2-14 Kidney Disease In Lupus

Front 1

Renal involvement in lupus nephritis involves...

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All components of the kidney

-Glomerulus (commonest)

-Tubulointerstitium

-Vasculature

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Pathogenesis of lupus nephritis

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-Immune complexes - composed of DNA and anti-DNA antibody (directed against nucleosomes); may also have chromatin, C1q, SSA, SSB and other antigens

-Immune deposits primarily in mesangium and subendothelial and subepithelial regions of GBM; also TBM (tubular basement membrane), vessels

-Complement activaiton via classical pathway

Front 3

Injury mediators in lupus

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TNF-alpha

IL-6

TGF-B

INT-gamma

PDGF

Chemokines

Front 4

Lupus nephritis in the European population

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-16% with SLE had LN (protein > 0.5 g, cellular casts or high BUN/creatinine) at diagnosis

-After 10 yr follow up: 28% had LN

-Much smaller black population

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Lupus nephritis in US population

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-Within 1 yr of diagnosis of SLE - 32%

-After 9-yr follow up - 47%, ESRD 4%

-Much larger black population

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US medicaid population + lupus nephritis

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-At 5 yr of diagnosis of SLE - 21%

-Eventually majority - 75% or more

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Racial differences in LN

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-Race: Blacks, Hispanics, Asians > Whites (non-whites develop LN earlier on course of SLE, have a younger age at diagnosis (<33))

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LN immunofluroescence findings

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-Positive for everything - "full house" IF

-IgG, IgA, IgM, C3, C1q

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EM findings for LN

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-Deposits in mesangium, subendothelial, and subepithelial locations

-Deposits may also occur in TBM, interstitium, and blood vessels

-Tubuloreticular inclusions in glomerular endothelial cells (also found in HIVAN)

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Vascular findings in LN

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Thrombotic microangiopathy (TMA)

-Isolated or with other LN manifestations

-Anti-phospholipid antibodies positive

1) Lupus anticoagulant

2) Anticardiolipin antibody

3) Antibody against VW factor convertase (ADAMTS13)

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Tubulointerstitial disease in LN

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-With or without immune deposits is not uncommon

-Prognostic

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LN WHO Type I - pathology

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Minimal mesangial LN

1) LM: normal

2) IF: mesangial deposits

3) EM: mesangial deposits

Typically no renal manifestations (UA normal)

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LN WHO Type II - pathology

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Mesangial proliferative LN

1) LM: mesangial hypercellularity/expansion

2) IF: mesangial deposits

3) EM: mesangial deposits

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LN WHO Type III pathology

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Focal and segmental LN

1) LM: <50% glomeruli effected

2) IF + EM: deposits in mesangium, subepithelial, subendothelial; glomerular tuft necrosis + crescents (proliferation of epithelial cells of glomerulus) --> these two features mean disease is active

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LN WHO Type IV pathology

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Diffuse proliferative LN

1) LM >50% glomeruli affected

2) IF and EM: Deposits in mesangium, subepithelial, subendothelial - wire loops, glomerular tuft necrosis + crescents (proliferation of epithelial cells of glomerulus) --> these two features mean disease is active

Front 16

LN WHO Type V pathology

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Membranous LN

1) LM: like idiopathic membranous glomerulonephropathy (deposits subepithelial) - thickened BM

2) IF: "full house" immunofluorescence

3) EM: like idiopathic MGN with deposits and tubuloreticular inclusion

More benign than type III/IV

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LN WHO Type VI pathology

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Advanced sclerosing LN

1) LM: global sclerosis of >90% glomeruli

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Clinical presentation of LN

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-Abnormal UA: proteinuria, active urinary sediment (RBCs, cellular casts)

-Proteinuria - glomerular range (>1 g/day), including nephrotic

-Abnormal kidney fxn

-Uncommon without systemic manifestations of SLE

-Kidney biopsy can show LN in absence of any clinical or lab abnormalities (rare)

Front 19

If you see tubuloreticular inclusions, think...

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lupus or HIV associated nephritis

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Diagnosis of LN

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-UA

-Random urine for protein and creatinine

-Renal electrolyte panel, Ca, PO4, albumin

-Sedimentation rate, ANA, C3, C4, and anti-dsDNA

-Additional serology - anti-SSA (Ro), anti-SSB (La), anticardiolipin antibody, lupus anticoagulant, anti-sm (smith) -> [highly specific but only 30-40% sensitive]

-Renal ultrasound

-Kidney biopsy (categorize class + guide therapy)

Front 21

Serology findings that indicate active disease

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Low C3, C4, and high dsDNA antibodies indicate active disease

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Most serious forms of LN?

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Diffuse or focal proliferative lupus nephritis (Class III or Class IV)

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Risk factors for progression of LN at presentation

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-Black/Hispanic

-HTN

-Elevated creatinine

-Degree of proteinuria

-Anemia (Hct <26)

-Severity of tubulointerstitial nephritis + crescents

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Treatment for LN for all patients

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1) Optimal BP control - target BP < 130/80

-ACE-i/ARB ideal agent

-Diltiazem - if you can't use ACEI/ARB

-Do not use dihydropyridine Ca-channel blockers alone (worsen proteinuria) - can use with ACEI/ARB

2) Reduce proteinuria - goal <0.5g/day or at least 60% of baseline

-ACEI/ARB; Diltiazem if not tolerated

3) Optimize lipid profile to reduce cardiovascular risk

-Statins

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Immunosuppression treatment in LN

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-Goal: induce remission (proteinuria <0.5 g/day, inactive urine sediment, stabilization, or improvement of kidney fxn)

-Induction phase

-Maintenance phase

-Therapy depends on histologic type -- need biopsy!

-Shift away from cyclophosphamide and in favor of MMF (micophenolate mofetil)

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Treatment for Membranous LN (Class V)

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-General measures as first line

-Prednisone + MMF if no response to general measures

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Treatment for Focal proliferative LN (Class III)

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-Prednisone + MMF - for lower risk pts only

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Immunosupression treatment for severe Class III and Class IV

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1) Induction: glucocorticoids + cyclophosphamide (for severe disease) or MMF (milder disease) (given for 2 yrs)

2) Maintenance: MMF is better - same effect but with fewer side effects than cyclophosphamide

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Epidemiology of lupus

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-Mainly young women

-Higher incidence in blacks vs whites

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Kidney presentation of lupus

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-Nephritic, nephrotic or both

-Hematuria +/- RBC casts

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Systemic sx of lupus

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Rash, arthralgias, alopecia, pericarditis

HTN common

Hypocomplementemia (C3 and C4)

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Classic antibody in nucleus

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ANA (dsDNA)

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LM findings in lupus nephritis

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By class:

1) Normal

2) Global or segmental mesangial hypercellularity only

3) + 4) Focal or diffuse endocapillary proliferative - can have crescents and necrosis

5) Membranous produces nephrotic syndrome

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IF findings in lupus nephritis

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-Granular mesangial and capillary wall deposits of all Ig and complements - "full house pattern"

-TBM and vesicular wall deposits common

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EM findings in EM

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Deposits in any compartment

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Class? Findings?

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Mesangial proliferative lupus nephritis (Class II)

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Class?

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Mesangial proliferative lupus nephritis - Class II - see mesangial hypercellularity and expansion

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Class?

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Class II IgG deposits

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Light microscope findings for Class III and IV LN?

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Front 40

Main difference between Class III and Class IV?

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Degree of glomeruli involvement

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Findings? Class?

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Class III/IV - crescents + cell necrosis

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Findings? Class?

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Class IV - fibrinoid deposits (diffuse proliferative LN)

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What are the deposits in this glomeruli?

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Thrombi

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Class?

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Class V - membranous LN

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Differentiate membranous LN from idiopathic MGN?

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With MGN, see IgG and C3 only on IF

Also, don't see mesangial deposits with idiopathic MGN

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Findings? Likely classes?

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Subendothelial deposits - likely Class III/IV

Blue line = glomerular basement membrane

Front 47

Where are the immune complex deposits located?

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In the mesangium - almost all forms of lupus have some mesangial deposits

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Where are these immune complexes deposited?

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Immune complexes are deposited subendothelially

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Findings?

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Wire looping of capillaries - massive amount of deposits between BM and endothelial cells - massive thickening of capillary wall (Class III/V)

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Findings? Class?

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Thick capillary walls on H+E - membranous class V (not as thick as wiring looping capillaries)

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Findings? Class?

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Spikes are indicative of excess basementmembrane material formed by the podocyte around an immune complex deposit as areaction to the subepithelialdeposit. Found only in membranous glomerulonephritis (and Class V of lupus nephritis).

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Class of lupus? Where are immune complexes located?

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Membranous Class V - granular deposits along capillary wall (subepithelial) but full house IF as opposed to membranous GN that is just IgG and C3

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Class?

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Class V membranous - subepithelial deposits create spikes of BM

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Immunofluorescence findings?

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-Deposits in the glomerular capillary wall, mesangium, tubular basement membrane, vascular wall immune deposits

-IgA, IgG, IgM, C3, C4, C1q (full house IF)