Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome

Zietse, Robert; Wenting, G J; Kramer, P.; Schalekamp, M. A. D. H.; Weimar, Willem

doi:10.1042/cs0820641

Cited by 57 publications

(31 citation statements)

References 20 publications

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“…Glomerular diseases treated with cyclosporine A also showed a reduction in proteinuria that was attributed to a restoration of the permselectivity of the GBM (34). Whether improved GBM permselectivity is an important effect of cyclosporine A in Alport syndrome, human or experimental, is unknown.…”

Section: Discussionmentioning

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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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%

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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“…CsA has multifactorial mechanisms of antiproteinuric actions. It can inhibit the activation of Tlymphocytes and the production of IL-2, improving the permeability of the glomerular basement membrane (30,31). On the other hand, CsA has an antiproteinuric effect independent of its immunosuppressive function in T cells,directly resulting from the stabilization of the podocyte actin cytoskeleton (32).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Glucocorticoids Alone and Combined with Cyclosporine A in Patients with IgA Nephropathy: A Prospective Randomized Controlled Trial

Liu

Fang

et al. 2014

Intern. Med.

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Objective The aim of this study was to investigate the effects of two different treatment regimes in patients with IgA nephropathy (IgAN): steroids alone and in combination with a medium dose of cyclosporine A (CsA). Methods Forty-eight IgAN patients 18-69 years of age with proteinuria >1.0 g/24 hours and an estimated glomerular filtration rate (eGFR) of >30 mL/min/1.73 m 2 were randomly given either steroids alone (methylprednisolone (MP) group; n=25) or steroids plus CsA treatment (combination group; n=23). The primary endpoint was the reduction of proteinuria by 50% or more of the baseline value. The secondary endpoint was an increase in the baseline serum creatinine level of 50% or a decrease in the baseline eGFR of 25%. Results After 12 months of treatment, all patients in the combination group and 87.50% of the patients in the MP group reached the primary endpoint. The complete remission rates in the combination group and MP group were 50.0% and 45.83%, respectively. The level of urinary protein excretion declined from 3.17 ± 3.25 g/24 hours to 0.36 ± 0.23 g/24 hours (p<0.001) in the combination group and from 2.60 ± 2.03 g/24 hours to 0.53 ± 0.71 g/24 hours (p<0.001) in the MP group. Two patients in the combination group reached the secondary endpoint, with a decrease in the eGFR of 25% from the baseline value, while no patients in the MP group achieved this goal. The patients in the combination group exhibited significant improvements in the eGFR after nine months (90.16 ± 28.78 vs. 80.46 ± 22.73 mL/min.1.73 m 2 , p=0.011), while the patients in the MP group showed significant increases in the eGFR after six months of treatment (92.18 ± 22.71 to 81.63 ± 18.36 mL/min/1.73 m 2 , p=0.019). Four patients (8.33%) developed severe pneumonia during treatment. Conclusion Both the full dose of steroids alone and combined treatment with steroids and a medium dose of CsA remarkably reduced the levels of proteinuria and ameliorated the renal function in the IgAN patients. Infection was the most serious complication during the treatment.

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“…The amount of serum albumin crossing the glomerular filtration barrier is reduced due to the reduction in the glomerular filtration rate. Zietse et al studied the effects of CyA on renal perfusion and the glomerular filtration barrier in patients with NS of various etiology [11]. Low doses of CyA led to the restoration of the charge selectivity of the glomerular barrier in minimal change disease, whereas in membranous glomerulopathy, changes in proteinuria were related to an increase in glomerular permselectivity and a decrease in filtrate flow through the shunt pathway.…”

Section: Mechanisms Of the Beneficial Effect Of Cyamentioning

confidence: 99%

Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies

Bensman

Niaudet

2010

Pediatr Nephrol

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It has been reported (this issue Pediatric Nephrology) that cyclosporine A (CyA) therapy in combination with corticosteroids, angiotensin-converting enzyme inhibitor, and an angiotensin receptor blocker decreased proteinuria in three patients with nephrotic syndrome (NS) due to WT1 mutations. Treatment with calcineurin inhibitors were found to induce a partial remission of proteinuria in several other children with genetic forms of NS, such as mutation in the podocine and in the phospholipase C epsilon gene. CyA therapy has also been reported to be beneficial to patients with Alport syndrome. Recent data have shown that the antiproteinuric effect of CyA in these cases may be due to a non-immunologic mechanism. CyA exerts an antiproteinuria effect by preventing the degradation of the actin organizing protein synaptodpodin and by a downregulation of TRPC6. This mechanism leads to the stabilization of the actin cytoskeleton in the kidney podocytes. This beneficial effect of CyA is interesting, but long-term results regarding function and nephrotoxicity are still missing.

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Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome

Cited by 57 publications

References 20 publications

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

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

Comparison of Glucocorticoids Alone and Combined with Cyclosporine A in Patients with IgA Nephropathy: A Prospective Randomized Controlled Trial

Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies

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