TREATMENT OF

NEPHRITIS
First...

Renal biopsy is useful in a patient with

acute renal failure when the cause
cannot be determined by a careful
history, physical examination, and
laboratory evaluation.
 Glomerular inflammation
(glomerulonephritis) often manifests
clinically as acute, rapidly progressive, or
chronic nephritis.
In general, the
aggressiveness of
treatment is tailored to
the aggressiveness of
the glomerulonephritis.
 The treatment of glomerulonephritis usually
involves the use of anti-inflammatory drugs
such as corticosteroids, and alkylating
agents such as cyclophosphamide,
chlorambucil, or azathioprine.
In patients who have pulmonary
hemorrhage with the pulmonary renal
vasculitic syndrome, plasma exchange is
useful.
PREDNISONE

Therapy with prednisone remains as

much an art as a science in that there
is no appropriate means of assessing
the pharmacokinetics of this drug.
 First, the dosage must be tailored to the
individual patient, based on body weight
or surface area and response to therapy.
Second, the amount of corticosteroid
used depends on the disease being
treated.
Mechanism of Action
Decreases inflammation by suppression of
migration of polymorphonuclear
leukocytes and reversal of increased
capillary permeability; suppresses the
immune system by reducing activity and
volume of the lymphatic system;
suppresses adrenal function at high doses.
Complication

Infections Dermatologic
Fluid and electrolytes Impaired wound healing
disturbances Petechiae and ecchymoses
Sodium retention Endocrine
Potassium loss Development of cushingoid
Hypertension state
Musculoskeletal Adrenocortical and pituitary
Steroid myopathy unresponsiveness

Osteoporosis DM

Aseptic necrosis Opthalmic

Gastrointestinal Posterior subscapular

cataracts
Peptic ulcer
Glaucoma
Pancreatitis
CYCLOPHOSPHAMIDE AND CHLORAMBUCIL

Cyclophosphamide and chlorambucil are

alkylating agents & Antineoplastic Agent.
Cyclophosphamide is converted in the
liver to an active metabolite.
Both drugs cross link the nucleic acid that
interferes with cell division and
transcription.
The usual oral dosage used for the
treatment of glomerular disease reduces
the leukocyte count to about 3,000 cells
per microliter.
Mechanism of Action (cyclophosphamide)

Interferes with the normal function of DNA

by alkylation and cross linking the strands
of DNA, and by possible protein
modification; cyclophosphamide also
possesses potent immunosuppressive
activity.
Note that cyclophosphamide must be
metabolized to its active form in the liver.
Mechanism of Action (chlorambucil)

Interferes with DNA replication and RNA

transcription by alkylation and cross-linking
the strands of DNA
Complication
Infections
Hemorrhagic cystitis
Mutagenesis
Impairment of fertility
Nausea and vomiting
Leukopenia
Interstitial pulmonary fibrosis
Alopecia
AZATHIOPRINE
To treat renal allografts.
It is an analogue of the purine-based
hypoxanthine.
Metabolites of azathioprine inhibit
enzymes required for DNA synthesis.
Azathioprine typically is used to treat
aggressive glomerular diseases (lupus
nephritis) or relapsing systemic vasculitis at
a starting dosage of 1 to 3 mg per
kilogram.
Mechanism of Action
Antagonizes purine metabolism and may
inhibit synthesis of DNA, RNA, and proteins;
may also interfere with cellular metabolism
and inhibit mitosis.
Complication
Because this suppression primarily takes
the form of neutropenia, infection is a
major side effect.
Azathioprine also carries a mutagenic
potential, with some form of tumor
(primarily dermal carcinomas) developing
in up to 5% of transplant recipients.
CYCLOSPORIN A
Cyclosporin A is reserved for conditions in
which other forms of anti-inflammatory or
immunosuppressive therapy have failed.
It is useful in patients with corticosteroid-
resistant minimal change disease and
massive nephrosis, in some patients with
nephrosis and FSGS or membranous
nephropathy who have not responded to
other forms of therapy.
Mechanism of Action
Cyclosporine suppresses some humoral immunity, but is more effective against T-cell-
dependent immune mechanisms such as those underlying transplant rejection and some
forms of autoimmunity.
It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting
expression of many lymphokines including IL-2, and the expression of antiapoptotic
proteins.
Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor protein present in
target cells.
This complex binds to calcineurin, inhibiting Ca2+-stimulated dephosphorylation of the
cytosolic component of NFAT.
When cytoplasmic NFAT is dephosphorylated, it translocates to the nucleus and
complexes with nuclear components required for complete T-cell activation, including
transactivation of IL-2 and other lymphokine genes.
Calcineurin phosphatase activity is inhibited after physical interaction with the
cyclosporine/cyclophilin complex. This prevents NFAT dephosphorylation such that NFAT
does not enter the nucleus, gene transcription is not activated, and the T lymphocyte
fails to respond to specific antigenic stimulation.
Cyclosporine also increases expression of transforming growth factor-b (TGF-b), a potent
inhibitor of IL-2-stimulated T-cell proliferation and generation of cytotoxic T lymphocytes
(CTL).
Complication
The major long term complication of
cyclosporin A therapy for glomerular
disease is interstitial fibrosis resulting from
chronic cyclosporin A toxicity.
Cyclosporin A causes chronic, irreversible
renal dysfunction and should be used for
no more than a year.
PLASMAPHERESIS
Plasmapheresis is used in the treatment of
pulmonary hemorrhage with anti-GBM
disease, pulmonary hemorrhage with
ANCA-associated systemic vasculitis, and
thrombotic thrombocytopenic purpura.
Complication
Immediate Long term
Hypotension
Hypocalcemia Infections

Disequilebrium syndrome Vascular

Valvular access problems thrombosis and
Hypothermia sclerosis
Allergic reactions to soluble
proteins and fresh frozen
plasma
Prolonged clotting times
Thrombocytopenia
Cardiac arrhythmia
Dyspnea
Convulsions
RENAL BIOPSY AND THE
TREATMENT OF SPECIFIC
FORMS OF NEPHRITIS
POSTINFECTIOUS GLOMERULONEPHRITIS

Therapy must be directed at eradication

of the infection with bactericidal
antibiotics.
In patients with only mild to In patients with substantial renal
moderate renal insufficiency failure associated with endocarditis

(a serum creatinine (a serum creatinine

less than 3 mg per
deciliter), antibiotic
therapy usually results
in the recovery of
renal function and
amelioration of
glomerular
inflammation.
more than 3 mg per
deciliter), several forms
of therapy have been
suggested, including
pulse
methylprednisolone,
plasma exchange,
and even the use of
immunosuppressive
agents such as
cyclophosphamide.
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
AND CRYOGLOBULINEMIA

Long-term antiviral therapy with interferon-

and other agents have a beneficial
effect in patients with
membranoproliferative glomerulonephritis
type I and mixed cryoglobulinemia.
HENOCHSCHNLEIN PURPURA

A renal biopsy is useful to determine

whether the disease process is Henoch
Schnlein purpura characterized by IgA
deposition in the kidney.
Anti-inflammatory and immunosuppressive
therapy usually is not warranted in Henoch
Schnlein nephritis unless there is severe
proliferative disease and crescents.
In such cases, therapy with pulse
methylprednisolone, prednisone, and
cytotoxic drugs may prove useful.