Histological lesions in expanded criteria renal allografts

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1 science 8 The shortage of organs for transplantation has forced the transplant community to create another donors subgroup expanded criteria donors (ECD). ECD kidneys are more likely to contain chronic histological lesions on biopsy. Histological lesions in expanded criteria renal allografts Domagala Piotr 1 *, Wszola Michal 1, Perkowska-Ptasinska Agnieszka 2, Durlik Magdalena 2, Paczek Leszek 3, Kwiatkowski Artur 1, Chmura Andrzej 1 1. Department of General Surgery and Transplantology, The Medical University of Warsaw, Warsaw, Poland 2. Department of Transplant Medicine and Nephrology, The Medical University of Warsaw, Warsaw, Poland 3. Department of Immunology, Transplantology and Internal Medicine, The Medical University of Warsaw, Warsaw, Poland #Corresponding author: Piotr Domagała, Department of General Surgery and Transplantology, The Medical University of Warsaw Warsaw, Poland, Nowogrodzka 59 street, e mail: piotr.domagala@wum.edu.pl, phone: , fax: RUNNING TITLE KEYWORDS WORD COUNT CONFLICT OF INTERESTS Histological lesions of ecd kidneys chronic histological lesions, expanded criteria donors, kidney graft survival, kidney transplantation, histological scores no conflicts of interest ABSTRACT Backgrounds: The shortage of organs for transplantation has forced the transplant community to create another donors subgroup expanded criteria donors (ECD). The aim of this study was to establish the relationship between expanded criteria donors parameters and chronic histopathological lesions and then histopathological lesions in relation to transplant kidney graft function and survival. Material and methods: One hundred and seventy two patients received renal transplants from deceased donors. The data on donors and recipients were collected. The patient and graft survival rates were noted. The delayed, slow graft function and creatinine concentration were analysed. The chronic lesions in kidney biopsies were evaluated according to Banff criteria (2007). Results: Kidneys procured from ECD (n=43) display chronic histological lesions like interstitial fibrosis (IF), tubular atrophy (TA), arteriosclerosis(as), arteriolar hyalinization (AH) and glomerulosclerosis (GS) significantly more frequently than standard criteria donor kidneys (n=128). TA was associated with higher creatinine concentration. Popular histological score systems (BANFF, Pirani, CADI) did not have correlate with kidney graft survival and function. Conclusions: ECD kidneys are more likely to contain chronic histological lesions on biopsy. There is a correlation between chronic histological lesions and kidney graft function.

2 9 science BACKGROUND Kidney transplantation is established as the optimal method of treatment for patients with end-stage kidney diseases. Among many benefits of kidney transplantation is a better control of cardiovascular disease in comparison to dialysed patients (1). Cardiovascular incidents are the main cause of death among dialyzed patients (2) and this should be the strongest motivation for kidney transplantation as soon as possible. Unfortunately, the number of patients on waiting lists is much higher than the number of kidney transplantation procedures worldwide (3). The shortage of organs has forced the transplant community to accept kidneys not only from ideal donors (4). It has lead to the creation of another donors subgroup expanded criteria donors (ECD). ECD kidneys have been defined as kidneys from donors aged 60 years and older, or from donors aged years with at least two of the following: cerebrovascular accident (CVA) as cause of death, serum creatinine above 1.5 mg/dl or a history of hypertension (5). The major problem and concern about ECD are the long-term results of transplantation. Nevertheless, it is certain that for some recipients on the waiting list it is valuable and beneficial to receive a kidney procured from ECD (6). It is obvious that a greater effort should be placed on the problem of analyzing factors that could help in discard a certain group of kidneys procured from ECD. The aim of this study was to establish the relationship between expanded criteria kidney donor parameters and chronic histopathological lesions and to investigate the correlation between histopathological lesions and transplant kidney graft function and survival. MATERIAL AND METHODS One hundred and seventy two patients received renal transplants from deceased donors between January 2006 and August The data on donors and recipients as well as method of kidney preservation were collected. The patient and graft survival as well as the immediate, delayed and slow graft function were analysed. The kidney transplant function was assessed by serum creatinine concentration 12 months post transplantation. Delayed graft function (DGF) was defined as a necessity for dialysis treatment in the first week post transplantation. Slow graft function (SGF) was defined as a serum creatinine concentration higher than 3.5 mg/dl at seven days post transplantation for patients that did not require dialysis treatment in the posttransplant course. Donors There were 98 deceased donors diagnosed with brain-death, aged from 8 to 75 years (mean age 42 ± 16.5), predominantly male (61.2% males), hospitalized in ICU for 1-17 days (mean ICU stay 4 days). The mean donor serum creatinine concentration was 1.1 mg/dl and the mean serum creatinine clearance was 87.1 ml/min/1.73 m2. Causes of death included CNS trauma (n=43), cerebrovascular accidents (n=43) and others (n=12). Vasopressors, most commonly dopamine, were administered in 88.8% of donors. Other organs, beside kidneys, were procured in 45% of donors. Donors were classified according to UNOS criteria. There were 23 donors classified as expanded criteria donors (23.5 %) and 75 donors classified as standard criteria donors (76.5 %) (Tab. 1). Kidney recipients There were 172 recipients with end-stage renal disease, aged from 17 to 72 years (mean age 44 ± 13.3), predominantly male (66% males), with mean body mass index 23 kg/m2. A case of primary non-function was excluded from further analysis (0.6%). Most of the recipients underwent kidney transplantation for the first time (72%). The mean duration of dialysis therapy prior to transplantation (hemodialysis in 88%) was over 4 years. Most recipients suffered from hypertension (88.8%), 20% of recipients had lipid disorders and 19.4% of them suffered from chronic coronary disease (Tab. 2). The most frequent causes of end-stage renal disease were as follows: chronic glomerulonephritis (38.6%), nephropathy caused by reflux or congenital urinary tract defects (15.2%), diabetic nephropathy (12.3%), polycystic kidney disease (7.6%), systemic disease (5.3%), nephropathy secondary to hypertension (4.1%). Among other causes (7.0%), the following were encountered: rheumatic disease, Henoch-Schoenlein disease, Alport syndrome, Rendu-Osler-Weber syndrome and toxicity. In 9.9% cases the cause of end-stage renal disease was unknown. Kidney procurement, preservation and transplantation Between January 2006 and August kidneys were procured. Immediately prior to surgery, the donors were given heparin IU and broad -spectrum antibiotic as a prophylaxis. Procurement of kidneys was typical and in situ perfusion was carried out with University of Wisconsin solution. Immediately following organ recovery and cooling to 4ºC, the kidney was placed in a thermally stable container filled with preservation solution (cold storage CS). 83 kidneys were stored by CS (48.5%) until transplantation and 88 kidneys were stored by machine perfusion (MP, Waters Instruments Inc. Rochester). The decision which type of storage was used was made depending on cassette and perfusion fluid availability. Eleven kidneys were discarded: two organs because of poor perfusion parameters, six due to malignant

3 science 10 lesions on pathology, two because of elevated prostate specific antigen and in one case because of lack of available recipient for the HCV positive kidney. 172 kidneys were transplanted with mean cold ischemia time of over 27 hours. There was no significant difference in cold ischemia time between standard criteria donor kidneys group and expanded criteria donor kidneys group (25.1±6.2 h vs 27.9±6.7 h, p=ns). The mean warm ischemia time was 35 minutes. Kidney biopsy In one hundred and forty seven cases renal biopsy specimens obtained in the perioperative period (bench surgery) were available. The biopsy was fixated with formalin and then stained by typical H&E technique. The chronic lesions, inherited from the donor, in kidney biopsies were evaluated by the same pathologist according to Banff criteria Cortical intestitial fibrosis (IF), cortical tubular atrophy (TA), arteriosclerosis (AS), total inflammation (TI), arteriolar hyalinization (AH), glomerulosclerosis (GS) and thrombotic changes (TC) in kidneys biopsies were evaluated. The presence of chronic lesions was defined as Banff score 1. Arteriosclerosis was the most frequent chronic lesion observed (35.5%). The presence of glomerulosclerosis was defined as the existence of more than 20% of glomeruli with sclerosis and was found in 11% of cases. Additionally, according to Banff criteria 2007, three histological scores were calculated. The BANFF score exploited the degree of arteriosclerosis, tubular atrophy, interstitial fibrosis and arteriolar hyalinization. The Pirani score, described by Remuzzi (7), was based on the degree of arteriosclerosis, tubular atrophy, interstitial fibrosis and glomerulosclerosis. The CADI score (chronic allograft damage index) was calculated as a sum of degree of five histological parameters: arteriosclerosis, tubular atrophy, interstitial fibrosis, inflammation and glomerulosclerosis (8). Recipients follow-up The recipients were followed-up from three to thirty five months. The incidence of delayed graft function (DGF) was 30.4% and slow graft function (SGF) was 52.5%. Average 1-year graft survival was 86.9% for the whole group and mean creatinine concentration was 1.58 mg/dl. Average 1-year patient survival was 92.9% for the whole group. Most patients received triple drug immunosuppressive therapy: steroids (100%), cyclosporine (51.8%) or tacrolimus (48.2%) and mycophenolate (90.6%). In case of highly immunized recipients, induction immunosuppression was added (26.9%). Statistical analysis Comparisons between variables in two groups were assessed Chi-square or Cochrane-Mantel-Haenszel test. Student-t test or Wilcoxon test were applied for differences between means and medians, respectively. Risk factors of kidney survival and kidney function one year post-transplant were analysed by multivariate logistic regression and Cox regression analysis. In multivariate analysis graft loss during 12 months and serum creatinine concentration higher than 2 mg/dl at 12 months post transplantation were used as the end-points. Receiver operating characteristic (ROC) curves were used to compare predictive value of three calculated scores. Within the survey, a critical level for hypothesis testing was set at The SAS software version 8.2 (SAS Institute Inc., Cary, NY, USA) was used for statistical analysis. RESULTS ECD kidneys presented chronic histological lesions like cortical interstitial fibrosis, cortical tubular atrophy, arteriosclerosis, arteriolar hyalinization and glomerulosclerosis significantly more frequently than standard criteria donor kidneys [Tab. 3]. The incidence of arteriosclerosis was 22.7% in SCD group and 62.9% in ECD group (p < 0.001) and the incidence of glomerulosclerosis ( 20%) was 2.2% and 36.4% respectively (p < 0.001). There were no differences in total inflammation and thrombotic changes between ECD and SCD group. A correlation was observed between chronic histological changes inherited from the donor and graft survival/function. Cortical tubular atrophy, arteriosclerosis, arteriolar hyalinization and glomerulosclerosis found in biopsies were associated with higher serum creatinine concentration. Cortical interstitial fibrosis and arteriosclerosis were associated with higher incidence of graft loss. Additionally, the recipients of kidneys with arteriosclerosis and glomerulosclerosis had a higher rate of slow graft function and the recipients of kidneys with arteriolar hyalinization had a higher rate of delayed graft function. The recipients of kidneys with cortical interstitial fibrosis had a higher incidence of graft loss in comparison to recipients of kidneys without these findings one year post transplantation (33.3% vs 82.4%, p = 0.035). The recipients of kidneys with the tubular atrophy had higher serum creatinine concentration in comparison to recipients of kidneys without these changes one year post transplantation (2.13 mg/dl vs 1.53 mg/dl, p = 0.048) [Tab. 4]. The recipients of kidneys with inherited arteriosclerosis had a higher incidence of slow graft function, higher serum creatinine concentration and lower graft survival one year post transplantation in comparison to recipients of kidneys without inherited arterioscle-

4 11 science rosis (respectively 69.4% vs 48.6%, p = 0.040; 1.92 mg/dl vs 1.42 mg/dl, p = 0.006; 63.2% vs 85.1%, p = 0.048). The recipients of kidneys with presence of arteriolar hyalinization had a higher rate of delayed graft function (43.6% vs 25.5%, p = 0.035) and higher serum creatinine concentration one year post transplantation (1.89 mg/dl vs 1.47 mg/dl, p = 0.001) [Tab. 5]. In the group of kidneys with inherited glomerulosclerosis a higher incidence of slow graft function and higher serum creatinine concentration was presentone year post transplantation in comparison to kidneys without inherited glomerulosclerosis (respectively 78.6% vs 48.0%, p = 0.032; 1.95 mg/dl vs 1.51 mg/ dl, p = 0.021) [Tab. 5]. No influence of total inflammation and thrombotic changes on kidney graft survival and function was found. The predictive value of combination of donor clinical parameters (ECD) and chronic kidney lesions (whose influence was found in univariate analysis) for graft survival and kidney function at one year post transplantation were estimated by multivariate analysis. Cortical tubular atrophy was proved to have negative influence on serum creatinine concentration at one year post transplantation. Additionally, ECD kidney recipients were more likely to have a creatinine concentration higher than 2mg/dl at one year post transplantation [Tab. 6]. The influence of BANFF, Pirani and CADI scores on graft function and survival one year post transplantation were estimated. None of those scores reached significance [Tab. 7]. The areas under the curves (AUCs) of three scoring systems were compared [Fig. 1] DISCUSSION Despite many papers dealing with transplantation of kidneys procured from expanded criteria donors (9), the correlation between clinical parameters of expanded criteria donors and chronic histological lesions, inherited from the donor, has not been found until now. Our results proved for the first time that there is a strong correlation between expanded criteria donor definition, according to clinical parameters given by UNOS (United Network for Organ Sharing), and appearance of chronic histological lesions like cortical interstitial fibrosis, cortical tubular atrophy, arteriosclerosis, arteriolar hyalinization and glomerulosclerosis. In our analysis, a correlation between chronic histological changes and graft survival and function was proved. We found a relationship between cortical tubular atrophy, arteriosclerosis, arteriolar hyalini- zation and glomerulosclerosis estimated in biopsies and higher serum creatinine concentration. Cortical interstitial fibrosis and arteriosclerosis were associated with higher incidence of graft loss. Only cortical tubular atrophy reached significance in multivariate analysis, probably due to the size of the studied group. Similar findings were described by other authors. Numerous papers have indicated the influence of chronic histological lesions on transplanted kidney survival and function. Snoeijs proved lower graft survival of kidneys with glomerulosclerosis in biopsy (10). Lopes showed a correlation between glomerulosclerosis, arteriosclerosis and cortical interstitial fibrosis and kidney function three months post transplantation (11). The data published by Matignon confirmed the negative influence of arteriolar hyalinization on episodes of delayed graft function (12). Also Arias found that there is a lower graft survival of kidneys with glomerulosclerosis, cortical interstitial fibrosis, cortical tubular atrophy and arteriolar hyalinization (13). There are few papers where influence of donor parameters and histological findings on kidney allograft outcome are considered together (14). Karpinski described a histological score system to find how chronic histological lesions influence results of kidneys transplantation which seems to be more accurate than donor parameters alone (15). On the other hand, there are few papers which do not confirm the correlation between chronic histological lesions and kidney allograft function (16, 17). The differences in methodology of kidney biopsy collecting and its evaluation may explain variations in the data published. Nevertheless, most authors underline the negative impact of chronic histological changes on kidney allograft function and survival. Some data show that the degree of glomerulosclerosis could be a powerful parameter to define severity of renal damage. According to these results, some centres recommend the transplantation of two kidneys from one donor ( en bloc ) if the degree of glomerulosclerosis is greater than 20% (18). Our study did not confirm the effectiveness of the histological scoring systems like BANFF, Pirani or CADI. These scores are based on quantification of the severity of histological lesions. Our findings differ from other papers probably due to the fact that the analysed population was not sufficient. An interesting composite scoring system based on clinical data (donor serum creatinine concentration, donor hypertension) and one histological lesion (glomerulosclerosis) was proposed by Anglicheau (19). Many authors emphasize the necessity of routine kidney biopsy in the perioperative period, even though

5 science 12 the kidney is procured from a standard criteria donor (20). The aim of the biopsy is to evaluate kidney and to find a pre-existing morphological lesion, inherited from the donor that may limit the functional level and vitality of the graft. Secondly, this can be crucial for protocol biopsies in the post transplant period when chronic changes may overlap new histological changes associated with acute rejection, chronic nephropathy or drug toxicity. Moreover, histological examination during graft procurement and storage enables to qualify kidney for transplantation or not. Based on our experience we recommend to collect kidney biopsy from every graft during perioperative period and during storage in every case there are doubts as to possible kidney damage and vitality. CONCLUSIONS Kidneys procured from expanded criteria donors are more likely to contain chronic histological lesions on biopsy. There is a strong correlation between chronic histological lesions and kidney graft function and survival. DISCLOSURE This work was not supported by any grants or industry donations. The manuscript was not prepared or supported by any commercial organization. The authors of this manuscript have no conflicts of interest to disclose. CITE THIS AS MEDtube Science Dec. 2014; 2(4), LIST OF THE TABLES Tab. 1. Donors characteristics Tab. 2. Recipients characteristics Tab. 3. Chronic histological lesions in kidney biopsies Tab. 4. Influence of chronic histological lesions (IF and TA) on kidney graft function and survival in univariate analysis Tab. 5. Influence of chronic histological lesions (AS, HA and GS) on kidney graft function and survival in univariate analysis Tab. 6. Multivariate Cox regression model evaluating histological lesions for the prediction of graft loss and kidney function at one year post transplantation Tab. 7. Multivariate logistic regression model evalu ating histological score system (BANFF, Pi rani, CADI) for the prediction of graft loss and kidney function at one year post transplanta tion TAB. 1. DONORS CHARACTERISTICS Donors (n=98) AGE (Y) 42 ± 16.5 CAUSE OF DEATH (N): CNS TRAUMA 43 CEREBROVASCULAR DISEASE 43 OTHER 12 HYPERTENSION (%) 18.4 SERUM CREATININE CONCENTRATION (MG/DL) 1.1 ECD / SCD ACCORDING TO UNOS (N) 23/75 DONOR TYPE HEMODYNAMIC CLASSIFICATION (N) A 11 LIST OF THE FIGURES FIG. 1. RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES FOR HISTOLOGICAL SCORING SYSTEMS AS PREDICTORS OF HIGH ( 2 MG/DL) CREATININE CONCENTRATION ONE YEAR POST TRANSPLANTA TION B 8 C 79 FEMALE / MALE 38/60 MULTIORGAN DONORS (%) 45 WEIGHT (KG) 72 HEIGHT (M) 1.7 BMI (KG/M2) 24.3 HYPOTENSION (%) 51 CARDIAC AREST (%) 28.6 ICU STAY (DAYS) 4 VASOPRESSORS (%) 88.8 URINE PER DAY (ML) 4298 SERUM CREATININE CLEARANCE (ML/MIN) 87.1 SERUM UREA CONCENTRATION (MG/DL) 36 HBV INFECTION (N) 6 HCV INFECTION (N) 8

6 13 science TAB. 2. RECIPIENTS CHARACTERISTICS Recipients (n=171) TAB. 3. CHRONIC HISTOLOGICAL LESIONS IN KIDNEY BIOPSIES AGE (Y) 44 ± 13.3 MALE / FEMALE (%) 66 / 34 WEIGHT (KG) 67 HEIGHT (M) 1.7 BMI (KG/M2) 23 HCV INFECTION (%) 27.1 HBV INFECTION (%) 16.6 CMV INFECTION (%) 67.9 HEMODIALYSIS (%) 88 DIABETES MELITUS (%) 13.5 HYPERTENSION (%) 88.8 CHRONIC CORONARY DISEASE (%) 19.4 ACUTE CORONARY SYNDROME (%) 3.5 ARYTHMIA (%) 5.3 LIPID DISORDERS (%) 20 IMMUNOLOGICAL CHARACTERISTIC HIGHEST PRA 15.2 LAST PRA 5.9 SCD (n=128) ECD (n=43) P INTERSTITIAL FIBROSIS 0.9% 12.5% CORTICAL TUBULAR ATROPHY 3.7% 22.5% < ARTERIOSCLEROSIS 22.7% 62.9% < TOTAL INFLAMMATION 1.0% 5.4% NS ARTERIOLAR HYALINIZATION 17.8% 52.5% < GLOMERULOSCLEROSIS 20% TAB % 36.4% < INFLUENCE OF CHRONIC HISTOLOGICAL LESIONS (IF AND TA) ON KIDNEY GRAFT FUNCTION AND SURVIVAL IN UNIVARIATE ANALYSIS IF (-) (n=141) IF (+) (n=6) P TA (-) (n=134) TA (+) (n=13) DGF (%) NS NS SGF (%) NS NS SERUM CREATI- NINE CONCEN- TRATION (MG/ DL) AT 1 YEAR GRAFT SURVIVAL (%) AT 1 YEAR NS NS P TAB. 5. INFLUENCE OF CHRONIC HISTOLOGICAL LESIONS (AS, HA AND GS) ON KIDNEY GRAFT FUNCTION AND SURVIVAL IN UNIVARIATE ANALYSIS AS (-) (n=71) AS (+) (n=39) P HA (-) (n=107) HA (+) (n=40) P GS<20% (n=109) GS 20% (n=14) P DGF (%) NS NS SGF (%) NS SERUM CREATI- NINE CONCEN- TRATION (MG/ DL) AT 1 YEAR GRAFT SURVIVAL (%) AT 1 YEAR NS NS TAB. 6. MULTIVARIATE COX REGRESSION MODEL EVALU ATING HISTOLOGICAL LESIONS FOR THE PREDIC TION OF GRAFT LOSS AND KIDNEY FUNCTION AT ONE YEAR POST TRANSPLANTATION Graft loss Serum creatinine 2 mg/dl OR p OR p ECD 1.7 NS INTERSTITIAL FIBROSIS 4.0 NS 1.57 NS CORTICAL TUBULAR ATROPHY 1.33 NS TAB. 7. MULTIVARIATE LOGISTIC REGRESSION MODEL EVALUATING HISTOLOGICAL SCORE SYSTEMS (BANFF, PIRANI, CADI) FOR THE PREDICTION OF GRAFT LOSS AND KIDNEY FUNCTION AT ONE YEAR POST TRANSPLANTATION Graft loss Serum creatinine 2 mg/dl OR p OR p ECD 1.33 NS INTERSTITIAL FIBROSIS 1.39 NS 1.64 NS ARTERIOSCLEROSIS 1.91 NS 1.87 NS ARTERIOLAR HYALINIZATION GLOMERULOSCLEROSIS 20% 1.35 NS 1.64 NS 2.35 NS 1.68 NS

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