لخّصلي

Membranous nephropathy (MN) is the predominant cause of nephrotic syndrome in adults.Furthermore, sirolimus has been reported to reduce proteinuria and decrease glomerular IgG deposition, as evidenced by immunofluorescence studies [16].Sirolimus (rapamycin), widely used to prevent allograft rejection in organ transplantation [13], exerts immuno- suppressive effects through inhibition of the mamma- lian target of rapamycin (mTOR)--a serine/threonine kinase critical for T-cell activation and proliferation [14].

Membranous nephropathy (MN) is the predominant
cause of nephrotic syndrome in adults. Approximately
70% of MN patients have circulating autoantibodies to
the phospholipase A2 receptor (PLA2R), while other
target antigens have been identified in the remaining
patients over the past decade [1, 2]. Spontaneous remis-
sion occurs in about 30% of individuals; however, 40–50%
of patients with persistent nephrotic syndrome progress
to end-stage kidney disease within 10 years [3].
Initial management of MN typically involves support-
ive care, with immunosuppressive therapy reserved for
patients at high risk factors of disease progression [4].
The traditional alternating regimen of glucocorticoids
and cyclophosphamide induces remission in 60–70% of
patients but is associated with significant adverse effects,
including hyperglycemia, myelosuppression, infections,
infertility, and malignancy [5, 6]. Randomized controlled
trials and cohort studies have demonstrated that rituxi-
mab and calcineurin inhibitors improve rates of complete
and partial remission [7–12]. Owing to a more favorable
safety profile, these agents are now preferred over cyclo-
phosphamide in patients with preserved kidney function.
In developing countries, calcineurin inhibitors such
as cyclosporine remain the primary treatment for MN,
largely due to drug availability and reimbursement con-
straints. However, their high relapse rate after discontin-
uation necessitates prolonged treatment, increasing the
risk of adverse events such as nephrotoxicity, hyperten-
sion, hyperuricemia, and anemia. This underscores the
urgent need for alternative or combination regimens that
preserve efficacy while minimizing toxicity.
Sirolimus (rapamycin), widely used to prevent allograft
rejection in organ transplantation [13], exerts immuno-
suppressive effects through inhibition of the mamma-
lian target of rapamycin (mTOR)—a serine/threonine
kinase critical for T-cell activation and proliferation
[14]. In experimental rat models of MN, sirolimus has
been shown to downregulate pro-inflammatory and
pro-fibrotic gene expression, reduce tubulointerstitial
inflammation and fibrosis, and inhibit compensatory kid-
ney hypertrophy [15]. Furthermore, sirolimus has been
reported to reduce proteinuria and decrease glomerular
IgG deposition, as evidenced by immunofluorescence
studies [16]. Despite these promising findings, no clinical
trials have evaluated sirolimus in patients with MN.
In this study, we conducted a randomized controlled
trial to evaluate the efficacy and safety of sirolimus in com-
bination with cyclosporine in patients with active MN.