Ask the Experts - Vascular Complications of Tacrolimus?
Ask the Experts - Vascular Complications of Tacrolimus?
Can high serum levels of tacrolimus cause vasculitis and/or arteritis (evident in the renal graft biopsy)? Can this result in renal vein thrombosis?
There is no good evidence that vascular inflammation or renal vein thrombosis represents clinical problems related to tacrolimus use.
An association of tacrolimus (TAC) with vasculitis/arteritis was observed in the early animal studies of this drug, but appeared to be restricted to the canine model. Ochiai and colleagues reported vasculitis and vascular fibrinoid necrosis in some of their dogs who underwent renal transplantation followed by TAC immunosuppression, but stressed that similar changes could be found in untreated animals. A contemporaneous report by Collier and coworkers concluded that TAC was not a suitable immunosuppressant in dogs because of these side effects. Todo and colleagues, who reported a good outcome in a dog model of liver transplantation with TAC immunosuppression, noted that the drug appeared to be more toxic in canines than in other species. Several years later, Ochiai's group published a brief report noting that vasculitis occurred in the canine renal transplant model regardless of whether TAC, rapamycin, or RS-61443 was given as the primary immunosuppressant. They hypothesized that the dog might be particularly susceptible to this complication. Toxicological study of TAC in the rat did not disclose any evidence of arteritis or arterial necrosis, and this would seem to support a species difference for this effect.
Tacrolimus use in the routine clinical setting has not been complicated by vasculitis or significant vascular necrosis. The major toxicities of the drug include nephrotoxicity, neurotoxicity, hypertension, and hyperglycemia. The histologic correlate of nephrotoxicity is a microvacuolization of renal tubular epithelial cells. This may be accompanied by similar changes in the arterial smooth muscle cells and is reversible upon lowering of the drug dosage. The vacuolar change is not accompanied by inflammation. One study of renal transplant patients who received TAC immunosuppression described rare foci of "pinpoint fibrinoid necrosis," unaccompanied by inflammation, in the arteriolar media in some patients. The significance of this change is not clear; it may represent the forerunner of the arteriolar hyaline change that is recognized as a manifestation of chronic drug toxicity in the cases of either TAC or cyclosporine use.
Elevated levels of TAC can be associated with microthrombus formation within the renal allograft, similar to changes seen with cyclosporine toxicity or hemolytic-uremic syndrome. Randhawa and colleagues reported 10 cases of this change and estimated a frequency of 1% in the renal transplant population. Microthrombi could be seen in the lumens of glomerular capillaries or arterioles. Reduction of the drug led to resolution of changes. The authors noted that the frequency of microthrombosis was similar to that seen with cyclosporine use. None of their patients developed renal vein thrombosis. However, one patient did show intrarenal arterial fibrinoid necrosis in conjunction with high drug levels. We have not seen this alteration in any other patient despite the use of TAC in literally thousands of transplant recipients.
In brief, known causes of renal thrombosis include technical problems, hypercoagulable states such as antiphospholipid antibody syndromes or factor V Leiden mutation, and posttransplant complications such as allograft rejection. Bakir and coworkers performed a multivariate analysis and found 5 factors that predisposed to posttransplant renal vein thrombosis: use of the donor right kidney, a past history of venous thrombosis, a past history of diabetic nephropathy, technical surgical problems, and hemodynamic instability in the peri- and postoperative interval. To date there has been no reported association of renal vein thrombosis with immunosuppressant use.
The question of vascular inflammation has also been raised and rebutted in the case of clinical liver transplantation. Allograft rejection may sometimes target portal vein branches or central hepatic venules in the liver parenchyma, thereby producing a "vasculitis." It had been suggested that central hepatic venulitis might actually represent a form of TAC toxicity. However, a follow-up study showed that such lesions correlated with acute rejection episodes, and increasing the dosage of TAC or administering other antirejection therapy would actually ameliorate this condition.
A review of the literature revealed a single case report of cerebral vasculitis associated with neurotoxicity in a liver transplant patient treated with TAC. Neurotoxicity, a known complication of TAC use, is not typically associated with vasculitis and it would be inappropriate to generalize this anecdotal report.
In summary, there is no compelling evidence to support the contention that TAC use predisposes to arteritis or renal vein thrombosis in the clinical setting.
Can high serum levels of tacrolimus cause vasculitis and/or arteritis (evident in the renal graft biopsy)? Can this result in renal vein thrombosis?
There is no good evidence that vascular inflammation or renal vein thrombosis represents clinical problems related to tacrolimus use.
An association of tacrolimus (TAC) with vasculitis/arteritis was observed in the early animal studies of this drug, but appeared to be restricted to the canine model. Ochiai and colleagues reported vasculitis and vascular fibrinoid necrosis in some of their dogs who underwent renal transplantation followed by TAC immunosuppression, but stressed that similar changes could be found in untreated animals. A contemporaneous report by Collier and coworkers concluded that TAC was not a suitable immunosuppressant in dogs because of these side effects. Todo and colleagues, who reported a good outcome in a dog model of liver transplantation with TAC immunosuppression, noted that the drug appeared to be more toxic in canines than in other species. Several years later, Ochiai's group published a brief report noting that vasculitis occurred in the canine renal transplant model regardless of whether TAC, rapamycin, or RS-61443 was given as the primary immunosuppressant. They hypothesized that the dog might be particularly susceptible to this complication. Toxicological study of TAC in the rat did not disclose any evidence of arteritis or arterial necrosis, and this would seem to support a species difference for this effect.
Tacrolimus use in the routine clinical setting has not been complicated by vasculitis or significant vascular necrosis. The major toxicities of the drug include nephrotoxicity, neurotoxicity, hypertension, and hyperglycemia. The histologic correlate of nephrotoxicity is a microvacuolization of renal tubular epithelial cells. This may be accompanied by similar changes in the arterial smooth muscle cells and is reversible upon lowering of the drug dosage. The vacuolar change is not accompanied by inflammation. One study of renal transplant patients who received TAC immunosuppression described rare foci of "pinpoint fibrinoid necrosis," unaccompanied by inflammation, in the arteriolar media in some patients. The significance of this change is not clear; it may represent the forerunner of the arteriolar hyaline change that is recognized as a manifestation of chronic drug toxicity in the cases of either TAC or cyclosporine use.
Elevated levels of TAC can be associated with microthrombus formation within the renal allograft, similar to changes seen with cyclosporine toxicity or hemolytic-uremic syndrome. Randhawa and colleagues reported 10 cases of this change and estimated a frequency of 1% in the renal transplant population. Microthrombi could be seen in the lumens of glomerular capillaries or arterioles. Reduction of the drug led to resolution of changes. The authors noted that the frequency of microthrombosis was similar to that seen with cyclosporine use. None of their patients developed renal vein thrombosis. However, one patient did show intrarenal arterial fibrinoid necrosis in conjunction with high drug levels. We have not seen this alteration in any other patient despite the use of TAC in literally thousands of transplant recipients.
In brief, known causes of renal thrombosis include technical problems, hypercoagulable states such as antiphospholipid antibody syndromes or factor V Leiden mutation, and posttransplant complications such as allograft rejection. Bakir and coworkers performed a multivariate analysis and found 5 factors that predisposed to posttransplant renal vein thrombosis: use of the donor right kidney, a past history of venous thrombosis, a past history of diabetic nephropathy, technical surgical problems, and hemodynamic instability in the peri- and postoperative interval. To date there has been no reported association of renal vein thrombosis with immunosuppressant use.
The question of vascular inflammation has also been raised and rebutted in the case of clinical liver transplantation. Allograft rejection may sometimes target portal vein branches or central hepatic venules in the liver parenchyma, thereby producing a "vasculitis." It had been suggested that central hepatic venulitis might actually represent a form of TAC toxicity. However, a follow-up study showed that such lesions correlated with acute rejection episodes, and increasing the dosage of TAC or administering other antirejection therapy would actually ameliorate this condition.
A review of the literature revealed a single case report of cerebral vasculitis associated with neurotoxicity in a liver transplant patient treated with TAC. Neurotoxicity, a known complication of TAC use, is not typically associated with vasculitis and it would be inappropriate to generalize this anecdotal report.
In summary, there is no compelling evidence to support the contention that TAC use predisposes to arteritis or renal vein thrombosis in the clinical setting.
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