Transcript Crescentic Glomerulonephritis

Crescentic
Glomerulonephritis
• RPGN defined as any glomerular disease
characterized by extensive crescents (usually
>50%) as the principal histologic finding and
by a rapid loss of renal function (usually a
50% decline in the glomerular filtration rate
[GFR] within 3 mo) as the clinical correlate.
• Transient azotemia with oliguria is common in
patients with acute glomerulonephritis
• Some patients have acute glomerulonephritis
and present with rapidly progressive renal
failure that develops within weeks to months
and displays little tendency for spontaneous
or complete recovery.
• Glomerular crescents can complicate any
glomerulopathy, even noninflammatory
glomerulopathy.
• In patients with noninflammatory
glomerulopathies, the crescents tend to be
fibrotic rather than cellular.
• Cellular crescents are a manifestation of a
severe inflammatory process.
Classification
Idiopathic or primary crescentic glomerulonephritis is
classified into the following types:
• Type I with linear deposits of immunoglobulin G (IgG)
(anti–glomerular basement membrane [GBM]
disease)
• Type II with granular deposits of immunoglobulin
(immune-complex mediated)
• Type III with few or no immune deposits (pauciimmune) - Antineutrophil cytoplasmic antibody
(ANCA)–associated (Renal-limited forms of ANCAassociated crescentic glomerulonephritis are thought
to be related to small vessel vasculitis [SVV] with
exclusive involvement of the glomerular capillaries.)
• Type IV combinations of types I and III
• Type V ANCA-negative renal vasculitis (5-10%)
Pathophysiology
RPGN can develop in any of the following clinical
settings:
• Complication of acute or subacute infectious process
• Renal complication of multisystem disease:
Secondary forms comprise more than 40% of cases.
• In association with use of certain drugs: A review of
published data on an association between
hydrocarbon exposure and anti-GBM antibodymediated disease suggests the possibility of a casual
relationship.
• Primary glomerular disease in which the kidney is the
sole organ involved and in which extrarenal
manifestations are caused by renal function
• Acute RPGN is mediated by antibody or cellular
immunity or by interaction of the two arms of the
immune system.
• Deposition of antibody along the basement
membrane and/or glomerular deposition of preformed
soluble immune complexes can result in
glomerulonephritis.
• Lymphocytes and macrophages, along with
deposited antibody, are important in the production of
proliferation and proteinuria.
• The involved lymphocytes are identified as T cells;
most are helper T cells with some suppressor T cells.
• Antibody- and cell-mediated immunity are together
responsible for many lesions observed in patients
with acute RPGN, and cell-mediated immunity
• Crescents are defined as the presence of 2 or more
layers of cells in the Bowman space.
• The presence of crescents in glomeruli is a marker of
severe injury.
• The initiating event is the development of a physical
disruption in the GBM.
• The lesions are mediated by processes involving
macrophages and cell-mediated immunity.
• Following disruption of the glomerular capillary,
circulating cells, inflammatory mediators, and plasma
proteins pass through the capillary wall into the
Bowman space.
• Cells and mediators from the interstitium enter the
Bowman space with disruption of the Bowman
capsule, which leads to development of crescents
• The major participants in crescent formation are coagulation
proteins, macrophages, T cells, fibroblasts, and parietal
epithelial cells. Activated macrophages contribute to the
crescents by proliferating and releasing procoagulant tissue
factor, interleukin-1 (IL-1) and tumor necrosis factor (TNF). T
cells are not prominent components, but they play an important
role in glomerular injury by antigen recognition and macrophage
recruitment.
• The reversibility of crescents correlates with relative
predominance of cellular components. Whether crescents
progress or resolve may depend upon the integrity of the
Bowman capsule and resulting cellular composition of the
crescent. Progression to fibrous crescents is more common
when capsular rupture occurs and fibroblasts along with
macrophages are prominent in the Bowman space. The
presence of fibrous crescents usually correlates with glomerular
sclerosis or irreversibility.
Mortality/Morbidity
• Renal failure at presentation carries an increased risk for endstage renal disease and death despite immunosuppressive
therapy.1 Death or dialysis occurs in 73% of patients who are
treated with conventional therapy and in 88% of patients if they
are oligoanuric at time of presentation.
Race
• No racial predilection exists.
Sex
• For RPGN types I and III, a predilection for males exists.
Age
• RPGN has a broad age distribution, as follows:
• RPGN type I generally occurs in young adults.
• RPGN types II and III generally occur in older adults; the peak
incidence occurs in the fourth to sixth decades of life.
Clinical
History
Clinical and laboratory presentations of all types of acute RPGN
are quite similar.
• Some patients present with signs and symptoms of renal
disease, for example, anemia, hematuria, fluid retention,
oliguria, or even uremia.
• Symptoms of weakness, nausea, and vomiting (indicative of
azotemia) usually dominate the clinical picture.
• Other patients present with signs and symptoms of their primary
etiology (eg, Goodpasture syndrome, Wegener granulomatosis,
systemic lupus erythematosus [SLE]).
• Still others give a history of a flulike or viral prodrome. Vague
aches and pains or frank arthritis, sinusitis, otitis, episcleritis,
skin rash, neuritis, or encephalopathy are uncommon and are
more common with a multisystem disease (suggesting
secondary form).
• Oliguria, abdominal or flank pain, and hemoptysis may occur
(eg, Goodpasture syndrome).
• Peripheral swelling may be present.
• Physical
• Blood pressure may be normal or
slightly elevated.
• Peripheral edema may be present in
10% of patients.
• Pallor is common.
• Skin rash: A lesion suggesting
leukocytoclastic vasculitis may be
present.
Causes
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Infectious diseases
Poststreptococcal
glomerulonephritis (PSGN)
Infective endocarditis
Occult visceral sepsis
Hepatitis B infection (with vasculitis
and/or cryoglobulinemia)
Multisystem diseases
SLE
Henoch-Schönlein purpura
Systemic necrotizing vasculitis
(including Wegener granulomatosis)
Microscopic polyarteritis
Goodpasture syndrome
Essential mixed (IgG and
immunoglobulin M [IgM])
cryoglobulinemia
Malignancy
Relapsing polychondritis
Rheumatoid vasculitis
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Drugs
Penicillamine
Hydralazine (rare case reports)
Allopurinol (with vasculitis)
Rifampin (rare case reports)
Propylthiouracil, thiamazole, carbimazole,
benzylthiouracil
Aminoguanidine
Primary glomerular disease
Idiopathic or primary crescentic
glomerulonephritis
Type I with linear deposits of IgG (anti-GBM
disease)
Type II with granular deposits of immunoglobulin
(immune-complex mediated)
Type III with few or no immune deposits (pauciimmune) - ANCA-associated (renal-limited
microscopic polyarteritis)
Type IV combinations of types I and IIIa
Type V ANCA-negative renal vasculitis (5-10%)
Superimposed on another primary glomerular
disease
Membranoproliferative glomerulonephritis
(MPGN) type II
Membranous glomerulonephritis
Differential Diagnoses
• Acute Renal Failure
• Nephritis, Interstitial
• Glomerulonephritis, Acute
• Thrombotic Thrombocytopenic Purpura
• Hemolytic-Uremic Syndrome
• Hypertension
• Hypertension, Malignant
Paradigm for the diagnosis of crescentic GN
Treatment & Medication
• Early and aggressive treatment is
warranted to preserve renal function
• A nephrologist should be involved early in
the disease course
• Renal diet: Provide a low-salt, low-protein
(0.8 g/kg/d) diet, if renal dysfunction is
present. Restrict potassium if the patient
has hyperkalemia. Avoid malnutrition
• No specific limitations are necessary other
than limiting activity after renal biopsy
Medication - Principles of therapy
• Supportive therapy involves control of
infection, control of volume status (providing
dialysis if required), and smoking cessation
• Specific therapy is directed toward providing
immunosuppressive therapy (eg,
glucocorticoids, cyclophosphamide,
azathioprine, mycophenolate [MMF]), plasma
exchange (in patients presenting with lifethreatening pulmonary hemorrhage or
advanced renal failure, ie, creatinine level of
>500 µmol/L1 ), and anticoagulant agents
• Recently, monoclonal antibodies (eg,
infliximab, rituximab), alemtuzumab,
pentoxifylline (reduces TNF), mizoribine (a
purine synthesis inhibitor), and antithymocyte
globulin have been used with encouraging
results in a small number of patients, but
controlled trials are needed
• At present, the mainstay of therapy remains
cyclophosphamide and steroids for induction
of remission
Glucocorticoids
• Pulses of intravenous
methylprednisolone (5-20 mg/kg)
followed by high-dose oral
prednisone (2 mg/kg) daily or on
alternate days for 2-3 months have
shown improved 1-year renal
survival rates of 40-70%
Methylprednisolone
Prednisone
• Potent anti-inflammatory
steroid with greater antiinflammatory potency and
fewer tendencies to induce
retention of salt and water
than prednisolone
• Adult: 0.5-1 g (5-20 mg/kg)
IV bolus qd for 3 d, followed
by prednisone 2 mg/kg PO
daily or on alternate days for
2-3 mo
• Pediatric: 30 mg/kg IV qd for
3 d, followed by prednisone
2 mg/kg PO qd
• Decreases inflammation
through multiple
mechanisms. Reduced to its
pharmacologically active
form prednisolone.
• When used on a long-term
basis, alternate-day therapy
may elicit fewer adverse
effects than daily therapy
• Adult: 2 mg/kg PO qd for 2-3
mo; then, taper dose
• Pediatric: Administer as in
adults
Methylprednisolone
Interaction:
• Coadministration with
digoxin may increase
digitalis toxicity secondary to
hypokalemia; estrogens may
increase levels of
methylprednisolone;
phenobarbital, phenytoin,
and rifampin may decrease
levels of methylprednisolone
(adjust dose); monitor
patients for hypokalemia
when taking medication
concurrently with diuretics
Contraindication:
• Documented
hypersensitivity; viral, fungal,
or tubercular skin infections
Prednisone
Interaction:
• Coadministration with
estrogens may decrease
clearance; concurrent use
with digoxin may cause
digitalis toxicity secondary to
hypokalemia; phenobarbital,
phenytoin, and rifampin may
increase metabolism of
glucocorticoids (consider
increasing maintenance
dose); monitor for
hypokalemia with
coadministration of diuretics
Contraindication:
• Documented
hypersensitivity; viral
infection, peptic ulcer
disease, hepatic dysfunction,
connective-tissue infections,
Methylprednisolone
Pregnancy
• C - Fetal risk revealed in
studies in animals but not
established or not studied in
humans; may use if benefits
outweigh risk to fetus
Precautions
• Hyperglycemia, edema,
osteonecrosis, peptic ulcer
disease, hypokalemia,
osteoporosis, euphoria,
psychosis, growth
suppression, myopathy, and
infections are possible
complications of
glucocorticoid use; may
result in partial loss of
hypertension control
Prednisone
Pregnancy
• B - Fetal risk not confirmed
in studies in humans but has
been shown in some studies
in animals
Precautions
• Abrupt discontinuation of
glucocorticoids may cause
adrenal crisis;
hyperglycemia, edema,
osteonecrosis, myopathy,
peptic ulcer disease,
hypokalemia, osteoporosis,
euphoria, psychosis,
myasthenia gravis, growth
suppression, and infections
may occur with
glucocorticoid use
Immunosuppressive agents
(cytotoxics)
• Addition of cytotoxic agents to
corticosteroids has yielded varying
success in treating patients with
crescentic glomerulonephritis.
• Although pulse cyclophosphamide is
often preferred in lupus nephritis, oral
cyclophosphamide appears to have an
advantage in Wegener granulomatosis.
• Oral versus intravenous: Recently
completed, prospectively randomized
Cyclophosphamide daily oral versus
PulSed (CYCLOPS) trial has shown
very little difference in time to remission
and time to relapse between daily oral
or intermittent intravenous
cyclophosphamide for induction therapy
• Cyclophosphamide 3 mg/kg/d for 12 weeks is
a common recommendation, but the duration
of therapy may be longer (4-6 mo) in patients
with pauci-immune glomerulonephritis.
• This therapy should be followed by the
administration of azathioprine (1.5-2 mg/kg/d)
or methotrexate (5-20 mg qwk as a single
dose) until the patient is in remission for at
least 6-12 months.
• The duration of azathioprine therapy to
prevent further relapses is unknown, but it
should be at least for 2 years
• Continuing cyclophosphamide for longer than
6 months is not necessary, as recently shown
by Cyclophosphamide versus Azathioprine
during Remission (CYCAZAREM) trial, where
the time to relapse was identical whether the
patient was given cyclophosphamide for less
than 6 months or more than 6 months.
• Recent evidence suggests that
mycophenolate mofetil (CellCept) 0.75-1 g
bid may also be effective in patients with
pauci-immune vasculitis.
Cyclophosphamide
• Activated in the liver to
its active metabolite, 4hydroxycyclophosphami
de, which alkylates the
target sites in
susceptible cells in an
all-or-none–type
reaction.
• Adult: 3 mg/kg PO qd
for 12 wk
• Pediatric: 2 mg/kg/d PO
qd
Azathioprine
• Mechanism by which
azathioprine affects
autoimmune diseases is
unknown. Slow acting,
and its effects may
persist after
discontinuation.
• Adult: 3 mg/kg PO qd
for 12 wk
• Pediatric: 2 mg/kg/d PO
qd
• Allopurinol may increase risk of
bleeding or infection and may
• Toxicity increases with
enhance myelosuppressive effects
allopurinol; concurrent use
of cyclophosphamide; may
with ACE inhibitors may
potentiate doxorubicin-induced
induce severe leukopenia;
cardiotoxicity; may reduce digoxin
may increase levels of
serum levels and antimicrobial
effects of quinolones;
methotrexate metabolites
chloramphenicol may increase halfand decrease effects of
life of cyclophosphamide, while
anticoagulants,
decreasing metabolite
neuromuscular blockers, and
concentrations; may increase effect
cyclosporine
of anticoagulants; coadministration
with high doses of phenobarbital
may increase rate of metabolism
and leukopenic activity of
cyclophosphamide; thiazide
diuretics may prolong
cyclophosphamide-induced
Contraindication:
• Documented hypersensitivity, severely
depressed bone marrow function
Pregnancy
• D - Fetal risk shown in humans; use only
if benefits outweigh risk to fetus
Precautions
• Regularly examine hematologic profile
(particularly neutrophils and platelets) to
monitor for hematopoietic suppression;
regularly examine urine for RBCs, which
may precede hemorrhagic cystitis; young
adults in reproductive age group should
be advised about the risk of infertility, and
appropriate steps should be taken to
avoid this problem (either considering use
of a sperm bank or use of leuprolide to
suppress gonadotrophic function during
the treatment course); malignancy of
urinary bladder or lymphatic system may
Contraindication:
• Documented
hypersensitivity
Pregnancy
• D - Fetal risk shown in
humans; use only if
benefits outweigh risk to
fetus
Precautions
• Increases risk of
neoplasia; caution with
liver disease and renal
impairment; hematologic
toxicities may occur
Antibiotics
• Therapy must be comprehensive and
should cover all likely pathogens in
the context of this clinical setting.
Trimethoprim-sulfamethoxazole
• Long-term treatment with TMP (160 mg) and SMX
(800 mg) bid has been reported in a prospective,
controlled, double-blind trial to sustain remission of
Wegener granulomatosis.
• The mechanism of this effect is not clear. Eradication
of Staphylococcus aureus in the anterior nares of
patients with Wegener granulomatosis has recently
been reported to sustain remission of Wegener
granulomatosis.
• TMP-SMX is also helpful as Pneumocystis carinii
pneumonia (PCP) prophylaxis in patients who are on
corticosteroids and other immunosuppressive agents
• Adult
• TMP 160 mg/SMX 800 mg
PO q12h; adjust dose per
renal function:
CrCl >25 mL/min: No change
CrCl 15-25 mL/min: Reduce
dose by 50%
CrCl <15 mL/min: Not
recommended
• Pediatric
• <2 months: Do not
administer
>2 months: 5-10 mg/kg/d PO
tid/qid, based on TMP
Interactions:
• May increase PT when used with
warfarin (perform coagulation
tests, and adjust dose
accordingly); coadministration
with dapsone may increase
blood levels of both drugs;
coadministration of diuretics
increases incidence of
thrombocytopenia purpura in
elderly; phenytoin levels may
increase with coadministration;
may potentiate effects of
methotrexate in bone marrow
depression; hypoglycemic
response to sulfonylureas may
increase with coadministration;
may increase levels of
• Contraindications:
• Documented hypersensitivity; megaloblastic anemia due to
folate deficiency
• Pregnancy
• C - Fetal risk revealed in studies in animals but not established
or not studied in humans; may use if benefits outweigh risk to
fetus
• Precautions
• Discontinue at first appearance of skin rash or sign of adverse
reaction; obtain CBC counts frequently; discontinue therapy if
significant hematologic changes occur; goiter, diuresis, and
hypoglycemia may occur with sulfonamides; prolonged IV
infusions or high doses may cause bone marrow depression (if
signs occur, administer 5-15 mg/d leucovorin); caution in folate
deficiency (eg, patients with chronic alcoholism, the elderly,
patients receiving anticonvulsant therapy, or patients with
malabsorption syndrome); hemolysis may occur in individuals
with G-6-PD deficiency; patients with AIDS may not tolerate or
respond to TMP-SMX; caution in renal or hepatic impairment
(perform urinalyses and renal function tests during therapy);
give fluids to prevent crystalluria and stone formation
Follow-up
Further Inpatient Care
• Intensive plasma exchange: Plasmapheresis (24 L of plasma qd or 3 times/wk), combined with
glucocorticoids and cytotoxic agents, is
beneficial in anti–GBM-mediated disease,
provided therapy is initiated before renal failure
has progressed to require dialysis support.
• Plasma exchange is also valuable as an
adjunctive measure in patients with positive
ANCA results who present with life-threatening
pulmonary hemorrhage (ie, MEthylprednisolone
versus Plasma EXchange [MEPEX]) or
advanced renal failure
Further Inpatient Care
• Plasma exchange increased the rate of renal
recovery in ANCA-associated systemic vasculitis that
presented with renal failure when compared with
intravenous methylprednisolone; however, patient
survival and adverse event rates were similar in both
groups
• In the absence of any response within 3-5 weeks,
acceptance of a diagnosis of end-stage renal
disease is preferable to death secondary to
iatrogenic causes
Further Inpatient Care
• High-dose intravenous immunoglobulin has been
reported to be successful in suppressing the activity
of pauci-immune ANCA-positive vasculitis. The
mechanism is not clear, but pooled normal
immunoglobulin contains antibodies that neutralize
ANCA and suppress complement activation through a
nonspecific effect of the immunoglobulin heavy
chains
• Intravenous immunoglobulin may have a role in the
temporary management of severe pauci-immune
vasculitis when severe infection is present in patients
in whom it is desirable to withhold cytotoxic agents
and high-dose corticosteroids until the infection is
controlled
Further Inpatient Care
• In difficult to treat cases of ANCA-associated
vasculitis, humanized monoclonal anti-CD52
antibodies (alemtuzumab, CAMPATH-1H) that
selectively deplete lymphocytes may be considered.
In a recent study by Walsh et al, CAMPATH-1H
induced remission in such a group of patients,
but relapse and adverse events were common.3
Further study of CAMPATH-1H as an induction
agent is warranted.
Further Outpatient Care
• After induction of remission with oral
cyclophosphamide and steroids, conversion to oral
azathioprine (2 mg/kg/d) at 3 months appears to be
safe and effective compared to continuation of
cyclophosphamide for 1 year (if clinical signs of
activity are minimal and preferably ANCA is
negative).
• The duration of maintenance therapy with
azathioprine to prevent further relapses is unknown
but should be at least for 2 years. Studies of longer
periods of azathioprine maintenance (2 y vs 4 y) are
in progress (eg, Randomized trial of prolonged
REmission-MAINtenance therapy in systemic
vasculitis [REMAIN]).
• Monitor BUN, electrolyte, and serum creatinine levels
in all patients.
• Drug-responsive relapses may occur as late as 2-4
years after remission.
• RPGN may recur after renal transplantation. At
present, after initiating dialysis, a waiting period of 36 months is recommended before considering renal
transplantation.
• No convincing evidence suggests that a bilateral
nephrectomy performed before a renal
transplantation reduces the risk of recurrent disease
in patients with renal allografts
• For patients who have achieved remission,
evaluation at 2-month intervals is usually sufficient.
The following testing is recommended:
o Urinalysis with special emphasis on the presence of
cellular casts: BUN, electrolyte, and serum creatinine
levels should be evaluated in all patients.
o C-reactive protein or ESR (whichever correlates
better with disease activity in a given patient)
o ANCA (in ANCA-positive patients at 6- to 9-mo
intervals): An increasing ANCA titer is often evidence
of an impending relapse. A 4-fold or higher rise in
ANCA titer may herald a relapse and require
preemptive intervention.
o Anti-GBM titers in patients with anti-GBM
Inpatient & Outpatient
Medications
• Administer oral cyclophosphamide for 4-6
months, followed by azathioprine or
methotrexate until the patient is in remission
for 6 months to 1 year.
• Administer prednisone as a low-dose
alternative for 6-9 months.
• Administer trimethoprim-sulfamethoxazole
160/800 mg bid (for Wegener
granulomatosis) if renal function normal.
Decrease the dose as guided by renal
function. A lower dosage as PCP prophylaxis
may be considered.
Transfer
Patients may need to be transferred
to another center for the following:
• Plasmapheresis
• Dialysis
• Ventilatory support
Deterrence/Prevention
• Because patients with pauci-immune
vasculitis typically have a prodrome lasting
for weeks to months—during which time they
experience 1 or more vague symptoms (eg,
intermittent fever, weight loss, anorexia,
arthralgias, shortness of breath, hemoptysis,
middle ear effusions, conjunctivitis,
episcleritis, nasal septal perforation, saddle
nose deformity)—a high index of clinical
awareness, early diagnosis, and treatment
may prevent significant morbidity and
mortality associated with this condition.
Prognosis
• In general, the prognosis is poor and aggressive
therapy is warranted. The chance of renal recovery
exceeds the chance of dying in most cases.
Intravenous methylprednisolone as an adjunctive
therapy plus less than 18% normal glomeruli and
severe tubular atrophy increased the chance of
therapy-related death over the chance of dialysis
independence. Plasma exchange treatment plus
severe tubular atrophy and less than 2% normal
glomeruli increased the chance of therapy-related
death over that of dialysis independence.5
• Fifty percent of patients require maintenance dialysis
within 6 months of disease onset.
• Spontaneous remission is uncommon, except among
patients with infection as the basis for formation of
antigen-antibody complexes, in whom removal of the
Poor prognostic factors are as follows:
o Large crescents in more than 80% of
glomeruli (especially if fibrocellular or
acellular)
o Initial serum creatinine level of more than 500
µmol/L or GFR of less than 5 mL/min at
presentation
o Oliguria
o Presence of anti-GBM antibody
o Age older than 60 years
o Coexistence of HLA-DR2 and HLA-B7
Patient Education
• Patients receiving immunosuppressive
therapy should be educated about early signs
of infection and advised to see their physician
or health care worker at the early signs of
infection in order to monitor WBC count.
• Patients on a high dose of prednisone should
be monitored for the development of diabetes
and peptic ulcer disease and receive therapy
to prevent steroid-induced osteoporosis.
Medicolegal Pitfalls
• A high index of clinical awareness is important in order to make
an early diagnosis in patients presenting with ill-defined fever,
weight loss, anorexia, arthralgias, hemoptysis, middle ear
effusions, deafness, nasal septal perforation, and saddle nose
deformity.
• Consider eradication of S aureus in anterior nares of patients
with Wegener granulomatosis for sustained remission.
• Be careful with immunosuppressive therapy (both cytotoxic
agents and high-dose corticosteroids) in patients who may have
active infection.
• Ensuring that the patient has no active infection is important
before starting immunosuppressive therapy in order to prevent
significant morbidity and mortality associated with treatment of
this disease.
• Intravenous immunoglobulin may be useful to control disease
activity when the patient has associated active infection and the
need to hold immunosuppressive agents.
• The adverse effects and toxicities of long-term corticosteroid
and immunosuppressive therapy must be discussed with the
patient.
• With long-term steroid use, monitoring the patient for the
development of diabetes, peptic ulcer disease, and osteoporosis
is important, as is prescribing cytoprotective agents (to prevent
peptic ulceration) and preventive therapy for steroid-induced
osteoporosis.
• In patients who are in the reproductive age group, discuss and
document the effect on fertility of cytotoxic therapy. Patients
should be counseled for sperm or egg preservation, or
consideration should be given to leuprolide therapy to inhibit
gametogenesis during treatment with cyclophosphamide
therapy.
• To prevent risk of hemorrhagic cystitis, patients on oral
cyclophosphamide should be encouraged to drink plenty of
fluids so that the metabolites of cyclophosphamide do not
concentrate in the bladder.
• The possibility of late malignancy associated with cytotoxic
therapy should be discussed and documented in the patient's
chart.
• Failure to diagnose or empirically treat pending diagnosis, with a