The Role of Connective Tissue Growth Factor in the Development of Kidney Disease After Organ Transplantation
| Status: | Completed |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 4 - Any |
| Updated: | 10/8/2017 |
| Start Date: | March 20, 2003 |
| End Date: | June 17, 2014 |
The Pathogenesis of Chronic Graft Failure After Kidney Transplantation
This study will examine whether measurements of connective tissue growth factor (CTGF) and
other cell proteins can identify which kidney transplant recipients are likely to develop
chronic allograft nephropathy (CAN), a disease of the transplanted kidney. CAN may occur
months to years after the transplant. The kidney becomes progressively scarred and eventually
loses all function, so that dialysis or another transplant is needed. A better understanding
of how CTGF and other proteins are involved in the development of CAN may provide new targets
for treating for the disease.
Patients who are scheduled to receive a kidney or combined kidney-pancreas transplant or who
have received a transplant recently (within 6 months) may be eligible for this study.
Participants will be enrolled before the transplant, if possible, or after the transplant,
and will undergo the following tests and procedures:
- Physical examinations at the screening visit, at 1, 6, 12, and 24 months, and then once
yearly.
- Blood sample collections at the screening visit, at 1, 6, 12, 18, and 24 months and then
once yearly.
- Urine sample collections at the screening visit, at 1, 6, 12, 18, and 24 months and then
once yearly.
- Kidney biopsies at the beginning of the study, at 1, 6, 12, and 24 months, and then once
a year for research purposes. Participants may refuse to have a research biopsy at any
time during the study. Also, patients who are having a kidney biopsy for another reason
at these time points will not have a second biopsy. The biopsy procedure takes about 15
minutes and is done in the hospital. The patient lies on his or her back and the skin
over the transplanted kidney is cleaned with alcohol and iodine. The area is numbed with
an injection of an anesthetic, and then a biopsy needle is placed through the kin. The
biopsy may be repeated up to three times to get enough tissue to test for CAN. Patients
lie flat for 4 hours after the procedure to reduce the risk of bleeding, and are
observed for another 2 hours for possible complications.
other cell proteins can identify which kidney transplant recipients are likely to develop
chronic allograft nephropathy (CAN), a disease of the transplanted kidney. CAN may occur
months to years after the transplant. The kidney becomes progressively scarred and eventually
loses all function, so that dialysis or another transplant is needed. A better understanding
of how CTGF and other proteins are involved in the development of CAN may provide new targets
for treating for the disease.
Patients who are scheduled to receive a kidney or combined kidney-pancreas transplant or who
have received a transplant recently (within 6 months) may be eligible for this study.
Participants will be enrolled before the transplant, if possible, or after the transplant,
and will undergo the following tests and procedures:
- Physical examinations at the screening visit, at 1, 6, 12, and 24 months, and then once
yearly.
- Blood sample collections at the screening visit, at 1, 6, 12, 18, and 24 months and then
once yearly.
- Urine sample collections at the screening visit, at 1, 6, 12, 18, and 24 months and then
once yearly.
- Kidney biopsies at the beginning of the study, at 1, 6, 12, and 24 months, and then once
a year for research purposes. Participants may refuse to have a research biopsy at any
time during the study. Also, patients who are having a kidney biopsy for another reason
at these time points will not have a second biopsy. The biopsy procedure takes about 15
minutes and is done in the hospital. The patient lies on his or her back and the skin
over the transplanted kidney is cleaned with alcohol and iodine. The area is numbed with
an injection of an anesthetic, and then a biopsy needle is placed through the kin. The
biopsy may be repeated up to three times to get enough tissue to test for CAN. Patients
lie flat for 4 hours after the procedure to reduce the risk of bleeding, and are
observed for another 2 hours for possible complications.
Following transplantation, recipients of organ allografts are placed on immunosuppression
indefinitely. Despite dramatic improvements in acute rejection rates and short-term graft
survival, long term graft survival has not changed appreciably over the past 20 years. In
kidney transplantation, the leading cause of late graft loss is chronic allograft nephropathy
(CAN). This disorder is clinically characterized by a progressive decline in kidney function,
associated with the characteristic histologic features of interstitial fibrosis and
inflammation, arteriosclerosis, glomerulosclerosis, and tubular atrophy. Both immunologic and
non-immunologic factors have been implicated in the development of CAN. However, the etiology
of this disorder has not been clearly defined nor is there specific therapy for treating CAN.
Implicated in the development of CAN in rodents and humans is transforming growth factor beta
(TGF-beta), a pleiotropic cytokine which is elevated in CAN recipients, and stimulates matrix
deposition within the graft. A downstream effector of TGF-b is connective tissue growth
factor (CTGF), which has been recently associated with other fibrotic renal diseases. In
preliminary studies in a mouse model of CAN, CTGF gene expression is increased in kidney
transplants with CAN. However, its role in human CAN is unknown.
The aim of this investigation is to identify whether CTGF may play a role in the pathogenesis
of CAN in humans. Our long-term objective is to determine whether CTGF and other cytokine
mediators may be novel targets for the therapy of CAN. Our goals are to: 1. Determine the
level of CTGF expressed in the urine and serum CTGF of recipients of kidney transplants; 2.
Identify whether urinary or serum CTGF might be a marker of CAN and be utilized as a
predictor for those at risk to develop the disease; 3. Identify other molecular messages and
proteins that may identify the development of CAN, as potential future targets of treatment.
In this prospective study, serial urine and serum samples will be obtained in recipients,
before, during, and after transplantation of a kidney allograft. The graft will be monitored
in the context of standard measures of renal function, which include serum creatinine and
creatinine clearance. These results will be correlated with other clinically descriptive
information regarding the recipient s transplant.
indefinitely. Despite dramatic improvements in acute rejection rates and short-term graft
survival, long term graft survival has not changed appreciably over the past 20 years. In
kidney transplantation, the leading cause of late graft loss is chronic allograft nephropathy
(CAN). This disorder is clinically characterized by a progressive decline in kidney function,
associated with the characteristic histologic features of interstitial fibrosis and
inflammation, arteriosclerosis, glomerulosclerosis, and tubular atrophy. Both immunologic and
non-immunologic factors have been implicated in the development of CAN. However, the etiology
of this disorder has not been clearly defined nor is there specific therapy for treating CAN.
Implicated in the development of CAN in rodents and humans is transforming growth factor beta
(TGF-beta), a pleiotropic cytokine which is elevated in CAN recipients, and stimulates matrix
deposition within the graft. A downstream effector of TGF-b is connective tissue growth
factor (CTGF), which has been recently associated with other fibrotic renal diseases. In
preliminary studies in a mouse model of CAN, CTGF gene expression is increased in kidney
transplants with CAN. However, its role in human CAN is unknown.
The aim of this investigation is to identify whether CTGF may play a role in the pathogenesis
of CAN in humans. Our long-term objective is to determine whether CTGF and other cytokine
mediators may be novel targets for the therapy of CAN. Our goals are to: 1. Determine the
level of CTGF expressed in the urine and serum CTGF of recipients of kidney transplants; 2.
Identify whether urinary or serum CTGF might be a marker of CAN and be utilized as a
predictor for those at risk to develop the disease; 3. Identify other molecular messages and
proteins that may identify the development of CAN, as potential future targets of treatment.
In this prospective study, serial urine and serum samples will be obtained in recipients,
before, during, and after transplantation of a kidney allograft. The graft will be monitored
in the context of standard measures of renal function, which include serum creatinine and
creatinine clearance. These results will be correlated with other clinically descriptive
information regarding the recipient s transplant.
- INCLUSION CRITERIA:
Recipients of living related, living unrelated, and cadaveric kidney transplants.
This study will be open to all patients currently enrolled in NIDDK transplant protocols as
well as patients recruited from other transplant centers.
Ability and willingness to provide informed consent (adults greater than or equal to 18.0
years) or assent (children 4 to 18.0 years).
EXCLUSION CRITERIA:
Inability to provide informed consent.
Inability to return to NIH for follow-up.
Inability or unwillingness to release outside medical records or pathology.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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