Kidney transplantation in children: Complications

INTRODUCTION — Advances in immunosuppressive therapy and post-transplant management have led to improvements in both graft and patient survival in pediatric kidney transplant recipients. However, long-term success has been limited by complications due to immunosuppression, rejection, and recurrent disease.

This topic will provide an overview of the complications of kidney transplantation in children. Some complications of kidney transplantation are unique to children, while others are observed in all transplant recipients. Additional issues concerning transplantation in children and issues in kidney transplantation common to both children and adults are presented elsewhere. (See "Kidney transplantation in children: General principles" and "Kidney transplantation in children: Outcomes".)

GRAFT DYSFUNCTION

Overview — The causes of kidney allograft dysfunction vary with the time after transplantation.

●Immediate (zero to one week postsurgery) – Causes of delayed graft function (immediate kidney failure persisting after transplantation) include postischemic acute kidney injury, vascular thrombosis of the renal artery or vein, urologic complications (ie, urinary leak or obstruction), and rarely, hyperacute rejection.

●Early (1 to 12 weeks postsurgery) – Among patients with initial graft function who develop early kidney insufficiency (ie, 1 to 12 weeks post-transplantation), the major causes of graft dysfunction are acute allograft rejection, calcineurin inhibitor toxicity, urinary obstruction, infection, hypovolemia, and recurrent disease.

●Late acute (after three months) – Allograft dysfunction that acutely develops more than three months after transplantation is most commonly due to acute allograft rejection, calcineurin inhibitor toxicity, urinary obstruction, hypovolemia, pyelonephritis, and recurrent or de novo kidney disease [1].

●Late chronic (years) – Slowly progressive kidney disease that occurs over a period of years after kidney transplantation most commonly results from chronic allograft injury, calcineurin inhibitor nephrotoxicity, hypertensive nephrosclerosis, viral infections, and recurrent or de novo kidney disease.

Delayed graft function — Kidney failure persisting immediately after transplantation is called delayed graft function (DGF). The definition of DGF varies in different studies, but generally refers to oliguria or the requirement for dialysis within the first week post-transplantation [2]. Previously, patients with DGF have had a 15 to 25 percent lower graft survival rate than those without DGF.

The major causes of DGF in children are the following (see "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction") [2]:

●Postischemic acute kidney injury is the most common cause of DGF

●Thrombosis or embolization of the renal artery or vein

●Accelerated rejection superimposed on ischemic acute tubular necrosis

●Urologic abnormalities (ie, urinary leak or hematoma)

●Hyperacute rejection (generally preventable) due to preformed anti-human leukocyte antigen (HLA) antibodies

●Factors related to the donor (ie, cardiovascular instability, older donor age, kidney function based on serum/plasma creatinine)

Acute kidney injury — Several factors may be responsible for postischemic acute kidney injury. These include the age and condition of the donor, specific recovery procedure, technique of organ preservation, adequacy of volume replacement during and after surgery, and the cold and warm ischemia times. Tubular damage may be aggravated by the use of cyclosporine or tacrolimus. There is evidence that the addition of sirolimus in combination with either cyclosporine or tacrolimus prolongs DGF. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors".)

Vascular thrombosis — Vascular thrombosis of the renal artery or vein is a common cause of graft failure in children receiving kidney transplants. The main risk for thrombosis is an extremely young donor or recipient. Other risk factors include hypercoagulability (such as that due to chronic nephrotic syndrome) and venous malformation in the recipient, pretransplant peritoneal dialysis, a hypotensive episode during or after surgery, the presence of multiple arteries, and bench surgery of graft vessels [3]. Although vascular thrombosis is usually observed within the first few days following transplantation, it can be seen as late as three weeks post-transplant.

The use of interleukin 2 receptor antagonists may be associated with a decreased risk of graft thrombosis. This was shown in a retrospective study of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database of transplant patients between 1998 and 2004 in which the incidence of thrombosis was significantly lower among those who received such antibodies (1.07 versus 2.4 percent) [4].

Other measures that may reduce the incidence of vascular thrombosis include:

●Careful hemodynamic monitoring of central venous pressure to ensure adequate allograft perfusion.

●Consideration of screening for inherited and acquired thrombophilic risk factors, especially if there is a family history or previous episode of thrombosis. Screening is currently available for protein C, S or antithrombin III deficiency, factor V Leiden, prothrombin gene mutations, and the presence of antiphospholipid antibodies. Prophylactic therapy with heparin, low-molecular-weight heparin, and/or aspirin to prevent thrombosis for those with an increased risk of thrombophilia has been successful in preventing graft loss [5]. In some centers, low-molecular-weight heparin is used prophylactically in all pediatric kidney transplant recipients [6]. (See "Thrombophilia testing in children and adolescents".)

●Correction of vascular depletion related to nephrotic syndrome [7,8].

In a study of kidney transplants performed in patients <19 years of age between 1995 and 2014 from the United States Renal Data System, the incidence of allograft loss due to renal vein thrombosis has decreased [9]. However, the cause of improvement could not be ascertained, due to limitations of information within the database.

Urologic complications — Early post-transplant urologic complications include [10]:

●Urinary leak due to ureteral necrosis, bladder injury, or obstruction.

●Urinary tract obstruction, most often due to clots in the urinary tract, postoperative edema, or surgical complication. It is detected as hydronephrosis by kidney ultrasonography. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and 'Surgical and urologic sequelae' below.)

Although ureteral stents have been proposed as a measure to reduce these complications, their efficacy remains uncertain. In one trial, the use of a ureteral stent at kidney transplantation significantly decreased urinary leak and obstruction with a reduction in overall medical costs [11]. In contrast, a retrospective study found no difference in graft survival and the risk of urinary leakage and ureteral stenosis between patients who had stent placement and those who did not [12]. In this report, stent placement also resulted in additional costs. Both studies demonstrated an increased risk of urinary tract infections with stent placement, especially if the stent remained in place beyond 30 days after transplant [11,12].

At our institution, stents are used in recipients who have bladder abnormalities with increased risk of urinary retention or high pressure, as well as when the transplant surgeon has concerns about the donor ureter. Our policy is to remove stents before the fourth week post-transplant. (See 'Surgical and urologic sequelae' below.)

Hyperacute rejection — Hyperacute rejection occurring within the first minutes following transplantation results from preformed host anti-HLA antibodies that bind to vascular endothelial cells of the graft, resulting in activation of the complement cascade and endothelial injury. Neutrophils, macrophages, and platelets are attracted to the antibody binding site and cause further cellular damage. Platelet aggregation on the damaged endothelium leads to fibrin deposition and vascular thrombosis [13]. There are also reports of hyperacute rejection associated with antiendothelial antibodies [14], which are not detected using standard crossmatch methods using donor lymphocytes.

Approximately 20 percent of children awaiting transplantation have panel-reactive anti-HLA antibodies (PRA) >80 percent [15]. However, only 3 percent of the children who received a kidney transplant between 2010 and 2012 in the United States had a PRA >80 percent [16]. Sensitization occurs following blood transfusions, pregnancies, and transplantation. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)

Desensitization protocols have included high-dose intravenous immune globulin, plasmapheresis, and rituximab, although there are no controlled studies in children [17]. Nationwide programs are needed to find fully compatible kidneys for each pediatric recipient [18]. (See "Kidney transplantation in adults: HLA-incompatible transplantation", section on 'Pretransplant HLA desensitization'.)

Acute rejection — Acute kidney allograft rejection is a frequent complication of pediatric kidney recipients, which may occur several days, weeks, or months after transplantation. It is defined as an acute deterioration in allograft function, generally detected by an elevation in the serum creatinine level, which is associated with specific pathologic changes in the graft obtained via an allograft biopsy. The two principal histologic forms of rejection are acute T cell mediated cellular rejection and acute antibody-mediated rejection, which are discussed in detail separately. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)

In children with kidney transplants, the rate of acute rejection has decreased over the past 30 years [19]. This decrease in the incidence of acute rejection appears to be due to the introduction of newer immunosuppressive agents [20]. Based on the NAPRTCS data, hospitalization within the first 24 months following transplantation is more frequently caused by post-transplant infections than acute rejection [20].

●Diagnosis

•Clinical signs – The classic signs of acute rejection, such as fever and graft tenderness, are observed less commonly with current immunosuppressive regimens. With these newer regimens, acute rejection episodes are often only detected by a rise in the serum concentration of creatinine.

•Renal biopsy confirmation – Acute rejection is confirmed histologically via kidney biopsy, a technique that can be performed with minimal risk in children [21,22]. In the case of a small pediatric recipient of an adult-sized kidney, rejection may be present with no or only a small elevation in serum creatinine. In this setting, kidney biopsy may be considered earlier when the results of the serum creatinine levels are equivocal.

There is ongoing debate on the role of protocol biopsy in children to detect subclinical rejection, assess response to therapy for rejection, and surveillance for chronic allograft nephropathy [23,24]. It remains to be demonstrated whether graft survival is improved by detecting these histologic changes, as suggested by results in adult patients. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)

●Monitoring for acute rejection – Among stable pediatric allograft recipients, the following strategy relating to the timing of serum creatinine concentration measurement is recommended [25]:

•Daily measurement during the first two weeks

•Twice to three times a week two to four weeks after transplantation

•Twice per week during the second month

•Weekly from the third to fourth month

•Twice a month from the fifth to eight months

•Monthly after the eighth month post-transplant

●Differential diagnosis – The following conditions may also present with an elevation in serum creatinine and need to be distinguished from acute rejection:

•Urinary tract obstruction (generally ureteral obstruction) is differentiated from acute rejection by an ultrasound finding of hydronephrosis

•Calcineurin inhibitor (CNI) nephrotoxicity is differentiated from acute rejection by kidney biopsy and/or a positive response of deceasing serum creatinine with lowering of CNI dose

•Cytomegalovirus (CMV) and BK polyomavirus (BKPyV) may cause graft dysfunction (see 'Viral infections' below and "Prevention of cytomegalovirus disease in kidney transplant recipients", section on 'Impact on graft function and mortality')

•Renal artery stenosis is an uncommon complication and is differentiated from acute rejection by imaging studies (see "Establishing the diagnosis of renovascular hypertension", section on 'Diagnostic test options')

•Pyelonephritis may occur, especially in children with abnormal urinary tracts, and may present with fever, abdominal pain, and decreased graft function

Chronic allograft injury — Similar to adults, the most common reported cause of graft loss after the first year among transplant recipients in children is chronic allograft injury (also known as chronic allograft nephropathy). This is a poorly understood disorder, and the etiology remains unknown. The revised 2005 Banff classification system renamed chronic allograft nephropathy to "interstitial fibrosis and tubular atrophy, without evidence of any specific etiology" because the terminology chronic allograft nephropathy was thought to discourage attempts to elucidate the underlying pathogenesis of this entity. (See "Kidney transplantation in adults: Chronic allograft nephropathy", section on 'Evaluation of IF/TA'.)

In general, the clinical diagnosis is suggested by the gradual deterioration of graft function as manifested by a slowly rising serum/plasma creatinine concentration, increasing proteinuria (occasionally causing nephrotic range proteinuria), and worsening hypertension. It occurs at least three months post-transplant in the absence of acute rejection, drug toxicity (principally calcineurin inhibitors), or other nephrologic diseases.

In a pediatric case series of 289 kidney allografts, the risk factors for chronic allograft injury included at least one previous episode of acute rejection and the administration of low doses of cyclosporine [26]. Kidney histology of biopsy samples reveals vascular proliferation of smooth-muscle cells, interstitial fibrosis, tubular atrophy, and glomerular sclerosis [27,28].

Multiple immunologic and nonimmunologic factors appear to contribute to the pathogenesis of this entity and are discussed in greater detail separately. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)

Calcineurin inhibitor toxicity — Following kidney transplantation, CNI (cyclosporine and tacrolimus) nephrotoxicity can either be acute (which is largely reversible with reduction in dosing) or progress to chronic kidney disease (which is not reversible). (See "Cyclosporine and tacrolimus nephrotoxicity".)

De novo post-transplant thrombotic microangiopathy may be associated with the use of cyclosporine, tacrolimus, and sirolimus [29-31]. Although it can be difficult to treat, in some cases, withdrawing the offending agent may lead to resolution of thrombotic microangiopathy. (See "Thrombotic microangiopathy after kidney transplantation", section on 'Epidemiology of de novo TMA'.)

Nonadherence — Nonadherence with immunosuppressive medications is an important contributing factor for graft failure [32]. The reported incidence of pediatric graft failure due to nonadherence ranges between 10 to 15 percent, although this rate of incidence is likely to be underestimated [33,34]. Rates of 5 to 50 percent have been reported [35]. Nonadherence correlates with poor outcome in patients with kidney transplants [36].

Several studies have shown a high incidence of nonadherence, particularly among adolescents and young adults [37-41]. A meta-analysis of medical regimen adherence in pediatric solid organ transplantation found that nonadherence to clinic appointments and tests was most prevalent, at 12.9 cases per 100 patients per year, followed by nonadherence to immunosuppression at 6 cases per 100 patients per year [42]. Poorer adherence was more likely in older patients and in those with a poorer psychological status and family dysfunction.

Adherence may be an issue when patients are transferred to an adult service. As a result, transition should be prepared in advance by both the pediatric and adult teams and individualized for each patient [43,44].

Educational and counseling programs can improve medical regimen adherence, which has the potential to improve graft survival [45].

Recurrence of primary disease — In most pediatric series, recurrence of primary disease is responsible for kidney allograft failure in 5 to 15 percent of cases [19,46,47]. In the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database, the overall graft failure rate due to recurrent disease is approximately 8 percent [48]. Among the glomerular diseases that may recur in the graft, the most frequent is focal segmental glomerular sclerosis (FSGS) [49].

Focal segmental glomerulosclerosis — Steroid-resistant idiopathic nephrotic syndrome due to primary FSGS accounts for 12 percent of the primary diagnoses of children undergoing kidney transplantation [19]. The overall risk of recurrence of nephrotic syndrome after transplantation is estimated to be approximately 30 percent [50]. FSGS is the most frequent cause of graft loss due to recurrent disease [49,51]. Recurrence of FSGS enhances the risk of allograft loss and is associated with an increased incidence of delayed graft function and acute rejection. Recurrence most often occurs within the first few days after transplantation. In patients with a first graft lost to recurrent disease, the recurrence rate is approximately 80 percent in a subsequent graft.

(See "Treatment of idiopathic nephrotic syndrome in children" and "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)

The risk of recurrence with FSGS is greater in children than adults [52,53]. Risk factors for recurrence in children include:

●Age of primary disease and progression of disease – Recurrence is more frequent when the disease begins after the age of six years and there is a rapid progression to end-stage kidney disease (ESKD). In most series, the disease recurs in one-half of patients when the duration of disease has been shorter than three years [54,55].

●Histology of primary disease - The histopathologic pattern observed in the first biopsy of the original disease is also an important predictive factor of disease recurrence. Recurrence occurs in 50 to 80 percent of patients in whom the initial biopsy reveals diffuse mesangial proliferation (suggestive of more rapidly progressive disease) but in only 25 percent of patients with minimal change disease [52,54].

●Underlying gene variant – Patients with FSGS due to mutations in genes encoding podocyte proteins appear to have a very low risk of recurring disease after kidney transplantation [56].

●Initial steroid response – Initial steroid resistance of the primary disease is predictive of post-transplant disease recurrence [57].

Treatment remains controversial and is discussed in greater detail separately. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Treatment'.)

Membranoproliferative glomerulonephritis — The risk of recurrent disease is high in pediatric kidney allograft recipients with a primary diagnosis of membranoproliferative glomerulonephritis (MPGN).

The literature that describes recurrence of MPGN is based on ultrastructural features observed by electron microscopy (EM), which classifies MPGN into subtypes I, II, and III. This classification system has been supplanted by one that uses immune complex and C3 deposition to describe primary MPGN. (See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation", section on 'Classification and pathogenesis'.)

●In children, MPGN type I is the primary diagnosis in approximately 2 percent of pediatric kidney transplants [19] and the rate of recurrence (approximately 20 to 30 percent) appears to be higher than that reported in adult patients [58]. Despite the risk of recurrence, graft survival is comparable to that of patients with other causes of kidney failure [51].

●Recurrent disease is a major contributor to poor graft survival for patients with MPGN type II [51,59]. Data from the NAPRTCS registry showed that MPGN type II was less common than MPGN type I as a primary diagnosis (0.8 percent) [19], however, the rate of recurrent disease was approximately 45 percent [59]. In this cohort of patients, the five-year graft survival was poor (50 percent), and 15 percent of graft failure was directly due to disease recurrence.

●MPGN III is a rare primary cause of ESKD in children, and there are no accurate data on its recurrence rate.

●In a series of 43 patients with MPGN who received a kidney transplantation, recurrence occurred in 21 (43 percent); younger age at diagnosis and the presence of crescents on initial biopsy were independently associated with recurrence, suggesting that the risk of recurrence is more related to the severity of glomerular changes than MPGN type [60].

In patients with both recurrent MPGN I and II disease, no successful therapeutic intervention has been identified. (See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation", section on 'Treatment'.)

Hemolytic uremic syndrome — In children with hemolytic uremic syndrome (HUS), the risk of post-transplant recurrent disease varies depending upon the underlying cause of the primary disease.

●In children with Shiga-like toxin associated or typical HUS generally caused by infection with Shiga-toxin producing Escherichia coli, the risk of post-transplant recurrence is less than 1 percent [61]. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Long-term outcome'.)

●In contrast, the recurrence risk in non-Shiga-like associated (atypical) HUS is higher, especially in those with genetic causes of HUS [61,62]. In particular, mutations that result in dysregulation of the complement system are associated with a 50 to 80 percent recurrence rate, and graft failure occurs in 90 percent of those with recurrent disease [63]. There is good evidence that eculizumab therapy (a humanized monoclonal antibody to C5) prevents recurrence of disease in both pediatric and adult patients with complement-mediated HUS due to gene mutations to complement factors H, I, and C3. This is discussed separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Kidney transplantation'.)

Primary hyperoxaluria — In patients with primary hyperoxaluria, recurrence of oxalate deposits in the graft is constant, leading most commonly to graft failure. In children, the best approach to prevent systemic oxalosis is combined liver and kidney transplantation or chronic pyridoxine treatment in the sub-group of patients who are pyridoxine-responsive [64]. Although most of the experience has been with simultaneous liver/kidney transplant when the patient has ESKD, there also has been reported success with preemptive liver transplant before the development of ESKD, thus delaying or avoiding the need for kidney transplant. (See "Primary hyperoxaluria", section on 'Management'.)

Other diseases — For the following primary kidney disorders, the recurrence rate is either not clinically significant or unknown:

●Membranous nephropathy – Membranous nephropathy is a rare cause of ESKD in children, and its recurrence rate is unknown [19].

●Immunoglobulin A (IgA) nephropathy – In patients with IgA nephropathy and IgA vasculitis (Henoch-Schönlein purpura) nephritis, the recurrence of IgA deposits in the graft is very common, but clinically relevant disease is infrequent [58]. (See "IgA nephropathy: Recurrence after transplantation".)

●Lupus nephritis – Lupus nephritis is the primary cause of ESKD in 1.5 percent of children undergoing kidney transplantation in North America [19], and more than 10 percent of children with lupus nephritis progress to ESKD [65]. However, recurrence of lupus nephritis in the transplanted kidney is rare. (See "Kidney transplantation in adults: Issues related to lupus nephritis".)

●Wilms tumor – In patients with Wilms tumor, the risk of recurrence or metastasis is negligible after two years of complete remission [66]. Kidney transplantation can, therefore, be performed safely after this period.

OTHER COMPLICATIONS — Although several complications of kidney transplantation usually do not present with graft dysfunction, there are risk factors that may contribute to allograft injury and dysfunction. These include hypertension, infection, diabetes mellitus, anemia, and urologic complications.

Hypertension — Hypertension is common after kidney transplantation in children. During the first month following transplantation, it occurs in 80 and 60 percent of recipients of allografts from deceased and living related donors, respectively [67]. The incidence decreases over time. In children, post-transplant hypertension is associated with an increased risk of chronic allograft injury, decreased allograft survival, cardiovascular complications, encephalopathy, neurologic sequelae, and mortality [68-71].

Causes — The causes of hypertension vary with the time after transplantation.

●During the early postoperative period, elevated blood pressure may be due to fluid overload, acute rejection, or adverse effect of specific immunosuppressive agents (eg, corticosteroids and calcineurin inhibitors [CNIs]) [72,73].

●After this period, the main causes of hypertension are the administration of corticosteroids and/or CNIs, renal artery stenosis, hypoperfused end-stage native kidneys or failed prior allografts, recurrence of primary disease, and urinary tract obstruction [67].

In some cases, obesity may contribute to hypertension. In a multicenter retrospective study of 234 pediatric kidney transplant recipients, the prevalence of metabolic syndrome (ie, abdominal obesity, hyperglycemia, dyslipidemia, and hypertension) increased from 19 to 37 percent from the time of transplant to one-year post-transplant [74]. Left ventricular hypertrophy detected by echocardiogram at one-year post-transplant was more common in patients with metabolic syndrome compared with those without (55 versus 32 percent).

Treatment — Therapy for post-transplant hypertension initially begins with the administration of antihypertensive agents, even if a correctable cause is present. In our center, we tailor our pharmacologic therapy based on the underlying cause for each individual patient. Angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are the two most common classes of antihypertensives used in children post-transplant; however, there are no clinical trials comparing different classes of medications regarding BP control and kidney survival [75]. ACE inhibitors and angiotensin receptor blockers should be used with caution, particularly if renal artery stenosis is suspected following ultrasound/Doppler examination. In such cases, angiography should be done and, if indicated, angioplasty may be successfully performed [76]. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Management approach'.)

Cardiovascular disease — Children with end-stage kidney disease (ESKD) are at increased risk for developing cardiovascular disease [77]. The risk factors that lead to atherosclerosis including dyslipidemia and hypertension and their management are similar to those in the general (algorithm 1). (See "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood", section on 'Chronic kidney disease' and "Overview of the management of the child or adolescent at risk for atherosclerosis".)

After transplantation, these (hypertension and dyslipidemia) and additional risk factors (eg, diabetes mellitus, hyperhomocysteinemia, and overweight) are exacerbated by the immunosuppressive drugs administered to prevent allograft rejection [78-80].

●CNIs are associated with hypertension and hyperhomocysteinemia

●Mammalian (mechanistic) target of rapamycin (mTOR) inhibitors including rapamycin is associated with dyslipidemia

●Corticosteroids are associated with hypertriglyceridemia, hypertension, increased body mass index, and diabetes mellitus

Changes in immunosuppressive protocols may reduce the risk of cardiovascular disease. This was illustrated by a study from the Cooperative European Paediatric Kidney transplant Initiative (CERTAIN) registry that reported that the use of tacrolimus and mycophenolate mofetil was associated with significantly lower concentrations of all lipid parameters compared with a regimen containing cyclosporine and mTOR inhibitors [81].

In adult kidney transplant recipients, cardiovascular disease is the most common cause of mortality. (See "Risk factors for cardiovascular disease in the kidney transplant recipient".)

Infections — Infections are a permanent risk in patients receiving immunosuppressive drugs. Infections now exceed acute rejection as the most common cause for hospitalization following transplantation [20,82]. Infections occur most frequently soon after transplantation (first six months) when the exposure to immunosuppression is at its highest degree [20,83]. Urinary tract infections (UTIs) and pulmonary infections are frequent during the early postoperative period [82].

Reported risk factors for infection include [82-84]:

●Younger recipient age

●Use of monoclonal or polyclonal antibody immunosuppressive induction therapy

●Indwelling hardware

●Higher number of human leukocyte antigen (HLA) mismatches

●Use of cyclosporine rather than tacrolimus as first anticalcineurin

Prophylactic treatment with trimethoprim-sulfamethoxazole may prevent UTI and reduce the incidence of infection with Pneumocystis carinii (jirovecii) [85]. (See "Prophylaxis of infections in solid organ transplantation".)

Urinary tract infection — UTI is a common finding post-transplant, especially in patients with a urologic etiology of ESKD [86]. Despite the risk of UTI post-transplantation, we do not use prophylactic antibiotics, but screen recipients by routinely obtaining urine cultures. It is uncertain whether UTI affects graft survival. Data from the United States Renal Data Systems showed children were at greater risk for graft loss after early, but not necessarily late, UTI [87]. However, other reports did not find a deleterious effect of UTI on graft function [86,88]. (See "Urinary tract infection in kidney transplant recipients", section on 'Monitoring for asymptomatic bacteriuria'.)

Viral infections — Viral infections are common [89]:

●Cytomegalovirus (CMV) – CMV infection may present as a primary infection in seronegative patients receiving a graft from CMV seropositive donors. It may also occur in seropositive recipients from either reactivation with the same host strain or from reinfection with the donor's strain. Infection may be asymptomatic or may present with fever, leukopenia, thrombocytopenia, pneumonitis, hepatitis, and allograft dysfunction. The incidence of significant clinical disease is higher in seronegative recipients with primary CMV infection. In addition, the disease is often more severe when the patient has been treated with antilymphocyte antibodies.

Both oral ganciclovir and valganciclovir have been shown to lower the risk of CMV disease and mortality while preserving kidney allograft function [90]. Because of the risk for the patient and for the kidney allograft, prophylactic therapy is recommended for the recipient of a kidney from a seropositive donor. A discussion of the prevention and treatment of CMV infection and/or disease is presented in detail separately. (See "Prevention of cytomegalovirus disease in kidney transplant recipients" and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients".)

●Varicella – In pediatric kidney recipients, varicella infection may be responsible for severe disease including encephalitis, pneumonitis, hepatic dysfunction, and death [91]. A varicella nonimmune pediatric recipient exposed to varicella should receive postexposure prophylaxis within 72 hours of exposure. If clinical symptoms of the disease develops, intravenous acyclovir should be given and, if administered, azathioprine or mycophenolate mofetil withdrawn. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)

Immunization with the live varicella vaccine is recommended prior to transplantation in all children without varicella antibodies. This procedure reduces disease incidence and helps prevents severe disease [92,93]. In one study, varicella infection occurred in 26 of 212 patients (12 percent) who received the vaccine, but in 22 of 49 (45 percent) who had no history of varicella and were not vaccinated [92]. Three deaths due to infection occurred among the nonvaccinated group, but in none of those who were immunized. Data are insufficient to determine whether live viral vaccines should be administered to transplant recipients still on immunosuppression. Small case series have reported that varicella vaccine was administered without complications, but it was not always efficacious [94,95]. In one small study, for example, four of six children who were nonimmune responded with high antibody titers to varicella vaccination [95].

●Epstein-Barr virus (EBV) – Primary infection with EBV is common in the EBV serology negative recipient (R-) who receives an allograft from an EBV serology positive donor (D+) [96]. Reactivation of EBV in a serology positive recipient is more likely to be asymptomatic.

In patients with chronic immunosuppression, post-transplant lymphoproliferative disease (PTLD) appears to be due to B cell proliferation induced by infection with EBV. The risk of PTLD is highest in the R- recipient who received an allograft from a D+ donor [97]. Since more infants and young children are R-, more of these patients will develop PTLD. However, once infected with EBV, adolescents are at significantly higher risk to progress to PTLD and have poorer outcomes compared with younger recipients [98]. Reductions in immunosuppression are recommended in this setting and some children will require treatment with rituximab. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

●Herpes simplex virus (HSV) – The risk of HSV either as primary infection or reactivation depends on the degree of immunosuppression and time after transplant. Both acyclovir and valacyclovir are effective agents in the treatment of HSV infection. (See "Treatment of genital herpes simplex virus infection".)

●BK polyomavirus (BKPyV) – BKPyV viral infection is an important cause of allograft dysfunction in pediatric kidney transplant recipients [99-102]. An analysis of the NAPRTCS registry demonstrated a 5 percent incidence of BKPyV-associated nephropathy (BKPyVAN) in kidney recipients [103]. Seronegative patients are at the greatest risk for developing BKPyVAN. The presence of a ureteral stent is associated with an increase in the risk of BKPyVAN [104].

In a small case series of 20 pediatric kidney recipients with BKPyV viremia, children with BKPyVAN presented later, and had higher viral loads and serum creatinine levels compared with those who were viremic without nephropathy [105]. Children with BKPyVAN who remained viremic (ie, persistent + polymerase chain reaction [PCR]) despite reduction of immunosuppression and antiviral treatment with cidofovir were at greater risk for loss of kidney function.

A screening and preemptive strategy similar to the one used in adult kidney recipients appears to be effective in preventing BKPyVAN in pediatric patients [106]. This approach involves monitoring for viremia by PCR, and reducing immunosuppression and/or administration of antiviral agents after the detection of very early systemic infection (+PCR). (See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy".)

●Human papillomavirus (HPV) – Warts due to HPV are common in pediatric kidney recipients. There have been no randomized controlled studies regarding the use of HPV vaccines in these patients, and so it remains uncertain whether or not this vaccine is immunogenic in the post-transplant, immunosuppressed patient [107]. Until such data are available, HPV vaccine should be administered according to current guidelines to female candidates (ages 9 to 26 years) prior to transplant. (See "Human papillomavirus vaccination".)

Malignancy — Immunosuppressive therapy in kidney transplant recipients is associated with an increased risk of malignancy as illustrated by the following [108-110]:

●Data from the NAPRTCS registry show an overall malignancy incidence of 2.6 percent [19]. Of the 310 confirmed malignancies, 262 were lymphoproliferative disease (LPD) and 48 were non-LPD. The median time from transplant to malignancy was 14.9 and 33 months for LPD and non-LPD, respectively. The reported incidence of non-LPD malignancies (solid tumors) was 6.7 times greater than in the general pediatric population (72 versus 11 per 100,000 person-years) [109]. The most common non-LPD malignancy was renal cell carcinoma.

●In a French retrospective study of 1326 children following solid organ transplantation [110], there was a 6 percent incidence of malignancy following transplantation, and LPD was diagnosed in 80 percent of the tumors. (See "Malignancy after solid organ transplantation" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

●A study of childhood kidney allograft recipients (n = 289) from the Australian and New Zealand Dialysis and Transplant Registry found an incidence for malignancy of 16.7 percent over a median follow-up period of 13.4 years [111]. In this cohort, nonmelanoma skin cancer was reported in 196 cases, and the most common other malignancies for the remaining patients included LPD, cervical cancer, and melanoma. Of note, the higher incidence of skin cancer in organ transplants in Australia and New Zealand compared with the United States and Europe may be due to greater sun exposure in a predominantly fair-skinned population [112]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Pediatric transplant recipients'.)

Management is discussed elsewhere and includes preventive measures by avoiding excess immunosuppression and a reduction of immunosuppressive therapy for those who develop malignancy. (See "Malignancy after solid organ transplantation", section on 'Reduction in immunosuppression'.)

Prognosis has improved after a diagnosis of PTLD with patient survival rates of 91 percent at one year and 87 percent at five years after the diagnosis and graft survival rates of 82 percent at one year and 65 percent at five years [113].

Other malignancies include skin cancers, renal cell carcinoma, thyroid papillary carcinoma, and ovarian seminoma [114]. Transitional cell carcinoma and gastric adenocarcinoma have been reported in patients who have undergone bladder augmentation [115,116]. It remains unknown if immunosuppression increases the risk of malignancy in patients with either enterocystoplasty or gastrocystoplasty. Routine ultrasound and endoscopic surveillance are recommended beginning 10 years after the bladder augmentation procedure.

Diabetes mellitus — The incidence of post-transplant diabetes mellitus ranges from 1 to 7 percent [117-119]. Risk factors include exposure to CNIs (particularly tacrolimus) and corticosteroid therapy and Black ancestry [118]. The risk of post-transplant diabetes mellitus is higher in patients with a primary diagnosis of cystinosis [120]. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)

Mineral bone disorders — Mineral bone disorders are due to preexisting renal osteodystrophy at the time of transplantation, and subsequent corticosteroid treatment, and reduced graft function [121]. Other contributory factors include hypophosphatemia due to residual hyperparathyroidism and elevated FGF23 and vitamin D deficiency [122]. Following transplantation, intervention is based on the results assessment for growth, leg deformities, and serum levels of calcium, phosphate, magnesium, alkaline phosphatase, 25-hydroxyvitamin D, and parathyroid hormone [121].

The clinical features and management of mineral and bone disease are discussed in detail separately. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)" and "Kidney transplantation in adults: Bone disease after kidney transplantation".)

Anemia — Anemia is extremely common among pediatric allograft recipients.

●In a retrospective cohort study of 167 such children, the prevalence of anemia was approximately 60 to 80 percent at 6 to 60 months post-transplantation, respectively [123]. In this series of patients, development of anemia was related to multiple factors, including iron deficiency, immunosuppressive therapy, bone disease, and decreased kidney function.

●A registry analysis of 3669 European pediatric patients reported a significant proportion of the transplant recipients were anemic and the anemia was associated with kidney allograft dysfunction and the type of immunosuppressants used [124]. Higher Hb levels were associated with better graft and patient survival and a decrease risk of hypertension.

●Parvovirus B19 infection has also been reported as a cause of severe anemia in pediatric kidney transplant recipients [125].

Treatment of anemia in children with CKD and adults following kidney transplantation are discussed separately. (See "Chronic kidney disease in children: Complications", section on 'Treatment of anemia' and "Anemia and the kidney transplant recipient", section on 'Treatment'.)

Surgical and urologic sequelae — Surgical sequelae include intraabdominal, urologic, and vascular complications and are a major cause of graft loss [126,127].

●Intraabdominal complications are more common in children with intraperitoneal transplants and include fluid collections (urinoma, seromas, lymphoceles) requiring surgical drainage and intestinal obstruction [127].

●Urologic complications include vesicoureteral reflux [128,129], urolithiasis [130] and ureteral stricture or obstruction. Ureteral obstruction due to stenosis may occur at the level of the anastomosis or at the pyeloureteral junction when the kidney has been turned by 180 degrees to facilitate vascular anastomosis. In one case series of 526 kidney transplants from a single tertiary center, ureteral obstruction occurred in 8 percent [131]. Posterior urethral valves appeared to be a risk factor for ureteral obstruction, perhaps due to pretransplant bladder ischemia, thickness, and collagen remodeling. Approximately one-half of patients presented within 100 days after kidney transplantation.

●Vascular complications include vascular (arterial or venous) stricture and thrombosis [127]. The risk of vascular complications is higher in younger patients (less than six years of age), which may lead to graft loss [126].

●Bladder dysfunction is common among patients with posterior urethral valves and meningomyeloceles. It may cause chronic obstruction and be associated with recurrent UTIs. (See "Clinical presentation and diagnosis of posterior urethral valves" and "Myelomeningocele (spina bifida): Urinary tract complications".)

●Lymphocele due to collections of lymph fluid leakage from severed lymphatics that overlie the iliac vessels may result in postobstruction due to urinary tract compression. In one retrospective study, lymphocele was detected in three percent of pediatric recipients transplanted after 2006 [132]. Risk factors associated with lymphocele were age >11 years, male sex, transplant before 2006, body mass index >95 percent, and multiple transplantations. In this series, lymphocele was associated with a 10 percent reduction of one-year graft survival.

SUMMARY AND RECOMMENDATIONS

●Introduction – Advances in immunosuppressive therapy and post-transplant management have led to improvements in both graft and patient survival in pediatric kidney transplant recipients. However, long-term success has been limited by complications due to immunosuppression, rejection, and recurrent disease. (See 'Introduction' above.)

●Graft dysfunction – Graft dysfunction is a common complication posttransplant, and its etiology vary with the time after transplantation. (See 'Graft dysfunction' above.)

•Immediate (zero to one week postsurgery) – Causes of delayed graft function (immediate kidney failure persisting after transplantation) include postischemic acute kidney injury, vascular thrombosis of the renal artery or vein, urologic complications (ie, urinary leak or obstruction), and rarely, hyperacute rejection. (See 'Overview' above.)

•Early (1 to 12 weeks postsurgery) – Among patients with initial graft function who develop early kidney insufficiency (ie, 1 to 12 weeks post-transplantation), the major causes of graft dysfunction are acute allograft rejection, calcineurin inhibitor toxicity, urinary obstruction, infection, hypovolemia, and recurrent disease.

•Late acute (after three months) – Allograft dysfunction that acutely develops more than three months after transplantation is most commonly due to acute allograft rejection, calcineurin inhibitor (CNI) toxicity, urinary obstruction, hypovolemia, pyelonephritis, and recurrent or de novo kidney disease.

•Late chronic (years) – Slowly progressive kidney disease that occurs over a period of years after kidney transplantation most commonly results from chronic allograft injury, CNI nephrotoxicity, hypertensive nephrosclerosis, viral infections, and recurrent or de novo kidney disease. Although chronic allograft injury is the most common cause of graft loss after the first year following transplantation, its underlying cause remains unknown. The diagnosis is suggested by a slowly rising serum Cr, increasing proteinuria, and worsening hypertension. (See 'Chronic allograft injury' above and "Kidney transplantation in adults: Chronic allograft nephropathy".)

●Acute rejection ‒ Acute rejection, a common cause of graft dysfunction in the first year of life (early and late acute presentation), is suggested by an acute elevation in the serum creatinine (Cr) level and is confirmed by histologic findings of acute antibody-mediated and cellular rejection. Serum Cr should be routinely monitored for early detection of acute rejection. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection" and 'Acute rejection' above.)

●CNI nephrotoxicity ‒ CNI nephrotoxicity may occur in the early and late acute phase of graft dysfunction and is the major diagnosis in the differential for acute rejection. CNI nephrotoxicity is largely reversible after dose reduction, but may progress to chronic kidney disease, which is usually irreversible. It is distinguished from acute rejection by kidney biopsy and/or a positive response of deceasing serum creatinine with lowering of CNI dose. (See 'Calcineurin inhibitor toxicity' above.)

●Recurrent primary disease – In children, recurrence of primary disease is responsible for graft failure in 5 to 15 percent of cases. Primary pediatric kidney diseases with a high recurrence rate in the transplanted kidney include focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, genetic forms of hemolytic uremic syndrome, and primary hyperoxaluria. (See 'Recurrence of primary disease' above.)

●Other complications – Other complications that occur in pediatric kidney recipients include hypertension, cardiovascular disease, infection, malignancy, diabetes mellitus, mineral bone disease, anemia, and surgical sequelae (eg, urologic and vascular complications). These may contribute to allograft injury and dysfunction. (See 'Other complications' above.)