Focal Segmental Glomerulosclerosis and the Nephro6c Syndrome Dr. A. Gangji Dr. P. Marge>s Part 1: Clinical
Pa#ent DM 18 year old McMaster student Back pain, severe fa#gue Oct 2006 Leg swelling to ER Nov 2006 Exam 150/90, 3+ edema to abdomen. Bloodwork: crea#nine 82 umol/l Serum albumin 13 g/l Urine 3+ protein, 1+ blood 24 hour urine 22 g/day protein T Chol 19.95, Tri 4.05, LDL 16.47, HDL 1.62
Pa#ent DM: Nephro#c Syndrome Diagnosed with nephro#c syndrome Ini#ated therapy with: Ramipril 10 mg daily, Furosemide 80 mg daily, Prednisone 60 mg daily, Atorvasta#n 20 mg daily Urine protein excre#on unchanged Renal biopsy
24 hour urine (mg/day) 0 Normal 150 Dipstick 2+ Albumin:creatinine (mg/mmol) 2 9 0 1000 trace 3+ 60 2000 1+ 120 180 3500 4+ Nephrotic Range
Nephro#c syndrome Proteinuria (>3.5 g/day) Edema Hypoalbuminemia (<25 g/l) Hypercholesterolemia Hypercoagulable state Hypoalbuminemia Nephro#c range proteinuria
Mechanism of Nephro#c Syndrome
Identification of Nephrotic Syndrome: - edema, hypoalbuminemia, urine protein > 3.5 g daily Non-specific therapies Diagnosis Primary (Idiopathic) Nephrotic Syndrome Secondary Nephrotic Syndrome Focal Segmental Glomerulosclerosis, Membranous Glomerulonephritis, Minimal Change Disease Systemic disease, drugs, infection, malignancy Disease specific therapy
The Nephron and Glomerulus
Primary Nephro#c Syndrome Primary: Membranous MCD FSGS MPGN I, II Other Glomerulopathies (IgA, Fibrillary GN, Immunotactoid GN) Topic III 100 Answer
Nephro#c syndrome: Diagnosis categorized by glomerular lesion Membranous GN (30-35%) Idiopathic (75%) Immune deposits in the GBM Systemic Lupus Erythematosis Drugs d- penicillamine, gold, captopril, NSAID Hepa##s B Malignancy (solid tumor, CLL) Focal Segmental Glomerulosclerosis (30-35%) Idiopathic Gene#c (MHC9?) HIV Drugs (heroin, pamidronate) Obesity
Categorized by glomerular lesion Minimal Change Disease Idiopathic (majority) NSAID, an#bio#cs, Lithium Hodgkin s Lymphoma
Categorized by glomerular lesion Associated with other glomerulonephri#dis MPGN, IgA, PIGN Idiopathic Hepa##s C Streptococcal infec#on
Nephro#c Syndrome: Electron Microscopy Podocyte foot process fusion and epithelial cells are effaced along GBM
Nephro#c syndrome: secondary causes Systemic Disease Diabetes Amyloidosis Systemic Lupus Erythematosis Infec#on HIV Hepa##s B or C Drugs NSAID Gold, d- penicillamine Pamidronate Captopril Lithium Malignancy Myeloma Lymphoma Solid tumor Clinical Clues: abrupt onset, severe symptoms, younger age = primary
Work up History Symptoms to suggest systemic illness, malignancy Risk factors for HIV, viral hepa##s Recent changes in drug regimen Blood work: Fas#ng glucose, crea#nine, electrolytes, liver enzymes, cholesterol 24 hour urine, serum and urine protein electrophoresis ANA, an#- dsdna, C3, C4 Hepa##s B, C, and HIV Chest xray Refer to nephrologist for considera#on of renal biopsy
Complica#ons of nephro#c syndrome Acute renal failure Secondary to volume contrac#on, ATN (avoid NSAID) Therapy (cyclosporin) Renal vein thrombosis Thromboembolism 8 fold increase risk Deep leg vein or renal vein Infec#on Pneumococcus, encapsulated organisms Hypercholesterolemia Osteoporosis Vit D deficiency, steroids Malnutri#on
Treatment Issues non- specific issues Edema (Volume) control Na restric#on ACEi / ARB Loop diure#cs Thromboembolism Warfarin for albumin < 20 g/l Infec#on Vaccina#on Hypercholesterolemia Sta#n therapy Osteoporosis Vit D replacement, bisphosphonate when on steroids Malnutri#on Normal protein diet
Pa#ent DM: Nephro#c Syndrome Nephro#c syndrome: Ramipril 10 mg daily, Furosemide 80 mg daily, Prednisone 60 mg daily, Atorvasta#n 20 mg daily Renal biopsy shows FSGS Progressive weight gain, anasarca Started cyclosporine Plasmapheresis, mycophenolate Ini#ated dialysis 6 months aler symptom onset First renal transplant 1 year later failed Remains on hemodialysis with plans for second renal transplant
Focal Segmental Glomerulosclerosis FSGS accounts for 20% of nephro#c syndrome in children and 40% in adults Most common primary glomerular disease causing end stage renal disease 4% of dialysis pts in US have FSGS Group of diseases with common pathology involving the glomerular podocytes 80% of FSGS is primary or idiopathic Associated with minimal change disease D Agati, NEJM 2011
Focal Segmental Glomerulosclerosis D Agati, NEJM 2011
FSGS Circula#ng Factor As of yet uniden#fied circula#ng permeability factor explains idiopathic FSGS FSGS can recur within hours aler renal transplanta#on Disease can be modulated by immunoabsorp#on or plasmapheresis Serum from pa#ents with idiopathic FSGS can induce podocyte injury in rats. Poten#al candidates: cardiotropin- like cytokine 1, soluble urokinase receptor
Prognosis Remuzzi et al, JCI 2006
D Agati, NEJM 2011
D Agati, NEJM 2011
Treatment for FSGS: Cyclosporine Cattran et al KI 1999
Treatment of FSGS: Rituximab Remuzzi et al, JCI 2006 Ahmed et al, NDT 2008
Recurrent FSGS Post Renal Transplant Risk of recurrence varies between 20 to 50% given heterogenous group of condi#ons Familial and slow progressing forms are at lower risk of recurrence An aggressive ini#al course in associa#on with heavy proteinuria leading to kidney failure with mesangial prolifera#on on biopsy have a high risk of recurrence Recurrence can be immediate Therapeu#c op#ons: Plasmapheresis, steroids, Cyclosporine or Tacrolimus, Rituximab
Summary - FSGS Common cause of nephro#c syndrome Represents a group of diseases with similar histology Idiopathic (circula#ng permeability factor) Gene#c Secondary Infec#on, drug, adap#ve Renal prognosis is poor in idiopathic FSGS Treatment involves non- specific therapies, high dose steroids, calcineurin inhibitor