Аннотация:Abstract:
INTRODUCTION AND AIMS: Although it is well proven that tubulointerstitial fibrosis (TIF)
plays an important role in progression of chronic glomerulonephritis (CGN), there are no
approaches for TIF monitoring in clinical practice for more precise control of the
immunosuppressive and renoprotective treatment effectiveness. Uromoduline (UMOD) is a
transmembrane glycoprotein produced by the thick ascending limb of the loop of
Henle. As the most abundant protein excreted in normal human urine and highly specific
for renal tubulocytes UMOD can be considered the candidate for urinary biomarker of TIF
progression. The aim of the study was to investigate the urinary excretion of UMOD and
collagen IV (COL4) in patients with CGN, its possible associations with proteinuria (PU) and
other clinical signs of CGN activity, glomerular filtration rate, morphologic
degree of nephrosclerosis.
METHODS: 82 CGN patients (45% men, 55% women; mean age 36.5 (28.0; 55.0)) were
examined. 69,5% patients developed arterial hypertension; in 31.7% of the study patients
the hypertension was sever or resistant (blood pressure (BP) ≥ 160/100 Hg mm before
treatment or BP ≥ 140/90 Hg mm although 3 or more antihypertensive drugs are used).
Nephrotic syndrome was revealed in 31.7%; glomerular filtration rate estimated using the
CKD-EPI formula (eGFR) < 60 ml/min/1.73 m2 was found in 31.7% of the study patients.
High degree of interstitial fibrosis (> 30%) was found in 38.2% patients. Morning urine
samples were analyzed by ELISA to determine the excretion of biomarkers (UMOD and
COL4). The results were adjusted to urinary creatinine concentrations.
RESULTS: Urinary excretion of COL4 positively correlated with age (Rs = 0.39; p < 0.001),
CKD duration (Rs = 0.25; p < 0.05), systolic and diastolic blood pressure (Rs = 0.22; p < 0,05
and Rs = 0.25; p < 0.05), PU (Rs = 0,50; p < 0,0001), serum fibrinogen (Rs = 0.57; p <
0.0001), and negatively correlated with eGFR (Rs = -0.36; p < 0.001), hemoglobin (Rs = -
0.32; p < 0.01). In contrast urinary excretion of UMOD only positively correlated with eGFR
(Rs = 0.37; p < 0.001), and negatively correlated with CKD duration (Rs = -0.43; p <
0.0001). High UMOD excretion (> 75th percentile) was although in group with high degree
of interstitial fibrosis nobody presented high level of UMOD.
Clinical and laboratory pattern of CGN patients stratified by urinary excretion of UMOD and
COL4
Urinary UMOD
/ COL4
Older
age
PU ≥ 0.5
g/d
Nephrotic
syndrome
Severe arterial
hypertension
eGFR < 60
ml/min/
1.73 m2
Anemia
High UMOD /
not high COL4,
n = 15
13.3% 46.7% 26.7% 13.3% 13.3% 13.3%
High UMOD /
high COL4, n
=5
40.0% 80.0% 60.0% 20.0% 0.0% 0.0%
Not high UMOD
/ not high
COL4, n = 44
18.2% 72.7% 22.7% 29.6% 31.8% 15.9%
Not high UMOD 62.5% 100.0% 56.3% 56.3% 62.5% 62.5%
/ high COL4, n
= 16
χ2 =
13.65; р
< 0.01
χ2 =
11.50; р
< 0.01
χ2 = 7.99; р <
0.05
χ2 = 7.25; 0.05 ≤ р
< 0.1
χ2 = 11.49; р
< 0.01
χ2 =
15.76; р
< 0.001
CONCLUSIONS: While COL4 excretion can be considered the universal biomarker signing
both CGN activity and progression, UMOD excretion is exclusively associated with
nephrosclerosis development. The combination of high COL4 and depleted UMOD
excretion was found in the most sever cases of CGN; this combination can reflect
tubulocytes transdifferentiation and apoptosis. Studying UMOD and COL4 urinary
excretion complex can be useful for estimation of CGN stage and prognosis. But prospective
studies are needed to verify it.