Kidney and Liver Transplant - Update and Issues
Case 3 -
Renal Transplant: Chronic Rejection and Chronic Nephropathy
Arthur H. Cohen, Juan Lechago and Cynthia C. Nast
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Chronic changes in the transplanted kidney may be the result of several independent but
sometimes coexisting factors including immunological, hemodynamic, ischemic, toxic, possibly infectious
and others. It should be noted that, although acute rejection generally is reasonably successfully
treated and managed and that short term graft survival is excellent, long-term survival of renal
transplants has not appreciably changed despite the use of more effective anti-rejection therapy. It is
often but not always possible to distinguish one form of injury from another and, therefore, to diagnose
precisely a specific lesion; there are times, however, when specific diagnoses are not possible. For
chronic morphological findings for which a specific diagnosis cannot be made, the non-committal and not
satisfying term chronic allograft or transplant
nephropathy has been advocated.
The most important of the chronic processes is chronic rejection. As with other lesions and disorders
in renal pathology, the definition of chronic rejection requires a contribution of clinical and
morphological features. Chronic rejection is defined typically as a progressive decline in renal
function beginning at least three months following transplantation with characteristic biopsy
(structural) findings. Some of the morphological features, when considered in conjunction with the other
biopsy findings, allow for a specific diagnosis of chronic rejection even in the absence of clinical
Grossly, the kidney has a dense fibrotic adherent capsule. It varies in weight depending
on degree of compensatory hypertrophy, duration and degree of chronic renal insufficiency, presence of
acquired cystic disease, and possible superimposition of acute rejection. This last consideration is
quite real inasmuch as immunosuppression may be reduced or stopped when a decision to remove a
chronically rejected kidney is made thereby initiating acute rejection. The cortical surface may be
diffusely smooth or may have variably sized scars. The cortex and medulla are atrophied. Larger
intrarenal arteries may be easily observed because of prominently thickened walls with narrowed or
Microscopically, there are alterations in all elements. Each will be described separately
with information from light microscopy, immunofluorescence or immunohistochemistry and electron
microscopy as appropriate.
Glomeruli are usually abnormal, with ischemic changes and
complete sclerosis always present. A constellation of changes (v.i.) is
quite characteristic for the lesion known as chronic transplant
glomerulopathy which many investigators consider to be a hallmark of chronic rejection. This,
however, is not present in all chronically rejected kidneys; some investigators report the lesion in
30-50% of these kidneys. The major findings are variable increase in mesangial cells and matrix and
thick capillary walls with double contours. This results in a light microscopic appearance similar to a
membranoproliferative glomerulonephritis type I pattern; however, there are no immune/electron dense
deposits. The second contour is most frequently the result of new subendothelial basement membrane
formation, although peripheral mesangial migration may also be found. Mesangiolysis and microaneurysm
formation are uncommon but impressive when present. In addition, segmental sclerosis, likely a
manifestation of compensatory intracapillary hypertension/hyperfiltration, is not uncommon. Endothelial
cells regularly exhibit diminution or loss of fenestrations. Subendothelial flocculent lucencies are
regularly observed. Similar material may be in the mesangium associated with mesangiolysis. Routine
immunofluorescence may disclose irregular granular IgM and C3 in capillary walls and the mesangium.
Linear fibrin is often in capillary walls. Positive C4d staining of peritubular capillaries has been
identified in a substantial number of kidney biopsies with structural features of chronic rejection.
This suggests that there is active continuing antibody mediated process in chronic rejection. Some
investigators have described C4d in glomeruli in this lesion and have suggested its role in the
pathogenesis of the glomerulopathy. The ultrastructurally defined lesions of peritubular capillary
basement membranes (see below) are thought to be tightly linked to C4d binding in peritubular capillary
The tubules and interstitium are
notable for considerable atrophy and fibrosis, respectively. In extreme instances, there may be
extensive tubular drop-out. Lymphocytes are present in variable numbers. Peritubular capillaries are
reduced in number/density. Some investigators have stressed ultrastructurally defined multi-layering of
peritubular capillary basement membranes, when quantitatively assessed, to be specific for chronic
rejection and a means of distinguishing it from the other chronic lesions. However, this belief is not
universally shared, although only few other disorders have similar structural features.
Arterial abnormalities are constant and are often called chronic allograft arteriopathy. The changes are mainly in the intima and, while
present most prominently in the larger arteries, affect arteries of all sizes. There is marked,
typically concentric, intimal fibrous thickening often with circumferential accumulation of smooth muscle
cells with the appearance of a new but thinner intra-intimal media. Lymphocytes and lipid-containing
monocytes (foam cells) are not uncommon in the intima. These processes result in significant luminal
narrowing or obliteration. Arterioles do not exhibit changes specific to chronic rejection but more
commonly reflect chronic cyclosporine toxicity, hypertension, diabetes mellitus and other factors.
The differential diagnosis of these changes taken together is
very narrow and includes only chronic rejection. On the other hand, the glomerular abnormalities, as
observed by light microscopy only, have a broad differential and include membranoproliferative
glomerulonephritis I (recurrent or de novo), other immune complex diseases, chronic thrombotic
microangiopathy, and focal and segmental glomerulosclerosis. When immunofluorescence and electron
microscopy are added to the tissue examination, one disorder can easily be distinguished from another.
The tubulo-interstitial changes are non-specific and obviously reflect chronic damage of
any type. Whether the ultrastructurally defined peritubular capillary basement membrane lesion is
diagnostic is not clearly settled. At the present time, a greater number of basement membrane layers
appears to provide some indication of chronic rejection.
The arterial changes are virtually diagnostic of chronic rejection. Although
hypertension, aging, etc. may be characterized by intimal fibrosis, the presence of lymphocytes and foam
cells is not a feature of those or other disorders.
The pathogenesis of the glomerulopathy is likely the result of
persistent or repetitive immunologic injury directed at endothelial cells. This may be a consequence of
T-cell and/or antibody origin, very possibly followed by production of matrix-promoting factors such as
TGF-beta and FGF-1. As mentioned earlier, hyperfiltration contributes to the sclerosing lesions.
The tubulointerstitial abnormalities are probably the consequence of chronic ischemia
because of the arterial lesions; in addition, chronic and repetitive immunologic injury to peritubular
capillary endothelium, with either repeated synthesis of basement membrane or destruction and subsequent
loss of peritubular capillaries, may well result in tubular ischemia with atrophy and fibrosis. As in
other scarring processes, TGF-beta activation may be an important contributing factor. Anti-TBM
antibodies, while uncommon, may also contribute to these changes.
Arterial abnormalities appear to be consequent to both alloimmune-dependent and
alloimmune-independent factors. The former are directed at endothelial cells and include T-cells
followed by antibody and are features of acute rejection; it is likely that many of the chronic
morphological abnormalities evolve from earlier immunological events. It should be noted, however, that
chronic arterial lesions may arise without accompanying parenchymal rejection, as evidenced in cardiac
transplants. In addition, non-immunological processes including repetitive deposition and organization
of fibrin-platelet thrombi associated with endothelial loss, and intimal lipid deposition as in
atherosclerosis, may have important roles.
As with chronic damage in native kidneys, chronic rejection may be complicated by acquired
cystic disease; although this is infrequently reported, it is not that uncommon. To date biologically
malignant tumors have not been described.
Because of the relatively common occurrence (3-9%) of de novo membranous
glomerulonephritis in grafts in place for greater than two years, some investigators have not
inappropriately considered this lesion to be a manifestation of chronic rejection. It is postulated that
it is a form of antibody mediated rejection directed at minor histocompatibility antigens likely on
glomerular visceral epithelial cells. The changes may occur in association with chronic transplant
glomerulopathy or alone. Unlike membranous glomerulonephritis in other settings, C3 is absent or of weak
intensity and proteinuria is not universally present.
Chronic changes in the transplanted kidney may also be the result of recurrent disease.
Although many may recur early in the post-transplant period, they do not necessarily become clinically or
pathologically significant until a considerably later time thus presenting pathologically as structural
changes with interstitial fibrosis, tubular atrophy and glomerular sclerosis. Therefore, distinguishing
among the various causes of chronic changes in the transplant often requires the use of
immunofluorescence and electron microscopy for precise diagnosis. In an interesting recent study using
mRNA extraction, Koop and coworkers documented that, in comparison to chronic rejection, chronic
cyclosporine toxicity was characterized by considerably increased lamin in
B2 and TGF-β. As of this writing, confirmatory studies have not been done.
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