Focal Segmental Glomerulosclerosis

FSGS is a histological diagnosis that includes primary (idiopathic) variants and secondary cases, in which an underlying cause can be identified. There are also an increasing number of genetic causes of FSGS, identified in patients with both familial and sporadic FSGS and usually affecting proteins found in the podocyte split diaphragm. Recurrence of primary FSGS is reported in 10% to 56 % of first transplants, with a true recurrence rate of approximately 30%. Some reports suggest a lower rate. For example, a recent report from the Australian and New Zealand Dialysis and Transplant Registry suggested a recurrence rate of biopsy-proven primary FSGS of 10% to 11%. When disease recurs, graft loss attributed to recurrence is reported in 30% to 50% of cases. Therefore, in transplant recipients with primary FSGS, approximately 10% to 20% of grafts are lost due to recurrent disease, with a reported relative risk for graft loss of 2.03 compared with other glomerular diseases. In the Australian and New Zealand registry data, 5-year graft survival in recipients with FSGS was 52% in patients with recurrent FSGS compared with 83% in patients without recurrent disease.

Factors that have been reported as associated with an increased risk for recurrent FSGS included young age, non-white ethnicity, live donor transplantation, mesangial hypercellularity, rapid progression to ESKD, high levels of pretransplant proteinuria, and recurrence of FSGS in a previous graft. However, clinical assessment of recurrence risk lacks specificity. A circulating factor(s) that mediates recurrence is likely, but has not been identified. The concentration of soluble urokinase plasminogen activator receptor has been proposed as a predictor of recurrence, but this has not been replicated. Despite living donation being an independent risk factor for disease recurrence, allograft survival is generally equivalent or superior to deceased donor grafts. Living donation, therefore, is not contraindicated for recipients with FSGS. Most reports suggest that genetic forms of the disease have a lower rate of recurrence, although this is not invariably so and recurrence does occur. The lower rate reported by most authors would suggest that genetic screening is indicated before transplantation in younger patients with steroid-resistant nephrotic syndrome to stratify for recurrence risk. In patients who have previously lost a transplant due to recurrent disease, the risk for subsequent recurrence is high, on the order of 80%. The benefits of retransplantation with likely recurrence compared with long-term, maintenance dialysis should be considered on a case-by-case basis.

Plasmapheresis often is used to treat recurrent disease and there are case series that report a beneficial effect. In approximately half of patients, proteinuria can be reduced, particularly if treatment is started early. There are reports of a beneficial effect of plasmapheresis before transplantation, reducing the rate of recurrence from 66% to 37% and potentially modifying risk in patients who have previously lost grafts due to recurrent disease. Good data to support a beneficial effect of plasma exchange on long-term allograft outcome are not available and not all studies report a benefit of plasmapheresis without other interventions. There are reports of the effectiveness of rituximab in treating recurrent FSGS, but again this is at the level of case reports and series and there also are reports of no benefit. Therefore there is insufficient evidence to recommend the routine use of rituximab to prevent recurrence.

FSGS has been reported as the leading form of de novo glomerular disease. Although it is possible for primary FSGS to occur de novo in a transplant kidney, many of these cases probably represent secondary cases. Clinically, de novo FSGS is associated with proteinuria typically occurring late (>12 months) after transplantation. The presence of de novo FSGS is a negative predictor of graft survival, although it follows a less aggressive clinical course than recurrent primary disease. A 5-year survival of 40% has been reported in patients with de novo FSGS, but the contribution of glomerular disease to graft failure is unclear.

Drugs have been implicated in the development of de novo FSGS. FSGS-like lesions can be seen in the glomeruli of patients with calcineurin inhibitor (CNI) nephropathy, due to the vasoconstrictor effects of CNIs on the microvasculature or increased growth factor expression. Sirolimus treatment can lead to heavy proteinuria, particularly if started in patients with preexisting proteinuria, with FSGS-like changes on biopsy. Sirolimus appears to have an effect on podocyte function, altering the expression of proteins associated with podocyte differentiation.

The collapsing variant of FSGS also has been described in transplanted kidneys, occurring in 0.6% of transplants. In most cases, the etiology is not known but has been reported in association with cytomegalovirus, parvovirus B19 infection, and antibodies to angiotensin II receptor type 1. De novo collapsing carries a worse prognosis than noncollapsing variants with all 10 grafts lost within 3 years in one series. There is no specific treatment for de novo FSGS, but treatment of any ongoing cause of renal injury, management of blood pressure, and renin–angiotensin system inhibition may be beneficial.

Membranous Nephropathy

MN is the most common cause of nephrotic syndrome in adults and progresses to ESKD in 20% to 30% of cases. MN occurs in both primary (previously idiopathic) and secondary forms. Recently, autoantibodies to the M-type phospholipase A2 receptor (PLA2R) have been identified. PLA2R appears to be the main immune target in primary disease, although other targets have been reported. Anti-PLA2R antibodies are present in about 70% of patients with primary MN and in a similar proportion of transplant candidates with a primary diagnosis of MN.

There is substantial variation in the reported recurrence of MN ranging from 10% to 50%, with rates varying due to duration of follow-up and the use of for-cause or protocol biopsy strategies. Dabade and colleagues identified recurrence in 8 of 19 patients (42%) in protocol biopsies 2 to 61 months after transplantation. Clinical features of disease were mild or absent. Grupper et al. identified a similar rate (48%) in protocol biopsies at 1 year. In contrast, when patients were biopsied due to proteinuria, a recurrence rate of 7% was reported. Patients who are anti-PLA2R antibody positive have a higher risk for recurrence (60% to 83%) compared with those who are antibody negative (28% to 53%). There is insufficient data to know whether the same is true when antibodies are directed against other antigenic targets. Heavy proteinuria at the time of transplantation is also a risk factor for recurrent disease.

Recurrent disease usually occurs within the first 2 years after a transplant and unlike disease in native kidneys, it rarely remits spontaneously. The effect of recurrent primary MN on allograft outcome is unclear with reports of both worse or equivalent outcomes in patients with recurrent primary MN. This difference may reflect whether recurrence is diagnosed on protocol biopsies and newer treatment strategies. It is clear that recurrent primary MN can lead to graft failure and when it does recur, up to 50% of death-censored graft losses can be attributed to recurrent disease.

There is accumulating evidence for the use anti-CD20 therapy (rituximab) for the treatment of recurrent primary MN. Complete or partial clinical remission has been reported in 80% of cases treated with rituximab. There is currently insufficient data to determine whether the presence of anti-PLA2R antibodies is predictive of the response to anti-CD20 treatment and treatment should be considered regardless of antibody status. Alkylating agents have been used to treat recurrent primary MN similar to the treatment of native kidney disease. There is no evidence at present for the preemptive treatment of transplant candidates with either rituximab or alkylating agents to prevent recurrent primary MN.

De novo MN has been reported in about 2% of allografts. It can occur months or years after transplantation and can vary in presentation from asymptomatic disease to severe nephrotic syndrome. The etiology of de novo MN may be different from primary or recurrent disease with anti-PLA2R antibodies being less common in patients with de novo MN. Debiec and colleagues reported the presence of anti-PLA2R antibodies in 50% of patients with recurrent MN but not in any of the patients with de novo MN ( n = 9). In addition, staining for PLA2R, which is frequently seen in primary and recurrent MN, is much less frequently observed in de novo disease. This suggests that antibodies in de novo MN are targeted against different antigens than those responsible for primary or recurrent disease, but these antigens remain to be identified. The effect of de novo MN on transplant survival, with some reports of high rates of allograft failure and others reporting that the allograft survival is not affected by the presence of de novo MN. The development of de novo MN is not a contraindication to retransplantation.

IgA Nephropathy

There is significant variability in the reported rate of recurrence of IgA nephropathy after transplantation. As with other conditions, this relates to the criteria for biopsy (protocol or clinical) and the duration of follow-up. Clinical recurrence occurs in approximately 30% of cases. Histological recurrence is more common and probably occurs in >50% or cases, with this percentage increasing the longer the period between transplantation and biopsy.

Generally, the outcome of transplantation in patients with IgA nephropathy is equivalent to or better than other primary diagnoses. However, despite good outcome overall in patients with IgA nephropathy, recurrence is associated with a higher risk for allograft failure, suggesting that recurrent IgA nephropathy does damage the allograft. Early recurrence of IgA nephropathy has been reported and this may be more common in younger transplant recipients with rapidly progressive, crescentic disease in their native kidneys.

De novo IgA nephropathy has been reported, but this has to be distinguished from undiagnosed recurrence or donor disease if the biopsy is performed early after transplantation. Crescentic de novo disease has been described, which is associated with a poor prognosis.

Antiglomerular Basement Membrane Disease

Antiglomerular basement membrane (anti-GBM) disease is a rare cause of ESKD. If transplant is performed when circulating anti-GBM antibodies are still detectable histological recurrence (linear IgG deposition in the capillary wall) is detectable in up to 55% of transplant biopsies. However, even in these patients with histological recurrence, clinical recurrence is uncommon, probably affecting less than 10% of recipients and transplant loss is rare. When clinical recurrence does occur, it is in patients who have circulating anti-GBM antibodies. Therefore it is recommended that transplantation be delayed until immunological remission and 6 to 12 months since disease was active. If relapse does occur some cases can be salvaged by treatment with cyclophosphamide and plasmapheresis, but the outcome is poor.

Although primary anti-GBM disease could occur in a transplant, it is a very rare disease and although reported, this is unlikely. The context in which anti-GBM disease can occur is in transplant recipients with a primary diagnosis of Alport syndrome. This condition results from a mutation in the gene encoding the α5 chain of type IV collagen, a major component within the GBM. Because of the abnormality in α5, collagen IV is not assembled correctly into a network of α3, α4, and α5. Therefore α3, the antigenic target in anti-GBM disease, is also not present in the GBM of patients with Alport syndrome. Thus, after transplantation, the recipient encounters α3 for the first time and generates antibodies against this target. Linear deposition of IgG along the GBM occurs commonly but the development of full-blown anti-GBM disease is rare. In a series of 30 patients, 15 had a renal biopsy and linear IgG deposition was seen in 5. No patient had other evidence of disease. The risk for de novo anti-GBM disease does not have an adverse effect on graft survival. In a series of 62 patients with Alport syndrome, Kelly and colleagues reported a 47% 20-year graft survival (better than the control cohort), although no patient developed anti-GBM disease in this series.

Membranoproliferative Glomerulonephritis and C3 Glomerulopathy

Recent progress in the understanding of the pathogenesis of MPGN has led to a revision of the classification depending on the presence of Ig-containing immune complexes (IC-MPGN) or dominant C3 (C3 glomerulopathy). The risk for recurrent disease and the potential impact on graft survival is dependent on the type of MPGN and therefore studies that do not differentiate between the different types of MPGN have to be interpreted with caution. Overall, the rate of recurrence is high for these diseases and recurrence is associated with an inferior graft outcome.

Using protocol biopsies, Lorenz and colleagues reported a risk for recurrent IC-MPGN of 41%, with a higher risk in those patients with monoclonal IgG deposition. Recurrence of MPGN with monoclonal deposition is associated with a poor prognosis. Only a minority of patients will have a detectable paraprotein (30%) and have a low risk for progression to multiple myeloma. The risk for recurrent disease in cases with polyclonal IgG deposition, including type I cryoglobulinemia, is lower provided the underlying cause is adequately treated.

C3 glomerulopathy, where there is dominant deposition of C3 in the glomerulus, is further divided into two diseases depending primarily on the electron microscopy appearance; dense deposit disease and C3 GN. The rate of recurrence of both subtypes of C3 glomerulopathy is high—70% in C3 GN ^67-69 and 50% to 100% in dense deposit disease. Recurrence of C3 glomerulopathy has an effect on transplant survival. A study using data from the North American Pediatric Renal Transplant Cooperative Study reported a 5-year graft survival of 50% in patients with a primary diagnosis of dense deposit disease compared with the database as a whole (74%). This 5-year survival is consistent with other reports in the literature. A similar 5-year allograft survival is reported for patients with C3 GN. In patients with either C3 GN or dense deposit disease, 5-year allograft survival of >50% is expected; therefore, transplantation is a realistic option for this patient cohort despite the risk for recurrence.

The cause of primary disease should be assessed in potential transplant recipients with a primary diagnosis of C3 glomerulopathy. However, insufficient data are available to comment on whether the cause of complement dysregulation (genetic or acquired) predicts risk for recurrence. Several factors have been reported to predict a higher risk for recurrence and poor outcome including low complement (C3 and C4) levels at the time of transplant in some, but not all reports. Young age, heavy proteinuria, and crescentic primary disease are also risk factors. There are reports of a response to treatment with the complement (C5) inhibitor eculizumab in patients with recurrent C3 glomerulopathy, particularly when there is biopsy evidence of glomerular inflammation.

De novo IC-MPGN is uncommon after transplantation and was found in only 13 of 399 (3.3%) renal transplant recipients in a French series. De novo disease is commonly associated with hepatitis C infection or in other systemic illnesses. The clinical presentation can vary from persistent subnephrotic proteinuria to nephrotic syndrome, declining renal function and graft loss. Any underlying condition should be sought and treated if found. When no cause is identified, augmented immunosuppression, usually including corticosteroids, has been used with inconsistent benefit.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a rare cause of ESKD accounting for 1% of cases with a suggestion that disease activity is reduced once patients develop ESKD. The reported incidence of SLE recurrence after transplantation varies widely, from 2.5% to 54%. The variation will depend on whether clinical recurrence or biopsy recurrence is reported. A retrospective analysis of the UNOS database suggests that the disease recurrence rate is low, affecting 2.4% of patients (167 of 6850). In contrast, a recurrence rate of 54% was reported when surveillance biopsies were performed. Clinically relevant recurrence is likely to be in the range reported from registry data (<5%).

From the UNOS data, the risk for graft failure is increased fourfold higher in patients who develop recurrence than in those without recurrence. However, the estimated attributable risk for graft failure due to recurrent disease is low at 7%. Although some studies have suggested that the outcome is worse in patients with SLE, most studies report a low rate graft loss as a result of recurrent lupus and equivalent transplant survival compared with patients with other primary diseases.

The UNOS data suggest that black race, female sex, and young age increase the risk for recurrence. There are cases of successful transplantation in patients with serologically active lupus ; however, there are reports that the risk for recurrence is higher in patients with clinical or serological disease activity at the time of transplantation than in those without. Therefore it is generally accepted that disease should be quiescent, or at least stable, and patients should be on minimal or no immunosuppression before transplantation. There is no relationship between time on dialysis before transplantation and risk for recurrence, so there is no indication that transplantation should be delayed if disease is quiescent. Although a period on dialysis before transplantation has been suggested, there is limited evidence to support this. One report suggested an increased risk for recurrent SLE in living related donor kidneys ; however, this has not been confirmed in other case series. The use of mycophenolate mofetil, which is known to be effective in native lupus nephritis, appears to reduce the rate of recurrent SLE.

Antiphospholipid Syndrome

Primary or secondary (most commonly in association with SLE) antiphospholipid syndrome (APS) can cause acute intrarenal vasoocclusive disease (thrombotic microangiopathy) or more chronic vascular changes, ultimately leading to ESKD. In patients undergoing renal transplantation, APS is associated with arterial and venous thrombosis, bleeding at the time of transplant, recurrence of nephropathy, and catastrophic APS. Consequently, laboratory evidence of active disease with antiphospholipid antibodies, lupus anticoagulant, or abnormal coagulation, is associated with worse allograft and patient survival. Given the association of SLE with APS, patients with a primary diagnosis of SLE should be screened for the presence of antiphospholipid antibodies. Plasma exchange and peri- and postoperative anticoagulation have been successfully used but anticoagulation is associated with an increased risk for bleeding. The relevance of isolated positive antibody tests, particularly anticardiolipin antibodies, in the absence of clinical features of APS, is less clear as anticardiolipin antibodies can be found in up to one-third of dialysis patients and do not increase the risk for adverse outcomes after transplantation.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

ESKD develops in approximately 20% of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Disease can relapse after transplantation with the reported rate of relapse ranging between 9% and 37%, with a pooled analysis suggesting a recurrence rate of 17%. The difference in reported rates is due to different regimens used to treat primary disease and the criteria used for diagnosis of recurrence. A more recent series of 35 patients, with patients on modern posttransplant immunosuppression (including tacrolimus and mycophenolate mofetil) reported a lower rate of recurrence (9%) during a 5-year follow-up period and only extrarenal manifestations were observed. Therefore the outcome after transplantation is favorable for patients with ANCA-associated vasculitis with 10-year patient and death-censored allograft survival of 87% and 70% to 84%, respectively. Graft loss due to recurrent disease is rare.

The risk for relapse is not influenced by the pattern of original disease (granulomatosis with polyangiitis or microscopical polyarteritis or whether the disease is renal localized) or ANCA type (proteinase-3 or myeloperoxidase specific). There are reports of relapse if transplantation is performed in patients with active disease or with high ANCA titers. Despite this, it is generally accepted that ANCA positivity at the time of transplant does not increase risk for recurrent disease or graft loss and is not a contraindication to transplantation. Of 35 cases (15 of whom were ANCA positive at the time of transplant) reported by Gera et al., none developed disease recurrence. Similarly, changes in ANCA titer posttransplant are not an accurate predictor of disease activity. Routine monitoring of ANCA titers either before or after transplant is therefore not justified. There is some evidence that the risk for relapse is increased if transplantation is performed within 1 year of clinical remission. A period of pretransplant disease quiescence is recommended in published guidelines, although the evidence supporting this is not strong. If recurrent disease does occur, there are reports of successful treatment with cyclophosphamide, plasmapheresis, and rituximab.

Henoch-Schonlein Purpura

Generally, the outlook after renal transplantation for patients with a primary diagnosis of Henoch-Schonlein purpura (HSP) is good, with similar death-censored graft survival compared with patients with other diagnoses. The risk for recurrence is lower than for IgA nephropathy with a rate of only 12% at 10 years reported in a multicenter European study. The proportion of graft losses attributed to recurrent HSP was 7.5% to 13.6% in the European series and UNOS database studies.

Systemic Sclerosis

Systemic sclerosis (SS) is a multisystem disease that that can cause acute kidney injury (scleroderma renal crisis) or a more indolent decline in function and is a rare cause of ESKD. A UNOS report suggested that although transplantation improved the outcome of patients with SS (68% 1-year graft survival) compared with remaining on dialysis, survival was less favorable than for other transplant recipients. More recently, a French Registry study reported the outcome of 36 transplants in 34 patients with a primary diagnosis of SS. Patient survival was 82.5% at 5 years, with death-censored graft survival of 92.8% at 5 years. There were three cases of renal crisis in this cohort and cardiac and gastrointestinal disease worsened in 45% and 26% of patients, respectively. A similar low rate of recurrent disease was reported from the UNOS registry with graft loss attributed to recurrent disease in only 3 of 142 transplants. Rapid loss of native renal function with progression to ESKD within 1 year of scleroderma renal crisis increased the likelihood of recurrence that may manifest early with an increase in nonrenal disease manifestations. The risk for recurrence does not appear to be related to posttransplant immunosuppression.

Hemolytic Uremic Syndrome and Other Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolysis and thrombocytopenia. End-organ damage occurs due to thrombi occluding small vessels and vascular injury to small and medium-sized arteries. TMAs were originally classified according to their clinical presentation, with hemolytic uremic syndrome (HUS) typically affecting the kidney and thrombotic thrombocytopenic purpura (TTP), typically causing neurological disease. It is clear that this does not reliably distinguish between these two diseases and diagnostic tests are now available that can help distinguish HUS and TTP. An inherited or acquired deficiency in ADAMTS13 is responsible for TTP, which can cause acute kidney injury, but rarely causes ESKD. Recurrence of previously undiagnosed TTP after renal transplantation has been reported.

HUS is most commonly due to infection with a Shigatoxin producing Escherichia coli (STEC HUS, 90% of cases). STEC HUS is a self-limiting illness that only rarely results in ESKD, although lesser degrees of CKD are common. The remaining 10% of cases, referred to as atypical HUS , are most commonly (60% of cases) due to an abnormality of complement activation, although other genetic or acquired abnormalities can cause atypical HUS. STEC HUS recurs very rarely after transplantation (0% to 1%) and is therefore not a contraindication to transplantation. The low rate of ESKD in patients with STEC HUS raises the possibility of an alternative diagnosis when ESKD occurs after an episode of STEC HUS, particularly an atypical, complement-mediated form of disease. In this situation, a genetic or acquired defect in complement regulation should be excluded. Similarly, if presumed STEC HUS recurs after a transplantation, alternative diagnoses should be considered. Alberti et al. described genetic defects in complement regulation in two patients with recurrent HUS, despite evidence of STEC infection during the initial presentation.

Unlike with STEC HUS, the renal prognosis of atypical HUS has historically been reported as poor, with 50% of patients developing ESKD. Patients with a pathological variant of complement factor H (CFH), complement factor I (CFI), C3, complement factor B (CFB), or high titer anti-CFH autoantibodies have an 80% to 90 % risk for recurrence and, without treatment with a complement inhibitor, most grafts are lost after recurrence. Patients with a variant membrane cofactor protein (which is expressed normally on the donor endothelium), low titer, or historical anti-CFH antibodies can be considered for transplantation as the recurrence risk is low. Patients in whom no cause of atypical HUS has been identified are at intermediate risk for recurrent disease. Recurrence typically occurs early after transplantation (60% in the first month), perhaps due to ischemia or drugs (calcineurin or mammalian target of rapamycin [mTOR] inhibitors) causing endothelial activation and precipitating disease. Recurrence of disease has been reported in patients treated with both calcineurin inhibitors and mTOR inhibitors, with higher rates of disease reported in patients receiving sirolimus.

The therapeutic use of complement inhibition to either treat or prevent recurrent disease, is effective and improves the prognosis of patients with atypical HUS undergoing transplantation. Prophylactic treatment has been recommended if disease is likely to recur. Recently, however, favorable outcomes have been reported for atypical HUS patients undergoing living donor kidney transplantation without prophylactic eculizumab. For patients with a genetic defect in proteins primarily synthesized in the liver (CFH, CFI, C3, and CFB) an additional option is combined liver and kidney transplantation. This restores normal complement inhibitor function and avoids the need for complement inhibitor therapy; however, it is associated with significant perioperative morbidity and mortality.

De novo posttransplant TMA can develop in the absence of previous atypical HUS or any known susceptibility factor. However, the relationship between atypical HUS and de novo TMA in transplanted kidneys is complex. Approximately 30% of patients who develop de novo posttransplant TMA carry mutations in complement regulatory proteins. In these cases, it may be difficult to distinguish between de novo and recurrent disease. The reported rate of de novo disease varies, with registry data usually reporting lower rates (<1%) than single-center studies (4% to 14%) De novo TMA is associated with both CNI and mTOR inhibitor treatment and can occur as a manifestation of acute antibody-mediated rejection. Typically, de novo TMA occurs early after transplantation and hematological features are less marked than when the TMA affects native kidneys. The diagnosis may only be apparent on kidney biopsy. Treatment will depend on the likely precipitant; reduction or withdrawal of CNI or sirolimus may be effective. A response to plasma exchange has been reported but is inconsistent. There have been reports of a response to eculizumab, but this should only be considered when ESKD could have been due to a TMA.

Diabetic Nephropathy

Diabetic nephropathy (DN) is the most common cause of ESKD in developed countries and therefore is the main reason why patients require renal transplantation. After transplantation, DN can develop in the graft as either recurrent or de novo disease. Histological recurrence can be seen within 2 to 4 years in patients with diabetes. DN in a transplant kidney presents with proteinuria and a slow decline in renal function over many years. Because of the slow decline in function, DN rarely causes allograft failure; patients are more likely to die with a functioning graft or have graft failure due to other causes.

In a prospective study of 48 patients with type 1 diabetes mellitus, tight glycemic control reduced the histological changes of DN after transplantation. Similarly, glycemic control achieved by simultaneous pancreas transplant protects against the development of DN in the transplanted kidney. Interventions that slow progression of disease DN in native kidneys, including blood pressure control and angiotensin-converting enzyme inhibition, may benefit but are not proven to slow disease progression in transplant recipients with DN.

De novo DN can develop in patients with new-onset diabetes after transplant and histological evidence has been reported 5 to 6 years after transplantation. Poorer graft and patient survival has been reported in patients who develop diabetes after transplant, although not in all series and not in children. The contribution of de novo DN to the reported increased risk for graft loss is not clear. Treatment should include optimizing glycemic control both to reduce the risk for nephropathy and other complications associated with diabetes.