Why Have Detection, Understanding and Management of Kidney Hypoxic Injury Lagged behind Those for the Heart?

Abstract

The outcome of patients with acute myocardial infarction (AMI) has dramatically improved over recent decades, thanks to early detection and prompt interventions to restore coronary blood flow. In contrast, the prognosis of patients with hypoxic acute kidney injury (AKI) remained unchanged over the years. Delayed diagnosis of AKI is a major reason for this discrepancy, reflecting the lack of symptoms and diagnostic tools indicating at real time altered renal microcirculation, oxygenation, functional derangement and tissue injury. New tools addressing these deficiencies, such as biomarkers of tissue damage are yet far less distinctive than myocardial biomarkers and advanced functional renal imaging technologies are non-available in the clinical practice. Moreover, our understanding of pathogenic mechanisms likely suffers from conceptual errors, generated by the extensive use of the wrong animal model, namely warm ischemia and reperfusion. This model parallels mechanistically type I AMI, which properly represents the rare conditions leading to renal infarcts, whereas common scenarios leading to hypoxic AKI parallel physiologically type II AMI, with tissue hypoxic damage generated by altered oxygen supply/demand equilibrium. Better understanding the pathogenesis of hypoxic AKI and its management requires a more extensive use of models of type II-rather than type I hypoxic AKI.

Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors

“…The use of biomarkers of AKI in the detection and assessment of AKI is expanding, and combined assays of several biomarkers enhance their sensitivity and specificity [ 14 , 27 , 28 ]. Yet, while their rise in young and stable patients with intact kidneys is highly indicative of acute renal injury [ 29 , 30 ], they are less predictive in older patients with additional morbidities, particularly preexisting renal impairment [ 14 ]. Therefore we used as a control group a comparable cohort of hospitalized adult diabetic patients on SGLT2i treatment upon admission who did not develop AKI.…”

“…Unfortunately, clinical and laboratory parameters that help differing pre-renal failure from ATI might be of little value in diabetic patients on SGLT2i, as orthostatic hypotension can represent autonomic nephropathy, and renal sodium handling and urine concentration might be affected by SGLT2i and other medications. Kidney biopsy is seldom performed in such scenario, and is of limited clinical value principally due to non-timely and non-diagnostic minute tissue sampling [ 13 , 14 ]. On the other hand, biomarkers of tubular injury, detected in serum or urine samples could be helpful, and being nephron-segment-specific, they may provide insight regarding the distribution pattern of tubular injury [ 14 , 15 ].…”

“…Kidney biopsy is seldom performed in such scenario, and is of limited clinical value principally due to non-timely and non-diagnostic minute tissue sampling [ 13 , 14 ]. On the other hand, biomarkers of tubular injury, detected in serum or urine samples could be helpful, and being nephron-segment-specific, they may provide insight regarding the distribution pattern of tubular injury [ 14 , 15 ]. Herein we report increased plasma levels and urine excretion of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of distal tubular segments, among hospitalized patients on SGLT2i presented with AKI, but unaltered urine and plasma levels of Kidney ischemia Molecule (KIM)-1, a biomarker originated from proximal tubules.…”

Glycocalyx Degradation in Ischemia-Reperfusion Injury

“…Yet, it likely bears little relevance to human hypoxic AKI, which most commonly arises in a functioning kidney due to mismatched oxygen supply and demand, particularly in the outer medulla. 3 In this region, a limited blood supply via vasa recta (required for the urinary concentrating capacity) hardly suffices for intense local tubular transport and oxygen expenditure, leading to a physiologically low pO 2 under normal conditions. 29 Hypoxic medullary injury may develop when the delicate balance of regional oxygen supply and demand is altered, for instance with the administration of nonsteroidal anti-inflammatory drugs, Figure 2 Endothelium glycocalyx erosion under ischemia reperfusion conditions.…”

“…Profound hypotension or intense systemic or regional inflammation may also lead to the development of I/R injury. 3 Importantly, I/R injury may also affect blood vessels, which may further compromise organ parenchymal integrity. Indeed, microvascular injury plays an important role in I/R injury (Figure 1).…”