Novel Therapies for Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a common disease with a complex pathophysiology. The old paradigm of identifying renal injury based on location—prerenal, intrarenal, and postrenal—is now being supplanted with a new paradigm based on observable kidney injury patterns. The pathophysiology of AKI on a molecular and microanatomical level includes inflammation, immune dysregulation, oxidative injury, and impaired microcirculation. Treatment has traditionally been supportive, including the avoidance of nephrotoxins, judicious volume and blood pressure management, hemodynamic monitoring, and renal replacement therapy. Fluid overload and chloride-rich fluids are now implicated in the development of AKI, and resuscitation with a balanced, buffered solution at a conservative rate will mitigate risk. Novel therapies, which address specific observable kidney injury patterns include direct oxygen-free radical scavengers such as α-lipoic acid, curcumin, sodium-2-mercaptoethane sulphonate, propofol, and selenium. In addition, angiotensin II and adenosine receptor antagonists hope to ameliorate kidney injury via manipulation of renal hemodynamics and tubulo-glomerular feedback. Alkaline phosphatase, sphingosine 1 phosphate analogues, and dipeptidylpeptidase-4 inhibitors counteract kidney injury via manipulation of inflammatory pathways. Finally, genetic modifiers such as 5INP may mitigate AKI via transcriptive processes.

Implementation of Proteomics Biomarkers in Nephrology: From Animal Models to Human Application?

“…The top disease network in CKD was attributed to cardiovascular disease (Figure A). In AKI, free radical scavenging was the top (dys)functional network (Figure B) confirming potential use of oxygen‐free radical scavengers in the treatment of AKI . Therefore, overall, the data extracted from these proteome‐based studies in preclinical kidney disease models appear to have validity when comparing to the currently known disease‐involved biological mechanisms.…”

The sympathetic nervous system in acute kidney injury

“…63 A single-centre study in 200 adults who underwent valvular heart surgery reported a significantly lower AKI incidence in patients treated with dexmedetomidine starting with anaesthesia induction and continued until 24 hours after surgery vs placebo controls (14% vs 33%). 3 Currently, reverse translational approaches are taken to better match animal models of renal IR to clinical situations that cause AKI. 65 Together, available data on the efficacy of sympatholytic drugs added peri-operatively to the patients' medications in clinical scenarios where renal ischaemia and sympathetic activation likely contribute to AKI are ambiguous.…”

“…A single brief ischaemia period as induced by clamping the renal pedicle or the renal artery in laboratory animals may not adequately model most clinical conditions that lead to AKI were fluid resuscitation, agents with potent anti-inflammatory actions and vasopressors such as noradrenaline are important therapeutic measures. 3 Currently, reverse translational approaches are taken to better match animal models of renal IR to clinical situations that cause AKI. [66][67][68] Their use in studies on the role of sympathetic activation may improve translatability of experimental data.…”

“…1,2 In the past, causes of AKI have been classified as being of prerenal, intra-renal and post-renal origin. 3,4 Risk factors such as pre-existing chronic kidney disease (CKD), diabetes mellitus, arterial hypertension, genetic factors as well as modifying factors such as severity, duration and frequency of renal injury increase the likelihood for the occurrence of AKI and its progression to acute (<90 days) kidney disease (AKD) and CKD respectively. 3,4 Risk factors such as pre-existing chronic kidney disease (CKD), diabetes mellitus, arterial hypertension, genetic factors as well as modifying factors such as severity, duration and frequency of renal injury increase the likelihood for the occurrence of AKI and its progression to acute (<90 days) kidney disease (AKD) and CKD respectively.…”

“…1 Irrespective of the localization of its primary cause, AKI is always the result of combined acting pathogenetic factors including macro-and microvascular dysfunction, parenchymal damage and inflammation. 3,4 Risk factors such as pre-existing chronic kidney disease (CKD), diabetes mellitus, arterial hypertension, genetic factors as well as modifying factors such as severity, duration and frequency of renal injury increase the likelihood for the occurrence of AKI and its progression to acute (<90 days) kidney disease (AKD) and CKD respectively. 1,5 Pathologic states that lead to AKI are frequently associated with acute activation of the sympathetic nervous system (SNS) and the development of AKI in turn may cause sympathetic activation.…”