Epidemiology
Of children with nephrotic syndrome (NS), 10–15% do not respond to corticosteroids and, among children with ESRD, 10–15% of them first present with the NS, i.e. the most common cause for renal Tx among acquired kidney diseases. Most of them show idiopathic focal and segmental glomerulosclerosis (FSGS) on renal biopsy examination, the yearly incidence of which seems to be increasing. The risk of recurrence in a first graft is 14–50%, with a risk of graft loss of 40–60%; in other words, the relative risk for graft failure from FSGS after Tx is 2.25 compared to non-recurrent diseases [
1,
3,
4]. The risk of recurrence in a second graft after a first graft loss to recurrence is 60–100%. Some risk factors have been reported, as shown in Table
2. However, current knowledge on the pathophysiology of NS suggests that it may be either an immunological disease or a genetic disease, with a common histological pattern, i.e. FSGS, but has a different risk of recurrence (Table
3).
Table 2
Risk factors for recurrence of the nephrotic syndrome [
1,
13,
14] (
HLA human leukocyte antigen)
Recurrence in a first graft | Gender | African–American recipients |
Onset of NS during childhood | Mesangial hypercellularity | Genetic and syndromic NS |
White and Asian recipients | Age at onset over 6 years | |
Rapid course to ESRD (< 3 years) | Presence of FSGS circulating factor | |
| Donor source | |
| HLA typing/matching | |
| Time interval on dialysis prior to Tx | |
| Type of immunosuppressive therapy | |
| Use of induction therapy | |
| Bilateral nephrectomy of native kidneys | |
Table 3
Two groups of steroid-resistant nephrotic syndromes (SRNS) leading to end-stage renal disease in children (GBM glomerular basement membrane, Sd syndrome)
A multifactorial disease
| A renal disease
|
T-cell dysregulation | Abnormal podocyte–GBM complex |
Podocyte as a target
| Podocyte as a disease
| |
Idiopathic FSGS | Genetic forms of NS
| Syndromic forms of NS
|
Finnish type NS (NPHS1) | WT1-associated SRNS |
Other recessive FSGS | Pierson Sd, Schimke Sd |
(NPHS2, NPHS3) | Charcot–Marie–Tooth SRNS |
Dominant FSGS |
(ACTN4, TRPC6, CD2AP) |
Circulating factor | No circulating factor |
Immunosuppression available | No effect of immunosuppression |
In some rare patients with the so-called ‘IgM nephropathy’ the disease has recurred after Tx, so that such form of steroid-resistant NS may be regarded as a distinct disease entity [
15].
Global approach to transplantation
Some general measures are currently available: (1) an exact diagnosis is required in any patient; (2) DNA should be analysed/stored according to local convenience; (3) in patients with persistent NS, pre-emptive Tx may be dangerous because of the presence of heavy proteinuria from native kidneys, with the risk of both graft thrombosis and delayed diagnosis of recurrence; (4) pre-Tx bilateral nephrectomy is therefore recommended, with the patient on dialysis for a limited period of time. In addition, pre-Tx native nephrectomy may reduce the risk of recurrence per se; a reduction of the antigenic load that stimulates the putative permeability factor has been advocated [
20].
Interestingly, the transplanted kidney provides a unique environment, since immunosuppressive agents [e.g. cyclosporine A (CsA)] that have not been successful on native kidneys may be effective in preventing post-Tx recurrence. Indeed, there is transient or no efficacy of such drugs on native kidneys because of their late use in the presence of advanced glomerular damage, whereas there is a potential benefit of early immunological intervention prior to Tx regarding the onset of glomerular damage in the graft.
In the absence of preventive measures, including pre-treatment of the recipient with CsA (with or without plasmapheresis), living donors should be avoided, since the relative risk of graft failure is 1.75 compared with that when kidneys from living donors are used in non-FSGS recipients [
21]. This suggests a potential role for unknown genetic parameters that may trigger the development of FSGS.
Active treatment of overt recurrence
Plasmapheresis using 4–5% albumin restitution (approximately ten sessions within 2 weeks, then weekly sessions for a total of 2 months, then adapted to individual response) has been successful in many patients. The use of more sophisticated methods, such as adsorption onto protein A columns or tryptophan immuno-adsorption, has no superior benefit [
22]. Plasmapheresis has been used with or without cyclophosphamide instead of mycophenolate/azathioprine for an average of 12 weeks, on the basis of its long-lasting effect on T-cells [
23]. Approximately 60% of patients attain complete remission, and the success rate is higher with early plasmapheresis, i.e. starting during the first 3–4 days after Tx. The adjunction of immunoglobulin replacement does not seem to have any benefit.
Controlled and randomized studies in children with primary SRNS have shown that CsA is effective in inducing remission. CsA may influence direct immunological phenomena and/or inhibit the effect of glomerular permeability factor; it may also act through vasoconstriction. High doses of CsA (either orally at a dose of 13–35 mg/kg per day, or with continuous infusion at a dose of 3 mg/kg per day in order to avoid nephrotoxic peak levels; blood concentration between 200 ng/ml and 350 ng/ml) for 1–3 weeks have given stimulating results in a significant number of patients [
24,
25]. The rationale behind maintaining high CsA blood concentration is to overcome the effect of high serum levels of low-density lipoprotein (LDL) (secondary to recurrent NS), which binds CsA and is further responsible for low levels of free available CsA. However, some patients have required further plasmapheresis, and others have experienced CsA nephrotoxicity. In the long term, approximately 60% of the patients are in complete remission. The use of CsA as a first-step treatment may limit the efficacy of plasmapheresis, which may, therefore, be postponed.
The benefit of another anti-calcineurin agent, i.e. tacrolimus, on native kidney NS is scarce and has not been demonstrated in post-Tx recurrent NS so far; some patients experiencing a successful post-Tx strategy using CsA have experienced a late recurrence when switched from CsA to tacrolimus [
14].
Antibody induction therapy using either anti-lymphocyte globulin or anti-interleukin (IL)2R antibodies (basiliximab, daclizumab) has given conflicting results, so that they are no longer used in such patients [
24]. Recently rituximab, a chimeric monoclonal antibody that acts by inhibiting CD20-mediated B-cell proliferation and differentiation, has been used in some patients with recurrent NS under various conditions [timing of the first dose, associated post-transplantation lymphoproliferative disorder (PTLD)] [
26]. Paediatric patients were given 375 mg/m
2 × 1–6 without significant short-term side effect; of six cases reported in children, four went into complete remission [
27‐
30] and two failed [
31], so further data, including long-term outcomes, are expected. Comparable results have been published in adults [
26].
Rescue treatments
Angiotensin-converting enzyme (ACE) inhibitors, angiotensin 2-receptor blockers and non-steroidal anti-inflammatory drugs may partially reduce proteinuria without significantly affecting graft survival.
Many individual approaches have been proposed, especially for recurrence in a second graft. The risk of recurrence in such patients is incredibly high, and a strategy different from that for the first Tx must be suggested. Pre-treatment using both high doses of CsA and plasmapheresis should be considered [
32]. In the post-Tx course any available option that was not attempted for the first graft may be proposed, such as high doses of CsA given intravenously, early plasmapheresis, cyclophosphamide, and rituximab.
Most children with haemolytic uraemic syndrome (HUS) present with a ‘typical’ form, with a 5–10% rate of ESRD, but 5–10% have an ‘atypical’ course (non-Shiga toxin-associated HUS), with a high risk of developing chronic kidney disease (CKD), so that HUS is the primary diagnosis in 2.5–5% of children with ESRD [
5]. Indeed, more than 50% of patients with non-Shiga toxin-associated HUS progress to ESRD, and the overall outcome of kidney Tx is poor (Table
1). However, such atypical HUS is a group of distinct diseases that may be due to deficient von Willebrand factor-cleaving protease (ADAMTS 13), metabolic disorders, or various disorders of complement regulation [
6,
8]. Complement abnormalities include specific gene mutations in factor H (20–30%), membrane cofactor protein (MCP, or CD46, 10–15%), factor I (10–15%), and factors B and C3; no gene mutation is found in 30–40% of the patients. In addition, approximately 5% of atypical HUSs are due to the presence of anti-factor H antibodies, leading to a secondary form of factor H deficiency. Patients with atypical HUS should, therefore, undergo complement factor determination (C3, factor H, factor I, factor B, and MCP expression), genotyping (factor H, factor H-linked genes, factor I, MCP, factor B and C3) and determination of anti-factor H antibodies prior to renal Tx so that the risk of graft failure can be evaluated [
6].
Graft failure is often due to endothelial damage, i.e. vascular thrombosis and disease recurrence. Disease recurrence is approximately 0% to 1% in children with typical HUS and 20% to 80% in atypical HUS (Table
1) [
5‐
7]. The average time to recurrence is around 1 month but can be late, after several months as well [
8]. Recurrence may be triggered by viral or bacterial infection and by allograft rejection; it may also be increased in living donor Tx. Clinical symptoms of recurrence are often severe. The overall management and the risk of post-Tx recurrence are strongly linked to the underlying genotype and associated pathophysiology of HUS. CsA may cause de novo HUS in recipients of organ and bone marrow transplants, but it has no specific effect on outcome of primary HUS recurrence [
33].
Patients with ADAMTS-13 deficiency present either with neonatal onset HUS or with a recurrent thrombotic thrombocytopenic purpura-like course. Few of them have received transplants, but recurrence is rather frequent and the patient can benefit from fresh frozen plasma infusion [
34].
In MCP mutation, HUS usually presents in children older than 1 year of age as a recurrent disease of native kidneys. The transplanted kidney brings a normal MCP, so that the risk of recurrence after Tx is less than 20% [
6,
35]. The option of using a living donor should not be ruled out when MCP mutation has been proven in the recipient and excluded in the donor.
In factors H, I or B mutations the clinical presentation is characterized by early symptoms, i.e. during the first 3 months of life. The recurrence rate in children with factor H deficiency is 66–76%, and most of them (77–93%) will lose their graft, so that living donors should be excluded [
5,
6,
35]. Comparable poor results have been found in patients with factor I mutation: 88% recurrence rate with 100% graft loss after 1 year [
6]. Very few patients with factor B or C3 mutation but no factor H deficiency have undergone Tx, but, again, the risk of recurrence seems to be rather high [
5,
6]. The risk of recurrence both in the autosomal recessive and dominant forms of HUS of unknown mechanism is not documented in children, but it is approximately 60% in adults [
5].
Factor H and factor I mutations are sometimes regarded as contraindications to kidney Tx. However, aggressive treatment with plasmapheresis using fresh frozen plasma (40–80 ml/kg per session) has provided interesting results in selected cases [
6]. Patients with graft loss despite plasmapheresis require either long-term dialysis or another innovative therapeutic option. Human plasma-derived factor H concentrate has been suggested but is not yet available, whereas the recent use of anti-C5 monoclonal antibodies (eculizumab) may allow encouraging results. Because factor H is synthesized in the liver, combined liver and kidney Tx (together with pre- and intra-operative plasmapheresis using fresh frozen plasma and low molecular weight heparin) has been proposed for patients with severe forms of HUS, with variable results, the more recent being the more encouraging [
6,
36,
37].
For patients with no identified mutation, there are two options: either wait until new genes are identified, or proceed with kidney Tx combined with intensive plasmatherapy [
6].
Membranoproliferative glomerulonephritis type 2
Membranoproliferative glomerulonephritis type 2 (MPGN-2) is an uncommon form of complement-dependent acquired renal disease that often leads to ESRD. It has been shown in adults that it recurs almost universally, and up to one-quarter of patients lose their graft from recurrence [
40]. A retrospective analysis of 75 children found that the 5-year graft survival rate in MPGN-2 was 50.0 ± 7.5%, compared with 74.3 ± 0.6% in patients with other primary diseases (
P < 0.001) [
42]. Organs from living related donors have a better 5-year survival rate than do those from deceased donors (65.9 ± 10.7% and 34.1 ± 9.8%, respectively,
P = 0.004). Disease recurrence was present in two-thirds of the 18 patients who underwent transplant biopsy and was responsible for all 11 graft losses. The risk of recurrence and graft loss is independent of both pre-Tx presentation and C3 concentration, but it is strongly associated with the presence of heavy proteinuria, which is the hallmark of clinical recurrence. The presence of glomerular crescents was negatively correlated with graft survival, and patients with histological recurrence experienced higher serum creatinine concentration and urine protein excretion. In addition, the risk of graft loss seems to be lower in adults than in children. There is no available treatment for MPGN-2 recurrence.
Recurrence has not been reported in the very rare patients with lipodystrophy (Barraquer–Simons disease) -associated MPGN-2.
In adults the risk of post-Tx recurrence of membranous nephropathy reaches 29% after 3 years, without evidence of specific risk factors; such a recurrence is associated with a high risk of graft loss, i.e. 38% and 52% after 5 years and 10 years, respectively [
43].
ESRD due to lipoprotein glomerulopathy is an exceptionally rare condition in children. In adults the risk of post-Tx recurrence approximates 100% after an average time interval of 7 months, and the risk of graft loss to recurrence involves most patients [
44]. Neither specific treatment nor prevention has been advocated, except lipid lowering and ACE inhibitor therapy. The use of living donors, therefore, cannot be recommended.
Primary hyperoxaluria type 1 (PH-1) is a recessive autosomal disease caused by a deficiency of hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT; cofactor: pyridoxal phosphate), which catalyses the conversion of glyoxylate to glycine. This leads to overproduction of oxalate and massive urinary excretion of monohydrated calcium oxalate. Once CKD has been reached due to progressive urolithiasis and nephrocalcinosis, insoluble oxalates accumulate throughout the body and mainly skeleton and vessels [
45]. Since the metabolic defect is in the liver, isolated kidney Tx cannot correct the primary metabolic defect but only the damaged target organ. Indeed, the risk of recurrence in the absence of liver Tx is 90–100%. A combined liver and kidney Tx is therefore required for most patients. However, in patients with a long period of ESRD, the oxalate release from the body may jeopardize the renal graft, with a picture of recurrence, despite the metabolic correction associated with synchronous liver Tx. This is the reason why patients with PH-1 should undergo transplantation pre-emptively when their glomerular filtration rate (GFR) approximates 30–20 ml/min per 1.73 m
2. Some patients who receive a transplant after a long period of time on dialysis may benefit from a sequential liver and kidney Tx so that systemic oxalate may be cleared by dialysis between the liver and kidney Tx procedures [
45].
For any patient, the diagnosis has to be confirmed from DNA analysis (or from AGT activity measured from a liver biopsy) before any procedure of organ Tx is considered. Indeed, some patients may present with hyperoxaluria without AGT deficiency, leading to a diagnosis of either PH-2 (glyoxylate reductase/hydroxypyruvate reductase deficiency) or non-PH-1 non-PH-2 where Tx strategy has not been clearly delineated. DNA analysis for patients with PH-1 is of pivotal interest, since (1) a small number of patients with the Gly170Arg
AGXT mutation (Western Europe) may present with evidence of pyridoxine responsiveness, sometimes allowing isolated kidney Tx with lifelong pyridoxine intake and (2) patients with the Ile244Thr
AGXT mutation (North Africa, Spain) do not respond to pyridoxine and, therefore, require combined liver and kidney Tx; (3) experience of other mutations is limited and leads to the recommendation of combined liver and kidney Tx [
45‐
47]. However, correlation with clinical phenotype and treatment response is complicated by the involvement of other genetic (e.g. modifier genes) and non-genetic (e.g. environmental) factors that affect disease severity [
48].
Recurrence with a low risk of graft loss
Berger disease
Up to 25% of patients with IgA nephropathy develop ESRD, and 35–60% will experience a histological recurrence of the disease [
11,
49,
50]. These patients present with persistent microscopic haematuria and proteinuria, and renal transplant biopsy often shows mesangioproliferative glomerulonephritis, and not only silent recurrent mesangial IgA deposits from protocol biopsy. The risk of recurrence is not correlated with donor status, recipient age, race, gender, or immunosuppression [
51]. After an average follow-up period of 61 months, 18 of 63 adult patients experienced recurrence, which led to graft loss in six [
50]. Younger adult patients seem to be more prone to the risk of recurrence, but recurrence rate in children has not been documented enough; however, the percentage of graft loss to recurrence is approximately 7% [
11,
52]. Proteinuria is associated with progressive loss of function in all patients with recurrent IgA nephropathy.
Henoch–Schönlein purpura
The recurrence rate of Henoch–Schönlein purpura (HSP) after transplantation in children is common from protocol biopsies, but most data come from series of adults. There is an increased risk of disease recurrence in the aggressive progression to ESRD and when a living related donor has been used, but there is no influence from the type of post-transplantation immunosuppression [
53,
54].
Results of kidney Tx in systemic lupus erythematosus (SLE) are rather good, since there is no significant risk of clinical recurrence [
9,
55]. Some series report a 30% histological rejection rate and a greater risk of thrombotic complications (particularly in patients with antiphospholipid antibody syndrome) [
9,
56]. Such an overall favourable outcome is probably due to the adequate immunosuppressive effect of anti-rejection regimens that keeps SLE in remission. In adults the overall graft survival rate is 87% after 1 year and 60% after 5 years [
56]. In children SLE is responsible for approximately 3% of ESRD leading to kidney Tx in North America; allograft survival is not different from that in non-lupus renal diseases, but patient survival is worse, i.e. 1.8 relative risk of death in multivariable analysis [
57].
Recurrence of idiopathic, pauci-immune, anti-neutrophilic, cytoplasmic antibody (ANCA)-associated (usually antimyeloperoxidase) necrotizing glomerulonephritis after renal Tx is rare, thanks to the adequacy of immunosuppression, so that the overall results are good. A combination of cyclophosphamide, corticosteroids and, sometimes, plasmapheresis has been successful in case reports [
58,
59]. Interestingly, sirolimus may lower ANCA titres before kidney Tx and, therefore, may be considered in the post-Tx immunosuppression regime [
60].
Wegener granulomatosis is a very rare cause of graft loss in children. The experience of renal Tx in adults shows that the risk of graft loss to recurrence ranges between 0% and 6%, with a comparable outcome to that in other non-diabetic primary diseases [
55,
61].
Kidney Tx has provided acceptable results for the small number of patients with ESRD due to methylmalonic acidaemia (MMA). However, systemic production of MMA persists after kidney Tx, despite dietary protein restriction, so that plasma MMA remains at a lower range than before Tx according to post-Tx GFR but still many times greater than that in healthy subjects [
62]. The progression of the disease after Tx therefore depends on both compliance and probably other individual metabolic parameters such as genotype, so that combined liver and kidney Tx has been proposed for selected patients, with variable results.