Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04354181 |
| Other study ID # |
CRE- 2020.058 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 24, 2020 |
| Est. completion date |
January 20, 2023 |
Study information
| Verified date |
February 2023 |
| Source |
Chinese University of Hong Kong |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Despite the advent of treating stones with Extracorporeal Shock Wave Lithotripsy (ESWL) and
Percutaneous nephrolithotomy (PCNL), the recurrence rate for renal stones remains high and
this may be due to poor compliance of patients with dietary and fluid advice, age, metabolic
abnormalities, medicines and the formation of "new stones" from clinically insignificant
residual fragments (CIRF).
Though some patients become stone-free after ESWL/PCNL or open surgeries, the majority
develop "new stones" and it is difficult to predict when these stones will recur until either
they have imaging perform or they developed symptoms. However, the use of regular imaging for
monitoring will be costly and involve radiation exposure. Therefore, a diagnostic tool is
needed to enable the clinician and/or patient to monitor for stone recurrence.
In the previous studies, some urine markers were identified that are related to stone
formation. The relationship of these urine markers with the recurrence of renal stone will be
further explore in this study. Also, potential markers that could predict stone recurrence
will be identified, and hence earlier intervention could be offered to patients.
Description:
Stone recurrences remain a major challenge in the management of renal stone patients, despite
the emergence of ESWL as an internationally accepted method for the minimally invasive
treatment of most renal stones . Depending on the location and size of a stone, the success
rates for ESWL can be greater than 80% for successful disintegration (fragmentation) of the
stone, and the rate at which patients remain stone-free after 3 months ranges from 40%-80%.
The rates of stone recurrence, defined as symptomatic episodes and/or interventions due to
residual fragments, after ESWL, PCNL and URETS range from 10%-60% and depend upon the
duration of the prospective follow-up study. In long-term follow-up studies after ESWL, the
recurrence rates have been shown to increase annually. This recurrence could be due to poor
patient compliance with dietary and fluid-intake advice, patient age, metabolic
abnormalities, the side-effects of medicines or the formation of new stones from the CIRFs
that result from ESWL.
The fragments of clinically insignificant or significant stones that remain after
ESWL/PCNL/URETS can pose a long-term risk for patients by serving as a nidus for new stone
formation. Patients are declared 'stone-free' after ESWL only if no fragments are detected on
radiographs, ultrasound scans or intravenous pyelograms with tomography and spiral computed
tomography (CT) scans. Fragments smaller than 5 mm are considered capable of spontaneous
passage, and such fragments are regarded as CIRF. Despite prophylactic measures to reduce
stone formation, the recurrence rate remains high. There is also a paucity of information
concerning the biochemical or metabolic evaluations of patients who have been tracked in the
long-term studies described above. Some specific biological effects from ESWL are well known;
for example, the urinary enzyme levels are known to increase. Although the enzyme levels
commonly return to normal in the short-term, the levels of these enzymes, and other
biomarkers such as glycosaminoglycans and cytokines, have not been tracked over longer
periods of time.
The urinary levels of both cytokines and mediators of inflammation are becoming increasingly
recognised as important markers for urologic diseases. In a study of the urinary levels of
IL-6, IL-1β and 1α in patients with stone disease, patients without bacterial cystitis showed
significant elevations of IL-6 but did not have marked increases in either IL-1β or 1α
relative to control subjects. The patients with bacterial cystitis showed elevations in all
three cytokines. Studies have also examined the injury to cells from oxalate toxicity and
calcium oxalate crystal exposure, using tests on tissue cultures and rat models [20-22]. Such
types of cellular damage have also been shown to attract crystal binding, which can lead to
crystal growth and aggregation. An inflammatory response has also been seen in experimental
nephrolithiatic rats, whereby crystals were shown to form in the tubular lumen and eventually
to move into the interstitium, causing inflammation and attracting macrophages or other
inflammatory cells. Recent advances in translational medicine have also identified new
molecules such as urinary kidney injury molecule-1 (uKIM-1). The levels of the uKIM-1
molecule have been found to be increased following lithotripsy, suggesting it might be a good
candidate for an acute kidney injury (AKI) molecule. Hence, studying the levels of cytokines
and the mediators of inflammation could help in understanding the pathogenesis of
urolithiasis. Such studies could also identify a reliable marker for the early diagnosis,
treatment and prevention of stone recurrence.
Small fragments (<5 mm) that have not passed spontaneously and are retained undetected in the
urinary tract can develop into new stones in the ensuing months or years. The investigators
hypothesise that such retained fragments are most likely to be attached to the urothelium,
thereby injuring the cells and the underlying tissue. The investigators also hypothesise that
depending on the growth rate of a fragment, this injury can invoke an inflammatory response
that begins as sub-clinical (i.e., asymptomatic). This kind of injury is akin to
stone-formation causing mechanical stimulation (i.e., irritation) of the epithelial cells,
which results in the production of cytokines and mediators of inflammation. These by-products
eventually become a 'plaque', similar to a Randall's plaque. These hypotheses have been
recently reviewed and have been suggested to indicate a likely pathway to calcium stone
formation.
In previous studies on the separation of urinary glycosaminoglycans (GAGs), the investigators
have reported the electrophoretic separation of urinary GAGs into their sub-classes on a
preparative scale. Chondroitin sulphates (CS) and HAs were cleanly separated from the heparan
sulphates (HS). On further analysis by high-performance liquid chromatography, HAs were
identified as the major contributors to the crystallisation-promoting properties observed in
the early electrophoretic fractions of stone-formers. The involvement of HAs in urolithiasis
was further supported from studies involving their extraction and identification in
calcium-containing stones. The investigators also confirmed that the in vivo role of HAs was
more likely to be a secondary effect rather than a cause of stone formation, although the
release and increase of HAs from injured tissues could accelerate the growth and deposition
of calcium and oxalate (e.g., on the CIRF).
In previous preliminary case-controlled study, the investigators had looked into a multitude
of potential biomarkers and inflammatory cytokines. The molecular candidates were from both
urine and serum samples, and six patient groups were assessed including active stone-formers
with and without infection and before and after the removal of stones. Also, normal controls
with and without urinary tract infections were assessed.
The most well-studied and characterised markers, which are also easily available, were
selected for the study. The markers included: (1) the inflammatory markers IL-1α, IL-6 and
IL-8, (2) the mediator macrophage inflammatory protein-1α (MIP-1α) and (3) the urinary
biochemical markers N-acetyl-β-D-glucosaminidase (NAG), neutrophil gelatinase-associated
lipocalin (NGAL) and HA. In addition, the metabolic biochemical parameters were also
investigated. These parameters included levels of sodium, potassium, calcium, magnesium,
ammonia, phosphate, sulphate, oxalate, citrate, urate, chloride and creatinine.The pH and
osmolality were also investigated.
The preliminary results have confirmed that urinary HA is a reliable indicator of active or
silent stones. The investigators reported this earlier in the initial findings of the
presence of urinary HA. The proportion of excreted HA was significantly high. This finding
was reported at the October 2018 meeting of the Société Internationale d'Urologie held in
Seoul, Korea. HA is a ubiquitously distributed component of the extracellular matrix. In its
native form, it exists as a high-molecular weight polymer, and lower-molecular weight forms
of HA species accumulate at sites of inflammation and tissue injury. Previous studies concur
that urinary HA is composed predominantly of lower-molecular weight (~10 kDa) species , which
suggests a role for these species as mediators of inflammation.
Of the inflammatory and urinary biochemical markers, IL-6 and IL-8 were predictably higher,
and NGAL was also significantly increased compared to controls and patients who had stones
removed. It is also interesting to note that the stone-former cohorts had lower citrate and
higher oxalate excretion, although just at the trend level. However, the medians differed
clearly from those of the control group, suggesting that the measurement of citrate and
oxalate is still a useful indicator of the risk of stone formation.
Therefore in this follow-up study, the investigators would like to investigate the time
points at which recurrent stone-formers should be monitored over the longitudinal study
period proposed herein.
