Objectives: Our aim was to determine the clinical significance of borderline lymphocytic infiltrates on indicated renal allograft biopsies in a living related renal transplant setting.
Materials and Methods: The study was conducted at the histopathology department of Sindh Institute of Urology and Transplantation. A retrospective review of 421 renal transplant patients was conducted from October 2007 to September 2008 to identify patients in whom a histologic diagnosis of borderline changes was made on dysfunctional renal allograft biopsies. Demographic, clinical, and laboratory data; biopsy findings; treatments given; and responses to treatment were collected and analyzed. Standard biopsy indications determined the need for graft biopsies. Biopsies were reported according to Banff criteria.
Results: Mean age was 26.92 ± 9.14 years (range, 10-45) for recipients and 38.46 ± 9.16 years (range, 19-50) for donors. Males were predominant among recipients (84.6% vs 15.4%), and females were predominant among donors (57.7% vs 42.3%). The best serum creatinine levels were 1.79 ± 1.15 mg/dL (range, 0.83-6.12). These were achieved after a median of 3 days (interquartile range, 2-7.25). Dysfunctional biopsies exhibiting borderline infiltrates were performed at a median duration of 5.5 days (interquartile range, 3-14.25). Mean serum creatinine at the time of biopsy was 2.34 ± 1.43 mg/dL (range, 1.25-8.25).
The biopsies showed borderline cellular infiltrates (interstitial inflammation 1 [i1] and tubulitis 1 and [t1] lesions). All recipients except one received antirejection treatment (antithymocyte globulin, n = 5; escalation of mycophenolate mofetil dosage, n = 1; pulse steroids, n = 19); all recipients responded with a decline in serum creatinine toward baseline, with a mean serum creatinine of 1.31 ± 0.42 mg/dL (range, 0.40-2.71).
This response was achieved at a median duration of 9.73 ± 5.32 days (range, 1-23) after starting treatment.
Conclusions: The borderline cellular infiltrates on dysfunctional renal allograft biopsies signify evolving phases of acute cellular rejection. These infiltrates responded favorably to antirejection treatment in our setting.
Key words : Banff classification, Cellular infiltrates, Rejection
Renal allograft biopsies play an important role in the diagnosis and treatment of renal transplant recipients. An accurate interpretation of these biopsies is of paramount importance for optimal treatment of these patients.1-3 The Banff classification of renal allograft pathology is widely used for interpreting pathologic lesions and classifying rejection processes.4,5 The Banff classification was formulated in 1991 and was first published in 1993. After a major revision of the classification in 1997, the Banff 1997 classification achieved the status of international benchmark for interpreting renal allograft biopsies. Since 1991, the Banff classification has recognized a category of “borderline changes” in the reporting of renal allograft pathologic lesions. This category exists only in the tubulointerstitial type of rejection. It is used when there is mild to moderate interstitial inflammation but the tubulitis is of a mild degree only and no arteritis is present. The clinical significance of this lesion has been controversial and is largely determined by the clinical features of the case.6-12 Most of the studies on borderline changes have been conducted in deceased donor transplant setups. The implications of this lesion may vary depending on the source of the donor organ.13,14 Since we commonly see such infiltrates in our setting, where the biopsy policies are very aggressive, we set out to determine the prevalence and clinical relevance of borderline lymphocytic infiltrates on dysfunctional renal allograft biopsies in a living related renal transplant setting.
Materials and Methods
The study was conducted at the histopathology department of Sindh Institute of Urology and Transplantation, Karachi, Pakistan. A retrospective review of the case files of 421 renal transplant recipients was conducted from October 2007 to September 2008 to identify patients in whom a histologic diagnosis of borderline changes was made on dysfunctional renal allograft biopsies. Borderline changes were diagnosed when there was a score of < 2 for interstitial inflammation and tubulitis and there was no arteritis, as shown in Figure 1. Patient demographics, clinical and laboratory data, biopsy findings, treatments given, and responses to treatment were collected and analyzed. Standard biopsy indications determined the need for renal allograft biopsies. All biopsies were reported by the same pathologists (MM and SS) according to the Banff criteria.4,5 Written informed consent was obtained from all participants in the study. All of the protocols for the study were performed according to the ethical standards set by the 1975 Declaration of Helsinki and the Declaration of Istanbul on organ trafficking and transplant tourism.
Statistical analysis was performed using Statistical Package for the Social Sciences version 10.0 (SPSS Inc., Chicago, IL, USA). Mean ± standard deviation and median ± interquartile range were used to summarize data.
A total of 377 patients underwent 226 renal allograft biopsies for a sudden and unexplained rise in serum creatinine. Among these 377 patients, rejection was found in 95 biopsies (25%). Among the rejections, 26 biopsies (27.4%) showed borderline changes and these formed the study population for the current report. The main demographic and clinical characteristics of the study population are shown in Table 1. The mean age of recipients was 26.92 ± 9.14 years (range, 10-45) and that of donors was 38.46 ± 9.16 years (range, 19-50). Males were predominant among recipients (84.6% vs 15.4%), and females were predominant among donors (57.7% vs 42.3%).
The best serum creatinine levels were 1.79 ± 1.15 mg/dL (range: 0.83-6.12). These levels were achieved after a median of 3 days (interquartile range, 2-7.25). The dysfunctional biopsies exhibiting borderline infiltrates were performed at a median posttransplant duration of 5.5 days (interquartile range, 3-14.25). The mean serum creatinine level at the time of graft dysfunction and allograft biopsy was 2.34 ± 1.43 mg/dL (range: 1.25-8.25). The biopsies showed borderline cellular infiltrates (interstitial inflammation 1 [i1] and tubulitis 1 [t1] lesions). All except one recipient received antirejection treatment (antithymocyte globulin, n = 5; escalation of mycophenolate mofetil dosage, n = 1; pulse steroids, n = 19). All recipients responded with a decline in serum creatinine toward baseline, with mean serum creatinine of 1.31 ± 0.42 mg/dL (range, 0.40-2.71). This response was achieved at a median duration of 9.73 ± 5.32 days (range, 1-23) after starting treatment. Figure 2 shows the timeline of changes in graft function and the timing of allograft biopsies.
Repeat allograft biopsies were performed within the study period in 14 out of 26 cases. The duration between the index biopsies and the repeat biopsies ranged from 7 days to 10 months.
Among the repeat biopsies, 4 were follow-up biopsies that were performed at 4, 5, 5, and 6 days and showed resolution of the borderline infiltrates.
The remaining 10 biopsies were performed after 1 week to 10 months postindex biopsy and showed other findings, as shown in Table 2. These other findings were most probably unrelated to the borderline infiltrates and represented new pathologic findings.
Renal graft function was well maintained in the whole cohort during short-term follow-up, as indicated by a serum creatinine of 1.49 ± 0.31 mg/dL at 6 months and 1.51 ± 0.34 mg/dL at 1 year.
An accurate histopathologic assessment of renal allograft biopsies is crucial to the treatment of renal transplant recipients because biopsy diagnoses are used to guide treatment strategies. The most widely used system for this is the Banff classification, which grades lesions using consensus definitions and arbitrary thresholds. There are 6 diagnostic categories in the Banff classification, which encompass the entire spectrum of pathologic lesions affecting the graft.4,5 However, because the focus is on the diagnosis and classification of rejection, 3 of the 6 categories are dedicated to the rejection classification. Banff diagnostic category 3 (ie, borderline changes) is the most controversial among all the diagnostic categories of renal allograft pathology. Its reported frequency varies widely and ranges from 46% to 74% on dysfunctional graft biopsies performed at different time points after transplant.1-10 This category is also the most ambiguous from the point of view of treatment strategies for the patient. In fact, this category does not represent a true pathobiological phenomenon. Rather, it is an artificial category of the graft pathology that is created primarily because of varying clinical criteria and timing of renal allograft biopsies. It is well known that the biological process of rejection is a gradual process that builds up slowly and gradually culminates in full-blown rejection. If a biopsy is performed very early during this course, the pathologic lesions will not have reached the threshold of diagnosis of rejection. Hence, there is a need to standardize not only the criteria for the diagnosis and the classification of pathologic lesions but also for clinical indications and timing of biopsies, which vary widely.
The results from our study show that renal allograft biopsies are performed very early in the course of rejection and at a lower level of rise in serum creatinine. In fact, nearly one-third of the biopsies are performed for < 10% rise in serum creatinine. These are the factors that give rise to a higher prevalence of borderline changes in our biopsies. In fact, this rate is comparable to what other major transplant centers have reported.6-10,15-17 We used the clinical course of the graft dysfunction for the definitive diagnosis of rejection, and the majority of these cases behaved as early forms of T-cell–mediated rejection. More recent molecular tests are being used to fine tune the diagnosis of T-cell–mediated rejection and have shown promising results.18-20 It is possible that the incorporation of molecular tests with the light microscopical features in Banff classification will help eliminate this diagnostic category in the future.18-20
The important point in this study is that these borderline changes represent early forms of rejection, rather than some other nonrejection pathologic lesions. There is a need, therefore, for more objective criteria to differentiate borderline rejection from nonrejection borderline lymphocytic infiltrates.11,12
There are limitations in this study. This was a small-scale, single-center study with a short-term follow-up. No protocol biopsies are done and no immunohistochemical or molecular tests were applied. Despite these limitations, we believe that our study highlights the nature of borderline infiltrates on renal allograft biopsies in a living related renal transplant setting.
The borderline cellular infiltrates on dysfunctional renal allograft biopsies signify evolving phases of acute cellular rejection. These infiltrates responded favorably to antirejection treatment in our setting.
Volume : 15
Issue : 1
Pages : 24 - 27
DOI : 10.6002/ect.mesot2016.O7
From the Departments of 1Histopathology, 2Immunology,
3Nephrology, and 4Urology, Sindh Institute of Urology and
Transplantation, Karachi, Pakistan
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Muhammed Mubarak, Professor of Pathology, Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi-74200, Pakistan
Phone: +922 19 921 5752
Figure 1. Borderline Changes on Renal Allograft Biopsy
Figure 2. Timeline of Renal Allograft Biopsy and Graft Functional Changes in 26 Patients With Borderline Changes
Table 1. Main Demographic and Clinical Characteristics of the Study Population
Table 2. Breakdown of Repeat Renal Allograft Biopsy Findings