- Research article
- Open Access
Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement – a randomized trial
BMC Nephrology volume 22, Article number: 111 (2021)
Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators.
In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning.
IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] μg/mmol creatinine p = 0.004 after IS vs. 5.5 [2.1;9.4] μg/mmol creatinine after PL, p < 0.001). No difference was found between the groups (p = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups (p = 0.064).
FENa increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p = 0.032). ENaC excretion was different within groups (p = 0.019).
A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL.
ClinicalTrials.gov Identifier: NCT02528448, 19/08/2015
Fluid treatment is widely used for maintaining cardiovascular stability in patients undergoing surgery, trauma, and critical disease. Both isotonic saline and balanced crystalloids are commonly used for fluid resuscitation [1, 2]. Isotonic saline has a high chloride content (154 mmol/L), whereas the balanced crystalloids have lower chloride contents but also differ in electrolyte composition. Ringer’s acetate, Ringer’s lactate and PlasmaLyte are all balanced crystalloids, and PlasmaLyte has the lowest chloride content (98 mmol/L). Infusion of fluids containing high chloride amounts are suspected to increase the need for renal replacement therapy. In several studies, isotonic saline induced hyperchloremic metabolic acidosis as opposed to fluids with a lower sodium and chloride content, especially when administered in high amounts [3,4,5]. Animal experiments have shown that hyperchloremic acidosis reduces renal blood flow (RBF) and induces kidney injury [3, 6,7,8,9]. High chloride concentrations during renal perfusion correlated with increased renal vasoconstriction and with declines in RBF and glomerular filtration rate (GFR) [7,8,9]. In addition, studies in healthy subjects comparing isotonic saline to fluids with lower sodium and chloride contents showed a decrease in RBF and GFR [8, 10].
Infusion of balanced IV solutions in patients admitted to an emergency department was associated with a lesser degree of acute kidney injury (AKI) than infusion of fluid solutions with higher chloride content [3, 5]. However, the importance of hyperchloremia and infusion of high chloride-containing solutions is still under much debate in the clinical setting [11,12,13]. In daily practice, traditional biomarkers such as plasma creatinine and GFR are used to estimate renal function. In case of AKI, changes in creatinine may require 24 h or more before being detectable. However, biomarkers such as neutrophil gelatinase-associated (NGAL) and kidney injury molecule-1 (KIM-1) have shown potential as acute indicators of AKI. Both are able to detect kidney injury and predict the risk of renal replacement therapy within hours [14,15,16,17,18].
We therefore hypothesized that fluids containing high amounts of chloride given as isotonic saline could induce hyperchloremic acidosis and cause subsequent changes in biomarkers of kidney injury. These effects may be detected by measuring renal function, urinary excretion of biomarkers of kidney injury, and plasma concentrations of vasoactive hormones.
We investigated this hypothesis in a randomized, double-blinded study, where patients undergoing primary uncemented hip replacement were given either isotonic saline (IS) or PlasmaLyte (PL) during the course of their surgery and recovery.
Materials and methods
The study was a randomized, double-blinded study in 40 patients undergoing primary uncemented hip replacement.
All patients were recruited from the Department of Orthopedic Surgery, Gødstrup Hospital, Holstebro; Denmark. Patients referred for elective hip arthroplasty were asked to participate. All patients were screened before participation. Screening examination included medical history, physical examination, office BP measurement, ECG, clinical biochemistry, and urine analysis. All patients were screened between August 2015 and February 2016.
Age > 18 years, patients undergoing primary uncemented hip replacement during spinal anesthesia.
Blood donated within the past month, eGFR < 30 ml/min, pregnancy, nursing, diabetes mellitus type 1, or unwillingness to participate.
Estimated perioperative bleeding exceeding 1000 ml, blood transfusion, development of post-operative infection, reoperation, or withdrawal of consent.
The main effect variable was u-NGAL. Other effect variables were u-KIM-1, free water clearance (CH2O), GFR, fractional excretion of sodium (FENa), fractional excretion of potassium (FEK), fractional excretion of chloride (FECl), u-albumin, urinary excretions of aquaporin-2 (u-AQP2), epithelial sodium channels (u-ENaCγ), Na-K-Cl cotransporter (u-NKCC2) and Na-Cl cotransporter (u-NCC), plasma concentration of renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo) and vasopressin (p-AVP), arterial blood gas levels of pH, chloride (P-Cl), base excess (SBEc), and bicarbonate (P-HCO3−).
Number of patients
With a significance level of 5% and a power of 80%, 16 patients in each group were needed to detect a 100 ng/mL difference in u-NGAL (SD 100 ng/mL). Due to expected drop-outs and complications during surgery, it was estimated that 20 subjects in each group should be included in the trial.
Patients were randomized to receive either isotonic saline (IS, 0.9% NaCl, 154 mmol/L chloride) or PlasmaLyte (PL, 98 mmol/L chloride). Both fluids were manufactured by Baxter A/S (Allerød, Denmark) and produced in 1000 ml Viaflo® bags (Baxter A/S). For blinding, each bag was concealed in identical white plastic. Three bags (identical fluid) were packed in boxes corresponding to each randomization number. The hospital pharmacy performed all blinding and packing.
The fluids were administered according to the guidelines from the Department of Anesthesiology, as a continuous intravenous infusion of 15 ml/kg/hour during the first hour of surgery and 5 ml/kg/hour the next two hours. To ensure hemodynamic stability due to blood loss, supplemental fluid could be administered to maintain a mean arterial pressure (MAP) of 70.
The hospital pharmacy generated the randomization list. The list was created in blocks of ten using the computer program “Randomization Generator”. Treatment assignment and allocation was concealed from clinicians, patients, and research staff until completion of the trial.
Prior to surgery, patients received paracetamol 1000 mg orally. A peripheral venous catheter was positioned in a cubital vein for medication and blood sampling. Perioperatively, the patients were monitored with ECG, pulse oximeter and non-invasive blood pressure monitoring.
Prophylactic doses of cefuroxime 1.5 g and tranexamic acid 15 mg/kg (maximum 1 g) were administered. According to local guidelines during spinal anesthesia a urine bladder catheter was inserted in all patients. Spinal anesthesia was achieved with the patient in a lateral position according to the guidelines from the department of anesthesiology. If MAP decreased below 70 mmHg, additional intervention fluid or intermittent doses of phenylephrine 0.1 mg were administered. If arterial saturation decreased below 96%, additional oxygen was provided with a nasal cannula. During the course of the trial, patients were not allowed to receive ephedrine, dexamethasone, or nonsteroid anti-inflammatory drugs.
Urine and blood sampling
The day prior to surgery, all patients performed a 24-h urine collection (urine 1, baseline).
Upon admission, urinary spot samples were collected (urine 2, admission).
When surgery was initiated, urine was collected over the course of 4 h (urine 3, surgery) via the urinary catheter. Hereafter, another urine collection proceeded until the following morning at 8.00 am (urine 4, post-surgery). Every 4 h, urine bags were emptied and the urine stored at 5 °C.
After the urinary catheter had been removed, another urinary spot sample was collected before the patient was discharged (urine 5, discharge). Then, 12–14 days after surgery, patients provided a 24-h urine collection (urine 6, follow-up).
Urine samples were analyzed for u-NGAL, u-KIM-1, u-NKCC2, u-NCC, u-AQP2, u-ENaCγ, osmolality, u-albumin, u-chloride, u-sodium, u-potassium, and u-creatinine.
Arterial and venous blood samples were drawn right before anesthesia and intervention (baseline). After surgery, blood samples were drawn within the first 2 h after arrival in the recovery room and in the morning of the postoperative day. All blood samples were analyzed for measurements of pH, SBEc, P-HCO3−, and plasma concentrations of Cl−, Na+, K+, albumin, creatinine, Hemoglobin (Hgb), osmolality, PRC, P-AngII, P-Aldosterone and P-AVP.
All urine and blood samples were kept frozen at − 80° or − 20 °C until assayed and were centrifuged again before analysis.
NGAL was determined by an enzyme-linked immunosorbent assay (ELISA) from Bioporto (Hellerup, Denmark) as previously described [19, 20]. Levels of minimal detection was 1.4 pg/ml. Variations were established as interassay max 8% and intraassay max 14%. KIM-1 was determined by an ELISA-kit (Quantijine ELISA) from R&D Systems (Minneapolis, USA) as previously described . Levels of minimal detection was 3.0 pg/ml. Coefficients of variation were 7.8% (interassay) and 4.4% (intraassay). All samples were analyzed with kits from the same batch.
u-AQP2 and u-ENaCγ were measured by radioimmunoassay as previously described [21,22,23]. Antibodies to synthetic peptides for ENaCγ were raised in rabbits and the affinity purified as previously described [21, 22, 24]. For ENaCγ the levels of minimal detection was 48 pg per tube; coefficients of variation were 6.7% (intra-assay) and 14% (inter-assay). Similarly, antibodies for AQP2 were raised in rabbits . These antibodies were raised to a synthetic peptide equivalent to the 15 COOH-terminal amino acids in human AQP2. Hereafter, an NH2-terminal cysteine was added for conjugation and affinity purification. The anti-AQP2 antibody was a gift from Søren Nielsen, The Water and Salt Research Center, Aarhus University, Denmark. For AQP2 the levels of minimal detection was 34 pg per tube; coefficients of variation were 5.9% (intra-assay) and 11.7% (inter-assay).
AngII and AVP were determined by radioimmunoassay as previously described [20, 24, 25]. The antibody against vasopressin was a gift from Professor Jacques Dürr, M.D., Tampa General Hospital, Tampa, Florida. NKCC2 and NCC was measured in urine by a radio radioimmunoassay as previously described [22, 26].
PRC and Aldosterone was determined by immunoradiometric assay as previously described . Plasma and urine concentrations of sodium, potassium, chloride, albumin, and creatinine were routinely analysed at the Department of Clinical Biochemistry, Gødstrup Hospital, Denmark. To determine pH, SBEc, P-HCO3−, and plasma concentrations of Cl−, a blood gas analyzer (ABL800 Radiometer) was used at the Department of Anaesthesiology, Holstebro, Denmark.
Free water clearance (CH2O) was calculated with use of the formula CH2O = UO – Cosm, where Cosm is osmolar clearance and UO is urinary output. Fractional excretions of sodium (FENa), potassium (FEK), and chloride (FECl) were calculated with the formula FEX = (Xu * V / Xp)/GFR, where Xu and Xp are urine and plasma concentrations of X and V is urine flow in ml/min.
Values showing normality are presented as means ± standard deviations (SD). If normality was not present, values are presented as medians with 25 and 75% percentiles in brackets.
Within group comparisons were performed with a paired t-test and an unpaired t-test was used for comparison between the groups. Nonparametric data with-in group were compared with a Wilcoxon signed-rank test and between groups with a Mann–Whitney U test. Comparison of two frequencies was done by chi-square test. Treatment effect was analyzed using a repeated measures general linear model (GLM). If data did not show normality, logarithmic transformation was performed prior to GLM. For the primary outcome variable statistical significance was defined as p < 0.05. All analyses on the secondary outcome variables were reviewed as hypothesis generating and there have not been made corrections for multiple testing. Statistical analyses were performed using PASW version 20.0.0 (SPSS Inc.; Chicago, IL, USA).
Fifty-two patients were screened for participation in the study. Eleven patients were unwilling to participate and 41 patients were randomized. Three patients were excluded due to perioperative bleeding above 1000 ml (n = 1, received IS), blood transfusion (n = 1, received IS) and suspected development of type 1 diabetes (n = 1, received PL). Thus, 18 patients who received IS and 20 patients who received PL were included in the analysis (Fig. 1). The two groups were comparable with regards to sex, age, body mass index, blood pressure, comorbidities, and screening biochemistry (Tables 1 and 2).
The two groups were comparable regarding duration of anesthesia, surgery and recovery, and length of hospital stay (Table 3). Blood loss and the amount of intravenous fluid given were the same in both groups. However, the total mass of chloride provided pr. Kg bodyweight to each patient, was higher in the IS group (0.09 g/kg in the PL group vs. 0.14 g/kg in the IS group, p < 0.001). No difference between the groups was observed in the number of patients receiving phenylephrine (6 in the PL group vs. 5 in the IS group, p = 0.8) or the average dose per patient (0.22 mg in the PL group vs. 0.46 mg in the IS group, p = 0.1).
Arterial blood pH, SBEc, cHCO3 and levels of plasma chloride
The levels of arterial blood pH (Fig. 2a), SBEc and cHCO3 (Table 4) was significantly lower in the IS group after surgery, and plasma concentrations of Cl were significantly higher in the IS group as compared to the PL group after surgery (Fig. 2b). These differences were not present the day after surgery.
Urinary NGAL and KIM-1
u-NGAL and u-KIM-1 increased steadily in both groups during the study period (Table 5, Fig. 3). However, no difference in the increase between groups was seen. No significant difference in u-NGAL levels was detected, when comparing the 24 h urine collection at baseline and two weeks later (Table 2). u-KIM-1 levels were significantly higher in the PL group compared to the IS group both at baseline and two weeks later. Both groups had a significant increase in u-KIM-1 two weeks after surgery as compared to baseline values (Table 2).
U-ENaC, u-AQP2, u-NCC and u-NKCC
The response in u-ENaC was not significantly different between groups. However, a difference was present within groups (p = 0.019). The PL group had a steady increase during the entire study period, whereas the IS group showed a more rapid increase during surgery and again at discharge (Table 5). u-AQP2 increased during surgery, post-surgery and at discharge in both groups. No difference was found between baseline and follow-up (Table 2). The differences were non-significant between the groups during the entire study (Table 5).
u-NCC excretion showed an increase as compared to baseline during the study for both groups. This increase was still present at follow-up (Table 2). But no significant difference in response was found. u-NKCC excretion showed a significant increase for both groups during surgery as compared to baseline. No difference was found for either group after surgery, but an increase was present for the saline group at discharge. No significant difference in response was found.
Creatinine clearance, free water clearance and urine output
During surgery, urine output (UO) was higher in the PL group (P = 0.012). But both groups showed a significant decrease post-surgery compared to baseline (Fig. 4). Post-surgery the PL group showed a significant decrease in CH2O as compared to baseline. No significant differences were found between the groups. Creatinine clearance (CrCl) was significantly higher in the PL group during both surgery and post-surgery compared to baseline. Yet, the IS group only had a significant increase in CrCl post-surgery compared to baseline. However, no significant differences were found between the groups (Table 6).
FENa, FEK and FECl
FENa showed a significant increase for both groups during surgery compared to baseline (Fig. 6). The increase was more pronounced in the PL group (p = 0.032). No difference was found for either group on the postoperative day. FEK showed a similar increase for both groups during surgery with a more pronounced increase in the PL group (p = 0.002). FEK remained increased in the IS group on the postoperative day but no difference was found between groups (Table 6). FECl showed a significant increase in the IS group after surgery. On the postoperative day a decrease was present in the PL group. However, the differences were non-significant between the groups during the entire study (Table 6).
Vasoactive hormones in plasma
Table 7 shows the concentration of vasoactive hormones at baseline, after surgery and on the postoperative day. P-AVP showed a significant increase during the study as compared to baseline for both groups. The differences were non-significant between the groups. P-AngII decreased after surgery for the IS group but increased for the PL group on the postoperative day. No significant difference was found between groups. PRC were significantly higher in the PL group at baseline and after surgery as compared to the IS group, but no significant difference was found between groups on the postoperative day. P-Aldo was lower in both groups as compared to baseline after surgery and for the IS on the postoperative day. Also, no differences were found between groups.
P-Na, p-K, p-albumin, p-creatinine and hgb
Table 8 shows p-Na which decreased significantly in both groups on the post-operative day as compared to baseline. No significant difference was found between groups. After surgery p-K showed a significant decrease for the PL group as compared to the IS group. The IS group had a significant decrease compared to baseline both after surgery and on the postoperative day.
p-albumin, p-creatinine and hgb decreased in both groups, with no difference between groups.
This study aimed to investigate whether IS infusion during elective surgery causes kidney injury, indicated by an increase in urinary markers of kidney injury: u-NGAL and u-KIM-1. In this randomized, double-blinded study, 0.9% NaCl (IS) infusion was compared with the balanced IV solution PlasmaLyte (PL) in patients with normal renal function. Both the IS and PL group had a marked increase in u-NGAL and u-KIM-1 excretion on the postoperative day with no difference between the two groups and our evidence does not support the hypothesis that IS causes more kidney injury than a balanced solution.
Animal studies have shown that high chloride-containing fluids induce an increased inflammatory response, coagulopathy, decreased renal perfusion and AKI . In humans, evidence to support that chloride contents in intravenous solutions affect clinical outcome is controversial . Several studies comparing IS with balanced solutions, suggest that these solutions may reduce the risk of AKI, the use of renal replacement therapy, coagulopathy, inflammation, the use of blood transfusion and mortality [28,29,30,31,32,33,34]. In contrast, several other clinical trials have shown no benefit to the use of the same balanced solutions [35,36,37,38,39]. Our trial does not support that high chloride-containing solutions causes more kidney injury than balanced solutions. However, our results may have been confounded by several factors.
Primarily, the response to IS infusion may be hidden within the response of the surgical procedure. A previous study by Mose et al. investigated the effect of hypertonic saline in healthy young subjects, without surgery . They found a small but significant increase in both u-NGAL and u-KIM-1. In our trial, we found a high increase in biomarkers for both groups. When comparing our results to Mose et al. it is possible that the major part of the biomarker response is due to the surgical procedure. Thus, making it probable that the presumed effect of the hyperchloremia in the IS group have been hidden by the surgical procedure.
Another study by Soliman et al. have investigated the development of AKI in 285 chronic kidney disease (CKD) patients (stage 3–5) after total joint arthroplasty and found a 30% incidence of AKI . However, in our study we only included patients with normal renal function (eGFR> 60 ml/min). Since, CKD increases the risk of developing AKI after surgery our results are difficult to compare.
In addition, a recent study conducted by Maheshwari et al. investigated 8616 mainly healthy surgical patients receiving either Lactated Ringer’s solution or IS. Interestingly, the study also found no difference in postoperative complications, in-hospital mortality, or postoperative AKI between the two groups . However, In Maheshwari et al. patients received modest amounts of fluid (1900 ml) which may not be sufficient to induce kidney injury .
In accordance, a large trial compared PL and IS in 4 intensive care units found no difference in the risk of AKI between the two solutions . The two groups also received similar volumes of fluid with a median of 2000 mL . In our study a comparable amount of fluid was used in each group (Table 2). In a clinical setting 2000 ml of fluid is a lesser amount when treating critically ill patients. Other studies with similar or smaller amounts of fluid have shown that IS increases the need of renal replacement therapy among the critically ill [42,43,44]. In summary, these studies combined with our findings may suggest that modest volumes of IS in previously healthy patients do not result in further kidney injury than balanced solutions. Contrary, infusion of IS in critically ill patients may result in increased risk of AKI and the need of renal replacement therapy [5, 34, 42,43,44].
In the last decade, several studies on new biomarkers have been published in the search of a new diagnostic tool for AKI. In our study, two biomarkers of kidney injury were measured, i.e. NGAL and KIM-1. These have been related to increased risk of renal replacement therapy and CKD in patients with AKI [14,15,16,17,18]. Yet, NGAL is related to neutrophil leucocytes, and bacteremia can elevate excretion . Accordingly, NGAL’s diagnostic properties can be affected in heterogeneous patient populations as the critically ill . In our study, we investigated a similar patient population of mainly healthy patients, suggesting NGAL as a reasonable choice of biomarker. Interestingly, another study measuring NGAL and KIM-1 in response to AKI found an AUC-ROC value of 0.938, a sensitivity of 90% and a specificity of 100% when combining the two biomarkers . This finding suggests, that the combination of these two biomarkers better predicts kidney injury than using only a single biomarker.
It is also possible that IS and PL share similar properties to induce kidney injury. In the above we have discussed the presumed nephrotoxicity of IS, but our results could also suggest that IS and PL are equally able to induce kidney injury. PL is said to be a balanced fluid, because its composition resembles plasma . In human plasma the normal chloride content is between 98 and 106 mmol/L . IS has a chloride content of 154 mmol/L and PL a chloride content of 98 mmol/L . As mentioned, several studies have shown IS to induce hyperchloremic acidosis when compared to a balanced solution [3, 4, 6, 8, 35]. Volta et al. have investigated 40 surgical patients and found significantly lower levels of NGAL excretion in patients receiving Ringer’s acetate as compared to IS . However, in our study investigating 38 patients in a similar setting, we found no difference in biomarker excretion. Additionally, an experimental study investigating 4 different crystalloids in an animal model of hypovolemic shock found the worst survival rate when using PL as compared to IS and lactated solutions . Several studies have found that balanced solutions appear to be more physiological than IS and have found IS to result in hyperchloremic acidosis and adverse renal outcomes in patients [3, 8, 42]. Nevertheless, further evidence proving balanced solutions to result in improved patient outcomes is needed.
During surgery, creatinine clearance (CrCl) increased significantly in the PL group, as opposed to the IS group. It is well known that sodium loading increases CrCl, however PL and IS share a similar sodium content (IS 154 mmol/l and PL 140 mmol/l). A substantial difference between the two fluids is the chloride content (IS 154 mmol/l and PL 98 mmol/l). A high chloride amount can cause a decrease in RBF and explain the lower CrCL and UO in the IS group [8, 10]. These findings may suggest that the use of PL is associated with an augmented ability to handle an acute water and salt load. As a measure of tubular function, we investigated tubular transport proteins (AQP2, ENaC, NCC and NKCC2) which increased in both groups after surgery. u-ENaCγ had a significantly different response between the two groups (Table 5), with a higher u-ENaCγ excretion during surgery in the IS group (Fig. 5). A previous study conducted by Jensen et al. investigated the renal response on sodium and water transport of heathy adults receiving glucose, isotonic or hypertonic saline . Their results were similar to ours, with an augmented u-AQP2 and u-ENaCγ response to saline infusion . The increase in ENaCγ could be explained by a decrease in sodium absorption in the proximal part of the nephron, which would be compensated by the distal part. However, the above do not explain the difference in ENaCγ excretion between the two groups. The groups did not differ with regard to vasoactive hormones or AVP and the ENaCγ excretion seems independent of aldosterone (Table 7). Furthermore, when considering the remaining tubular transport proteins: AQP2, NCC and NKCC2 no differences were present between the two groups. This finding could imply that IS is associated with increased sodium retention during an acute water and salt load as compared to PL. Though, the increase in ENaCγ does not necessarily imply increased transcription and activity, but could be due to alterations in synthesis or degradation . The augmented u-ENaCγ excretion as measure of increased sodium retention are substantiated by the decreased FENa (Fig. 6) and FEK (Table 6) in the IS group as compared to the PL group. The above, may indicate that isotonic saline can affect the kidneys response to an acute water and salt load.
In the current study, the power calculation (significance level of 5% and a power of 80%) was based on a rather large effect size (100 ng/mL) to ensure clinical relevance. The sample size (38 patients) was based on u-NGAL as the primary outcome measure. Furthermore, to explore the mechanisms of the intervention and differing responses, this study also examined several secondary outcome measures. However, the secondary outcome measures serves the purpose of a mechanistic hypothesis, which might increase the risk of committing a type 2 error. Although, the assessments of the secondary outcome measures can be considered as theoretical, these measures are of interest. Our results therefore should be viewed as hypothesis generating, hopefully contributing to further research in this area.
The major strength of this study is the randomized, double-blinded design. In both groups study conditions were comparable with regards to operative procedures, anesthesia and recovery period. To assess renal function a 24-h urine collection was performed both before admission and two weeks after surgery. The trial did not evaluate the long-term effect (> 14 days after surgery) of isotonic saline as compared to PL on renal function. However, a delayed kidney injury would be considered unlikely when no signs of renal impairment were seen 14 days after surgery.
In conclusion, this randomized, double-blinded study did find significantly higher levels of chloride and lower pH in the group receiving isotonic saline after intraoperative infusion of isotonic saline during hip arthroplasty. However, we found no difference between groups in the excretion of NGAL or KIM-1 and their responses to fluid infusion. Both NGAL and KIM-1 were significantly increased in both groups after surgery, despite absence of rises in creatinine. These results may indicate that surgery induced subclinical kidney injury. Our results also showed a delayed excretion of sodium in the IS group as compared to the PL group which may indicate that IS affects kidney function and sodium balance differently, compared to PL.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
- AKI :
Acute kidney injury
- AQP2 :
- AUC-ROC :
Area under a receiver operating characteristic curve
- BP :
- CH2O :
Free water clearance
- CKD :
Chronic kidney disease
- Cl− :
- CrCl :
- ECG :
- eGFR :
Estimated glomerular filtration rate
- ELISA :
Enzyme-linked immunosorbent assay
- ENaC :
Epithelial sodium channels
- FECl :
Fractional excretion of chloride
- FEK :
Fractional excretion of potassium
- FENa :
Fractional excretion of sodium
- GFR :
Glomerular filtration rate
- GLM :
General linear model
- Hgb :
- IS :
- K+ :
Kidney injury molecule-1
- MAP :
Mean arterial pressure
- Na+ :
- NCC :
- NGAL :
Neutrophil gelatinase-associated lipocalin
- NKCC2 :
- p-Aldo :
- p-AngII :
Plasma angiotensin II
- p-AVP :
- P-HCO3 − :
- p-K :
- p-Na :
- PL :
- p-Cl :
- PRC :
Plasma concentration of renin
- SBEc :
- SD :
- u-AQP2 :
Urinary excretions of aquaporin-2
- u-ENaCγ :
Urinary excretions of epithelial sodium channels
- u-NCC :
Urinary excretions of Na-Cl cotransporter
- u-NKCC2 :
Urinary excretions of Na-K-Cl cotransporter
- UO :
Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, et al. Hydroxyethyl starch 130/0.38–0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ. 2013;346:f839.
Perner A, Gordon AC, De Backer D, Dimopoulos G, Russell JA, Lipman J, et al. Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy. Intensive Care Med. 2016;42(12):1958–69. https://doi.org/10.1007/s00134-016-4577-z.
Yunos NM, Bellomo R, Glassford N, Sutcliffe H, Lam Q, Bailey M. Chloride-liberal vs. chloride-restrictive intravenous fluid administration and acute kidney injury: an extended analysis. Intensive Care Med. 2015;41(2):257–64. https://doi.org/10.1007/s00134-014-3593-0.
Barker ME. 0.9% saline induced hyperchloremic acidosis. J Trauma Nurs. 2015;22(2):111–6. https://doi.org/10.1097/JTN.0000000000000115.
Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, Slovis CM, Lindsell CJ, Ehrenfeld JM, Siew ED, Shaw AD, Bernard GR, Rice TW, SALT-ED Investigators. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819–28. https://doi.org/10.1056/NEJMoa1711586.
Yunos NM, Bellomo R, Taylor DM, Judkins S, Kerr F, Sutcliffe H, et al. Renal effects of an emergency department chloride-restrictive intravenous fluid strategy in patients admitted to hospital for more than 48 hours. Emerg Med Australas. 2017;29(6):643–9. https://doi.org/10.1111/1742-6723.12821.
Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71(3):726–35. https://doi.org/10.1172/JCI110820.
Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18–24. https://doi.org/10.1097/SLA.0b013e318256be72.
Bullivant EM, Wilcox CS, Welch WJ. Intrarenal vasoconstriction during hyperchloremia: role of thromboxane. Am J Phys. 1989;256(1 Pt 2):F152–7.
Oczachowska-Kulik AE, Ejlersen JA, Jensen JJ, Malmberg MH, Bech JN. Effects of low chloride versus high chloride infusion on glomerular filtration rate and renal plasma flow in healthy volunteers—a randomized, controlled, Crossover Study. Open J Nephrol. 2020;10(02):73–84. https://doi.org/10.4236/ojneph.2020.102009.
Bandak G, Kashani KB. Chloride in intensive care units: a key electrolyte. F1000Res. 2017;6:1930.
Yessayan L, Neyra JA, Canepa-Escaro F, Vasquez-Rios G, Heung M, Yee J. Effect of hyperchloremia on acute kidney injury in critically ill septic patients: a retrospective cohort study. BMC Nephrol. 2017;18(1):346. https://doi.org/10.1186/s12882-017-0750-z.
Shao M, Li G, Sarvottam K, Wang S, Thongprayoon C, Dong Y, Gajic O, Kashani K. Dyschloremia is a risk factor for the development of acute kidney injury in critically ill patients. PLoS One. 2016;11(8):e0160322. https://doi.org/10.1371/journal.pone.0160322.
Koyner JL, Vaidya VS, Bennett MR, Ma Q, Worcester E, Akhter SA, Raman J, Jeevanandam V, O'Connor MF, Devarajan P, Bonventre JV, Murray PT. Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol. 2010;5(12):2154–65. https://doi.org/10.2215/CJN.00740110.
Chen LX, Koyner JL. Biomarkers in acute kidney injury. Crit Care Clin. 2015;31(4):633–48. https://doi.org/10.1016/j.ccc.2015.06.002.
Beker BM, Corleto MG, Fieiras C, Musso CG. Novel acute kidney injury biomarkers: their characteristics, utility and concerns. Int Urol Nephrol. 2018;50(4):705–13. https://doi.org/10.1007/s11255-017-1781-x.
Klein SJ, Brandtner AK, Lehner GF, Ulmer H, Bagshaw SM, Wiedermann CJ, Joannidis M. Biomarkers for prediction of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Intensive Care Med. 2018;44(3):323–36. https://doi.org/10.1007/s00134-018-5126-8.
Moledina DG, Parikh CR. Phenotyping of acute kidney injury: beyond serum creatinine. Semin Nephrol. 2018;38(1):3–11. https://doi.org/10.1016/j.semnephrol.2017.09.002.
Kancir AS, Pleckaitiene L, Hansen TB, Ekelof NP, Pedersen EB. Lack of nephrotoxicity by 6% hydroxyethyl starch 130/0.4 during hip arthroplasty: a randomized controlled trial. Anesthesiology. 2014;121(5):948–58. https://doi.org/10.1097/ALN.0000000000000413.
Mose FH, Jörgensen AN, Vrist MH, Ekelöf NP, Pedersen EB, Bech JN. Effect of 3% saline and furosemide on biomarkers of kidney injury and renal tubular function and GFR in healthy subjects - a randomized controlled trial. BMC Nephrol. 2019;20(1):200. https://doi.org/10.1186/s12882-019-1342-x.
Jensen JM, Mose FH, Bech JN, Nielsen S, Pedersen EB. Effect of volume expansion with hypertonic- and isotonic saline and isotonic glucose on sodium and water transport in the principal cells in the kidney. BMC Nephrol. 2013;14(1):202. https://doi.org/10.1186/1471-2369-14-202.
Jensen JM, Mose FH, Kulik AE, Bech JN, Fenton RA, Pedersen EB. Abnormal urinary excretion of NKCC2 and AQP2 in response to hypertonic saline in chronic kidney disease: an intervention study in patients with chronic kidney disease and healthy controls. BMC Nephrol. 2014;15(1):101. https://doi.org/10.1186/1471-2369-15-101.
Pedersen RS, Bentzen H, Bech JN, Pedersen EB. Effect of water deprivation and hypertonic saline infusion on urinary AQP2 excretion in healthy humans. Am J Physiol Renal Physiol. 2001;280(5):F860–7. https://doi.org/10.1152/ajprenal.2001.280.5.F860.
Al Therwani S, Mose FH, Jensen JM, Bech JN, Pedersen EB. Effect of vasopressin antagonism on renal handling of sodium and water and central and brachial blood pressure during inhibition of the nitric oxide system in healthy subjects. BMC Nephrol. 2014;15(1):100. https://doi.org/10.1186/1471-2369-15-100.
Pedersen EB, Danielsen H, Spencer ES. Effect of indapamide on renal plasma flow, glomerular filtration rate and arginine vasopressin in plasma in essential hypertension. Eur J Clin Pharmacol. 1984;26(5):543–7. https://doi.org/10.1007/BF00543482.
Frank Holden M, Oczachowska-Kulik AE, Fenton RA, Bech JN. Effect of furosemide on body composition and urinary proteins that mediate tubular sodium and sodium transport-A randomized controlled trial. Physiol Rep. 2021;8(24):e14653.
Kawano-Dourado L, Zampieri FG, Azevedo LCP, Correa TD, Figueiro M, Semler MW, et al. Low- versus high-chloride content intravenous solutions for critically ill and perioperative adult patients: a systematic review and meta-analysis. Anesth Analg. 2018;126(2):513–21. https://doi.org/10.1213/ANE.0000000000002641.
Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. Jama. 2012;308(15):1566–72. https://doi.org/10.1001/jama.2012.13356.
Shaw AD, Schermer CR, Lobo DN, Munson SH, Khangulov V, Hayashida DK, Kellum JA. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care. 2015;19(1):334. https://doi.org/10.1186/s13054-015-1045-z.
Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93(4):817–22. https://doi.org/10.1097/00000539-200110000-00004.
Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R, SPLIT Investigators, ANZICS CTG. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. Jama. 2015;314(16):1701–10. https://doi.org/10.1001/jama.2015.12334.
Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102(1):24–36. https://doi.org/10.1002/bjs.9651.
Zampieri FG, Ranzani OT, Azevedo LC, Martins ID, Kellum JA, Liborio AB. Lactated ringer is associated with reduced mortality and less acute kidney injury in critically ill patients: a retrospective cohort analysis. Crit Care Med. 2016;44(12):2163–70. https://doi.org/10.1097/CCM.0000000000001948.
Funke BE, Jackson KE, Self WH, Collins SP, Saunders CT, Wang L, et al. Effect of balanced crystalloids versus saline on urinary biomarkers of acute kidney injury in critically ill adults. BMC Nephrol. 2021;22(1):54. https://doi.org/10.1186/s12882-021-02236-x.
Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, Anderson BA, Scherer LA. Saline versus plasma-Lyte a in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259(2):255–62. https://doi.org/10.1097/SLA.0b013e318295feba.
Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, Schermer CR. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250–4. https://doi.org/10.1097/MBC.0000000000000154.
Kim SY, Huh KH, Lee JR, Kim SH, Jeong SH, Choi YS. Comparison of the effects of normal saline versus Plasmalyte on acid-base balance during living donor kidney transplantation using the Stewart and base excess methods. Transplant Proc. 2013;45(6):2191–6. https://doi.org/10.1016/j.transproceed.2013.02.124.
Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, Wang L, Byrne DW, Shaw AD, Bernard GR, Rice TW, Bernard GR, Semler MW, Noto MJ, Rice TW, Byrne DW, Domenico HJ, Wang L, Wanderer JP, Ehrenfeld JM, Shaw AD, Hernandez A, Kumar AB, Self WH, Siew ED, Dunlap DF, Stollings JL, Sullivan M, Knostman M, Mulherin DP, Hargrove FR, Janz DR, Strawbridge S. Balanced crystalloids versus saline in the intensive care unit. The SALT randomized trial. Am J Respir Crit Care Med. 2017;195(10):1362–72. https://doi.org/10.1164/rccm.201607-1345OC.
Burdett E, Dushianthan A, Bennett-Guerrero E, Cro S, Gan TJ, Grocott MP, et al. Perioperative buffered versus non-buffered fluid administration for surgery in adults. Cochrane Database Syst Rev. 2012;12:Cd004089.
Soliman KM, Campbell RC, Fulop T, Goddard T, Pisoni R. Acute kidney injury in subjects with chronic kidney disease undergoing Total joint Arthroplasty. Am J Med Sci. 2019;358(1):45–50. https://doi.org/10.1016/j.amjms.2019.04.002.
Maheshwari K, Turan A, Makarova N, Ma C, Esa WAS, Ruetzler K, Barsoum S, Kuhel AG, Ritchey MR, Higuera-Rueda C, Kopyeva T, Stocchi L, Essber H, Cohen B, Suleiman I, Bajracharya GR, Chelnick D, Mascha EJ, Kurz A, Sessler DI. Saline versus lactated Ringer's solution: the saline or lactated Ringer's (SOLAR) trial. Anesthesiology. 2020;132(4):614–24. https://doi.org/10.1097/ALN.0000000000003130.
Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD, May AK, Weavind L, Casey JD, Siew ED, Shaw AD, Bernard GR, Rice TW, SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829–39. https://doi.org/10.1056/NEJMoa1711584.
Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, Kellum JA. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to plasma-Lyte. Ann Surg. 2012;255(5):821–9. https://doi.org/10.1097/SLA.0b013e31825074f5.
Volta CA, Trentini A, Farabegoli L, Manfrinato MC, Alvisi V, Dallocchio F, Marangoni E, Alvisi R, Bellini T. Effects of two different strategies of fluid administration on inflammatory mediators, plasma electrolytes and acid/base disorders in patients undergoing major abdominal surgery: a randomized double blind study. J Inflamm (Lond). 2013;10(1):29. https://doi.org/10.1186/1476-9255-10-29.
Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, Buemi M. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis. 2008;52(3):595–605. https://doi.org/10.1053/j.ajkd.2008.01.020.
Schiffl H, Lang SM. Update on biomarkers of acute kidney injury: moving closer to clinical impact? Mol Diagn Ther. 2012;16(4):199–207. https://doi.org/10.1007/BF03262209.
Xue W, Xie Y, Wang Q, Xu W, Mou S, Ni Z. Diagnostic performance of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for acute kidney injury in an obstructive nephropathy patient. Nephrology (Carlton). 2014;19(4):186–94. https://doi.org/10.1111/nep.12173.
Weinberg L, Collins N, Van Mourik K, Tan C, Bellomo R. Plasma-Lyte 148: a clinical review. World J Crit Care Med. 2016;5(4):235–50. https://doi.org/10.5492/wjccm.v5.i4.235.
Traverso LW, Lee WP, Langford MJ. Fluid resuscitation after an otherwise fatal hemorrhage: I. Crystalloid solutions J Trauma. 1986;26(2):168–75. https://doi.org/10.1097/00005373-198602000-00014.
Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper MA. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Invest. 1999;104(7):R19–23. https://doi.org/10.1172/JCI7840.
We thank our laboratory technicians Henriette Vorup Simonsen, Kirsten Nygaard and Anne Mette Ravn for doing laboratory analyses and skillful assistance in examining the subjects.
Support was provided solely from institutional and departmental sources.
Ethics approval and consent to participate
This study was approved by the Regional Committee on Biomedical Research Ethics (case number: 1–10–72-388-14) and the Danish Health and Medicines Authority (EudraCT number: 2014–004742-10). Informed, signed consent was obtained from each patient. The study was carried out in accordance with the Declaration of Helsinki and was monitored by the Good Clinical Practice-Unit from Aarhus and Aalborg Universities.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Østergaard, A.M., Jørgensen, A.N., Bøvling, S. et al. Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement – a randomized trial. BMC Nephrol 22, 111 (2021). https://doi.org/10.1186/s12882-021-02310-4
- Isotonic saline
- Hyperchloremic acidosis
- Acute kidney injury