sirolimus and Nephrogenic-Fibrosing-Dermopathy

A 52-year old woman with chronic renal failure presented with tender buttock nodules, bilateral non-tender periocular papules and yellow scleral plaques. The patient then developed sclerodermoid changes of the hands, as well as woody induration, oedema and hyperpigmentation of lower limbs. There was no previous exposure to gadolinium contrast. Her histology and clinical features were consistent with nephrogenic systemic fibrosis. Treatment with oral sirolimus resulted in a marked reduction of induration and oedema, and an improvement in distal upper limb and lower limb joint mobility.

Topics: Administration, Oral; Female; Gadolinium; Humans; Immunosuppressive Agents; Middle Aged; Nephrogenic Fibrosing Dermopathy; Sirolimus

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that occurs in some patients with renal insufficiency. Exposure to gadolinium-based contrast agents (GdCA) has been associated with the development of NSF. No uniformly effective treatment options exist. We present immunohistochemical evidence to show that the proliferating fibrocytes of NSF express phospho-70-s6 kinase (PI-3-K), a protein downstream of PI-3-K, and the target of the drug rapamycin. In our patient, use of rapamycin resulted in rapid clinical improvement marked by reduced edema, reduced skin induration, and decreased pain. This suggests a possible role for PI-3-K and rapamycin (mTOR) pathways in the pathogenesis of NSF. Drugs that inhibit these pathways may be a target for future therapy. While our patient did attribute disease onset to GdCA exposure, used on a single occasion for abdominal imaging, he was also exposed to iron, calcium, and darbepoetin alpha at the time of imaging.

Topics: Contrast Media; Gadolinium DTPA; Humans; Male; Middle Aged; Nephrogenic Fibrosing Dermopathy; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus

Not just de novo induction of diabetes mellitus, but also the progression of diabetic nephropathy may be enhanced under immunosuppressive therapy after organ transplantation. We evaluated whether sirolimus (SRL) or cyclosporine A (CsA) therapy would be a superior immunosuppressant in streptozotocin-induced diabetic nephropathy.. Diabetes was induced by intravenous injection of streptozotozin (60 mg/kg body weight) in 26 male Sprague-Dawley rats. Eight days after diabetes induction, animals were divided into three groups, which were treated with placebo (n=8), SRL (n=9), or CsA (n=9). Six nondiabetic placebo-treated rats were included as controls.. After 19 weeks of diabetes, SRL significantly decreased fibrosis as assessed by periodic acid Schiff staining and by specific extracellular matrix proteins such as fibronectin and laminin at messenger RNA and protein level compared with the diabetic placebo group. SRL ameliorated renal inflammation, glomerular hypertrophy, and podocyte loss as indicated by morphometric and immunohistological analysis. SRL lowered expression and activity of glomerular transforming growth factor-beta1/2 and vascular endothelial growth factor, all of which are considered central cytokines in the pathogenesis of diabetic nephropathy. In contrast, calcineurin phosphatase inhibition through CsA did not ameliorate any of the features of diabetic nephropathy compared with placebo treatment but slightly aggravated glomerular fibrosis without affecting transforming growth factor-beta1/2 or vascular endothelial growth factor.. Compared with CsA, SRL by anti-inflammatory, antifibrotic, and podocyte-protective effects clearly seems to be the superior treatment of prevention or amelioration of diabetic nephropathy in the rat.

Topics: Animals; Cyclosporine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; DNA Primers; Fibronectins; Immunosuppressive Agents; Laminin; Male; Nephrogenic Fibrosing Dermopathy; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sirolimus; Vascular Endothelial Growth Factor A

Topics: Anti-Bacterial Agents; Brain; Combined Modality Therapy; Disease Progression; Fatal Outcome; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Nephrogenic Fibrosing Dermopathy; Plasmapheresis; Polycystic Kidney, Autosomal Dominant; Renal Dialysis; Sirolimus