What is Outpatient AKI? Insights from the SPRINT AKI Cohort

In the report by Ascher, et al.,¹ we get a glimpse into what the future of outpatient nephrology practice might look like regarding initial evaluation and subsequent monitoring of our patients. In addition, new insights into the challenging clinical dilemma of outpatient AKI are revealed. The report is a subgroup analysis from the Systolic BP Intervention Trial (SPRINT) of patients who developed AKI in the outpatient setting 1 year after enrollment. At the time of study enrollment (baseline) and at the time of outpatient AKI, the following serum biomarkers were assessed: (1) uromodulin, (2) kidney injury molecule-1 (KIM-1), (3) soluble tumor necrosis factor receptor 1 (sTNFR1), and (4) sTNFR2. The association of these biomarkers at the time of AKI with kidney function recovery 1 year later was the primary endpoint. Lower levels of serum uromodulin and higher levels of serum KIM-1 and serum sTNFR1 were significantly associated with nonrecovery of kidney function.

To appreciate these study results and their implications for clinical practice, three key questions will be considered: (1) What patient population was studied? (2) Was the episode of AKI actually AKI? and (3) What do the biomarkers reflect?

What Patient Population Was Studied?

Participants in SPRINT were hypertensive with a high risk of subsequent cardiovascular events as judged by Framingham risk score (10 year risk >15%), CKD, pre-existing cardiovascular disease, or age 75 years or older. Patients with diabetes mellitus, eGFR <20 ml/min per 1.73 m², and proteinuria >1 gram/d were excluded. SPRINT addressed whether intensive treatment to a systolic BP ≤120 improved cardiovascular outcomes and mortality versus treatment to a systolic BP ≤140 or less. Patients were enrolled between 2010 and 2013; the study was stopped early because of favorable outcomes in the intensive treatment group. As such, SPRINT was one of the most influential BP studies conducted providing robust evidence for lower BP targets in practice today.

Of the 9361 SPRINT participants, 723 (approximately 8%) developed outpatient AKI. The SPRINT AKI cohort consisted of 652 of these patients who had plasma samples for biomarker analysis. AKI was defined by elevation of serum creatinine from baseline of ≥0.3 mg/dl, not requiring hospitalization or emergency department evaluation. Baseline serum creatinine was 1.26±0.50 mg/dl (mean±SD), and the median rise was 0.4 (interquartile range 0.3–0.6 mg/dl). Thus, a typical patient went from a baseline serum creatinine of around 1.3 mg/dl to 1.6–1.9 mg/dl. On the basis of current definitions, most of the patients in the SPRINT AKI cohort would be considered to have stage 1 AKI (serum creatinine rise ≤1.9-fold baseline).²

Of the 652 patients in the SPRINT AKI cohort, only 180 (33%) experienced kidney function recovery 12 months after the outpatient AKI episode. This result is arguably the most remarkable finding of this study because it is in stark contrast to outcomes in hospitalized patients with AKI. Even in the critically ill, 70%–90% of patients with stage 1 AKI recover kidney function before discharge which is associated similar levels of kidney function 1 year later in most patients.³ Thus, the SPRINT AKI cohort demonstrated worse kidney function outcomes than hospitalized patients with AKI.

Was the Episode of Outpatient AKI in the SPRINT Cohort Actually AKI?

Probably Not

In fact, most cases of outpatient AKI are probably not acute. To be correctly labeled as AKI, the ≥0.3 mg/dl rise in serum creatinine must occur within 48 hours²; a definition adopted on the basis of adverse outcomes observed in hospitalized patients. In most outpatient AKI cases, the timing of creatinine rise is unknown and unlikely to have occurred within 48 hours—especially in the asymptomatic patient at a routine clinic visit. Even so, most outpatient providers reasonably label a ≥0.3 mg/dl rise in creatinine, regardless of timing, as AKI—similar to the SPRINT AKI cohort. Notably, a standardized definition of outpatient AKI does not exist, and future study is needed to determine the implications of a 0.3 mg/dl rise in serum creatinine rise relative to a remote baseline. In this regard, the best studied definition of outpatient AKI is a ≥50% increase from baseline, with baseline defined as the average of three outpatient creatinines measured 25–365 days prior.⁴ With this definition, AKI occurs in approximately 3% of general outpatients and is associated with increased long-term mortality risk.⁴

While not necessarily acute, the AKI designation is clinically useful because the etiology could be acute—and evaluating for reversible, acute causes is the prime directive of outpatient AKI management. Clinicians are well aware that subacute causes, such as renal artery stenosis, and progression of CKD also need to be considered. In this regard, the SPRINT AKI cohort provides some insights. Because two-thirds of cases were associated with eGFR nonrecovery at 1 year, it is likely that these cases were not reversible and represented progression of CKD in many cases. While the SPRINT population represents only a subset of a general nephrology practice, this observation aligns with clinical experience because the search for reversible causes of outpatient AKI is often unrevealing.

What do the Biomarkers Reflect?

Of the three biomarkers of nonrecovery, only uromodulin⁵ (also known as Tamm-Horsfall protein) is truly a kidney-specific maker. It is exclusively produced within the epithelial cells of the thick ascending limb of the Loop of Henle and the distal convoluted tubule. Mice with knockout of uromodulin have worse AKI, and uromodulin is beneficial in mitigating the AKI to CKD transition by modulating interstitial inflammation, decreasing oxidative stress, and promoting a proreparative/antifibrotic phenotype. As a biomarker, serum levels are widely regarded as a marker of functional nephron mass and kidney function reserve. As such, lower serum levels are associated with an increased risk of AKI, onset of CKD, and CKD progression. Beyond kidney health, lower serum levels are associated with unfavorable glucose metabolism, diabetes, metabolic syndrome, and increased body mass index. Lower serum levels are also associated with increased risk of cardiovascular disease and all-cause mortality, even after adjustment for kidney function.

KIM-1, also known as T-cell Ig and mucin domain 1, is encoded by the Hepatitis A Virus Cellular Receptor 1 gene. While often considered kidney-specific, its mRNA is observed in 36 of the 51 tissue types cataloged by The Human Protein Atlas including colon, testis, lymph node, skin, and lungs.⁶ Within the kidney, levels are rapidly upregulated after AKI. While believed to be protective early after AKI, chronic expression of KIM-1 within the kidney is associated with a profibrotic phenotype and may play an important role in the AKI-to-CKD transition, as well as CKD progression itself. Outside of kidney health, KIM-1 is involved in immune regulation of diverse conditions, such as asthma, viral infections, and progression of certain cancers. As a biomarker, plasma levels are increased in patients with either AKI or CKD, and increased levels are associated with CKD progression.⁷ Beyond kidney health, elevated levels of plasma KIM-1 are associated with cardiovascular risk factors including BP, LDL, age, body mass index, and current smoking—independent of kidney function.⁸

sTNFR1 was the strongest predicter of AKI nonrecovery and is the least kidney-specific biomarker of the three. mRNA expression is detected in all 51 cell and tissue types represented in The Human Protein Atlas, notably adipose tissue, cardiomyocytes, vascular endothelial cells, renal endothelial cells, including the glomerulus, leukocytes, and hepatocytes.⁶ Functionally, sTNFR1 is a decoy receptor which binds circulating TNF-α, thus inhibiting TNF-α-mediated proinflammatory effects. As a biomarker, it is generally considered a marker of systemic inflammation. With respect to kidney disease, plasma sTNFR1 is best studied as a biomarker of CKD progression, particularly in inflammatory diseases, such as diabetes and lupus. Outside of kidney health, sTNFR1 is well-studied, and elevated levels are associated with mortality and other adverse outcomes in a wide variety of inflammatory conditions including cardiovascular disease, malignancy, sepsis, myocardial infarction, and coronavirus disease 2019.^9,10

So what do these biomarkers reflect in the SPRINT AKI cohort? Taken together, the unfavorable biomarker changes likely represent aspects of kidney and systemic health that conspire to promote CKD progression: uromodulin reflecting lower nephron mass, KIM-1 reflecting ongoing kidney damage and maladaptive repair, and sTNFR1 reflecting systemic inflammation. Because the biomarker changes observed are associated with unfavorable metabolic profiles and adverse cardiovascular outcomes, they may also indicate unfavorable states of the cardiovascular-kidney-metabolic syndrome that adversely affect kidney function. This possibility is particularly pertinent because none of the patients in SPRINT had diabetes, but did have a high risk of cardiovascular complications. While favorable levels of these biomarkers may be reassuring and guide continuation of beneficial anti-hypertensive therapies, unfavorable levels of these biomarkers might indicate the need to intensify therapies—especially those beneficial in cardiovascular-kidney-metabolic syndrome. Because SPRINT was conducted prior to the widespread adoption of sodium-glucose transport protein 2 inhibitors, one wonders whether outcomes in the patients with eGFR nonrecovery might be different today.

In summary, outpatient AKI is a poorly defined and understudied condition that may reflect CKD progression in some cases. It is abundantly clear that the eGFR markers creatinine and cystatin C, and the CKD stages derived from them, are insufficient to phenotype patients at risk of kidney function decline. With the growing recognition of the connections among kidney health, metabolism, and cardiovascular disease, evaluation and monitoring of patients should include biomarkers representing all of these conditions. Results from the SPRINT AKI cohort suggest that serum levels of uromodulin, KIM-1, and sTNFR1 may be suitable for this purpose. The development and implementation of such tools may reasonably be considered a research priority that has the potential to improve clinical care in the outpatient setting.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C601.

Author Contributions

Conceptualization: Sarah Faubel.

Writing – original draft: Sarah Faubel.

Writing – review & editing: Sarah Faubel.

Funding

None.