Long-term effects of cyclosporine A in Alport's syndrome

Callı́s, L; Vila, Amparo Marquina; Carrera, Marta; Gálvez-Nieto, José Luis

doi:10.1046/j.1523-1755.1999.0550031051.x

Cited by 85 publications

(50 citation statements)

References 16 publications

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“…Cyclosporine A has been used in transplantation and immune-mediated disease for many years; however, its therapeutic effects in the treatment of Alport syndrome has only recently been examined (20,21). In a small and uncontrolled study, cyclosporine A decreased or eliminated proteinuria and halted the progression of renal disease.…”

Section: Discussionmentioning

confidence: 99%

“…Beneficial effects have been reported for human Alport patients and in animal models using low-protein diets (17) and angiotensin-converting enzyme inhibitors (18,19). More recently, cyclosporine A was reported to be beneficial to patients with Alport syndrome in a small noncontrolled study (20,21). Massive proteinuria decreased or disappeared, whereas creatinine clearance remained stable throughout treatment.…”

Section: Mutations Have Been Identified In the Col4a3mentioning

confidence: 99%

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Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis)

Chen¹,

Jefferson²,

Harvey³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Alport syndrome refers to a hereditary disorder characterized by progressive renal disease and a multilaminar appearance to the glomerular basement membrane (GBM). In a small group of patients with Alport syndrome, cyclosporine A was reported to decrease proteinuria and maintain stable renal function over 7 to 10 yr of follow-up. The present study examined the effect of cyclosporine A on GBM structure and the progression to renal failure in a canine model of X-linked Alport syndrome. Affected male dogs and normal male dogs treated with cyclosporine A underwent serial renal biopsies. Body weight, serum concentrations of creatinine and albumin, and GFR were sequentially determined. Controls consisted of untreated dogs that developed end-stage renal failure by 8 mo of age. Renal biopsies were assessed for glomerulosclerosis and the percent of multilaminar GBM as measured by image analysis. Significant differences were found between treated and untreated affected dogs for weight, serum creatinine, and GFR. There was a significant delay in the progression of multilaminar change to the GBM, although treated affected dogs at termination had attained approximately 100% split GBM as did untreated affected dogs. A significant difference in the number of sclerotic glomeruli was also noted; treated dogs rarely developed obsolete glomeruli during the period studied. Interstitial fibrosis was not significantly affected by cyclosporine A treatment. These findings indicate that cyclosporine A is beneficial in slowing, but not stopping, the clinical and pathologic progression of Alport syndrome. At least part of this beneficial effect comes from a delayed deterioration of GBM structure, which in turn may be related to glomerular hemodynamics altered by cyclosporine A.

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Section: Discussionmentioning

confidence: 99%

Section: Mutations Have Been Identified In the Col4a3mentioning

confidence: 99%

Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis)

Chen¹,

Jefferson²,

Harvey³

et al. 2003

Journal of the American Society of Nephrology

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“…1). In addition to the effectiveness in glomerular diseases that are thought to be immunologically mediated, CNIs are also used to reduce proteinuria in Alport syndrome, which is a clear non-immunological disease caused by mutations of the type IV collagen of the GBM [42][43][44], further supporting the notion of additional CNI-mediated effects independent of T cells. Additional evidence derives from studies in children with genetic podocytopathies.…”

Section: Calcineurin Inhibitorsmentioning

confidence: 96%

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Müller-Deile

Schiffer

2015

Pediatr Nephrol

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Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active insideout signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.

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“…Cyclosporine A was found to delay progression of renal failure in humans and dogs in initial studies. 20,21 However, cyclosporine is also found to be rapidly associated with nephrotoxicity, thereby precluding its long-term use. 22 Angiotensin-converting enzyme inhibitors and/or angiotensin 2 type 1 receptor antagonists reduce urinary protein excretion and preserve glomerular filtration in dogs affected with X-linked AS, in Col4a3-/-mice, 23 and in a few pediatric patients.…”

Section: Pathophysiology and Therapeutic Approachesmentioning

confidence: 99%