Isolated vascular “v” lesions in liver allografts: How to approach this unusual finding

According to the Banff criteria for kidney allografts, isolated vascular or “v” lesions are defined as intimal inflammation, age‐inappropriate fibro‐intimal hyperplasia, or both, without the presence of associated interstitial T cell‐mediated rejection (TCMR). In general, these lesions portend a worse outcome for kidney allografts, particularly in those where the “v” lesions are identified in patients with coexistent donor specific antibodies (DSA) or later after transplantation. Although affected arteries are rarely sampled in liver allograft biopsies, we identified nine patients at a mean of 1805 days posttransplantation and compared these to matched controls. Almost half (4 of 9) of the study patient biopsies showed inflammatory arteritis associated with focal or diffuse C4d positivity, which was not observed in matched controls. One “v” lesion patient progressed to rejection‐related graft failure and two developed moderate/severe TCMR in subsequent biopsies, whereas only one rejection episode occurred in follow‐up biopsies, and no rejection‐related deaths or graft failures were detected in controls. In conclusion, patients with liver allograft isolated “v” lesions should undergo further evaluation and closer follow‐up for impending TCMR and/or underlying co‐existent chronic antibody‐mediated rejection (AMR).     

Renal allograft rejection in children and young adults: the Banff classification

In the Banff classification, arteritis and tubulitis are regarded as the principal histological lesions indicating acute renal allograft rejection. To test this claim, we examined 51 biopsies obtained from 21 children and young adults with transplant rejection. Two reviewers, blind to the clinical course, graded the biopsies according to the Banff scheme. In patients without significant tubulitis (borderline changes), rejection tended to be reversed easily (88%), often with methylprednisolone pulse (52%). In patients with arteritis or significant tubulitis (Banff I–III), rejection was reversed in only 23% (P < 0.001), in 9% with steroids, and in 14% with OKT3. Salvage of the graft was achieved in 26 of 35 (74%) with a score < 5 but in only 1 of 12 (8%) with a score ≥5 (P < 0.001). All 6 patients with vasculitis lost their grafts despite methylprednisolone pulse and OKT3. We conclude that the Banff classification predicts accurately the outcome of renal allograft rejection in children and may aid in choosing appropriate therapy.     

High levels of dd‐cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury

The clinical importance of subclinical, early T cell–mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor‐derived cell‐free DNA (dd‐cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd‐cfDNA. Forty‐two patients had elevated dd‐cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd‐cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] ?16.22% to ?1.39%) (?3.50 mL/min/1.73 m² IQR ?8.00 to ?1.00) vs 0% (?4.92%, 4.76%) in low dd‐cfDNA patients (P = .004), de novo donor‐specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd‐cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy.     

Prognostic value of the Banff classification

Abstract We evaluated whether classification of renal allograft biopsies according to the Banff schema is a predictive parameter for graft survival. All patients who received renal transplants between 1980 and 1994 at the University of Erlangen‐Nuremberg (n = 1141) were included. Patients who had undergone a renal biopsy (n = 306) were divided into groups according to the Banff classification. We observed a correlation (P < 0.05) between biopsy findings and the following patient characteristics: donor/recipient age, donor/recipient gender, panel reactive antibodies, maintenance immunosuppression, and primary renal disease. Compared to patients who did not undergo renal biopsy (55.9%), 5‐year graft survival was reduced in patients with moderate acute rejection defined by tubulitis (20.6%, P = 0.03) or arteritis (0%; P < 0.0001) and in patients with severe acute rejection (24.4%, P < 0.0001). Conclusions: (1). The Banff classification is a predictive parameter for renal allograft survival. (2). Certain characteristics predispose patients to certain biopsy findings.     

Free microRNA levels in plasma distinguish T-cell mediated rejection from stable graft function after kidney transplantation

The potential diagnostic value of circulating free miRNAs in plasma compared to miRNA expression in blood cells for rejection processes after kidney transplantation is largely unknown, but offers the potential for better and timely diagnosis of acute rejection. Free microRNA expression of specific blood cell markers was measured in 160 plasma samples from kidney transplant patients under standard immunosuppressive therapy (steroids ± mycophenolic acid ± calcineurin inhibitor) with stable graft function, urinary tract infection, interstitial fibrosis and tubular atrophy, antibody-mediated rejection (ABMR), Borderline (Banff3), tubulo-interstitial (Banff4-I) and vascular rejection (Banff4-II/III) applying RT-PCR. The expression levels of specific microRNAs miR-15B, miR-103A and miR-106A discriminated patients with stable graft function significantly (p-values 0.001996, 0.0054 and 0.0019 resp.) from patients with T-cell mediated rejection (TCMR) and from patients with urinary tract infection (p-values 0.0001, < 0.0001 and 0.0001, resp.). A combined measurement of several microRNAs after multivariate logistic regression improved the diagnostic value supported by subsequent cross-validation. In conclusion, the measurement of circulating microRNAs in plasma from patients with renal transplants distinguishes TCMR and urinary tract infection from stable graft function. In contrast to miRNA expression measurement in blood cells it does not allow a discrimination from ABMR or interstitial fibrosis and tubular atrophy.     

Borderline Changes in Renal Transplantation: Are We Aware of the Real Impact in Graft Survival?

BackgroundBorderline changes suspicious for acute T-cell–mediated rejection (BC) are frequently seen on biopsy specimens, but their clinical significance and clinical management are still controversial. Our goal was to compare clinical outcomes of kidney transplant recipients with biopsy-proven BC vs acute T-cell–mediated rejection (aTCMR) and the influence of treating BC on graft outcomes.MethodsA retrospective cohort study was performed in all kidney transplant recipients with biopsy-proven BC and aTCMR between January 2012 and December 2018, according to Banff 2017 criteria; patients with concomitant antibody-mediated rejection were excluded.ResultsWe included 85 patients, 30 with BC (35.3%) and 55 with aTCMR (64.7%). There was no difference between groups regarding demographics, HLA matching and sensitization, immunosuppression, or time of transplant. Treatment with steroids was started in 15 patients with BC (50%) and in all patients with aTCMR, with 4 of the latter additionally receiving thymoglobulin (7.2%). At 1 year post biopsy, overall graft survival was 71%, and despite presenting better estimated glomerular filtration rate (eGFR) at biopsy (33.3 ± 23.4 vs 19.9 ± 13.2 mL/min/1.73 m², P = .008), patients in the BC group presented the same graft survival as the aTCMR group according to Kaplan-Meyer survival curves. When analyzing the BC group (n = 30) and comparing the patients who were treated (n = 15) vs a conservative approach (n = 15), graft survival at 1 year was 87% for treated patients and 73% for nontreated patients (P = .651), with no difference in eGFR for patients with functioning graft. However, at longer follow-up, survival curves showed a trend for better graft survival in treated patients (70.2 ± 9.2 vs 38.4 ± 8.4 months, P = .087).ConclusionOur study showed that patients with BC did not present better graft survival or graft function at 1 year after biopsy or at follow-up compared with the aTCMR group, despite better eGFR at diagnosis. We found a trend for better graft survival in patients with BC treated with steroids compared with a conservative approach. These results reinforce the importance of borderline changes in graft outcomes and that the decision to treat can influence long-term outcomes.     

De novo donor-specific HLA antibodies reduce graft survival rates and increase the risk of kidney transplant rejection: A single-center retrospective study

BackgroundWe investigated the impact of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) on long-term death-censored graft survival and renal allograft rejection in kidney transplant recipients.MethodsThe sample for this retrospective cohort study comprised 121 recipients of kidney transplants with negative complement-dependent cytotoxicity crossmatches to their deceased donors. Recipients were divided into two groups: dnDSAs+ (n = 31) and dnDSAs- (n = 90). We evaluated rejection and long-term graft survival rates in the recipients along with pathologic changes in the transplanted kidneys.ResultsDnDSAs were identified in 31/121 patients (25.6%). The graft survival rate in the dnDSAs+ group was 87.1% (27/31) and that of the dnDSAs- group was 97.8% (88/90). The dnDSAs+ group had lower graft survival rates than patients without dnDSAs (p = 0.007). There was no difference in the graft survival rates between patients with high DSA mean fluorescence intensity (≥4000) and those with low intensity (<4000) (p = 0.669). There was also no difference in the graft survival rates of patients with HLA class I, II, and I + II dnDSAs (p = 0.571). The presence of dnDSA in serum was associated with a higher incidence of antibody- and T-cell–mediated rejection (p < 0.0001). Banff scores for arterial fibrointimal and arteriolar hyalin, thickening as well as C4d deposition differed for the dnDSAs+ and dnDSAs- groups (p < 0.05).ConclusionDnDSAs were found to be associated with decreased long-term graft survival rates and increased rejection rates, often accompanied by C4d deposition.     

Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.     

Antibody-mediated rejection in the Banff classifications of 2007 and 2017: A comparison of renal graft loss prediction capability

BackgroundAntibody-mediated rejection (ABMR) is the leading cause of kidney graft loss worldwide. Criteria for acute humoral rejection (currently labeled active humoral rejection) established by the 2007 Banff classification are highly specific but lack sensitivity. Modifications to the Banff classification were introduced for its 2013 and 2017 versions in order to identify more cases of this entity.PurposeWe intend to demonstrate that, compared to its 2007 version, the 2017 Banff classification bears an improved capacity for graft loss prediction when histologic criteria for active ABMR are met.Patients and methodsSingle-center retrospective cohort study. A random sample of 201 kidney recipients who underwent a graft biopsy since January 2004 was analyzed. Patients were classified as ever developing histologic characteristics of acute ABMR (2007 Banff) or not and renal survival between groups was compared. The same patients were then classified as ever developing histologic characteristics of active ABMR (2017 Banff) or not and renal survival was again compared. Presence of circulating donor-specific antibodies (DSA) was not taken into consideration.ResultsPatients were followed for a median 13.9 ± 7.9 years, during which grafts were biopsied on 537 occasions (2.7 ± 1.6 biopsies per graft). Baseline eGFR was 73.26 ± 17.6 ml/min and baseline creatinine 1.14 ± 0.25 mg/dl. Graft loss occurred in 38 recipients (18.9%) mainly due to ABMR (60.5%). Acute ABMR (2007 Banff) was identified in 11 recipients (5.5%) and graft survival did not differ between groups with and without active ABMR occurrence (log-rank p = 0.939). Active ABMR (2017 Banff) was found in 59 recipients (29%) and graft survival was better from the second post-transplant year onward in the group of patients without active ABMR occurrence (log-rank p = 0.001). Moderate microvascular inflammation was present in 89.6% of the 48 additional patients with active ABMR.ConclusionThe 2017 Banff classification identifies more patients who develop active ABMR and stratifies graft loss risk better than the 2007 version.     

Significance of revised criteria for chronic active T cell–mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation

Diagnostic criteria for chronic active T cell–mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P < .001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P < .001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.     

Correlation between the Banff 97 classification of renal allograft biopsies and clinical outcome

The 1997 fourth Banff meeting revised the consensus for describing transplant biopsies. We have conducted a retrospective analysis of biopsies correlated between the Banff 97 classification and clinical outcome. The patients (n=149), who had a total of 404 biopsy-proven rejections, were assessed and the biopsies taken from these patients were re-examined and classified according to the Banff 97 classification. Morphological changes in the glomeruli (g), interstitium (i), tubules(t), and arterial vessels (v) were scored. Severity of acute rejection was statistically associated with unresponsiveness to anti-rejection treatment (P<0.0001) and predicted an increased risk of graft failure (P<0.05). Each quantitative criterion (g, i, t, and v) was also statistically associated with unresponsiveness to anti-rejection treatment. Mean serum creatinine levels were significantly higher in the groups graded Banff 97 type I--III after 1 and 2 years of follow-up. The Banff 97 classification correlated with reversibility of rejection episodes and long-term graft survival.     

Inflammation in areas of fibrosis: The DeKAF prospective cohort

Inflammation in areas of fibrosis (i‐IFTA) in posttransplant biopsy specimens has been associated with decreased death‐censored graft survival (DC‐GS). Additionally, an i‐IFTA score ≥ 2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i‐IFTA and t‐IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90 days posttransplant (n = 598); mean (SD) 1.7 ± 1.4 years posttransplant. I‐IFTA, present in 196 biopsy specimens, was strongly correlated with t‐IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score = 0. Unlike previous studies, i‐IFTA = 1 (vs 0) was associated with worse 3‐year DC‐GS: (i‐IFTA = 0, 81.7%, [95% CI 77.7 to 85.9%]); i‐IFTA = 1, 68.1%, [95% CI 59.7 to 77.6%]; i‐IFTA = 2, 56.1%, [95% CI 43.2 to 72.8%], i‐IFTA = 3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i‐IFTA with decreased DC‐GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T‐IFTA was similarly associated with decreased DC‐GS. Of these indication biopsies, those with i‐IFTA ≥ 2, without meeting other criteria for CA TCMR had similar postbiopsy DC‐GS as those with CA TCMR. Those with i‐IFTA = 1 and t ≥ 2, ti ≥ 2 had postbiopsy DC‐GS similar to CA TCMR. Biopsies with i‐IFTA = 1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i‐IFTA and t‐IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.     

Impact of the immunotherapy induction on allograft outcome and survival in kidney transplant patients with donor-specific antibodies to HLA-DQB1

BackgroundThe presence of donor-specific antibodies (DSAs) against HLA-DQB1 is considered a significant barrier to good outcome and allograft survival in kidney transplantation (KT). This study aimed to assess the impact of induction immunotherapy on the outcome and allograft survival in KT patients with HLA-DQB1-DSA.MethodologyThirty-two patients who had undergone KT and found to be positive for HLA-DQB1-DSA were monitored at least one to 10 years. They were allocated into two groups of patients: G1 received induction immunotherapy (n = 14 patients; 43.75%), and G2 did not (n = 18 patients; 56.25%).ResultsIn G1, 6 (42.86%) patients experienced rejection episodes (RE), 2 (14.29%) due to antibody-mediated rejection (ABMR) and 4 (28.57%) due to T-cell-mediated rejection (TCMR). In G2, 13 (72.22%) patients experienced RE, 3 (16.67%) due to ABMR, and 10 (55.56%) due to TCMR. Graft loss occurred in 4 patients from G1, 2 (14.29%) due to ABMR and 2 (14.29%) due to non-immunological causes. In G2, 9 (50.00%) patients lost their grafts, 2 (11.11%) due to TCMR, 2 (11.11%) due to ABMR, and 5 (27.78%) due to non-immunological causes. The graft survival rate was 64.29% in G1 and 45.83% in G2. Glomerulitis and peritubular capillaritis were observed in 3 and C4d-positive patients with/or without induction who lost their grafts by ABMR by HLA-DQ DSA. Two patients from G2 lost their graft by TCMR due to interstitial lymphocytic infiltrate (i1), foci of mild tubulitis (t2), interstitial edema, moderate interstitial fibrosis and tubular atrophy. Better graft survival rates were shown in patients from G1 who received induction immunotherapy.ConclusionOur study suggests that patients with an immunological profile of HLA-DQ+ DSA+ treated by immunotherapy induction have a decreased risk of ABMR and increased allograft survival, and the presence of anti-HLA-DQB1 DSA+ detected before and after KT were associated with ABMR episodes and failure.     

Impact of the Banff '97 classification for histological diagnosis of rejection on clinical outcome and renal function parameters after kidney transplantation

BACKGROUND: Data on a systematic correlation of specific pathomorphologic lesions in renal allograft biopsy specimens with clinical outcome parameters are crucial to determine the relevance of kidney biopsy findings after transplantation for graft prognosis. Specific histologic lesions of the revised Banff '97 classification were correlated with clinical follow-up data. METHODS: The analysis was done on a series of 48 consecutive renal allograft biopsy specimens. Logistic regression was used to compare for response to rejection treatment dependent on histologic grading. Cox regression was applied to analyze the impact of the histologic findings on graft failure during ongoing follow-up. RESULTS: Severity of acute rejection was statistically associated with unresponsiveness to antirejection treatment (odds ratio 2.39, 95% confidence interval 1.13-5.03) and predicted an increased risk of graft failure (hazard ratio 2.16, 95% confidence interval 1.48-3.14). Intimal arteritis (hazard ratio 1.85, 95% confidence interval 1.40-2.45) was the only determinate of a poor survival prognosis. Mean serum creatinine level and the need for antihypertensive drugs were significantly higher in the Banff I-III graded groups after 1 and 2 years of follow-up, whereas patients with borderline rejection were not significantly different from the control group. CONCLUSION: We confirmed a significant association between the revised Banff '97 classification and graft outcome. Intimal arteritis was the only significant predictor of a poor survival probability. The distinction of borderline rejection and Banff grade I rejection seems to be important from a prognostic point of view.     

Banff criteria as predictors of outcome following acute renal allograft rejection.

BACKGROUND: The Banff classification of renal allograft rejection grades acute tubulointerstitial rejection (AIR) by severity of tubulitis and acute vascular rejection (AVR) by severity of arteritis. The intensity of tubulitis has not, however, been demonstrated to be of prognostic value and other features such as glomerulitis and eosinophil infiltration are of uncertain significance. This study was performed in order to determine the clinical value of this pathological classification. METHODS: Banff criteria were correlated with outcome in 134 consecutive graft recipients transplanted in our unit over a 3-year period (1994 1996) who experienced at least one biopsy-confirmed acute rejection episode. Of 197 biopsies performed for the diagnosis of rejection, 177 contained at least one artery and were suitable for Banff grading. Tissue eosinophil counts were available for 101 biopsies. Clinical severity of rejection was classified as mild (fully responsive to pulse steroid therapy), moderate (partially steroid responsive) and severe (steroid unresponsive/requiring ATG therapy). RESULTS: Graft failure ensued in 18 of 58 patients with AVR compared with 10 of 65 patients with AIR (P= < 0.05). Clinical severity of rejection correlated with the presence of arteritis, but not severity of tubulitis; rejections graded I, IIA and IIB according to the Banff' 93 classification were clinically severe in 3/68 (4%), 2/28 (7%) and 15/67 (22%) respectively (P= <0.05). The presence of glomerulitis showed no correlation with clinical severity or graft loss. Tissue eosinophilia (>10 eosinophils/mm2) was present in 18 of 33 patients who had at least one episode of AVR (v1/2), compared with 11 of 45 patients who suffered only AIR (P= <0.02). CONCLUSIONS: We conclude that: arteritis, but not severe tubulitis or glomerulitis, is an adverse prognostic factor in acute rejection and that tissue eosinophilia is associated with vascular rejection. Our findings support the 1997 revision of the Banff classification, replacing grades with types of acute rejection.     

Clinical and Pathological Analyses of Cases of Acute Vascular Rejection After Kidney Transplantation

Background

We performed a clinical and pathological analysis of cases of acute vascular rejection (AVR), characterized by intimal arteritis and transmural arteritis (Banff v score) after kidney transplantation, in an attempt to clarify the mechanisms underlying the development and prognostic significance of AVR.

Reassessing the Significance of Intimal Arteritis in Kidney Transplant Biopsy Specimens

Intimal arteritis (the presence of v-lesions) in kidney transplant biopsy specimens is believed to have major prognostic and diagnostic significance. We assessed the relationship of v-lesions to prognosis in 703 indication biopsy specimens and used microarray-based molecular tests to re-examine the relationship of v-lesions to rejection. v-Lesions were noted in 49 specimens (7%) and were usually mild (v1). The presence of v-lesions had no effect on graft survival compared with the absence of v-lesions. Pathologists using current conventions almost always interpreted v-lesions as reflecting T cell–mediated rejection (TCMR), either pure or mixed with antibody-mediated rejection (ABMR). The molecular scores questioned the conventional diagnoses in 29 of 49 specimens (59%), including ten that were conventional TCMR with no molecular rejection and nine that were conventional TCMR mixed with pure ABMR molecularly. The presence of tubulointerstitial inflammation (i-t) meeting TCMR criteria allowed subclassification of v-lesion specimens into 21 i-t-v-lesion specimens and 28 isolated v-lesion specimens. Molecular TCMR scores were positive in 95% of i-t-v-lesion specimens but only 21% of isolated v-lesion specimens. Molecular ABMR scores were often positive in isolated v-lesion biopsies (46%). Time of biopsy after transplantation was critical for understanding isolated v-lesions: most early isolated v-lesion specimens had no molecular rejection and were DSA negative, whereas most isolated >1 year after transplantation had positive DSA and ABMR scores. Therefore, v-lesions in indication biopsy specimens do not affect prognosis and can reflect TCMR, ABMR, or no rejection. Time after transplantation, DSA, and accompanying inflammation provide probabilistic basis for interpreting v-lesions.     

Should Immunosuppression After Kidney Transplant Be Adjusted Based on Renal Resistance During Pretransplant Hypothermic Machine Perfusion?

BackgroundThe hypothermic machine perfusion reduces delayed graft function after kidney transplant and allows, to some extent, predicting early graft function. However, it is difficult to identify exact perfusion criteria with which to exclude kidneys from transplant or modify post-transplant care. The aim of this study was to analyze whether renal resistance during the fourth hour of hypothermic machine perfusion is useful in the prediction of graft survival and acute rejection.Patients and MethodsData on pretransplant hypothermic machine perfusion parameters of 407 transplanted kidneys were available. Receiver operating characteristic curve analysis was performed to find an optimal cutoff value of ratio for predicting a higher risk class of considered group of patients. According to this, patients were divided into 2 groups: those who received kidneys with renal resistance lower than 0.19 mm Hg/mL/min (R1; n = 187) and those who received kidneys with renal resistance equal to or higher than 0.19 mm Hg/mL/min (R2; n = 220). Within R2, we additionally analyzed 2 subgroups: patients who received induction therapy (R2−Ind+; n = 124) and those who did not received induction therapy (R2−Ind−; n = 96).ResultsAcute rejection in R1 within 1 month post transplant was 2-fold lower compared with R2 and was 6.4% vs 13.1% (P = .03), respectively. One-year graft survival was higher in R1 compared with R2 and was 94.6% vs 88.5% (P = .03), respectively. Acute rejection in the R2−Ind+ subgroup within 1 month post transplant was 2.46-fold lower compared with the R2−Ind− subgroup and was 8% vs 19.7% (P = .01), respectively.ConclusionImmunosuppression treatment after transplant should be adjusted to perfusion parameters.     

Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts

Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000–2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria.