A decade of living donor transplantation inNorth American children: The 1998 AnnualReport of the North American PediatricRenal Transplant Cooperative Study(NAPRTCS)*

McDonald R, Donaldson L, Emmett L, Tejani A. A decade of livingdonor transplantation in North American children: The 1998 AnnualReport of the North American Pediatric Renal Transplant CooperativeStudy (NAPRTCS).Pediatr Transplantation 2000 : 4: 221±234. # Munksgaard, 2000

Abstract: This report of the North American Pediatric Renal TransplantCooperative Study (NAPRTCS) covers the years 1987±1997, andanalyzes data on 2904 living donor (LD) transplants performed in 2779patients. Since 1991, approximately 300 LD transplants have beenperformed each year at the participating centers of the NAPRTCS.Caucasian children account for 72% of all LD recipients while African±American children constitute only 11%. There has been a gradual declinein the number of transplants performed in children under the age of6 years from a peak of 30% in 1987, to 21% in 1997. Preoperativecalcineurin inhibitor therapy has dropped from 71% in 1987 to 38% in1997. Through 1996, at six months post-transplant 97% of recipientswere receiving prednisone, 88% were maintained on cyclosporin A, and79% were receiving azathioprine. Of patients transplanted in 1997, 47%are maintained on mycophenolate and 10% are maintained ontacrolimus. By day 15, 20% of index transplant patients have had anacute rejection and by the end of the ®rst year 47% have had a rejectionepisode. Among patients transplanted in 1995±1996, 40% had a rejectionin the ®rst year. Nine per cent of rejection episodes are irreversible inchildren under 2 years of age and 5% of the episodes are irreversible in 2±5-year-old children. Estimated graft survival probability at 1 year is 91%,at 3 years it is 84% and at 5 years it is 78.5%. Rejection accounts for 33%of graft loss and recurrence constitutes another 10%. In¯uentialprognostic variables for graft survival are race (African±American vs.others, relative risk (RR) 5 2.0, p , 0.001), . 5 random transfusions

Ruth McDonald1, Lynn Donaldson2,Lea Emmett3 and Amir Tejani3

1Children's Hospital, Seattle, Washington, USA,2The EMMES Corporation, Potomac, Maryland,USA, 3New York Medical College, Valhalla, NewYork, USA

Key words: renal ± transplantation ± pediatric ±

living donor

Amir Tejani MD, NAPRTCS, 19 Bradhurst Ave., Box

10, Hawthorne, NY 10532, USA

Tel.: + 1 914-345-0414

Fax: + 1 914-345-0229

E-mail: atejani@aol.com

Accepted for publication 5 January 2000

Abbreviations: CD, cadaver donor; CsA, cyclosporin A; DGF, delayed graft function; ESRD, end-stage renal disease; FSGS, focal segmental

glomerulosclerosis; HLA, human leukocyte antigen; IgA, immunoglobulin A; LD, living donor; MMF, mycophenolate mofetil; NIH, National

Institutes of Health; PRA, panel-reactive antibodies; RR, relative risk; RhGh, recombinant growth hormone; SDS, standard deviation score;

TGF, transforming growth factor.

*The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) is a voluntary collaborative effortcomprising over 150 pediatric renal disease treatment centers in the United States, Canada, Mexico and Costa Rica. It issupported by major, unrestricted educational grants from Novartis, AMGEN, and Genentech. Participating NAPRTCScenters are listed in Appendix 1.

Pediatr Transplantation 2000: 4: 221±234

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Copyright # Munksgaard 2000

Pediatric TransplantationISSN 1397±3142

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(RR 5 1.6, p , 0.001), T-cell induction therapy (RR 5 0.78, p 5 0.01),and later year of entry (1989±1990 vs. 1994±1995, RR 5 0.95, p5 0.004). Patient survival at 1 and 3 years was 97% and 96.5%,respectively, however, the 3-year patient survival of children under2 years was 89%. The mean height de®cit at baseline (n 5 2677) was ±1.86, at 1 year post-transplant (n 5 1459) it was ± 1.80, and at 5 yearspost-transplant (n 5 592) it was ± 2.06. This report, devoted speci®callyto LD pediatric transplants, raises issues regarding the use ofimmunosuppression such as preoperative calcineurin inhibitors and T-cell antibodies. Studies to address the high incidence of chronic rejectionand recurrence of original disease are necessary. Additional areas ofconcern are the high infant mortality and continued growth retardationpost-transplantation.

For several years now the NAPRTCS haspublished annual reports. In the early years,when the registry consisted of only the transplantcomponent and the database was small (1) thewriting of the report could be condensed into ®veor six printed pages (2). As the transplant datamatured the annual report became larger (3), andwith the inclusion of the dialysis component acombined transplant±dialysis report was pub-lished for 1993 (4) and for 1994 (5). By 1995 theannual report consisted of the transplant, thedialysis and the chronic renal insuf®ciencycomponents and required ingenuity to be wieldedinto a single report (6).

The pediatric nephrology community is largeand diverse, and it became obvious that a singlereport covering all three components was notuniversally appreciated; therefore from 1996 theannual report was published in two separatepublications ± one dealing with transplantationalone (7, 8) and the other combining the dialysisand chronic renal insuf®ciency components (9).This system appears to have worked well,however, when renal transplantation is reviewed,CD transplantation, because of its inferior graftsurvival and post-operative problems, occupies adisproportionately larger section. In NorthAmerica the magnitude of living donation forpediatric renal transplantation far exceeds that ofother countries. Because of its superior graftsurvival however, the severe problems in thiscategory tend to be masked; delayed graftfunction, chronic rejection, and disease recur-rence need to be addressed. It is with this intentthat we present this annual report separately forLD pediatric transplantation.

Materials and methods

Materials and methods have been reportedpreviously (2). Brie¯y, the NAPRTCS has 150participating medical centers in the United States,

Canada, Mexico and Costa Rica. Each center hasa principal investigator, associate investigatorsand data coordinators. On a voluntary basis thecenters regularly submit data, based on theirpatient populations, on (i) children with chronicrenal insuf®ciency; (ii) children undergoing dia-lysis; and (iii) children who have received a renaltransplant since 1987. The data on pediatrictransplantation are derived from 73 centers whichcollect information at the time of and at day 30post-transplantation. The initial informationconsists of recipient age, gender, race, originaldisease leading to ESRD status, type andduration of dialysis, PRA level, HLA typing,and height and weight at the time of transplanta-tion. Donor information consists of type, age,gender, race, cold and warm ischemia time, andHLA type. The information collected at 30 dayspost-transplantation consists of graft outcome,initial immunosuppressive therapy, complica-tions and rehospitalizations. Thereafter informa-tion is collected on each recipient every sixmonths regarding height, weight, serum creati-nine, type and dose of immunosuppressivetherapy, and the use of other concomitantmedications. In addition extensive informationis obtained for each rejection episode, withseparate data collected for graft failure andpatient demize.

Data are organized to provide analyses ofpatient and graft survival and morbidity, and therelationship of these endpoints to such variablesas graft source, immunosuppressive therapy andselected patient characteristics, i.e. age, race,primary renal disease, degree of HLA mismatch,and dialytic modality. At each six-month follow-up standardized height and weight Z scores arecalculated by subtracting the appropriate popu-lation age- and gender-speci®c means and divid-ing by the standard deviation for the normalpopulation. Standard univariate and multivariatestatistical methods are used for data analysis.Kaplan±Meir product limit estimates of graft

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survival and acute rejection incidence are con-structed and tested using the log-rank test.Relative risks of graft failure and acute rejectionare derived from Cox proportional hazardsregression models that are adjusted for selectedpatient and event characteristics.

Results

Donor characteristics

Table 1 displays the annual number of LDtransplants performed each year since the incep-tion of the registry. Documentation for 1997 isobviously incomplete and the numbers will berevised upward as additional data are received.There has been a numerical but not statisticalincrease in LD transplantation in the 1990 scompared with the numbers seen in earlier years,and the number of LD transplants appears to beconstant at around 300 per year since 1991. It isunclear whether this high volume is related toscarcity of cadaver kidneys or a re¯ection of thebetter graft survival of LD kidneys. In 84% of thetransplants a parent was the donor; motherscomprise 56% of this donor pool. In 26 patientsboth parents donated the kidney in a sequentialmanner. There were 212 sibling transplants, and12 of the sibling donors were under 18 years ofage. In addition there were 200 other live relatedtransplants and 43 live unrelated transplants.Among the LDs 81% were at least one-haploi-dentical, but in 9% there was only a single HLA-Bor HLA-DR match.

Recipient characteristics

There were 2904 LD transplants performed in2779 patients. Figure 1 displays race-, gender-and age-speci®c data over the last 10 years for therecipients. The preponderance of Caucasianchildren in the ranks of LD recipients (72%) isclear. Also of note is the gradual decline in thenumber of transplants performed in childrenunder the age of 6 years, from a peak of 30% in1987 to 21% in 1997.

Prior treatment. Dialytic therapy prior to theinitiation of transplantation is the norm for arenal transplant recipient, however, 35% of allLD transplants were performed in patients whohad never received maintenance dialysis.Hemodialysis and peritoneal dialysis each werecarried out in about a third of the patients.

Primary diagnosis. Table 2 lists the 10 mostcommon primary diagnostic categories leading

to ESRD and transplantation. Developmentaldisorders such as obstructive uropathy and dys-plasia are the structural lesions accounting foralmost a third of all transplants. When com-pared with CD there is a decrease in the inci-dence of systemic immunological disease as acause for ESRD, whereas membranoprolifera-tive glomerulonephritis does appear in the listof most common disorders.

Comment

There are numerous differences in the character-istics of both the donor and recipient of LDtransplants compared with CD transplants. Oneof the striking features of LD transplantation isthe high rate among Caucasian children, whoaccount for 63.5% of all recipients in the registry;of the LD transplants alone the rate is 72.4%. Incontrast children of African±American origin,who comprise 16% of all transplant recipients,constitute only 10.9% of LD recipients. Livedonation for Hispanic children remains compar-able with their numbers in the registry. Anotherimportant difference is the primary diagnosis inthe two types of transplants. Developmentaldisorders account for a higher percentage oftransplants in the LD group, whereas disorders(such as congenital nephrotic syndrome) whichdo not qualify among the 10 most commondiagnostic categories, have a higher incidence.Among acquired disorders, FSGS continues to bethe most common, but diseases such as membra-noproliferative glomerulonephritis are more fre-quent diagnoses in the LD patients. Some of thesediscrepancies between LD and CD transplantscan be explained by the racial mix. MoreCaucasian children receive a LD transplant,and developmental disorders, congenital nephro-tic syndrome and re¯ux nephropathy are morefrequently seen in the Caucasian population. Incontrast the dearth of systemic immunologicdisease as a diagnosis in the LD category can alsobe ascribed to the racial mix of the population.An additional interesting ®nding is the markedpaucity of patients in the diagnostic category ofIgA nephropathy ± an entity extremely commonin the Caucasian population, indicating that thisglomerular lesion is a rare cause for ESRD inchildren.

Pediatric LD recipients also differ in their priortherapy. Whereas peritoneal dialysis is thepretransplant modality in the overall majorityof children in our registry, for LD recipients bothperitoneal and hemodialysis are used in about athird of the patients, and the remaining thirdundergo a transplant without ever being dialyzed.

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223

Detailed analysis of the pre-emptive transplantcohort, which included a specialized question-naire (10), revealed that pre-emptive transplantwas most commonly requested ®rst by theparents, and secondly recommended forimproved growth by the nephrologist becausedialysis has been known to further decelerategrowth (11).

Immunosuppression

Preoperative immunosuppressive therapy, con-sisting of the administration of CsA from 3 to7 days prior to transplantation, was employed in55% of LD transplants. Overall however, thisform of pretransplant immunosuppression hasbeen reduced from a peak of 71% in 1987±1988,to 38% in 1996±1997. Prophylactic T-cell anti-body, in the form of either ATG/ALG or OKT3,was utilized in 37% of LD transplants. At day 30post-transplant 94% of patients were receivingprednisone, 88% were being maintained on CsA,and 82% were receiving azathioprine. The relativefrequency of these three drugs underwent littlealteration year to year through 1996. At sixmonths post-transplant, 97% of patients werereceiving prednisone, 89% were being maintainedon CsA and 79% were receiving azathioprine. At

5 years post-transplant the ®gures were 95%, 86%and 83%, respectively.

There is substantial reduction in the dosing ofboth prednisone and CsA over 5 years of graftfunction. The mean daily dose of prednisone atsix months post-transplant was 0.25 mg/kg, andwas reduced to 0.15 mg/kg at 5 years post-transplant. Thirty-two per cent of patients witha functioning graft at 5 years post-transplant aremaintained on alternate-day steroid therapy. Themedian CsA daily dose was 7 mg/kg at sixmonths post-transplantation, and was reducedto 4.85 mg/kg at 5 years. In recent years theintroduction of tacrolimus and MMF hasresulted in changes in combination strategies.Of the LD recipients transplanted in 1997, 47.5%are maintained on MMF and 10% are maintainedon tacrolimus.

Comment

One primary purpose of providing a separatereport on LD transplants is to stimulate discus-sion on immunosuppressive practices in thisgroup. For example, 38% of all patients continueto receive preoperative CsA. There are no data tosupport or suggest that prophylactic calcineurininhibition is bene®cial to the graft. There areretrospective data to support the use of prophy-lactic T-cell induction therapy in LD transplants.In a proportional hazards model the use of T-cellantibody on days 0 or 1 was associated withincreased LD graft survival (RR 5 0.78), how-ever, only 38% of the patients in our reportreceived such therapy. Presumably a concern withthe prophylactic use of T-cell antibody is theincreased incidence of malignancies (12). Thesafety and ef®cacy of prophylactic T-cell anti-body can only be determined in a prospectivestudy. An on-going NAPRTCS prospectiverandomized trial of induction therapy hasenrolled over 290 patients and when completedshould provide valuable information.

There are a number of other issues in LDtransplant immunosuppression. Previous studiesfrom the NAPRTCS (13) have suggested thattriple drug therapy may not be of particularbene®t for LD transplants, yet over 70% ofpatients at 5 years post-transplant continue toreceive triple therapy. There is concern regardingthe maintenance dose and the mode of adminis-

Table 1. Number of patients (Pts) and transplants (Tx) by year

1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 Total

Pts (n) 234 213 222 218 282 283 303 254 317 274 179 2779Tx (n) 234 215 232 225 301 295 315 271 338 292 186 2904

Per

cen

t

Transplant year

% male

% white

% recipient age<6yr

Fig. 1. Selected characteristics by year of registration.

McDonald et al.

224

tration of prednisone. At 5 years post-transplantthe median dose of prednisone in LD patients(0.15 mg/kg) is identical to the median dose forCD transplants. Considering that 81% of all LDgrafts are one-haploidentical would it not follow

that LD recipients could be maintained on lowerdoses of prednisone than CD patients? At 5 yearspost-transplant only 32% of these patients are onalternate-day therapy. Data from the NAPRTCS(14) have shown that graft survival of patients onalternate-day therapy is no different from that of

Table 2. Most common primary diagnostic categories

Primary diagnosis Number Per cent

Obstructive uropathy 510 18.4Aplastic/hypoplastic/dysplastic kidneys 427 15.4Focal segmental glomerulosclerosis 289 10.4Re¯ux nephropathy 172 6.2Chronic glomerulonephritis 105 3.8Medullary cystic disease/juvenile nephronophthisis 92 3.3Congenital nephrotic syndrome 85 3.1Polycystic kidney disease 82 3.0Syndrome of agenesis of abdominal musculature 81 2.9Membranoproliferative glomerulonephritis type I 72 2.6

Table 3. Frequency of acute rejections

Number Per cent

All transplants 2905 100.0Acute rejections (n)

0 1431 49.31 763 26.32 376 12.93 176 6.1i 4 159 5.5

Time (months)

Recipient age HLA-DR mismatches

ATG/OKT3 administration Recipient race

ATN Prior random transfusion

Per

cen

t re

ject

ion

Fig. 2. Time to ®rst rejectionepisode by selected characteristics.

A decade of LD transplantation

225

patients on daily prednisone. Should all LDrecipients receive alternate-day therapy to bene®tgrowth? It has been documented that at 2 yearspost-transplant growth is similar in LD and CDpatients (15), therefore should selected LDpatients be withdrawn from steroid treatment?Retrospective analyses of pooled data fromtransplant centers all around the country, aspresented here, cannot answer these questions.However a NAPRTCS multicenter, randomized,double-blind, prospective study, designed toenroll 600 patients in a steroid withdrawal trial,has been funded by the NIH and will be initiatedin the coming year. When completed, this largestudy, involving over 50 centers in NorthAmerica, should answer questions regarding thesafety of steroid withdrawal and its bene®cialeffects, if any.

Acute rejections

Frequency, time to ®rst rejection

In this report a rejection is de®ned as a rise inserum creatinine and the need for antirejectiontherapy. Tables 3 and 4 illustrate rejection ratiosin terms of frequency and age-speci®city. Less

than half of the total recipients of a LD kidney(49.3%) are recorded as not having undergone arejection episode. Rejection ratio is lowest inchildren under 2 years of age, and interestinglyhighest in those between 6 and 12 years of age. InFig. 2 time to ®rst rejection by selected categoriesis shown, whereas Fig. 3 shows the same bybiannual cohort. Figure 4 shows comparativetime to ®rst rejection for CD and LD kidneys.During the ®rst few weeks post-transplant, therejection patterns for the two groups areidentical. At day 15, 20% of both index patientgroups have had an episode of rejection, andby day 30, 28% of LD index kidneys have had arejection. By the end of the ®rst year 47% of LDrecipients have had a rejection episode. Table 5depicts relative risk factors of ®rst rejectionepisode and Table 6 depicts 12-month probabil-ity of ®rst rejection by transplant year.

Rejection outcome

Nine per cent of rejection episodes in childrenunder 2 years of age resulted in graft failure orpatient death and 5% of rejection episodes amongchildren 2±5 years old had a similar outcome.When the analysis was restricted to the ®rst acuterejection episode, 13% of LD recipients under2 years of age went on to irreversible rejection.

Comment

There has been a steady decrease in the 12-monthprobability of ®rst rejection by transplant year,however, 40% of LD recipients in 1995±1996 stillhad their ®rst rejection within the ®rst year. Datafrom the NAPRTCS have shown that a single

Per

cen

t re

ject

ion

Time (months)

1987–19881989–19901991–19921993–19941995–1996

Fig. 3. Time to ®rst rejection by bi-annual cohort.

Per

cen

t re

ject

ion

Time (months)

living donorcadaver donor

Fig. 4. Time to ®rst rejection episode by allograft source.

Table 4. Acute rejection ratios by age

Transplants (n) Rejections (n) Rejection ratio

Total 2905 2846 0.98Recipient age (yr)

0±1 215 138 0.642±5 480 429 0.896±12 997 1093 1.10. 12 1213 1186 0.98

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episode of acute rejection increases the RR for thedevelopment of chronic rejection three-fold (16)and chronic rejection is the most common causefor eventual graft failure, accounting for over33% of all graft losses. Reviewing the RR tablefor graft failure it is apparent that preoperativeimmunotherapy does not provide protection,however, absence of the use of T-cell antibodyfor induction does increase the risk. As pointedout earlier, only 38% of LD recipients receive T-cell induction therapy. The use of OKT3 isassociated with cytokine release syndrome, whichcan be negated by using one of the newer chimericIL-2r antibodies. Can universal use of suchinduction therapy reduce the incidence of earlyacute rejection? Retrospective analysis shownhere can only pose the question, however, a newlyfunded prospective study of the NAPRTCS isdesigned to use IL-2r induction therapy on allpatients and may provide a speci®c answer.

The rate of irreversible graft failure owing toacute rejection in infants and toddlers receiving aLD graft is of great concern. It has beensuggested that this results from an age-speci®cheightened immune response (17) or the inabilityto make an early diagnosis (18). The analysis ofsurveillance biopsies taken on days 5 and 12 post-transplant in the current NAPRTCS NIH-sponsored induction therapy study (19) mayprovide a better understanding of this vexingproblem.

Graft survival

Mean follow-up of patients with functioninggrafts is 41 months. Estimated graft survivalprobability at 1 year is 91%, at 3 years is 84%,and at 5 years is 78.5%. For comparison, Fig. 5depicts graft survival for CD and LD donors.Starting with a 10% superior graft outcome at1 year the graft survival advantage of LDtransplants rises to 15% at 7 years post-trans-plant. Figure 6 depicts LD graft survival byselected characteristics such as recipient age, race,transfusion history, and T-cell induction therapy.In¯uential prognostic variables for graft survivalare race (African±American vs. other, RR 5 2.0,p , 0.001) and . 5 transfusions (RR 5 1.6, p, 0.001). Prophylactic induction therapy with aT-cell antibody is associated with signi®cantlyincreased graft survival (RR 5 0.78, p 5 0.01).When reviewed by original disease (Fig. 7) FSGShas the worst outcome of all disorders. Lastly, therole of delayed graft function (DGF; previouslyreferred to as acute tubular necrosis) is shown inFig. 8. We de®ne DGF as the need for dialysisduring the ®rst week post-transplant; 159 of the2896 transplants (5.5%) were associated withDGF. Higher rates were seen in patients with . 5

Table 5. Relative risk (RR) of ®rst rejection episode

Characteristic RR p-value

Recipient race (Afric.±Amer. vs. Other) 1.32 0.001Recipient age (, 24 mo) 0.81 0.057HLA-DR mismatch

1 vs. 0 1.63 , 0.0012 vs. 0 1.31 0.001

No induction therapy 1.31 , 0.001Prior random transfusions

1±5 vs. 0 0.93 0.194. 5 vs. 0 1.13 0.056

Donor-speci®c transfusions 1.07 0.422Pre-op immunotherapy 0.97 0.636

mo, month(s)

Table 6. 12-Month probability (Pr) of ®rst rejection, by transplant year

Transplant year Pr SE

1987±88 0.556 0.0241989±90 0.530 0.0241991±92 0.467 0.0211993±94 0.441 0.0221995±96 0.393 0.022

Table 7. Per cent one-year graft survival by bi-annual cohort

Year %

1987±88 88.11989±90 90.71991±92 92.01993±94 91.31995±96 93.0

Per

cen

t gr

aft

surv

ival

Time (years)

living donorcadaver donor

Fig. 5. Per cent graft survival by allograft source.

A decade of LD transplantation

227

random transfusions, repeat transplants and inAfrican±American children. The RR in LDtransplants for the development of graft failureowing to DGF is 3.1. The study improvement inLD graft survival by annual cohorts is shown inTable 7 and in Fig. 9. When the year of entry isincluded in the proportional hazards model, alinear trend in improvement in graft survival isseen (RR 5 0.95, p 5 0.004).

Comment

Whereas it is salutary to note the steadyimprovement in LD graft survival from 1987 to1996, one has to realize that the excellent 1-yeargraft survival does not translate into prolongedgraft survival. Chronic rejection accounts for 33%

of LD graft loss and at 7 years post-transplantthe probability of graft survival is only 72%. With1-year graft survival approaching 93% for the1995±1996 cohorts it is clear that the currentcalcineurin inhibition-based immunosuppressivetherapy is unable to prevent chronic rejection.Chronic rejection is characterized by increasinginterstitial ®brosis. It has been shown thatproduction of the ®brogenic cytokine TGF-b1 isup-regulated in patients with chronic rejection(20), and calcineurin inhibitors, like CsA, tend tofacilitate TGF-b1 production (21). To achievelong-term graft survival of LD grafts, innovativestrategies may be necessary. One such strategy,utilizing costimulatory blockade without calci-neurin inhibition, has demonstrated inde®niterenal graft survival in the primate model (22).

Time (years)

Age Early ATG/ALG/OKT3 therapy

Race Transfusion history

Per

cen

t gr

aft

surv

ival

Fig. 6. Per cent graft survival byselected characteristics.

Table 8. Days hospitalized and causes at speci®ed intervals

Mo. 1±5(n 5 2356)

Mo. 6±11(n 5 2101)

Mo. 12±17(n 5 1854)

Mo. 18±23(n 5 1624)

Mo. 30±35(n 5 1244)

Mo. 42±47(n 5 920)

Mo. 54±59(n 5 662)

Days in hospitalmean 8.0 5.5 5.0 5.0 4.0 4.0 3.0median 13.5 9.4 9.1 7.5 7.6 6.3 6.5

Causes (%)Bacterial infect. 11.7 6.8 6.6 6.1 3.8 3.9 4.2Fungal infect. 0.8 0.2 0.2 0.2 0.2 0.1 0.3Viral infect. 13.2 7.1 4.7 4.9 4.2 2.8 4.2Rejection 23.9 9.5 6.6 6.6 5.8 3.8 4.2Hypertension 4.5 2.4 1.5 1.4 0.9 1.0 0.3Any reason 50.0 27.6 22.3 20.7 18.6 16.1 16.5

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Under an NIH grant this innovative approach,using humanized anti-CD40 ligand antibody(Biogen-hu5c8) as a primary immunosuppressantin LD transplantation, will shortly be tested in apilot project in selected centers of the NAPRTCS.

In reviewing causes of graft failure in LDtransplants an additional concern is recurrence oforiginal disease. A further analysis has shownthat these graft losses are primarily due tooxalosis and recurrent FSGS. A recentNAPRTCS abstract reviewing transplant out-come for oxalosis noted that the 2-year graftsurvival for LD transplants was 54%, comparedwith a 2-year CD graft survival of 77% (23). In anNAPRTCS abstract presented at the 18th AnnualMeeting of American Society of Transplantationit was noted that of 653 FSGS transplantpatients, graft loss owing to recurrence was27% in LD recipients, compared with 16% inCD recipients (p , 0.05) (24). While oxalosisaccounts for a very small percentage of CD

transplants, FSGS is the most common glomer-ular disorder leading to transplantation, andstrategies (25) to reduce graft loss to recurrentdisease among children who receive a LDtransplant are critical.

Morbidity, malignancy and mortality

We measure morbidity by the number ofhospitalization days. Table 8 displays the meanand median number of days spent in the hospitalfrom month 2 through month 59 at six-monthintervals for LD recipients with functioninggrafts. The table also displays the causes forhospitalization. After the ®rst year post-trans-plant the mean and median number of days spent

Per

cen

t gr

aft

surv

ival

Time (years)

Fig. 7. Per cent graft survival by diagnosis.

Per

cen

t gr

aft

surv

ival

Time (years)

no DGFDGF

Fig. 8. Post-week 1 graft survival by delayed graft functionstatus.

Per

cen

t gr

aft

surv

ival

Time (years)

1987–19881989–19901991–19921993–19941995–1996

Fig. 9. Per cent graft survival by bi-annual cohort.

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229

in the hospital are similar to those seen in CDrecipients. During the ®rst 3 years post-trans-plant rejection is the most common cause foradmission, however, during the 4th and5th years, infections, both bacterial and viral,have an equal frequency. A total of 35 malig-nancies, the majority of which were post-trans-plant lymphoproliferative disorders, werereported in 2659 LD recipients, which is lessthan the 57 malignancies reported in 2514 CDrecipients.

For primary LD recipients, 1-year patientsurvival was 97%, 2-year patient survival was96.5% and the 5-year patient survival was 94.5%.Comparable CD primary graft (2356) patientsurvival rates were 96.3%, 95.2% and 91.4%,respectively. Of the 2659 LD recipients 119 (4.5%)died, with infection being the most commoncause at 40%. Malignancy at 10% and cardio-pulmonary death at 13% were other commoncauses. When patient survival is reviewed by age,infants under 2 years have the worst outcome.

Comment

The usual age-related morbidities and mortalitiesof adults, such as myocardial infarction, strokeand organ-speci®c malignancies, are not observedin children and therefore patient survival post-transplantation is within a respectable range.Thus, in the main, increased attention must bedirected towards producing long-term graftsurvival that approaches patient survival in LDrecipients. A 3-year infant survival rate of 89%however, compared to the 96% overall survivalrate, is clearly unacceptable. In a 1994 study ofthe NAPRTCS that covered 1200 LD patients,we tried to identify factors that in¯uencemortality post-transplantation (26) and observedthat the age range 0±2 years was a risk factor(RR 5 1.35). In the current report of 2659 LDrecipients there were 215 infants transplanted, of

whom 24 have died. This is a high rate of loss andneeds further detailed analysis.

Growth post-transplantation

At each six-month follow-up we collect data onheight. From these data standardized Z scores arecalculated by subtracting the appropriate popu-lation age- and sex-speci®c means and dividing bythe standard deviation of the normal population.Table 9 depicts baseline, 1-year and 5-year Zscores for patients with LD transplants.

The mean height de®cit of 2677 patients attransplantation was ± 1.86 and at 1 year post-transplant the mean height de®cit for 1459patients with a functioning graft was ± 1.80; at5 years post-transplant for the 592 children witha functioning graft it had worsened to ± 2.06.When reviewed by gender the ®rst-year improve-ment is restricted only to males. Children under2 years of age have the maximum bene®t, with again of 0.75 SDS during the ®rst year, andchildren in the range 2±5 years also exhibitcatch-up growth, with a gain of almost 0.75SDS by 5 years.

Comment

Children under the age of 6 years comprise lessthan a quarter of the total LD transplantpopulation. For the remaining 75% there is noimprovement in the mean baseline de®cit. Earlierspecialized studies of the NAPRTCS havereviewed post-transplant growth at 24 months(27) at 36 months (28) and at 54 months post-transplant (29). At 54 months catch-up growth,de®ned as a gain of at least 0.5 SDS, was seen inonly 19% of 6±12 year-olds and in just 6% of 13±17 year-olds (29). It is generally presumed that aLD recipient will show better growth post-transplant. Earlier studies did support this

Table 9. Mean Z-scores (with SE) for selected recipient characteristics

Baseline(n 5 2677)

Month 24(n 5 1459)

Month 60(n 5 592)

Total ± 1.86 (0.03) ± 1.80 (0.04) ± 2.06 (0.06)Sex

male ± 1.94 (0.04) ± 1.84 (0.04) ± 2.07 (0.07)female ± 1.74 (0.05) ± 1.74 (0.07) ± 2.05 (0.00)

Age (yr)0±1 ± 2.39 (0.12) ± 1.76 (0.11) ± 1.67 (0.17)2±5 ± 2.49 (0.07) ± 1.88 (0.08) ± 1.74 (0.13)6±12 ± 1.94 (0.05) ± 1.93 (0.06) ± 2.34 (0.08)13±17 ± 1.44 (0.05) ± 1.61 (0.07) ± 1.94 (0.14)

Prior transplantno ± 1.81 (0.03) ± 1.75 (0.04) ± 2.03 (0.06)yes ± 3.00 (0.18) ± 2.75 (0.20) ± 2.48 (0.26)

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notion. When the ®rst population of 300 childrenwith a functioning graft was evaluated, the LDrecipients (n 5 165) showed an improvement of0.22 SDS compared with 0.13 SDS for the CDgroup (n 5 135) (27). At 54 months the LDgroup (n 5 300) showed an improvement of 0.15SDS compared with 0.08 for the CD group.However, as the present report shows, overallthere was no improvement in the baseline de®citfor the 592 children in the LD group with afunctioning graft at 5 years post-transplant.

Continued growth retardation post-transplantis multifactorial (27). Each rejection episode takesits toll and a rejection episode that is notcompletely reversed further decelerates growth.Using a repeated measures analysis with annualtime-varying creatinine measurement, we havepreviously observed that a 1-mg/dL rise in serumcreatinine is associated with a decrease of ± 0.15in the Z score. The steroid-induced inhibition ofgrowth has been well-described and the bene®cialeffect of alternate-day steroid therapy in selectedpatients has also been documented (14). Futurestrategies for transplant immunosuppression mayfocus on a steroid-free milieu, however, for alarge number of children with a functioningtransplant and growth retardation the use ofRhGh is the only solution. The currentNAPRTCS randomized trial, which will continuefor at least another year, should provide valuableinformation regarding the safety and ef®cacy ofRhGh post-transplantation.

References

1. ALEXANDER SR, ARBUS GS, BUTT KMH, et al. The 1989Report of the North American Pediatric RenalTransplant Cooperative Study. Pediatr Nephrol 1990:4: 542±553.

2. MCENERY P, ARBUS G, STABLEIN DM, TEJANI A. Renaltransplantation in children: a Report of the NorthAmerican Pediatric Renal Transplant CooperativeStudy (NAPRTCS). N Engl J Med 1992: 326:1727±1732.

3. MCENERY PT, ALEXANDER SR, SULLIVAN EK, TEJANI A.Renal transplantation in children and adolescents: the1992 Annual Report of the North American PediatricRenal Transplant Cooperative Study (NAPRTCS).Pediatr Nephrol 1993: 7: 711±720.

4. AVNER E, CHAVERS B, SULLIVAN EK, TEJANI A. Renaltransplantation and chronic dialysis in children andadolescents: the 1993 Annual Report of the NorthAmerican Pediatric Renal Transplant CooperativeStudy. Pediatr Nephrol 1995: 9: 61±73.

5. KOHAUT E, TEJANI A. The 1994 Annual Report ofthe North American Pediatric Renal TransplantCooperative Study (NAPRTCS). Pediatr Nephrol1996: 10: 422±434.

6. WARADY BA, HEBERT D, SULLIVAN EK, ALEXANDER SR,TEJANI A. Renal transplantation, chronic dialysis, and

chronic renal insuf®ciency in children and adolescents.The 1995 Annual Report of the North AmericanPediatric Renal Transplant Cooperative Study. PediatrNephrol 1997: 11: 49±64.

7. FELD LG, STABLEIN DM, FIVUSH BA, HARMON WE,TEJANI A. Renal transplantation in children from 1987±1996: the Annual Report of the North AmericanPediatric Renal Transplant Cooperative Study(NAPRTCS). Pediatr Transplantation 1997: 1: 146±162.

8. BENFIELD MR, MCDONALD R, SULLIVAN EK, STABLEIN

DM, TEJANI A. The 1997 Annual Renal Transplantationin Children Report of the North American PediatricRenal Transplant Cooperative Study (NAPRTCS).Pediatr Transplantation 1999: 3: 152±167.

9. LERNER GR, WARADY BA, SULLIVAN EK, ALEXANDER SR.Chronic dialysis in children and adolescents: the 1996Annual Report of the North American Pediatric RenalTransplant Cooperative Study. Pediatr Nephrol 1999:13: 404±417.

10. TEJANI A, INGULLI E. Growth in children post-trans-plantation and methods to optimize post-transplantgrowth. Clin Transplantation 1991: 5: 214±218.

11. TRACHTMAN H, HACKNEY P, TEJANI A. Pediatric hemo-dialysis: a decade's (1974±84) perspective. Kidney Int1986: 30: S15±S22.

12. OPELZ G, HENDERSON R FOR THE COLLABORATIVE STUDY.Incidence of non-Hodgkin lymphoma in kidneyand heart transplant recipients. Lancet 1993: 342:1514±1516.

13. TEJANI A, STABLEIN DM, FINE RN, ALEXANDER SR.Maintenance immunosuppression therapy and outcomeof renal transplantation in North American children ± areport of the North American Pediatric RenalTransplant Cooperative Study. Pediatr Nephrol 1993:7: 132±137.

14. JABS K, SULLIVAN EK, AVNER ED, HARMON WE.Alternate day steroid dosing improves growth withoutadversely affecting graft survival or long-term graftfunction: a report of the North American PediatricRenal Transplant Cooperative Study (NAPRTCS).Transplantation 1996: 61: 31±36.

15. TEJANI A, SULLIVAN EK. Long-term follow-up of growthin children post-transplantation. Kidney Int 1993: 44:S56±S58.

16. TEJANI A, CORTES L, STABLEIN DM. Clinical correlates ofchronic rejection in pediatric renal transplantation: areport of the North American Pediatric RenalTransplant Cooperative Study (NAPRTCS).Transplantation 1996: 7: 1054±1058.

17. DENNY T, YOGEV R, GELMAN R, et al. Lymphocytesubsets in healthy children during the ®rst ®ve years oflife. JAMA 1992: 267: 1484±1488.

18. ETTENGER RB, BLIFELD C, PRINCE H, et al. The pediatricnephrologist's dilemma: growth after renal transplanta-tion and its interaction with age as a possibleimmunologic variable. J Pediatr 1987: 111: 1022±1025.

19. BENFIELD MR, HERRIN J, FELD L, ROSE SR, STABLEIN

DM, TEJANI A. Safety of kidney biopsy in pediatrictransplantation: a report of the Controlled ClinicalTrials in Pediatric Transplantation (CCTPT) trial ofinduction therapy study group. Transplantation 1999:67: 544±547.

20. SUTHANTHIRAN M. Molecular analyses of human renalallografts: differential intragraft gene expression duringacute rejection and chronic rejection. Kidney Int 1997:51: S15.

21. PRASHAR Y, KHANNA A, SEHAJPAL P, SHARMA VK,

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SUTHANTHIRAN M. Stimulation of transforming growthfactor-b1 transcription by cyclosporine. FEBS Lett1995: 358: 109.

22. KIRK AD, BURKLY LC, BARRY DS, et al. Treatment withhumanized monoclonal antibody against CD154 pre-vents acute renal allograft rejection in nonhumanprimates. Nature Med 1999: 5: 686±693.

23. TEJANI A, SULLIVAN EK. Should living-related renaltransplants be performed for primary oxalosis?Presented at the 32nd Annual Meeting of theAmerican Society of Nephrology, Miami, FL,November, 1999.

24. BAUM MA, STABLEIN DM, PANZARINO V, TEJANI A,HARMON WE, ALEXANDER SR. Graft loss due torecurrence eliminates the graft survival advantage ofliving donor over cadaveric renal transplants in childrenwith focal segmental glomerulosclerosis: a report ofthe North American Pediatric Renal Transplant

Cooperative Study (NAPRTCS). Transplantation1999: 67: S234.

25. INGULLI E, TEJANI A, BUTT KMH, et al. High dosecyclosporin A therapy in recurrent nephrotic syndromefollowing renal transplantation. Transplantation 1990:49: 219.

26. TEJANI A, SULLIVAN EK, ALEXANDER SR, et al. Post-transplant deaths and factors that in¯uence mortalityrate (MR) in North American children. Transplantation1994: 57: 547±553.

27. TEJANI A, FINE RN, ALEXANDER SR, STABLEIN DM.Factors predictive of sustained growth in children post-transplantation. J Pediatr 1993: 122: 397±402.

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Appendix 1

Participating centers and contact physicians for the North American Pediatric Renal Transplant Cooperative Study

Center City and state InvestigatorAlberta Children's Hospital Calgary, Alberta, CN Julian Midgley, MDAlfred I. duPont Institute, Wilmington, DE Farahnak Assadi, MDAll Children's Hospital, St. Petersburg, FL Sharon Perlman, MDArizona Children's Renal Center, Tucson, AZ Amira Al-Uzri, MDArkansas Children's Hospital Little Rock, AR Eileen Ellis, MDBabies Hospital of New York New York, NY Martin A. Nash, MDBC Children's Hospital Vancouver, BC, CN David S. Lirenman, MDBoston City Hospital Boston, MA Melanie Kim, MDBridgeport Hospital Bridgeport, CT Thomas Kennedy, MDCardinal Glennon Hospital St. Louis, MO Ellen Wood, MDCarolina's Medical Center Charlotte, NC Roberta Gray, MDCedars-Sinai Medical Center Los Angeles, CA Elaine Kamil, MDChildren's & Infants Diagnostic Center Margate, FL Michael Freundlich, MDChildren's Hospital and Medical Center Seattle, WA Sandra L. Watkins, MDChildren's Hospital-Boston Boston, MA John Herrin, MBBS, FRACPChildren's Hospital-Columbus Columbus, OH Mark I. Mentser, MDChildren's Hospital Medical Center Cincinnati, OH C. Frederic Strife, MDChildren's Hospital Medical Center Akron, OH Ian Dresner, MDChildren's Hospital National Medical Center Washington, DC Kanwal Kher, MDChildren's Hospital-New Orleans New Orleans, LA Matti Vehaskari, MDChildren's Hospital-Oakland Oakland, CA Rose Ellen Morrel, MDChildren's Hospital of Alabama Birmingham, AL Mark Ben®eld, MDChildren's Hospital of LA Los Angeles, CA Gary Lerner, MDChildren's Hospital of Michigan Detroit, MI Shermine Dabbagh, MDChildren's Hospital of Oklahoma Oklahoma City, OK James Wenzl, MDChildren's Hospital of Orange County Orange, CA Dorit Ben-Ezer, MDChildren's Hospital of Philadelphia Philadelphia, PA Kathy Jabs, MDChildren's Hospital of Pittsburgh Pittsburgh, PA Demetrius Ellis, MDChildren's Hospital of the King's Daughter Norfolk, VA Irene Restraino, MDChildren's Hospital of Winnipeg Winnipeg, Manitoba, CN Malcolm Ogborn, MBBS, FRACPChildren's Memorial Hospital-Chicago Chicago, IL Richard A. Cohn, MDChildren's Mercy Hospital-Kansas City Kansas City, MO Bradley A. Warady, MDChildren's Renal Center-Galveston Galveston, TX Alok Kalia, MDChildren's Renal Center of Southern California Long Beach, CA Janita Russo, MDChrist Hospital Park Ridge, IL Kenneth Miller, MDCleveland Clinic Foundation Cleveland, OH Robert J. Cunningham, MDColumbia Hospital at Medical City Dallas Dallas, TX Ronald Hogg, MDColumbia Presbyterian St. Luke's Medical Center Denver, CO M. Katherine Fitting, MDConnecticut Children's Medical Center Hartford, CT Majid Rasoulpour, MDCook Children's Medical Center Fort Worth, TX Watson C. Arnold, MDDepartment of Pediatrics/PSP Lackland AFB, TX Jose Pascual-y-Baralt, Col, USAF, MC

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Duke University Medical Center Durham, NC John W. Foreman, MDEast Carolina University Greenville, NC Daniel McKanney, MDEast Tennessee State University Johnson City, TN Ahmad Wattad, MDEmanuel Children's Hospital Portland, OR Randy Jenkins, MDEmory Children's Center Atlanta, GA Barry L. Warshaw, MDFairfax Hospital for Children Annandale, VA Glenn Bock, MDGeisinger Medical Center Danville, PA Jill Largent, MDHospital for Sick Children-Toronto Toronto, Ontario, CN Denis Geary, MDHospital Infantil de Mexico Mexico City, MX Ricardo Munoz Arizpe, MDHospital Nacional de Ninos San Jose, Costa Rica Gilbert Madrigal Campos, MDHospital St. Justine Montreal, Quebec, CN Marie-Jose Clermont, MDJefferson Medical College Philadelphia, PA Ruth Gottlieb, MDJohns Hopkins University Baltimore, MD Barbara Fivush, MDJW Riley Hospital for Children Indianapolis, IN Sharon Andreoli, MDKosair Children's Hospital Louisville, KY Harold Harrison, MDLAC+USC Medical Center Los Angeles, CA Donna Elliott, MDLebonheur Children's Medical Center Memphis, TN Deborah Jones, MDLoma Linda University Medical Center Loma Linda, CA Shobha Sahney, MDLong Island College Hospital Brooklyn, NY Matthew Kaplan, MDLoyola University Medical Center Maywood, IL Rekha Agrawal, MDLutheran General Children's Medical Center Park Ridge, IL Ronald Kallen, MDMaine Medical Center/Pediatric Associates Portland, ME Matt Hand, MDMary Bridge Children's Hospital Tacoma, WA Robert Holleman, MDMassachusetts General Hospital Boston, MA Julie Ingel®nger, MDMayo Clinic Rochester, MN Dawn S. Milliner, MDMedical College of Georgia Augusta, GA Coral D. Hanevold, MDMedical College of Ohio at Toledo Toledo, OH Martin DeBeukelaer, MDMedical College of Virginia Richmond, VA James C. M. Chan, MDMedical College of Wisconsin Milwaukee, WI Cynthia Pan, MDMedical University of South Carolina Charleston, SC Valerie Panzarino, MDMichigan State University East Lansing, MI Donald Kaufman, MDMichigan State University-Kalamazoo Kalamazoo, MI Alfonso Torres, MDMonte®ore Medical Center Bronx, NY Frederick Kaskel, MDMontreal Children's Hospital Montreal, Quebec, CN Lorraine Bell, MDMount Sinai Medical Center New York, NY Kenneth V. Lieberman, MDNew England Medical Center Boston, MA Michael Linshaw, MDNew York Hospital New York, NY Valerie Johnson, MD, Ph.D.North Shore University Hospital Manhasset, NY Manju Chandra, MDOregon Health Sciences University Portland, OR Marc B. Lande, MDPediatric Consultants Reno, NV Michael Pokroy, MDPediatric Kidney Associates San Antonio, TX Judy Pugh, MDPenn State Geisinger Health System Hershey, PA Steven J. Wassner, MDPhoenix Children's Hospital Phoenix, AZ Mel Cohen, MDRainbow Babies & Children's Hospital Cleveland, OH Ira D. Davis, MDRhode Island Hospital Providence, RI Andrew S. Brem, MDRobert C. Byrd HSC-Charleston Charleston, WV Myra L. Chiang, MDRush-Presbyterian/St. Luke's Medical Center Chicago, IL Niki Becker, MDSchneider Children's Hospital New Hyde Park, NY Bernard Gauthier, MDScottish Rite Children's Medical Center Atlanta, GA Julius Sherwinter, MDSt. Barnabas Medical Center Livingston, NJ Isabel Roberti, MDSt. Christopher's Hospital for Children Philadelphia, PA H. Jorge Baluarte, MDSt. Francis Renal Institute-Honolulu Honolulu, HI James E. Musgrave, MDSt. Louis Children's Hospital St. Louis, MO S. Paul Hmiel, MD, Ph.D.Stanford University Medical Center Palo Alto, CA Steven Alexander, MDState University of New York-Stony Brook Stony Brook, NY Dilys White, MDSunrise Medical Center Las Vegas, NV Ragini Fredrich, MDSUNY Health Science Center-Brooklyn Brooklyn, NY Anup Singh, MDSUNY Health Science Center-Syracuse Syracuse, NY Frank S. Szmalc, MDTexas Children's Hospital Houston, TX Eileen D. Brewer, MDTexas Tech University Amarillo, TX Deogracias Pena, MDThe Children's Hospital Denver, CO Douglas Ford, MDThe Children's Hospital at Albany Medical Center Albany, NY Rod E. Urizar, MDThe Children's Hospital of Austin Austin, TX Phillip Berry, MDThe Children's Kidney Center of Buffalo Buffalo, NY James Springate, MD, Ph.D.The Children's Mercy Hospital-Kansas City Kansas City, MO Bradley A. Warady, MDThe Nemours Children's Clinic Orlando, FL Jorge Ramirez, MDThe University of Chicago Children's Hospital Chicago, IL Andrew J. Aronson, MDTulane Medical Center New Orleans, LA Frank G. Boineau, MDUC Davis Medical Center Sacramento, CA Sudesh Makker, MD

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UCI Medical Center Orange, CA Deepak Rajpoot, MDUCLA School of Medicine Los Angeles, CA Robert Ettenger, MDUCSF Children's Renal Center San Francisco, CA Donald E. Potter, MDUMDNJ Robert Wood Johnson Medical School New Brunswick, NJ Lynne Weiss, MDUniversity Hospital-London London, Ontario, CN David J. Hollomby, MDUniversity of Alberta Hospital Edmonton, Alberta, CN Verna Yiu, MDUniversity of California at San Diego San Diego, CA Jacques Lemire, MDUniversity of Florida Gainesville, FL Robert S. Fennell, MDUniversity of Illinois Chicago, IL Eunice G. John, MDUniversity of Iowa Hospitals Iowa City, IA Craig Porter, MDUniversity of Kentucky Medical Center Lexington, KY Elizabeth Jackson, MDUniversity of Maryland Hospital Baltimore, MD Robert McLean, MDUniversity of Massachusetts Medical Center Auburn, MA William Primack, MDUniversity of Miami/Children's Hospital Miami, FL Jose Strauss, MDUniversity of Michigan Ann Arbor, MI Timothy E. Bunchman, MDUniversity of Minnesota Hospital Minneapolis, MN Thomas E. Nevins, MDUniversity of Mississippi Medical Center Jackson, MS Radharkrishna Baliga, MDUniversity of Missouri Columbia, MO Ted D. Groshong, MDUniversity of Nebraska Medical Center Omaha, NE Helen Lovell, MDUniversity of New Mexico Albuquerque, NM John Brandt, MDUniversity of Rochester Rochester, NY Melissa Gregory, MDUniversity of South Florida Tampa, FL Alfonso Campos, MDUniversity of Tennessee Medical Center Knoxville, TN Maricarmen Malagon, MDUniversity of Texas HSC at Houston Houston, TX Ronald Portman, MDUniversity of Texas HSC at San Antonio San Antonio, TX Ihsan Elshihabi, MD, FAAPUniversity of Texas Southwest Medical Center Dallas, TX Mouin Seikaly, MDUniversity of Utah Salt Lake City, UT Joseph Sherbotie, MDUniversity of Vermont Burlington, VT Ann P. Guillot, MDUniversity of Virginia Charlottesville, VA Ariel Gomez, MDUniversity of Wisconsin Hospital Madison, WI Sharon M. Bartosh, MDValley Children's Hospital Fresno, CA Jerome Murphy, MDVanderbilt University Medical Center Nashville, TN Stanley Lee, MDWake Forest University Medical Center Winston-Salem, NC Shashi Nagaraj, MDWestchester County Medical Center Valhalla, NY Robert A. Weiss, MDWest Virginia University Morgantown, WV Dianne G. Muchant, MDYale University School of Medicine New Haven, CT Karen Gaudio, MD

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