Approach Considerations
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]
Medical Care
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] :
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Hydroxychloroquine
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MMF
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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] :
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Long-term therapy with ACEIs or ARBs for patients with proteinuria > 1 g/day, with up-titration of the dose based on blood pressure
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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
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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
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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.
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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.
Consultations
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.
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 kidney disease, but evidence in support of this view is still being debated. Fluid restriction may be required in patients with diuretic-resistant edema.
Complications
Patients should be monitored closely for steroid-induced diabetes, electrolyte abnormalities, abnormal gas exchange, and opportunistic infections.
Long-Term Monitoring
Renal function should be assessed regularly and hypertension should be treated aggressively. Patients should be monitored closely for steroid-induced diabetes and opportunistic infections.
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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.
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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).
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Diffuse proliferative glomerulonephritis (DPGN). Using electron microscopy, electron-dense deposits are visible in the mesangial, subendothelial, intramembranous, and subepithelial locations.
