The main functional goals of PN are to preserve as much normal tissue as possible without violating oncological principles and to avoid prolonged warm ischemia. Despite all the efforts, a functional decline in the range of 20% is anticipated early after PN. The importance of parenchymal preservation is more pronounced in the setting of imperative or absolute PNs. A retrospective study involving 360 patients with solitary kidneys showed a 6% increase in the incidence of de-novo severe chronic kidney disease (CKD) with each additional minute of warm ischemia. CKD risk was even greater for renal masses with complex morphometric features which would necessitate longer on-clamp duration for a proper PN. In addition, CKD has been shown to be a strong predictor of cardiovascular events and associated mortality in the long run.18,19
Several different technical modifications were introduced in an effort to shorten the duration and minimize the functional consequences of warm ischemia time (WIT) during PN, including early unclamping, renal hypothermia, segmental artery clamping and zero-ischemia technique.20–23 However, data regarding their actual influence on functional and perioperative outcomes is conflicting. Early hilar unclamping was found to be associated with increased blood loss and longer operative duration when compared to the standard approach.24 Studies about intraoperative cold ischemia showed inconsistent results, with marginal functional benefits only in diabetic and hypertensive patients.25 The zero-ischemia technique, which involves meticulous dissection of the renal vasculature, was found to be too laborious from the technical standpoint which limited its application to high-volume surgeons.
The need for a simple, effective and reproducible method which could augment the resilience of renal parenchyma against the ischemic insult related to the WIT of PN is currently unmet. RIPC may serve well to fill this gap as it was shown to encompass the potential to promote renoprotection in instances which might indirectly endanger kidney function, such as cardiovascular surgery. Repetition of brief ischemia and reperfusion episodes remotely may result in enhanced tolerance of the kidney to the anticipated, subsequent ischemic damage.26 This concept was proven by Huang et al., who became the first to demonstrate that remote myocardial preconditioning not only decreased the myocardial infarct area, but also reduced the severity of kidney injury.26 However, subsequent human and small-animal studies, concentrating on the relationship between RIPC and reversal of acute kidney injury (AKI), revealed somewhat disappointing results 27,28. Bedir et al. tested the renoprotective value of RIPC in a porcine solitary kidney model.10 Their modified study design, which included larger kidneys with a potentially better analogy to human counterparts and a solitary kidney model that eliminated the confounding effect of contralateral kidney on functional analysis, was deemed insufficient to disprove the negative outcomes obtained in prior RIPC studies. Nevertheless, using serum creatinine to monitor functional changes in the kidneys that were subjected to RIPC was their major limitation, as creatinine has poor sensitivity in detecting AKI.29 Huang et. al tried to overcome the drawbacks of creatinine-based assessment by measuring urinary retinol binding protein levels as a measure of glomerular filtration rate.9 In their study involving 82 patients, they showed that transient lower limb ischemia reduced renal impairment in the short-term but failed to provide a similar benefit in the long run, despite a positive but statistically insignificant trend in favor of RIPC. However, their outcomes would have been more supportive of RIPC, should they limited their analysis to patients with solitary kidney, which is hard to implement and standardize in a study involving human subjects.
As expected, creatinine levels showed a consistent rise in all groups except the sham group. When compared to the trend observed in the sham group, serum levels of the other biomarkers paradoxically declined along the time course of the study. Inappropriate timing of RIPC and/or PN or the inadequacy of the time interval spent between right nephrectomy and the other experimental procedures might be the underlying reasons for this controversy. We could have shown a more profound protective effect of RIPC if we had proceeded with PN after a longer period of time, allowing the study subjects to show sufficient reaction to the intervention being tested.30 However, the same trend was also evident for the groups who did not undergo RIPC. Moreover, conducting the pre- and post-intervention follow-up of the rats in the absence of metabolic cage might have influenced their kidney function. Undoubtedly, measuring the urinary levels of these biomarkers, lack of which is a drawback of this study, would have served to strengthen the accuracy of analysis. Lastly, small sample size together with a mortality rate of 5% could be considered as another limitation.
Although we were unable to demonstrate a beneficial impact of RIPC on renal functional preservation from the biomarker standpoint, we have observed a possible hint of its renoprotective effect on histological grounds. This was reflected by a slightly reduced mean infarct area in the RIPC + PN group when compared to the PN group alone. On the other hand, the zone of ischemia, the region between infarcted and unaffected kidney parenchyma was thicker in the former animals which could be explained due to the area protected from complete necrosis being added to ischemic zone. However, these alterations were not found significant statistically. Both groups had similar regeneration capacity as noted by the same Ki-67 proliferative indices.