Pediatric en bloc kidneys are traditionally considered “marginal” for transplantation into adults due to concerns for technical complications, graft thrombosis risk and hyperfiltration injury due to donor recipient body size and metabolic mismatch. There is evidence that pediatric en bloc kidneys undergo compensatory growth when exposed to the adult blood flow and metabolic demands.1,2 In one study, en bloc kidneys grew twofold by 3 to 6 months and nearly threefold by 6 months after transplantation.1 Animal studies have shown that predominant cell hypertrophy with minimal cell hyperplasia contribute to renal growth.3 Pediatric en bloc kidneys demonstrated functional reserve as evidenced by significant increase in both glomerular filtration rate (GFR) and renal plasma flow following amino acid loading.4 A similar response was absent in single adult kidneys. Growth of pediatric en bloc kidneys with functional reserve along with doubling of nephron mass from 2 kidneys could act as a cushion against hyperfiltration injury, thus potentially providing favorable function over an extended period of time. Excellent 1-year function of en bloc kidneys transplanted into adults with recipient to donor weight ratio up to 7.5 is consistent with this.5 Compared with adult deceased donor renal allografts, long-term function was superior with pediatric kidneys transplanted as either single or en bloc in previous studies.6-9
An earlier retrospective study from our center comparing outcomes of pediatric en bloc versus living donor kidney transplantation into adults found similar 5-year patient and graft survival but higher GFR up to 8 years of follow up and delayed onset of proteinuria in the en bloc kidney recipients.10 We now report extended long-term outcomes on this original group of patients.
MATERIALS AND METHODS
As mentioned, current study is an extension of the previously reported analysis that compared the outcomes of pediatric en bloc and living donor transplants performed at our center between January 1990 and December 2001.9 The study protocol was approved by the institutional review board. Data was obtained through retrospective chart review. The technique of pediatric en bloc kidney transplantation has been described in detail previously.10,11 Immunosuppression was similar between the groups including cyclosporine, azathioprine and prednisone prior to 1996 and cyclosporine, mycophenolate mofetil and prednisone for transplants between 1996 and 2001. The outcomes compared between the study groups in the present analysis included 25-year graft survival and graft function as estimated by annual GFR from years five through 17 posttransplantation. Abbreviated Modification of Diet in Renal Disease formula was used to estimate GFR.12
Values were expressed as either mean ± SD or as absolute numbers. Continuous variables were compared using one tail independent sample t test. Categorical variables were compared using χ2 test. Kaplan-Meier product limit method was used to generate graft survival curves. Graft was considered failed if patient returned to dialysis, got re-transplanted or died. Annual GFR was expressed as plot means with standard error bars. Linear mixed model was used to evaluate the long-term effects of each type of transplant on GFR. A P value less than 0.05 was considered statistically significant.
There were 72 pediatric en bloc and 75 living donor kidney recipients transplanted between January 1990 and December 2001 and included in the original study group.10 Demographic features of the groups are shown in Table 1. Pediatric donors were 16.9 ± 11.2 months old and weighed 10.7 ± 3.8 kg with terminal serum creatinine of 0.50 ± 0.45 mg/dL. Living donors were 40.1 ± 9.4 years old and serum creatinine was 0.90 ± 0.16 mg/dL at the time of donation. A creatinine clearance of at least 90 ml/min based on a minimum of two 24-hour urine collections was a requirement for eligibility as a living donor at our institution during the study period. Among the living donors, 58 were genetically related to the recipients and 17 were unrelated. There were no differences in the causes of native kidney failure including diabetes mellitus, hypertension, glomerular diseases and polycystic kidney disease between the groups. En bloc kidney recipients had higher dialysis vintage (23.0 ± 29.2 vs 14.3 ± 14.7 months, P = 0.03), and longer cold ischemia time (30.5 ± 9.8 vs 2.6 ± 0.9 hours, P < 0.001). Delayed graft function defined as need for dialysis within the first week of transplantation was more frequent in pediatric en bloc kidneys (26.4% vs 6.7%, P = 0.001).
Overall graft survival were similar between the pediatric en bloc and living donor kidney recipient groups up to 27 years of follow up as shown in Figure 1. Estimated GFR using Modification of Diet in Renal Disease equation was consistently higher in the pediatric en bloc kidney recipients as shown in Figure 2A. GFR was 33.0 mL/min higher in the pediatric en bloc kidney recipients at the beginning (P < 0.001). The slope of change over time did not significantly differ between the groups (P = 0.21). Individual plots of GFR in each group are shown in Figure 2B.
Our study showed equivalent long-term graft survival over 25 years of follow-up for pediatric en bloc kidneys transplanted into adults when compared with living donor kidney transplants. In addition, pediatric en bloc kidneys provided superior long-term function as evidence by the higher longitudinal GFR.
One concern with transplantation of pediatric en bloc kidneys is early surgical complications. Our initial report showed a 12.5% early graft thrombosis rate predominantly from donors younger than 12 months.10 A previous Organ Procurement and Transplant Network/United Network of Organ Sharing database analysis showed a 10% thrombosis rate for en bloc kidneys from donors younger than 5 years, and a recent large series reported a 15% graft loss from surgical complications.13,14 Risk factors for graft thrombosis identified in a large retrospective series involving 195 patients included older recipient age, donor weight less than 5 kg, intraoperative perfusion concerns, and right-sided allograft placement.15 Increased donor weight was found to be associated with higher rates of pediatric donor kidney recovery and single kidney transplantation (SKT) in a recent Organ Procurement and Transplant Network/United Network of Organ Sharing analysis.16 Risk factors associated with graft failure in this analysis included low donor weight, single versus en bloc transplantation, higher cold ischemia time, local versus non local donor and low versus high volume center. Previous studies have reported higher incidence of transplant renal artery stenosis (TRAS) thought to be related to small caliber renal arteries. There was a 6.4% incidence of TRAS among pediatric en bloc kidney recipients in our earlier report.10 However, in a recent large series involving 182 pediatric en bloc kidney transplants, only 2 patients developed angiographically proven TRAS.17
Estimated GFR was consistently higher in en bloc kidney recipients in our cohort. Our earlier analysis showed a longitudinal increase in GFR up to 5 years after en bloc kidney transplantation. This likely reflects the growth of en bloc kidney along with the higher “nephron dose” and functional reserve. Compared with living donor kidneys, the onset of proteinuria was delayed in en bloc kidneys (45.6 ± 33.6 months vs 23.4 ± 16.3 months, P = 0.002) which was independent of body mass index (BMI).10 Increasing recipient BMI was not a clear risk factor toward outcomes or graft function after transplantation with small pediatric kidneys in an analysis of patients from the Scientific Registry of Transplant Recipients.18 These observations argue against the concern for hyperfiltration injury in pediatric en bloc kidneys when exposed to adult hemodynamic stress.
In addition to our previous report and the current analysis, there has only been one other study to the best of our knowledge that compared outcomes of pediatric en bloc to living donor kidneys.19 In that study involving 20 en bloc kidneys, 5-year graft and patient survivals in en bloc group were similar compared with living donor kidney recipients. Five-year serum creatinine was also not significantly different between the groups.
A clinical question that frequently arises is the scenario when one can split en bloc kidneys safely for transplantation into 2 adults that results in acceptable outcomes. In 1 study, en bloc kidneys (n = 15) were separated for transplantation into 2 adults when each kidney measured greater than 6 cm long with a mean length of 6.3 ± 0.4 cm.20 Kidneys were transplanted as en bloc (n = 33) when individual kidney length was less than 6 cm with mean length of 5.8 ± 0.3 cm. Mean donor age and weight in the latter group were 16.0 ± 6.7 months and 10.8 ± 2.6 kg, respectively, similar to patients in our study. Longitudinal increments in creatinine clearance up to 12 months and 2-year graft survivals were similar between single kidney and en bloc kidney groups. Transplantation of pediatric kidneys 6 cm or greater in length as single into adults showed excellent outcomes with serial increase in glomerular size and improvement in creatinine clearance up to 12 months in another study.21 Traditionally, kidneys from donors 60 years or older and small pediatric donors are considered marginal. When compared with kidneys from donors 60 years or older, graft failure risk of pediatric single kidneys was consistently lower when donors weighed more than 10 kg in a previous registry analysis.22 A decision analysis model compared projected life years provided by transplantation of pediatric kidneys as either en bloc or single.23 There was a greater gain in life years by SKT into 2 recipients across all recipient age groups compared with transplanting kidneys as en bloc into 1 recipient except from donors weighing less than 10 kg where there was an estimated net loss of life years associated with SKT. Based on these observations, a pediatric donor weight around 10 kg and above or individual kidney length longer than 6 cm seem a reasonable target when en bloc kidneys can be separated for transplantation into 2 adults with acceptable outcomes.
Kidneys from donors younger than 12 months should be carefully evaluated for transplantation because of the increasing risk of thrombosis related to smaller donor vessels. Avoiding recipients with history of hypercoagulable state to reduce the risk for allograft thrombosis, along with early and aggressive hypertension management to minimize injury to these young kidneys are reasonable recommendations while considering en bloc kidney transplantation. Others have recommended avoiding high immunological risk patients for en bloc transplantation since early rejection can cause major functional renal mass loss thus hampering the ability of these kidneys to grow.24 Minimizing preservation time could also be beneficial.16
Retrospective design is a limitation for our study. However, relatively large number of pediatric en bloc transplants from a single center and extended follow up available add to the strength and validity of our findings.
In summary, pediatric en bloc kidneys conferred long-term graft survival similar to living donor kidneys over a 25-year period after transplantation along with superior graft function. This is despite an increased early thrombotic risk and delayed graft function. Special attention should be paid to minimize surgical complications and graft loss in the early posttransplant period. Superior GFR observed in the en bloc kidneys in the long term reflects higher “nephron dose” provided by the 2 mate kidneys that likely grew to adult size making them less susceptible to hyperfiltration injury. These findings support improved utilization of pediatric kidneys for transplantation into adults which not only helps to alleviate organ shortage but also provide excellent long-term function.
Presented as a poster at American Society of Nephrology Kidney Week, November 4, 2017, New Orleans, LA.
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