Glomerular Diseases

    .

     

     

    Introduction / Approach

    • Glomerulus --> primary filtration unit
      • Glomerular capillaries are supported by mesangium (made up of mesangial cells + structural matrix)
      • Capillary wall consists of (filtration barrier):
    1. Inner layer of cells (fenestrated epithelial cells)

    2. Basement membrane

    3. Outer layer of cells (podocytes) - form small openings to filter fluid

     

    • glomerulus.png(image from MKSAP16)

    • Glomerular capillary tufts surrounded by cup-like sac composed of parietal epithelial cells --> Bowman's Capsule

      • Bowman's Capsule collects the urine and passes it to renal tubule, which processes glomerular filtrate

    • Damage to glomerulus alters selective permeability of this capillary wall, results in:

      • Proteinuria! (clinical hallmark of glomerular diseases)

      • Hematuria (alters continuity of filtration barrier)

    • Progressive damage causes decline in glomerular filtration rate leading to advanced CKD/ESRD

     

    • Patters of Glomerular Disease
      • Nephrotic Syndromes - Leakage of plasma proteins is predominant
      • Nephritic Syndromes - (aka Glomerulonephritis) - Passage of both plasma proteins AND cells (erythrocytes, leukocytes).
      • Mixed  - Some present as either one, or mixture of both

     

    • Can be classified by clinical time course
      • RPGN - Rapidly Progressing GN - Rapid loss of function - weeks to months
        • Note: Different from AKI, which happens over days
      • Others - More chronic

     

    • Renal biopsy is the gold standard for diagnosis & guiding therapy

     

    Nephrotic Syndrome

    • Primary protein leakage across glomeruli
    • Characterized by a triad:
      • Nephrotic Syndrome Triad (Diagnosis)

          1.  Proteinuria:

               - Protein:Creatinine ratio of > 3.5

               - Timed Urine Protein Collection s> 3.5g/24hrs

          2.  Hypoalbuminemia (<35)

          3.  Edema

         

        Others (non-essential):

        - Hyperlipidemia

        - Coagulation Changes (loss of proteins other than albumin,

                                              or increased protein synthesis)

    • Clinical Manifestations: (protein loss or increased production by liver)
      • Thrombosis (antithrombin-3, Protein C, Protein S, overproduction of fibrinogen)
        • Particularly renal vein thrombosis
      • Immune Dysfunction (Complements, immunoglobulins)
      • Anemia  (transferrin, Epo)
      • Atherosclerosis (HDL, overproduction of LDL)
      • Hypothyroidism (loss of thyroid binding protein, thyroxine)
    • Approach to Diagnosis:   
      • Causes of nephrotic syndrome are divided into morphological descriptive terms (FSGS, Membraneous, etc.)
      • EACH morphological type has:
        • Primary Causes (usually idiopathic)
        • Secondary Causes (caused by infection, metabolic, malignancy, drugs, etc...)
      • Once nephrotic syndrome is diagnosed, the initial approach is to rule out secondary causes, which can help point to the morphological type (i.e. HIV for FSGS), and can be treated to stop the progression and possibly improve renal function.  
    • Workup:
      • Confirm Nephrotic Syndrome:
        • 24hr Urine Protein (if not done)
        • Protein:Creatinine Ratio
        • Albumin
        • Urine Dip/Microscopy (fat oval bodies)
      • Secondary Causes:
        • Infection: HIV, Hepatitis B, C serology, RPR
        • Metabolic: HbA1c, TSH, BP measurement
        • Malignancy: SPEP, UPEP, (Fat bad bx?) Blood counts/Lymph Node Exam
        • Drugs: Medication Review (NSAIDs, Lithium, Pamidronate, Interferon, Rifampin)
        • Inflammation: ANA, Anti-dsDNA, C3, C4 (SLE?), Cryoglobulins
        • RENAL BIOPSY
      • Consequences of Nephrotic Syndrome
        • Lipid Profile

    Causes

    • Primary vs. Secondary (part of systemic illness)
    • Primary:
      • Use morphologic descriptive terms

    NephroticSyndr3.png

    • Secondary Causes:
    • Glomerulopathy Pathology Notes

      Minimal Change

      Disease

      - Light Microscopy: looks normal

      - Electron Microscopy: Retraction of 

        epithelial foot processes

        (no longer have filtration slit 

        diaphragms)

       

      CAUSES:
      Primary (Idopathic)

      Secondary to:

      - Hodgkin's Lymphoma

      - Drugs: NSAIDs, Lithium, 

        Pamidronate, Inferferon, Rifampin

       Most common in children (2nd peak in older adults)

       

      Management: Responds to prednisone (1mg/kg/day or

      2mg/kg/eoDay, tx 8-16w relapses common, remission 

      achieved in 70% of cases).

      - 73% relapse rate, need to re-treat, may require immunotherapy

      Focal Segmental

      Glomeruloscerosis

      (40%)

      - Retraction of foot processes

      - Also have areas that are scarred 

        (sclerotic), which are focal (certain

        glomeruli), and segments of glomeruli

        (segmental) are sclerosed. 

       

      - Caused by released cytokines that

      injure capillary walls, incr permeability

      - Also seen in pts with previous 

       renal injury 

       

      CAUSES:

      Primary (Idiopathic) - 25%

      Familial (African Americans)

      Secondary:

       --->   Hyperfiltration Injury:

            - chronic HTN

            - DM

            - Reduced Nephron Mass (CKD

               Obesity, sickle cell, reflux

               nephropathy, or after

               nephrectomy)

      ----->  Toxins

        - Drugs (Pamidronate, Interferon)

          Heroin

        - HIV Infection

       

      - Most common cause of primary nephrotic syndrome in US

        (More common in African-Americans

       

      Management:

      - ACEi or ARBs to target BP < 130/80 (reduce

      progression & proteinuria)

      - Difficult to treat!

      - At onset, consider treating w/ steroids and calcineurin inhibitors

      - 39-45% become frequently-relapsing (many require

      chronic MMF,   Rituximab, cyclophosphomide)

       

      Response to treatment is the most important prognostic factor.

      40-90% progress to ESRD within 10y 

      Membranous 

      Glomerulopathy

      (30%)

      Immune complex disease

      Immunoglobulins (IgG) react with

      antigens in outer glomerular basement

      membrane. 

       

      Primary (Idopathic)

      Secondary:

         Inflammation: SLE

         Infection: HepB, HepC, Syphilis,

                         Malaria

         Medications: Penicillamine,

                             NSAIDs, Tiopronin

         Toxins: Mercury, Gold

         Malignancies, Thyroid Disease

       

      - Used to be most common, but now FSGS surpassed it

      - Still most common in Caucasians (typically > 50yo)

      - Second leading cause of ESRD (1st is FSGS)

       

      2/3 --> spontaneously remit!

      1/3 --> Progressive ESRD in 10 years. 

       

      - Highest risk of renal vein thrombosis

       

      - Risk Factors of Progression: Male, Age > 50, Elevated Creat, 

      HTN, secondary glomerular sclerosis & chronic

      tubulointerstitial changes on bx.

       

      --> High Risk --> treat - consider cyclophosphamide, steroids, 
                                calcineurin inhibitor, rituximab (recent trials)

      --> Low Risk --> observe, will likely remit

       

      Also treat to reduce proteinuria, manage HTN, hyperlipidemia)

       

       

      Fibrillary 

      Glomerulopathy

         

      Immunotactoid

      Glomerulopathy

         

    Treatment

    • Protein Supplementation
    • Diuretics for edema
    • Treat Hyperlipidemia (statin)
    • Na Restriction (< 2g/day)
    • ACEi/ARB (decr. proteinuria, slows immunologic progression of CKD)
    • Treat Cause:
      • Primary glomerular disorders --> Steroids +/- cytotoxic therapy
      • Cancer Screening (if membraneous)
      • Treat Underlying Disease
    • Avoid Complications:
      • Infections (Loss of Ig - encapsulated organisms)
      • Malnutrition (protein loss)
      • Thrombosis (25% - esp renal veins, loss of anticoagulants (I.e. ATIII)). 

     

    Specific Causes

     

    Condition Type of Renal Injury  
    Amyloidosis

    Renal Biopsy: 

    Amorphous material,

    effacing portions of glomeruli,

    vessels, interstitium, and

    demonstrate green biofringence

     on congo red stain

    (polarized microscopy).

    Pathologic deposition of protein of an 

    alternate structure that polimerizes into 

    solid structure into tissues

    • >20 types of proteins identified
    • Types:
      • AL Amyloid (most common)
        • Monoclonal light chain - usually lambda isotype
        • 20% have underlying multiple myeloma
        • Poor prognosis
      • AH Amyloid
        • Truncated monoclonal heavy chain
      • AA Amyloid
        • Amyloid AA protein --> acute phase reactant released in chronic inflammatory states like RA, TB, Osteomyelitis
        • Prognosis depends on cause
    • Other organs infected, but kidneys are most commonly affected
    • Presentation:
      • Nephrotic Syndrome
    • Diagnosis:
      • Biopsy required for dx:
        • Fat pad biopsy is best (minimally invasive), rectal also high yield.
        • Renal biopsy indicated if fat pad and rectal are non-diagnostic
        • Renal Biopsy: Amorphous material, effacing portions of glomeruli, vessels, interstitium, and demonstrate green biofringence on congo red stain (polarized microscopy). 
    • Treatment:
      • Treat underlying cause
    Multiple Myeloma
    • Amyloidosis
    • MPGN
    • Deposition disease
    • Monoclonal neoplasia and production of monoclonal immunoglobulin
    • Renal injury through several mechanisms. 
      • Amyloidosis
      • MPGN
      • Deposition disease
    • Range mild-to-severe
    • Proteinuria is generally mild
    • Diagnosis:
      • Renal Biopsy to exclude other disorders
    • Treatment
      • Fluids (high urine output, clear out protein)
      • Plasmapheresis for M-Protein is controversial
      • Systemic chemotherapy for myeloma
    HIV-Associated Nephropathy
    • FSGS (Collapsing Variant)
    • Immune Complex Mediated GN
    • Membranoproliferative GN
    • Lupus-Like GN
    • Membranous Glomerulopathy
    • Thrombotic Microangiopathy
    • Minimal Change Glomerulopathy
    • Amyloidosis
    • aka HIVAN 
    • Usually in advanced HIV, but can be seen early
    • Collapsing FSGS - occurs in 3.5-12% of pts with HIV infection
    • Can also cause renal damage by following mechanisms:
    • Presentation:
      • Nephrotic Syndrome
      • Progressive renal failure
      • Large kidneys on U/S
    • Diagnosis: clinical
    • Treat:
      • Treat HIV, reduces progression to ESRD.
      • ACEi/ARB for proteinuria and HTN also indicated
    Hepatitis B
    • Membranous Glomerulopathy
    • Membranoproliferative
      GN
    • Polyarteritis Nodosa
    • Deposition of HepB antigen and immune complexes into subepithelial membrane is responsible for increased glomerular permeability
    • Usually occurs in active HepB
    • Presents as Nephrotic Syndrome
    • Treatment:
      • Treat HBV (can reverse in kids, and some adults)
      • Immunosuppressants controversial
    Hepatitis C
    • Cryoglobulinemic GN
     
    Syphilis
    • Membranous Glomerulopathy
     


     

    Nephritic Syndrome

    • Injury or inflammation of the glomerulus --> allows passage of protein and erythrocytes and leukocytes into renal tubule
      • Resulting in reduced GFR, reduced renal function, abnormal BP regulation
    • Nephritic Syndrome

        1.  Proteinuria

        2.  Hematuria

        3.  Pyuria

        4.  Reduced Renal Function & Hypertension 

     

    • Notable mentions:
      • IgA Nephropathy
        • MOST COMMON cause of microscopic hematuria (i.e. urinalysis done by GP) in young patients.
          • Rule out all diseases, assume IgA nephropathy
          • Can prove on renal biopsy (but usually not necessary b/c no treatment)
        • 90% of people --> will have persistent microscopic hematuria throughout lifetime (creat will remain stable!!!)
        • Associated with: IBD, celiac disease, respiratory problems (b/c all IgA secreting)
        • 10% will have progressive renal failure
        • Need annual creatinine to ensure doesn't rise
        • Lab: Serum IgA immunoglobulin level (unreliable) - 50% may have elevated.  (specific, non-sensitive)
      • NOTE: Some patients have URTI + have gross hematuria.
        • Post-infectious GN --> 2-3w after infection  (only occurs once)
        • Severe IgA nephropathy --> immediately with URTI, (can recur at time of resp tract infections)
      • Rapidly Progressing Glomerulonephritis (RPGN)
        • Nephrologic emergency: rapid decline in renal function --> advanced CKD/ESRD in weeks-to-months if untreated.
        • Histology: see Crescents (Develop in bowman's space following glomerular capillary rupture).
          • Leading to extravasation of inflammatory cells, macrophages, fibrin --> parietal cell proliferation that takes on crescent shape. 
        • Prompt diagnosis and initiation of therapy must be started to prevent ESRD and advanced CKD

     

     

    Nephritis Approach.png

     

     

    HSP

    • A form of vasculitis (venulitis)
    • Get Acute Renal Failure, blood+protein in urine, just like IgA
    • Renal biopsy is the same as IgA nephropathy
    • Mostly in children, but sometimes in adults. 
    • HSP is IgA nephr
      • Fever
      • Purpuric Rash (arms, legs buttocks)
      • Abdo Pain
      • Hematochezia
      • Arthritis
    • Management:
      • Supportive care
      • Self-resolves with time.

     

    Alport

    • Genetic, X-Linked (women carriers, men have disease)
      • ESRD 2nd or 3rd decade of life. 
      • Male predominance
    • Abnormality of collagen 
    • Ass'd with: Deafness, Cataracts
    • Management:
      • Supportive care
      • Nothing alters course of disease

     

    Post-Infectious GN

    • Immune complex mediated
    • 1-3 weeks post-pharyngitis
    • Edema, Hypertension, gross hematuria,
    • Often lots of blood + protein in urine (can be into nephrotic range)
    • Managemetn:
      • Supportive Care
      • Self-Resolving

    SLE

    • Prognosis variable
    • Chronic +/- progressive renal insufficiency
    • Exacerbations possible

     

    Rapidly Progressive Glomerulonephritis (aka crescentic GN)

    • Red cell casts +/- protein
    • Crescents on biopsy (cellular infiltration of bowman's space)
    • 3 Examples:
      • Goodpasture's Syndrome (Acute Renal Failure + active urine + Hemoptysis)
        • Positive Anti-GBM antibody
        • Solvents, gasoline, fumes, may make it more vulnerable (but mostly genetic)
        • Treat with steroids (pulse solumedrol 500mg IV daily x3d) and cyclophosphamide
        • Plasma Exchange to remove antibody rapidly (7-14 days)
      • Wegener's Granulomatosis
        • Can be acute or chronic (often chronic)
        • Features: Sinusitis, Hemoptysis, Acute Renal Failure
        • C-ANCA + (aka MPO-3)
        • Treat with Steroids and Cyclophosphamide
        • Plasmapheresis is controversial (usually only if has hemoptysis or approaching dialysis)
      • Polyarteritis Nodosa 

     

    • Must do fluorescent microscopy (some immune-mediated, other pauci-immune)
    • Must have 1g

    Glomerulonephritis Workup

    • Complement levels
    • Hepatitis panel
    • Blood cultures
    • Antinuclear antibodies
    • ANCA
    • Anti–GBM antibodies
    • Antistreptolysin O antibodies

     

     

     

    IgA Nephropathy

    • Triggered by an infection --> release of immunoglobulins and activation of complement proteins that are deposited in the glomeruli, activating cytokine inflammatory pathways.
      • This causes acute nephritic syndrome regardless of the offending organism.
    • Characterized by:
      • Rapid onset of edema
      • Hypertension
      • Oliguria w/ low urine sodium
      • Erythrocyte casts in the urine sediment
    • Treating strep infection with antibiotics, reduces risk.
    • No biopsy necessary.. unless another concern or no hx of strep infection.
    • Treatment: Supportive care
      • Hypertension: anti-hypertensives
      • Fluid overload: diuretics
      • Renal Failure: Dialysis if needed.
    • Complications (Uncommon):
      • Rapidly-progressing glomerulonephritis
        OR
      • Persistent nephritic-nephrotic syndrome
         
      • May progress to adavnced kidney disease.
        • Can require intravenous pulse methylprednisolone, prednisone, cyclophosphamide, cyclosporine, and/or plasmapheresis. 

     

    Nephrotic Syndrome

    (INCOMPLETE)

     

    Decide Primary vs. Secondary

    • Primary
      • Minimal Change
      • Membranous Nephropathy
      • FSGS
      • Membranoproliferative
    • Secondary
      • DM
      • Amyloid
      • SLE (CTD)
      • Malignancy (Screening, FMHx cancer)
      • Drugs (DMARDS, gold, heroin, NSAIDs)
      • Infection (HepC, Syphilis, HIV)

     

    Workup Proteinuria

    • Need biopsy, esp if nephrotic range.
    • Need to know (i.e. if membranous, then anticoagulate).
    • Other workup:
      • Anti-GBM, Anti-dsDNA, C3/C4, ASOT

     

     

     

     

    Minimal Change Disease

    • More common in children
    • Not an immune complex glomerulonephritis!
    • Creatinine is normal 
    • Diagnosis:
      • Biopsy
      • Normal light and immunofluorescence microscopies but with effacement of podocyte foot processes on electron microscopy.
    • Treatment:
      • Steroids!  3mo of prednisone 1mg/kg/day then taper.
      • If relapse: rituximab, cyclophosphamide
      • Others:
        •  Lasix, ACEi

     

    Membranous Glomerulopathy

    • Immune abnormality 
    • Causes:
      • Primary (idiopathic)
        OR
      • Secondary
        • Infectious: Hepatitis B, C, Malaria, Syphilis,
        • Rheumatologic: SLE, DMII, RA
        • Drugs: NSAIDs, captopril, penicillamine
        • Malignancies: Breast, Colon, Stomach, Kidney, Lung
    • Prognostic Factors:
      • Baseline creatinine & degree of proteinuria
    • Diagnosis:
      • Biopsy!
      • Biopsy Findings of Membranous Glomerulopathy:  

        Diffuse glomerular membrane thickening without cellular infiltration

        Coarsely granular deposits (often IgG and C3)  along the capillary loops by immunofluorescence microscopy. 

         

        Electron Microscopy:  

        Moderate podocyte foot process effacement consistent with changes leading to protein leakage from the glomerulus.

    • Management
      • 1/3 may need treatment due to high risk of progression (alternate steroids and cyclophosphamide)
      • Anticoagulate!  (if alb < 20) [Based on Dr. Garland]
        • Membraneous is the only one you anticoagulate
        • Evidence weak
      • Warn the patient of symptoms of clot!

     

    FSGS

    • Usually primary
    • Secondary:
      • Morbid Obesity
      • HIV
      • etc. 

     

    Diabetic

     

    Amyloidosis

    • Protein deposition in kidneys, causing nephrotic syndrome and progressive renal insufficiency
    • Can be due to:
      • Chronic inflammation (IBD, osteomyelitis etc..)
      • Malignancy (myeloma)

    Glomerulonephritis

    Anti-GBM

    • Usually RPGN - blood, casts
    • Treatment
      • Prednisone
      • Plasmapheresis (if need acutely)
      • Cyclophosphamide (takes weeks to work)

     

    Alport Syndrome

    • Mutation in type IV collagen (structural component of glomerular basement membrane)
    • Causes microscopic hematuria, and progressive CKD
    • Inherited as X-linked dominant pattern

     

    Post-Strep Glomerulonephritis

    • Usually, 2-3w after streptococcal pharyngitis or cellulitis.
    • Classic GN features:
      • Proteinuria
      • Hematuria
      • Edema
      • Hypertension
      • AKI
    • Labs:
      • Low C3
      • Normal or mildly low C4
      • Positive antibodies:
        • antistreptolysin O (ASO)
        • Anti-deoxyribonuclease B (Anti-DNAse B)
        • Streptozyme test --> Preferred b/c measures 5 different antibodies (anti-ASO, anti-DNAse B, antihyalorunidase, antistreptokinase, antinicotinamide adenine dinucleotidase.) Sn 95%  after pharyngitis and 80% after cellulitis

    Appendix

    • Glomerulonephritis Clinical Manifestations (protein loss)
    • Proteins

      Clinical Manifestations

      Albumin

      Edema

      High-density lipoprotein

      Atherosclerosis

      Heparan sulfate

      Atherosclerosis

      α1-Acid glycoprotein

      Atherosclerosis

      Complement component factor B

      Infections

      Immunoglobulin (IgG)

      Infections

      Antithrombin III; proteins S and C

      Thrombosis

      Coagulation factors IX, XI, and XII

      Bleeding

      Iron-binding protein

      Anemia

      Erythropoietin

      Anemia

      Vitamin D–binding proteins

      Osteomalacia

      Thyroid-binding protein and thyroxine

      Hypothyroidism

      Altered Protein Synthesis

      Proteins

      Clinical Manifestations

      Insufficient synthesis of albumin

      Hypoalbuminemia

      Increased synthesis of apolipoprotein B; LDL cholesterol

      Atherosclerosis

      Increased synthesis of fibrinogen

      Thrombosis

      Increased synthesis of coagulation factors V, VII, VIII, and X

      Thrombosis

      Increased synthesis of α2-globulins and β-globulins

      Unknown

      Increased synthesis of immunoglobulin IgM

      Unknown

    Tag page (Edit tags)
    • No tags
    Page statistics
    27619 view(s), 20 edit(s) and 35791 character(s)

    Comments

    You must login to post a comment.