Correlation of total ischemic time to creatinine serum level and resistive index value in kidney transplant

Background: The transient period when the kidney donor was extracted until being anastomosed (total ischemic time) will aggravate many putative molecular ischemic-reperfusion injury mechanisms. Several studies have reported the risk of delayed graft function development, which can be reflected by creatinine serum (Cr) level and resistive index (RI) value. This study aims to determine the correlation of total ischemic time to Cr levels reduction in one-month posttransplantation and RI value. Methods: This was a cross-sectional retrospective study involving subjects who underwent kidney transplantation in Sanglah General Hospital. In this study, the primary parameters were total ischemic time, Cr level, and RI value. The total ischemic time is calculated using a stopwatch intraoperatively. Cr level was obtained from blood examination, and RI value was obtained from the ultrasonography test. Data analysis was analyzed statistically using SPSS 24.0, and p < 0.05 was considered significant. Results: About 17 kidney transplant subjects were included in this study. The mean total ischemic time was 105 minutes and 43 seconds. There was an insignificant negative correlation between Cr level reduction and total ischemia time (r = -0.36; p = 0.89). An analysis of the correlation of total ischemic time and RI value, there was a linear correlation, but statistically insignificant (r = 0.11; p = 0.66). Conclusion: Total ischemic time has a negative correlation with post-transplant creatinine serum level and a positive correlation with the post-transplant resistive index value, but these results are not statistically significant.


Introduction
The number of patients with end-stage renal disease (ESRD) is increasing every year. 1 The broaden development in health facilities supports kidney transplantation as the best choice for ESRD therapy in terms of better survival rate and quality of life achievement. 2 Many factors affect the success of kidney transplantation, included intraoperative factor. During surgery, the kidney graft will be exposed to the condition of ischemic time, where there is no blood flow to the graft. 3 Putu Astri Novianti 1  There are three potential periods for ischemic injury during a kidney transplant. First, the period before organ retrieval in the donor defined as "first warm ischemia time". Second, there is a period where the kidney graft is transported from the donor to the recipient in a cold solution, defined as cold ischemia time (CIT). Lastly by a period of second warm ischemia time (WIT) period during reanastomosis in the recipient, the kidney graft is taken out of cooling and reperfused by the recipient's blood. 3 Many studies showed that long ischemic time duration would cause hypoxia of the graft tissue and increase the risk of ischemia and reperfusion injury (IRI) and delayed graft function (DGF). DGF is defined as a failure of the renal transplant to function immediately, with the need for dialysis in the first post-transplantation week. This can be reflected by a decrease of less than 25% of the serum creatinine level and high resistive index. 3 However, studies showed controversial result and the magnitude of the failure risk was varied. Therefore, this study aims to determine the correlation of total ischemic time to creatinine serum levels reduction in one-month post-transplantation and resistive index value.

Methods
This study is an analytic cross-sectional study to determine the correlation of total ischemic time and creatinine serum level reduction

About 17 kidney transplant procedures have been carried out at
Sanglah Hospital from January 2016 to November 2019 with the characteristic of the samples in Table 1. Recipients consist of 14 males and three females. Based on the age, the mean recipient age is 31.09 + 7.33 years old, and the mean age of the donor is 49.65 + 9.93 years old.
All donors have the family-related pedigree to the patients (13 donors from mother, 1 donor from father, 3 donors from a sibling).
All data were normally distributed, thus could be analyzed parametrically ( Table 2). The mean creatinine serum level decrease progressively after kidney transplant procedure (1 month after surgery: 1.36 + 0.37 mg/dL, 1-day after surgery: 7.86 + 1.82 mg/dL, baseline:   (Table 3). There was an insignificant negative correlation between serum creatinine level reduction and total ischemia time (r = -0.36; p = 0.89). An analysis of the correlation of total ischemic time and resistive value, there was a linear correlation, but statistically insignificant (r = 0.11; p = 0.66).

Discussion
Kidney transplantation is recognized globally as the gold standard treatment of ESRD. Several studies show that kidney transplantation is associated with a significant reduction in long-term mortality risk and cardiovascular events, as well as clinically relevant improvements in quality of life. 4,5 Complications that could occur after kidney transplantation procedure, such as vascular complications (renal artery or vein stenosis, arteriovenous fistula, pseudoaneurysm); urological complications (urine obstruction or leakage, accumulation of peri-transplant fluid such as hematoma, seroma, lymphocele, urinoma, abscess formation, distal ureteral ischemic necrosis) 6 ; medical complications (anemia, hypertension, infection, graft rejection, malignancy). 7 Delayed graft function is one of the most concerning complications, which is majorly reported to be affected by a longer ischemic time during surgery. Nevertheless, proper functioning of the graft is essential for patients to re-establish body homeostasis and thus benefit from receiving the transplant. The injury during low oxygen and the restoration of oxygen had been proposed to induce ischemiareperfusion injury (IRI). IRI in kidney transplantation could cause DGF and associated with episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation plays an essential role in the pathogenesis of IRI. 3 Intraoperatively, the transplanted kidney will be exposed to two different processes, WIT and CIT. Total ischemic time is a combination of WIT and CIT. The first WIT is defined by the time between clamping of the donor's artery and vein until the graft is preserved in cold storage. In this period, cell damage can occur due to decreased oxygen supply to cells with a consequent reduction of aerobic metabolism to an anaerobic route. 3  The sign of the early phase of improper graft function is low glomerulus filtration rate (GFR), which can be indicated by a higher serum creatinine level. Adequate perfusion has a significant role in maintaining graft survival. Ischemia-induced hypoxia may impair graft microcirculation, leading to proximal tubular epithelial cell injury. 12 The tubular damage results in impaired proximal sodium reabsorption.
This impaired tubular transport of sodium activates tubular glomerular feedback (TGF) mechanism leading to increased afferent vasoconstriction and a concomitant decrease in GFR. 13 8%). RI also has a significant direct correlation with Cr. 14 Table 1 shows creatinine serum levels reduction in one-month post-transplant compared to pre-transplant and low RI values.
In this study, we showed that the mean creatinine serum level decreases progressively after kidney transplantation procedure. The mean value of resistive index before and after transplantation did not differ significantly. We also found that no significant statistical correlation between total ischemic time and creatinine level as well as the resistive index value. Regardless of that, the descriptive data showed that the longer the total ischemic time, the higher the serum creatinine level. This result differed from Nugroho et al., who showed a strong negative correlation between the length of the total ischemic time and the reduction in creatinine levels (r = -0.44, p = 0.008). 15 Simpkins et al., reported that prolonged CIT did not result in lower serum creatinine, increased acute rejection, or compromised allograft survival in any groups with > 2-h CIT compared with the 0-2 h group. 16 During the CIT period, cold preservation of the graft could slow anaerobic metabolism and its subsequent accumulation of metabolic waste products. However, it does not halt the consequences of cellular ischemia. 17 Living-donor has the advantage in minimizing CIT compared to the deceased donor because transplantation procedure could be performed in sequential (use same operating room) or simultaneous (use different operating room) manner. Prudhomee et al., showed CIT and DGF were significantly higher in the sequential group than the simultaneous group, and CIT was a significant predictor of DGF. 18 Several studies showed varied results about ischemic time (Table 4).
Despite reporting no differences in terms of renal function, it is important to note that the consequences of a long ischemic time are widely reported. There are many growing studies that addressed this issue regardless of its significance in the statistical calculation. Still, the descriptive analysis showed a negative effect of longer total ischemic 30 Published by: Indoscholar Publishing Services (www.indoscholar.com) time on renal function. Further study was needed for a more comprehensive analysis of this effect.

Conclusion
Total ischemic time has a negative correlation with posttransplant creatinine serum level and a positive correlation with the post-transplant resistive index value, but these results are not statistically significant.