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EARLY DIAGNOSIS OF CHRONIC ALLOGRAFT NEPHROPATHY BY MEANS OF PROTOCOL BIOPSIES early identification and treatment of CAN. Our current model of CAN also demonstrates why treatment is not a very effective strategy and why prevention of CAN has to be the goal of all transplant units. CAN is a diagnosis that has been arrived at through the pathologist’s microscope, rather than the clinic. Papers from the 1970’s through to the mid 1990’s commonly used the term “chronic rejection” to describe the clinical phenomenon of slowly and inexorably rising serum creatinine. Indeed this term can be found in papers from the past five years still loosely applied to chronic graft failure (15). It is important to understand the difference between the starting points for each of these terminologies and the consequent confusions that apply when one term is used interchangeably with the other. The term “CAN” arose from the Banff series of pathology conferences driven by such pathologists as Kim Solez, Robert Colvin, Michael Mihatsch, Daniel Serón and Lorraine Racusen (1). CAN is thus defined histologically, restricted to the renal allograft and is independent of aetiology (16). The original intent of the definition was to bring some order into the chaotic descriptions that were available for a chronically damaged allograft. Unfortunately there remains some opportunity for confusion since the underlying aetiology may also be discernable in the biopsy specimen, such as calcineurin inhibitor (CNI) nephrotoxicity and through the addition to the diagnostic features of some facets with presumed immunological aetiology. Ample opportunity to confuse has been added by those who describe pre-transplant donor renal biopsies as having CAN –clearly an absurdity. The features of CAN that are identified and scored in the Banff schema are tubular atrophy (Banff: ct) and interstitial fibrosis (Banff: ci). This should not be taken to mean that CAN is comprised of just these two appearances, nor that these are actually the most relevant to physiological, functional or prognostic indicators. It is simply that these two features are the most reliable, diffuse and easily visible changes in the biopsy, not subject to the vagaries of small samples that plague any definition relying on patchy changes in vessels or glomeruli. CAN grading from I to III simply identifies the proportion of the biopsy that is affected by these changes. It is unfortunate that the scoring of the chronic Banff “qualifiers” do not, in the current version, tie in well to the CAN grading. A revised version of the schema, with a name change to chronic sclerosing allograft nephropathy, may help us in the future. At the present time: CAN grade I requires ci1, ct1; CAN grade II requires moderate changes (ci2/ct2, or ci1/ct2, or ci2/ct1); while grade III requires severe changes (ci3/ct3, or ci2/ct3, or ci3/ct2). If there are none of the changes of “chronic rejection” such as vascular changes with disruption of the elastica, inflammatory cells in the fibrotic intima and proliferation of myofibroblasts in the intima, the grade of CAN is qualified with an “a”, but if these changes are present then it is rates “b”. 17
BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL The ground on which we have been able to build models of CAN is thus from histology and not from the clinical environment. Studies of biopsies taken in an attempt to diagnose clinical events are also uselessly misleading since they are biased by the clinical overlay that comes with the decision to undertake the biopsy. It is thus only from protocol biopsy studies that one can really build the conceptual models with which to test therapeutic interventions. Reports of long term protocol renal allograft biopsy series were scarce until the past five years or so. The longest series was published from our group in Sydney (REF JASN 66-79) in which 120 recipients of simultaneous pancreas and kidney transplant recipients were biopsied at 0, 3 and 12 months and then annually thereafter to ten years. Our series, like that from the Mayo Clinic (17) which was predominantly from living donor transplants, started with normal kidneys from young donors and very short cold ischemia times. We had previously published a shorter series of protocol biopsies taken from deceased donor grafts, which thus included the impact of preceding donor disease (9,18), while others have described the different impacts of varied immunosuppressive regimens (19-23). Chronic allograft nephropathy is the final common pathway of different causes of renal allograft damage. That damage may have started in the hypertensive donor or through cold ischaemia and reperfusion injury, through acute rejection, acute or chronic CNI nephrotoxicity and from sub-clinical rejection. It may be possible in a single biopsy to discern the relative influences of some of these factors, but in severe cases the biopsy is as uninformative as the “end stage kidney” that we are familiar with from native renal diseases. Our current working model is shown in Figure 1 and described below. We believe that it provides the foundation for understanding not only CAN, but also the relationships between the histological appearances and the clinical perspectives (2). The new genomic techniques for elucidating changes at the molecular level may also potentially be inculcated into explaining the model and the early evolution of CAN. Subclinical rejection Fibrosis of the kidney occurs in two separate phases (68), two thirds develops quite rapidly during the first year, with a slow and progressive accumulation beyond that time. Interestingly the interstitial fibrosis exceeds the tubular atrophy suggesting that it is related to more than simply the damage of tubules. The two strongest contenders for this effect are ischaemia-reperfusion injury and acute allograft immune response –acute rejection. In the Hannover protocol series of 258 patients (22) biopsied at 6, 12 and 16 weeks, CAN was present in 70 (37%) and absent in 120 at 26 weeks. The significant risk factors for CAN were receiving a deceased donor kidney, long cold ischaemia and acute rejection. In the Westmead series acute tubular necrosis was predictive for CAN and the use 18
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