Crescentic Glomerulonephritis

1
Crescentic Glomerulonephritis
2

• RPGN defined as any glomerular disease
  characterized by extensive crescents (usually
  gt50) 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

3

• 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.

4
Classification

• Idiopathic or primary crescentic
  glomerulonephritis is classified into the
  following types
• Type I with linear deposits of immunoglobulin G
  (IgG) (antiglomerular basement membrane GBM
  disease)
• Type II with granular deposits of immunoglobulin
  (immune-complex mediated)
• Type III with few or no immune deposits
  (pauci-immune) - Antineutrophil cytoplasmic
  antibody (ANCA)associated (Renal-limited forms
  of ANCA-associated 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)

5
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
  antibody-mediated 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
  disturbances

6

• 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
  without antibody may produce crescentic
  glomerulonephritis.

7

• 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

8

• 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.

9

• Mortality/Morbidity
• Renal failure at presentation carries an
  increased risk for end-stage 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.

10
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.
• Fifteen percent of patients may be asymptomatic.

11

• 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.

12
Causes

• 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
  (pauci-immune) - 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
• Immunoglobulin A (IgA) nephropathy

• 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

13
Differential Diagnoses

• Acute Renal Failure
• Nephritis, Interstitial
• Glomerulonephritis, Acute
• Thrombotic Thrombocytopenic Purpura
• Hemolytic-Uremic Syndrome
• Hypertension
• Hypertension, Malignant

14
Paradigm for the diagnosis of crescentic GN
15
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

16
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 life-threatening pulmonary hemorrhage or
  advanced renal failure, ie, creatinine level of
  gt500 µmol/L1 ), and anticoagulant agents

17

• 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

18
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

19

• Methylprednisolone
• Potent anti-inflammatory steroid with greater
  anti-inflammatory 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

• Prednisone
• 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

20
Methylprednisolone
Prednisone

• 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

• 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, and fungal or
  tubercular skin infections GI disease

21
Methylprednisolone
Prednisone

• 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

• 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

22
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.

23

• 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

24

• 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

25

• 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.

26
Cyclophosphamide
Azathioprine

• Activated in the liver to its active metabolite,
  4-hydroxycyclophosphamide, which alkylates the
  target sites in susceptible cells in an
  all-or-nonetype reaction.
• Adult 3 mg/kg PO qd for 12 wk
• Pediatric 2 mg/kg/d PO qd

• 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

27

• Allopurinol may increase risk of bleeding or
  infection and may enhance myelosuppressive
  effects of cyclophosphamide may potentiate
  doxorubicin-induced cardiotoxicity may reduce
  digoxin serum levels and antimicrobial effects of
  quinolones chloramphenicol may increase
  half-life of cyclophosphamide, while decreasing
  metabolite concentrations may increase effect of
  anticoagulants coadministration with high doses
  of phenobarbital may increase rate of metabolism
  and leukopenic activity of cyclophosphamide
  thiazide diuretics may prolong cyclophosphamide-in
  duced leukopenia and neuromuscular blockade by
  inhibiting cholinesterase activity

• Toxicity increases with allopurinol concurrent
  use with ACE inhibitors may induce severe
  leukopenia may increase levels of methotrexate
  metabolites and decrease effects of
  anticoagulants, neuromuscular blockers, and
  cyclosporine

28

• 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 occur

• 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

29
Antibiotics

• Therapy must be comprehensive and should cover
  all likely pathogens in the context of this
  clinical setting.

30
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

31

• 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 zidovudine

• Adult
• TMP 160 mg/SMX 800 mg PO q12h adjust dose per
  renal functionCrCl gt25 mL/min No changeCrCl
  15-25 mL/min Reduce dose by 50CrCl lt15 mL/min
  Not recommended
• Pediatric
• lt2 months Do not administergt2 months 5-10
  mg/kg/d PO tid/qid, based on TMP

32

• 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

33
Follow-up
Further Inpatient Care

• Intensive plasma exchange Plasmapheresis (2-4 L
  of plasma qd or 3 times/wk), combined with
  glucocorticoids and cytotoxic agents, is
  beneficial in antiGBM-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

34
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

35
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

36
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.

37
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-MAINtenanc
  e therapy in systemic vasculitis REMAIN).

38

• 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 3-6 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

39

• For patients who have achieved remission,
  evaluation at 2-month intervals is usually
  sufficient. The following testing is
  recommended  
• Urinalysis with special emphasis on the presence
  of cellular casts BUN, electrolyte, and serum
  creatinine levels should be evaluated in all
  patients.
• C-reactive protein or ESR (whichever correlates
  better with disease activity in a given patient)
• 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.
• Anti-GBM titers in patients with anti-GBM

40
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.

41
Transfer

• Patients may need to be transferred to another
  center for the following
• Plasmapheresis
• Dialysis
• Ventilatory support

42
Deterrence/Prevention

• Because patients with pauci-immune vasculitis
  typically have a prodrome lasting for weeks to
  monthsduring 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.

43
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 antigen can take place.

44

• Poor prognostic factors are as follows  
• Large crescents in more than 80 of glomeruli
  (especially if fibrocellular or acellular)
• Initial serum creatinine level of more than 500
  µmol/L or GFR of less than 5 mL/min at
  presentation
• Oliguria
• Presence of anti-GBM antibody
• Age older than 60 years
• Coexistence of HLA-DR2 and HLA-B7

45
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.

46
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.

47

• 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 resulting rise of serum
  creatinine to unsalvageable levels (gt6 mg/dL or
  500 µmol/L), is a potential medicolegal pitfall.