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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 4  |  Page : 684-692
Graft outcomes in pediatric kidney transplantation: Focus on the role of race


1 Pediatric Nephrology and Hypertension, MUSC Children's Hospital, Charleston, SC, USA
2 Pharmacy Services, MUSC Children's Hospital, Charleston, SC, USA
3 Transplant Surgery, MUSC Children's Hospital, Charleston, SC, USA

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Date of Web Publication9-Jul-2012
 

   Abstract 

While significant racial disparities in graft outcome persist among adult and pediatric kidney transplant recipients in the US, some international studies do not show these diffe­rences. The aim of this study is to examine predictors of graft outcomes and the impact of race in our pediatric kidney transplant cohort. Records of 109 pediatric kidney transplant recipients performed at our institution between 7/99 and 4/07 were studied. Patients were grouped based on race: African-American (AA) vs. non-AA. Fifty-five AA (12 ± 5 years) and 54 non-AA patients (11 ± 6 years) were studied. There were more females, pre-emptive transplants and living donors in the non-AAs. Survival analysis showed significantly higher rejection rates in AAs, P = 0.02, and lower unadjusted graft survival (P = 0.09). Cox Proportional Hazards Survival Regression Analysis revealed biopsy-proven acute rejection and delayed graft function contributed to worse graft survival, while pre-emptive transplantation had a favorable effect. Race was not an independent risk factor for decreased graft survival in the final model. In conclusion, our cohort showed several modifiable risk factors that can partially account for poorer graft survival in pediatric AA kidney transplant recipients.

How to cite this article:
Shatat IF, Taber DJ, Shrivastava S, Weimert NA, Sas DJ, Chavin KD, Orak JK, Baliga PK. Graft outcomes in pediatric kidney transplantation: Focus on the role of race. Saudi J Kidney Dis Transpl 2012;23:684-92

How to cite this URL:
Shatat IF, Taber DJ, Shrivastava S, Weimert NA, Sas DJ, Chavin KD, Orak JK, Baliga PK. Graft outcomes in pediatric kidney transplantation: Focus on the role of race. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Dec 2];23:684-92. Available from: https://www.sjkdt.org/text.asp?2012/23/4/684/98111

   Introduction Top


US transplant registries of kidney transplant recipients have consistently shown inferior allograft and patient survival in African-American (AA) kidney transplant recipients. Data from the United Network of Organ Sharing (UNOS) indicate that from 1992 to 2001, the 5-year allograft survival for US whites was 66%, compared with only 54% for US AAs. [1] In their 2005 report, the Organ Procurement and Trans­plantation Network (OPTN) revealed a similar trend. [2] In contrast to most US studies, French and Canadian authors have published compara­ble graft survival between patients of African descent and their Caucasian counterparts. [3],[4] The North American Pediatric Renal Trans­plant Cooperative Study (NAPRTCS) [5] noted graft survival was significantly lower in AA transplant recipients when compared with Caucasian recipients at three years (70.9% vs. 83.3%) and five years (59.9% vs. 77.7%). After controlling for confounding factors, AA reci­pients continued to have a higher risk for graft failure than white recipients (adjusted hazard rate 1.65; 95% confidence interval 1.46-1.86), but did not show differences in graft function at one year post-transplant.

A more recent study examining the USRDS [6] evaluated 13,692 US pediatric first-kidney transplant patients transplanted between 1980 and 2004 in order to identify trends in racial disparities in graft failure rates. After adjusting for multiple covariates, the rate of graft failure among AA was approximately two-fold higher than for white patients over the entire study period. The study also reported a slight im­provement in graft survival for AA pediatric recipients compared with white pediatric pa­tients over the study period, and AA race was less of a risk factor for early graft failure compared with late graft failure.

Racial disparities in graft outcome were attri­buted to a wide range of differences in base­line patient characteristics, such as variations in immune response, access to health care and socio-economic factors, [7],[8],[9],[10] etiology of end­stage renal disease (ESRD), adherence to immunosuppressive medications and immunosuppression pharmacokinetics.

We reviewed our pediatric kidney transplant experience at the Medical University of South Carolina in order to examine possible factors that may account for differences in graft out­comes across racial groups.


   Materials and Methods Top


Study design

Pediatric renal transplant recipients who re­ceived their allograft between 7/99 and 4/07 were evaluated. Patients were included in this analysis if they received a kidney transplant at the Medical University of South Carolina Transplant Center and were under 18 years of age at the time of transplant. Patients were ex­cluded if they received a multiorgan trans­plant or had previously received a non-renal transplant. No patients were excluded from this analysis secondary to loss of follow-up or primary graft non-function. Baseline patient and transplant characteristics were collected. In addition, immunosuppression, rejection episodes and renal function were ana­lyzed. CMV infection, post-transplant lymphoproliferative disorder (PTLD), compliance with follow-up visits, immunosuppressive medica­tions and etiology of ESRD were also evalua­ted. Patients were divided based on race into two groups (AA vs. non-AA) and compared for demographic and outcome differences. This study was approved by the Institutional Review Board of the Medical University of South Carolina, Charleston, South Carolina.

Immunosuppressive regimens

All patients received triple immunosuppressive regimens consisting of calcineurin inhibition (CNI), mycophenolate mofetil and corticosteroids. All induction therapy was based on protocol guidelines and transplant risk factors. Patients at high risk for acute rejec­tion, which included retransplants, panel reac­tive antibodies (PRA) >20% or cold ischemic time >24 h, received rabbit ATG (Thymoglobulin™, Genzyme Corp., Cambridge, MA, USA) at a dose of 1.5 mg/kg given daily (total five doses). All other patients received IL2RA induction basiliximab (Simulect® , Novartis Pharmaceuticals, New York, NY, USA) 10 mg/m 2 given intra-operatively and on postoperative Day 4, daclizumab (Zenapax® , Roche Pharmaceuticals, Nutley, NJ, USA) 1 mg/kg given intra-operatively and on postoperative Day 7 or did not receive induction based on surgeon's discretion. Patients transplanted prior to January 2005 received basiliximab and patients transplanted after that date received daclizumab. Choice of IL2RA was based on institutional contract pricing, as efficacy diffe­rences apparently do not exist between the two agents. Cortico-steroids were initiated in the operating room and were tapered down to low-dose prednisone (0.1-0.5 mg/kg/day) by three months post-transplant. Target 12-h whole blood trough concentrations for cyclosporine (Neoral® , Novartis Pharmaceuticals) were as follows: weeks 1-6, 200-275 ng/mL; weeks 7-12, 175-225 ng/mL; months 3-12, 125-175 ng/mL; greater than 1 year, >70 ng/mL, or as clinically indicated. Target 12-h whole blood trough concentrations for tacrolimus (Prograf® , Astellas Pharmaceuticals, Deerfield, IL, USA) were as follows: weeks 1-6, 10-15 ng/mL; weeks 7-12, 8-12 ng/mL; months 3-12, 6-10 ng/mL; greater than one year, >5 ng/mL, or as clin­ically indicated. During Thymoglobulin induc­tion, doses of calcineurin inhibitors were mini­mized, but returned to full dose before discon­tinuation of the induction regimen. All patients received mycophenolate mofetil (CellCept® , Roche Pharmaceuticals, Nutley, NJ, USA), with initial doses of 600 mg/m 2 PO twice daily. Doses were adjusted for efficacy, growth and toxicity.

Outcomes

The primary outcomes of the analysis were overall acute rejection and graft survival rates based on Kaplan-Meier analysis. Multivariate analysis was performed in order to determine which variables were independently associated with overall graft survival.

Definitions

Acute rejection was biopsy-proven and trea­ted with high-dose corticosteroids. Borderline rejections were included in the analysis if trea­ted as acute rejection. Patients were considered to have delayed graft function (DGF) if they required dialysis within the first week post-transplant. If a patient did develop DGF, biop­sies were obtained at the discretion of the physician caring for the patient. Primary graft non-function was defined as failure of graft function within seven days post-transplant. Graft failure was defined as return to chronic dialysis. Race of the study subjects was ex­tracted from their electronic medical records, which were family self-identified.


   Statistical Analysis Top


Baseline demographics and outcomes were compared between the two groups using the Student's T-test for continuous data and Fisher's Exact Test for nominal data. Kaplan-Meier analysis was conducted for both rejection-free survival and unadjusted graft survival. Because of baseline differences between the two groups for several key characteristics (number with living donors, number with pre-emptive trans­plants, etiology of ESRD), multivariate ana­lysis was performed using Cox Proportional Hazards Survival Regression Analysis for graft survival to determine which covariates could independently influence these outcomes. Covariates included in the original model in­clude age, gender, race, donor status, focal segmental glomerulosclerosis (FSGS) as an etiology of ESRD, pre-emptive transplant, DGF, PRA, history of non-adherence, cold ischemic time and biopsy-proven acute rejection (BPAR). Data was manually collected in an Excel spreadsheet (Microsoft, Seattle, WA, USA). Statistical analysis was conducted using SPSS version 11.0 (SPSS, Chicago, IL, USA). A P-value of <0.05 was considered statisti­cally significant.


   Results Top


A total of 109 patients were included in this analysis, of which 55 were AA and 54 were non-AA patients. [Table 1] displays baseline cha­racteristics. Mean age was not statistically dif­ferent between the two groups. Donor race and gender were comparable. The non-AA group had more female patients, pre-emptive trans­plants and living donors.
Table 1: Baseline demographic characteristics

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[Table 2] displays the immunological charac­teristics of the study population. There were no statistically significant differences with re­gards frequency of re-transplant, DGF, induc­tion or maintenance immunosuppressive the­rapy or PRA levels. Both groups had a similar baseline CMV sero-status and received comparable CMV prophylaxis. AA pediatric pa­tients demonstrated a greater number of HLA mis-matches (4.4 vs. 3.4).
Table 2: Immunological characteristics.

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[Table 3] displays the most common etiologies of pediatric ESRD referred for transplantation; etiologies were comparable in both groups, with the exception of higher percentage of FSGS in the AA group, P = 0.2.
Table 3: Causes of end-stage renal disease in our cohort.

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[Table 4] displays the primary and secondary outcomes; both groups had comparable fre­quencies of CMV, EBV and BK infections. There were 19 graft failure events, 13 of which were in the AA group. AA patients had a significantly higher number of biopsy-proven acute rejection episodes; 21 events compared with six in the non-AA group. While none of the AA patients had PTLD, four non-AA patients were diagnosed with PTLD, P = 0.057. Differences in non-adherence events were not statistically significant between the two groups.
Table 4: Primary and secondary outcomes.

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[Figure 1] displays the Kaplan Meier curves for (a) biopsy-proven acute rejection events and (b) graft survival in both groups. The AA group had more acute rejection events and lower graft survival compared with the non-AA group, P = 0.02 and 0.09, respectively. Median pa­tient follow-up/graft failure was 789 days (25%, 75%: 331, 1508). Predictors of graft survival were examined after adjusting for differences in baseline cha­racteristics using a Cox Proportional Hazard model [Table 5]. While etiology of ESRD, PRA, history of documented non-adherence and cold ischemia time did not remain in the model, DGF and BPAR were associated with worse graft survival; hazard ratio (HR) = 2.9 and 4.0, res­pectively. Receiving a pre-emptive transplant was associated with better graft survival, HR = 0.15, P = 0.03. Although the AA group had an HR = 1.3, it was not significantly associated with graft survival. Age and gender were forced into the model for their clinical relevance.
Figure 1:

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Table 5: Cox Proportional Hazard for graft survival.

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   Discussion Top


Ethnicity and race remains a controversial issue when it comes to kidney transplant out­comes. US transplant registries have shown consistently poor outcomes in AA transplant recipients compared with non-AA recipients. This study is one of the largest single-center pediatric cohorts comparing outcomes and risk factors associated with graft survival among racial groups.

Previously, investigators have examined immunologic and non-immunologic variables that may contribute to decreased allograft half-life in adult AA kidney recipients. Proposed immunological mechanisms include HLA D/R mis­matches (antigen level), altered antigen recog­nition sites (Allele level), cytokine gene poly­morphisms and a more vigorous immune res­ponse in AA. [7],[9],[10] Non-immunological factors were attributed to lower rate of living donor as the primary organ source, lower educational degree, decreased access to health care and al­tered immunosuppressant pharmacokinetics. [6],[8],[11],[12] Specific immunologic barriers, however, re­main in question as inferior graft half-lives continued to be observed in AA kidney transplant recipients, even in HLA-identical sibling transplants, when compared with white pa­tients (27 vs. 42 per year). [13] While some authors attribute differences in outcome to socioeconomic disparities as the primary etio­logy limiting access to treatment, Chakkera and colleagues found that racial disparities seem to persist even in a universal access-to-care system such as the Veteran administration hospital system. [14] In contrast to most US studies, French and Canadian authors have published comparable graft survival between patients of African descent and their Caucasian counterparts. [3],[4]

Fewer pediatric studies have examined this issue. In one pediatric study, [11] authors found that, as in adults, AA children are half as likely to be referred for transplantation as Caucasian children, reflecting a complex interplay of va­riables including education, parental support and compliance. Similarly, non-adherence was the main factor accounting for 71% of cases of late graft loss in a study by Jarzembowski and colleagues, [12] with a significantly higher rate of graft loss at five years in the AA recipients.

In a landmark study with almost 7000 pa­tients, the NAPRTCS [15] noted significantly worse graft survival, but not patient survival, for AA recipients of either deceased or living donor kidneys. Black patients experienced substan­tially more acute rejection than their Caucasian counterparts, supporting the potential contri­bution of immunologic differences to poorer outcomes. In that study, NAPRTCS also iden­tified over-representation of several known adverse risk factors in AAs, including FSGS as the etiology of ESRD. The same study group recently reported similar worse graft survival in black transplant recipients at three and five years. After controlling for confoun­ding factors, black recipients continued to have a higher risk for graft failure than white recipients, but did not show differences in graft function one year post-transplant. [5]

In our study, the cohort showed poorer un­adjusted graft survival in pediatric AA kidney transplant recipients compared with non-AA, P = 0.09. This discrepancy did not remain after adjusting for other variables [Table 5] and race failed to remain as an independent predictor of graft survival in the final model. It is likely that the failure of AA race to remain predictive of graft failure is due to the rela­tively small sample size and small number of events (i.e., graft failures).

Receiving a pre-emptive transplant had a favorable effect on graft survival. On the other hand, having a biopsy-proven acute rejection and DGF was associated with poor graft sur­vival. Given that predictors of graft survival were modifiable factors, the importance of early referral for transplant evaluation, re­ceiving a pre-emptive transplantation, empha­sizing the importance of adherence to pres­cribed immunosuppressive medications and mi­nimizing factors associated with DGF must be reinforced.

When we examined rejection-free graft survi­val between the two racial groups, Kaplan Meier survival analysis showed significantly lower rejection-free graft survival in the AA group, P = 0.02. Despite a higher rejection rate in the AA group, in the final model, race did not have an independent effect on graft sur­vival. This illustrates the importance of adjus­ting for other baseline characteristics, and may also be related to small sample size and event numbers.

Both groups had comparable baseline immunological characteristics. ESRD etiologies were comparable in both groups, with the exception of higher percentage of FSGS in the AA group, P = 0.2. The etiologies of ESRD in our cohort were consistent with previously des­cribed causes of ESRD in the pediatric popu­lation receiving kidney transplantation. [6] After obstructive uropathy and congenital dysplasia, FSGS was the most common etiology of ESRD. These etiologies are different from the most common ESRD causes in adults, and emphasize the additional risk that transplant surgeons and pediatric nephrologists have to address in planning for and managing pediatric kidney transplant patients: abnormal urodynamics, anatomy and risk of disease (FSGS) recurrence.

Authors of an analysis of the UNOS database (1993 through 2006) concluded that donor ethnicity influences kidney transplant outcomes. [16] Among black recipients of kidneys obtained after cardiac death, those who re­ceived kidneys from black donors had better long-term graft and patient survival than those who received kidneys from white donors. In our study, there were more AA donors in the AA group, but that was not statistically dif­ferent from the non-AA group (P = 0.12).

Of interest, there were four cases of PTLD, all of which occurred in the non-AA group, and trended toward statistical significance (P = 0.057). This observation that black children have a lower incidence of PTLD was previously reported by Dharnidharka and colleagues in their NAPRTCS analysis. [17] This finding might suggest more potent immune system surveil­lance in AA patients and warrants further investigation.

Our study was limited by its small sample size, retrospective design and lack of adjust­ment for possible differences in parental socio-economic status and education, and co-morbi­dities such as hypertension. However, the study also has unique strengths, especially from our comprehensive data base, which allowed us to examine and adjust for several pediatric-specific and other non-specific variables known to affect transplant outcomes in this popula­tion. These factors included underlying etiolo­gies of ESRD, adherence to prescribed medi­cations and follow-up visits, PRA levels, cold ischemia time and donor characteristics. More­over, as a single-center study, we had the ad­vantage of examining the effect of race while excluding center-to-center variation in clinical practices and possible differences in regional access to health care in this pediatric cohort.

Compared with adult transplant outcome studies, addressing the issue of race in pediatric kidney transplants not only requires attention to differences in baseline co-morbi­dities, access to health care and different etio­logies as the most common causes of ESRD but also poor adherence to immunosuppressive medications in the adolescent population.

Our study did not show race to be an inde­pendent predictor of graft survival in pediatric kidney transplantation. We did, however, de­monstrate that receiving a pre-emptive kidney transplant, having a biopsy-proven acute re­jection, and DGF were independently predic­tive of graft survival.

 
   References Top

1.United Network for Organ Sharing: 2002 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1992-2001. Rockville, MD: HHS/HRSA/ OSP/DOT; 2003.  Back to cited text no. 1
    
2.US Organ Procurement and Transplantation Network and the Scientific Registry of Trans­plant Recipients, Annual Report 2005 avai­lable from www.ustransplant.org/annual reports/ archives/2005/survival rates.htm (Last accessed on January 19, 2009) _  Back to cited text no. 2
    
3.Pallet N, Thervet E, Alberti C, et al. Kidney transplant in black recipients: Are African-Europeans different from African Americans? Am J Transplant 2005:5:2682-7.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Yeated K, Wiebe N, Gill J, et al. Similar Outcomes among black and white renal allo­graft recipients. J Am Soc Nephrol 2009:20: 172-9.  Back to cited text no. 4
    
5.Omoloja A, Mitsnefes M, Talley L, Benfield M, Neu A. Racial differences in graft survival: A report from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). Clin J Am Soc Nephrol 2007:2: 524-8.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Chavers BM, Snyder JJ, Skeans MA, Weinhandl ED, Kasiske BL. Racial disparity trends for graft failure in the US pediatric kidney transplant population, 1980-2004. Am J Transplant 2009:9:543-9.  Back to cited text no. 6
    
7.Kamoun M, Israni AK, Joffe MM, et al. Assessment of differences in HLA-A, -B, and -DRB1 allele mismatches among African-American and non-African-American reci­pients of deceased kidney transplants. Transplant Proc 2007:39:55-63.  Back to cited text no. 7
    
8.Schroppel B, Murphy B. Gene variants affecting bioavailability of drugs: Towards individualized immunosuppressive therapy? J Am Soc Nephrol 2003:14:1955-7.  Back to cited text no. 8
    
9.Hoffmann SC, Stanley EM, Cox ED, et al. Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant 2002:2:560-7.  Back to cited text no. 9
    
10.Hutchings A, Purcell WM, Benfield MR. Increased costimulatory responses in African-American kidney allograft recipients. Transplantation 2001:71:692-5.  Back to cited text no. 10
    
11.Furth SL, Hwang W, Neu AM, Fivush BA, Powe NR. Effects of patient compliance, parental education and race on nephrologists' recommendations for kidney transplantation in children. Am J Transplant 2003:3:28-34.  Back to cited text no. 11
    
12.Jarzembowski T, John E, Panaro F, et al. Impact of non-compliance on outcome after pediatric kidney transplantation: an analysis in racial subgroups. Pediatr Transplant 2004:8:367-71.  Back to cited text no. 12
    
13.Cecka JM. The UNOS Scientific Renal Transplant Registry, Clinical Transpl 2000:1-18.  Back to cited text no. 13
    
14.Chakkera HA, O'Hare AM, Johansen KL, et al. Influence of race on kidney transplant outcomes within and outside the Department of Veterans Affairs. J Am Soc Nephrol 2005: 16:269-77.  Back to cited text no. 14
[PUBMED]  [FULLTEXT]  
15.Benfield MR, McDonald RA, Bartosh S, Ho PL, Harmon W. Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study 2003: Pediatr Transplant 7:321-35.  Back to cited text no. 15
    
16.Locke JE, Warren DS, Dominici F, et al. Donor ethnicity influences outcomes following deceased-donor kidney transplantation in black recipients. J Am Soc Nephrol 2008:19:2011-9.  Back to cited text no. 16
    
17.Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), Transplantation 2001:71:1065-8.  Back to cited text no. 17
    

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Correspondence Address:
Ibrahim F Shatat
Associate Professor of Pediatrics, Division of Nephrology, CSB-428, MUSC Children's Hospital, 96 Jonathan Lucas Street, Charleston, SC, 29425
USA
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DOI: 10.4103/1319-2442.98111

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