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| ID | Type | Description | Link |
|---|---|---|---|
| 0468H1-4472 | Other Identifier | Pfizer (Wyeth) |
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| Name | Class |
|---|---|
| Wyeth is now a wholly owned subsidiary of Pfizer | INDUSTRY |
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This study is being done to investigate the impact of changing immunosuppressive medications from tacrolimus (Prograf®) to sirolimus (Rapamune®) between 6 and 24 months post transplant. The primary purpose of this research study is to evaluate whether the use of mycophenolate mofetil(MMF)/Cellcept® and tacrolimus(TAC)/Prograf® (Group 1) or mycophenolate mofetil(MMF)/Cellcept® and sirolimus/Rapamune® (Group 2) impacts the incidence of acute cellular rejection in post kidney transplant patients. This study will examine whether switching from tacrolimus to sirolimus will better preserve long-term kidney function.
For this research study, between 6 and 24 Months post-transplant, we plan to prospectively randomize 2:1 renal transplant patients to either:
A total of 400 patients are expected to be screened for the randomization. We expect to randomize 275 renal transplant patients into this protocol (275 donors to be recruited).
The following data will be collected at the time of randomization:
Recipient demographics: (i) age at transplantation, (ii) sex, and (iii) race.
Clinical history: (i) causes of end-stage renal disease, and (ii) past medical history.
Transplant related information: (i) donor age, (ii) cadaveric versus living kidney transplant, (iii) histocompatibility and cross match data, (iv) viral serology, (v) history of acute rejection and delayed graft function, (vi) use of induction therapy and immunosuppressants, (vii) use of ACEI and/or ARB, and (viii) level of renal allograft function-estimated GFR (e-GFR(12) using MDRD formula, proteinuria.
Peripheral blood leukocytes will be obtained from renal transplant recipients for baseline (prior to randomization) lymphocytes functional activity and characterization of lymphocytes subpopulations by flow cytometry analysis.
Peripheral donor leukocytes (from living donor patients) will also be obtained at the time of randomization. These donor leukocytes will be used as stimulator cells to study the functional activity of the recipient's lymphocytes function.
The recipients assigned to continue with tacrolimus and MMF will be routinely followed at the outpatient Comprehensive Transplant Center (CTC) with monthly labs. In addition to labs at baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study lymphocytes functional activity and to characterize lymphocytes subpopulations by flow cytometry analysis.
Post randomization: The recipients assigned to switch from tacrolimus to sirolimus and continue with MMF will be routinely followed at the CTC with monthly labs. During the period of conversion from tacrolimus to sirolimus, weekly labs will be obtained to monitor renal function and bone marrow function. In addition to labs at baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study lymphocytes functional activity to characterize lymphocytes subpopulations by flow cytometry analysis. Urine will be collected to assess tubular toxicity by evaluating urinary biomarkers.
Both groups of patients will be followed for 2 years post-randomization. In addition to monitoring renal allograft function, we will evaluate the incidence of acute rejection, patient and graft survival, impact of CI conversion on the lipid profile, incidence of hypertension, malignancies, opportunistic infections, and post-transplant diabetes mellitus (DM). For those willing to undergo an optional kidney biopsy, one will be performed at the end of the second year in order to evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups.
With the peripheral leukocytes obtained at baseline prior to randomization and at 6, 12 and 24 Months post-randomization, we will investigate possible modifications of lymphocytes function and the lymphocytes subpopulations that might have occurred as a consequence of the switch from tacrolimus to sirolimus.
Obtaining renal allograft tissue samples at 24 months post randomization can have potential important ramifications to help explain the mechanisms of fibrosis and tubular atrophy typically associated with CI and the role of CI elimination with the substitution of sirolimus (SRL). All data will then be analyzed comparing gene expression profiles of peripheral blood (Pax gene tubes are routinely collected at the different time points as part of the original study). Based on power analysis, we will perform 24 months post randomization biopsies in 70% of the total subjects enrolled in the study (approximately 46 subjects from the tacrolimus/MMF group and approximately 93 subjects from the sirolimus/MMF group).
We plan to obtain renal allograft biopsies at 24 Months for those that consent for this additional biopsy. This will be compared to the standard of care 12 months post-transplant biopsy to allow us to address the effect of immunosuppressive modifications on renal allograft pathology at 24 months post randomization. Renal allograft biopsies will also be stored in RNA later to further extend our knowledge on the effect of CI free immunosuppression on gene expression profiles.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | Active Comparator | Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus. |
|
| Transition to Sirolimus Group | Experimental | Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus |
|
| Donors | Other | Data and blood samples from the donors are collected in this study to contribute to the general knowledge to be used in assessing the two donor recipient groups, which are the target of this study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus | Drug | Sirolimus will initially be given at a dose of 2-4 mg orally (PO) daily. The dose will be modified to achieve 24 hours trough concentrations of 6-10 ng/ml by high-performance liquid chromatography (HPLC) assay. This medication will be given in an open label fashion. The first dose of sirolimus will be given at the time of randomization to those patients assigned to have tacrolimus switched to sirolimus. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Acute Cellular Rejection | The primary purpose of this research study is to evaluate whether the use of mycophenolate mofetil/Cellcept ® and either tacrolimus/Prograf ® (Group #1) or mycophenolate mofetil/Cellcept ® and sirolimus/Rapamune® (Group #2) impacts the incidence of acute cellular rejection in post-kidney transplant patients. This study will examine whether switching from tacrolimus to sirolimus will better preserve long-term kidney function. | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
| Measure | Description | Time Frame |
|---|---|---|
| Renal Allograft Function Calculated With e-GFR and Proteinuria | Evaluate whether CI conversion (tacrolimus→sirolimus) contributes positively or negatively on the renal allograft function calculated with e-GFR and proteinuria | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
| Evaluate if CI Conversion Impacts on Lipid Profile, Incidence of Hypertension, Malignancies, and Opportunistic Infections and Post-transplant DM |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lorenzo Gallon, MD | Northwestern Univesity, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Northwestern Memorial Hospital | Chicago | Illinois | 60611 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12954741 | Background | Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40. doi: 10.1056/NEJMoa021744. | |
| 12401874 | Background | Stoves J, Lindley EJ, Barnfield MC, Burniston MT, Newstead CG. MDRD equation estimates of glomerular filtration rate in potential living kidney donors and renal transplant recipients with impaired graft function. Nephrol Dial Transplant. 2002 Nov;17(11):2036-7. doi: 10.1093/ndt/17.11.2036. No abstract available. |
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Donor participants were no part of our outcome analysis because their participation was only on the basis of providing blood for testing the immune system of the recipients.
The analysis of the recipients was intention to treat therefore all recipient participants completed the study period
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| ID | Title | Description |
|---|---|---|
| FG000 | Control | Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus. |
| FG001 | Transition to Sirolimus Group |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 1, 2012 |
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| Demographic Data, Medical History, and Donor Data | Other | Age at transplant, sex, race, cause of end-stage renal disease, medical history, donor age, cadaveric vs. living kidney transplant, histocompatibility/cross match data, viral serology, history of acute rejection and delayed graft function, use of induction therapy and immunosuppressants, use of Angiotensin Converting Enzyme Inhibitor (ACEI) and/or Angiotensin Receptor Blockers (ARB) level of renal allograft function-estimated GFR (e-GFR(12) using Modification of Diet in Renal Disease (MDRD) formula, proteinuria. |
|
| Blood Draws for Control Group | Procedure | Subjects maintaining standard of care drug treatment of TAC and MMF will have monthly labs in addition to the baseline pre-randomization labs, at 6, 12, and 24 Months post-randomization. Peripheral blood leukocytes will be obtained. |
|
| Blood Draws for Experimental Group | Procedure | This group will have monthly labs taken but will also have weekly labs during the period of conversion to monitor renal function and bone marrow function. In addition to the baseline pre-randomization labs, and labs collected at 6, 12, and 24 Months post-randomization, peripheral blood leukocytes will be obtained. |
|
| Donor Blood Draws | Procedure | Peripheral blood leukocytes from living donors obtained at the time of randomization. These donor leukocytes will be used as stimulator cells to study the functional activity of the recipient's lymphocytes function. |
|
| Donor Information | Other | Donor age, cadaveric vs. living donor, and histocompatibility and cross match to recipient |
|
| Kidney Biopsy | Procedure | Kidney biopsy at 24 Months to compare to the standard of care biopsy taken at 12 Months. This information will help evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups. Renal allograft biopsies will be stored in RNA later (preservative) to further extend knowledge on the effect of calcineurin-inhibitors (CI) free immunosuppression on gene expression profiles. |
|
In addition to monitoring renal allograft function, evaluation will be conducted on the incidence of acute rejection, patient and graft survival, the impact of CI conversion on the lipid profile, the incidence of hypertension, malignancies, opportunistic infections and post-transplant DM (de novo diabetes mellitus). |
| Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
| Patient and Graft Survival | This study also reviews the impact of the immunosuppressive medications on patient and graft survival. | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
| Percentage of Regulatory T Cells | Specifically we reported here the percentage of regulatory T cells that were present in the two groups at 24 months post randomization. With peripheral leukocytes taken at baseline (first visit) prior to randomization and at 6, 12 and 24 Months post-randomization, researchers will also review possible modifications of lymphocytes function and of the lymphocytes subpopulations that might have occurred as a consequence of the switch from tacrolimus to sirolimus (randomization). | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
| 11773892 | Background | Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001 Dec 27;72(12):1934-9. doi: 10.1097/00007890-200112270-00012. |
| 9679823 | Background | Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation. 1998 Jul 15;66(1):59-66. doi: 10.1097/00007890-199807150-00010. |
| 9884274 | Background | Hornberger J, Best J, Geppert J, McClellan M. Risks and costs of end-stage renal disease after heart transplantation. Transplantation. 1998 Dec 27;66(12):1763-70. doi: 10.1097/00007890-199812270-00034. |
| 9075835 | Background | Goldstein DJ, Zuech N, Sehgal V, Weinberg AD, Drusin R, Cohen D. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: incidence and progression. Transplantation. 1997 Mar 15;63(5):664-8. doi: 10.1097/00007890-199703150-00009. |
| 6382005 | Background | Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984 Sep 13;311(11):699-705. doi: 10.1056/NEJM198409133111103. |
| 8887265 | Background | Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM. Chronic cyclosporine nephropathy: the Achilles' heel of immunosuppressive therapy. Kidney Int. 1996 Oct;50(4):1089-100. doi: 10.1038/ki.1996.415. No abstract available. |
| 8937936 | Background | Bennett WM. Insights into chronic cyclosporine nephrotoxicity. Int J Clin Pharmacol Ther. 1996 Nov;34(11):515-9. |
| 3546916 | Background | Myers BD. Cyclosporine nephrotoxicity. Kidney Int. 1986 Dec;30(6):964-74. doi: 10.1038/ki.1986.280. No abstract available. |
| 2240057 | Background | Puschett JB, Greenberg A, Holley J, McCauley J. The spectrum of ciclosporin nephrotoxicity. Am J Nephrol. 1990;10(4):296-309. doi: 10.1159/000168123. No abstract available. |
| 7861719 | Background | Young EW, Ellis CN, Messana JM, Johnson KJ, Leichtman AB, Mihatsch MJ, Hamilton TA, Groisser DS, Fradin MS, Voorhees JJ. A prospective study of renal structure and function in psoriasis patients treated with cyclosporin. Kidney Int. 1994 Oct;46(4):1216-22. doi: 10.1038/ki.1994.387. |
Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus
| COMPLETED |
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| NOT COMPLETED |
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Donor participants were no part of our outcome analysis because their participation was only on the basis of providing blood for testing the immune system of the recipients.
The analysis of the recipients was intention to treat therefore all recipient participants completed the study period
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| ID | Title | Description |
|---|---|---|
| BG000 | Control | Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus. |
| BG001 | Transition to Sirolimus Group | Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex/Gender, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||
| HLA mismatch | The number of human leukocyte antigens (HLAs) found on the cells of a donor organ but not found on the cells of the organ recipient | Mean | Standard Deviation | HLA antigens |
| ||||||||||||||
| Donor type | Count of Participants | Participants |
| ||||||||||||||||
| PRA >20% | A panel-reactive antibody (PRA) is a group of antibodies in a test serum that are reactive against any of several known specific antigens in a panel of test cells or purified HLA antigens from cells. A panel-reactive antibody test (PRA test) is an immunologic test routinely performed by clinical laboratories on the blood of people awaiting organ transplantation. This result is the number of participants on the study that had PRA > 20% at the time of Transplantation | Count of Participants | Participants |
| |||||||||||||||
| Diabetis mellitus | Number of participants that were diagnosed with Diabetes at the time of Transplantation | Count of Participants | Participants |
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| Elevated blood pressure | Number of participant with elevated blood pressure at the time of Transplantation | Count of Participants | Participants |
| |||||||||||||||
| Coronary artery disease (CAD) | Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart become hardened and narrowed due to the buildup of cholesterol and other substances, known as plaque | Count of Participants | Participants |
| |||||||||||||||
| Smoking | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Incidence of Acute Cellular Rejection | The primary purpose of this research study is to evaluate whether the use of mycophenolate mofetil/Cellcept ® and either tacrolimus/Prograf ® (Group #1) or mycophenolate mofetil/Cellcept ® and sirolimus/Rapamune® (Group #2) impacts the incidence of acute cellular rejection in post-kidney transplant patients. This study will examine whether switching from tacrolimus to sirolimus will better preserve long-term kidney function. | Posted | Count of Participants | Participants | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
|
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| ||||||||||||||||||||||||||||||
| Secondary | Renal Allograft Function Calculated With e-GFR and Proteinuria | Evaluate whether CI conversion (tacrolimus→sirolimus) contributes positively or negatively on the renal allograft function calculated with e-GFR and proteinuria | Posted | Mean | Standard Deviation | mL/min | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
|
| ||||||||||||||||||||||||||||||
| Secondary | Evaluate if CI Conversion Impacts on Lipid Profile, Incidence of Hypertension, Malignancies, and Opportunistic Infections and Post-transplant DM | In addition to monitoring renal allograft function, evaluation will be conducted on the incidence of acute rejection, patient and graft survival, the impact of CI conversion on the lipid profile, the incidence of hypertension, malignancies, opportunistic infections and post-transplant DM (de novo diabetes mellitus). | Posted | Number | number of incidents | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
|
| |||||||||||||||||||||||||||||||
| Secondary | Patient and Graft Survival | This study also reviews the impact of the immunosuppressive medications on patient and graft survival. | Posted | Number | number of incidents | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
|
| |||||||||||||||||||||||||||||||
| Secondary | Percentage of Regulatory T Cells | Specifically we reported here the percentage of regulatory T cells that were present in the two groups at 24 months post randomization. With peripheral leukocytes taken at baseline (first visit) prior to randomization and at 6, 12 and 24 Months post-randomization, researchers will also review possible modifications of lymphocytes function and of the lymphocytes subpopulations that might have occurred as a consequence of the switch from tacrolimus to sirolimus (randomization). | Posted | Mean | Standard Deviation | % of Treg Cells | Assessed at 6 Months, 12 Months, 24 Months, months 24 reported |
|
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24 months
Donor participants were no part of our outcome analysis because their participation was only on the basis of providing blood for testing the immune system of the recipients.
The analysis of the recipients was intention to treat therefore all recipient participants completed the study period
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control | Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus. Patients were followed for 24 months post randomization | 3 | 90 | 42 | 90 | 58 | 90 |
| EG001 | Transition to Sirolimus | Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus. Patients were followed for 24 months post randomization | 10 | 185 | 117 | 185 | 135 | 185 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Renal allograft loss | Renal and urinary disorders | Non-systematic Assessment |
| ||
| Proteinuria | Renal and urinary disorders | Non-systematic Assessment |
| ||
| Neutropenia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Malignancies | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections | Infections and infestations | Non-systematic Assessment |
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| Hyperlipidemia | Cardiac disorders | Non-systematic Assessment |
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| Diabetes | Endocrine disorders | Non-systematic Assessment |
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| BK viremia | Renal and urinary disorders | Non-systematic Assessment |
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| BK nephropathy | Renal and urinary disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lorenzo Gallon, MD | Northwestern University | 3126954457 | l-gallon@northwestern.edu |
| Apr 8, 2019 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D003710 | Demography |
| D055991 | Health Records, Personal |
| D001800 | Blood Specimen Collection |
| D035061 | Control Groups |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011154 | Population Characteristics |
| D015991 | Epidemiologic Measurements |
| D011634 | Public Health |
| D004778 | Environment and Public Health |
| D008499 | Medical Records |
| D011996 | Records |
| D003625 | Data Collection |
| D004812 | Epidemiologic Methods |
| D008919 | Investigative Techniques |
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D011677 | Punctures |
| D013514 | Surgical Procedures, Operative |
| D015340 | Epidemiologic Research Design |
| D012107 | Research Design |
| D008722 | Methods |
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| Sex female |
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| AA |
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| Hispanic |
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| other |
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| Cadaveric kidneys |
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