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Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney

Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney
Literature review current through: Jan 2024.
This topic last updated: Jan 12, 2024.

INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury in the kidney that may have different etiologies, including genetic diseases, infection, toxins, and obesity, as well as previous injury resulting in hyperfiltration of remaining viable nephrons.

Primary FSGS, which occurs in the absence of a known etiology, commonly progresses to end-stage kidney disease (ESKD). When kidney transplantation is performed, primary FSGS may recur in the kidney allograft.

An overview of FSGS in the kidney allograft is presented in this topic review. The pathogenesis, classification, clinical features, diagnosis, and treatment of FSGS in the native kidney are discussed elsewhere:

(See "Focal segmental glomerulosclerosis: Pathogenesis".)

(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

TERMINOLOGY — Focal segmental glomerulosclerosis (FSGS) may be recurrent or de novo. The following definitions will be used in this topic review:

Recurrent FSGS – Recurrent FSGS refers to the development of primary FSGS in the transplanted kidney in patients with primary FSGS as the cause of end-stage kidney disease (ESKD) in the native kidneys. Less commonly, FSGS may recur in patients with certain forms of genetic FSGS (eg, those with podocin mutations).

De novo FSGS – De novo FSGS is the development of primary or secondary FSGS in the transplanted kidney in patients who did not have FSGS in their native kidneys.

Primary FSGS – Primary FSGS refers to FSGS that is caused by a putative circulating factor that is toxic to the podocyte and results in generalized podocyte dysfunction. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of primary FSGS'.)

Secondary FSGS – Secondary FSGS generally occurs as an adaptive phenomenon that results from a reduction in nephron mass or direct toxicity from drugs or viral infections. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Genetic FSGS – Genetic FSGS refers to FSGS that is caused by a number of genetic mutations in genes that code for proteins expressed in podocytes and at the slit diaphragm. (See "Focal segmental glomerulosclerosis: Genetic causes".)

RECURRENT FSGS

Epidemiology and risk factors

Epidemiology – The rate of recurrent primary focal segmental glomerulosclerosis (FSGS) is difficult to ascertain since it is often not clear whether the patient had primary or secondary FSGS as the initial cause of end-stage kidney disease (ESKD) [1-13]. The best data come from the multicenter Post-Transplant Glomerular Disease (TANGO) cohort study of 11,742 adult kidney transplant recipients, 176 of whom had a biopsy-proven diagnosis of primary FSGS [1]. FSGS recurred in 57 patients (32 percent), with most recurrences occurring early after transplantation (median time to recurrence 1.5 months).

Other causes of FSGS, including infection, toxins, or obesity, may occur in the allograft but are uncommon, at least in patients for whom the cause of FSGS in the native kidney is known. In general, the conditions that caused FSGS in the native kidney are treated prior to transplantation.

Risk factors for recurrence – Several risk factors for recurrence of FSGS posttransplantation have been reported, including younger age of disease onset, rapid progression of initial disease, being White, prior native kidney nephrectomy, lower body mass index (BMI) at transplantation, and a history of recurrence in a prior allograft [1,14-17]. In the United States, White recipients of African-American kidneys may be at particularly high risk of recurrence [9]. On the other hand, Black recipients appear to represent a lower risk group, in which recurrence is less frequent [6,9].

A family history of FSGS generally predicts a lower risk of recurrence [18,19]. However, the risk of recurrence of familial FSGS may depend upon the specific mutation. Recurrent disease has been reported among patients with podocin mutations [19-24] and in one patient with a TRPC6 mutation [25]. Variants of the MYH9 and APOL1 genes, which are prevalent among African Americans, are highly associated with an increased risk of developing FSGS in the native kidney [26-30]; however, recipients with MYH9 and APOL1 high-risk alleles do not have an increased risk of recurrent FSGS in the allograft. While an earlier study found no association between APOL1 high-risk alleles and allograft survival [31], two subsequent studies have shown that patients with two APOL1 high-risk alleles may have an increased risk of allograft loss compared with those with only one or no high-risk alleles [32,33]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients'.)

Histologic subtype of FSGS in the native kidney [34,35], human leukocyte antigen (HLA) mismatch [17], and choice of transplantation immunosuppressive therapy [25,36,37] have not been shown to alter the risk of recurrence.

Pathogenesis — Recurrent primary FSGS is likely due to a circulating factor or the absence of a normal factor present in plasma, with either resulting in toxicity to the podocyte or glomerular capillary wall.

Several reports support this hypothesis [38-44]:

Serum from some patients with FSGS increases the permeability of isolated glomeruli to albumin. The ability of pretransplant serum to increase in vitro glomerular permeability may predict FSGS recurrence after transplantation [38,39]. As an example, in one study, the incidence of recurrence was 86 percent (six of seven) when glomerular permeability to albumin was substantially increased by exposure to patient serum [38]. By contrast, the incidence of recurrence was only 17 percent (4 of 19) among patients whose serum did not increase in vitro glomerular permeability. These findings also suggest that the permeability factor may be specific to only certain types of FSGS that are more likely to recur in the transplanted kidney.

Use of a regenerating protein adsorption column or plasma exchange can reduce protein excretion in a subgroup of patients with recurrent FSGS (figure 1) [40]. The factor that is removed increased protein excretion when injected into rats.

More prolonged remissions have been achieved using standard plasmapheresis that is initiated promptly after the onset of proteinuria [41] or the combination of plasmapheresis and cyclophosphamide [39].

Indirect support for a circulating recipient factor is provided by case reports, in which a kidney transplant recipient developed recurrent FSGS with marked proteinuria and foot process effacement on biopsy [45-47]. Upon removal of the kidney and retransplantation into a second recipient, there was almost complete resolution of proteinuria and reversal of histologic lesions.

The identity of the circulating permeability factor is not known with certainty, although the serum soluble urokinase plasminogen activator receptor (suPAR), apolipoprotein A1 (apoA-1), C-C motif chemokine ligand (CCL), anti-CD40 autoantibody, and anti-nephrin antibody are possible causative factors [48-52]. It is probable that additional factors exist. The potential role of suPAR in the pathogenesis of FSGS is discussed elsewhere. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'suPAR'.)

In some cases of recurrent FSGS, tumor necrosis factor (TNF)-alpha pathway activation was found to be the cause of the recurrence, suggesting that TNF-alpha blockade could be a potential targeted therapy [53-55].

Clinical manifestations — Patients with recurrent primary FSGS typically present with the rapid onset of proteinuria, which is frequently in the nephrotic range [2]. Increased protein excretion may be noted in the immediate to early posttransplantation period; in children, the median time to recurrent proteinuria is approximately 10 to 14 days after transplantation [6,36], while in adults, the median time to recurrence is approximately 1.5 months [1,56]. Less commonly, patients with recurrent primary FSGS may present later (several months or years) after transplantation.

Patients usually have symptoms and signs of nephrotic syndrome, including edema, hypoalbuminemia, and hyperlipidemia [2,6,36], and many patients have decreased allograft function. Some patients develop anasarca (ie, generalized and massive edema), with marked peripheral edema, abdominal distension resulting from ascites, marked scrotal or vulvar edema, and severe periorbital edema resulting in swollen-shut eyelids. Patients usually do not have gross hematuria, although microscopic hematuria may be present. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children" and "Overview of heavy proteinuria and the nephrotic syndrome".)

Screening and diagnosis

Posttransplantation surveillance — To help detect early recurrence posttransplantation, all patients with primary FSGS as the cause of ESKD in the native kidneys should be screened for proteinuria. We obtain a random or spot urine protein-to-creatinine ratio on the first postoperative day, the day of scheduled hospital discharge, weekly for four weeks, and then monthly for one year after transplantation [57]. If the ratio is >0.5 g/g, we obtain a 24-hour protein collection to confirm the result obtained with the random urine protein-to-creatinine ratio.

Protein excretion from native kidneys decreases significantly within one month of transplantation; thus, proteinuria that is detected more than one month after transplantation is most likely derived from the allograft and should trigger further investigation [58,59]. A kidney biopsy to exclude other causes of proteinuria should be performed if posttransplantation proteinuria exceeds 1 g/day and should include electron microscopy to detect early features of FSGS. (See 'Diagnostic evaluation' below and "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Patients presenting with proteinuria'.)

The rationale underlying aggressive screening is that recurrent primary FSGS may result in the rapid development of nephrotic syndrome with numerous sequelae, including massive volume overload, acute kidney injury (AKI), thrombosis, and hyperlipidemia. In addition, recurrent primary FSGS commonly leads to allograft loss. Although the efficacy of immunomodulatory therapies for recurrent FSGS is unproven, early institution of therapy is believed to be more likely to be effective than delayed treatment. (See 'Treatment' below and 'Prognosis' below.)

To ensure the ability to detect recurrent proteinuria following transplantation, some have advocated that patients with significant proteinuria of the native kidney should undergo pretransplantation medical nephrectomy (with an angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or nonsteroidal antiinflammatory drug [NSAID]), renal ablation, or surgical nephrectomy [57]. Secondary native ureteral ligation is also possible in case of doubt to avoid unnecessary treatment to the patient [60]. However, we believe that nephrectomy is probably only warranted for massive, refractory proteinuria (ie, resulting in clinically debilitating hypoalbuminemia), especially associated with malnutrition in children with such disorders as congenital nephrotic syndrome.

Other biomarkers, such as urinary apoA-1b [61,62], have been proposed to predict recurrent primary FSGS, but further investigation is required.

Diagnostic evaluation — The diagnosis of recurrent FSGS should be suspected in any patient with primary FSGS as the cause of ESKD in the native kidneys who presents with proteinuria greater than 1 g/day detected by routine screening (see 'Posttransplantation surveillance' above) or who develops symptoms and signs of nephrotic syndrome. Such patients should undergo a kidney allograft biopsy to confirm the diagnosis of FSGS. Patients who are diagnosed with FSGS by allograft biopsy should be evaluated for possible underlying causes and associated conditions, since clinical and histologic features alone cannot distinguish recurrent primary from de novo secondary FSGS with certainty.

Kidney biopsy — A definitive diagnosis of recurrent FSGS in the kidney allograft is made based upon kidney biopsy findings in the setting of significant proteinuria (>1 g/day). Allograft histology typically demonstrates characteristic features of FSGS that are identical to FSGS in the native kidney. However, a kidney biopsy early in the disease course may show no significant changes by light microscopy and may only reveal diffuse podocyte foot process effacement (if electron microscopy is performed), a finding that precedes the development of sclerotic lesions [56]. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Pathology'.)

Five histologic patterns of FSGS have been recognized, which are associated with different clinical manifestations and prognoses. It is not clear whether the histologic subtype observed in recurrent FSGS is generally the same subtype as that observed in the native kidney [34,35,63]. The histologic subtype of FSGS in the native kidney has not been shown to predict recurrence posttransplantation. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Histologic variants'.)

Evaluation for secondary causes — Once the diagnosis of FSGS is confirmed by kidney allograft biopsy, an evaluation for causes of secondary FSGS (table 1) should be performed since histologic features do not reliably distinguish between primary and secondary FSGS, and there is significant overlap in the clinical features. This is particularly relevant for patients with recurrent FSGS who present with a later onset (ie, >3 months) after transplantation since differentiating between recurrent primary FSGS and de novo secondary FSGS may be challenging in such patients. (See 'Later recurrence (>3 months posttransplantation)' below and 'De novo FSGS' below.)

The evaluation includes the following:

Tests for parvovirus B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyomavirus (BKPyV), hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [64,65], and if risk factors are present, HIV. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Diagnostic approach' and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Diagnosis' and "Kidney transplantation in adults: BK polyomavirus-associated nephropathy", section on 'Screening and diagnosis' and "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Initial testing' and "COVID-19: Diagnosis" and "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm'.)

A review of the patient's medications, looking for potentially causative agents, such as mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, bisphosphonates, interferon, heroin, and anabolic steroids. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Drugs and toxins'.)

Assessment of BMI.

In addition, some experts evaluate all patients with recurrent FSGS for hypogammaglobulinemia, which is associated with viral infections that may cause FSGS and has been observed in recipients of solid organ transplants [66,67]. Other experts, however, only evaluate for hypogammaglobulinemia among patients who are undergoing plasmapheresis, which is used for the treatment of recurrent primary FSGS, in order to ascertain that patients are receiving adequate repletion of antibodies that are removed during plasmapheresis sessions. (See 'Treatment' below.)

Prevention — In patients with primary FSGS as the cause of ESKD in the native kidneys, we do not administer any prophylactic measures to prevent recurrent FSGS. Although such patients may be at high risk of recurrence, the use of preventive measures (such as plasmapheresis or rituximab) in these patients has not been clearly shown to reduce rates of recurrence. Although data from case reports and small case series initially suggested that preemptive plasmapheresis lowers the risk of recurrent FSGS among patients at high risk for recurrence [68,69], larger studies have not confirmed these findings. As an example, in an observational study of 66 patients with primary FSGS, recurrent FSGS developed in 23 of 37 (62 percent) who received perioperative plasmapheresis with or without rituximab compared with 14 of 27 (51 percent) who did not receive any therapy [56].

Treatment

Initial therapy — The optimal approach to therapy of patients with recurrent primary FSGS is not known, and treatment strategies vary among transplant centers. Our approach to initial therapy is determined by the timing of recurrence (algorithm 1).

Early recurrence (≤3 months posttransplantation) — Most patients with recurrent primary FSGS in the kidney allograft present early (within the first three months) after transplantation. (See 'Clinical manifestations' above.)

For patients with recurrent primary FSGS who present within the first three months of transplantation, we suggest treatment with plasmapheresis (algorithm 1). It is hypothesized that recurrent primary FSGS that occurs within a short time after transplantation is caused by a circulating permeability factor (see 'Pathogenesis' above), which could theoretically be removed by plasmapheresis. Some contributors to this topic also administer rituximab in combination with plasmapheresis, based upon observational data showing a possible benefit with combination therapy and a trend toward more relapses when plasmapheresis is performed without rituximab [56]. However, other contributors administer plasmapheresis alone, based upon the lack of clear evidence of benefit with use of rituximab in this setting [13], and reserve the use of rituximab for patients who do not respond to plasmapheresis.

Plasmapheresis regimen – We initiate plasmapheresis early after the onset of recurrent disease. The optimal plasmapheresis regimen for the management of recurrent FSGS is unclear. Details to consider include the plasma volume to be replaced (1 versus 1.5 plasma volumes), choice of replacement fluid (albumin versus fresh frozen plasma [FFP]), and frequency of therapy. A typical plasmapheresis regimen is 1.5 plasma volume exchanges every other day for a total of two weeks using 5 percent albumin as the replacement solution. The need for further plasmapheresis is determined by the assessed response to therapy. (See 'Monitoring and modifying therapy' below.)

In general, albumin is given as the replacement fluid. If, however, the patient has had a recent kidney biopsy, then one or two units of FFP should be substituted for albumin at the end of the procedure to replete coagulation factors that may have been depleted by plasmapheresis. Some experts routinely administer a small dose of intravenous immunoglobulin (IVIG; ie, 150 to 200 mg/kg) after plasmapheresis sessions to replace depleted antibodies [56], whereas others give IVIG only if there is evidence of or concern for infection. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Dosing of rituximab – If rituximab is used, we administer rituximab 375 mg/m2 for one to two doses [13,56]. Rituximab is typically given immediately after a plasmapheresis session, and plasmapheresis should be skipped the following day to avoid removing a significant amount of rituximab with plasmapheresis [70,71]. Some experts wait until the initial two-week course of plasmapheresis has been completed before administering rituximab. The optimal timing and dose of rituximab are unclear.

There are no randomized trials evaluating the use of plasmapheresis with or without rituximab for recurrent primary FSGS. Observational studies in adults and children have suggested that plasmapheresis may induce remission of proteinuria in selected patients with recurrent FSGS [1,5,38,40,41,56,72-81]. As examples:

In the multicenter TANGO study of adults (age ≥16 years) with recurrent FSGS, treatment with plasmapheresis with or without rituximab was the most frequently used therapy (61 of 75 patients [81 percent]) [1]. Thirty-two patients received both plasmapheresis and rituximab, 25 received only plasmapheresis, and three received only rituximab. Plasmapheresis with or without rituximab was associated with complete remission in 13 patients (21 percent), partial remission in 22 (36 percent), and no response in 26 (43 percent). Two of the patients who achieved complete remission experienced disease relapse that was responsive to repeat treatment.

In another observational study of 38 adults with recurrent FSGS who received treatment with plasmapheresis, 20 (50 percent) received additional rituximab [56]. All but five patients (87 percent) responded to therapy (defined as a >50 percent decrease in proteinuria); four patients, all of whom did not receive rituximab, experienced graft loss due to recurrent FSGS.

One literature review found that 70 percent of children and 63 percent of adults with recurrent FSGS achieved complete or partial remission of proteinuria with plasmapheresis [82]. However, these studies, most of which were small, uncontrolled, and had short-term follow-up, may overestimate the benefit of plasmapheresis.

There are no data directly comparing plasmapheresis with other therapies, and it is unclear whether the combination of plasmapheresis plus rituximab is more effective than plasmapheresis alone. In one retrospective study of 148 adults with recurrent primary FSGS, rates of complete or partial remission were not significantly different between patients who received rituximab plus standard-of-care therapy (which included plasmapheresis, glucocorticoids, and calcineurin inhibitors) and those who received standard-of-care therapy alone [13]. However, the addition of rituximab may be beneficial for patients who do not respond to initial therapy with plasmapheresis alone [13,80]. (See 'Resistant disease' below.)

Later recurrence (>3 months posttransplantation) — Less commonly, primary FSGS may recur later (beyond three months) after transplantation. In patients presenting with later recurrence, it is particularly important to distinguish true recurrent primary FSGS from secondary causes of FSGS, which are unlikely to respond to therapies used to treat recurrent primary FSGS (algorithm 1). (See 'Early recurrence (≤3 months posttransplantation)' above.)

In patients without an identifiable cause of secondary FSGS, we suggest treatment with plasmapheresis, as discussed above for patients with early recurrence. (See 'Early recurrence (≤3 months posttransplantation)' above.)

In patients with an identifiable cause of secondary FSGS, we first administer therapy directed against the underlying cause since resolution of the FSGS usually occurs after addressing the underlying cause. As examples, patients with evidence of a viral infection that may cause FSGS should be treated for the viral infection, if possible. Patients who are taking a medication that is known to be associated with FSGS should discontinue this agent to see if proteinuria responds. If the patient does not achieve at least a partial remission (reduction in proteinuria ≥50 percent to a level between 0.3 and 3.5 g/day) with treatment of the underlying cause, we suggest treatment with plasmapheresis, as discussed above for patients with early recurrence. (See 'Early recurrence (≤3 months posttransplantation)' above.)

Monitoring and modifying therapy — In patients receiving treatment with plasmapheresis (with or without rituximab), we obtain a spot urine protein-to-creatinine ratio after completion of plasmapheresis and then at weekly intervals to assess the response to therapy. We use the following definitions of response [1,83]:

A complete response is a reduction in proteinuria to <0.3 g/day.

A partial response is a reduction in proteinuria of ≥50 percent to a level between 0.3 and 3.5 g/day.

No response is defined as not meeting either of the above two criteria.

Based upon these parameters, we determine the clinical response after two weeks of plasmapheresis and modify treatment as follows:

In patients who achieve a complete response, some contributors to this topic would discontinue plasmapheresis (and rituximab, if administered) and continue to monitor the patient at weekly intervals for two to three months, then monthly to one year, and then every one to three months thereafter. However, other contributors would continue plasmapheresis weekly for a total duration of three months to try to prevent disease relapse. (See 'Relapsing disease' below.)

In patients who achieve a partial response, most contributors of this topic would continue plasmapheresis, but clinical approaches vary among contributors. Some contributors would continue plasmapheresis once every two to three weeks for as long as the patient is tolerating the treatment without complications and proteinuria continues to improve. If the patient achieves a complete response, plasmapheresis is then discontinued.

Other contributors would continue plasmapheresis weekly for a total treatment duration of at least three months, as they would for patients who achieve a complete response.

In patients who do not respond to initial therapy, we discontinue plasmapheresis. Such patients are considered to have resistant disease and may require treatment with alternative therapies to attain remission. (See 'Resistant disease' below.)

General supportive measures — General supportive measures in all patients with recurrent FSGS include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have kidney protective benefits in patients with proteinuric chronic kidney disease (with or without diabetes), may also be of benefit in patients with recurrent FSGS, although studies in this patient population are lacking. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition [84]. These measures are similar to those used in patients with glomerular disease involving the native kidneys and are discussed in greater detail elsewhere:

Dietary sodium and protein restriction (see "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake')

Antihypertensive therapy (see "Hypertension after kidney transplantation")

Renin-angiotensin system inhibition (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors')

SGLT2 inhibitors (see "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria')

Lipid lowering (see "Lipid abnormalities after kidney transplantation")

Treatment of edema (see "Overview of the management of chronic kidney disease in adults", section on 'Volume overload')

Relapsing disease — Disease relapse (defined as a return of proteinuria to ≥3.5 g/day in someone who has undergone a complete or partial remission) may occur after a successful response to initial treatment. In one study, for example, 14 of 35 of patients (40 percent) who received initial treatment with plasmapheresis with or without rituximab developed at least one relapse, and two lost their allograft [56]. In patients who develop a relapse after responding to initial therapy, we suggest repeat treatment with plasmapheresis, using the same approach as that used to treat the initial recurrence. Some patients with relapsing disease may require long-term plasmapheresis titrated to proteinuria levels. (See 'Early recurrence (≤3 months posttransplantation)' above.)

There are limited data to guide the optimal treatment of disease relapse. In the TANGO study cited above, two of the patients treated with plasmapheresis and rituximab who achieved complete remission experienced disease relapse that was responsive to repeat treatment [1].

Resistant disease — The optimal treatment of patients with recurrent FSGS who do not respond to initial therapy with plasmapheresis (with or without rituximab) is unknown. Although a number of different therapeutic strategies have been tried, none have been shown to provide a clear benefit. In patients who do not respond to plasmapheresis alone, we suggest combination therapy with plasmapheresis and rituximab since the addition of rituximab in such patients has been shown to be beneficial in some series [13,80]. In patients who do not respond to plasmapheresis with rituximab, we suggest treatment with adrenocorticotropic hormone (ACTH) gel, although evidence in support of this approach is limited.

ACTH gel – ACTH gel has been used with variable success in patients with primary FSGS of the native kidneys that is resistant to conventional therapies (see "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Adrenocorticotropic hormone (ACTH)'). In one report of 20 transplant recipients with recurrent or de novo FSGS resistant to conventional therapy with plasmapheresis and rituximab, treatment with ACTH gel reduced mean proteinuria from 8.6 g/g to 3.3 g/g, and 10 patients (50 percent) achieved complete or partial remission [85].

Lipid apheresis – Lipid apheresis has been used as a therapy for children and adults with resistant nephrotic syndrome, including primary FSGS [86,87]. In one case series of seven children with recurrent FSGS presenting early (within hours to days) posttransplantation, treatment with lipid apheresis and pulse methylprednisolone resulted in partial or complete remission of proteinuria in all patients [88].

AbataceptAbatacept is a soluble fusion protein that inhibits the T cell protein, B7-1 (CD80) and has been used for the treatment of rheumatoid arthritis and other rheumatologic conditions. Although an initial report suggested benefit with the use of abatacept among patients with recurrent idiopathic FSGS [89], other studies evaluating the use of abatacept or belatacept, a B7-1 blocker with higher affinity, for recurrent FSGS have not demonstrated a benefit [90-93]. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)

Recurrent genetic FSGS — Recurrence of genetic FSGS is rare but has been reported in the patients with homozygous or compound heterozygous podocin mutations (see 'Epidemiology and risk factors' above). The optimal treatment of such patients is not known. We would treat such patients using the same approach used to treat patients with recurrent primary FSGS since these patients may respond to aggressive therapy (plasmapheresis with or without immunosuppressive therapy) [26-30]. (See 'Early recurrence (≤3 months posttransplantation)' above.)

Prognosis — Among patients with FSGS as a cause of ESKD in the native kidney, recurrent FSGS may result in allograft loss in a significant number of patients:

In the multicenter TANGO cohort study of 176 transplant recipients with biopsy-proven primary FSGS as the cause of ESKD, graft loss occurred in 39 percent of patients with recurrent FSGS, compared with 15 percent of those without recurrence, over a median of five years [1]. Graft loss occurred mainly in patients in whom remission could not be achieved, and the median time from recurrence to graft loss was seven months.

In an analysis of 736 kidney transplant recipients (666 adults and 70 children) in the Australia and New Zealand Dialysis and Transplant Registry with a history of ESKD due to biopsy-proven primary FSGS, those with recurrent disease posttransplantation had higher rates of graft loss at five years compared with those without recurrent disease (48 versus 17 percent) [17]. The majority of graft loss occurred in the first two years after disease recurrence.

The prognosis of recurrent secondary FSGS depends upon the underlying cause. In the native kidney, viral-induced FSGS tends to progress to ESKD, whereas FSGS related to hyperfiltration and obesity usually follows a more indolent course. Virtually no studies have examined prognosis of specific types of FSGS in the allograft, but one would expect that FSGS would carry a worse prognosis in a transplanted kidney, compared with a native kidney, given the lower number of functioning nephrons available to sustain glomerular filtration rate (GFR). (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Prognosis'.)

Retransplantation — Patients who develop recurrent disease in the first transplant are at very high risk (up to 75 percent) for recurrence in subsequent allografts [7,8]. Graft loss due to recurrent disease is seen in 10 to 80 percent of these patients, with the prognosis being worse in patients with persistent nephrotic syndrome [5-7].

Some clinicians have suggested that, if a first graft is lost to recurrent disease, a second transplant should be delayed for one to two years or avoided completely [94]. This delay, which may be most appropriate if recurrence is rapid, may result in the disappearance of the circulating nephrotoxic factors that are responsible for the glomerular injury. However, the efficacy of this approach is not proven. A third transplant in patients with two previous transplant losses due to recurrent FSGS should generally be avoided, especially if both prior graft losses occurred soon after transplantation with no response to extensive treatment.

DE NOVO FSGS — Some patients develop primary or secondary focal segmental glomerulosclerosis (FSGS) in the transplanted kidney even though they did not have FSGS in their native kidneys:

Epidemiology and risk factors – The incidence of de novo FSGS is difficult to estimate since the cause of end-stage kidney disease (ESKD) in the native kidney is unknown among many transplant recipients. In one study of 4913 transplant recipients, 57 patients developed biopsy-demonstrated FSGS in the transplanted kidney at a follow-up of 1.8 years; of these, 30 (53 percent) had known FSGS in the native kidney, and 27 (47 percent) did not have a kidney biopsy of the native kidney [95]. From these data, one can estimate that new FSGS develops in <0.6 percent of allografts since at least some of the patients in this group probably had undiagnosed FSGS in the native kidney. However, because of the relatively limited follow-up (less than two years), this study underestimated the rate of incidence of new-onset secondary FSGS related to hyperfiltration injury, which generally takes longer to develop.

Recipients of kidney transplants from donors with APOL1 high-risk alleles have been shown to have an increased risk of de novo collapsing FSGS in the allograft [96].

Pathogenesis – The pathogenesis of de novo primary FSGS in the transplanted kidney is likely the same as that in the native kidney [97,98]. In addition, any of the causes of FSGS in the native kidney may also occur in the allograft; these include infections, toxins, or obesity. These issues are discussed in more detail elsewhere. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of primary FSGS' and "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Clinical presentation – In contrast with patients with recurrent primary FSGS, patients who develop de novo FSGS generally present much later; among such patients, the onset of proteinuria generally occurs three months or more after transplantation. However, rapidly progressive graft failure can occur among patients with de novo FSGS of collapsing subtype [97-99].

Diagnosis – The diagnosis of de novo FSGS should be suspected in any kidney transplant recipient who presents with the new onset of proteinuria >1 g/day after transplantation. A kidney allograft biopsy is required to make a definitive diagnosis. Once the diagnosis of FSGS is confirmed by kidney allograft biopsy, an evaluation for causes of secondary FSGS (table 1) should be performed since histologic features do not reliably distinguish between primary and secondary FSGS and there is significant overlap in the clinical features. Patients without an identifiable secondary cause are considered to have de novo primary FSGS. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Patients presenting with proteinuria' and 'Evaluation for secondary causes' above.)

Treatment – In kidney transplant recipients with de novo FSGS, the approach to treatment depends upon whether the patient is considered to have primary or secondary FSGS:

Patients with de novo primary FSGS are treated as patients with recurrent primary FSGS. The rationale for this approach is that many patients with apparent de novo primary FSGS, especially those whose cause of ESKD in the native kidneys was not confirmed, may actually have recurrent FSGS. In patients whose cause of ESKD is known and who have de novo primary FSGS, treating for recurrent FSGS may also be reasonable since such patients have developed FSGS in the setting of already receiving immunosuppression with calcineurin inhibitors, mycophenolate, and glucocorticoids, agents that are frequently used to treat primary FSGS in the native kidneys. However, there is no high-quality evidence to support this approach. (See 'Initial therapy' above.)

Patients with an identifiable secondary cause for FSGS (eg, viral infection, toxin) should receive therapy directed at the underlying cause since this usually leads to resolution of the FSGS.

Prognosis – The prognosis of de novo primary FSGS is generally poor; untreated primary FSGS often follows a progressive course to ESKD. The rate of spontaneous, complete remission among patients with nephrotic syndrome is unknown but is probably <10 percent. This is discussed elsewhere. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

General principles – Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury in the kidney that may have different etiologies, including genetic diseases, infection, toxins, and obesity, as well as previous injury resulting in hyperfiltration of remaining viable nephrons. Primary FSGS, which occurs in the absence of a known etiology, commonly progresses to end-stage kidney disease (ESKD). When kidney transplantation is performed, primary FSGS may recur in the kidney allograft. Some patients develop de novo FSGS in the transplanted kidney even though they did not have FSGS in their native kidneys. (See 'Introduction' above and 'Terminology' above.)

Recurrent FSGS – Recurrent FSGS refers to the development of primary FSGS in the transplanted kidney in patients with primary FSGS as the cause of ESKD in the native kidneys. Recurrent primary FSGS is likely due to a circulating factor or the absence of a normal factor present in plasma, with either resulting in toxicity to the podocyte or glomerular capillary wall. (See 'Pathogenesis' above.)

Clinical manifestations – Patients with recurrent primary FSGS typically present with the rapid onset of proteinuria, which is frequently in the nephrotic range, in the immediate to early posttransplantation period. In children, the median time to recurrent proteinuria is approximately 10 to 14 days after transplantation, while in adults, the median time to recurrence is approximately 1.5 months. Less commonly, patients with recurrent primary FSGS may present later (several months or years) after transplantation. (See 'Clinical manifestations' above.)

Posttransplantation surveillance – To help detect early recurrence posttransplantation, all patients with primary FSGS as the cause of ESKD in the native kidneys should be screened for proteinuria. We obtain a random or spot urine protein-to-creatinine ratio on the first postoperative day, the day of scheduled hospital discharge, weekly for four weeks, and then monthly for one year after transplantation. If the ratio is >0.5 g/g, we obtain a 24-hour protein collection to confirm the result obtained with the random urine protein-to-creatinine ratio. (See 'Posttransplantation surveillance' above.)

Diagnostic evaluation – The diagnosis of recurrent FSGS should be suspected in any patient with primary FSGS as the cause of ESKD in the native kidneys who presents with proteinuria greater than 1 g/day detected by routine screening or who develops symptoms and signs of nephrotic syndrome. Such patients should undergo a kidney allograft biopsy to confirm the diagnosis of FSGS. Patients who are diagnosed with FSGS by allograft biopsy should be evaluated for possible underlying causes and associated conditions since clinical and histologic features alone cannot distinguish recurrent primary from de novo secondary FSGS with certainty. (See 'Diagnostic evaluation' above.)

Prevention – In patients with primary FSGS as the cause of ESKD in the native kidneys, we do not administer any prophylactic measures to prevent recurrent FSGS. Although such patients may be at high risk of recurrence, the use of preventive measures (such as plasmapheresis or rituximab) in these patients has not been clearly shown to reduce rates of recurrence. (See 'Prevention' above.)

Treatment – The optimal approach to therapy of patients with recurrent primary FSGS is not known, and treatment strategies vary among transplant centers. Our approach to initial therapy is determined by the timing of recurrence (algorithm 1):

-Early recurrence – For patients with recurrent primary FSGS who present within the first three months of transplantation, we suggest treatment with plasmapheresis, rather than rituximab monotherapy, adrenocorticotropic hormone (ACTH) gel, or other therapies (Grade 2C). Some, but not all, contributors to this topic administer plasmapheresis in combination with rituximab. (See 'Early recurrence (≤3 months posttransplantation)' above.)

-Later recurrence – For patients presenting with later recurrence (>3 months after transplantation), it is particularly important to distinguish true recurrent primary FSGS from secondary causes of FSGS, which are unlikely to respond to therapies used to treat recurrent primary FSGS. In patients without an identifiable cause of secondary FSGS, we suggest treatment with plasmapheresis rather than other therapies (Grade 2C). In patients with an identifiable cause of secondary FSGS, we first administer therapy directed against the underlying cause. If proteinuria does not improve with treatment of the underlying cause, we administer plasmapheresis. (See 'Later recurrence (>3 months posttransplantation)' above.)

-General supportive measures – General supportive measures in all patients with recurrent FSGS include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. (See 'General supportive measures' above.)

-Relapsing disease – For patients who develop a relapse after responding to initial therapy, we suggest repeat treatment with plasmapheresis rather than switching to an alternative therapy (Grade 2C). Some patients with relapsing disease may require long-term plasmapheresis titrated to proteinuria levels. (See 'Relapsing disease' above.)

-Resistant disease – For patients with recurrent primary FSGS who do not respond to initial therapy with plasmapheresis alone, we suggest combination therapy with plasmapheresis and rituximab (Grade 2C). For patients with recurrent primary FSGS who do not respond to therapy with plasmapheresis and rituximab, we suggest ACTH gel rather than lipid apheresis or other therapies (Grade 2C). Evidence in support of this approach is limited. (See 'Resistant disease' above.)

De novo FSGS – De novo FSGS is the development of primary or secondary FSGS in the transplanted kidney in patients who did not have FSGS in their native kidneys. In contrast with patients with recurrent primary FSGS, patients who develop de novo FSGS generally present much later; among such patients, the onset of proteinuria generally occurs three months or more after transplantation. The diagnosis of de novo FSGS should be suspected in any kidney transplant recipient who presents with the new onset of proteinuria >1 g/day after transplantation; a kidney allograft biopsy is required to make a definitive diagnosis. Patients with de novo primary FSGS are treated as patients with recurrent primary FSGS. Patients with an identifiable secondary cause for FSGS (eg, viral infection, toxin) should receive therapy directed at the underlying cause. (See 'De novo FSGS' above.)

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Topic 7342 Version 40.0

References

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