Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
Correspondence and offprint requests to: L. C. Paul, Department of Nephrology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Introduction
Chronic allograft nephropathy (CAN) is characterized by excessive tissue fibrosis and sclerosis, resulting in the disruption of the tissue architecture (Figure 1). The common thread of transplants with CAN is that they all have undergone previous tissue injury, and recent experimental data suggest that the excessive fibrosis results from impaired repair from injury.
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Only one kidney is transplanted and is usually exposed to several different forms of injury that may result in further reduction in renal mass such as brain-death injury [1], ischaemiareperfusion injury, prolonged cold storage, acute rejection episodes, and chronic exposure to nephrotoxic drugs. Reduction in renal mass initiates a number of changes in the remaining nephrons such as increased glomerular blood flow and pressure, and increased glomerular permeability for macromolecules, amongst others. Rat kidneys with CAN indeed have glomerular hypertension, and lowering of the glomerular pressure results in improved graft survival, decreased proteinuria, and preservation of structure [2]. However, similar degrees of glomerular hypertension do not result in CAN in syngeneic grafts within this time frame and glomerular hypertension is therefore a progression factor, not sufficient to explain CAN. Besides haemodynamics, when the glomerular permselective property is lost, increased filtration of macromolecules results in the delivery of abnormal amounts of protein in the tubular filtrate which may cause further damage of the nephron.
The normal tissue response to injury
Tissue injury results in tissue activation and damage, followed by a stereotypic inflammatory response characterized by the influx of mononuclear cells, proliferation of (myo)fibroblasts, deposition and degradation of extracellular matrix material, and scar formation. Interstitial fibroblasts cultured from diseased kidneys synthesize more collagen than normal renal fibroblasts and both interstitial macrophages and renal tubular epithelial cells have the potential to contribute to intrarenal collagen deposition. Moreover, locally produced inhibitors of metalloproteases such as TIMP-1,-2,-3 inhibit matrix-degrading enzymes, which augments the net scar formation [3]. The process of scar formation is to a large extent under the control of a myriad of cytokines, enzymes, and growth factors also produced by inflammatory and activated graft parenchymal cells.
Hypothesis to explain chronic allograft nephropathy
Chronic rejection theory
Although acute rejection is a strong risk factor for CAN, it seems unlikely that CAN is simply the end result of one or more acute rejection episodes. The decreased incidence and severity of acute rejection episodes observed after the introduction of cyclosporin and mycophenolate mofetil has not had a discernible effect on the rate of late graft loss. Moreover, we recently showed that the risk factor profile for acute rejection is different from that of CAN. However, immunohistochemistry of kidney grafts with CAN shows enhanced expression of cell adhesion molecules, together with tissue invasion with macrophages and T cells, with or without immunoglobulin and complement deposits, consistent with immune-mediated inflammation. Other features supporting an immune pathogenesis include the demonstration that pretransplant immunization with donor antigens accelerates the process, whereas manipulations aimed at the induction of immune tolerance inhibit CAN. Finally, animals with a disruption of either their B cell lineage, their CD4-positive cells, or their macrophages do not develop graft vasculopathy, a form of chronic rejection in isolated vessel transplants.
If CAN is an immune-mediated entity, in what way is it different from acute rejection? Are the differences related to the intensity or the specificity of the immune reactions involved or is the tissue in CAN more resistant to injury? In acute rejection, the bulk of the immune response is directed to donor MHC gene products, whereas the target antigens in CAN have not been defined to any great extent. However, lymphocytes from patients with chronic heart graft rejection react in vitro variably with different donor class II HLA antigen peptides, suggesting that incompatible MHC molecules are also the target in CAN. On the other hand, in a rat kidney transplant model of CAN we found antibody formation against cryptic organ-specific antigens of the glomerular and tubular basement membranes and glomerular mesangial cells, suggesting organ specificity of the response. Thus, it is possible that a relatively low-grade immune reaction against either the classical HLA antigens or against cryptic antigens exposed during previous tissue damage results in chronic inflammation in which a variety of cytokines are produced that control the synthesis of extracellular matrix production and/or its degradation, resulting in excessive fibrosis.
Cytokine excess theory
Repetitive tissue injury over a short period of time results in excessive production of cytokines that may drive the excessive fibrosis of CAN. The role of IFN- in the pathogenesis of graft vasculopathy is illustrated using neutralizing anti-IFN-
monoclonal antibodies or IFN-
knock-out mice [4]. Cytokines can potentially explain the interaction of infections and CAN [5]. TGF-ß has received much attention as a cytokine that plays a role in extracellular matrix production and degradation, and genotypically high TGF-ß producers seem at increased risk of losing their grafts late after transplantation.
We recently demonstrated that rats with CAN produce antibodies against various, as yet only partly characterized, molecules produced by activated graft cells such as biglycan and decorin [6], compounds that bind and inactivate TGF-ß and stimulate the release of matrix metalloproteinase collagenases by fibroblasts. It is conceivable that such antibodies bind to and inactivate biglycan and decorin in vivo, resulting in less TGF-ß binding molecules, decreased production of collagenases, and impaired fibrillogenesis. The role of decorin in limiting glomerular sclerosis has been illustrated in a rat model of mesangial glomerulonephritis [7].
Interference in the tissue repair following injury
Individuals with CAN or chronic rejection of other organs often produce antibodies against molecules involved in tissue repair following injury. Animals with chronic heart graft rejection mount an antibody response to heat-shock proteins, proteins made by cells exposed to inflammation, ischaemia, infections, and acute rejection episodes [8]. Heat-shock proteins mediate the assembly, folding, and translocation of intracellular polypeptides and protect against their degradation and interaction with receptors, and it is conceivable that antibodies to these molecules interfere with their function.
In rats with CAN, we recently found antibodies not only to biglycan and decorin, but also against mesangial cell focal adhesion plaques. Such antibodies could disrupt important signalling molecules associated with focal adhesion complexes and result in increased cell proliferation and matrix formation. Similarly, the antibodies against biglycan and decorin [6] could interfere with the function of these molecules in the regulation of proteolytic enzyme activity.
Loss of supporting extracellular matrix architecture
Another possibility to explain the excessive fibrosis of CAN is that the many forms of tissue damage incurred by such grafts result in an irreversible disruption of the three-dimensional extracellular matrix structure which, in turn, results in interstitial fibrosis. Whereas blood vessels can regenerate after tissue damage, renal tubular cells will undergo integrin-dependent apoptosis [9] or perhaps transdifferentiate to fibroblasts if they lose contact with the tubular basement membrane. Fibrosis may result to fill in the tissue space not occupied by parenchymal tissue.
Premature senescence theory
Somatic cells in culture are limited in the number of cell divisions they can undergo, a phenomenon referred to as the Hayflick limit. After this finite number of divisions, they become senescent and irreversibly shut down a number of processes such as replication and energy generation. The multitude of stresses that act on graft cells may lead to their premature senescence [10] and consequent failure to exert their regulatory influence over a variety of functions such as tissue repair after injury. Thus, according to this hypothesis fibrosis arises from an exhaustion of graft cells after multiple stresses.
Conclusion
CAN emerges in transplants that have undergone previous damage. The excessive fibrosis characteristic of CAN may result from persistent allo- or autoimmune responses against cryptic graft antigens, antibodies against molecules that play a role in tissue repair mechanisms, apoptosis as a result of lack of survival signals, or the accelerated senescence of graft parenchymal cells after multiple stresses.
References
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