Giving urine biochemistry a second chance in acute kidney injury monitoring

Abstract

Most studies assessing urine biochemistry for acute kidney injury (AKI) monitoring rely on paradigms from the 1970s. It was proposed that a single measurement of urinary parameters in the presence of increased serum creatinine (sCr) could help understand AKI pathophysiology and predict its duration. However, those studies produced variable and controversial results. Recently, an alternative “urine biochemical approach” has been proposed. In contrast with the traditional approach, it includes sequential urine electrolyte assessment, evaluation before AKI diagnosis, and interpretation of avid sodium retention as a marker of renal microcirculatory stress instead of low renal perfusion. This review highlights the rationale of this alternative approach, which is focused on early urinary biochemical changes that precede increases in sCr as well as signs of renal recovery before decreases in sCr. The relevance of urine composition in conjunction with urine volume for a proper evaluation of renal function is emphasized. This new approach aims to enhance the utility of urinary biochemical parameters in AKI monitoring, particularly in patients who are critically ill.

Key Words: Urine biochemistry; Urine electrolytes; Acute kidney injury; Monitoring; Urine biochemical approach; Fractional excretion of potassium; Urinary potassium/urinary creatinine concentration ratio; Urinary sodium concentration; Excreted mass of creatinine

Core Tip: The utility of urine biochemistry assessment for acute kidney injury (AKI) monitoring was proposed 50 years ago, being theoretically capable of defining AKI pathophysiology and distinguishing functional (“pre-renal”) and structural (“renal”) impairments. However, the actual usefulness of urine biochemistry was never confirmed due to variable and controversial results among studies. In this review, alternative considerations for when to assess urine electrolytes and how to interpret their values for renal function monitoring are proposed.

INTRODUCTION

Acute kidney injury (AKI) monitoring has been based on serum creatinine (sCr) levels and urine output (UO) for decades. Despite the limitations of these two variables for reliable renal function monitoring, they remain the cornerstones of AKI diagnosis. Their measurement is extremely accessible and affordable, which has likely led to their widespread use so far. Additionally, urine electrolyte composition assessment was proposed as an approach to gain information about AKI pathophysiology and to help in distinguishing functional declines in glomerular filtration rate (GFR) from structural tubular damage and, consequently, to aid supportive and therapeutic management decisions[1-3]. However, studies using this method to predict AKI duration (transient or persistent) have failed to demonstrate its utility, showing controversial findings[4-7]. Some authors have argued that numerous variables preclude the accurate interpretation of urinary electrolytes for AKI monitoring[8,9]. It is currently unknown, however, if this failure is merely a result of misinterpretation or inadequate methodology of the studies. Because of this inconsistency, urine biochemistry for AKI monitoring was suggested to be abandoned[8].

Our group has evaluated urinary electrolyte composition for many years, and we have reviewed some of the arguments against using urinary electrolytes for AKI monitoring. We recently outlined the principles of an alternative AKI monitoring method called the urine biochemical (UB) approach[10]. The aim of this review is to explain this alternative method and demonstrate the utility of this easily interpreted, low-cost, and intuitive tool to monitor rapidly changing renal function.

EVALUATION OF RENAL FUNCTION MEASURING EXCRETED MASS OF CREATININE INSTEAD OF OSCILLATIONS IN sCr OR UO

Systematically assessing the urine composition is the most reliable and practical way to measure the quantity of creatinine being excreted by the kidneys in a timely manner. sCr does not indicate renal function in real-time because it is a late measure of creatinine that is retained in the body due to an imbalance between creatinine production and excretion. sCr concentration also depends on other variables such as its volume of distribution and the transference velocity between intracellular and extracellular compartments (Figure 1)[11-14]. The urine, albeit a single compartment, may also be interpreted as the volume of distribution of the excreted creatinine, which may vary without changing the total amount of creatinine being excreted. Because urine has a role in keeping effective circulating volume, its own volume may vary independently of the amount of creatinine that needs to be excreted. In other words, it must be assumed that physiological variations in UO may occur that do not represent renal dysfunction, even when it is lower than 0.5 mL/kg/hour. We have observed many oliguric patients with very high urinary creatinine concentrations (CrU) (i.e. the mass of creatinine being excreted per unit of time is preserved), suggesting adapted renal function and no subsequent increase in sCr (“permissive oliguria”)[15]. This is particularly common postoperatively. Therefore, decreases in UO would not define AKI except when the capability to concentrate creatinine proportionally is jeopardized, reducing the excreted mass of creatinine. In this regard, assessment of CrU alongside UO is necessary to evaluate this capability.

Figure 1 Schematic representation of creatinine production, distribution, and excretion from the body and the information retrieved from urine biochemical parameters accordingly. CrU: Urinary creatinine concentration; KU: Urinary potassium concentration; sCr: Serum creatinine; UO: Urinary output.

Increasing sCr levels typically correspond to worsening renal function. Since the variations in sCr depend on a series of parameters such as creatinine production, volume of distribution, and degree of creatinine excretion impairment, they all must be considered when interpreting the sCr value. Increases in sCr are usually a consequence of creatinine accumulation and not a direct measurement of renal function. Still, alterations in renal function are not mandatorily synchronized with sCr. Changes in the GFR tend to occur faster than changes in sCr. Consequently, sCr is a late marker of AKI development as well as a late marker of renal recovery. It is possible to observe renal recovery while sCr is still increasing[10,16]. Considering GFR reestablishment a gradual process, there will be a phase in which, even with an improvement in creatinine excretion, it would still remain lower than creatinine production; consequently, in this phase, creatinine is still accumulating in the body, although in a lower proportion, flattening the slope of sCr increment, not to mention the dynamics of intercompartmental transference of creatinine into the blood, which is clinically unavailable. Hypothetically, if the amount of creatinine coming from the tissues and entering into the circulation is similar to creatinine being eliminated in the urine, this could also be a reason for a stabilization of sCr, even with an improved creatinine excretion (Table 1)[16].

Table 1 Sequential values of serum creatinine, diuresis, and urine biochemical parameters during acute kidney injury development and recovery¹.

Parameter	Day1	Day2	Day3	Day4	Day5	Day6	Day7	Day8	Day9
sCr (mg/dL)	1.7	3.9	4.4	4.5	4.4	4.0	3.4	3.2	2.6
KU (mEq/L)	-	15.8	6.9	6.6	6.1	7.0	5.7	17.9	-
CrU (mg/dL)	-	105	49	45	47	47	35	62	-
KU/CrU ratio	-	0.15	0.14	0.15	0.13	0.15	0.16	0.29	-
Diuresis /24 hours (mL)	-	3380	5620	7100	8180	8300
2-hour excreted mass of creatinine (mg/hour)							227.5
2-hour measured CrCl (mL/min)							111.5

¹A 30-year-old, 100 kg, muscular male was admitted to the intensive care unit due to suspected intraoperative ischemic alterations detected in cardiac monitoring during an elective otorhinolaryngologic surgery. He developed postoperative Kidney Disease: Improving Global Outcomes stage 3 acute kidney injury that was attributed to the use of anti-inflammatory drugs. The very low urinary potassium (KU) was compatible with polyuria (KU decreases with urine output increase), and the very low KU/urinary creatinine (CrU) ratio indicated a disproportionate increase in CrU, which indicated an increased mass of excreted creatinine at day 7 after surgery (normal: 0.5-1.0 mg/kg/hour). The measured creatinine clearance (CrCl) on that same day demonstrated a recovered glomerular filtration rate but a still significantly increased serum creatinine (sCr). We concluded that renal recovery occurred around D2, but it took some days to equilibrate creatinine excretion with creatinine production (leading to sCr stabilization around 4.5 mg/dL) and, in the subsequent days, elimination of the exceeding mass of creatinine that rapidly accumulated in the muscular patient´s body (leading to decreases in sCr). The patient received 3-5 L of crystalloids every day to prevent dehydration. However, we hypothesized that polyuria could be the result of hydration in a patient with an already recovered glomerular filtration rate.

CrU: Urinary creatinine concentration; KU: Urinary potassium concentration; sCr: Serum creatinine; CrCl: Creatinine clearance.

Variation in the mass of creatinine excreted by the kidneys per unit of time may be a more reliable surrogate of renal function than changes in sCr, especially considering stable creatinine production. UO is the diluted environment for the excreted creatinine, and its volume may vary widely (Figure 1). Oliguria may be considered functional as long as the excreted mass of creatinine is preserved and there are no signs of hypovolemia. Fluid administration, which is commonly used in systemic inflammatory states to revert oliguria, can be useless and even deleterious due to volume overload in this scenario.

URINARY POTASSIUM/CrU RATIO: SIMPLE PARAMETER FOR ADEQUACY BETWEEN UO AND CrU

There must be an equilibrium between UO and CrU to keep the excreted mass of creatinine stable, preventing increases in sCr. We have proposed that, in the presence of normal sCr and normal serum potassium (sK), the fractional excretion of potassium (FeK) can indicate the future tendency of sCr[17,18]. Besides sCr and sK, FeK´s formula is composed by the ratio between urinary potassium (KU) and CrU. KU is inversely related to UO, and an increased KU/CrU ratio (> 0.5) indicates that the CrU level is disproportionally low for the level of UO (Figure 2). A patient with oliguria may have an increased CrU, preserving the amount of creatinine being excreted (KU/CrU ratio around 0.5). This is the UB profile of patients in whom sCr does not increase despite oliguria. Conversely, a patient with a high UO may have a very low CrU and compromised mass of creatinine excreted. This is the typical finding in patients with nonoliguric AKI (Figure 2). Decreasing values of KU/CrU indicate an improved excretion of creatinine mass that is observed preceding sCr recovery (Table 1).

Figure 2 Distinct scenarios and proper interpretations of urinary potassium and urinary creatinine as well as their ratio, considering normal serum potassium and creatinine. AKI: Acute kidney injury; CrU: Urinary creatinine concentration; KU: Urinary potassium concentration; sCr: Serum creatinine; UO: Urine output.

URINARY SODIUM CONCENTRATION: AVID SODIUM RETENTION AS A MARKER OF RENAL MICROCIRCULATORY STRESS AND HYPERNATRIURESIS AS A MARKER OF INFLAMMATION RESOLUTION

Avid tubular sodium reabsorption has long been considered a hallmark of low renal blood flow (RBF) (the “pre-renal paradigm”). However, this paradigm has been challenged due to the observation of very low urinary sodium (NaU) levels in the presence of increased RBF. Some authors have suggested that NaU should be abandoned as a monitoring tool due to its disconnection with renal perfusion[8]. However, no studies have been performed to confirm or dispute this statement. We hypothesized that low NaU values represent renal microcirculatory stress (RMS) (even during high RBF) because the mechanisms that trigger avid sodium retention are mostly present at the glomerular level and not at the renal artery level. This dissociation between macrocirculation (hyperdynamic) and poorly perfused microcirculation is not uncommon in systemic inflammatory states. Therefore, the UB approach was proposed and focuses on renal function monitoring at the microcirculatory level, being more accurate and on-time than increases in sCr (Table 2)[10,16,19].

Table 2 Basic differences between the traditional and urine biochemical approaches for acute kidney injury monitoring.

Traditional approach	Urine biochemical approach
sCr and UO are the main monitoring tools. AKI may be diagnosed based on increases in sCr or decreases in UO, independently from each other	sCr is a late AKI monitoring tool because it is the result of creatinine accumulation in the body; Decreases in CrU excretion may be considered an earlier marker of renal dysfunction, and the mass of excreted creatinine should be monitored
Oliguria is considered renal dysfunction	Oliguria is considered dysfunctional when it jeopardizes creatinine excretion; “Permissive oliguria” is defined as a decrease in UO that is counterbalanced by proportional increases in CrU, keeping the excreted mass of creatinine stable and preventing increases in sCr
Urine electrolyte assessment is made after AKI diagnosis and helps to distinguish pre-renal from renal AKI (functional vs structural AKI) in a single-point NaU assessment	Urine electrolyte assessment is made before sCr alterations and identifies RMS, which is characterized by significant decreases in NaU due to avid sodium retention; Sequential assessment is needed to properly observe this phenomenon
Very low NaU in the presence of AKI is a marker of low RBF	Significant acute decreases in NaU are an alert sign of RMS development and risk of AKI and may occur independently of volemic status, particularly in systemic inflammatory states such as sepsis, trauma, or after surgery
Low FeNa and low FeUr in the presence of AKI are also markers of pre-renal AKI	FeK is more relevant than FeNa and FeUr; FeK increases before sCr in AKI development; The KU/CrU ratio, included in the formula for FeK, is a simple marker of adequacy between UO and CrU; A high KU/CrU ratio points towards impaired creatinine excretion leading to subsequent increases in sCr due to systemic creatinine accumulation

AKI: Acute kidney injury; FeK: Fractional excretion of potassium; FeNa: Fractional excretion of sodium; FeUr: Fractional excretion of urea; KU/CrU: Urinary potassium (mEq/L)/urinary creatinine concentration (mg/dL); NaU: Urinary sodium concentration; RBF: Renal blood flow; RMS: Renal microcirculatory stress; sCr: Serum creatinine; UO: Urine output.

Conversely, very high NaU (defined by the UB approach as an NaU value higher than the serum sodium level) is a specific marker of renal recovery and RMS resolution[17]. In critically ill patients, an increased body sodium balance usually occurs during the AKI phase. This explains the hypernatriuresis that subsequently takes place with cessation of the activated sodium-retaining mechanisms in parallel with systemic inflammation alleviation.

ELIMINATING sCr FROM THE REAL-TIME GFR EVALUATION

Critically ill patients frequently experience rapid changes in GFR. Creatinine kinetics are dependent on multiple parameters such as creatinine generation rate, volume of distribution, intercompartmental transference rate, velocity of GFR decline, etc. Oscillations in GFR occur faster than the time needed for sCr to reach a steady state. In this regard, it is possible that increases in sCr following an abrupt GFR decline occur faster than decreases in sCr following GFR recovery. Creatinine accumulation in the body (not only in the blood) can lead to a long-lasting creatinine washout period because the blood is the only pathway through which creatinine can reach the urine (which is the only pathway for creatinine excretion) (Figure 1 and Table 1). We believe that real-time measurement of the mass of excreted creatinine per unit of time is a better method for evaluating GFR as long as there are no abrupt changes in creatinine production during evaluation.

The creatinine clearance calculation uses sCr and may not be appropriate in a situation where sCr is not stable. We have proposed the use of the KU/CrU ratio as a possible surrogate for the mass of excreted creatinine because it does not utilize sCr. In addition, the KU/CrU ratio is a way to normalize CrU to UO, independent of its absolute value (Figure 2 and Table 1).

FUTURE DIRECTIONS FOR THE PROPER USE OF THE UB APPROACH

Inevitably, the UB approach has some limitations. First, obtaining a real-time urine sample is not always easy, except in patients with an indwelling urinary catheter. However, using urine (a waste product) to measure relevant parameters may minimize the need for blood sample collection. Second, some medications, especially diuretics, interfere with urine electrolyte concentrations, precluding their adequate interpretation. Interestingly, the magnitude of NaU increase after furosemide treatment has been used as a prognostic marker in cardiac failure[20]. To exclude the effect of diuretics on urine biochemistry, it is advisable to collect urine at least 6-8 hours after its administration.

There are several directions that future studies should explore. First, the impact on prognosis after early diagnosis of renal dysfunction, using either the mass of excreted creatinine per unit of time or the KU/CrU, should be studied. Second, studies determining the impact that the UB approach has on minimizing AKI progression are needed. Finally, the usefulness of the UB approach should be confirmed in patients with chronic renal failure. Most studies have focused on patients with normal baseline renal function who experience a predetermined insult to the kidneys, such as elective major surgery[16,19]. Larger, prospective, multicenter studies comparing the traditional and UB parameters for renal function monitoring are also needed.

CONCLUSION

Considering all the previous literature published using urine biochemistry and the paradigms such as a single, punctual NaU measurement to define “pre-renal” and “renal” AKI[1,2,21] and low NaU as a synonym of low RBF[21], the UB approach, if not useful in terms of minimizing AKI occurrence or improving prognosis, is at least a reappraisal of basic physiologic phenomena that still remain equivocally presented in most medical textbooks.