TY - JOUR
AU - Rabelink, Ton, J.
AB - erythropoietin, glitazones, ischemia-reperfusion injury stem cells, kidney donor Introduction Ischaemia–reperfusion injury to the kidney is a major insult in kidney transplantation and is responsible for delayed graft function in post-mortal donation. The incidence has been reported to be approximately one-quarter in kidneys obtained from deceased donors and up to 50% of kidneys after cardiac death procedures (non-heart beating donors). In the latter group, it causes primary graft failure in 10% of the donors [1]. Despite its great clinical relevance, few therapeutic options have evolved over the years to improve recovery of acute ischaemic renal injury or to successfully prevent it. In this review, we will first discuss briefly the pathophysiology of ischaemic injury to the donor kidney and then review new therapeutic options, such as growth factor therapy and cell therapy, with respect to their potential to modulate this pathophysiology. This review is not a comprehensive and complete review, but rather aims to put the new therapeutic options that are emerging into a clinical and pathophysiological framework. Pathophysiology Three phases in the pathophysiology of ischaemia–reperfusion injury to a potential kidney donor can be discerned, and each of these phases is potentially eligible for specific therapeutic interventions. The first phase is the priming of the kidney to hypoxia, and occurs during the harvesting of the organ. As has been extensively documented, the renal outer medulla operates at near critical hypoxia [2]. Reductions in renal perfusion therefore may rather easily lead to critical oxygen tensions in the outer medulla. The hypoxia by itself will elicit counter regulatory cellular responses in the endothelial and tubular cells of the outer medulla, through the various heterodimers of the hypoxia-inducible transcription factors (the so called HIFs) [3]. These responses are first aimed at limiting tissue injury to hypoxia. For example, the activity of enzymes such as neutrophil gelatinase-associated lipocalin, the major iron transporting enzyme, and the haemoxygenase-1 (HO-1) system are induced [4,5]. The carbon monoxide released from the latter enzyme will protect against apoptosis, while biliverdin and Fe2+ produced by HO-1 may protect the cell against oxyradicals [4]. The response to hypoxia also includes adaptive biological processes such as neoangiogenesis and erythropoiesis. To allow for these adaptive responses, endothelial cells and tubular cells become activated and, in a nuclear factor (NF)-κB and Akt-dependent manner, will start to express leucocyte-adhesion molecules and release chemokines, such as IP-10, MCP-1 and RANTES [6,7]. Another feature of hypoxia is the increase and subsequent release of cellular adenosine [8], which induces vasodilation and angiogenesis and also modulates tissue inflammation. Finally, both in endothelial cells and in tubular cells, hypoxia will increase xanthine oxidase activity, a phenomenon that evolves secondary to ATP depletion in these cells [9]. Taken together, these alterations in renal-cellular metabolism set the stage for reperfusion injury. Endothelial cells are primed for interaction with leucocytes, while the up-regulated xanthine oxidase may reinforce local inflammatory responses through excessive redox signalling upon reoxygenation [9]. The reperfusion phase is therefore not surprisingly characterized by entrapment of leucocytes and platelets that further compromise the blood flow in the outer medulla. This inflammatory response appears to involve not only neutrophils, but also T cells and myeloid cells [10]. In addition, the rapid increase in temperature in the cold-preserved organ during reperfusion may further contribute to these phenomena. The ongoing ischaemia also leads to redistribution of integrins within the tubular epithelial cells. As a consequence, these cells may detach [11]. In addition, apoptosis of tubular epithelial cells develops, particularly in the distal tubules. The sloughed cells may interact with each other through integrin receptors and lead to tubular obstruction [12]. Finally, a repair response evolves. Although the focus has traditionally been on the renal tubular cell, restoration of perfusion to the outer medulla is probably the critical requirement for renal recovery. This involves restoration of endothelial integrity and reversal of the endothelial activation status in the peritubular capillaries. Upon reperfusion and the restoration of oxygen and substrate delivery, the renal tubular epithelium has a remarkable potential to regenerate through a process of cellular proliferation, migration and differentiation of new proximal tubule cells [13]. Several growth factors such as epidermal growth factor, insulin-like growth factor 1 and hepatocyte growth factor have been identified, that may facilitate this regenerative response [14]. New therapeutic options Following the pathophysiological sequence of events in the development of ischaemic renal failure, several therapeutic targets can be identified. The first strategy targets the cellular adaptive responses to hypoxia. The potential of these cellular responses in organ protection is well illustrated by ischaemia pre-conditioning experiments. Lee [15] and Emala were able to demonstrate that repetitive short periods of renal ischaemia could attenuate post-ischaemic renal failure [15]. Interestingly, recent preliminary data suggest that remote pre-conditioning (i.e. repetitive cycles of ischaemia in the leg of a kidney donor) may also convey renal protection [S. Loukogeorgakis, UCL, UK, personal communication]. However, as pre-conditioning as a strategy is not so easy to apply, investigators have searched for pharmacological approaches to mimic this phenomenon. Most research has been done on the use of adenosine and more selective adenosine receptor subtype ligands. The complex actions of adenosine, which also include proinflammatory effects, and the lack of very specific receptor ligands that can tease out the beneficial from the harmful effects, have limited clinical development of these compounds [15,16]. Another interesting strategy is to enhance HIF transcriptional responses in the renal tissue. Recently, the group of Eckardt has shown encouraging results using pharmacological blockade of the HIF-degrading enzyme, prolyl hydroxylase (PHD). This intervention could reduce hypoxia-induced apoptosis and increments in creatinine in rodents [17]. These new drugs are, however, still in the early days of development, and information on their safety profile is still limited. Also new is the recognition of the role of heat shock proteins (HSPs) as cytoprotective factors [18]. HSPs not only inhibit apoptosis, they also facilitate refolding of denaturated proteins. The tubular expression of heat shock proteins can be increased using agents such as geranylgeranylacetone [19] or by liposomal delivery of cytoprotective HSPs. Erythropoietin (EPO), which is normally expressed in response to HIF activation, can also reinforce cellular defence mechanisms such as Akt signalling and regeneration of STAT5, which are both involved in protection against apoptosis [20]. In addition, EPO may have profound anti-inflammatory effects that can reduce amplification of tissue damage in the reperfusion phase [21]. In agreement with these mechanisms, EPO has been shown to reduce ischaemic renal failure in pre-clinical models [22]. It is clinically important to dissect this therapeutic effect of EPO from its effects on red cell mass, and its vasoconstrictive and prothrombotic effects, as all of these factors may aggravate renal injury rather than improving it. The key is probably to use low dosages of EPO or hyposialated, short-acting forms of EPO, that lack the bone marrow effects but are still capable to react with endothelial EPO receptors in the kidney [23]. Interestingly, it has been suggested that tissue-protective effects may be mediated by alternative EPO receptor composition [24]. This may also perhaps allow for future design of tissue protective ligands. Despite these promising data, we currently have no information on the clinical potential of EPO to reduce ischaemic renal injury. To our knowledge only one study, the Prospective Trial On Erythropoietin in Clinical Transplantation (PROTECT, NIH gov trialnr, NCT00157300) is currently exploring whether short-term EPO administration can reduce delayed graft function in kidneys from cardiac death donors. The reperfusion phase of renal failure is more accessible to clinical intervention as it does not require pre-treatment of the kidney donor. Therapy in the reperfusion phase would be most efficacious if it interfered with leucocyte–endothelial interaction and reduced the redox signalling that amplifies this interaction. Several strategies aimed at blocking integrin interactions, such as blocking antibodies against ICAM1 and P-selectin [25] (to inhibit neutrophil–endothelial cell interaction) or CTLA4 [26] (to inhibit T-cell activation), have therefore been explored in animal models of ischaemic renal failure. The transplanted kidney would be particularly suited to such strategies, as it can be selectively perfused with such agents. Indeed, perfusion of donor kidneys with oligodeoxynucleotides carrying decoy NF-κB binding sites, and thus inhibiting endothelial activation, reduces delayed graft function and rejection in experimental transplantation [27]. There is some limited experience with such strategies in the clinical arena. The mouse monoclonal antibody against ICAM-1 (enlimomab) could not reduce delayed graft function in kidney transplantation, even when given prior to reperfusion [28]. It has been suggested that such negative clinical results are related to the immunogenicity of the antibody [29]. Other humanized blocking antibodies against P-selectin and LFA-1 and the use of anti-thymocyte globulin for reperfusion injury have shown promising results in primates and are still in clinical development (source: http://imgt.cines.fr) [30]. A consequence of the increased leucocyte–endothelial interaction is the formation of thrombosis. Perfusion of the donor kidney with streptokinase, thus preventing such secondary peritubular thrombosis, also resulted in a significant improvement of functional capillary density and a significant decrease in tubular necrosis [31]. An interesting new pharmacological avenue to modulate tissue inflammation is the use of thiazolidinediones (TZDs). These drugs were designed and developed to induce peroxysome proliferator-activated receptors (PPARγ)-dependent transcription in adipocytes, thus influencing differentiation and metabolic function of adipocytes [32]. This results in improved free fatty acid metabolism and enhanced glucose sensitivity [33]. However, more recently, PPARγ agonists have also been shown to negatively regulate inflammatory gene expression in endothelial and myeloid cells [34,35]. The PPAR ligands exert these anti-inflammatory effects by preventing the degradation of transcriptional repressor molecules, a step that is essential in the activation of these cells [36]. Indeed, pre-clinical studies confirm that administration of TZDs can be an effective strategy to reduce ischaemic renal injury. However, as with EPO, no studies have been undertaken to test this concept in the clinical arena. A third therapeutic goal could be to augment processes that are operational in the repair phase. As discussed before, the tubular regenerative potential is remarkable, rendering restoration of kidney function dependent upon restoration of the microvascular integrity of the kidney. Goligorsky et al. [37] demonstrated that extensive endothelial injury and sloughing of the endothelial cells may occur in the reperfusion phase. The replicative potential of endothelial cells to restore vascular integrity is rather limited, particularly under conditions of oxidative stress and inflammation [38]. It is therefore of great interest that haematopoietic progenitor cells may also help to repair this injured vessel wall. Indeed, transplantation studies with vascular rejection have shown endothelial chimerism, indicating that these repair responses are indeed involved [39]. This also offers new therapeutic possibilities. For example, erythropoietin has also been demonstrated to be capable of mobilizing these vascular progenitor cells and enhancing their capacity to differentiate into a mature endothelial cell phenotype [40]. Therapeutic transplantation of these progenitor cells to enhance repair of damaged microcirculatory vessels is probably cumbersome as, at present, the exact characteristics of the vascular progenitor cell types involved cannot be clearly specified. They may include early progenitors such as the CD133-positive cells, more mature progenitors such as CD 34 and KDR-positive cells, as well as the abundantly present myeloid progenitor cells [41]. Particularly, this latter aspect cautions as to the possibility that endothelial repair derived from these cells may still resemble myeloid cells and do not fully share the anti-inflammatory properties of the original endothelial cells. In this respect, it is of great interest that certain pharmacological drugs such as PPAR-γ agonists and statins can modulate these responses (Loomans, unpublished observation). Another interesting strategy is to increase the presence of growth factors that can enhance local repair responses, both of the endothelial cells as well as of the tubular epithelium. One of the candidates that has received considerable attention is hepatocyte growth factor (HGF). HGF is best known for its interception of theTGFβ-Smad signalling pathway and has emerged as an anti-fibrotic drug [42]. However, HGF can also exert anti-inflammatory actions in a wide variety of cells including endothelial cells, dendritic cells and renal epithelial cells. In agreement, HGF has been shown to be protective in both models of ischaemic renal injury [43] as well as toxic renal injury [44]. Unfortunately, the clinical use of HGF may be limited by its extrarenal side-effects, in particular the association with tumorogenesis [45]. In fact, this limitation may be a paradigm in clinical development of single (i.e. high dose and without the context of the physiological micro milieu) growth factor therapy. Moreover, previous studies using single growth factor therapy in other fields have yielded rather disappointing results [46]. Most likely one requires a mix of growth factors, while such growth factors must also be present in the natural form (e.g. with respect to splice variants and protein glycosylation status). More recently, data have emerged showing that mesenchymal stem cells can be used as such physiological sources of mixtures of growth factors. These involve HGF, VEGF, as well as anti-inflammatory cytokines such as IL-10. In vitro data confirm the potent immune-modulatory actions of these cells [47]. Experimental data in ischaemia-reperfusion injury of the kidney also demonstrate that through a paracrine action, these cells may ameliorate renal injury and enhance renal recovery [48]. For prevention of delayed graft function in donor kidneys their use is less certain, as there is concern with respect to the potential of these cells to turn into immune-stimulatory cells in an allogeneic setting [49]. Moreover, clinical application of mesenchymal stem cells is hampered by the fact that purification of these cells is obtained using prolonged in vitro expansion protocols. This also precludes their use as an early intervention strategy. In conclusion, novel insight into the roles of hypoxic apoptosis, endothelial injury and repair, and the associated inflammatory response in the pathogenesis of ischaemic kidney injury (Figure 1), have led to the discovery of novel therapeutic targets for intervention (Table 1). Recently, a lot of attention has been drawn to the use of growth factors, progenitor cells or mesenchymal stem cells (MSCs). However, the clinical development of such strategies may be difficult and is not within reach. On the other hand, some of the therapeutic options build on well-established drugs such as erythropoietin and glitazones, or make use of rather harmless techniques such as (remote) pre-conditioning. They appear to be the most promising candidates for translation into clinical innovation. Fig. 1. Open in new tabDownload slide Summary of the potential therapeutic interventions (indicated by the red boxes) at the different stages of ischaemic injury in kidney transplantation: the adaptive responses to hypoxia, the reperfusion phase where leucocyte entrapment hampers peritubular perfusion, and the repair phase where endothelial integrity is restored and tubular epithelium regenerates. EC, endothelial cells. Fig. 1. Open in new tabDownload slide Summary of the potential therapeutic interventions (indicated by the red boxes) at the different stages of ischaemic injury in kidney transplantation: the adaptive responses to hypoxia, the reperfusion phase where leucocyte entrapment hampers peritubular perfusion, and the repair phase where endothelial integrity is restored and tubular epithelium regenerates. EC, endothelial cells. Table 1. Emerging therapy Mode of action . Compound . Development stage . Increase HIF signalling/proteins Prolyhydroxylase inhibitors Pre-clinical Erythropoietin Clinical, phase 3 Protection against apoptosis Heat shock proteins Pre-clinical Geranylgeranylactone Pre-clinical Adenosine receptor agonists Pre-clinical Ischaemic pre-conditioning Clinical Reduce leucocyte adhesion in PTCs Anti-CTLA-4 Pre-clinical Anti-ICAM-1 Clinical, phase 1 Glitazones Pre-clinical Mesenchymal stem cells Pre-clinical Increase re-endothelialization PTCs Erythropoietin Clinical Endothelial progenitor cells Pre-clinical Increase tubular regeneration Mesenchymal stem cells Pre-clinical Hepatocyte growth factor Pre-clinical Insulin-like growth factor Pre-clinical Epidermal growth factor Pre-clinical Mode of action . Compound . Development stage . Increase HIF signalling/proteins Prolyhydroxylase inhibitors Pre-clinical Erythropoietin Clinical, phase 3 Protection against apoptosis Heat shock proteins Pre-clinical Geranylgeranylactone Pre-clinical Adenosine receptor agonists Pre-clinical Ischaemic pre-conditioning Clinical Reduce leucocyte adhesion in PTCs Anti-CTLA-4 Pre-clinical Anti-ICAM-1 Clinical, phase 1 Glitazones Pre-clinical Mesenchymal stem cells Pre-clinical Increase re-endothelialization PTCs Erythropoietin Clinical Endothelial progenitor cells Pre-clinical Increase tubular regeneration Mesenchymal stem cells Pre-clinical Hepatocyte growth factor Pre-clinical Insulin-like growth factor Pre-clinical Epidermal growth factor Pre-clinical Open in new tab Table 1. Emerging therapy Mode of action . Compound . Development stage . Increase HIF signalling/proteins Prolyhydroxylase inhibitors Pre-clinical Erythropoietin Clinical, phase 3 Protection against apoptosis Heat shock proteins Pre-clinical Geranylgeranylactone Pre-clinical Adenosine receptor agonists Pre-clinical Ischaemic pre-conditioning Clinical Reduce leucocyte adhesion in PTCs Anti-CTLA-4 Pre-clinical Anti-ICAM-1 Clinical, phase 1 Glitazones Pre-clinical Mesenchymal stem cells Pre-clinical Increase re-endothelialization PTCs Erythropoietin Clinical Endothelial progenitor cells Pre-clinical Increase tubular regeneration Mesenchymal stem cells Pre-clinical Hepatocyte growth factor Pre-clinical Insulin-like growth factor Pre-clinical Epidermal growth factor Pre-clinical Mode of action . Compound . Development stage . Increase HIF signalling/proteins Prolyhydroxylase inhibitors Pre-clinical Erythropoietin Clinical, phase 3 Protection against apoptosis Heat shock proteins Pre-clinical Geranylgeranylactone Pre-clinical Adenosine receptor agonists Pre-clinical Ischaemic pre-conditioning Clinical Reduce leucocyte adhesion in PTCs Anti-CTLA-4 Pre-clinical Anti-ICAM-1 Clinical, phase 1 Glitazones Pre-clinical Mesenchymal stem cells Pre-clinical Increase re-endothelialization PTCs Erythropoietin Clinical Endothelial progenitor cells Pre-clinical Increase tubular regeneration Mesenchymal stem cells Pre-clinical Hepatocyte growth factor Pre-clinical Insulin-like growth factor Pre-clinical Epidermal growth factor Pre-clinical Open in new tab Conflict of interest statement. None declared. References 1 Keizer KM , de Fijter JW , Haase-Kromwijk BJ , Weimar W . 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TI - New horizons in prevention and treatment of ischaemic injury to kidney transplants
JO - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gfl690
DA - 2007-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/new-horizons-in-prevention-and-treatment-of-ischaemic-injury-to-kidney-opkb1cjeBD
SP - 342
EP - 346
VL - 22
IS - 2
DP - DeepDyve
ER -