Is Remote Ischemic Conditioning of Benefit to Patients Undergoing Kidney Transplantation?

ABSTRACT

Renal ischemia-reperfusion injury (IRI), an inevitable event during kidney transplantation procedure, can result in delayed graft function or even primary nonfunction. In addition to strategies to limit IRI such as advancements in organ allocation systems and preservation of organs, and reduction in cold and warm ischemia time, remote ischemic conditioning (RIC) has attracted much attention in recent years. With promising findings and data suggesting a potential benefit of RIC in animal kidney transplantation models, a few clinical trials have investigated the use of RIC in human kidney transplantation. Unfortunately, the findings from these investigations have been inconclusive due to a number of factors such as diverse time points of RIC, limited sample size, and complexity of kidney transplant patients. This brief commentary aims to discuss the effects of RIC on clinical outcomes and proinflammatory cytokines in patients undergoing kidney transplantation.

Keywords:

• ischemia
• reperfusion
• renal transplant
• ischemic preconditioning
• remote ischemic preconditioning
• kidney

This article is referred to by:

Modulation of Remote Ischemic Preconditioning by Proinflammatory Cytokines in Renal Transplant Recipients

Ischemia–reperfusion injury (IRI) is a composite of the injury conveyed through a period of diminished or lacking blood flow to a tissue or organ and the additional insult sustained on reperfusion, which restricts the amount of tissue that can be recovered, leading to further tissue damage and inflammation.¹ Renal IRI, an inevitable event during kidney transplantation procedure, can result in delayed graft function (DGF) or even primary nonfunction. In addition, studies have shown that IRI in kidney transplantation is associated with an increased risk of acute rejection, chronic renal fibrosis, and reduced overall graft function survival.^1,2 Although IRI has been described commonly in deceased donor kidney transplantation, living donor transplantation with a prolonged warm ischemia time can also cause significant IRI and poor early graft function.¹

In addition to strategies to limit IRI such as advancements in organ allocation systems and preservation of organs, and reduction in cold and warm ischemia time, remote ischemic conditioning (RIC), the phenomenon activated by brief nonlethal periods of ischemia applied to a remote organ or tissue followed by tissue reperfusion confer subsequent protection against IRI, has attracted much attention in recent years.¹ Since its first introduction in 1986,¹ the exact mechanism of this signal transduction is still currently undefined. However, there is increasing evidence that RIC helps reduce IRI via both humoral and neurological components such as the release of various molecules that stabilize the mitochondrial permeability transition pore and signal via Toll-like receptors in the proximal tubular epithelia ¹ In addition, it has also been proposed that RIC can induce renal epithelial cells to enter a short period of G1 cell-cycle arrest until the danger has passed or injury has been repaired.³ In high-risk patients undergoing cardiac surgery, RIC has been shown to reduce^{TABLE 1} the rate of acute kidney injury (AKI) the use of renal replacement therapy, and length of intensive care unit stay after cardiac surgery.³

With these promising findings and data suggesting a potential benefit of RIC in animal kidney transplantation models,¹ a few clinical trials have investigated the use of RIC in human kidney transplantation (Table 1).^1,2,4 Unfortunately, the findings from these investigations have been inconclusive due to a number of factors including the differences in research protocols, diverse time points of RIC preconditioning, perconditioning (during target organ ischemia but before reperfusion), and postconditioning (induced at the initiation of reperfusion), donor types, surgical technique, limited sample size, and complexity of kidney transplant patients including advanced age, coexistent comorbidities, and polypharmacy.² Zhou et al. recently conducted a meta-analysis of six clinical trials including 651 recipients to assess the effect of RIC on IRI during kidney transplantation.² From the finding of this meta-analysis, there was a potential association between RIC and a 0.8-fold decreased risk of DGF after kidney transplantation. However, the reduced risk was not statistically significant.² Based on their sample size calculation, the investigators suggested that at least 4,637 recipients are needed to be able to assess the effect of RIC on the risk of DGF.²

TABLE 1 Clinical trials of ischemic conditioning in kidney transplantation^1,2,4

Investigators	Number	Donor type	Outcomes
Loukogeorgakis et al., 2006	20	Living donor	Improved eGFR over 5 years follow-up.
Chen et al., 2013	60	Living donor	No differences in urine volumes, urinary biomarkers or serum creatinine.
Kim et al., 2014	60	Living donor	Hasten the recovery of graft function within 24 hr but did not affect the graft function thereafter.
van den Akker et al., 2014	60	Deceased donor	No benefit in terms of reduced DGF or better renal function
Wu et al., 2014	48	Deceased donor	Enhanced the early recovery of renal function in recipients after kidney transplantation.
MacAllister et al., 2015	406	Living donor	Small but clinically important increase in iohexol GFR at 1 year follow-up.
Nicholson et al., 2015	80	Living donor	No significant differences in eGFR at 1 month or 3 months.
Krogstrup et al., 2017	225	Deceased donor	No difference in graft recovery.
This issue, Journal of Investigative Surgery	28	Deceased donor	No improvement in eGFR; however, it modifies the inflammatory response.

In this edition of Journal of Investigative Surgery, ⁴ “modulation of remote ischemic preconditioning by proinflammatory cytokines in renal transplant recipients”, the investigators conducted a randomized controlled study assessing the effects of remote ischemic preconditioning (RIPC), applied in donors with brain death on IRI in 29 kidney transplant recipients (12 in the control group and 17 in the RIPC group). Not surprisingly, due to limited sample size as mentioned prior, this study also found no differences in eGFR between RIPC and control groups up to 3-month follow-up. However, this study interestingly demonstrated differences in the pro-inflammatory cytokines between two groups, especially TNF-α, which was significantly higher in RIPC than in control group up to 3-month post kidney transplantation. In addition, IL-6 level in RIPC group was substantially higher at 72 hr postkidney transplantation. Interestingly, IL-6 level in RIPC group subsequently decreased over time and was significantly lower than the level in control group at 30 days post kidney transplantation.

During renal IRI, TNF-α, a proinflammatory cytokine, is known to be elevated in both kidneys and serum.⁵ Binding of TNF-α to its membrane receptors can reactivate NF-κB and further augment TNF-α production in tubular cells, as well as the expression of inflammatory mediators such as chemokines and cytokines. In addition, depending on the type of signaling pathways activated by TNFR1 and TNFR2 binding, TNF-α can also induce apoptosis in ischemic tubular cells during IRI.⁵ In kidney transplantation, plasma and urine levels of TNF-α have also been found to be elevated in recipients with renal allograft rejection.⁵ Thus, it is an unexpected finding that TNF-α level was significantly higher with RIPC, an intervention that has been proposed to prevent IRI.³ Nonetheless, in addition to being a proinflammatory cytokine, TNF- α has a broad range of functions such as promoting lymphoid development, apoptosis, tissue repair, regenerative and proliferative processes.⁶ It is possible that elevated TNF-α in the setting of RIPC has a regenerative role rather than inflammatory, since IL-6 level, another cytokine in the acute phase response, was significantly lower in RIPC group at 30 days post kidney transplantation, despite the persistent elevation of TNF-α. The modulation of cytokine effects after RIPC was not observed in a previous clinical trial of RIPC in living donor kidney transplantation by MacAllister et al.⁷ Conversely, they demonstrated comparable serum levels of TNF-α and IL-6 in both RIPC and control groups. Moreover, published clinical trials have emphasized the clinical safety of RIPC in kidney transplantation and demonstrated potential beneficial effects (Table 1).^1,2,4

In summary, clinical data on the utility of RIC's renoprotective effects on DGF in kidney transplantation is currently limited, due to lack of large clinical trials. A study of the Association of Remote Ischemic Preconditioning in Abdominal Organ Transplantation (RIPCOT), currently closed to recruitment, enrolled 580 cadaveric donors and recipients of kidney, pancreas and liver transplant. The findings from this large clinical trial will help elucidate whether RIC is effective in preventing the deleterious effects of IRI.⁸ In addition, further studies assessing the cytokine modulation after RIPC, with an incorporation of biomarkers of AKI and cell cycle arrest (e.g., TIMP-2 and IGFBP7),^3,8,9 are required to understand the complex inflammatory and anti-inflammatory pathways involved and help devise effective interventions to prevent IRI.

CONFLICT OF INTEREST

The authors declare that they have no conflicting interest.

AUTHORS' CONTRIBUTIONS

All authors had access to the data and a role in writing the manuscript. All authors read and signed the final paper.