The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused ...on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody‐mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor‐specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
This report focuses on the clarification of the criteria for chronic active T cell–mediated rejection and antibody‐mediated rejection and the optimization of the inflammation threshold for the diagnosis of borderline for acute T cell–mediated rejection, and discusses the potential to use machine learning in diagnostics and personalized therapeutics in solid organ transplantation.
Abstract
Background and Aims
Post-transplantation patient care requires development and validation of non-invasive biomarkers to improve allograft monitoring and prevention from unnecessary and ...costly biopsies. Reports have suggested the association of donor derived cell-free DNA (dd-cfDNA) with allograft rejection. However, there is no proof of its added value on standard of care in large, unselected and deep phenotyped cohorts.
Method
We enrolled 1134 kidney transplant recipients having concomitant evaluation of allograft histology, anti-HLA DSA and functional parameters between April 2013 and June 2018 in the derivation cohort, representing 1415 biopsies. Dd-cfDNA was measured in plasma at the time of the biopsy. Diagnoses were performed using Banff 2019 criteria. 171 AMR, 34 TCMR and 17 mixed rejections occurred. Parameters associated with rejection were assessed using uni- and multivariable logistic regression. We then developed a risk model using the variables that were independently associated with kidney rejection. The validation cohort comprised 1929 evaluations including 499 evaluations in one Belgian center and 1430 evaluations in nine North American centers.
Results
Higher levels of dd-cfDNA were observed for AMR and TCMR or both compared to other diagnoses (Fig. 1A). Dd-cfDNA incrementally increased with Banff acute lesions without significant increase for chronic lesions. In multivariable analysis, the variables independently associated with rejection were anti-HLA DSA (P<0.0001), dd-cfDNA (P<0.0001), eGFR (P<0.033), proteinuria (P = 0.016), and previous history of rejection (P<0.0001). Dd-cfDNA remained independently associated with kidney allograft rejection in validation cohorts from Belgium (P = 0.0006) and North America (P<0.0001). Discrimination of the model without dd-cfDNA was 0.777 and 0.821 with its inclusion, showing its added value (Fig. 1B). The good discrimination performances of the model with dd-cfDNA were also confirmed in the validation cohorts from Belgium (AUC: 0.815) and North America (AUC: 0.826).
Conclusion
We here demonstrate the independent and added value of dd-cfDNA in addition to conventional features to predict rejection. This first integrative system shows improved performance for patient monitoring and could help physicians in decision-making process.
Because of increased access to kidney transplantation in elderly subjects, the prevalence of monoclonal gammopathies of unknown significance (MGUS) in kidney transplantation (KT) is growing. However, ...little is known about the consequences of MGUS on long-term outcomes.
We identified 70 recipients with MGUS present at transplantation (KTMG) and 114 patients with MGUS occurring after KT (DNMG), among 3059 patients who underwent a KT in two French kidney transplantation centers. We compared outcomes of KTMG with those of matched controls.
Baseline characteristics were similar except for an older age in KTMG compared with the DNMG group (62 vs 57 years, P = .03). Transient MGUS occurred more frequently in DNMG patients (45% vs 24%, P = .007). When compared with matched controls without MGUS, KTMG patients showed higher frequency and earlier post-transplant solid cancers (15% vs 5%, P = .04) and a trend for more bacterial infections (63% vs 48%, P = .08), without difference regarding patient and graft survival, rejection episodes or hematological complications. KTMG patients with an abnormal kappa/lambda ratio and/or severe hypogammaglobulinemia at the time of KT experienced shorter overall survival.
MGUS detection at the time of KT is neither associated with a higher occurrence of graft rejection, nor adversely affects graft or overall survival. MGUS should not contraindicate KT. However, MGUS at the time of KT may be associated with higher risk of early neoplastic and infectious complications and warrants prolonged surveillance. Measurement of serum free light chain should be performed before transplant to refine the risk evaluation of KTMG patients and propose personalized follow-up and immunosuppression.
Higher rates of severe COVID‐19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to ...chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score‐matching method to compare survival and severe disease‐free survival (defined as death and/or need for intensive care unit ICU) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID‐19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age interquartile range (IQR)) 64.7 years (55.3–73.1) in three French transplant centers. After a median follow‐up of 13 days (7–30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow‐up of 8.5 days (2–14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30‐day survival of 62.9% and 71% (p = .38) and severe disease‐free 30‐day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID‐19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.
Kidney transplant recipients matched to nontransplant patients for severe COVID‐19 risk factors present similar survival and incidence of severe COVID‐19, suggesting that chronic immunosuppression is not associated with the severity of COVID‐19.
Abstract
BACKGROUND AND AIMS
Post-transplantation patient care requires development and validation of noninvasive biomarkers to improve allograft monitoring and prevention from unnecessary biopsies. ...Preliminary reports have suggested the association of donor derived cell-free DNA (dd-cfDNA) with allograft rejection. However, there is no proof of its added value beyond standard of care patient management in large and deep phenotyped cohorts.
METHOD
A total of 1210 concomitant evaluations of allograft histology, anti-HLA DSA and functional parameters between 2013 and 2018 were included corresponding to 637 evaluations in the derivation cohort and 573 in the validation cohort. dd-cfDNA was measured in plasma at the time of the evaluation. Diagnoses were assessed using Banff 2019 criteria. Parameters associated with kidney allograft rejection were assessed using uni- and multivariable logistic regression. We developed a risk model using the variables that were independently associated with rejection.
RESULTS
Higher levels of dd-cfDNA were observed for AMR and TCMR or both compared to other diagnoses (Figure 1A). We found incremental dd-cfDNA levels with increasing Banff lesion scores for g, ptc, i, t, cg and C4d (Figure 1B). There was no association of dd-cfDNA levels with allograft inactive lesions. In multivariable analysis, dd-cfDNA (P < 0.0001) was associated with kidney allograft rejection independently of DSA (P < 0.0001), eGFR (P = 0.018), kidney allograft instability (P = 0.013) and previous rejection (P < 0.0001). Based on these parameters, we built an integrative idd-cfDNA model that showed good discrimination (AUC: 0.83), good calibration and added value beyond a model without dd-cfDNA (AUC of the model without dd-cfDNA: 0.77 versus 0.83 for the integrative model; P < 0.0001). We confirmed our results in the validation cohort with a good discrimination (AUC: 0.82) and a good calibration. This integrative score, including the dd-cfDNA, is being validated in Belgium and in the USA.
CONCLUSION
We demonstrate the independent and added value of dd-cfDNA in addition to conventional features to predict rejection. This first integrative system shows improved performance for patient monitoring and could help physicians in decision-making process.
Cardiorenal syndromes (CRSs) are reputed to result in worse prognosis than isolated heart failure (HF) and chronic kidney disease (CKD). Whether it is true for all major outcomes over the long-term ...regardless of CRS chronology (simultaneous, cardiorenal and renocardiac CRS) is unknown.
The 5-year adjusted risk of major outcomes was assessed in this nationwide retrospective cohort study in all 385 687 with either CKD or HF (out of 5 123 193 patients who were admitted in a French hospital in 2012).
Overall, 84.0% patients had HF and 8.9% had CKD (they had similar age, sex ratio, diabetes and hypertension prevalence), while 7.1% had CRS (cardiorenal: 44.6%, renocardiac: 14.5%, simultaneous CRS: 40.8%).The incidence of major outcomes was 57.3%, 53.0%, 79.2% for death; 18.8%, 10.9%, 27.5% for cardiovascular death; 52.6%, 34.7%, 64.3% for HF; 6.2%, 5.5%, 5.6% for myocardial infarction (MI); 6.1%, 5.8%, 5.3% for ischaemic stroke; and 23.1%, 4.8%, 16.1% for end-stage kidney disease (ESKD) for isolated CKD, isolated HF and CRS, respectively.As compared with isolated CKD or HF, the risk of death, cardiovascular death and HF was markedly increased in CRS, the worse phenotype being cardiorenal CRS, while the increased risk of MI and ischaemic stroke associated with CRS subtypes was statistically but not clinically significant. As compared with isolated CKD, the risk of ESKD was similar for cardiorenal CRS only and marginally increased for renocardiac and simultaneous CRS. We could not find a synergy between HF and CKD on major clinical outcomes in the whole population (n = 5 123 193 patients).
The additional impact of CRS versus isolated HF or CKD on long-term kidney and cardiovascular risk is highly heterogenous, depending of the event considered and CRS chronology. No synergy between HF and CKD could be demonstrated.
Abstract
BACKGROUND AND AIMS
As in the general population the prevalence of monoclonal gammopathies (MG) in kidney transplant (KT) candidates increases with age. Little is known about the ...epidemiology and long-term consequences of MG on overall survival, graft outcomes and infectious and neoplastic complications in patients undergoing KT.
METHOD
We retrospectively identified patients with MG at the time of transplant (KTMG) or appearing de novo after the KT (DNMG) in 3059 patients who underwent a KT from January 2007 to June 2019 at Necker Hospital Paris (N = 1978) and from January 1998 to December 2017 at CHU Poitiers, France (N = 1081). Using a propensity score, we established a control cohort of KTMG from Necker Hospital, matched on the main covariates influencing post KT outcomes.
RESULTS
We identified 70 (2.3%) KTMG and 114 (3.7%) DNMG patients, presenting with identical demographic characteristics except for an older age in KTMG (62 versus 57 years; P = 0.03). MG isotypes among the 184 KT recipients with MGUS were IgG (n = 117, 64%), IgA (n = 16, 9%) or IgM (n = 16, 9%). Interestingly, DNMG patients presented more frequently with bi- or triclonal MG than KTMG patients (n = 28, 25% versus n = 7, 10%, respectively; P = 0.02). At the time of KT, among 62 patients with available sFLC measurement in KTMG, 11 (17%) had an abnormal kappa/lambda ratio. Because of systematic evaluation of SPEP during follow-up, we observed that MG disappeared during follow up more frequently in DNMG compared to KTMG (n = 51, 45% versus n = 17, 24%, respectively; P = 0.007). Figure 1 represents the results of SPEP during follow-up.
FIGURE 1: Monoclonal gammopathy timescale. Serum protein electrophoresis follow-up from KT;each patient is represented by one line. Blueand green lines represent negative SPEP, performed before and after the detection of MG, and red lines represent positive SPEP with MG identification. Clinical last follow-up is represented by dots: red dot for death, blue dot for graft loss and green dot for last follow-up alive with functional graft.
Overall survival was poorer in KTMG than in DNMG (87 versus 176 months; P < 0.001). Cox model including age, sex, rank of transplantation and KTMG or DNMG revealed that age, rank of transplantation and KTMG were independent risk factors for death. Graft survival, occurrence of rejection and haematological complications were comparable between the two groups.
To better evaluate the effect of MGUS at the time of KT, KTMG patients from Necker Hospital were compared with matched KT recipients. There was no difference between KTMG and controls regarding the main baseline predictors of post-KT outcomes except for lower level of residual gammaglobulins 7.5 g/L (IQR 6–9.9) in KTMG versus 10.7 g/l (IQR 8.9–13.1) in controls (P < 0.0001). KTMG patients developed more frequently solid cancers (15% versus 5%; P = 0.04) and bacterial infections (63% versus 48%; P = 0.08). There was no significant difference regarding survival, frequency of rejection or haematological complications. However, KTMG patients with an abnormal kappa/lambda ratio at the time of KT tended to have poorer overall survival than those with normal kappa/lambda ratio and controls (respective medians 72, 87 and 103 months; P = 0.08) (Figure 2).
CONCLUSION
We report here the largest cohort of KT recipients who underwent systematic SPEP screening at the time of KT and yearly during post-transplant follow-up. We observed that MGUS prevalence in KT candidates is close to that reported in the general population. We confirm that outcomes of patients harboring MGUS at the time of KT are similar to those of matched controls without MGUS, supporting that MGUS should not be a contraindication for KT. Nevertheless, we observed that KTMG patients developed more frequently and earlier solid cancers and infections, suggesting that MGUS is associated with a relative immunodeficiency in these patients. We also showed that patients with abnormal sFLC kappa/lambda ratio experienced poor outcomes, claiming for systematic measurement of sFLC in the pre-KT workup.
Clinical last follow-up is represented by dots: red dot for death, blue dot for graft loss and green dot for last follow-up alive with functional graft.
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