Abstract
The aim of this study was to describe renal chloride metabolism following cardiopulmonary bypass (CPB) surgery in pediatric patients. A prospective observational trial in a tertiary pediatric intensive care unit (PICU) with 20 recruited patients younger than 2 years following CPB surgery was conducted. Urinary electrolytes, plasma urea, electrolytes, creatinine, and arterial blood gases were collected preoperatively, on admission to PICU and at standardized intervals thereafter. The urinary and plasma strong ion differences (SID) were calculated from these results at each time point. Fluid input and output and electrolyte and drug administration were also recorded. Median chloride administration was 67.7 mmol/kg over the first 24 hours. Urinary chloride (mmol/L; median interquartile range [IQR]) was 30 (19, 52) prior to surgery, 15 (15, 65) on admission, and remained below baseline until 24 hours. Plasma chloride (mmol/L; median [IQR]) was 105 (98, 107) prior to surgery and 101 (101, 106) on admission to PICU. It then increased from baseline, but remained within normal limits, for the remainder of the study. The urinary SID increased from 49.8 (19.1, 87.2) preoperatively to a maximum of 122.7 (92.5, 151.8) at 6 hours, and remained elevated until 48 hours. Plasma and urinary chloride concentrations were not associated with the development of acute kidney injury. Urinary chloride excretion is impaired after CPB. The urinary SID increase associated with the decrease in chloride excretion suggests impaired production and/or excretion of ammonium by the nephron following CPB, with gradual recovery postoperatively.
Keywords: acidosis/urine, chloride/urine, children, cardiac surgery, electrolytes
Introduction
Many studies have investigated the association between the electrolyte composition of intravenous fluids and plasma chloride concentrations, their impact on the development of acute kidney injury (AKI) and patient outcomes. 1 2 3 4 5 6 Results from these studies are divergent. Some studies showed that high chloride containing intravenous fluids were associated with an increase in morbidity and mortality, while others did not demonstrate an association. 3 4 5 6 7 8 9 10 The assumption underlying these studies is that hyperchloremia is a primary outcome of exogenous chloride administration, which in turn may be associated with increased morbidity and mortality. No studies have investigated whether critical illness-associated hyperchloremia, with or without AKI, may be an independent outcome of impaired renal chloride excretion.
Hyperchloremia is an established phenomenon following cardiopulmonary bypass (CPB) in both children and adults and has been observed both in the presence and absence of AKI. 3 5 6 9 11 It is unclear whether hyperchloremia is a result of increased chloride loading, impaired renal chloride excretion, or a combination of these processes. It is also unclear whether hyperchloremia is a primary consequence of AKI, or if it contributes to its development.
Chloride excretion is regulated by ammonia production in the proximal tubular cells and ammonium secretion in the intercalated cells of the collecting duct (ICCD). 12 By forming ammonium chloride, ammonium contributes to both nitrogen waste and net acid excretion. 13 Impaired ammonium excretion in the distal nephron, as seen in acquired distal renal tubular acidosis (RTA), is a recognized cause of hyperchloremic metabolic acidosis. 14 15 16
CPB is known to induce both a systemic inflammatory reaction as well as AKI in infants and children in 30 to 50% and 5 to 60% of patients, respectively. 6 17 18 19 20 We therefore sought to establish patterns of renal electrolyte handling following CPB with a consideration that the renal reaction to CPB may reflect that to critical illness more broadly. To create a homogenous group, we investigated patients younger than 2 years undergoing CPB. We hypothesized that following CPB, an increase in plasma chloride concentration is related to reduced or inadequate renal chloride excretion, independent of exogenous chloride administration; that reduced or inadequate renal chloride excretion is at least in part explained by defective or inadequate ammonium excretion by the kidneys; and that increased plasma chloride and decreased urinary chloride concentrations are associated with AKI.
Materials and Methods
Setting
This was a single-center study conducted at a tertiary pediatric intensive care unit (PICU) between January and April 2018.
Participants
We prospectively enrolled 20 patients younger than 2 years with congenital heart disease, who were to undergo CPB for corrective or palliative cardiac surgery. Consent was obtained pre-enrollment or by consent-to-continue if parents were unable to consent prior to the enrollment. Inclusion criteria were age younger than 2 years, status post-CPB surgery, presence of an indwelling urinary catheter (IUC), as well as an intra-arterial line (IAL). Exclusion criteria were no CPB surgery, 2 years of age or older, and anuric renal failure prior to cardiac surgery. Once the IUC or the arterial line was removed, measurements were stopped as reliable access to urinary and/or arterial blood gas values was not assured anymore. Therefore, patients dropped out of the study at differing time points related to the extent of recovery and decreased need for monitoring.
For this hypothesis generating pilot study, the sample size of 20 patients was chosen to ascertain whether any electrolyte metabolism effect could be observed. Patients were enrolled consecutively as they met inclusion criteria.
Study Procedures
Urine collection was standardized. To assure a fresh urine sample collection the IUC was clamped and—once 1 to 2 mL had accumulated—the urine was collected through the aspiration port of the IUC. Frusemide was the only diuretic used in any of the patients.
Data Collection
Patient demographics were collected at the time of enrollment. Plasma electrolytes, urinary electrolytes, and urinary ammonia data were collected prior to surgery (on induction of anesthesia), on admission to PICU, and at 6, 12, 24, 48, and 72 hours after PICU admission. Urinary electrolytes (including urinary ammonia), plasma electrolytes, creatinine, and arterial blood gases were analyzed at each time point. Additionally, fluid and electrolyte administration, fluid output, diuretic usage, and hemodynamic support were recorded. This included the fluid administration during surgery, including the amount of cardioplegia (Buckberg solution) and blood products given. The electrolyte composition of all administered fluids was recorded. The modified ultrafiltrate was sent for electrolyte analysis and the amount and electrolyte composition was recorded. For all fluids, we multiplied the amount given with the electrolyte content to estimate the total amount of electrolyte (in mmol) that was administered. Estimation of blood product composition was done by performing evaluation of a sample of each product on our blood gas analyzer. Patient management was per usual clinician discretion and not influenced by study enrollment. Duration of the IAL and IUC insertion was also determined by clinical need and not extended beyond this time, and data collection was discontinued when these catheters were removed. Serum albumin was monitored at all time points except for the 6 hours sample (blood gas taken only)—to limit the amount of blood taken.
We estimated the amount of chloride administered via intravenous fluids and subtracted the chloride excretion from this number. We labeled this calculation the “chloride excess.”
The urinary strong ion difference (SID, SID Urine ) was calculated from the collected data, using the following equation 21 :
SID Urine (mmol/L) = ([Na + Urine ] + [K + Urine ] + [Ca 2+ Urine ] + [Mg 2+ Urine ]) − ([Cl − Urine ] + [PO4 2− Urine ])
When plasma and urinary magnesium and phosphate concentration were not available, the calculations were made without incorporating these values.
The fractional excretion of sodium (FeNa) was calculated from urine and plasma sodium (mmol/L) and creatinine (Cr, μmol/L) using the following equation 22 :
FeNa (%) = ([{Na Urine } × {Cr Plasma }]/[{Na Plasma } × {Cr Urine }]) × 100
AKI was classified using the Acute Kidney Injury Network (AKIN) criteria. 23
Statistical Analysis
Due to the small sample size and resulting non-normal distribution of the data, median and associated interquartile range (IQR) were used to describe the majority of the parameters of interest. Mann–Whitney's U tests were used to compare selected parameters between patients without AKI or AKI Stage I, and with AKI Stages II and III. Analyses were undertaken in Stata SE 16.0 (StataCorp Pty Ltd, College Station, Texas, United States). Comparisons were considered significant at the 0.05 level, although all comparisons are acknowledged as exploratory; no adjustment for multiple comparisons was made.
Results
There were 21 patients enrolled in the study; one patient was subsequently excluded due to emergent establishment of extracorporeal life support (ECLS) postoperatively and subsequent anuria. Patient weight was (median) 6.0 kg, only two patients were ventilated preoperatively and the median CPB time was 63 minutes. Fifteen patients had biventricular and five patients had univentricular physiology ( Table 1 ).
Table 1. Patient demographics.
| Variable | Category | N | % |
|---|---|---|---|
| Total patients | 20 | 100 | |
| Gender | Male | 13 | 65 |
| Female | 7 | 35 | |
| Weight (kg) a | 6.0 | (4.6, 9.4) | |
| Age (d) a | 160 | (68, 458) | |
| Gestational age a | 38 | (37, 40) | |
| Ethnicity | Caucasian | 15 | 75 |
| Asian | 2 | 10 | |
| Maori/Pacific Island | 1 | 5 | |
| Mixed/other | 2 | 10 | |
| History | |||
| Diagnosed syndrome | |||
| Trisomy 21 | 2 | 10 | |
| Other | 3 | 15 | |
| Total | 5 | 25 | |
| Cardiac physiology | Biventricular | 15 | 75 |
| Univentricular | 5 | 25 | |
| Preexisting renal disease | 1 | 5 | |
| Vasoactive inotrope score a | 8 | (6, 10) | |
| Perioperative details | |||
| Mechanical ventilation in 48 h prior to surgery | 2 | 20 | |
| CPB time (min) | Overall a | 63 | (39, 132) |
| CPB time | ≤60 min (low) | 9 | 45 |
| 61–119 min (moderate) | 5 | 25 | |
| ≥120 min (high) | 5 | 25 | |
| Missing | 1 | 5 | |
Abbreviations: CPB, cardiopulmonary bypass; IQR, interquartile range.
Median (IQR).
Urinary chloride excretion decreased over the first 24 hours despite the serum chloride remaining unchanged, with a significant increase at 48 hours and beyond ( Fig. 1 and Table 2 ). This increase in chloride excretion occurred independent of diuretic administration but was more pronounced in patients receiving diuretics ( Table 3 ).
Fig. 1.
Boxplot of urinary chloride excretion (mmol/L).
Table 2. Comparison of biochemical parameters between those with and without AKIN Stage II or III renal impairment.
| Parameter | 6 h | 12 h | 24 h | ||||||
|---|---|---|---|---|---|---|---|---|---|
| No AKI ( N = 16) | AKI ( N = 4) | p -Value | No AKI ( N = 16) | AKI ( N = 3) | p -Value | No AKI ( N = 4) | AKI ( N = 9) | p -Value | |
| Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | ||||
| Plasma chloride (mmol/L) | 107.5 (105, 110) | 106.5 (100.5, 107) | 0.318 | 108.5 (106, 110.5) | 109 (104, 109) | 0.506 | 109.5 (105, 112) | 106 (96, 108) | 0.203 |
| Urinary chloride (mmol/L) | 15 (15, 38) | 15 (15, 30) | 0.398 | 21 (15, 65.5) | 15 (15, 68) | 0.611 | 42.5 (15, 89) | 48 (15, 72) | 0.748 |
| Urinary FeNa (fraction) | 0.21 (0.07, 0.33) | 0.23 (0.20, 0.28) | 0.953 | 0.15 (0.05, 0.43) | 0.08 (0.07, 0.09) | 0.758 | 0.09 (0.05, 0.49) | 0.12 (0.08, 0.61) | 0.490 |
| Plasma Na (mmol/L) | 143 (140, 144) | 139 (137, 143) | 0.232 | 141 (140, 143) | 140 (136, 145) | 0.588 | 139.5 (137, 142) | 134 (132, 140) | 0.287 |
| Urinary SID (mmol/L) | 129.8 (98.1, 151.9) | 92.5 (80.3, 117.7) | 0.173 | 112.5 (82.3, 137.4) | 105.4 (101.4, 133.6) | 0.999 | 82.2 (36.2, 93.5) | 85.6 (16.9, 124.7) | 0.937 |
| Urinary NH 4 (mEq/L) | 25 (7, 42) | 38 (17, 42) | 0.476 | 37.5 (21.5, 65.5) | 41.5 (30, 53) | 0.928 | 35 (22, 99) | 57 (6, 73) | 0.727 |
| SBE (mmol/L) | −3.3 (−5.7, 1.5) | −0.9 (−3.5, −0.7) | 0.925 | −2.8 (−5.2, −1.2) | 0.5 (−7.0, 1.1) | 0.472 | −2.1 (−5.5, −1.1) | 0.9 (−10.4, 1.6) | 0.692 |
Abbreviations: AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; IQR, interquartile range; SBE, standard base excess; SID, strong ion difference.
Table 3. Urinary chloride excretion by time point and diuretic use.
| Diuretics Median (IQR) |
No diuretics Median (IQR) |
||
|---|---|---|---|
| Urinary chloride | Surgery ( N = 19) | – | a |
| Admission ( N = 17) | – | a | |
| 6 h ( N = 18) | – | 15 (15, 38) | |
| 12 h ( N = 19) | 68 (42, 103) | 17 (15, 53) | |
| 24 h ( N = 13) | 60 (15, 98) | 35 (17, 50) | |
| 48 h ( N = 10) | 125 (99, 129) | 18 (18, 18) | |
| 72 h ( N = 5) | 134 (119, 160) | 114 (114, 114) | |
Abbreviation: IQR, interquartile range.
The change in plasma chloride did not reach statistical significance, although it showed a trend to increased values by the end of the study period ( Table 2 ). There was a median chloride excess of 22 mmol/kg body weight at 24 hours. Similarly, the plasma sodium did not change significantly during the study period. The urinary sodium (mmol/L; median [IQR]) increased from 22 (11, 62) preoperatively to 50 (33, 86) on admission and then decreased to 24 (15, 49) over the first 24 hours with significant increase thereafter. The fractional excretion of sodium (FeNa) (median [IQR]) remained <1% up to 72 hours with a subsequent increase following diuretic administration ( Table 4 ). Urinary ammonium (mmol/L; median [IQR]) decreased from 26 (6, 33) preoperatively to 11 (5, 23) on admission. It then increased to 28 (8, 42) at 6 hours where it remained stable, until decreasing further from 48 hours onward ( Fig. 1 and Table 2 ). Despite the apparent early increase in urinary ammonium excretion, the urinary chloride decreased, and the urinary SID increased ( Figs. 1 and 2 ). The preoperative urinary SID (median [IQR]) was 49.8 (19.1, 87.2). Postoperatively, it initially increased to 106.4 (80.6, 136) on admission to the ICU, peaked at 122.7 (92.5, 151.8) at 6 hours and then decreased thereafter ( Fig. 2 ). Plasma pH and standard base excess remained within normal ranges at all time points ( Table 2 ). The serum albumin level showed a nonsignificant decrease over the study period.
Table 4. Comparison of biochemical parameters between those with no AKI or AKIN Stage I and AKIN Stage II or III renal impairment.
| 6 h | 12 h | 24 h | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Parameter | No AKI ( N = 16) | AKI ( N = 4) | p -Value | No AKI ( N = 16) | AKI ( N = 3) | p -Value | No AKI ( N = 4) | AKI ( N = 9) | p -Value |
| Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | ||||
| Plasma chloride (mmol/L) | 107.5 (105, 110) | 106.5 (100.5, 107) | 0.318 | 108.5 (106, 110.5) | 109 (104, 109) | 0.506 | 109.5 (105, 112) | 106 (96, 108) | 0.203 |
| Urinary chloride (mmol/L) | 15 (15, 38) | 15 (15, 30) | 0.398 | 21 (15, 65.5) | 15 (15, 68) | 0.611 | 42.5 (15, 89) | 48 (15, 72) | 0.748 |
| Urinary FeNa (fraction) | 0.21 (0.07, 0.33) | 0.23 (0.20, 0.28) | 0.953 | 0.15 (0.05, 0.43) | 0.08 (0.07, 0.09) | 0.758 | 0.09 (0.05, 0.49) | 0.12 (0.08, 0.61) | 0.490 |
| Plasma Na (mmol/L) | 143 (140, 144) | 139 (137, 143) | 0.232 | 141 (140, 143) | 140 (136, 145) | 0.588 | 139.5 (137, 142) | 134 (132, 140) | 0.287 |
| Urinary SID (mmol/L) | 129.8 (98.1, 151.9) | 92.5 (80.3, 117.7) | 0.173 | 112.5 (82.3, 137.4) | 105.4 (101.4, 133.6) | 0.999 | 82.2 (36.2, 93.5) | 85.6 (16.9, 124.7) | 0.937 |
| Urinary NH 4 (mEq/L) | 25 (7, 42) | 38 (17, 42) | 0.476 | 37.5 (21.5, 65.5) | 41.5 (30, 53) | 0.928 | 35 (22, 99) | 57 (6, 73) | 0.727 |
| SBE (mmol/L) | −3.3 (−5.7, 1.5) | −0.9 (−3.5, −0.7) | 0.925 | −2.8 (−5.2, −1.2) | 0.5 (−7.0, 1.1) | 0.472 | −2.1 (−5.5, −1.1) | 0.9 (−10.4, 1.6) | 0.692 |
Abbreviations: AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; IQR, interquartile range; SBE, standard base excess; SID, strong ion difference.
Fig. 2.
Boxplot of urinary strong ion difference (SID) by time points.
The cumulative fluid balance (mL; median [IQR]) remained neutral over the first 24 hours following admission. After 24 hours, a negative fluid balance was seen ( Table 2 ).
As per the AKIN criteria, a total of seven patients (35%) were diagnosed with AKI. Two patients (10%) were classified as AKI Stage I, and five patients (25%) were classified as AKI Stage II. No patients were found to have AKI Stage III. When patients were dichotomized into “no AKI/Stage I AKI” versus “AKI Stage II,” no significant association was found between the incidence of AKI Stage II and any of the measured urine or plasma variables ( Table 4 ) for the 6, 12, or 24 hours time point.
Discussion
This study demonstrates a distinct pattern of decreased urinary chloride excretion and trend to an increase in plasma chloride from baseline over the first 24 to 48 hours post-CPB. This was accompanied by an increase in urinary SID suggesting inadequate urinary ammonia production and/or excretion. No metabolic acidosis was demonstrated in association with these findings.
We estimated the “chloride excess” to assess whether the decrease in urinary chloride excretion was related to a decrease in chloride input. This estimation is fraught with inaccuracies: chloride levels in blood products such as packed red cells, albumin, or fresh frozen plasma are variable as is the chloride loss from ongoing (even if small) hemorrhage after surgery. Our most conservative calculation estimated the chloride excess to be positive at 24 hours. Under normal physiological conditions, an increase in intravenous administration of chloride leads to increased urinary chloride concentration. 14 The opposite to this phenomenon was demonstrated in our study, suggesting impaired renal chloride excretion. Over the first 24 hours after CPB, urinary chloride excretion was below baseline, despite a positive chloride balance. We observed a trend to plasma hyperchloremia. This trend toward an increased plasma chloride concentration from preoperative levels was less than what the chloride excess would have suggested. Possible explanations for this are either the inaccuracy of estimating the chloride input or an increase in total body water due to impaired renal function, fluid loading, and third spacing, as is often observed after CPB surgery. 19 24 We did not see a significantly increased fluid balance at 24 hours, however.
The decrease in renal chloride excretion despite stable to increased plasma chloride levels is the most significant finding in our study. Renal clearance of excess chloride is usually achieved by increased excretion of ammonium by the ICCD that binds to chloride. 13 25 26 Renal ammoniagenesis starts in the proximal tubule where ammonia is synthesized and finishes in the ICCD where ammonium combines with chloride ions and is excreted as ammonium chloride. 13 25 26 Ammonium excretion in the urine can be measured indirectly via the urinary anion gap, measured as (Na) + (K) − (Cl). 16 The urinary anion gap is now often referred to as the urine SID, where SID Urine = (Na Urine ) + (K Urine ) − (Cl Urine ) = (Unmeasured Urine − ) − (Unmeasured Urine + ). 27 As hypothesized, our results show an increase in urinary SID in parallel to a decrease in measured urinary chloride over the first 24 hours suggesting a decrease or inadequate increase in urinary ammonium excretion, a finding that is consistent with a (temporary) distal RTA. 16 27 28 Balsorano et al demonstrated similar findings in their study, albeit not with the investigation of chloride excretion. 21 However, on direct measurement of urinary ammonium, we did not find a significant decrease in its concentration. The reason for this is unclear. Our patients, contrary to most patients experiencing AKI, did not have a metabolic acidosis and therefore no need to excrete acid load coupled with ammonium. One further possible explanation for this discrepancy is the testing complexity of urinary ammonia levels. Ammonia is known as an unstable molecule and testing must occur rapidly after collection. 25 While we attempted to assure that testing of samples occurred within 20 minutes of fresh urine collection, the time to test may have affected the results. Other urinary anions such as phosphate and sulfate were not measured as it is likely their concentration is low and would not explain the elevation in urinary SID we observed. 29 In this setting, the increase in urinary SID most likely indicates a temporary decrease in production and excretion of ammonium post-CPB surgery.
The association between plasma chloride and AKI has been investigated extensively. Several reports demonstrate the association between hyperchloremia and AKI. 1 2 5 8 9 10 30 31 32 Additionally, hyperchloremia may not just be associated with AKI but lead to mechanisms that are known to cause AKI. Increased plasma chloride concentration, detected by mesangial cells and the juxtaglomerular apparatus, leads to an increase in angiotensin II and endothelin, leading to vasoconstriction of the afferent arteriole and decreased renal blood flow. 33 34 35 Post-CPB hyperchloremia is a well-described phenomenon in children but reports vary whether it is or is not associated with the development of AKI. 6 Our study did not find a significant association between chloride metabolism and AKI, likely due to the small number of subjects in this pilot study. However, we hypothesize that urinary chloride excretion may serve as a marker for subclinical AKI, though due to small patient numbers, we were unable to prove this concept conclusively.
Contrary to the chloride metabolism, we did not observe similar patterns in the sodium metabolism, for reasons that are uncertain but possibly related to the fact that sodium metabolism is ammonium independent.
The diagnosis of AKI remains challenging. 36 37 The lag time between AKI and the increase of serum creatinine levels up to 24 to 48 hours is often beyond the discharge time from ICU; fluid administration can dilute serum creatinine and falsely lower its plasma concentration; at time points where patients were anuric, urinary electrolyte data were not available and urinary output as a marker for AKI is difficult to interpret following CPB, as many factors contribute to reduced urine output. 24 37 38 All these factors may have contributed to the lack of association between chloride concentrations in urine or plasma and AKI.
Our study has several limitations. The two most notable ones are the small sample size and the use of diuretics which influence urinary electrolyte excretion. The median ICU stay for pediatric cardiac surgical patients in our unit is 1.9 days, with many patients only staying for less than 24 hours. This led to low numbers particularly for the data points ≥ 24 hours. We would have liked to analyze the renal electrolyte excretion pattern according to inotropic score, bypass time, and underlying cardiac disease. No meaningful statistical results would have resulted from these subanalyses in an already small overall cohort, which is why we decided not to perform them. We deliberately left patients who received frusemide in the analysis and could show that independent of diuretic administration, an initial low urinary chloride excretion post-CPB surgery was followed by an increase in urinary chloride excretion, coinciding with overall recovery of the patient. This increase was more pronounced with diuretic use, but seen without diuretic use, albeit not as pronounced.
While we could have compared our findings with other biomarkers for prediction of AKI, superiority of these has not been clearly demonstrated. 39 40 41 42 Additionally, we were limited in the volume of blood samples collected from the patients for ethical reasons. Low patient numbers make meaningful statistical analysis difficult. The inability to generate data at time points of anuria may have also skewed the results. Additionally, the role of the neurohormonal system and its effects on renal electrolyte handling following CPB may have influenced our results but was not assessed due to ethical limitations of the amount of blood that could be collected for testing. These limitations can be explored in the large study that we plan to conduct.
Conclusion
This study demonstrated impaired renal chloride excretion in 24 hours following CPB. The increase in urinary SID suggests that inadequate ammonium production and/or excretion may contribute to impaired chloride excretion. Whether these findings are specific to renal impairment following CPB or renal injury related to critical illness more generally is yet to be established. Trials that examine the biochemical effects of intravenous fluid composition and electrolyte administration should evaluate renal chloride excretion to distinguish between hyperchloremia caused by a defect in urinary chloride excretion or hyperchloremia related to exogenous chloride administration. The numbers in our trial were too small to establish an association between AKI and urinary or plasma chloride concentrations. Larger studies are warranted to explore this relationship further.
Funding Statement
Funding The study received in-kind support from the Pediatric Intensive Care Unit, Queensland Children's Hospital, South Brisbane, Australia.
Conflict of Interest None declared.
Note
This study was performed at the Queensland Children's Hospital.
Ethical Approval
Ethical approval for this study was received from the Children's Health Queensland Human Research Ethics Committee (HREC/17/QRCH/310).
References
- 1.Yunos N M, 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(02):257–264. doi: 10.1007/s00134-014-3593-0. [DOI] [PubMed] [Google Scholar]
- 2.Suetrong B, Pisitsak C, Boyd J H, Russell J A, Walley K R. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care. 2016;20(01):315. doi: 10.1186/s13054-016-1499-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Acute Kidney Injury in Critical Illness Study Group . Yessayan L, Neyra J A, 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(01):346. doi: 10.1186/s12882-017-0750-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.SALT-ED Investigators . Self W H, Semler M W, Wanderer J P et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(09):819–828. doi: 10.1056/NEJMoa1711586. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Stenson E K, Cvijanovich N Z, Allen G L et al. Hyperchloremia is associated with acute kidney injury in pediatric patients with septic shock. Intensive Care Med. 2018;44(11):2004–2005. doi: 10.1007/s00134-018-5368-5. [DOI] [PubMed] [Google Scholar]
- 6.Kimura S, Iwasaki T, Shimizu K et al. Hyperchloremia is not an independent risk factor for postoperative acute kidney injury in pediatric cardiac patients. J Cardiothorac Vasc Anesth. 2019;33(07):1939–1945. doi: 10.1053/j.jvca.2018.12.009. [DOI] [PubMed] [Google Scholar]
- 7.Barhight M F, Lusk J, Brinton J et al. Hyperchloremia is independently associated with mortality in critically ill children who ultimately require continuous renal replacement therapy. Pediatr Nephrol. 2018;33(06):1079–1085. doi: 10.1007/s00467-018-3898-2. [DOI] [PubMed] [Google Scholar]
- 8.Oh T K, Kim C Y, Jeon Y T, Hwang J W, Do S H. Perioperative hyperchloremia and its association with postoperative acute kidney injury after craniotomy for primary brain tumor resection: a retrospective, observational study. J Neurosurg Anesthesiol. 2019;31(03):311–317. doi: 10.1097/ANA.0000000000000512. [DOI] [PubMed] [Google Scholar]
- 9.Oh T K, Song I A, Kim S J et al. Hyperchloremia and postoperative acute kidney injury: a retrospective analysis of data from the surgical intensive care unit. Crit Care. 2018;22(01):277. doi: 10.1186/s13054-018-2216-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Yunos N M, Bellomo R, Taylor D M 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(06):643–649. doi: 10.1111/1742-6723.12821. [DOI] [PubMed] [Google Scholar]
- 11.Mamikonian L S, Mamo L B, Smith P B, Koo J, Lodge A J, Turi J L. Cardiopulmonary bypass is associated with hemolysis and acute kidney injury in neonates, infants, and children*. Pediatr Crit Care Med. 2014;15(03):e111–e119. doi: 10.1097/PCC.0000000000000047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Wilcox C S. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71(03):726–735. doi: 10.1172/JCI110820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Weiner I D, Verlander J W. Recent advances in understanding renal ammonia metabolism and transport. Curr Opin Nephrol Hypertens. 2016;25(05):436–443. doi: 10.1097/MNH.0000000000000255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Batlle D C, Hizon M, Cohen E, Gutterman C, Gupta R. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med. 1988;318(10):594–599. doi: 10.1056/NEJM198803103181002. [DOI] [PubMed] [Google Scholar]
- 15.Gattinoni L, Carlesso E, Cadringher P, Caironi P. Strong ion difference in urine: new perspectives in acid-base assessment. Crit Care. 2006;10(02):137. doi: 10.1186/cc4890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Halperin M L, Richardson R M, Bear R A, Magner P O, Kamel K, Ethier J. Urine ammonium: the key to the diagnosis of distal renal tubular acidosis. Nephron. 1988;50(01):1–4. doi: 10.1159/000185107. [DOI] [PubMed] [Google Scholar]
- 17.Singh S P. Acute kidney injury after pediatric cardiac surgery. Ann Card Anaesth. 2016;19(02):306–313. doi: 10.4103/0971-9784.179635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.TRIBE-AKI Consortium . Li S, Krawczeski C D, Zappitelli M et al. Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery: a prospective multicenter study. Crit Care Med. 2011;39(06):1493–1499. doi: 10.1097/CCM.0b013e31821201d3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Yuan S M. Acute kidney injury after pediatric cardiac surgery. Pediatr Neonatol. 2019;60(01):3–11. doi: 10.1016/j.pedneo.2018.03.007. [DOI] [PubMed] [Google Scholar]
- 20.Boehne M, Sasse M, Karch A et al. Systemic inflammatory response syndrome after pediatric congenital heart surgery: incidence, risk factors, and clinical outcome. J Card Surg. 2017;32(02):116–125. doi: 10.1111/jocs.12879. [DOI] [PubMed] [Google Scholar]
- 21.Balsorano P, Romagnoli S, Evans S K, Ricci Z, De Gaudio A R. Urinary strong ion difference as a marker of renal dysfunction. A retrospective analysis. PLoS One. 2016;11(06):e0156941. doi: 10.1371/journal.pone.0156941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Schreuder M F, Bökenkamp A, van Wijk J AE. Interpretation of the fractional excretion of sodium in the absence of acute kidney injury: a cross-sectional study. Nephron. 2017;136(03):221–225. doi: 10.1159/000468547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.KDIGO AKI Guideline Work Group . Kellum J A, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1) Crit Care. 2013;17(01):204. doi: 10.1186/cc11454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Kwiatkowski D M, Krawczeski C D. Acute kidney injury and fluid overload in infants and children after cardiac surgery. Pediatr Nephrol. 2017;32(09):1509–1517. doi: 10.1007/s00467-017-3643-2. [DOI] [PubMed] [Google Scholar]
- 25.Weiner I D, Verlander J W. Role of NH3 and NH4+ transporters in renal acid-base transport. Am J Physiol Renal Physiol. 2011;300(01):F11–F23. doi: 10.1152/ajprenal.00554.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Weiner I D, Verlander J W. Renal ammonia metabolism and transport. Compr Physiol. 2013;3(01):201–220. doi: 10.1002/cphy.c120010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Ring T, Frische S, Nielsen S. Clinical review: renal tubular acidosis–a physicochemical approach. Crit Care. 2005;9(06):573–580. doi: 10.1186/cc3802. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Corey H E, Vallo A, Rodríguez-Soriano J. An analysis of renal tubular acidosis by the Stewart method. Pediatr Nephrol. 2006;21(02):206–211. doi: 10.1007/s00467-005-2081-8. [DOI] [PubMed] [Google Scholar]
- 29.Murray D, Grant D, Murali N, Butt W. Unmeasured anions in children after cardiac surgery. J Thorac Cardiovasc Surg. 2007;133(01):235–240. doi: 10.1016/j.jtcvs.2006.09.017. [DOI] [PubMed] [Google Scholar]
- 30.Yunos N M, 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):1566–1572. doi: 10.1001/jama.2012.13356. [DOI] [PubMed] [Google Scholar]
- 31.Yunos N M, Bellomo R, Story D, Kellum J. Bench-to-bedside review: chloride in critical illness. Crit Care. 2010;14(04):226. doi: 10.1186/cc9052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Yunos N M, Kim I B, Bellomo R et al. The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med. 2011;39(11):2419–2424. doi: 10.1097/CCM.0b013e31822571e5. [DOI] [PubMed] [Google Scholar]
- 33.Diedericks B J, Roelofse J A, Shipton E A, Gray I P, de Wet J I, Hugo S A. The renin-angiotensin-aldosterone system during and after cardiopulmonary bypass. S Afr Med J. 1983;64(24):946–949. [PubMed] [Google Scholar]
- 34.Verbrugge F H, Tang W H, Mullens W. Renin-angiotensin-aldosterone system activation during decongestion in acute heart failure: friend or foe? JACC Heart Fail. 2015;3(02):108–111. doi: 10.1016/j.jchf.2014.10.005. [DOI] [PubMed] [Google Scholar]
- 35.Lorenz J N, Weihprecht H, Schnermann J, Skøtt O, Briggs J P.Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport Am J Physiol 1991260(4 Pt 2):F486–F493. [DOI] [PubMed] [Google Scholar]
- 36.Goldstein S L. A new pediatric AKI definition: implications of trying to build the perfect mousetrap. J Am Soc Nephrol. 2018;29(09):2259–2261. doi: 10.1681/ASN.2018070727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Ricci Z, Di Nardo M, Iacoella C, Netto R, Picca S, Cogo P. Pediatric RIFLE for acute kidney injury diagnosis and prognosis for children undergoing cardiac surgery: a single-center prospective observational study. Pediatr Cardiol. 2013;34(06):1404–1408. doi: 10.1007/s00246-013-0662-z. [DOI] [PubMed] [Google Scholar]
- 38.Western Canadian Complex Pediatric Therapies Follow-Up Group . Morgan C J, Zappitelli M, Robertson C M et al. Risk factors for and outcomes of acute kidney injury in neonates undergoing complex cardiac surgery. J Pediatr. 2013;162(01):120–70. doi: 10.1016/j.jpeds.2012.06.054. [DOI] [PubMed] [Google Scholar]
- 39.Ichimura T, Bonventre J V, Bailly V et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998;273(07):4135–4142. doi: 10.1074/jbc.273.7.4135. [DOI] [PubMed] [Google Scholar]
- 40.Han W K, Bailly V, Abichandani R, Thadhani R, Bonventre J V. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62(01):237–244. doi: 10.1046/j.1523-1755.2002.00433.x. [DOI] [PubMed] [Google Scholar]
- 41.Kullmar M, Saadat-Gilani K, Weiss R et al. Kinetic changes of plasma renin levels predict acute kidney injury in cardiac surgery patients. Am J Respir Crit Care Med. 2021;203(09):1119–1126. doi: 10.1164/rccm.202005-2050OC. [DOI] [PubMed] [Google Scholar]
- 42.Hirsch R, Dent C, Pfriem H et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol. 2007;22(12):2089–2095. doi: 10.1007/s00467-007-0601-4. [DOI] [PubMed] [Google Scholar]