Overview of Primary Glomerulonephritidies

Madeleine V. Pahl, M.D., FASN Division of and 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 (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: (gross or microscopic) and/or (< 3g/day) • Acute glomerulonephritis (AGN) • Rapidly progressive (RPGN) • Chronic glomerulonephritis (CGN) • (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 • • 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 excretion and Cr = 2mg/dl. BP 180/98 is on no medication and is HIV, Hep C , 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 ) 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 (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 (, 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, , 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): 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: formation of membrane attack complex (MAC, C5b- C9) • Th2 helper cells appear to play a role • Thrombospodin type-1 domain-containing 7A (THSD7A) transmembrane protein, responsible antigen in 10% of idiopathic cases (Engl J Med. 2014;371(24):2277) • Neutral endopeptidase in rare antenatal form from transplacental transfer of IgG4 (Engl J Med. 2002;346(26):2053) • Other intracellular antigens, to cationic form of bovine serum albumin • Genetic associations Hypothetical mechanistic interpretation of idiopathic MN [Ponticelli and Glassock , cJASN 2013] Primary or Secondary MN? Useful tips

Primary/idiopathic Secondary • Anti PLA2R1 antibodies • Extensive mesangial and • Sensitivity 70-80% subendothelial deposits • Specificity 90-95% • IgG1, IgG2, IgG3 • Now available in US • Strong capillary wall • Co-expression of C1q, C3, IgG, IgM, IgA in PLA2R1 antigen lupus • IgG4 • Significant leukocyte infiltration with cancer Evaluation to rule out malignancy

[Ponticelli and Glassock , cJASN 2013] Membranous: Clinical Course

• Variable, renal survival is 65-85% at 10 yrs, and 60% at 15 yrs, spontaneous remission in 20-30% • Progressive renal failure more likely in: • men, > 50-60 yrs, greatest level of persistent proteinuria, HTN, reduced GFR • associated FSGS, interstitial fibrosis • May recur in renal transplant Membranous GN: Clinical Course Membranous Nephropathy: Treatment • Treatment depends on prognosis, ACEi useful • Low risk of progression: No immunotherapy • Moderate risk: 4-8g proteinuria/day • High risk: > 8g/day and reduced GFR • Relapsing disease • Resistant disease • Anti-coagulants in high risk patients: serum albumin < 2.5g/dl • Several large randomized clinical trials have evaluated the use of steroids (KI 55(Suppl 70): S56, 1999) • Pooled meta-analysis have failed to show any response to steroids alone (JASN 5:1553, 1995) Selection of treatment with

immunosuppressive agents 2011 Initial therapy be started only in patients with NS and with one of the following: • Proteinuria persistently exceeds 4 g/day and remains > 50% of the baseline value, and does not show progressive decline during antihypertensive and antiproteinuric therapy during observation of at least 6 months (1B); OR • the presence of severe, disabling, or life-threatening symptoms related to the nephrotic syndrome (1C); OR • SCr level has risen by 30% or more in 6 -12 months from diagnosis but eGFR is not < 25–30 and this change is not explained by superimposed complications (2C). [Ponticelli and Glassock , cJASN 2013] Membranous GN: Treatment (KI 55(Suppl 70): S56, 1999)

• Cyclophosphamide • 1.5-2.5 mg/kg/day PO for 6-12 mo. With 1-2 mg/kg/day alternate day steroids for 2 mo. Prednisone taper as soon as response evident (KI 32:579, 1987; Clin Nephrol 37:229, 1992) • Chlorambucil • Pulse methylprednisolone 1g IV X 3 days, 0.4 mg/kg/day PO X 27 days. Chlorambucil 0.2 mg/kg/day PO for 28 days repeated x 3 cycles (NEJM 327:599, 1992) • CsA • 4-6 mg/kg/dayin divided doses X 6-12 mo (Level 120-200 ng/ml) May add Prednisone 1-2 mg/kg alternate days, taper as soon as response evident (Clin Nephrol 42:147, 1994; KI 47:1130, 1995) Membranous GN: Treatment

• For those with sustained NS and deteriorating GFR “salvage” regimens of oral cyclophosphamide and steroids may be helpful, but not tested in randomized study • Observational studies in patients with preserved GFR and recurrent disease have reported good outcomes following the administration of Rituximab (Clin J Am Soc Nephrol. 2010;5(12):2188) Membranous GN: Alternative therapies

• Prospective study MMF and prednisolone found to be effective in moderate risk patients (Nephrology (Carlton). 2007;12(6):576 ) but another study shown it to be ineffective (Am J Kidney Dis. 2008;52(4):699) • Synthetic ACTH (Am J Kidney Dis. 2006;47(2):233) • Pentoxifylline (TNF-alpha antagonist) reduced proteinuria in 10 patients (Lancet 357:1672; 2001) • IV IgG (most recent comprehensive review by Ponticelli, Glassock cJASN 2013; June 27 epub) Case #4 (M Pahl)

• 34 yo woman with ESRD due to RPGN and biopsy proven crescenteric GN receives DDRT and develops nephrotic range proteinuria, hematuria and rising Cr 1 year post-transplant. Allograft biopsy reveals dense- deposit disease (DDD) MPGN II

Electron micrograph in dense deposit disease (DDD) showing dense, ribbon-like appearance of subendothelial and intramembranous material (arrow) and narrowing of the capillary lumen due to proliferation of cells (double arrow). Courtesy of Helmut Rennke, MD.

UpToDate® Membranoproliferative glomerulonephritis

• Presents with dysmorphic hematuria, variable proteinuria and renal dysfunction • Occasionally indolent with relatively bland urinary sediment • Hypo-complementemia is common (low C3, +/- low C4 in IC disease) Classification of MPGN

• Traditionally classified as Type I or Type II or Type III based on EM findings but this classification can result in overlap • New classification based on pathogenesis (ID by IF) • Mediated by IC • Complement disorders • Rare causes: ie endothelial injury

Activation of C3 convertase is involved in both complement-mediated and immune-complex- mediated MPGN In DDD C3convertase activity is increased by: • Generation of antibody that stabilizes C3 convertase (C3 nephritic factor) • Loss of functional Bomback, A. S. & Appel, G. B. (2012) Pathogenesis of the C3 factor H activity glomerulopathies and reclassification of MPGN Nat. Rev. Nephrol. doi:10.1038/nrneph.2012.213

DDD • Rare disease that affects children and young adults, • Has been associated with monoclonal gammopathies in older adults • Generally poor renal prognosis • Frequent recurrence in transplant

• Drusen formation in retina

• and partial lipodystrophy Diagnostic tests

• C3, C4, CH50 • C3NeF • Measurement of factor H levels • auto-antibodies directed at Factor H, B • Genetic evaluation of factor H and related genes Treatment of DDD

• Plasmapheresis: • plasma exchange with plasma infusion for factor H defects • plasma exchange with albumin for elevated C3Nef and normal factor H • unsuccessful, pulse steroids used in RPGN presentation • Rituximab • Eculizumab (anti C5)