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Impact of Banff Borderline Acute Rejection Among Renal Allograft Recipients
Impact of Banff Borderline Acute Rejection Among Renal Allograft Recipients J.R.A. Matoza, R.A. Danguilan, and S. Chicano ABSTRACT Objective. This study was performed to determine the incidence, treatment, and outcomes of Banff borderline acute rejection (AR) among renal transplant recipients. Patients and Methods. We reviewed the courses of adult kidney transplant recipients with borderline AR on clinically indicated biopsies performed at our center from January 2003 to July 2006. Patients with complete transplant records and serum creatinine values at 6 and 12 months were included in this study. The primary outcome measures were serum creatinine values at 1 to 2 weeks after treatment, and at 6 and 12 months after graft biopsy. Results. Among 428 renal graft biopsies, borderline AR was observed in 100 cases (23%). Patients were maintained on the same immunosuppression. The 86 who had complete data were included in the study. Seventy-eight percent of the patients received treatment with 3 days of methylprednisolone, while 22% were untreated. Mean serum creatinine values in the treated group were 2.9 ⫾ 1.0, 2.6 ⫾ 2.5, and 3.0 ⫾ 2.9 mg/dL at the time of biopsy, and at 6 and 12 months thereafter, respectively. In the untreated group, mean serum creatinine values were 2.2 ⫾ 1.0, 1.9 ⫾ 0.8, and 2.3 ⫾ 1.2 mg/dL during biopsy, and at 6 and 12 months thereafter, respectively. There was no significant difference in the serum creatinine at any of the measured time points between the 2 groups. Twelve patients had repeat renal graft biopsies which showed AR (6%), chronic allograft nephropathy (2.4%), and borderline changes (3.8%). Nine of the patients in the treated group eventually developed graft loss. Conclusions. Patients with borderline AR showed a progressive increase in serum creatinine over time. They should be followed closely; immunosuppression may need to be intensified.
I
MPROVEMENT IN renal allograft survival remains the ultimate goal in kidney transplantation. Although the rate of acute rejection (AR) has significantly decreased, these episodes have been considered to be an important factor leading to chronic allograft loss. There is increasing evidence that even subclinical rejection that is detected by protocol-mandated biopsies is an important pathologic entity.1 Subclinical rejection, defined as histologic evidence of AR or borderline changes in patients with stable renal function (less than 25% change in serum creatinine),2 may eventually lead to chronic allograft damage.1 Although this does not cause immediate deterioration of allograft function, the tubulointerstitial changes may exert damage in the long term. Thus timely therapeutic intervention may improve clinical outcomes.1,3
In the Banff scheme of renal allograft pathology, the category “borderline changes” includes biopsies with mild tubulitis in combination with at least mild interstitial inflammation in the absence of intimal arteritis.4 In a study by Meehan et al,5 23% of 351 renal allograft biopsies performed for graft dysfunction showed borderline changes in patients clinically diagnosed with AR. In this study, the majority (55%) of untreated borderline lesions progressed From the Departments of Adult Nephrology (J.R.A.M., R.A.D.) and Pathology (S.C.), National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to Dr Joyce Rosario A. Matoza, Department of Adult Nephrology, National Kidney and Transplant Institute, East Avenue, Quezon City, Philippines. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.07.004
Transplantation Proceedings, 40, 2303–2306 (2008)
2303
2304
to AR by Banff criteria.5 In contrast, Gloor et al6 reported that among the 11% of 114 patients who had borderline changes on protocol biopsies, 9/12 were not treated. Importantly, none of the patients with borderline changes developed AR in the 6 to 27 months follow-up.6 Thus, the importance of borderline changes on surveillance or clinically indicated biopsies is still uncertain. The present study describes our experience in the management of borderline changes observed among clinically indicated biopsies. The purpose of the study was to determine the incidence, clinical characteristics, treatment, and outcomes of biopsy-proven borderline AR among renal transplant recipients. This review will provide baseline information on the therapeutic strategies used for this pathologic entity. PATIENTS AND METHODS This retrospective cohort included all adult kidney transplant patients admitted from January 2003 to July 2006 with biopsyproven borderline AR (Banff criteria) in renal allografts that had complete pre- and posttransplantation data. Data were retrieved from the Philippine Renal Disease Registry7 and the medical records: recipient age at the time of transplantation, sex, primary renal disease, years post-kidney transplantation at the onset of graft dysfunction, number of HLA mismatches, donor age, type of donor, induction and maintenance immunosuppression, as well as treatment instituted for borderline AR and its outcome. Treatment of borderline AR was 3 daily doses of methylprednisolone 500 mg intravenously. The outcomes of treatment were categorized as “complete,” “partial,” or “no” response depending on the degree of fall in serum creatinine at 1 to 2 weeks after treatment. A complete response was defined as a return of the serum creatinine to a normal or decreased creatinine level of 25% or more from the lowest serum creatinine. Partial response indicated improvements in serum creatinine, but the values were not within 25% of the baseline level. No response was manifested by a continuous rise in serum creatinine or dialysis dependence within 1 to 2 weeks after giving rescue treatment. The primary outcome measures were serum creatinine values at 1 to 2 weeks after treatment, and at 6 and 12 months after renal graft biopsy. We noted repeated episodes of biopsy-proven AR. Descriptive statistics were presented as mean values ⫾ standard deviations for continuous variables, and as frequencies/percentages for categorical variables. Repeated measures analysis of variance (ANOVA) was used to determine the significance of differences between the serum creatinine values of patients at various time points as well as the interactions with the intervention, the time measurements, and the serum creatinine. The data were analyzed using SAS 9.0 and SPSS. An independent sample student t test was used to determine whether there was any significant difference in the 24-hour urinary creatinine clearance (mL/min) between the 2 groups. Significance was set at P ⱕ .05.
RESULTS
Among 428 first renal graft biopsies from January 2003 to July 2006, borderline AR was observed in 100 (23%), including 86 patients who had complete transplant records and comprised the study population. The demographic data, transplant courses, and immunosuppressive protocols
MATOZA, DANGUILAN, AND CHICANO Table 1. Patient Characteristics and Transplant Courses Patient Characteristics (n ⫽ 86)
Treated Group (n ⫽ 67)
Untreated Group (n ⫽ 19)
Sex (male/female) 50 (58%)/17 (20%) 13 (15%)/6 (7%) Recipient age (y), 38 ⫾ 11 39 ⫾ 14 mean ⫾ SD Donor age (y), mean ⫾ SD 32 ⫾ 7 33 ⫾ 10 Donor source Living (related/unrelated) 47 (55%)/18 (21%) 12 (14%)/7 (8%) Deceased 2 (2%) 0 Primary renal disease Chronic glomerulonephritis 42 (48%) 13 (16%) Hypertensive 11 (13%) 2 (2%) nephrosclerosis Diabetic nephropathy 9 (10.5%) 4 (5%) 2 (2%) 0 Autosomal dominant polycystic kidney disease Obstructive uropathy 3 (3.5%) 0 No. of HLA mismatches 3.1 ⫾ 1.0 2.5 ⫾ 1.1 Antibody induction None 49 (57%) 16 (19%) Alemtuzumab 3 (3.4%) 0 Basiliximab 8 (9.3%) 1 (1%) Daclizumab 7 (8%) 2 (2.3%) Initial immunosuppression Cyclosporine-based 54 (63%) 12 (14%) Tacrolimus-based 13 (15%) 7 (8%)
used for all patients are summarized in Table 1. Chronic glomerulonephritis was the most common primary renal disease. They were all primary transplants treated with calcineurin inhibitor (CNI)-based immunosuppression. Seventy-seven percent were on cyclosporine, while 23%, tacrolimus. Among the 86 patients, 67 (78%) were treated, and 19 (22%) were untreated. The mean time from transplantation to renal graft biopsy was 23 versus 18 months for the treated versus untreated groups, respectively. There was no significant difference in the 24-hour urinary creatinine clearance (mL/min) between the 2 groups (P ⫽ .57). Mean serum creatinine values at time of biopsy were 2.9 ⫾ 1.0 mg/dL in the treated and 2.2 ⫾ 1.0 mg/dL in the untreated group. Concomitant biopsy findings aside from borderline AR were CNI toxicity (23%), chronic allograft nephropathy (20%), acute tubular necrosis (2%), and chronic rejection (6%). Treatment for borderline AR included methylprednisolone without any change in prior immunosuppression (89%) with response rates of 20%, 63.3%, and 16.7%, for complete, partial, and no response, respectively. Six patients received methylprednisolone followed by a change in immunosuppression, and 1 followed by antithymocyte globulin (ATG). The majority of patients in the treated group only showed a partial response. There was no significant difference in graft outcome as measured by mean serum creatinine at 6 and 12 months whether patients received treatment (P ⫽ .73; Table 2).
BORDERLINE AR IN RENAL ALLOGRAFT RECIPIENTS Table 2. Graft Outcomes at 6 and 12 Months Following the Diagnosis of Borderline AR Graft Function
Initial immunosuppression Cyclosporine-based Tacrolimus-based Serum creatinine (mg/dL) At time of borderline AR At 6 months At 12 months Histologic diagnosis of patients with repeat renal graft biopsy Acute humoral rejection Acute cellular rejection Chronic allograft nephropathy Chronic transplant glomerulopathy Borderline AR Graft loss
Treated Group
Untreated Group
54 (63%) 13 (15%)
12 (14%) 7 (8%)
2.9 ⫾ 1.05 2.6 ⫾ 2.56 3.0 ⫾ 2.90
2.2 ⫾ 1.0 1.9 ⫾ 0.81 2.3 ⫾ 1.21
1 (1.4%) 5 (5%) 2 (2.4%) 4 (4.6%) 1 (1.4%) 9 (10%)
0 0 0 0 2 (2.4%) 0
DISCUSSION
The incidence of borderline AR in our study was 23%, which is similar to the 20% reported in earlier studies.8,9 Most patients in our investigation were on immunosuppression using cyclosporine, mycophenolate, and steroids. Borderline AR was common among patients with baseline immunosuppression using cyclosporine compared with tacrolimus. However, this is probably because the majority of our patients were on cyclosporine. The time of onset of graft dysfunction varied. Our study demonstrated that borderline AR can progress to cell-mediated AR, chronic rejection, and chronic allograft nephropathy, which were seen among those subjects who underwent repeat renal graft biopsies. This correlated with the causal role of subclinical rejection to contribute to the burden of chronic allograft nephropathy.3 Treatment with high-dose corticosteroids stabilized renal function in 65.7% of treated patients. This cohort demonstrated a similar serum creatinine between the 2 subgroups at various measured time points. Rush et al8 reported improved graft survival after treatment of acute subclinical rejection with high-dose steroids. Recent studies have shown that in the long term this intervention may not be sufficient,1,8 as confirmed by our study wherein a progressive increase in serum creatinine was observed at 6 and 12 months postbiopsy. This finding was probably due to a persistently low level of inflammation and an ongoing process of rejection. Several studies have demonstrated that corticosteroids are insufficient to prevent chronic allograft inflammation, and that a subclinical biopsy-proven rejection should also be managed by strengthening baseline immunosuppression, including a switch to tacrolimus and/or mycophenolate mofetil.1,3,6 Among the 12 patients who showed as complete response to steroid treatment for borderline AR, only 5 had normal renal function at 6 and 12 months. In our study, 9 patients in the treated group eventually developed graft loss. Among these
2305
patients, 8 were on cyclosporine, while only 1 was on tacrolimus as the initial immunosuppression. Of the documented graft losses, only 1 underwent a repeat renal graft biopsy which showed chronic transplant glomerulopathy. None of the graft losses were attributable to an underlying infection, obstruction, or drug-related toxicity as the cause of graft dysfunction. This observation emphasizes that borderline AR accompanied by abnormal graft function is a serious complication. It is possible that ongoing subclinical alloreactivity underlies these graft losses; the finding of inflammatory and molecular markers may support this pathogenic entity.11 Borderline AR should be monitored cautiously since it may lead to ongoing rejection and eventual graft loss. Steroid-resistant rejection should be treated aggressively. Among the 11 cases with steroid-resistant borderline rejection, 7 developed graft loss within 1 year, while 2 showed a partial response. Molecular markers using polymerase chain reaction to detect and quantify gene transcripts for cytokines and cytotoxic molecules in the renal graft may aid to uncover the mechanism of subclinical AR10 and provide information on whether increased immunosuppression is warranted. Intercurrent conditions, such as CNI toxicity, chronic allograft nephropathy, and acute tubular injury, may also influence treatment responses. The limitations of this study included the absence of protocol biopsies that could have detected subclinical rejection. The findings of borderline rejection could have been a sampling error that may have underestimated graft injury. Recipient panel-reactive antibody was not available in most cases, hindering us from evaluating the immunologic risk for our patients, although all were primary transplantations. In conclusion, the incidence of borderline AR was high among patients with baseline immunosuppression using cyclosporine compared with tacrolimus. In the setting of an elevated serum creatinine and borderline AR, renal grafts seem to have a poor outcome. Treatment with steroids was unable to improve renal function at 1 year. If long-term renal graft survival rates are to be achieved, immunosuppression may need to be intensified, which includes converting patients to tacrolimus and mycophenolate mofetil. Immunosuppressive regimens for borderline AR must be individually targeted to significantly reduce its impact on chronic graft damage. ACKNOWLEDGMENTS The authors recognize and appreciate the support of the Renal Disease Control Program (REDCOP). Special thanks to Jehan Matoza for her contribution in the data collection and Dinna Giron for her statistical analysis of the study.
REFERENCES 1. Kee TY, Chapman JR, O’Connell PJ, et al: Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation 82:36, 2006 2. Racusen LC, Solez K, Colvin RB, et al: The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713, 1999 3. Nankivell BJ, Borrows RJ, Fung CLS, et al: Natural history, risk factors and impact of subclinical rejection in kidney transplantation. Transplantation 78:242, 2004
2306 4. Danovitch G: Handbook of Kidney Transplantation, 4th Ed. Philadelphia: Lippincott Williams & Wilkins; 2005 5. Meehan SM, Siegel CT, Aronson AJ, et al: The relationship of untreated borderline infiltrates by the Banff criteria to acute rejection in renal allograft biopsies. J Am Soc Nephrol 10:1806, 1999 6. Gloor JM, Cohen AJ, Lager DJ, et al: Subclinical rejection in tacrolimus-treated renal transplant recipients. Transplantation 73: 1965, 2002 7. Philippine Renal Disease Registry: PRDR Annual Report. Philippine Society of Nephrology and Renal Disease Control Program. National Kidney and Transplant Institute; 2003–2006
MATOZA, DANGUILAN, AND CHICANO 8. Rush D, Nickerson P, Gough J, et al: Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 9:2129, 1998 9. Nickerson P, Jeffery J, Gough J, et al: Effects of increasing baseline immunosuppression on the prevalence of clinical and subclinical rejection: a pilot study. J Am Soc Nephrol 10:1801, 1999 10. Dias ECA, Veronese FJV, Goncalves LFS, et al: Molecular markers in subclinical acute rejection of renal transplants. Clin Transplant 18:281, 2004 11. Rush D: Insights into subclinical rejection. Transplant Proc 36(suppl 2):71S, 2004
I
MPROVEMENT IN renal allograft survival remains the ultimate goal in kidney transplantation. Although the rate of acute rejection (AR) has significantly decreased, these episodes have been considered to be an important factor leading to chronic allograft loss. There is increasing evidence that even subclinical rejection that is detected by protocol-mandated biopsies is an important pathologic entity.1 Subclinical rejection, defined as histologic evidence of AR or borderline changes in patients with stable renal function (less than 25% change in serum creatinine),2 may eventually lead to chronic allograft damage.1 Although this does not cause immediate deterioration of allograft function, the tubulointerstitial changes may exert damage in the long term. Thus timely therapeutic intervention may improve clinical outcomes.1,3
In the Banff scheme of renal allograft pathology, the category “borderline changes” includes biopsies with mild tubulitis in combination with at least mild interstitial inflammation in the absence of intimal arteritis.4 In a study by Meehan et al,5 23% of 351 renal allograft biopsies performed for graft dysfunction showed borderline changes in patients clinically diagnosed with AR. In this study, the majority (55%) of untreated borderline lesions progressed From the Departments of Adult Nephrology (J.R.A.M., R.A.D.) and Pathology (S.C.), National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to Dr Joyce Rosario A. Matoza, Department of Adult Nephrology, National Kidney and Transplant Institute, East Avenue, Quezon City, Philippines. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.07.004
Transplantation Proceedings, 40, 2303–2306 (2008)
2303
2304
to AR by Banff criteria.5 In contrast, Gloor et al6 reported that among the 11% of 114 patients who had borderline changes on protocol biopsies, 9/12 were not treated. Importantly, none of the patients with borderline changes developed AR in the 6 to 27 months follow-up.6 Thus, the importance of borderline changes on surveillance or clinically indicated biopsies is still uncertain. The present study describes our experience in the management of borderline changes observed among clinically indicated biopsies. The purpose of the study was to determine the incidence, clinical characteristics, treatment, and outcomes of biopsy-proven borderline AR among renal transplant recipients. This review will provide baseline information on the therapeutic strategies used for this pathologic entity. PATIENTS AND METHODS This retrospective cohort included all adult kidney transplant patients admitted from January 2003 to July 2006 with biopsyproven borderline AR (Banff criteria) in renal allografts that had complete pre- and posttransplantation data. Data were retrieved from the Philippine Renal Disease Registry7 and the medical records: recipient age at the time of transplantation, sex, primary renal disease, years post-kidney transplantation at the onset of graft dysfunction, number of HLA mismatches, donor age, type of donor, induction and maintenance immunosuppression, as well as treatment instituted for borderline AR and its outcome. Treatment of borderline AR was 3 daily doses of methylprednisolone 500 mg intravenously. The outcomes of treatment were categorized as “complete,” “partial,” or “no” response depending on the degree of fall in serum creatinine at 1 to 2 weeks after treatment. A complete response was defined as a return of the serum creatinine to a normal or decreased creatinine level of 25% or more from the lowest serum creatinine. Partial response indicated improvements in serum creatinine, but the values were not within 25% of the baseline level. No response was manifested by a continuous rise in serum creatinine or dialysis dependence within 1 to 2 weeks after giving rescue treatment. The primary outcome measures were serum creatinine values at 1 to 2 weeks after treatment, and at 6 and 12 months after renal graft biopsy. We noted repeated episodes of biopsy-proven AR. Descriptive statistics were presented as mean values ⫾ standard deviations for continuous variables, and as frequencies/percentages for categorical variables. Repeated measures analysis of variance (ANOVA) was used to determine the significance of differences between the serum creatinine values of patients at various time points as well as the interactions with the intervention, the time measurements, and the serum creatinine. The data were analyzed using SAS 9.0 and SPSS. An independent sample student t test was used to determine whether there was any significant difference in the 24-hour urinary creatinine clearance (mL/min) between the 2 groups. Significance was set at P ⱕ .05.
RESULTS
Among 428 first renal graft biopsies from January 2003 to July 2006, borderline AR was observed in 100 (23%), including 86 patients who had complete transplant records and comprised the study population. The demographic data, transplant courses, and immunosuppressive protocols
MATOZA, DANGUILAN, AND CHICANO Table 1. Patient Characteristics and Transplant Courses Patient Characteristics (n ⫽ 86)
Treated Group (n ⫽ 67)
Untreated Group (n ⫽ 19)
Sex (male/female) 50 (58%)/17 (20%) 13 (15%)/6 (7%) Recipient age (y), 38 ⫾ 11 39 ⫾ 14 mean ⫾ SD Donor age (y), mean ⫾ SD 32 ⫾ 7 33 ⫾ 10 Donor source Living (related/unrelated) 47 (55%)/18 (21%) 12 (14%)/7 (8%) Deceased 2 (2%) 0 Primary renal disease Chronic glomerulonephritis 42 (48%) 13 (16%) Hypertensive 11 (13%) 2 (2%) nephrosclerosis Diabetic nephropathy 9 (10.5%) 4 (5%) 2 (2%) 0 Autosomal dominant polycystic kidney disease Obstructive uropathy 3 (3.5%) 0 No. of HLA mismatches 3.1 ⫾ 1.0 2.5 ⫾ 1.1 Antibody induction None 49 (57%) 16 (19%) Alemtuzumab 3 (3.4%) 0 Basiliximab 8 (9.3%) 1 (1%) Daclizumab 7 (8%) 2 (2.3%) Initial immunosuppression Cyclosporine-based 54 (63%) 12 (14%) Tacrolimus-based 13 (15%) 7 (8%)
used for all patients are summarized in Table 1. Chronic glomerulonephritis was the most common primary renal disease. They were all primary transplants treated with calcineurin inhibitor (CNI)-based immunosuppression. Seventy-seven percent were on cyclosporine, while 23%, tacrolimus. Among the 86 patients, 67 (78%) were treated, and 19 (22%) were untreated. The mean time from transplantation to renal graft biopsy was 23 versus 18 months for the treated versus untreated groups, respectively. There was no significant difference in the 24-hour urinary creatinine clearance (mL/min) between the 2 groups (P ⫽ .57). Mean serum creatinine values at time of biopsy were 2.9 ⫾ 1.0 mg/dL in the treated and 2.2 ⫾ 1.0 mg/dL in the untreated group. Concomitant biopsy findings aside from borderline AR were CNI toxicity (23%), chronic allograft nephropathy (20%), acute tubular necrosis (2%), and chronic rejection (6%). Treatment for borderline AR included methylprednisolone without any change in prior immunosuppression (89%) with response rates of 20%, 63.3%, and 16.7%, for complete, partial, and no response, respectively. Six patients received methylprednisolone followed by a change in immunosuppression, and 1 followed by antithymocyte globulin (ATG). The majority of patients in the treated group only showed a partial response. There was no significant difference in graft outcome as measured by mean serum creatinine at 6 and 12 months whether patients received treatment (P ⫽ .73; Table 2).
BORDERLINE AR IN RENAL ALLOGRAFT RECIPIENTS Table 2. Graft Outcomes at 6 and 12 Months Following the Diagnosis of Borderline AR Graft Function
Initial immunosuppression Cyclosporine-based Tacrolimus-based Serum creatinine (mg/dL) At time of borderline AR At 6 months At 12 months Histologic diagnosis of patients with repeat renal graft biopsy Acute humoral rejection Acute cellular rejection Chronic allograft nephropathy Chronic transplant glomerulopathy Borderline AR Graft loss
Treated Group
Untreated Group
54 (63%) 13 (15%)
12 (14%) 7 (8%)
2.9 ⫾ 1.05 2.6 ⫾ 2.56 3.0 ⫾ 2.90
2.2 ⫾ 1.0 1.9 ⫾ 0.81 2.3 ⫾ 1.21
1 (1.4%) 5 (5%) 2 (2.4%) 4 (4.6%) 1 (1.4%) 9 (10%)
0 0 0 0 2 (2.4%) 0
DISCUSSION
The incidence of borderline AR in our study was 23%, which is similar to the 20% reported in earlier studies.8,9 Most patients in our investigation were on immunosuppression using cyclosporine, mycophenolate, and steroids. Borderline AR was common among patients with baseline immunosuppression using cyclosporine compared with tacrolimus. However, this is probably because the majority of our patients were on cyclosporine. The time of onset of graft dysfunction varied. Our study demonstrated that borderline AR can progress to cell-mediated AR, chronic rejection, and chronic allograft nephropathy, which were seen among those subjects who underwent repeat renal graft biopsies. This correlated with the causal role of subclinical rejection to contribute to the burden of chronic allograft nephropathy.3 Treatment with high-dose corticosteroids stabilized renal function in 65.7% of treated patients. This cohort demonstrated a similar serum creatinine between the 2 subgroups at various measured time points. Rush et al8 reported improved graft survival after treatment of acute subclinical rejection with high-dose steroids. Recent studies have shown that in the long term this intervention may not be sufficient,1,8 as confirmed by our study wherein a progressive increase in serum creatinine was observed at 6 and 12 months postbiopsy. This finding was probably due to a persistently low level of inflammation and an ongoing process of rejection. Several studies have demonstrated that corticosteroids are insufficient to prevent chronic allograft inflammation, and that a subclinical biopsy-proven rejection should also be managed by strengthening baseline immunosuppression, including a switch to tacrolimus and/or mycophenolate mofetil.1,3,6 Among the 12 patients who showed as complete response to steroid treatment for borderline AR, only 5 had normal renal function at 6 and 12 months. In our study, 9 patients in the treated group eventually developed graft loss. Among these
2305
patients, 8 were on cyclosporine, while only 1 was on tacrolimus as the initial immunosuppression. Of the documented graft losses, only 1 underwent a repeat renal graft biopsy which showed chronic transplant glomerulopathy. None of the graft losses were attributable to an underlying infection, obstruction, or drug-related toxicity as the cause of graft dysfunction. This observation emphasizes that borderline AR accompanied by abnormal graft function is a serious complication. It is possible that ongoing subclinical alloreactivity underlies these graft losses; the finding of inflammatory and molecular markers may support this pathogenic entity.11 Borderline AR should be monitored cautiously since it may lead to ongoing rejection and eventual graft loss. Steroid-resistant rejection should be treated aggressively. Among the 11 cases with steroid-resistant borderline rejection, 7 developed graft loss within 1 year, while 2 showed a partial response. Molecular markers using polymerase chain reaction to detect and quantify gene transcripts for cytokines and cytotoxic molecules in the renal graft may aid to uncover the mechanism of subclinical AR10 and provide information on whether increased immunosuppression is warranted. Intercurrent conditions, such as CNI toxicity, chronic allograft nephropathy, and acute tubular injury, may also influence treatment responses. The limitations of this study included the absence of protocol biopsies that could have detected subclinical rejection. The findings of borderline rejection could have been a sampling error that may have underestimated graft injury. Recipient panel-reactive antibody was not available in most cases, hindering us from evaluating the immunologic risk for our patients, although all were primary transplantations. In conclusion, the incidence of borderline AR was high among patients with baseline immunosuppression using cyclosporine compared with tacrolimus. In the setting of an elevated serum creatinine and borderline AR, renal grafts seem to have a poor outcome. Treatment with steroids was unable to improve renal function at 1 year. If long-term renal graft survival rates are to be achieved, immunosuppression may need to be intensified, which includes converting patients to tacrolimus and mycophenolate mofetil. Immunosuppressive regimens for borderline AR must be individually targeted to significantly reduce its impact on chronic graft damage. ACKNOWLEDGMENTS The authors recognize and appreciate the support of the Renal Disease Control Program (REDCOP). Special thanks to Jehan Matoza for her contribution in the data collection and Dinna Giron for her statistical analysis of the study.
REFERENCES 1. Kee TY, Chapman JR, O’Connell PJ, et al: Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation 82:36, 2006 2. Racusen LC, Solez K, Colvin RB, et al: The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713, 1999 3. Nankivell BJ, Borrows RJ, Fung CLS, et al: Natural history, risk factors and impact of subclinical rejection in kidney transplantation. Transplantation 78:242, 2004
2306 4. Danovitch G: Handbook of Kidney Transplantation, 4th Ed. Philadelphia: Lippincott Williams & Wilkins; 2005 5. Meehan SM, Siegel CT, Aronson AJ, et al: The relationship of untreated borderline infiltrates by the Banff criteria to acute rejection in renal allograft biopsies. J Am Soc Nephrol 10:1806, 1999 6. Gloor JM, Cohen AJ, Lager DJ, et al: Subclinical rejection in tacrolimus-treated renal transplant recipients. Transplantation 73: 1965, 2002 7. Philippine Renal Disease Registry: PRDR Annual Report. Philippine Society of Nephrology and Renal Disease Control Program. National Kidney and Transplant Institute; 2003–2006
MATOZA, DANGUILAN, AND CHICANO 8. Rush D, Nickerson P, Gough J, et al: Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 9:2129, 1998 9. Nickerson P, Jeffery J, Gough J, et al: Effects of increasing baseline immunosuppression on the prevalence of clinical and subclinical rejection: a pilot study. J Am Soc Nephrol 10:1801, 1999 10. Dias ECA, Veronese FJV, Goncalves LFS, et al: Molecular markers in subclinical acute rejection of renal transplants. Clin Transplant 18:281, 2004 11. Rush D: Insights into subclinical rejection. Transplant Proc 36(suppl 2):71S, 2004