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DOI: 10.3727/096368910X508825
E-ISSN 1555-3892
www.cognizantcommunication.com
Cell Transplantation, Vol. 19, pp. 723–729, 2010
Printed in the USA. All rights reserved.
Copyright  2010 Cognizant Comm. Corp.
Serum Tissue Inhibitor of Metalloproteinases 1 (TIMP-1) Predicts
Organ Recovery From Delayed Graft Function After
Kidney Transplantation From Donors After Cardiac Death
Mamoru Kusaka, Yoko Kuroyanagi, Manabu Ichino, Hitomi Sasaki, Takahiro Maruyama,
Kunihiro Hayakawa, Ryoichi Shiroki, Atsushi Sugitani, Hiroki Kurahashi, and Kiyotaka Hoshinaga
Department of Urology, Division of Molecular Genetics, Department of Organ Transplantation and Regenerative Medicine,
Fujita Health University School of Medicine, Toyoake, Aichi, Japan
Donors after cardiac death (DCD) have recently become an important source of renal transplants to alleviate
the shortage of renal grafts in kidney transplantation (KTx), although DCD kidneys often have complications
associated with a delayed graft function (DGF). A microarray-based approach using renal biopsy samples
obtained at 1 h after KTx from DCD identified the tissue inhibitor of metalloproteinases 1 (TIMP-1) gene
as a potential predictive marker for DGF. The current study measured serum TIMP-1 in patients undergoing
KTx and analyzed the time course after KTx. The average serum TIMP-1 level before KTx was 240 ± 10
ng/ml (n = 34). In patients undergoing KTx from a living donor (n = 23), the serum TIMP-1 levels showed
no increase after KTx (POD1: 226 ± 12, POD2: 211 ± 12, and POD3: 195 ± 10 ng/ml), but in one case, the
only patient who required post-KTx HD due to DGF, the level on POD1 was the highest among subjects
(361 ng/ml). In contrast, patients undergoing KTx from DCDs (n = 11), the serum TIMP-1 levels increased
rapidly after a KTx (POD1: 418 ± 32, POD2: 385 ± 42, and POD3: 278 ± 25 ng/ml). However, two patients
who avoided post-KTx HD due to the immediate function of the graft did not show increased levels (<370
ng/ml) on either POD1 or POD2. The peak serum TIMP-1 values appeared to correlate to the post-KTx
dialysis period. Furthermore, the increment of serum TIMP-1 on the early POD was found to be predictive
of immediate or delayed function of the grafts. These data suggest that monitoring of serum TIMP-1 levels
allow the prediction of graft recovery and the need for HD after a KTx from a DCD.
Key words: Donation after cardiac death (DCD); Delayed graft function (DGF); Kidney transplantation;
Tissue inhibitor of metalloproteinases 1 (TIMP-1)
INTRODUCTION
lish highly sensitive prognostic markers for DGF in KTx
from DCD.
Gene expression profiling was conducted using renal
biopsy samples obtained at 1 h after KTx from DCD.
Several genes significantly upregulated in DCD kidneys
were identified and they might reflect the performance
of the graft and be potential noninvasive biomarkers
(19). One of the good candidate genes that are potentially useful as a serum marker is the gene encoding
tissue inhibitor of metalloproteinases 1 (TIMP-1). The
matrix metalloproteinases (MMPs) and TIMPs system is
responsible for the degradation of extracellular matrix
(ECM) components involved in normal physiology and
tissue remodeling (31). There is mounting evidence that
the expression of TIMP-1 in the kidney is upregulated
in various condition related to degeneration of renal tis-
Because of a worldwide shortage of renal grafts,
transplantation from donors after cardiac death (DCD)
is becoming an alternative method to that from braindead donors (22,32,33). KTx of DCD grafts are still associated with a high incidence of delayed graft function
(DGF) and/or primary nonfunction (PNF) during the
early posttransplantation period. The incidence of PNF
is as small as 5%, but the majority of grafts undergo
some degree of DGF (9,13,14). DGF predisposes the
graft to both acute and chronic rejection, thus indicating
that DGF is a crucial risk factor for the short- and longterm survival of the graft and prognosis of the recipients
(5,10,11,20,25,27,28,34). These situations prompted the
attempt to understand the etiology of DGF and to estab-
Received June 1, 2009; final acceptance April 21, 2010. Online prepub date: June 3, 2010.
Address correspondence to Mamoru Kusaka, M.D., Department of UrologyFujita Health University School of Medicine, 1-98 Dengakugakubo,
Kutsukake-cho, Toyoake, Aichi, 470-1192 Japan. Tel: +81-562-93-2181; Fax: +81-562-93-7863; E-mail: [email protected]
723
724
sue, such as lupus nephritis (29), diabetic nephropathy
(28,30), drug nephrotoxicity (26), and acute pyelonephritis (6). The serum TIMP-1 levels have also been
shown to be elevated in patients with glomerulonephritis, nephrosclerosis, and diabetic nephropathy, and its
potential usefulness as a biomarker has been discussed
(2,8,12).
TIMP-1 is upregulated in the kidneys after ischemia/
reperfusion injury, cyclosporine-induced interstitial fibrosis, and chronic renal allograft rejection in animal
KTx models (1,3,15). In a clinical study, TIMP-1 was
upregulated in the transplanted kidneys treated by
cyclosporine 1 week after Tx (4). TIMP-1 is also associated with chronic renal transplant fibrosis (15,21,23).
TIMP-1 is upregulated in the transplanted kidneys 1
week after Tx from DCD (16). However, no report has
yet analyzed the serum TIMP-1 levels in KTx. This
study determined the serum TIMP-1 level in patients undergoing KTx and analyzed the time course of the
TIMP-1 expression after KTx to evaluate the usefulness
of serum TIMP-1 as a potential marker for predicting
the early functional recovery of transplanted DCD kidneys.
MATERIALS AND METHODS
Study Design
This investigation was approved by the Institutional
Review Boards. Written informed consent was obtained
from each patient or legal guardian before enrollment.
Patients undergoing either a living-related (LD; n = 23)
or DCD KTx (n = 11) were prospectively enrolled. The
immunosuppressive regimen of basiliximab, tacrolimus,
or cyclosporine with prednisone and mycophenolate mofetil was similar in all patients.
The clinical characteristics of the patients undergoing
KTx from DCD are shown in Table 1. All donors after
cardiac death from this hospital were classified as type
IV in this study. The cause of donor death was cerebrovascular disease in all cases. Although most of those
cases required hemodialysis (HD: 0–17 days) after KTx
because of DGF, the function of all of transplanted kidneys eventually recovered. There were no cases of either
rejection or calcineurin inhibitor nephrotoxicity, which
were confirmed by a biopsy during DGF.
Serum samples were collected before and following
KTx and stored in aliquots at −80°C. The primary outcome variable was the development of DGF, defined as
the need for HD within the first few weeks after transplantation. The decision to initiate HD was taken by the
primary transplant nephrologists and transplant surgeons, without any involvement from the study investigators. Other variables included age, gender, original
KUSAKA ET AL.
kidney disease, warm and total ischemic time, urine output, and the serial serum creatinine level.
ELISA for TIMP-1 Quantification
The ELISA for serum TIMP-1 was performed as previously described. Briefly, microtiter plates were precoated with a mouse monoclonal antibody raised against
human TIMP-1 (DTM100, R&D Systems, Minnesota,
USA) and blocked with buffer containing 1% BSA. The
wells were then coated with 50 µl of serum samples or
standards (TIMP-1 concentrations ranging from 0.08 to
10 ng/ml), and incubated with a polyclonal antibody
against TIMP-1-conjugated HRP. TMB substrate was
added for color development, which was read within 30
min at 450 nm with a microplate reader (Benchmark
Plus, BioRad, Hercules, CA, USA). All measurements
were made in triplicate. The inter- and intra-assay coefficient variations were 5–10% for batched samples analyzed on the same day. The laboratory investigators
were blinded to the sample sources and clinical outcomes until the end of the study.
Statistical Analyses
The results are expressed as the mean ± SEM. Statistical comparisons between groups were performed by
Student’s t-test, and differences were considered to be
significant at p < 0.05. Correlations were evaluated with
a linear straight-line regression. In significant difference
tests, p-values were calculated with the z conversion of
Fisher’s r. Values of p < 0.05 were also considered to
be statistically significant.
RESULTS
The mean serum TIMP-1 level pre-KTx (n = 34) was
240 ± 10 ng/ml. The values were similar to the reported
normal levels (190 ng/ml) and there was little variation
among the samples. Next, samples obtained at post-KTx
were examined. Patients who required HD in the postKTx period due to DGF (LD: n = 1, DCD: n = 9) had
serum TIMP-1 levels on POD1 (430 ± 33 ng/ml) that
were significantly higher than those who did not (LD:
n = 22, DCD: n = 2; 229 ± 12, ng/ml; p < 0.001) (Fig. 1).
The time course of serum TIMP-1 levels were analyzed before and after the KTx. Serum TIMP-1 levels
showed no increase after KTx (POD1: 226 ± 12, POD2:
211 ± 12, and POD3: 195 ± 10 ng/ml) in patients undergoing a KTx from a LD. However, in one case, the serum TIMP-1 level was higher than 360 ng/ml at POD1.
This patient was the only LD-KTx case who required
HD due to DGF (Fig. 2). In contrast, 9 of the 11 patients
undergoing KTx from DCD required HD due to DGF
patients. In these nine cases, serum TIMP-1 levels increased rapidly after the KTx (POD1: 418 ± 32, POD2:
SERUM TIMP-1 AS A PREDICTOR OF DCD KIDNEY ORGAN RECOVERY
725
Table 1. Patient Characteristics: Donation After Cardiac Death (DCD)
Patient
ID
DCD
DCD
DCD
DCD
DCD
DCD
DCD
DCD
DCD
DCD
DCD
1
2
3
4
5
6
7
8
9
10
11
Donor
Age
(Year)
Cause of
Donor
Death
Recipient
Age
(Year)
Gender
(M/F)
WIT
(min)
TIT
(min)
Dialysis
Post-Tx
(Days)
Duration
of HD
(Months)
22
63
58
52
68
15
52
61
75
64
50
CVA
CVA
CVA
CVA
CVA
CVA
CVA
CVA
CVA
CVA
CVA
39
37
56
60
32
36
50
59
47
45
63
F
M
M
M
M
M
M
M
M
F
M
3
1
1
5
57
20
29
15
2
15
4
463
1502
972
359
1508
399
820
1158
844
407
483
10
14
6
17
9
2
13
11
0
0
12
157
176
124
160
180
200
196
189
167
172
180
Immunosuppression
Regimen
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
Basiliximab,
FK, MMF, steroid
CsA, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
FK, MMF, steroid
CVA, cerebrovascular attacks; FK, tacrolimus; CsA, cyclosporine; MMF, mycophenolate mofetil.
385 ± 42, and POD3: 278 ± 25 ng/ml). However, the serum TIMP-1 levels were under 370 ng/ml on both POD1
and POD2 in the two patients who avoided post-KTx
HD due to the immediate function of the graft (Fig. 3).
To validate the usefulness of serum TIMP-1 as a predictor of DGF, the peak serum TIMP-1 levels (POD 1
or POD 2) were analyzed and the length of the postDCD KTx dialysis periods were compared. The peak
TIMP-1 level was found to correlate well with the length
of dialysis (p < 0.05) (Fig. 4A). However, it is possible
that the peak serum TIMP-1 levels are affected by the
primary diseases or pre-KTx levels, although the samples did not show a large variation. Therefore, the correlation with the increment value of TIMP-1 was determined. The increment values of TIMP-1 in DGF cases
also appear to correlate with the post-KTx HD period
Figure 1. Comparison of serum TIMP-1 concentrations at POD 1 after KTx between patients who
required HD during the post-KTx period due to DGF (LD: n = 1, DCD: n = 9) and those who did
not (LD: n = 22, DCD: n = 2; *p < 0.001).
726
KUSAKA ET AL.
Figure 2. The serum TIMP-1 concentrations following a KTx from a living donor (LD; n = 23). The serum TIMP-1 level showed
no increase after KTx from a LD. However, one patient had serum TIMP-1 levels over 360 ng/ml on POD1, and HD was therefore
required due to DGF (indicated by open circles with bold line).
Figure 3. Serum TIMP-1 concentrations following a KTx from DCDs (n = 11). Nine of 11 patients that underwent a KTx from a
DCD required HD due to DGF (indicated by open circles with bold lines). The patients that required HD due to DGF showed a
rapid increase in the serum TIMP-1 levels after a KTx (POD1: 435 ± 32, POD2: 412 ± 42, and POD3: 293 ± 26 ng/ml). However,
two patients had serum TIMP-1 levels under 370 ng/ml on both POD1 and POD2, and showed immediate function (indicated by
closed circles with narrow lines).
SERUM TIMP-1 AS A PREDICTOR OF DCD KIDNEY ORGAN RECOVERY
727
Figure 4. (A) Correlation between the peak serum TIMP-1 levels (POD 1 or POD 2) and the length of dialysis post DCD KTx.
The regression line is shown with the correlation coefficients (R2) and p-values. (B) Correlation between the increment value (the
peak TIMP-1 value minus the value of pre-KTx value) of serum TIMP-1 levels DGF and the length of dialysis post-DCD KTx.
The regression line is shown with the correlation coefficients (R2) and p-values. The cut-off value of 150 ng/ml clearly distinguished
patients who required HD due to DGF (open circles) and those who could avoid HD due to an immediate function (closed circles).
(Fig. 4B). The cut off value of the increment level of
150 ng/ml was predictive for the requirement of postKTx HD.
DISCUSSION
This study evaluated the efficacy of serum TIMP-1
as a predictor of graft recovery after Ktx, particularly a
KTx from DCD. The results demonstrated that serum
TIMP-1 was elevated within a couple of days post-KTx
and the levels were higher in DGF cases whether the
origin of the graft was a living donor or DCD. These
results suggest that the preexisting damage in the kidney
grafts may induce expression of proinflammatory cytokines that subsequently induce expression of MMPs/
TIMPs. Alternatively, the inflammation may accelerate
ECM turnover after reperfusion leading to de novo production of MMPs/TIMPs. However, the precise mechanistic relationship between TIMP-1 and DGF following
a KTx from a DCD is still unclear.
The correlation of the post-KTx HD period with the
peak serum TIMP-1 levels as well as the increment of
serum TIMP-1 levels in early POD indicates that the
serum TIMP-1 levels may reflect the severity of tissue
damage in the transplanted kidneys. This implicates the
potential efficacy of the serum TIMP-1 levels as a biomarker for prediction of DGF in DCD-KTx. In fact, the
cut-off value of the increment level of 150 ng/ml was
found to be predictive for requirement of post-KTx HD,
although the number of subjects in the current study was
small. The increment values of the serum TIMP-1 levels
might thus be a better marker than the peak values, because it is possible that the serum concentration itself
may vary according to the nature and the severity of the
underlying disease. The current results show that the
pre-KTx serum TIMP-1 levels were almost similar to
those of normal samples and not highly variable. However, another study has indicated higher serum TIMP-1
levels in patients with chronic renal diseases (24).
728
KUSAKA ET AL.
In addition to the critical shortage of renal allografts,
legal and ethical problems preclude brain-dead organ
donation in Japan. Therefore, most of the cadaveric kidneys used over the past 3 decades in Japan have been
derived from DCDs. Since April 1979 through the end
of 2008, 495 kidneys were retrieved from DCDs at this
center alone, thus representing approximately 10% of all
kidneys procured in Japan. These kidneys are often
transplanted under suboptimal conditions. Approximately 40% of the kidney grafts were derived from expanded criteria donors (13,17). The DCD from this hospital was classified mainly as type IV category donors,
but most were from the recently categorized “uncontrolled” DCD (7,9). Furthermore, these patients had
been waiting for a KTx for many years. All recipients
who received a KTx from a DCD in this study had required HD for at least 10 years. Under these conditions
for both donors and recipients, there was a high incidence of DGF and a prolonged period of ATN. Although the in situ regional cooling technique allows excellent renal function and good long-term graft survival,
the mean duration of posttransplant HD is still about 2
weeks (13,17). This situation, particular to Japan, prompted
the need for highly sensitive prognostic markers for
DGF in KTx from DCDs.
In summary, although the number of patients in this
study was small, the previous and present findings suggest that monitoring of serum NGAL (18) and TIMP-1
levels might be useful for the control of DGF during the
post-KTx period, and it should lead to the better outcome in KTx from a DCD.
7.
8.
9.
10.
11.
12.
13.
14.
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