FSGS is the most common cause of graft loss as a result of recurrent disease. For patients whose original disease was steroid-resistant nephrotic syndrome or confirmed FSGS, the disease recurs in 30% to 40% of patients undergoing primary transplantation. When the first transplant was lost to recurrence, FSGS recurs in 70% to 85% of those undergoing subsequent transplantation. About 20% to 30% of transplants in patients with the diagnosis of FSGS fail because of recurrence. The mean time to graft failure from recurrence is 17 months.

Recurrence is usually characterized by massive proteinuria, hypoalbuminemia, and nephrotic syndrome with edema or anasarca and hypercholesterolemia. It may present immediately or weeks to months after transplantation. Predictors of recurrence include rapid progression to ESRD from the time of initial diagnosis (<3 years), poor response to therapy, younger age at diagnosis (but older than 6 years of age), Caucasian ethnicity, and the presence of mesangial proliferation in the native kidney. A protein permeability factor has been isolated from sera of patients with FSGS, and its concentration was found to correlate with recurrence and severity of disease in the transplanted kidney. The precise nature of this factor remains unclear, and there is no clinically approved assay to detect it.

Early post-transplantation recognition of recurrent FSGS is important because plasmapheresis (which may lower the serum levels of protein permeability factor) and high-dose calcineurin inhibitor may lead to significant reduction in graft losses because of recurrence. In vitro studies using rat glomeruli show that cyclosporine or tacrolimus, incubated with sera from FSGS patients, will inhibit the proteinuric effect of such sera. Thrice-daily cyclosporine administration may be used in doses that maintain high blood levels (see Chapter 5), and the dose is tapered slowly after achieving remission of the nephrotic syndrome and as cholesterol concentration decreases, or if significant toxicity develops. Some centers have used a high-dose continuous intravenous infusion of cyclosporine with similar improvement, or have used high-dose or thrice-daily administration of tacrolimus. Cyclophosphamide has also been reported to induce remission. Rituximab may prevent recurrence; however, results have been mixed, and its use is more successful in children than adults. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are used as adjuncts to decrease proteinuria. Plasmapheresis is generally
used with a frequency that matches disease severity and is occasionally required on a weekly basis for prolonged periods. Plasmapheresis, in combination with a high-dose calcineurin inhibitor, is reported to be superior to either when given alone. Although there is currently no consensus on the treatment regimen for FSGS, the protocol outlined in Table 16.2 represents a summation of our own experience. For deceased donor transplantation, recurrence is less in patients on high-dose cyclosporine and post-transplantation plasmapheresis. For living related transplantation, high-dose tacrolimus is effective when combined with more than five plasma exchanges.

Some studies report that living related donor transplant recipients suffer from a higher rate of recurrence. The graft outcome in recipients of living donor grafts with FSGS recurrence is no better than the outcome observed in recipients of deceased donor grafts that have not experienced recurrence. These data have led some pediatric transplantation centers to reduce or discontinue the use of living related donation for patients with FSGS. However, the controlled settings of living donor transplantation may allow certain benefits in the event that FSGS does recur. The lower incidence of DGF in living donation may permit augmentation of the calcineurin inhibitor dose. In addition, the preplanning implicit in living donation permits preoperative and early postoperative plasmapheresis, an approach that may potentially prevent or decrease the severity of recurrent disease.

Alport syndrome, or hereditary glomerulonephritis, is a progressive disease often associated with neurosensory hearing loss and ocular abnormalities such as anterior lenticonus and cataracts. The inheritance pattern can be X-linked, autosomal recessive, and autosomal dominant. The abnormality in almost all patients stems from mutations in the α₃, α₄, or α₅ helices of type IV collagen. In more than 80% of patients, Alport syndrome results from mutations in the COL4A5 gene on the X chromosome.

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

Anti-GBM glomerulonephritis presents as rapidly progressive crescentic glomerulonephritis with linear deposits of immunoglobulin G (IgG) along the basement membrane and commonly leads to graft loss, with rates approaching 90%. It usually occurs within the first post-transplantation year. Asymptomatic cases with linear IgG deposits have also been reported. Treatment consists of plasmapheresis and cyclophosphamide, but such treatment is of only limited benefit. Retransplantation is associated with a high recurrence rate.

Histologic evidence of recurrence of membranoproliferative glomerulonephritis (MPGN) type I varies widely, with reported rates ranging from 20% to 50%. Clinical manifestations include proteinuria and deterioration of renal function. Risk factors for recurrence have been reported to include HLA-B8DR3, living related donation, and previous graft loss from recurrence. Graft loss occurs in up to 30% of cases. Histologic recurrence of type II disease occurs in virtually all cases, but graft loss is not inevitable and has been reported in up to 50% of patients. The presence of crescents in the native kidney biopsy and persistent proteinuria may predict severe recurrence that often leads to graft loss. There is no proven treatment for recurrence of MPGN in children. Anecdotal case reports describe success with high-dose corticosteroids, mycophenolate mofetil (MMF), or plasma exchange.

Histologic recurrence with mesangial IgA deposits is common and occurs in up to 60% of patients with IgA nephropathy and in 35% of patients with HenochSchönlein purpura (HSP). Most of the recurrences are asymptomatic, but graft loss may occur, often associated with crescent formation. Data from adult centers suggest that a fulminant presentation of IgA nephropathy as the original cause of ESRD predicts poor outcome in the transplanted kidney with disease recurrence. In children, up to 10% of graft failures have been ascribed to recurrent IgA nephropathy or HSP. There is no effective therapy for the prevention or treatment of recurrent IgA nephropathy. Anecdotal reports that MMF administration prevents progression to graft failure have not been substantiated. ACE inhibitors and ARBs can be used for reducing proteinuria and preserving renal function.

Hemolytic uremic syndrome (HUS) accounts for up to 5% of primary renal disease in children leading to ESRD. In children, the most frequent form of HUS is diarrhea-associated (D+), or “typical,” and is caused by verocytotoxin-producing Escherichia coli (VTEC). Although this is the most common form of HUS in childhood, it results in ESRD in only 5% to 10% of cases. “Atypical” HUS is far less common in children. It is characterized by a prodrome that lacks diarrheal association (i.e., “D-”); it has a relapsing course and a very poor renal prognosis.

When considering transplantation in patients whose original cause of ESRD was HUS, care must be directed to the form of HUS that the patient suffered. The diarrhea-associated, or typical, form does not usually recur after transplantation, whereas atypical HUS has a high propensity for recurrence. However, there are pitfalls in assessing recurrence of HUS. The D+/D− terminology can sometimes be misleading. Occasionally, patients with VTEC-associated HUS do not have diarrhea and therefore may be mistakenly labeled as D−. Similarly, diarrhea
disease can trigger HUS in a patient who is genetically predisposed to HUS and therefore erroneously is characterized as D+ HUS. In addition, it may be difficult to distinguish antibody-mediated vascular rejection from recurrent HUS, which presents histologically as thrombotic microangiopathy (TMA) (see Chapter 14). The calcineurin inhibitors may cause TMA in the transplanted kidney and produce a clinical picture that resembles HUS (see Chapters 5 and 9). Finally, other rarer causes of HUS in the post-transplantation patient may include use of valacyclovir; viral infections such as parvovirus, HIV and cytomegalovirus (CMV); and antibodies against the von Willebrand factor-cleaving metalloproteinase ADAMTS13. With these reservations in mind, it is reasonable to conclude that D+ HUS has a minimal recurrence rate, whereas the aggregate recurrence rate in D− HUS is 20% to 25%. The use of calcineurin inhibitors in both D− and D+ patients does not appear to trigger HUS recurrence, and avoidance of calcineurin inhibitors does not appear to prevent recurrence.

It has been recommended that at least 1 year of clinical quiescence occur before transplantation is attempted for patients with D− HUS, although this hiatus may not reduce the risk for recurrence. The prognosis is poor, with a 10% mortality rate and greater than 80% graft loss rate. For patients who have experienced recurrence, it is estimated that HUS will recur in about 50% of subsequent grafts.

Abnormal complement dysregulation has been associated with a severe form of D− HUS resulting in 60% disease recurrence and more than 90% graft failure. Patients have genetic defects in factor H, factor I, membrane cofactor protein (MCP), factor B, and C3. Pretransplantation genotyping for these mutations is recommended. Factor H deficiency or mutations that impair its function result in a state of continued complement activation with resulting low C3 and C4 levels. High-dose fresh-frozen plasma with plasma exchange has been advocated for this condition. Combined liver-kidney transplantation has been performed in a limited number of patients to restore normal circulating factor H with varying results.

An acquired factor H deficiency as a result of anti-factor H autoantibodies has been found in some children. Plasma exchange can be used to remove anti-factor H antibodies and immunosuppression with steroids and rituximab used to suppress further antibody production. Eculizumab, an anti-C5 monoclonal antibody, has successfully been used to treat D− HUS recurrence by decreasing the damage associated with anaphylatoxin C5a and preventing formation of membrane attack complex on cell surfaces. Randomized control trials of Eculizumab are in progress. Defects in factor I result in impaired protection of the endothelial surface against complement activation; graft recurrence and survival rates are similar to those associated with factor H mutations. Defects in MCP, a transmembrane complement regulator that is highly expressed in the kidney, are associated with a much lower recurrence rate than defects in factor H or I. Transplantation of a kidney that expresses normal MCP should correct the defect. Defects in Factor B, which increase C3bBb convertase stability and result in permanent activation of the complement pathway, have been identified: there is little experience with their clinical management.

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

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

Congenital nephrotic syndrome occurs in the first 3 months of life. It can be classified by mutations in the nephrin gene (NPHS1), podocin gene (NPHS2), or Wilms tumor suppressor gene (WT1). Congenital nephrotic syndrome of the Finnish type (CNSF) is an autosomal recessive disease that occurs as a result of a mutation in the NPHS1 gene. Although it is most commonly seen in Finnish patients, it is also found in other countries. The NPHS1 gene is located on chromosome 19 and has as its gene product the protein nephrin. Nephrin is a transmembrane protein, which is a member of the immunoglobulin family of cell adhesion molecules. It is characteristically located at the slit diaphragms of the glomerular epithelial foot processes. Close to 100 mutations of NPHS1 have been identified in CNSF, but more than 90% of all Finnish patients have one of two mutations—the so-called Fin major and Fin minor mutations.

Infants with CNSF are usually born prematurely and exhibit low birth weight and placentomegaly. CNSF manifests as heavy proteinuria, edema, and ascites, often in the first week of life and always by 3 months of age. Renal histology is nonspecific and shows expansion of glomerular mesangium and dilations in the proximal and distal tubules. Untreated, these children suffer from malnutrition, poor growth, frequent infections, and thromboembolic complications. ESRD occurs invariably by mid-childhood. Corticosteroids do not ameliorate CNSF, but in mild forms, ACE inhibition, together with indomethacin, may be successful. The best therapeutic success has come from the approach of early dialysis, nephrectomy, and transplantation.

CNSF does not recur after transplantation. However, de novo nephrotic syndrome has been reported in about 25% of cases. It presents with proteinuria, hypoalbuminemia, and edema that may start immediately or as late as 3 years after transplantation. All the patients with post-transplantation nephrotic syndrome have been reported to have the homozygous Fin major genotype. Antibodies against fetal glomerular structures are found in most patients with post-transplantation nephrotic syndrome, and antibodies to nephrin are found in more than 50%. About half of patients with this nephrotic syndrome respond to steroids and cyclophosphamide, but in those who do not respond, the graft is usually lost. Plasma exchange to decrease antinephrin antibodies has been a useful adjunct. In the NAPRTCS database, vascular thrombosis and death with a functioning graft (mostly as a consequence of infectious complications) occur in 26% and 29% of cases, respectively, and account for a higher rate of graft failure in this particular group.

Mutations in the NPHS2 gene located on chromosome 1 account for half of the congenital nephrotic syndrome cases in 80 European families and are autosomal recessive. Podocin is a podocyte-adapter protein required for proper targeting of nephrin into the slit diaphragm. Patients who are homozygous for podocin mutations develop early-onset steroid-resistant nephrotic syndrome, usually in infancy or early childhood, and usually progress to ESRD. Renal histology shows FSGS. Because podocin is a structural component of the glomerular filtration barrier, it was hypothesized that deficient podocin was the cause of renal disease and that recurrence would not occur. However, there are reports of recurrence in recipients from parents who are obligate carriers of
NPHS2 and in patients with heterozygous NPHS2 mutations. The mechanisms remain unclear. Response to plasma exchange has been variable.

Mutations in WT1 gene located on chromosome 11pl3 account for some cases of congenital nephrotic syndrome. WT1 transcription factor plays a crucial role in the embryonic development of the kidney and genitalia. It is abundantly expressed in podocytes and controls cellular functions, such as nephrin expression. Patients with WT1 mutations have moderate proteinuria, and renal biopsy reveals diffuse mesangial sclerosis (DMS) of glomeruli. WT1

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