Chinese Medical Journal 2010;123(21):3079-3083
Effects of the novel 6% hydroxyethyl starch 130/0.4 on renal function of recipients in living-related kidney transplantation

WU Yan,  WU An-shi,  WANG Jun,  TIAN Ming,  JIA Xin-yuan,  RUI Yan,  YUE Yun

WU Yan (Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China)

WU An-shi (Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China)

WANG Jun (Department of Anesthesiology, Third Hospital, Peking University, Beijing 100083, China)

TIAN Ming (Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China)

JIA Xin-yuan (Basic Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China)

RUI Yan (Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China)

YUE Yun (Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China)

Correspondence to:YUE Yun,Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China (Tel: 86-10-85231463. Fax:. E-mail:yueyun@hotmail. com)
Keywords
hydroxyethyl starch; renal function; living-related kidney transplantation
Abstract

Background  The optimal colloid for use during kidney transplantation is not clear. Patients undergoing living-related kidney transplantation (LRKT) were used to compare the protective effects of 6% hydroxyethyl starch 130/0.4 (HES 130/0.4) and 4% succinylated gelatine, as donor kidney procurement, ischemia time and surgical conditions are comparable. Stroke volume variation (SVV) was used to monitor intravascular volume to avoid renal allograft hypoperfusion. 

Methods  Eighty patients undergoing LRKT were divided into two groups: group H received 6% HES 130/0.4 and group G received 4% succinylated gelatine. All donors and recipients received 15–25 ml/kg of the relevant colloid during surgery. Arterial blood pressure (ABP), heart rate (HR), central venous pressure (CVP), SVV and cardiac index (CI), electrocardiography (ECG) and SpO2 were monitored continuously. SVV was kept between 6%–13% and mean arterial pressure at 100–130 mmHg. Samples of venous blood and urine were obtained 30 minutes after unclamping and on the mornings of post-operative days (POD) 1–4 to measure serum and urine β2-microglobulin, urine α1-microglobulin, microalbumin and N-acetyl-β-D-glucosaminidase. Blood urea nitrogen (BUN) and creatine were determined pre-operation (t0), 3 hours after surgery (t1) and on PODs 1 (t2), 2 (t3), 4 (t4), 7 (t5) and 10 (t6). Urine output was recorded at t1, t2, t5, t6.

Results  Age, body weight, body surface area (BSA), operation time, urine output and the colloid volume infused were comparable between the groups and hemodynamics were stable during surgery. BUN, serum creatine, serum β2-microglobulin and urine β2-microglobulin decreased significantly after surgery in both groups relative to the baseline. BUN decreased significantly in group H compared with group G at t1, t2 and t4. Urine microalbumin decreased significantly in group H on POD 4 compared with group G. Urine α1-microglobulin was not significantly different between the two groups.

Conclusion  Both colloids can be safely used for LRKT, but HES130/0.4 was associated with a more rapid recovery of renal function.

Delayed graft function (DGF) is considered to be the result of an accumulation of various harmful factors within the kidney graft during renal transplantation.1–4 Intervention should be implemented to prevent DGF before it occurs. Fluid therapy has a major influence on the recovery of kidney allograft function, and colloids play an important role.5,6 The optimal colloid for use in kidney transplantation remains unknown. Hydroxyethyl starch (HES) solutions are widely used as volume expanders.7–11 Although there are still some debates regarding whether HES impairs renal graft function,12,13 adverse events have only been seen in patients that received high molecular weight and highly substituted forms of HES (such as HES 200/0.6). Osmotic, nephrosis-like lesions were reported in 80% of transplanted kidneys after the use of routine volumes of HES 200/0.6 in brain-dead donors.14 Another prospective randomized trail comparing HES 200/0.6 and gelatin used for volume expansion in brain-dead donors found that HES impaired immediate restoration of renal function in kidney transplant recipients.15 The most likely mechanism for this may be swelling and vacuolization of the tubular cells, and tubular obstruction due to hyper-viscous urine.16 Also, the slow degradation of high molecular weight or highly substituted HES may increase plasma osmotic pressure, leading to renal dysfunction.17 Third grade, medium-molecular-weight HES with a low molar substitution (HES 130/0.4) has a better profile for renal protection, but its effect on the renal allograft during kidney transplantation is not clear. A recent retrospective study, in which the colloid were administered only to donors, found that, compared with gelatin, administration of HES 130/0.4 to brain-dead donors was associated with better renal function in recipients.18 However, the effects of HES 130/0.4 (given to the recipient during surgery) on renal function have not been investigated.

The purpose of this study was to evaluate the effects of HES 130/0.4 on the renal function of recipients after living-related kidney transplantation (LRKT). Either HES 130/04 or succinylated gelatin were given to both donors and recipients. Stroke volume variation (SVV) was used to monitor intravascular volume to avoid allograft hypo-perfusion.

METHODS

Patients
After approval by the Local Ethics Committee, 80 patients (and 80 donors) undergoing LRKT in Beijing ChaoYang Hospital were recruited between June and November 2009. All donors were healthy individuals between 22–37 years old. Recipients were between 18–70 years old. Patients and donors were randomized into two groups receiving either 6% HES 130/0.4 (Voluven®; Fresenius Kabi Germany) (group H) or 4% gelatin (Gelofusine®; B. Braun Australia) (group G). Exclusion criteria were left ventricular ejection < 50% or receipt of a previous graft.

Anesthesia and fluid maintenance
All patients and donors received general anesthesia. Midazolam, sufentanil, propofol, rocuronium and remifentanil were used for anesthesia induction and maintenance, with isoflurane applied as necessary. Donors received 7 ml/kg of the relevant colloid over a 30-minute period during anesthesia induction and 3 ml∙kg-1∙h-1 of crystalloid Ringer’s lactate solution for maintenance. During surgery, colloid was infused at 3 ml∙kg-1∙h-1 until the end of the procedure. Recipient arterial blood pressure (ABP), stroke volume variation (SVV; Vigileo® FloTrac System; Edward LifeSciences, USA), heart rate (HR), SpO2 and ETco2 were monitored on arrival in the operating room (OR). Recipients received 7 ml/kg of the relevant colloid over a 30-munite period during anesthesia induction. After tracheal intubation, central venous pressure (CVP) was monitored through a catheter placed in the right internal jugular sub-clavicular vein. Crystalloid of Ringer’s lactate solution (2 ml∙kg-1∙h-1) was infused for maintenance during surgery. The colloid infusion speed was adjusted to keep SVV ≤13%. Red blood cells were infused to keep Hbg ≥8 g/dl. Systolic ABP was kept above 160 mmHg after unclamping. If ABP could not be kept stable for more than 3 minutes, dopamine was infused at 1–10 µg∙kg-1∙min-1.

Measurement of renal function
Blood urea nitrogen (BUN) and serum creatinine concentrations (markers for glomerular filtration rate and general hydration) were determined pre-operation (t0), 3 hours after surgery (t1) and on post-operative days 1 (POD 1) (t2), POD 2 (t3), POD 4 (t4), POD 7 (t5) and POD 10 (t6). Urine output was recorded at t1–6. Urine alpha 1-microglobulin (α1-MG), beta 2-microglobulin (β2-MG), microalbumin (mALB), N-acetyl-β-D-glucosaminidase (NAG) and serum β2-MG levels were used as specific markers of glomerular and tubular injury,19 and were measured 30 minutes after unclamping, and on the morning of POD 1, POD 2, and POD 4. Samples of venous blood and urine were stored at –70°C for later batch analysis. These samples were measured using enzyme linked immunosorbent assays (ELISA; Rapidbio, USA), along with an automated ELISA reader (MULTISKAN MK3, Thermo, USA) and a spectrophotometer (UNICO, UV-2000, Shanghai, China).

Statistical analysis
Sample size estimation was based on renal function parameters. Differences in serum creatinine concentrations between the groups of up to 50 μmol/L were regarded as clinically irrelevant. According to our previous work, the post-operative SDs for serum creatinine were 66 μmol/L and 62 μmol/L; representative of at least 68 patients (34 in each group). Each donor:recipient pair was assigned a randomized number generated from a random number table. The investigator received a set of envelopes containing information regarding the colloid identified by the random numbers. The envelope was opened when the patient arrived in the OR. Data were analyzed using SPSS v.11.5 software (SPSS Inc., Chicago, IL, USA). Normally distributed data are presented as mean ± SD and intergroup analysis was carried out using an independent-t test for comparison of the means. Qualitative data were analyzed using the χ2 test. A P value <0.05 was considered to be significant.

RESULTS

Donors’ details
Donor demographic characteristics and the volumes of the relevant colloid and crystalloid fluids administered during surgery were similar. The warm ischemic times for all the allografts were within 3 minutes of each other and cold ischemic time within 1 hour (Table 1).


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Table 1. Donor’s demographics, operation time and fluid infusion during operation

Recipient demographics and operative details
Two patients (1 in each group) required further surgery due to anastomotic bleeding on POD 3 or POD 4. Another patient died from acute massive hemorrhage due to vessel rupture on POD 4. All other recipients fully recovered. Thus, 77 recipients (39 from group G and 38 from group H) met the criteria and were enrolled in the study. The demographics, pre-operative ejection fraction (EF) values, the volume of the relevant colloid and crystalloid fluids administered during surgery, the duration of surgery, and length of postoperative hospital was not significantly different between the two groups (Table 2). Intra-operative hemodynamic parameters, such as systolic ABP and CI, and volume control parameters including SVV and CVP were also similar between the two groups (Table 3).


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Table 2. Recipient’s demographics, pre-operation and intra-operation data base

Recipient urine output, BUN and serum creatinine levels
There were no significant differences in urine output between the two groups during or after surgery; however, the urine output of group H on POD 1 (t2) was greater than that of group G (12 062 ml vs. 10 725 ml) (Table 4). BUN and serum creatinine baseline levels were similar in both groups. After surgery, BUN was decreased significantly in group H compared with group G on POD 1 (P=0.024), POD 2 (P=0.012) and POD 4 (P=0.021). Serum creatinine decreased significantly in both groups post-operatively, but was not significantly different between the groups (Table 4).

Glomerular and tubular injury markers
All specific markers of glomerular and tubular injury, such as urine mALB levels, serum and urine β2-MG levels, urine a1-MG, and NAG levels, were not significantly different between the two groups (Table 5); however, urine mALB levels at t4 were significantly lower in group H.


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Table 3. Comparison of intra-operative heamodynamics and Hbg between the two groups during surgery
Table 4. Changes of routine renal function, BUN, serum Cr and urine output of recipients between the two groups after surgery
Table 5. Changes of kidney unit injury bio-protein markers of recipients between the two groups after surgery

DISCUSSION

In this study, we compared the effects of two colloids, gelatin and HES 130/0.4, on the renal function of LRKT recipients. The two groups were comparable in terms of the donors’ physical status, the kidney allograft ischemic time and the recipients’ pre-anesthetic evaluations.

As we know, maintaining an adequate intravascular volume is even more important than the type of perfusion fluid itself for good perfusion of the kidney.16,20,21 Using the intravascular volume parameter, SVV, we could adjust the rate of fluid administration to make sure that the patient maintained an optimal intravascular volume situation.22,23 Both colloids are widely used in major surgery for plasma volume expansion. Gelatin has no adverse effects on renal function and is normally used as a standard for volume substitution.24 However, the pharmacological properties of hydroxyethyl starch solutions have constantly improved over the last decade. For example, the latest HES generation, HES 130/0.4, has a total body clearance about 23–31 times faster than that of the first generation hetastarch, and exhibits the best risk/benefit ratio of all available HES.25 However, there is still some debates surrounding the effects of hetastarch solutions on renal function, especially in the field of kidney transplantation. These solutions have seldom been used in previous studies comparing the effects of colloids used in major surgery for volume expansion on subclinical markers of renal function.

A limitation of these studies was that glomerular and tubular injury was not clear. In a recent study, using urinary a1-MG and urinary IgG:creatinine as the markers of glomerular and tubular dysfunction, Mahmood and co-workers25 compared the effects of two kinds of HES (weight 200/0.62 and 130/0.4) and gelatin on renal function during aortic aneurysm surgery. They found that, when HES infusion was accompanied by double the volume of crystalloid, renal function improved compared with that after gelatin infusion.26 Blasco and colleagues18 compared the effects of HES 130/0.4 and HES 200/0.6 infusion into brain-dead donors on renal function after transplantation. They reported significantly lower rates of DGF and decreased serum creatinine levels in the HES 130/0.4 group compared with the HES 200/0.6 group.18 The limitation of the study is that they only administered colloid to the donors and there was a lack of the intra-operative data from the recipients. Both of these authors suggested that further studies should be undertaken, especially in the field of renal transplantation.

In the present study, BUN levels in group H decreased significantly compared with those in group G on POD 1 (P=0.024), POD 2 (P=0.012) and POD 4 (P=0.021). This indicated a relatively rapid recovery of renal function in group H, although kidney function in both groups recovered well. Both serum and urine β2-MG levels decreased in both of groups, indicating that tubular function also recovered well. Urine mALB levels in group H were significantly lower on POD 4 compared with group G, suggesting a more rapid recovery of glomerular filtration. Explanations for these differences mainly include improved hemorheology and reduced whole blood viscosity, as well as a reduction in renal capillary leakage in group H.26 Smaller molecules of starch reduce erythrocyte aggregation, so improved hemorheology is achieved by administering HES 130/0.4.28,29 There was no obvious increase in urine a1-MG and NAG levels, or other biological protein indicators, suggesting that there was no allograft kidney rejection.30

There are several limitations in this study. With regard to protein indicators of glomerular and tubular injury, more post-operative time-points could be sampled so that more developmental trends in the recovery of the kidney units are obtained. Moreover, long-term follow-up will be done in our next study, which might provide more comprehensive evidence regarding kidney function after LRKT.

In conclusion, the present results suggest that third-generation rapidly degradable, low substitution (HES 130/0.4) is associated with slightly better renal function compared with gelatin. However, further studies are required.

Acknowledgements: The authors thank Dr. WANG Wei and Dr. YIN Hang for their help to the study.

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