SummaryHematuria is a common finding in various glomerular diseases. This article reviews the clinical data on glomerular hematuria and kidney injury, as well as the pathophysiology of hematuria-associated renal damage. Although glomerular hematuria has been considered a clinical manifestation of glomerular diseases without real consequences on renal function and long-term prognosis, many studies performed have shown a relationship between macroscopic glomerular hematuria and AKI and have suggested that macroscopic hematuria-associated AKI is related to adverse long-term outcomes. Thus, up to 25% of patients with macroscopic hematuriaassociated AKI do not recover baseline renal function. Oral anticoagulation has been associated with glomerular macrohematuria-related kidney injury. Several pathophysiologic mechanisms may account for the tubular injury found on renal biopsy specimens. Mechanical obstruction by red blood cell casts was thought to play a role. More recent evidence points to cytotoxic effects of oxidative stress induced by hemoglobin, heme, or iron released from red blood cells. These mechanisms of injury may be shared with hemoglobinuria or myoglobinuria-induced AKI. Heme oxygenase catalyzes the conversion of heme to biliverdin and is protective in animal models of heme toxicity. CD163, the recently identified scavenger receptor for extracellular hemoglobin, promotes the activation of anti-inflammatory pathways, opening the gates for novel therapeutic approaches.

Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.

Chronic kidney disease is among the fastest growing causes of death worldwide. An increased risk of all-cause and cardiovascular death is thought to depend on the accumulation of uremic toxins when glomerular filtration rate falls. In addition, the circulating levels of several markers of inflammation predict mortality in patients with chronic kidney disease. Indeed, a number of cytokines are listed in databases of uremic toxins and uremic retention solutes. They include inflammatory cytokines (IL-1β, IL-18, IL-6, TNFα), chemokines (IL-8), and adipokines (adiponectin, leptin and resistin), as well as anti-inflammatory cytokines (IL-10). We now critically review the cytokines that may be considered uremic toxins. We discuss the rationale to consider them uremic toxins (mechanisms underlying the increased serum levels and evidence supporting their contribution to CKD manifestations), identify gaps in knowledge, discuss potential therapeutic implications to be tested in clinical trials in order to make this knowledge useful for the practicing physician, and identify additional cytokines, cytokine receptors and chemokines that may fulfill the criteria to be considered uremic toxins, such as sIL-6R, sTNFR1, sTNFR2, IL-2, CXCL12, CX3CL1 and others. In addition, we suggest that IL-10, leptin, adiponectin and resistin should not be considered uremic toxins toxins based on insufficient or contradictory evidence of an association with adverse outcomes in humans or preclinical data not consistent with a causal association.