INTRODUCTION
Kidney transplantation (KT) is the treatment of choice of pediatric end-stage renal disease (ESRD).[12] More than 17,000 thousand pediatric kidney-only transplants were performed in the United States between 1987 and 2012.[3] The prevalence of pediatric transplantation is low in developing countries <1–5 per million child population.[4] In Saudi Arabia, the prevalence of pediatric transplantation was 1.65 people per million constituting 8.5% of all renal transplantations.[5] The clinical outcomes after pediatric kidney transplantation have improved significantly over time for all recipient subgroups, especially for highly sensitized recipients. Most graft and patient survival improvements have come in the 1st year after transplantation,[3] with 1- and 5-year graft survival of 96% and 81%, respectively.[4] Few studies addressed pediatric renal transplantation in the Arab region, including Saudi Arabia; this study aims to review our center pediatric KT outcomes.
METHODS
Study design
A retrospective chart review-based cohort study involving 63 pediatric renal transplants was performed at the Armed Forces Hospitals Southern Region, the only transplant center in the south of Saudi Arabia, between November 2013 and March 2020. After approval from the Institutional Review Board Code: AFHSRMREC/2021/SURGERY/501, official written consent was taken to conduct the study from the parents of all patients. Donors and recipients' medical records were reviewed. The variables analyzed were the etiology of ESRD in the recipients, relationship to donors, kidney retrieval procedure, donor renal vascular anomalies, surgical complications, rejection episodes, immunosuppression regimens, compliance to immunosuppression, graft survival at 1 and 5 years, and overall patients' survival at 1 and 5 years.
Inclusion and exclusion criteria
We included all pediatric patients [between 2–18 years of age] who underwent renal transplants at the Armed Forces Hospitals Southern Region between November 2013 and March 2020. Standardized recipient selection and management were followed with no exclusion criteria used.
Definitions
Delayed graft function (DGF) was defined as the need for dialysis for any reason in the 1st week following transplantation. Renal allograft loss was defined as death with a functioning kidney graft, allograft nephrectomy, resumption of dialysis, re-transplantation, or return to the pretransplant serum creatinine (SCr) level. Chronic graft dysfunction was defined as a persistently raised SCr of 2 mg/dL or more for more than 3 months.
All recipients underwent a comprehensive pretransplant medical, psychosocial, and financial evaluation, emphasizing the cardiovascular system to determine operative risk. Table 1 summarizes the induction and maintenance immunosuppression used.
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Table 1: Immunosuppression
We used a standard open retroperitoneal surgical technique for all recipients. Regarding living donor nephrectomy, open and laparoscopic nephrectomies were performed in 41 (83.7%) and 8 (16.3%), respectively. We started the laparoscopic donor nephrectomy in 2017 by a well-trained surgeon who passed the learning curve before joining us.
Posttransplant, all patients received surgical site prophylaxis with a first-generation cephalosporin for 24 h, antifungal prophylaxis with nystatin for 1 month, and anti-pneumocystis prophylaxis with sulfamethoxazole-trimethoprim 5 mg/kg/day trimethoprim component once daily (dapsone if allergic to sulfa) for at least 12 months. Antiviral prophylaxis consisted of oral valganciclovir with the dose of 7 × body surface area × creatinine clearance, to a maximum dose of valganciclovir of 900 mg once daily for 3–6 months. Depending on donor and recipient cytomegalovirus serologic status, posttransplant renal allograft function was evaluated by measuring SCr levels and estimating glomerular filtration rate using the revised Schwartz equation.[6]
Study outcomes and statistical analysis
Endpoints included patient survival as well as uncensored and death-censored graft survival. Other study endpoints included DGF and renal allograft function and posttransplant medical complications and their management. Data were placed on an SPSS 13.0 spreadsheet (SPSS Inc., Chicago, IL, USA) for analysis.
Actuarial patient and graft survival curves were also computed using the Kaplan–Meier method. Categorical data were summarized as proportions and percentages, and continuous data were summarized as means and standard deviations.
Declaration of patient consent
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.
Ethics statement
The study was performed according to the guidelines in Declaration of Helsinki. Armed Forces Hospitals Southern Region ethical committee, IRB number: AFHSRMREC/2021/SURGERY/501.
RESULTS
Between November 2013 and March 2020, we performed KT in 63 children, 2 through 18 years of age (mean: 11.7 ± 3.75), including 43 (68.2%) patients who were aged 14 and younger with average body mass index (BMI)-height-age-z of 66.05 ± 6.65 percentile. Sixty-three recipients were included: 25 (39.7%) males and 38 (60.3%) females.
Forty-nine (77.8%) and 14 (22.2%) patients received living and standard criteria of brain death donor KT, respectively. Eight (16%) living donors were unrelated. Male donors constitute 59% and 100% of living and cadaveric KT, respectively. The donors' mean age was 30 ± 7.65 and 45.8 ± 9.61 years in living and cadaveric KT, respectively. Moreover, the donors' mean BMI was 27 ± 2.58 and 24.25 ± 3.48 in a living donor and a deceased donor, respectively. The right kidney was used in three patients from a living donor group and one from a deceased donor group. Five donors in the living donor group had complex vascular anatomy: three with two renal arteries, one with two renal veins, and one with a retro-aortic vein. Forty-one (65%) and 8 (35%) donors underwent open and laparoscopic nephrectomy, respectively. The average warm ischemia time was 1.6 ± 0.7 and 5 ± 2.1 min in open and laparoscopic nephrectomy, respectively [Table 2].
Table 2: Living versus deceased donor renal transplantations
The patients were followed up for a mean of 4.76 ± 3.4 years. The most commonly known etiologies of ESRD were Focal segmental glomerulosclerosis focal segmental glomerulosclerosis, posturethral valve, and dysplastic kidney (9.5% each), followed by systemic lupus (6.3%) and medullary sponge disease (3.2%). The reason for renal failure was unknown in 30% of cases. In the living donor KT group, 22 (44.8%) and 5 (10.4%) patients were on HD and PD, respectively. However, in the deceased KT group, 9 (64.3%) and 1 (7.1%) patients were on HD and PD, respectively. Twenty-six patients in both the groups (41.4%) had the preemptive transplant. The average duration on dialysis was 18.3 months [Table 2].
Thymoglobulin and basiliximab were used as induction therapy in 37 (58.7%) and 26 (41.3%) patients, respectively. Thymoglobulin was used in all patients before 2013 and in 29% of patients after that. All patients received triple immunosuppressive therapy: Tacrolimus, prednisolone, and mycophenolate mofetil. Surgical technique: Retroperitoneal implantation was done in all cases. Anastomosis to the aorta inferior vena cava and aorta common iliac vein was performed in 4 and 3 patients, respectively (average weight of these patients was 15 ± 4.1 kg). Moreover, common iliac artery-common iliac vein and common iliac artery-external iliac vein were used for vascular implantation in 35 and 21 patients, respectively.
In all cases, extravesical anastomosis between spatulated donor ureter and recipient bladder (neoureterocystostomy) with ureteral stent was performed. The stent was removed in 4–6 weeks. There were no problems in the closure of the wound in any patient. There are no cases with bladder dysfunction that required bladder augmentation in this series. The average period of stay in the hospital after transplantation was 8 ± 2.1 days.
Using the Clavien–Dindo classification grading system, posttransplant medical and surgical complications included hypertension (Clavien–Dindo Grade II), as the most common complication in the postoperative period and on long-term follow-up. Most of our patients were on one antihypertensive drug to control their blood pressure (54%), while 16% were on two or three medications. Pretransplant hypertension was diagnosed in 28 (43.7%) patients. Among them, 12 (42.9%) patients did not have any other obvious cause of chronic kidney disease. With regard to antihypertensive treatment, calcium channel blockers and beta-blockers were prescribed for 23 (82%) and 10 (36%) hypertensive patients, respectively. Moreover, a combination of calcium channel blockers and beta-blockers and angiotensin-converting enzyme inhibitors was prescribed for 6 (21.43%) and 3 (10.7%) patients, respectively.
Diabetes was diagnosed in 23% of patients (Clavien–Dindo Grade II). Acute rejection occurred in 11 (17.5%) patients (Clavien–Dindo Grade II). Usually, it was due to patient noncompliance with immunosuppression. However, most of them (85%) responded very well to treatment (pulse steroid plus antithymocyte globulin for cellular rejection or pulse steroid plus intravenous immune globulin and plasmapheresis in antibody-mediated rejection [ABMR]). There was no significant correlation between age at the time of transplantation, sex, source of the donor, year of transplant, and occurrence of acute rejection. Infections (Clavien–Dindo Grade II): A total of 10 episodes of infection (16%) related to the graft were encountered. Urinary tract infection by Escherichia coli was the most frequent organism. All patients responded to appropriate antibiotic therapy. No patients needed graft nephrectomy for intractable infection, or had an infection of the surgical wound or perinephric infection. Infections not directly related to the transplanted graft included respiratory infection, viral or bacterial, seen in 3 (4%) patients and bacteremia and line sepsis in 6 (9.5%) patients. There was no significant correlation between the occurrence of infection and rejection episodes.
No patients developed posttransplant lymphoproliferative disorder or malignancies. One patient developed thrombotic microangiopathy that was successfully treated by switching her to sirolimus 1 mg PO once daily. Her renal function after 30 months is normal. For graft dysfunction, there was no primary nonfunction. Four (6.3%) patients had DGF (Clavien–Dindoclassification Grade IVa) required dialysis for a mean duration of 2 weeks, three of them after deceased donor KT. Graft loss (Clavien–Dindo Grade IVa): Seven (11%) patients due to severe acute rejection, antibody and/or cell-mediated (57%), primary chronic allograft nephropathy (28.5%), and hyperoxaluria (14.5%). One patient had ureteric stricture 2 years posttransplant, and ureteric re-implantation was done. No major postoperative bleeding, renal artery, or vein thrombosis was reported. One patient developed a lymphocele that was treated conservatively.
With a mean follow-up of 55 months, 1-and 5-year graft survival rates for living-related and deceased donors were 97.2% and 86.4% and 96.4% and 76%, respectively. One-and 5-year patient survival rates were 100% [Table 2 and Figure 1]. There was no significant difference in the overall patient survival between the living and cadaver donor recipients up to 10 years of follow-up. There is no re-transplant. Outcomes were similar in patients < or ≥10 years and both sexes. The graft survival was comparable in laparoscopic versus open donor nephrectomy (P = 0.72).
Figure 1: Overall actuarial patient and graft survival
DISCUSSION
In our study, the most common age group was 2–14 years (68%), and our mean age was 11.7 ± 3.75 years. While according to the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2014 annual report, the most common age group was 13–17 years (39.2%), and 52.7% of patients were at or below 12 years of age.[7] It is thus clear that transplantation is performed in comparatively younger children (range: 6–12 years) in our setup. This difference may be attributed predominantly to the lack of a cadaveric donor program. The annual report of the NAPRTCS in 2014 also states that 40.9% of pediatric transplant recipients were female compared to 60% in our series.[7] Forty-one percent of the transplants were preemptive in our series as compared with 25% in the NAPRTCS registry;[7] this might be explained by the higher availability of living donors in our community from parents siblings, and other family members. It is also worth mentioning here that 77.7% of patients in this series received living donor renal transplantation compared with the NAPRTCS registry data, which showed 50% from cadaveric donors.[7] The mean age of the donors in our study was 30.73 ± 8.61 years, comparable to 37.6 ± 7.5 years as mentioned by Mehrabi et al.[8]
In a series by El Atat et al., the authors used the common iliac artery for anastomosis in 50 (96%) cases and the internal iliac artery in 2 (4%) patients.[9] Similarly, most arterial anastomoses were to the common iliac arteries in our series. Emiroğlu et al. in their series of 73 patients had reported the incidence of perirenal hematoma that required early postoperative re-exploration in 2 (2.7%) patients, lymphocele in 4 (5.5%) cases, and urinary leakage in 1 (1.4%) case, which resolved spontaneously in all 5 patients.[10] In other series, the incidence of lymphocele ranges from 0% to 20%.[11] The incidence of transplant renal artery stenosis ranges from 1% to 23% in different series on pediatric renal transplantations.[91213] Decreased blood supply to the donor ureter and faulty surgical techniques are the leading causes of urologic complications; however, other problems, such as immunosuppressive drugs and rejections, can cause late obstruction. However, low-dose steroid protocols and meticulous operative techniques tend to reduce incidence or urologic complications.[14]
In a recent study by Beetz et al., perioperative surgical complications requiring revision were observed in 15.4% of cases. Leading causes for revision were vascular complications such as thrombosis or stenosis 6.8%, which were more common in the case of young donors (i.e., donor age <6 years, previous nephrectomy, and en bloc grafts, followed by postoperative hemorrhage 4.5%, ureteral complications 3.6%, and lymphoceles 3.2%. Furthermore, they stated that these surgical morbidities did not significantly affect graft survival.[15]
In our cohort, postsurgical complications were noted in two patients. We had 1 (1.58%) patient of ureteric stricture compared with the literature (2.5%–25%).[11161718] Fortunately, we had no postoperative bleeding, renal artery or renal vein thrombosis, renal artery stenosis, or lymphocele complications. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because there remain many unidentified potential antigens leading to ABMR, children and adults are at different stages of their immune system development, and, thus, the full pathophysiology of alloimmunity is still not completely understood, and the efficacy and safety of treatment in adults may not be directly translated to children.[19] Hart et al. found that in the 2016–2017 cohort, the overall incidence of acute rejection within the 1st year was 11.4%, with some variation by age: highest for ages younger than 6 years (12.5%) and lowest for ages 6–10 years (7.9%).[4]
In our cohort, we had 11 (17.5%) patients who had acute rejection; usually, it was due to medications' noncompliance. There was no significant correlation between age at the time of transplantation, sex, source of the donor, year of transplant, and occurrence of acute rejection.
While Oomen et al. concluded that negative prognostic factors of graft function were higher donor age and higher recipient age, presence of obstructive uropathology, a re-transplant, and the occurrence of BK viremia,[20] El-Husseini et al. stated that the independent determinants of graft survival in live donor pediatric and adolescent renal transplant recipients are acute rejection and posttransplant hypertension.[21] Kidney transplantation in pediatric patients has become a routinely successful procedure owing to precise surgical techniques, better immunosuppressive management, and early diagnosis/effective treatment of complications. One and 5 year patient survival rates were 98% and 94%, and 1 and 5 year graft survival rates were 93% to 95% and 77% to 85%.[12223] The NAPRTCS registry data show 1- and 3-year graft survival rates of 96.4% and 93.4% (2007–2013) in living donor renal transplantations.[7] Moreover, for the cohort of recipients who underwent a transplant in 2009–2013, graft survival was highest for living donor recipients aged younger than 11 years (93.1% at 5 years) and lowest for deceased donor recipients aged 11–17 years (77.2% at 5 years).[4] In the developing country, the patients' survival rate at 1 and 3 years posttransplant was nearly 100%. The corresponding graft survivals were 97.1%, 94.12%, and 91.2%, respectively.[24]
Greco et al. have reviewed various methods of live donor nephrectomies by systematically analyzing 57 comparative studies available in the literature. There was no difference in functional graft outcome between open and laparoscopic donor nephrectomies.[25] Likewise, we also found no significant difference in outcomes between the two groups. In our cohort, there was no difference in graft survival between donor kidneys with single or multiple arteries, which was similar as reported in the literature.[26] Srivastava et al. found that only 61% of the patients were strictly compliant to immunosuppressant whereas at 5 years posttransplant.[27] Shellmer et al. concluded that noncompliance is more prevalent in adolescent transplant recipients than younger children. Low-income family and child functioning are risk factors of nonadherence.[28] In our cohort, noncompliance was the main reason for graft loss.
Limitations
It is a single center study. Similar studies across multiple centers may help validate the results stuadies.
CONCLUSION
Renal transplant in pediatric patients is a safe procedure in our practice setting, based on patient and graft survivals, with a low graft loss rate from surgical problems. Despite the low volume of cases, our center shows success with pediatric renal transplant procedures. Still, there is room for improvement by expanding the paired exchange program and increasing the number of laparoscopic donor nephrectomies.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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