Staci Smith DONephrology Grandview Hospital

Overview of LupusTypes of lupusHistory

Common manifestations SLE Nephritis

WHO classificationBiopsy IndicationsBiopsy FindingsTreatment

hematuria proteinuria glomerulonephritis

red blood cell casts

SLE Minimal Change Dz Membranous GN FSGS MPGN RPGN Ig A Nephropathy Anti GBM Dz

Goodpasture’s Wegener’s

Hepatitis B, C AIDS Amyloidosis HSP Cryoglobulinemia Vasculitides Poststrept/ Poststaph GN                                              

         

red cell castsvirtually diagnostic of glomerulonephritis or vasculitis

only one needed absence does not exclude diagnosis

Systemic Lupus:most common and affects major organs

Discoid Lupus: affects only the skinnot fatal, but can cause severe scarring

Drug-induced Lupus: is systemic Lupus caused by medications

when the medicine is stopped, the disease goes away

autoimmune disorder multisystem microvascular inflammation

defined by clinical picture and generation of autoantibodiesmostly against double stranded DNA

autoantibodies mostly against double stranded DNA and the Smith antigen Ab to Smith (Sm) antigen is very specific for SLE

25% of patients

not known when Lupus first appeared Hippocrates noted similar diseases in Ancient Greece

facial rash that resembles the markings of a wolf 1851 French-man named Pierre Cazenave

first clinical records more than 1.4 million Americans are affected by SLE

Serological Tests to Aid Diagnosis of SLE

Test % positive in SLEANA 95%

Anti-nDNA 60%

Anti-nRNP 80%

Anti-Sm 20%

Anti-Ro 30%

Anti-La 10%

Rim Diffuse

Nucleolar Speckled

American College of Rheumatology presence of 4 of 11 criteria can establish SLE Dx

96% sensitive and specificupdated 1995

Serositis –pleuritis, pericarditis

Oral ulcers - painless Arthritis – 2 or more peripheral joints

Photosensitivity

Blood Abnormalities –thrombocytopenia, lymphopenia, lymphopenia (x2),hemolytic anemia

Renal – casts, proteinuria, hematuria

ANA positive Immune Abnormalities – ANA, Anti DS DNA, Smith Ag, false (+) syphilis

Neurologic - seizures, psychosis

Malar Rash- spares nasolabial folds

Discoid Rash – scaling,scaring

SOAP BRAIN

MD

Lupus nephritisone of the most serious manifestations of SLE

typically arises within 5 years of diagnosis commonly within the first 6 to 36 months

Renal failure rarely occurs before American College of Rheumatology classification criteria are met.

total incidence of renal involvement among patients with SLE exceeds 90 %

abnormal urinalysis with or without an elevated Crin approximately 50% at diagnosis timeproteinuria present in 80%40% have hematuria and/or pyuria

‘Silent’ lupus nephritisnormal urinalysisno proteinuria normal serum creatinine levels

However, renal biopsy reveals pathological changes

Six types of renal involvement with SLE

Why do renal biopsy?to determine stage of diseasehistological evidence is present in most SLE pts even if they do not have clinical manifestations of renal disease

Pattern of glomerular injury related to the site of formation of the immune deposits

is primarily due to anti DS DNA

Indications for Renal Biopsy with SLE Patients

Proteinuria of >1g/day

conventionally 1-2g/dayLess proteinuria does not preclude biopsy if major serologic abnormalities, especially hypocomplementemiaAt the other extreme, the presence of full-blown nephrotic and nephritic syndromes

Progressive azotemia

Decreasing renal function in assocation with active urinary sediment

Ambiguity or inconsistency of data

Lupus nephritis of indeterminate duration, severity and potential responsiveness

Overlapping clinical features

Situations where clinical and laboratory data are compatible with different classes of lupus nephritis, for which different approaches to management are warranted

Redirection of therapy

Partially treated or incompletely responsive lupus nephritis

Morphological Classification of Lupus Nephritis(modified WHO Classification)

Class Biopsy finding

I Normal glomerulus

II Pure mesangial alteration

III Focal proliferative glomerulonephritis

IV Diffuse proliferative glomerulonephritis

V Membranous glomerulopathy

VI Advanced glomerulosclerosis

light micrograph capillary lumens open glomerular capillary wall thickness

similar to that of the tubular basement membranes

mesangial cells and matrix are located in the central or stalk regions of the tuft

segmental areas of increased mesangial matrix and cellularity

light micrograph

Divided by active and/or chronic lesions:Class III (A):

active lesionsClass III (A/C):

active and chronic pathologyClass III (C):

chronic inactive lesions with scarring a.k.a. focal sclerosing lupus nephritis

usually associated with subsubendothelialendothelial deposits

areas of cellular proliferation

thickening of glomerular capillary “wire loop”

subendothelial deposits deposition of immunoglobulins and complement results in thickening of the glomerular capillary wall

subsetssegmental = < 50% of glomerulidiffuse = >50% of glomeruli

subendothelial deposits

thickening of glomerular capillary wall

Class five the one form of lupus nephritis that may present with no other clinical or serologic manifestations of SLE

typically presents with signs of nephrotic syndrome

microscopic hematuria and hypertension also may be seen

Cr concentration is usually normal or only slightly elevated

sclerosis of more than 90% of glomeruli

represents healing of previous inflammatory injury as well as the advanced stage of chronic class III, IV, or V lupus nephritis

immunosuppressive therapy is NOT likely to be beneficial

diffuse (class IV) or severe focal (class III) proliferative glomerulonephritis,

severe or progressive membranous lupus (class V)

marked nephrotic syndrome rising serum creatinine membranous in association with class III or class IV diseasemixed disease

No internal organ involvement First line: NSAID’s Cyclooxygenase-2 specific inhibitor

may induce thrombotic risk in patients with antiphospholipid antibodies

Low dose hydroxychloroquine200mg twice a day

Manifestations not often responsive to glucocorticoidsThrombosis—includes strokesGlomerulonephritis Resistant thrombocytopenia or hemolytic anemia

Previously untreated patients Active lupus nephritis or severe manifestationsdecreased renal function and /or high-grade proteinuria

First line: high doses of corticosteroidsabout 1mg/kg/day

Cytotoxic drugs or other immunosuppressive drugs

Active and severe GN depsit high dose steroids

Responded to corticosteroids but require an unacceptably high dose to maintain a response.

Side effects from corticosteroids

Chronic damage on a renal biopsy

requires 6–12 months to work well 1–3 mg/kg/day(initial dose) 1–2 mg/kg/day(maintenance dose) Advantage:probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement

Side effects: Bone marrow suppression, leukopenia, infection(herpes zoster), infertility, malignancy, early menopause, hepatic damage, nausea

Advantagereduces flares, reduces renal scarring, reduces glucocorticoid doses

Side effectsbone marrow suppression, leukopenia, infection, malignancy, nausea,etc

requires 2–16 weeks to work well Initial dose:1-3 mg/kg/day orally or 8–20 mg/kg intravenously once a month plus mesna

Maintenance dose:0.5–2 mg/kg/day orally or 8–20mg/kg intravenously every 4–12 wks

Mesna

mycophenoalte mofetil may be an alternative to cyclophosphamide as initial therapy

particularly among patients who refuse or cannot tolerate cyclophosphamide

Biggest side effect is diarrhea, also myelosuppression

fewer side effects than cyclophosphamide

interferes with the activation and differentiation of B cells

lysis mediated by:ComplementFc receptor-bearing cytotoxic cellInducing apoptosis

selective transient depletion of the CD20+ B-cell subpopulation

Avoid possible disease triggers-sulfa antibiotics, sun, high estrogen-containing birth control pills,alfalfa sprouts

Prevent atherosclerosis Prevent osteoporosis Prevent infection Prevent progression of renal disease

Prevent clots in patients with antiphospholipid antibodies

hematuria proteinuria glomerulonephritis

red blood cell casts

autoimmune disorder multisystem microvascular inflammation

defined by clinical picture and generation of autoantibodiesmostly against double stranded DNA

Serositis –pleuritis, pericarditis

Oral ulcers - painless Arthritis – 2 or more peripheral joints

Photosensitivity

Blood Abnormalities –thrombocytopenia, lymphopenia, lymphopenia (x2),hemolytic anemia

Renal – casts, proteinuria, hematuria

ANA positive Immune Abnormalities – ANA, Anti DS DNA, Smith Ag, false (+) syphilis

Neurologic - seizures, psychosis

Malar Rash- spares nasolabial folds

Discoid Rash – scaling,scaring

SOAP BRAIN

MD

Morphological Classification of Lupus Nephritis(modified WHO Classification)

Class Biopsy finding

I Normal glomerulus

II Pure mesangial alteration

III Focal proliferative glomerulonephritis

IV Diffuse proliferative glomerulonephritis

V Membranous glomerulopathy

VI Advanced glomerulosclerosis

Happy Thanksgiving !