Untitled - Roche Trasplantes

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EARLY DIAGNOSIS OF CHRONIC ALLOGRAFT NEPHROPATHY BY MEANS OF PROTOCOL BIOPSIES long term cyclosporine dosage with a cut off point at a maintenance dose of about 5 mg/ kg/day. The histological appearance that is classically described is of a nodular hyaline change in the wall of renal arterioles (14). In our data, however, this classical change often gave way to more diffuse change with narrowing of the lumen and evidence of glomerular ischaemia. The question thus arises as to whether the arteriolar change may be associated with hypertension or with diabetes in our series. We were able to dispel these two possibilities since treated hypertension succeeded the appearance of arteriolar hyalinosis and did not preceed it as would be expected if it had a role in aetiology, also 60% of hypertensive and 68% of normotensive patients had arteriolar changes. With respect to the possibility of an effect from diabetes, the simultaneous glucose tolerance test performed with each protocol biopsy showed identical glucose handling in those with and those without arteriolar changes (38). Glomerular disease The final pathway for damage to the nephron is exhibited through glomerulosclerosis, with which irreversible loss of glomerular and nephron function occurs. Glomerular filtration rate is also closely linked to the glomerular sclerosis, especially as the number of functioning nephrons falls and glomerular hyperfiltration capacity is exceeded. There are at least three different mechanisms of destruction and pathologies that can be discerned in transplant glomeruli. Recurrent glomerulonephritis Occurs at different frequencies in different diseases and may account for a significant number of graft failures, such as in focal and segmental glomerular sclerosis (FSGS), or be essentially irrelevant such as in systemic lupus erythematosus (SLE) (15). No more will be said here about recurrent disease except to note that an increase in proteinuria by >500 mg/day or an absolute excretion rate of >1,500 mg/day are a reliable guide to the need for a diagnosis of the glomerular pathology (39), except possibly in patients treated with sirolimus or everolimus. Chronic transplant glomerulopathy In which the earliest signs, seen on electron microscopy include splitting of the basement membrane. This may be associated with the deposition of C4d and chronic antibody mediated damage to the glomerulus (40). It has been well accepted since the 1960’s that antibody to HLA mediates hyperacute and forms of acute rejection. Transplant glomerulopathy was recognised as early as 1963 with enlarged glomeruli, mesangial matrix expansion, changes in mesangial cells and splitting of both the glomerular and peritubular basement membranes (41). Perhaps lulled into a false sense of security by the improvement in crossmatching techniques, or perhaps by the confounding factors sur- 21
BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL rounding the presence of anti-HLA antibody at the time of and subsequent to chronic allograft failure, it has taken many years to piece together the events that surround chronic humoral rejection. The turning point has come with the development of reliable techniques to detect the complement component C4d on the membrane of endothelial cells in the allograft and engagement with the Banff schema (42). Anti-HLA antibody is now known to predict a poor long term outcome (43) and the immune consequence of antibody binding to complement on the endothelial cell surface to preceed transplant glomerulopathy (44). Experimental evidence is now also linking these phenomena perhaps explaining one of the underlying mechanisms for vascular disease in the allograft (45). The recent demonstration of antibody to agrin –a component of the glomerular basement membrane– may explain the poor correlations between anti-HLA antibody and glomerulopathy (46). Transplant glomerulopathy is clearly identified as a cause for long term graft loss (47). Ischaemic glomerular sclerosis Associated with other features of chronic allograft nephropathy, seen progressively from three or four years post-transplantation (48). In the early post-transplant period glomerular loss is associated with generalised ischaemic damage but is quite restricted in extent, at least in younger donors. The later and more significant phase of glomerular loss follows as a consequence of earlier interstitial fibrosis and arteriolar hyalinosis (48). The severity of interstitial fibrosis at one year correlated with the severity of glomerulosclerosis at four and five years, but even grafts with no interstitial fibrosis eventually developed glomerulosclerosis. A second factor influencing glomerular destruction was shown to be the severity of arteriolar hyalinosis, with substantial increases in the percentage of sclerosed glomeruli for each grade increase in Banff designated arteriolar hyalinosis. These factors are familiar from prognostic studies in native renal diseases such as IgA nephropathy and it should come as little surprise to see the influence apparent in transplanted kidneys. Thus glomerulosclerosis is associated with both the results of acute and untreated subclinical rejection, perhaps accounting for the correlations between chronic graft loss and early acute rejection noted in the 1980’s and 1990’s, as well as with indices of CNI nephrotoxicity, especially arteriolar hyalinosis. Prevalence of chronic allograft nephropathy The prevalence of CAN may only be determined from protocol biopsy of unselected patients. All studies that report the prevalence of CAN based upon functional indices or selected histology driven by clinical indications dramatically underestimate the true prevalence. There is no doubt that the prevalence of CAN depends upon many factors including the donor age, indices of ischaemia and rejection, and upon the immunosuppression used. One controlled study of cyclosporine compared to tacrolimus showed a prevalence of CAN at two years to be 72.3% and 62.0% at two years respectively (19). The 22
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