Although the benefits of moderate exercise in patients at high cardiovascular risk are well established, the effects of strenuous exercise remain unknown. We aimed to study the impact of strenuous ...exercise in a very high cardiovascular risk model. Nephrectomized aged Zucker obese rats were trained at a moderate (MOD) or high (INT) intensity or were kept sedentary (SED) for 10 weeks. Subsequently, echocardiography and ex vivo vascular reactivity assays were performed, and blood, aortas, perivascular adipose tissue (PVAT), and left ventricles (LVs) were harvested. An improved risk profile consisting of decreased body weight and improved response to a glucose tolerance test was noted in the trained groups. Vascular reactivity experiments in the descending thoracic aorta demonstrated increased endothelial NO release in the MOD group but not in the INT group, compared with SED; the free radical scavenger TEMPOL improved endothelial function in INT rats to a similar level as MOD. An imbalance in the expression of oxidative stress-related genes toward a pro-oxidant environment was observed in the PVAT of INT rats. In the heart, INT training promoted eccentric hypertrophy and a mild reduction in ejection fraction. Obesity was associated with LV fibrosis and a transition toward β-myosin heavy chain and the N2Ba titin isoform. Exercise reverted the myosin imbalance, but only MOD reduced the predominance of the N2Ba titin isoform. In conclusion, moderate exercise yields the most intense cardiovascular benefits in a high-cardiovascular-risk animal model, while intense training partially reverts them.
ObjectiveImprovement in insulin alternatives is leading to a delayed presentation of microvascular and macrovascular complications of diabetes. The objective of this study was to evaluate the ...long-term outcomes of older (≥50 years) diabetic patients who receive a pancreas transplantation (PT).Research design and methodsWe retrospectively evaluated all 338 PTs performed at our center between 2000 and 2016 (mean follow-up 9.4±4.9 years). Recipient and graft survivals were estimated for up to 10 years after PT. Major adverse cardiovascular events (MACEs) before and after PT were included in the analysis.ResultsThirty-nine patients (12%) were ≥50 years old (52.7±2.3 years) at the day of PT, of which 29 received a simultaneous pancreas–kidney transplantation (SPK) and 10 a pancreas after kidney transplantation (PAK). SPK recipients were first transplants, whereas in the PAK up to 50% were pancreas re-transplantations. Recipient and pancreas graft survivals at 10 years were similar between the group <50 years old and the older group for both SPK and PAK (log-rank p>0.05). The prevalence of MACE prior to PT was similar between both groups (31% vs 29%). Following PT, older recipients presented inferior post-transplant MACE-free survival. In a multivariate regression model, diabetes vintage (HR 1.054, p=0.03) and pre-transplantation MACE (HR 1.98, p=0.011), but not recipient age (HR 1.45, p=0.339), were associated with post-transplant MACE.ConclusionsLong-term survival of older pancreas transplant recipients are similar to younger counterparts. Diabetes vintage, but not age, increased the risk of post-transplantation MACE. These results suggest pancreas transplantation is a valuable treatment alternative to older diabetic patients.
Mesenchymal stromal cells (MSCs) from different sources possess great therapeutic potential due to their immunomodulatory properties associated with allograft tolerance. However, a crucial role in ...this activity resides in extracellular vesicles (EVs) and signaling molecules secreted by cells. This study aimed to evaluate the immunomodulatory properties of donor and recipient MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs on kidney outcome in a rat kidney transplant model.
The heterotopic-kidney-transplant Fisher-to-Lewis rat model (F-L) was performed to study mixed cellular and humoral rejection. After kidney transplantation, Lewis recipients were assigned to 10 groups; two control groups; four groups received autologous MSCs (either AD- or BM- MSC) or EVs (derived from both cell types); and four groups received donor-derived MSCs or EVs. AD and BM-EVs were purified by ultracentrifugation. Autologous cell therapies were administered three times intravenously; immediately after kidney transplantation, 4 and 8 weeks, whereas donor-derived cell therapies were administered once intravenously immediately after transplantation. Survival and renal function were monitored. Twelve weeks after kidney transplantation grafts were harvested, infiltrating lymphocytes were analyzed by flow cytometry and histological lesions were characterized.
Autologous AD- and BM-MSCs, but not their EVs, prolonged graft and recipient survival in a rat model of kidney rejection. Autologous AD- and BM-MSCs significantly improved renal function during the first 4 weeks after transplantation. The amelioration of graft function could be associated with an improvement in tubular damage, as well as in T, and NK cell infiltration. On the other side, the application of donor-derived AD-MSC was harmful, and all rats died before the end of the protocol. AD-EVs did not accelerate the rejection. Contrary to autologous MSCs results, the single dose of donor-derived BM-MSCs is not enough to ameliorate kidney graft damage.
EVs treatments did not exert any benefit in our experimental settings. In the autologous setting, BM-MSCs prompted as a potentially promising therapy to improve kidney graft outcomes in rats with chronic mixed rejection. In the donor-derived setting, AD-MSC accelerated progression to end-stage kidney disease. Further experiments are required to adjust timing and dose for better long-term outcomes.
Obesity increases the risk of developing chronic kidney disease (CKD), which has a major negative impact on global health. Bariatric surgery (BS) has demonstrated a substantial improvement of ...obesity-related comorbidities and thus, it has emerged as a potential therapeutic tool in order to prevent end-stage renal disease. A limited number of publications to date have examined the beneficial effects and risks of BS in patients with non-advanced stages of CKD. We aimed to investigate the safety of BS in patients with CKD stages 3–4 (directly related or not to obesity) and both the metabolic/renal outcomes post-BS. A total of 57 individuals were included (n = 19 for CKD-group; n = 38 for patients with obesity, but normal eGFR control-group). Weight loss and obesity comorbidities resolution after BS were similar in both groups. Renal function (eGFR CKD-EPI) improved significantly at the 1-year follow-up: Δ10.2 (5.2–14.9) (p < 0.001) for CKD-group and Δ4.0 (−3.9–9.0) mL/min/1.73 m2 (p = 0.043) for controls. Although this improvement tended to decrease in the 5-year follow-up, eGFR remained above its basal value for the CKD-group. Noteworthy, eGFR also improved in those patients who presented CKD not directly attributed to obesity. For patients with CKD, BS appears to be safe and effective regarding weight loss and obesity comorbidities resolution, irrespective of the main cause of CKD (related or not to obesity).
We aimed to determine the epidemiology, risk factors, and impact of bacterial infection on pancreatic function after pancreas transplantation. Data for pancreas transplant recipients were ...retrospectively reviewed between 2000 and 2014 for at least 1 year. We collected and analyzed post‐transplant data for bacterial infection, morbidity, and mortality. During the study period, 312 pancreas transplants were performed. In total, 509 episodes of bacterial infection were diagnosed in 191 patients (61%). Multidrug‐resistant (MDR) organisms were present in 173 of the 513 isolated microorganisms (33%). Risk factors independently associated with bacterial infection were acute allograft rejection (OR 1.7, 95%CI 1.1‐3), the need for post‐transplant hemodialysis, (OR 5.3, 95%CI 1.8‐15.7) and surgical re‐intervention (OR 2.8, 95%CI 1.5‐5.1), which was also considered a risk factor for infections caused by MDR bacteria. Graft survival was associated with the occurrence of one or more episodes of bacterial infection (log‐rank test = 0.009). Surgical re‐intervention was independently associated with graft loss (OR 2.5, 95%CI 1.3‐4.7). To conclude, pancreas recipients frequently experienced bacterial infections associated with the need for hemodialysis or surgical re‐intervention. Infection by MDR organisms is a growing concern in these patients and was related to graft survival. Graft loss was independently associated with surgical re‐intervention.
Obesity and kidney transplantation (KTx) are closely related. Obesity increases the risk of chronic kidney disease and can be a relative contraindication for KTx. Besides, KTx recipients are ...predisposed to obesity and its comorbidities. Consequently, bariatric surgery (BS) emerges as a powerful therapeutic tool either before or after KTx. Since evidence regarding the best approach is still scarce, we aimed to describe renal and metabolic outcomes in a single centre with more than 15-year experience in both surgeries. Methods: A retrospective study including patients who had received a KTx either before or after BS. Usual metabolic and renal outcomes, but also new variables (as renal graft dysfunction) were collected for a minimum follow-up of 1-year post-BS. Results: A total of 11 patients were included: n = 6 (BS-post-KTx) and n = 5 (BS-pre-KTx). One patient was assessed in both groups. No differences in the main outcomes were identified, but BS-post-KTx group tended to gain more weight during the follow-up. The incidence of renal graft dysfunction was comparable (4/6 for BS-post-KTx, 3/5 for BS-pre-KTx) between groups. Conclusions: BS in patients with KTx appears to be safe and effective attending to metabolic and renal outcomes. These results seem irrespective of the time course, except for weight regain, which appears to be a common pattern in the BS-post-KTx group.
Living-donor kidney transplant (LDKT) recipients undergoing desensitization for Human Leukocyte Antigen (HLA)-incompatibility have a high risk of developing antibody-mediated rejection (ABMR). The ...purpose of the study is to evaluate if residual B cell activity after desensitization could be estimated by the presence of circulating B cell-derived extracellular vesicles (BEVs).
BEVs were isolated by Sepharose-based size exclusion chromatography and defined as CD19+ and HLA-II+ extracellular vesicles. We analyzed stored serum samples from positive crossmatch LDKT recipients before and after desensitization at first post-transplant biopsy and at 12-month protocol biopsy (
= 11). Control groups were formed by hypersensitized patients who were not submitted to desensitization (
= 10) and by low-risk recipients (
= 9). A prospective validation cohort of 11 patients also included the analysis of B cells subpopulations in recipients' blood and lymph nodes recovered upon graft implantation, along with BEVs analysis before and after desensitization.
We found out that CD19+ and HLA-II+BEVs dropped significantly after desensitization and relapse in patients who later developed ABMR was evident. We validated these findings in a proof-of-concept prospective cohort of 6 patients who received the same desensitization protocol and also in a control group of 5 LDKT recipients. In these patients, B cell subpopulations were also studied in recipients' blood and lymph nodes that were recovered before the graft implantation. We confirmed the significant drop in BEVs after desensitization and that this paralleled the reduction in CD19+cells in lymph nodes, while in peripheral blood B cells, this change was almost undetectable.
BEVs reflected B cell residual activity after desensitization and this could be a valid surrogate of humoral alloreactivity in this setting.
Background:
Despite recent advances in immunosuppression treatment, antibody-mediated rejection (ABMR) remains the leading cause of kidney graft loss. Information about prognostic markers and the ...efficacy of treatment is scarce.
Methods:
Retrospective study with kidney recipients diagnosed an active ABMR from January 1, 2004 to December 31, 2019 to explore the influence of persistent inflammation in follow-up biopsies on graft survival after ABMR treatment.
Results:
About 116 patients were included. Active ABMR were treated with a combination of plasma exchange (PE), intravenous immunoglobulin (IVIg), rituximab, and steroids. At 6 months of treatment, 63 (54.3%) patients presented a stabilization or improvement in kidney-graft function. The effectiveness varied depending on the timepoint of the presentation between transplantation and rejection, which is lower for those with late ABMR (63 vs. 21% for early vs. late ABMR, respectively). Ninety patients (77%) underwent a control biopsy after ABMR treatment, from which 46 (51%) responded to the treatment. Microvascular inflammation (MVI) persisted in 64 (71%) biopsies, whereas tubulitis persisted in 17 (19%) biopsies. Death-censored graft survival at 1 year was significantly lower in patients with persistent MVI (86% vs. 95% without persistent MVI,
P
= 0.002), or with persistent tubulitis (44% vs. 66% without tubulitis,
P
= 0.02). In the Cox Regression analysis, the persistence of MVI hazard ratio (HR), 4.50 (95%CI, 1.35–14.96),
P
= 0.01 and tubulitis HR 2.88 95%CI (1.24–6.69),
P
= 0.01) in follow-up biopsies significantly increased the risk of graft failure.
Conclusion:
Persistent inflammation in follow-up biopsies after ABMR treatment was associated with an increased risk of graft loss, even without meeting Banff rejection criteria.
Study Registration:
Agencia Española de Medicamentos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTRINM-2017-01.
Background.
In kidney transplant recipients, there is discordance between the development of cellular and humoral response after vaccination against SARS-CoV-2. We sought to determine the interplay ...between the 2 arms of adaptive immunity in a 3-dose course of mRNA-1273 100 μg vaccine.
Methods.
Humoral (IgG/IgM) and cellular (N- and S-ELISpot) responses were studied in 117 kidney and 12 kidney-pancreas transplant recipients at the following time points: before the first dose, 14 d after the second dose‚ and before and after the third dose, with a median of 203 and 232 d after the start of the vaccination cycle, respectively.
Results.
After the second dose, 26.7% of naive cases experienced seroconversion. Before the third dose and in the absence of COVID-19, this percentage increased to 61.9%. After the third dose, seroconversion occurred in 80.0% of patients. Naive patients who had at any time point a detectable positivity for S-ELISpot were 75.2% of the population, whereas patients who maintained S-ELISpot positivity throughout the study were 34.3%. S-ELISpot positivity at 42 d was associated with final seroconversion (odds ratio‚ 3.14; 95% confidence interval‚ 1.10-8.96;
P
= 0.032). Final IgG titer was significantly higher in patients with constant S-ELISpot positivity (
P
< 0.001).
Conclusions.
A substantial proportion of kidney transplant recipients developed late seroconversion after 2 doses. Cellular immunity was associated with the development of a stronger humoral response.
Despite the high incidence of posttransplant infections, postinfectious acute glomerulonephritis (PIAGN) in renal allograft is a rare entity, without effective treatment and a bad prognosis. We ...describe two cases of PIAGN: the first one was developed 2 years after kidney transplantation, secondary to Staphylococcus aureus bacteremia with presence of extracapillary proliferation in biopsy. The patient was treated with methylprednisolone and plasma exchanges without response, remaining dialysis dependent. The second case was reported 5 years after kidney transplantation, secondary to influenza A infection. Kidney biopsy showed an IgA-dominant PIAGN and methylprednisolone boluses were initiated without clinical response, suffering a progressive worsening and loss of kidney graft. Due to the aggressive clinical course of this entity, PIAGN should be considered in the differential diagnosis of acute kidney graft failure in the context of an infection. Elderly patients have a higher risk of more severe acute renal dysfunction, requiring dialysis in a great proportion of cases.
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