POKFULAM, Hong Kong—Tacrolimus (Prograf®, Astellas Pharma, Inc) produced significant improvements in proteinuria and in hypoalbuminemia in a pilot study of six patients with proteinuria despite quiescent lupus nephritis. The findings suggest that tacrolimus may be an effective treatment for proteinuria due to membranous lupus nephritis (MLN), according to the research group led by Tak Mao Chan, MD, at the University of Hong Kong, in Pokfulam. The study is reported in Lupus.¹

"The data from this pilot study showed that the addition of tacrolimus to maintenance low-dose immunosuppression and angiotensin inhibition/blockade is an effective treatment in patients with persistent proteinuria due to membranous lupus nephritis, so that proteinuria was reduced by more than half in five of six patients, and hypoalbuminaemia was corrected in four patients," writes lead author K. C. Tse, MD, from the nephrology division at the University of Hong Kong's Queen Mary Hospital.

Persistent proteinuria still problematic

According to Dr. Tse, this study was launched because a significant number of lupus patients have proteinuria that continues after resolution of acute proliferative nephritis and despite continuation of angiotensin inhibition or blockade. This might be the result of concomitant membranous lupus (MLN) or of glomerular scarring, but is of concern because of the correlation between proteinuria severity and subsequent renal function deterioration.

The investigators point out that proteinuria that results from glomerular damage or from sclerosis following inflammatory lesions may benefit from angiotensin blockade but that there is no generally effectiveoptimal treatment for MLN remains elusive.

Tacrolimus was an attractive candidate as a possible alternative to cyclosporine. Tacrolimus is a macrolide antibiotic that inhibits calcineurin and therefore inhibits T-cell signal transduction, as well as interleukin-2 (IL-2) transcription. Calcineurin inhibitors such as tacrolimus have the dual actions of reducing proteinuria and suppressing immune activation and reducing proteinuria. The drug has been widely studied because it is used to prevent rejection of transplanted organs and, as a topical formulation, used in treating severe atopic dermatitis. Dr. Tse writes that long-term use of tacrolimus compared to cyclosporine also is associated with less coarsening of facial features and with less excessive hair growth than long-term cyclosporine.

This pilot study tested tacrolimus in patients with quiescent lupus and inactive urinary sediment who had persistent proteinuria despite being treated with angiotensin inhibition or blockade. Four of the six patients had biopsy-documented MLN.

Inclusion criteria included biopsy-proven lupus nephritis, quiescent serological markers, no red blood cells on urinalysis, proteinuria exceeding 1 g/day, and serum albumin below 40 g/L despite treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Patients were also required to be on maintenance immunosuppressive treatment (prednisolone up to 10 mg/day, with or without azathioprine up to 100 mg/day or mycophenolate mofetil up to .75 g bid).

Four of the six patients had biopsy-documented MLN and membranous features on the last renal biopsy before starting tacrolimus. Four of the six patients had baseline proteinuria of >3 g/day, and four had serum creatinine >110 μmol/L. Four of 6 patients had membranous features on the last renal biopsy before starting tacrolimus. All patients had proteinuria >1 g/day for more than 12 months.

The tacrolimus dose was titrated from .05 mg/kg bid to maintain 12-hour trough levels of 4–6 μg/dL. Patients stopped azathioprine or mycophenolate mofetil but continued prednisolone at the previous maintenance dose, as well as previous dosages of angiotensin converting enzymes or angiotensin receptor blockers.

Patients were monitored every 4–12 weeks for 2 years. The primary outcome variable was proteinuria. Secondary endpoints included changes in serum albumin, creatinine, creatinine clearance, blood glucose, lipid profile, anti-dsDNA, C3, and blood pressure.

Proteinuria halved in five of six patients

"Five of the six patients showed a marked reduction of proteinuria by 50% or more, and hypoalbuminaemia was corrected in four of these five patients. These improvements were more pronounced in patients with biopsy-proven membranous lupus nephropathy," Dr. Tse writes.

For the group as a whole, proteinuria decreased significantly from baseline to 24 months (P = .047), and serum albumin increased significantly (P = .032).

Safety concerns with tacrolimus include diabetes and nephrotoxicity. No diabetes was seen in this study, but chronic calcineurin inhibitor nephrotoxicity developed in a patient whose baseline serum creatinine had been 136 μmol/L, whose proteinuria did not improve after 10 months of tacrolimus treatment, and whose trough blood tacrolimus levels were all below 4.00 μg/L.

The authors urge prospective, controlled studies of tacrolimus in lupus nephritis but warn that prolonged use calcineurin inhibitors "should not be taken lightly" and should probably be monitored with repeat renal biopsies in high-risk patients.

"[R]esults from this pilot study suggest that tacrolimus can be an effective treatment for membranous lupus nephritis. In view of the potential for chronic nephrotoxicity, prolonged tacrolimus therapy should probably be reserved for patients who have not responded satisfactorily to non-nephrotoxic treatment, including angiotensin inhibition or blockade," Dr. Tse concludes.

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Reference

1. Tse KC, Lam MF, Tang SCW, et al.  A pilot study on tacrolimus treatment in membranous or quiescent lupus nephritis with proteinuria resistant to angiotensin inhibition or blockade. Lupus. 2007;16:46-51.