Hybrid Immunity Overcomes Defective Immune Response to COVID-19 Vaccination in Kidney Transplant Recipients.

Introduction: Comorbidities and immunosuppressive therapies are associated with reduced immune responses to primary COVID-19 mRNA vaccination in kidney transplant recipients (KTRs). In healthy individuals, prior SARS-COV-2 infection is associated with increased vaccine responses, a phenotype called hybrid immunity. In this study, we explored the potential influence of immune suppression on hybrid immunity in KTRs. Methods: Eighty-two KTRs, including 59 SARS-CoV-2-naïve (naïve KTRs [N-KTRs]) and 23 SARS-CoV-2-experienced (experienced KTRs [E-KTRs]) patients, were prospectively studied and compared to 106 healthy controls (HCs), including 40 SARS-CoV-2-naïve (N-HCs) and 66 SARS-CoV-2-experienced (E-HCs) subjects. Polyfunctional antibody and T cell responses were measured following 2 doses of BNT162b2 mRNA vaccine. Associations between vaccine responses and clinical characteristics were studied by univariate and multivariate analyses. Results: In naïve KTRs, vaccine responses were markedly lower than in HCs and were correlated with older age, more recent transplantation, kidney retransplantation after graft failure, arterial hypertension, and treatment with mycophenolate mofetil (MMF). In contrast, vaccine responses of E-KTRs were similar to those of HCs and were associated with time between transplantation and vaccination, but not with the other risk factors associated with low vaccine responses in naïve KTRs. Conclusion: In conclusion, hybrid immunity overcomes immune suppression and provides potent humoral and cellular immunity to SARS-CoV-2 in KTRs.

Humoral and cellular immune correlates of protection against COVID-19 in kidney transplant recipients.

As solid organ transplant recipients are at high risk of severe COVID-19 and respond poorly to primary SARS-CoV-2 mRNA vaccination, they have been prioritized for booster vaccination. However, an immunological correlate of protection has not been identified in this vulnerable population. We conducted a prospective monocentric cohort study of 65 kidney transplant recipients who received 3 doses of BNT162b2 mRNA vaccine. Associations among breakthrough infection (BTI), vaccine responses, and patient characteristics were explored in 54 patients. Symptomatic COVID-19 was diagnosed in 32% of kidney transplant recipients during a period of 6 months after booster vaccination. During this period, SARS-CoV-2 delta and omicron were the dominant variants in the general population. Univariate Analyses identified the avidity of SARS-CoV-2 receptor binding domain binding IgG, neutralizing antibodies, and SARS-CoV-2 S2-specific interferon gamma responses as correlates of protection against BTI. No demographic or clinical parameter correlated with the risk of BTI. In multivariate analysis, the risk of BTI was best predicted by neutralizing antibody and S2-specific interferon gamma responses. In conclusion, T cell responses may help compensate for the suboptimal antibody response to booster vaccination in kidney transplant recipients. Further studies are needed to confirm these findings.

Ticlopidine and clopidogrel, sometimes combined with aspirin, only minimally increase the surgical risk in renal transplantation: a case-control study.

BACKGROUND: Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery. METHODS: We retrospectively reviewed the records of 702 adult patients with a kidney transplant alone between 2000 and 2010. Nineteen (2.7%) patients were taking clopidogrel or ticlopidine when called in for transplantation. Furthermore, 10 of these 19 patients were also taking low-dose aspirin (ASA). We compared the risk of bleeding peri- and postoperatively, and the occurrence of cardiovascular complications within 30 days after renal transplantation between 19 cases and 39 controls randomly selected within the cohort. RESULTS: Platelets were administered to 7 cases (37%) versus 0 controls (P<0.001). A single case (5.3%) presented with significant bleeding during surgery following an implantation biopsy, and required 4 red bood cell (RBC) units. During the first day, 3 of the 19 cases (16%) and 1 of the 39 controls required RBC (P=0.1). No reoperation was performed for bleeding. After the transplant, clopidogrel or ticlopidine was resumed in only two patients. The platelet count and haemoglobin were similar between cases and controls at Day 30. No cardiovascular event occurred in cases or controls during the first month post-transplantation. At 5 years, graft and patient survival was similar in cases and controls. CONCLUSIONS: Clopidogrel and ticlopidine, sometimes in combination with ASA, are associated with a low risk of bleeding during renal transplantation and does not seem to be a contraindication for renal transplant surgery.

Large decrease of anti-tetanus anatoxin and anti-pneumococcal antibodies at one year after renal transplantation.

AIMS: In kidney transplant recipients (KTR), antibody (Ab) synthesis is hampered by AZA and CsA. We here report in a prospective cohort study, the effects of mycophenolate mofetil (MMF) associated to a calcineurin inhibitor on plasma levels of anti-tetanus anatoxin Ab (TAnAb) and anti-pneumococcal Ab (PnPsAb). METHODS: Serum titers of the TAnAb and the PnPsAb against serotypes 14, 19F and 23F were measured in 94 KTR on Day 0 (T0) and 1 year (T12) after renal transplantation and in 49 healthy controls. RESULTS: 1) At T0, TAnAb were detected in only 71% of patients vs. 98% of controls (p < 0.0001) and the titers were significantly lower in KTR (1.46 UI/ml vs. 2.74 in controls, p = 0.01); they further decreased between T0 and T12 (1.46 UI/ml to 0.31, p < 0.0001). The calculated half-life (t1/2) of TAnAb was 7.7 months, as compared to more than 10 years in a normal population. 2) In KTR, PnPsAb titers decreased significantly between T0 and T12 (p < 0.005); the t1/2 of the different PnPsAb ranged from 9.2 to 11.9 months. CONCLUSIONS: In KTR treated by MMF and CNI, the TAnAbs and PnPsAbs titers decrease significantly and profoundly during the first year. Immunization pre-transplantation should be encouraged to maintain adequate post-transplant Abs levels.

Shipping donor kidneys within Eurotransplant: outcomes after renal transplantation in a single-centre cohort study.

BACKGROUND: Shipment of organs during the allocation process aims to improve human leucocyte antigen (HLA) matching but can also have a detrimental effect by prolonging cold ischaemia. The overall effect of organ exchange on post-transplant outcomes in the Eurotransplant (ET) region has not been investigated. METHODS: This is a retrospective single-centre cohort study to investigate the effect of shipment of renal allografts on cold ischaemia times and the incidence of acute rejection (AR) and graft survival in 661 transplantations of deceased donor kidneys. RESULTS: Forty-six per cent (N = 301) of the patients received a locally procured and 54% (N = 360) a shipped donor kidney. Locally procured donors tended to be older, more often hypertensive and had less frequently died from trauma. Recipients of shipped kidneys were at higher immunological risk, being younger, more frequently retransplanted and immunized against HLA antigens. Shipped kidneys had a 2.2-h prolongation of cold ischaemia time (18.0 versus 20.2 h; P < 0.0001) but significantly less HLA A, B and DR mismatches (2.20 versus 2.84; P < 0.0001). Recipients of shipped kidneys had an increased incidence of first-year AR [19 versus 13%; odds ratio 1.62 (1.06-2.49); P = 0.026] and death-censored graft loss [hazard ratio 1.6 (1.1-2.4); P = 0.01] that was no longer statistically significant after adjustments for risk factors by multivariable modelling. CONCLUSIONS: Shipment of kidneys in the ET region is associated with a modest increase in cold ischaemia time and significantly better HLA matching. This allows for successful transplantation of higher risk patients with no significant penalty with regard to AR rates or death-censored graft survival.

Posttransplant major histocompatibility complex class I chain-related gene A antibodies and long-term graft outcomes in a multicenter cohort of 779 kidney transplant recipients.

BACKGROUND: The impact of major histocompatibility class I chain-related A (MICA) antibodies on renal graft outcomes is unclear. The goal of this work was to assess the impact of posttransplant MICA antibodies, assayed at 1 year, with two commercially available kits, on long-term renal graft outcomes. METHODS: We retrospectively tested sera from 779 kidney transplant recipients with two single-antigen flow bead assays 1 year after transplantation. Samples were considered positive for MICA if they were positive in both tests or positive for MICA specificities that were present in one kit only. The main outcome was 4-year death-censored graft survival. RESULTS: The prevalence of MICA antibodies was 5.4% at 1 year. MICA+ patients were more frequently human leukocyte antigen (HLA) sensitized and regrafted. Four-year death-censored graft survival was not different between MICA+ and MICA- patients (97% vs. 94%, P=0.28). By Cox multivariate analysis, independent risk factors for graft loss were as follows: number of HLA DR mismatches, acute rejection within the first year posttransplantation, 1-year serum creatinine, and the presence of HLA antibodies at 1 year, but not the presence of MICA antibodies. CONCLUSIONS: These data do not support an independent pathogenic role for MICA in long-term renal graft injury and question the interest of posttransplant monitoring of MICA antibodies with single-antigen flow bead assays currently available.

Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: effect on malignancies after renal transplantation in a single-centre retrospective cohort study.

BACKGROUND: Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. METHODS: A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). RESULTS: In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). CONCLUSION: Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Influenza A/H1N1 vaccine in patients treated by kidney transplant or dialysis: a cohort study.

BACKGROUND AND OBJECTIVES: In 2009, the pandemic influenza A/H1N1 accounted for worldwide recommendations about vaccination. There are few data concerning the immunogenicity or the security of the adjuvanted-A/H1N1 vaccine in transplanted and hemodialyzed patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Sera from 21 controls, 53 hemodialyzed (HD) patients, and 111 renal transplant recipients (RT) were sampled before (T0) and 1 month after (T1) a single dose of Pandemrix® vaccine (GSK Biologicals, AS03-adjuvanted). We measured the neutralizing antibodies against A/H1N1/2009, the geometric mean (GM) titers, the GM titer ratios (T1/T0) with 95% confidence intervals, and the seroconversion rate (responders: ≥4-fold increase in titer). The HLA and MICA immunization was determined by Luminex technology. RESULTS: The GM titer ratio was 38 (19 to 78), 9 (5 to 16), and 5 (3 to 6) for controls, HD patients, and RT patients, respectively (P < 0.001). The proportion of responders was 90%, 57%, and 44%, respectively (P < 0.001). In RT patients, the prevalence of histocompatibility leukocyte antigen (HLA) class I, histocompatibility leukocyte antigen class II, and MHC class I-related chain A immunization, was, respectively, 15%, 14%, and 14% before and 14%, 14%, and 11% after vaccination (P = 1, 1, and 0.39). CONCLUSIONS: The influenza A/H1N1-adjuvanted vaccine is of limited efficacy but is safe in renal disease populations. The humoral response is lower in transplanted versus hemodialyzed patients. Further studies are needed to improve the efficacy of vaccination in those populations.

Select screening in a specific high-risk population of patients suggests a stage migration toward detection of non-muscle-invasive bladder cancer.

BACKGROUND: More than 25% of bladder cancer (BC) cases are still muscle-invasive at first diagnosis. Screening is unproven to enable the detection of more non-muscle-invasive tumors. BC association with aristolochic acid nephropathy (AAN) was reported after intake of slimming pills containing Chinese herbs. OBJECTIVE: We evaluated whether a BC screening protocol in a high-risk and unique patient population had an impact on the stage of tumor presentation. DESIGN, SETTING, AND PARTICIPANTS: Forty-eight AAN-affected patients were enrolled in a screening program, establishing BC incidence during prospective screening cystoscopies and biopsies biannually for up to 10 yr. Two patients were lost to follow-up, and three refused screening after consenting. MEASUREMENTS: Patients were evaluated for presence of BC and tumor stage at diagnosis. RESULTS AND LIMITATIONS: BC was diagnosed in 25 patients (52%). Among 43 patients who underwent screening cystoscopies (median follow-up: 94 mo), 22 were first diagnosed with non-muscle-invasive BC but none with muscle-invasive tumors and none died of BC. Three women who declined follow-up were diagnosed and died with advanced metastatic disease. The limitations of our findings include the small sample size of this case series, the absence of a real control group, and the particular risk factor in these patients that differs from the usual risk factors, such as smoking or industrial chemicals. CONCLUSIONS: BC screening in high-risk groups may allow identification of tumors before muscle invasion. The optimal screening schedule and the relevance of the present findings in smoking-related BC remain to be defined.

Thrombophilic factors in Stage V chronic kidney disease patients are largely corrected by renal transplantation.

BACKGROUND: The aim of our study was to evaluate the prevalence of acquired thrombophilic factors in Stage V chronic kidney disease (CKD) patients according to dialysis modality, the rate of correction of these factors 1 month after renal transplantation and their impact on cardiovascular or thromboembolic events at 1 year. METHODS: Three hundred and ten patients were prospectively screened for seven thrombophilic factors at transplantation; 215 of them were also assayed 1 month after. All the patients received prophylactic acetylsalicylic acid, started before transplantation. RESULTS: The prevalence of thrombophilic factors was significantly higher in patients under dialysis (n = 289) than in patients not yet on dialysis (n = 21) (74 versus 52.4%; P = 0.03) but was similar in haemodialysis and peritoneal dialysis patients (74.2 versus 73.2%). One month after transplantation, the global prevalence of thrombophilic factors had dropped from 74.4 to 44.7% (P < 0.001). Most thrombophilic factors had disappeared after transplantation: antithrombin deficiency: 13.5 versus 0.9%; P < 0.001, protein C deficiency: 12.1 versus 1.9%; P < 0.001, protein S deficiency: 3.7 versus 1.4%; P = 0.1, lupus anticoagulant: 37.7 versus 8.4%; P < 0.001 and antiphospholipid antibodies: 29.3 versus 12.6%; P < 0.001. The prevalence of activated protein C resistance, which reflects inherited factor V (FV) Leiden, was unchanged (1.9%), while the prevalence of elevated factor VIIIc increased from 20.9 to 30.7%, P < 0.001. The incidence of cardiovascular or thromboembolic events 1 year after transplantation was similar in patients with more than or equal to one thrombophilic factor at 1 month (5.2%) versus thrombophilic-free patients (6.7%). CONCLUSION: Acquired thrombophilic factors are highly prevalent among Stage V CKD patients. Most thrombophilic factors are corrected 1 month after transplantation.

Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients.

Little is known about the proportion of renal transplant candidates who are considered ineligible by the transplant center, the reasons of their ineligibility and their survival during dialysis. In this retrospective, single-center study of 445 adult patients referred between 2001 and 2006, 36 (8%) were deemed ineligible for medical contraindications. The leading reason was cardiovascular (CV) (75%), specifically aorto-iliac, and/or limb vessels atheromatosis or calcifications; ischemic heart disease; or a combination thereof. Nine patients had other contraindications that were absolute for three of them; six patients displayed a combination of relative contraindications. When compared to eligible patients (N = 409), those ineligible were significantly older (60 yr vs. 48), more often diabetics (50% vs. 15%), obese (39% vs. 17%) suffering from coronary artery disease (53% vs. 11%) and peripheral arterial disease (86% vs. 11%). Their primary nephropathy was more often diabetic and/or hypertensive/nephroangiosclerosis (61% vs. 23%), and their median dialysis vintage prior to evaluation was longer (29 months vs. 10, p < 0.0001). The actuarial survival of ineligible patients was significantly lower than that of eligible patients (at five yr: 53% vs. 88%). Adequate control of CV risk factors before dialysis and early referral for transplantation might help to improve eligibility of renal transplant candidates.

Bortezomib: a new player in pre- and post-transplant desensitization?

Several desensitization strategies have been investigated for the reversal of acute antibody-mediated rejection or for the removal of preformed anti-HLA antibodies, with the aim to promote access to renal transplantation. Today, their success appears limited or incomplete. Bortezomib, a selective inhibitor of the 26S proteasome, which is largely used in the treatment of multiple myeloma, could be a novel promising desensitizing agent. Its mechanism of action and preliminary clinical use in renal transplantation is reviewed here.

Revisiting nephrogenic systemic fibrosis in 6 kidney transplant recipients: a single-center experience.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a fibrotic disorder occurring in patients with renal dysfunction. Exposure to gadolinium (Gd)-based contrast agents (GBCAs) during renal impairment is associated with development of NSF. METHODS: A cross-referenced search of kidney transplantation and radiology databases at a single institution revealed the prevalence of NSF in the transplant population. Clinical records and skin biopsy specimens from 6 patients with kidney transplant given a diagnosis of NSF were reviewed to identify contributing factors. RESULTS: Between January 1999 and December 2006, NSF was diagnosed in 6 of 705 patients with kidney transplant (0.9%). Renal function was impaired in all patients. Of 33 patients with kidney transplant exposed to GBCAs, 5 (15.2%) developed NSF. Disease onset ranged from 7 days to 11 months after exposure to GBCAs. All 5 patients exposed to GBCAs who developed NSF were also treated with a beta-blocker and clinical improvement was observed with discontinuation. The sixth case NSF appeared unrelated to Gd, without a known exposure, and testing of tissue via mass spectrometry revealed no Gd. Symptoms of NSF in this patient disappeared after administration of darbepoetin was switched from subcutaneous to intravenous injection. One patient with NSF who manifested the highest Gd level in tissue died 22 months after disease onset. LIMITATIONS: The study represents the retrospective experience of only a single center. CONCLUSIONS: NSF can develop in kidney transplant recipients with altered graft function. In these patients, exposure to GBCAs appears associated with development of NSF. The role of beta-blockers in the course of the disease merits further investigation.

Major histocompatibility complex class 1 chain-related antigen a antibodies: sensitizing events and impact on renal graft outcomes.

BACKGROUND: Major histocompatibility complex class 1 chain-related antigen A (MICA) antibodies (Abs) have been associated with renal graft loss in one large cohort. The triggering factors for MICA Abs and their autologous or allogeneic specificity have not been well defined. More data on the impact of MICA on renal grafts outcome are needed. METHODS: We tested sera from 494 controls and 597 patients with chronic kidney disease (CKD) for MICA using Luminex. Forty CKD MICA+ patients were genotyped for MICA alleles to determine their auto- or allospecificity. We compared MICA+ with MICA- renal transplant recipients with regard to acute rejection episodes and long-term survival. RESULTS: Blood transfusions, previous transplantation, and more than two pregnancies were independent risk factors for the presence of MICA Abs, as were CKD stage V status and male gender. Among the 40 genotyped patients, allo-Abs alone were present in 32 patients, both auto- and allo-Abs in 4 patients, and auto-Abs alone in 4 patients. When we compared MICA+ with MICA- patients, the incidence of acute rejection episodes during the first year (10.2% vs. 12.8%), as well as 1-year creatinine and proteinuria, were similar in both groups. At 10 years, actuarial patient (97.8% vs. 87.6%) and overall graft survival (76% vs. 72%) were similar between MICA+ and MICA- patients. CONCLUSIONS: In summary, (1) sensitizing events for MICA Abs are the same as for human leukocyte antigen Abs; (2) MICA Abs did not adversely affect renal graft outcomes in our cohort.

Late onset of bladder urothelial carcinoma after kidney transplantation for end-stage aristolochic acid nephropathy: a case series with 15-year follow-up.

BACKGROUND: Aristolochic acids are nephrotoxins and predispose to upper-tract urothelial carcinoma. The risk of bladder urothelial carcinoma after kidney transplantation and its relationship to upper-tract urothelial carcinoma is not well defined. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Single-center cohort of 38 women given kidney transplants for end-stage aristolochic acid nephropathy. OUTCOMES & MEASUREMENTS: The prevalence of upper urinary tract urothelial carcinoma was determined by collecting pathological results of specimens obtained by means of bilateral ureteronephrectomy. We also established the cumulative incidence of bladder urothelial carcinoma in biopsies performed during prospective screening cystoscopies during a 15-year follow-up. RESULTS: Upper-tract urothelial carcinoma was found in 17 patients with aristolochic acid nephropathy (44.7%). During follow-up, bladder urothelial carcinoma was diagnosed in 15 patients 68 to 169 months after cessation of aristolochic acid exposure (39.5%): 8 urothelial carcinoma in situ, 4 noninvasive low-grade papillary urothelial carcinoma, and 3 infiltrating urothelial carcinoma. 12 of 17 patients (71%) with a history of upper-tract urothelial carcinoma developed bladder urothelial carcinoma during follow-up, whereas this occurred in only 3 of 21 patients (14%) without upper-tract urothelial carcinoma (P < 0.01). Despite local and/or systemic chemotherapy, 3 patients died and 2 radical cystectomies were performed. LIMITATIONS: Small sample size of this case series. CONCLUSIONS: Upper-tract and bladder urothelial carcinoma are dramatic complications in kidney transplant recipients with aristolochic acid nephropathy, confirming the carcinogenic properties of aristolochic acids. We identified upper-tract urothelial carcinoma as a potent risk factor for the subsequent development of bladder urothelial carcinoma after kidney transplantation for aristolochic acid nephropathy. Because this complication may occur years after aristolochic acid discontinuation, we suggest regular cystoscopies in addition to the bilateral ureteronephrectomy in kidney transplant recipients with aristolochic acid nephropathy.