Pediatric renal transplantation: Results and prognostic factors

Summary

Background/Objective

As renal transplantation may increase survival rates and improve quality of life for children with end-stage renal disease, we investigated the long-term outcomes and prognostic factors of pediatric renal transplantation.

Methods

A retrospective study was conducted to review 25 pediatric renal transplantations, either from live or deceased donors, in our hospital from 1995 to 2008. The cumulative graft survival rate was calculated using the Kaplan-Meier method. Log rank tests were employed to identify categorical prognostic factors for graft survival of the pediatric renal transplantations, and Cox regression analysis for numeric factors.

Results

The mean age of our study subjects was 11.63 ± 3.76 years, and the mean follow-up period was 49.24 ± 33.72 months. The 12-month and 36-month graft survival rates were 92% and 82.14%, respectively. The rejection-free survival rates were 88% and 72.88% in the first and third years, respectively. All of the patients were alive during the follow-up period. Acute rejection (p = 0.0175) and male sex (p = 0.0384) were found to be significant factors for graft survival.

Conclusion

For pediatric patients, we found that renal transplantation is now a safe and effective surgical procedure for children with end-stage renal disease. Acute rejection and male gender were identified as prognostic factors for poor graft survival.

Keywords

end-stage renal disease;non-adherence;pediatric renal transplantation;prognostic factor;recipient sex

1. Introduction

Renal replacement therapy for pediatric patients with end-stage renal disease can be difficult. Children on dialysis, either peritoneal dialysis or hemodialysis, have a higher incidence of morbidity and mortality.¹ In addition, renal transplantation in pediatric patients seems to be associated with more technical complications and poorer graft survival than in adults.^{2 ;  3} Recently, Tangeraas et al⁴ reported that early transplantation can provide better prospects for survival, growth, and development in infants or small children than maintenance on chronic dialysis. Since uremia in children is associated with developmental delays and encephalopathy, many studies agree that renal transplantation should be performed as soon as possible.^{1; 4 ;  5}

Renal transplantation is an effective treatment for children with end-stage renal disease to improve the survival rate and growth development.^{5 ;  6} Recent advancements in immunosuppressive drugs and surgical techniques have improved the prognosis of pediatric renal transplantation, and a successful outcome depends on many factors such as the use of an adult living donor, delicate and skilled operative procedure, peri- and postoperative care, early or preemptive transplant, and long-term follow up.^{4; 7 ;  8} However, graft failure and death continue to occur as a result of infection, rejection, and adverse events from drugs.^{5; 9; 10 ;  11} Children and adults differ in terms of biology and psychology, and their patterns of nonadherence to medications are also distinct.^{11; 12 ;  13}

In this study, we aimed to investigate the experience in our hospital with regard to the long-term outcomes of pediatric renal transplantation from 1995–2008 by evaluating the impact of different factors on graft survival and rejection-free survival rates, and then to identify risk or prognostic factors.

2. Methods

The medical records of children aged younger than 18 years who received a renal transplant between January 1995 and December 2008 were retrospectively reviewed. There were 25 transplants in 24 patients enrolled in the cohort study. Each transplantation was regarded as independent; therefore, we analyzed patient and graft survival rates in 25 transplantations. We retrieved information on recipient age, recipient sex, native renal disease, donor characteristics, mismatches of human lymphocyte antigens (HLAs), vascular anastomosis sites, patient and graft survival, acute rejection episodes, cause of graft failure, and cause of death. Graft failure was defined as failure of a renal transplant, return to dialysis, or finalizing the date for a new preemptive transplantation. Acute rejection episodes were defined as a rise in serum creatinine of at least 30% from baseline levels and accompanied by clinical symptoms and signs, including fever and oliguria. Rejection could also be diagnosed on the basis of pathologic proof with a renal biopsy.

All grafts were placed extraperitoneally in the iliac fossa. A modification of the approach used for renal transplantation in adults was used. Ipsilateral nephrectomy was performed if the extraperitoneal space was inadequate to accommodate the grafts. Live donor grafts were harvested by laparoscopic nephrectomy or traditional nephrectomy. The donor artery was anastomosed to the external iliac artery, common iliac artery, internal iliac artery, or descending aorta; the site depended on graft size and relative anatomy and was made tension free by using the running suture technique. Venous anastomosis was performed using the same method and connected to the external iliac vein, common iliac vein, or inferior vena cava. When the kidney graft showed two arteries, the vessels were anastomosed using connecting patches to allow for a single anastomosis.

To overcome the size discrepancies between kidneys from adult donors and small child recipients, wound closure was performed using an absorbable mesh of polyglactin 910, a synthetic copolymer made from 90% glycolide and 10% l-lactide (Vicryl Mesh, Johnson & Johnson International, Brussels, Belgium) to avoid organ compression, and the skin was primarily closed.¹⁴ If the patient had been undergoing peritoneal dialysis prior to renal transplantation, then the catheter was preserved and removed once the graft being functioning. Ureteroneocystostomy was performed using the Lich-Gregoir procedure with interrupted sutures to implant the graft ureter into the recipients urinary bladder.^{14 ;  15}

Immunosuppression was induced in all patients with either a cyclosporine- or tacrolimus-based regimen consisting of 8–10 mg/kg/day of cyclosporine or 0.15–0.3 mg/kg/day of tacrolimus. The doses were adjusted to maintain a trough whole blood concentration of 300–400 ng/mL for cyclosporine or 8–12 ng/mL for tacrolimus. No antibody-depleting agents were used for induction. A bolus dose of intravenous methylprednisolone (10 mg/kg) was given before vascular reperfusion, with tapering to 0.5 mg/kg/day oral prednisolone by Day 8. The steroids were stopped after 3 months. Mycophenolate mofetil was used at 40 mg/kg/day given in divided doses from 1998 in our hospital. The white blood cell counts were maintained above 4000/mm³. Methylprednisolone pulse therapy (10 mg/kg/day for 3 days) was the primary therapy for acute rejection.

Continuous variables were described as mean values and ranges, and categoric data by proportions. Log rank tests were employed to identify categorical prognostic factors for graft survival of pediatric renal transplantation, and Cox regression analysis for numeric factors. Prognostic factors including acute rejection, gender, age at transplantation, donor type, donor age, and HLA mismatch were analyzed using NCSS statistical analysis and graphics software 2000 for Windows.

3. Results

There were 25 transplantations, 14 of whom were boys (56%) and 11 were girls (44%) with a mean age of 11.6 ± 3.76 years (range 1.75–16 years; Table 1). Among the study participants, one patient underwent renal and heart transplantation and one had undergone renal transplantation twice. Most of the recipients underwent the transplant between 12 and 15 years of age, followed by those aged 7–11 years.

Table 1. Age distribution of the transplant recipients.

Patients, n	<2 yr	2–6 yr	7–11 yr	12–15 yr	16–18 yr
Male	1	0	2	10	1
Female	0	1	6	2	2

All of the patients had end-stage renal disease before transplantation. The diagnoses included chronic glomerulopathy (n = 5), lupus nephritis (n = 2), reflux nephropathy (n = 1), angiomyolipoma (n = 1), polycystic disease (n = 1), bilateral renal artery stenosis (n = 1), and congenital renal hypoplasia (n = 1). However, for more than one-half of the patients (n = 13), the underlying etiology was unknown. The patients underwent renal replacement therapy including hemodialysis (40%), peritoneal dialysis (16%), alternating between hemodialysis and peritoneal dialysis (8%) and without treatment (36%) before transplantation.

There were 15 living donor transplantations (60%), and the mean age of the donors was 40.8 years (25–50 years). There were 10 deceased donor transplantations (40%), and the average age of the deceased donors was 22.8 years (7–44 years). The HLA mismatches ranged from 1 to 6, and the average was 3 ± 0.6. The most common vascular anastomosis sites were the external iliac artery (60%) and the external iliac vein (68%) to the renal artery and renal vein (Table 2). Other artery anastomosis sites were the common iliac artery (24%), internal iliac artery (8%), and descending aorta (8%). Besides the external iliac vein, the common iliac vein (16%) and inferior vena cava (16%) were chosen as the venous anastomosis site. Only one person with transplantation received ipsilateral nephrectomy.

Table 2. Vascular anastomosis sites.

Vascular anastomosis (n = 25)	Artery	Vein
External iliac/internal iliac	15/2	17/0
Common iliac	6	4
Aorta/inferior vena cava	2/0	0/4

After renal transplantation, the mean serum creatinine level on postoperative Day 7 was 1.14 ± 0.72 mg/dl. All of the patients in this study series had immediate graft function. The average follow-up period was 49.24 ± 33.72 months. There was no surgical mortality and all of the patients were alive during the follow-up period. The 1-, 2- and 3-year graft survival rates were 92%, 87.62%, and 82.14%, respectively, and the 1-, 2- and 3-year rejection-free survival rates were 88%, 78.96%, and 72.88%, respectively.

There were four graft failures after transplantation; the first case was an 11-year-old boy who underwent renal transplantation twice. In his case, graft failure occurred the first time due to venous thrombosis. Although the second graft was followed-up for 9 months, failure resulted due to acute rejection with ureter stricture. Thus, this case accounted for the failure of two grafts resulting from two surgical complications. Another surgical complication, urinary leak, occurred in a 1-year, 8-month-old recipient. Fortunately, revision ureteroneocystostomy solved the problem and rescued the graft. A third case of graft loss occurred in a 15-year-old boy who had acute rejection 34 months after transplantation. The fourth graft loss was in a 13-year-old girl who was followed-up for 18 months; in her case, acute rejection was also the main reason for graft failure.

The other postoperative complications in our patients were mostly infections, including pneumonia n = 4), urinary tract infection (n = 3), acute gastroenteritis (n = 3), and other miscellaneous infections. All of the infectious complications were successfully treated with antimicrobial agents and support treatment. One of our patients had post-transplant lymphoproliferative disease (B cell lymphoma) and was cured using monoclonal rituximab antibodies, which target the CD20 marker on B lymphoma cells. All of the post-transplant complications are listed in Table 3.

Table 3. Post-transplant complications in the pediatric renal transplantations (n = 25).

Complications	Diagnosis	Patients, n (%)
Surgical	Renal vein thrombosis	1 (4.0)
	Ureter implantation/urinary leakage	2 (8.0)
Oncological	Post-transplant lymphoproliferative disease	1 (4.0)
Infectious	Bronchopneumonia/pneumonia	4 (16.0)
	Urinary tract infection	3 (12.0)
	Acute gastroenteritis	3 (12.0)
	Wound abscess	1 (4.0)
	Epididymitis	1 (4.0)
	Chickenpox	1 (4.0)
	Herpes simplex	1 (4.0)
	Acute otitis media	1 (4.0)

Survival analysis was performed to identify the prognostic factors for renal transplant graft survival (Table 4). In our cohort study, a total of six cases were compatible with acute rejection. There were four cases of acute cellular rejection and one of acute cellular rejection with antibody mediated rejection by pathological diagnosis. Only one case was diagnosed by clinical diagnosis, and this case responded to steroid pulse therapy. Acute rejection and recipient gender were found to be significant prognostic factors for graft survival (p = 0.0175 and 0.0384, respectively). The 3-year graft survival rates for patients with and without acute rejection were 50.00% and 94.74%, respectively. The male and female patients had 64.29% and 100% graft survival rates, respectively, at 3 years. The patients who had live and deceased donors had 92.31% and 66.67% 3-year graft survival rates, respectively. Neither donor source nor immunosuppressive drugs were significant prognostic factors for graft survival, which may be explained by the small sample size and different follow-up periods.

Table 4. Survival analysis for the prognostic factors of renal transplant graft survival.

Log-rank test	Category	Patients, n	3-yr graft survival, %	p value
Acute rejection	Positive	6	50.00	0.0175
	Negative	19	94.74
Recipient sex	Male	14	64.29	0.0384
	Female	11	100.00
Donation source	Living	15	92.31	0.1307
	Deceased	10	66.67
Immunosuppressiona	Tacrolimus	17	93.33	0.1921
	Cyclosporine	7	71.43

Coxs regression	Regression coefficient	Standard error	Risk ratio	p value
Donor age (yr)	−0.0383	0.0380	0.9624	0.3385
HLA mismatch	0.1948	0.4302	1.2151	0.6599
Recipient age (yr)	0.0338	0.1388	1.0344	0.8027

HLA = human lymphocyte antigen.

a. One patient with renal vein thrombosis did not receive immunosuppressive drugs.

Patient age, donor age, and HLA mismatch were not significant factors for graft survival.

4. Discussion

Children with end-stage renal disease can receive long-term dialysis therapy; however, the mortality rate for these children is estimated to be 30 times higher than for those without chronic kidney disease, and four times higher than for those who receive renal transplantation.¹ Renal transplantation is a safe and effective surgical procedure to help children with end-stage renal disease. In our series, no patients died during the transplant follow-up period, and the 3-year graft survival rate was 82.14%, compatible with that of the University of Minnesota.⁴ Nevertheless, all of our patients had immediate graft function, suggesting that the operative techniques, including live donor nephrectomy, deceased donor nephrectomy and transplantation for the recipients, were effective.

Overcoming the size discrepancy between small pediatric recipients and large adult organs is essential for the success of pediatric renal transplantation. We used an absorbable mesh to facilitate closure of the abdominal wound without compression of the graft. In addition, with the application of absorbable mesh, pediatric recipients may not need to receive ipsilateral nephrectomy to increase the abdominal capacity. In our series, the youngest recipient was aged 1 year and 8 months, and he did not require ipsilateral nephrectomy to receive his mothers kidney. Ipsilateral nephrectomy was conducted in only one case, a 2-year-old girl only weighing 10 kg who received a large renal graft from her father who weighed 70 kg.¹⁶ Ipsilateral nephrectomy, which increases the transplant operation time and risk, may therefore be omitted from pediatric renal transplantation.

As we did not routinely remove the ipsilateral native kidney, we performed vascular anastomosis mostly in the external iliac artery and vein, instead of the inferior vena cava and descending aorta. It has been reported that a higher success rate can be achieved in pediatric renal transplantation when the site of vascular anastomosis is the inferior vena cava and descending aorta rather than the external iliac artery and vein.^{9 ;  14} However, we had a low incidence of vascular complications and acceptable outcomes employing mesh repair to accommodate the relatively protruding low poles of the graft kidneys. In addition, we believe that an extraperitoneal approach to pediatric renal transplantation can facilitate wound closure, early feeding and oral immunosuppression, which are all extremely important for the success of pediatric renal transplantations.^{14 ;  17}

In this study, acute rejection and recipient sex were found to be statistically significant factors by log-rank analysis. Since renal function can be damaged by allograft rejection, acute rejection should be the decisive factor for the long-term outcomes of renal transplantations. Interestingly, male gender was also a significant prognostic factor for pediatric renal transplantation. Six patients experienced acute rejection in our series, of whom four were boys. Based on the history taken from family members and the patients' immunosuppressive drug levels, nonadherence to the immunosuppressive regimens was highly suspected as the reason for acute rejection and graft failure.

Nonadherence to immunosuppressive medications is one of the main factors contributing to graft rejection, graft loss, and mortality.^{12 ;  18} An inexplicably low trough level of immunosuppressive drugs is proof that medications have been omitted. On the other hand, an unexpectedly high level also indicates non-adherence to the medications. We hypothesize that boys tend to be more active and are thus less likely to adhere to the immunosuppressive drugs.¹² However, we did not have any standardized methods of assessing adherence in this study.

As for donor source, pediatric transplants from deceased donors have been reported to have higher acute rejection rates than those from live donors.^{4; 7 ;  9} Live donors, therefore, should be a better source of choice to avoid acute rejection in pediatric renal transplantation. However, the difference in graft survival rates between living (92.31%) and deceased (66.67%) donors did not reach statistical significance in our study, although this may be because our patient number was small.

In conclusion, we found that renal transplantation is now a safe and effective surgical procedure to help children with end-stage renal disease. Acute rejection and male sex were identified as prognostic factors for poor graft survival rate.

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