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Antonio V. Cayco, MD Section of Nephrology
GLOMERULAR DISEASES Antonio V. Cayco, MD Section of Nephrology
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OBJECTIVES Introduction Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation General Principles of Management
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CAUSES OF ESRD IN THE PHILIPPINES: Renal Registry Data, PSN, 2003
Cause/Etiology (%) ESRD Cases Diabetes mellitus 33 Glomerulonephritis 25 Hypertension 19
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Afferent arteriole Parietal EC Capillary loop Endothelium Macula densa Mesangium JG cells Urinary space Visceral EC Efferent arteriole
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Mesangium Normal Glomerulus
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Normal glomerulus
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PATHOLOGY Definition of Terms Glomerulopathy vs. Glomerulonephritis
Primary vs. Secondary Diffuse vs. Focal Global vs. Segmental Fibrosis vs. Sclerosis Membranous vs. Proliferative Endocapillary vs. Extracapillary
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Fibrosis – increase in the deposition of collagen fibers Sclerosis – increase in the amount of homo-genous nonfibrillar extracellular material Sclerosis
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Segmental – lesion involves < 50% of the glomerulus Sclerosis Global – lesion involves > 50% of the glomerulus Sclerosis
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Diffuse Global Glomerulosclerosis
Focal – lesion seen in less than 50% of glomeruli Diffuse – lesion seen in more than 50% of glomeruli
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Proliferation – increase in the glomerular cell number
Mesangial cells Normal glomerulus Mesangial cells Proliferation – increase in the glomerular cell number Mesangial proliferativeGN
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Endocapillary proliferation Extracapillary proliferation
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Normal glomerulus Membranous – expansion and thickening of the glomerular basement membrane (GBM) by immune deposits
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Primary Mechanisms of Glomerular Injury
Mechanism of Injury Renal Insults/ Defects Glomerular Disease Immunologic Immunoglobulin Immune-complex GN Cell-mediated injury Pauci-immune GN Cytokine Primary FSGS Complement activation MPGN Type II Metabolic Hyperglycemia DM Nephropathy Fabry’s disease/ sialidosis FSGS Hemodynamic Systemic hypertension HTN Nephrosclerosis Intraglomerular hypertension Secondary FSGS
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Primary Mechanisms of Glomerular Injury
of Injury Renal Insults/ Defects Glomerular Disease Toxic E. coli-derived verotoxin Thrombotic microangiopathy Therapeutic drugs (NSAIDs) Minimal change disease Recreational Drugs (Heroin) FSGS Deposition Amyloid fibrils Amyloid nephropathy Infectious HIV HIV Nephropathy Subacute Endocarditis Immune complex GN Inherited Genetic defect for 5 chain of type IV collagen Alport’s Syndrome Abnormally thin basement membrane Thin basement membrane disease
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Immunologic Glomerular Injury
Humoral Antibody-Mediated Injury Autoantibodies against intrinsic antigens (example: Goodpasture’s syndrome) Autoantibodies against extrinsic “trapped antigens (example: Postinfectious GN) Trapping of circulating immune complexes (example: Cryoglobulinemic GN) Cellular Mediated Injury
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Two Final Common Pathways in Glomerular Injury
GN Loss of nephrons Glomerular hyperfiltration Glomerular HTN Non-selective prtoteinuria Glomerular sclerosis Tubulointerstitial inflammation Ischemia Tubulointerstitial atrophy/fibrosis Two Final Common Pathways in Glomerular Injury
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OBJECTIVES Introduction Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation General Principles of Management
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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Syndrome Diagnosis History Physical Examination
Ancillary Laboratory Tests Chemistry Serology Urinalysis
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Syndromes in Glomerular Diseases
Clues to Diagnosis Common Findings Rapidly Progressive Renal Failure (RPRF) Anuria Oliguria Decline in GFR over weeks HTN, Hematuria, Proteinuria, Pyuria Nephritic Hematuria, RBC casts, Azotemia, Oliguria, Edema, HTN Proteinuria,
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Syndromes in Glomerular Diseases
Clues to Diagnosis Common Findings Nephrotic Syndrome Proteinuria > 3.5 gms Hypoalbuminemia Hyperlipidemia Lipiduria Casts Edema Asymptomatic urinary abnormality (AUA) Isolated hematuria Isolated proteinuria
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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C-ANCA: Cytoplasmic Antineutrophil Cytoplasmic Antibodies
Antibodies against Proteinase 3 Associated with Wegener’s ggranulomatosis
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P-ANCA: Perinuclear Antineutrophil Cytoplasmic Antibody
Antibodies against myeloperoxidase Associated with a variety of vasculitides Non-specific for Wegener’s granulomatosis
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Clinical Diagnosis Disease Renal Syndrome Clinical Features
Diabetic nephropathy Nephrotic CRF Chronic course, (+) DM retinopathy, nl-sized kidneys, bland urine sediment Goodpasture’s syndrome Nephritic RPRF antiGBM-aby (+), cANCA (-), nl C3 Wegener’s granulomatosis antiGBM-aby (-), cANCA (+),
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Clinical Diagnosis Disease Renal Syndrome Clinical Features
Lupus nephritis Nephritis RPRF antiGBM-aby (-), cANCA (-), low C3, ANA (+), (+) ACR criteria for the diagnosis of SLE Poststreptococcal GN antiGBM-aby (-), cANCA (-), low C3, ASO (+), prior Streptococcal infection
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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Indications for a Kidney Biopsy
Unexplained ARF Unexplained RPRF Adult nephrotic syndrome w/out systemic disease Proteinuria < 2 g/d w/ deterioration of renal function Proteinuria > 2 g/d DM w/ acute onset of proteinuria and renal failure DM with proteinuria but w/out retinopathy Selected cases of Lupus nephritis
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Crescent
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Membrane thickening Mesangial expansion Cellular proliferation MPGN
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Deposits Splitting MPGN
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Normal glomerulus
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Fusion of foot processes Minimal Change Disease
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Sclerosis FSGS
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Foot process fusion FSGS
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Membranous Nephropathy
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Deposits Membranous GN
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Mesangial proliferation
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Mesangial IgA Deposits
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IgA Nephritis
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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Clinicopathologic Correlation
Syndrome Diagnosis Histologic Etiologic Nephritic Diffuse Proliferative GN Immune complex GN (>70%)* Pauci-immune GN (<30%)** Nephrotic Membrano- Immune complex GN* Thrombotic microangiopathy RPRF Crescentic GN Immune complex GN (45%)* Pauci-immune GN (45%)** Anti-GBM disease (10%) Isolated hematuria Mesangial IgA nephropathy HSP * SLE, Postinfectious GN, IE, Cryoglobulinemia ** Wegener’s granulomatosis, Microscopic PAN
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Clinicopathologic Correlation
Syndrome Diagnosis Histologic Etiologic Nephrotic Minimal Change Disease (MCD) Idiopathic, drugs, heroin, HIV, lymphoma Focal Segmental Glomerulosclerosis (FSGS) Idiopathic, HIV, heroin, secondary forms from reduced nephron number Membranous Glomerulopathy Idiopathic, infections, drugs, autoimmune diseases, paraneoplastic syndrome CRF Nodular sclerosis DM nephropathy Chronic GN
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Wire Loop Cellular proliferation Lupus nephritis
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TRI Lupus Nephritis
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Postinfectious GN
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Postinfectious GN
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DM Nephropathy
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Collapsing FSGS Sclerosis
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Tubuloreticular Inclusion bodies
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Amyloid
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SAMPLE CASE 28 year old female referred for acute onset of pedal edema X 1 week No other associated signs and symptoms Single; sexually active; silent past medical history; not on any medications; no history of IVDA ROS: denies other symptoms Well-nourished, not obese BP = 120/80, clear BS Grade III pedal edema
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SAMPLE CASE Serum creatinine = 0.7 mg/dl (nl)
Albumin = 2 g/L (low); Cholesterol = 300 mg/dl (high); FBS = 100 mg/dl (nl) CXR: normal; UTS of kidneys: normal Urinalysis: +4 protein, 0-1 RBC/hpf, 0-1 WBC/hpf, no casts 24-hour urine study: creatinine clearance of 98 cc/min and proteinuria of 4.5 g/day
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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SAMPLE CASE What is the renal syndrome present? Nephritic syndrome
Nephrotic Syndrome Rapidly progressive renal failure Asymptomaric urinary abnormality
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SAMPLE CASE Answer: Nephrotic syndrome Edema Hypoalbuminemia
Hyperlipidemia Proteinuria > 3.5 g/day
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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SAMPLE CASE Is it possible to make a clinical diagnosis? Yes or No ?
If yes, what is your clinical diagnosis? If no, is a kidney biopsy indicated?
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SAMPLE CASE Answer: No No signs of systemic disease, ROS negative for other symptoms PE normal except for edema Normal FBS Adult nephrotic syndrome – unlike children, no room for empiric steroid therapy Kidney biopsy indicated
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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Sclerosis
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Foot process fusion
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SAMPLE CASE Histologic Diagnosis: Focal segmental glomerulosclerosis
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Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation
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SAMPLE CASE What are the possible causes of FSGS?
What additional test/s is/are needed? Is this primary vs. secondary FSGS?
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Etiology of FSGS Idiopathic (Majority) Systemic Diseases or Drugs HIV
Diabetes mellitus Fabry’s disease Sialidosis Charcot Marie-Tooth Disease Heroin
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Etiology of FSGS Congenital Oligonephropathies Acquired nephron loss
Surgical resection Reflux nephropathy Chronic GN/ renal disease Other adaptive responses Sickle-cell nephropathy Obesity with sleep apnea Familial dysautonomia
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SAMPLE CASE No signs of systemic diseases
No history or sign (normal kidneys on UTS) of nephron loss Not obese No history of IVDA/ heroin use Sexually active – need to rule out HIV HIV ELISA test ordered – negative Final diagnosis: Idiopathic Primary FSGS
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OBJECTIVES Introduction Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation General Principles of Management
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General Principles of Management
Disease-specific therapy for primary and secondary GN Therapy to retard the progression of disease Therapy to address complications
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Two Final Common Pathways in Glomerular Injury
Disease-specific therapy GN Loss of nephrons Glomerular hyperfiltration Glomerular HTN Non-selective prtoteinuria Glomerular sclerosis Tubulointerstitial inflammation Ischemia Tubulointerstitial atrophy/fibrosis Two Final Common Pathways in Glomerular Injury
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Disease-Specific Therapy for Primary (Idiopathic) GN
Syndrome Disease Therapy Nephritic MPGN Aspirin plus dipyridamole Nephrotic MCD Steroids FSGS Membranous Steroids plus chlorambucil (Ponticelli protocol)
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Disease-Specific Therapy for Secondary GN
Syndrome Disease Therapy Nephritic Poststreptococcal GN Penicillin; supportive RPRF Wegener’s granulomatosis Steroids plus PO cyclophosphamide Goodpasture’s syndrome Plasmapharesis Lupus nephritis IV Steroids, IV cyclophosphamide Nephrotic Hep B membranous GN Interferon MCD due to NSAIDs Discontinue offending drug
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Two Final Common Pathways in Glomerular Injury
GN Loss of nephrons Glomerular hyperfiltration Measures to delay progression Glomerular HTN Non-selective prtoteinuria Glomerular sclerosis Tubulointerstitial inflammation Ischemia Tubulointerstitial atrophy/fibrosis Two Final Common Pathways in Glomerular Injury
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Renoprotective Strategies (Hebert, 2000)
Control blood pressure (< 127/75). (1) Use of ACE-I for BP. (1) Control of blood glucose for diabetics.(1) Limit protein intake to 0.8 g/kg IBW/day.(1) Limit NaCl intake (2-3 g/day).(3) Control lipids using statins (HMG-CoA reductase inhibitor therapy). (2) Avoid cigarette smoking. (2) Avoid regular intake of NSAIDs.(3) ( ) Level of Recommendation
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Renoprotective Strategies (Hebert, 2000)
Control plasma homocysteine level using folic acid (2-15 mg/d). (3) Control hyperinsulinemia (exercise and weight reduction). (3) Use of antioxidants (Vit C and Vit E). (3) Correct anemia (HgB 11-12). (2) Avoid hypokalemia. (3) Control hyperphosphatemia. (3) Low dose ASA. (3) Estrogen replacement for women. (3) ( ) Level of Recommendation
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Treatment of Complications
Diuretics to control edema. ACE-I/AII-RBs to control BP. Anticoagulants (warfarin) for hypercoagulable states. Statins for hyperlipidemia Measures to prevent osteoporosis for patients on steroids (Calcium, Vit D, biphosphonates). Co-trimoxazole to prevent Pneumocystic pneumonia for patients on steroids
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SUMMARY Introduction Approach to Glomerular Diseases
Syndrome Diagnosis Clinical Diagnosis Histologic Diagnosis Clinicopathologic Correlation General Principles of Management
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HUS Thrombi
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DM Nephropathy
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DM Nephropathy
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Membranous GN (Silver stain)
Spikes
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Immunofluoresence- Membranous GN
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Mesangial proliferation Lupus Nephritis
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Membrane thickening Lupus Nephritis
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TRI Membranous Lupus GN
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Immunofluorescence- Postinfectious GN
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RPGN
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Immunofluoresence: Anti-GBM Disease
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