Synthetic ACTH for Treatment of Glomerular Diseases: A Case Series

Rationale: Synthetic adrenocorticotropic hormone (Tetracosactide) has been used in the treatment of refractory glomerular diseases. Literature surrounding the use of this medication is limited to small case series and there is conflicting data on the rate of adverse events associated with this medication. Presenting concerns of the patient: Glomerulonephritis not in remission after at least 6 months of treatment with conservative care. Stable doses of concurrent immunosuppression were permitted. Diagnoses: Membranous nephropathy, IgA nephropathy, minimal change disease, and focal and segmental glomerulosclerosis. Intervention: Intramuscular synthetic adrenocorticotropic hormone (Tetracosactide, Synacthen Depot) with doses of either 1 mg weekly or 1 mg twice weekly. Outcomes: Five of 12 patients had at least a partial remission with Tetracosactide. Median time to response was 6 months for responders. Five of the 12 patients had adverse events documented, 2 of which led to treatment discontinuation. No patients with focal and segmental glomerulosclerosis responded to treatment. Lessons Learned: Higher rate of adverse events than previously reported with synthetic adrenocorticotropic hormone and uncertain treatment efficacy.

MO1028EFFECTIVENESS AND KIDNEY PROGNOSIS IN THE TREATMENT OF CORTICORRESISTANT NEPHROTIC SYNDROME IN PEDIATRICS

Background and Aims To report the response to different treatments and the renal prognosis in a cohort of patients with corticosteroid-resistant nephrotic syndrome (CRNS). Method Retrospective observational study in patients with CRNS. For this, the results of the histology, the different treatment guidelines used in each case and the evolution of renal function were collected, determining the results in terms of remission and renal survival in the different groups. Results Of the initial cohort of 37 patients, 33 were included, excluding 4 patients with Finnish-type genetic CRNS. The mean age at diagnosis was 6.1 years. 54.5% were women. Regarding the initial biopsy, 45.5% corresponded to minimal changes (15 patients), 27.3% (9) focal and segmental glomerulosclerosis, 15.1% (5) diffuse mesangial proliferation and 12.1% (4) others. The mean follow-up was 53 months (3-115 months). 27 patients (84.4%) received cyclosporine (CyA), 66.7% (18) of them presented complete remission and 22.2% (6) partial response. Of the patients in complete remission, 33% had at least one relapse after 17 months of treatment (7–27 months). Rituximab was administered in 12 patients (37.5%), of which 7 had not previously responded to immunosuppressants. 100% of frequent relapsers presented complete remission after administration of Rituximab, although 3 had subsequent relapses (60%) after 21 months of treatment (12-34 months). 57% of the patients who did not respond to immunosuppressants did not respond to Rituximab either, with Ofatumumab allowing complete remission in one of them. When relating the results with the histology, we saw how the remission in minimal changes and diffuse mesangial proliferation was 100% and 80%, respectively, although it was 33.3% in focal and segmental glomerulosclerosis. Similarly, renal failure was more frequent in patients with focal segmental glomerulosclerosis (77.7%). Of the remissions (24; 72.7%), 3 were partial (9.1%) and 6 (18.2%) did not respond to any immunosuppressive treatment, with the need for kidney transplantation in 2 of them (6%) and with 1 deceased due to an infectious cause (3%). Conclusion Histology and, especially, focal and segmental glomerulosclerosis, play a prognostic role in the CRNS with a lower remission rate and a greater deterioration in renal function and the need for associated kidney transplantation.

HBV Hepatitis and Related Renal Nephropathies: Pathogenesis and Treatment

The extrahepatic manifestations of hepatitis B virus (HBV) infection include reactive arthritis, vasculitis (panarteritisnodosa), and primary glomer-ulonephritis (membranous nephropathy, membranoproliferative glomerulonephritis, and, less frequently, IgA nephropathy, focal and segmental glomerulosclerosis, and minimal change disease). No specific histomorphological patterns have been reported in association with HBV infection. The treatment of HBV-related glomerulopathies is essentially antiviral. Peginterferon and nucleos(t)ide drugs are the treatment of choice. Cortico-steroids have been proved to be ineffective (except in panarteritisnodosa), while immunosuppressants can lead to exacerbation of HBV infection.

Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets.

P0288CLINICOPATHOLOGICAL FEATURES OF FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS: STEPS FOR AN ACCURATE CLASSIFICATION - A SINGLE CENTRE CASE SERIES

Background and Aims Focal and segmental glomerulosclerosis (FSGS) is a histological pattern that is defined by the presence of segmental sclerosis of at least one glomerulus in the kidney biopsy. However, the etiological classification of this lesion remains challenging in clinical practice. FSGS can be divided into primary/idiopathic, genetic or secondary. Nowadays here is no biochemical marker that allows clinicians to distinguish between these categories nor a pathognomonic feature associated to a particular subtype of FSGS. Also, genetic testing is not suitable for all patients. Although it is crucial to determine the cause of FSGS, this is not easily done in clinical practice. Herein we present a series of patients with histologic diagnosis of FSGS in which clinical and histological criteria were applied in order to establish the etiologic classification of FSGS. Method A retrospective analysis of 359 patients who performed kidney biopsy from January 2010 to December 2018 was performed. Patients with histological features of FSGS were identified. Clinical, laboratorial and pathological data were collected, including treatment and outcome. Patients were classified as having genetic FSGS if they accomplished at least one of the following: a) nephrotic syndrome resistant to corticosteroids; b) non-nephrotic proteinuria or nephrotic syndrome with normal serum albumin; c) non-nephrotic proteinuria or nephrotic syndrome with focal foot process effacement or d) non-nephrotic proteinuria with diffuse foot process effacement. The remaining patients were classified as secondary FSGS (if they presented a disease known to be associated with FSGS) or primary FSGS. Each group was divided according to treatment with corticoid, other immunosuppressive agents or and RAAS blockage. Renal outcomes were assessed (progression to ESKD). Results A total of 359 kidney biopsies were performed between January 2010 to December 2018, 66 with a histological pattern of FSGS. 65% (N=43) were males, 71% (N=47) were Caucasian and 23% (N=15) were black. 74% (N=49) had past medical history of hypertension, 26% (N=17) diabetes mellitus and 5% (N=3) had HIV. The majority of patients were classified as having secondary FSGS (52%, N=34), 23% (N=15) were classified as primary and as 25% (N=17) genetic/idiopathic. From the genetic group 58.8% (N=10) were treated with corticoid, 12% (N=2) with other IS agents and 71% (N=12) with ACE/ARB. 29% (N=5) evolved to ESKD (median time to dialysis 11 IQR 1-30). In the primary FSGS group 40% (N=6) were treated with corticoid, 7% (N=1) with other IS agents and 80% (N=12) with ACE/ARB. 27% (N=4) evolved to ESKD (median time to dialysis 0 months, IQR 0-33). In the genetic group 59% (N=10) were treated with corticoid, 12% (N=2) with other IS agents and 71%(N=12) with ACE/ARB. 29% (N=5) evolved to ESKD (median time to dialysis 11 months, IQR 1-30). Conclusion FSGS is a very prevalent glomerular disease and its correct etiologic classification aids in better treatment choice. Although its etiology is not straightforward in most of the patients, some clinical and histological characteristics aid in FSGS classification.