Transplant Glomerulopathy: New Clues in the Puzzle of Chronic Allograft Nephropathy?

Abstract

Department of Nephrology and Urology, Istituto ScientificoOspedale Maggiore di Milano, Via Commenda 15, 20122Milano, Italy*Corresponding author: Claudio Ponticelli, ponticelli@policlinico.mi.itChronic allograft nephropathy (CAN) is the leading causeof late kidney allograft failure. A number of alloantigen-dependent and independent mechanisms may be involvedin the pathogenesis of CAN and may operate simultan-eously, making it difficult to recognize the relative roleof a single factor. Even biopsy is of little help in manyinstances, as it frequently shows nonspecific fibrosingchanges. Two exceptions are represented by transplantarteriopathy and transplant glomerulopathy (TGP). In thisissue, Akalin et al. investigated the role of chemokines inTGP and provided new insight into the pathogenesis ofthis clinicopathological entity.The term TGP defines a peculiar pattern of glomerularchanges seen in a number of transplanted kidneys withCAN. Different criteria have been used to define TGP inthe past. This may depend on the fact that TGP mayshow evolving features over time. In an early stage,lesions are focal and segmental. There is a diminishedpatency of the capillary lumina due to a swelling of theendothelial and activation of mesangial cells withmesangial expansion. Later, glomeruli appear enlargedwith microaneurysm formation due to mesangiolysisand partial reduplication of glomerular basement mem-brane. In a more advanced stage, a prominent anddiffuse reduplication of the glomerular basementmembrane is seen, due to electron lucent thickeningof the lamina rara interna and new apposition of base-ment membrane-like material which confer a typicaldouble contour aspect. Immunofluorescence is gener-ally negative or may show nonspecific IgM deposits.Diagnosis may be difficult as it is possible to confuseTGP with membranoproliferative glomerulonephritisor thrombotic microangiopathy. Therefore, immuno-fluorescence, electron microscopy and clinical data areneeded to make a precise diagnosis. TGP is usuallyrecognized late after transplantation and is usually asso-ciated with proteinuria and progressive graft dysfunc-tion. The prognosis is poor. Most patients show anaccelerated graft loss after a diagnosis of TGP ismade. At present there is no evidence that any form oftreatment can reverse the downhill course of TGP.TGP is considered to be a typical feature of late rejec-tion, but its pathogenesis is still undefined. Theoreticallythe same mechanisms responsible for endothelial cellinjury and intimal proliferation of transplant arteriopathymight also be involved in the pathogenesis of TGP.However, the two features are often not associated,nor any correlation between the severity of TGP andthe extent of vascular injury has been found (1).The involvement of humoral immunity has also beensuggested. However, again no correlation has beenfound between TGP and C4d staining in peritubularcapillaries (2), a finding which is now considered to bea reliable marker of antibody-dependent immunologicalactivity (3,4). Finally, TGP is not caused by immune-complex deposition as immunofluorescence is generallynegative.Chemokines are a superfamily of structurally related cyto-kines having chemoattractant properties for leukocytepopulations. Experimental and clinical studies haveshown that chemokines may mediate leukocyte recruit-ment and facilitate dendritic and T-cell trafficking intoheart, liver, and kidney allografts. Thus, the current opinionis that chemokines may play a critical role in the pathogen-esis of rejection. Akalin et al. found that intraglomerularand periglomerular leukocytes in biopsies with TGPshowed in all cases an expression of inducible costimula-tor (ICOS), of the chemokine receptor CXCR3 and of itsligands, monokine induced by interferon gamma (Mig) andinterferon-gamma-induced protein (IP-10). Instead in noneof the control biopsies with allograft nephropathy but with-out TGP were ICOS, chemokines, or their receptorsexpressed. Because Mig and IP-10 attract TH1 lympho-cytes, and ICOS and CXCR3 are expressed on activated Tcells,theinterpretationwasthatinTGPthedonorglomeru-lar antigens trigger an effector T-cell response whichleads to the persistent generation of specific chemokines.In turn, chemokines attract and arm effector cells, whicheventually lead to progressive glomerular damage. Thereport was based on a small group of biopsies and needsto be confirmed by further studies. Nevertheless, thestriking difference between TGP and controls supportsthe hypothesis that chemokines and T cells are deeplyinvolved in the pathogenesis of TGP.