Fine-Needle Aspiration Biopsy Allows Early Detection of Acute Rejection in Children after Renal Transplantation. Transplantation 2001: 71: 736.

FINE-NEEDLE ASPIRATION BIOPSY—NEW APPLICATION FOR AN OLD TECHNIQUE The most direct way to evaluate events within a transplanted kidney is to sample the graft itself. The most widely used sampling method, and the accepted standard, is the traditional core needle biopsy, which provides a histological snapshot of events at the biopsy site. Until the introduction of the no.18-gauge, spring-loaded biopsy technology for percutaneous biopsies, the standard no.14-gauge hand-held Trucut needle discouraged frequent, repetitive use of core needle biopsy for monitoring purposes. Although the current biopsy technology makes sampling safer, and therefore applicable to more frequent use, complications such as perirenal hemorrhage, obstruction from blood clots in the renal pelvis and perforation of other viscera still provide some limitation to its repetitive use. Core needle biopsy is therefore generally used to clarify the cause of renal dysfunction rather than as a tool for routine monitoring of intrarenal events. Fine needle aspiration biopsy (FNAB) of renal allografts with cytologic rather than histological analysis was popularized in the 1980s by Hayry and von Willebrand (1). This rapid, safe, repeatable, and dependable technique permitted serial monitoring of intrarenal events after transplantation, especially regarding detecting and after the inflammatory white blood cell infiltrates of acute cellular rejection. In efficient units, the entire procedure, including sampling, processing, and interpretation could be completed within 2 hours. The FNAB technique was gaining popularity when the biopsy technique currently used for core needle biopsy was introduced. The biopsy technique rapidly achieved dominance and today, very few units use the FNAB technique. In this issue of Transplantation, Their et al. from Helsinki describe their experience with routine FNAB monitoring in a group of pediatric kidney transplant recipients treated with cyclosporine, azathioprine, and prednisone immunosuppression (2). A total of 984 FNABs were obtained from 78 patients. Aspirates obtained before, during, and after acute rejection were available for analysis. Despite a 57% incidence of acute rejection, no grafts were lost from this cause. More than 90% of acute rejection episodes were completely reversed. The authors conclude that this minimally invasive FNAB sampling technique made an important contribution to the good outcome by helping establish an earlier diagnosis of acute rejection in the usually difficult pediatric transplant population, with only limited need for core needle biopsy. They caution, however, that the FNAB findings “are not completely specific for rejection, and both the cytological and clinical data must be taken into account when the decision of the possible rejection therapy is made.” This caveat, which applies to core needle biopsy as well, was exemplified by eight patients who received treatment for rejection with no immunoactivation on FNAB, and 39 patients with cytological findings of immunoactivation who were not treated for rejection. Clearly, the management of findings from protocol sampling requires a disciplined rather than knee-jerk approach, because of the potential dissociation of graft morphology from clinical findings at any given time. In pediatric renal transplantation, outcomes until recently had not improved to the same degree or at the same rate as in the adult population. Because loss from acute rejection continues to plague the pediatric group, finding a simple, minimally invasive way to monitor intrarenal events without pain or general anesthesia remains a challenging objective. Is FNAB part of the solution? The Helsinki experience would suggest it is. Interestingly, some of the excellent results seen in the FNAB monitored patients may be due to the fact that at least 30% of “rejections” treated were probably identified in a subclinical state, with no increase in creatinine, fever, or other clinical signs of rejection. This parallels the experience of Rush et al. (3) in adults, who found that at least 30% of clinically stable kidney transplant recipients have subclinical rejection noted on protocol core needle biopsies during the early posttransplant months, and that antirejection treatment at diagnosis improves later functional outcome. If the deleterious role of subclinical rejection in the genesis of chronic graft nephropathy and the benefits of its early treatment are verified, FNAB may be a more acceptable sampling or monitoring alternative for clinicians reluctant to do protocol core needle biopsies on clinically “stable” recipients. An interesting question to address is why FNAB is used so infrequently today in so few transplant centers. It is clearly safe for repeated sampling and monitoring. Refinements in sample evaluation give it a sensitivity and specificity of >90% for the diagnosis of acute rejection, and strong concordance with simultaneous core needle biopsies (4). Intra- and interobserver reproducibility for the diagnosis of acute rejection is also acceptable. FNAB can identify acute pyelonephritis, intracellular viral inclusion bodies, the infiltrate of posttransplant lymphoproliferative disorders, graft infarcts, changes suggestive of acute tubular necrosis and cyclosporine nephrotoxicity, and even recurrent glomerulonephritis in the graft (4). It does, however, lack the ability to preserve and display endothelial and other cells from vascular walls. This eliminates its ability to diagnose vascular rejection, which may be present without a significant interstitial infiltrate. And it cannot identify tubulitis. Vasculitis and tubulitis are important components of the now standard Banff histological diagnostic and grading systems for rejection. The convergence of improved core needle biopsy sampling with the spring-loaded biopty technology, the widespread acceptance of the Banff criteria for the histologic diagnosis and grading of rejection, and the generally greater comfort of clinicians with histological diagnostic patterns over evaluation of individual cells seem to explain the diminished importance of FNAB in clinical renal transplantation. Also, FNAB has not proven helpful in chronic graft nephropathy states. The role of FNAB in research, however, cannot be diminished. The need for graft sampling to further characterize the nature of the rejection processes, to tailor treatments and to measure outcomes of interventions will undoubtedly continue. In most cases, FNAB can provide adequate numbers of renal tubular and infiltrating cells to assist in this process. FNAB sampling not only allows for cytomorphological characterization of the different disorders causing graft dysfunction, but it provides sufficient material for flow cytometry, immunophenotyping, and DNA PCR analysis, as well as sufficient sampling material for culture. Oliveira et al. (5) from Portugal have applied a variety of analytic techniques to FNAB specimens to elucidate processes and mechanisms in renal transplants, including culturing the aspirate for assessment of proliferative response of graft infiltrating cells and for cytokines/chemokine analysis, as well as for flow cytometry. In summary, it is not likely that FNAB monitoring will replace the biopsy core needle biopsy technique for routine clinical use. Its unique sampling and diagnostic characteristics, however, make it appropriate for research, and for special situations where a core needle biopsy is less acceptable. These potentially include management of pediatric kidney transplants, as described in this issue of Transplantation, and monitoring patients for subclinical rejection where FNAB may be safer for frequent protocol sampling than contemporary core needle biopsy.

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