NAPRTCS Annual Report

Transcription

1 North American Pediatric Renal Trials and Collaborative Studies NAPRTCS 2006 Annual Report Renal Transplantation Dialysis Chronic Renal Insufficiency This is a privileged communication not for publication.

2 This study is sponsored by major grants from: AMGEN, Incorporated Genentech, Incorporated NAPRTCS also thanks the following contributors: Roche Laboratories, Incorporated Wyeth Research Gambro Gambro BCT Astellas Luitpold Pharmaceuticals

3 North American Pediatric Renal Trials and Collaborative Studies 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 Rockville, Maryland 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)

4 This report was developed under the auspices of the NAPRTCS Board of Directors 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 Ashley Newton

5 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 B-1 Appendix C: Special Studies and Analyses C-1 i

6 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 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

7 Section 4 Exhibit 4.1A Frequency of Acute Rejections 4-5 Exhibit 4.1B Acute Rejection Ratios 4-5 Exhibit 4.1C Biopsy Rate of Reported Acute Rejections Over Time 4-6 Exhibit 4.2 Time to First Rejection Episode, by Allograft Source and Transplant Year 4-7 Exhibit 4.3A Exhibit 4.3B Exhibit 4.4 Relative Hazard (RH) of First Rejection Episode, First Transplant, Relative Hazard (RH) of First Rejection Episode, First Transplant, Time to First Rejection Episode, by Selected Characteristics Among Transplants ( ) 4-10 Exhibit 4.5A Rejection Reversal Outcome by Selected Characteristics 4-12 Exhibit 4.5B Rejection Reversal Outcome by Selected Characteristics for First Acute Rejection Episode Only 4-13 Exhibit 4.6 Rejection Reversal Outcome by Transplant Year 4-14 Exhibit 4.7 Summary of Late First Rejections, by Selected Characteristics 4-15 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 Deceased 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 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 iii

8 Exhibit 5.11 Exhibit 5.12 Exhibit 5.13 Exhibit 5.14 Serial Serum Creatinine for Functioning Grafts, by Race and Induction Antibody Therapy 5-19 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 Days 7-5 Exhibit 7.2B Transplant Month Hospitalization Days ( ) 7-6 Exhibit 7.2C Transplant Month Hospitalization Days ( ) 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 (Deceased 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 Percent Patient Survival of Index Transplants, by Age at Transplantation Living Donor 7-12 iv

9 Exhibit 7.6B Percent Patient Survival of Index Transplants, by Age at Transplantation Deceased Donor 7-12 Exhibit 7.7 Causes of Death Following Index Renal Transplantation 7-13 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 Year 9-5 Exhibit 9.2A Peritoneal Dialysis Access 9-6 Exhibit 9.2B Peritoneal Access Data by Initiation Year 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 Year 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 Time to Dialysis Termination for Index Cases, by Age and Race/Ethnicity 9-14 v

10 Exhibit 9.9 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 Exhibit 9.11 Time to Dialysis Termination for Index Cases, by Reason for Termination 9-17 Exhibit 9.12 Selected CAPD and APD Patients 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 Exhibit 11.8 Hemodialysis at Follow-up vi

11 Exhibit 11.9 Hemodialysis Access Revision Exhibit Time to Deceased Donor Transplantation, by Era Exhibit Time to Deceased Donor Transplantation, by Age Exhibit KT/V by Modality, Age, Race, Visit and Baseline BMI Exhibit URR for Hemodialysis Patients by Age, Race, Visit and Baseline BMI Exhibit KT/V Over Time - PD Patients Exhibit KT/V Over Time - HD Patients 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 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 Exhibit 13.6 Exhibit 13.7 Exhibit 13.8 Mean Baseline Laboratory Measurements, by Year of CRI Registration Baseline Concomitant Drug Therapy, by Year of CRI Registration Baseline Medical Events History, by Year of CRI vii

12 Registration (Percent) Exhibit 13.9 Baseline Renal Function, by Age at CRI Registration Exhibit Mean (and SE) Baseline Height SDS, Weight SDS and BMI SDS Exhibit 13.11A Baseline Height SDS, by Age at CRI Registration Exhibit 13.11B Baseline Weight SDS, by Age at CRI Registration Exhibit Baseline Renal Function, by Height Z-Score Exhibit Baseline Renal Function, by Height Z-Score and Age at Entry Exhibit Baseline Renal Function, by Height SDS and Age at Entry Section 14 Exhibit 14.1 CRI Termination Summary 14-3 Exhibit 14.2 Frequency and Percent CRI Termination, and Reasons 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 Progression to ESRD, by Baseline Calculated Creatinine Clearance 14-7 Exhibit 14.6 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 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 and Calculated Creatinine Clearance: Means and Changes from Baseline (+SE), by Age at Entry Exhibit 15.6B Schwartz Calculated Creatinine Clearance by Primary Diagnosis viii

13 Exhibit 15.6C Delta Schwartz Calculated Creatinine Clearance by Primary Diagnosis Exhibit 15.7A Exhibit 15.7B Exhibit 15.8A Exhibit 15.8B Exhibit 15.9 Exhibit Exhibit Month Growth Data and Renal Function Data, for rhgh Treated and Untreated Short Control (Z < -1.88) and Control Patients 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 Month Growth and Renal Function Data, for rhgh Treated and Untreated Short Control (Z < -1.88) and Control Patients 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 Growth Hormone Utilization for All Age-Sex-Appropriate CRI Patients with Height Z-Score of or Worse, and Tanner Stage I, II, III at the Baseline, or 6-Month, or 12-Month Visit Growth Hormone Utilization for All Age-Sex-Appropriate CRI Patients with Height SDS of or Worse, and Tanner Stage I, II, III at the Baseline, and 6-Month, and 12-Month Visits Growth Hormone Utilization for Current Age-Sex-Appropriate CRI Patients with Height SDS of or Worse, and Tanner Stage I, II, III at the Most Recent Completed Visit in ix

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15 I. INTRODUCTION

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17 Introduction INTRODUCTION The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) is a research effort organized in 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 January 4, 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

18 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 15,500 (nearly 1,000 more than in last year's report) 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 749. Registryspecific sample sizes can be determined by summing the subgroup totals. For example, the number of transplant patients 8,990 is given by 4, , 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 15, CRI only Dialysis only Transplant only CRI and dialysis CRI and transplant Dialysis and transplant 4,262 1,730 4, , CRI, dialysis, and transplant

19 Introduction Forms have been submitted for 9,837 renal transplants: 8,990 are for index transplants (i.e., first transplant reported to registry) while 847 represent additional reported transplants in the same patient since the study's start on January 1, The 8,990 index transplants are comprised of 4,380 cases where transplantation was the initial reported modality and 4,610 cases where transplantation occurred subsequent to an initial report of patient registration in the dialysis (n=3,036) or CRI (n=1,574) registries. Modality initiation forms have been submitted for 7,805 independent courses of dialysis. An independent course of dialysis therapy is defined to have occurred when a patient is maintained on a hemodialysis or peritoneal dialysis course for 30 or more days. Of these, 5,995 represent index initiations and 1,810 are for initiations subsequent to the index course. The 5,995 index dialysis courses are comprised of 4,096 cases where dialysis is reported as the initial therapy and 1,899 cases of dialysis initiation subsequent to failure of the index graft (n=667) or termination of CRI status (n=1,232). Initial CRI status forms have been submitted for 6,405 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 2,840 of the 6,405 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) 3

20 Introduction therapy and the second was a study of rhgh therapy in pediatric dialysis patients. In the transplant study, patients were randomized to standard dose (0.05/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. 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 (0.10/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 enrolled patients into large, randomized trials to evaluate potential to withdraw steroid therapy in transplant patients. 4

21 II. TRANSPLANTATION

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23 Transplantation SECTION 1: TRANSPLANT PATIENT CHARACTERISTICS Patient and transplant characteristics are summarized in Exhibit 1.1 for the entire 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 2005 however has increased by 594 since the previous year s report. As of database closure for this report, 9,837 renal transplants had been reported for 8,990 pediatric patients. This represents 594 new transplants and 555 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 61% of the cohort, black patients 17%, 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 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 63% in 2002, compared to less than 45% 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 deceased 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 13% in 2000 and 8% in Recipient history is further characterized in Exhibit 1.2. The most common primary diagnoses remain obstructive uropathy and aplastic/hypoplastic/dysplastic kidneys, each present in about 16% of patients. Focal segmental glomerulosclerosis (FSGS) is the third most common (12%) 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

24 Transplantation 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% (860/8,990) 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 deceased donor (13%) source organs; between males (28%) and females (20%); among age groups, with rates of 19%, 24%, 28%, 23%, and 20.4% for recipients 0-1, 2-5, 6-12, 13-17, and years old; and across races with whites, blacks, Hispanics, and other races having preemptive transplantation rates of 30%, 14%, 16%, and 17%, respectively. Immediately prior to the primary transplant, the percentages of patients maintained exclusively on hemodialysis and peritoneal dialysis were 30.0% and 39.3%. 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 36.9% of the index non-primary transplants (Exhibit 1.3). Exhibit 1.4 details recipient age at transplant. Of the 92 transplants occurring in children younger than 12 months old, there were 6, 22, and 62 transplants, respectively, within the 3-5, 6-8 and 9-11 months age categories, and two were less than 3 months. Only 32 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, two in 2004, and two in 2005 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 69% 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 (85%) diagnoses (see Exhibit 1.6) and the relative incidence of these diagnoses decreases with age. Thirty-nine 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, 50% are white. Systemic lupus erythematosis is predominantly a disease of females (82%) with a female-specific race distribution given by 26% white, 39% black, and 25% 1-2

25 Transplantation 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%, 48%, and 5%. 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

26 Transplantation EXHIBIT 1.1 PATIENT REGISTRATIONS, TRANSPLANTS, AND SELECTED CHARACTERISTICS, BY YEAR OF REGISTRATION %Male %White %Living Donor %Recipient age <6 yrs %DD donor age <10 yrs PERCENT TRANSPLANT YEAR 1987 '88 ' '91 '92 '93 '94 '95 '96 '97 '98 ' '01 '02 '03 '04 '05 Total No. of Pts No. of Tx

27 Transplantation EXHIBIT 1.2 RECIPIENT AND INDEX TRANSPLANT CHARACTERISTICS N (8990) % (100.0) Sex Male Female Race White Black Hispanic Other Primary Diagnosis Aplasia/hypoplasia/dysplasia Obstructive uropathy Focal segmental glomerulosclerosis Reflux nephropathy Chronic glomerulonephritis Polycystic disease Medullary cystic disease Hemolytic uremic syndrome Prune Belly Congenital nephrotic syndrome Familial nephritis Cystinosis Idiopathic crescentic glomerulonephritis Pyelo/interstitial nephritis Membranoproliferative glomerulonephritis - Type I SLE nephritis Renal infarct Berger's (IgA) nephritis Henoch-Schonlein nephritis Membranoproliferative glomerulonephritis - Type II Drash syndrome Wegener's granulomatosis Wilms tumor Oxalosis Membranous nephropathy Other systemic immunologic disease Sickle cell nephropathy Diabetic glomerulonephritis Other Unknown

28 Transplantation EXHIBIT 1.3 TRANSPLANT CHARACTERISTICS N % Total Transplants Index Transplants Primary Transplants Repeat Transplant Maintenance Dialysis Immediately Prior to Transplant Hemodialysis only Peritoneal dialysis only Primary Transplant Preemptive Splenectomy Naive Tissue Removed Index Non-primary Transplants Prior Transplants Removed

29 Transplantation EXHIBIT 1.4 AGE AT TRANSPLANTATION N (9243) % (100) Age at Transplantation Age Grouping >

30 Transplantation 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=8990) 0-1 (N=514) 2-5 (N=1365) 6-12 (N=3050) (N=3456) 18 (N=605) Gender Male Female Race White Black Hispanic Other Diagnosis Renal plasias Obstructive uropathy Other Focal segmental glomerulosclerosis

31 Transplantation EXHIBIT 1.6 SEX, RACE, AND BIOPSY DISTRIBUTIONS, BY PRIMARY RENAL DIAGNOSIS Diagnosis N % Not % Male % White Biopsied Total Diagnosis Aplasia/hypoplasia/dysplasia Obstructive uropathy Focal segmental glomerulosclerosis Reflux nephropathy Chronic glomerulonephritis Polycystic disease Medullary cystic disease Hemolytic uremic syndrome Prune Belly Congenital nephrotic syndrome Familial nephritis Cystinosis Idiopathic crescentic glomerulonephritis Pyelo/interstitial nephritis Membranoproliferative glomerulonephritis - Type I SLE nephritis Renal infarct Berger's (IgA) nephritis Henoch-Schonlein nephritis Membranoproliferative glomerulonephritis - Type II Drash syndrome Wegener's granulomatosis Wilms tumor Oxalosis Membranous nephropathy Other systemic immunologic disease Sickle cell nephropathy Diabetic glomerulonephritis Other Unknown

32 Transplantation EXHIBIT 1.7 PRIMARY DIAGNOSIS BY AGE 1-10

33 SECTION 2: DONOR HISTORY AND ANTIGEN MISMATCHES NAPRTCS 2006 Transplantation As described in Exhibit 2.1, 48% of all transplants have involved a deceased donor source, 42% came from a parent, with the remaining 10% coming from other living donors. Parents comprise 80.6% of living donors: a cross-classification of parent and child sexes (n=4,129 pairs with complete data) reveals that mothers comprise the majority of parent-donors (55.5%), fathers donate to sons 63.1% of the time, while mothers make 59.9% of their donation to sons (p=0.040). There have been 348 transplants between siblings, and 170 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. For these young sibling donors, 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 to 17 per year since then. Among deceased donor source transplants, 69 (1.6%) have come from donors less than 24 months old and 1020 (23.1%) from donors who were between 2 and 12 years of age; the use of deceased 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 deceased donor sources, compared to 0.9% (27/2,950) in transplants between 1992 and Of deceased donor source allografts, 12.5% were preserved by machine perfusion and 70.1% had cold ischemia times of 24 hours or less, with 17 (0.4%) exceeding 48 hours. The maximum cold time was 64.5 hours. Donor-specific transfusions were performed in 5.6% of living donor grafts but this procedure has been used only occasionally since The total number of random transfusions given to recipients differed by donor type: 49.2% of living donor graft recipients and 33.9% of deceased donor graft recipients had zero previous transfusions, while 13% and 27.9%, respectively, had more than five transfusions. The percent of patients without prior random transfusions has increased from 17% in 1987 (26.5% living and 9.6% deceased donor recipients) to 65.4% in 2005 (67.7% living and 62% deceased donor recipients). Time trends in the utilization of donor-specific and random transfusions are provided in Exhibit 2.2. To date, there have been 40 confirmed transplants across ABO blood group compatibility barriers out of 9,070 transplants with complete blood group data; there are 28 O recipient/a donor pairs, 4 O recipient/b donor pair, 4 B recipient/a donor pairs, 2 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 2-1

34 Transplantation 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 low (1:4) are associated with satisfactory graft outcome and are deserving of further study. Overall, 87.5% (7,936/9,070) of donor and recipient blood types were identical. Whereas blood group O is present in 56.4% of donors and 47.2% of recipients, blood group AB is present in 1.4% of donors and 3.8% 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, 77% 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 14% of cases. No matches in either the B or DR loci occurred in 37% of the transplants from deceased donor sources; a single locus match (of B and DR) occurred in 32%. Known matches of all 6 A, B and DR alleles occurred in 2.3% of deceased donor source transplants and in 3.4% 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 deceased donor. For children ages 6-12, the proportion receiving living donor transplants is similar to the proportion receiving deceased donor transplants. However, children 13 years of age are more likely to receive a deceased donor transplant. 2-2

35 Transplantation EXHIBIT 2.1 DONOR INFORMATION N (9837) % (100.0) Donor Source Live donor/parent Live donor/sibling Live donor/other related Live donor/unrelated Deceased donor Donor Age Living Deceased > Deceased Donor Source Transplants Machine Perfusion Used Cold Ischemia Time < 24 hours > 24 hours

36 Transplantation EXHIBIT 2.2 USE OVER TIME OF DONOR-SPECIFIC AND RANDOM BLOOD TRANSFUSIONS Living Donor 0 Random transfusions 1-5 Random transfusions >5 Random transfusions Donor-specific transfusions PERCENT TRANSPLANT YEAR Deceased Donor 0 Random transfusions 1-5 Random transfusions >5 Random transfusions PERCENT TRANSPLANT YEAR 2-4

37 Transplantation EXHIBIT 2.3 PERCENT HLA MISMATCHES HLA-A Living (n=5122) Donor Source Deceased (n=4697) HLA-B HLA-DR HLA-B and -DR HLA-A, -B, and -DR

38 Transplantation EXHIBIT 2.4 AGE AT TRANSPLANT AND DONOR SOURCE 2-6

39 Transplantation 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 initial day and dose 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 living donor transplant recipients had decreased from 47% in 2001 to 38% in Because of the changes in therapy in recent years, analyses are restricted to more recent transplants (>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 8% (of transplants) for OKT3 to 89% for prednisone. Methylprednisolone and azathioprine, when used, were typically initiated on the day of operation. Polyclonal antibody ATG was used in 17% of living donor and 26% of deceased source transplants, while the respective rates of monoclonal antibody usage are 33% and 37%. Cyclosporine was used for 56% of transplants and, of those, 26% began cyclosporine on Day 0, 27% on Day 1, and 38% 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 The rate of induction antibody use at transplant or one day post transplant, by transplantation year was as follows: 3-1

40 Transplantation PERCENT INDUCTION ANTIBODY, AT TRANSPLANT OR ON 1 DAY POST TRANSPLANT 1996 (n=625) 1997 (n=593) 1998 (n=540) 1999 (n=552) 2000 (n=427) 2001 (n=427) 2002 (n=487) 2003 (n=375) 2004 (n=343) 2005 (n=172) None OKT Basiliximab Daclizumab ATG/ALG Exhibit 3.4 presents immunosuppressive therapy dosages for patients with functioning grafts for selected drug combinations after Median daily prednisone doses decrease over the first 2 years after transplantation, while the percentage of transplanted patients receiving alternate day therapy increases from 6.5% at Month 6 to 15.9%, 27.6%, and 36.3% at Months 12, 24, and 48, respectively. Tacrolimus recipients receive lower steroid and higher MMF doses than those on cyclosporine. Continued slow increases in alternate day steroid use are observed at 6 years (45.2%). At 5 years post transplant, 37.6% of living donor versus 39.1% of deceased 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±0.11 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 , from 27% of living donor and 24% of deceased donor organ recipients, to 1% in each group in The regimen of prednisone, tacrolimus, and mycophenolate mofetil has become more popular. It is used in 48% of living donor and 53% of deceased donor organ transplant in , compared to about 12% of all transplants in

41 Transplantation 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=593) 1998 (N=542) 1999 (N=553) 2000 (N=451) 2001 (N=491) 2002 (N=445) 2003 (N=378) 2004 (N=345) 2005 (N=174) Cyclosporine Tacrolimus Mycophenolate Azathioprine Sirolimus Substantial increases in tacrolimus, mycophenolate mofetil, and sirolimus usage are observed, with a significant decrease in azathioprine usage. Azathioprine usage has decreased sharply from 34% in 1997 to 2% in The majority of sirolimus therapy (90%) was initiated within the first two days post-transplant. The mean and median dosages were 5.5 and 4.0 mg/m 2, respectively. Cyclosporine was used in 78% of the 1997 transplants at Day 30, and it continues to show a decline in utilization to 8.7% in 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 32% of the patients received combination immunosuppressives with prednisone, cyclosporine, and MMF, compared to approximately 14% of patients with prednisone, cyclosporine and azathioprine. Note that therapy strategies appear similar for deceased donor 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 deceased donor graft donors. Because of the differential graft survival in black and non-black patients, cyclosporine blood levels have been examined. At Day 30 mean and 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

42 Transplantation median cyclosporine level was 183 ng/ml (versus 177 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 WHERE TRANSPLANT YEAR IS >1995 Method Black Other Cyclosporine HPLC 161.5/169.4± /149.8±4.0 TDX 201.5/235.6± /227.4±5.3 Monoclonal RIA-specific 146/178.5± /184.8±5.5 TAC HPLC 5.9/6.4± /8.8±1.7 IMX 6.2/6.5± /6.3±0.2 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 deceased donor 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 54% of both living donors and deceased donor source recipients with minimal decreases thereafter. At one year, prophylactic antibiotics are used in 43% of hemolytic uremic syndrome patients and in 47% of those with focal segmental glomerulosclerosis, versus 68% of patients diagnosed with reflux nephropathy and 68% with obstructive uropathy. An anti-convulsant medication was given initially to 6% of the transplant recipients, with no difference observed among recipients of deceased donor organs versus living donor organ recipients. 3-4

43 Transplantation EXHIBIT 3.1 MEDICATION DATA - FIRST 30 DAYS TRANSPLANTS AFTER 1995 Therapy Percent Treated Median Day of Initiation Median Initial Dose (mg/kg/d) Percent Treated Day 30 Median Day 30 Dose (mg/kg/d) Prednisone Methylprednisolone Cyclosporine Azathioprine Tacrolimus Mycophenolate Mofetil* ATG/ALG Monoclonal Antibody 35 0 OKT Basiliximab Daclizumab Sirolimus** *Median initial and Day 30 daily dose in mg per body surface area were and mg/m 2 /Day respectively. **Median initial dose in mg per body surface area was 3.1 mg/m