Abstract
Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased- and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve–controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (rτ = −0.26; P = 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.
Chronic allograft nephropathy (CAN) is the most prevalent cause of renal graft failure in studies that censored for patient death. The histopathology is not specific and consists of graft atherosclerosis, multilayering of the peritubular capillaries, transplant glomerulopathy and glomerulosclerosis, interstitial fibrosis, and tubular atrophy (1). At present, it remains unknown to what extent these lesions result from an alloimmune response or from other types of injury, including ischemia/reperfusion, earlier (subclinical) acute rejection episodes, hypertension, hyperlipidemia, diabetes, and drug-related nephrotoxicity (2)
The calcineurin inhibitors (CNI) cyclosporine microemulsion (CsA) and tacrolimus play a controversial role in this process because their immunosuppressive efficacy is counterweighted by their nephrotoxic potential and unfavorable cardiovascular profile, including hypertension, hyperlipidemia, and new-onset diabetes (3–5). Most studies that compared a CsA- with a tacrolimus-based regimen reported an advantage for tacrolimus in the prevention of acute rejection (6,7) as well as subclinical acute rejection (SAR) (8). Despite the improvements that are seen with a contemporary immunosuppressive regimen, SAR still has a high prevalence, largely depending on the time point after transplantation at which a biopsy is taken (9–12).
Protocol biopsies that were obtained 2 yr after transplantation identified donor age, acute rejection, and CNI nephrotoxicity as the most significant predictors of CAN (13). Studies with surveillance biopsies, both in deceased- and living-donor renal grafts, agree that interstitial fibrosis correlates with renal graft survival and with graft function at 2 yr (14,15). Sirius red, a specific staining for collagen types I and III, is considered a precise and reliable estimate of renal cortical extracellular matrix accumulation and represents the best parameter to predict the development of progressive renal failure (15,16).
We developed a population-based model with limited sampling and Bayesian estimation to standardize systemic drug exposure for CsA and tacrolimus after renal transplantation (17,18). We applied these Bayesian estimators to compare an exposure-controlled dosing strategy to prevent structural changes, quantified by morphometric analysis of nonpolarized Sirius red staining of 6- and 12-mo protocol biopsies. In a previous study, we found no difference in the profibrogenic effect as measured by Sirius red staining of either of the currently available CNI in biopsies that were obtained 6 and 12 mo after renal transplantation (19). At the molecular level, no differences were found in the extent of protein deposition of TGF-β and interstitial collagens, as well as cortical mRNA levels of TGF-β and collagens α1(I) and α1(III) (20).
The histologic features of CAN, although most often mild, may occur early after renal transplantation, with a reported prevalence up to 40% in surveillance biopsies performed as early as 3 mo after transplantation (21,22). Treatment of SAR in 1-, 2-, or 3-mo protocol biopsies support the clinical relevance of early detection and treatment of SAR (9). However, there is no doubt that extra boluses of steroids or recycling of the steroid taper add significantly to posttransplantation morbidity. The aim of our study was to evaluate the impact of not treating SAR at 6 mo in the context of a prospective study with area-under-the-curve (AUC)-controlled systemic exposure on chronic rejection, quantified by histomorphometric analysis of nonpolarized Sirius red staining, in serial protocol biopsies at 6 and 12 mo after transplantation.
Materials and Methods
Patients
Eligible patients were renal transplant candidates who were ≥18 yr of age and scheduled to receive a first or second graft from a deceased (non–heart-beating included) or living (non–HLA-identical) donor. We excluded sensitized patients (panel reactive antibodies >50%) and patients who were receiving a dual-organ transplant. Because it has been estimated that at least 23 biopsies per treatment modality are required to demonstrate a 10% difference in renal allograft fibrosis as quantified by nonpolarized Sirius red staining (23), we decided to include at least 120 patients. Between October 2000 and October 2002, 126 renal transplant recipients were randomly assigned to receive either a cyclosporine- or a tacrolimus-based immunosuppressive regimen. This open-label, prospective, randomized trial was conducted in Leiden and Amsterdam, The Netherlands. Formal approval from the institutional ethics committee was obtained at the participating sites, and written informed consent was obtained before enrollment in the trial.
Monitoring of CNI
CsA (Neoral, Novartis, Arnheim, The Netherlands) and tacrolimus (Prograf, Fujisawa, Houten, The Netherlands) were started orally 3 h before surgery (initial dose 4 mg/kg twice daily for CsA and 0.1 mg/kg twice daily for tacrolimus). CsA and tacrolimus AUC0-12h were estimated at weeks 2, 4, 6, 8, 12, 17, 21, 26, 39, and 52 using a population based, two-compartment pharmacokinetic model combined with limited sampling and Bayesian fitting (17,18). After each AUC assessment, dosage adjustments were made to reach predefined target AUC: CsA AUC0-12h 5400 ng/h per ml within the first 6 wk and 3250 ng/h per ml after 6 wk. Tacrolimus AUC was aimed at 210 ng/h per ml within the first 6 wk and 125 ng/h per ml after 6 wk. Immunosuppressive co-medication consisted of prednisolone (in both groups 100 mg at days 1 through 3, tapered to 10 mg after day 22), mycophenolate mofetil (MMF; 1000 mg twice daily in the CsA group and 500 mg twice daily in the tacrolimus group), and basiliximab prophylaxis (20 mg on days 0 and 4).
Protocol Biopsies
Biopsies at 6 and 12 mo were taken as part of the study protocol with a 14-G needle. Renal biopsies, blinded for the treatment group, were scored by two independent pathologists according to the Banff ’97 working classification (24). For minimization of the interobserver variability, every fifth biopsy was scored by both pathologists, and the findings were discussed. Presence of SAR was based on the absence of functional deterioration and histologic findings indicative of rejection on the basis of the tubulitis (“t”) and mononuclear cell infiltration (“i”) scores. Abnormal findings were divided into two categories: Borderline SAR (bSAR) including “t” score = 1 and “i” score >0 and SAR defined by “t” score = 2, and “i” score ≥0. Chronic allograft nephropathy (CAN) was divided into three grades, on the basis of the Banff scores for interstitial fibrosis and tubular atrophy. Morphometry of Sirius red–stained specimens was performed using a Zeiss microscope equipped with full-color 3CCD camera and KS-400 image analysis software from Zeiss-Kontron (Munich, Germany). Computerized digital analysis was used to quantify the area of staining in each slide. An average of 10 microscopic sections were examined from each slide. Using the ×20 objective, an average of 63.2 ± 19.5% of the total cortex was analyzed in each biopsy.
Treatment of Acute Rejection Episodes
A clinically suspected acute rejection episode was confirmed by a percutaneous graft biopsy and graded according to the Banff ’97 classification (24) by an experienced local renal pathologist. An acute rejection episode was treated with methylprednisolone (Solu-Medrol, Pharmacia, The Netherlands) 1000 mg/d for three consecutive days. Rabbit anti-thymocyte globulin (Merieux, Amstelveen, The Netherlands) was given in case of a steroid-resistant rejection episode and for a second acute rejection episode. Rejection was considered steroid resistant when no stabilization or improvement within 20% of baseline creatinine occurred within 7 d after treatment with Solu-Medrol. By design, surveillance biopsies were scored retrospectively and SAR was not treated.
Efficacy Parameters and Adverse Effects
Renal function (creatinine clearance) was calculated by the Nankivell formula (25) and determined at 6 wk and 3, 6, 12, and 24 mo after transplantation. Other secondary efficacy parameters included the following: Patient and graft survival, incidence and severity of acute rejection episodes, BP, lipids, and HbA1c. The incidence of new-onset diabetes was defined by the need for any antidiabetic drug (insulin and/or oral antidiabetic drugs), in the absence of diabetes at baseline. Prescription of lipid-lowering drugs (statins) and the number of antihypertensive drugs were recorded during the study.
Statistical Analyses
All analyses were performed according to the intention-to-treat principle. Results are given as mean ± SD for interval and ordinal variables. Frequencies of nominal (categorical) variables are given as numbers and percentages. For comparison between two categories of interval variables, independent samples t test was used. When statistical assumptions for parametric analysis of interval variables were not met and in case of ordinal data, Mann-Whitney’s two-independent samples test was used and exact P values were calculated. Nominal variables were analyzed with cross-tables, and exact significance was calculated. The incidence of acute rejection and diabetes was estimated using Kaplan-Meier product-limit method, and the resulting curves were compared with log-rank test. All analyses were performed using SPSS statistical software package (version 10.07; SPSS, Inc., Chicago, IL).
Results
Patient Characteristics
A total of 126 patients were randomly assigned for treatment with either CsA or tacrolimus. The treatment groups were well matched for demographic and transplant characteristics (Table 1). In the CsA-treated group, more patients received a second transplant (eight patients versus one in the tacrolimus group). Only one of these patients experienced an acute rejection episode, and in the analyses, this inequality in distribution did not confound the comparison between the treatment groups.
Demographic and transplantation characteristics at baseline
AUC-Guided Dosing
Figure 1 shows to what extent the actual measured AUC of CsA and tacrolimus were kept near the target AUC. MMF was given in a fixed dose in both groups: 1000 mg twice daily in the CsA group and 500 mg twice daily in the tacrolimus group. The mean mycophenolic acid (MPA) AUC0-12 at 2, 6, 12, 26, and 52 wk were 23.4, 39.7, 46.9, 44.7, and 43.1 ng/h per ml in the CsA patients and 20.6, 28.4, 29.5, 28.0, and 30.4 ng/h per ml in the tacrolimus patients, respectively. On the basis of the known interaction between CsA and MMF (26), we hypothesized that this choice would result in a comparable mean exposure to MPA in both groups. Beyond week 6, however, the MPA-AUC in the CsA-treated patients were consistently and significantly higher, most likely as a result of the defined reduction in the target AUC for CsA beyond 6 wk.
Area-under-the-concentration-over-time curves (AUC ± SD; ng/h per ml) using the Bayesian estimator to guide dosing of cyclosporine (CsA; A) or tacrolimus (B) in de novo renal transplant recipients (dotted lines indicate the predefined AUC targets).
Patient and Graft Survival
One-year patient survival was 96.8 versus 98.4% and 1-yr graft survival was 95.2 versus 90.5% in CsA- and tacrolimus-treated patients, respectively. In the CsA group, there were two deaths, and one patient underwent transplantectomy at day 320 after transplantation because of posttransplantation lymphoproliferative disorder, localized in the graft. In the tacrolimus group, one patient died, two patients experienced primary nonfunction after non–heart-beating donor procedures, two patients experienced early graft loss after surgical complications, and one additional patient experienced graft loss as a result of acute humoral rejection.
Acute Rejection
The cumulative incidence of acute rejection episodes in this study at 6 mo was 11.5% (14 of 126); no late clinical acute rejection occurred (Figure 2). The incidence of biopsy-proven acute rejection episodes was higher in patients who were randomly assigned to CsA (16.2%), as compared with patients who received tacrolimus (6.6%). Although clinically relevant, this difference did not reach statistical significance (P = 0.12) in this relatively small cohort of patients. Steroid resistance, requiring anti-thymocyte globulin therapy, occurred in 6 and 2% of CsA- and tacrolimus-treated patients, respectively.
Proportion of acute rejection–free renal transplant recipients who were randomly assigned to receive controlled systemic exposure and tapering of CsA or tacrolimus.
Protocol Biopsies
At 6 mo, biopsies were available in 83 and 82% of the patients who were randomly assigned to CsA and tacrolimus, respectively. At 12 mo, these percentages were 88% for the CsA group and 84% for the tacrolimus group. Reasons for missing primarily were not enough specimen for proper Banff classification scoring, increased bleeding risk, and secondary refusal by patients to undergo a protocol biopsy. No quantitative differences in the degree of renal fibrosis were observed between CsA and tacrolimus at 6 mo (Sirius red–positive area mean ± SD: CsA 12.5 ± 3.7 versus tacrolimus 12.4 ± 5.4%; P = 0.78) or at 1 yr (CsA 13.7 ± 5.6 versus tacrolimus 13.3 ± 5.9%; P = 0.73).
SAR
The prevalence of SAR at 6 mo was 30.8% (bSAR 23.4% and SAR 7.4%). The prevalence was significantly (P = 0.012) higher in patients who received CsA therapy (38.8%; bSAR 24.5% and SAR 14.3%), as compared with tacrolimus (15.5%; bSAR 11.1% and SAR 4.4%). Prevalence of SAR at 12 mo was 19% (CsA 16%, tacrolimus 22%; NS). We analyzed transplant and outcome characteristics in patients according to the presence or absence of SAR in the 6-mo biopsies (Table 2). No differences in donor age, degree of histocompatibility for HLA antigens, or delayed graft function were found. The percentage of patients with previous episodes of acute rejection also was comparable (10.3 versus 10.8% with or without SAR, respectively). SAR in the 6-mo biopsy was found more frequent with CAN grade ≥2 in the same biopsy but was not associated with differences in Sirius red–stained cortical area in 6- and 12-mo serial biopsies, proteinuria, or progressive loss of GFR (Figure 3). No difference in systemic exposure of immunosuppressants, either in the CsA- or tacrolimus-treated patients, or MMF was found. These results are summarized in Table 3.
Renal allograft function over time according to the presence of subclinical acute rejection in 6-mo protocol biopsies in renal transplant recipients who were randomly assigned to receive controlled systemic exposure and tapering of CsA or tacrolimus.
Characteristics according to the presence of SAR in 6-mo protocol biopsiesa
Banff scores in 6-mo protocol biopsies and systemic exposure of CNI and MMFa
CAN Score
The prevalence of CAN in the 6-mo protocol biopsies was 53% (CsA 51%, tacrolimus 57%) and 63% at 1 yr (CsA 61%, tacrolimus 65%). At 6 mo, CAN grade 1 was found in the majority (76%) of cases and grade 2 or 3 in 20 and 4%, respectively. The analyses according to Banff CAN grade at 6 mo are summarized in Table 4. CAN grade ≥2 was associated with kidneys from elderly deceased donors, in particular older than 60 yr. Donor age correlated significantly (rτ = 0.34; P = 0.003) with cortical tubulointerstitial fibrosis in pretransplantation biopsies. Fibrosis in the pretransplantation biopsy correlated with inferior graft function at week 6 (rτ = −0.32; P = 0.007), month 3 (rτ = −0.26; P = 0.029), and month 6 (rτ = −0.26; P = 0.033). The CAN score correlated significantly with the percentage of Sirius red–positive cortical area (P < 0.001). Inferior function was found in biopsies with CAN grade ≥2 (Figure 4) but not with concomitant SAR and correlated with a significantly higher proportion of kidneys from deceased and older donors (Table 5). The prevalence of SAR in the 6-mo biopsies that showed CAN ≥2 was significantly higher (58.3 versus 26.8%; P < 0.05), but no differences in Sirius red–stained cortical area in 12-mo biopsies (P = 0.93), degree of proteinuria, or progressive loss of renal function were found (Table 5). There were no differences with respect to matching, delayed graft function, or acute rejection history. No correlation between CAN and initial or maintenance systemic exposure for CsA, tacrolimus, or MMF was found (Table 3).
Renal allograft function over time according to Banff criteria acute rejection and CAN grade in 6-mo protocol biopsies in renal transplant recipients randomly assigned to receive controlled systemic exposure and tapering of CsA or tacrolimus.
Transplant characteristics and histologic and clinical parameters according to CAN grade in 6-mo protocol biopsies
Characteristics according to the presence of SAR and the CAN grade in 6-mo protocol biopsies
Antihypertensive Drugs, Lipid-Lowering Therapy, and New-Onset Diabetes
No significant differences in systolic or diastolic BP were observed between the two groups, but tacrolimus-treated patients tended to require fewer antihypertensive drugs (Table 6). Cholesterol levels at 6 and 12 mo were significantly higher in the CsA group, despite that a slightly higher proportion of patients were receiving lipid-lowering drugs. New-onset diabetes occurred significantly (P = 0.007) more frequently in patients who were randomly assigned to tacrolimus as compared with CsA (Figure 5). No patients in whom all antidiabetic drugs could be discontinued were reported. Within the tacrolimus group, an AUC >210 ng/h per ml at week 2 was significantly associated with a higher probability to develop diabetes (odds ratio 4.00; P = 0.05).
Cumulative incidence of new-onset diabetes at 6 mo in renal transplant recipients who were randomly assigned to receive controlled systemic exposure and tapering of CsA or tacrolimus.
Cardiovascular adverse effect profile in renal transplant recipients with controlled systemic exposure of cyclosporine or tacrolimus
Discussion
This is the first study to evaluate the impact of SAR on fibrosis in serial protocol biopsies under controlled systemic exposure of one of the currently available CNI. Banff criteria acute rejection was found in 30.8% of protocol biopsies that were performed 6 mo after transplantation, with a significantly higher prevalence in CsA-treated transplant recipients. The mere presence of SAR, however, was not associated with more interstitial fibrosis in serial biopsies, degree of proteinuria, or progressive loss of graft function up to 2 yr of follow-up. Because, by protocol, we did not treat SAR, these results provide evidence that the vast majority of asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious, at least in the intermediate term, and could be adaptive rather than destructive. Sirius red, a specific staining for collagen types I and III, is considered a precise and reliable estimate of renal cortical extracellular matrix accumulation (15,16). Types I and III collagen represent 80 and 15 to 20%, respectively, of the total collagen synthesized by fibroblasts, and especially the early accumulation of collagen type I, along with collagens III and IV, was found to be a more specific marker for chronic rejection (28).
Comparable to previous observations, donor age and fibrosis in the pretransplantation biopsy was associated with inferior graft function (29,30). Donor age or quality of the donor organ at implantation was not associated with a higher prevalence of SAR at 6 mo. Although SAR was found more frequently in combination with moderate to severe CAN, the presence of these interstitial infiltrates was not associated with differences in serial quantitative Sirius red staining, proteinuria, or renal allograft function. Recently, a similar incidence and severity of interstitial fibrosis in surveillance biopsies from living- and deceased-donor kidneys was found, challenging the impact of injury related to brain death and/or prolonged preservation (14). In addition, protocol biopsies of kidneys from a heart-beating or non–heart-beating donor revealed no significant difference in quantitative Sirius red staining in relation to prolonged periods of warm ischemia (31).
Results from studies that focus on optimal therapeutic index of CNI depend on the drug monitoring strategy that is used and especially the target ranges of drug levels that are accepted. Trough levels of both CsA and tacrolimus are not closely correlated with drug exposure (17,18,32–34), the risk for allograft rejection (35,36), or their adverse effects (37,38). The AUC0-12h and derived parameters, such as absorption profiles, have been shown to correlate more closely with clinical outcome also in patients who received prophylaxis with basiliximab (39).
One year after transplantation, the prevalence of SAR has largely abated, indicating that, at a later stage, progressive histologic alterations are dominated by CNI-related vasculopathy and/or glomerulosclerosis (21). Most tubular atrophy and fibrosis begin early after transplantation as a consequence of the summated effects of tissue injury from ischemia-reperfusion, acute rejection (14), and/or, given the initial higher dosing, early (chronic) CNI nephrotoxicity (21,27). This notion is supported by a study that investigated protocol biopsies that were obtained 2 yr after transplantation (13). Histopathologic signs of CAN were reported in 62.0% of the patients who were treated with tacrolimus and in 72.3% of the CsA-treated patients, which occurred in the absence of discernible changes in renal function. Renal transplant function is an inadequate measure of ongoing tissue injury either as a result of ongoing rejection or early interstitial CNI toxicity, but quantitative histomorphometry using Sirius red at 6 mo has been shown to correlate strongly with GFR in patients with established CAN and time to graft failure (15,16). The semiquantitative cumulative Banff algorithm, dominated by interstitial fibrosis and tubular atrophy, also may not be precise enough. The assessment of the severity of CAN in serial biopsies and, to a lesser extent, SAR not only is subjected to significant interobserver variability but also lacks specificity (40–42). Laminin β2 and TGF-β mRNA levels in the renal cortex, however, allow for distinguishing chronic CNI toxicity from chronic rejection with high sensitivity and specificity (43). The nephrotoxic potential of CsA and tacrolimus is indistinguishable clinically (6,44), histologically (19), or at the renal molecular level (20). Six months after implantation, no significant differences were found in the extent of protein deposition as well as cortical mRNA levels of TGF-β, but a wide variability within both treatment groups (20). TGF-β expression in biopsies that were performed 3, 6, and 12 mo after transplantation was associated with a significant increase in interstitial fibrosis (45).
Under controlled systemic exposure and subsequent tapering, graft fibrosis accompanied by SAR in the same biopsy at 6 mo was not associated with progressive damage or functional impairment. In contrast to previous studies, we observed no late clinical acute rejection, and the AUC method makes inadequate immunosuppression an unlikely cause of ongoing rejection (9,30,37). The risk profile for inferior function at 2 yr included inadequate early immunosuppression with CsA, poorer matching for HLA class I antigens, and late clinical acute rejection (10,30). The occurrence of late clinical acute rejection in these studies was significantly associated with the development of an increased serum creatinine at 24 mo or CAN at 1 yr (10,30). Evaluation of serial protocol biopsies that were taken from the first year in the subgroup of pediatric transplant recipients with established CAN revealed that the superimposition of recurrent or persistent SAR but not borderline changes was associated with histologic progression and subsequent functional deterioration. Treatment of acute rejection at 1 yr with steroid pulses had no beneficial effect on the course of these cases (10). It remains controversial whether SAR, borderline changes, or even inflammation, generally not qualifying for borderline rejection, suggest a different functional prognosis with longer times of follow-up (46).
SAR in protocol biopsies that were performed as early as 14 d after living-donor transplantation most likely represents a donor-specific immune response as it correlates with HLA-DR mismatching, underscoring that clinical immunosuppression is imperfect (12,47). Newer drug regimens significantly reduced the incidence of both early and late clinical acute rejection, but the prevalence of SAR remained essentially unchanged (48). Untreated borderline infiltrates in clinical biopsies that were performed 2 to 3 mo after transplantation tended to persist, but the majority (72%) did not progress to clinical acute rejection within the next 40 d (49). Of note, cases with evidence of acute CNI toxicity (58%) in addition to the borderline infiltrates had a low rate of progression to acute rejection despite CNI dosage reduction. We cannot exclude that a significant proportion of patients with SAR in earlier protocol biopsies (≤3 mo) do benefit from additional treatment or a modification of their immunosuppressive regimen as suggested by the work of Rush et al. (9). This study stratified for donor source, but patients in the control group were less well matched and received kidneys from older donors. Probably more important, however, treatment of early SAR up to month 3 resulted in a three-fold decreased incidence of late (beyond month 6) clinical acute rejection (9). The strong correlation between late acute rejection and chronic rejection as well as late graft loss has been reported consistently (37,50). In our study, under controlled systemic exposure and tapering of either CsA or tacrolimus, early acute rejection rates were low and no late acute rejection occurred, indicating that individualized CNI exposure may be at least as effective in the prevention of late clinical acute rejection as treating early SAR with high-dosage steroids.
We clearly lack a reliable metric at the time of biopsy to decide whether additional treatment is beneficial, because there is no doubt that extra boluses of steroids or recycling of the steroid taper add significantly to posttransplantation morbidity. Minimization or, preferably, elimination of CNI nephrotoxicity, an important determinant for late or progressive deterioration of graft function in a substantial proportion of renal and nonrenal allograft recipients, seems to be a key decision to potentially modify long-term outcome (51,52). At present, we lack a reliable metric to decide whether asymptomatic interstitial infiltrates represent ongoing rejection or the exponent of a regulatory response that is self-limiting, is not harmful to the graft, and does not need drug adjustments. We suggest delaying drug withdrawal or minimization until the risk for SAR is diminished or preferably ruled out by reliable biomarkers either in a surveillance biopsy (53) or in biologic fluids. The relevance of AUC-guided monitoring then may be found in the control over drug exposure for the remaining drug or the drug that is considered for conversion (54).
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
E.M.S. and A.T.R. contributed equally to this study.
- © 2006 American Society of Nephrology
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