Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.

Tertiary hyperparathyroidism is a common cause of hypercalcemia after kidney transplant. We designed this 12-month, prospective, multicenter, open–label, randomized study to evaluate whether subtotal parathyroidectomy is more effective than cinacalcet for controlling hypercalcemia caused by persistent hyperparathyroidism after kidney transplant. Kidney allograft recipients with hypercalcemia and elevated intact parathyroid hormone (iPTH) concentration were eligible if they had received a transplant ≥6 months before the study and had an eGFR>30 ml/min per 1.73 m². The primary end point was the proportion of patients with normocalcemia at 12 months. Secondary end points were serum iPTH concentration, serum phosphate concentration, bone mineral density, vascular calcification, renal function, patient and graft survival, and economic cost. In total, 30 patients were randomized to receive cinacalcet (n=15) or subtotal parathyroidectomy (n=15). At 12 months, ten of 15 patients in the cinacalcet group and 15 of 15 patients in the parathyroidectomy group (P=0.04) achieved normocalcemia. Normalization of serum phosphate concentration occurred in almost all patients. Subtotal parathyroidectomy induced greater reduction of iPTH and associated with a significant increase in femoral neck bone mineral density; vascular calcification remained unchanged in both groups. The most frequent adverse events were digestive intolerance in the cinacalcet group and hypocalcemia in the parathyroidectomy group. Surgery would be more cost effective than cinacalcet if cinacalcet duration reached 14 months. All patients were alive with a functioning graft at the end of follow-up. In conclusion, subtotal parathyroidectomy was superior to cinacalcet in controlling hypercalcemia in these patients with kidney transplants and persistent hyperparathyroidism.

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance.

Kidney transplant recipients might be at higher risk for severe coronavirus disease 2019 (COVID‐19). However, risk factors for relevant outcomes remain uncertain in this population. This is a multicentric kidney transplant cohort including 104 hospitalized patients between Mar 4 and Apr 17, 2020. Risk factors for death and acute respiratory distress syndrome (ARDS) were investigated, and clinical and laboratory data was analyzed. The mean age was 60 years. Forty‐seven patients (54.8%) developed ARDS. Obesity was associated to ARDS development (OR 2.63; p=0.04). Significant age differences were not found among patients developing and not developing ARDS (61.3yr vs 57.8yr, p=0.16). Seventy‐six (73%) patients were discharged while 28 (27%) died. Death was more common among the elderly (55yr and 70.8yr, p<0.001) and those with preexisting pulmonary disease (OR 2.89 , p=0.009). At admission, higher baseline lactate dehydrogenase (257 IU/ml vs 358 IU/ml, p=0.001) or ARDS conferred higher risk of death (HR 2.09, p=0.044). In our cohort, ARDS was equally present among young and old kidney recipients. However, the elderly might be at higher risk of death, along with those showing higher baseline LDH at admission.

The description of protective humoral and T‐cell immune responses specific against SARS‐CoV‐2 has been reported among immunocompetent (IC) individuals developing COVID‐19 infection. However, its characterization and determinants of poorer outcomes among the at‐risk Solid Organ Transplant (SOT) patient population has not been thoroughly investigated. Cytokine‐producing T‐cell responses such as IFN‐γ, IL‐2, IFN‐γ/IL‐2, IL‐6, IL‐21 and IL‐5 against main immunogenic SARS‐CoV‐2 antigens and IgM/IgG serological immunity were tracked in SOT (n=28) during acute infection and at 2 consecutive time‐points over the following 40 days of convalescence and were compared to matched IC (n=16) patients admitted with similar moderate/severe COVID‐19. We describe the development of a robust serological and functional T‐cell immune responses against SARS‐CoV‐2 among SOT patients, similarly to IC patients during early convalescence. However, at the infection onset, SOT displayed lower IgG seroconversion rates (77% vs 100%; p=0.044), despite no differences on IgG titters, and a trend towards decreased SARS‐CoV‐2‐reactive T‐cell frequencies, especially against the membrane protein (7[0‐34] vs 113[15‐45] p=0.011, 2[0‐9] vs 45[5‐74], p=0.009 and 0[0‐2] vs 13[1‐24], p=0.020, IFN‐γ, IL‐2 and IFN‐γ/IL‐2 spots, respectively). In summary, our data suggest that despite a certain initial delay, SOT achieve comparable functional immune responses than the general population after moderate/severe COVID‐19.