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Vol. 28. Issue. 4.August 2008
Pages 361-473
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Chronic renal graft disease
Patología crónica del injerto renal
Eduardo Vázquez Martula
a Servicio Anatomía Patológica, Hospital Universitario Juan Canalejo La Coruña, La Coruña, España,
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El fracaso crónico de la función del injerto es multifactorial siendo una de las principales razones de pérdida irreversible de la función renal. Existen causas secundarias a mecanismos etiopatogénicos inmunológicos y no inmunológicos. La enfermedad vascular del donante y la nefrotoxicidad crónica por anticalcinueurínicos hegemonizan los mecanismos no inmunológicos con una repercusión histopatológica consistente en importante hialinosis arteriolar y glomeroesclerosis. La estrecha y confirmada relación entre patología crónica vascular del donante y mala función inicial y tardía del injerto son razones que defienden la realización de la biopsia del riñón donante. La hialinosis arteriolar es una característica histopatológica aunque no específica, que indica nefrotoxicidad crónica. Entre los mecanismos inmunológicos que últimamente adquieren gran relevancia debemos considerar el rechazo humoral mediado por anticuerpos antidonante como principal causante de la pérdida de función y que se manifiesta histológicamente en una glomerulopatía del trasplante, multilaminación de la membrana basal del capilar peritubular, y en la vasculopatía crónica. El depósito difuso de C4d en los capilares peritubulares confirman este mecanismo etiopatogénico. La población celular inflamatoria intersticial sobre todo la presencia de macrófagos y células plasmáticas tienen un significado pronóstico. Se revisan las principales causas etiopatogénicas más importantes del fracaso crónico junto con las características histopatológicas con actualización bibliográfica.
Chronic graft nephropathy (CGN) has been conceptually defined as a progressive kidney function impairment unrelated to discontinuation of immunosuppressive treatment, disease recurrence, and vascular or urological complications. 1 The current decrease in the incidence of acute rejection is one of the reasons explaining that CGN is the second leading cause of graft loss, the first cause being patient death.2 Fifty percent of patients lose the graft at 5 years.3 The search for the main etiopathogenetic mechanisms, the detection of predictive histopathological lesions, and a better understanding of prognostic criteria are the main current discussion factors.4-6
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Chronic graft nephropathy (CGN) has been conceptually defined as a progressive kidney function impairment unrelated to discontinuation of immunosuppressive treatment, disease recurrence, and vascular or urological complications. 1 The current decrease in the incidence of acute rejection is one of the reasons explaining that CGN is the second leading cause of graft loss, the first cause being patient death.2 Fifty percent of patients lose the graft at 5 years.3 The search for the main etiopathogenetic mechanisms, the detection of predictive histopathological lesions, and a better understanding of prognostic criteria are the main current discussion factors.4-6

Since the 8th Banff conference held in Edmonton (Canada) in 2005,7 a consensus was reached by clinical and

pathologists not to use the term CGN as a diagnostic term because its generic use conceals other multiple

immune or non-immune causes,5,8 preventing a more specific diagnosis and, thus, appropriate treatment. The concept of chronic graft disease secondary to an immune mechanism should therefore be distinguished from those

other chronic diseases unrelated to an immune process. Among these diseases, particular mention should be made

of high blood pressure, chronic toxicity, obstruction, reflux, and/or bacterial chronic interstitial nephritis, as well as viral interstitial nephritis.7 This multiplicity of causes with different but imbricate or overlapped etiopathogenetic

mechanisms is one of the main difficulties for making an adequate histopathological study and finding clinical correlations.


The prior concept of CGN, as modified in Banff 2005,7 consists of slowly progressive functional impairment of the

graft whose histopathological substrate is characterized by interstitial fibrosis, tubular atrophy, arteriolar hyaline disease, and glomerulosclerosis. It should be reminded that this concept is fully descriptive and non-specific, because all these histopathological characteristics suggesting chronicity are common to any chronic renal condition in which the proportion of glomerular sclerosis, fibrosis, and tubular atrophy is also related to the degree of renal failure, irreversibility of the process, and therefore a poorer prognosis. In order to establish a clinical correlation and suggest therapeutic schemes, a search for the etiopathogenetic mechanisms involved is required.

Correlation between histopathological damage and prognosis has led since the 90s to the search for objective and reproducible parameters, in which special mention should be made to two protocols or study groups, Banff7 and the CADI system,9 pursuing a same objective, namely quantification of different histopathological parameters of chronicity, including glomerular disease, grade and extent of interstitial fibrosis, tubular atrophy, and vascular lesion. Three grades with a clinical correlation are classified based on this methodology, with grade III cases having a poorer prognosis (table I).

Despite these diagnostic guidelines, however, in the attempts made to ascertain the interobserver degree of specificity and reproducibility, kappa indices in these biopsies have been very low, less than 0.40.10 This fact could be explained by multiple reasons, including inconsistent interobserver experience, the negative role of inconsistent

quality and representativeness of the biopsy, overlapping of different diseases, particularly at vascular level, and

finally, absence of morphometric studies limiting a significant subjectivity burden on observers.11

It should be noted that the chronic graft phase is the evolutionary product of a dynamic biological fact in which

intercurrent immune and non-immune factors, such as infectious, toxic, and ischaemic factors making assessment

of each patient difficult may coincide and coexist. As already discussed by Furness,12 paradoxically «¿ we may

have abundant data but a limited understanding of what is happening in the patient».

However, it has been documented that a severe grade of chronicity (Banff¿s grade III) with extensive interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and a high percentage of glomerulosclerosis has an adverse influence on graft prognosis, with a very low 10-year survival. Only in 57.9% of grade II cases graft survival was longer than 10 years with a significant p value (p < 0.01), By contrast, low chronicity rates involving mild atrophy and interstitial fibrosis and no vascular disease were associated to 10-year survival of more than 80% of grafts.13

It has been recommended to include among histopathological parameters to be quantified in the biopsy in chronic

stages the concept of chronic «active» nephropathy, encompassing the coexistence of focal or diffuse subcapsular or perivascular interstitial inflammatory infiltrates and vascular disease with intimal lesion.7,14 When the prognostic impact is assessed, it is important to distinguish this active phase from the inactive phase, characterized by interstitial fibrosis, tubular atrophy, vascular sclerosis, and glomerular sclerosis only. This information should therefore be included in the pathological report for better clinical information.

This information would however be inadequate if, when assessing biopsy diagnostic criteria, other significant and

controversial factors related to graft prognosis in this evolutionary period are not considered.

¿ Donor kidney disease secondary to advanced age, arteriosclerosis, diabetes, or hypertension.

¿ Subclinical rejection demonstrated by the protocol biopsy.

¿ Relationship to antibody-mediated humoral rejection.

¿ Cell type of inflammatory infiltrate and/or cell subpopulations.

¿ Calcineurin inhibitor-induced chronic nephrotoxicity.

¿ Relationship between transplant glomerulopathy, chronic vascular disease, and immune mechanism.


The social pressure exerted by the long waiting lists of patients pending transplantation has led in recent years to the use of less strict criteria for donor selection. Patients over 60 years of age, with diabetes or hypertension, and kidneys from people dying from a cerebrovascular accident (CVA) and in asystole with warm ischaemia are currently being accepted as donors. However, it has been documented that a history of hypertension, smoking, death from CVA, serum creatinine higher than 150 mL/dL, asystole, and atherosclerotic vascular disease together with very prolonged cold ischaemia has an impact on both poor early function and predisposition to graft acute rejection and chronic failure.15-18

These wider donor selection criteria make it advisable to perform a biopsy before implantation to ascertain the

histological status of the graft.19 Such biopsy has been shown to be useful and to be associated with a better prognosis as compared to groups where no prior biopsy was performed.20 It is generally accepted that greater than 20% glomerulosclerosis, diffuse and concentric arteriolar hyalinosis, and a significant interstitial fibrosis would mark the limit to contraindicate such grafts, not only because of the poor early function and increased morbidity, but also because of the great probability of development of chronic graft disease. 21-23 An additional significant reason for requesting a donor kidney biopsy is to facilitate subsequent assessment of the condition during the

transplant course.

Thus, the earliest damage that may be seen in the first graft biopsy, and that should be histologically assessed, is a

damage, either vascular, tubulointerstitial or glomerular, «inherited» from the donor.

In a study conducted on our prior patients where 66 cases of CGN, with biopsy assessment after the sixth posttransplant month were reviewed, lesions characterizing chronic disease, such as fibrosis and tubular atrophy,

were related to grafts with no initial function and with a higher percentage of glomerulosclerosis.24


The possibility of knowing the early lesion stages at times when the pathological process has not reached an irreversible level has been and continues to be the main objective for indicating protocol biopsies that allow us for

detecting in sufficient advance a given histopathological lesion and monitoring its course and response to treatment.

Protocol biopsies performed in patients with stable function have been shown to allow for detecting subclinical rejections that may be treated, as well as the presence of «tubulitis», fibrosis, and vascular disease in biopsies from

patients with no kidney function impairment.25,26 Some series where protocol biopsies were performed found

rejection criteria in up to 30% of patients with stable kidney function.27 Performance of these biopsies has shown a relationship of several histopathological parameters such as interstitial fibrosis, glomerulosclerosis, and mononuclear infiltrate with progressive kidney function impairment.28 Protocol biopsies also appear to have shown a direct relationship of recurrent rejection episodes, as well as acute rejection after the fourth month, with development of chronic nephropathy.29

However, histopathological assessment may be difficult in these early stages because minimal lesions and/or

lesions classified as borderline, usually focal in character, with little histopathological impact, of uncertain significance, and even with different response to treatment are more commonly seen.30,31 This limits the validity of the results, which together with increased costs and ethical problems, are the factors argued by some authors to advise against performance of these biopsies.32


Together with arteriolar hyalinosis, a sign of chronicity and poor graft evolution, 13 CGVD continues to be an objective and specific histological marker of chronic rejection mediated by an immune mechanism.33 CGVD has traditionally been considered as a characteristic histopathologic lesion of chronic graft rejection, together with transplant glomerulopathy (TG).34,35 Histopathological features of CGVD include a reduction in vessel lumen size caused by a concentric myointimal proliferation in which a cell component, preferentially consisting of CD3-positive

lymphocytes, macrophages, foamy histiocytes, and myofibroblastic cells, is seen36 (fig. 1). This lesion progresses

and becomes more sclerosing, with a trend to an increased luminal occlusion and intimal signs of sclerosis. At this

more advanced stage, differential diagnosis with lesions secondary to hypertensive vascular disease and/or advanced atherosclerotic lesions is more difficult. A useful histological key to differentiate both lesions consists of the existence of a concentric, segmental reduplication of the internal elastic lamina in cases of atherosclerosis

and/or peripheral vascular disease, which does not occur when the vascular lesion results from CGVD, when the

internal elastic lamina remains unchanged. However, it should always be reminded that the vascular lesion is a

dynamic event, and chronic vasculopathy lesions of an immune origin may be overlapped with atherosclerotic

and/or hypertensive lesions.

In addition to lesion of mediumsized muscular arteries, arteriolar involvement should also be assessed. Arteriolar

sclerosis and hyalinosis is a significant histological marker of chronic nephropathy,13,37 but as occurs with arterial pathology, it may be result from multiple causes, not only atherosclerosis, hypertension, and diabetes, but also

calcineurin inhibitor toxicity.


The continued toxic action of calcineurin inhibitors is one of the main causes of chronic graft failure.37 Since cyclosporin A (CyA) started to be used as a potent immunosuppressant, multiple histological changes related to the toxicity of this drug class have been reported.37-40

Acute toxicity is limited to tubular damage consisting of the presence of microvacuolization of an identical size,

hence the term of «isometric» microvacuolisation, and to a slight vascular damage, not always evident at this first

stage.37 Necrosis of arteriolar smooth muscle cells and nodular hyalinosis has been considered as a lesion characteristic of CyA toxicity,41 but it should be admitted that such hyalinosis is a nonspecific finding in itself.

Another histological feature reported consists of interstitial fibrosis and glomerulosclerosis,38-41 characteristics

that are common to chronic renal graft evolution regardless of the cause. In order to identify specific signs that

allow for differentiating this toxicity from that due to other causes, it should be noted that there are studies that

appear to show that fibrosis induced by CyA shows a lower proportion of collagen III than chronic rejection

biopsies.42 Some authors think that arteriolar hyalinosis is a highly consistent characteristic and the one having a

greatest impact on prognosis.43 By contrast, there are other conclusions not showing a clear relationship between

the grade of renal failure and the severity of arteriolar hyalinosis attributed to toxicity.43

To sum up, we may conclude that:

1. Histopathological diagnosis of calcineurin inhibitor-induced chronic toxicity is an exclusion diagnosis.

2. In patients with chronic kidney disease, lesions due to nephrotoxicity only are difficult to separate from those caused by atherosclerosis, hypertension, or chronic rejection.

3. Arteriolar hyalinosis, together with glomerulosclerosis, should be considered as poor prognostic criteria not always related to the degree of kidney function impairment.

4. Arteriolar hyalinosis and glomerulosclerosis are the most commonly reported histological lesions.


TG is a histological form of glomerular lesion not previously described in native kidneys, consisting of a diffuse thickening of the glomerular capillary wall with formation of double contours, basement membrane lamellation, subendothelial electron-lucent area with no or minimal electron-dense deposits, increase and widening of the mesangial space, and finally «mesangiolysis»34,44,45 (fig. 2).

TG incidence ranges from 7% if all transplant pathology is included and more than 25% if chronic graft disease or patients biopsied after the third month are only analysed.46,47 In our review of more than 1,114 biopsies from transplant patients accumulated from 1985 to 2008, and including glomerular disease only, TG is the most common and leading glomerular graft disease, including de novo and recurrent glomerulonephritis, with an incidence of 37.2%. In some reviews of protocol biopsies in grafts with no impaired kidney function, incidence may be up to 49%.48 In another review conducted by us of all biopsies from patients with chronic kidney function impairment after the sixth month, TG was found in 11% (personal experience).

One of the main problems for diagnosing TG is its high degree of heterogeneity, as it is common to find in evolved

cases coexisting ischaemic glomerular lesions alternating with segmental or global sclerosis in a setting of chronic

disease (personal experience).

Because of the presence of double contours in the glomerular basement membrane (GBM), differential diagnosis

should consider two very similar conditions, mesangiocapillary glomerulonephritis (MCG, de novo or relapsing)

and chronic thrombotic microangiopathy (TMA). Differential diagnosis requires a study with electron microscopy

and immunofluorescence. MCG is characterised by abundant C·3 deposits located in mesangium and capillary walls, particularly at subendothelial level, that should not be present in TG or TMA, in which deposits are usually focal or absent.49

Both with light microscopy and electron microscopy and immunofluorescence, a great similarity exists between TG and chronic TMA, as described in the adult haemolytic uremic syndrome (HUS),49,50 and both conditions are completely superimposable from the light microscopy, immunofluorescence, and ultrastructural viewpoints. This fact has led to postulate that both conditions may have a common etiopathogenetic mechanism. The most significant differences are multilamellation of the lamina densa in electron microscopic studies in TG51 and, clinically, the

absence of a haemolytic uremic syndrome. However, TMA is not always associated to HUS in series of transplant

patients,52 nor the absence of multilamellation rules out a diagnosis of TG.

Classical studies on MCG pathogenesis53 reported that endothelial cell necrosis, cleavage, and lesion lead to a

regenerative process resulting in formation of a new GBM and GBM reduplication. If a hypothetic «accomodation»

phenomenon of the graft to an immune mechanism of repeated, subclinical chronic humoral rejection is accepted,

we could also accept the possibility of a phenomenon of «accomodation» and endothelial subclinical lesion not triggering a HUS secondary to endothelial damage. Such «accomodation» events would allow for a chronic evolution of the graft, preventing massive lysis of endothelial cells from being able to trigger complement and coagulation

activation as occurs in HUS. To support this hypothesis, a factor H deficiency has been reported in the acute phase of TG, in which a significant endothelial impairment highly superimposable to what occurs in TMA exists. Endothelial

damage promoted by T lymphocytes in the acute phase of TG would predispose to intraglomerular platelet aggregation and TMA development.54


Many reports state that factors related to a poor prognosis of renal graft are related to the presence and/or persistence of specific anti-donor antibodies together with histological markers consisting of glomerulitis, capillaritis of the peritubular capillary (PTC), presence of vascular fibrinoid necrosis, and diffuse C4d deposits in PTC (TableII). All these signs are required to be present to diagnose antibody-mediated acute rejection or humoral rejection.

7,14,55,56 In review studies, anti-donor antibodies are detected in up to 96% of patients who have experienced acute rejection, a relationship being found with chronic rejection.57

TG, whose etiopathogenesis is not well known, has traditionally been considered a glomerular form of chronic

rejection.7 There were already reports relating TG with a humoral mechanism of rejection. In an experimental study conducted in 1994 on different mouse strains to show the type of histological lesion related to anti-donor antibodies, glomerular lesions superimposable to TG were reported.58 Recent data support the hypothesis of the involvement of an antibody-mediated immune mechanism (humoral rejection) in chronic graft disease and TG.57-59 This hypothesis is mainly based on the finding of C4d deposits in the basement membrane of the peritubular capillary in 30% to 74% of patients with specific anti-donor antibodies.60,61 Our own review revealed highly positive C4d deposits in PTC in 10 out of 21 biopsies from 17 patients with TG (personal communication pending publication) (fig. 3). There are studies relating multilamellation of GBM, described as a typical ultrastructural lesion in TG, and PTC62,63 to C4d deposits and reporting that such deposits preceded TG64 (fig. 4).

There is thus a connection between humoral rejection and C4d deposits, TG, and capillaropathy supporting a same etiopathogenesis where a primary change in endothelial cells would trigger lesions in the glomerular basement

membrane and PTC, including multilamellation. However, while this immune theory is very attractive, it should be

noted that a change in the basement membrane of PTC consisting of thickening and «rarefaction» related to an

ischaemic mechanism has been reported.65

To sum up, after reviewing the literature and in accordance with the Banff criteria for identification of an immune

mechanism causing chronic graft failure, we think that the following criteria should be met (table III):

¿ Presence of specific anti-donor antibodies, and/or

¿ TG with double contours and/or multilamellation in GBM, and/or

¿ Significant multilamellation of the PTC basement membrane, and/or

¿ Chronic vascular disease based on arterial myointimal proliferation, and/or

¿ Presence of diffuse C4d deposits in PTC.


Since the early histopathological studies of graft biopsies, an attempt has always been made to correlate the

severity and type of inflammatory infiltrate with prognosis. Classical studies reported that severity of such infiltrates and a decreased T4/T8 ratio, as well as changes of this ratio in peripheral blood, involved a poorer prognosis.66,67 While the T-lymphoid component is the leading element in the histological picture of acute cell rejection, involvement of B cell population, plasma cells, and macrophages, highly correlated to graft prognosis and chronic evolution, cannot be forgotten. Presence of B cells has been associated to a poorer graft prognosis and steroid resistance.68 Because of the possibility that this type of rejection with predominance of B lymphocytes may be treated with another type of immunosuppressant (rituximab), it could be advisable to study cell subpopulations using immunohistochemistry procedures, particularly in patients with interstitial lymphocyte infiltrates resistant to standard immunosuppressive therapy. The correlation of macrophages and plasma cells with a poorer prognosis has already been discussed in the literature, and their presence should be noted in diagnosis or the biopsy report.7,14,69,70,71 Some authors found, in biopsies taken more than six months after transplant, a relationship

between C4d deposits in peritubular capillaries and plasma cell infiltrates in up to 52% of cases, whereas only 13% of biopsies negative for C4d had a population of plasma cells.72 A comparison of protocol biopsies from two patient populations dependent on immunosuppressive therapy, either cyclosporine A or tacrolimus, showed lower proportions of CD45, CD3, and CD68 in the tacrolimus group.73

As regards inflammatory cell populations, it may therefore be concluded that identification of populations rich in

CD20 cells, in addition to involving a poorer prognosis, may have an impact on the therapeutic approach. Inflammatory infiltrates with a population of plasma cells and macrophages, particularly after the sixth month, are associated to a poorer prognosis. Finally, there is a clear evidence of the relationship of plasma cell and macrophage populations to humoral rejection, and also to a chronic evolution and a poor prognosis of the graft.


¿ CGN should not be used as a diagnostic term because it encompasses multiple histopathological conditions secondary to different immune and non-immune ethiopatogeneses and pathophysiological mechanisms.

¿ This term should be replaced by a designation describing interstitial fibrosis, tubular atrophy, and glomerular

sclerosis when an etiology is not known and an etiopathogenetic mechanism cannot be established.

¿ Among non-immune factors, inherent donor pathology, particularly vascular lesions, and continued toxic damage induced by calcineurin inhibitors have a preponderant role.

¿ Transplant glomerulopathy (TG), as well as PTC capillaropathy, chronic vascular disease, and C4d deposits in

PTCs, suggest a humoral rejection mechanism mediated by anti-donor antibodies.

¿ Identification of the type of interstitial inflammatory population associated to chronic lesions is important because of the poor prognosis associated to macrophages and plasma cells.

¿ The protocol biopsy may predict for graft evolution and allow for early treatment. There is, however, an ongoing controversy about cost/benefit and ethical issues.

¿ Pathologists facing a biopsy of a transplant patient with chronic kidney function impairment should try and establish the main etiopathogenetic mechanism, for which a C4d study, electron microscopy, and analysis of cell subpopulations in the event of late acute rejection or a poor response to treatment should be performed.

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