Michiel G.H. Betjes

Immune cell dysfunction and inflammation in end-stage renal disease

Uraemia causes inflammation and reduces immune system function as evidenced by an increased risk of viral-associated cancers, increased susceptibility to infections and decreased vaccination responses in patients with end-stage renal disease (ESRD). The substantially increased risk of atherosclerosis in these patients is also probably related to uraemia-associated inflammation. Uraemia is associated with a reduction in the number and function of lymphoid cells, whereas numbers of myeloid cells in uraemic patients are normal or increased with increased production of inflammatory cytokines and reactive oxygen species. Similar to healthy elderly individuals, patients with ESRD have increased numbers of specific proinflammatory subsets of T cells and monocytes, suggesting the presence of premature immunological ageing in these patients. These cells might contribute to inflammation and destabilization of atherosclerotic plaques, and have, therefore, been identified as novel nonclassical cardiovascular risk factors. The cellular composition of the immune system does not normalize after successful kidney transplantation despite a rapid reduction in inflammation and oxidative stress. This finding suggests that premature ageing of the immune system in patients with ESRD might be related to a permanent skewing of the haematopoetic stem cell population towards myeloid-generating subsets, similar to that seen in healthy elderly individuals.

Frequency, determinants, and prognostic effects of acute kidney injury and red blood cell transfusion in patients undergoing transcatheter aortic valve implantation

Objectives: To determine the frequency and independent predictors of acute kidney injury (AKI) in addition to the prognostic implications of both AKI and periprocedural red blood cell (RBC) transfusions on 30 day and cumulative late mortality in patients undergoing transcatheter aortic valve implantation (TAVI). Background: RBC transfusions have been reported to predict AKI following TAVI. Data on the prognostic implications of both factors, however, are lacking. Methods: 126 consecutive patients underwent TAVI with the Medtronic CoreValve Revalving System. AKI was defined according to the valve academic research consortium definitions as an absolute increase in serum creatinine ≥0.3 mg dL−1 (≥26.4 μmol L−1) or a percentage increase ≥50% within 72 hr following TAVI. Results: Five patients on chronic haemodialysis and three intraprocedural deaths were excluded, leading to a final study population of 118 patients. AKI occurred in 19% of the patients necessitating temporary haemodialysis in 2%. Independent predictors of AKI included: previous myocardial infarction (OR: 5.72; 95% CI: 1.64–19.94), periprocedural (<24 hr) RBC transfusions (OR: 1.29; 95% CI: 1.01–1.70), postprocedural (<72 hr) leucocyte count (OR: 1.18; 95% CI: 1.02–1.37), and logistic EuroSCORE (OR: 1.08; 95% CI: 1.01–1.14). In patients with AKI, 30‐day mortality was 23% and cumulative late mortality (median: 13 months) was 55%. AKI (OR: 5.47; 95% CI: 1.23–24.21) and postprocedural leucocyte count (OR: 1.20; 95% CI: 1.03–1.38) were independent predictors of 30‐day mortality while AKI (HR: 2.79; 95% CI: 1.36–5.71) was the only independent predictor of late mortality. Conclusions: AKI following TAVI occurred in 19% of the patients. RBC transfusion was found to be an independent predictor of AKI, which in turn predicted both 30‐day and cumulative late mortality.

Premature aging of circulating T cells in patients with end-stage renal disease

Progressive loss of renal function is associated with a dysregulation of circulating T cells that may underlie their impaired T-cell immunity. Here we tested whether end-stage renal disease (ESRD)-related T-cell alterations are compatible with the concept of premature immunological aging. Younger patients (25-45 years old) with ESRD were found to resemble older healthy controls (60-80 years old) as they had a significant loss of naive T cells and a relative increase of memory T cells showing progressive terminal differentiation. A significant decrease in the content of T-cell receptor excision circles and telomere length in patients with ESRD confirmed these phenotypic data. The loss of naive T cells in patients with ESRD was associated with an excessive age-related decrease of recent thymic emigrants, indicating a premature decline in thymic function. Additionally, increased homeostatic proliferation of naive T cells was found in patients with ESRD, similar to that of older healthy individuals, with an increased susceptibility for activation-induced apoptosis. Therefore, both decreased thymic output and increased susceptibility of naive T cells for apoptosis may play a role in the loss of naive T cells in ESRD patients. Thus, our results are compatible with premature aging of the T-cell system of patients with ESRD comparable with that of healthy individuals 20-30 years older.

Expansion of cytolytic CD4+CD28− T cells in end-stage renal disease

Cytomegalovirus (CMV) seropositivity is associated with increased risk for atherosclerotic disease in patients with end-stage renal disease. This association is due to a unique peripheral blood CD4(+) T cell population which lack CD28 (CD4(+)CD28(-) T cells). Here we found that this patient population has a significant age-dependent increase of CD4(+)CD28(-) T cells that comprise over half of the circulating CD4 T cells in some. Patients over 50 years of age have a 50-fold higher percentage of CD4(+)CD28(-) T cells compared to seronegative patients and a 5-fold higher percentage when compared to seropositive healthy controls. Stimulation by CMV-antigen or by polyclonal stimulation using PMA and ionomycin showed that CD4(+)CD28(-) cells in patients with end stage renal disease degranulated and secreted interferon gamma thus indicating that they are cytolytic. The average anti-CMV IgG titer displayed a remarkable age-dependent increase only in patients with end stage renal disease. These findings are highly suggestive of repetitive antigenic stimulation of the immune system in patients with end stage disease by subclinical CMV reactivation which might contribute to increased atherosclerotic risk.

Hyponatremia and Inflammation: The Emerging Role of Interleukin-6 in Osmoregulation

Although hyponatremia is a recognized complication of several inflammatory diseases, its pathophysiology in this setting has remained elusive until recently. A growing body of evidence now points to an important role for interleukin-6 in the non-osmotic release of vasopressin. Here, we review this evidence by exploring the immuno-neuroendocrine pathways connecting interleukin-6 with vasopressin. The importance of these connections extends to several clinical scenarios of hyponatremia and inflammation, including hospital-acquired hyponatremia, postoperative hyponatremia, exercise-associated hyponatremia, and hyponatremia in the elderly. Besides insights in pathophysiology, the recognition of the propensity for antidiuresis during inflammation is also important with regard to monitoring patients and selecting the appropriate intravenous fluid regimen, for which recommendations are provided.

Encapsulating peritoneal sclerosis: the state of affairs

Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) with a 50% mortality rate. EPS is characterized by progressive and excessive fibrotic thickening of the peritoneum, leading to encapsulation of the bowels and intestinal obstruction. At present, EPS cannot be detected with certainty during its early stages; however, a progressive loss of ultrafiltration capacity often precedes its development. Studies that attempted to elucidate the pathogenesis of EPS have shown that the duration of exposure to PD fluids is the most important risk factor for EPS, and that young age and possibly the effects of peritonitis are additional contributory factors. The pathophysiology of EPS is probably best described as a multiple-hit process with a central role for transforming growth factor β. A form of EPS that develops shortly after kidney transplantation has also been recognized as a distinct clinical entity, and may be a common form of EPS in countries with a high transplantation rate. Criteria have been developed to identify EPS by abdominal CT scan at the symptomatic stage, but further clinical research is needed to identify early EPS in asymptomatic patients, to clarify additional risk factors for EPS and to define optimal treatment strategies.

Effects of hypoxia on the immunomodulatory properties of adipose tissue-derived mesenchymal stem cells

Adipose tissue-derived mesenchymal stem cells (ASC) are of great interest as a cellular therapeutic agent for regenerative and immunomodulatory purposes. The function of ASC adapts to environmental conditions, such as oxygen tension. Oxygen levels within tissues are typically much lower than under standard culture conditions and ASC used for therapy therefore encounter a change from normoxic to hypoxic conditions. The effect of hypoxia on the regenerative potential of ASC has been investigated in a number of studies. The effect of hypoxia on the immunomodulatory function of ASC, however, remains to be determined. In the present study the effect of hypoxic (1% oxygen) culture conditions on human ASC was examined. ASC showed no signs of toxicity under low oxygen levels and no major immunophenotypical changes were observed, apart from a down regulation of the marker CD105. Oxygen tension had no effect on the proliferation of ASC and colony forming unit efficiency remained the same under 1 and 20% oxygen. Under both oxygen levels ASC were capable of strong upregulation of the immunomodulatory molecules indoleamine 2,3-dioxygenase (IDO) and programed death ligand-1 upon stimulation with IFN-γ and TNF-α, and, in addition, IDO activity as measured by the accumulation of l-kynurenine was not affected under hypoxia. The ability of ASC to inhibit anti-CD3/CD28 stimulated CD4+ and CD8+ T cell proliferation was not hampered by hypoxia. The results of the present study demonstrate that the immunosuppressive capacity of ASC is maintained under hypoxic conditions. These findings are important for the therapeutic use of ASC and may be applied for the in vitro generation of ASC with improved functionality for therapeutic use.

RISK FACTORS ASSOCIATED WITH ENCAPSULATING PERITONEAL SCLEROSIS IN DUTCH EPS STUDY

♦ Objective: Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with a multifactorial pathophysiology and possible increasing incidence. The aim of the present study was to evaluate the independent associations of PD duration, age, dialysis fluids, and kidney transplantation with EPS. ♦ Methods: A multicenter case–control study was performed in the Netherlands from 1 January 1996 until 1 July 2007. The population comprised 63 patients with EPS and 126 control patients. Control patients were selected from the national registry and were matched for date of PD start. Associations were analyzed using a log linear regression model. Primary outcome was appearance of EPS. ♦ Results: Compared with control patients, patients with EPS were younger at the start of PD (34.7 ± 15.4 years vs. 51.5 ± 14.7 years, p < 0.0001). The cumulative period on PD was longer in EPS patients than in control patients (78.7 ± 37.8 months vs. 32.8 ± 24 months, p < 0.0001), and the cumulative period on icodextrin was also longer in EPS patients (32.7 ± 23.3 months vs. 18.1 ± 15.7 months, p = 0.006). Compared with control patients, more EPS patients underwent kidney transplantation (47 vs. 59, p < 0.0001). With regard to the period after transplantation, the yearly probability of EPS increased in the year after transplantation to 7.5% from 1.75%. In multivariate regression analysis, cumulative PD duration, age at PD start, transplantation, time from last transplantation to EPS, calendar time, time on icodextrin, and ultrafiltration failure were independently associated with EPS. Transfer from PD to hemodialysis for reasons other than suspected EPS could not be identified as a risk factor for EPS. ♦ Conclusions: Duration of PD, age at PD start, kidney transplantation, time since last transplantation, ultrafiltration failure, and time on icodextrin were associated with a higher risk of EPS.

Human Adipose Tissue-Derived Mesenchymal Stem Cells Abrogate Plasmablast Formation and Induce Regulatory B Cells Independently of T Helper Cells

Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B‐cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue‐derived MSC (ASC) interact with B cells to affect their proliferation, differentiation, and immune function. ASC supported the survival of quiescent B cells predominantly via contact‐dependent mechanisms. Coculture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19+CD27highCD38high antibody‐producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B‐cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL‐10‐producing CD19+CD24highCD38high B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B‐cell response in immune disease. Stem Cells 2015;33:880–891

Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting: Lessons Learned from First Clinical Trials

The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of preclinical data into early clinical settings. This position paper highlights the main topics explored on the safety and efficacy of mesenchymal stem cells as a therapeutic agent in solid organ transplantation and emphasizes the issues (proper timing, concomitant immunossupression, source and immunogenicity of mesenchymal stem cells, and oncogenicity) that have been addressed and will be followed up by the MiSOT Consortium in future studies.