Immunosuppressive Therapy (ISRx) in Renal Disease - Landau

Question 1

Major renal diseases appoached successfully with ISRx

Answer 1

Chronic glomerulonephritis
Membranous GN
Membrano- Proliferative GN
IgA Nephropathy
Acute interstitial nephritis
Nehrotic syndrome
Minimal Change Disease
FSGS?
Thrombotic thrombocytopenic purpura
Systemic vasculitis
Chronic tubulointerstitial nephritis?

Question 2

What are the major immunosuppressive drugs?

Answer 2

Glucocorticoids
Calcineurin inhibitors
Antiproliferative/antimetabolic agents (prevent DNA proliferation)
Other:
Plasmapheresis
Novel monoclonal Antibodies
Anti-CD20 (Rithuximab)
Advantages
Proven efficacy in transplantation and autoimmune dis.
Disadvantages
Lifelong use
Nonspecific suppression of entire immune system

Question 3

Effects of corticosteroids/glucocorticoids

Answer 3

Bind to intracellular GC-receptor –>
Translocation of the complex to the nucleus –>Interaction with specific DNA sequences (GC-responsive elements [GREs]) –>
Decline in NF-kB –> decreased secretion of cytokines (combat microbes):
IL-2 (T-cell activation), GM-CSF, IL-6 & IL-8
Suppression of other cytokine - encoding genes (TNF, IFN-g, IL-1, etc.)

Suppression of neutrophil secretory products (in granules-important for acute infection)
Collagenases, elastases, plasminogen activator

Reductions in all circulating leukocytes
 Except neutrophils (high WBC with neutrophil predominance)

Neutrophils “demarginate” (detach from endothelial cells)–>
increased numbers in blood.
Decreased ability to exit the circulation and enter sites of infection and tissue injury.

Iatrogenic Cushing Syndrome

Skin striae, compressed vertebral fracture from steroid induced osteoporosis

MC effects cause hypertension (treat with Ca-channel blocker and beta blockers-not diuretics)

Children: decreased height, changes in mood and appetite

As time goes on, more likelihood of side effects

Question 4

Types of alkylating agents and their effect and toxicity

Answer 4

Cyclophosphamide, chlorambucil, melphalan
Chemically modifying nucleotides –> DNA breakage (by binding to DNA) –> errors in DNA replication and transcription–>cell division interference –>inhibition of lymphocyte proliferation and bone marrow suppression.
The degree of inhibition of immune function is dependent upon the dose and duration of therapy

Gonadal toxicity
greatest risk in sexually mature males and lowest in prepubertal children
Bone marrow suppression
Increased susceptibility to infection (especially cystitis) and hemorrhoids
Late malignancy
Bladder (lower with IV “pulse” cytoxan)
But: “Pts with rheumatoid arthritis, SLE, and other autoimmune illnesses are at increased risk of developing lymphoma independent of treatment.”

Question 5

Calcineurin Inhibitors

Mechanism and effect

Toxicity

Answer 5

Cyclosporine and tacrolimus, both:
Bind to different (but related) intracellular targets
Inhibit normal T-cell signal transduction and proliferation
Interact with many commonly used drugs
Undergo hepatic metabolism (CYP3A)
Plasma drug levels can be measured (calcineurin pathway by binding to NF-AT, regulator of IL2 so inactivates T-cell proliferation)

Prevents acute rejection of kidney transplants

Renal toxicity (hyaline deposites and interstitial fibrosis, sometimes not reversible)
Hypertension (both cyclosporin and tacrolimus)
Cyclosporin toxicity:

Tremor
Neurotoxicity - rare
Hirsutism
Gingival hypertrophy
Secondary tumors
Opportunistic infections (but less than alkylating angents and Cs)

Question 6

Rapamycin effects

Answer 6

Acts on m-TOR pathway (inhibits) of cell proliferation through IL-2 signalling (can’t send it’s message)

No major effect on cancer but some other immunosuppressive action

Less nephrotoxc side effects

Acts through tubular sclerosis complex genes (TSC1/2)

Question 7

Mycophenolate mofetil

(Toxic) Effects

Answer 7

Teratogenic (not for pregnant women)

Blocks inosine monophosphate dehydrogenase (IMPDH II more than I)-affects the synthesis pathway (over salvage). More for proliferating lymphocytes than other cells

Diarrhea and abdominal pain at dose limit

Also used for lupus

Question 8

Anti-CD20 Monoclonal Ab use and effects

Answer 8

Rituximab
Removes B cells
Used in B cell lymphomas, autoimmune thrombocytopenia, haemolytic anemia
Being tested in RA, SLE & Wegener’s granulomatosis
Over 100 patients treated with severe lupus
Disease activity improved in about 80%
Anti-dsDNA antibodies usually fall
Few infections
Occasional infusion reactions
Other side-effects rare
Contraception should be used

B cell activation –>
Cytokine production
IG production modified
Ag processed for presentation to T cells,
Proliferation & diff. into plasma cells.
Rituximab perturbs these processes.

Adverse effects: Fever, chills, Rash, angioedema, Leucopenia, thrombocytopenia, Infection

Question 9

Pulmonary renal syndromes Ab

Answer 9

Check anti-GBM Ab’s and ANCA
Anti GBM Ab’s cross react with alveolar basement membrane
ANCA = antineutrophil cytoplasmic antibodies
P-ANCA (perinuclear) specific for myeloperoxidase (in neutrophils)
C-ANCA (cytoplasmic) specific for proteinase 3
Both antigenic targets are in the cytoplasm
(it is all in the alcohol-fixation)

Cytokines/ priming factors induce PMN’s to express more ANCA Ags. on cell surface –> ANCA binding to PMN’s –> PMN activation –> endothelial cells damage –> Vasculitis

Question 10

Alport Syndrome

Answer 10

Hereditary Nephritis

A generalized inherited disorder of BM
not just renal !
Clinically:
Hematuria (of glomerular origin-proteinuria)
Progressive nephritis (up to ESRD)
Non congenital Sensorineural Deafness
Ocular abnormalities (cornea mutation)
Abnormal type IV collagen composition of BM
X-linked, found in children

Causes disorganization of GBM, loss of podocytes

Structural mutation-not inflammatory

Cyclosporin treatment is helpful regardless -indicate benefit of ISRx for conditions that are not autoimmune