FSGS ACTH Gel: Part of the Answer? (2018)

In this issue, T. Alhamad et al1 retrospectively reviewed 20 cases of posttransplant recurrent and de novo focal segmental glomerular sclerosis (FSGS) treated by an adrenocorticotropic hormone (ACTH) analogue gel. FSGS recurrence has been reported in up to 20% to 40% of patients and rose up to 80% for a second or more transplantation if a recurrence was previously observed. Focal segmental glomerular sclerosis recurrence treatment is based on strategies that associate removing of the putative circulating factors, such as plasmapheresis and immunoadsorption, associated with high doses of immunosuppressive agents, including steroids, calcineurin inhibitors (CNI)2,3 and B cell–depleting agents as rituximab.4 No guidelines for FSGS recurrence treatment have been proposed, and despite these therapeutic strategies, graft loss rises up to 60% after FSGS recurrence.5 Moreover, many patients are subjected to severe infectious complications related to intensification of immunosuppression.4 Hence, there is a crucial need for new therapeutic strategies. Adrenocorticotropic hormone injection has been one of the first therapies used to treat nephrotic syndrome in children6 and was replaced by oral prednisone when it was safely available. Recent description of non–corticosteroid-mediated therapeutic effect recently brought back ACTH analogue to the forefront. Adrenocorticotropic hormone is an agonist for all melanocortin receptors 1 to 5 (MC1-5R). It has been shown that podocytes directly express the melanocortin receptor MC1R. We treated rats with (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Adrenocorticotropic hormone analogue treatment has been shown to reduce proteinuria in a rat nephrotic model of passive Heymann nephritis induced.7 In this model, the specific MC1R agonist MS05 reduced proteinuria by 60% compared with untreated PHN (P < 0.01). On native kidney, a prospective study evaluated ACTH treatment of idiopathic steroid-resistant or steroid-dependent FSGS including 24 patients from 2 centers. Adrenocorticotropic hormone analogue treatment was not homogeneously used but was associated with immunosuppressive agents, such as steroids, mycofenolate mofetil and CNI. Adrenocorticotropic hormone treatment allowed partial remission in 5 (23%) patients, and complete remission in 2 (9%) of them.8 Median estimated glomerular filtration rate did not significantly change. A meta-analysis collected 288 patients treated with ACTH including 56 patients with FSGS and minimal change disease.9 The overall response rate was 50%. Relapse was frequent after ACTH discontinuation (17%). In this meta-analysis, incidence rates of sides effects were calculated with a DerSimonian-Laird random-effects model that take into account interstudy variability. Most frequent adverse effects were edema (incidence rate 0.10), insomnia (0.08), hyperglycemia (0.07), mood swings (0.07), hyperpigmentation (0.06), hyperpigmentation (0.06), hypertension (0.06), and weight gain (0.05). No severe adverse reactions were reported. These data suggest that ACTH gel could be a promising treatment with a good safety profile. However, these study designs included heterogeneous protocol, either natural or synthetic ACTH analog, with diverse doses and time of administration leading to a great variability in adverse effects incidence. No clinical factor was able to predict the patients' clinical response to ACTH. In kidney transplantation setting, Mittal et al10 reported a patient showing a remission under ACTH treatment of a refractory FSGS recurrence. However, no study compared ACTH analogue to oral glucocorticoid in adults with glomerular disease. In this issue, Alhamad et al. reported the first series of recurrent FSGS patient treated by ACTH. A total number of 20 patients with recurrent or de novo FSGS after renal transplantation were retrospectively included. Focal segmental glomerular sclerosis recurrence was observed within the first weeks of transplantation and up to 13 months and was assessed by kidney biopsy in 18 of 20 patients. Patients were considered refractory to conventional therapy including plasma exchange for 15 (75%) patients and rituximab for 10 (50%) of them with a mean proteinuria of 8.6 ± 7.6 g/g. Eighty units of ACTH gel were administered subcutaneously twice a week for at least 6 weeks. Then proteinuria significantly decreased to a mean of 3.3 ± 2.3 g/g. Adrenocorticotropic hormone analogue treatment did not significantly change glomerular filtration rate. A total number of 4 (20%) patients achieved complete remission and 6 (30%) patients a partial remission. However, 8 (40%) patients had allograft failure, including 5 (20%) attributed to FSGS recurrence. Three patients died during follow-up. In this first study including renal transplant recipients, the response rate to ACTH gel was low but proteinuria significantly decreased. The patients' characteristics are heterogenous including recurrent FSGS, de novo onset, various time of recurrence after transplantation and different treatment strategies, highlighting the absence of consensus therapeutic strategies of FSGS recurrence. However, these patients' characteristics are representative of other FSGS recurrence cohort of patients. There is a need for a prospective randomized study with a consensus therapeutic strategy with standardized dose of steroids, CNI, plasma exchange, and rituximab to avoid any confounding factors. Two studies are currently registered on clinicaltrial.gov, 1 recruiting patient for ACTH treatment of FSGS recurrence prevention and 1 prospective study for FSGS recurrence treatment that soon will be recruiting and will hopefully provide significant answers.