- Email: [email protected]
Cyclosporine nephrotoxicity: how does it affect renal allograft function and transplant morphology?
Cyclosporine Nephrotoxicity: How Does It Affect Renal Allograft Function and Transplant Morphology? K. Morozumi, A. Takeda, K. Uchida, and M.J. Mihatsch ABSTRACT Chronic CSA nephrotoxicity is the second most important diagnosis responsible for the late graft failure. CSA associated arteriolopathy (CAA) is a well-known lesion of chronic CSA nephrotoxicity. The clinicopathological characteristics and the significance of CSA nephrotoxicity have changed following reduction in CSA doses and implementation of monitoring of blood levels. Seventy-four CAA patients on CSA therapy were classified as functioning (n ⫽ 30) or loss groups (n ⫽ 44). There was no significant difference in severity of CAA. The concomitant lesion of chronic rejection, but not the severity of CAA, was the most important risk factor for graft loss. Among 54 recipients with focal segmental glomerulosclerosis lesions (FGS), 32 (59%) were diagnosed as CAA associated glomerulopathy (CAG). Eighteen of the 32 CAG patients lost their grafts upon follow-up. Decreasing the CSA dosage to maintain lower blood levels than the usually optimal concentrations, but not discontinuation of CSA, has been useful to retard the progression of graft dysfunction in half of 15 isolated pure CAG patients. Patients with increasing daily proteinuria exceeding 2 grams lost their graft function despite CSA reductions. CAA is not a specific lesion of chronic CSA nephrotoxicity; the FGS lesion is also a nonspecific lesion often seen in renal allografts. Isolated chronic CSA arteriolopathy of severe degree has a fairly good prognosis under controlled CSA therapy. The FGS lesion accompanying CAA is considered to be CSA-associated glomerulopathy. These data contribute to therapeutic plans for renal transplant patients during long-term CSA treatment.
W
ITH THE INTRODUCTION of cyclosporine (CSA) as an immunosuppressive agent, the clinical results of renal transplantation significantly improved. Nephrotoxicity was first noted by Calne in 1978.1 An international workshop of pathologists formulated a preliminary classification system for acute and chronic CSA nephrotoxicity. This time-related classification of CSA nephrotoxicity proven to be unsatisfactory. A new classification of CSA nephrotoxicity from the clinicopathological context has been broadly acepted2,3 (Fig 1). CSA nephrotoxicity is classified into two major categories: functional and structural. The former is the consequence of vasoconstriction of the afferent arteriole, the latter is the structural lesions affecting the afferent arteriole, glomerulus and tubulointerstitium. The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane). Increased sympathetic tone may also be present, although © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 251S⫺256S (2004)
renal vasoconstriction occurs even in denervated kidneys. Different individual sensitivities as well as many other risk factors seem to determine the nephrotoxicity. Whether there is a “safe” dose of CSA that is effective immunologically but does not cause progressive renal dysfunction is difficult to answer, because of the lack of well controlled prospective trials. The clinicopathological characteristics and the significance of CSA nephrotoxicity have changed due to lowering drug doses and the development of blood level monitoring. Acute CSA nephrotoxicity have to be reversible, significantly decreased after therapeutic blood level monitoring of From the Kidney Center (K.M., A.T., K.U.), Nagoya Daini Red Cross Hospital, Nagoya, Japan, Institute for Pathology (M.J.M.), Basel University, Basle, Switzerland. Address reprint requests to Kunio Morozumi, MD, Kidney Center, Nagoya Daini Red Cross Hospital, 2-9, Myoken-cho, Showa-ku, Nagoya, Aichi, 466-8650 Japan. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.027 251S
252S
MOROZUMI, TAKEDA, UCHIDA, ET AL
Fig 1.
Classification of CSA nephrotoxicity from clonico-pathological context
low dose CSA. The annual graft loss rate after the first year posttransplant remains from 3% to 5%, a figure that has not changed in the CSA era. Chronic CSA nephrotoxicity seems to be the second most important diagnosis responsible for the late graft failure.4 Chronic CSA nephrotoxicity, however, is one of the pivotal nonimmunologic mechanisms affecting chronic allograft failure. CSA associated arteriolopathy (CAA) on graft biopsies is well known as a characteristic lesion of chronic CSA nephrotoxicity. There are few reports on the long outcome of renal transplant patients with biopsy-proven chronic CSA nephrotoxicity after the diagnosis of CAA. The relation between chronic CSA nephrotoxicity and graft outcomes is still unsolved and an important clinical problem after introduction of the microemulsion CSA. MORPHOLOGY OF CHRONIC CSA NEPHROTOXICITY
Renal biopsies in recipients of long-term CSA use revealed an obliterative arteriolopathy (suggesting primary endothelial damage), ischemic collapse or scarring of the glomeruli, and focal areas of tubular atrophy with a striped form of interstitial fibrosis. CSA associated arteriolopathy (CAA) is a well-known, characteristic lesion of chronic CSA nephrotoxicity.5 These changes have been seen with either lowdose or higher dose CSA therapy, although they seem to occur earlier in patients treated with the higher doses. We classified the severity of CAA as four grades: very mild (grade I) to diffuse and severe CAA (grade IV), as shown in Fig 2. CAA grade II or a more severe grade were compatible with typical CAA lesions.
The factors responsible for chronic CSA nephrotoxicity are not well understood. The development of interstitial fibrosis is associated with increased expression of osteopontin,6 chemokines,7 and transforming growth factor-beta.8,9 TGF-beta appears to be induced in part by decreased secretion of nitric oxide10 as well as increased local concentrations of angiotensin II. Glomerular alterations that develop in patients with typical CAA represent new transplant glomerulopathy lesions only recognized after the clinical application of CSA. The focal segmental glomerulosclerosis (FGS) lesion is an especially important glomerular alteration in the CSA era. The incidence of the FGS lesion in renal allograft biopsies in the CSA era showed a significant increase compared with that in the prior immunosuppressant era. We diagnosed FGS lesions in approximately 1.5% of graft biopsies in the previous era, and in 54 of 517 recipients (10.5%) in the CsA era. The FGS lesion is well known to have many causes, eg, glomerulonephritis, recurrent FGS, reflux nephropathy, and chronic rejection. Thirty-two patients (59%) with FGS and severe CAA greater than grade III were considered to be cases of probable CAA-associated glomerulopathy (CAG), because of the lack of other causes for typical FGS. However, some of the 32 biopsies were accompanied by mild rejection, mild glomerulonephritis diagnosed by immunofluorescent microscopy and other diagnoses. Only 15 biopsies were diagnosed as isolated pure CAG after excluding those with any kind or any degree of concomitant lesions among 32 FGS with severe CAA.
CYCLOSPORINE NEPHROTOXICITY
253S
Fig 2. Light micrograph of each grade of ciclosporin associated arteriolopathy (CAA) (a) grade I is very mild CAA, (b) grade II is typical CAA, (c) grade III is diffuse and typical CAA or focal and severe CAA, (d) grade IV is diffuse and severe CAA.
Immunofluorescent microscopy revealed nonspecific deposition of C3 and/or IgM in both the glomerulus and the arteriole in almost all patients. No specific ultrastructural findings of CAG were noted. Allografts with chronic dysfunction show variable glomerular lesions, including collapse of glomerular tufts, duplication of glomerular basement membranes, glomerular hypertrophy, mesangial expansion, and/or focal glomerulosclerosis. FGS lesion should be considered as a typical morphologic alteration of glomerular hyperfiltration resulting from nephron reduction of any etiology. While it is believed that most of these glomerular lesions relate to chronic rejection and/or nonspecific nephropathy, we have reported that CSA associated glomerulopathy accompanied by CAA represents a new glomerular lesion of transplant pathology. Although both thrombosis and proliferation of endothelial cells in the vascular pole (pouch lesion) are less common special types of acute CSA glomerulopathy, which were mainly observed in renal biopsies from patients receiving high-dose CSA therapy in the early 1980s. In contrast, the FGS lesion is the most frequent stigma of CSA glomerulopathy, and one of the most important diagnoses in long-surviving renal allografts under low-dose CSA therapy. We have shown that the FGS lesion as an index of CSA
glomerulopathy is closely correlated with the severity of CAA. Besides, the incidence of CSA glomerulopathy at two independent transplant units in Switzerland and Japan was surprisingly similar.11 CLINICOPATHOLOGICAL ANALYSIS OF CHRONIC CSA NEPHROTOXICITY Long-term Outcome of the Patients with CAA
Seventy-four patients with CAA grade II and severe grade were analyzed by classification into two groups based upon graft outcomes after follow-up; the functioning group (n ⫽ 30) and the graft loss group (n ⫽ 44). Geographic data at the time of graft biopsy and morphological characteristics are shown in Table 1. The mean serum creatinine and daily proteinuria values in functioning cases were 1.86 mg/dL and 1.09 g/day; those of lost grafts were 2.72 mg/dL and 2.37 g/day, respectively. Both serum creatinine level and daily proteinuria in the graft loss cases were significantly higher than those of functioning grafts (P ⬍ .001 and P ⬍ .05). There was no significant difference in CSA trough levels or in the severity of CAA grade between two groups. Fortyfour patients lost their grafts after mean follow-up of 37 months. In 30 functioning grafts, the mean serum creatinine
254S
MOROZUMI, TAKEDA, UCHIDA, ET AL
Table 1. Profiles of 74 CAA Patients. Thirty Functioning Grafts and 44 Graft-Loss Groups are Shown. Serum Creatinine Level and Daily Proteinuria at Biopsy in Graft Loss Patients are Higher than in Functioning Grafts. Other Variables Are Not Different Between Two Groups. Distribution of CAA Grades and Concomitant Lesions in Two Groups of 74 CAA Patients. There is No Significant Difference of CAA Grade Between Two Groups. Concomitant Lesions have very Different Distribution in Two Groups Functioning group n ⫽ 30
Geographic data Donor age (y.o) Recipient age (y.o) Bx time (after RTx) (months) Bx–sCr (mg/dL) Bx–proteinuria (g/day) Bx–CS traough level (ng/mL) CAA grade Follow-up (after Bx) (months) Present sCr (mg/dL) Present proteinuria (g/day) CAA Grade CAA-2 CAA-3 CAA-4 Concomitant lesion Isolated CAA FGS(CAG) ⫹ ␣ CR ⫹ ␣
52.8 33.0 63 1.86 1.09 98.8 2.8 56 2.15 1.00 10 16 4 10 9 1
and daily proteinuria was 2.15 mg/dL and 1.00 g/day at that time. Figure 3 shows the changes in serum creatinine level after diagnosis of CAA at every follow-up point for the functioning graft group. No increase in creatinine was observed, although CSA therapy was continued after diagnosis of chronic CSA nephrotoxicity. The distribution of concomitant lesions in the functioning group was significantly different from graft-loss group (P ⬍ .001). The majority of isolated CAA (10/12) were observed in the functioning group, in contrast to the vast majority of
Fig 3.
Graft loss group n ⫽ 44
ns ns ns P ⫽ .000036 P ⫽ .0234 ns ns
55.4 30.8 66 2.72 2.37 94.9 2.8 37
P ⫽ .57
18 18 8
P ⫽ .0002
2 10 21
patients (21/22) with CAA and concomitant with CR lost their grafts. Isolated CAA had no adverse effects on long-term graft outcomes. On the contrary, graft outcomes among recipients with concomitant CR and CAA were significantly poor. Interestingly, a concomitant lesion of chronic rejection (but not the severity of CAA) was the most important risk factor for graft loss among CAA patients. Also the presence of isolated CAA was not the main cause of graft dysfunction for the vast majority of renal transplant recipients using CSA.
Changes of serum creatinine level after diagnosis of CAA in functioning grafts at every point of follow-up.
CYCLOSPORINE NEPHROTOXICITY
Fig 4.
255S
Outcome of the graft with FGS lesion under CSA therapy.
Clinical Significance of CAG in Renal Allografts Under Long-term CSA Therapy
The graft outcomes of recipients with FGS are shown in Fig 4. The incidence of graft loss was similar in all FGS recipients (32/54) and in patients with CAA-associated glomerulopathy (18/32). The mean serum creatinine and daily proteinuria values among the lost grafts were 2.45 mg/dL and 3.33 g/day, those of functioning grafts, 1.83 mg/dL and 2.43 g/day at the time of biopsy, respectively. The mean serum creatinine value among graft loss cases of CAG was higher than that of functioning grafts (P ⬍ .05). There was no significant difference in recipient and donor ages, posttransplant biopsy date, serum creatinine or daily proteinuria at the time of biopsies between the functioning versus graft loss groups in pure CAG patients. In isolated CAG patients followed for an average of 52.9 months, CSA must be monitored to maintain lower blood levels than the usual optimal target concentrations as a single daily dose of 125 to 150 mg. CSA blood trough levels must be strictly controlled to maintain trough levels less than 100 ng/mL. Eight of 15 isolated CAG patients maintained graft function under reduced CSA doses. After 53.4 months follow-up the mean serum creatinine value and daily proteinuria were 2.16 mg/dL and 1.1 g/day, respectively. In contrast, the remaining seven recipients had gradually impaired graft function. The patients with increasing daily proteinuria exceeding 2 grams lost their graft even after reducing CSA doses. Among renal transplant patients receiving CSA monotherapy, Montagnino and his colleagues reported that patients administered a single daily dose showed significantly less CSA injury than patients administered in two divided doses.12 We have administered lower CSA as a
single daily dose to advanced CAG patients, when the diagnosis of FGS lesion with severe CAA is established.13 Fate of Chronic CSA Nephrotoxicity After Dose Reduction or Discontinuation of CSA
Myers suggested that long-term cyclosporine use carried a risk of renal failure based upon an analysis of heart transplant recipients in 1984.14 It has argued that scheduled CSA withdrawal is a useful way to prevent deterioration of function in renal transplants.15–17 The replacement of CSA with a non-nephrotoxic immunosuppressant may ameliorate renal dysfunction among patients with CSA-induced nephrotoxicity. Another method to possibly lessen the risk of developing CSA-induced nephrotoxicity is a strategy of early complete CSA withdrawal. For stable patients on optimal doses of CSA without adverse side effects, CSA withdrawal is an inappropriate clinical strategy, because optimal doses can be safely used, avoiding both chronic CSA nephrotoxicity and the risk of acute/chronic rejection.18 It should be avoided that withdrawal brings dire consequence of acute rejection. On the other hand, Burke and his colleagues, reporting the longterm efficacy and safety of CSA in renal-transplant recipients at six transplant centers in 1994,19 showed that the majority of renal-transplant patients tolerated long-term CSA therapy without evidence of progressive toxic nephropathy. Higher CSA concentrations correlated with better graft function and a reduced risk of rejection. We have reported that severe CSA arteriolopathy and deterioration of graft function caused by severe CSA nephrotoxicity disappeared or tremendously improved after discontinuation or reduction of CSA. Discontinuation of CSA
256S
therapy should be carefully decided to avoid the risk of acute and/or chronic rejection. CONCLUSION
Both immunologic and nonimmunologic factors participate in the pathogenesis of chronic allograft dysfunction. Chronic rejection is the most important diagnosis leading to late renal allograft failure. Two or more independent diagnoses are not unusual in the renal transplant pathology of kidneys in the CSA era. The diagnosis of chronic rejection is difficult in many patients without specific morphologic characteristics. These facts required the term “chronic allograft nephropathy” to express the situation leading late renal allograft failure. Prevention of chronic allograft failure is the most important clinical problem in renal transplantation. Chronic CSA nephrotoxicity is one of the central targets to improve the long-term outcome of renal grafts. CSA is an epoch-making immunosuppressive agent with adverse effects of which chronic nephrotoxicity is an important problem. Our understanding of chronic CSA nephrotoxicity is well established. CSA associated arteriolopathy is not specific for chronic CSA nephrotoxicity. The FGS lesion is also a nonspecific stigma which often develops in renal allografts. Isolated chronic CSA arteriolopathy of severe degree has a fairly good prognosis under controlled CSA therapy; chronic rejection concomitant with severe CAA produces a significantly poor outcome. Focal segmental sclerotic lesions accompanying CAA are considered as a new concept of CSA-associated glomerulopathy (CAG). Increasing proteinuria in patients with CAG is a useful indicator of a poor outcome. These results will contribute to developing appropriate therapeutic plans for the renal transplant patients under long-term CSA treatment. REFERENCES 1. Calne RY, White DJG, Thiru S, et al: Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2:1323, 1978 2. Mihatsch MJ, Thiel G, Ryffel B: Morphology of cyclosporine nephropathy. Prog Allergy 38:447, 1986
MOROZUMI, TAKEDA, UCHIDA, ET AL 3. Mason J: The pathophysiology and toxicity of cyclosporine in humans and animals. Pharmacol Rev 42:423, 1989 4. Bennett WM, Demattos A, Meyer MM, et al: Chronic CSA nephropathy: The Achilles’ heel of immunosuppressive therapy. Kidney Int 50:1089, 1996 5. Mihatsch MJ, Ryffel B, Gudat F: The differential diagnosis between rejection and CSA toxicity. Kidney Int 48:S63, 1995 6. Pichler RH, Franceschini N, Young BA, et al: Pathogenesis of CSA nephropathy: Roles of angiotensin II and osteopontin. J Am Soc Nephrol 6:1186, 1995 7. Benigni A, Bruzzi I, Mister M, et al: Nature and mediators of renal lesions in kidney transplant patients given CSA for more than one year. Kidney Int 55:674, 1999 8. Shihab FS, Bennett WM, Tanner AM, et al: Angiotensin II blockade decreases TGF-1 and matrix proteins in CSA nephropathy. Kidney Int 52:660, 1997 9. Islam M, Burke JF Jr, McGowan TA, et al: Effect of anti-transforming growth factor-beta antibodies in CSA-induced renal dysfunction. Kidney Int 59:498, 2001 10. Shihab FS, Yi H, Bennett WM, et al: Effect of nitric oxide modulation on TGF-beta1 and matrix proteins in chronic CSA nephrotoxicity. Kidney Int 58:1174, 2000 11. Takeda A, Morozumi K, Uchida K, et al: Is CSA-associated glomerulopathy a new glomerular lesion in renal allografts using CyA? Transplant Proc 25:515, 1993 12. Montgnino G, Trantino A, Maccario M, et al: Long-term results with CSA monotherapy in renal transplant patients: A multivariate analysis of risk factors. Am J Kidney Dis 35:1135, 2000 13. Takeda A, Morozumi K, Koyama K, et al: Severe CSA arteriolopathy with focal segmental glomerulosclerosis is not a fatal finding in chronic renal allograft failure after year 5 of transplantation using CSA. Transplant Proc 29:96, 1997 14. Myers BD, Ross J, Newton L, et al: CSA-associated chronic nephropathy. N Engl J Med 311:699, 1984 15. Helderman JH, Goral S: Cyclosporin withdrawal: to be or not to be! Nephrol Dial Transplant 13:31, 1998 16. Gauthier P, Helderman H: CSA avoidance. J Am Soc Nephrol 11:1933, 2000 17. Newstead CG, Johnston PA, Will EJ, et al: The case for withdrawal of cyclosporin after renal transplantation. Nephrol Dial Transplant 13:28, 1998 18. Morozumi K, Thiel G, Albert FW, et al: Studies on morphological outcome of CSA-associated arteriolopathy after discontinuation of CSA in renal allografts. Clin Nephrol 38:1, 1992 19. Burke JF, Pirsch JD, Ramos EL, et al: Long-term efficacy and safety of CSA in renal-transplant recipients. New Engl J Med 331:358, 1994
W
ITH THE INTRODUCTION of cyclosporine (CSA) as an immunosuppressive agent, the clinical results of renal transplantation significantly improved. Nephrotoxicity was first noted by Calne in 1978.1 An international workshop of pathologists formulated a preliminary classification system for acute and chronic CSA nephrotoxicity. This time-related classification of CSA nephrotoxicity proven to be unsatisfactory. A new classification of CSA nephrotoxicity from the clinicopathological context has been broadly acepted2,3 (Fig 1). CSA nephrotoxicity is classified into two major categories: functional and structural. The former is the consequence of vasoconstriction of the afferent arteriole, the latter is the structural lesions affecting the afferent arteriole, glomerulus and tubulointerstitium. The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane). Increased sympathetic tone may also be present, although © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 251S⫺256S (2004)
renal vasoconstriction occurs even in denervated kidneys. Different individual sensitivities as well as many other risk factors seem to determine the nephrotoxicity. Whether there is a “safe” dose of CSA that is effective immunologically but does not cause progressive renal dysfunction is difficult to answer, because of the lack of well controlled prospective trials. The clinicopathological characteristics and the significance of CSA nephrotoxicity have changed due to lowering drug doses and the development of blood level monitoring. Acute CSA nephrotoxicity have to be reversible, significantly decreased after therapeutic blood level monitoring of From the Kidney Center (K.M., A.T., K.U.), Nagoya Daini Red Cross Hospital, Nagoya, Japan, Institute for Pathology (M.J.M.), Basel University, Basle, Switzerland. Address reprint requests to Kunio Morozumi, MD, Kidney Center, Nagoya Daini Red Cross Hospital, 2-9, Myoken-cho, Showa-ku, Nagoya, Aichi, 466-8650 Japan. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.027 251S
252S
MOROZUMI, TAKEDA, UCHIDA, ET AL
Fig 1.
Classification of CSA nephrotoxicity from clonico-pathological context
low dose CSA. The annual graft loss rate after the first year posttransplant remains from 3% to 5%, a figure that has not changed in the CSA era. Chronic CSA nephrotoxicity seems to be the second most important diagnosis responsible for the late graft failure.4 Chronic CSA nephrotoxicity, however, is one of the pivotal nonimmunologic mechanisms affecting chronic allograft failure. CSA associated arteriolopathy (CAA) on graft biopsies is well known as a characteristic lesion of chronic CSA nephrotoxicity. There are few reports on the long outcome of renal transplant patients with biopsy-proven chronic CSA nephrotoxicity after the diagnosis of CAA. The relation between chronic CSA nephrotoxicity and graft outcomes is still unsolved and an important clinical problem after introduction of the microemulsion CSA. MORPHOLOGY OF CHRONIC CSA NEPHROTOXICITY
Renal biopsies in recipients of long-term CSA use revealed an obliterative arteriolopathy (suggesting primary endothelial damage), ischemic collapse or scarring of the glomeruli, and focal areas of tubular atrophy with a striped form of interstitial fibrosis. CSA associated arteriolopathy (CAA) is a well-known, characteristic lesion of chronic CSA nephrotoxicity.5 These changes have been seen with either lowdose or higher dose CSA therapy, although they seem to occur earlier in patients treated with the higher doses. We classified the severity of CAA as four grades: very mild (grade I) to diffuse and severe CAA (grade IV), as shown in Fig 2. CAA grade II or a more severe grade were compatible with typical CAA lesions.
The factors responsible for chronic CSA nephrotoxicity are not well understood. The development of interstitial fibrosis is associated with increased expression of osteopontin,6 chemokines,7 and transforming growth factor-beta.8,9 TGF-beta appears to be induced in part by decreased secretion of nitric oxide10 as well as increased local concentrations of angiotensin II. Glomerular alterations that develop in patients with typical CAA represent new transplant glomerulopathy lesions only recognized after the clinical application of CSA. The focal segmental glomerulosclerosis (FGS) lesion is an especially important glomerular alteration in the CSA era. The incidence of the FGS lesion in renal allograft biopsies in the CSA era showed a significant increase compared with that in the prior immunosuppressant era. We diagnosed FGS lesions in approximately 1.5% of graft biopsies in the previous era, and in 54 of 517 recipients (10.5%) in the CsA era. The FGS lesion is well known to have many causes, eg, glomerulonephritis, recurrent FGS, reflux nephropathy, and chronic rejection. Thirty-two patients (59%) with FGS and severe CAA greater than grade III were considered to be cases of probable CAA-associated glomerulopathy (CAG), because of the lack of other causes for typical FGS. However, some of the 32 biopsies were accompanied by mild rejection, mild glomerulonephritis diagnosed by immunofluorescent microscopy and other diagnoses. Only 15 biopsies were diagnosed as isolated pure CAG after excluding those with any kind or any degree of concomitant lesions among 32 FGS with severe CAA.
CYCLOSPORINE NEPHROTOXICITY
253S
Fig 2. Light micrograph of each grade of ciclosporin associated arteriolopathy (CAA) (a) grade I is very mild CAA, (b) grade II is typical CAA, (c) grade III is diffuse and typical CAA or focal and severe CAA, (d) grade IV is diffuse and severe CAA.
Immunofluorescent microscopy revealed nonspecific deposition of C3 and/or IgM in both the glomerulus and the arteriole in almost all patients. No specific ultrastructural findings of CAG were noted. Allografts with chronic dysfunction show variable glomerular lesions, including collapse of glomerular tufts, duplication of glomerular basement membranes, glomerular hypertrophy, mesangial expansion, and/or focal glomerulosclerosis. FGS lesion should be considered as a typical morphologic alteration of glomerular hyperfiltration resulting from nephron reduction of any etiology. While it is believed that most of these glomerular lesions relate to chronic rejection and/or nonspecific nephropathy, we have reported that CSA associated glomerulopathy accompanied by CAA represents a new glomerular lesion of transplant pathology. Although both thrombosis and proliferation of endothelial cells in the vascular pole (pouch lesion) are less common special types of acute CSA glomerulopathy, which were mainly observed in renal biopsies from patients receiving high-dose CSA therapy in the early 1980s. In contrast, the FGS lesion is the most frequent stigma of CSA glomerulopathy, and one of the most important diagnoses in long-surviving renal allografts under low-dose CSA therapy. We have shown that the FGS lesion as an index of CSA
glomerulopathy is closely correlated with the severity of CAA. Besides, the incidence of CSA glomerulopathy at two independent transplant units in Switzerland and Japan was surprisingly similar.11 CLINICOPATHOLOGICAL ANALYSIS OF CHRONIC CSA NEPHROTOXICITY Long-term Outcome of the Patients with CAA
Seventy-four patients with CAA grade II and severe grade were analyzed by classification into two groups based upon graft outcomes after follow-up; the functioning group (n ⫽ 30) and the graft loss group (n ⫽ 44). Geographic data at the time of graft biopsy and morphological characteristics are shown in Table 1. The mean serum creatinine and daily proteinuria values in functioning cases were 1.86 mg/dL and 1.09 g/day; those of lost grafts were 2.72 mg/dL and 2.37 g/day, respectively. Both serum creatinine level and daily proteinuria in the graft loss cases were significantly higher than those of functioning grafts (P ⬍ .001 and P ⬍ .05). There was no significant difference in CSA trough levels or in the severity of CAA grade between two groups. Fortyfour patients lost their grafts after mean follow-up of 37 months. In 30 functioning grafts, the mean serum creatinine
254S
MOROZUMI, TAKEDA, UCHIDA, ET AL
Table 1. Profiles of 74 CAA Patients. Thirty Functioning Grafts and 44 Graft-Loss Groups are Shown. Serum Creatinine Level and Daily Proteinuria at Biopsy in Graft Loss Patients are Higher than in Functioning Grafts. Other Variables Are Not Different Between Two Groups. Distribution of CAA Grades and Concomitant Lesions in Two Groups of 74 CAA Patients. There is No Significant Difference of CAA Grade Between Two Groups. Concomitant Lesions have very Different Distribution in Two Groups Functioning group n ⫽ 30
Geographic data Donor age (y.o) Recipient age (y.o) Bx time (after RTx) (months) Bx–sCr (mg/dL) Bx–proteinuria (g/day) Bx–CS traough level (ng/mL) CAA grade Follow-up (after Bx) (months) Present sCr (mg/dL) Present proteinuria (g/day) CAA Grade CAA-2 CAA-3 CAA-4 Concomitant lesion Isolated CAA FGS(CAG) ⫹ ␣ CR ⫹ ␣
52.8 33.0 63 1.86 1.09 98.8 2.8 56 2.15 1.00 10 16 4 10 9 1
and daily proteinuria was 2.15 mg/dL and 1.00 g/day at that time. Figure 3 shows the changes in serum creatinine level after diagnosis of CAA at every follow-up point for the functioning graft group. No increase in creatinine was observed, although CSA therapy was continued after diagnosis of chronic CSA nephrotoxicity. The distribution of concomitant lesions in the functioning group was significantly different from graft-loss group (P ⬍ .001). The majority of isolated CAA (10/12) were observed in the functioning group, in contrast to the vast majority of
Fig 3.
Graft loss group n ⫽ 44
ns ns ns P ⫽ .000036 P ⫽ .0234 ns ns
55.4 30.8 66 2.72 2.37 94.9 2.8 37
P ⫽ .57
18 18 8
P ⫽ .0002
2 10 21
patients (21/22) with CAA and concomitant with CR lost their grafts. Isolated CAA had no adverse effects on long-term graft outcomes. On the contrary, graft outcomes among recipients with concomitant CR and CAA were significantly poor. Interestingly, a concomitant lesion of chronic rejection (but not the severity of CAA) was the most important risk factor for graft loss among CAA patients. Also the presence of isolated CAA was not the main cause of graft dysfunction for the vast majority of renal transplant recipients using CSA.
Changes of serum creatinine level after diagnosis of CAA in functioning grafts at every point of follow-up.
CYCLOSPORINE NEPHROTOXICITY
Fig 4.
255S
Outcome of the graft with FGS lesion under CSA therapy.
Clinical Significance of CAG in Renal Allografts Under Long-term CSA Therapy
The graft outcomes of recipients with FGS are shown in Fig 4. The incidence of graft loss was similar in all FGS recipients (32/54) and in patients with CAA-associated glomerulopathy (18/32). The mean serum creatinine and daily proteinuria values among the lost grafts were 2.45 mg/dL and 3.33 g/day, those of functioning grafts, 1.83 mg/dL and 2.43 g/day at the time of biopsy, respectively. The mean serum creatinine value among graft loss cases of CAG was higher than that of functioning grafts (P ⬍ .05). There was no significant difference in recipient and donor ages, posttransplant biopsy date, serum creatinine or daily proteinuria at the time of biopsies between the functioning versus graft loss groups in pure CAG patients. In isolated CAG patients followed for an average of 52.9 months, CSA must be monitored to maintain lower blood levels than the usual optimal target concentrations as a single daily dose of 125 to 150 mg. CSA blood trough levels must be strictly controlled to maintain trough levels less than 100 ng/mL. Eight of 15 isolated CAG patients maintained graft function under reduced CSA doses. After 53.4 months follow-up the mean serum creatinine value and daily proteinuria were 2.16 mg/dL and 1.1 g/day, respectively. In contrast, the remaining seven recipients had gradually impaired graft function. The patients with increasing daily proteinuria exceeding 2 grams lost their graft even after reducing CSA doses. Among renal transplant patients receiving CSA monotherapy, Montagnino and his colleagues reported that patients administered a single daily dose showed significantly less CSA injury than patients administered in two divided doses.12 We have administered lower CSA as a
single daily dose to advanced CAG patients, when the diagnosis of FGS lesion with severe CAA is established.13 Fate of Chronic CSA Nephrotoxicity After Dose Reduction or Discontinuation of CSA
Myers suggested that long-term cyclosporine use carried a risk of renal failure based upon an analysis of heart transplant recipients in 1984.14 It has argued that scheduled CSA withdrawal is a useful way to prevent deterioration of function in renal transplants.15–17 The replacement of CSA with a non-nephrotoxic immunosuppressant may ameliorate renal dysfunction among patients with CSA-induced nephrotoxicity. Another method to possibly lessen the risk of developing CSA-induced nephrotoxicity is a strategy of early complete CSA withdrawal. For stable patients on optimal doses of CSA without adverse side effects, CSA withdrawal is an inappropriate clinical strategy, because optimal doses can be safely used, avoiding both chronic CSA nephrotoxicity and the risk of acute/chronic rejection.18 It should be avoided that withdrawal brings dire consequence of acute rejection. On the other hand, Burke and his colleagues, reporting the longterm efficacy and safety of CSA in renal-transplant recipients at six transplant centers in 1994,19 showed that the majority of renal-transplant patients tolerated long-term CSA therapy without evidence of progressive toxic nephropathy. Higher CSA concentrations correlated with better graft function and a reduced risk of rejection. We have reported that severe CSA arteriolopathy and deterioration of graft function caused by severe CSA nephrotoxicity disappeared or tremendously improved after discontinuation or reduction of CSA. Discontinuation of CSA
256S
therapy should be carefully decided to avoid the risk of acute and/or chronic rejection. CONCLUSION
Both immunologic and nonimmunologic factors participate in the pathogenesis of chronic allograft dysfunction. Chronic rejection is the most important diagnosis leading to late renal allograft failure. Two or more independent diagnoses are not unusual in the renal transplant pathology of kidneys in the CSA era. The diagnosis of chronic rejection is difficult in many patients without specific morphologic characteristics. These facts required the term “chronic allograft nephropathy” to express the situation leading late renal allograft failure. Prevention of chronic allograft failure is the most important clinical problem in renal transplantation. Chronic CSA nephrotoxicity is one of the central targets to improve the long-term outcome of renal grafts. CSA is an epoch-making immunosuppressive agent with adverse effects of which chronic nephrotoxicity is an important problem. Our understanding of chronic CSA nephrotoxicity is well established. CSA associated arteriolopathy is not specific for chronic CSA nephrotoxicity. The FGS lesion is also a nonspecific stigma which often develops in renal allografts. Isolated chronic CSA arteriolopathy of severe degree has a fairly good prognosis under controlled CSA therapy; chronic rejection concomitant with severe CAA produces a significantly poor outcome. Focal segmental sclerotic lesions accompanying CAA are considered as a new concept of CSA-associated glomerulopathy (CAG). Increasing proteinuria in patients with CAG is a useful indicator of a poor outcome. These results will contribute to developing appropriate therapeutic plans for the renal transplant patients under long-term CSA treatment. REFERENCES 1. Calne RY, White DJG, Thiru S, et al: Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2:1323, 1978 2. Mihatsch MJ, Thiel G, Ryffel B: Morphology of cyclosporine nephropathy. Prog Allergy 38:447, 1986
MOROZUMI, TAKEDA, UCHIDA, ET AL 3. Mason J: The pathophysiology and toxicity of cyclosporine in humans and animals. Pharmacol Rev 42:423, 1989 4. Bennett WM, Demattos A, Meyer MM, et al: Chronic CSA nephropathy: The Achilles’ heel of immunosuppressive therapy. Kidney Int 50:1089, 1996 5. Mihatsch MJ, Ryffel B, Gudat F: The differential diagnosis between rejection and CSA toxicity. Kidney Int 48:S63, 1995 6. Pichler RH, Franceschini N, Young BA, et al: Pathogenesis of CSA nephropathy: Roles of angiotensin II and osteopontin. J Am Soc Nephrol 6:1186, 1995 7. Benigni A, Bruzzi I, Mister M, et al: Nature and mediators of renal lesions in kidney transplant patients given CSA for more than one year. Kidney Int 55:674, 1999 8. Shihab FS, Bennett WM, Tanner AM, et al: Angiotensin II blockade decreases TGF-1 and matrix proteins in CSA nephropathy. Kidney Int 52:660, 1997 9. Islam M, Burke JF Jr, McGowan TA, et al: Effect of anti-transforming growth factor-beta antibodies in CSA-induced renal dysfunction. Kidney Int 59:498, 2001 10. Shihab FS, Yi H, Bennett WM, et al: Effect of nitric oxide modulation on TGF-beta1 and matrix proteins in chronic CSA nephrotoxicity. Kidney Int 58:1174, 2000 11. Takeda A, Morozumi K, Uchida K, et al: Is CSA-associated glomerulopathy a new glomerular lesion in renal allografts using CyA? Transplant Proc 25:515, 1993 12. Montgnino G, Trantino A, Maccario M, et al: Long-term results with CSA monotherapy in renal transplant patients: A multivariate analysis of risk factors. Am J Kidney Dis 35:1135, 2000 13. Takeda A, Morozumi K, Koyama K, et al: Severe CSA arteriolopathy with focal segmental glomerulosclerosis is not a fatal finding in chronic renal allograft failure after year 5 of transplantation using CSA. Transplant Proc 29:96, 1997 14. Myers BD, Ross J, Newton L, et al: CSA-associated chronic nephropathy. N Engl J Med 311:699, 1984 15. Helderman JH, Goral S: Cyclosporin withdrawal: to be or not to be! Nephrol Dial Transplant 13:31, 1998 16. Gauthier P, Helderman H: CSA avoidance. J Am Soc Nephrol 11:1933, 2000 17. Newstead CG, Johnston PA, Will EJ, et al: The case for withdrawal of cyclosporin after renal transplantation. Nephrol Dial Transplant 13:28, 1998 18. Morozumi K, Thiel G, Albert FW, et al: Studies on morphological outcome of CSA-associated arteriolopathy after discontinuation of CSA in renal allografts. Clin Nephrol 38:1, 1992 19. Burke JF, Pirsch JD, Ramos EL, et al: Long-term efficacy and safety of CSA in renal-transplant recipients. New Engl J Med 331:358, 1994