal mineral metabolism and extraskeletal manifestations. Earlier research
has shown that adult survivors of pediatric onset ESRD frequently (39%) suffer
from bone disease1.The abnormalities of bone turnover consist of either high
turnover or low turnover. High turnover bone disease results in thickened, but
irregular trabeculae and eventually to a decreased bone volume. Low turnover
bone disease, also referred to as adynamic bone disease, is characterized by
decreased bone volume and changed architecture of the trabeculae2. Both low and
high turnover disease lead to a decreased bone mineral density and
osteoporosis. Bone mineral density (BMD) is most frequently measured with Dual
Energy X-Ray Absorptiometry (DEXA) which has many of advantages: it is
non-invasive, easy and relatively cheap. Furthermore, it has a low dose
radiation. For example, a DEXA-scan provides only 30 microSV, whereas qCT
provides 5000 to 10000 microSV. This makes DEXA-scanning favorable, especially
in the pediatric population. But DEXA also encounters a few problems. First of
all, since DEXA provides a two dimensional reproduction of what actually is a
three dimensional figure, it can underestimate the bone mineral density.
Especially in the growing bone, as in children, this may lead to frequent
misdiagnosing3;4;. Moreover, in ROD, where low bone turnover can lead to high
bone mineral density, but low bone strength, the sensitivity of DEXA is
insufficient for clinical purpose . And since the resolution of DEXA is low,
DEXA isn*t capable to distinguish between cortical and trabecular bone.
Finally, the association between bone mineral density measured with DEXA and
fracture risk in chidlren is yet not clear5. The current Gold Standard to
assess bone quality and bone strength is a bone biopsy, but due to its
invasiveness this is not applicable in children. Therefore, a less invasive,
but accurate way of assessing bone quality and strength is needed. Quantitative
Ultrasound (QUS) to assess peripheral skeletal bone mineral status has been
studied in children. Although it has many advantages such as low radiation,
possibility to use it bedside and low costs, normative data in children are
lacking. There are also important differences in accuracy and technical
characteristics between several QUS-machines, which limits its usefulness in
daily practice6. Conventional radiography is also frequently used to diagnose
low bone density or osteoporosis. However, low bone density and bone loss is
not detected with radiography until approximately 30% of bone loss has
occurred. Besides, the way the film is developed, the extent of soft-tissue
thickening and the variability in radiographic exposure all nfluence the
quality and the interpretation of the imaging7. Finally, (micro) Magnetic
Resonance Imaging (MRI) is an imaging technology that has the ability to
acquire high resolution images of both cortical and trabecular bone. MRI uses
a strong magnetic field and a sequence of radiofrequency pulses to produce a
three-dimensional image.
By imaging trabecular bone, trabecular bone itself is not actually visualized,
but the network of trabeculae is shown indirectly trough visualization of the
marrow. It appears as a signal void surrounded by high-signal-intensity fatty
bone marrow. The appearance is influenced by technical variability, such as
gradient echo sequences, longer echo times and higher field strengths. Most
frequently bone MRI is performed on the calcaneus, knee and wrist with high
resolution 3 Tesla MRI. One disadvantage of MRI is the amount of time it takes
to perform MRI and possible artefacts that could overestimate the trabecular
bone6. However, it is non-invasive, provides no radiation and showed great
improvement in fracture discrimination in adults with high reproducibility in
comparison with other imaging techniques8-10. Furthermore, MRI can discriminate
differences in trabecular structure depending on the age of the patient, BMD
and osteoporotic status. Since MRI for this cause is not common, there are no
guidelines yet for the use for daily practice in assessing bone mineral
status6.
Oxalosis associated bone disease
Primary hyperoxaluria is a rare autosomal recessive disorder of glyoxylate
metabolism which results in overproduction of oxalate11;12. Oxalate is mainly
eliminated by the kidneys and is both filtered in the glomerulus and secreted
by the tubules 12. High concentration of oxalate causes formation of crystals
within the tubules and eventually leads to a decline in renal function and even
End-Stage Renal Disease (ESRD) in over 50% of all patients. With decreasing
renal function, plasma oxalate levels are increasing, which causes extrarenal
tissue deposition. Sites of deposition include myocardium, bone, retina,
vessels and nerves 13. The only curative treatment is liver transplantation.
Therefore treatment is mainly focused on preventing and delaying the onset of
ESRD12. Due to improvement of the non-curative treatment of oxaluria, survival
is prolonged, which has lead to new problems, such as oxalosis associated bone
disease. Oxalosis associated bone disease is a combination of both renal
osteodystrophy and oxalate deposition, leading to bone pain, growth
retardation, deformities and even pathological fractures 13. Gold standard in
diagnosing oxalosis associated bone disease is bone biopsy. However, this is an
invasive procedure. X-ray shows a wide variety of findings (osteosclerosis,
bone resorption, rickets, bone-in-bone appearance), but none of them reflects
the actual clinical severity of the bone disease 13-15. Also, there are
indications that X-ray is not a sensitive method for detecting bone disease in
oxalosis. Studies with pQCT have shown more reliable results in order to detect
and monitor skeletal disorders in primary hyperoxaluria13. In other bone
diseases, microMRI has shown to be able to discriminate differences in e.g.
trabecular structure16. MRI is potentially more sensitive than pQCT and has not
the disadvantage of radiation burden. Early detection of metabolic bone disease
by oxalosis might prevent the development of irreversible disabilities by
earlier treatment.

The objective of this study is to assess the diagmostic accuracy of microMRI to
detect ROD in children with ESRD and metabolic bone disease by oxalosis in
patients suffering from oxalosis.

This is a multi-center, observational study in five groups; healthy young and
adult volunteers, pdiatric patients with ESRD (either on dialysis or after
renal transplantation), adult patients with ESRD (either on dialysis or after
renal transplantation) and adult oxalosis patients.
Pediatric patients from the Academic Medical Center (AMC) with ESRD will be
asked to participate in this study. Each pediatric patient will have one MRI
scan of approximately 45 minutes within 3 months after conventional radiography
and/or DEXA scan. Each oxalosis patient will also have one MRI scan of
approximately 45 minutes, within 3 months after conventional radiography.
Finally, adult patients with ESRD who will need a bone biopsy for the clinical
indication of therapy-resistant ROD be asked to participate in this study as
well. MRI will be performed within 6 weeks after bone biopsy. Patients will be
included after giving informed consent.

Participation in this study will not lead to immediate advantage for the
patient. However, with this study we might be able to diagnose ROD and oxalosis
associated bone disease in an earlier stage of the disease. As a consequence,
we might be able to improve the health outcome in children with ESRD and
oxalosis patients in the future. MRI examination is non-invasive and is a
non-ionizing examination. Participants will have to lie still in the MRI for
approximately 45 minutes. Participation in this study will require one extra
visit to the hospital. There will be no delay in the treatment for the disease
of the patients.