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Vascular microthrombosis in renal transplant recipients treated with tacrolimus
Vascular Microthrombosis in Renal Transplant Recipients Treated With Tacrolimus C. Antoine, S. Thakur, E. Daugas, R. Fraoui, S. Boudjeltia, P. Julia, D. Nochy, and D. Glotz
T
ACROLIMUS has been reported to be a useful immunosuppressive agent in the prevention of allograft rejection, initially in liver1 and more recently in kidney transplantation.2 Structurally quite distinct from Cycloporin, FK506 presents similar immunosuppressive properties and side effects such, as nephrotoxicity.3 PATIENTS AND METHODS Tacrolimus was introduced at Ho ˆpital Broussais as part of a randomized prospective multicenter trial (#FG-506-02-04, Fujisawa, GmbH, Munich). This study compared sequential therapy with A.T.G. (Thymoglobulin, Pasteur Me´rieux, Lyon) followed by Tacrolimus to initial therapy with Tacrolimus. Both groups received similar steroids and azathioprine (2 mg/kg) doses. Tacrolimus trough blood level monitoring was regularly performed to reach 10 to 15 ng/mL. Twenty renal allograft patients were enrolled in this study between February 1996 and August 1997, 11 of them in the induction arm. Fifteen renal biopsies (in 13 patients) were performed for significant elevation of serum creatinine or delayed graft function lasting for more than 15 days posttransplant.
RESULTS
Morphological findings of renal allograft biopsies showed microglomerular thrombosis in 3 cases and microarteriolar thrombosis in one, in the absence of acute rejection (as assessed through Banff’s classification). The median time of
onset for the thrombotic complications was 83.5 days (range from 3 to 180 days). Clinical history and follow– up of the 4 patients are summarized in Table 1. Organ harvesting and preservation were satisfactory. Only the fourth patient developed a primary cytomegalovirus (CMV) infection, which occurred just after the thrombotic complication. There was no cytomegalitic inclusion on the kidney graft. She was the only patient to show a significant Tacrolimus through blood level increase and a hemolytic uremic syndrome. Of note, evolution was excellent in all cases of glomerular microthrombosis, even though Tacrolimus dosage was unchanged in 2 of 3 patients. DISCUSSION
Arteriolar microthrombosis has been already reported in the literature4 – 6 and attributed to Tacrolimus nephrotoxicity. However, isolated glomerular micro–thrombosis has not, to the best of our knowledge, been reported. In a previous clinical trial, Randhawa6 reported the histopathological changes in 51 renal allograft biopsies From the Service de Ne´phrologie et INSERM U430, Hoˆpital Broussais, Paris, France. Address reprint requests to Dr Corinne Antoine, Service de Ne´phrologie, Hoˆpital Broussais, Paris, France.
Table 1. Age Sex
Native Renal Disease
A.T.G.
48 Male
Unknown
44 Male
IgA mesangial No glomerulonephritis Hypertension Yes
52 Male
34 Female Focal segmetal glomerulo– sclerosis
No
No
Complications
None
Delay/Tx
D3
D16 Uretal ste´nosis pulmonary edema D180 Urinary tract infection and leak Herpes zoster D135 CMV primary infection 1 two recurrences
Microthrombosis
HUS
FK506 Through Level
FK506 Withdrawal
Glomerular
No
9 –12 ng/mL
Yes
Glomerular
No
9 –12 ng/mL
No
Glomerular
No
9 –12 ng/mL
No
Arte´riolar
111 .20 ng/mL
Yes
Renal Biopsy Indication
Follow– up
Acute renal Reversible failure 1 proteinuria Reversible Delayed graft function Prote´inuria Reversible no Acute renal Reversible failure 1 proteinuria
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00821-5
Transplantation Proceedings, 30, 2813–2814 (1998)
2813
2814
from patients immunosuppressed with Tacrolimus and compared them to those seen in 30 biopsies from patients on cyclosporine. The author suggested that vascular Tacrolimus–induced lesions (including thrombotic microangiopathy) are similar. Besides, some authors reported successful use of Tacrolimus in case of cyclosporine–induced HUS.7,8 We observed isolated glomerular microthrombosis in 20% of our biopsies, with Tacrolimus blood trough levels within the normal range. The outcome was favorable, even though Tacrolimus therapy remained unchanged. In contrast, arteriolar microangiopathy seen in the fourth case could not be improved by Tacrolimus decrease and controlled only by Tacrolimus withdrawal. The prevalence, prognostic significance, and recommended treatment of microthrombosis confined to the glomerulus under Tacroli-
ANTOINE, THAKUR, DAUGAS ET AL
mus therapy are currently unknown and should be investigated.
REFERENCES 1. Williams R et al: Transplant Int 9(suppl 1):144, 1996 2. Mayer AD et al: Transplantation 64:436, 1997 3. US Multicenter Liver Study Group. Transplant Proc 27:1114, 1995 4. Gharpure S et al: Bone Marrow Transplant 16:715, 1995 5. Japanese FK 506 Study Group: Transplant Proc 26:1933, 1994 6. Randhawa PS, Shapiro R, Jordan ML, Starzl TE and Demetris AJ. Am J Surg Pathol 17:60, 1993 7. Abdalla AH, Al–Sulaiman MH, Al–Khader AA. Transplant Int 7:382 1994 8. McCauley J et al: Lancet 2:1516, 1989
T
ACROLIMUS has been reported to be a useful immunosuppressive agent in the prevention of allograft rejection, initially in liver1 and more recently in kidney transplantation.2 Structurally quite distinct from Cycloporin, FK506 presents similar immunosuppressive properties and side effects such, as nephrotoxicity.3 PATIENTS AND METHODS Tacrolimus was introduced at Ho ˆpital Broussais as part of a randomized prospective multicenter trial (#FG-506-02-04, Fujisawa, GmbH, Munich). This study compared sequential therapy with A.T.G. (Thymoglobulin, Pasteur Me´rieux, Lyon) followed by Tacrolimus to initial therapy with Tacrolimus. Both groups received similar steroids and azathioprine (2 mg/kg) doses. Tacrolimus trough blood level monitoring was regularly performed to reach 10 to 15 ng/mL. Twenty renal allograft patients were enrolled in this study between February 1996 and August 1997, 11 of them in the induction arm. Fifteen renal biopsies (in 13 patients) were performed for significant elevation of serum creatinine or delayed graft function lasting for more than 15 days posttransplant.
RESULTS
Morphological findings of renal allograft biopsies showed microglomerular thrombosis in 3 cases and microarteriolar thrombosis in one, in the absence of acute rejection (as assessed through Banff’s classification). The median time of
onset for the thrombotic complications was 83.5 days (range from 3 to 180 days). Clinical history and follow– up of the 4 patients are summarized in Table 1. Organ harvesting and preservation were satisfactory. Only the fourth patient developed a primary cytomegalovirus (CMV) infection, which occurred just after the thrombotic complication. There was no cytomegalitic inclusion on the kidney graft. She was the only patient to show a significant Tacrolimus through blood level increase and a hemolytic uremic syndrome. Of note, evolution was excellent in all cases of glomerular microthrombosis, even though Tacrolimus dosage was unchanged in 2 of 3 patients. DISCUSSION
Arteriolar microthrombosis has been already reported in the literature4 – 6 and attributed to Tacrolimus nephrotoxicity. However, isolated glomerular micro–thrombosis has not, to the best of our knowledge, been reported. In a previous clinical trial, Randhawa6 reported the histopathological changes in 51 renal allograft biopsies From the Service de Ne´phrologie et INSERM U430, Hoˆpital Broussais, Paris, France. Address reprint requests to Dr Corinne Antoine, Service de Ne´phrologie, Hoˆpital Broussais, Paris, France.
Table 1. Age Sex
Native Renal Disease
A.T.G.
48 Male
Unknown
44 Male
IgA mesangial No glomerulonephritis Hypertension Yes
52 Male
34 Female Focal segmetal glomerulo– sclerosis
No
No
Complications
None
Delay/Tx
D3
D16 Uretal ste´nosis pulmonary edema D180 Urinary tract infection and leak Herpes zoster D135 CMV primary infection 1 two recurrences
Microthrombosis
HUS
FK506 Through Level
FK506 Withdrawal
Glomerular
No
9 –12 ng/mL
Yes
Glomerular
No
9 –12 ng/mL
No
Glomerular
No
9 –12 ng/mL
No
Arte´riolar
111 .20 ng/mL
Yes
Renal Biopsy Indication
Follow– up
Acute renal Reversible failure 1 proteinuria Reversible Delayed graft function Prote´inuria Reversible no Acute renal Reversible failure 1 proteinuria
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00821-5
Transplantation Proceedings, 30, 2813–2814 (1998)
2813
2814
from patients immunosuppressed with Tacrolimus and compared them to those seen in 30 biopsies from patients on cyclosporine. The author suggested that vascular Tacrolimus–induced lesions (including thrombotic microangiopathy) are similar. Besides, some authors reported successful use of Tacrolimus in case of cyclosporine–induced HUS.7,8 We observed isolated glomerular microthrombosis in 20% of our biopsies, with Tacrolimus blood trough levels within the normal range. The outcome was favorable, even though Tacrolimus therapy remained unchanged. In contrast, arteriolar microangiopathy seen in the fourth case could not be improved by Tacrolimus decrease and controlled only by Tacrolimus withdrawal. The prevalence, prognostic significance, and recommended treatment of microthrombosis confined to the glomerulus under Tacroli-
ANTOINE, THAKUR, DAUGAS ET AL
mus therapy are currently unknown and should be investigated.
REFERENCES 1. Williams R et al: Transplant Int 9(suppl 1):144, 1996 2. Mayer AD et al: Transplantation 64:436, 1997 3. US Multicenter Liver Study Group. Transplant Proc 27:1114, 1995 4. Gharpure S et al: Bone Marrow Transplant 16:715, 1995 5. Japanese FK 506 Study Group: Transplant Proc 26:1933, 1994 6. Randhawa PS, Shapiro R, Jordan ML, Starzl TE and Demetris AJ. Am J Surg Pathol 17:60, 1993 7. Abdalla AH, Al–Sulaiman MH, Al–Khader AA. Transplant Int 7:382 1994 8. McCauley J et al: Lancet 2:1516, 1989