cosyntropin and Glomerulonephritis--Membranous

The melanocortin system is a neuroimmunoendocrine hormone system that constitutes the fulcrum in the homeostatic control of a diverse array of physiological functions, including melanogenesis, inflammation, immunomodulation, adrenocortical steroidogenesis, hemodynamics, natriuresis, energy homeostasis, sexual function, and exocrine secretion. The kidney is a quintessential effector organ of the melanocortin hormone system with melanocortin receptors abundantly expressed by multiple kidney parenchymal cells, including podocytes, mesangial cells, glomerular endothelial cells, and renal tubular cells. Converging evidence unequivocally demonstrates that the melanocortin-based therapy using the melanocortin peptide adrenocorticotropic hormone (ACTH) is prominently effective in inducing remission of steroid-resistant nephrotic syndrome caused by various glomerular diseases, including membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis, suggesting a steroidogenic-independent mechanism. Mechanistically, ACTH and other synthetic melanocortin analogues possess potent proteinuria-reducing and renoprotective activities that could be attributable to direct protection of glomerular cells and systemic immunomodulation. Thus, leveraging melanocortin signaling pathways using ACTH or novel synthetic melanocortin analogues represents a promising and pragmatic therapeutic strategy for glomerular diseases. This review article introduces the biophysiology of the melanocortin hormone system with an emphasis on the kidney as a target organ, discusses the existing data on melanocortin therapy for glomerular diseases, and elucidates the potential mechanisms of action.

Topics: Adrenocorticotropic Hormone; alpha-MSH; Cosyntropin; Endothelial Cells; Glomerulonephritis; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hormones; Humans; Kidney; Kidney Glomerulus; Melanocortins; Mesangial Cells; Nephrosis, Lipoid; Nephrotic Syndrome; Podocytes; Receptors, Melanocortin; Signal Transduction

New therapeutic agents are warranted in idiopathic membranous nephropathy. Synthetic ACTH may be advantageous with reported remission rates up to 85% and few side effects. We conducted a prospective open label cohort study from 2008 till 2010 (NCT00694863). We prospectively selected patients with idiopathic membranous nephropathy and high risk for progression (defined as βeta-2-microglobulin (β2m) excretion of >500 ng/min). For comparison, we selected matched historical controls treated with cyclophosphamide. The prospectively selected patients received intramuscular injections of synthetic ACTH during 9 months (maximal dose 1 mg twice a week). The primary endpoints concerned the feasibility and incidence of remissions as a primary event. Secondary endpoints included side effects of treatment and the incidence of remissions and relapses at long-term follow-up. Twenty patients (15 men) were included (age 54±14 years, serum creatinine 104 μmol/l [IQR 90–113], urine protein:creatinine ratio 8.7 g/10 mmol creatinine [IQR 4.3–11.1]). Seventeen patients (85%) completed treatment. 97% of injections were administered correctly. Cumulative remission rate was 55% (complete remission in 4 patients, partial remission 7 patients). In a group of historical controls treated with cyclophosphamide and steroids, 19 of 20 patients (95%) developed a remission (complete remission in 13 patients, partial remission in 6 patients) (p<0.01). The main limitation of our study is its small size and the use of a historical control group. We show that treatment with intramuscular injections of synthetic ACTH is feasible. Our data suggest that synthetic ACTH is less effective than cyclophosphamide in inducing a remission in high risk patients with idiopathic membranous nephropathy. The use of synthetic ACTH was also associated with many adverse events. Therefore, we advise against synthetic ACTH as standard treatment in membranous nephropathy.

Topics: Adult; Cosyntropin; Cyclophosphamide; Edema; Feasibility Studies; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Pilot Projects; Prospective Studies; Recurrence; Remission Induction; Risk Factors; Sleep Wake Disorders; Treatment Outcome

In patients with idiopathic membranous nephropathy (IMN), immunosuppressive therapy is usually considered when severe nephrotic syndrome or risk for progressive renal failure exist. Recently, several studies showing beneficial effects of synthetic adrenocorticotropic hormone (ACTH) under such circumstances have been published. The objective of the present case series was to evaluate long-term ACTH effects on proteinuria and renal function.. Four patients with biopsy-proven membranous nephropathy and nephrotic syndrome were enrolled (median age 50 years (range 38 - 61), median GFR 39.5 ml/min (range 20 - 62), median proteinuria 9.6 g/d (range 6.0 - 20.0). Prior immunosuppressive treatment regimens included steroids, cyclosporine A, cyclophosphamide, mycophenolate mofetil or azathioprine. The patients received a synthetic ACTH analogue intramuscularly for a median duration of 8 months (range 3 - 24). ACTH dosage was adjusted according to side effects between 0.25 and 2.25 mg/week. Follow-up lasted between 24 and 82 months after therapy initiation.. All 4 patients exhibited partial (n = 2) or complete (n = 2) remissions of their nephrotic syndrome within the first year. After discontinuation of ACTH therapy, proteinuria remained low in 3 of 4 cases, whereas 1 patient exhibited undulating proteinuria. Glomerular function (as assessed by glomerular filtration rate, GFR) was maintained in all patients. Side effects were minor and included weight gain, elevated blood pressure and hyperglycemia.. In all 4 cases with IMN, ACTH treatment induced a lasting disease remission with relatively few side effects.

Topics: Adult; Cosyntropin; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Hormones; Humans; Male; Middle Aged; Proteinuria; Remission Induction

Topics: Aged; Cosyntropin; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Nephrotic Syndrome