Address for Correspondence: Kunio Morozumi, M.D. c/o Nagoya City University School of Medicine Department of Medicine III 1 Kawasumi Mizuho Nagoya Aichi 467 Japan Tel: +81-52-853-8660 Fax: +81-52-852-3796
Chronic graft failure is one of the most important renal allograft topics in the cyclosporine A(CyA) era. Graft survival rate after the second year of transplantation has not improved with the advent of the potent immunosuppressive agent CyA and other newer agents. The causes of chronic graft failure can be divided into two major categories, i.e., immunologic and nonimmunologic graft injury. We are well aware of the importance of the nonimmunologic causes of late renal graft loss, however, chronic rejection due to presumed immunologic causes seems to be the most important cause of chronic graft failure. CyA has tremendously changed clinico-pathological characteristics of both acute and chronic rejection. Morphological changes in renal allografts with chronic rejection using CyA were usually milder and less specific than those in the steroid azathioprine era. Furthermore, concomitant lesions of glomerulonephritis, chronic CyA nephrotoxicity and acute rejection frequently accompany chronic rejection. Therefore, two questions distress many pathologists and nephrologists: Which lesion, e.g., chronic rejection, chronic CyA nephrotoxicity or glomerulonephritis, is a key determinant of the long-outcome of the graft? Which changes are specific for the diagnosis of chronic rejection? This study was carried out to identify and determine the significance of lesions specific for chronic rejection in the CyA era.
The mean interval from operation to graft biopsy revealing chronic rejection was 1070 ±905 (SD) days. The mean value of serum creatinine and daily proteinuria at the time of graft biopsy were 2.8 ±1.2mg/dl and 1.8 ±2.4gram/day, receptively. The majority of the recipients with high serum creatinine over 3mg/dl lost graft function and half of the patients with lower serum creatinine than 2mg/dl also lost graft function until the recent follow-up point. The outcome of the recipients who developed profuse proteinuria exceeding 3.5 gram/day was worse than that of those with mild proteinuria. However, the graft function of the patients without proteinuria showed slowly deterioration of graft function.
Distribution of histologic diagnosis and the outcome of each group is shown in Table 1. Only 13 among 69 biopsies (19%) showed isolated chronic rejection without concomitant lesions. A concomitant chronic rejection and CyA associated arteriolopathy was the most common finding and occurred in 27 biopsies (39%). The incidence of a combined chronic and acute rejection (so-called acute on chronic rejection) was 33% and this was the second most frequent diagnosis. A combination of three or more diagnoses was not rare. The prognosis of the patients with a concomitant acute on chronic rejection was worse than that of the concomitant CyA arteriolopathy group.
Electron microscopic diagnosis of chronic rejection
1) multi-splitting of peritubular capillary wall
Figure 1 shows the typical circumferential multi-splitting of capillary basement membrane and infiltration of lymphocytes under the endothelium. The prevalence of peritubular capillary splitting was studied in each type of chronic rejection; 1) Interstitial type, 2) Vascular type with transplant glomerulopathy (TPG) and 3) Vascular type without TPG. Typical vascular chronic rejection and/or well developed chronic transplant glomerular lesions is easy to make a diagnosis, however, interstitial type is very difficult especially in patients with CyA nephrotoxicity. Table 2 shows the prevalence of peritubular and glomerular capillary wall lesions in each chronic rejection group. Seven (58%) out of 12 biopsies of interstitial type showed a typical peritubular capillary lesion but only 2 of 12 (17%) developed glomerular capillary lesion. In patients showing chronic vascular rejection without TPG by light microscopy glomerular capillary basement membrane splitting was found in 64% whereas peritubular capillary lesions were found in 43%. In the patients showing chronic vascular rejection with TPG, the incidence of both glomerular (80%) and peritubular (69%) capillary lesion were high. Table 3 shows the relationship between glomerular and peritubular capillary lesions in each type of chronic rejection. Only one patient showed both peritubular and glomerular capillary lesions out of 5 patients with typical peritubular lesion in chronic interstitial group. On the contrary, 4 patients out of 5 with no peritubular capillary lesions also revealed no glomerular lesions.
Multi-layering of better peritubular capillary basement membrane seen by electron microscopy was first suggested by Monga [4, 5] as a diagnostic indicator for chronic rejection. Monga reported the diagnostic possibilities of peritubular lesions and the morphologic similarities between glomerular and peritubular capillary lesions. The immunosuppressive regimen used in Monga's study was conventional in 45% and CyA in 55%. The present study also revealed the diagnostic utility of the peritubular capillary lesion. However, the relevant similarities between peritubular and glomerular capillary lesions were confirmed only in the chronic vascular rejection with TPG in our study. Typical chronic vascular rejection and typical well developed glomerular lesions required no new and expensive and/or complicated diagnostic criteria for chronic rejection. The peritubular capillary lesion and the glomerular lesion seem to be independent at least in the chronic interstitial rejection group in the CyA era. Using CyA as the main immunosuppressive agent approximately 60% of chronically failing grafts developed the peritubular capillary lesion. In acute cellular rejection without glomerular change, an infiltration of activated lymphocytes into the peritubular capillary subendothelial layer is often observed. The direct injury of endothelial cell owing to transplant immunity plays an important role in the pathogenesis of peritubular capillary lesions in chronic rejection. Therefore, the peritubular capillary lesion is a worthwhile addition as a new criterion for chronic rejection. Non specific laboratory data, mild and non-specific morphological findings and a presence of concomitant lesions result in a difficult diagnosis of chronic rejection in cyclosporine era. A negative result of peritubular capillary lesion in interstitial group is found mainly in the recipients with a concomitant severe CyA arteriolopathy. Diffuse fibrosis leads to the diagnosis of chronic transplant nephropathy using Banff diagnostic criteria, but no evidence for chronic rejection was observed by electron microscopy in this group.
To make an effective therapeutic plan for chronic graft failure, the timing of graft biopsy should be carefully considered. Graft biopsy performed too late does not lead to a successful treatment, therefore early graft biopsy should be contemplated.
Finally we try to summarize the morphologic diagnostic criteria of chronic rejection in the CyA era. New diagnostic criteria for chronic rejection are urgently needed to improve the long-term outcome of renal allografts. Classical vascular and glomerular lesions corresponding to chronic rejection are still useful. Multi-splitting of peritubular capillary basement membrane is specific and valuable as a criterion for chronic rejection, especially in patients with a light microscopic pattern of the interstitial type. A new approach using immuno-histochemical analysis will be a great help to improve the diagnostic specificity and sensitivity of chronic rejection in the future.
|surviving||graft loss or
|b) CR + CAA||n=21||8||13|
|c) CR + CAA + AR||n=2||0||2|
|d) CR + CAA + GN||n=3||3||0|
|e) CR + CAA + AR + GN||n=1||1||0|
|f) CR + AR||n=16||3||12||1|
|g) CR + AR + GN||n=5||0||4||1|
|h) CR + GN||n=8||3||5|
|total||n=69||AR: acute rejection
CAA: CsA associated arteriolopathy
|1. Interstitial type||(+)||(-)|
|GBM lesion (n=12)||2||10|
|*Severe CAA with a concomitant mild interstitial CR has no MSPTC.|
|2a. Vascular type||(+)||(-)|
|TPG (-)||MSPTC (n=14)||6||8|
|GBM lesion (n=15)||9||5|
|2b. Vascular type||(+)||(-)|
|TPG (+)||MSPTC (n=13)||9||4|
|GBM lesion (n=15)||12||3|
|1. Interstitial type||MSPTC||(+)||(-)|
|2a. Vascular type
|2b. Vascular type