The Relationship of the Severity and Category of Acute Rejection With Intimal Arteritis Defined in Banff Classification to Clinical Outcomes.

BACKGROUND: It is unclear if the category of acute rejection with intimal arteritis (ARV) is relevant to short- and long-term clinical outcomes and if the graft outcomes are affected by the severity of intimal arteritis. METHODS: One hundred forty-eight ARV episodes were reviewed and categorized according to the 2013 Banff criteria of AMR: T cell-mediated rejection with intimal arteritis (v) lesion (TCMRV; n = 78), total antibody-mediated rejection with v lesion (AMRV), which were further divided into suspicious AMRV (n = 37) and AMRV (n = 33). The Banff scores of intimal arteritis (v1, v2 and v3) represented low, moderate, and high ARV severity. RESULTS: The grafts with TCMRV, suspicious AMRV (sAMRV), and AMRV showed similar responses to antirejection therapy, whereas the grafts with v2- or v3-ARV responded significantly poorer compared to those with v1-ARV. The 8-year death-censored graft survival (DCGS) rate was 56.8% of TCMRV versus 34.1% of total AMRV (Log rank, P = 0.03), but the 1- and 5-year DCGS rates were comparable between the 2 groups; moreover, the 1-, 5-, and 8-year DCGS rates of v1-ARV were evidently higher than v2- and v3-ARV (each pairwise comparison to v1-AVR yields P < 0.01); in contrast, the DCGS rates were similar between sAMRV and AMRV. The existing donor-specific antibodies or moderate microvascular inflammation or C4d-positive staining or intensive tubulointerstitial inflammation played a less significant role on the long-term graft survival. CONCLUSIONS: Compared to the category, the ARV severity is more closely associated with the initial response to antirejection therapy and long-term graft failure. The sAMRV and AMRV might represent a spectrum of the same disorder.

Pathologic characteristics of early or late acute cellular rejection and outcome after kidney transplant.

OBJECTIVES: To determine the pathologic features of early- and late-onset acute cellular rejection that may contribute to graft loss after kidney transplant. MATERIALS AND METHODS: There were 247 patients who had acute cellular rejection included in the study. The biopsy that showed the highest acute cellular rejection severity was evaluated for each patient (total, 247 biopsies) and classified as early (time of biopsy, ≤ 6 mo) or late (time of biopsy, > 6 mo) acute cellular rejection. RESULTS: The mean scores of interstitial inflammation (interstitial inflammation and tubulitis), scarring (interstitial fibrosis/tubular atrophy), and vascular disorders (arteriolar hyaline thickening and vascular intimal fibrosis) were significantly higher in late than early acute cellular rejection. Death-censored graft survival at 8 years after kidney transplant was higher in patients who had early (88%) than late acute cellular rejection (66%; P ≤ .001). Early and late acute cellular rejection with either low- or high-grade interstitial fibrosis/tubular atrophy had similar death-censored graft survival. In patients who had late acute cellular rejection, death-censored graft survival was significantly higher when there was low- (survival, 79%) than high-grade vascular intimal fibrosis (survival, 48%; P ≤ .006). Long-term graft loss was significantly associated with the number of biopsies, intimal arteritis, and tubulitis in patients who had early acute cellular rejection, and vascular intimal fibrosis in patients who had late acute cellular rejection. CONCLUSIONS: High-grade vascular intimal fibrosis was a risk factor for poor long-term graft survival in late acute cellular rejection after kidney transplant.

The severity of acute cellular rejection defined by Banff classification is associated with kidney allograft outcomes.

BACKGROUND: It is unclear if the severity or the timing of acute cellular rejection (ACR) defined by Banff classification 2009 is associated with graft survival. METHODS: Borderline changes, TCMR I (interstitial rejection), and TCMR II/III (vascular rejection) were defined as low, moderate, and high ACR severity, respectively. Approximately 270 patients who had at least one episode of ACR were enrolled, 270 biopsies were chosen which showed the highest ACR severity of each patient and were negative for donor-specific antibodies (DSA), C4d, and microcirculation changes (MC). Six months were used as the cutoff to define early and late ACR; 370 patients without biopsy posttransplantation were recruited in the control group. RESULTS: Up to 8-year posttransplantation, death-censored graft survival (DCGS) rates of control, borderline, TCMR I, and TCMR II/III groups were 97.6%, 93.3%, 79.6%, and 73.6% (log rank test, P<0.001); the control group had significantly higher DCGS rate than the three ACR groups (each pairwise comparison yields P<0.05). The DCGS rate of late ACR was significantly lower compared with early ACR (63.6% vs. 87.4%, P<0.001). Intimal arteritis (Banff v-lesion) was an independent histologic risk factor correlated with long-term graft loss regardless of the timing of ACR. The v-lesions with minimal or high-grade tubulitis displayed similar graft survival (72.7% vs. 72.9%, P=0.96). CONCLUSION: All types of ACR affect long-term graft survival. Vascular or late ACR predict poorer graft survival; the extent of tubulointerstitial inflammation (TI) is of no prognostic significance for vascular rejection.

The efficacy and safety of cyclosporine reduction in de novo renal allograft patients receiving sirolimus and corticosteroids: results from an open-label comparative study.

This study evaluated the safety and efficacy of a sirolimus, corticosteroid, and cyclosporine reduction regimen in an open-label, 12-month trial of 420 de novo renal allograft recipients at 49 European transplant centers. One month post-transplantation, 357 patients were randomized to receive standard-dose cyclosporine (sCsA, n = 179) or reduced-dose cyclosporine (rCsA, n = 178). All patients also received sirolimus and corticosteroids. The primary end points were the rate of biopsy-confirmed acute rejection (BCAR) and renal function, as measured by serum creatinine. Baseline demographic and donor characteristics were similar between groups. BCAR rates at 12 months were not significantly different: 11.2% for rCsA patients and 16.2% for sCsA patients. Mean serum creatinine (±SEM) was significantly lower (1.75 ± 0.10 vs. 1.97 ± 0.07 mg/dl, P < 0.001), and creatinine clearance (±SEM; Nankivell method) was significantly higher (57.8 ± 1.78 vs. 49.5 ± 2.46 ml/min, P < 0.001) in patients receiving rCsA versus sCsA at 1 year, respectively. Patient and graft survival exceeded 98% in both groups. No significant differences in infection or malignancy were noted between groups. The rCsA with sirolimus and corticosteroid regimen resulted in excellent 12-month patient and graft survival, a low incidence of BCAR, and improved renal function in renal allograft recipients. Sirolimus administered with rCsA and corticosteroids provided adequate immunosuppression while reducing the potential for the nephrotoxic effects of cyclosporine. These findings may help to improve long-term renal allograft outcomes.

Comparison of first and second kidney transplants from the same deceased donor.

BACKGROUND: Cold ischaemic time (CIT) may negatively influence graft function, increase the risk of acute rejection, and have adverse effects on graft and patient survival. This holds true especially for expanded criteria donors. As multi-centre studies on the impact of CIT are potentially biased, we performed a retrospective single-centre analysis of both kidneys from the same deceased donor transplanted consecutively into two recipients. METHODS: A retrospective analysis of 80 kidneys from 40 donors transplanted into 80 recipients between January 1989 and December 2007 was conducted. Transplantations were performed successively due to logistic reasons resulting in a longer CIT for the second transplantation. We compared the outcome of the first (Rank 1) vs. the second (Rank 2) transplantation of the same donor. Ten donors/20 kidneys were allocated in the Eurotransplant Senior Program (ESP). RESULTS: Overall, no significant difference was found for the number of rejections, delayed graft function (DGF), functional data (creatinine, creatinine clearance and GFR) or graft survival despite a significant difference in CIT of Rank 1 recipients (8.3 h) vs. Rank 2 recipients (14.3 h). Subgroup analysis of kidneys transplanted in the Eurotransplant Senior Program (CIT Rank 1: 7 h vs. Rank 2: 12 h) also showed no difference for all the items studied. Donor kidneys ≥65 years transplanted at Rank 2 had a higher rate of DGF when compared with kidneys from donors <65 years transplanted at Rank 1, and function was better for the young Rank 1 recipients for all the time points measured. Graft- and patient survival did not differ. CONCLUSIONS: We found no difference between the successively transplanted kidneys of the same donor, not even for the expanded criteria donor organs. Nevertheless, assuming a 'safe' CIT is not justified, and CIT should always be kept as short as possible.

"Old-for-old" cadaveric renal transplantation: surgical findings, perioperative complications and outcome.

OBJECTIVE: To evaluate the surgical findings and outcome of locally allocated, blood-group-compatible but HLA-unmatched cadaveric kidneys in first renal transplantation of donor/recipient pairs aged 65 years and above (Eurotransplant Senior Program=ESP). METHODS: 26 patients of the study group (donor age 70.4 +/- 3.6/recipient age 67.7 +/- 2.8) were compared to 30 controls aged 60 and above (mean recipient age 62.6 +/- 2.3/mean donor age 43.8 +/- 15.3). For controls kidney allocation included HLA matching. RESULTS: Cold ischemic time (ESP vs. controls 501 vs. 883 min; p<0.05) and mean number of HLA mismatches (4.2 +/- 1.36 vs. 1.6 +/- 1.62; p<0.05) differed significantly. Delayed graft function was lower in the study group (12% vs. 43%; p<0.05), rejection episodes in the ESP group were numerous but did not differ significantly from the controls (46% vs. 30%; p=0.21). More intraoperative complications and a higher incidence of donor organ arteriosclerosis (p<0.05) were seen in the ESP group. Three-year graft survival uncensored and censored for death with functioning graft did not differ, even though mean creatinine and creatinine clearance differed significantly beginning at month three. Three-year patient survival (55% vs. 81%) differed in favour of the control group, even though the difference was not significant due to small number of patients. CONCLUSION: "Old-for-old" kidney transplantation with local allocation yields graft survival rates comparable to HLA-matched young grafts and is a good approach to extend the donor and recipient pool. Careful patient selection is advised.

Effects of angiotensin-converting enzyme inhibition and calcium channel blockade on cardiac apoptosis in rats with 2K1C (two-kidney/one-clip) renovascular hypertension.

Apoptosis plays a role in the regulation of heart mass and architecture, and might contribute to the cardiac remodelling seen in renovascular hypertension. It is not known whether the beneficial effects of angiotensin-converting enzyme (ACE) inhibition or calcium channel blockade on cardiac remodelling are linked to the modulation of apoptosis. To test this hypothesis, we established four groups of rats: (i) sham-operated controls, (ii) a group that underwent the two-kidney/one-clip (2K1C) procedure, (iii) a group with 2K1C treated for 12 weeks with quinapril (6 mg x day(-1) x kg(-1)), and (iv) a group with 2K1C treated for 12 weeks with diltiazem (24 mg x day(-1) x kg(-1)). Treatment started 2 weeks after clipping. Systolic blood pressure was reduced to a similar extent by quinapril and diltiazem (2K1C, 223+/-19 mmHg; 2K1C+quinapril, 149+/-15 mmHg; 2K1C+diltiazem, 160+/-40 mmHg; both P <0.01 compared with 2K1C alone). Left ventricular weight, interstitial fibrosis and perivascular fibrosis were reduced significantly by both drugs. The apoptotic index (apoptotic cells/total cell number) was increased 21.6-fold (P <0.01) after quinapril treatment as compared with the 2K1C group, but was not affected by calcium channel blockade. In conclusion, our study demonstrates that ACE inhibition, in contrast with calcium channel blockade, may cause regression of cardiac hypertrophy/remodelling in 2K1C renovascular hypertensive rats through enhanced apoptosis.