eMedicine Specialties > Nephrology > Glomerular Diseases

Glomerulonephritis, Diffuse Proliferative: Treatment & Medication

Author: Moro O Salifu, MD, MPH, FACP, Associate Professor, Department of Internal Medicine, Chief, Division of Nephrology, Director of Nephrology Fellowship Program and Transplant Nephrology, State University of New York Downstate Medical Center
Coauthor(s): Barbara G Delano, MD, MPH, Director of Home Hemodialysis and Peritoneal Dialysis, Professor, Department of Internal Medicine, Division of Nephrology, State University of New York at Brooklyn
Contributor Information and Disclosures

Updated: May 11, 2009

Treatment

Medical Care

Early, aggressive therapy is indicated because of the high risk of ESRD. Initiate the following as induction therapy: 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. Additional induction and maintenance therapy may be indicated, depending on the type of DPGN. Evidence suggests that mycophenolate mofetil (MMF) treatment benefits problematic patients who are refractory to conventional therapies for glomerulopathies.⁴

• 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.⁵ MMF treatment appears to aid problematic patients who are refractory to conventional therapies for glomerulopathies, with fewer adverse effects.^4,6 As a result, mycophenolate mofetil should be the drug of choice for use 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).⁷ 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 another study, oral mycophenolate mofetil (initial dose, 1000 mg/d, increased to 3000 mg/d) was compared with monthly intravenous cyclophosphamide (0.5 g/m² of body surface area, increased to 1 g/m² of body surface area) as induction therapy for active lupus nephritis over a 6-month period.⁸ The study protocol specified adjunctive care and the use and tapering of corticosteroids.
      
      Complete remission was observed in 22.5% of patients who received mycophenolate mofetil, as compared with 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.
  • 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.⁹ After 9 months, 65% of patients receiving multitarget therapy had experienced complete remission of the nephritis, compared with 15% of patients who received cyclophosphamide treatment. In addition, most adverse events occurred less frequently in the multitarget treatment patients than they did in the cyclophosphamide group.
• 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 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.¹⁰
• Anti-GBM antibody–induced diffuse proliferative glomerulonephritis/crescentic glomerulonephritis
  • Initiate treatment early.
  • 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 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/m² 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

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.

Corticosteroids

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.

Cytotoxins

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.

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