AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Diffuse proliferative glomerulonephritis (DPGN) is a term used to describe a distinct histologic form of glomerulonephritis common to various types of systemic inflammatory diseases, including autoimmune disorders (eg, systemic lupus erythematosus [SLE]), vasculitis syndromes (eg, Wegener granulomatosis), and infectious processes. More than 50% of the glomeruli (diffuse) demonstrate increased mesangial, epithelial, endothelial (proliferative), and inflammatory cells (ie, glomerulonephritis). In contrast, when fewer than 50% of the glomeruli are involved, the condition is termed focal proliferative, an entity with a potential to progress to DPGN. The diagnosis is often suspected in a patient presenting with systemic inflammatory disease who manifests hematuria, proteinuria, and active urinary sediment or azotemia (ie, rise in serum blood urea nitrogen, creatinine); histologic findings from kidney biopsy tissue are used to confirm the diagnosis.

Sporadic forms of renal diseases manifesting as focal, segmental, necrotizing, and crescentic glomerulonephritis or DPGN with undetermined incidence include microscopic polyangiitis; Churg-Strauss syndrome; essential mixed cryoglobulinemia, which also may manifest as membranoproliferative glomerulonephritis; Henoch-Schönlein purpura; and connective tissue diseases.

In severe forms, epithelial proliferation obliterates the Bowman space (ie, crescents). The resulting acute renal failure may manifest as an acute anuria or a steady decline in renal function. Spontaneous remission is rare, and treatment results are anecdotal.

Pathophysiology

Most cases of DPGN result from the deposition of immune complexes in the mesangium, glomerular basement membrane (GBM), subendothelial or subepithelial locations. Antibodies may form immune complexes with circulating DNA before deposition (ie, immune complex deposition) or may bind directly to nonglomerular antigens already planted in the mesangium or GBM (ie, in situ immune complex formation). In anti-GBM disease, the antibodies act against the GBM. The pathogenesis of antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis is unknown, although microvasculitis is the predominant feature without immune complex formation.

Activation of the complement system through the classic pathway by immune complexes or direct cell-mediated injury in ANCA-associated glomerulonephritis results in the recruitment of inflammatory cellular infiltrates (eg, lymphocytes, macrophages, neutrophils), proliferation of the mesangial and endothelial cells, and necrosis. Cellular crescents and fibrin thrombi may be present in more severe cases. The net result is obliteration of the capillary loops and sclerosis, predisposing the patient to hypertension and renal failure.

The cellular and immunologic attack of the glomerulus renders the GBM permeable to protein, red blood cells, and white blood cells. Therefore, urinalysis during active inflammation characteristically shows an active urinary sediment, ie, red blood cells or casts, white blood cells or casts, and variable degrees of proteinuria (ie, nephritic pattern).

Anti-GBM disease is an autoimmune disease in which autoantibodies are directed against type IV collagen in the GBM. Binding of these autoantibodies to the GBM induces rapidly progressive glomerulonephritis (RPGN) and crescentic glomerulonephritis. The clinical complex of anti-GBM nephritis and lung hemorrhage is Goodpasture syndrome. The typical morphologic pattern using light microscopy is DPGN, with focal necrotizing lesions and crescents in more than 50% of glomeruli (ie, crescentic glomerulonephritis). Acute nephrotic syndrome is rare, and a bimodal peak in incidence exists. Although any age group may be affected, the first peak in incidence occurs in the third to the sixth decades of life and the second occurs in the sixth to the seventh decades of life.

In patients with Wegener granulomatosis, renal biopsy findings typically reveal focal, segmental, necrotizing, pauci-immune glomerulonephritis with crescent formation.

In microscopic polyarteritis nodosa (PAN), the usual histopathologic lesion is a pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. In Churg-Strauss syndrome, a minority of patients may develop focal segmental necrotizing glomerulonephritis; in mixed cryoglobulinemias, the characteristic morphologic lesions are diffuse mesangial proliferative or membranoproliferative glomerulonephritis. For Henoch-Schönlein purpura, light microscopic appearances can vary from mild mesangial proliferation and expansion to diffuse proliferation with glomerular crescents.

In rheumatoid arthritis (RA), lesions of mesangial proliferative glomerulonephritis and basement membrane thickening caused by subepithelial immune deposits may be observed. Occasional cases of focal mesangial proliferative glomerulonephritis with mesangial deposition of immunoglobulin G (IgG) and complement have been described in polymyositis and dermatomyositis.

In addition to poststreptococcal glomerulonephritis, the nephritic syndrome and RPGN can complicate acute immune-complex glomerulonephritis due to other viral, bacterial, fungal, and parasitic infections. Some of these warrant specific mention. Diffuse proliferative immune complex glomerulonephritis is a well-described complication of acute and subacute bacterial endocarditis and usually is associated with hypocomplementemia. The glomerular lesion typically resolves following eradication of the cardiac infection. Shunt nephritis is a syndrome characterized by immune complex glomerulonephritis secondary to infection of ventriculoatrial shunts inserted for treatment of childhood hydrocephalus.

The most common offending organism is coagulase-negative Staphylococcus. Renal impairment usually is mild and is associated with hypocomplementemia. Nephrotic syndrome complicates 30% of cases. Acute proliferative glomerulonephritis can also complicate chronic suppurative infections and visceral abscesses. Patients typically present with a fever of unknown origin and an active urine sediment. Although renal biopsy is used to detect immune deposits containing IgG and C3, serum complement levels usually are within the reference range.

Frequency

United States

The incidence of SLE in urban areas varies from 15-50 cases per 100,000 population per year. Renal involvement is evident clinically in 40-85% of patients with SLE. DPGN is the lesion observed in 35-40% of biopsies in lupus nephritis, and as many as 30% of these patients progress to terminal renal failure.

Anti-GBM disease is a rare disorder of unknown etiology with an annual incidence of 0.5 cases per million. About 50-70% of patients have lung hemorrhage; anti-GBM antibodies develop in the serum of more than 90% of patients with anti-GBM nephritis according to findings on specific radioimmunoassay.

Renal injury occurs in 80% of patients with Wegener granulomatosis. Renal biopsy tissue typically reveals focal, segmental, necrotizing, pauci-immune glomerulonephritis with crescent formation, which may progress to DPGN.

Cytoplasmic ANCAs are detected at presentation in 80% of patients with renal disease and in 10% more during follow-up. In contrast to the lung, granulomas rarely develop in the kidney.

Most cases of acute poststreptococcal glomerulonephritis are sporadic, although the disease can occur as an epidemic. The characteristic lesion visible using light microscopy is DPGN. Crescents may be present, and extraglomerular involvement usually is mild.

Nephritis is present in 80% of cases of Henoch-Schönlein purpura and manifests as a nephrotic urine sediment and moderate proteinuria. Macroscopic hematuria and nephrotic range proteinuria are uncommon.

International

The incidence of DPGN in renal biopsies varies from approximately 10-27% in Europe and 30% in the Middle East to 41% in Japan. Worldwide, the most common glomerulopathy is due to immunoglobulin A (IgA) nephropathy, accounting in most series for 10-40% of all glomerulonephritis. Up to 80% of patients with Henoch-Schönlein purpura (ie, anaphylactoid purpura), which is a distinct systemic vasculitis syndrome that is characterized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, and gastrointestinal signs and symptoms, have DPGN.

In 1987, after the introduction of assays for antineutrophil cytoplasmic antibodies (ANCA), the diagnosis of ANCA-positive vasculitis (ie, Wegener granulomatosis, microscopic polyarteritis) rose from 1.5 cases per million to about 6-7 cases per million.

Mortality/Morbidity

Advances in immunosuppressive therapy and renal replacement therapy have markedly reduced the mortality and morbidity rates of DPGN in the last 2 decades. A significant portion of morbidity and mortality rates in DPGN is due to complications of immunosuppressive therapy, including drug toxicity and infection.

• In one short-term study consisting of 25 patients with severe lupus whose cases were followed for 9.4 months, the combined crude mortality (1 patient) plus end-stage renal disease ([ESRD] 1 patient) rate was 8%.
• In one 10-year follow-up study of 86 patients treated aggressively (ie, with high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) for severe lupus nephritis, patient survival at 5 and 10 years was 95% in the group that had remission. In the group without remission, patient survival was 69% at 5 years and 60% at 10 years. Renal survival rates were 94% at 5 and 10 years in the remission group but 46% at 5 years and 31% at 10 years in the group with no remission.
• Mortality due to poststreptococcal glomerulonephritis is rare. Prior to the introduction of immunosuppressive therapy, more than 80% of patients with anti-GBM nephritis developed ESRD within 1 year, and many patients died from pulmonary hemorrhage or complications of uremia and infection. Renal failure is a poor prognostic marker for survival in patients with Wegener granulomatosis. In a series of 104 patients who presented to the Cleveland Clinic Foundation from 1982-1997, 11 of 23 patients who required dialysis died. In a Norwegian study of 108 patients with Wegener granulomatosis and renal involvement, 2- and 5-year renal survival rates were 86% and 75%, respectively. The 2- and 5-year patient survival rates were 88% and 74%, respectively. IgA nephropathy has an indolent course with a favorable outcome.
• The actuarial renal survival rate in adults after 10 years is 80-85% in most of the European and Asian studies, is slightly less in studies from the United States, and is more than 90% in the few studies of children. Renal death due to DPGN in IgA nephropathy is rare.

Race

Lupus nephritis has a 3-4 times greater incidence in black patients than in white patients. IgA nephropathy is more common in people of Asian origin than it is in whites of African American origin. Wegener granulomatosis is extremely rare in blacks compared to whites

Sex

• Men tend to have more aggressive disease than women. However, for SLE, the female-to-male incidence ratio is 9:1 for women of childbearing age. By comparison, the female-to-male ratio is only 2:1 for disease developing during childhood or in people aged 65 or older. Males who develop SLE have the same incidence of renal disease as do females.
• Microscopic PAN is more common in males (ie, male-to-female ratio of 2:1). The distribution of Wegener granulomatosis among the sexes is roughly equal, with a slight male predominance. Males have a 2.7 times higher incidence of IgA nephropathy than females.

Age

• Patients with Goodpasture syndrome typically are young males aged 5-40 years (the male-to-female ratio is 6:1). In contrast, patients presenting during the second peak in incidence, occurring in the sixth decade of life, rarely experience lung hemorrhage and have an almost equal sex distribution.
• SLE occurs in all age groups, with the peak incidence occurring in women of childbearing age. Over 85% of patients are younger than 55 years.
• Wegener granulomatosis develops in people of any age. Approximately 15% of patients are younger than 19 years, and only rarely does the disease occur before adolescence. The mean age of onset is approximately 40 years. The mean age of patients at onset in reports of PAN and microscopic polyangiitis is 48 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Focus the history on the causes of DPGN and the associated symptoms. While a minority of patients may be asymptomatic (ie, <15%) and are diagnosed during routine laboratory examination, most patients manifest signs of the primary disease as well as those relating to renal injury.

• Suspect DPGN in patients with SLE, infectious disease processes, a recent streptococcal throat infection, or in patients with sinopulmonary disease who have recent onset of the following:
• • Hypertension
  • Microscopic or gross hematuria
  • Nonnephrotic or nephrotic range proteinuria or an increase in proteinuria from baseline
  • Serum creatinine of more than 0.4 mg/dL from the reference range or the baseline
  • Oligoanuria and symptoms of uremia in severe cases of RPGN with crescent formation
• Also suspect DPGN in a patient with other systemic diseases who has recent onset of the same findings listed above.
• Nonspecific symptoms, including nausea, vomiting, fatigue, or weight loss may indicate uremia or symptoms of the primary disease process.
• A history of rash; photosensitivity; oral ulcers; arthralgias; arthritis; serositis; or a renal, neurologic, hematologic, or immunologic disorder suggests SLE as the primary disease.
• A history of cough, dyspnea, hemoptysis, and renal disease suggests Goodpasture syndrome, but other pulmonary-renal syndromes must be ruled out, including SLE pneumonitis, Wegener granulomatosis, cryoglobulinemia, renal vein thrombosis with pulmonary embolism, legionella infection, and congestive heart failure.
• Patients with Wegener granulomatosis present with sinopulmonary disease (ie, paranasal sinus pain and drainage with purulent or bloody nasal discharge and occasional nasal mucosal ulceration/perforation, leading to saddle nose deformity), serous otitis media (ie, blockage of the eustachian tube), cough, dyspnea, and hemoptysis.
• Patients with IgA nephropathy (ie, Berger disease) may present with the classic findings of flank pain and gross hematuria following upper respiratory infections. Others may simply have indolent microhematuria found incidentally. Much less commonly, patients present with acute glomerulonephritis, renal failure, and nephrotic syndrome.

Physical

• If azotemia is present, exclude prerenal and postrenal causes (see Azotemia).
• Nonspecific findings that suggest DPGN
• • Hypertension
  • Fever, present in both infectious and noninfectious glomerulonephritis
• Findings pertaining to SLE include the often acute onset of conjunctivitis, episcleritis, photosensitivity, oral ulcers, malar rash (eg, erythema of the nose and malar eminences in a butterfly distribution), discoid lupus, pleural or pericardial friction rub, psychosis, seizures, nonerosive arthritis, or arthralgia
• Findings relating to pauci-immune disease (eg, anti-GBM disease, Wegener granulomatosis) and Goodpasture syndrome
• • Sinusitis, otitis, saddle nose deformity, hemoptysis
  • Lung consolidation, which suggests pulmonary hemorrhage
• Findings relating to IgA nephropathy (usually postinfectious) and other infectious glomerulonephritis
• • Pharyngitis, gastroenteritis
  • Impetigo, which is the most common cause of poststreptococcal glomerulonephritis worldwide

Causes

• Immunoglobulin A (IgA) nephropathy and SLE are the most common causes. Other etiologies are less frequent but are more likely to lead to RPGN.
• Systemic diseases
• • Lupus nephritis class IV, IgA nephropathy
  • Goodpasture syndrome, Wegener granulomatosis, microscopic polyangiitis, Henoch-Schönlein purpura
  • Cryoglobulinemia, vasculitis
• Infectious causes
• • Poststreptococcal glomerulonephritis, which occurs 2-4 weeks after streptococcal sore throat or skin infection
  • Infective endocarditis, hepatitis B, hepatitis C
• Histologic transformation
• • In patients with class IV lupus nephritis, histologic transformation from one class to another is recorded in up to 40% of repeat biopsies.
  • The most likely transformation is from class II or III to class IV. Any other class may be superimposed on class V.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Goodpasture syndrome is not the only cause of the pulmonary-renal syndrome (ie, renal failure, lung hemorrhage). Other important causes of pulmonary-renal symptoms include the following:

Severe cardiac failure complicated by pulmonary edema (often blood-tinged sputum) and prerenal azotemia

Renal failure from any cause complicated by hypervolemia and pulmonary edema

Immune complex–mediated vasculitides, including SLE, Henoch-Schönlein purpura, and cryoglobulinemia

Pauci-immune vasculitides, including Wegener granulomatosis and microscopic polyangiitis

Infections, such as Legionnaire disease

Renal vein thrombosis with pulmonary embolism

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Urinalysis
• • No specific urinary finding can be used to accurately predict the presence of DPGN.
  • However, the finding of red blood cells and red blood cell casts strongly suggests glomerulonephritis. Proteinuria, white blood cells, and white blood cell casts may be present or absent. Renal biopsy should be obtained for histologic diagnosis and, in lupus, for classification.
  • In patients with lupus who already have a histologic classification, an increase in urinary sediment abnormality should raise the suspicion of histologic transformation. A repeat biopsy may be indicated if reclassification will guide management.
• A 24-hour urine collection is used for determination of protein and creatinine excretion. Creatinine in a 24-hour urine collection is used to determine completeness of the collection as well as to calculate creatinine clearance. On average, in adults younger than 50 years, creatinine excretion less than 15-20 mg/kg (lean body mass) for women or less than 20-25 mg/kg (lean body mass) for men suggests undercollection of the urine specimen. Values greater than these suggest overcollection. Both overcollection and undercollection lead to inaccurate estimation of creatinine clearance and, therefore, of glomerular filtration rate (GFR). A 24-hour urinary protein excretion in excess of 3.5 g is in the nephrotic range. A finding below 3.5 g indicates nonnephrotic proteinuria. A specific pattern for DPGN is not identified, but nephrotic range proteinuria is more common.
• Complete blood count (CBC) findings
• • Anemia
  • Leukopenia, lymphopenia, and thrombocytopenia are often observed in SLE.
• Serum chemistry
• • Serum creatinine and urea nitrogen often are elevated.
  • Serum albumin may be low if the patient is nephrotic.
• Serologic tests
• • Positive antinuclear antibodies (ANAs) indicate lupus nephritis. Ninety-five percent of patients with SLE have positive ANA; however, it is not specific.
  • Positive tests for anti–double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies are more specific for lupus (rising titers may indicate active or chronic disease).
  • Depressed complement levels of C3, C4, and CH50 may suggest SLE, infectious glomerulonephritis, poststreptococcal glomerulonephritis, or cryoglobulinemia.
  • ANCAs are positive (>1:40) in almost all cases of Wegener granulomatosis. Eighty to 95% are cytoplasmic ANCA (C-ANCA), while 5-20% are perinuclear ANCA (P-ANCA). In one study, a positive result for C-ANCA was used to identify Wegener granulomatosis, with a sensitivity and specificity of 65% and 88%, respectively, while a positive result for P-ANCA was used to identify Wegener granulomatosis with a sensitivity and specificity of 75% and 98%, respectively.
  • Tests results that are positive for anti-GBM antibodies indicate consideration of anti-GMB disease (ie, idiopathic) and Goodpasture syndrome. Circulating anti-GBM antibodies are present in over 90% of patients, although the antibody titer does not correlate well with the manifestations or course of either the pulmonary or renal disease.
  • A high titer of antistreptolysin O (ASO) shows recent streptococcal infection, indicating the possibility of poststreptococcal glomerulonephritis. Healthy children of school age (eg, 6-12 y) commonly have titers of 200-300 Todd units per mL. After streptococcal pharyngitis, the antibody response peaks at about 4-5 weeks. Antibody titers decline rapidly in the next several months and reach a slower decline after 6 months. Because 20% of patients with documented infection do not show a rise in the titer of antistreptolysin, other antistreptococcal antibodies such as anti-deoxyribonuclease (DNAse) B, anti-DNAse, and antihyaluronidase should be tested if ASO findings are negative.
  • Throat culture findings for group A beta-hemolytic streptococci usually are negative at the time of glomerulonephritis, while ASO titers peak.
  • Serum IgA levels are elevated in as many as half of patients with IgA nephropathy.

Imaging Studies

• Renal sonogram: This test is used to determine renal size, confirm the presence of 2 kidneys, and rule out structural lesions that may be responsible for azotemia.

Procedures

• Kidney biopsy
• • Indications, contraindications, and complications of percutaneous renal biopsy are discussed in the article Azotemia.
  • Renal biopsy is the criterion standard for diagnosis of anti-GBM nephritis. Obtain a renal biopsy for histologic diagnosis and, in lupus, for classification.
  • In patients with lupus who already have a histologic classification, an increase in urinary sediment abnormality should raise the suspicion of histologic transformation. A repeat biopsy may be indicated if reclassification will influence management.

Histologic Findings

Light microscopy

Light microscopy (see Media file 1) shows a marked hypercellularity of endothelial (ie, endocapillary) and mesangial cells, capillary loop thickening (ie, wire loops) or obliteration, and inflammatory cell infiltration. In severe forms, epithelial cell proliferation with crescent formation, necrosis, and sclerosis may be present. Inflammatory infiltration and fibrosis also may present in the interstitium. Endocapillary proliferation is typical of poststreptococcal glomerulonephritis.

Immunofluorescent microscopy

This technique shows (except for anti-GBM disease) a granular deposition of immunoglobulins, complement, and fibrin along the GBM, tubular basement membranes, and peritubular capillaries (see Media file 2). Linear deposition occurs in the GBM in anti-GBM disease (see Media file 2). Findings on immunofluorescence are negative in ANCA-associated glomerulonephritis. If radioimmunoassay is not available, indirect immunofluorescence can be used to detect circulating anti-GBM antibodies in 60-80% of patients by incubating the patient's serum with stored sections of healthy human kidneys

Electron microscopy

Using electron microscopy (see Media file 3), electron dense deposits are visible in the mesangial, subendothelial, intramembranous, and subepithelial locations. In SLE, the mesangial and subendothelial deposits produce the typical wire loop lesions observed using light microscopy. Tuboreticular inclusions may be observed within endothelial cells but are not pathognomonic. Tuboreticular inclusions also may be observed in HIV nephropathy. In anti-GBM disease, the deposits are linear and intramembranous. In poststreptococcal glomerulonephritis, the deposits are subepithelial and appear as humps. Few or no deposits are visible in ANCA-associated glomerulonephritis.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Because of the high risk of ESRD, early aggressive therapy is indicated. Pulse methylprednisolone of 1 g daily for 3 days, followed by 1 mg/kg for 4-6 weeks and then tapered to 5-10 mg/d for maintenance therapy by 6 months, should be initiated as induction therapy. Alternatively, prednisolone 1 mg/kg (not to exceed 80 mg/d) can be started and tapered as above. Additional induction and maintenance therapy may be indicated depending on the type of DPGN.

• Diffuse proliferative glomerulonephritis due to lupus
• • Pulse methylprednisolone, in combination with mycophenolate mofetil or cyclophosphamide, is indicated for DPGN due to lupus nephritis. Studies show that mycophenolate mofetil is equal to or better than cyclophosphamide in inducing remission of lupus nephritis and has fewer adverse effects. As a result, mycophenolate mofetil should be the drug of choice in combination with steroids.
  • In one study, 42 patients were randomized to receive prednisolone and mycophenolate for 12 months (21 patients, group 1) or prednisolone plus cyclophosphamide for 6 months followed by prednisolone and azathioprine for 6 months (21 patients, group 2). Of the 21 patients treated with mycophenolate mofetil and prednisolone (group 1), 81% had a complete remission and 14% had a partial remission, as compared with 76% and 14%, respectively, of the 21 patients treated with cyclophosphamide and prednisolone followed by azathioprine and prednisolone (group 2). Mycophenolate therapy was associated with fewer side effects than cyclophosphamide.
  • In a more recent study, oral mycophenolate mofetil (initial dose, 1000 mg/d, increased to 3000 mg/d) was compared with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1 g per square meter of body-surface area) as induction therapy for active lupus nephritis over a 6-month period. The study protocol specified adjunctive care and the use and tapering of corticosteroids.
  • The study showed that complete remission was observed in 22.5% of patients who received mycophenolate mofetil as compared to 5.8% of patients treated with cyclophosphamide (p=0.005). There was no difference in the rate of partial remissions (29% vs 24%, respectively). There were fewer severe infections and hospitalizations, but patients receiving mycophenolate experienced more diarrhea. The investigators concluded that mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.
  • Plasmapheresis, total lymphoid irradiation, and cyclosporine produce variable results but may be considered in severe, refractory cases. Azathioprine is often used as an alternative to cyclophosphamide, particularly in patients concerned about infertility.
• Diffuse proliferative glomerulonephritis due to immunoglobulin A nephropathy
• • Treatment is controversial, due in part to the indolent course of the disease. Patients with proteinuria less than 3 g/d, minimal glomerular changes only, and preserved renal function (creatinine clearance >70 mL/min) may benefit from treatment with prednisone. Those with aggressive disease as manifested by hypertension, progressive azotemia, and nephrotic syndrome may also be offered a trial of prednisone. Gross hematuria alone does not merit steroid use.
  • In patients with progressive disease, fish oil should be considered. Most, but not all, studies thus far show benefit, albeit at high doses.
  • A tonsillectomy may reduce proteinuria and hematuria in those patients with recurrent tonsillitis.
  • Corticosteroids in combination with cyclophosphamide may be tried in those who manifest crescentic DPGN on renal biopsy, although no controlled trials exist. In one recent study, the use of mycophenolate mofetil did not retard disease progression.
  • No specific therapy is currently offered for milder forms of IgA nephropathy, although the use of ACE inhibitors and/or angiotensin receptor blockers is generally recommended.
• Anti-GBM antibody–induced diffuse proliferative glomerulonephritis/crescentic glomerulonephritis
• • Initiate treatment early.
  • Induction with steroids, as noted above, plus cyclophosphamide 0.5-1 mg per square meter of body-surface area intravenously for 3 months should be initiated, followed by maintenance therapy with azathioprine 1-1.5 mg/kg/d and tapering doses of steroids.
  • Immunosuppression should be discontinued by 12 months, as there has been no benefit of additional therapy beyond this period. Studies show that plasmapheresis is effective in anti-GBM disease. It is most effective if the patient is not yet on dialysis. It should be provided over a course of 2 weeks.
• Pauci-immune diffuse proliferative glomerulonephritis/crescentic glomerulonephritis
• • Induction with steroids, as noted above, plus cyclophosphamide 0.5-1 mg per square meter of body-surface area intravenously for 3 months should be initiated, followed by maintenance therapy with azathioprine 1-1.5 mg/kg/d and tapering doses of steroids.
  • Immunosuppression should be discontinued by 24 months, as there has been no benefit of additional therapy beyond this period. Studies show that plasmapheresis is effective in DPGN due to pauci-immune glomerulonephritis even if the patient is on dialysis or has a serum creatinine level of greater than 5.6 mg/dL. It should be provided over a course of 2 weeks. Patients who cannot tolerate or are not responsive to cyclosporine may benefit from mycophenolate mofetil, although large trials are lacking.
• Diffuse proliferative glomerulonephritis due to infectious complications
• • The prognosis is good when crescent formation is absent.
  • Patients who are acutely uremic or show progression to end-stage renal failure need dialytic therapy or kidney transplantation.
• Recurrences: Clinicians generally manage a recurrence in the native kidney or after transplantation similarly, adding appropriate supportive therapy for chronic renal failure.

Consultations

• Involve a nephrologist in the initial management and as part of the multidisciplinary team.
• Involve a surgeon when progression to dialysis is inevitable for the creation of an arteriovenous fistula or a graft for dialysis or for insertion of a peritoneal dialysis catheter in the abdomen and for evaluation for kidney transplantation.
• Consult an otolaryngologist (ENT) and a pulmonologist for diagnosis and management of sinopulmonary disease in cases of Wegener granulomatosis and Goodpasture syndrome, respectively.

Diet

• Salt restriction (ie, <2 g/d) is recommended in all patients with hypertension and nephrosis.
• Protein restriction (ie, 40-60 g/d or 0.6-0.8 mg/kg/d) may slow progressive renal disease, but evidence in support of this view is still being debated.
• In those with diuretic-resistant edema, fluid restriction may be required.

Activity

No restriction in activity is required, and patients should be encouraged to maintain physical activity as tolerated.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Corticosteroids and cytotoxic therapy can induce remission. Corticosteroids are potent anti-inflammatory agents and immunosuppressants. These drugs suppress both cellular and humoral response to tissue injury, thereby reducing inflammation. Oral prednisone generally is required for maintenance therapy. Cytotoxic drugs induce alkylation of DNA.

Drug Category: Corticosteroids

Have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Drug Category: Cytotoxins

Inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients should be monitored closely for steroid-induced diabetes, electrolyte abnormalities, abnormal gas exchange, and opportunistic infections.

Further Outpatient Care

• Renal function should be monitored closely.
• Hypertension should be treated aggressively.
• Patients should be monitored closely for steroid-induced diabetes and opportunistic infections.

Deterrence/Prevention

• No clear risk factors are associated with development of DPGN; thus, no known preventive methods can be advocated.

Complications

• End-stage renal disease
• Complications of steroid or cytotoxic therapy are discussed under Medication. The commonly encountered complications include diabetes, opportunistic infections, and infertility.
• Complications of the specific diseases are discussed in other articles.

Prognosis

• Evidence of glomerulosclerosis, fibrous crescents, tubular atrophy, and, particularly, interstitial fibrosis using light microscopy indicates advanced disease and a poor prognosis.
• Being a male is a higher risk factor for a bad prognosis. Other risk factors associated with a bad prognosis include heavy proteinuria, hypertension, interstitial fibrosis, oliguria, and azotemia at presentation.
• Renal survival is best with IgA and worse with anti-GBM disease. In some series, the rate of progression to ESRD in class IV lupus was 50% during a 2-year follow-up.
• Overall, about 50% of patients with DPGN require dialysis within 6-12 months after presentation.

Patient Education

• Educate patients on the disease process, renal prognosis, complications of therapy, and importance of adhering to the treatment plan. The importance of keeping appointments must be emphasized.
• For those with advanced renal failure, options for renal replacement therapy (ie, hemodialysis, peritoneal dialysis, transplantation) should be fully discussed.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.
• For further information, see Mayo Clinic - Kidney Transplant Information.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Delay in diagnosis and treatment may result in rapid progression to ESRD.
• Inadequate monitoring of cytotoxic therapy may result in life threatening complications.

Special Concerns

• Infertility may result from use of cyclophosphamide; thus, informed consent should be obtained before instituting this form of therapy.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Diffuse proliferative glomerulonephritis (DPGN). Light microscopy (trichrome stain) shows globally increased cellularity, numerous polymorphonuclear cells, cellular crescent (at left of photomicrograph) and fibrinoid necrosis (brick red staining at right of photomicrograph). These findings are characteristic of diffuse proliferative glomerulonephritis.
	View Full Size Image
Media type:  Photo

Media file 2:  Diffuse proliferative glomerulonephritis (DPGN). Immunofluorescent microscopy shows (except for anti–glomerular basement membrane [GBM] disease) a granular deposition of immunoglobulins, complement, and fibrin along the GBM, tubular basement membranes, and peritubular capillaries (image 2a). Linear deposition occurs in the GBM in anti-GBM disease (image 2b).
	View Full Size Image
Media type:  Photo

Media file 3:  Diffuse proliferative glomerulonephritis (DPGN). Using electron microscopy, electron dense deposits are visible in the mesangial, subendothelial, intramembranous, and subepithelial locations.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Aasarod K, Iversen BM, Hammerstrom J. Wegener''s granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant. May 2000;15(5):611-8. [Medline].
• Andrews M, Edmunds M, Campbell A. Systemic vasculitis in the 1980s--is there an increasing incidence of Wegener''s granulomatosis and microscopic polyarteritis?. J R Coll Physicians Lond. Oct 1990;24(4):284-8. [Medline].
• Austin HA, Balow JE. Natural history and treatment of lupus nephritis. Semin Nephrol. Jan 1999;19(1):2-11. [Medline].
• Bosch X, Mirapeix E, Font J. [Neutrophil anticytoplasmic antibodies: their diagnostic utility in vasculitis and glomerulonephritis]. Med Clin (Barc). Mar 26 1994;102(11):412-7. [Medline].
• Chan TM, Li FK, Tang CS. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. Oct 19 2000;343(16):1156-62. [Medline].
• Chan TM, Tse KC, Tang CS. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol. Apr 2005;16(4):1076-84.
• Clark WF, Moist LM. Management of chronic renal insufficiency in lupus nephritis: role of proteinuria, hypertension and dyslipidemia in the progression of renal disease. Lupus. 1998;7(9):649-53. [Medline].
• Coppo R, Gianoglio B, Porcellini MG. Frequency of renal diseases and clinical indications for renal biopsy in children (report of the Italian National Registry of Renal Biopsies in Children). Group of Renal Immunopathology of the Italian Society of Pediatric Nephrology and Group of Renal. Nephrol Dial Transplant. Feb 1998;13(2):293-7. [Medline].
• D''Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis. Aug 2000;36(2):227-37. [Medline].
• Flanc RS, Roberts MA, Strippoli GF. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis. Feb 2004;43(2):197-208. [Medline].
• Frisch G, Lin J, Rosenstock J. Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrol Dial Transplant. Oct 2005;20(10):2139-45.
• Garrett PJ, Dewhurst AG, Morgan LS. Renal disease associated with circulating antineutrophil cytoplasm activity. Q J Med. Oct 1992;85(306):731-49. [Medline].
• Ginzler EM, Dooley MA, Aranow C. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. Nov 24 2005;353(21):2219-28.
• Golbus J, McCune WJ. Lupus nephritis. Classification, prognosis, immunopathogenesis, and treatment. Rheum Dis Clin North Am. Feb 1994;20(1):213-42. [Medline].
• Grotz W, Wanner C, Keller E. Crescentic glomerulonephritis in Wegener''s granulomatosis: morphology, therapy, outcome. Clin Nephrol. Jun 1991;35(6):243-51. [Medline].
• Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. Jun 1997;29(6):829-42. [Medline].
• Huong DL, Papo T, Beaufils H. Renal involvement in systemic lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore). May 1999;78(3):148-66. [Medline].
• Ioannidis JP, Boki KA, Katsorida ME. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int. Jan 2000;57(1):258-64. [Medline].
• Jindal KK. Management of idiopathic crescentic and diffuse proliferative glomerulonephritis: evidence-based recommendations. Kidney Int Suppl. Jun 1999;70:S33-40. [Medline].
• Kasinath BS, Neilson EG, Hebert L. Short-term prognosis of severe proliferative lupus nephritis. Am J Kidney Dis. Oct 1986;8(4):239-43. [Medline].
• Lim CS, Chin HJ, Jung YC. Prognostic factors of diffuse proliferative lupus nephritis. Clin Nephrol. Sep 1999;52(3):139-47. [Medline].
• Little MA, Pusey CD. Rapidly progressive glomerulonephritis: current and evolving treatment strategies. J Nephrol. Nov-Dec 2004;17 Suppl 8:S10-9.
• McCarty DJ, Manzi S, Medsger TA Jr. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum. Sep 1995;38(9):1260-70. [Medline].
• Mekhail TM, Hoffman GS. Longterm outcome of Wegener''s granulomatosis in patients with renal disease requiring dialysis. J Rheumatol. May 2000;27(5):1237-40. [Medline].
• Nolin L, Courteau M. Management of IgA nephropathy: evidence-based recommendations. Kidney Int Suppl. Jun 1999;70:S56-62. [Medline].
• Ong LM, Hooi LS, Lim TO. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology. Oct 2005;10(5):504-10.
• Ong LM, Hooi LS, Lim TO. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology. Oct 2005;10(5):504-10.
• Polenakovic M, Grcevska L. Survival rate of patients with glomerulonephritis. Acta Med Croatica. 1992;46(1):15-20. [Medline].
• Research Group on Progressive Chronic Renal Disease. Nationwide and long-term survey of primary glomerulonephritis in Japan as observed in 1,850 biopsied cases. Research Group on Progressive Chronic Renal Disease. Nephron. 1999;82(3):205-13. [Medline].
• Shoji T, Nakanishi I, Suzuki A. Early treatment with corticosteroids ameliorates proteinuria, proliferative lesions, and mesangial phenotypic modulation in adult diffuse proliferative IgA nephropathy. Am J Kidney Dis. Feb 2000;35(2):194-201. [Medline].
• Tomino Y. IgA nephropathy. From molecules to men. Contrib Nephrol. 1999;126:III-IX, 1-115. [Medline].
• Wyatt RJ, Julian BA, Baehler RW. Epidemiology of IgA nephropathy in central and eastern Kentucky for the period 1975 through 1994. Central Kentucky Region of the Southeastern United States IgA Nephropathy DATABANK Project. J Am Soc Nephrol. May 1998;9(5):853-8. [Medline].
• Yahya TM, Pingle A, Boobes Y. Analysis of 490 kidney biopsies: data from the United Arab Emirates Renal Diseases Registry. J Nephrol. May-Jun 1998;11(3):148-50. [Medline].

Article Last Updated: Aug 23, 2006