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enal Transplantation in Children Younger Than 6 Years Old

.D. Garcia, V.B. Bittencourt, F. Pires, E. Didone, E. Guerra, S.P. Vitola, J. Antonello, D. Malheiros,. Tumelero, and V.D. Garcia

ABSTRACT

Herein we report our experience in renal transplantation in 38 children (40 transplants),ages 1 to 5 years, between 1989 and 2005. Demographics as well as patient and graftsurvivals are reported. Mean age at transplantation was 3.3 � 1.3 years, and mean weightwas 14 kg (range, 5.7–25 kg); 92.5% were Caucasian, 7.5% African-Brazilian. The mainetiology for end-stage renal disease (ESRD) was uropathic/vesicoureteral reflux (45%)followed by glomerulopathy (25%), congenital/hereditary diseases (10%), and hemolyticuremic syndrome (12.5%). Prior to transplantation, 5% were on hemodialysis, 85% onperitoneal dialysis, and 10% preemptive. All children were followed for at least 6 monthsposttransplantation, except 2 who died in the first month. In 75% of cases, kidneys wereobtained from living-related donors, and in 25% from deceased donors. Thirty-ninekidneys were extraperitoneally placed. Primary immunosuppressant therapy consisted ofcyclosporine (61%), tacrolimus (39%), mycophenolate (49%), and azathioprine (51%). Asteroid-free protocol was used in 17% of patients. In the last 21 cases, basiliximab ordaclizumab was added. There were 13 (32.5%) graft losses (4 artery/vein thromboses, 3chronic rejections, 3 deaths, 3 other causes). The 5-year patient and graft survival rateswere 89.6% and 72.2%. We have concluded that renal transplantation can be performed

with good long-term results in children younger than 6 years old.

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UCCESSFUL KIDNEY TRANSPLANTATION re-mains the most effective renal replacement therapy for

hildren with end-stage renal failure.1,2 Pediatric renalransplantation presents several challenges, especiallymong the younger age groups.3,4 Graft and patient surviv-ls were often reported to be not very good among youngecipients compared with older children or adults, but theesults have improved.1,5–9 The objective of this paper waso report a single-center experience with renal transplanta-ion in children younger than 6 years old.

ATIENTS AND METHODS

rom March 1977 to September 2005, 300 pediatric renal trans-lantations were performed in our institution. Forty renal trans-lantations were performed in 38 children ages 5 years or younger;he first one was performed in March 1989. Two children requiredsecond transplantation. These patients were operated and cared

or by the same pediatric renal transplant team. The mean age ofhe recipients at transplantation was 3.3 � 1.3 years, and the meanody weight was 13.7 � 3.2 kg (range, 5.7–25 kg). The majority92.5%) were Caucasian, and 7.5% were African-Brazilian.

The diseases that led to renal failure in the 38 children included

ongenital urological disorders (n � 19), hemolytic-uremic syn- c

2007 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 39, 373–375 (2007)

rome (n � 5), congenital nephrotic syndrome (n � 3), glomeru-onephritis (n � 6), nephrosialidosis (n � 1), ischemic corticalecrosis (n � 1), glomerulocystic disease (n � 1), recessiveolycystic kidney disease (n � 1), and one unknown etiology.Transplantation was performed as soon as possible after stabi-

izing the medical issues, achieving nutritional optimization, andttaining at least 5 kg weight, but preferably 10 kg. Thirty-sixatients were on dialysis before transplantation: 33 (82.5%) onontinuous ambulatory peritoneal dialysis (CAPD) and 3 on he-odialysis. Preemptive transplantation was performed in 4 chil-

ren.Kidneys from living-related donors (28 parents and 2 grand-others) were used in 30 patients (75%) and from deceased

onors in 10 (25%). The mean age of the living donors was 29.9ears (range, 19–55 years), and the mean age of the deceasedonors was 15.1 years (range, 6–43 years).All grafts except 1 were placed extraperitoneally. The anastomo-

is of the donor renal vein was performed to the cava or iliac veins,

From the Complexo Hospitalar Santa Casa, FFFCMPA, Portolegre, RS, Brazil.Address reprint requests to Clotilde Druck Garcia, Rua Correa

ima 1493, CEP 90850-250, Porto Alegre, RS, Brasil. E-mail:

dgarcia1@uol.com.br

0041-1345/07/$–see front matterdoi:10.1016/j.transproceed.2007.01.006

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374 GARCIA, BITTENCOURT, PIRES ET AL

nd the arterial anastomosis to the aorta or common iliac artery.he ureter was preferentially implanted using the Gregoire tech-ique. No anticoagulation therapy was administered to the pa-ients.

The primary immunosuppressive therapy consisted initially ofrednisone, azathioprine, and cyclosporine. Since 1999, mycophe-olate mofetil (MMF) has been used instead of azathioprine, ande started using tacrolimus in the primary protocol in 2000. Therimary immunosuppressant therapy consisted of cyclosporine (61%)r tacrolimus (39%), and mycophenolate (48.8%). A steroid-freerotocol was used in 17% of patients, all of them on tacrolimus andycophenolate. The CsA remaining 21 cases received inductionith basiliximab or daclizumab. Cyclosporine and later Neoral haveeen initially used in 8 to 14 mg/kg doses split bid. Doses wereradually tapered to attain a C2 800 to 1000 ng/L until the 6thonth, and 600 to 800 ng/L thereafter. After 2000, tacrolimus has

een used at 0.15 mg/kg doses bid with a goal trough level of 10g/mL in the first 3 months and 5 ng/mL later on. Tight immuno-uppressant management was achieved with frequent blood drug-evel monitoring. MMF was used at 600 mg/m2 doses bid, andeplaced with mycophenolate sodium (MPS) after 2003.

The mean posttransplantation follow-up was 4.0 � 3.5 years.stimated glomerular filtration rate (GFR) was calculated using

he Schwartz formula. Estimation of patient and graft survivals wasbtained using the Kaplan-Meier method.

retransplantation Management

ix patients with obstructive uropathy and 1 with huge vesi-oureteral reflux underwent urological surgery prior to transplan-ation. Most children were on tube feedings and, whenever possi-le, we waited until they achieved 9 to 10 kg body weight and 80 cmeight, to better receive an adult kidney, when a living donor wasvailable. Some of the children were transplanted with a graft fromdonor of a lower weight or height whenever they were not doingell on dialysis.

ESULTS

he overall patient survival at 1 and 5 years was 89.6%. Theand 5 year graft survivals were 79.8% and 72.2%, respec-

ively. The estimated GFR was 79 � 23 mL/min at the 1stear, 71 � 20 mL/min at the 3rd year, and 68 � 15 mL/mint the 5th year.

Thirteen patients (32.5%) experienced 1 or more rejec-ion episodes, 5 of which were steroid-resistant and rescuedith OKT3 (n � 3) or tacrolimus (n � 2). All patientsxcept 3 recovered renal function. One failure was due to aenal artery thrombosis. The last 21 patients receivedasiliximab/daclizumab as part of the induction therapy; ancute rejection episode occurred in 3 (14.3%).

There were 13 (32.5%) graft losses (4 artery/vein throm-oses, 3 chronic rejections, 3 deaths, 3 other causes). Threehildren developed renal artery thrombosis: 1 immediatelyfter transplantation, 1 associated with a severe acuteejection, and 1 secondary to angioplasty for graft arterialtenosis at the site of the vascular anastomosis. All of themost their grafts.

Cytomegalovirus (CMV) prophylaxis was not used. Theatients were followed weekly with CMV antigenemia in

he first 3 months. Two patients developed CMV disease. p

wo patients had varicella. There was 1 case of malignancy,Wilms’s tumor in the native kidney.At the time of transplantation, the mean height Z score

as �1.3 (�3.8 to 0.1); at the 1st year it was �0.89 � 1.4,t the 3rd year it was �0.87 � 1.5, and at the 5th year it was0.74 � 1.61.

ISCUSSION

ransplantation in children younger than 6 years accountedor 13.3% of all pediatric transplantations performed in ournit. Pediatric transplantation activity was initiated in 1977

n our institution, but only in 1989 was the first transplan-ation performed in a small child, after acquiring CAPDxperience in this special group.

The majority (75%) of transplants were performed withiving-related donors. Although good results have also beeneported with the use of deceased donors,1,7,10 grafts fromiving donors show early immediate function and a lowerurgical complication rate.2,11,12 The child’s family is en-ouraged to identify potential living-related donors, includ-ng grandparents. We used 2 grandmothers as donors (40nd 55 years old), with no complications.

Within the infant group, the best results were attainedith adult-sized kidneys.13–15 Kidneys from deceased �5-ear-old donors provided the poorest graft survival inhildren, as much as 30% lower than adult-sized kid-eys.16,17 Although adult kidneys provide better graft sur-ival in infants, there is an associated higher incidence ofcute tubular necrosis, graft thrombosis, and primary graftonfunction. These problems have been generally attrib-ted to marked discrepancy in the size between the adultidney and the infant recipient.15

Vessel thrombosis was the most frequent cause for graftoss among our patients, in agreement with other stud-es.6,10 There were 3 graft losses (2 patients) due to renalrtery thrombosis, and 1 to venous thrombosis. Our resultsave improved with attention to technical factors as sug-ested by Najarian et al,2 Rosenthal et al,12 and Salvatierrat al,1 including those related to surgical technique andggressive fluid rejection. We only lost 2 grafts due toonimmunological cause in the last 10 years. To preventraft thrombosis and primary nonfunction and to achieve aow postoperative acute tubular necrosis (ATN), it is im-ortant to have a perfect vessel anastomosis.15,18 Redun-ancy of any vessel can result in kinking that predisposeshe patient to graft thrombosis. Then, the transplantedenal artery and vein should be shortened to prevent evenhe slightest redundancy after wound closure.

To avoid delayed graft function and ATN improves theong-term results.13–15 In order to attain this, it is necessaryo have the maximum intravascular volume. Large kidneysequester a large percentage of circulating blood volumend cardiac output.

Before kidney reperfusion, the infant’s CVP was in-reased to 15 to 18 cm of saline, with 5% albumin and/or

acked red blood cells. During the reperfusion it is impor-

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RENAL TRANSPLANTATION IN CHILDREN �6 YEARS 375

ant to maintain an adequate blood pressure and fillingressures via volume expansion. Continuing aggressivearly postoperative fluid resuscitation is necessary, mainlyn infants.

Our current immunosuppressant protocol includes in-uction with daclizumab, tacrolimus, MPS, and prednisone.ow-risk recipients of living donor grafts are included in a

teroid-free protocol that includes daclizumab, tacrolimus,nd MPS. Acute rejection occurred in 32.5% of the pa-ients, similar to other series.10 The use of basiliximab/aclizumab decreases the incidence of rejection,19,20 ashown in our experience.

The patient survival was 89.6% at 1 and 5 years. The grafturvival rates were 79.8% and 72% at 1 and 5 years,espectively. Salvatierra’s group has had better results withmaller children: 100% 2-year graft survival.15 The grafturvival results of the North Italy Transplant Program usingeceased donors were 74.5% and 70.5% at 1 and 5 years.10

The graft function in these patients decreased with time,s Salvatierra et al13 had published, due to decreasedntravascular volume to perfuse adult kidneys in these smallatients.Growth improved in our patients, but in general, they did

ot attain the normal height for their age, as alreadyeen.6,11 Growth hormone is an effective and safe treatmentn transplanted children.21 Treatment with growth hormones expensive, and only 1 child used it with good results andith no rejection episodes.We have concluded that renal transplantation is the best

hance for uremic young children to attain adequate devel-pment and a normal life. We recommend renal transplan-ation for small children as soon as they attain a goodlinical condition, preferably from a living-related donor.he use of new immunosuppressants, such as anti-IL2

eceptor antibodies, maximum hydration, and special careuring the vessel anastomosis are important factors towarduccessful renal transplantation in small children.

EFERENCES

1. Salvatierra O, Alfrey E, Tanney DC, et al: Superior outcomesn pediatric renal transplantation. Arch Surg 132:842, 1997

2. Najarian JS, Frey DJ, Matas AJ, et al: Renal transplantationn infants. Ann Surg 212:353, 1990

3. Ojogho O, Sahney S, Cutler D, et al: Superior long-term

esults of renal transplantation in children under 5 years of age. Amurg 68:1115, 2002

r2

4. Ettenger RB: Children are different: the challenges of pedi-tric renal transplantation. Am J Kidney Dis 20:668, 1992

5. Cochat P, Castelo F, Glastre C, et al: Outcome of cadaveridney transplantation in small children. Acta Paediatr 83:78, 19946. Kari JA, Romagnoli J, Duffy P, et al: Renal transplantation in

hildren under 5 years of age. Pediatr Nephrol 13:730, 19997. Tam JC, Earl JW, Willis NS, et al: Pharmacokinetics of

yclosporin in children with stable renal transplants. Pediatr Neph-ol 15:167, 2000

8. Vester U, Offner G, Hoyer PF, et al: End-stage renal failuren children younger than 6 years: renal transplantation is theherapy of choice. Eur J Pediatr 157:239, 1998

9. Humar A, Arrazola L, Mauer M, et al: Kidney transplantationn young children: should there be a minimum age? Pediatrephrol 16:941, 200110. Dall’Amico R, Ginevri F, Ghio L, et al: Successful renal

ransplantation in children under 6 years of age. Pediatr Nephrol6:1, 200111. Fernando ON: Long-term outcomes in pediatric transplan-

ation. Transplant Proc 31:3126, 199912. Rosenthal JT, Ettenger RB, Ehrlich RM, et al: Technical

actors contributing to successful kidney transplantation in smallhildren. J Urol 144:116, 1990

13. Salvatierra O Jr, Singh T, Shifrin R, et al: Successfulransplantation of adult-sized kidneys into infants requires main-enance of high aortic blood flow. Transplantation 66:819, 1998

14. Salvatierra O Jr, Sarwal M: Renal perfusion in infantecipients of adult-sized kidneys is a critical risk factor. Transplan-ation 70:412, 2000

15. Millan MT, Sarwal MM, Lemley KV, et al: A 100% 2-yearraft survival can be attained in high-risk 15-kg or smaller infantecipients of kidney allografts. Arch Surg 135:1063, 2000

16. Feld LG, Stablein D, Fivush B, et al: Renal transplantationn children from 1987–1996: the 1996 Annual Report of the Northmerican Pediatric Renal Transplant Cooperative Study. Pediatrransplant 1:146, 199717. Davis ID, Bunchman TE, Grimm PC, et al: Pediatric renal

ransplantation: indications and special considerations. A positionaper from the Pediatric Committee of the American Society ofransplant Physicians. Pediatr Transplant 2:117, 199818. Yata N, Nakanishi K, Uemura S, et al: Evaluation of the

nferior vena cava in potential pediatric renal transplant recipients.ediatr Nephrol 19:1062, 200419. Nashan B, Moore R, Amlot P, et al: Randomised trial of

asiliximab versus placebo for control of acute cellular rejection inenal allograft recipients. CHIB 201 International Study Group.ancet 350:1193, 199720. Swiatecka-Urban A, Garcia C, Feuerstein D, et al: Basilix-

mab induction improves the outcome of renal transplants inhildren and adolescents. Pediatr Nephrol 16:693, 2001

21. Fine RN, Sullivan EK, Kuntze J, et al: The impact ofecombinant human growth hormone treatment during chronic

enal insufficiency on renal transplant recipients. J Pediatr 136:376,000