Adverse effect of donor arteriolosclerosis on graft outcome after renal transplantation
Eva Pokorná,
tefan Vítko,
Maria Chadimová and
Otto Schück
Transplant Centre, Institute of Clinical and Experimental Medicine, Prague, Czech Republic
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Abstract
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Introduction. In recent years less strict criteria for renal graft donors have been applied. Our study was designed to investigate whether the histological picture, with special reference to vascular changes of the donor kidney, has an effect on the development and level of graft function, and on 48-month graft survival.
Methods. Three morphologically distinct groups were formed from 150 consecutive cadaveric kidneys donors transplanted into 290 recipients. A control group (C) consisted of kidneys with a completely normal histological picture. Group M1 included kidneys with mild arteriolosclerosis and group M2 (n=122) was comprised of kidneys showing significant arteriolosclerosis. The onset of graft function was assessed by the need for dialysis treatment post-transplantation and the levels of serum creatinine and creatinine clearance at 6, 12, 24 and 36 months post transplant.
Results. The proportion of sclerotic glomeruli (P<0.001) and the incidence and severity of interstitial fibrosis was greater in groups M1 and M2 than in the control group (M1, P<0.01; M2, P<0.001). The incidence of vascular fibrinoid necrosis in M2 was greater than in controls (P<0.001). The onset of graft function did not differ significantly between the groups. Group M2 showed a significantly lower level of graft function (P<0.001). The 4-year graft survival rate of group M2 was 74.2%, significantly lower than in the combined group C+M1 (P=0.03).
Conclusion. Significant vascular lesions in the donor kidney should be taken into account when predicting graft function and survival.
Keywords: arteriolosclerosis; marginal donor; procurement renal biopsy; transplant outcome
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Introduction
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The critical shortage of organs suitable for transplantation has led, in recent years, to an expansion of the indication criteria for cadaveric donors. Kidney removal is also indicated in so-called marginal donors (M). This term refers to individuals with confirmed brain death who are more than 55 years old and/or who suffered from arterial hypertension [1,2]. Donors with a cause of brain death other than head injury are also considered to be suboptimal. This group includes individuals with cerebral haemorrhage due to congenital cerebrovascular anomalies, and haemorrhage or ischaemia secondary to atherosclerotic lesions [3].
The impact of cadaveric donor age on the onset of kidney function, the level of kidney function achieved and kidney graft survival have been investigated previously [1,36]. Findings reported to date suggest that the level of kidney function obtained from older donors is significantly lower than that of grafts obtained from younger individuals [7].
Studies exploring the relationship between cadaveric donor kidney morphology and the level of function and graft survival have been scanty and have focused on the relationship between the proportion of sclerotic glomeruli in the donor kidney and graft survival [810]. When extending the indication criteria for cadaveric kidney donors to older individuals and individuals with arterial hypertension, a higher incidence of vascular lesions is to be expected [11].
Our study was designed to evaluate whether the histological picture of the donor kidney, specifically the finding of severe arteriolosclerosis, affects the onset of function, level of graft function at various intervals after transplantation and graft survival rate.
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Material and methods
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The study was conducted from June 1993 to January 1996 in one transplant centre and included 150 consecutive cadaveric kidney donors used for transplantation. A functional examination and representative renal biopsy were perfomed for all. During the study period, 221 kidney donors were harvested. Biopsies were not taken in 44 cases for various reasons. Nine donors were not studied because their kidneys had not been transplanted (six cases due to deteriorated renal function, one due to HBsAg positivity and two donors had renal adenocarcinoma), and 18 donors did not have a representative finding on renal biopsy, because the tissue of renal capsula predominated. Three kidneys were transplanted abroad (HIT project) and were not included, seven kidneys were not transplanted because of surgical complications or donor trauma affecting one kidney. There were 290 graft recipients included in the study.
Procurement renal biopsy
Biopsy was performed by wedge excision from the renal cortex after perfusion (Euro-Collins solution in 64%, UW solution in 36% of cases). Each biopsy sample was fixed by 10% formaldehyde and stained with haematoxylineosin, periodic acid-Schiff, aldehyde fuchsin, silver impregnation and Orange G. The biopsy samples were evaluated by one blinded pathologist using light-microscopy. The number of glomeruli was determined [total number of glomeruli, number of sclerotic glomeruli and the proportion of sclerotic glomeruli (in %), were established]. The severity of vascular lesions (arteriolosclerosis, fibrinoid necrosis), interstitial fibrosis and tubular damage (epithelial desquamation, vacuolization) was estimated semiquantitatively (0, absence; 1, mild; 2, moderate; 3, severe lesions). A biopsy of both kidneys was obtained from the first 29 donors. Because the histological findings from both kidneys were similar, only one kidney was biopsied from the remaining donors. (The correlation between the left and right kidney for arteriolosclerosis was r=0.99, P<0.0001 and proportion of glomerulosclerosis was r=0.88, P<0.0001, n=29.) Histology was performed on a total of 179 samples from 150 cadaveric donors. On average, there were 28±17 glomeruli per sample (range 8101). Biopsy results were not available at the time of transplantation in 92% of the cases, and were not considered in determining the suitability of the kidney grafts for transplantation.
Definitions of groups
Based on the incidence and severity of vascular lesions (arteriolosclerosis), the whole series was subdivided into three groups: a control group with 29 donors and 55 recipients including kidneys with normal vascular finding, a group (marginal, group M1), with 59 donors and 113 recipients consisting of kidneys with mild arteriolosclerosis (focal, no significant narrowing of the arteriolar lumen) and a second marginal group (M2) with 62 donors and 122 recipients comprised of kidneys with significant vascular pathology (arteriolosclerosis, arteriolar lumen narrowing, focal or circular, by one-third or more). The extent of fibrinoid necrosis and interstitial fibrosis were noted, as were the proportion of sclerotic glomeruli. Before kidney removal, the following clinical parameters were obtained: age, gender, cause of brain death, history of arterial hypertension (treatment by at least one antihypertensive drug), presence of proteinuria [semiquantitativelyabsence (0), 1 and 2 arbitrary units/a.u./] and serum creatinine. The parameters evaluated in kidney recipients included age, gender, current level of panel reactive antibodies (PRA), number of HLA mismatches in A+B+DR, number of previous transplantation procedures and duration of cold ischaemia time.
Graft function and survival
The onset of graft function was defined as immediate if the recipient had no dialysis following transplantation, delayed if the recipient required at least one dialysis session in the immediate post-transplant period, or non-functional. The level of function was assessed according to the lowest value of serum creatinine (SCr) achieved in the first hospitalization period and at 6, 12, 18, 24 and 36 months after transplantation (grafts with lost function were not included, because changing values of SCr in dialysed patients is dificult to define), and 24 h creatinine clearance (CCr) at 3 weeks and 6, 12, 18, 24 and 36 months after transplantation. All grafts were included and CCr of grafts with lost function was taken as 0 ml/s. The date of graft failure was defined as the date of return of the patient to chronic dialysis, minimum and maximum follow-up periods were 31 and 64 months, respectively (median 45 months).
Immunosuppression and rejection episode
All recipients received triple immunosuppressive therapy including steroids (prednisone, starting dose 0.5 mg/kg/day and maintenance dose 10 mg/day), cyclosporin A (starting dose 5 mg/kg/day, a maintenance dose to achieve blood levels between 300 and 600 ng/ml was administered, nonspecific RIA methodImmunotech) and azathioprine (starting dose 2 mg/kg/day, maintenance dose 1.5 mg/kg/day). Patients with >50% PRA or retransplantation received OKT3 or antithymocyte globulin as additional prophylactic therapy. Each acute rejection episode was either biopsy confirmed or suspected (administration of anti-rejection therapy with an effect on function).
Statistical methods
The means of continuous variables were evaluated using ANOVA, markedly non-symmetrical data were analysed using the KruskalWallis test and Scheffe's method for pairwise mean comparisons. A linear trend of means was tested by appropriate contrast. To compare two groups, the MannWhitney test was employed, while the chi-square test was used to compare the proportion in contingency tables. Linear regression analysis was applied for modelling correlations between two variables, the biserial correlation test for correlation between continuous and dichotomous variables, and the measure of association test (correlation coefficient gamma) for correlation between two discontinuous variables. Graft and patient survival rates were assessed using the KaplanMeier method whereas the CoxMantel method was used for comparisons. Multiple regression (Cox proportion hazards model) was used to analyse the factors affecting graft survival.
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Results
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Donors
Although the groups were formed based on the presence and severity of arteriolosclerosis, the kidneys also differed in the proportion of sclerotic glomeruli, and the incidence and severity of fibrinoid necrosis and interstitial fibrosis (Table 1
). M1 and M2 donors were significantly older than the control group (P<0.0001). A donor history of arterial hypertension and the cause of brain death other than head injury in M2 were significantly higher than in C. SCr and the incidence of proteinuria prior to removal and the male-to-female ratio did not differ between the groups (Table 2
). There were signicantly different histological findings between younger (age <30 years) and older (age >50 years) individuals, as shown in Table 3
. The correlations between age and morphological changes in glomeruli, vessels and interstitium were significant (Table 4
). The correlation between donor age and the incidence of arterial hypertension was r=0.33, P<0.0001; and that between age and cause of brain death (other than head injury) was r=0.41, P<0.0001 (biserial correlation test). The correlation between the cause of brain death (head injury vs other diagnosis) and the incidence and severity of arteriolosclerosis in the kidney was significant (measure of association test, correlation coefficient gamma=0.56, SE=0.10, P<0.0001).
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Table 3. Comparison of morphological changes in renal biopsy samples from donors aged below 30 years (I) and over 50 years (II)
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Recipients
The proportion of kidney recipients in all groups (C, M1, M2) did not differ statistically with respect to age, gender, levels of actual PRA antibodies, number of HLA mismatches in A+B+DR, duration of cold ischaemia time and the number of retransplantations (Table 5
).
Onset and level of graft function
Early graft function did not differ between the groups (Table 6
). The levels of SCr were significantly higher in M2 than in the control group. Graft function estimated as 24 h CCr at different time post-transplant was significantly lower in grafts obtained from donors with moderate and severe arteriolar changes, whereas graft function in controls and recipients with mild changes (M1) was not statistically different (Table 7
). The correlation between the incidence and severity of arteriolosclerosis and mean level of SCr and 24 h CCr was statistically significant in all evaluated periods (Table 7
).
Acute rejection episodes
The incidence of acute rejection episodes among the groups was not significantly different (44% of recipients in C, 48% in M1, and 43% in M2 did not have any acute rejection episodes, two or more acute rejection episodes occurred in 13% of recipients in C, in 16% of M1 recipients and in 20% of M2 recipients).
Graft and patient survival
Comparison of the survival rates between the groups (Table 8
) revealed significantly lower (P=0.03) graft survival rates in the severe arteriolosclerosis group (M2) compared with the combined group of donors with a normal finding or the presence of minimal arteriolosclerosis (C+M1). The patient survival rate was not different between groups (Table 8
).
Multivariant analysis (Cox proportion hazards model) of the effects of age, glomerulosclerosis and vascular lesions (arteriolosclerosis and fibrinoid necrosis) on graft survival showed a statistically significant effect for vascular changes (P=0.02). The effect of vessel changes has been demonstrated as an age-independent factor with respect to graft survival.
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Discussion and conclusion
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Studies evaluating morphological findings of the donor kidney and graft function usually limit themselves to the finding of glomerulosclerosis and do not recommend transplantation of kidneys with >20% (in some studies even 15%) sclerotic glomeruli [8,12]. In contrast, other studies do not recommend this parameter to assess the suitability of a kidney for transplantation as biopsy samples obtained from the superficial part of the cortex exhibit a higher incidence of sclerotic glomeruli [13] and if the sample contains a small number of glomeruli (<20), the percentage of sclerotic glomeruli cannot be determined with a sufficient degree of accuracy. As a rule, the finding of vascular lesions in the whole kidney and both kidneys is homogeneous [14].
Our findings support the assumption that severe vascular lesions in the donor kidney, while not having an effect on early development of function, do affect the level of kidney graft function in the later post-transplant period. Mild vascular lesions (M1 donors) do not play a major role in the level of post-transplant graft function (assessed SCr and CCr), however, severe vascular lesions (donors included in M2) exhibited a significant correlation with the level of post-transplant graft function. We also demonstrated a downward trend in CCr at 2 and 3 years in individuals receiving kidney grafts from M2 donors. The lower levels of CCr in recipients of kidneys from M2 donors (compared with C donors) could not be explained by higher rates of rejection episodes. It is clear from the results that the incidence of vascular lesions (arteriolosclerosis) increased significantly with increasing age and cause of death other than head injury.
In addition, increasing donor age is associated with increasing proportions (per cent) of sclerotic glomeruli and the incidence of interstitial fibrosis. Our study demonstrated a correlation between the incidence of vascular lesions and the proportion of sclerotic glomeruli (r=0.44, P<0.0001). As a result, it can be assumed that the lower level of graft function in individuals receiving kidney grafts from M2 donors is due to fewer nephrons and to the effect of a mechanism proposed by Brenner and Milford [15]. Inadequate graft function may also be due to interstitial fibrosis. An explanation for this finding could be provided by reports made by Bohle et al. [16] who demonstrated an important role for tubulointerstitial changes in the progression of chronic renal disease.
Considering the above findings, the presence of vascular lesions classified as M2 in our groups, i.e. arteriolosclerosis resulting in a narrowing of the vascular lumen by more than one-third in all examined vessels seems to be a predictor of a lower level of graft function. In contrast, mild vascular lesions (as seen in our M1 donors) did not have a significant adverse effect on the level of graft function. A significant effect of severe vascular lesions in the donor kidney also manifested itself in graft survival rates (although the number of grafts at follow-up is limited). Analysis did not reveal a significant difference in the survival rates (over 48 months) of grafts obtained from C and M1 donors; however, when comparing the survival rates of M2 donors and C+M1 donors, a difference with borderline statistical significance (P=0.03) was found. Multivariant analysis considering the effects of age, arterial hypertension and vascular lesions in the kidney on graft survival indicates that vascular lesions in the donor kidney are an age-independent factor. This finding supports the assumption that the severity of vascular lesions in the kidney of a marginal donor cannot be predicted. It further suggests that there is a group of marginal donors in whom renal biopsy may be helpful in deciding whether to use the kidney for transplantation.
Our findings support biopsy of marginal donors older than 55 years of age, who have a history of arterial hypertension and the cause of death was non-traumatic brain injury due to spontaneous haemorrhage. Detection of severe vascular lesions (referred to as M2 in our classification) predicts that graft function in the post-transplant period will not reach the level seen in ideal donors or those with only mild vascular lesions (M1). In addition, 4-year survival rate for grafts from M2 donors is lower than those from ideal and M1 donors. Despite the lower survival rates of grafts from M2 donors, they should be used, since the 48 months survival rate is acceptable (72%) and there is a critical shortage of organs for transplantation. Considering the shorter survival rate of these grafts (and lower level of function), they should be transplanted preferentially to older recipients [5,17].
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Notes
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Correspondence and offprint requests to: Eva Pokorná, MD, Transplant Centre, Institute of Clinical and Experimental Medicine, Vídeòská 1958/9, 140 21 Prague 4, Czech Republic. E-mail: eva. pokorna{at}medicon. cz. 
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Received for publication: 26. 6.99
Revision received 13. 1.00.