Lupus Nephritis



Lupus Nephritis


Shane M. Meehan, MBBCh





Key Facts


Terminology



  • Systemic autoimmune disease manifested by inflammation of skin, joints, kidneys, and central nervous system



    • IgG autoantibodies to DNA, RNA, proteins, phospholipids


Etiology/Pathogenesis



  • Autoantibodies cause immune complex deposition, vasculitis, thrombotic microangiopathy


  • Multiple genetic risk factors


Microscopic Pathology



  • Glomerular pathology quite varied and is basis of ISN/RPS classification



    • Mesangial proliferation


    • Thickened GBM (extreme is “wire loop”)


    • Endocapillary hypercellularity


    • Necrosis, crescents


    • Thrombotic microangiopathy may dominate


  • IF: IgG deposits in glomeruli are essential for diagnosis



    • Usually accompanied by IgM, IgA, C1q, and C3 (“full house”)


    • TBM deposits in ˜ 50%


  • EM: Amorphous and structured deposits



    • Mesangial, subendothelial, and subepithelial deposits


  • Tubulointerstitial inflammation common


Top Differential Diagnoses



  • Cryoglobulinemia


  • MPGN, types I/III


  • Postinfectious GN






Endocapillary hypercellularity image, “wire loop” thickened capillary walls image, fibrinoid exudate image, and the rarely seen hematoxylin bodies image are indicative of active lupus glomerulonephritis.






PAS shows lupus glomerulonephritis with prominent mesangial hypercellularity and segmental “wire loop” thickening of the capillary walls image. Lupus has a great spectrum of renal lesions.


TERMINOLOGY


Synonyms



  • Lupus glomerulonephritis (GN), systemic lupus erythematosus (SLE)-associated kidney disease



Definitions



  • Systemic autoimmune disease manifested by inflammation of skin, joints, kidneys, and central nervous system, and with pathogenic IgG autoantibodies targeting nuclear, cell surface, and plasma protein self-antigens


ETIOLOGY/PATHOGENESIS


Autoimmune Disease



  • Autoantibodies to nuclear antigens in 95%: Double-stranded DNA (dsDNA; nucleosomes), Ro (a ribonucleoprotein), La (an RNA binding protein), Sm (a ribonucleoprotein)



    • Other autoantigens



      • C1q and membrane phospholipids such as phosphatidylserine


      • Laminin, heparan sulfate proteoglycans, and podocyte antigens


      • Some autoantibodies promote coagulation: Lupus anticoagulant, antiphospholipid antibodies, and ADAMTS13


  • Autoantibodies may be detectable years before disease onset


  • Breakdown of tolerance to self-antigens, trigger unknown



    • “Waste disposal” hypothesis



      • Defective phagocytosis of apoptotic cells leads to abnormal pathways of disposal of these cells


      • Abnormal disposal allows exposure of immune system to intracellular sequestered antigens


      • Exposure to these self-antigens activates self-reactive T and B cells and development of autoantibodies


Environmental Triggers and Aggravating Factors



  • Sunlight (UV)


  • Drugs: Hydralazine, procainamide, quinidine


Genetic Factors



  • 10% have relatives with SLE


  • Higher concordance for monozygotic twins (25-69%) than dizygotic twins (1-2%)


  • Polymorphisms/mutations of > 25 genes increase risk in genome-wide association studies



    • C1, C2, or C4 deficiency, probably causing defective clearance of immune complexes and apoptotic cells


    • Fcγ receptor IIB (inhibitory receptor on B cells)


    • Toll-like receptors (TLRs) 7 and 9


    • Interferon (IFN) and tumor necrosis factor (TNF) signaling


    • HLA-DR2 and 3


    • TREX1, a DNA-degrading enzyme


Pathogenesis



  • Immune complex (IC) formation and deposition in the kidney



    • Circulating IC trapped in capillaries and mesangium



      • Histone-rich nucleosomal antigens are trapped in glomeruli, possibly initiating IC deposition


    • In situ formation of IC due to planted or intrinsic antigen


    • Complement fixation



      • C3a and C5a attract neutrophils and macrophages


      • Endothelial activation by cytokines and complement


    • Inflammatory cells bind IC via Fc, complement receptors, and are activated



    • Persistent or recurrent inflammation leads to changes in intrinsic glomerular cell numbers and function and matrix homeostasis


  • Thrombotic microangiopathy



    • Associated with lupus anticoagulant, antiphospholipid antibodies, and, rarely, antibodies to ADAMTS13


    • Arises independently of glomerular inflammation and IC


  • Vasculitic glomerulonephritis



    • Necrosis with little or no IC deposition


    • Endothelial damage by uncertain mechanism


  • Podocytopathy



    • Minimal change lesion, focal segmental glomerulosclerosis, or collapsing glomerulopathy


  • T-cell-mediated autoimmune reactivity may also play a role


Insights From Animal Models



  • Several spontaneous inbred mouse strains develop lupus-like glomerulonephritis, shown to be multigenic



    • NZB/NZW F1, MRL/lpr, BSXB


  • Many specific genetic deficiencies promote murine lupus in susceptible strains



    • C4, C3, FcγRIIB, CD19, fas, Ro


CLINICAL ISSUES


Epidemiology



  • Incidence



    • 12-64/100,000 worldwide


    • 10-20% have pediatric-onset disease


    • ˜ 80% have nephritis during the course of the disease



      • 50-67% of pediatric patients have nephritis at onset


  • Age



    • Median age at onset is 11-12 years



      • < 20% under 8 years


      • Occurs in children < 2 years of age


  • Gender



    • F:M = 4:3 in 1st decade; 5:1 in 2nd decade



      • 9:1 in adult onset


  • Ethnicity



    • 1:250 females of African ancestry in USA


    • 1:1,400 females of European ancestry in USA


Presentation



  • Gradual or sudden onset


  • Variable presentation, correlates with pathologic classification



    • Isolated hematuria: ISN/RPS classes I, II, and III


    • Nephritic syndrome: Classes III and IV


    • Isolated proteinuria: Classes II and III


    • Nephrotic syndrome: Classes IV and V


    • Acute renal failure: Class IV


    • Chronic renal failure: Class VI


  • Other features: Fever, lymphadenopathy, serositis, skin rash (malar, butterfly), anemia, arthritis, thrombotic manifestations


Laboratory Tests



  • Autoantibodies



    • 95% have autoantibodies to nuclear components



      • > 95% ANA (speckled pattern)


      • 60-90% anti-dsDNA; > 90% in infantile SLE


      • 20-50% anti-Sm (highly specific for SLE)


      • 25-42% anti-ribosomal P


      • 23-37% anti-Ro (SSA)


    • 50% anticardiolipin



      • 30% lupus anticoagulant


    • 30-50% anti-C1q



      • Associations with lupus nephritis (LN) strongest for antibodies to dsDNA and C1q


  • Complement levels



    • ↓ C3 in 30-50%, ↓ C4 in 67-80%, more common in active disease



Treatment



  • Drugs



    • Immunosuppressive therapy used to decrease or arrest IC deposits, inflammation, and necrosis



      • Glucocorticoids, mycophenolate mofetil, cyclophosphamide



      • Chlorambucil and azathioprine


    • Anti-B-cell antibodies targeting CD20 (rituximab and belimumab) under evaluation


  • Transplantation



    • Clinically significant recurrence is rare (˜ 2%)



      • IF studies detect subclinical recurrence in ˜ 40%


Prognosis



  • Typically remitting and recurring course


  • 25% develop end-stage renal failure



    • 10-year renal survival is ˜ 75-90%


    • 10-year patient survival is 65-95%


    • Mortality is ˜ 20% for adolescent-onset disease


  • Common causes of death



    • Infection, especially pneumonia


    • Chronic renal failure


    • Severe disease flares


    • Premature coronary atherosclerosis


General Approach



  • Kidneys are biopsied in SLE to determine type of renal disease, acute inflammatory activity, and extent of glomerular and tubulointerstitial scarring


  • Accurate assessment requires at least 20 glomeruli


  • 2004 ISN/RPS classification is standard for lupus glomerulonephritis


MICROSCOPIC PATHOLOGY


Histologic Features



  • Lupus nephritis affects glomeruli, peritubular capillaries, muscular blood vessels, tubules, and interstitium with a spectrum of lesions


  • Glomeruli



    • Glomerular lesions determine ISN/RPS classification (classes I-VI)



      • Lesions can be active (acute) or chronic (sclerosing)


      • Focal (< 50% of glomeruli affected; III) or diffuse (≥ 50% of glomeruli affected; IV)


      • Segmental (part of a glomerulus) or global (> 50% of a glomerulus)


      • Distinction between III and IV is only by extent of these lesions (< 50% or ≥ 50%, respectively)


    • Normal (I)



      • Requires mesangial IgG to diagnose lupus class I


      • Class I is seen in < 1% of biopsies for cause


    • Mesangial hypercellularity (II)



      • By itself, not considered an active lesion


      • Class II is seen in 10-15% of biopsies


    • Endocapillary hypercellularity (III, IV)



      • Proliferation of intrinsic glomerular cells and accumulation of leukocytes with capillary luminal reduction


      • Class III is seen in 10-20% of biopsies


      • Class IV is seen in 40-70% of biopsies


    • Extracapillary hypercellularity (crescents) (III, IV)



      • Proliferation of parietal epithelium, accumulation of leukocytes, especially macrophages


      • Defined as > 2 cells thick, > 25% of circumference of capsule


      • Cellular or fibrous


      • Glomerular basement membrane rupture associated with crescents


    • Karyorrhexis, fibrinoid necrosis (III, IV)


    • Prominent subendothelial deposits (“wire loops”) (III, IV)



      • Trichrome stain useful


    • Hyaline “pseudothrombi” (III, IV)


    • Hematoxylin bodies specific but rare (III, IV)



      • In vivo LE cell


    • Membranous lesions (V)



      • Diffuse thickening of GBM with granular subepithelial deposits (trichrome) with silver-positive “spikes”


      • Class V is seen in 20% of biopsies


      • Overlaps of III or IV and V in ˜ 10%


    • Chronic glomerular lesions



      • Included in count of involved glomeruli for III vs. IV, if believed to be due to LN


      • Glomerular sclerosis, segmental or global


      • Glomerular fibrous adhesions


      • Fibrous crescents


      • GBM duplication


    • Variants



      • Some patients with minimal lupus (I-II) present with podocytopathy (minimal change disease and focal segmental glomerulosclerosis)


      • Focal segmental glomerular sclerosis can be a late scarring phase of lupus nephritis or secondary to loss of nephrons


      • Pathology may be dominated by lesions of thrombotic microangiopathy with little immune complex disease


  • Tubules and interstitium



    • Tubulointerstitial lesions are most commonly seen in association with class III and IV glomerular lesions



      • May be active or chronic


      • Occur ± IgG and C3 positive immune deposits


    • Active lesions are composed of T cells, macrophages, B cells, plasma cells, and neutrophils; with edema and tubulitis



      • Tubulointerstitial immune deposits may be associated with lymphoid aggregates


    • Chronic lesions are characterized by interstitial fibrosis and tubular atrophy


    • Occasional cases have predominately tubulointerstitial disease with only minimal glomerular disease (e.g., class II)


  • Vessels: 6 patterns observed



    • Normal (negative IF)


    • Uncomplicated vascular immune deposits



      • Normal-looking vessels with IgG, IgA, IgM, C3, and C1q by IF


    • Noninflammatory lupus vasculopathy



      • Hyaline deposits with Ig and C by IF


    • Necrotizing lupus vasculitis



      • Fibrinoid necrosis and leukocytoclasis ± immune deposits


    • Thrombotic microangiopathy



      • ± class III or IV glomerular lesions


    • Arterial and arteriolar sclerosis



      • Nonlupus vasculopathy without immune deposits



ANCILLARY TESTS


Immunofluorescence



  • Detection of IgG deposits in glomeruli essential for diagnosis



    • Usually accompanied by IgA, IgM, C3, and C1q (“full house”)


    • Kappa and lambda equal


    • IgG1 and IgG3 are predominate subclasses


    • Fibrin in necrotizing lesions and thrombi


  • Glomerular patterns



    • Mesangial only (class I, II)


    • Capillary wall, focal or diffuse, coarse granular, elongated (class III, IV)


    • Capillary wall, diffuse, finely granular (class V)


  • Tubules



    • Granular IgG with variable other components common in tubular basement membrane (˜ 50% of cases)


  • Vessels



    • IgG and other components sometimes seen in small arteries, arterioles, and peritubular capillaries


Electron Microscopy



  • Amorphous electron-dense deposits present in glomeruli in varied locations and to a variable extent



    • Mesangium, subendothelium, subepithelium


    • Subepithelial deposits sometimes penetrate GBM


    • Substructure may be focally manifested as “thumbprint” pattern


  • Extraglomerular deposits of similar nature



    • Tubular basement membrane, Bowman capsule, peritubular capillaries, interstitium, small arteries


  • Glomerular endothelial cells have tubuloreticular structures



    • Clusters of vesicles and tubules of diameter 20-25 nm in endoplasmic reticulum


    • Consequence of elevated levels of interferon


DIFFERENTIAL DIAGNOSIS


Type II Mixed Cryoglobulinemia



  • Fibrillary substructure of deposits


  • Macrophage predominance in glomerular capillaries


  • Deposits can be sparse, usually little subepithelial



    • IgM-predominant immunoglobulin


  • “Pseudothrombi” do not distinguish


  • Often associated with hepatitis C virus


C3 Glomerulopathy and Membranoproliferative GN, Types I/III



  • C3-dominant deposits, IgG, and IgM in a band-like pattern along capillary walls


  • Usually no C1q


  • Lupus serologies negative


Postinfectious GN



  • IgG and C3 in a characteristic coarse granular (“lumpy-bumpy”) pattern, with hump-like deposits along subepithelium


  • Usually little C1q


  • Deposits in GBM (“humps”) do not have “spikes”


Idiopathic Membranous GN



  • Absence of subendothelial, mesangial, and extraglomerular deposits, and tubuloreticular inclusions


  • Antibodies to phospholipase A2 receptors


  • Deposits typically do not penetrate the GBM


Drug-Induced LN



  • Many drugs implicated, e.g., propylthiouracil, isoniazid, hydralazine, procainamide, chlorpromazine


  • Few have anti-dsDNA antibodies or renal disease (5%)



    • High frequency of antihistone antibodies


  • Proof requires improvement after drug withdrawal


Lupus-Like GN in HIV



  • Negative or low titer ANA and negative dsDNA antibodies by definition


  • 50% diffuse, 45% focal, and 5% membranous pattern


  • ˜ 20% of renal biopsies in HIV-infected patients


IgA Nephropathy



  • IgA-dominant deposits without tubuloreticular inclusions or extraglomerular immune deposits


C1q Nephropathy



  • Abundant mesangial immune deposits, with predominance of C1q


  • No clinical evidence of lupus


Pauci-Immune Crescentic GN



  • Little or no endocapillary hypercellularity with little Ig and complement deposition


Sjögren Syndrome



  • Distinction based on serology and clinical features


DIAGNOSTIC CHECKLIST


Clinically Relevant Pathologic Features



  • Histologic predictors of poor renal outcome



    • Class of LN broadly correlates with outcome but is less of a predictor because of tendency for class changes in follow-up biopsies



      • In general, mesangial and membranous lesions have better prognosis than focal or diffuse proliferative lesions


    • Amount of subendothelial deposits


    • Activity index


    • Chronicity index


  • ISN/RPS class, activity and chronicity indices, and presence of tubulointerstitial or vascular disease are essential for clinical management


Pathologic Interpretation Pearls



  • Lupus nephritis is in differential diagnosis of almost every renal biopsy


  • Heterogeneity of glomerular lesions by LM, glomerular and extraglomerular IgG, and endothelial tubuloreticular inclusions are most important diagnostic clues to LN


  • Hematoxylin bodies are pathognomonic but rare



GRADING


ISN/RPS Classification of Lupus Glomerulonephritis (2004)



  • Based on light and immunofluorescence microscopy; electron microscopy not required



    • ≥ 20 glomeruli should be sampled for accurate classification


    • Tubulointerstitial disease and thrombotic microangiopathy scored separately


    • Classification requires distinction of active and chronic lesions and determination of extent of glomerular involvement by these injury processes



      • Single glomerulus may have both acute/active lesions and chronic/sclerosing lesions


      • Heterogeneity of interglomerular and intraglomerular changes makes classification of these lesions difficult


  • Transformation of glomerular lesions in repeat biopsies over months to years



    • Class II lesions upgrade to class III, IV, and V lesions


    • Class III lesions upgrade to class IV and V


    • Most class IV lesions have no change on follow-up biopsy


    • Class V lesions may develop proliferative (class III or IV) lesions


  • Classes broadly correlate with outcome



    • Classes I and II: Best survival


    • Class IV: Worse survival than class III



      • Debate whether segmental and diffuse forms of class IV are different


    • Class V: Good long-term survival


    • Class VI: End-stage disease


Activity and Chronicity Indices

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lupus Nephritis

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