Correspondence

Post-Transplantation Proteinuria and Sirolimus

N Engl J Med 2005; 353:2088-2089November 10, 2005

Article

To the Editor:

Proteinuria may develop in renal-transplant recipients who have converted from treatment with calcineurin inhibitors to treatment with sirolimus1; the mechanism of this occurrence is unknown. We hypothesized that the antiangiogenic properties of sirolimus might be responsible. We determined the plasma concentrations and renal expression of vascular endothelial growth factor (VEGF) in a specimen from a renal-allograft biopsy performed to evaluate post-transplantation proteinuria during sirolimus conversion in a patient with Kaposi's syndrome.

A 68-year-old man with alcoholic cirrhosis and end-stage renal disease due to IgA nephropathy underwent cadaveric liver and renal transplantation in May 1996. Eight years later, cutaneous lesions typical of Kaposi's syndrome developed. His immunosuppressive treatment was modified: cyclosporine and mycophenolate mofetil were withdrawn, and sirolimus (3 mg per day) was started. Chronic arteriolopathy associated with cyclosporine nephrotoxicity, without glomerular damage, was documented before the introduction of sirolimus. During follow-up, most cutaneous lesions disappeared, and the patient's renal function remained stable (serum creatinine level, 2.9 mg per deciliter). One year after treatment with sirolimus was initiated, proteinuria developed (protein excretion, 2 to 3 g per day) without hematuria; the patient's prednisone dose at the time was 15 mg per day.

The patient's plasma level of VEGF had increased by a factor of 19 after one year of sirolimus therapy (1975 pg per milliliter). Renal biopsy revealed 30 glomeruli: 5 were normal, 15 fibrotic, 10 ischemic, and 5 had lesions characteristic of collapsing focal segmental glomerulosclerosis, characterized by severe retraction of the glomerular membranes and hyperplasia of the overlying podocytes, some of which contained intracytoplasmic protein-resorption droplets. Sparse diffuse swelling of podocytes was noted (Figure 1AFigure 1Findings in a Renal-Transplant Recipient with Proteinuria and Collapsing Focal Segmental Glomerulosclerosis.). Immunofluorescent staining showed segmental tuft deposits of C3 and IgM.

Immunohistochemical staining for monoclonal anti-VEGF antibodies was positive in glomerular epithelial cells but not in tubular cells. However, VEGF was overexpressed in collapsed glomeruli and podocyte swelling (Figure 1B) was noted. Immunohistochemical staining for VEGF in normal, control kidneys was sparse in glomeruli and absent in tubular epithelial cells.

Nephrotic-range proteinuria was reported in 64 percent of renal-transplant recipients whose treatment was switched from calcineurin inhibitors to sirolimus, and focal segmental glomerulosclerosis was found in 30 percent.2 Overexpression of VEGF in visceral and parietal glomerular cells (as in the patient we treated) has been documented in rats with protein-overload nephrosis3 and collapsing glomerulopathy as seen in HIV nephropathy.4 Down-regulation of VEGF has been associated with heavy proteinuria and endotheliosis resembling preeclampsia.5 Because VEGF is a potent enhancer of vascular-wall permeability, we speculate that it may have some role in the development of glomerular proteinuria by altering glomerular permeability. Our observations suggest that sirolimus may induce post-transplantation proteinuria related to collapsing focal segmental glomerulosclerosis associated with VEGF overexpression in podocytes.

Hassane Izzedine, M.D.
Isabelle Brocheriou, M.D., Ph.D.
Camille Frances, M.D.
Pitié–Salpêtrière Hospital, 75013 Paris, France
hassan.izzedine@psl.ap-hop-paris.fr

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