J. G. Simpson

Cyclosporine: immunology, toxicity and pharmacology in experimental animals.

Cyclosporine (CsA) is the first of a new order of pharmacological immune suppressants and represents a significant advance in the clinical control of graft rejection. In laboratory animals, its capacity to prolong allograft survival has been well documented, including reports of indefinite donor-specific immunological tolerance after shortterm CsA treatment. There is also evidence that CsA can inhibit the onset or progress of a variety of experimental autoimmune diseases. Underlying these properties of the drug is its capacity to selectively interfere with T helper cell activation and lymphokine production, although some direct effects on B cells have also been reported. In addition, sparing of suppressor cells may in part explain the mode of action of CsA which, at the molecular level, is not understood.CsA-induced nephrotoxicity in the rat has been extensively studied and is characterized by reversible proximal tubular cell damage. This problem may be aggravated by concomitant administration of other potentially nephrotoxic drugs, such as gentamicin, or by therapeutic agents which interfere with the metabolism of CsA.CsA is metabolized in the liver and excreted in the bile. Although the pathway of hepatic metabolism of CsA has not been precisely elucidated, animal studies suggest that agents capable of inducing metabolism of the drug CsA could be used to alleviate its nephrotoxic properties.

IgA Nephropathy Is Not a Rare Disease in the United Kingdom

A retrospective analysis of all renal biopsies performed in the Grampian Region of Scotland during 1977-1980 revealed that IgA nephropathy was the most frequently encountered glomerular lesion. The commonest indications for renal biopsy were the presence of asymptomatic urinary abnormalities (90/184; 48.9%) especially asymptomatic haematuria (42/184; 22.8%). A histological diagnosis was made in 36 of the 42 patients presenting with asymptomatic haematuria (85.7%); 16 of the 26 cases of IgA nephropathy presented in this way. Overall, IgA nephropathy was detected in 14.1% of all biopsies and accounted for 21.8% of primary glomerular diseases. This study indicates that IgA nephropathy is apparently more common in Grampian than elsewhere in the United Kingdom. However, it is suggested that this does not represent a true variation in the prevalence of the condition; IgA nephropathy is probably a common cause of haematuria in the United Kingdom.

Breast cancer in thyroid disease: fact or fallacy?

The incidence of breast cancer was examined prospectively in 2523 patients registered in a thyroid follow-up system. No significant differences were found between the observed and expected numbers of cases in any of the sub-groups defined by age, underlying pathology, or type of treatment. These results provide no indication that the risk of breast cancer is increased in patients treated for thyroid disease.

Inhibition of Drug-Induced Eosinophilia by Cyclosporin A

Administration of cyclophosphamide to Sprague‐Dawley rats 2 days before immunization with ovalbumin in complete Freunds adjuvant resulted in a striking blood, bone marrow. and tissue eosinophilia. The number of circulating eosinophils reached a maximum (50‐fold increase above normal) 2 weeks after immunization, and eosinophils were also prominent in bone marrow, lymph nodes (paracortical areas), spleen (while and red pulp), and liver. The eosinophilia could be inhibited by daily oral administration of cyclosporin A (CsA), although its effect was dependent both on the duration of treatment and on the dosage of CsA. A similar, inhibitory action of CsA was demonstrated with respect to methotrexate‐induced eosinophilia. This experimental model may prove useful in the study of factors regulating eosinophil production and in examining the prospective value of CsA in the treatment of conditions where eosinophils play a central role.

Cyclosporin A-induced nephrotoxicity in the rat: Relationship to increased plasma renin activity

Cyclosporin A (CsA; 50, 100 or 150 mg/kg) was administered by gavage, daily for 4 days, to groups of normotensive rats. An additional group of animals received the drug vehicle. CsA-induced nephrotoxicity, characterized by reduced glomerular filtration rate (GFR) and urinary sodium flow, enzymuria and proximal tubular cell damage was accompanied by elevated plasma renin activity (PRA).These changes were dose-related at 50 and 100 mg/kg CsA, but were not increased by administration of 150 mg/kg. Circulating trough drug levels were related to dosage.Four days after CsA withdrawal in animals given 50 mg/kg, there was reduced nephrotoxicity and PRA had returned to normal, even though circulating CsA levels had not diminished. Rats given 100 and 150 mg/kg, however, showed no reduction in nephrotoxicity or in PRA. Hyperglycaemia was evident at 4 days in animals given 100 and 150 mg/kg CsA and persisted 4 days after drug withdrawal.There were no accompanying abnormalities in islet cell structure.Continuous administration of CsA (50 mg/kg) to rats for 14 days caused elevated PRA on day 4 but a return to normal levels by day 7. In contrast, significant GFR impairment was evident by day 7 whilst enzymuria was significantly increased from day 4 onwards.CsA nephrotoxicity in the rat is clearly associated with activation of the renin-angiotensin-aldosterone system. Possible mechanisms leading to increased renin release are discussed.

Immunosuppressive activity and toxicity of cyclosporin A in rats pretreated with high dose cyclophosphamide.

Cyclophosphamide (Cy; 150 mg/kg) was administered (i.p.) to groups of Sprague-Dawley rats followed two days later by immunization with ovalbumin (OVA). From that time, cyclosporin A (CsA; 25 mg/kg) or its vehicle was given (p.o.) for a further 13 days. Control animals tested 14 days after immunization, showed strong Arthus-like and modest delayed-type skin reactions to OVA, in contrast to almost total inhibition in animals tested with Cy, CsA or both. Similar effects were observed with respect to serum anti-OVA antibody levels.Despite itself producing lymphopenia, CsA had no additional effect on the lymphocyte depletion caused by Cy. Both drugs, either alone or in combination, caused neutrophilia and monocytosis. An additional eosinophilia due to Cy was prevented by CsA. Cy induced splenomegaly, nodal extramedullary haemopoiesis and increases in both tissue eosinophils and marrow neutrophils. There was also lymphoid depletion in both spleen and lymph nodes which was enhanced by CsA. Thymic lymphoid atrophy was found only when CsA was given.Despite the powerful immunosuppressive properties of both drugs, detailed biochemical and structural analyses showed no other synergistic toxicity, apart from modest hepatic abnormalities. In particular, there was no enhancement of the nephrotoxicity of CsA.

Inhibition by cyclosporin A of IgE production and cyclophosphamide-induced eosinophilia in rats immunized with non-parasite antigens

Administration of cyclosporin A (CS-A; 25 mg/kg daily) to rats from the time of immunization with ovalbumin (OVA) in complete Freunds adjuvant abolished the production of anti-OVA antibodies, including IgE. Cyclophosphamide (Cy; 150 mg/kg) given 2 days before immunization also inhibited specific antibody production but at the same time induced a striking eosinophilia. Combined administration of both drugs resulted in the inhibition by CS-A of the Cy-induced eosinophilia. The results suggest that IgE synthesis and eosinophil proliferation may be under the control of separate T cell subsets. This rat model may prove useful in studies on the regulation of eosinophil production and the role of these cells in disease processes.

Secondary Polycythaemia Associated with Idiopathic Membranous Nephropathy

A 44-year-old man developed idiopathic membranous nephropathy and true secondary polycythaemia. With advancing azotemia, polycythaemia gradually resolved and venesection was no longer required. Only 2 cases of polycythaemia associated with membranous nephropathy have been reported previously. Secondary polycythaemia is a rarely reported association of membranous nephropathy and may increase the risk of thromboembolism, which might be prevented with venesection.

Renal Tubular Function in Experimental and Clinical Cyclosporin (CsA) Nephrotoxicity

The use of cyclosporin A (CsA) in both organ transplantation and in the treatment of autoimmune disease may ultimately be limited by the drug’s nephrotoxic properties (Klintmalm et al, 1981). Indeed a major clinical problem has been the differentiation of rejection from CsA-induced nephrotoxicity, following renal transplantation. This nephrotoxicity is characterised by impaired renal function and histologically, predominantly by tubular changes (Blair et al, 1982; Thiru et al, 1983). Although the pathogenesis of CsA-induced nephrotoxicity is still unclear, alterations in glomerulotubular function have been demonstrated (Battle et al, 1986; Gnutzman et al, 1986; Dieperink et al, 1986a, b).