Christos Evangelos Chadjichristos

Background: Delayed graft function (DGF) is a major early complication after kidney transplantation. Galectin-3 (Gal3), a mediator of inflammation and fibrosis, is associated with renal injury, but its role in predicting DGF remains unclear. This study evaluated whether early postoperative Gal3 levels predict DGF and clinical outcomes. Methods: This single-center retrospective cohort study included adult kidney transplant recipients from deceased donors (January 2021–December 2022). Gal3 was measured preoperatively, at intensive care unit (ICU) admission, and at ICU discharge. The primary outcome was DGF, defined as renal replacement therapy within 7 days. A base clinical model (age, cold ischemia time, creatinine at ICU admission) was compared with a Gal3-extended model, assessed by area under the curve (AUC), Brier score, calibration, bootstrap optimism correction, and categorical net reclassification improvement. Results: Among 182 patients, 35 (19.2%) developed DGF. Gal3 at ICU admission was significantly higher in DGF patients (52.3 vs. 40.0 ng/ml, P < .001) and was independently associated with DGF (odds ratio per 5-ng/ml increase: 1.19; 95% confidence interval: 1.05–1.35; P = .008). Adding Gal3 modestly improved the AUC from 0.705 to 0.744 and the Brier score from 0.144 to 0.139. The Gal3-extended model retained superior discrimination after bootstrap correction. An exploratory prediction score demonstrated increasing DGF risk across score categories. Conclusion: Gal3 measured at ICU admission was independently associated with DGF and provided modest incremental risk-stratification value. External validation is required before clinical implementation.

Cardiorenal syndrome (CRS) encompasses the bidirectional and complex interaction between cardiac and renal dysfunction. The present review focuses on CRS types 3 and 4, highlighting the negative effects of acute kidney injury and chronic kidney disease, respectively, on cardiac function. The present review focuses on pathophysiological mechanisms, associating renal impairment with cardiovascular events, paying particular attention to systemic inflammation, oxidative stress, endothelial damage and neurohormonal activation. From fundamental science to clinical applications, the investigation of CRS remains a challenge. In this context, some experimental models mimicking CRS types 3 and 4 have been used, including 5/6 nephrectomy, unilateral ureteral obstruction, renal ischemia‑reperfusion and adenine‑ or cisplatin‑induced kidney injury. While these models are valuable for studying such disease mechanisms, their limitations in mimicking human pathophysiology are discussed, and their strengths and weaknesses are critically addressed. Advancing and refining preclinical models should be prioritized in future research to enhance clinical relevance and accelerate the development of targeted therapies for CRS.

Increased albuminuria represents a risk factor for chronic kidney disease (CKD), and it is associated with the development and progression of kidney inflammation and fibrosis. The expression of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker for kidney damage, is increased in CKD patients and experimental animal models of kidney damage. However, it is unknown whether NGAL is necessary for the promotion of kidney inflammation and fibrosis associated with the albumin exposition. Male C57BL6/J wild-type (WT) and NGAL (knockout) KO mice (8-12 weeks, n = 5-6) were subjected to the albumin overload (AO) model (10 mg/g/day i.p.) or Vehicle (0.9% NaCl i.p.) for 7 days. Kidney function and inflammatory and fibrotic status in the kidney were assessed. In WT and NGAL-KO mice, AO significantly increased plasma protein (1.3-fold, p < 0.001) and albuminuria (5.6-fold, p < 0.01). In WT mice, AO induced a significant increase in F4/80-positive kidney macrophages, which was prevented in NGAL-KO mice (p < 0.01). This effect was in accordance with the prevention of kidney increases in TNF-α and iNOS mRNA levels after AO (p < 0.05). Finally, AO significantly increased collagen deposition in the kidneys of WT mice (p < 0.05) and the expression of collagen-1, which was prevented in NGAL-KO mice (p < 0.01). Our results suggest that NGAL is required for albumin-induced kidney inflammation and fibrosis in mice in the AO model, which appears to be independent of changes in kidney function.

Galectin-3 (Gal-3) expression is abnormally increased after renal ischemic injury, in various studies, further promoting tissue damage. Gal-3 may interact with the endothelial layer to induce inflammation during renal injury, linking the systemic and tissue compartments. However, this mechanism has not been investigated after acute kidney injury (AKI). To this end, wild-type (WT) and Gal-3-/- mice underwent renal ischemia followed by reperfusion (rIR). Bone marrow transplantation was used to differentiate Gal-3 expression in renal tissue from systemic bone marrow cells. WT mice were injected with recombinant Gal-3 to study systemic issues. Gal-3 expression was assessed by immunofluorescence, western blot, and scRNAseq. Systemic pathways were analyzed with plasma proteomics. Immunofluorescence and scRNAseq showed increased Gal-3 expression after rIR, in different tubular segments and infiltrating immune cells within damaged kidneys. In bone marrow transplanted mice, renal dysfunction, damage, and inflammation were higher when Gal-3 was expressed in renal tissue. Gal-3 upregulation was associated with endothelial activation and renal inflammation after rIR, both of which were prevented in Gal-3-/- mice. Similar results were confirmed by plasma proteomics, as these mice showed reduced endothelial damage and rIR-associated inflammatory pathways. Systemic injection of recombinant Gal-3 increased the endothelial adhesion molecule CD146 expression in the kidney, without promoting renal injury. Interestingly, isolated renal tubules showed increased Gal-3 levels, interacting with CD146 to promote cytokine secretion and immune cell infiltration in the kidney. Thus, Gal-3 may promote endothelial activation via direct interaction with the endothelial activation marker CD146 after AKI, leading to renal injury and further systemic inflammation.

Introduction: Sepsis, the most severe manifestation of infection, remains both common and life-threatening. Beyond the acute phase, growing evidence highlights that sepsis survivors face an increased risk of chronic organ dysfunction, including kidney and heart failure. While early immune mechanisms of sepsis have been extensively studied, the biological processes underlying delayed post-sepsis organ sequelae remain poorly understood. Methods: Using murine models of sepsis, we investigated the long-term impact of sepsis on organ immune landscapes and tissue repair. Fate-mapping experiments were conducted to trace macrophage origin and persistence. Single-cell RNA sequencing of the heart and kidney was performed to characterize macrophage subpopulations and transcriptional reprogramming following sepsis. Functional consequences of this immune remodeling were assessed by challenging post-septic animals with angiotensin II to evaluate secondary injury susceptibility and fibrotic remodeling. Results: Sepsis induced transient multiorgan failure but led to a sustained expansion of tissue macrophages. Fate-mapping demonstrated that this expansion was largely driven by the recruitment and engraftment of monocyte-derived macrophages. Single-cell transcriptomic analyses revealed that post-septic macrophages acquired a distinct proinflammatory and profibrotic signature, consistent with persistent microenvironmental activation. Functionally, this altered macrophage landscape impaired organ resilience, as evidenced by increased mortality and exacerbated cardiac and renal fibrosis upon secondary challenge. Discussion: Our findings identify macrophage reprogramming as a central mechanism linking sepsis to long-term organ vulnerability. The persistence of monocyte-derived macrophages with maladaptive transcriptional profiles promotes fibrotic remodeling and impaired tissue repair. Targeting macrophage recruitment or reprogramming may represent a promising strategy to prevent chronic organ failure among sepsis survivors. SIGNIFICANCE STATEMENT: Sepsis survivors often develop chronic organ dysfunction, yet the mechanisms linking acute infection to long-term damage remain unclear. We show that sepsis triggers expansion of inflammatory and profibrotic macrophages derived from bone marrow precursors in the kidney and heart. These alterations were associated with impaired organ resilience to subsequent injury, which suggest macrophage-driven maladaptive repair as a potential target to improve long-term outcomes after sepsis.

Sepsis is a life-threatening condition affecting, each year, an estimated 49 million people and causing 11 million deaths. Short-term mortality of sepsis was substantially reduced during the past decades and is still improving. Besides its short-term lethality, awareness regarding long-term consequences of sepsis is rising. Among all organs affected during sepsis, the kidney is the most vulnerable. Up to 40% of patients suffering from sepsis develop AKI, and sepsis is the leading cause of AKI among critically ill patients. Half of patients will recover from AKI during their stay; however, several studies have pointed out that those patients were at higher risk for the development of subsequent CKD. In patients suffering from transient AKI, a second injury was found to hasten kidney fibrogenesis. Taken together those findings challenge the concept of ad integrum recovery and strongly suggest maladaptive repair AKI, together with profound and durable alterations at the intraorgan level. Factors driving AKI to CKD after sepsis are poorly understood and could be of multiple origins. Kidney macrophages have pleiotropic roles in health and disease. After sepsis, a proportion of kidney macrophages undergoes pyroptosis in an “altruist” maneuver to recruit inflammatory cells. Empty niches are later colonized by circulating monocyte arising from bone marrow in a process called emergency myelopoiesis but also by expansion of resident cells. The role of monocytes and macrophages in the acute phase of sepsis is well described; however, their role in the resolution of inflammation is just beginning to be understood. In the present review, we will discuss the fate of kidney resident macrophages and recruited monocytes in sepsis-induced AKI. We will review the evidence linking changes in the immune landscape and maladaptive repair after sepsis. Finally, we will consider how targeting macrophage recruitment and polarization might influence sepsis long-term consequences.

Background: We have previously reported that the gap junction protein connexin 43 (Cx43) was upregulated in chronic renal disease in humans and rodents and plays a crucial role in the progression of experimental nephropathy. In this study, we investigated its role after renal ischemia/reperfusion (rIR), which is a major mechanism of injury in acute renal injury (AKI) and renal transplant graft dysfunction. Methods: Wild-type mice (WT) and mice in which Cx43 expression was genetically reduced by half (Cx43 ±) were unilaterally nephrectomized. The left renal artery was subsequently clamped, with reperfusion of varying duration. Mice with tubular- or endothelial-specific deletion of Cx43 were also used to assess the effect of this connexin in each cell type after rIR. Kidneys were assessed for histological evaluation, immunohistochemistry, and RT-PCR. Results: Blood urea nitrogen and creatininemia were progressively elevated in WT mice and picked up 48 h after rIR. At the same time point, severe tubular necrosis and dilation occurred in the cortico-medullary junction of the injured kidneys with accompanying massive neutrophil infiltration. Interestingly, Cx43 expression was progressively increased within the tubulointerstitial compartment during kidney damage progression and was paralleled closely by that of markers of renal dysfunction. Cx43 ± mice showed fewer tubular lesions, less inflammation, and further improved renal function. Similar results were observed in mice where Cx43 was specifically deleted within the vascular endothelium. In contrast, Cx43 deletion in renal tubules did not significantly improve renal structure and function after rIR. Conclusion: Our findings suggest that endothelial Cx43 plays a crucial role in AKI.

The glomerular filtration barrier (GFB), composed of endothelial cells, glomerular basement membrane, and podocytes, is a unique structure for filtering blood while detaining plasma proteins according to size and charge selectivity. Structurally, the fenestrated endothelial cells, which align the capillary loops, are in close proximity to mesangial cells. Podocytes are connected by specialized intercellular junctions known as slit diaphragms and are separated from the endothelial compartment by the glomerular basement membrane. Podocyte-endothelial cell communication or crosstalk is required for the development and maintenance of an efficient filtration process in physiological conditions. In pathological situations, communication also has an essential role in promoting or delaying disease progression. Podocytes and endothelial cells can secrete signaling molecules, which act as crosstalk effectors and, through binding to their target receptors, can trigger bidirectional paracrine or autocrine signal transduction. Moreover, the emerging evidence of extracellular vesicles derived from various cell types engaging in cell communication has also been reported. In this review, we summarize the principal pathways involved in the development and maintenance of the GFB and the progression of kidney disease, particularly in kidney transplantation.

Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials.