—  SHORT COURSE #61  —

Kidney and Liver Transplant - Update and Issues

Case 1 - Acute Tubular Necrosis and Calcineurin Inhibitor Nephrotoxicity

Arthur H. Cohen, Juan Lechago and Cynthia C. Nast



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Acute tubular necrosis usually occurs early in the post-transplant period as a result of ischemia [1, 2] . The morphology is similar to that in the native kidney with tubular cells displaying flattening; however in transplants epithelial cells have been reported to show reduced loss of proximal cell brush border staining with fewer casts and increased complete cell necrosis [2]. The epithelial cells slough from the basement membrane into the tubular lumina, and infrequently may leave denuded areas of basement membrane; in cases of severe tubular injury there is tubular rupture with extra-tubular Tamm-Horsfall protein in the interstitium. As healing proceeds there is basophilia of the tubular epithelium and mitotic figures are evident. The interstitium is variably edematous but without an inflammatory infiltrate. Post-transplant acute tubular necrosis is associated with older donors, donors and recipients with more severe atheromatous vascular disease, and prolonged cold ischemia time [4]. This process often is referred to as delayed graft function and is self-limited requiring no therapy although reduction in cyclosporine levels may speed resolution. When tubular necrosis occurs after engraftment and lasts for weeks or months it is termed primary prolonged nonfunction, and may undergo healing by organization with eventual tubulo-interstitial scarring.

Cyclosporine and tacrolimus are calcineurin inhibitors widely used as anti-rejection agents in renal and hepatic allograft recipients. These agents can induce toxicity in allograft and native kidneys, with similar mechanisms of action and histologic appearances for the two agents [5, 6, 7] . The most common form of acute nephrotoxicity involves the tubular epithelial cells which display a variant of acute tubular necrosis. Proximal cells are flattened with loss of brush borders and tubular lumina are relatively dilated. Cells show individual necrosis but this is not a widespread or pronounced finding. The most diagnostic feature is isometric vacuolization of proximal tubular epithelium in which the cytoplasm of tubular cells contains small uniform clear vacuoles. This often affects all cells in a single tubule prolife; however only in a fraction of cases are the isometric vacuoles found. The interstitium often has mild edema, but no significant lymphocytic infiltrates are in the interstitium or in the walls of tubules. In patients receiving Neoral and mycophenolate, prominent perivenous lymphoid aggregates are occasionally identified without tubulitis [8]. The tubular changes may be accompanied by an arteriolopathy characterized by arteriolar wall thickening due to muscular hypertrophy. There may be necrosis and drop-out of individual smooth muscle cells in arteriolar walls; this is followed by the accumulation of insudates (IgM and complement) in a nodular pattern along the outer aspects of these walls. Juxtaglomerular apparatus are enlarged. Glomeruli are unremarkable or display ischemic changes with thickening and wrinkling of capillary walls.

Chronic nephrotoxicity extends injury of the tubulo-interstitium to that of chronic interstitial nephritis. There is a focal "striped" pattern of tubular atrophy with interstitial fibrosis and a paucity of associated mononuclear inflammatory cells [9]. Tubular inflammation within atrophic tubules is sparse. Arteriolar changes as described above may be observed, with arteriolar hyalinization thought to be the most sensitive marker of cyclosporine nephrotoxicity [10] and further enlargement of juxtuglomerular apparatus also is seen. Glomerular changes of ischemia are not unusual and focal and segmental as well as global sclerosis have been described as consequences of cyclosporine administration [10, 11, 12] . Abnormalities of arteries are not features of chronic calcineurin inhibitor toxicity, but it is quite common to have chronic rejection and/or nephrosclerosis occurring in concert with chronic cyclosporine/tacrolimus nephrotoxicity and it may be difficult to differentiate these processes.

A more infrequent form of nephrotoxicity is hemolytic uremic syndrome which can be induced by both cyclosporine and tacrolimus, although more commonly by the former [13, 14, 15] . Approximately 15-20% of cases occur in native kidneys of patients receiving calcineurin inhibitors for reasons other than renal transplantation [13, 16] . The morphology is identical to other thrombotic microangiopathies with thromboses in glomerular capillaries, arterioles and less frequently interlobular arteries. Glomeruli are ischemic to varying degrees, and may have capillary wall double contours, mesangiolysis, and a lobular appearance. Capillary walls, arterioles and arteries stain for fibrin by immunofluorescence, and ultrastructurally there are wide subendothelial lucent zones in glomerular capillary walls with flocculent electron dense and lucent material. Arterioles and small arteries have muscular hypertrophy, fibrin in the walls and loose mucoid intimal thickening with luminal narrowing. In severe cases there is focal cortical necrosis.

  Tubules Interstitium Arterioles
Acute Toxicity Flattened cells
Dilated lumina
Isometric vacuoles 		± edema Muscular hypertrophy
Myocyte necrosis
Nodular insudates
Chronic Toxicity Atrophic Striped fibrosis Muscular hypertrophy
Nodular insudates
Hemolytic Uremic Syndrome Variable ischemic necrosis Edema Thrombosis
Fibrin in walls
Loose intimal thickening

The pathogenesis of calcineurin inhibitor nephrotoxicity is likely multifactorial. These agents cause afferent arteriolar vasoconstriction in a dose dependent manner inducing mild renal ischemia with subsequent acute tubular injury as a form of ischemic damage and there may be direct tubular toxicity [17, 18] TGF-beta levels are increased in acute cyclosporine toxicity but not in acute rejection [19 ] contributing to the acute and chronic tubulo-interstitial damage while the chronic tubulo-interstitial injury has a vascular etiology. Studies indicate factors released by tubular cells play a role as well [20] and there is a shift in expression of collagen types within the interstitium [21, 22, 23, 24] . The hemolytic uremic syndrome is more an idiosyncratic abnormality with a multifactorial pathogenesis encompassing endothelial injury, platelet activation and abnormalities of the clotting and fibrinolytic systems although the mechanisms are not well understood.

Patients with acute nephrotoxicity present with acute renal failure and usually are biopsied to exclude transplant rejection. T here may be therapeutic trough levels of drug but nephrotoxicity may develop due to high peak levels [25]. In some institutions the 2 hour cyclosporine levels are being measured (C2 levels) to evaluate patients for toxic peak levels ; if these are found treatment consists of reduction in medication dosage. Infrequently, there may be high peak levels with low trough levels, and features of acute rejection may coincide with findings of acute calcineuin-inhibitor nephrotoxicity. The chronic form of nephrotoxicity clinically is associated with a slow deterioration of renal function over months, and may be more common in patients treated with cyclosporine. Hemolytic uremic syndrome may occur as the full-blown syndrome with low platelet count, abnormal peripheral smear, hypertension and renal failure or may be very subtle with few clinical signs. It is crucial to make the diagnosis as quickly as possible to prevent graft loss secondary to infarction. Therapeutic options include changing from cyclosporine to tacrolimus , cellcept or sirolimus while reducing or eliminating the offending agent, and possibly anticoagulation or plasma exchange depending on the severity of the microangiopathic injury. Patients who have lost a renal allograft to drug-induced hemolytic uremic syndrome have been successfully retransplanted.

References

  1. Rohr MS: Renal allograft acute tubular necrosis. II. A light and electron microscopic study of biopsies taken at procurement and after revascularization. Ann Surg 197:663- 671, 1983.

  2. Wiecek A, Nowicki M, Kokot F, and Ritz E: Acute renal failure of the transplanted kidney – pathophysiology, diagnosis and prevention. Ann Transplant 1: 5-9, 1996.

  3. Olsen S, Burdick JF, Keown PA, Wallace AC, Racusen LC, Solez K: Primary acute renal failure ("acute tubular necrosis") in the transplanted kidney: morphology and pathogenesis. Medicine 68:173-187, 1989.

  4. Lechevallier E, Dussol B, Luccioni A, et al: Posttransplantation acute tubular necrosis: risk factors and implications for graft survival. Am J Kidney Dis 32:984-991, 1998.

  5. Randhawa PS, Shapiro R, Jordan ML, Starzl TE, and Demetris AJ: The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Clinical significance and comparison with cyclosporine. Am J Surg Pathol Jan; 17:60-8, 1993.

  6. Adler JL, Rostaing L: Cyclosporin nephrotoxicity: pathophysiology and comparison with FK-506. Curr Opin Nephrol Hypertens 7:539-45, 1998.

  7. Davies DR, Bittmann I, Pardo J: Histopathology of calcineurin inhibitor-induced nephrotoxicity. Transplantation 69: Suppl 12 SS11-13, 2000.

  8. Nast CC, Moudgil A, Zuo X-J, Wilkinson A, Danovitch GM, Jordan SC: Cyclosporine microemulsion and mycophenolate mofetil related lymphoid aggregates are not associated with acute rejection. Transplantation 72:251-256, 2001.

  9. Mihatsch MJ, Morozumi K, Strom EH, Ryffel B, Gudat F, Thiel G: Renal transplant morphology after long-term therapy with cyclosporine. Transplant Proc 27:39-42, 1995.

  10. Nankivell BJ, Borrow RJ, Fung CL, O'Connell PJ, Chapman JR, Allen RD: Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation 78:557-565, 2004.

  11. Falkenhain ME, Cosio FG, Sedmak DD: Progressive histologic injury in kidneys from heart and liver transplant recipients receiving cyclosporine. Transplantation 62:364-370, 1996.

  12. Paller MS, Cahill B, Harmon KR, Miller RB, Sinaiko AR, Burke B, Manivel JC: Glomerular disease and lung transplantation. Am J Kidney Dis 26:527-531, 1995.

  13. Trimarchi HM, Truong LD, Brennan S, Gonzalez JM, and Suki WN: FK506-associated thrombotic microangiopathy: report of two cases and review of the literature. Transplantation 67:539-44, 1999.

  14. Young BA, Marsh CL, Alpers CE, Davis CL: Cyclosporine-associated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation. Am J Kidney Dis 28:561-571, 1996.

  15. Bren AF, Kandus A, Lindic J, et al: Cyclosporine-triggered hemolytic-uremic syndrome in kidney graft recipients: a series of 12 cases. Transplant Proc 33:3691-92, 2001.

  16. Mercadal L, Petitclerc T, Assogba U, Beaufils H, and Deray G.: Hemolytic and uremic syndrome after heart transplantation. Am J Nephrol 20:418-20, 2000.

  17. Glyaei AJ, de Mattos AM, Bennett WM: Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. Drug Saf 21:471-88, 1999.

  18. Healy E, Dempsey M, Lally C, Ryan MP: Apoptosis and necrosis: mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line. Kidney Int 54:1955-1966, 1998.

  19. Pankewycz OG, Miao L, Isaacs R, Guan J, Pruett T, Haussmann G, Sturgill BC: Increased renal tubular expression of transforming growth factor beta in human allografts correlates with cyclosporine toxicity. Kidney Int 50:1634-1640, 1996.

  20. Benigni A, Bruzz I, Mister M, et al: Nature and mediators of renal lesions in kidney transplant patients given cyclosporine for more than one year. Kidney Int 55:674-685, 1999.

  21. Nast CC, Adler SG, Artishevsky A, Kresser CT, Ahmed K, Anderson PS: Cyclosporine induced elevated procollagen alpha 1 (I) mRNA levels in the rat renal cortex. Kidney Int 39:631-638, 1991.

  22. Abrass CK, Berfield AK, Stehman-Breen C, Alpers CE, and Davis CL: Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies. Am J Kidney Dis 33:11-20, 1999.

  23. Burdmann EA, Andoh TF, Yu L, Bennett WM: Cyclosporine nephrotoxicity. Semin Nephrol 23:465-476, 2003.

  24. Bakker RC, Koop K, Sijpkens YW, et al: Early interstitial accumulation of collagen type I discriminates chronic rejection from chronic cyclosporine nephrotoxicity. J Am Soc Nephrol 14:2142-2149, 2003.

  25. Sijpkens YW, Mollat MJ, Siegert CE: Risk factors of cyclosporine nephrotoxicity after conversion from Sandimmune to Neoral. Clin Nephrol 55:149-155, 2001.