Diffuse Proliferative Glomerulonephritis

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 antigens before deposition (ie, immune complex deposition) or may bind directly to nonglomerular antigens already present 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 on the glomerulus renders the GBM permeable to protein, red blood cells (RBCs), and white blood cells (WBCs). Therefore, urinalysis during active inflammation (or glomerulonephritis) characteristically shows an active urinary sediment, with RBCs or casts, WBCs 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 seen on 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 granulomatosis with polyangiitis (GPA; previously known as Wegener granulomatosis), kidney biopsy findings typically reveal focal, segmental, necrotizing, pauci-immune glomerulonephritis with crescent formation.

In microscopic polyangiitis (MPA), the usual histopathologic lesion is a pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. In eosinophilic granulomatosis with polyangiitis, 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.[1]

In addition to poststreptococcal glomerulonephritis, 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 sediment. Although renal biopsy is used to detect immune deposits containing IgG and C3, serum complement levels usually are within the reference range.

Systematic diseases causing DPGN  include the following:

• Lupus nephritis class IV
• IgA nephropathy
• Goodpasture syndrome
• Granulomatosis with polyangiitis (GPA)
• Microscopic polyangiitis MPA)
• Henoch-Schönlein purpura
• Cryoglobulinemia
• Vasculitis

Immunoglobulin A (IgA) nephropathy and SLE are the most common etiologies. In patients with lupus nephritis class IV, 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.

GPA (formerly known as Wegener granulomatosis), MPA, and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) are termed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs).[2] GPA, MPA, and EGPA are also termed pauci-immune glomerulonephritis and are characterised by necrotizing inflammation of the small vessels: arterioles, capillaries, and venules with little or no deposition of immune complexes in the vessel wall (pauci-immune). About 10% of patients presenting with MAP, GPA, and EGPA are ANCA negative.[3]

Post-infectious glomerulonephritis may occur in association with bacterial, viral, fungal, protozoal, and helminthic infection but is most often secondary to streptococcal sore throat or skin infection and occurs 2-4 weeks after infection. Other common infectious causes of DPGN are infective endocarditis, hepatitis B, and hepatitis C. Shunt nephritis is an immune complex–mediated glomerulonephritis that develops as a complication of chronic infection on ventriculoatrial or ventriculojugular shunts inserted for the treatment of hydrocephalus[4]

COVID-19 has been associated with a cluster of of 8 cases of anti-GBM disease.[5]  

Frequency

United States

The reported prevalence of kidney disease in systemic lupus erythematosus is about 38%, and the incidence of end-stage renal disease (ESRD) attributed to lupus nephritis in adults is 4.5 cases per million in the general population.[6]

IgA nephropathy accounts for about 10% of biopsies performed for glomerular disease in the United States. Prevalence rates are lower in the United States than in Asian countries.

Anti–glomerular basement membrane (GBM) disease is a rare disorder of unknown etiology with an annual incidence of 0.5-1 case per million.[7] 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.

Cytoplasmic antineutrophil cytoplasmic antibodies (ANCAs) are detected at presentation in 80% of patients with renal disease and in 10% more during follow-up. In contrast with ANCA-associated disease involving 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 on 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 kidney biopsies varies from approximately 10-27% in Europe and 30% in the Middle East to 41% in Japan. The most common glomerulopathy is due to immunoglobulin A (IgA) nephropathy.

Distribution of IgA nephropathy varies in different geographic regions throughout the world. High prevalence rates are observed in Singapore, Japan, Australia, Hong Kong, Finland, and southern Europe, whereas low prevalence rates are the rule in the United Kingdom, Canada, and the United States. IgA nephropathy is observed in up to 40% of all biopsies performed for glomerular disease in Asia, compared with 20% in Europe and 10% in North America.

Worldwide, 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.

The prevalence of AAV in Europe is estimated at to be 46–184 per million with annual incidence rates per million estimated at  2.1–14.4 for GPA, 2.4–10.1 for MPA and 0.5–3.7 EGPA.[2]

Race

Lupus nephritis differs with ethnicity. Whites (12–33%) are less likely to have lupus nephritis than Blacks (40–69%), Hispanics (36–61%), or Asians (47–53%).[6]  Additionally, Black and Hispanic patients with SLE develop lupus nephritis earlier than White patients and have worse outcomes, including death and ESRD,[8]

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.[9]

Microscopic PAN is more common in males (ie, male-to-female ratio of 2:1). The distribution of granulomatosis with polyangiitis 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.

Granulomatosis with polyangiitis 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.

Evidence of glomerulosclerosis, fibrous crescents, tubular atrophy, and, particularly, interstitial fibrosis on light microscopy indicates advanced disease and a poor prognosis.  Males are at a higher risk factor for a poor prognosis.[9]  Other risk factors associated with a poor prognosis include heavy proteinuria, hypertension, interstitial fibrosis, oliguria, and azotemia at presentation. Overall, about 50% of patients with DPGN require dialysis within 6-12 months after presentation. 

About 10% of acute kidney injuries in adults are attributed to glomerulonephritis mainly associated with granulomatous polyangiitis (GPA), microscopic polyangiitis (MPA), and anti–glomerular basement membrane (GBM) disease. The prognosis improves with early diagnosis and treatment.[10]

Renal survival is best with IgA nephropathy, which has an indolent course with a favorable outcome. Death due to DPGN in IgA nephropathy is rare.

Patient and kidney survival in untreated anti-GBM disease is poor. Patient and kidney survival have shown improvement with treatment, but disease progression can be very rapid, and outcome is related to the severity at presentation. A retrospective analysis of 123 patients with anti-GBM glomerulonephritis seen at six centers between 1986 and 2015 reported a 5-year kidney survival rate of 34%. However, the success rate improved significantly in patients diagnosed after 2007. Dialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate were associated with poor kidney outcome in this series.[11]

Lupis nephritis (LN) is a major risk factor for morbidity and mortality in SLE; 10% of patients with LN will develop ESRD.[8]  In some series, the rate of progression to ESRD in class IV lupus nephritis was 50% during a 2-year follow-up.[12, 9, 13, 14] Patients with LN also have a higher standardized mortality ratio (6–6.8 versus 2.4) and die earlier than SLE patients without LN. However, 10-year survival improves from 46% to 95% if disease remission can be achieved.[8]

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 the morbidity and mortality in DPGN is due to complications of immunosuppressive therapy, including drug toxicity and infection.

Treatment has dramatically improved the prognosis of patients diagnosed with ANCA-associated vasculitis (AAV). The median survival from diagnosis without treatment is 5 months, whereas 88% of treated patients survive 1-year and 78% survive for 5 years. Almost 50% of deaths are related to infection and 20% from disease-related complications in the first year. In subsequent years, cardiovascular disease and malignancy are the major causes of mortality, followed by infectious (20%) and vasculitis-specific (6%) causes. Severe renal involvement and diffuse alveolar hemorrhage are the major causes of vasculitis-related mortality.[15]

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. However, in a study of atypical anti-GBM nephritis characterized by an indolent course, no pulmonary involvement, and undetectable circulating α3NC1 antibodies, the 1-year patient and renal survival rates were 93% and 85%, respectively.[16]

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 kidney failure, options for renal replacement therapy (ie, hemodialysis, peritoneal dialysis, transplantation) should be fully discussed.

For patient education information, see Blood in the Urine.

For further information, see Mayo Clinic - Kidney Transplant.

Focus the history on the causes of diffuse proliferative glomerulonephritis (DPGN) and the associated clinical manifestations. While a minority (< 15%) of patients may be asymptomatic and are diagnosed on the basis of routine laboratory test findings, most patients manifest signs and symptoms of the primary disease as well as those relating to renal injury. Nonspecific manifestations (eg, nausea, vomiting, fatigue, weight loss) may indicate uremia or the primary disease process. 

Suspect DPGN in patients with systemic lupus erythematosus (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
• Non-nephrotic or nephrotic-range proteinuria or an increase in proteinuria from baseline
• Serum creatinine of more than 0.4 mg/dL above the reference range or the patient's baseline
• Oliguria or anuria and symptoms of uremia in severe cases of rapidly progressive glomerulonephritis (RPGN) with crescent formation

Also suspect DPGN in a patient with other systemic diseases who has recent onset of the same findings listed above. 

Features in the history may provide clues to an undiagnosed primary disease process. The following suggest SLE  as the primary disease:

• Rash
• Photosensitivity
• Oral ulcers
• Arthralgias, arthritis
• Serositis
• A renal, neurologic, hematologic, or immunologic disorder

A history of cough, dyspnea, hemoptysis, and kidney disease suggests Goodpasture syndrome, but other pulmonary-renal syndromes must be ruled out, including the following:

• SLE pneumonitis
• Granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis)
• Cryoglobulinemia
• Renal vein thrombosis with pulmonary embolism
• Legionella infection
• Congestive heart failure

GPA presents as follows:

• 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, kidney failure, and nephrotic syndrome.

If azotemia is present, exclude prerenal and postrenal causes. Hypertension and fever (present in infectious and noninfectious glomerulonephritis) are nonspecific findings that suggest DPGN. 

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–glomerular basement membrane (GBM) disease, GPA) and Goodpasture syndrome include the following:

• Sinusitis, otitis, saddle nose deformity, hemoptysis
• Lung consolidation, which suggests pulmonary hemorrhage

Findings relating to IgA nephropathy (usually postinfectious) and other infectious glomerulonephritides include the following:

• Pharyngitis
• Gastroenteritis
• Impetigo, which is the most common cause of poststreptococcal glomerulonephritis worldwide

On urinalysis, no specific finding can be used to accurately predict the presence of diffuse proliferative glomerulonephritis (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. Kidney biopsy should be obtained for histologic diagnosis and, in lupus, for classification.

In patients with systemic lupus erythematosus (SLE) 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. 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 are as follows:

• Anemia
• Leukopenia, lymphopenia, and thrombocytopenia are often observed in SLE

On serum chemistry studies, serum creatinine and blood urea nitrogen levels often are elevated. Serum albumin may be low if the patient is nephrotic.

Serologic test results may include the following:

• Positive antinuclear antibodies (ANAs) indicate lupus nephritis; 95% of patients with SLE have positive ANA, but this finding 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.
• Antineutrophil cytoplasmic antibody (ANCA) assays are positive (>1:40) in almost all cases of granulomatosis with polyangiitis (GPA; Wegener granulomatosis): 80-95% 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 GPA, with a sensitivity and specificity of 65% and 88%, respectively, while a positive result for P-ANCA was used to identify GPA with a sensitivity and specificity of 75% and 98%, respectively.
• Tests results that are positive for anti–glomerular basement membrane (GBM) antibodies indicate consideration of anti-GBM 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 antistreptolysin titer, 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.

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

Indications, contraindications, and complications of percutaneous kidney biopsy are discussed in the article Azotemia. Kidney biopsy is the criterion standard for diagnosis of anti-GBM nephritis. Obtain a biopsy for histologic diagnosis and, in SLE, for classification of lupus nephritis.

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 in such cases, if reclassification will influence management.

Light microscopy

Light microscopy (as seen in the image below) 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 be present in the interstitium. Endocapillary proliferation is typical of poststreptococcal glomerulonephritis.

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.

Immunofluorescent microscopy

This technique shows (except in anti-GBM disease) a granular deposition of immunoglobulins, complement, and fibrin along the GBM, tubular basement membranes, and peritubular capillaries (as seen in the image below). Linear deposition occurs in the GBM in anti-GBM disease. 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.

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).

Electron microscopy

Using electron microscopy (as seen in the image below), 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.

Diffuse proliferative glomerulonephritis (DPGN). Using electron microscopy, electron-dense deposits are visible in the mesangial, subendothelial, intramembranous, and subepithelial locations.

Early, aggressive therapy is indicated in diffuse proliferative glomerulonephritis (DPGN) because of the high risk of progression to end-stage renal disease (ESRD). Initiate induction therapy with 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. Alternatively, prednisolone 1 mg/kg (not to exceed 80 mg/d) can be started and tapered as above.[17]

Additional induction and maintenance therapy may be indicated, depending on the type of DPGN. Evidence suggests that mycophenolate mofetil (MMF) treatment benefits patients with DPGN that is refractory to conventional therapies for glomerulopathies.[18]

Diffuse proliferative glomerulonephritis due to lupus

Pulse methylprednisolone, in combination with MMF or cyclophosphamide, is indicated as the initial treatment for DPGN due to lupus nephritis.[19, 20]  Several trials suggested equivalence or superiority of MMF in achieving short-term renal responses.[21, 22] However, in the largest trial, the Aspreva Lupus Management Study (ALMS), MMF and cyclophosphamide were found to be equivalent at the 24-week end point. Adverse event rates were similar for each drug, although the types of adverse events differed. A 3-year follow-up study of ALMS (ALMS Maintenance) showed a trend for patients who had received induction with cyclophosphamide to have better long-term kidney outcomes than those induced with MMF, regardless of choice of maintenance immunosuppression.[23]

A meta-analysis of 187 studies done between 1970 and 2015 evaluated the change in ESRD risk and found that the 10- and 15-year risk of developing ESRD due to lupus nephritis decreased by 10% from 1970 to the mid-1990s, which coincided with the introduction of cyclophosphamide induction therapy. No further risk reduction was seen, but a slight increase in risk occured in the late 2000s, coinciding with an increase in the use of MMF induction therapy.[24]

In a study of 40 patients with class V+IV lupus nephritis, investigators found that multitarget therapy using a combination of MMF, tacrolimus, and steroids achieved a higher rate of complete remission than did intravenous cyclophosphamide therapy.[25] After 9 months, 65% of patients receiving multitarget therapy had experienced complete remission of the nephritis, compared with 15% of patients who received cyclophosphamide. In addition, most adverse events occurred less frequently in the multitarget treatment patients than in the cyclophosphamide group.

Other treatments for lupus nephritis include the following[26] :

• Hydroxychloroquine
• MMF
• Biologic therapies (eg, belimumab, rituximab, abatacept)

Kidney transplantation in patients with ESRD secondary to lupus nephritis is typically delayed to allow for quiescence of lupus-related immune activity. However, a review of national ESRD surveillance data by Plantinga and colleagues determined that White patients with lupus nephritis–ESRD who were transplanted after 3 or more months on dialysis were at increased risk of graft failure. No such association was seen in Black recipients.[27]

Diffuse proliferative glomerulonephritis due to immunoglobulin A nephropathy

Treatment is controversial, due in part to the indolent course of the disease. Currently, multiple treatment options are available; no one therapy is appropriate for all patients. Some trials of corticosteroid therapy for IgA nephropathy have shown positive outcomes. However, the possible benefit from corticosteroids should be weighed against the risks of immunosuppression for the individual patient. No specific therapy is currently offered for milder forms of IgA nephropathy, although the use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or both is generally recommended.[28]

Current recommendations include the following[29] :

• Long-term therapy with ACEIs or ARBs for patients with proteinuria > 1 g/day, with up-titration of the dose based on blood pressure 
• ACEI or ARB therapy for proteinuria of 0.5-1 g/d with upward titration as far as tolerated to achieve proteinuria of 1 g/d 
• Blood pressure treatment goals: < 130/80 mm Hg with proteinuria of 1 g/d; < 125/75 mm Hg if initial proteinuria is > 1 g/d 
• A 6-month course of corticosteroid therapy may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control), and a GFR > 50 ml/min/1.73m ².
• Fish oil may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control) 

IgA proliferative glomerulonephritis with monoclonal immunoglobulin deposits was successfully treated with chemotherapy using elotuzumab and lenalidomide in a patient with multiple myeloma.[30]

Anti-GBM antibody–induced diffuse proliferative glomerulonephritis/crescentic glomerulonephritis

Induction therapy should be initiated with high-dose corticosteroids early. After the diagnosis is confirmed, cyclophosphamide and plasmapheresis should be started. Anti-GBM antibody titers should be regularly monitored.[31]  Plasmapheresis is stopped when the circulating antibodies are no longer detectable, usually after 14 days. Corticosteroids are continued for at least 6 months, and cyclophosphamide for 3 months. Immunosuppression must be sufficient both to prevent further antibody production and to treat kidney inflammation.[7]

Immunosuppression should be discontinued by 12 months, as no benefit has been demonstrated with more prolonged therapy. Plasmapheresis is most effective if the patient is not yet on dialysis.

Autoantibodies seem to disappear spontaneously after 12–18 months but relapses have been reported in the literature. Mean time to recurrence has been estimated to be 4.3 years, with a range of 1–10 years; late recurrences may occur with a frequency of 2–14%. Retreatment with intense immunosuppression and plasmapheresis is generally successful in re-inducing remission. There are case reports of refractory disease treated with MMF or rituximab, but there is not enough evidence of efficacy.[7]

Pauci-immune diffuse proliferative glomerulonephritis/crescentic glomerulonephritis

Induction with steroids, as noted above, plus cyclophosphamide 0.5-1 mg/m2 of body surface area intravenously for 3 months should be initiated, followed by maintenance therapy with azathioprine 1-1.5 mg/kg/d[32] and tapering doses of steroids. In one study, rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.[33] .

Immunosuppression should be discontinued by 24 months, as no benefit has been demonstrated for more prolonged therapy. The use of plasmapheresis in DPGN due to pauci-immune glomerulonephritis was controversal until publication of the PEXIVAS trial in 2020, which showed no significant benefit of plasmapheresis in DPGN due to pauci-imune glomerulonephritis.[17]

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 ESRD need dialysis or kidney transplantation. Clinicians generally manage a recurrence in the native kidney or after transplantation similarly, adding appropriate supportive therapy for chronic kidney disease.

A nephrologist should be a member of the multidisciplinary team and consulted in the initial management. 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 granulomatosis with polyangiitis and Goodpasture syndrome, respectively.

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 kidney disease, but evidence in support of this view is still being debated. Fluid restriction may be required in patients with diuretic-resistant edema.

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

Renal function should be assessed regularly and hypertension should be treated aggressively. Patients should be monitored closely for steroid-induced diabetes and opportunistic infections.

In its clinical practice guidelines for glomerulonephritis, Kidney Disease: Improving Global Outcomes (KDIGO) offers the following general principles in the management of glomerular disease[34] :

• Kidney biopsy is required for diagnosis; repeat biopsy should be considered when a change in therapy is considered or following a relapse 
• Key outcome measures for the management of glomerulonephritis include assessment of kidney function, particularly measurement of proteinuria and glomerular filtration rate (GFR)

The following complications are a consequence of the clinical presentation rather than the specific histolopathologic pattern. Active management of should always be considered and may have a significant positive impact on the natural history of the disease[34] :

• Hypertension
• Proteinuria
• Hyperlipidemia
• Nephrotic edema
• Hypercoagulability
• Risk of infection

In its clinical practice guidelines for glomerulonephritis, KDIGO makes the following recommendations for evaluation of patients with IgA nephropathy[29] :

• All patients should be assessed by biopsy for secondary causes of IgA nephropathy
• Risk of progressession should be evaluated by measurement of proteinuria, blood pressure, and estimated glomerular filtration rate (eGFR) at the time of diagnosis and during follow-up
• Pathological findings can be used to assess prognosis

KDIGO recommendations for IgA nephropathy treatment include the following[29] :

• Long-term therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is recommended for patients with proteinuria >1 g/day with up-titration of the dose based on blood pressure (grade 1B).
• ACEI or ARB therapy is suggested for proteinuria of 0.5-1 g/d (grade 2D).
• Upward titration of the ACEI or ARB as far as tolerated is suggested, to achieve proteinuria of 1 g/d (grade 2C).
• Blood pressure treatment goals: < 130/80 mm Hg with proteinuria of 1 g/d; < 125/75 mm Hg if initial proteinuria is >1 g/d (not graded)
• A 6-month course of corticosteroid therapy may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control), and a GFR >50 ml/min/1.73m ² (grade 2C).
• Fish oil may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control) (grade 2D).

KIDGO guidelines recommend against using mycophenolate mofetil, antiplatelet agents, or tonsillectomy for the treatment of IgA nephropathy (grade 2C). In addition, the following treatments are recommended against unless the patient has crescentic IgA nephropathy with rapidly deteriorating kidney function[29] :

• Corticosteroids combined with cyclophosphamide or azathioprine (grade 2D)
• Immunosuppressive therapy in patients with GFR < 30 ml/min/1.73m ² (grade 2C)

Crescentic IgA nephropathy is defined by KIDGO as IgA nephropathy with crescents in more than 50% of glomeruli in the renal biopsy with rapidly progressive renal deterioration.[29]

Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN) Guidelines

Clinical guidelines for managment of IgA nephropathy have been developed by the Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN). These guidelines are meant to to address the clinical situation and establish a standard treatment in Japan, and recommend focusing the managent of IgA nephropathy on prevention of renal dysfunction. Treatments to suppress IgA nephropathy progression are based on the following patient factors[35] :

• Kidney function
• Urinary protein level
• Age
• Renal histopathological findings

Treatments to be considered, if necessary. are as follows:

• Reduce blood pressure
• Reduce salt intake
• Normalize lipid and glucose metabolism
• Reduce body weight
• Smoking cessation 

In patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-3b, the guidelines give a strong recommendation (grade A) for the use of ACEI or ARB therapy to control progression of renal dysfuntion. In patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-2, the guidelines recommendations include the following[35] :

• High-dose oral steroid therapy: prednisolone at 0.8–1.0 mg/kg for about 2 months, followed by gradual tapering over about 6 months (grade B)
• Steroid pulse therapy: methylprednisolone 1 g for 3 days by infusion (or IV) every other month, 3 times plus prednisolone 0.5 mg/kg, every other day, for 6 months (grade B) 

The following treatment options may be considered, but only weak evidence supports these recommendations (grade C1)[35] :

• ACEI or ARB therapy to reduce proteinuria in patients with urinary protein level of 0.5–1.0 g/day
• Steroid therapy to reduce proteinuria in patients with urinary protein level of 0.5–1.0 g/day and CKD stage G1-2
• Tonsillectomy alone or combined with steroid pulse therapy to improve urinary findings and lower the progression of renal dysfunction
• Off-label use of cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, and mizoribine to improve the renal prognosis
• Antiplatelet agents: dipyridamole to reduce proteinuria and control the progression of kidney dysfunction; dilazep to reduce proteinuria
• Fish oil to improve the renal prognosis

In its clinical practice guidelines for glomerulonephritis, KDIGO makes the following recommendations for treatment of class IV lupus nephritis (LN)[6] :

• Initial therapy with corticosteroids (grade 1A), combined with either cyclophosphamide (grade 1B) or mycophenolate mofetil (MMF) (grade 1B)
• In cases of increasing serum creatinine level and/or worsening proteinuria during the first 3 months of treatment, a change should be made to an alternative initial therapy, or a repeat kidney biopsy should be performed to guide further treatment. (grade 2D)
• After completion of initial therapy, maintenance therapy is initiated with azathioprine or MMF, and low-dose oral corticosteroids (grade 1B)
• For maintenance therapy in patients intolerant of MMF and azathioprine, calceineurin inhibitors (CNIs) with low-dose corticosteroids may be used. (grade 2C)
• After complete remission is achieved, maintenance therapy should be continued for at least 1 year before tapering the immunosuppression. (grade 2D);  If complete remission has not been achieved after 1 year of maintenance therapy, consider performing a repeat kidney biopsy before determining if a change in therapy is indicated. (Not graded)
• While maintenance therapy is being tapered, if kidney function deteriorates and/or proteinuria worsens, increase treatment to the level of immunosuppression that controlled the LN. (grade 2D)
• For patients who have failed more than one initial regimen consider treatment with rituximab, intravenous immunoglobulin IVIG), or CNIs. (grade 2D)

For relapsed disease, KDIGO offers the following recommendations[6] :

• Treat with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission (grade 2B)
• If resuming the original therapy would put the patient at risk for excessive lifetime cyclophosphamide exposure, then a non–cyclophosphamide-based regimen should be used (grade 2B)
• Consider a repeat kidney biopsy if there is suspicion that the histologic class of LN has changed, or there is uncertainty whether increasing serum creatinine level and/or worsening proteinuria represents disease activity or chronicity. (not graded)

KDIGO guidelines recommend cyclophosphamide and corticosteroids plus plasmapheresis for treatment of anti–glomerular basement membrane (GBM) glomerulonephritis, except in patients who are dialysis dependent and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage (grade 1B). Treatment should be initiated immediately upon diagnosis confirmation. If the diagnosis is strongly suspected, high-dose corticosteroids and plasmapheresis can be administered until diagnosis is confirmed (not graded). Maintenance immunosuppressive therapy is not recommended (grade 1D) and kidney transplantation should be deferred until anti-GBM antibodies have been undetectable for a minimum of 6 months (not graded).[7]

For the initial treatment of of pauci-immune glomerulonephritis with or without circulating antineutrophil cytoplasmic antibody (ANCA), KDIGO guidelines recommend cyclophosphamide and corticosteroids (grade 1A). Rituximab with corticosteroids can be used as an alternative initial treatment in patients without severe disease or if cyclophosphamide is contraindicated (grade 1B). Cyclophosphamide therapy should be discontinued after 3 months in patients who remain dialysis-dependent and who do not have any extrarenal manifestations of disease (grade 2C). The addition of plasmapheresis is recommended for the following [3] :

• Patients requiring dialysis or with rapidly increasing serum creatinine level (grade 1C)
• Patients with diffuse pulmonary hemorrhage (grace 2C)
• Patients with overlap syndrome of ANCA vasculitis and anti-GBM disease (grade 2D)

Rituximab should be added for treatment of disease resistant to induction therapy with cyclophosphamide and corticosteroids (grade 1C). IVIG  (grade 2C) or plasmapheresis (grade 2D) may be considered as alternative therapies.[3]  

KDIGO guidelines recommend maintenance therapy for patients who have achieved remission (grade 1B) and should be continued for at least 18 months in patients who remain in complete remission. (grade 2D) No maintenance therapy is recommended for patients who are dialysis-dependent and have no extrarenal manifestations of disease (grade 1C). Recommendations for choice of agent include the following[3] :

• Azathioprine is the preferred maintenance therapy (grade 1B)
• MMF may be used for maintenance therapy if azathioprine is contraindicated (grade 2C) 
• Methotrexate is an alternative if both azathioprine and MMF are contraindicated (grade 1C)
• Trimethoprim-sulfamethoxazole can be used as an adjunct therapy in patients with upper respiratory tract disease (grade 2B)
• Etanercept is not recommended for adjunctive therapy (grade 1A)

Severe relapse (life- or organ-threatening) of ANCA vasculitis should be treated following the recommendations for initial treatment above (grade 1C).  For other relapses, immunosuppressive therapy should be reinstated or increased in intensity with agents other than cyclophosphamide, including instituting or increasing corticosteroids, with or without azathioprine or MMF. (grade 2C)[3]  

Kidney transplantation should be delayed until patients are in complete extrarenal remission for 12 month. (grade 1C) However, transplantation should not be delayed  for patients who are in complete remission but are still ANCA-positive (grade 1C).[3]

European League Against Rheumatism (EULAR), European Renal Association (ERA) and European Dialysis and Transplant Association (EDTA) Guidelines

Joint guidelines for the management of ANCA-associated vasculitis were released by the European League Against Rheumatism (EULAR), European Renal Association (ERA) and European Dialysis and Transplant Association (EDTA) in 2016. For initial treatment or major relalpse of life or organ-threatening disease, glucocorticoids with either cyclophosphamide or rituximab is recommended; and, for initial treatment of non-organ- threatening disease, glucocorticoids and either methotrexate or MMF is recommended. Similar to KDIGO, the addition of plasmapheresis is recommended for thepatients with either of the following[2] :

• A serum creatine level of ≥500 mmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis
• Severe diffuse alveolar hemorrhage

For treatment of disease resistant to induction therapy, the guidelines recommend switching from cyclophosphamide to rituximab or from rituximab to cyclophosphamide. At least 24 months of maintence therapy with a combination of low-dose glucocorticoids plus azathioprine, rituximab, methotrexate, or MMF is recommended for patients who have achieved remission.[2]

Additionally the guidelines recommend the investigation of persistent unexplained hematuria in patients with prior exposure to cyclophosphamide. Because hypoimmunoglobulinemia has been reported after treatment with rituximab, testing of serum immunoglobulin levels prior to each course of rituximab and in patients with recurrent infection is recommended.[2]

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

Class Summary

These agents have 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.

Prednisone (Deltasone, Orasone, Meticorten, Sterapred)

Most patients require long-term oral prednisone after inducing remission. Immunosuppressants for treatment of autoimmune disorders may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Methylprednisolone (Solu-Medrol)

For pulse therapy. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Class Summary

Inhibit cell growth and proliferation.

Cyclophosphamide (Cytoxan)

DOC in DPGN. Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Low dose is used when creatinine clearance is < 33 mL/min.

Maintain white blood cell count >2000/mL.

A dose of 50-100 mg/m2 PO qd is associated with a higher incidence of hemorrhagic cystitis.

Mycophenolate (CellCept, Myfortic)

Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, Cellcept) is a prodrug that once hydrolyzed in vivo, releases the active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic) is an enteric-coated product that delivers the active moiety.

Azathioprine (Azasan, Imuran)

Used for maintenace therapy after initial induction of remission in ANCA-associated glomerulonephritis

Rituximab (Rituxan, Riabni, Rituximab-abbs)

Shown in clinical trials to be as effective as cyclophosphamide and more effective for relapsing disease