Renal involvement in systemic diseases

Question 1

Early symptoms of systemic autoimmune disorders and undifferentiated connective tissue disease

Answer 1

Polyclonal hypergammaglobulinemia

Autoantibodies

Inflammatory markers, Modest elevations in CRP and ESR

Lymphocyte infiltration of target tissues

Immune complex deposition

Serositis - pericarditis, etc

Arthralgia and arthritis

Vasculitis

Raynaud’s phenomenon, cold immunoglobulins

Question 2

What is UCTD, undifferentiated connective tissue disease, what is its prognosis

Answer 2

Syndrome with many characteristics of autoimmune disease but not classifiable as a specific one.

50% progress to a specified disease

40% remain chronic UCTD for life

10% spontaneously regress

Question 3

How is SLE diagnosed?

Answer 3

If a patient has at least 4 of the clinical or laboratory criteria, and at least one of each type
or
If the patient has biopsy-proven lupus nephritis as well as positive anti-nuclear or anti-DNA antibodies.

Question 4

Clinical criteria for SLE

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Answer 4

the SLICC classification criteria

1) Acute cutaneous lupus - light sensitive erythematous malar rash
2) Chronic cutaneous lupus - discoid chronic rash with lesions in three stages, erethematous, keratotic, and scarred. Face, scalp, and chest.
3) Non-scarring alopecia, body hair loss
4) Oral or nasal mucocutaneous ulcers
5) Serositis - pericarditis or pleuritis/pleural effusion.
6) Synovitis - joint pain in two or more joints, or multiple tender and stiff joints in the morning lasting for 30 minutes.
7) Urine - Proteinuria or RBC casts in the urine
8) Neurologic SLE symptoms: CNS- seizures, psychosis, myelitis (CNS inflammation) or PNS- Cranial or peripheral neuropathy
9) Hemolytic anemia
10) Leukopenia at least once
11) Thrombocytopenia at least once.

Question 5

Immunologic criteria for SLE

6

Answer 5

1) ANA’s Anti-nuclear antibodies. Very sensitive, in 95% of SLE. But not specific, seen in normal individuals as well.
2) Anti-dsDNA
3) Anti-Smith srn-RNA antibodies
4) Anti-phospholipid abs
5) low complement levels - indicating complement activation
6) Positive direct Coombs test.

Question 6

SLE typical patient

Answer 6

A woman of childbearing age
9:1 ratio female to males.
More common in aftrican-carribeans, and asians.

Goes through Relapsing, Remitting phases, flares of symptoms of the disease

Question 7

Drug induced lupus, what causes it

what is the hallmark antibody of DIL

Answer 7

Many drugs can induce it.
Most frequent: Hydralazine, Isoniazid, and Procainamide

It is typically reversible with drug removal.
95% will have anti-Histone antibodies.

Question 8

Other symptoms of SLE not mentioned in the clinical criteria

Answer 8

Generalized symptoms:
Fatigue
Fever
Weight loss
Chronically weak immune system and frequent infections. 

Skin symptoms:
ACLE, SCLE, CCLE: acute, subacute, and chronic skin rash.
Erythema exsudativum multiforme - exudating skin rash, face and mouth.
Rowell s yndrome, annular/ringed-rimmed rash all over body.

Cardiac symptoms:
In addition to pericarditis and effusion-
Libman-Sacks endocarditis of the Mitral valve.
- non infective vegetations of fibrin and immune cells
Myocarditis - life threatening, arrythmia possibility

Vasculitides:
Raynaud’s syndrome and cold agglutinins
Vasculitis and petechial/purpural rashes.
Livedo reticularis

Antiphospholipid syndrome: CLOTS
Coagulable state
Livedo reticularis
Obstetric miscarriages
Thrombocytopenia

GI symptoms:
Nausea, vomitting
Peptic/gastric ulcers

Eye symptoms:
Conjunctivitis

Question 9

Lupus nephritis

what are the two most common types:

Answer 9

Class 4: Diffuse proliferative GN
Subendothelial IC deposition, mesangial and endothelial proliferation.
Nephritis syndrome and possible RPGN.

second most common:
Class 3: Focal proliferative GN
Same, but just in some glomeruli.

Question 10

Associated autoimmune diseases often seen in lupus patients

Answer 10

20% have concurrent Sjogrens syndrome
5-10% have concurrent autoimmune thyroid disease

Lupus pernio - a chronic, raised, hardened, purple/deep red skin rash. Pathognomonic for sarcoidosis.

Question 11

Lupus subgroups, (not only SLE)

Answer 11

SLE: chronic relapsing remitting multisystemic dieases

Discoud Lupus Erthematosus: isolated chronic skin symptoms

Drug induced lupus

Neonatal lupus - rare type, affects newborns.

Question 12

Lupus nephropathy classes

Answer 12

1-6
Normal
Mesangial
Focal proliferative
Diffuse proliferative
Membranous
ESRD

Class I: Normal by LM, EM and IF microscope (< 5% of SLE patients).

Class II (mesangial lupus GN): 10‐25% of patients.
Mild clinical symptoms. Immune complexes deposits in the mesangium
with a slight increase in the mesangial matrix and cellularity

Class III (focal proliferative GN): 25‐30%
Lesions are present in portions of fewer than 50% of the glomeruli.
Typically, one or two foci show swelling and proliferation of endothelial
and mesangial cells, infiltration by neutrophils and/or fibrinoid deposits
with capillary thrombi.
Clinically associated with mild nephritis syn, microscopic hematuria and proteinuria,

Class IV (diffuse proliferative GN): 35-60%
Most serious form of renal SLE lesion, and also the most common
Most glomeruli show endothelial and mesangial proliferation affecting
the entire glomerulus, leading to diffuse hypercellularity of the
glomeruli.
c. EM / IF shows electron‐dense subendothelial immune‐complexes causing nephritis and potentially RPGN
d. In the course of time, glomerular injuries give rise to scarring
(glomerulosclerosis). Most of these patients have hematuria with
moderate to severe proteinuria, hypertension and renal insufficiency.

Class V (membranous GN) 10‐15%
b. Widespread thickening of capillary wall caused by subepithelial deposition immune complexes. Increased deposition of basement‐membrane.
c. Patients with this histological change almost always have severe
proteinuria, nephrosis

Class VI: Advanced sclerosing lupus nephritis: End stage renal deisease and comploete sclerosis of the glomeruli.

Question 13

Treatment of severe SLE

Answer 13

1) Induction therapy: 
6 months of methylprednisolone, plus 1 mg/kg/day oral glucocorticoids tapered to minimum effective dose
PLUS
IV cyclophosphamide 
or
Mycophenolate motefil
or
Azathioprine

2) Maintenance therapy
Lower dose glucocorticoids
Plus
Mycophenolate
or 
Azathioprine

3) adjunct treatment
Hydroxychloroquine - blocks TLRs and alters lysosomal pH affecting their function.

Question 14

What are the major systemic diseases with renal involvement?

13

Answer 14

1. SLE
2. Diabetes Mellitus
3. Goodpasteur syndrome
4. Henoch-Schonlein purpura
5. Vasculatides:
   a. Polyarteritis nodosa
   b. Microscopic Polyangiitis
   c. Wegeners granulomatosis
6. Rheumatoid Arthritis
7. Sjogrens syndrome
8. Sarcoidosis
9. Chronic active hepatitis B
10. Paraproteinemias,
    a. Multiple myeloma
    b. Light chain deposition disease
11. Amyloidosis
    a. AL primary light chain amyloidosis
    b. AA serum A amyloid
    c. Beta 2 macroglobulin amyloidosis.
12. Hypertensive nephropathy
13. Sickle cell disease

Question 15

Treatment of mild, moderate, and severe SLE flares

SLE maintenance therapy

Answer 15

Mild flares, NSAIDS,

Moderate flares or joint symptoms, methotrexate

Severe flares with potential organ damage,
1) IV cyclophosphamide and high dose prednisolone
or
2) Mycophenolate motefil and Azathioprine
and possibly supplement with
3) Rituximab

Question 16

Cyclophosphamide MoA

Answer 16

A chemotherapeutic/immunosuppressant

Forms its active metabolite only in cells that have LOW levels of ALDH, which is primarily T-cells.

Main effect is via elimination/inhibition of T-cell activity.

Question 17

Hydroxychloroquine MoA

Answer 17

Diffuses into Lysosomes and other cytoplasmic vesicles, acts as a base, and increases their pH

Increases Lysosomal pH, inhibiting the activation of lysosomal enzymes

Also affects pH in macrophage vesicles that pair class 2 MHC complexes with their peptides for presentation to T-cells.