AKI and CKD

PubMed search of the keywords “acute kidney injury (AKI)” or “chronic kidney disease (CKD)” shows doubling of the number of hits in the last decade when compared to all years before. Even when taking a certain “inflation” in scientific publication into account, this observation reflects the enormous interest in these syndromes. In fact, the incidence of AKI is increasing in the population of general hospitalized patients.1 Furthermore, in-hospital mortality is high in AKI patients, which emphasizes the need for an effective treatment.2 AKI and CKD are closely related, since a substantial number of patients with AKI develop CKD.3 Thus, renal protection against AKI, as an important risk factor in CKD development, is of particular interest. However, increasing incidence and mortality of AKI prove that preventive and therapeutic options are limited. Basic, translational and clinical renal research are challenged to improve our knowledge in physiology and pathophysiology and to discover new and better therapeutic approaches. A series of papers has been published in Acta Physiol (Oxf.) within the last 2 years, which deal with several aspects of AKI and CKD and with renal physiology. Corresponding to its functional characteristics, an adequate and controlled perfusion is crucial for the kidney. Myogenic response of renal preglomerular vessels, tubuloglomerular feedback and a third unknown mechanism guarantees a stable renal blood flow (RBF) and glomerular filtration rate (GFR). Numerous vasoactive substances of systemic and local origin modulate the tone of preglomerular arteries and arteriole, the main effectors in RBF autoregulation. In this context, endothelial derived substances are important. Pinilla E and co-workers showed that the endothelium-derived hyperpolarization factor (EDHF) of rat preglomerular arteries depends on large calcium-activated potassium channels (KCa1.1) as well as intermediate-conductance calcium-activated potassium channels (Kca1.3). Small-conductance calcium-activated potassium channels (KCa2.3) are expressed in the vasculature but do not contribute functionally to EDHF.4 The findings do not only improve our knowledge about renal dilatory vessel function but may also help to understand RBF- and GFR-control. Renal vessels are key players in renal pathologies. Several studies, performed in models of AKI and CKD, pointed out the role of an imbalance between oxidants and antioxidants in favour of the oxidants (oxidative stress) for increased renal vessel tone.5 Reactive oxygen species (ROS) are involved in cell signalling. For instance, superoxide from NADPH oxidases mediates angiotensin II–induced renal vascular constriction.6 However, unbalanced redox states contribute to vessel dysfunction and impaired medullary and cortical blood flow in AKI and transition to CKD. The physiological and pathophysiological dimension of ROS in renal vasculature have been reviewed by Xu et al,5 revealing a pivotal role of disturbed redox metabolism in AKI and CKD. This is supported by the finding of a protective effect of antioxidant therapy in models of CKD. Interestingly, mineralocorticoid receptors (MR) also induce oxidative injury. In the last decade, cumulative evidence has emerged that mineralocorticoid receptors contribute to the progress of AKI to CKD, and that oxidative injury may play a prominent role.7 In addition to that, MR mediates vascular inflammation, calcification and thus increase vascular stiffness and induce hypertension; factors which promote the development of CKD. Renal oxygenation, a major focus area in kidney research, is determined by RBF. The kidney has a particular oxygenation pattern characterized by a high oxygenation of the cortex and a comparably low oxygen tension in the medulla.8 Although medullary blood flow is also much lower in the medulla compared to the cortex, perfusion alone does not determine oxygenation. Oxygen consumption of renal epithelial cells is an important factor, which has impressively been shown by Haddock et al.9 In their human intervention study, furosemide, an inhibitor of the Na+-K+-2Cl- co-transporter, increased renal medullary oxygenation without changes in renal perfusion. In that respect, mathematical modelling can help to understand physiology, for example, the factors determining renal local oxygenation.10 Gardiner RS and co-authors give a nice introduction into the principles of mathematical and computational modelling and show the power of models in renal physiology.11 Models can support kidney research especially when the measurement of critical variables is technically difficult or unfeasible. In the case of renal oxygenation, the clarification of the interplay of factors determining the oxygenation may have clinical implication. Renal medullary hypoxia goes along with AKI of varying aetiology and is probably causative for renal damage. Acute deterioration of medullary oxygenation is a pathogenetic factor for AKI associated with, for example, cardiac surgery.12 A way to predict medullary oxygenation during surgery is measuring the oxygen partial pressure (pO2) in the bladder. Ngo JP and co-authors studied confounding factors for oxygenation prediction and development of AKI in patients undergoing cardiac surgery requiring cardiopulmonary bypass.13 They concluded that urine pO2 provides the best estimate of medullary oxygenation during the phase of cardiopulmonary bypass. Systemic hyperoxia and low urine flow are confounders influencing the relationship between urine and medullary pO2. However, no less interesting is the role of the sympathetic nervous system (SNS) in AKI pathogenesis, which has been reviewed by O. Grisk with a focus on ischemia/reperfusion injury.14 AKI is often accompanied by an activation of the SNS, but it remains open whether this is causative for the development of AKI. Equally unclear is if and how adrenergic activation in the damaged kidney tissue occurs and if inhibition of the SNS prevents the progression of AKI or CKD in patients. The excellent review demonstrates the methodical problems and identifies future area for research in this field. Chronically injured kidneys interact with distant organs such as the lung, the heart and vessels, a fact that has been known for long time in clinical medicine. There is increasing evidence that AKI is linked to distant organ injuries. Pathways of this interaction include inflammation, oxidative stress and pro-apoptotic events. Studies suggest affection of the gastrointestinal tract, the liver, the lung and the heart in AKI.15 Signalling pathways from kidney to the heart may include renal nerves. Huo and co-workers demonstrated a beneficial action of renal nerve denervation (RND) in a model of pressure-induced cardiac remodelling in rats.16 RND prevented decreased cardiac function, interstitial fibrosis, apoptosis and attenuated increased autophagy in a chronic setting. Although mechanistic relation between RND and the effect on function and autophagy in the heart remain to be examined, the observation has potential for translation to the human situation. Furthermore, clinicians often see an impaired cognitive function in patients with AKI. Results of a recently published article may give an answer regarding the underlying pathophysiological mechanisms.17 Authors observed an increased reactivity of small brain arteries to angiotensin II and identified the fibroblast growth factor (FGF2) and the binding protein FGFBP1 as potential mediators of the angiotensin II sensitization. The finding suggests a compromised cerebral blood in AKI, which might be causative for the cognitive impairment. The continuous efforts made to develop renoprotective strategies are reflected in several recently reported study results. Hu J and colleagues deal with the calcineurin inhibitor nephrotoxicity, an issue in transplantation medicine. They describe a signalling pathway of cyclosporine A (CsA)–induced juxtaglomerular COX-2 suppression via activation of the renin–angiotensin system. Angiotensin II type 1 receptor blockade blunted the CsA effect and normalized kidney function in their study in rats.18 In a model of ischemia/reperfusion injury (IRI), Zhou S and co-workers found that recombinant ADAMTS13 improves the outcome in mice.19 rADAMTS13 restored dilatory microvascular function, alleviated renal dysfunction and reduced renal reactive oxygen species levels. Hoff U and co-workers focused on the CYP-eicosanoid pathway and found increased levels of 20-HETE but no change in free EETs during ischemia in an acute IRI model in rats.20 Treatment with a 14,15-EET analogue before ischemia improved renal oxygenation, renal function as well as renal inflammation and tubular apoptosis. The study shows that imbalance of HETE-20/EETs contributes to the IR injury. Since patients with postoperative AKI had increased preoperative HETE-20, an individually designed therapy targeting the CYP-eicosanoid system has a renoprotective potential. Stimulation of the soluble guanylyl cyclase (sGC) has been introduced in cardiovascular medicine.21 The range of clinical applications of sGC stimulators and activators is constantly increasing. The kidney has also been targeted and recent investigation in mouse and human renal vessels demonstrate vessel dilatation caused by sGC stimulation, pointing at a potency of these drugs for improvement of reduced renal perfusion observed in AKI and CKD.22, 23 Nowadays, the treatment of AKI is still mostly symptomatic. Specific strategies for prevention of AKI and the transition to CKD are often missing. It seems that the most critical factors, the mechanism and their way of interaction, have in most cases not been detected yet. However, the development of better mathematical and computational models as well as the increase in translational approaches raise hope for further progress in AKI and CKD research. There is no conflict of interest to declare.