Kidney transplantation in children: Outcomes

INTRODUCTION — Kidney transplantation remains the best treatment for children with end-stage kidney disease. Kidney allograft and patient survival have increased with improvements in the care of young patients and advances in immunosuppressive therapy. (See "Overview of kidney replacement therapy for children with chronic kidney disease", section on 'Preemptive transplantation as preferred kidney replacement therapy modality'.)

Outcome of kidney transplantation and the factors that affect allograft and patient survival in children will be reviewed here.

General principles of immunosuppression and complications of kidney transplantation in children are discussed separately. (See "Kidney transplantation in children: General principles" and "Kidney transplantation in children: Immunosuppression" and "Kidney transplantation in children: Complications".)

In addition, issues of kidney transplantation survival and outcome that are common to both children and adults are presented in separate topic reviews. (See "Kidney transplantation in adults: Risk factors for graft failure" and "Kidney transplantation in adults: HLA matching and outcomes".)

FACTORS AFFECTING ALLOGRAFT SURVIVAL — The outcome of kidney transplantation in children has improved over the last several decades [1-5]. This was illustrated in a study based on data from the United States Scientific Registry of Transplant Recipients that reported improvements of one-year graft survival for transplants performed in 1987 versus 2010 (81 versus 97 percent), five-year graft survival for transplants performed in 1987 versus 2006 (59 versus 78 percent), and 10-year graft survival for transplants performed in 1987 versus 2001 (47 versus 60 percent) [2]. (See "Kidney transplantation in children: Immunosuppression" and 'Effect of immunosuppressive regimens' below.)

Factors that affect allograft survival in children include the following [6-16]:

●Improved immunosuppressive regimen

●Source (living versus deceased donor) of donor kidney and age of donor

●Preemptive transplant

●Human leukocyte antigen (HLA) compatibility

●Recipient factors (eg, age and race [17])

●Delayed graft function (DGF)

●Acute rejection

●Infections

●Adherence

●Repeat transplant [18]

●Underlying primary disease

Effect of immunosuppressive regimens — Since the earlier days of pediatric kidney transplantation, the development of the immunosuppressive agents used in current practice improved allograft survival [7,10,16,19-23]. In particular, the use of calcineurin inhibitors (particularly tacrolimus) and the change in antimetabolite agent from azathioprine to mycophenolate mofetil have reduced the incidence of acute rejection and graft survival [10,22,23]. Immunosuppressive agents and their effects on graft survival are discussed separately. (See "Kidney transplantation in children: Immunosuppression".)

Donor source and age

●Living versus deceased donor – Allograft survival is higher in children with living donor allografts compared with those with deceased donor allografts, with reported 9 to 35 percent improvement in five- to seven-year allograft survival rates [10,24,25]. Despite the general desirability of living donor allografts, a deceased donor may be preferred in settings in which there is a high risk of recurrent disease leading to loss of the allograft, as with rapidly progressive focal glomerulosclerosis. Support for this exception is provided by the finding that five-year allograft survival of living and deceased donor allografts was not significantly different for children with focal glomerulosclerosis (69 and 60 percent) [26]. Other diseases with a high recurrence rate in the allograft include atypical hemolytic uremic syndrome and primary hyperoxaluria. (See "Kidney transplantation in children: General principles", section on 'Donor choice'.)

●Donor age

•Deceased donors – Poorer allograft survival is associated with the transplantation of kidney allografts from deceased donors younger than two years of age or older than 50 years of age [27,28]. In the former, poorer allograft survival may be due to a higher incidence of primary nonfunction and allograft thrombosis.

Data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry showed the following five-year allograft survival of kidneys from deceased donors based on donor ages [10]:

-<2 years of age – 51 percent

-2 to 17 years of age – 68 percent

-18 to 49 years of age – 73 percent

-≥50 years of age – 58 percent

In a study based on United Network for Organ Sharing data from 1987 to 2003, en bloc kidney transplantation compared with single kidney had a lower rate of DGF and better five-year allograft survival when deceased donors were younger than five years of age [29].

•Living donors – In contrast with data regarding deceased donors, allograft failure is similar in older living donors (age 50 to 75 years of age) compared with younger-aged living donors [30].

Preemptive transplant — Several studies have reported improved allograft and patient survival of preemptive transplantation compared with transplantation performed after treatment with dialysis, as illustrated by the following [12-15,31,32]:

●For first kidney transplants in children, the Eurotransplant registry reported a six-year graft survival of 82 percent in patients receiving a preemptive transplant compared with 69 percent in those undergoing dialysis [31]. Preemptive transplantation also resulted in lower rates of acute rejections (52 percent versus 37 percent rejection-free at three years).

●Multivariate analysis of data from the United States Renal Data System showed that preemptive transplantation was associated with lower allograft failure (hazard ratio 0.75, 95% CI 0.64-91) and mortality (hazard ratio 0.59, 95% CI 0.43-0.82) compared with children on dialysis for >1 year or those on dialysis >18 months over a median four-year follow-up [32].

Human leukocyte antigen matches — Similarly to adults, superior HLA matching between recipient and donor, whether deceased donor or living related, is associated with improved allograft outcomes in children [33-38]. (See "Kidney transplantation in adults: HLA matching and outcomes".)

Identical HLA matches result in the best outcomes. However, children rarely have brothers or sisters (some of whom are HLA identical) old enough to be an organ donor; as a result, most living donated allografts are from a parent, who is an obligate one haplotype match. Optimal HLA matching is preferred to minimize sensitization, particularly for young recipients who will need retransplantation [34-36]. (See "Kidney transplantation in adults: HLA matching and outcomes", section on 'Long-term graft survival'.)

The impact on HLA matching for pediatric kidney transplantation was highlighted by an analysis from the United Kingdom Transplant Registry that reported better 10-year graft survival rates from deceased donors with only zero to one HLA mismatches versus living donors with four to six HLA mismatches [37].

However, maximization of HLA matching is not entirely beneficial for those awaiting a deceased donor allograft. Restricting deceased donor offers to only well HLA-matched donors may significantly prolong the transplant candidate's wait time, increasing morbidities associated with end-stage kidney disease and dialysis. In addition, improved matching may not prolong long-term graft survival in children who receive deceased donor allograft [39,40].

Recipient factors

●Age – In the past, the results of kidney transplantation in children appear to vary with the age of the recipient, with younger recipients having poorer outcome [10,41]. With the improvement in care, similar excellent long-term allograft survival to that of older children is seen in young children [42-44], especially in those who receive living donor kidneys [10,42].

Data from 2014 NAPRTCS registry show the following five-year survival rates based on donor source and recipient age [10]:

•Living related donor, recipient age between:

-0 to 1 year of age – 84 percent

-2 to 5 years of age – 86 percent

-6 to 12 years of age – 84 percent

->12 years of age – 79 percent

•Deceased donor, recipient age between:

-0 to 1 year of age – 63 percent

-2 to 5 years of age – 75 percent

-6 to 12 years of age – 73 percent

->12 years of age – 68 percent

For adolescents who are at increased risk of allograft failure, contributory factors include nonadherence and transition to adult care during this vulnerable period [41,45-49].

●Race – In the United States, multivariate analysis of data from the United States Renal Data System (kidney transplant from 2000 through September, 2011) reported that Black children had poorer graft survival over a median follow-up time of 4.5 years compared with White and Hispanic children [17]. This analysis controlled for neighborhoods based on income level and source of health care insurance (public versus private).

Delayed graft function — DGF, defined by the need of dialysis during the first week or first 72 hours following transplantation, is associated with poor outcome [11,50,51]. Causes of DGF include postischemic acute kidney injury, vascular thrombosis of the renal artery or vein, urologic complications (ie, urinary leak or obstruction), and, rarely, hyperacute rejection due to preformed anti-HLA antibodies. (See "Kidney transplantation in children: Complications", section on 'Delayed graft function'.)

It occurs more frequently in patients who receive deceased donor allograft, and the incidence of DGF increases with cold ischemia time. In the NAPRTCS cohort, the five-year allograft survival was lower in patients receiving a deceased donor allograft with a cold ischemic time greater than 24 hours compared with those with a lower cold ischemic time (63 versus 72 percent) [10]. Intraoperative vascular volume maintenance is most important to prevent DGF, especially in young recipients.

Acute rejection episodes — In the 2014 NAPRTCS report, the rate of allograft failure or death due to acute rejection was 5 percent in children who received living donor kidneys and 8 percent in those with deceased donor kidneys [10]. In another cohort of children who received deceased donor allografts, the estimated allograft half-life was shorter in patients who had acute rejection episodes than in those who did not (6.6 versus 12.5 years) [52]. An analysis of Organ Procurement and Transplant Network [11] data also showed an increased relative risk of allograft failure for pediatric recipients who were treated for acute rejection in the first years post-transplant [11]. (See "Kidney transplantation in children: Complications", section on 'Acute rejection'.)

In addition to acutely threatening survival of the allograft, acute rejection episodes markedly increase the risk of developing chronic rejection, thereby enhancing possible allograft loss over time. In one study of nearly 3500 children, multivariate analyses found that the relative risks of chronic rejection increased with an acute rejection episode and were even greater with two such episodes (relative risk 3.1 and 4.3, respectively) [53]. Given this association, the prevention of such events by providing optimal immunosuppressive therapy is extremely important. The beneficial effects of improved immunosuppressive regimens and optimal HLA matching on allograft survival are, in part, because of their role in lowering the risk of acute rejection. (See "Kidney transplantation in children: Complications", section on 'Chronic allograft injury' and "Kidney transplantation in children: Immunosuppression" and "Kidney transplantation in adults: Chronic allograft nephropathy", section on 'Alloantigen-dependent factors'.)

Infections — Infections are a permanent risk in patients receiving immunosuppressive treatment and may impact allograft survival. (See "Kidney transplantation in children: Complications", section on 'Infections'.)

●Cytomegalovirus infection is associated with increased mortality and morbidity [54]. Prophylaxis of cytomegalovirus infection may be associated with improved patient and allograft survival. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients".)

●Polyomavirus, mainly BK polyomavirus, affects 3 to 8 percent of children with kidney allografts and may be responsible for allograft nephropathy and allograft failure. Risk factors for BK polyomavirus infection are intense immunosuppression and acute rejection. (See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy".)

●In contrast, there appears to be no correlation between a history of urinary tract infection (either before or after transplant) and decreased allograft survival [55]. (See "Kidney transplantation in children: Complications", section on 'Urinary tract infection'.)

Nonadherence — Nonadherence to immunosuppressive treatment contributes to both acute and chronic rejection. An analysis of the United States Renal Data System showed that, among pediatric kidney transplant recipients, greater adherence was significantly associated with improved long-term allograft survival [56].

A systematic review of the literature that identified 16 studies reported a wide range of nonadherence from 5 to 70 percent [57]. Among these studies, there was variability in how adherence was assessed (eg, drug level assays, pill counting, patient self-reporting). Factors associated with nonadherence included:

●Poor socioeconomic status

●Family/caregiver stress and conflicts

●Lack of parental\caregiver supervision

●Patient depression

●Cosmetic side effects of medications

●Large number of medications

●Size of tablets and difficulty swallowing tablets

●Taste of medication

●Poor patient knowledge

●Striving for increased autonomy and independence

Nonadherence is a risk factor for graft loss [14,24,48,49,57,58].

●In the 2010 NAPRTCS transplant report, 5 percent of primary allograft loss was due to patient discontinuation of medications.

●In a study based on Organ Procurement and Transplantation Network data, 3.4 percent of allografts in pediatric Black recipients were lost due to nonadherence as a contributory factor compared with 1.5 percent among other races [24]. Significantly lower incidence of nonadherence was observed in children under the age of 10 (0.9 percent) when compared with early adolescents aged 10 to 14 (2.2 percent) and older teenagers aged 15 to 20 (2 percent).

Although it is clear from the above evidence that increasing adherence would improve kidney transplantation outcome, data on interventions to improve adherence are lacking. One study conducted in adult transplant recipients showed that a multidimensional program including home visits, follow-up calls, and educational material resulted in a lower nonadherence in the intervention group compared with the control group over the three-month study period [59]. However, the differences between the two groups faded after nine months.

Primary disease — Allograft survival may be altered due to the underlying primary disease:

●Increased risk of recurrent disease is associated with focal glomerulosclerosis, atypical (complement-mediated) hemolytic uremic syndrome, and membranoproliferative glomerulonephritis, which may lead to kidney allograft failure [60]. (See "Kidney transplantation in children: Complications", section on 'Recurrence of primary disease'.)

●In patients with hyperoxaluria, oxalate continues to deposit in the transplant unless concomitant or sequential liver transplantation has been performed. (See "Primary hyperoxaluria", section on 'Transplantation'.)

●In contrast, although lower urinary tract malformations (eg, posterior urethral valves) are associated with bladder complications leading to potential urinary leaks and obstruction and infection, these do not appear to alter long-term allograft function [61-63]. (See "Kidney transplantation in children: Complications", section on 'Urologic complications' and "Kidney transplantation in children: Complications", section on 'Surgical and urologic sequelae' and "Management of posterior urethral valves", section on 'Renal transplantation'.)

PATIENT SURVIVAL — Patient survival is better in pediatric kidney transplant recipients than in adults, and mortality has decreased [1,41,64-69]. Data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) 2014 annual report showed that, for those transplanted since 1996, the three-year patient survival exceeded 98 percent in all recipients of living related or deceased donors [10]. The three-year survival rate has significantly improved for infants who received deceased donor allograft, from 78.6 percent for those transplanted between 1987 and 1995 to 94.8 percent in the cohort transplanted after 1996 [10]. The data from the United States showed similar improvements of patient survival, with five-year patient survival after receiving a first transplant of 90 percent in 1987, 93 percent between 1990 and 1994, and 95 percent between 1995 and 2004 [2,70].

Centers from other countries report similar results of improved patient survival in young children [71-73].

Survival with a functioning graft in children receiving a first kidney transplant has also increased [70]. In the United States, the survival rate with a functioning graft in children receiving a first kidney allograft from 1990 to 2010 was 82 percent over a median follow-up time of 8.4 years [70].

Mortality remains higher for infants compared with older children [1,10]. This was illustrated by the following three-year survival rates of children registered in the NAPRTCS database who were transplanted between 1996 and 2013, as follows [10]:

●Living donor:

•All recipients – 98 percent

•Recipients ≤1 year of age – 96 percent

•Recipients between 2 and 5 years of age – 98 percent

•Recipients between 6 and 12 years of age – 98 percent

•Recipients >12 years of age – 98 percent

●Deceased donor:

•All recipients – 98 percent

•Recipients ≤1 year of age – 95 percent

•Recipients between 2 and 5 years of age – 96 percent

•Recipients between 6 and 12 years of age – 99 percent

•Recipients >12 years of age – 98 percent

As with adults, survival is superior among children with a kidney allograft compared with those who remain on dialysis. This was best shown in an observational study of nearly 6000 patients under 19 years of age who were placed on the kidney transplant waiting list [74]. Compared with those who remained on the list, a significantly lower mortality rate was noted in those who underwent transplantation (13.1 versus 17.6 deaths/1000 patient-years). This survival benefit was observed beginning six months post-transplant.

Overall, the major causes of death are cardiovascular disease, infection, and malignancy [10,75-78]. The main causes of death during the first three months are infections (principally cytomegalovirus infection) and hemorrhage. However, the incidences of malignancies and cardiovascular disease are lower when compared with those reported for adults. (See "Kidney transplantation in children: Complications", section on 'Acute rejection'.)

Non-kidney manifestations of the underlying disease also may have an effect on patient survival. In one study comparing patient survival rates of children with and without autosomal recessive polycystic kidney disease (ARPKD), death resulting from sepsis due to cholangitis and liver involvement was a factor in those with ARPKD [79].

Mortality after transplantation is also affected by the underlying kidney disease, with higher mortality rates observed for oxalosis, congenital nephrotic syndrome, and Drash syndrome [80].

GROWTH AFTER KIDNEY TRANSPLANTATION — Although most children have improved statural growth after successful kidney transplantation, approximately one-half will attain normal height [81]. Factors associated with complete catch-up growth include excellent kidney allograft function (normal or almost normal glomerular filtration rate), corticosteroid-free immunosuppressive therapy, young age of recipient (less than six years of age), and living donor source [81-83]. (See "Growth failure in children with chronic kidney disease: Prevention and management", section on 'Reducing glucocorticoid exposure' and "Kidney transplantation in children: Immunosuppression", section on 'Glucocorticoid-sparing regimen'.)

Recombinant growth hormone therapy may be beneficial in improving growth in prepubertal children with growth impairment after kidney transplantation. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

OTHER COMPLICATIONS — Other long-term complications following kidney transplantation in children include hypertension, cardiovascular disease, recurrent infection, malignancy, type 2 diabetes, mineral-bone disorders, surgical sequelae, and recurrence of the primary disease, which affect graft survival. These are discussed elsewhere. (See "Kidney transplantation in children: Complications".)

SUMMARY

●Immunosuppression effect on graft survival – The outcome of kidney transplantation in children has improved over the last several decades, a period that coincides with the introduction and widespread use of calcineurin inhibitors and other immunosuppressive agents. (See 'Effect of immunosuppressive regimens' above.)

●Other factors affecting graft survival

•Donor source and age – Allograft survival is better with kidneys from living versus deceased donors. Poorer allograft survival is associated with kidney allografts from deceased donors younger than two years of age or older than 50 years of age. In the former, poorer allograft survival may be due to a higher incidence of primary nonfunction and allograft thrombosis. (See 'Donor source and age' above.)

•Preemptive transplant – Preemptive transplant is associated with improved allograft and patient survival compared with transplantation performed after dialysis treatment. (See 'Preemptive transplant' above.)

•Human leukocyte antigen (HLA) match – Better histocompatibility matching between donor and recipient improves allograft survival, with the possible exception of deceased donor allografts. (See 'Human leukocyte antigen matches' above.)

•Recipient factors – Although the overall allograft survival is excellent for recipients of all ages, infants and adolescent recipients have a poorer allograft survival rate. In the United States, Black children have a poorer allograft survival rate compared with White and Hispanic children. (See 'Recipient factors' above.)

•Delayed graft function (DGF) – DGF, defined by the need of dialysis during the first week or first 72 hours following transplantation, is associated with poor outcome. Causes of DGF include postischemic acute kidney injury, vascular thrombosis of the renal artery or vein, urologic complications (ie, urinary leak or obstruction), and, rarely, hyperacute rejection due to preformed anti-HLA antibodies. (See "Kidney transplantation in children: Complications", section on 'Delayed graft function'.)

•Acute rejection – Acute rejection episodes are associated with acute allograft loss. In addition, acute rejection is associated with chronic rejection and graft loss. (See 'Acute rejection episodes' above.)

•Infections – Infections due to cytomegalovirus or polyomavirus, mainly BK polyomavirus, are associated with decreased allograft survival time. However, urinary tract infections are not associated with graft loss. (See 'Infections' above.)

•Nonadherence – Nonadherence to immunosuppressive treatment contributes to both acute and chronic rejection. (See 'Nonadherence' above.)

•Primary disease – Increased allograft failure may be due to recurrent disease associated with focal glomerulosclerosis, atypical (complement-mediated) hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and primary oxaluria. (See 'Primary disease' above.)

●Patient survival – Patient survival is better in pediatric kidney transplant recipients than in adults and has increased. The major causes of death are infection and cardiopulmonary disease. (See 'Patient survival' above.)

●Growth impairment – Most children have improved statural growth after successful kidney transplantation. Catch-up growth is only observed with normal or nearly normal allograft function. The most important factors limiting growth after kidney transplantation are poor kidney allograft function and corticosteroid therapy. (See 'Growth after kidney transplantation' above.)

●Other complications – Children who receive a kidney allograft are at risk for long-term complications that include hypertension, cardiovascular disease, recurrent infection, malignancy, type 2 diabetes, mineral-bone disorders, and surgical sequelae, which may affect graft survival. (See "Kidney transplantation in children: Complications".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patrick Niaudet, MD, who contributed to earlier versions of this topic review.