Mayo Clinic/ RPS Consensus Report on Classification, Diagnosis, and Reporting of Glomerulonephritis

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1 Mayo Clinic/ RPS Consensus Report on Classification, Diagnosis, and Reporting of Glomerulonephritis Sanjeev Sethi, MD, PhD Department of Laboratory Medicine and Pathology

2 Disclosure Relevant Financial Relationships None Off-Label/Investigational Uses None Learning Objectives Medical Knowledge Patient Care Practice-Based Learning and Improvement

3 Glomerulonephritis Nephrologist Transplant nephrologist Pathologist The elephant that is Glomerulonephritis Hematologist Rheumatologist Infectious disease sp Molecular biologist Complementologist By-Dr. D. Cattran, Toronto

4 What happens in glomerulonephritis (GN) Deposition of injurious elements along the glomerular capillary walls Ig, complement, fibrin Leads to inflammation- proliferative changes Followed by healing/resolving- leads to remodeling of the capillary walls, sclerosis, scarring end stage kidney disease

5 Inflammation leads to patterns of injury: pathologist view point is very pattern-centric Mesangial proliferative glomerulonephritis Diffuse (exudative or endocapillary) proliferative glomerulonephritis Crescentic and necrotizing glomerulonephritis Membranoproliferative glomerulonephritis Sclerosing glomerulonephritis.

6 Normal

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8 Glomerulonephritis Over the last years we have made remarkable progress in understanding the etiology and pathophysiology of glomerulonephritis This is very relevant to the evaluation, management and prognosis of glomerulonephritis Sometimes, this progress and understanding does not spill over into the kidney biopsy pathology report There was a need to come up with a basic consensus document to address this issue

9 What is MPGN? Chronic deposition of debris along the glomerular capillary walls Ig, complement, fibrin Leads to inflammation- proliferative changes Followed by healing/resolving- leads to remodeling of the capillary walls Thus MPGN is a pattern of injury characterized by inflammation and healing

10 Pathology of MPGN Enlarged and hypercellular glomeruli: inflammation Mesangial proliferation and endocapillary proliferation: inflammation or the proliferative phase Thickened capillary walls, cellular interposition, with double contour formation: resolving or membranophase IF: Immunoglobulins, kappa and/or lambda light chains, C3 staining EM: subendothelial deposits, cellular interposition and new basement membrane formation: double contours

11 MPGN MPGN Normal

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13 US Electron Microscopy BC Ep CL End Ep CL NORMAL

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16 MPGN- old classification, based on location of deposits on EM MPGN type I (subendothelial deposits) MPGN type II (DDD) (intramembranous deposits) MPGN type III (subendothelial, intramembranous and subepithelial deposits) MPGN I Primary and Secondary MPGN MPGN III MPGN II (DDD)

17 Patient # 1 Mr. GS is a 47-yr old man with proteinuria, hematuria and renal failure Serum creatinine 4.7 mg/dl, creatinine clearance 14 ml/min, urinary protein 2 gms/24 hours. Urinalysis- Rbcs and few Rbc casts Clinical Syndrome: Nephritic Syndrome Low complement titers

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19 IgM C3 l k

20 Subendothelial deposits Double contour

21 Patient # 2 Mr. SS is a 66 year old man who has a past medical history of urinary abnormalities characterized by nephrotic range proteinuria, microscopic hematuria, and hypertension. He now presents with generalized edema, proteinuria of 6.7 gms/24 hours. Urinary sediment shows numerous RBC s, hyaline and waxy casts. Serum creatinine 1.4 mg/dl. Serologies for ANA, hepatitis, cryo s are negative. Low C3 and C4 levels. Clinical Syndrome: Nephrotic/nephritic syndrome Renal Biopsy was done

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23 C3

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25 Patient # 3: 18 yr old girl, physical during basketball practice revealed hematuria (6-10 rbc s/hpf). 1 week later repeat UA showed 6-10 rbc s/hpf and proteinuria 7 gms/24 hours. Cr 0.7 mg/dl.

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27 Negative IgG, IgM, IgA, kappa and lambda Light chains

28 Patient # 4 61-year old man with monoclonal gammopathy (IgG kappa protein with M spikes ranging from 0.5 to 0.9 g/dl over time), low complement titers (low C3 normal C4), and gross hematuria, few RBC casts. Serum creatinine 1.3 mg/dl Bone marrow 8% plasma cells: MGUS Biopsied in 07 and 09

29 Double contours Mesangial & Endocapillary proliferation

30 C3 Mesangial deposits Negative IgG, IgM, IgA, C1q, kappa and lambda

31 Mesangial deposits Capillary wall deposits: subendothelial and subepithelial deposits

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34 Patient 1, 2 - MPGN type I (subendothelial deposits) Case 3- MPGN type II (DDD) (intramembranous deposits) Case 4- MPGN type III (subendothelial, intramembranous and subepithelial deposits)

35 From the cases shown, it can be clearly seen that based on Immunofluorescence Microscopy- One can have Immune deposits +/- Complement (patients 1 and 2) Or Complement alone (patients 3 and 4)

36 Membranoproliferative Glomerulonephritis Patient 1: MPGN, immune-complex mediated, polyclonal IgM, secondary to Hepatitis C Patient 2: MPGN, immune-complex/ig mediated, secondary to monoclonal IgM kappa Patient 3: MPGN (DDD), complement-mediated, secondary to AP dysfunction, secondary to mutation in Factor H Patient 4: MPGN, complement-mediated, secondary to AP dysfunction, related to anti-factor H antibodies

37 MPGN, complement-mediated Case 3: Dense deposit disease Case 4: C3 glomerulonephritis C3 glomerulopathy Due to alternative pathway of complement dysfunction

38 MPGN a simple classification MPGN type I and III C3 Glomerulopathy Sethi, Fervenza, Seminars of Nephrology, 2011

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40 Thinking about it for 2-3 years, the more I travelled the more I felt the need but Met with Lorraine Racusen and Mark Haas, Mysore, India, Aug 2014 Came back and ran it by Fernando Fervenza. Basically asked him for the money.

41 November 2014, ASN, Philadelphia Called Helmut Rennke Lorraine Racusen and Michael Mengel- Lunch Sundaram Hariharan/Surya Seshan/Neeraja Terry Cook/Ian Roberts Tony Chang/Agnes Fogo/Ingeborg/Charlie Alpers Vivette D Agati/Glen Markowitz Dick Glassock/Jai/Jerry/Dan Cattran The ones that got away- -charles Jennette, Pierre Ronco, Chris Winearls, Brad Rovin.

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44 Two simple questions We need to address the basic classification of GN based on etiology/pathophysiology How do we incorporate this into the pathology report: Logical Sequential Reproducible And most importantly address the key clinical questions

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49 Classification of Glomerulonephritis Pathogenic type Specific Disease entity Pattern of injury: focal or diffuse Scores or class Immune-complex GN** IgA nephropathy, IgA vasculitis, lupus nephritis, infection-related GN fibrillary GN with polyclonal Ig deposits Mesangial, endocapillary, exudative, membrano-, proliferative, necrotizing, crescentic, sclerosing or multiple* -Oxford/MEST scores for IgA nephropathy - ISN/RPS class for lupus nephritis Pauci-immune GN MPO-ANCA GN, PR3-ANCA GN, ANCAnegative GN Necrotizing, crescentic, sclerosing or multiple* Focal, crescentic, mixed or sclerosing class (Berden/ EUVAS class) Anti-GBM GN Anti-GBM GN Necrotizing, crescentic, sclerosing or mixed* Monoclonal Ig GN** Monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, immunotactoid glomerulopathy, fibrillary GN with monoclonal Ig deposits Mesangial, endocapillary, exudative, membrano-, proliferative, necrotizing, crescentic, sclerosing or multiple* C3 glomerulopathy C3 glomerulonephritis, dense deposit disease Mesangial, endocapillary, exudative, membrano-, proliferative, necrotizing, crescentic, sclerosing or multiple*

50 Immune-complex GN IgA nephropathy Infection-related glomerulonephritis Lupus nephritis Fibrillary glomerulonephritis

51 Pauci-immune GN MPO-ANCA GN PR3-ANCA GN ANCA-negative GN

52 Anti-GBM GN

53 Monoclonal Ig GN Proliferative glomerulonephritis with monoclonal Ig deposits Monoclonal Ig deposition disease Immunotactoid and fibrillary glomerulonephritis

54 C3 glomerulopathy C3 glomerulonephritis Dense deposit disease

55 Primary diagnosis Disease entity/pathogenic type Pattern of injury Scores/class/grade Additional features: Clinical modifiers Extent of chronic changes: glomerulosclerosis/ifta/arteriosclerosis

56 Secondary diagnosis- some examples Diabetic nephropathy Thin GBM ATN Interstitial nephritis

57 Some examples.patient # 1 Mr. GS is a 47-yr old man with proteinuria, hematuria and renal failure Serum creatinine 2.7 mg/dl, creatinine clearance 34 ml/min, urinary protein 2 gms/24 hours. Urinalysis- RBCs and few RBC casts History of hepatitis C, low complement titers

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59 IgM C3 l k

60 Subendothelial deposits Double contour

61 What is the primary diagnosis? A. Immune complex GN (hepatitis C/clinical) B. Monoclonal Ig GN C. Pauci-immune (ANCA) GN D. Anti-GBM GN E. C3 glomerulonephritis

62 Diagnosis Primary disease: Immune-complex glomerulonephritis (hepatitis C/clinical) Pattern of injury: Membranoproliferative glomerulonephritis Additional features: with features of cryoglobulinemic glomerulonephritis (hepatitis C/clinical), focal (20%) global glomerulosclerosis, moderate (30%) tubular atrophy and interstitial fibrosis moderate arteriosclerosis and moderate hyaline arteriolosclerosis

63 Patient #2 58-year old man with nephrotic syndrome, hypertension, hyperlipidemia and edema. Serum creatinine 1.6 mg/dl UA RBC/HPF, with RBC casts Urine IFE kappa light chains

64 Kidney Biopsy IgG C3 Kappa Lambda

65 What is the primary diagnosis A. Immune complex GN B. Proliferative GN with monoclonal deposits C. Pauci-immune (ANCA) GN D. Anti-GBM GN E. C3 glomerulonephritis

66 Diagnosis Primary disease: Proliferative glomerulonephritis with monoclonal Ig deposits Pattern of injury: Membranoproliferative glomerulonephritis Additional features: focal global glomerulosclerosis (30%), moderate (40%) tubular atrophy and interstitial fibrosis, moderate arteriosclerosis and moderate hyaline arteriolosclerosis Ancillary study: IgG subtyping reveals IgG3 subclass, negative for IgG1, IgG2 and IgG4

67 Patient # 3 61-year old man with monoclonal gammopathy (IgG kappa protein with M spikes ranging from 0.5 to 0.9 g/dl over time), low complement titers (low C3 normal C4), and gross hematuria, few RBC casts. Serum creatinine 1.3 mg/dl Bone marrow 8% plasma cells: MGUS Biopsied in 07 and 09

68 Double contours Mesangial & Endocapillary proliferation

69 C3 Mesangial deposits Negative IgG, IgM, IgA, C1q, kappa and lambda

70 Mesangial deposits Capillary wall deposits: subendothelial and subepithelial deposits

71 What is the primary diagnosis? A. Immune complex GN B. Monoclonal Ig GN C. Pauci-immune (ANCA) GN D. Anti-GBM GN E. C3 glomerulonephritis

72 Diagnosis Primary disease: C3 glomerulonephritis Pattern of injury: Membranoproliferative glomerulonephritis Additional features: Focal (20%) global glomerulosclerosis, mild (20%) tubular atrophy and interstitial fibrosis, mild arteriosclerosis and moderate hyaline arteriolosclerosis

73 Patient # 4 A 68-year-old woman presents with acute renal failure, hematuria, proteinuria, and pulmonary infiltrates. Serum creatinine of 3.8 mg/dl. Hemoglobin is low at 5.8. The patient has positive MPO/pANCA and ANA titers. Remaining serological evaluation is negative Urine analysis shows numerous red blood cells and few RBC casts

74 Negative IF and EM studies

75 What is the primary diagnosis? A. Immune complex GN (hepatitis C/clinical) B. Monoclonal Ig GN C. Pauci-immune (ANCA) GN D. Anti-GBM GN E. C3 glomerulonephritis

76 ANCA GN Kidney, needle biopsy: Primary diagnosis: MPO-ANCA glomerulonephritis (MPO/clinical) Pattern of injury: necrotizing and crescentic glomerulonephritis Prognostic class: Focal ( 50% normal glomeruli) Additional features: Focal global glomerulosclerosis (10%), mild tubular atrophy and interstitial fibrosis (10%), mild arteriosclerosis and moderate hyaline arteriolosclerosis

77 Patient 5 RS is a 21 college student who presents to his physician with dark urine which he noticed a day or two following a URI. It becomes clear that Mike has had similar episodes in the past as a teenager (intermittent hematuria) Physical examination is unremarkable-no edema, BP normal. Lab show normal serum creatinine and BUN. Dipstick shows 1+ protein and 4+RBC. Urinalysis shows numerous RBCs and only occasional RBC casts. Complement normal. Renal biopsy was done

78 Pattern: Mesangial proliferative GN

79 Segmental sclerosis

80 IgA

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82 What is the primary diagnosis? A. IgA nephropathy B. Monoclonal Ig GN C. Pauci-immune (ANCA) GN D. Anti-GBM GN E. C3 glomerulonephritis

83 IgA nephropathy Primary diagnosis: IgA nephropathy Pattern of injury: Mesangial proliferative and sclerosing glomerulonephritis Score/Grade: Oxford classification: M1 E0 S1 T0 Additional features: Focal (20%) global glomerulosclerosis, mild (20%) tubular atrophy and interstitial fibrosis, mild arteriosclerosis and severe hyaline arteriolosclerosis

84 Patient #6 63-year old woman with subacute rise in serum creatinine from 1.8 to 3.7 mg/dl over the last 3 weeks. UA- 2+ protein 3+ blood, RBC/HPF PR3+ canca + Remaining serology negative

85 Negative IF and EM studies

86 Kidney, needle biopsy: Primary diagnosis: PR3-ANCA glomerulonephritis (PR3/clinical) Pattern of injury: necrotizing and crescentic glomerulonephritis Prognostic class: Mixed (<50% normal glomeruli) Additional features: Severe ATN, Focal global glomerulosclerosis (33%), moderate tubular atrophy and interstitial fibrosis (30%), mild arteriosclerosis and moderate hyaline arteriolosclerosis

87 Lupus nephritis Primary disease: Lupus nephritis Pattern of injury: Diffuse proliferative and sclerosing glomerulonephritis, with focal (10%) cellular crescents Score/grade: ISN/RPS class IV-G (A/C) Additional features: Glomerular and arteriolar fibrin thrombi (anti-phospholipid antibodies/clinical) focal global glomerulosclerosis (20%), mild tubular atrophy and interstitial fibrosis (20%), moderate arteriosclerosis and moderate hyaline arteriolosclerosis

88 Anti-GBM glomerulonephritis Primary disease: Anti-GBM glomerulonephritis Pattern of injury: Necrotizing and crescentic glomerulonephritis, severe Additional features: Clinicopathologic features of Goodpasture syndrome (anti-gbm antibody/clinical), focal global glomerulosclerosis (40%), moderate tubular atrophy and interstitial fibrosis (40%), mild arteriosclerosis and moderate hyaline arteriolosclerosis

89 Summary The main aim and purpose of consensus meeting was to classify glomerulonephritis based on the underlying pathophysiology and etiology. Based on the current knowledge there are five basic classes of GN: immune complex GN pauci-immune GN anti-gbm GN monoclonal Ig GN C3 glomerulopathy Specific entities exist within each group The consensus document provides guidelines for the kidney biopsy report on glomerulonephritis

90 Shortcomings and limitations/needs further work Difficult cases- the diagnosis is not clear cut Limited biopsy sample Multiple diagnoses-gn + non GN diagnosis New disease entities Far from complete, work in progress, future modifications

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