University of Groningen
Perioperative renal protective strategies in kidney transplantation
Nieuwenhuijs, Gertrude Johanna
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Publication date: 2019
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Nieuwenhuijs, G. J. (2019). Perioperative renal protective strategies in kidney transplantation. Rijksuniversiteit Groningen.
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A. Clinical dilemma
To date, 10% of the worldwide population suffers from chronic kidney disease (CKD). Prevalence of the disease will most likely grow over the next decade due to the increase in the elderly population and greater prevalence of diabetes and hypertension. In 2015 CKD was ranked 12th
in the global list of causes of death.1 In 2010, 2.618 million patients had developed end stage
renal disease (ESRD) and received renal replacement therapy (RRT), either dialysis or kidney transplantation. The population of patients needing RRT worldwide was estimated about 4.902 million (95% CI 4.438-5.431 million) in a conservative model and 9.701 million (95% CI 8.544-11.021 million) in a high estimate model, illustrating the magnitude of the disease burden of ESRD.2 For patients with ESRD, transplantation is still the optimal treatment. Long term survival
with kidney transplantation is dramatically better than dialysis and transplantation provides a sustainably higher quality of life. Unfortunately, there is a worldwide shortage of suitable donor organs for (kidney) transplantation. The number of renal transplantations performed worldwide in 2016 was 69.500.3 Due to the persistent shortage of donor kidneys, many transplant centers
have established large living donor programmes and transplant teams are also now accepting more older and higher risk organs retrieved from deceased donors. The use of these extended criteria donors (ECD) has affected outcomes after transplantation due to an often suboptimal quality of the donor organ. 4,5 As we will face more complex donors in the future with a reduced
viability such as unstable donation after brain death (DBD) donors, donation after circulatory death (DCD) donors, and extended criteria donors (ECD), the challenge in transplantation is to be able to use these donor sources, however, without compromising successful immediate function and long-term graft survival after transplantation. It is therefore imperative that the condition of every graft-to-be ought to be optimised prior to or at time of transplantation, achieving the best possible post-transplant function and avoiding primary non function (PNF), delayed graft function (DGF), and rejection with chronic graft failure.
Perioperative medicine
Perioperative medicine involves the care of the patient that prepares for, undergoes, and recovers from a surgical procedure. It is patient-focused, multidisciplinary and the ultimate goal is to deliver the best possible health care from the moment the patient starts with his or her pre-operative assessment until he or she leaves the hospital in full recovery. Perioperative medicine ranges from preoperative risk assessment and optimization of high risk patients, to implementation of perioperative protocols (e.g. enhanced recovery after surgery, ERAS) and timely identification and effective treatment of postoperative deterioration or complications. Anesthesia societies all over the world are recognising a central role of the anesthesiologist in this rapidly evolving area of medicine. It extends the role of the anesthesiologist beyond the operating theatre to the wider hospital and the community. According to Grocott and Pearse perioperative medicine is the future of anesthesia.6 They postulate an interesting paradigm shift considering the response
to surgery the primary “disease process” and the consequent organ dysfunction the condition to focus on.6 Traditionally, surgical care has focused on the operation and the disease being
the complex interplay between the underlying disease, the immune response to tissue injury of the surgical procedure and anesthesia as well as with the patient’s comorbidity and physiological reserve capacity.
Anesthesia per se has become very safe over the years. Injury directly ascribed to the conduct of anesthesia is rare and mortality rates solely attributable to anesthesia are reported between 0.03 and 1.71 per 10,000 anesthetic procedures.7 The substantial variation in patient outcome
between institutions and countries, however, indicates that there may be avoidable injury during or after surgery in which anesthesia may play a contributing role. Most patients develop some degree of postoperative morbidity due to physiological changes and the endocrine and inflammatory responses to surgery and anesthesia. The long-term impact of these early postoperative consequences has been increasingly recognised. Khuri and colleagues performed a retrospective analysis of prospectively collected data in 105.951 patients undergoing eight different surgical procedures to identify determinants of long-term survival after major surgery.8
In this analysis the most important determinant was the occurrence of one of the 22 defined postoperative complications, ranging from superficial wound infection to acute kidney injury and cardiac arrest, within the 30-day postoperative period. The occurrence of complications reduced the median patient survival by 69% in the total patient study group, independent of patient’s preoperative risk.8 Even after full recovery, complications like pneumonia, deep wound
infection and pulmonary embolism still negatively influences patient survival. The inflammatory response due to surgical induced trauma and anesthesia in its broadest definition may be one of underlying mechanisms of this phenomenon.9-13 Prolonged elevation of different cytokines IL-1b,
IL-6, IL-8 and TNF-α), hormones (cortisol, aldosterone), acute phase proteins (C-reactive protein, CRP) and activation of the coagulation system are seen after surgery. Increasing evidence has been gained that intra-operative interventions like maintenance of normothermia, prevention of acidosis, optimization of the intraoperative fluid therapy, or choice of anesthetic technique reduce the incidence in postoperative complications.14-19 Hence, consequences or effects of our
intraoperative choices and interventions will expand beyond the operating theatre and may attribute to postoperative adverse events or enhance recovery. To my opinion one of the roles of the anesthesiologist in perioperative medicine should be to gain better insight in intraoperative patient and organ protective strategies, allowing to reduce postoperative short and long-term complications.
Postoperative complications after kidney transplantation
During the procedure of organ donation and transplantation a number of potentially harmful processes will inevitably occur, affecting the viability of the kidney graft. Both donor and recipient are subjected to anesthesia and surgery, which will produce a sequence of systemic and local changes including a significant pro-inflammatory and pro-coagulatory response as described above.20 The donor organ is by definition exposed to a number of phases of injury from the
moment the donor suffers from cerebral injury until the kidney is reconnected to the circulation in the recipient. These phases include a profound systemic and local inflammatory and pro-coagulatory response during donor management and retrieval, associated with hypoxia and ischemia of the kidney. In addition, prolonged warm ischemia in the DCD donor will affect the
viability of the donor kidney. These combined effects on the graft-to-be result in a cascade of renal damage that will reveal itself at the time of transplantation when the donor kidney is reperfused in the recipient and has been named ischemia-reperfusion injury (IRI).21 Typically, IRI will clinically
manifest as immediate non function of the transplant with the need for dialysis treatment until the graft recovers from the insult and starts eventually to function. This ‘secondary’ recovery is called delayed graft function (DGF). In case the injury has been too extensive to repair the transplanted kidney will never recover and regain function which implies graft failure with permanent requirement of dialysis treatment for the patient. This is called primary non (and never) function (PNF). Currently, there are 22 definitions of DGF based on dialysis requirement, serum creatinine levels, urine output or a combination of these three.22 The most commonly used definition is
at least one dialysis treatment during the first week after transplantation. The incidence of DGF in living donor kidney transplantation (LDKT) based upon this definition is low with incidences reported between 1-8% with an average of 5%.23,24 In brain dead donors the incidence increases
to 15-25% and may rise up to 72% when kidneys are transplanted and retrieved from donation after circulatory death (DCD) donors.25 DGF is a clinically relevant problem. It is associated with
an increase in morbidity, patient anxiety, prolonged hospitalisation and additional diagnostic procedures and costs. Furthermore, DGF is an important risk factor for acute rejection (AR) and the combination of DGF and AR reduces graft and patient survival.25,26 A meta-analysis of 34
studies between 1988 and 2007 showed a pooled incidence of AR of 49% in patients with DGF compared to 35% in patients without DGF with a relative risk (RR) 1.38 (95% CI 1.29–1.47).27 Most
of these studies are performed in patients cohorts in the 90’s, but also in the present era when using modern immunosuppressive drugs, Wu and colleagues showed that the hazard ratio for AR is 1.66 (95% CI: 1.14, 2.42) in an unadjusted and 1.55 (95% CI: 1.03, 2.32) in a multivariable adjusted model in patients experiencing DGF compared to without DGF.28 Also, in the absence of AR, DGF
has shown to be an independent risk factor for long term graft loss due to interstitial fibrosis and tubular atrophy (IFTA).29 Research regarding decreasing the incidence of DGF and/or rejection in
kidney transplantation, predominantly focuses on donor treatment, organ preservation and post-operative recipient management, the vast majority involving immunosuppressive strategies. In this regard, the perioperative period as a window of opportunity to reduce DGF and improve outcome after kidney transplantation is undervalued. This is regrettable as most of the injury inflicted by ischemia and reperfusion will occur during the reperfusion phase in the recipient.30
The general aim of this thesis therefore is to evaluate renal protective strategies applied to the recipient during the transplantation procedure, and how can the anesthesiologist contribute to the improvement of short and long-term outcomes after kidney transplantation.
B. Rationale
Mechanisms in injury and repair
Since several aspects of of IRI and the coagulation system will be addressed and discussed in this thesis, an overview of relevant mechanisms in injury and repair is given in chapter 2.
Conditioning
Conditioning is a broad term generally used to describe strategies inducing biochemical changes that attenuate IRI. Dependant on the timing of application of the strategy it is referred to as pre- (before ischemia), per- (during ischemia) or post- (directly upon reperfusion) conditioning. It was first described in 1986 by Murray and collegues. They reported that subjecting the heart to four brief ischemic episodes followed by reperfusion, preceding a prolonged ischemic insult reduced myocardial infarct size by 75% in a canine model.31 This phenomenon is called
ischemic preconditioning (IPC). Subsequently, it was found that ischemic conditioning (IC) upon reperfusion of the heart (ischemic post-conditioning, IPostC) or applied to a remote tissue or organ (remote ischemic conditioning, RIC) had a similar protective effect on the myocardium.32,33
Following the heart (R)IC was also described for various other organs including liver, brain, lungs and kidney.34-37 Furthermore several non-ischemic stimuli (like hyperthermia or transient
pacing)38,39 and pharmacological substances (like volatile anesthetics, opioids, erythropoietin,
nicorandil) were also found to be able to confer cellular tolerance to a major ischemic period by underlying mechanisms similar to those mediating IC.40-45 In chapter 3-7 three different
conditioning strategies are tested.
1. Pharmacological conditioning with the use of erythropoietin derivate ARA290
Erythropoietin (EPO) is produced and secreted by the kidney in response to anemia. It stimulates erythropoiesis in the bone marrow. Next to this, EPO possesses anti-apoptotic, anti-inflammatory and cytoprotective effects. It is released in different cell lines and organs upon innate immune cell activation including the kidney and acts as the systems’ own protector against tissue stress or injury.46-48 In renal I/R models it has been shown that the administration of EPO before as
well as after reperfusion is able to attenuate renal IRI.49,50 Erythropoiesis is mediated by binding
of EPO to the homodimeric complex of two EPO receptors (EPOR2) on erythroid progenitor cells.51 Cytoprotection is presumed to be mediated by an alternative receptor consisting of a
heterodimeric binding of an EPOR and a β common receptor (βcR, also known as CD131).52
Collino and colleagues called this receptor complex the Inate Repair Receptor (IRR) pointing out its protective role in inflammation in tissue injury to reduce damage and initiation of healing and repair.53 The affinity of EPO for the EPOR-βcR complex is approximately 80 times lower than its
affinity for the EPOR2.54 This implicates that high plasma concentrations of EPO are required when
exogenous EPO is used to induce cytoprotection. This is a major drawback in the clinical setting because of the simulative effect of EPO on various progenitor pools (including megakaryocyte progenitors) in the bone marrow and the risk of cardiovascular and thromboembolic complications. High dose of EPO raises not only the hematocrit but also enhances platelet count and activity and endothelial activation.55 To avoid these adverse events various cytoprotective
EPO derivatives have been developed that only activate the EPOR-βcR complex and do not stimulate hematopiosis.56 ARA290 is an 11 amino acid peptide that selectively binds to the
EPOR-βcR complex. It has an ultra-short half-life of several minutes. ARA290 has been shown to have no erythropoietic properties and to be renoprotective in a rodent model of renal I/R.56,57 In chapter 3
and 4 the hypothesis that the administration ARA290 post reperfusion is renoprotective in a renal I/R model in rats (chapter 3) and pigs (chapter 4) is tested. Additionally, we focussed on optimum timing of administration and investigated the anti-inflammatory properties of ARA290.
2. (Remote) ischemic conditioning
Chapter 5 provides an overview of the molecular mechanisms underlying both ischemic and remote ischemic conditioning of the kidney. This chapter discusses the results of the animal experiments and clinical trials performed in this research area, reporting renal endpoints. Additionally on-going clinical trials exploring (R)IC in renal context are reviewed. In chapter 6 the concept of RIC in renal transplantation is brought from bench to bedside in the CONTEXT study. In this study the RIC procedure is initiated after start of surgery and consists of 4 cycles of 5 min inflation of a tourniquet around the thigh followed by 5 minutes of reperfusion, before reperfusion of the kidney. Primary endpoint is the estimated time to a 50% decrease in plasma creatinin. The complete study protocol of the CONTEXT study can be found as addendum 1.
3. Anesthetic conditioning with volatile anesthetics agents
Experimental data have demonstrated that some of the generally used anesthetics and analgesic agents are able to modulate IRI by underlying mechanisms partially similar to those mediating IC. This phenomenon is called anesthetic conditioning (AC) and is in particular attributed to volatile anesthetic (VA) agents, like sevoflurane or isoflurane, and to a much lesser extend to the intravenous anesthetic agent propofol. Therefore we designed the Volatile Anesthetic Protection Of Renal transplant (VAPOR) trial. This two-step study looks at the effect of two commonly used anesthetic regimens (propofol-remifentanil anesthesia vs sevoflurane-remifentanil anesthesia) on renal outcome in kidney transplantation. In chapter 7 the results of the VAPOR-1 trial, a single center proof of concept study in LDKT are reported. We hypothesized that a sevoflurane based anesthesia is able to induce renal AC and thereby reduces post-transplant renal injury reflected by lower levels of kidney injury biomarkers compared to propofol based anesthesia.
Preoperative coagulatory state of renal transplant recipients
A rare form of delayed graft function is renal artery or vein thrombosis. Although the incidence is low it is major cause of (up to 45%) of early graft loss.58-60 International guidelines to prevent
renal graft thrombosis in the intra-and early post-operative period are lacking due to concerns over increased risk of bleeding complications and lack of agreement of which patients have to be considered high risk. Therefore various intra- and postoperative antithrombotic strategies are used among centers, ranging from no anti-coagulation therapy to unfractionated heparin (UFH) for several days post transplantation in high risk patients. In the University Medical Center of Groningen preemptively transplanted patients are given 5000 IU of UFH intraoperatively before clamping of the vessels and non-preemptively transplanted, dialysis dependent,
patients are not. Historically, dialysis dependent patients (especially hemodialysis, HD) were considered hypocoagulable due to the residual effect of heparin used during dialysis and the continuous activation of platelets through contact with the dialysis membrane.61,62 Therefore, in
various risk stratification algorithms patients on HD are considered low risk and “no thrombotic prophylaxis” in the perioperative transplantation period is advised.63 Recent insights, however,
suggest otherwise.64 In chapter 8 the coagulatory state of preemptively and dialysis dependant
transplanted patients before and after kidney transplantation is evaluated. Results are compared with living kidney donors undergoing laparoscopic donor nephrectomy.
Intraoperative fluid management
Several studies suggest that a supra-normal fluid state during the transplantation procedure is associated with a reduced risk of DGF.65-71 Unfortunately, many of these studies, are retrospective
and often comprise a variety of donor types with variable incidences of DGF hampering an adequate analysis. Although an “adequate” intravascular volume or slight overhydration is suggested and avoidance of hypovolemia is advised,67,72-74 it is unclear how this adequate fluid
state should be defined or measured. So to date there is no consensus on fluid management during kidney transplantation, neither on type of fluid nor the volume or the recommended way to monitor fluid administration. Recently goal directed fluid therapy (GDFT) has been shown to improve patient outcome after major (abdominal) surgery.75-77 GDFT uses advanced
hemodynamic monitoring to evaluate and optimize the individual fluid state, cardiac output and oxygen supply to the tissues.78 Fluid administration and vasopressic or inotropic support in these
protocols is guided by fluid responsiveness and individual goals based upon the Frank Starling curve. Fluid responsiveness indicates a state in which an increase in vascular volume increase the stroke volume (SV) and cardiac output (CO). Frequently used dynamic parameters to guide GDFT are stroke volume variation (SVV), derived from a pulse contour analysis, or pulse pressure variation (PPV), derived from the arterial waveform. A SVV or PPV > 12 - 13% has been proven to be a good predictor of fluid responsiveness.79-83 Since kidney transplant patients present in
a variety of fluid states at the time of surgery this personalized intra operative fluid approach seemed very attractive in this group of patients and was implemented in our kidney transplant programm. In chapter 9 we will evaluate the impact of the implementation of a GDFT protocol in our LDKT population.
The results of this thesis and future perspectives will be discussed in chapter 10.
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