Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still mix up CKD with chronic kidney insufficiency or failure, For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus, health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is “solved” by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated aging and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality which is 10- o 100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients (AAKP) and the European Kidney Health Alliance (EKHA). Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected conditions, and CKD is projected to become the fifth leading global cause of death by 2040. New therapeutic approaches are needed. Mitochondrial dysfunction and oxidative stress have emerged as drivers of kidney injury in acute and chronic settings, promoting the AKI-to-CKD transition. In this work, we review the role of mitochondrial dysfunction and oxidative stress in AKI and CKD progression and discuss novel therapeutic approaches. Specifically, evidence for mitochondrial dysfunction in diverse models of AKI (nephrotoxicity, cytokine storm, and ischemia-reperfusion injury) and CKD (diabetic kidney disease, glomerulopathies) is discussed; the clinical implications of novel information on the key role of mitochondria-related transcriptional regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha, transcription factor EB (PGC-1α, TFEB), and carnitine palmitoyl-transferase 1A (CPT1A) in kidney disease are addressed; the current status of the clinical development of therapeutic approaches targeting mitochondria are updated; and barriers to the clinical development of mitochondria-targeted interventions are discussed, including the lack of clinical diagnostic tests that allow us to categorize the baseline renal mitochondrial dysfunction/mitochondrial oxidative stress and to monitor its response to therapeutic intervention. Finally, key milestones for further research are proposed.

BackgroundReceptor-interacting protein kinase 3 (RIPK3), a component of necroptosis pathways, may have an independent role in inflammation. It has been unclear which RIPK3-expressing cells are responsible for the anti-inflammatory effect of overall Ripk3 deficiency and whether Ripk3 deficiency protects against kidney inflammation occurring in the absence of tubular cell death.MethodsWe used chimeric mice with bone marrow from wild-type and Ripk3-knockout mice to explore RIPK3′s contribution to kidney inflammation in the presence of folic acid–induced acute kidney injury AKI (FA-AKI) or absence of AKI and kidney cell death (as seen in systemic administration of the cytokine TNF-like weak inducer of apoptosis [TWEAK]).ResultsTubular and interstitial cell RIPK3 expressions were increased in murine AKI. Ripk3 deficiency decreased NF-κB activation and kidney inflammation in FA-AKI but did not prevent kidney failure. In the chimeric mice, RIPK3-expressing bone marrow–derived cells were required for early inflammation in FA-AKI. The NLRP3 inflammasome was not involved in RIPK3′s proinflammatory effect. Systemic TWEAK administration induced kidney inflammation in wild-type but not Ripk3-deficient mice. In cell cultures, TWEAK increased RIPK3 expression in bone marrow–derived macrophages and tubular cells. RIPK3 mediated TWEAK-induced NF-κB activation and inflammatory responses in bone marrow–derived macrophages and dendritic cells and in Jurkat T cells; however, in tubular cells, RIPK3 mediated only TWEAK-induced Il-6 expression. Furthermore, conditioned media from TWEAK-exposed wild-type macrophages, but not from Ripk3-deficient macrophages, promoted proinflammatory responses in cultured tubular cells.ConclusionsRIPK3 mediates kidney inflammation independently from tubular cell death. Specific targeting of bone marrow–derived RIPK3 may limit kidney inflammation without the potential adverse effects of systemic RIPK3 targeting.

Background: Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. Tubular cell death, including necroptotic cell death, is a key feature of AKI. Cyclophilin A (CypA) is an intracellular protein that has been reported to be released during necroptosis. We have now explored CypA as a potential marker for kidney injury in cultured tubular cells and in clinical settings of ischemia-reperfusion injury (IRI), characterized by limitations of current diagnostic criteria for AKI. Methods: CypA was analyzed in cultured human and murine proximal tubular epithelial cells exposed to chemical hypoxia, hypoxia/reoxygenation (H/R) or other cell death (apoptosis, necroptosis, ferroptosis) inducers. Urinary levels of CypA (uCypA) were analyzed in patients after nephron sparing surgery (NSS) in which the contralateral kidney is not disturbed and kidney grafts with initial function. Results: Intracellular CypA remained unchanged while supernatant CypA increased in parallel to cell death induction. uCypA levels were higher in NSS patients with renal artery clamping (that is, with NSS-IRI) than in no clamping (NSS-no IRI), and in kidney transplantation (KT) recipients (KT-IRI) even in the presence of preserved or improving kidney function, while this was not the case for urinary Neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, higher uCypA levels in NSS patients were associated with longer surgery duration and the incidence of AKI increased from 10% when using serum creatinine (sCr) or urinary output criteria to 36% when using high uCypA levels in NNS clamping patients. Conclusions: CypA is released by kidney tubular cells during different forms of cell death, and uCypA increased during IRI-induced clinical kidney injury independently from kidney function parameters. Thus, uCypA is a potential biomarker of kidney injury, which is independent from decreased kidney function.

In a recent issue of ckj, Piedrafita et al reported that urine tryptophan and kynurenine are reduced in cardiac bypass surgery patients that develop acute kidney injury (AKI), suggesting reduced activity of the kynurenine pathway of nicotinamide adenine dinucleotide (NAD+) synthesis from tryptophan. However, nicotinamide (NAM) supplementation aiming at repleting NAD+ did not replete kidney NAD+ and did not improve glomerular filtration or reduce histological injury in ischemic-reperfusion kidney injury in mice. The lack of improvement of kidney injury is partially at odds with prior reports that did not study kidney NAD+, glomerular filtration or histology in NAM-treated wild-type mice with AKI. We now present an overview of research on therapy with vitamin B3 vitamers and derivate molecules [niacin, NAM, nicotinamide riboside (NR), NRH and nicotinamide mononucleotide (NMN)] in kidney injury, including an overview of ongoing clinical trials, and discuss the potential explanations for diverging reports on the impact of these therapeutic approaches on preclinical acute and chronic kidney disease.

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