الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Renal transplantation is the treatment of choice for patients with end-stage renal disease (ESRD). Renal allograft biopsy plays an important role in the diagnosis and management of renal allograft dysfunction.
The present study was a retrospective study comprising 40 prospective cases of renal allograft dysfunction. Our aim was to describe the pathological findings in the graft biopsy and to correlate it with the clinical findings at the time of biopsyo and with c4d immunohistochemical staining in renal allograft biopsies.
The study included 30 males (75%) and 10 females (25%) with the male to female ratio 3:1. Patients’ age ranged from 23 years to 62 years with a mean age of 39.65 years ( SD=10.979)
Age at the time of transplantation ranged from 17 to 59 years with the mean age of 35.9 years. The duration between transplantation and graft dysfunction varied from 0.15 months to 156 months (5 days to 13 years) with a mean of 43.4 months SD= 44.4 and the median duration was 27 months. Six biopsies (15%) were taken within the first 6 months post transplantation (early renal allograft dysfunction) and 34 biopsies (85%) were taken after more than 6 months of transplantation (late renal allograft dysfunction).
All cases (100%) had elevated serum creatinine level. The mean serum creatinine at the time of biopsy was 4.25 mg/dl. 3 cases (7.5%) had fever and 3 cases (7.5%) had proteinuria.
All the studied cases received the renal allograft from living related donors. The baseline maintenance immunosuppression consisted of triple-drug therapy including hydrocortisone (HC), cyclosporine (CYA) and mycophenolate mofetil (MMF).
The 40 included renal allograft biopsies were examined and scored according to the Banff 2009 update and the revised Banff 2013 criteria for ABMR. Thirty two cases (80%) were rejection and 8 cases (20%) were non rejection. Out of the 32 rejection cases; 27 were ABMR (67.5%), 2 cases (5%) were cellular rejection, and 3 cases (7.5%) were combined ABMR and cellular rejection.
Out of the 27 cases diagnosed as ABMR, 9 cases (22.5 %) were acute active and 18 cases (45 %) were chronic active. Out of the 3 cases showing evidence of combined ABMR and cellular rejection; 2 were combined acute active ABMR and borderline cellular rejection and one case was combined chronic active ABMR and chronic cellular rejection.
Out of the 8 non rejection cases; 4 cases (10 %) showed evidence of infection, 3 cases (7.5 %) were CNI nephrotoxicity and one case (2.5 %) was recurrent glomerulonephritis.
Infection was the cause of renal allograft dysfunction in 4 cases (10%), 3 of which (7.5%) were pyelonephritis and one was viral infection (2.5%).
Chronic CNI nephrotoxicity was seen in 6 cases. It was the only cause of dysfunction in 3 cases (7.5%) and the other 3 cases were accompanied by chronic active ABMR and are included under this category. Only one case (2.5%) was diagnosed as recurrent GN.
In our study, 6 cases showed early renal allograft dysfunction (within the first 6 months after transplantation), all were caused by an acute rejection episode. Acute active ABMR was seen in 4 out of 6 cases (66.7%) and acute cellular rejection was the underlying cause in 2 cases (33.3%).
Thirty four of our cases showed late dysfunction of the renal allograft (more than 6 months after transplantation). Late allograft dysfunction was found to be due to variable causes, mainly chronic rejection. chronic rejection was found in19 cases (55.9%). late acute rejection occurred in 7 cases (20.5%). chronic CNI nephrotoxicity was the cause of dysfunction in 3 cases (8.8 %), pyelonephritis was also the cause of late dysfunction in 3 cases (8.8 %), recurrent glomerulonephritis was found in one case (2.9%) and viral infection was also found in one case (2.9 %).
C4d immunostaining was performed on all 40 biopsies in our study. C4d staining was detected in a linear fashion along the entire circumference of PTCs. Nonspecific tubular positivity and some glomerular staining were observed in some biopsies. According to the Banff 2013 revised criteria for ABMR, c4d more than zero by immunohistochemistry was considered positive.
The overall prevalence of C4d positivity in all renal allograft biopsies was 75% (30 of 40). Fourteen biopsies (35%) showed diffuse staining while 8 (20%) revealed focal staining and 8 (20%) showed minimal positivity. C4d positivity was noted in 93% of rejection biopsies. It was positive in all cases of ABMR whether acute or chronic. No cases of c4d negative ABMR were found in our study. Biopsies showing only acute cellular rejection, infection or CNI toxicity were C4d-negative.
We used Spearman Rank correlation test to assess the correlation between the pathologic findings in the biopsy and the clinical findings at the time of biopsy. Also we tested correlations between c4d positivity and the various clinical and pathologic findings.
Regarding the association between clinical data and histologic findings, no statistical significant correlation was found between the patient age and any of the histologic findings in the graft biopsy. A statistically significant positive correlation was found between increasing duration post transplantation and the development of cortical tubular atrophy and interstitial fibrosis (p=0.01). Also, there was a statistically significant positive correlation between the duration post transplantation and the development of nodular arteriolar hyalinosis in the graft biopsy (p=0.004). Nodular hyalinosis was seen to develop late post transplantation and its degree increased with increased duration post transplantation. On the other hand, statistically significant negative correlation was found between the duration post transplantation and the presence of peritubular capillaritis in the graft biopsy (p=0.02). Other histologic features showed no statistically significant correlation with the duration post transplantation. Also, the serum creatinine level at the time of biopsy showed a statistically significant positive correlation with the presence of peritubular capillaritis (p=0.003). However, serum creatinine level did not show any statistically significant correlation with any of the other histologic features in the graft biopsy.
Testing for association between the clinical data and c4d positivity by Spearman Rank correlation test revealed a statistically significant negative correlation between c4d positivity and the duration posttransplantion (p=0.047). Increased duration posttransplant was associated with decreased positivity for c4d. Also, a statistically significant positive correlation was found between serum creatinine level and c4d positivity (p=0.026). Serum creatinine level was found to be higher in cases with positive staining for c4d.
Regarding the association between c4d positivity and the histologic findings in the biopsy, peritubular capillaritis was strongly positively correlated with c4d (p=0.00). All cases with peritubular capillaritis were seen to be positive for c4d immunohistochemical staining with varying degrees of positivity (minimal, focal or diffuse). Also, glomerulitis was strongly positively correlated with c4d (p=0.00). On the other hand, c4d positivity showed statistically significant negative correlation with the presence of nodular arteriolar hyalinosis in the graft biopsy. No statistically significant correlation was found between c4d positivity and any of the other histologic findings in the graft biopsy.
We concluded that still rejection is the main cause of graft dysfunction despite of the use of triple immunosuppressive regimens and although in our study, ABMR was the main cause of graft dysfunction; however this is not a conclusive result, since we do not have data about donor specific antibodies (DSAs) and also because of the limited number of the studied cases.