Juncos, Luis A.

Aging is unavoidable and driven, at least in part, by the biologic process termed senescence. Senescence is characterized by cell cycle arrest incurred by one or more stressors wherein there is cellular upregulation of cyclin-dependent kinase inhibitors, p16 Ink4a and/or p21 Cip1 . Senescent cells are metabolically active and resistant to apoptosis, have increased β -galactosidase activity, and express a senescence-associated secretory phenotype (SASP). The SASP produces an array of inflammatory, cytotoxic, fibrotic, and vasoactive factors. Senescence is a diffusible process as, largely through the SASP, a focus of senescent cells can recruit adjacent cells and cells in distant organs, thereby expanding its scope way beyond its original focus. Senescence predisposes not only to chronic diseases (including CKD) but also acute processes (including AKI). This review provides evidence that age increases the risk of human AKI and summarizes clinical factors that predispose older individuals to AKI. It provides an overview of the biology of senescence, and it discusses the role of intrarenal senescent cells in the pathogenesis of AKI, the significance of the extrarenal milieu and distant organs in predisposing to AKI with age, heme as a prosenescent species, and the role of senescence in the AKI to CKD transition. The risk for AKI with aging, in large part, reflects the fact that virtually all processes implicated in AKI, irrespective of age, occur as the kidney ages. Processes discussed include senescent cells, vascular responses, diabetes, impaired NAD + content, sirtuin expression, mitochondrial dysfunction, impaired autophagy, epigenetic changes, telomere shortening, impaired nephroprotectant expression, inflammaging, and immunosenescence. The review concludes by discussing the basis for senolytics (agents that kill senescent cells), senomorphics (agents that block SASP factors), and other aspects of senotherapies.

Key Points Understanding how heme proteins/heme induce AKI and whether NAD + -boosting ameliorates heme protein–mediated AKI is clinically relevant. Heme proteins/heme directly decrease kidney NAD + content and NAD + -boosting is markedly protective in heme protein–mediated AKI. These findings provide new insights in heme protein–mediated AKI and support interest in NAD + -boosting as a therapeutic strategy in AKI. Background Understanding how heme proteins and heme induce AKI is clinically relevant from numerous perspectives, and, in this regard, a widely used model of heme protein–mediated AKI (HP-AKI) involves the glycerol model in mice. Using this model, we have previously demonstrated that NAD + content is decreased in HP-AKI. Because there is significant current interest in NAD + -boosting as a strategy in clinical AKI, we examined the effect of NAD + -boosting in this model. Methods NAD + -boosting was achieved by the administration of nicotinamide mononucleotide (NMN) in the glycerol model of HP-AKI. The effect of NMN, compared with vehicle, was examined in mice with HP-AKI and with sham AKI at day 1 after HP-AKI was induced. Results The administration of NMN preserved kidney NAD + content in HP-AKI, and compared with the administration of vehicle in HP-AKI, NMN improved glomerular filtration markers; reduced histologic injury as assessed by tubular necrosis, dilation, and cast formation and by assessment of dystrophic calcification; reduced expression of kidney injury marker 1, a sensitive marker of AKI; preserved mitochondrial ultrastructure and increased expression of proteins that promote mitochondrial integrity; reduced apoptosis as assessed by terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling staining and genes and protein expression that contribute to apoptosis, while increasing expression of an anti-apoptotic gene; reduced expression of several renal injury-related genes; and mitigated the severity of the senescence phenotype, as assessed by multiple markers. Finally, the administration of myoglobin or heme in vivo diminished kidney NAD + content in mice with intact kidneys. Conclusions These findings demonstrate the remarkable protective effects of NAD + -boosting by NMN in HP-AKI as revealed by a multitude of markers relevant to AKI. The reduction in NAD + content in the kidney in HP-AKI may reflect the direct effects of heme proteins and/or heme. We suggest that these findings support current interest in NAD + -boosting as a therapeutic strategy in clinical AKI.

Abstract Acute kidney injury (AKI) is a syndrome that entails a rapid decline in kidney function with or without injury. The consequences of AKI among acutely ill patients are dire and lead to higher mortality, morbidity, and healthcare cost. To prevent AKI and its short and long‐term repercussions, understanding its pathophysiology is essential. Depending on the baseline kidney histology and function reserves, the number of kidney insults, and the intensity of each insult, the clinical presentation of AKI may differ. While many factors are capable of inducing renal injury, they can be categorized into a few processes. The three primary processes reported in the literature are hemodynamic changes, inflammatory reactions, and nephrotoxicity. The majority of patients with AKI will suffer from more than one during their development and/or progression of AKI. Moreover, the development of one usually leads to the instigation of another. Thus, the interactions and progression between these mechanisms may determine the severity and duration of the AKI. Other factors such as organ crosstalk and how our concurrent therapies interact with these mechanisms complicate the pathophysiology of the progression of the AKI even further. In this narrative review article, we describe these three main pathophysiological processes that lead to the development and progression of AKI. © 2022 American Physiological Society. Compr Physiol 12: 3767–3780, 2022.

ACE2 protein binds heme, which we reasoned would promote heme entry into the kidney and, accordingly, heme protein-mediated acute kidney injury. Our findings support this hypothesis. This study is the first to demonstrate the biological relevance of ACE2-heme binding, uncover a new pathway of heme-dependent kidney injury, and identify myoglobin and heme as novel determinants of ACE2 expression. Our study explains why plasma levels of myoglobin and heme predict poor outcomes in patients with COVID-19.

Key Points The rat arteriovenous fistula (AVF) model exhibits marked upregulation of p16 Ink4a and p21 Cip1 and multiple markers of senescence. Fisetin, an established vasoprotective senolytic agent, when administered for 3 weeks, increases AVF blood flow and AVF outward remodeling. Heme is shown to be a novel prosenescence metabolite, and when chronically administered, it decreases AVF blood flow. Background Maturational failure of dialysis arteriovenous fistulas (AVFs) not uncommonly occurs and is of considerable and timely importance. Our prior studies demonstrate that senescence, a phenotypic process that promotes vascular and other diseases, occurs in the murine AVF. In this study, we examined whether senescence also occurs in the rat AVF model and the effect of compounds that inhibit or accelerate senescence. Methods The rat AVF was created in the femoral vessels by an end vein-side artery anastomosis. In the AVF, we assessed the expression of critical drivers of senescence, specifically, the cell cycle inhibitors p16 Ink4a and p21 Cip1 , and such indices of a senescence phenotype as senescence-associated β -galactosidase (SA- β -gal) activity, SA- β -gal staining, and a senescence-associated secretory phenotype. We examined the effects of compounds that retard or accelerate senescence on AVF blood flow. Results The AVF evinced upregulation of p16 Ink4a and p21 Cip1 when assessed 3 days after AVF creation. The AVF also demonstrated increased SA- β -gal activity in the artery and vein; staining for SA- β -gal in the AVF artery, anastomosis, and vein; and a prominent senescence-associated secretory phenotype. Fisetin, an established senolytic that is protective in other models of vascular injury, when administered for 3 weeks, increased AVF blood flow and outward remodeling. Hemin, when administered for 3 weeks, decreased AVF blood flow. We demonstrate that hemin is a novel inducer of a senescence phenotype in endothelial cells, as reflected by several senescence indices. However, when administered relatively acutely (for 5 days), hemin increased AVF blood flow by heme oxygenase–dependent mechanisms because the latter was entirely prevented by a competitive inhibitor of heme oxygenase activity. Conclusions The rat AVF exhibits senescence within 3 days of its creation. Chronic administration of a senolytic compound (fisetin) increases AVF blood flow, whereas chronic administration of a prosenescence compound (hemin) decreases AVF blood flow.

ABSTRACT Background and hypothesis The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health-care payers. Methods A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health-care payer with a lifetime time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced-cost biosimilar rituximab. Results Rituximab for the treatment of membranous nephropathy was cost effective (assuming a willingness-to-pay threshold of $50 000 per quality-adjusted life year (QALY) gained; in $US 2021) compared with cyclosporine, with an ICER of $8373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was $28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favorable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine. Conclusions Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars.

Introduction: Morbidity and mortality attributable to hypertension are higher in African American (AAEH) compared to Caucasian essential hypertensive (EH) patients, possibly related to a differential effect on vascular injury and repair. While circulating endothelial progenitor cells (EPC) preserve endothelial integrity IEC detach from sites of injury and represent markers of vascular damage. We hypothesized that plasma levels of IEC and inflammatory markers would be higher in AAEH compared to EH patients. METHODS: Inferior vena cava levels of CD34+/KDR+ (EPC) and VAP-1+ (IEC) cells were measured by FACS in EH and AAEH under fixed sodium intake (150 mEq/d) and blockade of the renin-angiotensin-system, and compared to systemic levels in normotensive control subjects (n=19 each). Systemic levels of inflammatory cytokines and EPC homing factors were measured by Luminex. Results: Blood pressure, serum creatinine, lipids, antihypertensive medications, and EPC levels did not differ between EH and AAEH patients. Circulating IEC were higher in AAEH, and inversely correlated with EPC levels (Figure). Systemic levels of inflammatory cytokines and EPC homing factors were higher in AAEH compared to EH patients (Table), and correlated directly with IEC. Conclusion: Despite preserved kidney function and controlled BP, circulating inflammatory markers were elevated in AAEH and correlated with increased IEC and decreased EPC levels. Increased release of cytokines and IEC in AAEH may impair EPC reparative capacity and predispose to hypertensive vascular injury. This process may aggravate vascular damage and accelerate hypertension-related morbidity/mortality rates in AAEH.

INTRODUCTION: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in differentiating acute tubular necrosis (ATN) from other types of acute kidney injuries (AKIs) in cirrhosis, particularly hepatorenal syndrome (HRS). However, NGAL is not currently available in clinical practice in North America. METHODS: Urinary NGAL was measured in a prospective cohort of 213 US hospitalized patients with decompensated cirrhosis (161 with AKI and 52 reference patients without AKI). NGAL was assessed for its ability to discriminate ATN from non-ATN AKI and to predict 90-day outcomes. RESULTS: Among patients with AKI, 57 (35%) had prerenal AKI, 55 (34%) had HRS, and 49 (30%) had ATN, with a median serum creatinine of 2.0 (interquartile range 1.5, 3.0) mg/dL at enrollment. At an optimal cutpoint of 244 μg/g creatinine, NGAL distinguished ATN (344 [132, 1,429] μg/g creatinine) from prerenal AKI (45 [0, 154] μg/g) or HRS (110 [50, 393] μg/g; P < 0.001), with a C statistic of 0.762 (95% confidence interval 0.682, 0.842). By 90 days, 71 of 213 patients (33%) died. Higher median NGAL was associated with death (159 [50, 865] vs 58 [0, 191] μg/g; P < 0.001). In adjusted and unadjusted analysis, NGAL significantly predicted 90-day transplant-free survival ( P < 0.05 for all Cox models) and outperformed Model for End-Stage Liver Disease score by C statistic (0.697 vs 0.686; P = 0.04), net reclassification index (37%; P = 0.008), and integrated discrimination increment (2.7%; P = 0.02). DISCUSSION: NGAL differentiates the type of AKI in cirrhosis and may improve prediction of mortality; therefore, it holds potential to affect management of AKI in cirrhosis.