Dolores Redondo-Pachón

Adaptive NKG2C+ NK Cell Response and the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients

CMV infection in kidney transplant recipients (KTRs) has been associated with an increased risk for graft loss and reduced host survival. CMV promotes persistent expansions of NK cells expressing the CD94/NKG2C receptor. The NKG2C (KLRC2) gene is frequently deleted, and copy number influences the adaptive response of NKG2C+ NK cells. The distribution of NKG2C+ NK cells and NKG2C genotypes (NKG2C+/+, NKG2C+/del, NKG2Cdel/del) were studied in cross-sectional (n = 253) and prospective (n = 122) KTR cohorts. Assessment of CMV viremia was restricted to symptomatic cases in the retrospective study, but was regularly monitored in the prospective cohort. Overall, the proportions of NKG2C+ NK cells were significantly higher in KTRs who had suffered posttransplant symptomatic CMV infection in the cross-sectional study. Yet, along the prospective follow-up (3, 6, 12, and 24 mo), posttransplant NKG2C+ NK cell expansions were not observed in every patient with detectable viremia who received preemptive antiviral therapy, suggesting that the adaptive NK cell response may be inversely related with the degree of CMV control. Remarkably, the incidence of posttransplant viremia was reduced among cases with high pretransplant levels of NKG2C+ NK cells. The NKG2C genotype distribution was comparable in KTR and healthy controls, and greater proportions of NKG2C+ cells were detected in NKG2C+/+ than in NKG2C+/del patients. Yet, a trend toward increased NKG2C+/del and reduced NKG2C+/+ frequencies associated with symptomatic infection was appreciated in both cohorts. Altogether, our results indirectly support that adaptive NKG2C+ NK cells are involved in the control of CMV in KTRs.

Bone Density, Microarchitecture, and Tissue Quality Long-term After Kidney Transplant.

Background Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is used to assess bone health in kidney transplant recipients (KTR). Trabecular bone score and in vivo microindentation are novel techniques that directly measure trabecular microarchitecture and mechanical properties of bone at a tissue level and independently predict fracture risk. We tested the bone status of long-term KTR using all 3 techniques. Methods Cross-sectional study including 40 KTR with more than 10 years of follow-up and 94 healthy nontransplanted subjects as controls. Bone mineral density was measured at lumbar spine and the hip. Trabecular bone score was measured by specific software on the dual-energy x-ray absorptiometry scans of lumbar spine in 39 KTR and 77 controls. Microindentation was performed at the anterior tibial face with a reference-point indenter device. Bone measurements were standardized as percentage of a reference value, expressed as bone material strength index (BMSi) units. Multivariable (age, sex, and body mass index-adjusted) linear regression models were fitted to study the association between KTR and BMD/BMSi/trabecular bone score. Results Bone mineral density was lower at lumbar spine (0.925 ± 0.15 vs 0.982 ± 0.14; P = 0.025), total hip (0.792 ± 0.14 vs 0.902 ± 0.13; P < 0.001), and femoral neck (0.667 ± 0.13 vs 0.775 ± 0.12; P < 0.001) in KTR than in controls. BMSi was also lower in KTR (79.1 ± 7.7 vs 82.9 ± 7.8; P = 0.012) although this difference disappeared after adjusted model (P = 0.145). Trabecular bone score was borderline lower (1.21 ± 0.14 vs 1.3 ± 0.15; adjusted P = 0.072) in KTR. Conclusions Despite persistent decrease in BMD, trabecular microarchitecture and tissue quality remain normal in long-term KTR, suggesting important recovery of bone health.

Strategies for an Expanded Use of Kidneys From Elderly Donors

Abstract The old-for-old allocation policy used for kidney transplantation (KT) has confirmed the survival benefit compared to remaining listed on dialysis. Shortage of standard donors has stimulated the development of strategies aimed to expand acceptance criteria, particularly of kidneys from elderly donors. We have systematically reviewed the literature on those different strategies. In addition to the review of outcomes of expanded criteria donor or advanced age kidneys, we assessed the value of the Kidney Donor Profile Index policy, preimplantation biopsy, dual KT, machine perfusion and special immunosuppressive protocols. Survival and functional outcomes achieved with expanded criteria donor, high Kidney Donor Profile Index or advanced age kidneys are poorer than those with standard ones. Outcomes using advanced age brain-dead or cardiac-dead donor kidneys are similar. Preimplantation biopsies and related scores have been useful to predict function, but their applicability to transplant or refuse a kidney graft has probably been overestimated. Machine perfusion techniques have decreased delayed graft function and could improve graft survival. Investing 2 kidneys in 1 recipient does not make sense when a single KT would be enough, particularly in elderly recipients. Tailored immunosuppression when transplanting an old kidney may be useful, but no formal trials are available. Old donors constitute an enormous source of useful kidneys, but their retrieval in many countries is infrequent. The assumption of limited but precious functional expectancy for an old kidney and substantial reduction of discard rates should be generalized to mitigate these limitations.

Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter, prospective, randomized, double-blind clinical trial

There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo‐controlled, double‐blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010‐023746‐67). Patients with transplant glomerulopathy and anti‐HLA donor‐specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012‐2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (−4.2 ± 14.4 vs. −6.6 ± 12.0 mL/min per 1.73 m2, P‐value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P‐value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.

Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation

Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value.

Impact of preformed and de novo anti-HLA DP antibodies in renal allograft survival.

The influence of antibodies against HLA-DP antigens detected with solid-phase assays on graft survival after kidney transplantation (KT) is uncertain. We evaluated with Luminex® the prevalence of pre- and posttransplant DP antibodies in 440 KT patients and their impact on graft survival. For 291 patients with available pretransplant samples, DP antibodies were present in 39.7% KT with pretransplant HLA antibodies and 47.7% with DSA. Graft survival of KT with pretransplant class-II DSA was worse than with non-DSA (p=0.01). DP antibodies did not influence graft survival. Of 346 patients monitored post-KT, 17.1% had HLA class-II antibodies, 56% with DP antibodies. Class-II DSA was detected in 39%, 60.9% of them had DP antibodies. Graft survival was worse in patients with class-II DSA (p=0.022). DP antibodies did not change these results. The presence of isolated DP antibodies was a rare event both pre- and posttransplantation (1.03 and 0.86%). The presence of pretransplant and posttransplant DSA is associated with a negative impact on graft survival. However, the presence of DP antibodies does not modify this impact significantly.

Dual kidney transplantation as a strategy to use expanded criteria donors: a systematic review

The objective of this review was to assess whether dual kidney transplantation (DKT) is better than single KT (SKT) for optimizing the use of expanded criteria donor kidneys. We did a systematic literature search and meta‐analyses when possible, pooling data for calculating relative risks (RR) of major outcomes. Twenty‐five studies met the inclusion criteria. One‐year serum creatinine was better after DKT vs. SKT (mean difference −0.27 [−0.37, −0.17], P < 0.001), with less incidence of acute rejection (RR 0.66 [0.52, 0.85], P < 0.001) and without differences at five years. Less DGF was seen in DKT (RR 0.88 [0.76, 1.02], P = 0.09). Mortality at 1 and 3 years was similar after dual or SKT, but mortality at five years was lower after DKT (RR 0.71 [0.53, 0.94], P = 0.02). One‐year graft loss was similar between dual (n = 4158) and SKT (n = 51 800) (RR 0.97 [0.87, 1.09], P = 0.62). Three‐ and five‐year graft loss was not considered because of high heterogeneity between studies. In conclusion, short‐term graft function and long‐term patient survival are better in recipients receiving DKT vs. SKT. However, these differences are based on few retrospective reports with a relatively low number of cases. Good quality randomized controlled trials are needed to assess whether the investment of two kidneys in one recipient is justified in face of the current organ shortage.

Usefulness of the KDPI in Spain: A comparison with donor age and definition of standard/expanded criteria donor

INTRODUCTION Kidney donor shortage requires expanding donor selection criteria, as well as use of objective tools to minimize the percentage of discarded organs. Some donor pre-transplant variables such as age, standard/expanded criteria donor (SCD/ECD) definition and calculation of the Kidney Donor Profile Index (KDPI), have demonstrated correlations with patient and graft outcomes. We aimed to establish the accuracy of the three models to determine the prognostic value of kidney transplantation (KT) major outcomes. MATERIAL AND METHODS We performed a retrospective study in deceased donor KTs at our institution. Unadjusted Cox and Kaplan-Meier survival, and multivariate Cox analyses were fitted to analyze the impact of donor age, SCD/ECD and KDPI on outcomes. RESULTS 389 KTs were included. Mean donor age was 53.6±15.2 years; 163 (41.9%) came from ECD; mean KDPI was 69.4±23.4%. Median follow-up was 51.9 months. The unadjusted Cox and Kaplan-Meier showed that the three prognostic variables of interest were related to increased risk of patient death, graft failure and death-censored graft failure. However, in the multivariate analysis only KDPI was related to a higher risk of graft failure (HR 1.03 [95% CI 1.01-1.05]; p=0.014). CONCLUSIONS SCD/ECD classification did not provide significant prognostic information about patient and graft outcomes. KDPI was linearly related to a higher risk of graft failure, providing a better assessment. More studies are needed before using KDPI as a tool to discard or accept kidneys for transplantation.

Impact of persistent and cleared preformed HLA DSA on kidney transplant outcomes

Preformed HLA donor-specific antibodies (DSA) only detected with Luminex have been associated with increased risk of antibody-mediated rejection (ABMR) and graft failure after kidney transplantation (KT). Their evolution after KT may modify this risk. We analyzed postransplant evolution of preformed DSA identified retrospectively and their impact on outcomes of 370 KT performed 2006-2014. Antibodies were monitored prospectively at 1-3-5 years after KT and if any dysfunction. Early acute ABMR was more frequent among patients with preformed DSA class-I or I + II than isolated class-II (29.4% vs 4.5%, p = 0.02). One year post-KT, 20 of 34 patients with functioning KT had persistent DSA. Preformed DSA class-II persisted more frequently than class-I/I + II (66.7% vs 33.3%; p = 0.031). The only risk factor independently associated with persistence was pretransplant MFI. Patients with de novo DSA had the highest risk of ABMR (HR 22.2 [CI 6.1-81.2]). Although recipients with persisting preformed DSA had significantly increased ABMR risk (HR 14.7 [CI 6.5-33.0]), those with cleared preformed DSA also had a higher risk than those without DSA (HR 7.01 [CI 2.2-21.8]). Preformed DSA are a very important risk factor for ABMR and graft loss. Patients who clear preformed DSA still show an increased risk of ABMR and graft loss after KT.

Maintenance low dose systemic glucocorticoids have limited impact on bone strength and mineral density among incident renal allograft recipients: A pilot prospective cohort study

Soon after kidney transplant (KT), a decrease in parathormone and bone mineral density (BMD) occur, but little is known on the impact of KT on novel bone quality parameters including trabecular bone score (TBS) and bone material strength index (BMSi). We aimed to study BMD, TBS and BMSi in the first year after KT, in patients not treated with any bone therapy. A cohort including 36 patients underwent KT on a low-glucocorticoid-dose protocol (5 mg daily-prednisone from post-operative-day 42 onwards) and was observed for 12 months prospectively. At 3 months, phosphorus and parathormone decreased, while calcium increased. We also observed at 3 months a transient mild 2.9% bone loss at femoral neck (BMD change 0.752 ± 0.15 vs 0.730 ± 0.15; p = 0.004), but no change at either spine or total hip. Both TBS and BMSi remained stable. At 12 months, lumbar (but not total hip or femoral neck) BMD slightly decreased by 2.1% vs baseline (0.950 ± 0.15 vs 0.930 ± 0.5; p = 0.046), while TBS and BMSi remained unmodified. In KT patients on low-dose glucocorticoids and no bone therapy, there were small BMD decreases at femoral neck (at 3 months) and lumbar spine (at 12 months), but no change in either TBS or BMSi. Low-dose post-KT glucocorticoid treatment shows limited impact on bone, supporting steroid-restrictive protocols.