1 Introduction

Acute kidney injury (AKI) is a well-known complication of both cardiac and major non-cardiac surgeries, with relevant prognostic implications [1]. Its incidence is quite variable depending on both patient and surgery characteristics. The fact that AKI is associated with an increased perioperative morbimortality leads to the rationale that an early detection of its development is a potential way to mitigate its progression and, perhaps, ameliorate patient's outcome.

In this worrisome scenario, much effort has been dedicated to define not only risk factors for postoperative AKI development but also reliable functional and/or structural biomarkers which can sign for renal impairment earlier than the classic urine output (UO) decrease and serum creatinine (sCr) increase, both definitively late markers and, therefore, not appropriate for precocious AKI diagnosis. Besides that, oliguria may be a physiological response to the surgical stress, not mandatorily a sign of renal dysfunction. It is common practice (particularly regarding postoperative patients) to link decreased UO with hypovolemia leading frequently to an unjustified aim to increase fluid administration postoperatively. The drawbacks of a positive cumulative fluid and sodium balance were well described previously for both clinical and surgical patients [2].

In the last two decades, a broad group of urine and serum biomarkers have been identified as potential early markers of renal damage or, at least, renal dysfunction [3]. Unfortunately, their widespread use has not yet been implemented mainly because of lack of availability and high cost, especially in developing countries and low-income centers.

2 How have we reached the relevance of urine biochemistry in AKI monitoring?

Since our group is based on a developing country with limited resources, we sought to find alternative tools that could detect early AKI development but using parameters widely available even in low-income intensive care units (ICUs). In this regard, urine electrolytes measurement was thought to be of potential utility. At the beginning, our first approach measuring urine electrolytes was not thinking of AKI development, but, instead, we started to measure them sequentially in spot urine samples in order to understand acid–base disturbances and for the urinary anion gap calculation [4], later called the urinary strong ion difference. The physicochemical approach to acid-base disorders emphasizes the relevance of electrolytes (cations and anions) concentrations both in urine and in blood to determine pH variations. Besides the relevant insights that repeatedly measured urinary ions brought to our understanding of acid-base homeostasis, we observed that, in patients that developed AKI, there was an anticipated progressive change in the urinary electrolyte composition, particularly of sodium and potassium as well as in their correspondent fractional excretions [5, 6].

2.1 Renal microcirculatory stress preceding postoperative AKI diagnosis

These progressive modifications in the urinary electrolyte composition are mainly a result of surgery-induced renal microcirculatory stress (RMS), which is a pathophysiological condition that corresponds to a step before frank AKI development. Many intraoperative factors such as hypovolemia, increased intraabdominal pressure (particularly in major abdominal surgeries) may lead to sympathetic nervous and renin-angiotensin-aldosterone system activation, the main triggers of avid sodium retention and increased tubular potassium secretion. It is important to emphasize that both macrohemodynamic (decreased renal blood flow) as well as intrarenal disturbances (shunts, tubuloglomerular feedback, neurohormonal activation) ultimately contribute to RMS [7]. We believe that the magnitude of RMS is a major determinant of subsequent AKI development, being a surrogate of significant decreases in glomerular filtration rate (GFR) in parallel with preserved global tubular function. We say "global" because some degree of tubular injury may occur even in this very early phase but usually not of sufficient magnitude to jeopardize the renal capability to avidly reabsorb sodium and secrete potassium.

3 The holy grail: urine biochemistry assessment before AKI diagnosis

Independently of the severity or duration of AKI, we were able to observe that, in the very early phase of AKI development (before increases in sCr), the urine electrolytes behavior was similar and standardized in both surgical and critically ill patients. The behavior of urinary sodium (NaU) as well as the fractional excretion of potassium (FeK) brought particular attention. Abrupt decreases in NaU occurred one or two days before AKI diagnosis in parallel with significant increases in FeK both in transient as well as in persistent AKI [5, 6]. The fact that significant decreases in NaU preceding AKI were accompanied by stable values of fractional excretion of sodium (FeNa, ≅ 0.5%) suggested that decreased sodium filtration by the glomeruli was probably more relevant than additional avidity of tubular sodium reabsorption. This finding may explain why FeNa was not found to be a reliable tool for early AKI prediction in previous studies, including surgical patients [8]. Critically ill patients with no AKI have also a similarly decreased FeNa [5]. In fact, even healthy people have a low FeNa (≅ 1%) as an evolutive adaptation to preserve circulating blood volume. The great difference resides on higher NaU values inferring preserved glomerular sodium filtration in the absence of AKI development. Besides urine electrolytes, other simple, easily assessed urinary parameters such as urinary pH has also been associated with AKI development when assessed preoperatively [9].

4 Let's put aside the "below 20, above 40" rule for NaU interpretation

We have recurrently emphasized that the concept of "high NaU" must be changed [10]. A NaU greater than 40 mEq/L, as usually used to diagnose acute tubular necrosis (ATN) in AKI patients, must be viewed as an "intermediate" value. NaU below 20 mEq/L is usually the result of low sodium filtration and avid tubular reabsorption but is not a synonym of "pre-renal" AKI because it can be found in any situation of renal microcirculatory stress [11], even in the presence of normovolemia and adequate/increased renal blood flow [12]. The truly high NaU is actually a result of high sodium filtration, which is, most of the times, not the case in the presence of ATN and may be classified as values close to or higher than serum sodium (sNa) (see below).

5 Urinary sodium concentration: better tool than FeNa for AKI monitoring

It is noteworthy that FeNa monitors only renal tubular sodium reabsorption capability while NaU is a result of both sodium filtration and tubular reabsorption. Yet, NaU depends also on the sodium intake. Although sodium intake may vary widely, patients submitted to major surgeries are usually exposed to a sodium amount (in the form of crystalloids) quite bigger than their usual sodium intake by oral ingestion. Therefore, NaU values above the concomitant sNa would be expected except for the fact that sodium-retaining mechanisms are simultaneously activated. We have previously suggested that the finding of NaU > sNa is a specific marker of normal or improving renal function, usually related to absence of or solving systemic inflammation [13] which is a well-recognized activator of sodium-retaining mechanisms.

A previous study has suggested that the fractional excretion of urea (FeUr) could be useful instead of FeNa in order to anticipate AKI development in cardiac surgery patients [8]. Patients with AKI had significantly lower FeUr 6 h after surgery in comparison to those without AKI. The theoretical major advantage of FeUr is that it is not influenced by diuretic use since most of the urea reabsorption occurs at the proximal tubular level. Therefore, enhanced urea reabsorption is not jeopardized by diuretic use, as occurs with FeNa. In a previous study by our group [5], FeUr decreased from D-2 to D-1 both in transient and persistent AKI but the values were not significantly different between AKI and no-AKI patients.

6 It is now time to give more attention to FeK!

Until recently, little attention has been given to FeK in comparison to FeNa and FeUr. However, FeK is known to increase in parallel with decreases in GFR in order to prevent major increases in serum potassium. Therefore, it is a potential tool for an anticipated diagnosis of a decreasing GFR. To our knowledge, our group was the first to propose sequential FeK measurement as a reliable AKI monitoring tool in critically ill patients [6]. In surgical patients, FeK was found to be increased at ICU admission even in patients that did not develop AKI (normal FeK value is around 10–12%) [14]. Interestingly, its value rapidly decreased to normal values in the subsequent days in these patients. In AKI patients, FeK was also increased at ICU admission but, distinct from no-AKI patients, its value was much higher and remained high in the subsequent days [14]. Our interpretation is that some degree of GFR decrease may occur even in patients that will not develop AKI but urine biochemical alterations are an early phenomenon, more intense and persistent in patients with postoperative AKI (Fig. 1). As mentioned above for FeNa, a disadvantage of FeK is also diuretic interference in its value.

Fig. 1
figure 1

Schematic hypothesis for the NaU concentration and FeK behavior in distinct and progressive levels of renal compromise in the early postoperative period (first 48 h), assessed while sCr is normal (elective surgeries in patients with no previous renal dysfunction). Major surgery can be considered a period of abrupt increases in Na+ intake due to crystalloids infusion. When RMS is not triggered during or soon after surgery, NaU increases transiently reaching sometimes supra-normal levels (perhaps a transient supra-normal GFR) and no AKI occurs. When RMS is triggered, AKI development depends on the intensity of the stress. The greater the stress, the greater the fall in NaU level and the increase in FeK. It is important to emphasize that, in the early AKI development, it is usually difficult to distinguish transient and persistent AKI, except for, perhaps, the intensity of the movements. Superimposed ATN may lead to subsequent, limited increases in NaU in persistent AKI, which must not be considered "high level" because truly high NaU values are only found in patients with high GFR (see text). NaU urinary sodium, FeK fractional excretion of potassium, sCr serum creatinine, RMS renal microcirculatory stress, GFR glomerular filtration rate, AKI acute kidney injury, ATN acute tubular necrosis

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Some authors proposed the use of 2-h urinary potassium excretion as an early marker of AKI and a surrogate of creatinine clearance, particularly in the absence of recent furosemide exposure [15]. This parameter has the advantage of being measured with no need of blood collection, in contrast to FeK. However, it takes more time to be measured (at least 2 h) and an increased FeK may delay the decrease in urinary potassium excretion so that, theoretically, increases in FeK occur earlier than decreases in urinary potassium excretion.

7 The role of urine biochemistry assessment to correctly interpret postoperative oliguria

Oliguria is a well-known phenomenon especially after major surgeries. It is usually defined as a decreased UO to less than 0.5 mL/kg/h. It has been questioned if this threshold value could be the same for clinical and surgical patients and a lower value has been proposed to be more appropriate for surgical patients (0.3 mL/kg/h) [16]. Interestingly, lower intra-operative UO was found in some studies to correlate with postoperative AKI development (as defined by increases in sCr) [16] but not in others [17]. Such heterogeneity might be related to oliguria severity and duration but a neglected piece of this puzzle is, from our point of view, the urine biochemical composition (Fig. 2).

Fig. 2
figure 2

Potential utility of sequential NaU and FeK measurements before, during and after major elective surgery for the early detection of AKI development, considering normal baseline sUr and sCr. The presence and magnitude of RMS is a major risk factor for postoperative AKI development. FeK is a future index of sCr so that increases in its value usually precede increases in sCr. Significant and rapid decreases in NaU is a hallmark of RMS development which may occur with or without subsequent increases in sCr. Using this flowchart it is possible to preclude AKI or mitigate its progression earlier by treating reversible causes and better understanding the cases of PO. sUr Serum urea, PO permissive oliguria, NASID non-steroidal anti-inflammatory drug

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8 Can urine biochemistry profile determine the cases of postoperative "permissive oliguria"?

"Permissive oliguria (PO)" was a term proposed in cases of oliguria which do not represent a pathological finding but, instead, the cases in which oliguria is a physiological response to surgical stress, with no subsequent increases in sCr [18]. Diagnosing PO is of major clinical relevance because it does not demand therapeutical interventions and is not per se an alert sign of ongoing kidney dysfunction. We believe that urine flow assessment solely is not enough to distinguish "permissive" and "non-permissive" oliguria. The major point to separate these two situations is the ability of the kidneys to preserve adequate creatinine clearance in a reduced urine volume. In other words, in PO, a very high urinary creatinine concentration is observed so that the mass of creatinine excreted per unit of time is preserved, precluding increases in sCr [19]. In other words, PO is usually characterized by reduced UO with normal FeK (Fig. 2).

9 What will come next?

In conclusion, the real utility of urine electrolytes measurement is far from being adequately explored. Misinterpretation of the values for decades (the classic “pre-renal” paradigm) and late assessment (after AKI diagnosis) are certainly major reasons for its discrimination in daily practice. Since most of the previous studies exploring this tool assessed critically ill patients, our group are now developing a prospective, multicenter study to sequentially measure urine electrolytes in elective surgical patients starting at the preoperative period until at least 48 h after surgery in order to properly characterize if their behaviors are capable to detect AKI earlier (subclinical AKI). Because their monitoring are widely available and not expensive, answering this question is of major relevance, particularly for low-income centers.