Kidney Transplantation in Children

Pornpimol Rianthavorn

Samhar I. Al-Akash

Robert B. Ettenger

Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1752

INTRODUCTION

Kidney transplantation is universally accepted as the therapy of choice for children with end-stage renal disease (ESRD). Approximately two thirds of pediatric patients with ESRD ultimately receive a kidney transplant. Successful transplantation in children and adolescents not only ameliorates uremic symptoms but also allows for significant improvement of delayed skeletal growth, sexual maturation, cognitive performance, and psychosocial functioning. The child with a well-functioning kidney can lead a quality of life that cannot be achieved by any dialysis therapy.

Current success in pediatric renal transplantation is attributed to improvements in transplantation technology, immunosuppressive therapy and the provision of age-appropriate clinical care (1). For pediatric patients of all ages, transplantation results in better survival than dialysis. Five-year survival rates in transplanted patients range from 94% to 97% while in dialyzed patients the survival rate ranges from 75% to 87%. Nevertheless, success in pediatric kidney transplantation is still a challenging undertaking. Children and adolescents are constantly growing, developing, and changing. Each developmental stage produces a series of medical, biologic, and psychological challenges that must be appropriately addressed if truly successful graft outcome and rehabilitation are to be realized.

Much of the statistical data reviewed in this chapter comes from databases that have provided an invaluable resource for the advancement of pediatric transplantation. These databases have permitted the evaluation and extrapolation of data from multiple pediatric renal transplant programs that tend to be small compared with their adult counterparts. Major databases referred to are the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), the Scientific Registry of Transplant Recipients (SRTR), and the United States Renal Data System (USRDS) annual report.

EPIDEMIOLOGY OF END-STAGE RENAL DISEASE IN CHILDREN

Incidence

The incidence and prevalence of treated pediatric ESRD have been increasing since 1989. As of 2000, the incidence rate of new cases of ESRD in children 0 to 19 years of age
was 15 per million U.S. child population per year. The point prevalence of ESRD in this population is 70 per million child population. The incidence of ESRD increases with age, with the highest incidence observed in children between 15 and 19 years of age (28 per million). Adolescents compose about 50% of treated pediatric ESRD patients.

There is a wide variation by race in the incidence rates of treated ESRD. African American children have the highest incidence rate of 27 per million, compared with 12 per million White, 15 per million Asians and Pacific Islanders, and 17 per million Native Americans. The incidence is higher in African Americans across all age groups but is most prominent in the 15- to 19-year-old age group (60 per million African Americans compared with 20 per million whites). Over the past 20 years, incident rates for white pediatric patients have remained constant, but for African American patients, and patients of races other than Caucasian, the rates of ESRD have more than doubled. The incidence of glomerulonephritis as a cause of ESRD is 2 to 3 times higher in African American pediatric patients than in Caucasians; there is no racial predilection in patients with congenital/hereditary/cystic diseases. According to the NAPRTCS dialysis registry, patients with focal segmental glomerulosclerosis (FSGS) make up almost 24% of all African American dialysis patients, and more than 30% of adolescent African American dialysis patients. Boys have higher incidence of treated ESRD than girls in all age groups.

Etiology

Glomerular diseases account for about 30% and congenital, hereditary, and cystic diseases for 26% of cases of pediatric ESRD (Table 14.1). While incidence rates for glomerular diseases have remained steady in the pediatric population, the incidence rates for patients with congenital, hereditary, and cystic diseases have trended upward over the past 20 years.

In contrast to adults, ESRD due to diabetes mellitus or hypertension is rare in children. Children appear to start ESRD therapy with a higher estimated glomerular filtration (eGFR) rate than do adults; in 2001, approximately 50% of patients 0 to 19 years of age had an eGFR >10 mL/min., compared to approximately 38% in patients ≥20 years old.

The etiology of ESRD varies significantly by age. Congenital, hereditary, and cystic diseases cause ESRD in more than 52% of children 0 to 4 years of age, whereas glomerulonephritis and FSGS account for 38% of cases of ESRD in patients 10 to 19 years of age. The most common diagnosis in transplanted children is structural disease (49%), followed by various forms of glomerulonephritis (14%) and FSGS (12%) (Table 14.2).

ACCESS TO TRANSPLANTATION

As of 2003, the NAPRTCS registry reports that 7,651 children received 8,399 transplants since 1987. At the time of transplantation, about 46% of pediatric recipients of kidney
transplants are older than 12 years of age, 34% are 6 to 12 years of age, 15% are between the ages of 2 and 5 years, and about 5% are younger than 2 years of age. Approximately 60% are male, 62% are Caucasian, 16% are African-American, and 16% are Hispanic.

TABLE 14.1. Incidence of treated end-stage renal disease in pediatric patients^a according to primary disease, 1993-1997

Primary renal disease		Incidence (%)
Glomerulonephritis (GN)		29.8
	Focal segmental glomerulosclerosis	10.0
	Membranoproliferative GN	2.5
	Rapidly progressive GN	2.1
	IgA nephropathy	1.6
	Goodpasture syndrome	0.7
	Membranous nephropathy	0.5
	Other proliferative GN	1.5
	Unspecified GN	10.3
Cystic, hereditary, and congenital disease		26.0
	Renal hypoplasia, dysplasia	8.9
	Congenital obstructive uropathy	6.7
	Alport syndrome, other familial disease	2.7
	Autosomal dominant polycystic disease	2.0
	Autosomal recessive polycystic disease	1.0
	Prune belly syndrome	1.1
	Congenital nephrotic syndrome	1.2
	Medullary cystic disease (nephronophthisis)	1.1
	Cystinosis	0.7
	Other	0.3
Interstitial nephritis, pyelonephritis		9.1
	Nephrolithiasis, obstruction, gout	3.2
	Chronic interstitial nephritis	2.0
	Chronic pyelonephritis, reflux nephropathy	2.7
	Nephropathy caused by other agents	0.9
Secondary GN, vasculitis		8.9
	Systemic lupus erythematosus	4.6
	Hemolytic uremic syndrome	1.9
	Henoch-Schönlein purpura	0.9
	Wegener granulomatosis	0.7
Hypertension		4.8
	Hypertension, no primary renal disease	4.5
	Renal artery stenosis or occlusion	0.3
Miscellaneous conditions		3.8
	Diabetes mellitus	1.6
	Neoplasms	0.6
	Tubular necrosis (no recovery)	1.0
Uncertain etiology		7.1
^a Patients younger than 20 years of age.
Modified from U.S. Renal Data System: USRDS 1999 Annual Data Report, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, 1999

TABLE 14.2. Causes of end-stage renal disease in pediatric transplant recipients, 1987-1998

Primary disease	Percentage of patients
Structural disease	48.7
Glomerulonephritis	14.5
Focal segmental glomerulosclerosis	11.8
Hemolytic uremic syndrome	2.6
Congenital nephrotic syndrome	2.6
Familial nephritis (Alport syndrome)	2.4
Cystinosis	2.2
Renal infarct	1.8
Other	13.4

Pediatric transplants constitute 4% to 6% of all transplants in the United States. The number of kidney transplants has remained essentially constant during the last decade, with 760, 674, and 723 having been performed in 1993, 1997, and 2001, respectively. However, because of the increasing popularity of transplantation in the entire ESRD community, the number of renal transplants in the adult community has risen from 9,693 in 1993 to 13,448 in 2001. In the pediatric population, transplants from deceased donors have actually decreased from 391 to 289, a decrease of over 26%. At the same time, the number of kidney transplants from deceased donors into adult recipients has increased from 7,212 to 7,913.

The rates for both living-related and cadaver renal transplantation are higher in children than in adults. For children 0 to 19 years of age, there were 29 live donor transplants and 27 cadaver donor transplants per 100 dialysis patient years. These figures are more than double the corresponding rates for adults 20 to 44 years of age. The highest rates of transplantation are in the 5- to 9-year-old group, with 40 live donor transplants and 46 cadaver donor transplants performed per 100 dialysis patient years.

Currently, over half of all pediatric kidney transplants come from living donors. From 1998 to 2003, 58% of pediatric transplants come from living donors. This trend is undoubtedly a result of the awareness that transplantation is the best therapeutic option for children with ESRD combined with the increased waiting times for cadaver donor organs. For the last date when comparable data were available for adults (2001), 41% of kidneys came from living donors.

Children continue to represent an ever-decreasing percentage of the waiting list for deceased donors. In 1992, there were 630 patients younger than 18 years of age on the waiting list for a deceased donor organ and in 2001 that number had increased to 701, representing an increase of 11%. For comparison, in the same time period, the number of adult patients rose by almost 30,000, or over 100%, from 21,443 to 50,443.

Median waiting times have remained roughly constant for pediatric patients. For the last year that these data could be calculated (2001), children 1 to 5 years of age waited a median time of 205 days for a kidney transplant; children 6 to 10 years waited a median of 338 days, and adolescents waited a median of 422 days. The median waiting time for all pediatric transplants is approximately one half of the time for adults to receive a transplant.

TIMING OF TRANSPLANTATION

Renal transplantation is considered when renal replacement therapy is indicated. In children, dialysis may be required before transplantation to optimize nutritional and metabolic conditions, to achieve an appropriate size in small children, or to keep a patient stable until a suitable donor is available. Many centers want a recipient to weigh at least 8 to 10 kg, both to minimize the risk for vascular thrombosis and to accommodate an adult-sized kidney. In infants with ESRD, a target weight of 10 kg may not be achieved until 12 to 24 months of age. At experienced centers, however, transplantation has been successful in children who weighed less than 10 kg or were less than 6 months of age.

Preemptive transplantation (i.e., transplantation without prior dialysis) continues to account for 24% of all pediatric renal transplantations. The major reason cited by patients and families for the decision to undertake preemptive transplantation is the desire to avoid dialysis (2). Candidates for preemptive transplantation should have careful psychological assessment before transplantation because there may be a tendency for noncompliance in this group of recipients. Nevertheless, there appears to be no impairment in graft outcome in pediatric recipients who have undergone preemptive transplantation when compared with those who have undergone dialysis before transplantation, and some data suggest a small improvement in allograft outcome (3,4). The reasons for the improved graft survival are unknown. Because of the prolonged waiting time for cadaveric donors, most kidneys for preemptive transplants are from living donors.

PATIENT AND GRAFT SURVIVAL

Patient survival after transplantation is superior to that achieved by dialysis for all pediatric age groups. The 1-, 2-, and 5-year patient survival rates are 97.4%, 96.5%, and 95.7%, respectively, for all primary transplants. Survival rates for recipients of primary transplants are excellent for both deceased and living donor groups: the 1-, 2-, and 5-year rates for recipients of living donor kidneys are 98%, 97%, and 95%, respectively; comparable values for deceased donor kidneys are 97%, 96%, and 92%, respectively.

The patient survival for pediatric transplant recipients has improved in the past 15 years. From 1987 to 1994, the 5-year patient survivals were 92.8% and 94.9% in recipients of kidneys from deceased and living donors, respectively; from 1995 to 2002, the comparable figures are 95.5% and 95.9%. The improvement in patient survival in recipients of deceased donors is significantly improved when current results are compared with the early results.

Patients younger than 2 years of age have the lowest graft survival rates: 90% and 81% at 3 years for recipients of living and deceased donor kidneys, respectively. This situation has improved recently. The 3-year patient survival rate for deceased donor recipients has increased from 78% in the period 1987 to 1994 to 90% from 1995 to-2002; in living donor recipients, the comparable improvement has increased from 89% to 94%,

Infection accounts for 31% of deaths. Other causes include cardiopulmonary disease (16%), malignancy (11%), and dialysis-related complications following graft failure
(3%). About 45% of patients who die do so with a functioning graft.

Of the more than 8,000 pediatric kidney transplantations reported to NAPRTCS since 1987, about 26% have failed. Twenty-three percent of primary transplants and 37% of retransplants have failed. Seventy-five percent of those transplants that failed resulted in a return of the patient to dialysis; 6% were retransplanted preemptively and 9% died with a functioning graft.

With increasing length of follow-up, chronic rejection continues to be the leading cause of graft failure in pediatrics. Chronic rejection accounts now for 33% of graft failures, with acute rejection accounting for 16%. Other causes include vascular thrombosis (11%), recurrence of original disease (6.6%), patient noncompliance (4.6%), primary nonfunction (2.4%), infection (2%), malignancy (1.3%), and death due to other causes (9.3%). Although some causes of graft failure, such as graft thrombosis and recurrence of the original disease, have remained constant during the past 10 years, loss from acute rejection has decreased dramatically. Technical issues remain a challenge. Approximately 3.8% of all grafts performed will be lost to a combination of vascular thrombosis, primary nonfunction, and miscellaneous technical causes.

PROGNOSTIC FACTORS INFLUENCING GRAFT SURVIVAL

Dramatic improvements have been made in short- and long-term graft survival rates. Over the past 15 years, the graft survival has been 93% at 1 year and 80% at 5 years for live donor transplant recipients and 84% and 66% for cadaveric graft recipients. Transplants performed recently have even better outcome. In the past 7 years 1- and 5-year graft survivals are 95% and 83% in living donor transplants. In deceased donor transplants, these values are 91% and 73% (5). The following factors are important determinants of improving graft survival in pediatric patients.

Donor Source

Short- and long-term graft and patient survival rates are better in recipients of live donor transplants in all pediatric age groups. Registry data show that recipients of kidneys from living donors have a 10% to 20% advantage in graft survival at 1, 3, and 5 years. Younger transplant recipients benefit the most from live donor transplantation and enjoy a 20% to 30% better graft survival rate 5 years after transplantation. Shorter cold ischemia time, better human leukocyte antigen (HLA) matches, lower acute rejection rates, and better preoperative preparation help account for the better outcome in recipients of live donor kidneys.

Recipient Age

Graft outcome from 1987 to 2003 are shown in Table 14.3. Data from the past 5 years have changed perceptions of the effect of recipient age in pediatric transplantation. In the past, children younger than 6 years of age, especially those younger than 2 years of age, have had lower graft survival rates than older children, especially with deceased donor kidneys (Table 14.3). Now that trend seems to be reversed. There are even some studies that suggest that infant recipients of adult kidneys with immediate function may have the longest half-lives of any type of kidney transplant (6,7). Data from the SRTR published in 2003 documents that pediatric recipients under the age of 11 who received living donor transplants had 5-year graft survival rates that were as good if not better than those in most other older age groups (Table 14.4). The rates were 92% for those younger than 1 year, 81% for those 1 to 5 years old, and 80% for those 6 to 10 years old. The results for deceased donor recipients were also better in this age group than in adults generally. Recipients 1 to 5 years of age have a 5-year graft survival of 68%, and those who are 6 to 10 years old have a 5-year rate of 72%, the best of all age groups.

On the other hand, the long-term graft survival rates in adolescents are not as good as that seen in the younger children, even though the shorter term outcome is equivalent. The 1-, 3-, and 5-year graft survival rates for adolescent recipients of deceased donor kidneys is 94%, 87%, and 73%, respectively. The 5-year outcome in the adolescents is inferior to the graft survival of every group except the group of recipients >65 years, where the two results are virtually the same (8). With regard to deceased donor kidneys, the results in adolescents, the graft outcomes were 91%, 75%, and 54%. The results for 5 years are the poorest of all age groups. Higher rates of medication noncompliance, an unexplained high incidence of graft thrombosis (9), and a high recurrence rate of FSGS (10), which is the most common acquired cause of ESRD in this age group, have all been cited as potential causes for these outcomes.

TABLE 14.3. Recipient age and graft survival in pediatric kidney transplant recipients (1987-2003)

Recipient age (yr)	Living-donor		Cadaver donor
	6 mo	5 yr	6 mo	5 yr
<2	88	80	70	54
2-5	92	82	83	70
6-12	95	83	87	69
>12	95	78	90	63

TABLE 14.4. Graft survival (%) in patients transplanted between 1997 and 2002 (SRTR 2002)

Recipient age (yr)	Living-donor			Cadaver donor
	1 yr	3yr	5yr	1 yr	3 yr	5yr
1-5	93	91	81	87	81	68
6-10	98	96	80	87	89	72
11-17	94	87	73	91	75	54
18-34	95	87	76	90	80	62
35-49	95	90	79	90	81	66
50-64	94	88	74	87	77	63
SRTR, Scientific Registry of Transplant Recipients.

Donor Age

For all deceased donor recipients, kidneys from donors aged 11 to 17 years provide optimal graft survival and function. This group is followed next by donors 18 to 34, 6 to 10, and then 35 to 49 years. Grafts from patients <5 years old fare more poorly, and grafts from patients older than 50 years fare most poorly. Although transplanted kidneys grow in size with the growth of the recipient, transplantation with cadaver kidneys from donors younger than 6 years old is associated with markedly decreased graft survival. The 5-year graft survival rate for recipients of cadaver kidneys from donors younger than 1 year of age is only about 45%, compared with 58% and 64% for recipients of grafts from donors 2 to 5 years of age and older than 6 years of age, respectively. Kidneys from donors aged 11-17 years have the best 5-year graft survival of approximately 72%. Children younger than 5 years old receiving a kidney from a donor younger than 6 years old have the highest relative risk of graft failure (11).

Deceased donor kidneys from donors older than 50 years of age are more likely to result in suboptimal long-term outcome (see Chapter 1). The older the donor, the greater is the decline of renal function with time. This finding is consistent with recently generated data that links chronic allograft dysfunction with limited repair capacities because of tissue injury. This long-term renal dysfunction is an important consideration in pediatric renal transplantation because graft function has an important effect on posttransplantation growth.

Race

In recipients of live donor kidneys, African American race is the most significant factor associated with poor outcome. African American race is second only to young recipient age (less than 2 years) as a predictor of graft failure in recipients of cadaver donor kidneys. At 5 years posttransplant, African Americans have graft outcomes of 53% and 69% for recipients of deceased donor and living related kidneys, respectively; for white and Hispanic recipients, graft survival at 5 years is 70% and 64% for recipients of deceased donor kidneys, and 82% for living donor grafts. When taken as a group, African American patients not only have poorer graft survival, but poorer renal function in addition.

Human Leukocyte Antigen Matching in Children

In pediatric transplantation, most living donor transplants come from parents, and as noted above, these transplants are being done with increasing frequency and have excellent graft outcome. Long-term graft survival is best when the donor is an HLA-identical sibling. When considering transplants from HLA haploidentical sibling donors, recent studies suggest that there is improved outcome when donor and recipient share “non inherited maternal antigens,” as distinct from “noninherited paternal antigens.” With regard to deceased donor transplantation, NAPRTCS data suggest improved outcome with the sharing of both HLA-B and HLA-DR antigens.

Presensitization

Repeated blood transfusions expose the recipient to a wide range of HLA antigens and may result in sensitization to these antigens, leading to higher rates of rejection and graft failures. The graft failure rate increases in both live donor and deceased donor transplant recipients with more than five blood transfusions before transplantation compared with those who had five or fewer transfusions. There is a 41% increase in the likelihood of graft failure in the living donor recipient with more than five transfusions. For recipients of deceased donor transplants, there is an increased risk of 32%.

Blood transfusions have become less common since human recombinant erythropoietin became an integral part of ESRD therapy. It is surprising however, that the recent USRDS data finds that hemoglobin levels in children on dialysis are lower than their adult counterparts, and there currently exists evidence for more aggressive management of anemia to forestall transfusions. Sensitization may also result from rejection of a previous transplant, and the 5-year graft survival for repeat cadaveric transplantations is about 20% lower.

Immunologic Factors

Immunologic parameters in younger children are different from those in adults and older children. Such differences include higher numbers of T and B cells, higher CD4+-to-CD8+ T-cell ratio, and increased blastogenic responses. These differences may account for increased immune responsiveness to HLA antigens and may be partly responsible for the higher rates of rejection observed in children that were observed in the past. With the improved understanding and management of immunosuppression in pediatric patients, these higher rates of rejection have been significantly ameliorated.

Technical Factors and Delayed Graft Function

The surgical techniques of kidney transplant for older children and adolescents are similar to those used in adults. Placement of the vascular anastomosis depends on the size of the child and the vessels. An extraperitoneal approach is usually accomplished with the venous anastomosis done to the common or external iliac vein, and the arterial anastomosis done to the common or external iliac artery. These vascular anastomoses are more cephalad than what is usual for adult transplants.

Small children present difficult operative challenges. The relatively large size of the graft may result in longer anastomosis times, longer ischemia time, and subsequently higher rates of early graft dysfunction. When possible, the transplanted kidney is usually placed in an extraperitoneal location,
although with very small children, the placement can be intraabdominal. The aorta and inferior vena cava are usually used for anastomosis to ensure adequate blood flow, but smaller vessels may be used. Vascular anastomosis may be problematic in a child with a previous hemodialysis access placed in the lower extremities or with a previous kidney transplant. Children should be evaluated thoroughly before transplantation to identify any potential anastomotic difficulties. Unidentified vascular anomalies may lead to prolonged anastomosis times and subsequently higher rates of delayed graft function (DGF) and graft thrombosis.

Occasionally, native kidney nephrectomy is necessary at the time of transplantation. While this can be done routinely in living donor transplantations where there is little cold ischemia time, it is preferable to avoid this, when possible, in the recipients of deceased donor transplants. Native nephrectomy at the time of deceased donor transplantation often prolongs the surgical procedure and predisposes to “third spacing” which can complicate fluid management and contribute to an increase in DGF.

DGF occurs in about 5% of live donor and18% of deceased donor transplants and is associated with a reduced graft survival. In children with DGF (defined by the requirement for dialysis within the first week of transplantation), the 3-year graft survival rates are reduced by about 20% and 30% in recipients of deceased and live donor kidneys, respectively. In living donor transplants, risk factors for DGF are more than five prior transfusions, prior transplantation, native nephrectomy, and African American race. In deceased donor transplants, cold ischemia time >24 hours is an additional risk factor.

Antibody Induction

Antibody induction with either polyclonal or monoclonal antibodies is used either for prophylaxis against rejection or in a sequential manner to avoid nephrotoxicity resulting from early use of calcineurin inhibitors. While the NAPRTCS database continues to show a 13% to 14% reduction in the proportional hazard of graft loss in both living and deceased donor transplantation, the effect of antibody induction has decreased over time. Evaluations of its use from registry databases are hampered by confounding variables and selection factors. In addition, the agents used for induction have changed markedly; monoclonal antibodies directed against CD 25 (the interleukin 2 [IL-2] receptor) are used in >50% of all pediatric transplants done presently in the Unites States, and their use is associated with a low incidence of early acute rejection. OKT3, on the other hand, is virtually unused for induction today.

Transplantation Center Volume

Transplant outcome in high-volume pediatric renal transplant centers has been reported to be superior to that found in lower-volume centers. High-volume centers (defined by the performance of more than 100 pediatric transplants between 1987 and 1995) reported a lower incidence of graft thrombosis and DGF, improved long-term graft survival, and more frequent use of antibody induction (12).

Cohort Year

The results of pediatric renal transplantation have been dramatically improving. Deceased donor transplants performed from1987 to 1990 had a 1-year graft survival rate of 75%, whereas live donor transplants had a 1-year survival rate of 89%. In 1992 to 2002, the 1-year graft survival rates for live and deceased donor transplants were 96% and 92%, respectively. Longer term outcome has also improved. Five-year graft survival in living donor transplants improved from 78% in 1987 to 1994 to 83% in 1995 to 2002. Similarly, the 5-year graft survival in deceased donor transplantation increased from 70% in 1987 to 1994 to 73% in 1995 to 2001. Graft outcome in transplants from deceased donors performed in 1995 to 2001 is now equivalent to the graft survival in living donor transplantation performed from 1987 to 1994.

CONTRAINDICATIONS TO TRANSPLANTATION

There are very few absolute contraindications to kidney transplantation. Administration of immunosuppressive medications to immunocompromised patients such as patients who are human immunodeficiency virus (HIV) positive requires special contemplation. Preexisting malignancy especially with metastasis precludes patients from transplantation. Patients with severe devastating neurological dysfunction may not be suitable candidates, however, the wishes of the parents, as well as the potential for long-term rehabilitation must be considered.

RECURRENCE OF ORIGINAL DISEASE

Recurrent disease in the renal graft accounts for graft loss in almost 7% of primary transplantations and 10% in repeat transplantations (13). This far exceeds the figure for adult transplantation, which is on the order of 2%.

Both glomerular and metabolic diseases can recur after transplantation, with most recurrences caused by glomerular disease. The most common causes of recurrence in children are discussed next.

Glomerular Diseases

FSGS is the most common cause of graft loss due to recurrent disease (14). In patients whose original disease were steroid-resistant nephrotic syndrome or confirmed FSGS, the disease recurs in 30% to 40% of patients undergoing primary transplantation; when the first transplant was lost to recurrence, FSGS recurs in 50% to 80% of those undergoing subsequent transplantation (15, 16, 17, 18, 19, 20, 21, 22, 23). The NAPRTCS database
has found that grafts in approximately 20% to 30% of patients with the diagnosis of FSGS fail because of recurrence. In patients with the original disease of FSGS whose grafts fail, the mean time to failure is 17 months.

Recurrence is usually characterized by massive proteinuria, hypoalbuminemia, and often the full-blown picture of nephrotic syndrome with edema or anasarca and hypercholesterolemia. It may present immediately or weeks to months after transplantation. Predictors of recurrence include rapid progression to ESRD from the time of initial diagnosis (less than 3 years) (13,20,24,25), poor response to therapy, younger age at diagnosis (but older than 6 years of age), black race, and presence of mesangial proliferation in the native kidney (22,24,26,27). In recent years, a protein permeability factor has been isolated from sera of patients with FSGS, and its concentration was found to correlate with recurrence and severity of disease in the transplanted kidney (28). The precise nature of this factor remains unclear, and there is no clinically approved assay (29,30).

Early posttransplant recognition of recurrent FSGS is important because plasmapheresis (which may lower the serum levels of protein permeability factor), and/or high-dose calcineurin inhibitor may lead to significant reduction in graft losses due to recurrent FSGS. In vitro studies using rat glomeruli have shown that cyclosporine or tacrolimus, incubated with sera from FSGS patients, will inhibit the proteinuric effect of such sera. Thrice daily cyclosporine may be used in doses that maintain whole blood trough levels by Fluorescence polarization immunoassay (FPIA) or Enzyme multiplied immunoassay technique (EMIT) of between 200 and 400 ng/mL or higher and is tapered slowly after achieving remission of the nephrotic syndrome and as cholesterol concentration decreases, or if significant toxicity develops. Some centers have used high-dose continuous intravenous (IV) cyclosporine with similar improvement. Still others have used high-dose or thrice daily tacrolimus. Each of these has been associated with remission. Cyclophosphamide has been found to induce remission by some investigators. Finally, in limited experience, sirolimus has been suggested to be effective in preventing recurrence. This is based only on anecdotal data, and, paradoxically, similarly anecdotal data have suggested that new onset FSGS may occur when calcineurin inhibitors are stopped and sirolimus begun. Plasmapheresis is generally used with a frequency that matches disease severity and is occasionally required on a weekly basis for prolonged periods.

Living related donor transplant recipients have been reported in some studies to suffer from a higher rate of recurrence. Recent registry data from NAPRTCS has also suggested that the graft outcome in recipients of living donor grafts with FSGS recurrence is no better than the outcome observed in recipients of deceased donor grafts that have not experienced recurrence. These data have led many pediatric transplant centers to reduce or discontinue the use of living related donation in patients with FSGS. However, the controlled settings of live donor transplantation may allow certain benefit in patients with FSGS recurrence. Living donation may dramatically reduce the incidence of post-transplant DGF. In the setting of FSGS recurrence, it is important to avoid delayed graft function so that the dose of cyclosporine or tacrolimus can be augmented. In addition, the preplanning implicit in living donation permits preoperative and early postoperative plasmapheresis. Our experience suggests that this approach may prevent or decrease the severity of recurrent disease, but this approach must be tested in a controlled clinical trial. Thus, at our center, the potential for recurrence of FSGS is not regarded as a contraindication to living donor transplantation.

Alport syndrome.

Alport syndrome, or hereditary glomerulonephritis, is a progressive disease often associated with neurosensory hearing loss and ocular abnormalities such as anterior lenticonus and cataracts. Its inheritance pattern can be X-linked, autosomal recessive, and autosomal dominant. The abnormality in almost all patients stems from mutations in the α3, 4, or 5 helices of type 4 collagen. In over 80% of patients, Alport syndrome results from mutations in the COL4A5 gene on the X chromosome.

Strictly speaking, Alport syndrome itself does not recur; however, antiglomerular basement membrane (anti-GBM) glomerulonephritis may occur in approximately 3% to 4% of patients after transplantation and lead to graft loss. The antibodies causing the anti-GBM nephritis are usually directed against the α5 chain of the noncollagenous portion of type IV collagen in the GBM, but antibodies against the α3 chain have also been described. The risk appears to be greatest in patients with mutations of COL4A5 that prevent synthesis of the α5 chain.

Anti-GBM glomerulonephritis presents as rapidly progressive crescentic glomerulonephritis with linear deposits of IgG along the basement membrane and most commonly leads to graft loss. It usually occurs in the first posttransplant year, but does not have to occur in the early posttransplant period. Asymptomatic cases with linear IgG deposits have also been reported. Fortunately, this complication is rare and affects only 3% to 4% of recipients with Alport syndrome. Treatment consists of plasmapheresis and cyclophosphamide, but such treatment is of only limited benefit. Retransplantation is associated with a high recurrence rate.

Membranoproliferative glomerulonephritis.

Histological evidence of recurrence of membranoproliferative glomerulonephritis (MPGN) type I varies widely, with reported rates from 20% to 70%. Graft loss occurs in up to 30% of cases (31). There is no proven treatment for recurrence of MPGN I in children. Anecdotal case reports describe success with high-dose corticosteroids, mycophenolate mofetil, or plasma exchange.

Histological recurrence of type II disease occurs in virtually all cases. However, often this recurrence is benign without causing graft dysfunction or loss. Some studies suggest that graft loss from recurrent MPGN II may be as high as 30% to 50% of cases (32,33). In the 2000 NAPRTCS database, 78 patients with MPGN II received allografts and 24
(13%) of these grafts failed at a mean time posttransplant of 29 months. Ten (42%) of these grafts failed because disease recurred. Presence of crescents in the native kidney may predict severe recurrence that often leads to graft loss. As with MPGN I, plasmapheresis, mycophenolate mofetil (MMF) and high-dose corticosteroids have been reported to be beneficial in a few cases of recurrent type II disease.

IgA Nephropathy and Henoch-Schönlein Purpura.

Histological recurrence with mesangial IgA deposits is common and occurs in about half of patients with IgA nephropathy and in about 30% of patients with Henoch-Schönlein purpura (34, 35, 36, 37, 38). Most of the recurrences are asymptomatic, but graft loss may occur, often associated with crescent formation. Data from adult centers suggest that a fulminant presentation of IgA nephropathy as the original cause of ESRD predicts poor outcome in the transplanted kidney with disease recurrence. In the NAPRTCS database, only 5% to 8% of graft failures were due to recurrence in patients with IgA nephropathy or Henoch-Schönlein purpura nephritis.

Hemolytic uremic syndrome (HUS).

HUS accounts for 2.5% to 4.5% of primary renal disease in children leading to ESRD. In children, the most frequent form of HUS is diarrhea-associated (D+), or “typical,” and is caused by verotoxin-producing E. coli (VTEC). This is the most common form of HUS in childhood, but it results in ESRD in only 10% of cases. “Atypical” HUS is far less frequent in children. This group of entities is characterized by a prodrome that lacks diarrheal association (i.e., “D-”), a relapsing course, and a very poor renal prognosis.

When considering transplantation in patients whose original cause of ESRD was HUS, care must be directed to the form of HUS that the patient suffered. The diarrhea-associated, or “typical,” form does not usually recur after transplantation, while atypical HUS has a high propensity for recurrence. However, there are pitfalls in assessing recurrence of HUS. The D+/D− terminology can sometimes be misleading. Occasionally, patients with VTEC-associated HUS do not have diarrhea and therefore may be mistakenly labeled as D−. Similarly, diarrhea disease can trigger HUS in a patient who is genetically predisposed to HUS, and therefore erroneously be characterized as D+ HUS. In addition, it has been known for decades that it may be difficult to distinguish humorally mediated vascular rejection from recurrent HUS, which presents histologically as thrombotic microangiopathy (TMA). Finally, the calcineurin inhibitors cyclosporine and tacrolimus have occasionally caused TMA in the transplanted kidney. In some of these cases there is a clinical picture that resembles HUS. Despite these caveats, it is reasonable to conclude that D+ HUS has a recurrence rate of <1%, while the recurrence rate in D− HUS ranges from 20% to 25% (39, 40, 41, 42, 43).

A review of the literature in VTEC-associated D+ HUS in children suggests that not only is the recurrence rate surpassingly small, but that renal transplantation in children with this disease is not associated with an increased incidence of allograft failure. The use of cyclosporine in these D+ patients is also not associated with a triggering of HUS recurrence.

When the literature is reviewed in case of HUS without diarrheal prodrome, recurrence occurs in 5% to 50% of patients with an aggregate recurrence rate of 21% of patients. It had been previously recommended that at least 1 year of clinical quiescence occur before transplantation was attempted in patients with D− HUS. However, recent experience suggests that a prolonged interval between initial HUS and transplantation does not reduce the risk of recurrence. It is difficult to ascertain the effect of calcineurin inhibition on recurrence of D− HUS (44); avoidance of cyclosporine or tacrolimus did not prevent recurrence and graft loss in 2 children with this condition. The patient and graft outcome in recurrent atypical HUS is poor. Ten percent have died and 83% have lost the graft. In patients who have experienced recurrence, it is estimated that HUS will recur in approximately 50% of subsequent grafts.

Atypical HUS can be further subdivided based on the condition’s pathogenesis or genetics. It has recently been shown that a genetic defect of complement factor H production is associated with a severe form of D− HUS. Factor H deficiency induces continuous complement activation resulting in low C3 and C4 levels. While there are only a few cases of this condition in pediatric renal transplantation, this form of D− HUS appears to have an associated rate of recurrence of >50%. High-dose fresh frozen plasma with plasma exchange has been advocated in this condition. Recently, liver transplantation or combined liver/kidney transplantation has also been successful in a limited number of patients; the rationale for these approaches is that factor H is synthesized in the liver. The recurrence rate in the few reported patients with factor H gene mutations but normal factor H concentrations appears to be markedly less than those with factor H deficiency.

In children with D− HUS and a presumed autosomal recessive inheritance, the risk of recurrence appears to exceed 60%. This risk is as high in children as it is in adults. The use of cyclosporine or the type of donor (living-related donor vs. deceased donor) does not appear to affect the rate of recurrence. In patients with putative autosomal dominant form of D− HUS, the recurrence rate appears to be similar to those with autosomal recessive D− HUS (44).

The problem with the diagnosis and management recurrent HUS is made even more challenging by the clinical entity of TMA that may accompany the use of cyclosporine, tacrolimus and other immunosuppressive agents in some patients. Other rarer causes in the posttransplant patient may include valacyclovir, viral infections such as parvovirus, HIV, and possibly cytomegalovirus (CMV), and antibodies against the von Willebrand factor-cleaving metalloproteinase ADAMTS13.

In calcineurin-associated TMA, pathological features may be localized only to the kidney without evidence of hemolysis or thrombocytopenia in >50% of cases. TMA in this situation typically presents shortly after starting treatment with cyclosporine or tacrolimus, but can occur at any time after transplantation. This form of TMA manifests
with a decline in urine output, a decrease in the rate of decline in serum creatinine, or an elevated serum creatinine level, with or without hematuria or proteinuria. Because of the nonspecific clinical course, a renal biopsy may be necessary to confirm the diagnosis. The most important aspects of therapy are stopping the calcineurin inhibitor and starting plasmapheresis/fresh frozen plasma in addition to augmenting the rejection prophylaxis regimen to compensate for the discontinuation of the calcineurin inhibitor. Restarting cyclosporine or tacrolimus after recovery of the graft function has been reported to be successful but with recurrent TMA rates of 20% to 30%. In some series, substitution of cyclosporine for tacrolimus (or vice versa) has been successful.

Living donor transplantation is not contraindicated in patients whose original disease was D+ HUS. On the other hand, living donor transplantation is not advocated for patients with D− HUS. This is because of the high recurrence rate in such patients. In addition, it has been noted that some parental carriers of D− HUS might not manifest the disease until later in life, and organ donation would put such carriers at excessive risk.

Antiglomerular basement membrane disease.

Anti-GBM disease is rare in children. A high level of circulating anti-GBM antibody before transplantation is thought to be associated with a higher rate of recurrence. Therefore, a waiting period of 6 to 12 months with an undetectable titer of anti-GBM antibody is recommended before transplantation to prevent recurrence. Reappearance of anti-GBM antibody in the serum may be associated with histologic recurrence. Histological recurrence has been reported in up to half of cases, with clinical manifestations of nephritis in only 25% of these cases. Graft loss is rare, and spontaneous resolution may occur.

Congenital nephrotic syndrome.

Congenital nephrotic syndrome occurs in the first 3 months of life. It can be classified as either congenital nephrotic syndrome of the Finnish type (CNSF) or diffuse mesangial sclerosis (DMS).

CNSF is an autosomal recessive disease that occurs as a result of a mutation in the NPHS 1 gene. While it is most commonly seen in Finnish patients, it is also found in other countries (45). The NPHS 1 gene is located on chromosome 19 and has as its gene product the protein nephrin. Nephrin is a transmembrane protein, which is a member of the immunoglobulin family of cell adhesion molecules. It is characteristically located at the slit diaphragms of the glomerular epithelial foot processes. More than 50 mutations of NPHS 1 have been identified in CNSF, but over 90% of all Finnish patients have one of two mutations—the so called “Fin major and Fin minor” mutations.

Infants with CNSF are usually born prematurely and exhibit low birth weight and placentomegaly. CNSF manifests as heavy proteinuria, edema, and ascites, often in the first week of life and always by 3 months of age. Untreated, these children suffer from malnutrition, poor growth, frequent infections and thromboembolic complications. ESRD occurs invariably in mid childhood. Corticosteroids do not ameliorate CNSF, but in mild forms, angiotensin-converting enzyme inhibition together with indomethacin may be successful (46,47). The best therapeutic success has come from the approach of early dialysis, nephrectomy, and transplantation.

CNSF does not recur after transplantation. However, de novo nephrotic syndrome has been reported in approximately 25% of cases. It presents with proteinuria, hypoalbuminemia, and edema that may start immediately or as late as 3 years after transplantation. All of the patients with posttransplant nephrotic syndrome have been reported to have the homozygous Fin major genotype. Antibodies against fetal glomerular structures are found in the majority of patients with posttransplant nephrotic syndrome, and antibodies to nephrin are found in over 50% (48). Approximately half of patients with this nephrotic syndrome respond to steroids and cyclophosphamide, but in those who do not respond, the graft is usually lost (49). Within the NAPRTCS database, vascular thrombosis and death with a functioning graft (mostly due to infectious complications) occur in 26% and 23% of cases, respectively, and account for higher rate of graft failure in this particular group.

DMS can be found in isolated form or as part of Denys-Drash syndrome. The latter is a syndrome composed of progressive renal disease with nephrotic syndrome and DMS, Wilms tumor, and male pseudohermaphroditism. Most patients with DMS have been found to have mutations of the WT-1 gene located on chromosome 11p13 (50,51). Patients with DMS who have received kidney transplants have not been observed to develop nephrotic syndrome.

Membranous nephropathy.

Recurrence of membranous nephropathy is rare in children, since it is unusual for the disease of membranous nephropathy to cause ESRD in children. The NAPRTCS database reports that of 7,651 pediatric patients who developed ESRD since 1987, only 36 (0.5%) had membranous nephropathy as a diagnosis. In adults, some series have reported a recurrence rate of approximately 25%, with the clinical hallmark being proteinuria; while some reports suggest that recurrence leads to graft dysfunction, other reports suggest that there is no effect on graft outcome. In the 500 transplants performed in pediatric patients at the University of California, Los Angeles (UCLA), 2 have had membranous nephropathy and in each of those, we have observed recurrence of the biopsy picture, mild nephrotic syndrome and stability of graft function. De novo membranous nephropathy occurs more frequently and affects less than 10% of transplanted children. It usually presents later (4 months to 6 years after transplantation) than recurrent membranous nephropathy, which usually becomes apparent within the first 2 years (the mean follow-up at the time of diagnosis is 10 months in recurrent disease, compared with 22 months in de novo disease). The occurrence of de novo membranous nephropathy does not appear to affect graft outcome in the absence of rejection.

Other Glomerular Diseases

Systemic lupus erythematosus (SLE).

In the pediatric transplant literature, recurrence of SLE had been considered rare, with minimal clinical sequelae. Recent data suggests that this is not the case. It is true that the NAPRTCS 2000 registry database showed only 1 graft failure from recurrence in 117 patients with SLE. However, studies in adults have reported clinically significant recurrence in approximately 10% to 30% of transplants (52). Recurrence and subsequent graft failure do not usually manifest until from 4 to 7 years after transplantation. This is important because in pediatric nephrology, it is most common to observe lupus nephritis progress to ESRD in adolescence. Since it is standard clinical practice to defer transplantation until the SLE has become “quiescent” for at least 6 to 12 months (53), it is likely that the patient with SLE who receives a kidney transplant in the pediatric transplant program may not suffer from recurrence until she/he transfers to an internal medicine nephrologist. This represents an important opportunity for pediatric and adult transplant physicians to develop cooperative approaches in such areas as transplantation immunosuppression, clinical monitoring and follow-up to examine which factors impact recurrence.

C and P ANCA + glomerulonephritides can recur in the transplanted kidney. Wegener’s granulomatosis and pauciimmune glomerulonephritis recurs in a small number of patients and can cause graft loss. Cyclophosphamide appears to be beneficial in the treatment of recurrent Wegener’s granulomatosis. There is similar anecdotal experience with cyclophosphamide and corticosteroids in P ANCA + pauciimmune glomerulonephritis. Thus, it is important to monitor patients closely after transplantation.

Metabolic Diseases

Primary hyperoxaluria type I.

Oxalosis results from deficiency of hepatic peroxisomal alanine glyoxylate aminotransferase (AGT). Deficiency of this enzyme leads to deposition of oxalate in all body tissues, including the kidneys, myocardium, and bone. Renal transplantation alone does not correct the enzymatic deficiency, and therefore, graft loss is inevitable in these cases because of oxalate mobilization from tissue deposits and subsequent deposition in the graft. Therapy with a combined or two-stage liver and kidney transplantation has led to higher rates of success. The transplanted liver corrects the enzymatic deficiency and thus prevents further oxalate production. The well-functioning transplanted kidney excretes the mobilized plasma oxalate. Success of this approach is greatly facilitated by immediate graft function with a good diuresis.

In practice, aggressive long-term hemodialysis before transplantation serves to decrease the patient’s body oxalate load to safe levels, preventing as much as possible tissue oxalate deposition. During this preparatory period, one aims to bring the plasma oxalate level to less than 50 mg/mL. Often this is not possible, however, and as a practical matter, the medical/surgical teams try to expedite transplantation. At transplantation, a large donor kidney is used whenever possible to vigorously excrete the body oxalate burden. Early use of a calcineurin inhibitor is deferred until the serum creatinine falls to the range of 1.0-2.0 mg/dL. Until this occurs, immunosuppression is accomplished with MMF, corticosteroids and antibody induction. If early renal transplant dysfunction occurs, daily hemodialysis is continued. Once good renal function is established, calcineurin-inhibitor therapy is begun. In addition, posttransplant treatment includes pyridoxine, neutral phosphate, citrate, and noncalciuric diuretics.

If possible, liver or combined transplantation early in the course of renal disease, preferably before the glomerular filtration rate (GFR) decreases below 20 to 25 mL/min. per 1.73 m², serves to optimize outcome and prevent severe complications of the disease that may lead to irreversible morbidity and handicap.

Nephropathic cystinosis.

Transplantation in children with cystinosis corrects the transport defect in the kidney but not other organs affected by the disease. Hypothyroidism, visual abnormalities, and central nervous system manifestations are not corrected by transplantation and require ongoing therapy with cysteamine and thyroid hormone. Cystine crystals can be found in the renal graft interstitium within macrophages of host origin. This does not result in recurrence of Fanconi’s syndrome or graft dysfunction.

Sickle cell anemia.

The graft survival rate in patients with sickle cell disease is low, with only about 25% of grafts functioning beyond 1 year after transplantation. The improvement in the hematocrit results in higher numbers of abnormal red blood cells, leading to sickling episodes in the renal graft.

Wilms Tumor.

The recurrence rate after kidney transplantation for patients who have been treated for Wilms tumor is about 13%. Most patients who develop recurrences after kidney transplantation have been transplanted less than 2 years after therapy of their tumors. Factor associated with recurrence include incomplete tumor removal and metastasis (54). Mortality for recurrent Wilms tumor after kidney transplantation is approximately 80%. The recommendations are to wait at least 2 years after completion of therapy of Wilms tumor before proceeding with kidney transplantation. Due to the high risk of developing Wilms tumor, patients with Denys-Drash syndrome should undergo bilateral nephrectomy prior to transplantation (55).

PRETRANSPLANTATION EVALUATION

Evaluation of the Potential Living Donor

The evaluation and preparation of a living donor for a child is essentially the same as for an adult. As a general rule, it is possible to consider an adult donor of almost any size for a child, no matter how young. Live donation from siblings is usually restricted to donors who have reached their 18th birthday, although the courts have given permission for younger children to donate under extraordinary circumstances.

Histocompatibility matching considerations are not different for pediatric recipients of kidneys from live donors. HLA-identical transplants are optimal and enable the lowest amount of immunosuppression to be used, thereby minimizing steroid and other side effects. The first living donor for a child is most frequently a one-haplotype-matched parent. There are some theoretical reasons why maternal live donor transplants may fare better than paternal ones, but differences in outcome, if any, are small. Siblings may become donors as they reach the age of consent.

When considering transplantation from siblings, data suggest that kidneys from haploidentical donors with noninherited maternal HLA antigens fare better in the long term than do those from donors with noninherited paternal HLA antigens. Second-degree relatives and zero-haplotype-matched siblings may also be considered as donors. The excellent results of nonbiologically related live donor transplants are not dependent on high degrees of HLA matching.

Evaluation of the Recipient

The evaluation of the potential pediatric transplant recipient is similar to that performed in adults, but because certain problems occur with more frequency in children, the emphasis may be different. It is important to establish the precise cause of ESRD in children whenever possible. Surgical correction may be required for certain structural abnormalities before transplantation. The precise cause of metabolic or glomerular disease should also be established if possible, because of the possibility of posttransplantation recurrence. Discussions of some common medical, surgical, and psychiatric issues in pediatric transplant candidates follow.

Neuropsychiatric Development

Infants.

Infants with ESRD during the first year of life may suffer neurologic abnormalities. These include alterations in mental function, microcephaly, and involuntary motor phenomena, such as myoclonus, cerebellar ataxia, tremors, seizures, and hypotonia. The pathogenesis is unclear, although aluminum toxicity has been incriminated. Preemptive kidney transplantation or institution of dialysis at the earliest sign of head-circumference growth rate reduction or developmental delay may ameliorate the problem. Some studies describe an improvement in psychomotor delay in some infants with successful transplantation, with a significant percentage of infants regaining normal developmental milestones. Tests of global intelligence show increased rates of improvement after successful transplantation.

Older Children.

It is often difficult to assess to what extent uremia contributes to cognitive delay and impairment in older children. Uremia has an adverse, but often reversible, effect on a child’s mental functioning, and it may often cause psychological depression (56). It may be necessary to institute dialysis and improve the uremic symptomatology before making a precise assessment of the child’s mental function. Initiation of dialysis often clarifies the picture and permits progression to transplantation in situations in which it might otherwise have not seemed feasible. On the other hand, severely retarded children respond poorly to the constraints of ESRD care. A child with a very low IQ cannot comprehend the need for procedures that are often confusing and uncomfortable. In this situation, the family must be involved and supported in the decision to embark on a treatment course that does not include chronic dialysis or transplantation.

Seizures.

A seizure disorder requiring anticonvulsant medication may be present in up to 10% of young pediatric transplant candidates. Before transplantation, seizures should be controlled, whenever possible, with drugs that do not interfere with calcineurin inhibitors, sirolimus, or prednisone metabolism. Benzodiazepines are a good choice when circumstances permit. Carbamazepine does reduce calcineurin inhibitor and prednisone levels, but its effect is not as strong as that of phenytoin (Dilantin) or barbiturates. Should it prove necessary to use a drug that lowers immunosuppressive drug levels, a moderately augmented dose of prednisone may be given twice daily. The calcineurin inhibitor may need to be administered three times per day or the dose adjusted upward to achieve the desired trough levels, which should be monitored closely.

Psychoemotional Status

Psychiatric and emotional disorders are not by themselves contraindications to dialysis and transplantation; however, the involvement of health care professionals skilled in the care of affected children is mandatory. Primary psychiatric problems may be amenable to therapy and should not exclude children from consideration for transplantation. Recent experience with psychotropic drugs, such as selective serotonin reuptake inhibitors (SSRIs), has been very positive. As with antiseizure medications, it is important to recognize that certain drugs may interfere with the metabolism of some immunosuppressive medications. This has not been found to be an issue with SSRIs especially citalopram and sertraline.

Noncompliance is a particularly prevalent problem in adolescent transplant recipients. Patterns of medication and dialysis compliance should be established as part of the transplant evaluation. Psychiatric evaluation should be performed in high-risk cases. If noncompliance is identified or anticipated, interventions should be in place before transplantation. These should include both social and psychiatric interventions, where possible. Psychosocial support systems must be identified and nurtured. Frequent medical and social work monitoring is crucial if the patient is to be rehabilitated both medically and psychosocially to the point where the patient is a candidate for transplantation. The best outcomes will be achieved when there is close coordination between the medical and mental health providers. It is particularly important for the transplant and dialysis teams to stay in
close communication as they prepare the patient for transplantation.

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