J. Exp. Path. (I990) 71, 245-255
The effects of cyclosporin A on glucose homeostasis and the kidney in the normal rat P.H. Whiting*, K.J. Thomson, N.J. Saunders and J.G. Simpson Department of Clinical Biochemistry* and Pathology, University of Aberdeen, Aberdeen, UK Received for publication 24 April I989 Accepted for publication 25 October I989
Summary. The effects of administering cyclosporin A (CsA), for periods of up to 84 days, on glucose homeostasis and renal function were studied in adult male Sprague-Dawley rats. Marked glucose intolerance was demonstrated at a variety of drug doses, accompanied in the longer term by hyperglycaemia. Early on and at high CsA dose, the abnormal islet cell function was accompanied by islet cell vacuolation; in the long-term dose groups, more chronic structural islet changes were present. Although abnormalities in renal function and structure were noted during this study, they were not directly related to the pancreatic changes observed. Keywords: cyclosporin A, nephrotoxicity, glucose intolerance, rat
The administration of cyclosporin A (CsA) to animals (Thomson et al. I984; Ryffel et al. I988), to human recipients of a variety of transplants (Mihatsch et al. I985) and to patients with uveitis (Nussenblatt et al. I983) is associated with the development of nephrotoxicity, characterized functionally by reduced glomerular filtration rate and structurally by a tubulopathy. Clinically, significant nephrotoxicity is now less common because of lower drug dosages, but it can still be severe. The toxic effects of CsA are not confined to the kidney: a number of other organs and tissues can be affected (Thomson et al. I984), amongst which is the pancreas. CsA has been shown to alter glucose homeostasis and pancreatic function in animals (Andersson et al. I984; Helmchen et al. I984; Yale et al.
1985; Laube & Hahn I985; Hahn et al. 1986). In renal transplant recipients, glucose intolerance can occur with CsA treatment, improving following conversion from CsA to steroids (Harris et al. I986). A complicating factor in the relationship between CsA and the pancreas is that the renal dysfunction induced by CsA can cause glycosuria, which may make diabetic control more difficult to achieve (Chan et al. I988). There have been no reports that CsAinduced pancreatic islet damage can be severe enough to cause diabetic nephropathy. Nonetheless, CsA is now the immunosuppressant of choice in diabetics undergoing renal and/or pancreatic transplantation (Sutherland I983) and in juvenile type I diabetic patients (Stiller et al. I984). This study was designed to investigate the tem-
Correspondence: Dr P.H. Whiting, Department of Clinical Biochemistry, Medical Buildings, Foresterhill, Aberdeen AB9 2ZD, UK. 245
P.H. Whiting et al. poral relationship between the onset of renal received drug vehicle alone or CsA at IO, 2 5 and pancreatic dysfunction in surgically or 50 mg/kg body weight over a period of i4 intact rats. days. Glucose homeostasis and renal function were assessed on days 4, 7, iO and 14, while at least five animals were killed at each Materials and methods time point for renal and pancreatic morphology. Animals (b) Long-term study. Glucose homeostasis Adult male Sprague-Dawley rats (mean and renal function were assessed monthly in initial weight 2 75 g) were supplied and groups of rats treated with either drug maintained by the University Animal vehicle or CsA at IO or 20 mg/kg body Department. They were allowed free access weight for 28, 56 or 84 days. All animals to both food (Oxoid Pasteurised Breeding were killed at the end of the study and the Diet) and tap water unless otherwise stated. kidneys and pancreases retained for histology. (c) Reversibility study. A group of animals Cyclosporin A (CsA) was treated with CsA at Io mg/kg weight for CsA (OL-2 7-400, Sandoz Ltd, Basle, Switzer- 28 days, followed by a similar period where land) was prepared in IO% ethanol in olive no drug was given. The functional assessoil, at 10, 20, 25 or 50 mg/ml. CsA or its ments were carried out at days 28 and 56, vehicle was administered to the conscious the animals being killed for histology on day animal by gavage using a 4FG cannula 56. (Portex Ltd, Hythe, Kent, UK). Blood sampling Protocol Blood samples, other than during glucose tolerance testing, were obtained by tail clipThree study protocols were employed. (a) Short-term study. Groups of animals ping under light ether anaesthesia. The
246
Table 1. The effect of CsA on glucose homeostasis Area under the OGTT curve (mmol/l/min) Treatment period
(days) 4 7 10 14 28 56 84
CsA dose administered (mg/kg body weight)
Vehicle alone 734±28 810±62 826± 9 829±84 880±112 841±83 834±64
10
20
25
50
644±166t
NP NP NP NP
902±78* 1952±416*** 1356±117*** 1256±325** NP
1189±266*** 1638±294*** 1391±177*** 1428±252*** NP NP NP
831±164t 755 ± 100t 1018±141* 1142±133* 1520±241*** 1195±199**
1709±297***t 1716±288*** 1410± 162***
NP NP
Results are expressed as the mean ± s.d. and there were five estimations at each time point. Results compared to treatment with vehicle alone at each time point: * P
The effects of cyclosporin A on glucose homeostasis and the kidney in the normal rat P.H. Whiting*, K.J. Thomson, N.J. Saunders and J.G. Simpson Department of Clinical Biochemistry* and Pathology, University of Aberdeen, Aberdeen, UK Received for publication 24 April I989 Accepted for publication 25 October I989
Summary. The effects of administering cyclosporin A (CsA), for periods of up to 84 days, on glucose homeostasis and renal function were studied in adult male Sprague-Dawley rats. Marked glucose intolerance was demonstrated at a variety of drug doses, accompanied in the longer term by hyperglycaemia. Early on and at high CsA dose, the abnormal islet cell function was accompanied by islet cell vacuolation; in the long-term dose groups, more chronic structural islet changes were present. Although abnormalities in renal function and structure were noted during this study, they were not directly related to the pancreatic changes observed. Keywords: cyclosporin A, nephrotoxicity, glucose intolerance, rat
The administration of cyclosporin A (CsA) to animals (Thomson et al. I984; Ryffel et al. I988), to human recipients of a variety of transplants (Mihatsch et al. I985) and to patients with uveitis (Nussenblatt et al. I983) is associated with the development of nephrotoxicity, characterized functionally by reduced glomerular filtration rate and structurally by a tubulopathy. Clinically, significant nephrotoxicity is now less common because of lower drug dosages, but it can still be severe. The toxic effects of CsA are not confined to the kidney: a number of other organs and tissues can be affected (Thomson et al. I984), amongst which is the pancreas. CsA has been shown to alter glucose homeostasis and pancreatic function in animals (Andersson et al. I984; Helmchen et al. I984; Yale et al.
1985; Laube & Hahn I985; Hahn et al. 1986). In renal transplant recipients, glucose intolerance can occur with CsA treatment, improving following conversion from CsA to steroids (Harris et al. I986). A complicating factor in the relationship between CsA and the pancreas is that the renal dysfunction induced by CsA can cause glycosuria, which may make diabetic control more difficult to achieve (Chan et al. I988). There have been no reports that CsAinduced pancreatic islet damage can be severe enough to cause diabetic nephropathy. Nonetheless, CsA is now the immunosuppressant of choice in diabetics undergoing renal and/or pancreatic transplantation (Sutherland I983) and in juvenile type I diabetic patients (Stiller et al. I984). This study was designed to investigate the tem-
Correspondence: Dr P.H. Whiting, Department of Clinical Biochemistry, Medical Buildings, Foresterhill, Aberdeen AB9 2ZD, UK. 245
P.H. Whiting et al. poral relationship between the onset of renal received drug vehicle alone or CsA at IO, 2 5 and pancreatic dysfunction in surgically or 50 mg/kg body weight over a period of i4 intact rats. days. Glucose homeostasis and renal function were assessed on days 4, 7, iO and 14, while at least five animals were killed at each Materials and methods time point for renal and pancreatic morphology. Animals (b) Long-term study. Glucose homeostasis Adult male Sprague-Dawley rats (mean and renal function were assessed monthly in initial weight 2 75 g) were supplied and groups of rats treated with either drug maintained by the University Animal vehicle or CsA at IO or 20 mg/kg body Department. They were allowed free access weight for 28, 56 or 84 days. All animals to both food (Oxoid Pasteurised Breeding were killed at the end of the study and the Diet) and tap water unless otherwise stated. kidneys and pancreases retained for histology. (c) Reversibility study. A group of animals Cyclosporin A (CsA) was treated with CsA at Io mg/kg weight for CsA (OL-2 7-400, Sandoz Ltd, Basle, Switzer- 28 days, followed by a similar period where land) was prepared in IO% ethanol in olive no drug was given. The functional assessoil, at 10, 20, 25 or 50 mg/ml. CsA or its ments were carried out at days 28 and 56, vehicle was administered to the conscious the animals being killed for histology on day animal by gavage using a 4FG cannula 56. (Portex Ltd, Hythe, Kent, UK). Blood sampling Protocol Blood samples, other than during glucose tolerance testing, were obtained by tail clipThree study protocols were employed. (a) Short-term study. Groups of animals ping under light ether anaesthesia. The
246
Table 1. The effect of CsA on glucose homeostasis Area under the OGTT curve (mmol/l/min) Treatment period
(days) 4 7 10 14 28 56 84
CsA dose administered (mg/kg body weight)
Vehicle alone 734±28 810±62 826± 9 829±84 880±112 841±83 834±64
10
20
25
50
644±166t
NP NP NP NP
902±78* 1952±416*** 1356±117*** 1256±325** NP
1189±266*** 1638±294*** 1391±177*** 1428±252*** NP NP NP
831±164t 755 ± 100t 1018±141* 1142±133* 1520±241*** 1195±199**
1709±297***t 1716±288*** 1410± 162***
NP NP
Results are expressed as the mean ± s.d. and there were five estimations at each time point. Results compared to treatment with vehicle alone at each time point: * P
