Kidney Transplantation in Children





Introduction


Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD) in children and confers improved survival, skeletal growth, health-related quality of life, and neuropsychological development compared with dialysis.


The medical and surgical care of ESRD and kidney transplantation in children poses unique challenges. Growth and neurocognitive development are impaired during chronic kidney disease (CKD) and are a unique focus of pediatric nephrology care. The diagnosis of ESRD in children creates an extra burden for caretakers and siblings. Therefore treatment of ESRD and kidney transplant in the pediatric population focuses on family-centered care and often utilizes a multidisciplinary approach. Psychological development is also addressed as children acquire the skills and attitudes needed to live an independent life as an adult with a chronic medical condition.


Children who receive kidney transplants have longer expected remaining lifetimes than adults at the time of kidney transplant ( Table 37.1 ). Therefore it is particularly important to maximize graft function and graft survival in this population. Children are also undergoing immune system development and maturation at the time of transplant. This, coupled with longer survival time, underscores the importance of optimizing control of alloimmunity while minimizing side effects during long-term immunosuppression.



Table 37.1

Expected Remaining Lifetime (in years) of Prevalent Patients by Initial ESRD Modality as Reported in the 2017 USRDS Annual Report

Data from: US Renal Data System. 2017 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases; 2017.







































Age Group Dialysis Patients Transplant Patients General Population
0–4 23.6 56.9 77.1
5–9 24.3 56.3 72.3
10–13 24.1 52.2 67.8
14–17 20.9 48.8 63.9
18–21 17.7 45.2 60.0
22–29 16.0 42.0 54.2


The number of children receiving kidney transplants every year is small, and even the largest centers in the US rarely transplant more than 30 children per year. Therefore it has been extremely important to maintain national and international databases to identify areas for research and improvement in outcomes among pediatric kidney transplant recipients.


There are two databases for pediatric kidney transplantation in wide use in North America. The United Network for Organ Sharing (UNOS) collects information for every kidney transplant in the US within the Organ Procurement and Transplantation Network (OPTN). Waitlist, demographic, and survival statistics from this database are reported annually through the Scientific Registry of Transplant Recipients (SRTR) report. Although this registry contains pediatric recipients, there are several pediatric-specific variables (growth, for example) that are not reported in this registry. Furthermore, the definition of pediatric recipients in SRTR is age less than 18 years, whereas at the time of writing, the US Renal Data System (USRDS), which reports on all forms of renal replacement therapy for ESRD in the US, including kidney transplant, started including patients up to age 21 years in pediatric statistics. In 1987, the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) began a voluntary registry that included up to 159 medical centers in the US, Canada, and Mexico. By 2010, the registry contained information for 11,603 kidney transplants in 10,632 children. More recently, the Improving Renal Outcomes Collaborative ( www.irocnow.org ) has been established as a learning network focused on quality improvement and research using chronic care models in pediatric kidney transplant centers in North America.


Other databases around the world have also been used to study risk factors and outcomes in pediatric kidney transplantation. The Canadian Pediatric End-Stage Renal Disease database has been constructed by linking registry data with administrative data from their universal health care delivery system to study outcomes for children with ESRD in Canada. The European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) registry collects outcomes data for adult and pediatric ESRD patients from national and regional registries of 35 European and Mediterranean countries. The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) collects data on all dialysis and transplant patients, including children, in Australia and New Zealand. In 2004 the Collaborative Brazilian Pediatric Renal Transplant Registry (CoBrazPed-RTx) was established and has collected outcome data from 1751 pediatric kidney transplant recipients performed at 13 centers through December 2013.


Most figures and statistical references in this chapter are from the SRTR and NAPRTCS databases, but we also cite literature from studies of other registries around the world.




Epidemiology of End-Stage Renal Disease in Children


Incidence


Among adults, especially in developed countries, the prevalence of ESRD continues to increase, resulting in overwhelming demand for kidney transplantation. For example, in the US, there were 120,688 newly reported cases of ESRD in 2014 and 678,383 prevalent ESRD patients, including those with a functioning graft. The incidence and prevalence of ESRD in children represents a very small fraction, less than 2%, of the overall ESRD population in the US. Although the incidence of ESRD among adults has stabilized in recent years, the incidence among children has decreased annually between 2008 and 2014.


Etiology


Although diabetic nephropathy and hypertensive nephropathy are the most common causes of ESRD in adults, these diseases are rare in childhood. Rather, the most common causes of ESRD in children are congenital, cystic, and hereditary diseases, which combined account for 38% of incident cases. The most common hereditary disorders are congenital obstructive uropathies (9.5%) and renal hypoplasia/dysplasia (10%). Primary glomerular disease is the second most common etiology, accounting for 25% of new cases, predominantly due to focal segmental glomerulosclerosis (FSGS). Secondary glomerulonephritis and vasculitis account for 12% of new cases, of which lupus nephritis is the most common. The underlying etiology of ESRD also varies by age of presentation. As expected, congenital anomalies of the kidney and urologic tract (CAKUT) and hereditary/cystic disorders are the most common underlying causes of ESRD among young age groups, whereas primary glomerular diseases and secondary glomerulonephritis are the leading causes in adolescents ( Fig. 37.1 ).




Fig. 37.1


Causes of end-stage renal disease (ESRD) in children stratified by age as reported by the US Renal Data System (USRDS) 2017 report. Primary glomerulonephritis (GN) diseases include focal glomerulosclerosis, membranous nephropathy, membranoproliferative GN, IgA nephropathy, and other proliferative GN. Congenital anomalies of the kidney and urologic tract (CAKUT) include congenital obstructive uropathy, renal hypoplasia/dysplasia, and reflux nephropathy. Secondary GN includes lupus nephritis, hemolytic uremic syndrome (HUS), Henoch-Schonlein (HSP), and vasculitis. Cystic, hereditary, and congenital (C/H/C) disorders include polycystic kidney diseases (dominant or recessive), Alport syndrome, congenital nephrotic syndrome, medullary cystic kidney diseases, including nephronophthisis, cystinosis, primary oxalosis, sickle cell disease, and other congenital malformation syndromes. Other causes include 7% of total patients in the reporting period with unknown etiology and 6.7% with missing data on etiology.

US Renal Data System. 2017 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases; 2017.


Overall, the male-to-female ratio for incident ESRD is 1.3 (56% of new cases are male), but is highest in the youngest patients, who predominantly suffer from congenital disorders (roughly 3:1 male–female ratio), some of which only occur in males (i.e., obstruction due to posterior urethral valves). In contrast, secondary glomerulonephritis, especially lupus nephritis, is more common in females (1:4 male–female ratio). Overall, 66% of children with ESRD in the US identify as white race.


The industrialized nations (North America, Europe, Japan, Australia, New Zealand) have similar distribution of etiologies as USRDS data presented previously. In the developing world, single-center studies and survey reports suggest CAKUT and hereditary/cystic disorders are more common, whereas acquired disorders are less common than in industrialized nations.




Access to Transplantation


In the US, roughly 800 children receive kidney transplants each year, comprising less than 5% of the total number of kidney transplants performed each year. Children under the age of 18 years represent 1.5% of total patients listed for kidney transplant in the US (1509 children vs. 97,680 adults listed as of the end of 2015). Of the pediatric patients on the waiting list in 2015, 57% were over the age of 11 years. Data from the SRTR indicate that the total number of kidney transplants in children (<18 years) in the US decreased from a peak of 899 in 2005 to 718 in 2015.


The transplant community has consistently supported timely access of deceased donor kidneys to pediatric recipients. As a result, children have the highest rates of kidney transplantation for all age groups (98.3 per 100 active waitlist years, compared with 18.8 per 100 for adults). Data from the USRDS report that median waiting times from initiation of dialysis until transplant for pediatric patients (0–21 years) range from 10 to 17 months depending on age ( Fig. 37.2 ).




Fig. 37.2


Pediatric kidney transplant statistics over time for the US as reported by the US Renal Data System (USRDS). Panel A shows the number of kidney transplant performed each year in the US for pediatric patients aged 0 to 21 years. Panels B–D show median wait times from incident dialysis by age, race, and donor type.

US Renal Data System. 2017 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases; 2017.


Historically, living-related donor transplants were more common in children than deceased donor transplants. This was likely driven by parents’ understanding of the benefit of living donation for their child. However, the rate of living donor transplants in children has been declining since 2002 (see Fig. 37.2 ). For example, in 2015, only 33.7% of pediatric recipients received living-donor kidney transplants, compared with 50.1% in 2004. SRTR data from transplants performed in 2015 showed that, for the first time, children under the age of 6 years were more likely to receive a deceased-donor transplant (53%) instead of a living-donor transplant (47%), when historically, this age group had the highest rates of living-donor transplant.


In October 2005, OPTN implemented a new allocation policy for kidney transplants from deceased donors under the age of 35 years to increase access to transplantation from young donors for pediatric (ages <18 years) recipients, which is known as Share-35. This kidney allocation policy emphasized the importance of younger donors and shorter waiting times for children over human leukocyte antigen (HLA) matching to minimize dialysis time. Although Share-35 shortened pediatric wait times across races and decreased average donor age, the policy also resulted in pediatric recipients receiving kidneys with high HLA mismatching. The long-term consequences of these trends on overall graft survival in children will need future study. Similar trends in reduced wait times and increased rate of deceased-donor transplants with concomitant decrease in living-donor transplant in pediatric recipients have been observed in Europe when pediatric prioritization was implemented.


The absolute number and proportion of deceased-donor kidney transplants in pediatric recipients increased after institution of the Share-35 policy from 40% to 50% during 1998 to 2005 to 61% to 65% during 2006 to 2009 and was accompanied by a decrease in the absolute number of living-donor transplants. It is unclear at this time if the trend in fewer living-donor transplants is a direct consequence of the policy change or due to the increasing prevalence of comorbidities in parents (obesity and diabetes in particular) that preclude them from donating, as the downward trend in living-donor transplants predates the policy (see Fig. 37.2 ).


In December 2014, a new Kidney Allocation System (KAS) in the US was employed with the goal to improve utility and longevity of allografts, increase transplant access to sensitized patients, and improve racial/ethnic disparities. The new system replaced the previous kidney donor classification of standard- versus expanded-criteria donors with a more refined metric known as the Kidney Donor Profile Index, or KDPI, to predict the quality and longevity of the deceased-donor kidneys and to appropriately match predicted graft survival with expected recipient survival. Pediatric recipients under this new allocation policy receive priority for the highest quality donor kidneys (with KDPI less than 35%), owing to the fact that young recipients have the longest remaining life-expectancy posttransplant (see Table 37.1 ). However, there have been some concerns that the KDPI metric does not accurately predict graft survival in pediatric recipients compared with other pediatric-specific predictive models.


The actual effect of the new allocation system on children is still under evaluation, and more studies are needed. There was initially a noticeable decrease in transplantation rate in children <6 years of age. Similar to adult recipients, transplant rates increased for the highly sensitized pediatric candidates (with cPRA greater than 98%) and significantly declined for moderately sensitized candidates with cPRA of 80% to 97%. Most pediatric recipients under the new allocation system (e.g., 65.4% in 2015) received a kidney from a donor with KPDI less than 20%. The number of HLA mismatches was higher among deceased-donor recipients than among living-donor recipients; 83.5% of deceased-donor recipients and 24.1% of living-donor recipients had more than three HLA mismatches in 2013 to 2015.




Timing of Transplantation


Transplantation is initially considered when renal replacement therapy is imminent. Due to increased risk of graft loss and mortality in infants and children under 2 years of age, most pediatric centers perform transplants in children once they achieve a weight above 10 to 15 kg. Reports from a few centers have described successful transplant outcomes in children under 15 kg. Infants and young children with ESRD frequently have delayed growth, so often a child will be older than 2 years of age before achieving the threshold size and weight for their transplant center.


On average, 30% of pediatric kidney transplant recipients in the US from 2013 to 2015 received transplantation before dialysis (e.g., preemptive transplants). An additional 24% of pediatric kidney transplant recipients in the same time period received dialysis treatment for less than 1 year at the time of transplant.


There is conflicting evidence for a benefit of preemptive transplant for patient and graft survival in pediatric transplant recipients. Time on dialysis before transplant continues to be a risk factor for decreased graft survival, although some recent analyses suggest short times on dialysis (less than 2 years) in children may not have as big an effect as longer periods. Increasing time with ESRD during childhood is also associated with impaired growth and development and can result in disruption of education. Accordingly, preemptive transplant may have quality of life benefits to children beyond graft survival.




Patient and Graft Survival


Patient survival for pediatric kidney transplant is excellent, with overall 5-year patient survival of 97.7% among pediatric recipients in 2006 to 2010 as reported by SRTR. Data from the USRDS consistently show lower mortality rates for children receiving kidney transplants compared with children on dialysis. The adjusted relative risk for mortality for children receiving renal replacement therapy decreases with increasing age. The highest mortality for both dialysis and transplant was in the 0 to 4-year-old age group, but transplant still provided extra survival benefit. In an analysis of the USRDS database, children who had received a kidney transplant had a lower mortality rate (13.1 deaths/1000 patient years) than children remaining on the waitlist (17.6 deaths/1000 patient years). Unlike similar studies in adults, there was no significant excess mortality within the first 6 months posttransplant.


Historically, graft survival rates in children were inferior to adults. However, in the past 20 years, graft survival in children of all ages now rivals the rates seen in adults. Graft survival improved dramatically for children during the 1980s and 1990s, but little progress has been made since 2000 ( Fig. 37.3 ). The adolescent age group (11–17) has a worse 5-year graft survival compared with children receiving a transplant under the age of 11 years (see Fig. 37.3 ).




Fig. 37.3


Outcomes for pediatric kidney transplant recipients in the US as reported by the Scientific Registry of Transplant Recipients (SRTR) 2015 report. Death-censored graft survival for pediatric recipients of living donor (A) and deceased donor (B) kidney transplants. Graft failure (D) and patient survival (E) among pediatric recipients from 2006–2010 stratified by age and donor type. Incidence of acute rejection by 1 year for pediatric recipients over three eras, stratified by age group (in years) (C). DD , deceased donor; LD , living donor.

Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 2017;17(Suppl 1):21–116.


Prognostic Factors Influencing Graft Survival


The following factors have been found to be important determinants of short-term and long-term graft survival in pediatric kidney transplants. Some of these factors are more predictive of short-term survival, whereas others influence long-term graft survival. For example, an analysis of the UNOS database from 1995 until 2002 demonstrated that the most significant risk factors for early graft loss (by 3 months posttransplant) in children who received deceased-donor kidney transplants were prolonged ischemia time (>36 h; odds ratio [OR] = 3.38 vs. <36 h) and recipient age 2 to 5 years (OR = 2.02 vs. 6–12 years). Long-term graft survival was most affected by race (relative risk [RR] = 1.93 for African American vs. others), adolescent recipients (RR = 1.50 for 13–20 years vs. 6–12 years), and FSGS as primary diagnosis (RR = 1.27 vs. others).


Donor Source


Children in all age groups receiving kidney transplants from living donors have superior short-term and long-term graft survival (see Fig. 37.3 ) compared with children receiving deceased-donor grafts. The improved outcomes for living-donor kidney transplants are thought to be due to reduced cold ischemia time, improved HLA-matching, and improved preoperative preparation of the recipient. Survival of living unrelated donor grafts has even been found to be superior to that of grafts from younger deceased donors. In addition, living donation from older relatives (e.g., a grandparent) has been found to have superior long-term outcomes in pediatric recipients compared with deceased-donor transplant. The most poorly HLA-matched grafts from the oldest living donor had survival similar to or better than any deceased donor in an analysis of USRDS. Finally, for deceased-donor kidneys, outcomes are superior for pediatric recipients of grafts from donation after brain death than donation after circulatory death due to increased risk of graft loss by 4 years in the latter.


Recipient Age


An analysis of OPTN data has shown the best long-term graft survival occurred in middle-aged adult recipients and children younger than 12 years, whereas the worst outcomes were seen in adolescent and young adult recipients. Several studies have confirmed that recipients aged 17 to 24 years have the highest risk of graft loss, prompting further research in how to best support this age group to optimize outcomes.


Donor Age and Size


Multiple reports in the literature indicate that donation from young adults improves graft survival. The “ideal” donor age derived from these analyses has been determined to be more than 6 years old and less than 45 to 50 years old. Donor age appears to be more important in determining graft survival for deceased-donor transplants than for living-donor transplants.


Interestingly, children receiving grafts from deceased donors younger than age 18 years have improved relative glomerular filtration rate (GFR) over time compared with children receiving kidneys from deceased or living adult donors. Senescence of somatic kidney cells has been postulated to be the underlying cellular mechanism responsible for this effect. In other words, renal allografts from young donors are able to adapt to the increasing metabolic demand of a growing recipient, whereas kidneys from older donors have decreased capacity for cell survival and regeneration and undergo accelerated aging under the stress of transplantation.


Transplants from very young donors (younger than age 5 years) to pediatric recipients have historically been avoided due to reports of increased risk of graft loss. In a recent analysis of the NAPRTCS database, primary graft nonfunction was found to be more frequent in kidney transplants from very young donors (3.7% compared with 0.3% in transplants from donors aged 6 to 35 years or “ideal donors”). However, longer term, the 3-year graft survival and estimated glomerular filtration rate (eGFR) of functioning grafts from very young donors was equivalent to ideal donors. In a more recent study, graft survival rate was almost 90% for recipients of infant donor kidneys implanted either en bloc or singly.


Recipient Race


African American race has been demonstrated in multiple studies to associate with worse long-term graft survival, including increased risk for delayed graft function, acute rejection, and graft loss. It is unclear whether the relative role of genetics (e.g., higher rates of FSGS) versus racial disparities explains these findings. For example, African American children are more likely to be older at the time of transplant, receive fewer living-donor transplants, and have longer duration of dialysis before transplant, all of which are associated factors contributing to worse long-term outcomes. After controlling for 19 variables, including age, primary diagnosis, preemptive transplant, rejection experience, HLA-B mismatch, immunosuppression, and gender, black patients still had higher risk for graft failure (Hazard Ratio [HR] = 1.6, 95% confidence interval [CI] 1.46–1.86).


HLA Matching


Degree of HLA mismatch is an important prognostic factor for long-term graft survival for both deceased- and living-donor transplants. Although the ideal situation would be donation from an HLA-identical sibling, this has occurred in only 3.4% of pediatric living-donor transplants reported in NAPRTCS. Most live kidney donations come from haplo-identical parents. An analysis of NAPRTCS in 2000 suggested that a six-antigen matched deceased-donor kidney had equivalent graft survival and rejection rates as haplo-identical living-donor transplants. However, long-term graft survival (5 years) was actually 10% better for the children who received six-antigen matched deceased-donor kidneys.


There is some evidence that donation from a sibling with noninherited maternal antigens confers survival benefit for the graft and may be due to bidirectional immune regulation between donor and recipient immune cells. Grafts from mothers in these studies had poorer outcomes. This has particular relevance for pediatrics because mothers represent the majority of parental donors.


There is debate as to the effect of degree of HLA mismatch on acute rejection and graft survival. An analysis of 9029 pediatric recipients in the Collaborative Transplant Study in Europe found a hierarchical relationship for an effect of increasing mismatches at the A-, B-, and DR-loci on graft survival. Similarly, there are inconsistent findings on the role of HLA-DR matching and graft survival. In 2008 Gritsch, et al. reported that children in the US receiving zero HLA-DR mismatched deceased-donor kidneys had comparable 5-year graft survival to children who had received 1- or 2-DR mismatched kidneys. A recent analysis of European pediatric kidney transplants found that whereas two HLA-DR mismatches associated with lower graft survival in children receiving transplants from 1988 to 1997, this effect was not seen in a more recent era (1998–2007). They did, however, describe a disturbing association of HLA-DR double-mismatch with increased risk of developing non-Hodgkin lymphoma. This interesting finding needs to be validated in additional cohorts of pediatric kidney transplant recipients.


Sensitization occurs with increasing HLA-mismatch and specifically the degree of HLA-DR mismatch. As stated earlier, children have longer expected remaining lifetimes after transplantation and increased expectancy for multiple transplants. Therefore development of HLA-sensitization from mismatched primary transplants has been demonstrated to be a barrier to subsequent transplant.


Presensitization


NAPRTCS reported that >5 transfusions significantly increased the frequency of delayed graft function (defined as dialysis in the first transplant week) and graft failure (HR = 1.22, p = 0.016 for living-donor transplants and HR = 1.25, p < 0.001 for deceased-donor transplants). This effect was presumed to be due to increased sensitization. The use of blood transfusion has decreased with increasing use of erythropoietin to treat anemia during ESRD, and the largest risk for sensitization in pediatric transplant candidates is prior solid-organ transplantation.


Delayed Graft Function and Thrombosis


Delayed graft function (DGF) is uncommon (approximately 6%) in pediatric kidney transplant recipients, as reported in the 2015 SRTR report. A single-center retrospective study of 126 pediatric kidney transplant recipients from 2004 to 2011 showed similar rate of 9% DGF and identified vascular cause of brain death and donor age >15 years as possible risk factors for DGF. Overall, technical causes of graft loss (vascular thrombosis, primary nonfunction, and others) contributed to 13% of all graft failures reported in NAPRTCS since 1987, suggesting that these events occur in about 3% of pediatric transplants. Several studies of pediatric transplant registries in the UK, Ireland, and the Netherlands reported similar rates of thrombosis. Risk factors for graft thrombosis in children include recipient age <6 years, donor age <6 years, cold ischemia time >24 hours, and history of peritoneal dialysis.




Contraindications to Transplantation


Children with ESRD have fewer comorbid conditions that might mitigate against major surgery or use of immunosuppressive medications than adults, so the risks of kidney transplantation are often greatly outweighed by the benefits. Therefore most children with ESRD are eventually referred for transplant.


There are few absolute contraindications to kidney transplant in children. Situations that might not be appropriate for referral or listing include active or untreated malignancy, active or untreated infection, and multiple or progressive medical conditions with overall poor prognosis for recovery (e.g., severe brain injury or multiorgan failure). Transplant is considered after a reasonable disease-free period for children with prior malignancies.


Mild, isolated mental retardation is not a contraindication to transplant, per se, as improvement in neurocognitive development has been seen after transplant. Children with devastating neurologic dysfunction may not benefit appreciably from transplant, but the potential for rehabilitation, self-care, and parental preferences should be considered. Finally, issues with medical compliance or unstable family situations can delay consideration for kidney transplant.




Recurrence of Original Disease


Recurrent disease is a significant cause of graft loss in children, accounting for 6.9% of graft losses in the NAPRTCS cohort. Recurrence in the transplanted kidney can occur with primary glomerulonephritis, secondary glomerulonephritis, and metabolic diseases.


Primary Glomerulonephritis


Focal Segmental Glomerulosclerosis


FSGS recurs in approximately 15% to 60% of children with nephrotic syndrome undergoing renal transplant and is the most common cause of graft loss due to recurrence. Although several small single-center studies in the 1990s suggested clinical features of young age of diagnosis, rapid progression to ESRD, and mesangial proliferation on native biopsy to be associated with posttransplant recurrence, many of these predictive factors have failed to be durably replicated. A recent analysis of UNOS data showed an overall recurrence rate of 15% in children receiving kidney transplant between 1988 and 2008. FSGS recurrence occurred more frequently in Caucasian and younger recipients. Although receipt of a living-donor kidney was previously described as a risk factor for FSGS recurrence, in this analysis, donor type did not remain significant in multivariate analysis. This may be explained by the confounding effect of younger recipient age because rates of living-donor transplantation increase with decreasing recipient age. The significance of young recipient age in this study may also indirectly support earlier associations between younger age at FSGS diagnosis and/or rapid progression to ESRD and FSGS recurrence. Another clinical feature recently associated with FSGS recurrence is the response to steroid therapy during native FSGS disease. In an analysis of 150 pediatric patients transplanted in Europe for ESRD due to steroid-resistant nephrotic syndrome, it was found that the patients with initial steroid sensitivity who developed steroid resistance during treatment of their native kidney disease had the highest rate of recurrence (92.9%) posttransplant compared with children who had steroid-resistance from the outset (30%). These findings suggest that the development of secondary steroid resistance during treatment of idiopathic nephrotic syndrome may predict posttransplant recurrence.


Patients with FSGS recurrence have inferior graft survival compared with other ESRD etiologies. Furthermore, the effect of FSGS recurrence on graft loss is more significant in children compared with adults. Higher rates of acute tubular necrosis (ATN) in both living-donor and deceased-donor transplants have been reported in children with FSGS compared with children with other causes of ESRD. It has been suggested that the increased rate of ATN, possibly due to early FSGS recurrence, plays a role in the decreased graft survival for children with FSGS. This observation influenced some centers to offer living-donor transplant (which has lower rates of ATN in general) with pretransplant plasmapheresis in an attempt to prevent rapid FSGS recurrence and improve graft survival; however, the use of plasmapheresis pretransplant has not proven consistently beneficial in small trials.


Recurrence of FSGS often presents early after kidney transplantation in children, with a reported median time to recurrence of 6 to 14 days, although heavy proteinuria often can be detected within hours after transplant. It is usually characterized by nephrotic-range proteinuria (protein/creatinine ratio >2 mg/mg) and hypoalbuminemia, but can present as complete nephrotic syndrome, including anasarca and hypercholesterolemia. Whereas recurrent disease typically presents within the first 2 years after transplant, the presentation of nephrotic syndrome after 2 years is generally considered to be secondary to calcineurin inhibitor (CNI) toxicity, chronic rejection, or de novo disease.


Biopsies early after recurrence often demonstrate normal histology on light microscopy with effacement of podocyte foot processes on electron microscopy. Later biopsies have characteristic segmental lesions of FSGS with endocapillary proliferation and foam cell accumulation and can progress to glomerular sclerosis and interstitial fibrosis. Unfortunately, histology classification has not been shown to be predictive of treatment response in recurrent FSGS.


The pathophysiology of primary idiopathic FSGS in native kidneys and recurrent FSGS after transplant remains unclear. It is likely a multifactorial process involving cytokines secreted by T cells, a humoral factor that alters podocyte cytoskeletal structure, and a balance between circulating permeability factors and inhibitors of such factors.


Genetic forms of FSGS have low rates of recurrence, estimated at around 3% for patients with homozygous and compound heterozygous podocin (NPHS2) mutations. Recurrence of nephrotic syndrome in children with NPHS2 mutations does not appear to be due to antipodocin antibodies. Further study is needed to clarify the pathogenesis of recurrence in this population.


A circulating factor has been proposed to cause increased albumin permeability of the slit diaphragm during FSGS recurrence, but the identity, source, and pathologic effects of such a factor are yet to be fully elucidated. Bioassays of albumin permeability have had conflicting results in predicting FSGS recurrence and have not proven to be specific or highly predictive of response to therapy or long-term renal outcome in patients with nephrotic syndrome. Furthermore, demonstration of a neutralizing effect of normal serum or urine from nephrotic patients on albumin permeability suggests that loss or deficiency of a natural inhibitor may play a role. Serum soluble urokinase receptor (suPAR) has been proposed as a circulating factor capable of causing FSGS. Two-thirds of the patients with FSGS in this study had elevated serum suPAR concentrations compared with healthy controls and patients with other glomerular diseases. Furthermore, patients who had FSGS recurrence after transplant had the highest serum concentrations of suPAR, providing hope for a clinically predictive test. However, a small prospective study found no correlation with suPAR levels and remission of proteinuria in adult patients treated for recurrent FSGS. Further research is needed in understanding the pathogenesis of FSGS recurrence and to identify predictive clinical tests.


In light of the limited understanding of the underlying pathophysiology, the treatment of recurrent FSGS is not well established. The most commonly reported therapies for recurrent FSGS are plasmapheresis or protein A immuno-adsorption therapy. A review of the literature found that 49 of 70 children (70%) receiving plasmapheresis for FSGS recurrence achieved partial or full remission. Early detection of recurrence and initiation of plasmapheresis appears to provide the best results. However, these studies likely overrepresent the benefit of plasmapheresis given small sample sizes and the use of only historical groups for comparison in a few of the studies or no comparison group in others. In general, it is recommended that children at risk should have daily monitoring of protein/creatinine ratios in the early posttransplant period to allow rapid detection of FSGS recurrence and early initiation of treatment.


Some centers perform plasmapheresis either before a planned living donor transplant or in the perioperative period of a deceased-donor transplant. It is unclear if this practice offers any benefit over early detection and treatment of established recurrence.


High-dose cyclosporine with or without adjunctive plasmapheresis and/or high-dose steroids has shown efficacy in achieving complete or partial remission of posttransplant FSGS recurrence in children. The antiproteinuric effect of CNIs has been postulated to be due to T cell suppression and inhibition of cytokine secretion thought to be injurious to podocytes, as well as to a direct effect on the stabilization of the podocyte cytoskeleton. The alkylating agent cyclophosphamide has also been reported to be efficacious in some children with recurrent FSGS, usually in combination with plasmapheresis. Reduction in proteinuria has also been reported with the use of angiotensin blockade either alone or in conjunction with plasmapheresis.


Finally, there have been anecdotal cases reporting prolonged remission of proteinuria in children with recurrent FSGS after plasmapheresis and B cell depletion with rituximab. This was first reported for a child who incidentally achieved remission of FSGS recurrence after rituximab therapy to treat posttransplant lymphoproliferative disease (PTLD). More recently, there have been small case reports demonstrating efficacy of another humanized anti-CD20 antibody, ofatumumab, in inducing remission of native kidney FSGS or FSGS recurrence in patients resistant to rituximab therapy. The true value of this approach remains to be established.


Congenital Nephrotic Syndrome


Congenital nephrotic syndrome (CNS), by definition, occurs within the first 3 months of life and is most commonly due to mutations in the NPHS1 gene, encoding nephrin, a major structural component of the slit diaphragm. Infants with CNS are frequently born prematurely, have enlarged placentas, and present with nephrotic-range proteinuria, anasarca, and hypoalbuminemia. Secondary causes (i.e., neonatal cytomegalovirus [CMV], congenital rubella, human immunodeficiency virus [HIV], hepatitis B, toxoplasmosis, syphilis, and infantile lupus) should be excluded. The genetics of CNS are proving more complex in recent years with the identification of additional genetic mutations (including genes previously only associated with FSGS).


Recurrence of nephrotic syndrome has been reported in 25% of children with CNS due to homozygous Fin-major mutations in nephrin (NPHS1) with mean time to recurrence of 12 months posttransplant (range of 5 days to 2 years). Antinephrin antibodies have been implicated in a majority of these children.


Vascular thrombosis and death from infection (with a functional graft) have been described more often in children with CNS after transplant compared with children with other primary diseases. Hypercoagulability due to urinary losses of antithrombin III (ATIII) along with younger age at the time of transplant likely contribute to the increased risk of these complications.


Diffuse mesangial sclerosis (DMS) can also present as nephrotic syndrome in early infancy and is associated with mutations of the Wilm tumor suppressor gene 1 (WT1). Denys-Drash syndrome consists of progressive glomerulopathy (DMS) and male pseudohermaphroditism (although genotypic females have also been described) and is due to heterozygous mutations within exon 8 or 9 of WT1. Children with Denys-Drash syndrome are at increased risk of developing Wilm tumor; therefore bilateral nephrectomy is often performed once they develop ESRD. Frasier syndrome presents with normal female genitalia with streak gonads, XY karyotype, and progressive glomerulopathy (DMS on histology) and is due to splice mutations within exon 9 of WT1. Children with Frasier syndrome are at risk of developing gonadoblastoma and therefore should undergo oophorectomy. There have also been reports of isolated DMS in children with WT1 mutations without other syndromic features who may not be at risk for malignancy.


Other than one report of membranoproliferative glomerulonephritis (MPGN) in a child with Denys-Drash, no other studies report recurrence of nephrotic syndrome in children with WT1 mutations undergoing kidney transplant. Overall, children with Denys-Drash have comparable patient and graft survival as children with other causes of ESRD.


Alport Syndrome


Alport syndrome (AS) is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane (GBM) defects due to alterations in the type IV collagen matrix. AS presents with persistent microscopic hematuria and proteinuria that can progress to renal failure and is often associated with sensorineural hearing loss and ocular abnormalities. It is the prototype of inherited nephritis and accounts for 2% of children with ESRD in the US. The most common and severe form is inherited in an X-linked recessive pattern and is associated with early progression to ESRD (50% of boys by age 25 years). Autosomal recessive and autosomal dominant forms have also been described.


The genetics of X-linked AS were defined more than 20 years ago as a mutation in the gene encoding the α5 chain of type IV collagen (COL4A5). Patients with mutations resulting in a truncated protein (i.e., large rearrangement, premature stop, or frame-shift mutations) tend to progress to ESRD earlier (50% by age 19 years). Female carriers of COL4A5 mutation are considered to have a less severe course, but some do develop ESRD in late adulthood. Development of hearing loss and progression of proteinuria appear predictive of a more severe course in female carriers. Evaluation of potential living donors, especially female relatives, should include evaluation for hematuria and proteinuria, as the heterozygous carrier state carries a risk of developing ESRD after donation.


Autosomal recessive forms involving mutations in the α3 (COL4A3) and α5 (COL4A4) chains have also been described. Rare autosomal dominant mutations in COL4A3 and COL4A4 have also been reported with less severe renal disease, fewer cases of hearing loss, and absence of reported ocular changes.


Although Alport syndrome itself does not recur, development of de novo antibodies directed to the glomerular basement membrane (anti-GBM) has been reported to occur in approximately 3% to 5% of AS males within the first year after transplant. Late occurrence has also been described.


Antibodies are generated against the type IV collagen α5 or α3 chains. Patients with mutations resulting in complete absence or severe truncation of these proteins appear to be at highest risk of developing anti-GBM antibodies. It should be noted that the anti-GBM antibodies in these patients are specific for different epitopes of the noncollagenous domains of the α3α4α5(IV) collagen network than the Goodpasture allo-epitope, and therefore may not be detectable in the serum using the clinically available enzyme-linked immunosorbent assay (ELISA) used to diagnose spontaneous anti-GBM nephritis in Goodpasture disease.


Early reports described rapidly progressive anti-GBM disease with nearly 90% to 100% graft loss. With better recognition of this entity, reports of subclinical anti-GBM (i.e., demonstration of linear IgG deposits along the GBM in transplant biopsies without graft dysfunction) suggest a broader spectrum of clinical disease. Despite the poor graft outcome described during anti-GBM nephritis in AS, the severe form does not occur frequently enough to affect overall graft survival statistics for AS patients. Chronic rejection is the most common cause of graft loss in this population. Patients who have lost a prior graft to anti-GBM disease are at higher risk of recurrence after a subsequent transplant, although some have reported successful retransplantation.


MPGN/C3 Glomerulopathy


MPGN describes a pattern of glomerular injury with common histologic features of glomerular capillary wall thickening (membrano-) and hypercellularity in the glomerular tufts (-proliferative). MPGN was historically classified into three morphologic types based on electron microscopy findings: type I with presence of immune deposits in the subendothelial and mesangial areas, type II with electron-dense deposits within the basement membrane, and type III with complex GBM formation with subendothelial and subepithelial electron-dense deposits that are bridged by intramembranous deposits. A unifying characteristic of all types of MPGN is hypocomplementemia (low C3). This traditional system resulted in overlap among MPGN type I and type III while considering MPGN type II, known as dense deposit disease (DDD), as a separate entity because it has unique pathogenic and clinical features.


Recent advances in our understanding of MPGN pathogenesis has led to a new classification system for the diagnosis and management of these disorders. In the new system, MPGN is classified as either mediated by immune complexes (immune complex mediated MPGN) or by complement dysregulation and activation of the alternative complement pathway, now termed C3 glomerulopathy. This differentiation is made based on immunofluorescence microscopy. Immune complex mediated MPGN is defined by the presence of immunoglobulin staining on immunofluorescence microscopy and is most commonly associated with underlying autoimmune disease or infections. Therefore recurrence and management are dependent on the underlying systemic disease resulting in renal pathology. In contrast, complement-mediated MPGN (i.e., C3 glomerulopathy) results from dysregulation and persistent activation of the alternative complement pathway with deposition of complement products in the glomeruli and the mesangium with predominantly bright C3 and minimal immunoglobulin staining on immunofluorescence microscopy. Genetic defects in the proteins involved in the alternative complement cascade and/or autoantibodies have been identified in patients with C3 glomerulopathy, which is further classified into DDD, C3 glomerulonephritis (C3GN), and CFHR5 nephropathy. DDD is distinguished from C3GN on electron microscopy by the presence of large, sausage-shaped, osmophilic dense deposits within the GBMs. In contrast, in C3GN the deposits tend to be mesangial and subendothelial.


The major defect in DDD and C3GN is excessive activation of the alternative complement pathway. The alternative complement pathway is normally autoactivated by spontaneous cleavage of the C3 to C3b which leads to the formation of the C3 convertase by the binding factor B and properdin. Normally the activity of this pathway is tightly regulated by the activity of the C3 convertase, which is inhibited by factor H. In patients with DDD and C3GN, increased activity of C3 convertase is most commonly caused by (1) stabilization and reduced degradation of C3 convertase enzyme by autoantibodies (called C3 nephritic factor; C3NeF) or (2) deficiency or autoantibody directed against the natural inhibitor of C3bBb, factor H. Low levels or defective factor B, factor I, and C3 have also been described in DDD and C3GN.


C3 glomerulopathies have a progressive course with development of ESRD in up to 50% of patients and high recurrence after transplantation.


Historic reports of outcomes for patients with MPGN type I and III are challenging to apply to patients diagnosed under the new classification system.


An analysis of UNOS data showed MPGN type I has a significant negative effect on graft survival compared with other forms of glomerulonephritis. Disease recurrence was the most common cause of graft loss (14.5%) for patients with MPGN type I in this study. Graft loss has been reported in about 50% of patients with recurrent MPGN type I. Low complement levels (C3) at the time of transplant and younger age at time of transplant have been associated with increased risk of recurrence. Another report of serial protocol biopsies identified that some patients have asymptomatic recurrence of MPGN type I.


An analysis of the NAPRTCS database showed significantly worse 5-year graft survival (50.0%) for children with MPGN type II (DDD) compared with the database as a whole (74.3%). The most common cause of graft failure in children with DDD was recurrent disease (14.7% of graft losses). Of the children with DDD who had posttransplant biopsies ( n = 18) in the registry, 67% had recurrent DDD. No correlation was found between pretransplant presentation or C3 levels with the risk of recurrence or graft loss. In a single-center retrospective study, DDD was reported to recur in 60% of children, whereas the rate of graft loss was similar to other children, transplanted at that center. Finally, an analysis of the UNOS database, including children and adults, reported graft loss due to recurrence in 30% of patients with DDD and significantly worse graft survival compared with patients with other forms of glomerulonephritis.


There is minimal data about transplant outcomes for patients with C3GN. Zand et al. evaluated 21 adult and pediatric renal transplant recipients with a history of C3GN as a cause of the ESRD. C3GN recurred in 66.7% of the patients with graft failure in 50% of recurrent C3GN at median time 28 months. The median time to graft failure posttransplant was longer in patients with C3GN compared to DDD (6–7 years vs. 2.5 years, respectively).


Recurrent MPGN presents with hematuria, progressive proteinuria, and deteriorating graft function. Low or low-normal C3 levels have been reported. There are no randomized trials to determine efficacy of treatment of posttransplant recurrence of C3GN and DDD. Nonspecific treatments, including the use of angiotensin blockade, steroids, anticoagulation, or antiplatelet therapy, have been reported in the literature with variable success. In patients with genetic deficiency in factor H, plasma infusion can be used to correct the deficiency. Plasma exchange has been reported in small case series for removal of circulating autoantibodies like C3 nephritic factor or antifactor H antibodies and to replace defective proteins in the case of activating mutations in C3. Rituximab has been reported in cases involving autoantibodies. More recently, the use of an anti-C5 antibody (eculizumab) has been proposed to block the downstream effects of uncontrolled C3 convertase activity, but the clinical utility, long-term implications, and identification of patients who would benefit most from this therapy still need to be defined.


Secondary Glomerulonephritis


IgA and Henoch-Schonlein Purpura


IgA nephropathy accounts for 3% of incident cases of ESRD in children in the US. Histologic recurrence in adult transplant recipients with IgA nephropathy has been reported to be 30% to 35%. Transplant patients with abnormal urinalysis (hematuria or proteinuria) are more likely to show histologic evidence of recurrence. The role of recurrence in graft loss is variable in these reports. In some single-center studies, as many as 40% to 50% of patients with recurrence have been reported to have graft failure; however, a recent analysis of patients in East Asia found that chronic rejection had a larger effect on long-term graft survival rate in patients with IgA nephropathy.


Henoch-Schonlein purpura (HSP) nephritis is a rare cause of ESRD in children, accounting for only 0.4% of incident cases in the US. Histologic recurrence of HSP has been reported in as high as 70% of patients within 2 years after transplant, with clinically evident recurrence (hematuria, moderate proteinuria, and hypertension) in 15% to 35%. Long-term graft survival, however, does not appear to be greatly affected by recurrence. An analysis of adolescents and young adults in the UNOS database revealed graft loss due to recurrent disease in 13.6% of patients with HSP.


Hemolytic-Uremic Syndrome


Hemolytic-uremic syndrome (HUS) accounts for approximately 1.5% of children with ESRD in the US. HUS is characterized by the clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, and it can be due to secondary causes (infectious, drug-induced, auto-antibodies) or primary genetic defects in complement regulatory components that lead to persistent activation of the alternative pathway of the complement cascade.


The most common cause of HUS in children (accounting for approximately 90% of cases) is associated with colitis due to shiga-toxin producing bacteria ( E. coli, Shigella dysenteriae, others). Epidemiologic studies estimate that 5% to 10% of children with shiga-toxin producing E. coli (STEC) infections develop HUS, with children under the age of 5 years carrying the highest risk. Of the children that develop HUS, about two-thirds develop oliguric renal failure. ESRD occurred in 10% to 15% of children with HUS in a meta-analysis of long-term prognosis (>1 year) after diarrhea-associated HUS. The presence of anuria or prolonged oliguria has been associated with higher risk for long-term sequelae, including CKD, proteinuria, and hypertension in as many as 30% of HUS survivors. The risk of disease recurrence after transplant in this particular group appears to be very low (<1%), and graft survival is similar to children with nonglomerular primary disease.


Infections with bacteria other than STEC that produce shiga- or shiga-like toxins, including Shigella dysenteriae and Citrobacter sp, have also been implicated in the etiology of HUS in children. Furthermore, urinary tract infections with STEC have also been found in children with HUS presenting without diarrhea.


Finally, invasive Streptococcus pneumoniae infections have also been linked with a rare, but severe, form of HUS that has higher rates of progression to ESRD than the classical diarrhea-associated disease. Cases typically have large bacterial burden with empyema and bacteremia, but cases with meningitis or pericarditis have also been described. Bacterial neuraminidase exposes a crypt-antigen known as the Thomsen-Freidenrich (or T-) antigen on erythrocytes, platelets, and endothelium, and this is thought to play a role in endothelial activation and subsequent microvascular thrombus formation. T-antigen exposure can be confirmed on patient erythrocytes using the lectin Arachis hypogea. Recurrence of pneumococcal HUS after transplantation has not been reported for these patients.


HUS that cannot be associated with infection or other secondary causes (often referred to as atypical HUS) accounts for 5% to 10% of all cases in children and carries a higher risk to progress to ESRD without treatment. Genetic or acquired disorders of complement regulation are identified in about 60% to 70% of these cases. They also have higher risk of recurrence and graft loss posttransplant. Therefore identifying these cases is paramount for (1) preemptive treatment to prevent progression to ESRD and (2) planning for successful transplantation.


In recent years, a clear link has been established between disordered regulation of the alternative pathway of the complement system and atypical HUS (aHUS). Mutations have been described in three important regulatory proteins of the alternative pathway: complement factor H (CFH; 20%–30% of aHUS registry cases), complement factor I (CFI; 2%–12%), and membrane cofactor protein (MCP; 10%–15%). Gain-of-function mutations in genes encoding complement factor B (CFB; 1%–2%) and complement C3 (10%) and loss-of-function mutations in thrombomodulin (THBD gene) have also been associated with aHUS. Finally, autoantibodies to factor H are detectable in 5% to 10% of patients with aHUS, but up to 40% of these patients also carry a mutation in CFH, CFI, MCP, or C3.


Atypical HUS is also increasingly recognized as a complex, polygenic disease. First, incomplete penetrance is common in most of these mutations, suggesting that “multiple hits” contribute to a predisposition to aHUS. Second, various polymorphisms in genes encoding CFH, MCP, CFH-related protein (CFHR1), and C4b-binding protein (C4b-BP) have been associated with aHUS. Furthermore, bigenic abnormalities have been described in about 10% of patients; therefore mutational analysis of all complement components is recommended during the workup of patients suspected to have aHUS. Finally, cases of de novo thrombotic microangiopathy (TMA) after kidney transplant in patients with non-HUS causes of ESRD have also been found retrospectively to have CFH or CFI mutations.


Historically, studies on the outcomes of children with HUS have used simple delineation of cases based on the presence or absence of prodromal diarrhea. This delineation is not always clinically straightforward because shiga-toxin-related cases may present without diarrhea, and 20% to 30% of cases of aHUS due to genetic complement disorders are preceded by a diarrheal illness (including STEC infection). Furthermore, as mentioned previously, there are nondiarrheal bacterial infections associated with HUS (STEC urinary tract infection [UTI] and Pneumococcus ). A recent guideline has been published in an effort to standardize diagnostic workup and treatment for children with atypical HUS. Children without diarrheal prodrome or pneumococcal infection or those with recent diarrhea and certain clinical characteristics associated with increased risk of genetic predisposition ( Box 37.1 ) should undergo a full diagnostic evaluation for the cause of HUS, including investigation for shiga-toxin-producing bacteria as well as mutational analysis.



Box 37.1

Suggested Evaluation of Children with Hemolytic Uremic Syndrome

Adapted from Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009;24:687–96.


Risk factors that should prompt a diagnostic workup for atypical HUS, even if diarrhea is present, include:




  • Age of onset under 6 months old



  • Insidious onset



  • Relapse of HUS or a suspected previous case of HUS



  • Previous unexplained anemia



  • Nonsynchronous family history of HUS



  • Presentation with severe hypertension



  • Presentation of HUS posttransplant (for any organ)



Diagnostic workup includes:




  • Serum/plasma C3 level (although normal values do not exclude inherited disorders of complement regulation)



  • Plasma/serum concentration of factor H and factor I



  • Antifactor H antibody titers



  • Membrane cofactor protein (MCP: CD46) surface expression on mononuclear leukocytes by flow cytometry



  • Gene mutation analysis for factor H, factor I, MCP, factor B and C3



  • Plasma vWF protease activity (ADAMTS13)



  • Homocysteine and methylmalonic acid levels (plasma and urine) to evaluate for defects in cobalamin metabolism




Recurrence after transplant can present as graft thrombosis or graft failure with hematologic signs of HUS (microangiopathic hemolytic anemia and thrombocytopenia). The risk of recurrence after transplant varies depending on the genetic mutation identified ( Table 37.2 ), and before the development of anticomplement therapy was approximately 60% overall. The Global aHUS Registry (NIH clinical trials identifier NCT01522183 ), of which approximately 20% have received kidney transplant, may provide additional information on outcomes with current therapeutic approaches. High rates of recurrence (80%) and graft loss (80%–100%) have been reported for patients with factor H or factor I mutations. In theory, patients with isolated mutations in the membrane-bound MCP protein should not develop recurrent HUS because the allograft would have wild-type, functional MCP protein. An analysis of the International Registry of Recurrent and Familial HUS/Thrombotic Thrombocytopenic Purpura (TTP) included three patients with documented MCP mutations, all with excellent graft function at 3 to 13 years posttransplant. However, HUS recurrence has been reported in a few patients with MCP mutation. Possible explanations include endothelial microchimerism, in which endothelial cells of recipient origin (expressing the mutated form of MCP) repopulate the transplanted kidney, or additional, undiagnosed, genetic susceptibility of the recipient (in circulating or fluid phase complement components). Living donation is not advised for children with potential aHUS given the high risk of recurrence and the uncertain effects of gene-gene interactions even from related donors found not to carry the same mutation as the recipient.



Table 37.2

Risk of ESRD and Transplant Recurrence for Hereditary Forms of Atypical HUS

Adapted from Nester, CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship TH, Kavanagh D, Noris M, Pickering M, Sanchez-Corral P, Skerka C, Zipfel P, Smith RJ. Atypical aHUS: State of the Art. Mol Immunol. 2015;67:31–42.



























































Gene Frequency of Mutations Risk of ESRD Risk of Recurrence
CFH 24%–27% 52%–65% 80%–90%
MCP 5%–9% 6%–63% 15%–20%
C3 2%–8% 43%–67% 40%–50%
CFI 4%–8% 17%–83% 70%–80%
CFB <1%–4% 70% Unknown
THBD 5% 23% Unknown
CFHR5 <1%–4% Unknown Unknown
DGKE <1% Unknown Unknown
CFHR 3%–10% Unknown Unknown
CFH antibody 3%–6% Unknown Unknown

C3 , complement 3; CFB , complement factor B; CFH , complement factor H; CFHR , complement factor H-related protein; CFI , complement factor I; DGKE , diacylglycerol kinase epsilon; MCP , membrane cofactor protein; THBD , thrombomodulin.


Plasma therapy has historically been the cornerstone of treatment for children with aHUS with CFH mutations. Infusion of fresh frozen plasma (FFP) can provide functional factor H, factor I, and C3 for patients with deficiencies in these factors, whereas plasma exchange withdraws anti-CFH antibodies and mutated forms of factor H. Preemptive plasma exchange (PE) initiated before and continuing for some time after transplant has been successful in preventing aHUS recurrence in a small number of patients with CFH mutation, but delayed recurrence can occur with tapering of therapy or during infections (especially CMV infection). Furthermore, several patients with CFH or CFI mutations have been reported to have graft loss after HUS recurrence despite PE, although these cases did not receive preemptive PE. Finally, patients with MCP mutation do not appear to benefit from plasma therapy. Liver transplant alone or in combination with kidney transplant has been reported for children with factor H mutation with the rationale that the transplanted liver would provide wild-type factor H. Although early attempts resulted in acute thrombotic events and high mortality rates, several centers in Europe have reported improved outcomes with ancillary plasma exchange and anticoagulation therapies. However, the risk of morbidity and mortality has limited the use of this approach. Successful transplantation in patients with complement factor H autoantibodies have been reported with the use of preemptive plasma exchange with or without rituximab.


Although CNIs have been associated with de novo HUS after solid-organ transplant, avoidance of CNIs has not been shown to affect the risk of recurrence in genotyped patients with aHUS.


Finally, the use of the anti-C5 monoclonal antibody, eculizumab, to prevent membrane attack complex formation holds promise for both the prevention and treatment of recurrence in children with aHUS undergoing renal transplantation. Moreover, the use of eculizumab may prevent progression to ESRD and obviate the need for renal transplantation. Optimal dosage and interval between eculizumab infusions remain to be fully defined, and the high cost of this agent may limit access. Although studies of long-term outcomes are not available, a requirement for life-long therapy is anticipated.


Membranous Nephropathy


Membranous nephropathy is rare in children at only 0.5% of incident ESRD in the US, so risk of recurrence in children after transplant is not clear.


Systemic Lupus Erythematosis


Data on lupus nephritis recurrence in children are scarce. This is likely owing to the late presentation of recurrence, which for most patients who are transplanted as adolescents would occur in adulthood. An analysis of the NAPRTCS registry reported similar patient and graft survival for children with systemic lupus erythematosis (SLE) compared with matched controls. There was an increased incidence of recurrent rejection episodes in SLE patients receiving living donor transplants for which there is no current explanation.


c-ANCA and p-ANCA-Positive Glomerulonephritis


Pauci-immune glomerulonephritis associated with antineutrophil cytoplasmic antibody with cytoplasmic (c-ANCA) or perinuclear (p-ANCA) staining patterns are a rare cause of ESRD in children, estimated at 2% of incident ESRD cases in the US. Recurrence rates of the small vessel vasculitides (SVV) in the adult literature are low at about 5% to 6%, and recurrence of granulomatosis with polyangiitis (or GPA; formerly known as Wegener granulomatosis) is rare. Average time to recurrence is 31 months, but it can occur within weeks to many years after transplant. Graft loss due to recurrence has been reported in 2% to 7% of adults transplanted with diagnosis of SVV.


Renal recurrence is often heralded by microscopic hematuria and proteinuria with focal or diffuse pauci-immune necrotizing glomerulonephritis seen on biopsy. The ANCA pattern or titers at the time of transplant do not appear to be predictive of disease recurrence. Similar to SLE, a waiting period of 6 to 12 months of inactive disease is recommended before transplant. Persistently positive ANCA serologies, however, should not preclude transplant because they are not an accurate marker of disease activity. There are anecdotal reports of the use of cyclophosphamide, corticosteroids, mycophenolate, and plasmapheresis for treatment of recurrence in patients with GPA and p-ANCA associated glomerulonephritis.


Metabolic Disease


Primary Hyperoxaluria Type I (Oxalosis)


Primary hyperoxaluria type I (PH1, also known as oxalosis) is a rare autosomal recessive disorder caused by a defect in hepatic alanine:glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. AGT deficiency results in overproduction of oxalate, resulting in massive renal excretion of insoluble calcium oxalate leading to nephrolithiasis and nephrocalcinosis. As GFR declines with progressive renal involvement, oxalate accumulates and results in systemic oxalosis. More than 100 different mutations have been described, and there is considerable phenotypic heterogeneity, even within family members with identical mutations.


The most severe form presents in infancy with renal failure necessitating dialysis. In children with less severe presentation and early diagnosis, conservative management with pyridoxine (thought to reduce oxalate production in a subset of B6-responsive patients), increased fluid intake, and citrate treatment might delay progression of kidney disease. Some centers advocate for preemptive liver transplant or combined liver–kidney transplant because liver transplantation corrects the underlying metabolic disorder. The use of hemodialysis before transplant has also been advocated to reduce systemic oxalate levels to mitigate injury to the allograft. Data from the NAPRTCS registry indicate poor patient and graft survival for children with oxalosis after kidney-only transplant with high rates of recurrence and death from sepsis. Recent longitudinal studies from Europe suggest improved outcomes in recent years, with the best outcomes in children who were diagnosed early and underwent combined kidney–liver transplant.


Nephropathic Cystinosis


Cystinosis is a rare, autosomal recessive disease due to a defect in the lysosomal cystine transporter (encoded by the cystinosin gene), resulting in intracellular accumulation of cystine, proximal tubule dysfunction (renal Fanconi syndrome), and progressive kidney disease. Since the development of the cystine-depleting drug, cysteamine, progression to ESRD may be delayed. Although nephropathic cystinosis does not recur posttransplant, protocol biopsies have shown interstitial deposition of cystine crystals without apparent clinical consequences. Graft survival rates for children with cystinosis are comparable or even improved compared with peers with other ESRD etiologies. Extrarenal manifestations of continued cystine accumulation (i.e., visual impairment, hypothyroidism, endocrine pancreatic insufficiency, and myopathy) have become more apparent as the lifespan of patients with cystinosis increases and likely are postponed by continued cysteamine treatment posttransplant.




Pretransplant Evaluation


Evaluation of Potential Living Donor


Evaluation of a potential living donor (see Chapter 7 ) for a pediatric recipient is similar to that for adults, with the exception of preference for younger aged donors. Living donors are evaluated for comorbid conditions that would either increase their own risk for developing ESRD or affect the recipient (i.e., certain viral infections). Adult-sized kidneys from living donors have excellent potential for long-term graft survival in pediatric recipients. Although the ideal situation would be donation from an HLA-identical sibling, most live-kidney donations for pediatric recipients come from haplo-identical parents because siblings are often not able to provide informed consent due to their age.


Evaluation of Recipient


Many similarities exist in the medical evaluation of potential pediatric and adult transplant recipients (see Chapter 4 ). However, certain conditions occur more frequently in children, so the medical evaluation of pediatric recipients has a slightly different emphasis. The following section describes the common medical, surgical, and psychological issues taken into consideration during the pretransplant evaluation of a pediatric patient.


Medical Evaluation of Issues Related to ESRD


Cardiovascular Disease


Hypertension is a common problem in children with CKD. Although chronic fluid overload can result in left ventricular hypertrophy and dilated cardiomyopathy, florid heart failure is uncommon in pediatric CKD patients. Evaluation of heart function should be performed before transplant to identify risk for impaired cardiac output that can negatively affect perioperative fluid allograft perfusion.


Pediatric recipients are at risk for exacerbated hypertension posttransplant, including malignant hypertension, due to the combination of volume expansion, corticosteroid therapy, and CNI exposure in the postoperative period. Optimized blood pressure control in children with ESRD, including the use of bilateral nephrectomy in cases refractory to medical management, is paramount to successful transplant outcomes.


GN of Unknown Etiology


The underlying cause of ESRD should be identified in preparation for transplant to anticipate the risk of recurrence. Complement levels (C3 and C4), antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and antidouble-stranded DNA (antidsDNA) titers should be performed in children with suspected glomerulonephritis as a cause of ESRD. As mentioned in the previous section, children suspected of having HUS as a cause of ESRD should be evaluated for atypical forms of HUS, including mutational analysis and complement levels. Finally, identifying a hereditary disease as the cause of ESRD also aids in the evaluation of potential living related donors.


Nephrotic Syndrome


CNS poses a unique challenge in preparation for kidney transplant due to prolonged hypogammaglobulinemia, malnutrition, chronic anasarca, recurrent infections, and high-risk thrombosis that arise from chronic, uncontrolled urinary losses of various proteins. Some centers perform preemptive unilateral or bilateral nephrectomy in these children and interim peritoneal dialysis before transplantation. This allows normalization of serum albumin and IgG levels, resolution of hypercoagulability, and optimization of nutrition with concomitant improvement in growth before transplant. Another approach includes “medical nephrectomy” via the use of renin-angiotensin system blockade and prostaglandin inhibitors to effectively reduce GFR and minimize proteinuria with or without unilateral nephrectomy.


In children with idiopathic nephrotic syndrome, proteinuria typically diminishes as they approach ESRD. Active nephrotic syndrome is a prothrombotic state due to urinary losses of antithrombotic factors leading to increased risk of perioperative thromboembolic events. Furthermore, hypoalbuminemia can complicate postoperative fluid management because of increased third spacing, thereby increasing the risk of electrolyte derangement and graft hypoperfusion. Continued proteinuria from native kidneys may also mask the detection of early FSGS recurrence posttransplant. Therefore active nephrotic syndrome is the most common indication for native nephrectomies before transplant in children.


Renal Osteodystrophy


Aggressive treatment of secondary hyperparathyroidism, renal osteodystrophy, and adynamic bone disease with vitamin D analogs and calcimimetics is vitally important for children with ESRD to optimize growth and anemia management before transplant. In general, secondary hyperparathyroidism improves after transplant, but it can often take several months to a year for parathyroid hormone (PTH) levels to completely normalize. Persistent hyperparathyroidism after kidney transplant can result in hypercalcemia and/or hypophosphatemia, and it affects growth potential. Ideally, pediatric transplant candidates should have intact PTH levels within the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) or Kidney Disease Improving Global Outcomes (KDIGO) target range for CKD stage 5 (200–300 pg/mL or 2–3 times the upper limit of normal). However, transplant may proceed safely despite higher PTH levels provided serum calcium and phosphorus levels are under acceptable control.


Nutrition and Growth


Poor feeding and linear growth delay are prominent features of chronic renal failure in young children. As mentioned previously, most centers prefer pediatric patients to achieve a weight of 10 to 15 kg before kidney transplant, and infants on dialysis may not reach this goal before 2 years of age. Often gastrostomy tube placement and recombinant growth hormone (rGH) therapy are needed to optimize growth before kidney transplant in young children. Gastrostomy tubes can also ensure adequate hydration in small children who may be unable to meet the increased posttransplant fluid requirements orally. Adequate nutrition is also important to optimize healing from transplant surgery. Therefore pediatric clinical dieticians play a vital role in pretransplant evaluation.


Evaluation of Extrarenal Disease


Infections


Pediatric transplant candidates, like adults, should be free from active infection to minimize complications posttransplant. There are several infectious disease considerations that should be considered in pediatric transplant recipients.


Urinary Tract Infections


Many children with ESRD have abnormal urinary tract anatomy, bladder outlet obstruction, or vesicoureteral reflux (VUR) that place them at increased risk for recurrent UTI posttransplant. Indeed, UTI is the most common bacterial infection in children awaiting kidney transplant. Aggressive antibiotic treatment and prophylaxis is helpful in suppressing UTI in most children. Preemptive native nephrectomy has been performed in children with a history of recurrent UTI, severe VUR, and hydronephrosis to reduce the risk of urosepsis posttransplant.


Cytomegalovirus


Children are more likely to be CMV naïve at the time of transplant than adults. Anti-CMV IgM and IgG titers as well as polymerase chain reaction (PCR) detection of CMV viral nucleic acid should be obtained at the time of pretransplant evaluation to plan for postoperative CMV prophylaxis. If initial serologic studies are negative, repeat studies at the time of transplant can confirm immunologic naiveté in the recipient. Donor CMV titers are also indicated to stratify the risk for developing posttransplant CMV disease.


Epstein-Barr Virus


Similar to CMV, many children undergoing evaluation for kidney transplant are naïve to EBV exposure. Primary EBV infection posttransplant increases the risk of PTLD. Although the use of costimulation blockade (e.g., belatacept) is not currently approved in children, the concern for increased risk of PTLD for seronegative recipients has profound implications for the use of belatacept in the pediatric kidney transplant population; see Chapter 19). Anti-EBV IgM and IgG titers as well as EBV PCR should be assessed at the time of evaluation and, if initially negative, repeated at the time of transplant to confirm seronegativity and absence of infection. As with CMV, donor EBV serologies are helpful in stratifying the risk of early PTLD as a naïve recipient is exposed to infected leukocytes at the time of transplant.


Hepatitis B and C


Annual screening for hepatitis B (HBV) remains the standard of care for children on dialysis. HBV infection in children is uncommon due to the success of newborn vaccination programs. Although hepatitis C (HCV) infection is rarely reported in the general pediatric population, there are small studies suggesting that up to 20% of children receiving long-term hemodialysis have detectable HCV antibodies or viral antigens and nucleic acid on screening tests. The clinical significance of these results is not clear as the children in these reports were asymptomatic. Nevertheless, children undergoing evaluation for transplant should have HBV and HCV serologic testing along with serum aminotransferase levels to exclude the presence of active infection before transplant.


Immunization Status


Routine childhood immunizations should be completed, if possible, before kidney transplant. Live attenuated virus vaccines (i.e., measles-mumps-rubella and varicella vaccines) are generally contraindicated in immunosuppressed patients due to the increased risk of disseminated disease by the vaccine virus strain. Therefore children awaiting transplant should receive live virus vaccination at least 1 to 2 months before transplant. Other, nonlive-virus vaccinations (i.e., hepatitis A, Tetanus-diptheria-acellular pertussis or Tdap, expanded 13-valent pneumococcal, meningococcal, and human papilloma virus or HPV) should also be administered before transplant because the immunosuppressant therapy can impair immunologic response to these vaccines. Children awaiting transplant should also receive annual influenza vaccination. Antibody titers against hepatitis B, hepatitis A, measles, mumps, rubella, and varicella should be evaluated to determine whether a booster vaccination is needed within 6 months of transplant. Further research is needed to develop optimal vaccine protocols to minimize waning of protective immunity posttransplant.


Hemostasis


As mentioned earlier, thrombosis is a significant cause of graft loss in very young recipients. However, identifying children at highest risk for this complication has been difficult. Retrospective studies have identified the following risk factors for graft thrombosis in pediatric recipients: recipient age under 5 years, history of peritoneal dialysis, high urine output pretransplant, young donor age (<5 years old), and prolonged cold ischemia times (>24 h). Central venous lines are the most common vascular access for children receiving hemodialysis, and line-associated thrombosis is a common event in this patient population. Data linking prior history of catheter-associated thrombosis in children on dialysis with risk of graft thrombosis after transplant are not established.


There are few data on the prevalence of inherited hypercoagulability that may predispose some children to graft thrombosis. In adults, inheritance of factor V Leiden or prothrombin (G20210A) mutations significantly increase the risk of graft thrombosis. Adults with SLE, especially in the presence of detectable antiphospholipid antibody or β2-glycoprotein-1, are at particularly high risk of thromboembolic events. There are insufficient data to determine the risk of posttransplant thrombosis in children with hyperhomocysteinemia or 5,10-methylene tetrahydrofolate reductase (MTHFR) polymorphisms.


Children with a history of recurrent thrombotic events, a strong family history of thrombophilia, or significant proteinuria should undergo coagulation workup by a specialist to determine whether chronic anticoagulation therapy is warranted. Evaluation of hypercoagulability includes measurement of prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen, ATIII level, protein C and protein S levels, and activated protein C resistance (to monitor factor V Leiden). Adolescents with a history of SLE should be screened for antiphospholipid antibody, anticardiolipin antibody, and β2-glycoprotein-1. Further workup, including mutational analysis in other genes associated with inherited thrombophilia should be undertaken under the advice of a pediatric hematologist.


Prior Malignancy


In general, children with ESRD do not need screening for preexisting malignancy, but a prior history of malignancy warrants additional evaluation. Wilm tumor is the most common malignancy resulting in ESRD in children. A waiting period of 2 years after treatment for Wilm tumor is recommended and has resulted in excellent outcomes with a low risk of recurrence after transplant. However, reevaluation of the recommended waiting time is being considered due to the high morbidity and mortality associated with dialysis, and improvements in the prevention and treatment of acute rejection since the original recommendations were established. Kidney transplant in children with a history of other extrarenal malignancies is generally considered after a recurrence-free period of 2 to 5 years.


Surgical Evaluation


Children undergoing kidney transplant evaluation often need multiple surgical interventions, including bladder augmentation, placement of Mitrofanoff continent urinary diversion, vesicostomy closure, gastrostomy tube placement, or native nephrectomy before or at the time of transplant. Therefore it is vital that a surgical plan be established among pediatric surgeons, transplant surgeons, and urologists before kidney transplant in children to coordinate surgical approaches and spare or maintain the vascular supplies that are unique for each procedure.


Vascular Evaluation


The abdominal vasculature should be assessed for patency in preparation for transplant surgery. Children with prior history of femoral lines (including dialysis catheters) or inflammatory conditions of the abdomen (such as multiple abdominal surgeries or recurrent peritonitis) are at increased risk of thrombosis of the inferior vena cava (IVC) or iliac vessels, thereby complicating vascular anastomoses of the graft. Magnetic resonance venogram (MRV) or computed tomography angiography (CTA) are sensitive techniques for assessing IVC patency as well as providing a detailed anatomic survey of abdominal vasculature. In patients at lower risk of thrombosis, Doppler ultrasound is useful to screen for IVC and iliac vein patency, but may be dependent on operator expertise, especially in small children.


Urologic Evaluation


As mentioned earlier, nearly 25% of children receiving kidney transplants have underlying urologic abnormalities, including lower tract obstruction, vesicoureteral reflux, or bladder dysfunction. Therefore pediatric urologists play an important role in the management of these patients before and after transplantation.


All children under consideration for kidney transplant should have a renal ultrasound to evaluate for hydronephrosis, hydroureter, and bladder wall thickening. A voiding cystourethrogram (VCUG) should be performed in selected children, including those with a history of urologic causes of ESRD, history of UTIs, hydronephrosis on ultrasound, or signs (e.g., thickened bladder wall on ultrasound) or symptoms suggestive of dysfunctional voiding.


Urodynamic studies are indicated for selected children with urinary tract abnormalities to assess bladder capacity, compliance, voiding pressure, leak point pressure, and postvoid residual (see Chapter 12 ). Early, aggressive treatment of neurogenic or dysfunctional bladder is critical as elevated bladder pressures have been associated with increased risk of developing reflux into the transplanted kidney and worse graft survival. Medical management of neurogenic bladder often includes anticholinergic therapy combined with intermittent catheterization and should be continued after transplant. Children with a history of posterior urethral valves should be assessed for persistent anatomic obstruction after valve ablation or have a neourethra (e.g., Mitrofanoff) that can be intermittently catheterized after transplant to prevent lower urinary tract obstruction.


In some cases, poor bladder compliance persists despite appropriate medical management, necessitating bladder augmentation with small bowel or colon segments before transplant. However, otherwise healthy but small capacity, defunctionalized bladders in children with oliguric ESRD do not require augmentation to achieve excellent graft outcomes. Typically, urologic correction should be undertaken 3 to 6 months before transplant to allow for adequate healing before immunosuppression.


Because many children with urologic disorders have nonoliguric renal failure, careful assessment of daily urine volume by history and 24-hour urine collection is warranted to plan for posttransplant fluid management and need for native nephrectomy.


Native Nephrectomy


The most common indications for native nephrectomy in children undergoing kidney transplant are excessive urine output, high-grade vesicoureteral reflux with recurrent or recalcitrant pyelonephritis, continued heavy proteinuria (see Primary Glomerulonephritis section for risk for recurrent diseases with nephrotic-range proteinuria section), uncontrolled hypertension, and risk of renal malignancy.


Unique to pediatrics, excessive urine output (>20 mL/kg/24 h) occurs more often in small children receiving an adult-size graft and has been associated with risk of renal transplant thrombosis. Furthermore, high urine output after the immediate posttransplant period (>4 L/day) can complicate fluid management for small children for whom it would be difficult to consume such large volumes to avoid hypovolemia.


Nephrectomy of a native kidney with severe reflux (grade 3 or 4) should be considered to reduce the risk for early UTI or urosepsis in the setting of immunosuppression. Preemptive native nephrectomy has been advocated for certain patients for which the underlying renal disease results in continued urinary losses of electrolytes (i.e., for Bartter syndrome) or heavy proteinuria (i.e., FSGS or CNS) complicating the optimal nutritional and medical management of children before transplant. Reduction in heavy proteinuria due to FSGS after nephrectomy may reduce the risk of thrombotic events by correcting the hypercoagulable state and allow for earlier recognition of recurrent FSGS after transplant. As mentioned earlier, children with CNS may benefit from improved nutrition and reduced risk for infection after nephrectomy. Finally, children with autosomal recessive polycystic kidney disease (ARPKD) often require unilateral or bilateral nephrectomy of rapidly enlarging kidneys to allow for both improved respiratory status and adequate space in the abdomen for a future kidney graft. Children with disorders related to mutations in the WT1 gene, such as Denys-Drash syndrome and Frasier syndrome, are at increased risk for developing Wilm tumor over time. Therefore bilateral nephrectomy is considered once they approach ESRD.


Many centers, including ours, perform pretransplant native nephrectomies for patients on dialysis with recalcitrant hypertension with good short-term results, including achievement of age-normative blood pressures and a reduction in the number and dosage of antihypertensive medications. The efficacy of bilateral nephrectomy in improving blood pressure control for children on dialysis or preventing posttransplant hypertension has not been extensively studied. Results reported from our center involving unilateral or bilateral nephrectomy of diseased native kidneys have shown good results during short-term follow-up. Similarly, children with multicystic dysplastic kidney disease or reflux nephropathy resulting in a unilateral poorly functioning kidney have been reported to have resolution of hypertension or diminution of antihypertensive medications after nephrectomy. However, a recent retrospective study did not demonstrate an effect of bilateral nephrectomy on the risk of posttransplant hypertension or left ventricular hypertrophy. Prospective longitudinal studies are needed to evaluate whether bilateral nephrectomy for hypertension improves long-term cardiovascular morbidity in children receiving kidney transplant.


The surgical approach to nephrectomy (retroperitoneal vs. transperitoneal; open vs. laparoscopic) should be based on the center’s expertise and the needs of the patient (e.g., receiving peritoneal dialysis). Although a recent report from Italy suggests that renal embolization in children may be a minimally invasive alternative to nephrectomy for indications other than risk of malignancy, we have observed unacceptable morbidity from this procedure and would not recommend this approach.


Neurologic Development


Developmental Delay


It is increasingly recognized that children with CKD have higher rates of neurocognitive delays. Factors that have been associated with increased risk for neurocognitive deficits include longer duration of CKD, increased severity (i.e., advanced stages of CKD), and younger onset of disease.


Children with ESRD during infancy have significant developmental delay due to uremia. In the absence of structural brain abnormalities, psychomotor delay can improve after transplant, with many infants regaining normal developmental milestones. Although overall neurodevelopmental outcomes are favorable after transplant, in a prospective study of children undergoing kidney transplant before the age of 5 years, lower IQ and learning disabilities were most common in children born prematurely and those who had multiple hypertensive crises and/or seizures during dialysis. This study suggests that prevention of hypertension-related morbidity may improve neurodevelopmental outcomes for young children after kidney transplant.


Other infants needing dialysis in the first year of life may have structural neurologic abnormalities resulting from insults associated with premature birth or anoxic/ischemic injury (e.g., hypoxic ischemic encephalopathy, periventricular leukomalacia after intraventricular hemorrhage, or microcephaly). Children with structural neurologic abnormalities can present with hypotonia, spasticity, myoclonus, severe cognitive delays, and seizures. Children with severe mental retardation may not respond well to the constraints of ESRD care, where the need for multiple, and often painful, procedures can be confusing and uncomfortable. In such situations, the potential for rehabilitation, self-care, and parental preferences should be considered during joint decision making between the medical team and family/caregivers in determining whether long-term dialysis or transplantation should be pursued.


Seizures


Up to 20% of children with ESRD are treated for seizure disorder typically related to hypertensive crises, and about 5% require ongoing anticonvulsant therapy posttransplant. Adequate seizure control should be obtained before transplantation, preferably with anticonvulsants that do not interfere with the metabolism of commonly used immunosuppressant medications. Phenytoin (Dilantin), barbiturates, and carbamazepine can significantly reduce serum levels of CNIs and prednisone. Newer anticonvulsants may not interfere with immunosuppressant drug levels, but it is prudent to check for updates in drug-drug interactions when planning for transplant.


Psychosocial Issues


Psychoemotional Status


A multidisciplinary approach with involvement of physicians, child psychologists, and child life specialists is important for the preparation of children and their families for kidney transplantation. Children with emotional or psychiatric disorders often require additional mental health resources including psychiatric care. Acquisition of coping skills, problem-solving skills, and behavior modification can improve a child’s experience with the inherent complexity of dialysis or transplantation medical care. Pharmacotherapy for depression, bipolar disorder, and attention deficit hyperactivity disorder are important adjunctive therapies. Reduced clearance with impaired renal function, clearance by dialysis, and interference with the metabolism of immunosuppressive medications should be considered when selecting psychotropic medications in children with ESRD. Most selective serotonin reuptake inhibitors (SSRIs) do not interfere with immunosuppressive medications.


Nonadherence


Suspected nonadherence contributes to approximately 44% of graft losses and 23% of late acute rejection episodes reported in the literature for adolescent kidney transplant recipients. Patterns of medication and dialysis treatment compliance should be assessed for every child undergoing evaluation for kidney transplant to identify patients at high risk for nonadherence posttransplant. Social, behavioral, and psychiatric interventions should be initiated before transplant for those patients with identified or anticipated issues with noncompliance. Identification and nurturing of psychosocial support systems and frequent medical and social work follow-up are often required to prepare the pediatric candidate for transplantation. Again, the best chance of rehabilitation and preparation for transplant is achieved when there is close coordination between medical and mental health providers. It is also of particular importance for the transplant and dialysis medical teams to maintain close communication as the recipient prepares for transplant.


Evaluation Updates


Pediatric candidates for kidney transplant should be reevaluated at regular intervals (generally every 6–12 months) to identify any changes in their medical condition or psychosocial status that might alter the risk of commencing with transplantation. A simplified version of the initial medical evaluation is appropriate for update visits.




Perioperative Management of Pediatric Renal Transplant Recipients


Preoperative Management


Children presenting for imminent kidney transplant surgery should be clinically stable without signs of active infection. A final set of laboratory studies is obtained to evaluate for any electrolyte or metabolic derangements that require dialysis or medical treatment before anesthesia induction.


Intravascular volume status is important before transplant surgery as children with hypovolemia (especially those with high urine output) are at increased risk of graft thrombosis and graft hypoperfusion leading to ATN. Therefore, if dialysis treatment is indicated before surgery, excessive fluid removal should be avoided. Similarly, children with residual urine output should receive intravenous (IV) fluids to maintain intravascular volume while oral intake is restricted awaiting surgery.


Subclinical infections of skin, dialysis access site, peritoneal fluid, and urinary tract should be evaluated with a thorough history, physical examination, and laboratory studies, including urinalysis and urine culture, peripheral white blood cell count with differential blood cultures for those with indwelling venous catheters, and peritoneal cell count and culture for those maintained on peritoneal dialysis. A recent episode of peritonitis or peritoneal dialysis (PD) catheter exit-site infection does not preclude transplantation, but the child should complete 10 to 14 days of antibiotics and have a negative peritoneal fluid culture off antibiotics before transplant.


As mentioned earlier, CMV and EBV serologies should be repeated if previous results revealed immunologic naiveté. Final HLA crossmatch should be performed within 1 week before living-donor kidney transplant or in the hours preceding deceased-donor transplant.


Intraoperative Management


Small children can present operative challenges given the relatively large size of an adult kidney graft compared with recipient size. Children weighing more than 30 kg are often treated surgically as small adults with graft placement in the standard extraperitoneal pelvic location and vascular anastomoses to the common iliac artery and vein. However, in small children intraabdominal placement may be preferable with vascular anastomoses to the infrarenal aorta and IVC. The surgical approach should be individualized with appropriate matching of blood vessel size and attention to expected circulatory volume requirements.


Intraoperative management of the pediatric kidney transplant recipient is focused on achieving optimal graft perfusion and preventing complications arising from underlying ESRD. In small children, a central venous catheter is often inserted for close monitoring of central venous pressures. Central venous pressures (CVP) should be maintained at 12 to 18 cmH 2 O and mean arterial pressures (MAP) above 70 mmHg via infusion of crystalloid or 5% albumin before clamp release to ensure adequate perfusion to the adult-sized transplanted kidney.


It is important to recognize the challenge that this can pose in children under 30 kg, as a kidney graft from an adult can sequester 150 mL to 250 mL of blood, which can represent well over 10% of a small child’s total circulating volume. In infants, up to 50% of cardiac output is directed to perfusion of an adult-sized kidney graft. Transfusion with packed red blood cells (pRBC) is often necessary in the smallest recipients to avoid severe anemia. In addition, continuous dopamine infusion at 2 to 3 μg/kg/min is often necessary, especially in infants, to maintain higher MAP and is continued for 24 to 48 hours postoperatively to allow the graft to slowly accommodate to lower MAP in the recipient. Finally, mannitol (1 g/kg) with or without furosemide (1 mg/kg) is often administered before clamp removal to facilitate diuresis. Mannitol infusion may also prevent sudden shifts in serum sodium and acute decreases in serum osmolality, which increases the risk for postoperative neurologic complications.


Blood gases and lactate levels should be monitored intraoperatively because clamping of the aorta or iliac artery can result in lactic acid accumulation, metabolic acidosis, and vasoconstriction. Intraarterial injection of calcium channel antagonists (e.g., verapamil or papaverine) or nitroglycerin have been used to overcome arterial spasm that impairs graft perfusion.


For most immunosuppression protocols, intravenous methylprednisolone sodium succinate (Solu-Medrol) is administered at the beginning of the surgical case. In addition, many pediatric transplant centers use intravenous biologic agents for induction therapy, which are also administered intraoperatively.


Postoperative Management


Children are monitored in the intensive care unit setting for the immediate postoperative period. In the first 2 to 3 days, the postoperative management is focused on optimizing graft perfusion and mitigating the effects of fluid overload (e.g., electrolyte derangements and hypertension). As mentioned earlier, small children often require dopamine infusion for 24 to 48 hours posttransplant to maintain graft perfusion and allow gradual accommodation of the graft to the lower mean arterial pressures of the recipient.


Fluid management in small children requires fastidious care due to their small size and potentially very large posttransplant urine volumes. Urinary losses are replaced in equal volumes with intravenous 0.45% or 0.9% sodium chloride infusion for the first 24 to 48 hours. Dextrose should be withheld from the initial IV fluids given for urine replacement to avoid hyperglycemia and osmotic diuresis. Replacement of insensible water losses should be administered as a separate infusion with dextrose-containing crystalloid. Hypokalemia and hypophosphatemia may develop in the first few postoperative days. Potassium and/or phosphate salts can be added to the replacement fluids as appropriate.


As the kidney graft regains urinary concentrating ability, urine output declines to levels that are more reasonably achievable as daily oral intake. Urine replacement with IV crystalloid can be discontinued at that time, and intake goals of 150% to 200% of calculated maintenance needs should be started by mouth. Children with intraabdominal graft placement are susceptible to prolonged postoperative ileus due to displacement of the colon and intestines with an adult-sized graft occupying almost the entire right side of the abdomen. These children often require continuation of maintenance IV fluids beyond the first few days until they can tolerate oral fluids and nutrition. Small recipients (<15 kg) of large adult kidneys are at risk for developing the uncommon complication of abdominal compartment syndrome with increased intraabdominal pressure complicated by oliguria and hypotension.


Hypertension is commonly observed in children after transplant. In some instances, elevated blood pressures improve with adequate analgesia. Fluid overload can also contribute to postoperative hypertension and often improves once spontaneous mobilization of fluid occurs. Aggressive treatment of mild to moderate hypertension is typically not recommended early posttransplant to avoid sudden changes in MAP and decreased graft perfusion. This being said, children who were on multiple antihypertensive medications before transplant may need reinstitution of at least some of their previous medications to avoid severe rebound hypertension and the accompanying adverse effects.


Postoperative allograft ultrasound is performed routinely in many pediatric transplants centers, although there is no consensus on the timing or necessity of the imaging. Information gained by ultrasound includes assessment of vascular patency, increased resistive indices suggestive of risk of delayed graft function, identification of surgical complications (e.g., lymphocele), and detection of collecting duct dilatation to identify those at risk for future urologic complications.


Goals for hospital discharge of the pediatric transplant recipient include adequate oral fluid intake to prevent hypovolemia (and subsequent graft hypoperfusion), stable immunosuppression regimen, completion of family and caregiver education, access to medications, and arrangement of outpatient follow-up.

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Dec 26, 2019 | Posted by in NEPHROLOGY | Comments Off on Kidney Transplantation in Children
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