https://doi.org/10.52973/rcfcv-e34428
Received: 30/03/2024 Accepted: 12/06/2024 Published: 04/09/2024
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Revista Científica, FCV-LUZ / Vol. XXXIV, rcfcv-e34428
ABSTRACT
Advanced age, called geriatrics, negatively affects the aging–
related physiological changes on bodysystems. non–steroidal anti–
inammatory drugs (NSAIDs) used in geriatric pets or humans have
negative effects on the kidneys. For this purpose, , the effects of
Meloxicam and Flunixin Meglumine, which are NSAIDs frequently used
in Veterinary Medicine, on the liver and kidney structure and function
in geriatric male rats were evaluated. Twenty–four male geriatric
rats (30–36 month old) and twenty–four 3–month–old young male
Wistar albino rats were used in the study. Six groups were created,
with eight rats in each group: young control (YC), young Meloxicam
(YM), young Flunixin Meglubine (YFM), geriatric control (GC), geriatric
meloxicam (GM), geriatric Flunixin Meglubine (GFM). Control groups
(YC and GC) received an intraperitoneal injection of saline using the
same volume as in the othergroups. Meloxicam was administered
at 5.8 mg·kg
-1
to the YM and GM groups, and Flunixin Meglumine at
2.5mg·kg
-1
intraperitoneally to the YFM and GFM groups once a day for
5 days. Neutrophil Gelatinase–Associated Lipocalin (NGAL), Cystatin
C (Cyc–c), Kidney Injury Molecule–1 (KIM–1), Interleukin–18 (IL–18),
Urea, Creatinine (Crea), Albumin (Alb), and Total Protein (TP) levels,
were determined in sera and urine samples. Serum NGAL, Cys–C,
and KIM–1 levels in the GC group were found to be signicantly higher
than those in the YC group (P<0.05). Administration of both NSAIDs
caused an increase in serum Cyc–c and NGAL levels in both young and
geriatric rats (P<0.05). Since both Meloxicam and Flunixin Meglumine
administration caused an increase in NGAL and Cys–c levels in
young and geriatric rats, adjusting the drug dose and frequency of
administration by evaluating the pretreatment renal function should
be considered as a preventive measure.
Key words: Geriatric rat; Meloxicam; Flunixin Meglumine; KIM–1;
NGAL; CYS–C; kidney
RESUMEN
La edad avanzada, llamada geriatría, tiene efectos negativos sobre
los cambios siológicos que se producen con el envejecimiento en
los sistemas. Se sabe que los fármacos no esteroides utilizados
en edades geriátricas tienen efectos negativos sobre los riñones.
Para ello, en este estudio; se evaluaron los efectos del Meloxicam
y el Flunixin Meglumina, fármacos no esteroides frecuentemente
preferidos en Medicina Vveterinaria, sobre los riñones de ratas
geriátricas. En el estudio se utilizaron 24 ratas geriátricas macho y
24 ratas albinas Wistar macho jóvenes de 3 meses de edad. Se crearon
6 grupos, con 8 ratas en cada grupo: control joven (YC), Meloxicam
joven (YM), Flunixin Meglubina joven (YFM), control geriátrico (GC),
Meloxicam geriátrico (GM) y Flunixino Meglubina geriátrico (GFM). No
se adminsitro ningun farmaco a los grupo YC y GC. Se administraron
5,8 mg·kg
-1
de meloxicam a los grupos YM y GM y 2,5 mg·kg
-1
de
unixima meglubina por vía intraperitoneal a los grupos YFM y GFM
durante 5 días. Lipocalina asociada a gelatinasa de neutrólos (NGAL),
cistatina C (Cyc–c), molécula de lesión renal–1 (KIM–1) e interleucina–18
(IL–18), urea, creatinina (Crea), albúmina (Alb) y proteína total (TP),
que son marcadores de daño renal a partir de las muestras de suero
y orina obtenidas, se midieron. Se encontró que los niveles séricos
de NGAL, Cys–C y KIM–1 en el grupo GC fueronsignicativamente
más altos que los del grupo YC (P<0,05). La administración de ambos
fármacos provocó un aumento de los niveles séricos de Cyc–c y
NGAL tanto en ratas jóvenes como geriátricas (P<0,05). Dado que
tanto la administración de meloxicam como de unixina meglubina
provocan un aumento de los niveles de NGAL y Cys–c en ratas jóvenes
y geriátricas, se puede considerar como medida preventiva ajustar
la dosis del fármaco y el tiempo de aplicación mediante la evaluación
de las funciones renales iniciales antes de iniciar la terapia.
Palabras clave: Rata geriátrica; Meloxicam; Flunixin Meglumina;
KIM–1; NGAL; CYS–C; riñón
Effect of Meloxicam and Flunixin Meglumine on some Kidney parameters in
Geriatric male rats
Efecto del meloxicam y el Flunixin meglumina sobre algunos
parámetros renales en ratas macho geriátricas
Ahmet Ufuk Komuroglu
1
* , Yıldıray Basbugan
2
, Nazmi Yuksek
2
, Nuri Altug
3
, Ugur Ozdek
1
, Semiha Dede
4
1
Van Yuzuncu Yıl University, Health Service Vocational School of Higher Education. Van, Türkiye.
2
Yuzuncu Yil University, Internal Medicine, Faculty of Veterinary Medicine. Van, Türkiye.
3
Necmettin Erbakan University, Veterinary Faculty. Konya, Türkiye.
4
Van Yuzuncu Yıl University, Department of Biochemistry, Faculty of Veterinary Medicine. Van, Türkiye.
*Correspondence author: aukomuroglu@yyu.edu.tr
Effect of Meloxicam and Flunixin Meglumine in geriatric rats / Komuroglu et al. ____________________________________________________
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INTRODUCTION
Aging refers to the natural and progressive life stages that continue
through development, adulthood, and nally at old age. Although it is
often misunderstood, aging is not a pathological process but involves
normal changes over time that occur throughout the life of every
living organism [1]. The World Health Organization (WHO) denes
49–59 years of age as middle age, 60–74 years of age as elderly, and
75 years of age and above as the oldest old [2]. Due to the wide variety
of species and breeds of animals, there is no specic age that can
be dened as geriatric. However, animals that reach 75% of their
lifespan are dened as geriatric [2]. When the average human lifespan
is calculated as 80 years and the rat lifespan is 3 years, 13.8 rat days
are reported as 1 human year [3]. WHO considers people over the age
of 60 to be elderly. In line with this equation, rats aged 27 months and
above are considered elderly (geriatric) [4, 5].
With aging, several clinical and pathological changes occur in the
kidneys, such as a decrease in kweight, sclerogenic changes in the
glomeruli, inltration of chronic inammatory cells, thickening of the
intracranial vascular intima, and cells and brosis in the stroma, and
these changes lead to a decrease in renal functions as age progresses
[5]. Elderly kidneys lose their capacity to retain sodium and water
and concentrate urine due to exposure to harmful processes. The
process of aging is linked to interstitial brosis and the development
of glomerulosclerosis [6].
Some pet owners delay seeing their geriatric animal to the
Veterinarian for treatment because they fear that the veterinarian
may detect a serious illness and recommend euthanasia. In fact, many
diseases in older animals can be treated. Even without treatment,
many things can be done to improve the quality of life of animals [7].
Nonsteroidal anti–inammatory drugs, used in both veterinary
medicine and human medicine, are frequently used to control
inammation. NSAIDs hinder the production of prostaglandins by
inhibiting cyclooxygenase, leading to advantageous outcomes such
as decreased inammation and discomfort [8]. Flunixin megluminine
and Meloxicam are among the non–steroidal anti–inflammatory
drugs. Meloxicam is a COX2–preferring NSAID, blocking both the
anti–inammatory and protective actions of COX1 and COX2. The
suppression of prostaglandins by NSAIDs may result in reduced
blood flow to the kidneys, decreased glomerular filtration rate
(GFR), accumulation of nitrogenous waste products in the blood
(azotemia), retention of salt and water, and the development of
systemic hypertension [9, 10].
Nephrotoxicity is dened as rapid deterioration in kidney functions
due to the toxic effects of drugs and chemicals. Some drugs can
affect renal function in one or more ways [11]. Traditional markers of
nephrotoxicity and renal dysfunction are serum urea and creatinine.
These markers are not specic because they have low sensitivity
in detecting early renal damage. Therefore, more sensitive and
specic markers are needed to predict renal damage early. KIM–1
and Cys–C have been reported to be the main proteins reecting
renal glomerular and/or tubular damage during nephrotoxicity [12].
NSAIDs cause upregulation of KIM–1 due to ischemia–reperfusion
injury [13]. NGAL binds to granulocytes. Therefore, it is associated
with nephrotoxicity as it is responsible for inammation during renal
ischemia and renal damage [14]. In addition, interleukins such as
IL–18 play important and integral roles in renal tubular injury and
repair, thus are considered biomarkers of renal injury during drug–
induced nephrotoxicity [15]. High IL–18 levels are associated with
renal tubular atrophy and interstitial brosis. Additionally, elevated
urinary IL–18 correlates with acute kidney injury and drug–induced
nephrotoxicity [16]. These markers can be detected in both urine and
blood to evaluate drug–induced nephrotoxicity. Therefore, measuring
these markers can help predict kidney damage, providing an important
picture of disease progression and clinical outcomes.
MATERIALS AND METHODS
This study received permission from Van Yüzüncü Yıl University
Animal Experiments Local Ethics Committee with the decision dated
06/02/2020 and numbered 2020/01. The study was carried out at
Van Yüzüncü Yıl University Experimental Medicine Application and
Research Center.
Wistar albino rats (Rattus norvegicus) were used in this study.
Twenty-four geriatric rats (30–36 month old) and twenty-four 3–
month–old male rats were used. They were divided into 6 groups,
with 8 rats in each group. Meloxicam group was administered to rats
at a dose of 5.8 mg·kg
-1
[17] and unixin meglumine was administered
at 2.5 mg·kg
-1
[18, 19].
○
Group 1. (n: 8) Young Control group (YC); No medication was
applied, only 0.3 ml physiological saline IP was applied for 5 days.
○ Group 2 (n: 8) Geriatric control group (GC); No medication was
applied, only 0.3 ml physiological saline IP was applied for 5 days.
○
Group 3 (n: 8) Young Meloxicam group (YM); 5.8 mg·kg
-1
Meloxicam
IP was administered for 5 days
○
Group 4 (n: 8) Geriatric Meloxicam group (GM); 5.8 mg·kg
-1
Meloxicam IP was administered for 5 days
○
Group 5 (n: 8) Young Flunixin meglubine group (YFM); 2.5 mg·kg
-1
Flunixin meglubin IP was administered for 5 days
○
Group 6 (n: 8) Geriatric Flunixin meglubin group (GFM); 2.5 mg·kg
-1
Flunixin meglubin IP was administered for 5 days
After the last drug administration, the rats were placed in metabolic
cages (Tecniplast®) and 24–h urine samples were collected. After urine
samples were taken, the rats were euthanized using xylazine 10 mg·kg
-1
IP (2% Rompun® Bayer) and Ketamine (HCl) (10% Alfamine® Atafen)
75 mg·kg
-1
IP injectable anesthetics, and the animals were sacriced
by high volume blood collection under anesthesia. The blood taken
was centrifuged (Nuve, NF 800R, Turkey) at 4000 G for 10 min and the
serum was separated. Serum and urine samples were stored (Dt, Fydl–
268, Turkey) at -40 °C until the day of study. Kidney damage markers
NGAL (Catalog No: E0762Ra, BT LAB), KIM–1 (Catalog No: E0549Ra,
BT LAB), Cyc–c (Catalog No: E0145Ra, BT LAB) and IL–18 (Catalog No.
E0117Ra, BT LAB) were obtained from serum and urine samples levels
were determined with species–specic ELISA kits. Additionally, urea,
cretainine, albumin and total protein levels were measured from blood
and urine samples (Abott, Architect ci16200, Germany).
Histopathological Analysis
Liver and kidney tissue samples were fixed in 10% buffered
formalin for 48–72 h and then trimmed and processed for routine
histopathological examination. Tissue samples were embedded in
paran for serial sectioning. Longitudinal 4–5 μm sections were
stained with hematoxylin and eosin (HE) and examined under a light
microscope (Leica DMRB, Germany); images were also taken via the
attached camera (Basler Ace, Germany)
TABLE I
Serum Cyc–c, KIM–1, NGAL, IL–18, Urea, Crea, TP, Alb and glucose levels in Old and Young rats administered Meloxicam and Flunixin meglumine
Parameters Young Control Young Meloxicam
Young Flunixin
meglumine
Geriatric control Geriatric Meloxicam
Geriatric Flunixin
meglumine
Cyc–c (ng·mL
-1
) 5.71 ± 0.46
d
7.02 ± 0.81
c
7.30 ± 0.67
c
8.52 ± 0.67
b
9.59 ± 1.24
a
9.34 ± 0.94
ab
KIM–1 (pg·mL
-1
) 1.90 ± 0.39
c
2.63 ± 0.46
b
2.58 ± 0.62
b
3.52 ± 0.61
a
3.71 ± 0.61
a
3.74 ± 0.55
a
NGAL(ng·mL
-1
) 13.72 ± 1.35
e
16.61 ± 1.74
d
17.18 ± 2.90
d
23.76 ± 3.45
c
32.60 ± 2.81
a
28.79 ± 3.51
b
IL–18 (pg·mL
-1
) 71.957 ± 6.80
a
74.71 ± 5.73
a
75.69 ± 7.50
a
78.00 ± 7.80
a
80.263 ± 7.78
a
79.17 ± 7.57
a
BUN (mg·dL
-1
) 35.49 ± 5.18
a
35.74 ± 6.11
a
36.07 ± 4.74
a
38.64 ± 5.73
a
39.92 ± 3.38
a
40.65 ± 3.32
a
Crea (mg·dL
-1
) 0.68 ± 0.25
b
0.68 ± 0.11
b
0.70 ± 0.12
b
0.78 ± 0.10
ab
0.90 ± 0.09
a
0.89 ± 0.11
a
TP (g·L
-1
) 56.78 ± 4.06
ab
54.85 ± 4.85
b
57.90 ± 5.48
ab
57.27 ± 5.97
ab
60.85 ± 5.05
a
59.90 ± 5.35
ab
Alb (g·L
-1
) 30.90 ± 1.99
b
30.78 ± 1.95
b
31.72 ± 3.60
b
31.41 ± 3.65
ab
33.55 ± 3.05
ab
36.10 ± 2.90
a
a,b
: Dierent letters in each row indicate statistical signicance, P<0.05. Cys–c: Cystatin C. KIM–1: Kidney Injury Molecule–1. NGAL: Neutrophil Gelatinase–Associated
Lipocalin. IL–18: Interleukin–18. BUN: Blood urea nitrogen. Crea: Creatinine. TP: Total Proteine. Alb: Albumine
TABLE II
Cyc-c, KIM-1, NGAL, IL-18, Urea, Crea and Protein levels in urine samples of old and young rats
Parameters Young Control Young Meloxicam
Young Flunixin
meglumine
Geriatric control Geriatric Meloxicam
Geriatric Flunixin
meglumine
Cyc–c (ng·mL
-1
) 9.20 ± 2.41
b
12.01 ± 2.52
ab
13.11 ± 2.63
a
11.70 ± 2.38
ab
12.55 ± 3.35
a
13.87 ± 3.06
a
KIM–1 (pg·mL
-1
) 1.60 ± 0.40
c
2.07 ± 0.46
bc
2.69 ± 0.56
ab
2.88 ± 0.42
a
3.19 ± 0.58
a
2.99 ± 0.47
a
NGAL(ng·mL
-1
) 33.06 ± 5.58
c
39.86 ± 5.87
abc
43.86 ± 6.83
ab
33.71 ± 8.06
bc
40.52 ± 5.68
abc
45.31 ± 8.73
c
IL–18 (pg·mL
-1
) 54.93 ± 6.23
a
57.19 ± 4.69
a
57.52 ± 5.70
a
59.28 ± 5.93
a
61.00 ± 5.91
a
60.17 ± 5.75
a
BUN (mg·dL
-1
) 1198.23 ± 117.72
a
1219.31 ± 148.80
a
1212.70 ± 153.38
a
1275.28 ± 189.24
a
1317.48 ± 111.55
a
1341.69 ± 109.85
a
Crea (mg·dL
-1
) 32.73 ± 7.18
a
32.36 ± 4.88
a
33.10 ± 4.10
a
33.97 ± 3.52
a
38.34 ± 3.56
a
37.36 ± 3.99
a
Protein (mg·L
-1
) 99.82 ± 7.42
a
98.45 ± 6.83
a
104.99 ± 9.51
a
100.27 ± 10.13
a
107.86 ± 7.98
a
106.84 ± 11.19
a
Protein/Cre 3.212 ± 0.87
a
3.092 ± 0.46
a
3.202 ± 0.44
a
2.992 ± 0.50
a
2.832 ± 0.30
a
2.892 ± 0.46
a
a,b,c
: Dierent letters in each row indicate statistical signicance, P<0.05. Cys–c: Cystatin C. KIM–1: Kidney Injury Molecule–1. NGAL: Neutrophil Gelatinase–Associated
Lipocalin. IL–18: Interleukin–18. BUN: Blood urea nitrogen. Crea: Creatinine
_____________________________________________________________________________Revista Cientifica, FCV-LUZ / Vol. XXXIV, rcfcv-e34428
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The data were expressed as mean ± standard deviation (SD). The
data were compared using one–way analysis of variance (ANOVA),
followed by the TUKEY multiple comparison test in order to compare
the differences in each treatment. The differences were considered
signicant at P<0.05.
RESULTS AND DISCUSSION
The physiological activities of the young rats were normal and no
clinically adverse events were observed. In geriatric rats; fur shedding
was observed, their physiological activities were relatively slower
compared to young rats.
Serum Cys–C, KIM–1 and NGAL levels in the GC, GM and GFM groups
were signicantly higher compared to the YC, YM and YFM (P<0.05).
Serum IL–18 levels did not show signicant differences across the
groups (P>0.05) (TABLE I). The Cys–C level was considerably greater
in the GM group compared to the GC group (P<0.05) but comparable
to the GFM group (P>0.05). Cystatin–C levels in the YM and YFM groups
were considerably elevated compared to the YC group (P<0.05) (TABLE
I). The blood Cys–C level in the GC group was substantially greater
than that in both the YC group and the medication groups (P<0.05).
There was no signicant difference between KIM–1 levels in the GC, GM,
GFM groups (P>0.05). The serum KIM–1 level was found to be signicantly
lower in the YC group compared to the YM and YFM groups. (P<0.05).
Serum NGAL levels in the GC group were found to be signicantly
lower than the GM and GFM groups. Serum NGAL levels in the GM group
were found to be signicantly higher than those in the GFM group.
Serum NGAL levels in the YC group were found to be signicantly
lower compared to the YM and YFM groups. Serum IL–18 levels of
the GC, GM and GFM groups were no signicant difference (P>0.05).
There was no signicant difference in IL–18 levels between young
groups (P<0.05).
There was no signicant difference between serum urea levels in
all groups. Serum creatine levels in the GM and aged GFM were found
to be signicantly higher than all other groups (P<0.05).
Although the serum total protein level of the GM group was higher
than all groups, there was a signicant difference only in the YM group.
The albumin level of the GFM group was found to be signicantly
higher compared to the YC, YM, YFM and GC groups.
Urinary Cys–C levels of YFM, GFM and GM were signicantly higher
than the YC group (P<0.05), although it was also higher than the GC
group, this elevation was not signicant (P>0.05) (TABLE II). Urinary
KIM–1 levels of all geriatric groups were found to be signicantly
higher than the YC group. Urinary NGAL level in the GFM group was
found to be signicantly higher than the YC group (P<0.05) (TABLE II).
There was no signicant difference between urine IL–18, Urea,
creatinine and protein levels in all groups (P>0.05).
FIGURE 1. A) YC; The normal histological appearance of the liver is observed. B) GC; The normal histological appearance of the liver is observed. C) YM group;
The presence of necrotic hepatocytes is observed in the parenchyma of the liver. D) GM group; The presence of necrotic hepatocytes is observed in the liver
parenchyma (arrows). E) YFM group; The presence of necrotic hepatocytes is observed in the liver parenchyma (arrows). F) GFM group; The presence of necrotic
hepatocytes (arrows) in the liver parenchyma and congestion (stars) in the portal veins are observed H & E
Effect of Meloxicam and Flunixin Meglumine in geriatric rats / Komuroglu et al. ____________________________________________________
4 of 8
Histopathological Examination
Liver
In the examination of tissue sections of YC (FIG. 1 A) and GC (FIG. 1 B)
rats, the normal histological structure of the liver was observed. In the
examination of liver sections of YM group (FIG. 1C) rats, a few necrotic
hepatocytes were found in the parenchyma, but their appearance was
similar to the YC. A signicant increase in the number of necrotic
hepatocytes in the liver parenchyma was detected in the GM group
(FIG. 1D) rats. In the examination of liver sections of YFM (FIG. 1E) and
GFM group (FIG. 1F) rats, the presence of necrotic hepatocytes in a
density similar to the GM group was detected in both groups, while
congestion was also present in the vena portae and sinusoids in the
GM group rats. While pyknosis, karyorrhexis and karyolysis were
observed in the nuclei of necrotic hepatocytes, their cytoplasms
had an eosinophilic appearance.
Kidney
In the examination of tissue sections of YC (FIG. 2A) and GC (FIG. 2B)
rats, the normal histological structure of the kidney was observed.
In the examination of kidney sections of YM group (FIG.2C) rats,
congestion was observed in the glomerular capillaries. Sclerosis was
detected in some glomeruli in the kidney sections of GM group (FIG.2D)
rats. It was observed that these shrank and adhesion occurred as a
result of the disappearance of Bowman’s space. In the examination
of kidney sections of YFM (FIG. 2E) and GFM group (FIG.2F) rats, there
were degeneration, necrosis and glomerular atrophy in the mesangial
cells. In the glomeruli where these changes were observed, the
glomerular ball and Bowman’s space were enlarged. However, it was
determined that these changes occurred more in the GF group rats.
Monitoring the medications used by the geriatric population is
very important for their health and well–being. This population uses
nonsteroidal anti–inammatory drugs for many conditions. Even
if these medications are taken correctly, they can be harmful due
to the normal changes that come with aging. Despite the elderly
population could mantain a normal kidney and liver function, they
have lower drug metabolism and elimination rates than younger
adults [20]. As people age, kidney function declines, regardless of
disease. geriatric individuals are more susceptible to renal failure
because of inherent physiological changes associated with aging [21].
It has been reported that the initial stages of chronic renal failure are
more likely to occur in patients aged 65 and over who take NSAIDs
for 2 months [20]. NSAID–related kidney damage mostly occurs due
to reduced glomerular ltration rate and disrupted hemodynamics,
resulting in nephron ischemia. Increased risk of injury is associated
with high–dose or prolonged exposure to NSAIDs, volume depletion,
renal vasoconstriction, and poor autoregulation. Therefore, geriatric
individuals are more susceptible to NSAID–associated kidney damage
[22]. NSAIDs can both reduce prostaglandin production and lead to
deterioration of renal function under conditions where effective
circulating volume is reduced, this rate being as high as 13% in
patients living in geriatric care homes [23]. For this purpose, in
FIGURE 2. A) YC; The normal histological appearance of the kidney is observed. B) GC; The normal histological appearance of the kidney is observed. C) YM group;
Congestion is observed in the glomerular capillaries. D) GM group; Glomerular sclerosis is observed (arrows). E) YFM group; Expansion of Bowman’s space is
observed (asterisk). F) GFM group; Expansion of Bowman’s space is observed (stars) H & E
_____________________________________________________________________________Revista Cientifica, FCV-LUZ / Vol. XXXIV, rcfcv-e34428
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this study, we used the NSAIDs meloxicam and uniski to reduce
the levels of renal markers NGAL, KIM–1, CYS–c and IL–18 in aged
rats. Serum Cyc–c, KIM–1, NGAL levels were found to be statistically
signicant in the comparison between the young people who were
not administered medication and the elderly group who were not
administered medication (TABLE I). This indicates that there are
some changes in the kidney tissue with aging and that it loses its
normal physiological structure.
The kidney typically maintains a consistent glomerular ltration
rate by controlling intraglomerular pressure, mostly inuenced by
renal prostaglandins [24]. NSAIDs, which impact prostaglandins,
may inuence intra–glomerular pressure and result in glomerular
dysfunction. Prostaglandin–metabolizing enzymes like COX–1 and
COX–2 are mainly found in renal tissues. Both selective and non–
selective COX inhibitors may cause severe kidney adverse effects,
resulting in acute and chronic renal failure [24].
NGAL is a small protein found in the bloodstream that is signicantly
affected by many different diseases and is a valuable indicator of
numerous health issues. NGAL is a top indicator of acute renal
damage [25]. Plasma and urine levels of NGAL signicantly increase
in inammation, ischemia, and nephrotoxic states [26]. NGAL has
been proposed to have a crucial function in renal disorders [27]. NGAL
levels rise quickly within hours after acute tubular necrosis and then
decrease to baseline levels within days as injured tubules regenerate.
NGAL is particularly sensitive in diagnosing early nephrotoxicity and
acute kidney damage. Animal studies have shown that the genes that
codify NGAL are highly upregulated in kidney damaged [28]. It has
been reported that chronic NSAID exposure signicantly increases
urinary NGAL levels in adults with spondyarthritis. It has been stated
that NGAL may be a determinant in the initial step of NSAID–mediated
kidney damage. It has been reported that urinary NGAL levels continue
to increase in patients taking multiple NSAID doses, but decrease
when drug use is not repeated [29]. In the presented study, serum
NGAL levels of old rats were found to be signicantly higher than
young rats (P<0.05) (TABLE I). Serum NGAL levels of geriatric rats
treated with meloxicam were found to be signicantly higher than
both the geriatric control group and the aged unixin meglumine
administered groups. The urinary NGAL level of old rats treated with
unixin meglumine was found to be higher than all groups, but it
was signicantly higher only than the young control. Administration
of NSAIDs meloxicam and unixin meglumine to old rats may have
caused kidney damage and increased serum NGAL levels.
Cys–C, an important member of the cysteine protease inhibitor
superfamily, is a soluble, non–glycosylated secretory protein that
is constantly produced by nucleated cells in the body and is widely
found in body uids [30]. Cys–C passes through the blood into the
glomerulus and is fully reabsorbed and broken down in the proximal
renal tubules. Tubular injury leads to impaired cystatin C reabsorption
in the proximal tubule. Therefore, Cys–C is considered to have the
potential to detect both glomerular and proximal kidney damage [31].
Additionally, Cys–c is not affected by muscle mass like creatinine and
detects GFR changes more accurately in older people [22]. In the
case of renal tubular damage, Cys–C reabsorption decreases, and its
serum level increases in the early stages of damage. Serum Cys–C
level may rise to high levels with decreased glomerular ltration rate
and may, therefore, identify mild renal failure [32]. In the presented
study, serum and urine Cys–C levels of rats administered meloxicam
and unixin meglumine were found to be signicantly higher than
Effect of Meloxicam and Flunixin Meglumine in geriatric rats / Komuroglu et al. ____________________________________________________
6 of 8
the young control group. Serum Cys–c levels of both control and
drug–treated old rats were found to be signicantly higher than young
control and drug–treated young rats.
KIM–1 is a transmembrane proximal tubular protein and is expressed
in response to kidney injury [33]. KIM–1 is thought to be one of the
very specic and sensitive biomarkers whose urine levels increase
during the day in experimental models of toxic molecules or ischemic
kidney injury [34]. In a study conducted on elderly people aged 70–79
with preserved physical functions, no signicant difference was found
between urinary KIM–1 levels in NSAID users and non–users [22].
Serum KIM–1 levels in all old rat groups were found to be signicantly
higher than in all young rat groups. Although the serum KIM–1 level of
old rats administered meloxicam and unixin meglumine was higher
than the old control group, this increase was not signicant. Although
the serum KIM–1 levels of young rats administered meloxicam and
unixin meglumine were higher than the young control, this increase
was not signicant. Drug administration in both old and young rats
may increase serum KIM–1 levels by causing renal tubular damage.
Interleukin–18 (IL–18) is a proinammatory cytokine produced from
proximal tubular cells and has been proven to play an important role in
acute kidney injury and is a mediator of tubular damage [35, 36]. It was
found that kidney IL–18 content increased signicantly in Potassium
dichromate–induced acute kidney injury in rats [35]. IL–18 participates
in the pathogenesis of many renal diseases such as renal ischemic
reperfusion injury, allograft rejection, autoimmune disease, and
obstructive uropathy [11]. In a study conducted in elderly people with
preserved physical functions who used and did not use NSAIDs, it
was found that the urinary IL–18 level in those who used NSAIDs was
10% lower compared to those who did not use it [22]. Although both
serum and urine levels of IL–18 were high in the geriatric groups, this
elevation was not signicant.
Urea and creatinine serve as biochemical parameters of kidney
damage, therefore, an increase in these parameters may indicate
kidney disorders [37]. Keratin, a non–protein nitrogen compound, is
produced in muscle during keratin–phosphocreatine metabolism and
secreted by ltration from the glomeruli [38]. Like urea, creatinine
secretion is affected by the glomerular ltration rate, as a result, any
change that lowers the glomerular ltration rate (GFR) will cause the
serum creatinine level to rise [39]. Serum urea and creatinine levels
in rats treated with diclofenac, an NSAID, were signicantly higher
than the control group [40]. It has been stated that NSAIDs cause
a decrease in GFR, and as a result, serum urea and keratin levels
may increase [40]. In a study conducted on dogs, it was reported
that serum urea and creatinine levels did not change when blood
samples taken on the fth and tenth days of meloxicam application
were compared for 10 days [41]. In the presented study, serum urea
and creatinine levels in the geriatric control group were higher than
the young control and the young rats treated with the drugs, but this
increase was not signicant. Serum urea and creatinine levels of old
rats administered meloxicam and unixin meglumine were higher
than the geriatric control but were not signicant.
CONCLUSION
In humans or animals entering the geriatric period with aging,
deteriorations occur in the normal physiological and histological
structure of the kidney . Renal function should be monitored during
the use of NSAIDs such as meloxicam and unixin meglumine. It may
be useful to monitor KIM–1, NGAL, Cyc–c and IL–18 levels in people
taking type of drugs, especially in the elderly. If the level of these
markers increases, it may indicate kidney damage, and the use of the
drug may be re–evaluated. Therefore, during the use of meloxicam
and unixin meglumine, attention should be paid to the dose and
duration of use to reduce the risk of kidney injury or damage.
ACKNOWLEDGEMENTS
This study was supported by Van Yüzüncü Yıl University Scientic
Research Project Coordination Unit as project number TSA–2020–8947.
Conict of interest
The authors declare no conicts of interest.
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