docPathology of Membranous Glomerulonephritis – an Update
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Pathology of Membranous Glomerulonephritis – an Update
Membranous Glomerulopathy Update – 2015 Patrick D. Walker, M.D. Nephropath Little Rock, Arkansas USA First, where have we been… • From the beginning, humans have been naming things • We Produce Classification Schemes • First we separated ‘Injury’ from ‘Disease’ – Then sub-classified each Then – We ‘Ascribed Cause’ • Injuries were classified leading to Rx – Poultice for wounds – Setting and clay casts for broken bones – And on… • Diseases were caused by Evil – Evil spirits or Evil gods 5000 years from 1st written records of disease/injury/Dx/Rx • We have learned more about – Anatomy – Disease – Diagnosis and Prognosis – Treatment • But we still Classify Modern era – Glomerular Disease • 1840 – Bright’s Disease • 1950 – Acute, Subacute and Chronic Glomerulonephritis • 1960 – Minimal Change sorted from Membranous Glomerulopathy Modern Era – What happened • The widespread application of light, immunofluorescence and electron microscopy to the renal biopsy leads to • An explosion of understanding of the diverse subtypes of renal disease Renal Pathology • 1800’s and 1900’s Technology • Still Needed in 2015 Lister 1830 IF developed in 1940’s Ruska and Knoll Fighting with the original Electron Microscope c 1930 The Renal Biopsy – Clinical Use • Medical Renal Disease – Cause Not Clinically Apparent – Glomerular Diseases – Renal Transplant Dysfunction – Acute Kidney Injury Required in Glomerular Disease • Glomerular syndromes are not specific for an individual glomerular disease • Correct diagnosis requires – Renal pathologist and Renal pathology laboratory – Interaction between Nephrologist and Pathologist Classification • We are still discovering new patterns of disease • So we are still ‘Naming’ Things’! • We will discuss where membranous glomerulopathy fits in, but first… Classification Schemes • FSGS • Vasculitides • Lupus • MPGN • HSP • Diabetic Nephropathy • Membranous GN • C3G • Banff for Transplants • More Classification Schemes • FSGS • Vasculitides • Lupus • MPGN • HSP • Diabetic Nephropathy • Membranous GN • C3GN • Banff for Transplants • More Classification Schemes • • • • • FSGS Lupus HSP Membranous GN Banff for Transplants • • • • • Vasculitides MPGN Diabetic Nephropathy C3GN More Eminence-Based NOT Evidence-Based Revolution • Move to apply ‘Root Cause’ to the classifications – Increase diagnostic, prognostic and therapeutic accuracy This is a whole other talk! • Genomics • mRNA • Proteomics • Blood and Urine Markers Huge changes are coming • And it is exciting to be involved in this work • But, again, back to the topic at hand • Membranous Glomerulopathy 37 F with Proteinuria History • 37 F with lower extremity edema • Weight gain of 6 Kg (13 lbs) over 4 months • No other symptoms Physical Examination • Vitals: Ht: 165 cm (5’ 5”) Wt: 61 Kg (135 lbs) – BP 104/68, P 73 • Only positive, 1+ lower extremity edema Laboratory • Creatinine 0.7 mg/dl • U/A 3+ Protein, 1+ Blood – U P/C = 4.1 • Albumin 5.2 g/dl Laboratory • Serologies Negative – ANA, Hepatitis B & C, – SPEP/UPEP Negative for Monoclonal Spike – ANCA Pending • C3 and C4 WNL Clinical Differential Diagnosis Clinical Differential Diagnosis • Idiopathic Nephrotic Syndrome – Membranous Glomerulopathy – Focal segmental Glomerulosclerosis – Minimal Change Disease • Secondary – Lupus – Amyloid – A Host of others A Renal Biopsy was Performed IgG IgG C3 Kappa Lambda Diagnosis • Membranous Glomerulopathy • Interstitial Fibrosis, Very Mild Membranous Glomerulopathy • 2nd most common cause of idiopathic nephrotic syndrome in adults – FSGS is first in USA, India and likely everywhere • Development of nephrotic syndrome over weeks to months • May be primary or secondary Primary v Secondary MG • Very important to distinguish primary and secondary – given the vastly different implications for Work Up! Conditions Associated with Membranous Glomerulopathy Infections Hepatits B Hepatitis C Hydatid disease Parasitic disease Streptococcal infections Syphilis Drugs Bucillamine Captopril Formaldehyde Gold Lithium 2-Mercaptoproprionly glycine Mercury NSAID Penicillamine Trimethadione Autoimmune Disease ANCA-positive crescentic GN Anti-GBM disease Autoimmune enteropathy Primary biliary cirrhosis Chronic demyelinating radiculopathy Chronic thyroiditis Cryoglobulinemia Graves disease Hashimoto disease Lupus-like syndromes Mixed connective tissue disease Renal tubular antigen Renal tubular dysfunction Rheumatoid arthritis Sjögren's’s syndrome Systemic lupus erythematosus Others Allogeneic stem cell transplant Autosomal dominant polycystic kidney disease Glomerular cystic disease Polyarteritis nodosa Renal vein thrombosis Sarcoid Sickle Cell Trait Neoplasms Carcinoma Melanoma Wilm’s tumor CLL Hodgkin’s disease Non-Hodgkin’s lymphoma Modified from Heptinstall’s Pathology of the Kidney and AFIP Non-Neoplastic Kidney Disease Distinguishing Primary from Secondary • Historical use of the renal biopsy for clues – Mesangial deposits – IgG subtypes – Multiple Ig’s on immunofluorescence • There is an extreme paucity of data supporting any of these!!! Primary v Secondary MG • So the hunt for a true ‘root cause’ for membranous has been going on for years • Major Breakthrough in 2009 PLA2r in Membranous Glomerulopathy • PLA2r = Phospholipase A2 Receptor as a Target Antigen in MG 2009 PLA2r in Membranous Glomerulopathy Primary MG – PLA2r antibodies in 26/37 cases Secondary MG – (6 SLE and 2 HBV) all negative PLA2r in Membranous Glomerulopathy • Serum antibodies against PLA2r in 26/37 cases of PRIMARY MG – that is 70% • All 8 cases of Secondary MG were negative for serum antibodies against PLA2r • Main focus was on antibodies in SERUM What about PLA2r in renal bxs? • Chris Larsen, one of our renal pathologists at Nephropath, took on this challenge • He demonstrated that the renal biopsy was as sensitive and specific as serum PLA2r in Renal Biopsies PLA2r Positive PLA2r Negative PLA2r in Membranous Glomerulopathy • What is going on? – Marked increased in PLA2r on the surface of podocytes? – IF is too insensitive to detect PLA2r in normal glomeruli PLA2r in Membranous Glomerulopathy • What is going on? – There must also be some change in the PLA2r since there are Anti-PLA2r antibodies in serum PLA2r in Membranous Glomerulopathy • Diagnostic Utility – Determine if MG is due to anti-PLA2r antibodies using serum and/or the renal biopsy – If present, can be used to monitor treatment and progression PLA2r in Membranous Glomerulopathy • Diagnostic Utility – Only rarely are secondary causes found and these are likely unrelated to the presence of primary membranous – This limits the need for extensive screening Membranous Glomerulopathy • Other known causes of primary MG • Recall, only 70% of know primary MG is due to anti-PLA2r antibodies Membranous Glomerulopathy • Anti-Neutral Endopeptidase – The human equivalent of rat megalin – The basis of Heymann nephritis in rats Membranous Glomerulopathy • Newborn had nephrotic syndrome and AKI • Detailed study revealed the presence of – Anti-Neutral Endopeptidase (NEP) antibodies Membranous Glomerulopathy • Anti-NEP antibodies were then found in the mother – Mother was deficient in NEP (no phenotypic changes) • Had a miscarriage 2 months prior to term delivery – Developed antibodies after the miscarriage Membranous Glomerulopathy • Trans-placental transfer of the Anti-NEP antibodies occurred • The Anti-NEP antibodies cleared in the baby after 40 days • 1st report of a target podocyte antigen in MG occurring in rare inherited disorder Membranous Glomerulopathy • Anti-Bovine Serum Antibodies in children with MG – Rare association – Newborns develop antibodies against altered BSA • Alterations due to ??? – Develop MG Membranous Glomerulopathy • Thrombospondin Type 1, Domain Containing 7A – THSD7A Antibodies to THSD7A • Accounts for 10% of Primary MG – Localized to podocytes – N-glycosylated – Disease activity correlates with antibody levels – Can be detected in renal biopsies Membranous Glomerulopathy • The cause of 80% of Primary MG is now known, so they are no longer primary or idiopathic • Multiple rare causes Membranous Glomerulopathy • Fifty years after membranous glomerulopathy was separated from minimal change disease… • We have moved from a name (classification) to Root Cause • From here, we are better able to produce targeted therapy Thank you
