Kidney volume increases during long-term ciclosporin a treatment.

PURPOSE: Previously, we have for the first time reported enlargement of the pig kidney during long-term ciclosporin (CsA) treatment. In this paper, we summarize our findings of renal enlargement during long-term protocols with various dosages and durations of CsA administration as well as discuss possible pathogenetic mechanisms. MATERIALS AND METHODS: Twenty-two adolescent Gottingen minipigs were allocated into four groups: group A (n = 6) served as controls for 6 months; group B (n = 5) were treated with CsA (10 mg/kg per day) for 6 months, group C (n = 4), with CsA (20 mg/kg per day) for 6 months, and group D (n = 7) with CsA (10 mg/kg per day) orally for 12 months. At regular intervals, renal length and total volume were measured using magnetic resonance imaging; renal biopsies were performed for histological examination. RESULTS: A significant increase in kidney volume occurred in all CsA-treated pigs (groups B, C, and D); whereas the volume remained stable in the control animals (group A). A small but significant rise in kidney length was observed in groups A, B, and C, probably due to the normal growth of the animals. Histological examination was normal after treatment with CsA doses of 10 and 20 mg/kg per day for 6 months but showed definite interstitial fibrosis and glomerulosclerosis after treatment with 10 mg/kg per day CsA for 12 months. CONCLUSION: Long-term CsA treatment produced renal enlargement in pigs before the development of histological changes in the kidney. Thus, renal enlargement may represent an early stage of chronic CsA nephrotoxicity.

Changes in renal dimensions evaluated by magnetic resonance imaging and ultrasonography during long-term ciclosporin-A treatment.

PURPOSE: To investigate changes in renal dimensions during long-term treatment with ciclosporin-A (CsA). MATERIAL AND METHODS: Five mini-Göttingen pigs were treated with CsA (10 mg kg(-1) day(-1)) for 6 months; 3 untreated animals served as controls. Renal length was measured by magnetic resonance imaging (MRI) and ultrasonography (US); renal volume by MRI. Examinations were performed at baseline (0 weeks) and after the start of CsA treatment at intervals of 5 weeks (5-25 weeks). RESULTS: Comparison of baseline and end-point data (0 weeks vs. 25 weeks) revealed a statistically significant increase in renal volume in CsA-treated animals (87.1 cm3 vs. 55.9 cm3, P=0.002). Renal volume remained unchanged in the control group. A significant increase in renal length was found both in the CsA-treated pigs (MRI: 96 mm vs. 84 mm, P<0.001; US: 94 mm vs. 81 mm, P<0.001) and in the control group (MRI: 97 mm vs. 85 mm, P<0.001; US: 89 mm vs. 81 mm, P=0.018). No difference was found between MRI and US measurements based on 40 paired units (MRI variance: 2.4-30.3% and US variance: -5.1-40.6%, P=0.133). CONCLUSION: During long-term CsA treatment, renal volume increases in mini-pigs, but there is no correlation between the increase in volume and the increase in length in this pig model.

Chronic cyclosporine nephrotoxicity: a pig model.

Cyclosporine A (CsA) is one of the keystones in immunosuppressive treatment after solid organ transplantation, despite its major side effects such as nephrotoxicity. The chronic nephrotoxic effects of CsA seen in humans have been difficult to reproduce in small-animal models. The aim of the present study was to examine the chronic nephrotoxicity produced by therapeutic dosages of CsA in a pig model. Among 11 Gottingen minipigs included in the study, three died, yielding data from five animals given CsA (10 mg/kg/d, orally) for 6 months, and three controls. Body weight, blood pressure, glomerular filtration rate (GFR) by plasma clearance of (51)Cr-ethylenediamine-tetraacetic acid, CsA concentration, serum creatinine, and other values were measured every 5 weeks. Our results showed that the whole blood trough CsA levels were lower in pigs than in humans treated with similar CsA doses. Renal biopsies, which were obtained successfully, except one case of macroscopic hematuria, showed no histological changes in the kidney. No significant increase in serum creatinine or blood pressure was observed. Surprisingly, there was a significant increase in GFR during CsA treatment. We conclude that the pig model displays a hyperfiltration that warrants further investigation.