Editorial

Transplant Glomerulopathy: New Clues in the Puzzleof Chronic Allograft Nephropathy?

Claudio Ponticelli* and Giovanni Banfi

Department of Nephrology and Urology, Istituto ScientificoOspedale Maggiore di Milano, Via Commenda 15, 20122Milano, Italy*Corresponding author: Claudio Ponticelli, ponticelli@policlinico.mi.it

Chronic allograft nephropathy (CAN) is the leading cause

of late kidney allograft failure. A number of alloantigen-

dependent and independent mechanisms may be involved

in the pathogenesis of CAN and may operate simultan-

eously, making it difficult to recognize the relative role

of a single factor. Even biopsy is of little help in many

instances, as it frequently shows nonspecific fibrosing

changes. Two exceptions are represented by transplant

arteriopathy and transplant glomerulopathy (TGP). In this

issue, Akalin et al. investigated the role of chemokines in

TGP and provided new insight into the pathogenesis of

this clinicopathological entity.

The term TGP defines a peculiar pattern of glomerular

changes seen in a number of transplanted kidneys with

CAN. Different criteria have been used to define TGP in

the past. This may depend on the fact that TGP may

show evolving features over time. In an early stage,

lesions are focal and segmental. There is a diminished

patency of the capillary lumina due to a swelling of the

endothelial and activation of mesangial cells with

mesangial expansion. Later, glomeruli appear enlarged

with microaneurysm formation due to mesangiolysis

and partial reduplication of glomerular basement mem-

brane. In a more advanced stage, a prominent and

diffuse reduplication of the glomerular basement

membrane is seen, due to electron lucent thickening

of the lamina rara interna and new apposition of base-

ment membrane-like material which confer a typical

double contour aspect. Immunofluorescence is gener-

ally negative or may show nonspecific IgM deposits.

Diagnosis may be difficult as it is possible to confuse

TGP with membranoproliferative glomerulonephritis

or thrombotic microangiopathy. Therefore, immuno-

fluorescence, electron microscopy and clinical data are

needed to make a precise diagnosis. TGP is usually

recognized late after transplantation and is usually asso-

ciated with proteinuria and progressive graft dysfunc-

tion. The prognosis is poor. Most patients show an

accelerated graft loss after a diagnosis of TGP is

made. At present there is no evidence that any form of

treatment 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. Theoretically

the same mechanisms responsible for endothelial cell

injury and intimal proliferation of transplant arteriopathy

might also be involved in the pathogenesis of TGP.

However, the two features are often not associated,

nor any correlation between the severity of TGP and

the extent of vascular injury has been found (1).

The involvement of humoral immunity has also been

suggested. However, again no correlation has been

found between TGP and C4d staining in peritubular

capillaries (2), a finding which is now considered to be

a reliable marker of antibody-dependent immunological

activity (3,4). Finally, TGP is not caused by immune-

complex deposition as immunofluorescence is generally

negative.

Chemokines are a superfamily of structurally related cyto-

kines having chemoattractant properties for leukocyte

populations. Experimental and clinical studies have

shown that chemokines may mediate leukocyte recruit-

ment and facilitate dendritic and T-cell trafficking into

heart, liver, and kidney allografts. Thus, the current opinion

is that chemokines may play a critical role in the pathogen-

esis of rejection. Akalin et al. found that intraglomerular

and periglomerular leukocytes in biopsies with TGP

showed in all cases an expression of inducible costimula-

tor (ICOS), of the chemokine receptor CXCR3 and of its

ligands, monokine induced by interferon gamma (Mig) and

interferon-gamma-induced protein (IP-10). Instead in none

of the control biopsies with allograft nephropathy but with-

out TGP were ICOS, chemokines, or their receptors

expressed. Because Mig and IP-10 attract TH1 lympho-

cytes, and ICOS and CXCR3 are expressed on activated T

cells, the interpretation was that in TGP the donor glomeru-

lar antigens trigger an effector T-cell response which

leads to the persistent generation of specific chemokines.

In turn, chemokines attract and arm effector cells, which

eventually lead to progressive glomerular damage. The

report was based on a small group of biopsies and needs

to be confirmed by further studies. Nevertheless, the

striking difference between TGP and controls supports

the hypothesis that chemokines and T cells are deeply

involved in the pathogenesis of TGP.

American Journal of Transplantation 2003; 3: 1043–1044 Copyright # Blackwell Munksgaard 2003Blackwell Munksgaard

ISSN 1600-6135

1043

In conclusion, the study of Akalin et al. not only sheds some

light on the pathogenesis of TGP but also outlines the role of

chemokines in grafts with deteriorating graft function, a role

already supported by numerous experimental and clinical

studies. It is now ever more evident that distinct effector

pathways are operating in rejection. These pathways may

eventually converge in determining graft dysfunction (5).

Their deleterious effect can be further potentiated by non-

immunological mechanisms that are often involved in

chronic allograft nephropathy. At present we do not have

any effective therapy for TGP. In view of the potential role of

chemokines in driving T cell responses, strategies based on

the use of chemokine and/or chemokine receptor antag-

onists could be promising. However, further studies are

needed to identify which are the key players among the

numerous chemokines and chemokine receptors in order

to better target future therapeutical interventions.

References

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glomerulopathy as a cause of late graft loss. Am J Kidney Dis

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2. Nickeleit V, Zeiler M, Gudat F, Thiel G, Mihatsch MJ. Detection of

the complement degradation product C4d in renal allografts: Diag-

nostic and therapeutic indications. J Am Soc Nephrol 2002; 13:

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3. Mauiyyedi S, Della Pelle P, Saidman S et al. Chronic humoral

rejection: Identification of antibody-mediated chronic renal allo-

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Ponticelli and Banfi

1044 American Journal of Transplantation 2003; 3: 1043–1044