DISCUSSION
The main finding of current study is that, a significant change in renal
cortical elasticity was not found between patients with DM-II versus
healthy subjects or in albuminuria versus no-albuminuria subgroups.
DM-II causes microstructural changes in renal parenchyma before a
significant drop in eGFR occurs (3). A moderately increased uACR
indicates presence of kidney damage and is associated with future risk
of progression to kidney dysfunction and cardiovascular complications
independent of eGFR (16). We recognize that histological changes can be
present in a number of subjects with DM-II before pathologic amount of
urinary albumin can be detected (3, 7). Hence, one may argue that biopsy
is required for definitive confirmation of typical diabetic changes in
glomeruli (8). However, biopsy is not performed routinely in all cases
with DM-II and mostly reserved for certain indications (9). In the
landmark study by Fioretto P et al, microalbuminuric DM-II patients with
normal eGFR underwent kidney biopsy for research purposes rather than
for a clinical indication (18). They found histopathological changes
(either typical glomerular or atypical tubulointerstitial and vascular
changes), in 70% of DM-II subjects. That was the basis that a
moderately elevated uACR in the setting of preserved eGFR was used as
representative of early diabetic renal injury in the current study where
biopsy was not available. We have found that, the early diabetic
histologic changes in kidneys do not necessarily translate into
disturbed elasticity, as we have not observed a difference in SWV values
between albuminuria and no-albuminurai subjects.
Conventional kidney US findings alone are inadequate for early
recognition of kidney damage in most cases. Indeed the typical US
findings of CKD represent late changes (4-6), which are already
irreversible. Moreover the conventional US findings of CKD are not
specific for diabetic nephropathy and diverse etiologies share the
common imaging changes. Elastography, on the other hand, has emerged as
a tool for assessment of increased tissue stiffness caused by damages to
organs including liver, breast, thyroid, prostate and kidney. The
relatively novel US shear-wave elastography method was used to assess
kidney stiffness in our study. 2D-SWV measurement by this technique has
provided comparable results to previously described methods including
transient elastography and acoustic radiation force imaging in depicting
liver fibrosis (15). Although SWV values are positively correlated with
amount of fibrosis in liver diseases (19), it is negatively correlated
with CKD stages and eGFR (6, 12). The underlying mechanism of the
inverse relationship between stiffness and eGFR in patients with CKD
remains unclear. Altered renal perfusion has been proposed to affect
stiffness measurements and explain this paradox (20). The ARFI derived
SWV has been found to be higher in patients with DM-II versus healthy
controls in one study (21). Moreover others revealed increased SWV in
DM-II induced early kidney damage but no CKD (i.e. eGFR still more than
60 ml/min/1.73m²) versus diabetic CKD (i.e. eGFR already less than 60
ml/min/1.73m²) (17). Interestingly our results does not support these
findings. The whole kidney average SWV’s were not found to be increased
neither in DM-II vs healthy controls nor in mAlb+ vs mAlb- subjects in
current study. The contradiction between both studies can be explained
by the differences in study populations. Goya et al (17) did not report
any exclusion criteria in terms of comorbidities that may interfere with
elasticity results (hypertension, systemic diseases, other diabetic
organ complications, risk factors for vascular diseases). On the other
hand our population comprised a very selective group that presence of a
confounder of elasticity would be very unlikely. Another factor that may
influence the results is the sonographic technique used for elasticity
assessment. We used 2D-SWV measurement, whereas others used the ARFI
method.
The left middle and right upper portions’ elasticity seemed to be
selectively disturbed in mAlb+ cases at univariate comparison. One may
argue that this may be attributable to the potentially asynchronous
severity of changes in different portions of kidneys (8, 10). Indeed,
heterogeneous renal histopathologic changes may occur in albuminuric
patients with DM-II (22, 23). However, both renal portions SWV values
were not independent predictors of mAlb+ status when adjusted for age by
multivariate analysis. Hence focal impaired elasticity in mAlb+ group as
compared to mAlb- group can not be considered plausible.
The impairment of whole kidney elasticity probably requires more
profound histological changes due to diabetic nephropathy. Previous
studies have shown reduced global kidney SWV values along with decreased
eGFR values with or without severe proteinuria (6, 12, 19). However
these findings probably require more severe kidney damage beyond
glomerulosclerosis such as tubulointerstitial fibrosis and vascular
changes which are deemed irreversible. We believe early recognition of
disturbed kidney elasticity as a surrogate marker of early kidney damage
is not possible by 2D-SWV measurement at this stage. However due to
conflicting results when compared with the previous work using ARFI
technique, further controlled longitudinal studies in larger series with
biopsy and histopathology being used as reference standard are required
in this regard.
The reproducibility of 2D-SWV was good in the current study with an
interobserver agreement ICC value of 0.66, which is close to previous
reports.
The major strength of our work is that it is the first study to evaluate
the ability of novel 2D-SWV US elastography technique in revealing early
kidney damage in patients with DM-II. Furthermore, application of strict
inclusion criteria to eliminate the potential confounders of disturbed
elasticity and proteinuria is another strength of our work. The sample
size was also calculated a priori, and the number of patients included
are adequate to reveal a difference between the SWV values of the study
groups.
The main limitations in current study is the absence of
histopathological confirmation of kidney damage. We believe, a
combination of moderate albuminuria with preserved eGFR is a quite
pragmatic way to reveal the early diabetic kidney damage, where biopsy
is not available. Although very unlikely, absence of a non-diabetic
cause of moderately increased uACR cannot be guaranteed based on
exclusion of diseases by history and symptoms alone.
In conclusion, the kidney elasticity does not seem to be disturbed in
patients with diabetes and a preserved eGFR with or without moderate
albuminuria.
CONFLICT OF INTEREST: None.