Nephrotoxic Effects of Cyclosporine

Cyclosporine A (CsA), a widely used immunosuppressive drug, is associated with toxic effects to various organs and systems, including the kidneys, and liver when used long term (1, 2). Once CsA's primary sites on cyclophilins and calcineurin-calmodulin sites have been saturated, it binds to cellular membranes causing impairment or loss of membrane function. Because of additional risk factors and variable sensitivity of patients, toxic effects may develop even when blood concentrations of CsA are within the therapeutic range. As most patients develop impairment of renal function at doses greater than 5 mg/kg, a dose of about 4 mg/kg is recommended. The most common adverse effects of CsA are dose-dependent and include:

• decreased renal function (57%)
• hypertension (47%)
• hypertrichosis (43%)
• infections (32%)

FUNCTIONAL TOXICITY
The current classification of nephrotoxic effects of CsA recognizes toxicity with and without histopathologic changes (3). Functional toxicity can occur at any time post transplantation and, characteristically, patients present with decreasing urinary output, increased serum creatinine, and decreased glomerular filtration and renal plasma flow rates. Hyperkalemia, hyperuricemia, hypomagnesemia and metabolic acidosis are commonly present. In most patients, the renal allograft biopsy is entirely normal. While endothelin and renal prostaglandins may be implicated in the pathogenesis of this syndrome, it most likely arises from cyclosporine-induced vasoconstriction of the afferent arterioles.

TOXIC INJURY WITH HISTOPATHOLOGIC CHANGES
Three types are seen:
1. Acute Renal Failure With Oliguria Or Anuria
After transplantation, patients have delayed kidney graft function with oliguria or anuria and increased serum creatinine and potassium concentrations. Initially, an allograft biopsy will show variable multifocal tubular cell necrosis and interstitial edema which can progress to persistent fibrosis.

Signs of epithelial regeneration precede resolution of oliguria or anuria and calcific deposits may be encountered in necrotic tubular cells. The general consensus is that the lesions are secondary to ischemic and other insults, and not to the toxic effects of CsA. However, superimposed functional toxicity cannot be excluded.

2. Renal Insufficiency With Toxic Tubular Cell Injury
This type of injury is thought to be caused by the action of intact CsA molecules on the cellular membranes of tubular cells. Injury occurs rapidly, within hours or days, with trough concentrations of CsA greater than 300 ng/ml. The clinical and laboratory findings are comparable to those found in functional toxic injury but tend to be quantitatively greater. Evidence of tubular cell injury, usually present, can be detected through determination of glutathione transferase and ?2-microglobulin in urine. Three types of tubular changes are found alone or in combination.

• Isometric Vacuolization of Tubular Cells. Most commonly detected in proximal tubules, may occur without change in cell size (isometric vacuolization), or with increase in cell size. Results from dilation of the endoplasmic reticulum.
• Microcalcifications. In tubular cells or in the adjacent interstitium, probable a reaction to cell death.
• Megamitochondria. In proximal tubules, usually seen as large, rounded or elliptical cytoplasmic inclusions smaller than the size of the nucleus. May show paracrystalline structure by electron microscopy.

3. Microangiopathy and Tubulointerstitial Injury.
Presentation is progressive deterioration of renal function and hypertension. Glomerular filtration rate and renal plasma flow are decreased, and serum creatinine concentration and vascular resistance are increased. Some patients present with typical features of the hemolytic uremic syndrome. The following types of lesions are found in arterioles, glomeruli, and tubulointerstitium.

• Arteriolar Changes: Three types are seen: thrombosis; hyalinization, diffuse or nodular; and intimal mucoid thickening.
  Thrombosis: The initial insult probably results in single cell necrosis, either endothelial or smooth muscle, and may be associated with fibrin platelet thrombi, or occlusive thrombosis of the afferent arterioles.
  Hyalinization: Subsequent to single or multiple cell necrosis, there is permeation of the vascular wall of arterioles by plasma-derived proteins imparting a glassy or hyaline type change to the wall. As lesions of the afferent arterioles proceed, there is virtual replacement with hyaline material resembling the ordinary type seen in afferent arterioles. The deposits of hyaline material may also occur in an irregular distribution and may be eccentric relative to the vascular wall in the form of a small hyaline nodules (nodular hyalinization).
  Mucoid thickening: A loose amorphous material with several clear spaces is seen in the intima with some or most of the media replaced by necrotic material derived from smooth muscle cells. This type of change is not limited to arterioles as occasionally it may involve terminal intralobular arteries.
• Glomerular Changes: Consists of capillary thrombosis almost always associated with arteriolar changes, particularly arteriolar thrombosis. Thrombosis of the vascular pole with features of hemolytic uremic-like syndrome may also occur. May resolve with dissolution of thrombi, or may heal with segmental sclerosis. ?
• Tubulointerstitial Changes: Consists of striped tubular atrophy and interstitial fibrosis. Areas of normal tubules and interstitium and areas of tubular atrophy and interstitial fibrosis alternate with each other throughout the renal cortex. In general, the areas of tubular atrophy show thickened tubular basement membranes and atrophic tubules with interstitial fibrosis and mononuclear cell infiltration, including lymphocytes and histiocytes. Striped fibrosis and tubular atrophy may occur alone or in association with arteriolar, glomerular and tubular changes in the same biopsy, or in subsequent biopsies of the same patient and are nonspecific findings. The structural basis for striped fibrosis resides in the peculiar arrangement of vasa recta and segments of the nephron in the renal cortex, and the susceptibility of certain nephron segments to ischemic injury.

Whereas the adverse effects of CsA can be minimized with better dosing and monitoring, they are still rather prevalent and are a limitation to its use. However, there is now a growing body of information regarding the immune response to foreign antigens and therein lies the hope for induction of graft tolerance using new therapeutic strategies such as peptides of the major histocompatibility complex and agents that block co-stimulatory molecules (4-6).

References

1. Burke Jr JF, Pirsch JD, Ramos EL, et al: Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med 1994;331:358-63.
2. Goldstein DJ, Zuech N, Shegal V, et al: Cyclosporine-associated end-stage nephropathy after cardiac transplantation. Transplantation 1997;63:664-8.
3. Mihatsch MJ, Ryffel B, Gudat F, Thiel G: Cyclosporine Nephropathy, in Renal Pathology with Clinical and Functional Correlations. (2nd ed), edited by Tisher CC, Brenner BM Philadelphia, JB Lippincott Company, 1994, pp 1641-81.
4. Sayegh MH, Krensky AM: Novel immunotherapeutic strategies using MHC derived peptides. Kidney Int 1996;49(S 53):S13-S206.
5. Akalin E, Chandraker A, Russell ME, et al: CD28-B7 T cell costimulatory blockade by CTLA4Ig in the rat renal allograft model. Inhibition of cell-mediated and humoral immune responses in vivo. Transplantation 1996;62:1942-5.
6. Roy First M: An update on new immunosuppressive drugs undergoing preclinical and clinical trials: Potential applications in organ transplantation. Am J Kidney Dis 1997;29:303-17.