11/6/2016

Objectives Glomerular Diseases in Primary Care Discuss diagnosis of glomerular diseases

Sadiq Ahmed, MD, FACP, FASN Identify Nephritic and Nephrotic syndromes Associate Professor of Medicine Division of Nephrology Bone & Mineral Review clinical features, diagnosis and Metabolism treatment of glomerular emergency or RPGN University of Kentucky

Glomerulonephritis Microscopic Hematuria

Asymptomatic Microscopic Hematuria More than 2 RBC per HPF on a spun Nephritic Syndrome (3000 r.p.m for 5 minutes) urine Acute glomerulonephritis sediment or some prefers number of RBC more than 10,000/ml of Rapidly progressive glomerulonephritis hemocytometer chamber. Chronic glomerulonephritis

Nephrotic Syndrome

Nephritic Syndrome Microscopic Hematuria

Glomerular origin(Dysmorphic): There is • Collection of findings associated with glomerular inflammation in proteinuria ,serum creatinine may be elevated proximity to endothelial surface with dysmorphic RBC & → Renal referral/work up for GN • Defined by hematuria, presence of dysmorphic RBCs or RBC casts on microscopic examination

Non Glomerular origin(Isomorphic): →Urology • One or more of the following referral/Check upper U.tract by CT for stone, – Mild to moderate proteinuria – Mild to moderate edema neoplasm, cystic disease etc. Consider need for – Hypertension cystoscopy. – Increased creatinine – Oliguria

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Figure 25.7a

Clinical differences : Nephrotic vs Nephritic

Nephrotic syndrome Nephritic syndrome

Proteinuria Gross >3.5GM Moderate < 3GM

Serum Albumin Reduced Normal or mild reduction

Hematuria Absent or trace Marked Bland urine sediment RBC cast /dysmorphic Active urine sediment Edema Marked Moderate

Lipids Marked elevation Minimal elevation /normal

Urine volume Normal /reduced Reduced

Nephrotic Syndrome Nephritic syndrome

Minimal change disease • Post infectious GN FSGS • Lupus Nephritis class II, III,IV Membranous Nephropathy • RPGN Diabetic Nephropathy • Anti‐GBM Amyloidosis • Immune complex crescentic GN • Class V Lupus Nephritis Pauci immune. ANCA + crescentic necrotizing GN • IgA nephritis & HSP • MPGN I,II,III

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Clinical Clues to Glomerular Diseases Tests for Glomerular Diseases

Hematuria, Foamy urine , Elevation of Cr • CBC with diff, Renal panel, UA & Urine Protein and Creatinine • Pulmonary infection / Infiltrate / Hemoptysis Ratio • Hepatitis B, C & HIV infections • C3, C4, Ch50 • Arthralgia • ASO titre • Skin Rash • ANA, Anti Double Stranded DNA • Volume over load / new onset edema • ANCA ( C‐ANCA, P‐ANCA) • New onset Hypertension • Anti GBM Antibodies • Diseases – Endocarditis, Shunt infection, SLE, • Serum Protein Electrophoresis, Serum Protein IF, Free light chain Lymphoproliferative disorders etc assay • IVDU • Hep‐B, C and HIV

RPGN Clinical presentation of RPGN

Clinical condition that evolve with rapidly progressive decline in renal function and • Rapid loss of renal function characterized by an inflammatory process that • Active urinary sediment results in the formation of cellular crescents & • called crescentic glomerulonephritis. Oliguria • Hematuria/Proteinuria This is glomerular emergency.

How Crescents are formed? RPGN

Glomerular crescent formation is an etiologically nonspecific response to glomerular capillary rupture due to acute inflammatory injury

• Rupture of GBM → spillage of inflam. mediators • Neutrophil margination • Karyorrhexis • Thrombosis • Fibrin exudation • Epithelial response

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RPGN:Case Electron microscopy of RPGN

65 YO Wmale presents to the ER with 3 weeks history of arthralgia and fatigue & URI. On exam. BP is 150/80 and there is a petechial rash visible in lower extremities and also 1+ edema. Hb is 9.4gm/dl, Creatinine 5.8mg/dl Urinalysis shows 20‐ 50 RBC/hpf & 1+ protein CxR showed bilateral infiltrate.

3 major Immunopathologic categories RPGN:Case What is the most likely cause of his renal failure? of crescentic GN • Type I A. Anti GBM disease – Anti‐GBM crescentic GN B. Lupus nephritiis • Type II C. Henoch Schoenlein – Immune complex crescentic GN purpura with crescentic • Post infectious, SLE, IgA, MPGN, Fibrillary GN D. Cryoglobulinemia • Type III E. ANCA associated – Pauci‐immune crescentic GN vasculitis – 80% ANCA positive

Crescentic GN and Systemic Vasculitis ANCA test methodology • Iimmunofluroscnce technique 75% of patients with ANCA GN have some sort of – On ethanol fixed neutrophils PR3‐ANCA causes a systemic small vessel vasculitis. GPA,MPA or EGPA charecteristic cytoplasmic granular centrally accentuated immunofluroscence pattern called cANCA while MPO‐ ANCA causes a perinuclear pattern called pANCA 50‐60% patients with Anti GBM disease have • Antigen specific testing pulmonary cappillaritis – Antigen type (PR3 or MPO) is determined through antigen‐ specific methods. More specific • ELISA or capture ELISA Immune complex crescentic GN has the lowest • Bead based multiplex assay frequency of systemic vasculitis. HSP, • Appropriate paring is important for definitive DX Cryoglobulinemic GN etc. – cANCA with PR3‐ANCA & pANCA with MPO‐ANCA

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Differential Dx of ANCA disease C‐ANCA. Cytoplasmic granular centrally P‐ANCA. Perinuclear Imm. fluoroscent accentuated Imm.fluoroscent pattern‐ pattern‐ MPO Cleveland clinic journal of Medicine Supp.3,V 79, Nov.2012 PR3 GPA MPA EGPA

ENT Necrotizing None Allergic Lung Nodule, Cavity, Infiltrate Allergy, Asthma Infiltrate

Kidney ++++ ++++ ++ Nerve ++ +++ ++++ Granuloma +++++ None ++++ Eosinophil None None ++++ Skin ++ ++++ ++++ ANCA 80‐95% PR3 40‐80% MPO 40% MPO

5‐20% MPO 35% PR3 35% PR3

0‐20% negative 0‐20% negative Up to 60% negative

Types of Crescentic GN in consecutive Renal Treatment of ANCA Vasculitis Biopsies in Univ. of North Carolina

• Pulse steroids 1 GM daily for 3 days followed by Prednisone 1 mg / Kg daily

• Cyclophosphamide or Rituximab

• Plasmapheresis • Diffuse Alveolar hemorrhage • Severe Renal failure

RPGN Type I: Goodpasture’s Syndrome RPGN Type I: Goodpasture’s Syndrome

• Anti‐GBM antibody‐induced disease. The anti‐GBM antibodies cross‐ react with pulmonary alveolar • Cells accumulate in Bowman’s space, form crescents. basement membranes to produce the clinical picture of • The Goodpasture antigen is a peptide within the pulmonary hemorrhage noncollagenous portion of the α3‐chain of associated with renal failure. collagen type IV.

• What triggers the formation of these antibodies is unclear

• There is linear deposition of antibodies and complement components along the GBM.

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Frequency of crescents in different types of glomerular Treatment of Good Pastures Syndrome diseases in University of North Carolina. Kidney International, Vol 63 (2003) pp.1164‐1177

Numbers % with any % with >50% Average %of • Plasmapheresis daily ASAP crescents crescents crescents Anti‐GBM 105 97.1 84.8 77 ANCA GN 181 89.5 50.3 49 • Pulse Steroids 1 GM daily for 3 days and then 1 Lupus‐III & IV 784 56.5 12.9 31 mg / Kg daily HSP 31 61.3 9.7 27 IgA 853 32.5 4 21 Post‐infectious 120 33.3 3.3 19 • Cyclophosphamide IV or PO Type I MPGN 307 23.8 4.6 25 Type II MPGN 16 43.8 18.8 48 Fibrillary GN 101 22.8 5 26 Mon. Ig dep. dx 54 5.6 0 13 TMA 251 5.6 0.9 20 Membranous 1092 3.2 0.1 15

RPGN IgA nephropathy Which type of glomerulonephritis usually do not present as RPGN ? Autoimmune systemic disease –kidneys are A. IgA nephritis bystanders B. Lupus nephritis C. Fibrillary GN Defective glycosylation of IgA1 fraction with with D. FSGS galactose deficiency

75% of patients with IgA nephropathy has galactose deficient IgA1 level above 90th percentile

Glomerular and tubular injury by immune complexes containing containing pathogenic IgA1 Watt Rj, Julian BA, New Eng. J Med 2013;368;2402‐2414

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IgA Nephropathy Clinical outcome of IgA nephropathy

• Variable clinical course • In USA IgA nephropathy is the commonest • 96% 20 years renal survival if risk factors are glomerular disease absent • In adults 1 case per 100,000 • Risk factors for dialysis or death are • In children 0.5 case per 100,000 – Urine protein > 1GM • 10 times more common in Japan – Hypertension BP > 140/90 – Severity of the histologic lesion – Reduced renal function at the time of diagnosis • N Engl J Med 2013; 368:2402‐2414

Treatment of IgA Nephropathy Rx of IgA with rapidly declining GFR KDIGO: Kidney Int Suppl 2012;2:S209‐S217

Recommendation: • Steroid + Cyclophosphamide for crescentic IgA • ACEI/ARB if urine protein 0.5 to 1gm/day (>50% glomeruli with crescents) with rapid • 6 month of steroids If urine protein > 1 gm after 3‐6m of ACEI/ARB and GFR > 50 deterioration in GFR • Fish oil • Supportive care if kidney biopsy shows acute BP Target: tubular injury and intratubular erythrocyte casts • <130/80 if urine protein <1 g/day but <125/75 if >1 g/day

Rx of IgA without proven benefit Case: In Hospital

KDIGO: Kidney Int Suppl 2012;2:S209‐S217 49 YO W obese male with DM & HTN is admitted with fever, • Steroids + Cyclophosphamide or Azathioprine, unless chronic diabetic foot ulcer complicated by MRSA osteomyelitis. crescentic IgA with rapid decline in GFR He became hypotensive and dehydrated but now improved with IVFs. He is on vancomycin. He received IV contrast 10 days • Immunosuppressive Rx with GFR of <30 unless ago for a CT scan. crescentic IgA nephropathy with rapid decline in GFR Exam is unremarkable except bandaged Rt foot and bilateral • MMF lower extremities edema. • Antiplatelet agents Labs: Creatinine 2.8 ( was 1.3 6 days ago), Serum albumin 2.9, • Tonsillectomy C3 is low but C4 normal. UA: ++ protein on dip and 23 RBC / HPF

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Case: In Hospital Infection related Glomerulonephritis What is the cause of Renal Failure?

• APIGN A. AKI ‐ ATN from – APSGN( Acute Post Strep GN) infection/sepsis & hypotension – Staph , GNR, Treponema, Salmonella, Brucella, Mycoplasma, Legionella, Borrelia, Bartonella, Coxeella B. Vancomycin Nephrotoxicity. C. Contrast Induced • Current Active Infection Nephropathy – Endocarditis, Shunt infection, Hepatitis C D. Glomerulonephritis

Acute Diffuse Proliferative Glomerulonephritis Acute Diffuse Proliferative Glomerulonephritis • Acute post‐strep GN is the most common cause of this reaction • There is swelling & pattern. proliferation endothelial cells

• This chokes off their blood • Produces nephritic syndrome 2 supply, making the gloms weeks after a resp. or skin infection hypercellular and bloodless with "nephritogenic strain" of group • This explains the oliguria, A, beta‐hemolytic streptococci. edema, and hypertension

• Deposits of circulating • There is deposition of circulating immune complexes fix complement and attract immune complexes which fix neutrophils complement and attract PMN's.

Acute Diffuse Proliferative GN: Post‐strep. GN Outcome Acute Diffuse Proliferative Glomerulonephritis • Children: 95% recover

• Immunofluorescence: coarse • Adults: granular deposits containing – Usually good prognosis. immunoglobulin and complement. – Some develops rapidly progressive disease, chronic renal failure may cause ESRD • Electron microscopy: granules are large, dense, hump‐shaped deposits located subepithelially (i.e., on the epithelial side of the GBM).

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Systemic Lupus Erythematosus Systemic Lupus Erythematosus • The kidney is a frequent target of injury in SLE. • Antinuclear antibody, an antibody to nucleosomal DNA‐ • Mechanism of injury is histone complexes, is very immune complex deposition sensitive but not specific. in mesangium, endothelium & • Anti‐ds (double stranded) DNA glomerular basement is more specific for lupus. This membranes test may correlate with the degree of activity of lupus, in • Other forms of injury may general,and with the level of include a thrombotic process nephritis. involving the glomerular • Antiphospholipid antibody is capillaries & extraglomerular vasculature, thought to be present in 30% of patients with caused by antiphospholipid SLE. This is associated with antibodies. thromboembolic complications.

WHO Classification of Lupus Nephritis Pulmonary‐ Renal Syndrome

Class I • Goodpasture’s disease Minimal or no detectable abnormalities , rare, seen in renal biopsies from less than 5% of SLE patients. • Granulomatous polyangiitis Class II Mesangial lupus glomerulonephritis • Microscopic polyangiitis Class III • SLE Focal proliferative glomerulonephritis Class IV • Cryoglobulinemia Diffuse proliferative glomerulonephritis • ARF with pulmonary edema/embolism/pna Class V Membranous glomerulonephritis None of these patterns are specific for lupus

Thank You For Your Attention

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