ISSN: 2378-3176 UNOAJ

Urology & Nephrology Open Access Journal
Case Report
Volume 2 Issue 3 - 2015
Comparative Analysis of Long Term Survival of Pediatric and Adult Living Donor Renal Transplantation: Single Center 10 Years Experience
Ahmed Akl1*, Ahmed H Neamatalla1, Ayman M Nagib1, Mohamed Adel Bakr1, Ashraf Foda1, Ehab W Wafa1, Ahmed A Shokeir2 and Mohamed A Ghoneim2
1Department of Nephrology, Urology and Nephrology Center, Egypt 2Department of Urology, Urology and Nephrology Center, Egypt
Received: March 01, 2015 | Published: April 09, 2015
*Corresponding author: Ahmed I Akl, Urology and Nephrology center, Mansoura, Egypt, Tel: 20502262222; Fax: 2050223717; Email: @
Citation: Akl A, Neamatalla AH, Nagib AM, Bakr AM, Foda A (2015) Comparative Analysis of Long Term Survival of Pediatric and Adult Living Donor Renal Transplantation: Single Center 10 Years Experience. Urol Nephrol Open Access J 2(3): 00040. DOI: 10.15406/unoaj.2015.02.00040

Abstract

Our objective was to highlight the results of comparative analysis of pediatric and adults living donor renal transplantation in a single center experience extended for more than 30 years. The study comprised of 1902 adults and 338 children aging 18 years or younger. Male sex was dominant among recipients of both groups in contrary to female sex that constituted for 75.9 % for adults and 63.6 % for pediatrics. No statistical difference was encountered for patient survival at 5 and 10 years for both groups. A significant difference was observed between pediatrics and adults 10 years graft survival. Moreover comparable patients are living enjoying good graft function for both groups at last follow up. The significant outcome predictors for graft survival for pediatrics were primary immunosuppression, acute rejection and post transplant hypertension while the corresponding factors for adults included donor age >40 years, primary immunosuppression, acute rejection, and post transplant hypertension. Multivariate analysis revealed that acute rejection sustained its impact for pediatrics while donor age >40 years, primary immunosuppression, acute rejection and post transplant hypertension still had a significant effect on outcome for the adults.

Keywords: Living donor transplantation; Pediatrics transplantation; Adult transplantation; Long term graft survival

Abbreviations

ATN: Acute Tubular Necrosis; Aza: Azathioprine; CsA: Cyclosporine A; MMF: Mycophenolate Mofeti

Introduction

Renal transplantation is the treatment option of choice for children suffering from end stage renal diseases [1]. Children have a unique situation that differs from the adults. Compliance on dialysis, school attendance, growth and puberty beside surgical, immunologic and psychological aspects are contributing factors for that difference between children and adults [2].
Numerous reports allover the world highlighted aspects and results of adult transplantation. However pediatric transplantation outcome was published at a lesser extent. Scare comparative studies between the two population groups are reviewed in the literature. Herein, we highlighted the results of comparative analysis of pediatric and adult living donor kidney transplantation in a single center experience extended from more than 30 years.

Materials and Methods

Between March 1976 and June 2011, 2240 consecutive living donor renal transplantation were carried out at Mansoura urology and nephrology center, Egypt, 1902 were above 18 years (adult group 84.9 %) while 338 were, aged 18 years or below (pediatric recipients, 15.1%). Demographic characteristics, primary immunosuppression plan, original kidney diseases, causes of death either with functioning graft or with failed one, rejection episodes, complications beside condition and clinical grading at last follow up.
For recipients, our exclusion criteria for transplantation included sensitization with a Positive lymphocytotoxic cross match, recent malignancy, addiction, psychiatric disorders, type I diabetes mellitus, active infection and significant extra-renal organ disease (pulmonary, hepatic and cardiac). Contraindications to donation included: age above 60 years or below 21 years, active infections, diabetes, any minimal renal functional impairment, proteinuria or hematuria. Hypertension and serology test results positive for HIV, HBV or HCV.
The graft function was monitored by periodic estimation of serum creatinine and creatinine clearance. Data were organized to provide analyses of patient and graft survival rates and the predictors for 10-year graft survival. Evaluation of the possible variables that may affect the graft survival was carried out using univariate analysis and multivariate analysis. Studies factors included age, sex, original kidney disease, relationship of donor and recipient, ABO blood group equality, pre-transplant blood transfusion, HLA and DR matching, pre-transplant dialysis, cold ischemia time, number of renal arteries, urinary re-continuity, time to diuresis, time of transplantation, occurrence of acute tubular necrosis (ATN), primary and secondary immunosuppression, total dose of steroids in the first 3 months, development of acute rejection and post-transplant hypertension. ATN was defined by the need for dialysis during the first week after transplantation. Hemodialysis was the comments form of dialysis before transplantation (92%).
Most patients that received transplants before 1988 were treated with daily oral administration of 7.5-15 mg prednisolone (the mean daily dose at 6 months post-transplantation was 0.3 mg/kg and was reduced thereafter) and 2.5 mg/kg azathioprine (Aza) as combined therapy. From 1988 to 1998 a triple-therapy regimen comprising daily prednisolone between 5 mg and 10 mg (the mean daily dose at 6 months post-transplant was 0.25 mg/kg and was reduced thereafter), azathioprine 2 mg/kg and cyclosporine A (CsA) was administered. Alternate-day prednisolone was used in 48 patients (22%). Cyclosporine whole-blood trough levels were maintained between 100 ng/ml and 150 ng/ml. Tacrolimus and mycophenolate mofetil (MMF) have been introduced as a primary therapy since 1998, and sirolimus has been used since 2002, in addition to prednisolone. No induction therapy was used. Acute rejection episodes (requiring confirmation of renal pathology by biopsy prior to anti-rejection treatment) were treated with intravenous bolus doses of methylprednisolone (250-500 mg/day) for three to five consecutive days. Steroid-resistant patients were treated with plasmapheresis (15 patients) on alternate days for up to 10 days and/ or ATG (six patients) or OKT3 (two patients). Plasmapheresis was performed with Gambro AK 10 and AK 100 machines.
A 1.4 volume pheresis was performed with replacement of plasma by 5% albumin. The duration of pheresis and blood flow rate was determined according to patient height, weight, hematocrit, and tolerance to anticoagulation. TB was diagnosed by one or more of the following methods:
a) Demonstration of acid-fast bacilli in urine and sputum and/or growth in different culture specimens.
b) Demonstration of mycobacterial tuberculous antigens in urine, sputum or blood using polymerase chain reaction.
c) Demonstration of caseating granuloma by histopathologic examination.
d) Radiological findings indicating TB in a chest X-ray or a CT scan. Standard deviation scores for height were calculated as follows: observed height−expected height for age/standard deviation of mean height for age. Graft failure was defined as the start of any other form of renal replacement therapy, or a creatinine clearance of less than 10 ml/min per 1.73 m2. Death with functioning graft was considered as graft failure.

Statistical Analysis

Kaplan–Meier curves and log-rank tests were used to describe and compare the graft survival rates in stratified univariate analyses. Tests of significance were carried out using the chi-square method, with a P value of <0.05 taken to indicate statistical significance. All P values were two-sided. A multivariate analysis of graft survival was performed using Cox proportional hazards regression models to adjust for potentially confounding variables that could influence outcomes. The SPSS statistics package (SPSS V11.0, SPSS Inc., USA) was used for these analyses [3].

Results

Our overall experience of living donor renal transplantation constituted 15.1% pediatrics and 84.9% adults. The male sex was dominant among both groups (63.6% vs 75.9%), as regard the donor female sex it was 68.3% in the pediatrics versus 50.2% in adults. The mean age of recipients was 13.7 + 3.9 years and 32.3+ 9.1 years for both groups and the corresponding figures for donor age was 37.7 + 8.2 years and 35.6 + 10.5 years respectively (Table 1A) chronic GN and PN represented 19.5%, 11.5% as original kidney disease for pediatrics and 9%, 12.4% for adults. Majority of donors were related (83% vs 17%), with same blood group (80.3% vs 19.6%) and 50% HLA matching was (80.6% vs 74.9%). Hypertensive recipients were 42.3% vs 61.1% while pre-emptive transplantation was carried out in 9.2% in pediatric group and 3.9% of adult group. Concerning immunosuppression, induction therapy was utilized in 52.1% and 50.3% for both groups. The CsA based immunosuppression protocols adapted for pediatrics 59.2% and for 60.7% adults were comparable, similarly the pre transplant blood transfusion (39.1% vs 43.4%) (Table 1B).

 

Pediatrics No. (%)
(No.=338)

Adults No. (%)
(No.=1902)

P- value

Recipient Male sex

215 (63.6)

1443 (75.9)

<0.001

Donors female sex

231 (68.3)

955 (50.2)

<0.001

 

Age of donors
<30
30-50

>50

 

67(19.8)
251 (74.3)

20 (5.9)

 

 

774 (40.7)
930 (48.9)
198 (10.4)

 

 

<0.001

 

 

Original kidney disease
-Ch. GN
-Ch PN

-ESK

 

 

66 (37.1)
39 (21.9)

71 (27.7)

 

 

171 (23)
235 (31.7)
547 (42.1)

 

 

<0.001

 

Consanguinity
-Related

-Unrelated

 

 

306 (90.5)

32 (9.5)

 

 

1554 (81.7)
348 (18.3)

 

<0.001

Same Blood group

262 (77.5)

1537 (80.9)

0.155

Pre-Tx dialysis

307 (90.8)

1827 (96.1)

<0.001

Pre-Tx HTN

143(42.3)

1162 (61.1)

<0.001

Bilharziasis

29 (8.6)

502 (26.4)

<0.001

50% HLA Matching

233 (80.6)

1291 (74.9)

0.037

Induction therapy

176 (52.1)

956 (50.3)

0.540

Primary plan IS
-Aza based
-Csa based
-Fk   based
-Rapa based

-Steroid free

 

 

23 (6.8)
200 (59.2)
21 (6.2)
3 (0.9)

82 (24.3)

 

 

286 (15.2)
1154 (60.7)
112 (5.9)
136 (7.2)
170 (8.9)

 

 

 

<0.001

 

Blood transfusion

-  yes

 

 

132 (39.1)

 

826 (43.4)

 

0.097

 

Primary Ur. Continuity
- U-V

- U-U

 

 

326 (96.4)

10 (3)

 

 

1877 (98.6)
20 (1.1)

 

0.020

Immediate diuresis

299 (88.5)

1769 (93)

0.004

Table 1A:Demographic characteristics.

 

Pediatrics No.
(No.=338)

Adults No.
(No.=1902)

P-value

Re-Transplantation

4 (1.2)

79 (4.2)

0.022

P.O. Mortality (10 years)

43(12.7)

323 (17)

0.105

Post transplant hypertension

171 (50.6)

1163 (61.1)

<0.001

Post transplant DM

17 (5)

413 (21.7)

<0.001

Post transplant malignancy

7 (2.1)

96 (5)

0.016

Secondary IS
Yes

 

147 (43.5)

 

884 (46.5)

 

0.310

Secondary IS
-Aza based
-Csa based
-Fk   based
-Rapa based

 

4 (1.2)
79 (23.4)
49 (14.5)
---

 

35 (1.8)
534 (28.1)
197 (10.4)
5 (0.3)

 

 

0.656

Urologic complications

25 (7.4)

132 (6.9)

0.417

Bacterial infection

49 (14.5)

389 (20.5)

0.006

Viral infection

30 (8.9)

209 (11)

0.143

11-ATN

22 (6.5)

97 (5.1)

0.287

Rejection (yes)

127 (41.1)

745 (41.6)

0.870

Rejection frequency (>2)

108 (32)

491 (25.8)

0.024

Rejection type
-Acute cellular
-Acute vascular
- Chronic

 

115 (34)
10 (3)
85 (25.1)

 

663 (34.9)
71 (3.7)
382 (20.1)

 

 

0.035

Serum creatinine
-First year
-2nd year
-3rd year
-4th year
-5th year

 

1.28+0.77
1.46+0.82
1.60+1.09
1.72+1.10
1.77+1.09

 

1.40+0.66
1.52+0.81
1.62+0.92
1.65+1.01
1.69+1.02

 

0.006
0.270
0.834
0.364
0.292

Table 1B:Demographic characteristics.

With functioning graft

Pediatrics No.

Adults No.

C.V.

3 (21.4)

46 (18.3)

Resp.

1 (7.1)

28 (11.1)

Blood + Trauma

3 (21.4)

3 (1.2)

Malignancy

2 (14.3)

25 (9.9)

GIT + liver

--

31 (8.7)

Infection

--

27 (10.7)

Cerebral

--

17 (6.7)

Unknown

--

1 (0.4)

With failed graft

Pediatrics No.

Adults No.

C.V.

10 (31.3)

40 (24.4)

Resp.

2 (6.3)

22 (13.4)

GIT + liver

2 (6.2)

21 (12.8)

Infection

2 (6.3)

12 (7.3)

Malignancy

--

9 (5.5)

Unknown

16 (50)

55 (33.5)

Table 1B:Demographic characteristics.

The post-transplant results outlined in table 1.B revealed comparable mortality at 10 years (12.7% vs 17%), post transplant hypertension (50.6% vs 61.1%), secondary immunosuppression (43.5% vs 46.5%), urologic complications (7.4% vs 6.9%), acute cellular rejection (34% vs 34.9%), acute vascular rejection (3% vs 3.7%). While pediatric recipients experienced higher ATN (6.5% vs 5.1%), chronic rejection (25.1% vs 20.1%). On the other hand, adults had increased post transplant DM 21.75% vs 5% in pediatric group, Malignancy (2.1% in pediatrics vs 5% in adults), re-transplantation (1.2% vs 4.2%) immediate diuresis ( 88.5% vs 93%), bacterial infections ( 14.5% vs 20.5% ) and viral infection (8.9% vs 11%). The leading causes of death with functioning grafts in pediatric group are trauma and bleeding, CV and respiratory, while the causes of mortality with failed graft included CV, GIT and liver dysfunction, respiratory. On the other hand the causes of death with functioning grafts in adults are CV, respiratory, GIT, hepatic and malignancy. The prominent causes of death with failed graft in adults CV, GIT, hepatic (Table 2).
At last follow up more or less patients are living enjoying graft function (57.1% vs 53.5%). Serum creatinine was significantly lower (1.28+0.77mg/dl) in pediatric group compared to Adult group (1.40+0.66mg/dl) in the first year but later it become comparable (Table 1B). The actuarial patient survival at 5 and 10 years were 91.6+1.74 and 81.63+2.92 for pediatrics and 89.51+0.76, 77.36+1.25 for adults. The corresponding figures for the graft survival were 83.9+2.28 , 58.34+3.53 for pediatrics and 87.24+0.84 , 66.78+1.38 for adults respectively, p<0.001 (Figure 1 & 2).

Figure 1:Patient survival.

The actuarial patient survival at 5 and 10 years were 91.6+1.74 and 81.63+2.92 for pediatrics and 89.51+0.76 , 77.36+1.25 for adults p=0.106.

Figure 1:Graft survival.

The actuarial graft survival were 83.9+2.28 , 58.34+3.53 pediatrics and 87.24+0.84 , 66.78+1.38 for adults respectively, p=0.0002.

Outcome predictors of graft survival for pediatrics were Donor age ≥40 years, type of primary immuno suppression, acute rejection and post transplant hypertension by univariate analysis for both groups. While those who act independently in multivariate analysis were only acute rejection for pediatrics. While for adults were Donor age ≥ 40 years, steroid free based primary immunosuppression, acute rejection and post transplant hypertension (Table 3 & 4).

 

 

Pediatric group
(No. 338)

 

Adults group
(No. 1902)

 

10 years survival

 

P value

 

10 years
survival

 

P value

Recipient age
(<12 / ≥12)

 

78.4/71.2

 

0.162

 

-----------

 

-------

Donor age
(<40 /≥40)

 

77.5 / 66.4

 

0.190

 

83.1/70.2

 

<0.001

Recipient sex
(Male/Female)

 

68.7 / 83.5

 

0.352

 

79.7/79.9

 

0.897

Donor Male/
Recipient Male

 

70.3

 

 

81.2

 

Recipient female

81.3

 

84.3

 

Donor female/
Recipient Male
Recipient female

 

63.2
81.1

 

0.254

 

77.9
73.3

 

0.400

Original kidney disease

GN

64.6

 

76.7

 

Ch. Pyeloneph.

76.5

 

82.3

 

Hereditary GN

70.7

 

80.8

 

End stage

73.9

0.747

79

0.096

Prior blood transfusion (No/yes)

 

73.7/72.4

 

0.436

 

77.3/81.8

 

0.503

Pre-emptive Tx

Yes

85.3

 

70.7

 

Dialysis

73.4

0.726

80

0.447

Donor source
Related/unrelated

73.2/74

0.897

80.3/76.7

0.509

Primary IS

Aza based

58.6

 

85.5

 

Calcineurine based

73.4

 

78.6

 

Steroid free

94.1

0.017

81.3

0.064

Time to diuresis
Immediate/delayed

74/67.1

      0.320

        79.8/79.1

     0.745

ATN
(No/Yes)

          74.7/63

      0.164

         79.8/78.4

     0.854

Acute Rejection
(No/Yes)

          80.3/66

      0.023

         83.5/70.8

    <0.001

Post transplant hypertension
(No/Yes)

       76.9/71.9

      0.374

          85/77.4

   <0.001

Post transplant DM
(No/Yes)

 

74/73.3

 

0.780

 

79.8/78.8

 

0.726

Table 3: Univariate analysis of risk factors of graft survival.

 

 

Pediatric group
(No. 338)

Adults group
(No. 1902)

 

Exp (B)

 

P value

 

Exp (B)

 

P value

Donor age
<40
>40

 

1.34 (0.82-2.20)

 

0.241

 

1.61 (1.28-2.03)

 

<0.001

Primary IS
Aza based
Calcineurine based
Steroid free based

 

0.65 (0.31-1.36)
2.22 (0.03-1.84)

 

0.249
0.163

 

1.21 (0.90-1.63)
1.71 (1.08-2.71)

 

0.206
0.023

Acute rejection
No
Yes

 

1.72 (1.06-2.81)

 

0.030

 

2.01 (1.61-2.51)

 

<0.001

Post transplant HTN
No
Yes

 

1.05 (0.62-1.80)

 

0.853

 

1.44 (1.11-1.87)

 

0.007

Table 4:Multivariate analysis of risk factors of graft survival.

Discussion

Transplantation is the ideal treatment for pediatrics and young adults. Higher academic qualifications, normal marital life and job recruitments were associated with transplantation compared to regular haemodialysis [2].

In our results long term graft outcome was to be superior in adults compared to pediatrics as was reported by other groups [4]. The actuarial graft survival at 5 and 10 years were 87.24+0.84 , 66.78+1.38 for adults and 83.9+2.28, 58.34+3.53 for pediatrics (p<0.001). Numerous factors share in this long term inferiority in graft survival among pediatrics, the most important is poor compliance and recurrence of original kidney disease [3,5].
Donor age was between 30-50 years in pediatrics as the majority of donors were parents while in adults were younger as majority was either siblings or spouses. Pediatrics was encouraged for pre-emptive transplantation to avoid dialysis complications and rapid restoration of normal social life. While pre-emptive transplantation carries many advantages, it was reported that it may be associated with higher incidence of graft thrombosis. In our series we noticed higher incidence of graft thrombosis in pre-emptive group [6].
We report better graft outcome in our series compared to other reports as all transplantation were done from living donor source. Deceased transplantation is not feasible yet in Egypt. It was believed that religion and cultural factors were behind the difficulties of starting the Deceased program in Egypt. After the success of deceased program in Islamic countries like Iran and Saudi Arabia. Egypt has launched new regulation and national law to regulate transplantation including the initiation of a national deceased program.
Initially, steroid avoidance was adopted for pediatrics in favor to avoid steroid related stunted growth, currently steroid avoidance is the standard immunosuppression protocol for both pediatrics and adults. In our series pediatrics tolerated well steroids avoidance with no impact on long term graft survival, our results in parallel with what have been published from other reports [7]. No significant impact of immunosuppression was noted on long term graft survival in pediatrics. In adults steroid avoidance carried 1.7 independent risks on long tem graft survival which can be explained by higher incidence of rejection compared to steroid based group; as well it was noticed high levels of tacrolimus after withdrawal of steroids with higher incidence of nephrotoxicity [8]. The prevalence of post transplant hypertension in pediatric group was 50.6% and comparable to previously reported from other studies [9].
Acute rejection was an independent risk factor of graft failure. One acute rejection increases the risk of long term graft failure 1.7 times in pediatrics. While 2.01 times the risk of lower graft survival following acute rejection in adults compared to those did not suffer acute rejection. As well donor age and post-transplant hypertension were independent risk factors in adults but have no impact in pediatric recipients.

Conclusion

In conclusion in spite of improved long term results more efforts must be directed toward management of risk factors that hinder further achievements.

References

  1. Mir S, Erdogan H, Serdaroglu E, Kabasakal C, Hoscoskun C (2005) Pediatric renal transplantation: single center experience. Pediatr Transplant 9(1): 56-61.
  2. Rocha S, Fonseca I, Silva N, Martins LS, Dias L, et al. (2011) Impact of pediatric kidney transplantation on long-term professional and social outcomes. Transplant Proc 43(1): 120-124.
  3. Briganti E, Russ G, McNeil JJ, Atkins RC, Chadban SJ (2002) Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med 347: 103-109.
  4. Navarro TM, Espinosa RL (2010) Children as receptors of living donors. Nefrologia 30(2): 85-93.
  5. Choy BY, Chan TM, Lai KN (2006) Recurrent glomerulonephritis after kidney transplantation. American Journal of Transplantation 6(11): 2535-2542.
  6. Mahmoud A, Said MH, Dawahra M, Hadj-Aissa A, Schell M, et al. (1997) Outcome of preemptive renal transplantation and pretransplantation dialysis in children. Pediatr Nephrol 11(5): 537-541.
  7. Delucchi A, Valenzuela M, Lillo AM, Guerrero JL, Cano F, et al. (2011) Early steroid withdrawal in pediatric renal transplant: five years of follow-up. Pediatr Nephrol 26(12): 2235-2244.
  8. Gheith OA, Nematalla AH, Bakr MA, Refaie A, Shokeir AA, et al. (2011) Steroid avoidance reduce the cost of morbidities after live-donor renal allotransplants: a prospective, randomized, controlled study. Exp Clin Transplant 9(2): 121-127.
  9. Hernandez-Infante E, Garcia-Martinez C, Berltran-de-la-Luz S, Reyes-Acevedo R, Romo-Franco L, et al. (2010) Prevalence of post transplant hypertension in pediatric kidney transplant recipients: effects on long term allograft survival. Rev Invest Clin 62(5): 398-405.
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