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"Protocol biopsies as routine management of kidney transplant recipients"

Daniel R. Salomon, M.D.

Associate Professor.
Director, Center for Organ and Cell Transplantation.
Department of Molecular and Experimental Medicine
'The Scripps Research Institute'. La Jolla, CA. USA


The thesis is that a protocol-driven kidney transplant biopsy in a patient with essentially stable renal graft function will yield a result directing immunosuppressive therapy and enhance long term transplant survival and function. While I strongly support continued research in this area, I do not think that this premise has been proven or sufficiently refined to be ready for general implementation. A biopsy-based treatment strategy is both invasive and expensive, but even more critically, requires a significant intensification of baseline immunosuppression for those patients triggering the treatment criteria. Thus, I will argue that the burden of proof still remains on us.

Let me begin by stipulating that the immunological underpinnings of the thesis are soundly based on work in both experimental animal models and clinical practice. Renal transplant function is an inadequate measure of ongoing tissue injury due to rejection. The kidney's ability to hypertrophy and compensate for loss of functioning nephrons is one mechanistic explanation for the disparity between measured function and ongoing tissue damage. Certainly in many patients with chronic rejection, by the time we become aware of renal dysfunction the biopsy presents extensive interstitial and vascular injury and fibrosis. Moreover, a series of publications from Rush and colleagues have provided good evidence that protocol biopsies can indeed reveal histological changes consistent with acute and/or chronic rejection in patients with stable and by clinical standards ostensibly "normal" renal transplant function.

The fact is that all immunosuppression is imperfect and thus, essentially all transplants generate an alloimmune response. So how do we interpret histological criteria for rejection in a protocol biopsy of a transplant with stable function when we admit that all transplants will generate an immune response? In other words, theoretically, a biopsy at some early point post transplant must show this immune response. Indeed, most of our current paradigms for the induction and maintenance of tolerance require an immune response. Thus, we also have to consider the possibility that short-term treatment of acute immune responses might alter long-term allograft survival or limit our opportunities to reduce immunosuppression later. Clearly, the simple presence of T cells, B cells and/or macrophages is not sufficient to conclude rejection is present and requires treatment. Can we make a distinction based on time post transplant? For example, an immune response at 3 weeks might be "normal" but at 12 weeks be indicative of insufficient immunosuppression? Perhaps adding tissue injury criteria to the equation would help though a number of renal injury mechanisms are operating in most transplant patients including drug toxicities, underlying diseases such as diabetes and acquired pathologies such as hypertension and compensatory hyperfiltration. Of course, all inflammatory cell infiltrates are not equivalent. Thus, many groups have suggested use of various markers to identify T cell subsets, cell activation markers and more recently PCR-based identification of proinflammatory transcripts in tissue or urine5, or novel technologies such as urine spectroscopy.

I remain uncertain about exactly what proponents of protocol biopsies are planning for general implementation. Particularly, if the objective is also to detect subclinical chronic rejection, is the process of protocol biopsies intended to extend to the lifetime of the transplant? If so, what is the optimal biopsy timing and frequency in patients over one year post transplant? Is it going to be useful to track changes in serial protocol biopsies before making an intervention or will decisions be based on a single biopsy result? How can an iterative analysis of serial biopsies be done in a standardized fashion? More importantly, will biopsies done years post transplant consistently provide enough warning of underlying acute rejection that treatment will prevent or at least delay impending chronic rejection?

Alternatively, the argument could be that the future of a renal allograft is "written" in the first year and that confines the universe of time for protocol biopsies. Again, I find this a very interesting and important hypothesis. Our view of these issues is that an optimal result would be that protocol transplant biopsies would only be used sparingly if at all. The key is to determine if we can use PBL gene and protein expression signatures instead.

Finally, much evidence suggests that chronic allograft nephropathy is a complex mix of renal injury mechanisms. If we set aside the underlying acute rejection hypothesis for a moment, it must be proven that chronic allograft nephropathy detected in protocol biopsies provides an indication of a therapy-responsive injury. That will also require establishing the window of time post transplant within which such a conclusion is correct. In other words, chronic allograft nephropathy histology identified five years post transplant is rarely therapy-responsive. Moreover, many would argue that the underlying mechanisms are probably very different than what is happening in the first year regardless of the similar histology.

Another objective of genomic studies is to gain some mechanistic insights into the nature of chronic allograft nephropathy defined histologically in the first year as compared to that discovered relatively later. Thus, we will be able to compare gene expression profiles from protocol biopsies done in the first 3 to 6 months that show early chronic changes by biopsy to those done more than a year post transplant with clearly documented increasing creatinine.

It is interesting to return to the thought that newer immunosuppressive drug regimes have significantly reduced the incidence of acute rejection but had much less impact on long term graft survival. This point was also raised in one of the studies by Rush et al. where they suggest that despite the reduction in clinical acute rejection with newer drug regimes there is not a parallel decrease in the subclinical acute rejection detectable by protocol biopsy. Of course, the standard practice remains to steadily reduce immunosuppression as a function of time post transplant such that levels of immunosuppression typically used at one year would never be considered adequate to prevent acute rejection at one month. This is often even more the case with the newer agents where the thinking has been that because these agents are more "powerful" we can now discontinue steroids or avoid long-term immunosuppressive complications by reducing or stopping key drugs after 6 months without rejection. I have never been comfortable with this logic in the context of my belief that maintaining adequate long-term immunosuppression is important and given the fact that we still do not have a "test" to measure the adequacy of immunosuppressive therapy.

In conclusion, it is probable that protocol biopsies in a subset of kidney transplant patients with normal and stable renal function will reveal evidence of a therapy-responsive and subclinical acute rejection. Ultimately the evidence must prove that preemptive therapy based on a protocol biopsy actually improves long-term graft survival and function significantly. The possibilities of integrating the latest technologies for molecular diagnosis of rejection, particularly validating the use of PBL, must also be considered and compared to the biopsy, alone, for utility and predictive value.

Our strategy for this Program Project will be to take the first step by establishing an extensive data set for gene and protein expression signatures for protocol biopsies and PBL sampled simultaneously. These signatures can then be compared to the acute rejection and chronic allograft nephropathy signatures we will develop in parallel. In other words, even if a protocol biopsy can predict long-term graft function or survival, if minimally invasive alternatives can be developed with equal utility than they will be preferred. Nonetheless, the clinical validation of such molecular approaches will owe much to the parallel biopsy material. If so, the protocol biopsy will take its place in history as the procedure that allowed validation of these preferred strategies.