 |
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
|
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Correspondence to Norberto Perico, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: 39-035-319888; Fax: 39-035-319331;
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Many studies have attempted to lower antirejection drug doses, but results have been discouraging so far. Steroids can be reduced successfully in the short term in at least two thirds of patients. That, however, results in higher risk of acute rejection and graft failure, even after relatively long periods from withdrawal (6). Calcineurin inhibitors are important factors contributing to deterioration of the transplant kidney in the long term (7–9). This prompted some investigators to reduce or avoid cyclosporine in their antirejection protocols by a delay, however, of few years after transplantation to minimize insufficient immunosuppression and consequent immune-mediated events that may lead to chronic nephropathy (6). In a recent elegant review, Pascual et al. (10) concluded that "corticosteroids and calcineurin inhibitors have been the corner-stone of immunosuppressive regimen for many years, and their elimination from current regimens will require a sound and well valuable basis."
We report the results of a randomized trial in which patients have been assigned to per-protocol biopsy or no-biopsy after 1 yr of standard treatment with steroid, CsA, and azathioprine. Therapy with steroids and CsA was discontinued or reduced on the basis of biopsy findings. Our primary purpose was to establish the effect of discontinuing or reducing antirejection drugs on drug-related complications and whether this could be achieved, however, at expenses of more rejection and possibly of worse renal function in the long term. All patients then underwent a second biopsy after 3 more years of follow-up to evaluate the effects of changing antirejection regimen on kidney structure.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
20% in the previous 3 mo; no written informed consent.
|
Randomization
After signing written informed consent, the patients were randomly assigned to biopsy (group 1) or no-biopsy group (group 2). In the former group, transplant patients underwent steroid withdrawal, CsA discontinuation or reduction, or no change in their immunosuppressive therapy according to biopsy-based assignment to no lesions, chronic CsA nephropathy, or chronic graft rejection, respectively. Patients randomized to no-biopsy continued on their standard triple-drug regimen of immunosuppression. Randomization was performed at the Laboratory of Biostatistics of the Clinical Research Center for Rare Diseases "Aldo e Cele Daccò" of the Mario Negri Institute for Pharmacological Research. No change of therapy was scheduled for group 2; therefore, it was considered unethical to perform baseline renal biopsy in these patients.
Study Protocol
After randomization, urine samples were collected for measurement of 24-h urinary protein excretion starting the day before baseline renal function evaluation. All patients then underwent renal hemodynamic measurements by assessing GFR and renal plasma flow (RPF), respectively, by the plasma clearance of unlabeled iohexol (11) and the renal clearance of para-aminohippuric acid (PAH) under a steady state of diuresis as described previously (12). In parallel, the CsA pharmacokinetic profile was also determined. Both before and at 30 and 60 min after CsA administration, as well as at hourly intervals thereafter for 12 h, blood samples were collected from a peripheral vein for measurement of CsA levels in the blood. On the morning of the study, blood was drawn for estimation of serum creatinine concentration and other biochemical and hematologic parameters. Four to seven days after the renal hemodynamic evaluation, patients on randomization to per-protocol biopsy were again admitted to the Unit of Nephrology to perform kidney graft biopsy. In all cases, the renal biopsy was done as a part of the research protocol to assess the possible presence of graft lesions and thus to modify drug dosage schedule accordingly.
The patients with normal graft histology pattern underwent steroid discontinuation. The recipients who had biopsy-documented diagnosis of CsA nephropathy were submitted to CsA withdrawal or dose reduction. The remaining patients with histology evidence of chronic graft rejection continued on their conventional immunosuppressive regimen.
All patients randomized to biopsy or no-biopsy received standard clinical care as it would be appropriate for any change in immunosuppression. Patients had chemistry and CsA drug level monitoring weekly for 4 wk, biweekly for 2 mo, and then monthly through the follow-up period. Patients continued on routine antihypertensive medications. No effort was made to change dietary salt or protein intake.
At 1, 2, and 3 yr after enrollment, patients were reevaluated for renal hemodynamic parameters and CsA pharmacokinetic profile, as at baseline. During the 3-yr follow-up period, any adverse event, including acute graft rejection, graft loss, infections, fatal and nonfatal cardiovascular disease, diabetes, osteoporosis, intrahepatic and extrahepatic lithiasis, and cancer, were monitored. At the end of the study period, patients from group 1 underwent a second graft biopsy for histologic examination. As a comparison, kidney biopsies were also obtained from group 2 patients.
Renal Transplant Per-Protocol Biopsy Assessment
Kidney graft tissue was processed for light microscopy by fixation in Dubosq-Brazil fluid and embedded in paraffin. Specimens were stained with Masson’s trichrome, hematoxylin and eosin, periodic acid-Schiff (PAS) reagent, and silver staining. By light microscopy, the patterns were categorized into no lesions, CsA nephropathy, and chronic graft rejection as follows:
No Lesions
This condition was defined when normal pattern or minor nonspecific changes (focal interstitial inflammation without tubulitis, endothelial swelling, venulitis) (13) were observed.
CsA Nephropathy
Renal biopsy revealed accepted features of chronic CsA nephrotoxicity including: (1) tubular changes (isometric vacuolization of proximal tubular cells, inclusion bodies corresponding to giant mitochondria, microcalcification, and irregular foci of tubular atrophy); (2) interstitial lesions (striped or patchy fibrosis); (3) vascular-early lesions (vacuolization and clear cell transformation of smooth muscle cells) and vascular-late lesions (circular nodular hyaline deposits in the afferent arteriolar wall, narrowing or occlusion of vascular lumen); (4) glomerular lesions (sclerosis or ischemic collapse, juxtaglomerular apparatus hyperplasia). Chronic CsA nephropathy was diagnosed when tubular atrophy and striped interstitial fibrosis were found either alone or in association with any of the morphologic lesions described above (13,14).
Chronic Rejection
This condition was defined accordingly to the following changes: (1) tubular (diffuse tubular atrophy, wrinkling and thickening of tubular basement membrane, and simplification of the epithelial cells); (2) interstitial (fibrosis and mononuclear cell inflammation); (3) vascular (arteriosclerosis with intimal proliferation and thickening of vessel wall of interlobular and arcuate arteries, elastic lamina fragmentation); and (4) glomerular (wrinkled, thickened, and collapsed capillary wall and mesangial expansion, sclerosis). Chronic graft rejection was diagnosed when diffuse tubular atrophy or diffuse interstitial fibrosis were documented alone or in association with interstitial inflammation, arteriosclerotic lesions, or glomerulopathy (13,15). Although possibly suggestive of overlapping lesions, arteriolar hyalinosis in the presence of such changes did not modify the assignment to diagnosis of rejection.
Semiquantitative analysis of changes was performed in accordance to the Banff schema, 1997 version (16), by an investigator who was unaware of the diagnosis assigned to each patient. Thickening of glomerular capillary wall was also scored from mild to severe, and the percentage of glomeruli with segmental or global sclerosis as well as the presence of inflammatory infiltrates were recorded. The analysis was performed by an investigator who was blinded to the clinical status of the patients.
Management of Corticosteroid Withdrawal
After baseline evaluation in patients with no graft histology lesions, daily steroid dose was initially reduced of 2 mg every 15 d up to 4 mg/d. Thereafter, an alternate daily regimen was established with 8/0 mg, 6/0 mg, 4/0 mg, and 2/0 mg, respectively, with dosage change every 15 d until complete drug withdrawal. No modification of the remaining immunosuppressive therapy was introduced, so patients continued with the same CsA and azathioprine dosage.
Management of CsA Dose Discontinuation or Reduction
After diagnosis of CsA nephropathy and baseline determination of renal function and hemodynamics, CsA dosage was progressively reduced by 0.5 mg/kg every 15 d until complete discontinuation. With this regimen, however, acute graft rejection occurred in the first four patients when CsA dose was lowered to the extent that the blood CsA trough levels were less than 20 ng/ml. The Independent Ethical Committee — appointed to evaluate the safety and efficacy profiles of the drug discontinuation regimens — recommended to modify the protocol in such a way that the patients should adopt an extreme CsA dose reduction rather than total discontinuation. The amended protocol implied reduction of CsA by 0.5 mg/kg every 2 mo until the target blood CsA through level of 30 to 70 ng/ml was achieved. CsA tapering in all patients was completed within 6 mo. Dosage of steroid and azathioprine was not modified.
Analytical Procedures
Plasma concentration of iohexol was determined by HPLC as described previously (11). The plasma profiles were analyzed by one-compartment open model system, and the calculated clearance of iohexol (as an index of GFR) corrected according to the Bröchner-Mortensen formula (17).
Plasma and urine concentrations of PAH were measured by a colorimetric method (18), and renal clearance was calculated according to the standard formula. The average of the six determinations was considered and expressed per 1.73 m2 of body surface area.
Blood CsA concentration was determined by HPLC (19). The blood concentration-time profile of CsA was recorded for all patients together with the trough level before morning CsA dose. The area under the blood concentration curve from the time equals zero to the last sampling point (AUC0–12 h) was calculated by the trapezoidal rule.
Routine chemical and hematologic analyses were performed using standard laboratory techniques.
Statistical Analyses
Values were expressed as mean ± SD and range where appropriate. Difference in final (post-test) values of hemodynamic and pharmacokinetic parameters among the groups were analyzed by a general linear model (repeated measures ANOVA) (20). In a full factorial design, we also tested for the influence of the changes between the final and basal values. The comparisons were adjusted for the values at baseline (pre-test). Adverse events related to immunosuppressive drugs were compared by means of the long-rank test. Between-groups comparisons of histology scores were carried out using Kendall’s 
. Within-group comparisons of histology scores were performed using Wilcoxon signed ranks test. The statistical significance level was defined as P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
No Lesions
Five patients had a normal kidney graft at histologic examination. In three of them, very minor tubular atrophy and interstitial fibrosis were observed. No other histologic alterations, including glomerular and vascular lesions, were found in any of these patients. They were therefore considered for the steroid withdrawal protocol.
CsA Nephropathy
Thirteen of thirty patients had evidence of CsA-induced nephrotoxicity at histologic examination. In all of them, irregular foci or stripes of tubular atrophy accompanied by fibrosis were the predominant finding. Areas of atrophic tubules embedded in a fibrotic interstitium were adjacent to areas exhibiting normal tubules. In five patients, very mild interstitial inflammatory changes were seen in few areas. Glomerular lesions, as focal-segmental or global sclerosis and ischemic collapse, were documented in four patients. Minimal to mild arteriolopathy was seen in two patients. This was characterized by vacuolization of smooth muscle cells and necrosis of individual endothelial cells and smooth muscle cells and nodular protein deposits. All these patients entered a CsA withdrawal/tapering regimen.
Chronic Rejection
Twelve patients had a diagnosis of chronic rejection. Diffuse tubular atrophy or interstitial fibrosis were scored mild to severe in all patients. In the fibrotic interstitium, a sparse mononuclear cell infiltrate was usually present in almost all patients. Dense inflammatory infiltrates were detected in six patients. Glomerular sclerotic lesions were present in five patients. In two patients, mild or severe vascular alterations were found, including intimal hyperplasia. Patients with histologic evidence of chronic graft rejection did not modify their immunosuppressive therapy.
Table 2 reports the correlation between biopsy findings and clinical characteristics of patients assigned to the three subgroups. Three of five patients of the subgroup with no lesion at biopsy had previously one acute rejection. Similarly, 8 of 13 patients belonging to the subgroup with histology evidence of CsA nephropathy and 8 of 12 recipients with biopsy evidence of chronic graft rejection experienced an acute rejection early posttransplant. It is noteworthy that in the latter subgroup most patients had acute rejection episodes. Baseline mean serum creatinine concentration, blood CsA trough level, and urinary protein excretion rate were numerically but not statistically significant different among the three biopsy subgroups.
|
|
No acute rejection was documented in the subgroup of biopsy patients who remained on conventional immunosuppressive regimen. One patient lost the graft. The recorded major adverse events included cardiovascular events, osteoporosis, and cholecysto/intrahepatic lithiasis. SBP and DBP did not change significantly over the study period (SBP: Pre, 137 [range 124 to 145] mmHg; Post, 133 [range 119 to 147] mmHg; DBP: Pre, 87 [range 81 to 94] mmHg; Post, 89 [range 85 to 92] mmHg).
In the no-biopsy control group, the patients had no acute graft rejection episodes, and all were alive at the end of the observation period. A patient lost the graft and returned on dialysis replacement therapy. Moreover, four patients developed neoplasia (two renal cell carcinoma of a native kidney; one colon carcinoma; one breast carcinoma), four had diabetes, one experienced a nonfatal cardiovascular event (myocardial infarction), one had recurrent infections, three osteoporosis, and five cholecysto/hepatic lithiasis. On average, SBP and DBP values were comparable at baseline and at the end of follow-up (SBP: Pre, 138 (range 124 to 156) mmHg; Post, 136 (range 123 to 161) mmHg; DBP: Pre, 86 [range 66 to 95] mmHg; Post, 86 [range 77 to 95] mmHg).
Considered together, there were numerically fewer events in the biopsy group than in the no-biopsy group, although the difference did not achieve statistical significance (P = 0.06). A more significant trend (P = 0.05) was found when the subgroup of biopsy patients with steroid withdrawal alone or in combination with the CsA dose reduction subgroup was considered. Among the individual events, the incidence of diabetes was significantly lower in the biopsy than no-biopsy group (P < 0.0374). Moreover, numerically more clinical events in the no-biopsy group than in the biopsy subgroup on standard immunosuppression were found, which could reflect the relative lower number of patients enrolled in the latter subgroup.
Renal Function and Hemodynamics
In biopsy patients with steroid withdrawal, serum creatinine concentration did not change significantly as compared with baseline (Pre: 1.10 ± 0.22 mg/dl [range 0.80 to 1.40]; Post: 1.21 ± 0.33 mg/dl [range 0.90 to 1.70]). Moderate renal insufficiency was found at 1 yr post-randomization in two patients initially entering the CsA discontinuation program, who experienced acute graft rejection within a few months after enrollment. When they were shifted to a low-dose CsA regimen, no further significant increase in serum creatinine concentration was observed. In a third patient belonging to the same group, who completely recovered graft function after the acute rejection episode, serum creatinine slowly and progressively increased during the last year of the follow-up. In a patient who underwent CsA dose reduction, serum creatinine level increased during the second year follow-up, due to de novo intracapillary and extracapillary glomerulonephritis, as documented at graft biopsy, but remained stable thereafter. In the remaining nine patients who underwent CsA dose reduction, serum creatinine level did not change significantly during the entire study period. Overall in the CsA discontinuation/reduction group, serum creatinine concentration increased numerically but not significantly over baseline during the 3-yr follow-up period (Pre: 1.16 ± 0.30 mg/dl [range 0.58 to 1.60]; Post: 1.65 ± 0.78 mg/dl [range 0.90 to 3.04]). In the subgroup of biopsy patients on standard immunosuppressive regimen serum creatinine values (Pre: 1.43 ± 0.29 mg/dl [range 1.00 to 2.00]; Post: 1.68 ± 1.39 mg/dl [range 0.84 to 6.00]) increased progressively in a patient who reached the end-stage renal disease during the last year of follow-up. In the other 11 patients, serum creatinine concentration remained substantially unchanged over the 3-yr follow-up. In no-biopsy control patients, there were no significant changes in serum creatinine concentration, except in one of them, who showed progressive deterioration of graft function up to end-stage renal disease (Pre: 1.22 ± 0.27 mg/dl [range 0.80 to 1.80]; Post: 1.42 ± 0.94 mg/dl [range 0.80 to 6.00]).
The time-course of GFR largely mirrored that of serum creatinine concentration. In both biopsy and no-biopsy groups, mean GFR slowly declined during the study period, with significant difference (P < 0.05) over baseline only achieved in the latter (biopsy: pre, 68.48 ± 20.02; post, 62.70 ± 22.86 ml/min per 1.73 m2; No-biopsy: pre, 66.17 ± 16.06; post, 60.35 ± 16.53 ml/min per 1.73 m2). As shown in Table 4, mean GFR in biopsy patients who discontinued steroids was comparable at baseline and at the end of follow-up. In transplant recipients with CsA dose reduction, GFR values showed a mild tendency to decline without reaching statistical significance. No significant change in mean GFR was found in the biopsy patients on standard immunosuppressive regimen. By contrast, a mild but significant decline in mean GFR was documented in the control no-biopsy group over the 3-yr follow-up.
|
More significant were the observed changes in RPF values (Table 4). In both biopsy and no-biopsy groups, mean RPF declined during the observation period (biopsy: pre, 320 ± 84; post, 234 ± 90 ml/min per 1.73 m2; no-biopsy: pre, 296 ± 100; post, 237 ± 84 ml/min per 1.73 m2), the difference over baseline being statistically significant (P < 0.05). A tendency to mean RPF decline during the 3-yr follow-up was found in all study subgroups, but a statistical significance was achieved only in biopsy patients with standard immunosuppressive regimen and in the control no-biopsy recipients. As a consequence, filtration fraction tended to increase in all study groups, except in the biopsy patients with CsA dose reduction.
Characteristics of CsA Pharmacokinetics
Table 5 shows CsA pharmacokinetic parameters, including trough concentration and AUC0–12 h, in the four groups of patients. In biopsy patients who discontinued steroids, mean blood CsA trough level did not change to a significant extent during the follow-up (Figure 2). In the group of patients with CsA dose reduction blood CsA trough level, which ranged from 68 to 221 ng/ml at baseline, declined progressively during the drug-tapering phase and thereafter remained consistently within values ranging from 25 to 81 ng/ml (Figure 2). A mild but significant increase in CsA trough concentration was found in biopsy patients with standard immunosuppression. In the control no-biopsy group, CsA trough level at the end of the 3-yr follow-up was numerically but not significantly higher than baseline value.
|
|
Other Biochemical Parameters
None of biopsy patients who discontinued steroids had overt proteinuria at baseline nor developed proteinuria thereafter (Table 6). A patient from the biopsy group with CsA dose reduction developed nephrotic proteinuria due to de novo glomerulopathy. In this group, proteinuria declined to normal values in two patients and developed in two others. In most of the remaining patients, urinary protein excretion did not change during the 3-yr follow-up. A similar trend was found for patients belonging the biopsy and no-biopsy groups with standard immunosuppression.
|
Mean values of glycemia (Table 6), serum sodium, and potassium concentrations (data not shown) were comparable before and at the end of the study period in all groups.
Histopathologic Findings
The biopsy finding at the end of follow-up in comparison with data at baseline and the results of semiquantitative evaluation are summarized in Table 7.
|
For 8 of 13 patients with biopsy evidence of CsA toxicity at baseline, a second evaluable biopsy was available (Table 7). Among the five remaining patients, three withdrew consent to biopsy, one died before the end of the study, and one had insufficient biopsy material available for analysis. In most cases, no major lesions were observed, with no significant changes over baseline score (Table 7). A reduction of the chronic tubular damage score over baseline could be recorded in five of eight patients, and the score was unchanged in other two patients. Worsening of tubular score was found in only one patient. A similar trend was found for chronic interstitial lesions, which ameliorated or remained unchanged in most patients (Table 7). Arteriolar lesions were no longer detectable in one patient, whereas mild insudative changes were found in two patients. Glomerular sclerotic lesions were found in two additional patients, and thus in half of the patients at the 3-yr biopsy in this group (Table 7).
In the subgroup of biopsy patients who remained on standard immunosuppressive regimen, seven biopsies were available for analysis at the final evaluation (Table 7). Chronic tubular or interstitial lesions worsened or were unchanged in most patients (n = 5). Arteriolar insudative lesions and/or medial necrosis of the arterial wall were found in two patients and worsened in one. The scores for chronic glomerular lesions were higher or they did not modify over baseline in this group. In one patient, the glomerular score could not be assessed due to absence of glomeruli in the sample. Severe glomerular sclerotic lesions became detectable in more than two thirds of the patients. Changes in this group were assigned score values that were comparable to those found in the no-biopsy group (Table 7).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Lowering antirejection drug doses with the aim to reduce the devastating side effects of long-term use of steroids and CsA has been attempted before with controversial outcomes (6). In most studies, steroid withdrawal from a triple immunosuppressive regimen of prednisone, CsA, and azathioprine at different intervals from transplantation was associated with large variability in the incidence of acute rejection, ranging from 14 to 60% (22–27). Others, through the Canadian multicenter trial of steroid withdrawal 3 mo after kidney transplantation, reported increased graft loss in the steroid discontinuation group after 5 yr of follow-up (28). Our results indicate that steroids can be safely stopped after 1 to 2 yr from surgery without acute rejection or graft loss. This, however, applies to those very patients who had no-biopsy evidence of underlying immune process. Actually, we found the plasma clearance of iohexol — a reliable mean of GFR — was comparable over the 3-yr follow-up in the patients on steroid withdrawal and in those who remained on standard triple immunosuppression. Similar results have been reported in the US multicenter trial (26), in which the steroid withdrawal group had a final creatinine clearance of 6.39 ml/min lower than the control group, difference not clinically relevant. The important novelty from the present study in this respect is that those elected to eliminate steroids had no biopsy evidence of acute or chronic rejection, a clue that per se was taken to predict low risk for subsequent rejection after steroid withdrawal. Previous attempts were driven by clinical criteria alone such that patients who already had subclinical rejection could be exposed to higher risk of overt rejection while on no steroids.
Withdrawal of CsA was much more difficult. In patients with biopsy evidence of CsA toxicity, we initially attempted to completely withdraw CsA. However, despite a very slow 4-mo tapering program, complete CsA discontinuation was associated with acute graft rejection in the first four patients enrolled. Most of previous studies, in which CsA was withdrawn at different times after kidney transplantation, actually showed a high incidence of acute rejection (6,29–32). In 165 kidney transplant patients, on the other hand, weaning of CsA beyond 1 yr posttransplant resulted in a very low incidence (9.1%) of rejection in 6 mo after complete CsA discontinuation (32). Such favorable results were obtained by increasing azathioprine dosage for 1 mo and by enhancing oral prednisone to levels much higher than in our study. Conversely here, we amended the protocol to avoid complete CsA discontinuation, following the recommendation of the Ethical Committee, which eventually translated into a major finding of this study. Thus, because high steroids would offset the benefit of lowering CsA, we adopted extremely low CsA dose in association with the same steroid and azathioprine doses as for the standard control triple drug therapy. Remarkably, lowering CsA dose to a target blood CsA trough in the range of 30 to 70 ng/ml was never associated with acute rejections in the remaining patients during the 3 yr follow-up. This is in agreement with a previous study in kidney recipients with CsA nephropathy who lowered the drug dose to a target CsA trough level of >50 ng/ml without evidence of acute rejection episodes (33).
The predictable impact of maintaining such a low blood level of CsA in the long-term is a slower rate of renal function deterioration and eventual graft loss in respect to the standard CsA regimen (7,8,34,35). Chronic CsA nephropathy is indeed one of the most important recognized causes of chronic renal allograft dysfunction (34,36,37). How to intervene therapeutically is still matter of debate. Studies showed that the tendency to persistent elevation in serum creatinine, despite recommended CsA blood level, can be reversed by progressively reducing CsA dose (38,39). In cases of biopsy-proven CsA nephropathy and renal function impairment, GFR improved after lowering CsA dose (33). Others, however, advise against lowering CsA (31). Here we found that in patients with chronic CsA nephropathy lesions, lowering CsA to very low targets never caused renal function deterioration, as measured by true GFR. RPF was also preserved, at variance with the significant reduction in those who did not modify the regimen. Mechanisms behind the benefit of CsA reduction are unknown. Some degree of renal vasoconstriction occurs in CsA-treated patients (12,40). The preservation of renal function and perfusion after CsA reduction are attributable to reversal of afferent arteriole constriction induced by CsA (40) or possibly stabilization or regression of arteriolar lesions (41,42) in line with second biopsy findings.
The results of analysis of serial biopsies importantly indicate that lowering antirejection drugs did not negatively affect the graft. In fact, patients who discontinued steroids were even protected against severe lesions of chronic allograft nephropathy that instead developed in those on standard immunosuppression over the follow-up. CsA reduction also resulted in stabilization or improvement of tubular and interstitial damage in some patients.
Although the immunosuppressive regimen we have studied, namely CsA, steroid, and azathioprine, is no longer commonly in use at least in United States, the present work can be viewed as a proof of concept that protocol biopsy is a useful methodologic approach to adjusting long-term immunosuppression in kidney transplant recipients late posttransplantation.
In conclusion, per-protocol biopsy more than 1 yr after kidney transplantation, even when baseline graft function is normal, is a safe procedure to guide change of immunosuppressive regimen and to lower the risk of major side effects. Steroid withdrawal in the documented absence of histologic lesions is of considerable advantage and might become a recommended strategy to improve long-term outcome. In patients with chronic CsA nephropathy but normal renal function, complete CsA withdrawal should be avoided because of very high risk of acute rejection episodes. On the other hand, substantial reduction of CsA leading to extremely low CsA trough level has no major detrimental effect on renal function and histology during 3-yr follow-up, while free of rejection episodes and despite no concomitant increase in steroid and azathioprine dose. Conversion of triple immunosuppressive regimen based on protocol biopsy may contribute to improve quality of life of transplant recipients and prolong graft survival.
|
Acknowledgments |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. Lam, N. Partovi, L. S. Ting, and M. H. Ensom Corticosteroid Interactions with Cyclosporine, Tacrolimus, Mycophenolate, and Sirolimus: Fact or Fiction? Ann. Pharmacother., July 1, 2008; 42(7): 1037 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Scholten, A. T. Rowshani, S. Cremers, F. J. Bemelman, M. Eikmans, E. van Kan, M. J. Mallat, S. Florquin, J. Surachno, I. J. ten Berge, et al. Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2622 - 2632. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
HOME
CURRENT ISSUE
ARCHIVES
JASN Express
ONLINE SUBMISSION
AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP |
