[Delayed graft function : an ongoing clinical challenge]. / Reprise retardée de fonction du greffon après transplantation rénale : un challenge clinique toujours d'actualité.

Delayed Graft Function (DGF) is defined as the need for dialysis during the first week after transplantation. DGF is frequent and mostly derived from the ischemia/reperfusion cascade to which the graft is subjected throughout the transplantation process. A graft biopsy is recommended after 7 days of DGF to exclude an episode of acute rejection. Note that DGF per se is associated with an increased risk of acute graft rejection, as well as with a shorter long-term graft survival. Several strategies are being studied to mitigate the ischaemic damage, thereby improving graft quality. Among these, cellular therapy using mesenchymal stromal cells (MSC) is promising, in particular via the administration of MSC in the machine perfusion during the preservation of the graft. We will discuss here the different definitions of DGF and the main predictive factors of DGF, as well as the impact on the graft outcomes. The current strategies to prevent DGF will be briefly reviewed.

La reprise retardée de fonction du greffon rénal (DGF en anglais pour Delayed Graft Function), définie notamment par la nécessité de dialyse durant la 1ère semaine après transplantation, reste un événement fréquent. La DGF résulte principalement des phénomènes d'ischémie/reperfusion auxquels le greffon est soumis tout au long du processus de transplantation. Néanmoins, une biopsie du greffon est préconisée après 7 jours de DGF afin d'exclure une cause non ischémique telle qu'un rejet aigu. La DGF est per se associée à un risque accru de rejet du greffon, ainsi qu'à une moins bonne survie du greffon rénal au long cours. Plusieurs stratégies sont étudiées afin d'atténuer les dommages ischémiques et améliorer la qualité du greffon. Parmi celles-ci, la thérapie cellulaire par cellules stromales mésenchymateuses est prometteuse, notamment via l'administration de celles-ci dans la machine de perfusion lors de la préservation du greffon. Nous aborderons les différentes définitions de la DGF ainsi que ses principaux facteurs prédictifs, l'impact sur le devenir du greffon et, brièvement, les stratégies actuelles dans le cadre de la prévention de la DGF.

The prospective screening for SARS-CoV-2 S1/S2 antibodies delineates the factual incidence of COVID-19 and shows a sustained serological response post COVID-19 in kidney transplant recipients.

BACKGROUND: The impact of immunosuppression on the occurrence of Coronavirus Disease 2019 (COVID-19) remains unclear. METHODS: We conducted a prospective screening of anti-S1/S2 IgGs against SARS-CoV-2 Spike protein from March, 1 2020 to May, 15 2021 (prior to the vaccination campaign) in a cohort of 713 kidney transplant recipients (KTRs). In a first phase, the factual incidence and seroprevalence of COVID-19 was established in this cohort: cases diagnosed by serology were added to RT-PCR-based diagnoses to obtain the overall incidence of COVID-19 in both symptomatic and asymptomatic KTRs. In the second phase, the kinetics of the post-COVID-19 humoral response were studied, taking into account the severity of the disease defined by the need for oxygen therapy (group S, "severe") or not (group nS, "not severe"). RESULTS: The combined diagnostic approaches identified 138 COVID-19 cases (19.2%), with 37 diagnoses by serology (26.8%). The rate of asymptomatic KTRs reached 20.3% (28/138). Thirteen patients (9.4%) died from COVID-19. The seroconversion rate was 91.7% (99/108). The peak anti-S1/S2 IgG level was 85 [30-150] AU/ml and was similar between the S and nS groups (117 [38; 186] AU/ml versus 73 [23; 140] AU/ml). A high probability of persistence of anti-S1/S2 IgG post-COVID-19 was observed, with only 10.1% (7/69) of the patients having negated their serology during the 9-month follow-up. CONCLUSION: Our pragmatic serological screening combined with RT-PCR tests provides a better estimation of the real incidence of COVID-19 in KTRs. A significant proportion of KTRs develop humoral immunity post COVID-19, which most often persists beyond 9 months.

The uptake of [18F]-fluorodeoxyglucose by the renal allograft correlates with the acute Banff scores of cortex inflammation but not with the 1-year graft outcomes.

Introduction: [18F]FDG PET/CT noninvasively disproves acute kidney allograft rejection (AR) in kidney transplant recipients (KTRs) with suspected AR. However, the correlation of biopsy-based Banff vs. PET/CT-based scores of acute inflammation remains unknown, as does the prognostic performance of [18F]FDG PET/CT at one year post suspected AR. Methods: From 2012 to 2019, 114 [18F]FDG-PET/CTs were prospectively performed in 105 adult KTRs who underwent per cause transplant biopsies. Ordinal logistic regression assessed the correlation between the extent of histological inflammation and the mean standardized [18F]FDG uptake values (mSUVmean). Functional outcomes of kidney allografts were evaluated at one year post per cause biopsy and correlated to mSUVmean. Results: A significant correlation between mSUVmean and acute Banff score was found, with an adjusted R 2 of 0.25. The mSUVmean was significantly different between subgroups of "total i", with 2.30 ± 0.71 in score 3 vs. 1.68 ± 0.24 in score 0. Neither the function nor the survival of the graft at one year was statistically related to mSUVmean. Discussion: [18F]FDG-PET/CT may help noninvasively assess the severity of kidney allograft inflammation in KTRs with suspected AR, but it does not predict graft outcomes at one year.

Diagnostic yield of 18 F-FDG PET/CT imaging and urinary CXCL9/creatinine levels in kidney allograft subclinical rejection.

Subclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient." SCR detection relies on surveillance biopsy. Noninvasive approaches may help avoid biopsy-associated complications. From November 2015 to January 2018, we prospectively performed positron emission tomography/computed tomography (PET/CT) after injection of F18 -fluorodeoxyglucose (18 F-FDG) in adult kidney transplant recipients with surveillance biopsy at ~3 months posttransplantation. The Banff-2017 classification was used. The ratio of the mean standard uptake value (mSUVR) between kidney cortex and psoas muscle was measured. Urinary levels of CXCL-9 were concomitantly quantified. Our 92-patient cohort was categorized upon histology: normal (n = 70), borderline (n = 16), and SCR (n = 6). No clinical or biological difference was observed between groups. The mSUVR reached 1.87 ± 0.55, 1.94 ± 0.35, and 2.41 ± 0.54 in normal, borderline, and SCR groups, respectively. A significant difference in mSUVR was found among groups. Furthermore, mSUVR was significantly higher in the SCR vs normal group. The area under the receiver operating characteristic curve (AUC) was 0.79, with 83% sensitivity using an mSUVR threshold of 2.4. The AUC of urinary CXCL-9/creatinine ratios comparatively reached 0.79. The mSUVR positively correlated with ti and acute composite Banff scores. 18 F-FDG-PET/CT helps noninvasively exclude SCR, with a negative predictive value of 98%. External validations are required.

"Acute kidney dysfunction with no rejection" is associated with poor renal outcomes at 2 years post kidney transplantation.

BACKGROUND: "Acute kidney dysfunction with no rejection" (ADNR) corresponds to acute kidney injury without histological evidence of acute rejection (AR) in kidney transplant recipients (KTR). The prognosis of ADNR is unknown. METHODS: From 2007 to 2015, we categorized KTR with for-cause kidney biopsy within the first 12 months post kidney transplantation (KTx) into ADNR (n = 93) and biopsy-proven AR (n = 22). Controls (C, n = 135) included KTR with no ADNR or AR within the first 24 months post-KTx. A piecewise linear regression with a single fixed-knot at 12 months served to establish intercepts and slopes of MDRD-eGFR variations from 12 to 24 months. The percentage of KTR with ≥30% reduction of eGFR from 12 to 24 months was calculated as a surrogate marker of future graft loss. RESULTS: The median time for for-cause biopsy was 22 [10-70] and 13 [7-43] days for ADNR and AR, respectively. At 12 months, eGFR was significantly higher in C (57.6 ± 14.9 mL/min/1.73m2) vs. ADNR (43.5 ± 15.4 mL/min/1.73m2, p < 0.0001) and vs. AR (46.5 ± 15.2 mL/min/1.73m2, p < 0.0065). The proportion of KTR with ≥30% reduction in eGFR from 12 to 24 months reached 16.3% in C vs. 29.9% in ADNR (p = 0.02) and vs. 15% in AR (not significant). CONCLUSIONS: ADNR is associated with poor outcomes within 2 years post-KTx.

Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study.

Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs (∼2 × 106/kg) on day 3 ± 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m2, compared to 32.5 ml/min/1.73m2 in controls and 29.3 ml/min/1.73m2 in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied.

The closure of arteriovenous fistula in kidney transplant recipients is associated with an acceleration of kidney function decline.

Background: The creation of arteriovenous fistula (AVF) may retard chronic kidney disease progression in the general population. Conversely, the impact of AVF closure on renal function in kidney transplant recipients (KTRs) remains unknown. Methods: From 2007 to 2013, we retrospectively categorized 285 KTRs into three groups: no AVF (Group 0, n = 90), closed AVF (Group 1, n = 114) and left-open AVF (Group 2, n = 81). AVF closure occurred at 653 ± 441 days after kidney transplantation (KTx), with a thrombosis:ligation ratio of 19:95. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease equation. Linear mixed models calculated the slope and intercept of eGFR decline versus time, starting at 3 months post-KTx, with a median follow-up of 1807 days (95% confidence interval 1665-2028). Results: The eGFR slope was less in Group 1 (-0.081 mL/min/month) compared with Group 0 (-0.183 mL/min/month; P = 0.03) or Group 2 (-0.164 mL/min/month; P = 0.09). Still, the eGFR slope significantly deteriorated after (-0.159 mL/min/month) versus before (0.038 mL/min/month) AVF closure (P = 0.03). Study periods before versus after AVF closure were balanced to a mean of 13.5 and 12.5 months, respectively, with at least 10 observations per patient ( n = 99). Conclusions: In conclusion, a significant acceleration of eGFR decline is observed over the 12 months following the closure of a functioning AVF in KTRs.

Activation of the calcium-sensing receptor before renal ischemia/reperfusion exacerbates kidney injury.

Activation of the calcium-sensing receptor (CaSR) by ischemia/reperfusion (I/R) favours apoptosis in cardiomyocytes, hepatocytes and neurons. Its role in renal I/R is unknown. We investigated the impact of pharmacological preactivation of the CaSR on kidney structure and function in a murine model of bilateral renal 30-min ischemia and 48-hour reperfusion, and in a 6-year cohort of kidney transplant recipients (KTR). C57BL/6J mice were administered daily with CaSR agonist, R-568, or with vehicle for 48 hours. Evaluation of serum urea and creatinine levels, renal histology and urine metabolome by nuclear magnetic resonance showed that R-568 was not nephrotoxic per se. Following I/R, serum urea and creatinine levels increased higher in R-568-treated animals than in controls. Jablonski's score was significantly greater in R-568-treated kidneys, which showed a higher rate of cell proliferation and apoptosis in comparison to controls. Next, we retrospectively identified 36 patients (10.7% of our cohort) who were treated by CaSR agonist, cinacalcet, at the time of kidney transplantation (KTx). After matching these to 61 KTR upon type of donor, cold ischemic time, residual diuresis, and donor age, we observed that delayed graft function, i.e. need for dialysis in the first week after KTx, occurred in 42 and 23% of cinacalcet-treated and control groups, respectively (p≤0.05). These data suggest that pharmacological preactivation of the CaSR before renal I/R exacerbates kidney injury.

Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion.

Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of specific target-oriented therapy. The pathophysiology of AKI commonly involves ischaemia/reperfusion (I/R) events, which cause both immune and metabolic consequences in renal tissue. Similarly, at the time of kidney transplantation (KT), I/R is an unavoidable event which contributes to early graft dysfunction and enhanced graft immunogenicity. Mesenchymal stromal cells (MSCs) represent a heterogeneous population of adult, fibroblast-like multi-potent cells characterized by their ability to differentiate into tissues of mesodermal lineages. Because MSC have demonstrated immunomodulatory, anti-inflammatory and tissue repair properties, MSC administration at the time of I/R and/or at later times has been hypothesized to attenuate AKI severity and to accelerate the regeneration process. Furthermore, MSC in KT could help prevent both I/R injury and acute rejection, thereby increasing graft function and survival. In this review, summarizing the encouraging observations in animal models and in pilot clinical trials, we outline the benefit of MSC therapy in AKI and KT, and envisage their putative role in renal ischaemic conditioning.

Urinary and dietary sodium and potassium associated with blood pressure control in treated hypertensive kidney transplant recipients: an observational study.

BACKGROUND: In kidney transplant (Kt) recipients , hypertension is a major risk for cardiovascular complications but also for graft failure. Blood pressure (BP) control is therefore mandatory. Office BP (OBP) remains frequently used for clinical decisions, however home BP (HBP) have brought a significant improvement in the BP control. Sodium is a modifiable risk factor, many studies accounted for a decrease of BP with a sodium restricted diet. Increased potassium intake has been also recommended in hypertension management. Using an agreement between office and home BP, the present study investigated the relations between the BP control in Kt recipients and their urinary excretion and dietary consumption of sodium and potassium. METHODS: The BP control defined by OBP <140/90 mmHg and HBP <135/85 mmHg was tested in 70 Kt recipients (mean age 56 ± 11.5 years; mean graft survival 7 ± 6.6 years) treated with antihypertensive medications. OBP and HBP were measured with a validated oscillometric device (Omron M6®). The 24-hour urinary sodium (Na+) and potassium (K+) excretions as well as dietary intakes were compared between controlled and uncontrolled (in office and at home) recipients. Non parametric Wilcoxon Mann-Whitney Test was used for between groups comparisons and Fisher's exact test for frequencies comparisons. Pearson correlation coefficients and paired t-test were used when sample size was >30. RESULTS: Using an agreement between OBP and HBP, we identified controlled (21%) and uncontrolled recipients (49%). Major confounding effects susceptible to interfere with the BP regulation did not differ between groups, the amounts of sodium excretion were similar (154 ± 93 vs 162 ± 88 mmol/24 h) but uncontrolled patients excreted less potassium (68 ± 14 vs 54 ± 20 mmol/24 h; P = 0.029) and had significantly lower potassium intakes (3279 ± 753 vs 2208 ± 720 mg/24 h; P = 0.009), associated with a higher urinary Na+/K + ratio. Systolic HBP was inversely and significantly correlated to urinary potassium (r = -0.48; P = 0.002), a positive but non significant relation was observed with urinary sodium (r = 0,30;P = 0.074). CONCLUSIONS: Half of the treated hypertensive Kt recipients remained uncontrolled in office and at home. Restoring a well-balanced sodium/potassium ratio intakes could be a non pharmacological opportunity to improve blood pressure control.

Results of kidney transplantation from controlled donors after cardio-circulatory death: a single center experience.

The aim of this study was to determine results of kidney transplantation (KT) from controlled donation after cardio-circulatory death (DCD). Primary end-points were graft and patient survival, and post-transplant complications. The influence of delayed graft function (DGF) on graft survival and DGF risk factors were analyzed as secondary end-points. This is a retrospective mono-center review of a consecutive series of 59 DCD-KT performed between 2005 and 2010. Overall graft survival was 96.6%, 94.6%, and 90.7% at 3 months, 1 and 3 years, respectively. Main cause of graft loss was patient's death with a functioning graft. No primary nonfunction grafts. Renal graft function was suboptimal at hospital discharge, but nearly normalized at 3 months. DGF was observed in 45.6% of all DCD-KT. DGF significantly increased postoperative length of hospitalization, but had no deleterious impact on graft function or survival. Donor body mass index ≥30 was the only donor factor that was found to significantly increase the risk of DGF (P < 0.05). Despite a higher rate of DGF, controlled DCD-KT offers a valuable contribution to the pool of deceased donor kidney grafts, with comparable mid-term results to those procured after brain death.

Polyomavirus in renal transplantation: a hot problem.

Polyomavirus BK has emerged as an important complication after kidney transplantation. Although, BK nephropathy develops in only 1% to 5% of renal transplant recipients, its prognosis when present is very poor. The most accepted risk factor is the level of immunosuppressive treatment, but the serostatus of donor and recipient and the absence of human leukocyte antigen C7 in donor and/or recipient influence the BK virus (BKV) reactivation. The gold standard in diagnosing BKV nephropathy (BKVN) continues to be biopsy with use of immunohistochemistry for large T antigens. Urinary decoy cells and blood BKV DNA polymerase chain reaction are used in the screening, but their positive predictive values are poor. However, their use as predictors of the evolution of BKVN is more valuable. The reduction of immunosuppressive therapy currently represents the first-line treatment for BKVN. Cidofovir and leflunomide can be used when BKVN continues to progress. In the event of graft loss, retransplantation is possible with a low risk of recurrence when the infection is no longer active.