Stephen A. Paget, MD, FACP, FACR


March 04, 2003


A 21-year-old white man presents with WHO type 4 diffuse proliferative glomerulonephritis (DPGN), hypertension, low serum C3, C4 complement and high serum level of anti-DNA antibodies, and spilling 6 gm urinary protein per day. No other clinical sign of systemic lupus erythematosus (SLE) was present. He was given high-dose corticosteroids and monthly pulse cyclophosphamide (Cytoxan; Bristol-Myers Oncology, Princeton, New Jersey). His urinary protein resolved; 5-10 red blood cells (RBC) per high-power field persisted; serum creatinine remained at 1.0 mg/dL; blood pressure returned to normal; and steroids were discontinued after the fifth month. Now at month 7, the urinary protein level is back to 2+, RBCs are at 25-50 per high-power field, complement fractions are lower, and the serum level of anti-DNA antibodies is higher. His blood pressure and serum creatinine levels are within normal range.

What would be better? Mycophenolic acid? Oral Cytoxan? Re-biopsy?

Response from Stephen A. Paget, MD, FACP, FACR

As defined by long-term studies at the National Institutes of Health, the most effective treatment for DPGN due to SLE is intermittent infusions of cyclophosphamide. The usual regimen is 0.5-1.0 g/m2 of cyclophosphamide given as an IV infusion monthly for 6 months and then every 3 months thereafter for a total of 2 years. Each infusion is given along with IV hydration, an antinausea regimen, and mesna at a dose of three quarters that of the cyclophosphamide dose. The latter is given to minimize bladder toxicity associated with metabolites of cyclophosphamide. Courses of less than 2 years total may be associated with recurrences of the renal inflammation. Commonly, oral prednisone is given along with the cyclophosphamide at doses of 0.5-1.0 mg/kg, usually to control both the kidney inflammation and the common extrarenal manifestations of SLE. At times, daily pulses of methylprednisolone sodium succinate (Solu-Medrol; Pharmacia & Upjohn Company; Kalamazoo, Michigan) 250-1000 mg x 3 days are given instead of oral steroids in the setting of severe, active disease. Steroid taper is appropriate once the patient has improved with respect to the renal and/or extrarenal disease manifestations.

An optimal renal response would be a significant improvement in all of the parameters that stimulated the use of cyclophosphamide in the first place:

  • 6 g of protein in a 24-hour urine collection decreasing to normal (150 mg) or to certainly less than 1000 mg/24 hours;

  • Normalization of the serum creatinine and creatinine clearance;

  • Disappearance of hematuria;

  • Normalization of C3 and C4 complement, anti-DNA and ANA; and

  • Normalization of blood pressure and edema and other signs of nephrotic syndrome.

At times, only some of these parameters improve or normalize. Usually, other SLE manifestations will come under control at the same time, including arthritis, serositis, fever, and rash, among others. Most rheumatologists will increase/titrate the cyclophosphamide dose from the initial 0.5 g/m2 by 250 mg increases up to a high of 1.0 g/m2 or to a white blood cell count low of 3000/mm3.

In the patient that you describe, I would collect a 24-hour urine to define the creatinine clearance and 24-hour protein. If the patient's proteinuria is over 1000 mg or the creatinine clearance has decreased, I would continue the IV cyclophosphamide but make sure that the doses have been raised as noted above. Also, you can employ daily pulses of Solu-Medrol from 250 mg to 1000 mg over 1-3 days surrounding the cyclophosphamide infusions in order to reset the inflammatory state. For now, I would not abandon cyclophosphamide. However, some patients do break through cyclophosphamide or are unresponsive to it. Some of these patients are responsive to mycophenolate mofetil (CellCept; Roche Laboratories Inc.; Nutley, New Jersey) at doses of 1000 mg twice daily. A randomized, controlled trial comparing cyclophosphamide with CellCept in the treatment of lupus DPGN is under way via FDA funding, and results should be available soon. There are also many other potential biologic agents that will soon become available for the treatment of SLE and SLE kidney disease.


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