Table 1.
Promising hemodynamic–based therapeutic targets to treat AKI
| Alteration and Target | Setting | Mechanisms | Potential Downside | Stage |
|---|---|---|---|---|
| Global RBF | ||||
| MAP | Shock states, sepsis | Improved early renal perfusion | Vasopressor load, medullary hypoxia, tubular workload | Two small clinical studies, one phase 3 clinical |
| ANP low dose | Cardiac surgery | Improved renal perfusion | Ineffective in late AKI, hypotension in large dose | One small RCT |
| Renal (de)congestion | Heart failure, sepsis, ICU AKI | Improved renal perfusion, tissue edema | Induction of prerenal response | Observational trials |
| Glomerular hemodynamics | ||||
| Selective renal adenosine 1 receptors agonists | I/R, sepsis AKI | Activation of tubuloglomerular feedback, prevention of tubular cell danger load and medullary hypoxia | Reduced cortical perfusion | Mice I/R, sepsis AKI |
| Selective renal adenosine 1 receptors antagonists | Radiocontrast AKI, nephrotoxic AKI | Suppression of tubuloglomerular feedback, improved GFR and postglomerular perfusion | Medullary hypoxia, tubular workload | Small animals studies |
| Angiotensin II | Early hyperemic sepsis AKI | Increased glomerular filtration pressure | Systemic effects, tubular danger load, renal ischemia | Sheep hyperdynamic sepsis and AKI |
| Vasopressin/terlipressin | Early sepsis AKI | Increased glomerular filtration pressure | Systemic effects, tubular danger load, renal ischemia | Small clinical, post hoc RCT analysis (VASST), preclinical large animals |
| Glomerular inflammation | Sepsis AKI | Glomerular endothelial protection | Ineffectiveness of anti-TNF strategies in human trials | TNFR1 knockout mice |
| Peritubular microcirculation | ||||
| NOS-targeted therapy (e.g., iNOS inhibition, eNOS preservation) | Sepsis AKI, I/R | Preserved microvascular perfusion, suppression of local inflammation, oxidative stress and bioenergetic failure | Unclear timing, both damaging and protective consequences | Preclinical studies, limited human evidence |
| RNOS-targeted therapy | Sepsis AKI, I/R | Preserved microvascular perfusion, suppression of local inflammation and bioenergetic failure | Unclear timing, variety of drugs, both damaging and protective consequences | Preclinical studies |
| IκB kinase inhibition | Sepsis AKI | Attenuation of iNOS while increasing eNOS | Biphasic roles—limiting inflammation early, limiting recovery later on? Proapoptotic effects? | Mice sepsis and endotoxemia |
| Endothelin-1 antagonism | I/R, sepsis, progression to CKD | Improved renal microcirculation, reduction in oxidative stress and inflammation | Role of other receptors and their distribution unknown | Mouse I/R, porcine endotoxemia |
| Vascular integrity | ||||
| Toll–like receptors 4 manipulation | I/R, sepsis, inflammation | Limiting DAMPS–induced vascular injury | Biphasic roles—limiting inflammation early, limiting recovery later on? Immune suppression? | Small animal I/R, Tx, endotoxemia |
| S1P1R agonists | Prevention of I/R | Prevention of endothelial barrier dysfunction | Unclear | Human trial in Tx ongoing, mice I/R, cell culture |
| Vasculotrophic strategies (VEGF, EPC, MSC, angiopoietin-1) | Microvascular regeneration | Limiting vascular dropout | Safety limits? | Small animal I/R |
| ENT inhibition | I/R | A2B adenosine receptors–mediated prevention of post–ischemic no reflow phenomenon | Unclear | Mice I/R |
| Soluble thrombomodulin | I/R | Attenuated endothelial permeability, cellular adhesion | Unclear | Rat I/R |
| Others | ||||
| Supplemented resuscitation fluids (ethylpyruvate analog) | Sepsis, shock, inflammation | Glycocalyx-protecting interventions, antioxidant effects | Unclear | Small animal sepsis |
| HIF activators | I/R | Tolerance to tissue hypoxia | Only pretreatment? Risk of fibrogenesis? | Small animal models |
Because multiple mechanisms are involved in the development of microvascular dysfunction, it is unlikely that a single-pathway intervention would be effective. Evaluation of effectiveness of combined therapies compared with single therapy and determination of the optimal timing of the components of combination therapy are required. MAP, mean arterial pressure; ANP, atrial natriuretic factor; NOS, nitrogen oxygen species; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; RNOS, reactive nitrogen oxygen species; IκB, inhibitor of kappa B kinase; S1P1R, sphingosine-1 phosphate 1 receptor; VEGF, vascular endothelial growth factor; EPC, endothelial progenitor cell; MSC, mesenchymal stem cell; ENT, equilibrative nucleoside transporter; HIF, hypoxia-induced factor; ICU, intensive care unit; I/R, ischemia-reperfusion; DAMPS, damage-associated molecular pattern molecules; A2B, adenosine A2B receptor; RCT, randomized controlled trial; VASST, vasopressin and septic shock trial; TNFR1, tumor necrosis factor receptor 1; Tx, transplantation.