Overview of Primary Glomerulonephritidies Madeleine V. Pahl, M.D., FASN Division of Nephrology and Hypertension University of California, Irvine Objectives • To define common primary glomerular disorders • To discuss involved pathophysiology • To review their clinical presentation • To review clinical course and therapy Definition (R. J. Glassock) • A disease where the sole organ involved is the kidney (the glomeruli) • Clinical manifestations due to the consequences or pathophysiologic derangements that resulted in glomerular damage • In contrast secondary disorders have manifestations due to systemic disease and glomerular injury Presentation: Clinical Syndromes • Asymptomatic: hematuria (gross or microscopic) and/or proteinuria (< 3g/day) • Acute glomerulonephritis (AGN) • Rapidly progressive glomerulonephritis (RPGN) • Chronic glomerulonephritis (CGN) • Nephrotic Syndrome (NS) Clinical Syndromes: AGN • Abrupt onset of variable degrees of hematuria, proteinuria, reduced GFR, sodium and fluid retention, HTN and oliguria • Tendency to spontaneous recovery • Association with bacterial infection Clinical Syndromes: RPGN • More insidious onset, not abrupt • Dominated by progressive loss of GFR and oliguria • Little tendency for spontaneous recovery • Classification and terminology of this group of disorders (Type I, II, II) Clinical Syndromes: CGN • Clinical expression of a wide variety of glomerular diseases • Vague, all inclusive term refers to progressive reduction in GFR • Varying degrees of hematuria, proteinuria, HTN • Course may be protracted but usually relentless Clinical Syndromes: NS • Heavy proteinuria (> 3-3.5g/day ) • Reduced serum albumin • Edema • HTN • Hyperlipidemia • Lipiduria Pathology • Minimal change • Focal and segmental glomerulosclerosis • Proliferative GN • Pure mesangial proliferative • Endocapillary proliferative • Extra-capillary proliferative (crescentic) • Membrano-proliferative • Membranous GN • Fibrillary/ Immunotactoid GN, Collageno-fibrotic GN, Lipoprotein GN (deposits of Apo E Nephron 83: 193, 1999) It’s nephrotic syndrome It’s membranous GN It’s It’s cancer idiopathic related It’s SLE It’s drug related Normal Glomerular Histology From tutorial: J. Charles Jennette, M.D. Minimal Change Disease UpToDate® MPGN: I UpToDate® Common Primary Glomerulonephritidies • Minimal Change Disease • Focal Segmental Glomerulosclerosis (FSGS) • IgA Nephropathy (Bergèr’s Disease) • Membranoproliferative GN (Types I, II, III) • Membranous GN Case #1 (R. J. Glassock) • 32 yo Hispanic male develops edema and HTN. Has 22g/day urinary protein excretion and Cr = 2mg/dl. BP 180/98 is on no medication and is HIV, Hep C antibody, HBSAg negative. Focal Segmental Glomerulosclerosis • Incidence among all biopsied patients rising, up to 25% of all adults • Most common pattern among African Americans, some secondary forms more common in whites (obesity and hereditary) • Children usually present with NS, adults with asymptomatic proteinuria UpToDate® FSGS UpToDate® FSGS: Histopathologic Variants • Glomerular “tip” lesion: • epithelial cell proliferation and sclerosis in segment adjacent to origin of proximal tubule, • common in whites with heavier proteinuria, preserved GFR, good response to treatment and outcome • “Collapsing/malignant” variant: • global collapse of capillary loops with visceral epithelial cell proliferation (similar to HIV), • Some think hypercellular variant is a type of collapsing FSGC • common in AA with massive proteinuria, worse prognosis • Perihilar variant : • frequently seen with secondary hyperfiltration • Obesity: • fewer glomeruli with FSGS but remaining with glomerulomegally. FSGS-Pathophysiology • Increased circulating levels of soluble urokinase receptor (suPAR) may be a common causative factor (Nat Med. 2011;17(8):952) • Controversial role of Parvovirus B-19 (KI 59:2126, 2001) • Evidence for hyperfiltration: Glomerulomegally and obesity, sleep apnea, or remnant kidney • Genetic Disease: NPHS1 or 2 (nephrin) , alpha actinin 4, TRPC-6 (calcium permeable cation channels) , INF-2 (formin family of actin regulating proteins) Myo1-E (non-muscle myosin) • Genetic Defect: role of MYH9 or APOL1 in African Americans (Nat Genetics. 2008 Oct;40(10):1185-92; Science. 2010 Aug 13;329(5993):841-5) FSGS: Clinical Course • Tendency for progressive renal failure, ESRD in 5-20 yrs • Factors associated with progression: • magnitude of proteinuria, higher serum Cr, • AA ethnicity, response to corticosteroids, • degree of sclerosis, TI damage, “collapsing” variety • Recurrence in allograft in up to 30%. Treatment with plasmapheresis (Clin Nephrol 56:271, 2001) and Rituximab (Transplantation. 2009 Aug 15;88(3):417-20) FSGS: Primary vs. Secondary • Clinical: primary commonly Obesity Idiopathic p presents with acute/subacute Age 44 32 < 0.001 symptomatic NS vs. Cr 1.55 1.96 NS progressive increase in NS (%) 7 54 < 0.001 proteinuria, less edema Proteinuria 4.24 6.89 < 0.004 • Pathology: foot process (g/day) fusion greater in idiopathic disease Foot 41 75 < 0.001 process fusion (%) Kidney Int. 2001 Apr;59(4):1498 FSGS: Treatment • Prednisone 0.5-2.0 mg/kg/day. Total duration of 6 month before declaring pt steroid resistant, then alternate day. Complete and partial response rate 50-60% ( JASN 9:1333, 1998) • Cytotoxic therapy (cyclophosphamide, chlorambucil, MMF) may be useful but not proven (KI 55(S70): S26, 1999). • CsA at 5 mg/kg/day may be effective, relapses common, long term use may be required (KI 55(S70): S26, 1999). • Plasmapheresis in transplant recurrence • Rituximab (Nat Rev Nephrol 2013 9(3):154 Case #2 • 29 yr old Asian man admits to episodes of dark urine associated with mild flank pain. BP 146/90, Urine analysis reveals significant hematuria, protein excretion 1.5 g/day serum Cr = 1.5 IgA Nephropathy • First described in the late 60’s by Bergèr (J Urol Nephrol 74:694, 1968) • Most common GN worldwide, Japan 50% of all primary GN’s, US prevalence 10-15% • Rare in AA, common in Southwest American Indians • Familial form in Kentucky and Italy linked to genetic locus at 6q22-23 (Nat Genet 26:354, 2000) • Presenting symptoms: 40-50% with gross hematuria, 30-40% microscopic hematuria, < 10% with AGN, or NS (?minimal change) • Recurrence after transplant UpToDate® IgA UpToDate® IgA: Pathophysiology (NephSAP JASN suppl 1(1):July 2002) • Deposition of IgA1 but not IgA2 with IgG and C3 in mesangial extracellelular space, • complement activation in-situ, cytokines, chemokines and growth factor activaton • Origin of IgA1 is bone marrow/lymphoid plasma cells (?stem cell disease) • Pt’s overproduce IgA1 in response to ubiquitous antigens (food, bacteria, viruses) • IgA1 is under-galactosylated: • binds to mesangium, self-aggregates into polymeric molecules, provokes autoimmunity with IgG-antiIgA1 complexes, prevents efficient removal by Kupfer cells IgA: Clinical Course • Variable course: • complete remissions reported in up to 23%, most follow benign course, • those that show progression usually take many years (1-3 ml/yr, in NS 9 ml/yr KI 40:1050, 1991) • Australia 41% of ESRD cases are due to IgA • Can develop AKI from ATN following macroscopic hematuria, crescentic GN Determinants of Progression • Oxford classification (mesangial hypercellularity, segmental sclerosis, endocapillary hypercellularity, TA/IF) KI 2011; 80(3): 310) • Renal Risk Score: get points HTN, protein excretion > 1g, global optical pathology score (GOS) to predict risk of death or dialysis at 10 and 20 yrs (JASN 2011; 22(4):752) • Poorly galactosylated IgA1 levels (JASN; 2012 23(9): 1579) Biopsy Proven IgA: Treatment (KI 55(Suppl 70): S56, 1999) BP should be proteinuria controlled with ACEi < 1g 1-3 g > 3g observation GFR GFR nl Renal Insufficiency > 70 ml/min < 70 Fish Oils observation Fish Oils Prednisone IgA: Treatment of Rapidly Progressive Course (KI 55(Suppl 70): S56, 1999) Re-biopsy ATN Crescenteric ?Pulse steroids Dialysis Plasmapheresis Immunosuppressors IgA: Treatment of Macroscopic Hematuria (KI 55(Suppl 70): S56, 1999) Monitor kidney function Stable Recurrent with tonsillitis Deterioration observation Tonsillectomy Consider re-biopsy Treat according to findings Case #3 (R. J. Glassock) • 65 yr old man develops NS. Noticed edema 3 months ago, now severe. Admits to occasional cough and mild intermittent chest pain and SOB. Urine has 20 mg protein/mg Cr, serum Cr = 1.9 mg/dl. Membranous Glomerulonephropathy • Characterized by proteinuria, 75% NS and normal or reduced GFR • Common in adults > 40, represents 40% of NS in adults • Commonly presents with insidious proteinuria, often severe, may selective or non-selective • Thrombotic complications, including RVT incidence of 5-35% MAJOR CAUSES OF MEMBRANOUS GN Idiopathic (75% in adults) Anti-PLA2R antibody SLE WHO class V Drugs: penicillamine bucillamine gold Anti-TNF NSAID Troponin (Thiola) captopril Infections: Hep C (rare) syphillis malaria Malignancy (5-20% > 65 yrs old) Renal cell, gastric, colonic Hematopoetic cell transplant GVHD Kidney transplant De-novo vs recurrence Sarcoid rare IgG4-related disease Rare, major renal form is TI nephritis Membranous GN UpToDate® Membranous: Pathophysiology • M-type phospholipase A2 receptor (PLA2R): podocytes transmembrane receptor, antigen in idiopathic MN (Engl J Med. 2009;361(1):11) • Association with HLA-DQA1 allele, may facilitate autoimmune response to PLA2R1, presence of PLA2R1 polymorphism, or production of hypogalactosylated IgG4 anti-PLA2R1 that activates mannan C’ pathway • Role of external/virus stimuli?? • Injury is C’-dependent: