Glomerulonephritis is an important manifestation in about 1/2 of patients with Systemic Lupus
Nephritis (SLE; lupus). Despite recent national guidelines recommending use of induction
therapy with high-dose corticosteroids and immunosuppressive agents, followed by prolonged
maintenance therapy, up to 1/3 of these patients continue to have active nephritis and
ongoing protein in the urine (proteinuria). It has long been recognized that both the level
and chronicity of proteinuria in patients with lupus nephritis are associated with disease
severity and with long-term prognosis, including the possibility of progression to complete
kidney failure, which may occur in about 1/4 of patients. Pentoxifylline (PTX) is an oral
medication introduced 45 years ago for treatment of vascular insufficiency. It has also
recently been found to reduce proteinuria in patients with diabetic nephropathy. The
mechanism of this unexpected and intriguing finding is not certain, but may in part involve
inhibiting the production of TNF-alpha, an inflammatory cytokine known to be present in urine
and kidneys of patients with lupus nephritis. Our hypothesis is that this inexpensive,
generic drug, PTX, can significantly reduce proteinuria in patients with lupus nephritis.
To test this hypothesis, we plan to initiate a 6-month, double-blind, placebo-controlled
randomized clinical trial of PTX or placebo in 40 patients with active lupus nephritis. This
trial will include 6-8 patients from each of 5 different academic medical centers that
specialize in the treatment of lupus nephritis. Our primary objective of this trial will be
to measure urine protein each month to determine the extent to which PTX is able to reduce
urine protein, and how rapidly this occurs.
Concurrently, we will carefully follow these patients each month to determine whether PTX
administration is also associated with stabilization of renal function, or with improvement
in other manifestations of lupus, such as clinical disease activity or abnormal laboratory
findings. A major secondary objective will be to explore the possible mechanism(s) whereby
PTX reduces proteinuria. For this purpose, we will use the monthly urine specimens to measure
TNF-alpha, and levels of several other proteins (IL-1, IL-6, IL-2, MCP-1, TGF-beta, PDGF, and
IFN-alpha) that have been shown to contribute to inflammation and scarring in lupus
nephritis. Comparison of levels of these inflammatory proteins with level of protein in the
urine should help us to determine whether one or more of these proteins is a contributor to
the severity or persistence of lupus nephritis.
This information may also allow us to learn whether repeated measurements of these proteins
can serve as biomarkers to assist in the ongoing management of patients with lupus nephritis.
Finally, we hope to eventually measure levels of these inflammatory proteins in blood samples
from the patients, to determine if PTX treatment can suppress (or enhance) such levels, and
whether these changes are associated with reduced lupus disease activity, or improvement in
other manifestations of lupus. Ultimately, it is our hope that the data from this clinical
trial using a generic repurposed drug will permit us to conclusively confirm that PTX can
significantly reduce proteinuria in patients with lupus nephritis, which would be of great
benefit for the thousands of people who suffer with this most severe type of lupus.
Phase:
Phase 4
Details
Lead Sponsor:
MetroHealth Medical Center
Collaborators:
Lupus Research Alliance Ohio State University The Cleveland Clinic The Research Foundation for the State University of New York University of Cincinnati Yale University