Background: Acute changes in serum creatinine are labeled clinically as acute kidney injury (AKI). However, not all acute changes in serum creatinine are deleterious and need to be acted upon. Summary: Intravenous fluids in response to AKI should be judiciously administered, and volume overload should be avoided. Since congestion is the driver of poor outcomes in patients with acute decompensated heart failure and must be managed, AKI that occurs at the expense of decongestion does not confer increased risk. We still do not have evidence of therapies that reduce AKI which will translate into any meaningful improvements in clinical outcomes. Finally, particularly in the setting of application of therapies designed to reduce cardiorenal risk, acute changes in serum creatinine are often in the opposite direction of the ultimate clinical outcomes, both renal and nonrenal. Key Messages: Given the complexities and the nuance of acute changes in serum creatinine, it has ruled itself as an unreliable surrogate for randomized controlled trials and often hinders appropriate care in the clinical setting.

© 2022 S. Karger AG, Basel

Serum creatinine, measured ubiquitously and frequently in hospitalized patients, as well as in the outpatient setting, most often as part of a chemistry panel, is an indirect measure of kidney function. In the last 2 decades, tons of literature on acute changes in serum creatinine, labeled now as the more dangerous sounding “acute kidney injury (AKI),” with connotations even to myocardial infarction (“kidney attack”) [1], have made innumerable clinicians place ever more attention on fluctuations of serum creatinine concentrations. Even consortia have been created with exclamations points to again forebode to the community how potentially dangerous AKI is (AKI!Now).

What could go wrong? Why should not we pay more attention to acute changes in serum creatinine or AKI? We know that a multitude of observational studies have demonstrated that AKI is associated with an increased risk of subsequent CKD, recurrent AKI, hospitalizations, cardiovascular events, and mortality [2]. Thus, the prevailing theory is that if we can apply interventions to prevent, reduce, or speed up recovery from AKI, we should be improving outcomes.

The first roadblock against that theory is that even in the most severe form of AKI (acute tubular necrosis), specific treatments for AKI are still lacking. Interventions such as dopamine, fenoldopam, adenosine antagonists, growth factors, natriuretic peptides, antioxidants, off-pump cardiac bypass, erythropoietin, anti-inflammatory agents (including melanocyte-stimulating hormone agonists and human recombinant alkaline phosphatase), anticoagulants, and anti-fibrotic agents have all failed to demonstrate a significant reduction in the frequency or severity of AKI in rigorous and robust randomized clinical trials [3].

The second issue, that extends the issue from the previous issue, is that all AKIs are not created the same. AKI is a highly complex heterogenous syndrome, not a uniform disease. Any nephrologist who sees patients in the hospital knows a very basic fact: most cases of AKI are secondary to other organ dysfunction(s), and most cases of AKI are multifactorial in etiology. Isolated cases of AKI that are the primary reason for hospitalization are the minority of cases and when occurs is due to a glomerulonephritis or drug-induced toxicity. Thus, if the AKI is such a complex syndrome in the majority of patients, how can it be expected for a drug that targets one pathway to be efficacious? How can we have a meaningful impact on clinical outcomes in the setting of severe heart failure, respiratory failure, liver failure, severe sepsis, metastatic cancer, or other conditions, such as complicated cardiac and noncardiac surgeries that contribute to AKI, by just focusing on targeting kidney function or tubular injury/recovery? How can we continue to serum creatinine clinically and in randomized trials, when it is a marker /endpoint that can have blunted rise by either decreased generation of creatinine or dilution from excessive intravenous fluid administration?

In fact, without specific AKI therapies, the most common reaction to said changes in serum creatinine is to give intravenous fluids. This occurs as the reflex despite the fact that many patients administered fluids are not truly volume responsive, and the totality of evidence suggests that volume overload is a major contributor to excess mortality in patients with AKI [4]. The overzealous administration of IVF comes in the face an explosion of papers on the impact of congestion on the kidneys and kidney function over the past several years [5, 6]. Continued efforts to better educate clinicians on the potential harms of IVF and to make more judicious decisions regarding volume administration in the setting of AKI are needed.

Third, have we maligned AKI inappropriately? When is AKI good or at least benign? Indeed, it has now been demonstrated repeatedly that if “AKI” occurs in conjunction with decongestion in patients hospitalized with acute decompensated heart failure (ADHF), their outcomes are essentially equivalent to those who did not suffer AKI with ADHF [5, 7]. While it is tempting to dismiss these changes in creatinine as purely functional or hemodynamic in nature (which is probably true in the majority), there are recent data that support that even if AKI is coexisting with injury as measured by urinary AKI biomarkers, the same relationship holds. First, in a post hoc analysis of the ROSE trial that examined nesiritide versus dopamine in patients with ADHF, both changes in kidney function (assessed by changes in serum cystatin C and SCr) and changes in markers of kidney injury (NGAL, N-acetyl-β-D-glucosaminidase, KIM-1) were assessed. Paradoxically, patients who exhibited both a decline in kidney function and an increase in kidney injury markers had lower risk of death over 6 months [8]. A similar post hoc analysis of the CARRESS-HF trial demonstrated that patients who were decongested aggressively had more AKI by both rises in serum creatinine and increases in tubular injury biomarkers but paradoxically had better kidney function and more recovery from AKI when measured 60 days later [9]. Thus, it is clear that mild to moderate changes in kidney function (i.e., <30% decline in eGFR or <1.5 mg/dL change in serum creatinine) that occur during ADHF should not be used as safety endpoints in trials of strategies for decongestion.

One prime example of the fallacy of hyperfocus on kidney function came to bear in the PrevAKI trial, in which patients as identified by high risk for AKI by the FDA-approved biomarkers [TIMP-2] × [IGFBP7] were randomized to receive the KDIGO computed tomography surgery bundle (avoidance of nephrotoxic agents, discontinuation of angiotensin-converting enzyme inhibitors [ACEis] and angiotensin receptor blockers [ARBs] for the first 48 h after surgery, close monitoring of SCr and urine output, avoidance of hyperglycemia for the first 72 h after surgery, consideration of alternatives to radiocontrast agents, close hemodynamic monitoring by using a pulse contour cardiac output catheter with an optimization of the volume status and hemodynamic parameters according to a prespecified algorithm) or standard of care [10]. AKI was indeed lower in those randomized to the KDIGO bundle. AKI was reduced from 71.7% to 55.1%, and moderate and severe AKI was reduced from 44.9 to 25.7%. However, while not powered to detect differences in clinical endpoints, in an epic blow to the nephrocentric myopic serum creatinine focused crowd, not only were hard outcomes such as mortality, requirement for renal replacement therapy, or persistent renal dysfunction not better in those that were randomized to the KDIGO bundle, but in some cases, the proportion with the clinical outcomes was greater (renal replacement therapy at day 60, major adverse kidney event at 30 and 60 days) [10].

The occasional paradoxical relationship between acute changes in kidney function and long-term outcomes is not just a phenomenon isolated to hospitalized patients. This has been witnessed in studies or trials in which intraglomerular pressures are modulated. In the Veterans Administration Diabetes in Nephropathy Study (VA NEPHRON-D) trial, patients who developed AKI in the dual renin-angiotensin-aldosterone arm had an adjusted hazard ratio for death 0.45 (95% confidence interval, 0.23–0.88), compared to those that developed AKI in the monotherapy arm [11]. In a propensity-matched analysis over 2 years following a hospitalization for AKI from the Alberta Kidney Disease Network, patients that received ACEi or ARBs after an episode of AKI had a 25% increase in risk for AKI [12]. However, despite the excess risk of AKI in those that received ACEi or ARBs, the risk of all-cause mortality was 15% lower in those treated with ACEi or ARBs. In a post hoc analyses of the Systolic Blood Pressure Intervention Trial (SPRINT), in which patients were randomized to SBP targets <120 mm Hg versus <140 mm Hg, there was a 64% increase in the risk for AKI with intensive BP control [13] despite the well-publicized decrease in all-cause mortality and CV events [14]. Finally, examination of the trials of sodium-glucose cotransporter-2 inhibitors reveals that estimated glomerular filtration abruptly declines upon initiation in a substantial proportion of individuals, yet these drugs have profound renal and cardiovascular protective properties long term [15]. Imagine if any of the above strategies or agents were novel, without well-known systemic mechanisms, that were being studied in phase 2 trials. RAASi (single or dual therapy), intensive BP control, sodium-glucose cotransporter-2 inhibitor would all be thrown to the wayside for causing “more AKI.” It is sure to be that in the near future, a new drug will not only end up causing early AKI but also have systemic benefits that outweigh these acute changes in kidney function. Thus, we cannot reliably use serum creatinine or AKI as an endpoint in trials without examining these in context within the following: (a) biomarkers that reflect true tubular injury, (b) the drug’s mechanism of action, or (c) the effect of the drug on other clinical endpoints.

In summary, not all acute changes in SCr are deleterious and need to be acted upon. IVF in response to AKI should be judiciously administered, and volume overload should be avoided. Since congestion is the driver of poor outcomes in patients with ADHF and must be managed, AKI that occurs at the expense of decongestion does not confer increased risk. We still do not have evidence of therapies that reduce AKI (e.g., off-pump cardiac bypass surgery or the KDIGO bundle) which will translate into any meaningful improvements in clinical outcomes. Finally, particularly in the setting of application of therapies designed to reduce cardiorenal risk, acute changes in serum creatinine are often in the opposite direction of the ultimate clinical outcomes, both renal and nonrenal. Thus, given the complexities and the nuance of acute changes in serum creatinine, it has ruled itself as an unreliable surrogate for randomized controlled trials and often hinders appropriate care in the clinical setting.

Steven G. Coca reports the following: employer: Icahn School of Medicine at Mount Sinai; Mount Sinai owns part of Renalytix; consultancy: Renalytix, Takeda, Nuwellis, Vifor, Bayer, Boehringer-Ingelheim, Reprieve Cardiovascular, Axon, and 3ive; ownership interest: Renalytix and pulseData; research funding: Renalytix, ProKidney, Renal Research Institute, and XORTX; patents or royalties: Renalytix; advisory or leadership role: Renalytix and Reprieve Cardiovascular; and other interests or relationships: associate editor for Kidney360, editorial boards of JASN, CJASN, and Kidney International.

The author received no funding.

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