North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2005 Annual Report Renal Transplantation Dialysis Chronic Renal Insufficiency This is a privileged communication not for publication.
This study is sponsored by major grants from: Novartis Pharmaceutical Corporation AMGEN Inc. Genentech, Inc. NAPRTCS also thanks the following contributors: Roche Laboratories, Inc. Wyeth Research Watson Pharmaceuticals
North American Pediatric Renal Transplant Cooperative Study Clinical Coordinating Center Data Coordinating Center William Harmon, M.D. Donald Stablein, Ph.D. NAPRTCS Lynya Talley, Ph.D. 1 Autumn Street The EMMES Corporation 5th Floor 401 N. Washington Street, Suite 700 Boston, Massachusetts 02115 Rockville, Maryland 20850 617-355-7707 301-251-1161 Board Members William Harmon, MD (President) Richard Fine, MD (Vice President/Treasurer) Steven Alexander, MD (Secretary) Bradley Warady, MD (Member at Large) Mark Benfield, MD (Member at Large) Stuart Goldstein, MD (Chair, PCC) Ruth McDonald, MD (Chair, Special Studies Committee and Vice-Chair, PCC)
This report was developed under the auspices of the Operations Committee and prepared by Lynya Talley, Ph.D. and Donald M. Stablein, Ph.D. With assistance from Data Coordinating Center Staff Stuart Berlin Angela Norman Kumar Thotapally Danielle Weidenhamer-Quarles
TABLE OF CONTENTS PAGE I INTRODUCTION 1 II TRANSPLANTATION Section 1: Transplant Patient Characteristics 1-1 Section 2: Donor History and Antigen Mismatches 2-1 Section 3: Therapy 3-1 Section 4: Rejection 4-1 Section 5: Graft Function 5-1 Section 6: Growth 6-1 Section 7: Morbidity, Malignancy, and Mortality 7-1 III DIALYSIS Section 8: Dialysis Patient Characteristics 8-1 Section 9: Dialysis Access Data 9-1 Section 10: Erythropoietin Use in Dialysis Patients 10-1 Section 11: Dialysis Follow-up 11-1 Section 12: Growth 12-1 IV CHRONIC RENAL INSUFFICIENCY Section 13: CRI Patient Demographics 13-1 Section 14: Termination of Chronic Renal Insufficiency Status 14-1 Section 15: CRI Follow-up Data 15-1 V APPENDICES Appendix A: Participating Centers and Contact Physicians A-1 Appendix B: Bibliography C 1988-2004 B-1 Appendix C: Special Studies and Analyses C-1 i
LIST OF EXHIBITS Section 1 Exhibit 1.1 Patient Registrations, Transplants, and Selected Characteristics, by Year of Registration 1-4 Exhibit 1.2 Recipient and Index Transplant Characteristics 1-5 Exhibit 1.3 Transplant Characteristics 1-6 Exhibit 1.4 Age at Transplantation 1-7 Exhibit 1.5 Age at Index Transplant, by Patient's Sex, Race, and Diagnosis 1-8 Exhibit 1.6 Sex, Race, and Biopsy Distributions, by Primary Renal Diagnosis 1-9 Exhibit 1.7 Primary Diagnosis by Age 1-10 Section 2 Exhibit 2.1 Donor Information 2-3 Exhibit 2.2 Use Over Time of Donor-Specific and Random Blood Transfusions 2-4 Exhibit 2.3 Percent HLA Mismatches 2-5 Exhibit 2.4 Age at Transplant and Donor Source 2-6 Section 3 Exhibit 3.1 Medication Data First 30 Days, Transplants after 1995 3-5 Exhibit 3.2 Week 1 Calcineurin Inhibitor Use, by Induction Antibody 3-6 Exhibit 3.3 Induction Antibody Use, by Year 3-6 Exhibit 3.4 Exhibit 3.5 Exhibit 3.6 Exhibit 3.7 Mean (SE) Daily Drug Dosages, by Drug Combination and Year Post-Transplant 3-7 Percent of Patients with Functioning Grafts Receiving Immunosuppressive Medication 30 Days Post Transplant, by Year of Transplant 3-8 Percentage of Patients Receiving Designated Maintenance Immunosuppression Regimens, by Donor Source and Time of Follow-up 3-9 Percentage of Patients Receiving Concomitant Medications, by Donor Source and Time Post-Transplantation 3-10 ii
Section 4 Exhibit 4.1A Frequency of Acute Rejections 4-4 Exhibit 4.1B Acute Rejection Ratios 4-4 Exhibit 4.2 Time to First Rejection Episode, by Allograft Source and Transplant Year 4-5 Exhibit 4.3A Exhibit 4.3B Relative Hazard (RH) of First Rejection Episode, First Transplant, 1987-1995 4-6 Relative Hazard (RH) of First Rejection Episode, First Transplant, 1996-2004 4-7 Exhibit 4.4 Time to First Rejection Episode, by Selected Characteristics 4-8 Exhibit 4.5A Rejection Reversal Outcome by Selected Characteristics 4-10 Exhibit 4.5B Rejection Reversal Outcome by Selected Characteristics for First Acute Rejection Episode Only 4-11 Exhibit 4.6 Rejection Reversal Outcome by Transplant Year 4-12 Exhibit 4.7 Summary of Late First Rejections, by Selected Characteristics 4-13 Section 5 Exhibit 5.1 Causes of Graft Failure 5-7 Exhibit 5.2 Percent Graft Survival by Allograft Source 5-8 Exhibit 5.3 Graft Failure Summary, by Allograft Source and Transplant Characteristics 5-9 Exhibit 5.4 Percent Graft Survival for Recipients of Living Donor Source Allografts 5-11 Exhibit 5.5 Percent Graft Survival for Recipients of Cadaver Donor Source Allografts 5-12 Exhibit 5.6 Percent Graft Survival for Annual Cohort Group 5-14 Exhibit 5.7 Graft Survival by Donor Source and HLA-Antigen Disparity 5-15 Exhibit 5.8 Percent Graft Survival, by Donor Source and Diagnosis 5-16 Exhibit 5.9 Exhibit 5.10 Exhibit 5.11 Post Week 1 Graft Survival by Donor Source and Acute Tubular Necrosis Status 5-17 Serial Serum Creatinine and Calculated Creatinine Clearance Measures for Functioning Grafts, by Age at Transplant 5-18 Serial Serum Creatinine for Functioning Grafts, by Race and Induction Antibody Therapy 5-19 iii
Exhibit 5.12 Exhibit 5.13 Exhibit 5.14 Graft Function, i.e. Graft Survival and Mean Calculated Clearance at Annual Follow-up, by Donor Source 5-20 Graft Function, i.e. Graft Survival and Mean Calculated Clearance at Annual Follow-up, by Donor Source and Initial Use of Antibody Preparations 5-21 Graft Function, i.e. Graft Survival and Mean Calculated Clearance at Annual Follow-up, by Donor Source and Race 5-22 Section 6 Exhibit 6.1 Exhibit 6.2 Exhibit 6.3 Exhibit 6.4 Mean (with SE) Standardized Height and Weight Scores, by Selected Characteristics and Times Post-Transplantation 6-3 Mean Change from Baseline (with SE) in Standardized Height and Weight Scores in Subjects with Graft Function, by Age at Transplant 6-4 Mean (with SE) of Standardized Height at Time of Initial Transplant, by Year of Transplant 6-5 Mean (with SE) of Standardized Height at Initial Transplant Over Time, by Year of Transplant and Age at Transplant 6-6 Section 7 Exhibit 7.1 Hospitalization Days During the First Post-Transplant Month, by Year of Transplantation and Donor Source 7-4 Exhibit 7.2A Transplant Month Hospitalization 7-5 Exhibit 7.2B Transplant (1987-1995) Month Hospitalization 7-6 Exhibit 7.2C Transplant (1996-2004) Month Hospitalization 7-7 Exhibit 7.3A Exhibit 7.3B Hospitalization Results for Patients with Functioning Grafts in Specified Follow-up Periods (Living Donor Transplants) 7-8 Hospitalization Results for Patients with Functioning Grafts in Specified Follow-up Periods (Cadaver Donor Transplants) 7-9 Exhibit 7.4 Selected Characteristics of Transplants with Malignancy 7-10 Exhibit 7.5A Percent Patient Survival, by Primary Allograft Source 7-11 Exhibit 7.5B Percent Patient Survival, by Era and Primary Allograft Source 7-11 Exhibit 7.6A Exhibit 7.6B Percent Patient Survival of Primary Transplants, by Age at Transplantation Living Donor 7-12 Percent Patient Survival of Primary Transplants, by Age at Transplantation Cadaver Donor 7-12 Exhibit 7.7 Causes of Death Following Index Renal Transplantation 7-13 iv
Section 8 Exhibit 8.1 Dialysis Patient Demographics 8-4 Exhibit 8.2 Number and Percent Distributions of Patient Race/Ethnicity, by Dialysis Modality and Age at Initiation 8-7 Exhibit 8.3 Post Initiation (1 Month and 12 Months) Concomitant Drug Therapy 8-8 Exhibit 8.4 Post Initiation (24 Months and 36 Months) Concomitant Drug Therapy 8-9 Exhibit 8.5 Baseline Education Status 8-10 Exhibit 8.6 Baseline Education Status, by Race 8-11 Exhibit 8.7 Baseline Education Status, by Age 8-12 Exhibit 8.8 Percent Full-Time School Attendance 8-13 Exhibit 8.9 Percent Patient Survival, by Age at Dialysis Initiation 8-14 Exhibit 8.10 Causes of Death Following the Index Course of Dialysis 8-15 Section 9 Exhibit 9.1A Modality Initiation and Termination 9-4 Exhibit 9.1B Termination Reasons for Non-Transplanted Patients by Vintage 9-5 Exhibit 9.2A Peritoneal Dialysis Access 9-6 Exhibit 9.2B Peritoneal Access Data by Vintage 9-7 Exhibit 9.3 Catheter Characteristics for Peritoneal Dialysis Accesses 9-8 Exhibit 9.4A Hemodialysis Access 9-9 Exhibit 9.4B Hemodialysis Access Data by Vintage 9-10 Exhibit 9.5 Frequency Distribution of Dialysis Access Status, by Selected Characteristics 9-11 Exhibit 9.6 Reasons for Change of Modality, by Selected Characteristics 9-12 Exhibit 9.7 Time to Dialysis Termination for Index Cases 9-13 Exhibit 9.8 Exhibit 9.9 Time to Dialysis Termination for Index Cases, by Age and Race/Ethnicity 9-14 Time to Dialysis Termination for Index Cases, by PD Catheter Characteristics 9-15 Exhibit 9.10 Time to Dialysis Termination for Index Cases, by HD Access 9-16 v
Exhibit 9.11 Time to Dialysis Termination for Index Cases, by Reason for Termination 9-17 Exhibit 9.12 Selected CAPD and APD Patient Demographics 9-18 Exhibit 9.13 Exhibit 9.14 Exhibit 9.15 Time to Dialysis Termination for Selected CAPD/APD Cases, by Modality 9-19 Time to Transplantation and Change of Modality for Selected CAPD/APD Cases, by Modality 9-20 Time to First Peritonitis Episode For Selected CAPD/APD Cases, by Modality 9-21 Section 10 Exhibit 10.1 Percent EPO Use, by Months on Dialysis 10-3 Exhibit 10.2 Percent EPO Use at Baseline (Day 30) 10-4 Exhibit 10.3 Route and Frequency of EPO Administrations 10-5 Exhibit 10.4 Mean EPO Dose (Units/Kg/Week) 10-6 Exhibit 10.5 EPO Frequency (%) at 6 Months, by Modality and Age at Dialysis Initiation 10-7 Exhibit 10.6 Distribution of Hematocrit at 6 Months, by EPO Use 10-7 Exhibit 10.7 Mean and Median Hematocrit Levels at 6 Months, by EPO Use 10-7 Section 11 Exhibit 11.1 Peritoneal Dialysis at Follow-up 11-4 Exhibit 11.2 Number and Percent of Peritonitis Episodes, by Age 11-5 Exhibit 11.3 Peritonitis Infection Rates, by Age and Catheter Characteristics 11-6 Exhibit 11.4 Time to First Peritonitis Infection 11-7 Exhibit 11.5 Time to First Peritonitis Infection, by Age at Peritoneal Dialysis Initiation 11-7 Exhibit 11.6 Time to First Peritonitis Infection, by Catheter Access Characteristics 11-8 Exhibit 11.7 Peritoneal Dialysis Access Revision 11-10 Exhibit 11.8 Hemodialysis at Follow-up 11-11 Exhibit 11.9 Hemodialysis Access Revision 11-12 vi
Exhibit 11.10 Time to Cadaver Transplantation, by Era 11-13 Exhibit 11.11 Time to Cadaver Transplantation, by Age 11-13 Exhibit 11.12 KT/V by Modality, Age, Race, Visit and Baseline BMI 11-14 Exhibit 11.13 URR for Hemodialysis Patients by Age, Race, Visit and Baseline BMI 11-15 Section 12 Exhibit 12.1 Exhibit 12.2 Exhibit 12.3 Exhibit 12.4 Mean (SE) Height Z-Scores, by Selected Characteristics and Times Following Dialysis Initiation 12-3 Mean (SE) Weight Z-Scores, by Selected Characteristics and Times Following Dialysis Initiation 12-4 Mean Change from Baseline (with SE) in Standardized Height and Weight Scores, by Age, at Times Following Dialysis Initiation 12-5 12-Month Growth Data, for rhgh-treated and Untreated Short Control (z < -1.88) and All Control Patients by Age 12-7 Section 13 Exhibit 13.1A CRI Patient Characteristics 13-3 Exhibit 13.1B CRI Diagnoses 13-4 Exhibit 13.1C CRI Diagnoses by Race and Gender 13-5 Exhibit 13.1D CRI Patient Education Status 13-6 Exhibit 13.2 Age at CRI Registration 13-7 Exhibit 13.3 Primary Diagnosis, by Race and Age 13-8 Exhibit 13.4 Percent Distribution of Baseline Tanner Stage, by Age at CRI Registration 13-9 Exhibit 13.5 Mean Baseline Laboratory Measurements 13-10 Exhibit 13.6 Exhibit 13.7 Exhibit 13.8 Mean Baseline Laboratory Measurements, by Year of CRI Registration 13-11 Baseline Concomitant Drug Therapy, by Year of CRI Registration 13-12 Baseline Medical Events History, by Year of CRI Registration (Percent) 13-13 Exhibit 13.9 Baseline Renal Function, by Age at CRI Registration 13-14 Exhibit 13.10 Mean (and SE) Baseline Height, Weight, SDS and BMI 13-14 vii
Exhibit 13.11A Baseline Height SDS, by Age at CRI Registration 13-15 Exhibit 13.11B Baseline Weight SDS, by Age at CRI Registration 13-15 Exhibit 13.12 Baseline Renal Function, by Height Z-Score 13-16 Exhibit 13.13 Baseline Renal Function, by Height Z-Score and Age at Entry 13-17 Exhibit 13.14 Baseline Renal Function, by Height SDS and Age at Entry 13-18 Section 14 Exhibit 14.1 CRI Termination Summary 14-3 Exhibit 14.2 Frequency and Percent CRI Termination, and Reason for Termination by Selected Patient Characteristics 14-4 Exhibit 14.3 Risk of Progression to ESRD (Transplant and Dialysis Initiation) 14-6 Exhibit 14.4 Progression to ESRD 14-7 Exhibit 14.5 Exhibit 14.6 Progression to ESRD, by Baseline Calculated Creatinine Clearance (ml/min/1.73 m 2 ) 14-7 Progression to ESRD, by Race, Gender, Age at Entry, Primary Diagnosis, and Baseline Laboratory Results 14-8 Exhibit 14.7 Progression to ESRD Due to Transplantation and Dialysis Initiation 14-10 Section 15 Exhibit 15.1 CRI Follow-up Data 15-5 Exhibit 15.2 Exhibit 15.3 Exhibit 15.4 Exhibit 15.5 Exhibit 15.6A Mean (+SE) Height Z-Score, by CRI Visit and Selected Baseline Characteristics 15-6 Mean Change from Baseline (+SE) in Height Z-Score, by CRI Visit and Selected Baseline Characteristics 15-7 Mean (+SE) Weight Z-Score, by CRI Visit and Selected Baseline Characteristics 15-8 Mean Change from Baseline (+SE) in Weight Z-Score, by CRI Visit and Selected Baseline Characteristics 15-9 Serum Creatinine (mg/dl) and Calculated Creatinine Clearance (ml/min/1.73 m 2 ): Means and Changes from Baseline (+SE), by Age at Entry 15-10 Exhibit 15.6B Schwartz Calculated Clearance by Primary Diagnosis 15-11 Exhibit 15.6C Delta Schwartz Calculated Creatinine Clearance by Primary Diagnosis 15-12 viii
Exhibit 15.7A Exhibit 15.7B Exhibit 15.8A Exhibit 15.8B Exhibit 15.9 Exhibit 15.10 Exhibit 15.11 12-Month Growth Data and Renal Function Data, for rhgh Treated and Untreated Short Control (z < -1.88) and Control Patients 15-13 12-Month Growth Data and Renal Function Data, for rhgh Treated and Untreated Short Control (z < -1.88) and Control Patients Excluding 0-1 Year Old Patients 15-14 18-Month Growth and Renal Function Data, for rhgh Treated and Untreated Short Control (z < -1.88) and Control Patients 15-15 18-Month Growth and Renal Function Data, for rhgh Treated and Untreated Short Control (z < -1.88) and Control Patients Excluding 0-1 Year Old Patients 15-16 Growth Hormone Utilization for All Age-Sex-Appropriate CRI Patients with Height Z-Score of -1.88 or Worse, and Tanner Stage I, II, III at the Baseline, or 6-Month, or 12-Month Visit 15-17 Growth Hormone Utilization for All Age-Sex-Appropriate CRI Patients with Height SDS of -1.88 or Worse, and Tanner Stage I, II, III at the Baseline, and 6-Month, and 12-Month Visits 15-18 Growth Hormone Utilization for Current Age-Sex-Appropriate CRI Patients with Height SDS of -1.88 or Worse, and Tanner Stage I, II, III at the Most Recent Completed Visit in 2003 15-19 ix
I. INTRODUCTION
Introduction INTRODUCTION The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) is a research effort organized in 1987. At the outset of the study, the operational objective of this group was to obtain the voluntary participation of all renal transplant centers in the United States and Canada in which multiple (>4) pediatric patients received renal allografts annually. Scientific objectives included capture of information about current practice and trends in immunosuppressive therapy with an ultimate goal of improving care of pediatric renal allograft recipients in North America. In 1992, the study was expanded to include pediatric patients who receive maintenance hemodialysis or peritoneal dialysis therapy. In 1994, data collection began on patients with chronic renal insufficiency (CRI), defined as a Schwartz calculated creatinine clearance 75 ml/min/1.73 m 2. Now, not only do we hope to register and follow greater than 80% of the children receiving renal allografts in the United States and Canada, but to study the clinical course and natural history of patients with renal dysfunction and to continue following these patients as they move among the end-stage renal disease (ESRD) therapeutic modalities, thus allowing the NAPRTCS to become a complete ESRD patient data system. The NAPRTCS has three functioning organizational bodies: the Clinical Coordinating Center, the Data Coordinating Center, and the participating Clinical Centers. Appendix A details the structure and members of the Coordinating Centers and the participating Clinical Centers are listed in Appendix B. This report summarizes data received at the Data Coordinating Center through December 15, 2004. We continue to be particularly pleased and grateful for the enthusiastic response of the volunteer clinical centers, without which this project could not be successful. At the outset of NAPRTCS, "children" were defined as patients who had not yet attained their 18th birthday at the time of their index transplant. The index transplant is defined as the first transplant reported to NAPRTCS during the study period. When the study expanded in 1992 to include maintenance dialysis patients, the age criterion was expanded to include patients who had not yet attained their 21st birthday at the time of index transplant or at the time of index initiation of dialysis, whichever came first. The expanded age criterion was adopted for CRI patients. Data submission for the study is organized to enable analysis of both patient and event characteristics. Among transplant patients, for example, we are interested in graft survival, 1
Introduction morbidity, and the relationships that these endpoints have to patient characteristics such as race/ethnicity, sex, and primary renal disease, and to transplant (i.e., event) characteristics such as age at transplantation, donor source, immunosuppressive treatment, and HLA antigen mismatches. Analogous patient and event characteristics are defined in both the CRI and dialysis populations. As data have matured, it has been our intent to design special studies that focus on issues such as quality of life, rehabilitation, physical and mental development, and other questions of interest for particular patient subgroups. In this manner, the study has served and continues to serve as a resource to investigators whose research activities are consistent with the goals and objectives of the program. A list of special studies and analyses is shown in Appendix C. Transplantation follow-up status forms are submitted 6 months following transplant and every 6 months thereafter. For dialysis, follow-up status forms are submitted 30 days after initiation, 6 months after initiation, and every 6 months thereafter. CRI follow-up status forms are submitted at 6-month intervals following the initial reported clinic visit. As of database closure for this report, over 14,500 patients had been registered in NAPRTCS, as shown in the table below. Of these patients, data have been reported to all three registries (CRI, dialysis, and transplantation) for 684. Registry-specific sample sizes can be determined by summing the subgroup totals. For example, the number of transplant patients 8,435 is given by 4,219 + 744 + 2,788 + 684. These data do not necessarily represent a complete accounting of a patient s clinical course: a patient may have received care for his CRI at a NAPRTCS center, received maintenance dialysis at a non-naprtcs center, and rejoined the study when transplantation was performed at a NAPRTCS center. NAPRTCS PATIENT REGISTRATIONS N % All Patients 14,575 100.0 CRI only Dialysis only Transplant only CRI and dialysis CRI and transplant Dialysis and transplant 3,971 1,641 4,219 528 744 2,788 27.2 11.3 28.9 3.6 5.1 19.1 CRI, dialysis, and transplant 684 4.7 2
Introduction Forms have been submitted for 9,243 renal transplants: 8,435 are for index transplants (i.e., first transplant reported to registry) while 808 represent additional reported transplants in the same patient since the study's start on January 1, 1987. The 8,435 index transplants are comprised of 4,181 cases where transplantation was the initial reported modality and 4,254 cases where transplantation occurred subsequent to an initial report of patient registration in the dialysis (n=2,833) or CRI (n=1,421) registries. Modality initiation forms have been submitted for 7,357 independent courses of dialysis. An independent course of dialysis therapy is defined to have occurred when a patient is maintained on a given modality for 30 or more days. Of these, 5,641 represent index initiations and 1,717 are for initiations subsequent to the index course. The 5,641 index dialysis courses are comprised of 3,910 cases where dialysis is reported as the initial therapy and 1,731 cases of dialysis initiation subsequent to failure of the index graft (n=638) or termination of CRI status (n=1,136). Initial CRI status forms have been submitted for 5,927 patients. In NAPRTCS, patients are eligible for the chronic renal insufficiency component if, at the first reported clinic visit, the Schwartz calculated creatinine clearance is 75 ml/min/1.73 m 2 or lower. In total, we have received a CRI Termination Form for 2,534 of the 5,927 CRI patients. This report summarizes both patient-level and therapy-level data. In general, descriptive information will focus on the transplant or dialytic modality as the unit of observation. Variables pertinent to the patient (e.g., sex, race, primary diagnosis) will use the number of patients as the denominator. Formal analysis of failure times patient and graft survival and rejection-free intervals include only the first transplant during the study period (the index transplant) for each patient. Occasional missing information on individual characteristics results in the analysis of slightly different subgroups. Continued capture of this information is part of the ongoing data collection process. In addition to the registry components, NAPRTCS initiated its first randomized prospective clinical trial (Protocol IN01) in 1995, the first ever controlled clinical trial of OKT3 induction therapy in children and adolescents. Nested within the primary random assignment to the OKT3 or No OKT3 groups, patients were randomized to receive either Sandimmune or Neoral maintenance cyclosporine therapy. Randomized prospective trials of growth hormone have been performed: one was designed to evaluate the post transplant use of recombinant human growth hormone (rhgh) therapy and the second was a study of rhgh therapy in pediatric dialysis patients. In the transplant 3
Introduction study, patients were randomized to standard dose (.05/mg/kg/day) therapy or a delayed treatment control group. After the initial no treatment period of 12 months, control group patients received rhgh therapy for the duration of the study which is a total of 42 months. In the dialysis study, all patients receive standard dose rhgh therapy during the first 12 months, after which patients are randomized either to continue on standard dose therapy or to receive a double dose (.10/mg/kg/day). Patients continued on their "randomized" dose for an additional 12 months. Through the collaborative Clinical Trials in Pediatric Transplantation effort sponsored by the NIAID, NAPRTCS sites have completed enrollment into a large double-blind, randomized trial to evaluate potential to withdraw steroid therapy in transplant patients. Increased accrual to such studies is an important current group objective. 4
II. TRANSPLANTATION
Transplant SECTION 1: TRANSPLANT PATIENT CHARACTERISTICS Patient and transplant characteristics are summarized in Exhibit 1.1 for the 18-year history of the cooperative study. Because of reporting lags, annual accrual totals are still likely to increase, particularly for the later years. The number of transplants for 2004 however has increased by 530 since the previous year s report. As of database closure for this report, 9,243 renal transplants had been reported for 8,435 pediatric patients. This represents 530 new transplants and 496 patients with their first registry transplant since the last report. The percentage of males in the registry, about 59%, has been relatively constant over time. White patients comprise 62% of the cohort, black patients 16%, and Hispanic patients 16%. The percentage of white patients in a given year has decreased from a high of 72% in 1987 to under 55% in 2004. There had been a steady increase in the percent of living donors: in 1998, living donation has accounted for about 58% of transplants with living donations peaking at 64% in 2002, compared to 43% in the first four years of the registry. However, the percentage has been under 60% in the last 2 years. Fifty-two percent of all allografts have come from a living donor. Since the study s initiation, fewer transplants have been reported over time that involve young recipients (<6 years old) or young cadaver donors (<10 years old). While the percentage decrease in recipients <6 years old has been gradual in 2000 and 2001 young recipients accounted for 18% and 21% of all transplants, compared to 25% in 1987 the decline in the use of young donors (<10 years old) has been more precipitous, resulting in a percentage point decrease from 38% in 1988 to 14% in 1999 and 6% in 2004. Recipient history is further characterized in Exhibit 1.2. The most common primary diagnoses remain as obstructive uropathy and aplastic/hypoplastic/dysplastic kidneys, each present in about 16% of patients. Focal segmental glomerulosclerosis (FSGS) is the third most common (11%) and continues to be the most prevalent acquired renal disease. The five most frequent diagnoses, excluding unknown and other diagnoses, total 52% of the cases, while the remaining diagnoses are each present in no more than 3% of patients. A diagnosis was established for 94% of patients, while biopsy or nephrectomy confirmation of diagnosis is known not to have occurred in 44% of patients. The distributions of the five most prevalent diagnoses vary between black and white patients. For blacks, FSGS is most prevalent (23%), followed by obstructive uropathy (15%), aplasia/hypoplasia/dysplasia (14%), chronic glomerulonephritis (GN) (4%), and SLE nephritis (4%). The prevalences of cystinosis, reflux nephropathy, and hemolytic uremic syndrome were under 2% among black transplant patients. Among whites, however, the order of the five most prevalent 1-1
Transplant diagnoses is: obstructive uropathy (17%), aplasia/hypoplasia/dysplasia (17%), FSGS (9%), reflux nephropathy (6%), and medullary cystic disease (4%). The relative order of these prevalent primary diagnoses among Hispanics is similar to that for white patients. At the time of their index transplant, 10% (827/8,435) of patients were receiving their second (or greater) transplant. Twenty-five percent of primary transplants were preemptive, as these patients had never received maintenance dialysis (Exhibit 1.3). The rate of preemptive transplantation differs significantly (p<0.001) between recipients of living (33%) and cadaver (13%) source organs; between males (28%) and females (20%); among age groups, with rates of 20%, 24%, 28%, 23%, and 21% for recipients 0-1, 2-5, 6-12, 13-17, and 18-20 years old; and across races with whites, blacks, Hispanics, and other races having preemptive transplantation rates of 30%, 14%, 16%, and 16%, respectively. Immediately prior to the primary transplant, the percentages of patients maintained exclusively on hemodialysis and peritoneal dialysis were 29.8% and 39.4%. At the time of primary transplant few spleens had been removed (<1%) and all native renal tissue had been removed in 23% of patients; transplanted grafts have been removed in 37.1% of the index nonprimary transplants (Exhibit 1.3). Exhibit 1.4 details recipient age at transplant. Of the 89 transplants occurring in children younger than 12 months old, there were 5, 21, and 61 transplants, respectively, within the 3-5, 6-8 and 9-11 months age categories, and two were less than 3 months. Only 29 infant transplants have been performed since 1996, six in 1996, three in 1997, three in 1998, five in 1999, one in 2000, four in 2001, six in 2002 and one in 2004 although these numbers may increase as enrollment reports increase. In Exhibit 1.5, it is observed that the sex distribution is most unbalanced in the youngest age groups where 70% of 0-1 and 66% of 2-5 year old patients are male; the distribution is more even among adolescents. This is due to the fact that males comprise the majority of the aplasia/hypoplasia/dysplasia (62%) and obstructive uropathy (86%) diagnoses (see Exhibit 1.6) and the relative incidence of these diagnoses decreases with age. Forty percent of male patients fall into these two diagnostic categories, compared to 21% of females. The contrast is particularly steep in the obstructive uropathy group, a diagnosis shared by 23% of the males, but only 6% of females. Exhibit 1.6 provides for each primary diagnosis the percentages of patients who are male, white race, and known not to have had a biopsy or nephrectomy confirmation of diagnosis. Of transplant registrants with FSGS, 51% are white. Systemic lupus erythematosis is predominantly a disease of females (82%) with the female-specific race distribution given by 25% white, 39% black, and 25% 1-2
Transplant Hispanic. The percentages of patients without a histologically confirmed tissue diagnosis are 71%, 69%, and 69% in aplastic/hypoplastic/dysplastic, obstructive uropathy, and reflux nephropathy patients, respectively. The comparable rates for FSGS, hemolytic uremic syndrome, and lupus nephritis are 6%, 47%, and 4%. Exhibit 1.7 categorizes primary diagnoses as either FSGS, GN, structural or other and demonstrates how these distributions differ according to age at transplant. GN is comprised of the following primary diagnoses (chronic glomerulonephritis, idiopathic crescentic glomerulonephritis, mebranoproliferative glomerulonephritis Type I and Type II, SLE nephritis, Henoch-Schonlein nephritis, Berger s (IgA) nephritis, Wegener s granulomatosis, and membranous nephropathy. Structural diagnoses (prune belly, reflux nephropathy and aplasia/hypoplasia/displasias) account for the largest proportion of primary diagnoses among children ages 5 and under; whereas, GN diagnoses are more prevalent with increasing age. 1-3
Transplant EXHIBIT 1.1 PATIENT REGISTRATIONS, TRANSPLANTS, AND SELECTED CHARACTERISTICS, BY YEAR OF REGISTRATION 100 80 %Male %White %Living Donor %Recipient age <6 yrs %CAD donor age <10 yrs PERCENT 60 40 20 0 87 89 91 93 95 97 99 01 03 TRANSPLANT YEAR 1987 '88 '89 1990 '91 '92 '93 '94 '95 '96 '97 '98 '99 2000 '01 '02 '03 '04 Total No. of Pts 531 501 464 497 498 546 572 545 626 544 547 474 487 399 429 381 259 135 8435 No. of Tx 542 529 506 549 563 602 620 621 687 622 588 533 536 436 465 412 289 143 9243 1-4
Transplant EXHIBIT 1.2 RECIPIENT AND INDEX TRANSPLANT CHARACTERISTICS N (8435) % (100.0) Sex Male 5009 59.4 Female 3426 40.6 Race White 5189 61.5 Black 1385 16.4 Hispanic 1351 16.0 Other 510 6.0 Primary Diagnosis Obstructive uropathy 1355 16.1 Aplasia/hypoplasia/dysplasia 1349 16.0 Focal segmental glomerulosclerosis 968 11.5 Reflux nephropathy 442 5.2 Chronic glomerulonephritis 292 3.5 Polycystic disease 242 2.9 Medullary cystic disease 240 2.8 Hemolytic uremic syndrome 231 2.7 Prune Belly 220 2.6 Congenital nephrotic syndrome 215 2.5 Familial nephritis 188 2.2 Cystinosis 174 2.1 Idiopathic crescentic glomerulonephritis 160 1.9 Membranoproliferative glomerulonephritis - Type I 158 1.9 Pyelo/interstitial nephritis 156 1.8 SLE nephritis 140 1.7 Renal infarct 123 1.5 Berger's (IgA) nephritis 110 1.3 Henoch-Schonlein nephritis 104 1.2 Membranoproliferative glomerulonephritis - Type II 75 0.9 Wilms tumor 47 0.6 Drash syndrome 46 0.5 Wegener's granulomatosis 44 0.5 Oxalosis 43 0.5 Membranous nephropathy 40 0.5 Other systemic immunologic disease 32 0.4 Sickle cell nephropathy 14 0.2 Diabetic glomerulonephritis 9 0.1 Other 708 8.4 Unknown 510 6.0 1-5
Transplant EXHIBIT 1.3 TRANSPLANT CHARACTERISTICS N % Total Transplants 9243 100.0 Index Transplants 8435 91.3 Primary Transplants 7608 82.3 Repeat Transplant 1635 17.7 Maintenance Dialysis Immediately Prior to Transplant Hemodialysis only 2753 29.8 Peritoneal dialysis only 3640 39.4 Primary Transplant 7608 100.0 Preemptive 1869 24.6 Splenectomy 52 0.7 Naive Tissue Removed 1744 23.2 Index Non-primary Transplants 827 100.0 Prior Transplants Removed 307 37.1 1-6
Transplant EXHIBIT 1.4 AGE AT TRANSPLANTATION N (9243) % (100) Age at Transplantation 0 89 1.0 1 395 4.3 2 408 4.4 3 326 3.5 4 305 3.3 5 338 3.7 6 341 3.7 7 386 4.2 8 413 4.5 9 422 4.6 10 523 5.7 11 505 5.5 12 536 5.8 13 664 7.2 14 658 7.1 15 746 8.1 16 777 8.4 17 710 7.7 18 701 7.6 Age Grouping 0-1 484 5.2 2-5 1377 14.9 6-12 3126 33.8 13-17 3555 38.5 >17 701 7.6 1-7
Transplant EXHIBIT 1.5 AGE AT INDEX TRANSPLANT BY PATIENT'S SEX, RACE, AND DIAGNOSIS [Numbers in Table are Percents] Age at Index Transplantation Total (N=8435) 0-1 (N=474) 2-5 (N=1276) 6-12 (N=2871) 13-17 (N=3251) >17 (N=560) Gender Male 70 66 59 56 55 Female 30 34 41 44 45 Race White 76 64 62 59 56 Black 8 14 14 19 24 Hispanic 10 16 17 16 13 Other 6 6 6 6 7 Diagnosis Renal plasias 29 24 17 11 9 Obstructive uropathy 19 23 16 14 10 Other 51 44 54 62 65 Focal segmental glomerulosclerosis 1 9 13 12 15 1-8
Transplant EXHIBIT 1.6 SEX, RACE, AND BIOPSY DISTRIBUTIONS, BY PRIMARY RENAL DIAGNOSIS Diagnosis N % Not % Male % White Biopsied Total 8435 59 65 44 Diagnosis Obstructive uropathy 1355 86 68 69 Aplasia/hypoplasia/dysplasia 1349 62 69 71 Focal segmental glomerulosclerosis 968 57 51 6 Reflux nephropathy 442 44 79 66 Chronic glomerulonephritis 292 42 52 26 Polycystic disease 242 51 78 48 Medullary cystic disease 240 50 88 34 Hemolytic uremic syndrome 231 56 84 47 Prune Belly 220 98 64 62 Congenital nephrotic syndrome 215 52 71 12 Familial nephritis 188 80 65 27 Cystinosis 174 49 91 56 Idiopathic crescentic glomerulonephritis 160 35 58 5 Membranoproliferative glomerulonephritis - Type I 158 45 62 3 Pyelo/interstitial nephritis 156 47 78 24 SLE nephritis 140 18 28 4 Renal infarct 123 48 82 63 Berger's (IgA) nephritis 110 55 73 6 Henoch-Schonlein nephritis 104 40 77 15 Membranoproliferative glomerulonephritis - Type II 75 51 79 4 Wilms tumor 47 53 81 9 Drash syndrome 46 59 72 7 Wegener's granulomatosis 44 41 83 7 Oxalosis 43 58 90 26 Membranous nephropathy 40 58 54 8 Other systemic immunologic disease 32 13 62 6 Sickle cell nephropathy 14 57 0 29 Diabetic glomerulonephritis 9 33 33 33 Other 708 53 67 36 Unknown 510 52 34 69 1-9
Transplant EXHIBIT 1.7 PRIMARY DIAGNOSIS BY AGE FSGS GN Other Structural 100 80 Percent 60 40 20 0 0-1 2-5 6-12 >12 1-10
SECTION 2: DONOR HISTORY AND ANTIGEN MISMATCHES NAPRTCS 2005 Transplant As described in Exhibit 2.1, 48% of all transplants have involved a cadaver source, 42% came from a parent, with the remaining 10% coming from other living donors. Parents comprise 81% of living donors: a cross-classification of parent and child sexes (n=3,569 pairs with complete data) reveals that mothers comprise the majority of parent-donors (56%), fathers donate to sons 63% of the time, while mothers make 60% of their donation to sons (p=0.044). There have been 335 transplants between siblings, and 163 live-donor grafts have been from donors under the age of 21. Thirteen living donors were under 18 years of age: 12 were transplants between siblings and 1 was a transplant from parent to child. Between siblings, the numbers of 3-, 4-, 5-, and 6-antigen matches were 1, 2, 2, and 7, respectively. The number of unrelated living donors has increased from an average of 3 per year in 1987-1995 to 17 per year since then. Among cadaver transplants, 67 (1.6%) have come from donors less than 24 months old and 1063 (23.9%) from donors who were between 2 and 12 years of age; the use of cadaver donors <10 years old has declined since the study s start (see Exhibit 1.1). Prior to 1992, infant donors comprised 2.9% (42/1,466) of cadaver donor sources, compared to 0.9% (25/2,711) in transplants between 1991 and 2004. Thirteen percent of cadaver allografts were preserved by machine perfusion and 69% had cold ischemia times of 24 hours or less, with 17 (0.3%) exceeding 48 hours. The maximum cold time was 64.5 hours. Donor-specific transfusions were performed in 7% of living donor grafts but this procedure has been used only occasionally since 1995. The total number of random transfusions given to recipients differed by donor type: 48% of living donor graft recipients and 32% of cadaver graft recipients had zero previous transfusions, while 14% and 29%, respectively, had more than five transfusions. The percent of patients without prior random transfusions has increased from 17% in 1987 (27% living and 10% cadaver donor recipients) to 65% in 2004 (67% living and 62% cadaver). Time trends in the utilization of donor-specific and random transfusions are provided in Exhibit 2.2. To date, there have been 34 confirmed transplants across ABO blood group compatibility barriers out of 8,564 transplants with complete blood group data; there are 25 O recipient/a donor pairs, 2 O recipient/b donor pair, 4 B recipient/a donor pairs, 1 B recipient/ab donor pair, and 2 A recipient/b donor pair. A special analysis of an early cohort of these patients concluded that pediatric kidney transplantation across ABO compatibility barriers is an uncommon practice, but suggested based on preliminary experience that such transplants involving recipients whose anti-a titer history is 2-1
Transplant low (1:4) are associated with satisfactory graft outcome and are deserving of further study. Overall, 88% (7,501/8,564) of donor and recipient blood types were identical. Whereas blood group O is present in 56% of donors and 47% of recipients, blood group AB is present in 1.4% of donors and 4.0% of recipients. Histocompatibility antigen data are shown in Exhibit 2.3. We count an allele as matching only if identical known alleles are reported for both donor and recipient. Among the living donor transplants, 76% had at least one match at each of the A, B, and DR loci, and there were mismatches at all 6 A, B, and DR loci for 13% of cases. No matches in either the B or DR loci occurred in 36% of the transplants from cadaver source donors; a single locus match (of B and DR) occurred in 32%. Known matches of all 6 A, B and DR alleles occurred in 2.5% of cadaver source transplants and in 3.5% of living donor source transplants. Exhibit 2.4 compares donor sources with varying ages at transplant. Children under 5 years of age are more likely to receive a transplant from a living donor rather than a cadaver donor. For children ages 6-12, the proportion receiving living donor transplants is similar to the proportion receiving cadaver donor transplants. However, children 13 years of age are more likely to receive a cadaver donor transplant. 2-2
Transplant EXHIBIT 2.1 DONOR INFORMATION N (9243) % (100.0) Donor Source Live donor/parent 3888 42.1 Live donor/sibling 335 3.6 Live donor/other related 411 4.5 Live donor/unrelated 167 1.8 Cadaver 4427 48.0 Donor Age Living Cadaver 0-1 67 1.6 2-5 417 10.0 6-12 579 13.9 13-17 13 0.3 617 14.8 18-20 150 3.2 443 10.6 21-30 1026 22.1 684 16.4 31-40 2109 45.5 617 14.8 41-50 1167 25.2 493 11.8 > 50 170 3.7 260 6.2 Cadaver Source Transplants Machine Perfusion Used 484 12.5 Cold Ischemia Time < 24 hours 2809 69.2 > 24 hours 1252 30.8 2-3
Transplant EXHIBIT 2.2 USE OVER TIME OF DONOR-SPECIFIC AND RANDOM BLOOD TRANSFUSIONS 100 80 Living Donor 0 Random transfusions 1-5 Random transfusions >5 Random transfusions Donor-specific transfusions PERCENT 60 40 20 0 100 80 87 89 91 93 95 97 99 01 03 TRANSPLANT YEAR Cadaver Donor 0 Random transfusions 1-5 Random transfusions >5 Random transfusions PERCENT 60 40 20 0 87 89 91 93 95 97 99 01 03 TRANSPLANT YEAR 2-4
Transplant EXHIBIT 2.3 PERCENT HLA MISMATCHES HLA-A Living (n=4801) Donor Source Cadaver (n=4427) 0 14.2 8.4 1 69.7 38.5 2 16.1 53.1 HLA-B 0 11.0 8.4 1 70.8 32.4 2 18.2 59.2 HLA-DR 0 13.9 10.1 1 64.0 40.2 2 22.1 49.7 HLA-B and -DR 0 5.2 3.5 1 13.5 6.4 2 56.8 22.1 3 9.6 32.0 4 14.9 35.9 HLA-A, -B, and -DR 0 3.4 2.5 1 4.6 2.4 2 17.3 5.5 3 50.2 14.0 4 8.5 24.4 5 2.7 25.3 6 13.4 26.0 2-5
Transplant EXHIBIT 2.4 AGE AT TRANSPLANT AND DONOR SOURCE 50 40 PERCENT 30 20 Living Donor Cadaver Donor 10 0 0-1 2-5 6-12 13-17 > 17 AGE (years) 2-6
Transplant SECTION 3: THERAPY The NAPRTCS collects information on post-transplant immunosuppressive medications and dosages at Day 30, Month 6, and every six months thereafter. In addition, a record of the date of initiation and dosages of immunosuppressive medication used during the first post-transplant month is collected. Detailed description of pre-operative immunosuppressive therapy is not collected, but it was employed in 50% of living donor transplants. The frequency of use among all recipients had decreased from 48% in 2001 to 40% in 2004. Because of the changes in therapy in recent years, analyses are restricted to more recent transplant (>1995). Exhibit 3.1 details immunosuppressive medication data for transplants in 1996 and beyond for the first 30 days post-transplant therapy. Note that the frequency of use of various drugs ranges from 9% (of transplants) for sirolimus to 91% for prednisone. Methylprednisolone and azathioprine, when used, were typically initiated on the day of operation. Polyclonal antibody ATG was used in 16% of living donor and 25% of cadaver source transplants, while the respective rates of monoclonal antibody usage are 40% and 45%. Cyclosporine was used for 63% of transplants and, of those, 21% began cyclosporine on Day 0, 24% on Day 1, and 40% during Days 2-6. Although early graft failures decrease the number of patients still available for immunosuppressive therapy by Day 30, the percentages being treated with prednisone is relatively stable. Over the month, median doses of prednisone decreased to approximately 1/3 of the initial amount and, median doses of cyclosporine increased by 1.0 mg/kg. The median ATG/ALG course was 7 days. For monoclonal antibody, the median length of course of OKT3 was 9 days; for basiliximab patients, it was 2 days; and for daclizumab recipients, the median course was 5 days. Exhibit 3.2 shows the percentage of week 1 calcineurin inhibitor use by type of induction antibody while Exhibit 3.3 presents the induction antibody use from 1996 to 2004. The rate of induction antibody use at transplant or one day post transplant, by transplantation year was as follows: 3-1
Transplant PERCENT INDUCTION ANTIBODY, AT TRANSPLANT OR ON 1 DAY POST TRANSPLANT 1996 (n=585) 1997 (n=568) 1998 (n=510) 1999 (n=513) 2000 (n=419) 2001 (n=451) 2002 (n=397) 2003 (n=284) 2004 (n=142) None 49.8 51.9 42.5 41.7 48.5 45.3 41.9 39.2 44.8 OKT3 22.0 14.8 10.2 5.1 0.5 0.9 1.0 0.7 0 Basiliximab 0.7 4.7 16.1 23.9 31.7 34.2 31.8 30.8 Daclizumab 5.0 18.9 26.1 21.5 16.7 16.5 18.0 17.5 ATG/ALG 28.1 27.7 23.8 11.1 5.6 5.4 6.5 10.3 7.0 Exhibit 3.4 presents immunosuppressive therapy dosages for patients with functioning grafts for selected drug combinations after 1995. Median daily prednisone doses decrease over the first 2 years after transplantation, while the percentage of transplanted patients receiving alternate day therapy increases from 6.1% at Month 6 to 13.6%, 25.9%, and 33.0% at Months 12, 24, and 48, respectively. Continued slow increases in alternate day steroid use are observed at 6 years (40%). At 5 years post transplant, 32.7% of living donor versus 40.2% of cadaver donor transplants are reported to receive alternate day steroids. Note that there is little change in the proportion of patients receiving prednisone, cyclosporine, and azathioprine at each time point. Among those receiving cyclosporine, the mean and standard error of the daily milligram per kilogram doses are 7.7±0.09, 6.9±0.09, 6.0±0.08, and 4.6±0.12 at Months 6, 12, 24, and 60, respectively. Exhibit 3.5 shows the marked changes in day 30 post transplant dosing strategies that have been observed in the past years. These are substantially caused by the introduction of new drugs such as mycophenolate mofetil and tacrolimus. Although it has substantially effected the later cohort years, the whole experience of the registry has been minimally affected. Use at Day 30 of combination cyclosporine, prednisone, and azathioprine has declined since 1996-1997, from 30% of living donor and 27% of cadaver organ recipients, to 2% and 1% of transplants, respectively, in 2000-2004. The regimen of prednisone, tacrolimus, and mycophenolate mofetil has become more popular. It is used in 39% of living donor and 43% of cadaver organ transplant in 2000-2004, compared to about 9.5% of all transplants in 1996-1997. 3-2
Transplant Approximately 80% of patients receive 3-drug therapy at 6 months post transplant with mycophenolate mofetil replacing azathioprine in recent cohorts. Among transplanted grafts with 30 days function that have occurred since 1996, the following drug utilization rates were observed: PERCENT DRUG UTILIZATION - DAY 30 POST TRANSPLANT 1997 (n=568) 1998 (n=510) 1999 (n=513) 2000 (n=419) 2001 (n=451) 2002 (n=397) 2003 (n=284) 2004 (n=142) Cyclosporine 80.5 73.9 70.2 58.0 49.5 29.2 15.9 7.0 Tacrolimus 15.0 22.9 24.8 34.8 42.6 58.4 62.0 72.5 Mycophenolate 45.3 68.4 70.0 64.7 54.8 57.4 53.9 60.6 Azathioprine 35.4 20.6 16.2 14.1 13.3 1.8 4.9 2.8 Sirolimus 0.2 6.2 16.6 22.2 21.8 11.3 Substantial increases in tacrolimus, mycophenolate mofetil, and sirolimus usage are observed, with a significant decrease in azathioprine usage. Azathioprine usage has decreased sharply from 60% in 1996 to 3% in 2004. The majority of sirolimus therapy (87%) was initiated within the first two days post-transplant. The mean and median dosages were 4.7 and 4.0 mg/m 2, respectively. Cyclosporine was used in 82% of the 1996 transplants at Day 30, and it continues to show a decline in utilization. Of cyclosporine recipients since 1996 with known formulation, 84% reported use of Neoral. Exhibit 3.6 displays the percentage of patients at selected follow-up time points who were receiving the six most common maintenance regiments since 1995, by graft donor source. Through 3 years, about 35% of the patients received combination immunosuppressives with prednisone, cyclosporine, and MMF, compared to approximately 22% of patients with prednisone, cyclosporine and azathioprine. Note that therapy strategies appear similar for cadaver recipients and live donor recipients. For example, dual therapy with prednisone and cyclosporine or prednisone and tacrolimus is received by similar percentages of recipients from living and cadaver graft donors. Because of the differential graft survival in black and non-black patients, cyclosporine blood levels have been examined. At Day 30 mean median values are within 9 ng/ml for two of the most common measurement methods, HPLC and TDX. For black patients, at 1-year post transplant, 3-3
Transplant mean cyclosporine level was 183 ng/ml (versus 168 ng/ml for others); cyclosporine blood levels are shown in the table below. MEDIAN / MEAN ± SE ONE YEAR BLOOD LEVELS (NG/ML) BY RACE/ETHNICITY Method Black Other Cyclosporine HPLC 123/152±7.9 119/130±2.1 TDX 215/239±7.3 207/234±3.6 Monoclonal RIA-specific 156/189±9.4 155/169±3.2 TAC HPLC 5.7/6.3±0.6 6.0/10.6±2.5 IMX 5.9/6.2±0.5 5.7/6.2±0.3 The percentage of patients receiving concomitant anti-hypertensive, prophylactic antibiotic, and anti-convulsant medications, by donor source, are displayed in Exhibit 3.7. A substantial percentage of transplanted children receive anti-hypertensives and antibiotics throughout the followup period. During the first 3 years, an absolute difference in anti-hypertensive medication usage of about 5 percentage points is observed between cadaver and living donor source recipients. Although the percentage receiving such therapy decreases in the first few years of follow-up, over half of the children are receiving anti-hypertensives throughout the period. Prophylactic antibiotic use decreases for both donor source groups during the first 12 months after transplant. At one year, prophylactic antibiotics are used in 49% of living donor and 44% of cadaver donor source recipients with minimal decreases thereafter. At one year, prophylactic antibiotics are used in 37% of hemolytic uremic syndrome patients and in 37% of those with focal segmental glomerulosclerosis, versus 55% of patients diagnosed with reflux nephropathy and 61% with obstructive uropathy. An anti-convulsant medication was given initially to 7% of the transplant recipients, with a greater frequency observed among recipients of cadaver organs (9.0% vs. 6.0%). 3-4
Transplant EXHIBIT 3.1 MEDICATION DATA - FIRST 30 DAYS TRANSPLANTS AFTER 1995 Therapy Percent Treated (n=4010) Median Day of Initiation Median Initial Dose (mg/kg/d) Percent Treated Day 30 (n=3869) Median Day 30 Dose (mg/kg/d) Prednisone 91 3 1.7 92 0.53 Methylprednisolone 80 0 8.5 Cyclosporine 62 1 8.9 60 9.98 Azathioprine 33 0 2.4 21 2.03 Tacrolimus 32 1 0.19 31 0.22 Mycophenolate Mofetil* 56 1 29.2 52 30.3 ATG/ALG 18 0 11.7 Monoclonal Antibody 34 0 OKT3 9 0 0.12 Basiliximab 17 0 0.47 Daclizumab 15 1 1.1 Sirolimus** 9 1 0.15 *Median initial and Day 30 daily dose in mg per body surface area were 897.0 and 949.5 mg/m 2 /Day respectively. **Median initial dose in mg per body surface area was 3.1 mg/m 2. 3-5
Transplant EXHIBIT 3.2 WEEK 1 CALCINEURIN INHIBITOR USE, BY INDUCTION ANTIBODY 100 80 Neither Cyclosporine Tacrolimus PERCENT 60 40 20 0 None OKT3 Basiliximab Daclizumab ATG/ALG EXHIBIT 3.3 INDUCTION ANTIBODY USE, BY YEAR PERCENT 100 80 60 40 20 None OKT3 Basiliximab Daclizumab ATG/ALG 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 TRANSPLANT YEAR 3-6