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      Different Effect of Cyclosporine A and Mycophenolate Mofetil on Passive Heymann Nephritis in the Rat

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          Background: While cyclosporine A (CsA) is an effective therapy for nephrotic syndrome, it has nephrotoxic side effects. We compared the anti-proteinuric effects and nephrotoxicity in rats with passive Heymann nephritis (PHN) of CsA and mycophenolate mofetil (MMF). Methods: PHN was induced in female Wistar rats. Two treatment groups consisting of 8 rats each received either 25 mg of CsA or 25 mg of MMF/kg body weight/day and were compared with untreated controls. Kidney function and proteinuria were monitored over 4 weeks. Western blots were used for densitometric analysis of renal cyclooxygenase-2 (COX-2) protein expression. Thromboxane B<sub>2</sub> (TxB<sub>2</sub>) and 6-keto-PGF<sub>1α</sub> were determined by radioimmunoassays (RIAs) in renal tissue and urine. Results: Rats with PHN exhibited a marked proteinuria of 12.76 ± 4.42 vs. 0.73 ± 0.28 mg/24 h (p < 0.01) and showed increased glomerular concentrations of TxB<sub>2</sub> and 6-keto-PGF<sub>1α</sub> (992.6 ± 216.9 and 1,187.0 ± 54.2 pg/mg protein, respectively) compared with healthy controls (595 ± 196.17 and 729 ± 297.84, respectively) and a strongly induced COX-2 protein expression. CsA and MMF treatment reduced PHN-related proteinuria to 2.10 ± 1.47 and 1.47 ± 7.2 mg/24 h, respectively. In rats with PHN, CsA induced a significant deterioration of renal function and enhanced urine excretion of thromboxane A<sub>2</sub>, paralleled by a significant, twofold increase in COX-2 protein expression and renal prostaglandins. By contrast, MMF treatment in rats with PHN was not nephrotoxic and had no effect on prostaglandin production. COX-2 protein expression under MMF was suppressed. Conclusion: While the antiproteinuric efficacy of MMF and CsA in PHN was comparable, the absence of nephrotoxicity might favor MMF in the treatment of nephrotic syndrome. The CsA-induced increase in COX-2 expression and COX-2-dependent prostacyclin may indicate a mechanism that compensates nephrotoxicity in the diseased and CsA-exposed kidney.

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          Most cited references 23

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          Renal complications of nonsteroidal anti-inflammatory drugs.

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            A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats.

            We have previously shown that cyclooxygenase-2 (COX-2) expression is low in the renal cortex of adult rats, but is increased in macula densa/cortical thick ascending limb and in glomerular podocytes after subtotal renal ablation. To evaluate the functional consequences of this increased COX-2 expression, male rats were subjected to subtotal renal ablation and divided into four groups: (1) treatment with the selective COX-2 inhibitor SC58236, (2) treatment with vehicle, (3) treatment with the angiotensin-converting enzyme inhibitor enalapril, and (4) treatment with enalapril + SC58236. The administration of drugs was begun on the third day after ablation and continued for 6 to 10 weeks. Within one week after ablation, vehicle-treated rats developed hypertension. Although enalapril led to significant reductions in blood pressure, either alone or in combination with the COX-2 inhibitor, SC58236 alone did not significantly alter ablation-induced hypertension. However, the SC58236-treated animals exhibited levels of proteinuria at six weeks after ablation that were comparable to those seen with enalapril (vehicle, 47 +/- 4; enalapril, 27 +/- 2; SC58236, 30 +/- 2 mg/day; N = 7, P < 0.01, each group compared with vehicle), and continued SC58236 treatment led to persistent reductions in proteinuria at 10 weeks after renal ablation (vehicle, 77 +/- 4; SC58236, 50 +/- 4 mg/day; N = 6, P < 0. 01). SC58236 treatment also significantly reduced the percentage of glomeruli exhibiting segmental or global sclerosis at 10 weeks (32.6 +/- 7.8% vs. 10.9 +/- 2.8%, N = 6, P < 0.03). Furthermore, SC58236 treatment partially inhibited increases in transforming growth factor-beta1 mRNA expression and increases in collagen III and collagen IV mRNA expression. These studies indicate that chronic treatment with a specific COX-2 inhibitor may retard the progression of progressive renal injury, and suggest that such compounds can be used in combination with angiotensin-converting enzyme inhibitors. Further studies are required to determine the mechanism by which COX-2 inhibition is renoprotective.
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              Use of mycophenolate mofetil in resistant membranous nephropathy.

              Membranous nephropathy (MN) is a common cause of nephrotic syndrome. Optimal therapy for this disease is still debated. We report our experience using mycophenolate mofetil (MMF), an immunosuppressive agent widely used in transplant recipients, to treat 16 nephrotic patients with MN. All patients had biopsy-documented MN; secondary forms were ruled out. Fifteen patients had steroid-resistant disease; cytotoxic agents had failed in 6 patients and cyclosporine therapy had failed in 5 patients. Patients were treated with MMF (dose range, 500 to 2,000 mg) for a mean of 8 months. Six patients experienced a halving of proteinuria, which occurred after a mean duration of 6 months of therapy. Partial remissions occurred in 2 patients. There were no significant changes in mean values for serum creatinine, serum albumin, or proteinuria. Mean cholesterol levels were significantly less. Side effects of MMF were infrequent and generally mild. In summary, MMF appears to reduce proteinuria in some patients with idiopathic MN previously resistant to steroids, cytotoxic agents, or cyclosporine. Further trials with this agent are warranted.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 2005
                27 April 2005
                : 100
                : 2
                : e104-e112
                aKlinik für Nephrologie und Rheumatologie, bInstitut für Pharmakologie und Klinische Pharmakologie der Heinrich-Heine Universität Düsseldorf, Düsseldorf and cKlinik für Nephrologie und Innere Medizin, Städtisches Klinikum Solingen, Deutschland
                85029 Nephron Exp Nephrol 2005;100:e104–e112
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 2, References: 38, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/85029
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