Literature search and review of mechanism of renal toxicity forciclosporin.

Fråga: Literature search and review of mechanism of renal toxicity forciclosporin.

Sammanfattning: "In conclusion, to cite Humes (6), we can summarize: ""Cyclosporine has the ability to interact with renal tubular cell membranes in a relatively specific manner and at low concentrations. Despite this interaction, the acute decline in renal excretory function produced by ciclosporin is due predominantly to functional declines in RBF rather than structural derangements in renal tubular cell integrity. Ciclosporine does, however, possess a toxic potential to injure renal cortical cells, so that a chronic tubulointerstitial nephropathy may develop with long-term use of this immunosuppressive agent."""

Svar: Ciclosporin is a selective inhibitor of T lymphocyte function, andit reduces the production of interleukin-2 and other immunomodulator substances (1,2,27,28). The compound is extremely lipophilic and binds to lipoproteins and erythrocytes (3-5). Less than one per cent of administered ciclosporin is excreted unchanged.

Although the results of renal transplantation have improved substantially since the introduction of ciclosporin, paradoxically the most important side effect of the drug has turned out to be its nephrotoxicity. Other important adverse effects are hepatotoxicity, hypertension, tremor, and gingival hyperplasia.

The clinical consequences of acute ciclosporin-induced nephrotoxicity are an increase in plasma creatinine, decreased GFR, hyperkalemia and hyperuricemia (1,2,6,8,9,10). These changes are similar both in transplant recipients and in patients without any renal disease (11) treated with ciclosporin. Acute rejection and ciclosporin nephrotoxicity present with similar symptoms. Some nephrotoxicity is reported to occur in almost 80 per cent of renal transplant patients using the drug (8,9). A rapid increase in serum creatinine, decrease in diuresis and increase in weight, as well as a body temperature over 37.5 C were common symptoms in rejection episodes, but not seen to the same extent in ciclosporin nephrotoxicity (especially fever). However, these criteria often are not sufficiently discriminating for differential diagnosis (12). Among 53 bone marrow transplant recipients, 63 per cent of the patients had acute nephrotoxicity episodes and the mean increase in serum creatinine during ciclosporin treatment was 50 per cent (29) in all patients.

Histopathological features are much the same in rejection episodes and in ciclosporin nephrotoxicity. Interstitial fibrosis, focal glomerular sclerosis and tubular atrophy may be induced by ciclosporin, but are present also in rejection (6,8,9). Giant mitochondria, initially believed to indicate nephrotoxicity, were seen in proximal convoluted tubules (11). Chronic tubulointerstitial nephritis and fibrosis has been reported with long-term use of this drug (6,14,30).

Ciclosporin binding to proximal tubular segments (31), renal brush border membranes, and cortical mitochondria is best explained by a partitioning process of the lipophilic drug into the phospholipid phase of the membrane rather than binding to a specific membrane component (6) as was proposed also for lymphocytes and cultured kidney cells (7).

Renal cortical DNA synthesis was studied in rats treated with ciclosporin, and an increase was found (6). This finding could reflect a regenerative process after focal cell injury. The degree of cell injury is, however, small enough to maintain tubular integrity. Thus, the low-grade toxic potential of ciclosporin for renal tubular cell injury in this system is not sufficient to produce structural acute renal failure. It may however be sufficient to cause a chronic tubulointerstitial disease process within the kidney over a long period of time after the initial injury (6). It has been suggested that ciclosporin nephrotoxicity may be secondary to functional decline in renal blood flow (6).

Ciclosporine induced a decrease in the GFR (3,6,8,15,17,18), in thesynthesis of prostaglandins - especially PGI1 - (3,8,16,17,19,21,22) and changes (increase of renin) in the reninangiotensin axis (3,8,7,18,22). These functional alterations make the foundation for the following hypothesis (6,8,9,15-20). The primary site of toxic action of ciclosporin maybe the preglomerular arteriole, where vascular tone is increased dose-dependently. The resulting glomerular hypoperfusion is compensated by autoregulation. After a prolonged exposure to ciclosporin, glomerular PGE2 synthesis appears to become exhausted and the resulting possible disequilibrium between reduced renal PGE2 synthesis, increased thromboxane production and, probably, unaltered angiotensin activity could diminish the autoregulatory response and lead to the observed fall in filtration rate.

It has been proposed, as primary mechanism, that interleukin-2 inhibition is followed, in lymphocyte T-helper cells, by a decrease in the production and release of other lymphokines and, specifically, of prostacyclin stimulating factor (PSF), an important factor in PGI1 (prostacyclin) and PGE2 production (23). Thelack of PSF inhibits production of prostacyclin (which is a vasodilator) by the vascular endothelial bed, and the ultimate result might be a uremia-like syndrome (16,17,19,20) or even hepatorenal syndrome (21). Prostaglandin E2 reduces both nephrotoxicity and immunosuppressive effects of ciclosporin in rats (24).

These prostaglandin alterations are in agreement with the potentiation of ciclosporin nephrotoxicity by indomethacin and other non-steroidal antiinflammatory drugs (2,17,25,26).

It is not clear whether the alteration of prostaglandin synthesis is a first step of ciclosporin nephrotoxicity or is a reflex due to the effect of ciclosporin on renal blood flow, but a direct inhibition of phospholipase A2 might be a manifestation of the activity of ciclosporin on immunocompetent cells (16,26). 1 Buren CT van: Cyclosporine: progress, problems, and perspectives. Organ Transplantation 1986; 66: 435-449 2 Kahan BD: Cyclosporine: the agent and its actions. Transplant Proc 1985; 17(suppl 1): 5-18 3 Caterson RJ, Duggin GG, Critchley L, Baxter C, Horvarth JS, Hall BM, Tiller DJ: Renal tubular transport of cyclosporine A (CSA) and associated changes in renal function. Clin Nephrol 1986; 25(suppl 1): S30-S33 4 Ptachcinski RJ, Venkataramanan R, Burckart GJ: Clinical pharmacokinetics of cyclosporin. Clin Pharmacokinet 1986; 11: 107-132 5 Grevel J, Nuesch E, Abisch E, Kutz K: Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subjects. Eur J Clin Pharmacol 1986; 31: 211-216 6 Humes HD, Jackson NM, O´Connor RP, Hunt DA, White MD: Pathogenetic mechanisms of nephrotoxicity: insights into cyclosporine nephrotoxicity. Transplant Proc 1985; 17(4 suppl 1): 51-62 7 Gerkens JF, Bhagwandeen SB, Dosen PJ, Smith AJ: The effect of salt intake on cyclosporine-induced impairment of renal function in rats. Transplantation 1984; 38: 412-417 8 Thiel G: Nephrotoxicity of ciclosporin. TIPS 1986; 7: 167-169 9 Bennett WM, Pulliam JP: Cyclosporine nephrotoxicity. Ann Intern Med 1983; 99: 851-854 10 Klintmalm GBG, Iwatsuki S, Starzl TE: Nephrotoxicity of cyclosporin A in liver and kidney transplant patients. Lancet 1981; 1: 470-471 11 Palestine AG, Nussenblatt RB, Chan CC: Side effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med 1984; 77: 652-658 12 Klintmalm G: Cyclosporin A nephrotoxicity in human transplant patients. Clinical, pharmacological and morphological findings. MD Thesis, Stockholm 1984 13 Klintmalm G, Ringden O, Groth CG: Clinical and laboratory signs in nephrotoxicity and rejection in cyclosporine-treated renal allograft recipients. Transplant Proc 1983; 15: 2815-2820 14 Klintmalm G, Bohman SO, Sundelin B, Wilczek H: Interstitial fibrosis in renal allografts after 12 to 46 months of cyclosporin treatment. Beneficial effects of lower doses in early posttransplantation. Lancet 1984; II: 950-954 15 Duggin GG, Baxter C, Hall BM, Horvarth JS, Tiller DJ: Influence of cyclosporine A (CSA) on intrarenal control of GFR. Clin Nephrol 1986; 25(suppl 1): S43-S45 16 Stahl RAK, Kudelka S: Chronic cyclosporine A treatment reduces prostaglandin E2 formation in isolated glomeruli and papilla of ratkidneys. Clin Nephrol 1986; 25(suppl 1): S78-S82 17 Sullivan BA, Hak LJ, Finn WF: Cyclosporine nephrotoxicity: studies in laboratory animals. Transplant Proc 1985; 17(4 suppl 1): 145-154 18 Siegl H, Ryffel B, Petric R, Shoemaker P, Muller A, Donatsch P, Mihatsch M: Cyclosporine, the renin-angiotensin-aldosterone system, and renal adverse