To the best of our knowledge this is the first study evaluating the influence of rocuronium and sugammadex, compared to cisatracurium and neostigmine, on graft function after renal transplantation. We retrospectively analyzed medical records of patients who had undergone kidney transplantation, whose neuromuscular block was reached by cisatracurium or rocuronium and the reversal obtained by neostigmine and sugammadex, respectively. We found that: 1) during the first 24 hours after the transplantation, blood creatinine and urea levels were significantly lower in the rocuronium-sugammadex group; 2) there was no difference in serum and urinary electrolyte levels between the considered groups; and 3) the use of both neuromuscular agents and their reversals were not independent risk factors for acute kidney injury after the transplantation.
Creatinine is commonly used as a measure of kidney function . The diagnosis of renal failure is usually suspected when serum creatinine in greater than the upper limit of the normal range . In the early post-transplant period the graft function also depended on the donor characteristics . In this study, variables that may affect the graft function were the donor’s age, the ischemic time and the Karpinski score, which were not different between the groups and, interestingly, the graft function was well restored during the first 72 hours after the transplantation, since the blood creatinine levels decreased as expected . However, this happened much more often in the sugammadex group, even if it was rapidly cleared unchanged via glomerular filtration without tubular secretion, absorption or metabolism .
During the renal transplantation surgery, the unclamping of the arterial vessels resulted in reperfusion of the transplanted kidney with an immediate urine production in more than 90% of patients. This is proof of the restoration of glomerular function. Theoretically, once the glomerular filtration was resumed in the early post-operative period, sugammadex may be easily excreted by the transplanted kidney . In our patients, the serum creatinine levels and diuresis were fully restored suddenly after the first 24 hours following the transplantation, even in patients treated with rocuronium and sugammadex. This may be due to the fact that the rocuronium-sugammadex complex may be removed according their physiologic pharmacokinetics after the restoration glomerular filtration. Accordingly, there was no increase in serum creatinine levels in the rocuronium-sugammadex group. Indeed, the serum creatinine levels were lower in the rocuronium group compared to the cisatracurium group, even if the cisatracurium underwent Hofmann degradation and ester hydrolysis.
In this study, blood urea levels were significantly lower in the rocuronium-sugammadex group, supporting the good recovery of the graft function. However, we found a slight increase in blood urea levels during the first three days after transplantation. This finding may have many explanations. The transplanted patients received corticosteroids to prevent graft rejection, which has a catabolic action which may contribute to serum urea rising [13,14]. Furthermore, to counteract acute tubular necrosis (ATN), kidney transplanted patients were treated with diuretic drugs that may increase urea levels [15,16,17].
Serum and urinary electrolytes did not indicate any significant difference between the two groups. The modification of their concentrations was in accordance with the restored kidney function. Potassium excretion was demonstrated by its increase in urinary levels and the concurrent decrease of its blood concentrations. Ghoneim et al. have reported similar sodium and potassium serum concentrations in pediatric patients undergoing general anesthesia and treated with sugammadex or neostigmine .
In this study we found that the use of both neuromuscular agents and their reversals were not independent risk factors for acute kidney injury after transplantation, while proper renal biomarkers, such as blood creatinine and urea levels, may play a role [19,20]. Isik et al. have reported an increase of the renal biomarker cystatin C in patients undergoing general anesthesia and treated with neostigmine, but not in patients receiving sugammadex for neuromuscular block reversal. The authors concluded that sugammadex indicated a higher tolerability than neostigmine. The authors also affirmed that neither drug causes renal failure but only a subclinical kidney damage; in fact, the effect on kidney function was evidenced only by cystatin C but no clinical signs of renal failure or changes in creatinine, blood urea nitrogen, sodium, potassium, or calcium were recorded, since in both groups they found a significant reduction in post-operative serum calcium concentration, as we also did in our study . The better renal function exhibited by the roc+sug group compared to the cis+neo group is also supported by in vitro studies, which indicate that neostigmine is more cytotoxic and genotoxic than sugammadex, causing apoptosis and necrosis of human embryonic renal cells . Sugammadex, by comparison, indicated a protective effect against ischemia-reperfusion injury in an in vivo model of cerebral ischemia, probably due to the gamma cyclodextrin ring of sugammadex . This beneficial effect can partly explain the better renal function after transplantation observed in our study in the group receiving sugammadex, even if the exact mechanism still has to be elucidated. Detrimental effects of sugammadex on renal function have been reported in the literature. Histological changes were found and alteration of more sensitive kidney function markers (i.e. N-acetyl-beta-glucosaminidase, microalbuminuria, and beta 2-microglobulin) were observed, but in all cases there was no evidence of clinically evident damage [24,25,26]. Other studies did not confirm the alterations of both classical and new renal damage biomarkers associated with the use of sugammadex and neostigmine .
In this study we found that a blood urea level at 48 hours of 142 mg/dl (median, IQ range 113–187) increased the risk of having an acute kidney injury by 5%, while a blood creatinine level at 24 hours of 3.40 (median, IQ range 2.6–4.8) decreased the risk of having an acute kidney injury by 11.7%. To find general risk factors for acute kidney injury after kidney transplantation was beyond the aim of this study. We performed a multivariate analysis with the aim to assess whether the rocuronium plus sugammadex might be a risk factor for kidney injury after renal transplantation. The role of different creatinine levels after renal transplantation has been discussed in various studies that have found a general agreement between the levels of serum creatinine and graft failure . In general, a longitudinal increase of serum creatinine levels may be used to predict graft failure . A recent study has found that one unit increase in serum creatinine level suggests a fourfold increased risk of graft failure . Our data support the close relationship between serum creatinine and graft function.
Finally, we found no difference in the need for post-operative dialysis between the considered groups. The need for post-operative dialysis may not be worsened by the use of rocuronium + sugammadex or cisatracurium + neostigmine.
This study has many limitations. We did not measure hemodynamic changes during surgery and in the post-operative period. The graft perfusion can be an important factor affecting transplanted kidney function. However, no significant differences in hemodynamic parameters between neostigmine and sugammadex have been reported in previous studies [30,31,32].
Furthermore, since our analysis was conducted retrospectively, we investigated only routine biomarkers of renal function; probably more detailed information about graft damage may be drawn from more sensitive biomarkers, such as NAG, urinary albumin, and beta2-microglobulin.