Acute and chronic kidney diseases are significant global health concerns. While elevated serum creatinine levels are widely recognized as indicators of kidney dysfunction and are associated with increased morbidity and mortality [1-4], the clinical significance of low serum creatinine levels is often underestimated. This article delves into the meaning of low creatinine, its potential causes, and why it should be considered a noteworthy clinical finding, especially in critically ill patients.
Recent research has brought to light the fact that low serum creatinine can be an important predictor of adverse outcomes [5]. A landmark study published in Critical Care Medicine by Udy et al. analyzed a vast dataset from the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation, encompassing over one million adult patients admitted to intensive care units (ICUs) between 2000 and 2013. This retrospective analysis investigated the correlation between peak serum creatinine concentration within the first 24 hours of ICU admission and hospital mortality [5]. The study excluded patients on chronic dialysis, readmissions, and renal transplant recipients to focus specifically on the impact of creatinine levels in the general ICU population.
The key findings of this extensive study revealed some critical insights:
- Low Peak Creatinine and Increased Mortality: A peak serum creatinine concentration below 60 µmol/L (0.68 mg/dL) in the initial 24 hours following ICU admission was independently linked to a heightened risk of mortality.
- Severely Low Creatinine Poses Significant Risk: Patients with extremely low serum creatinine levels, specifically below 30 µmol/L (0.34 mg/dL), representing 0.6% of the study population, faced over twice the adjusted odds of in-hospital death compared to those with creatinine levels in the reference range (70–79 µmol/L or 0.79 – 0.89 mg/dL). Alarmingly, this risk surpassed even the risk associated with very high creatinine levels (above 180 µmol/L or 2.04 mg/dL).
These findings were remarkably consistent across various admission types, including medical, surgical, trauma, and infection-related cases. Furthermore, the association remained independent of factors such as gender, age, and year of admission. While body mass index (BMI) data was available for a subset of patients (9%), analysis within this group indicated that the relationship between low serum creatinine and hospital mortality held true across all BMI categories. Although the specific reasons for low creatinine levels and the causes of death were not determined in this study, these results carry significant implications for clinical practice, urging a re-evaluation of how we interpret and respond to low creatinine values.
Creatinine: Beyond a Kidney Function Marker
It’s crucial to recognize that serum creatinine is not solely a marker of renal function. Creatinine is a byproduct of creatine metabolism, which is intrinsically linked to muscle metabolism. Creatine, initially synthesized from the amino acids glycine and arginine in the liver and kidneys, is transported to skeletal muscle cells. Dietary meat intake also contributes to creatine levels. Once in muscle cells, creatine is converted to phosphocreatine, serving as a readily available reservoir of high-energy phosphates essential for muscle function. The total amount of creatinine generated is influenced by muscle function, dietary meat consumption, and the body’s own (de novo) creatine production. In healthy individuals, creatinine production remains relatively constant. However, during critical illness, substantial and sustained decreases in creatinine production can occur rapidly. Therefore, serum creatinine concentration reflects a delicate balance between creatinine production and creatinine clearance by the kidneys.
While creatinine is freely filtered by the glomeruli in the kidneys and is not reabsorbed or metabolized by the kidneys (although some tubular secretion occurs), it has been a cornerstone in clinical practice for assessing renal function. However, serum creatinine as a marker of kidney health has limitations. It may take 24–36 hours for serum creatinine to rise noticeably after an acute kidney injury. It can also overestimate kidney function due to tubular secretion, and certain medications that inhibit tubular secretion can artificially increase creatinine levels without actual changes in kidney function. Additionally, creatinine distributes throughout total body water, and its concentration can be influenced by variations in fluid volume status.
Common Causes of Low Serum Creatinine
The causes of low serum creatinine concentration are generally recognized and encompass:
- Reduced Muscle Mass: Conditions leading to muscle wasting, such as frailty, sarcopenia (age-related muscle loss), malnutrition, and chronic diseases, can decrease creatinine production.
- Liver Disease: Severe liver disease can impair creatine synthesis, consequently reducing creatinine production.
- Significant Fluid Overload: Excessive fluid volume dilutes creatinine concentration in the blood, leading to lower measured levels.
- Poor Nutritional Status: Inadequate protein intake and overall malnutrition can reduce the availability of creatine precursors and muscle mass, lowering creatinine production.
- Augmented Renal Clearance: Conditions like pregnancy can increase kidney filtration rate, leading to slightly lower serum creatinine levels.
While previous studies have linked lower creatinine levels to increased mortality in specific populations, such as chronic dialysis patients, individuals initiating renal replacement therapy in the ICU, and older adults [6-9], the significance of low serum creatinine in the broader population of critically ill patients was less clear until recently. The study by Udy et al., with its massive dataset of over a million patients, provides compelling evidence in this area. Prior to this, Cartin-Ceba et al. conducted a retrospective analysis of 11,291 critically ill patients across three ICUs over 47 months and, similar to Udy et al., demonstrated that both high and low serum creatinine levels were risk factors for poor outcomes [10]. Their findings indicated that low baseline serum creatinine was independently associated with increased hospital mortality in a dose-dependent manner, and these patients also experienced longer ICU stays.
Potential Mechanisms Linking Low Creatinine and Poor Outcomes
The precise mechanisms underlying the association between low serum creatinine and adverse outcomes remain under investigation. The studies by Udy et al. and Cartin-Ceba et al. [5, 10], while providing crucial epidemiological data, do not offer definitive mechanistic explanations. Without detailed information on underlying conditions, it is plausible that low serum creatinine may simply be a marker for pre-existing conditions like chronic liver disease, reduced muscle mass, and poor nutritional status, all of which are independently associated with increased mortality risk in critically ill patients. Both studies focused on creatinine concentrations measured within the first 24 hours of ICU admission. One potential confounding factor suggested by the authors is that the results might be influenced by chronic fluid overload or aggressive fluid administration before ICU admission, which could dilute creatinine levels.
It is likely that the relationship between low serum creatinine levels and mortality is more complex than initially perceived. For instance, serum creatinine can sometimes overestimate kidney function, and a subset of patients with creatinine levels below the normal range might still have underlying renal impairment. Intriguingly, Udy et al. also observed that among patients with serum creatinine below 50 µmol/L (0.57 mg/dL) within the first 24 hours of admission, adjusted hospital mortality increased with rising admission albumin levels, reaching the highest risk in those with plasma albumin levels of 45 g/L or greater [5]. The authors propose that low serum creatinine in the context of adequate albumin levels might suggest significant physical deconditioning or muscle wasting [5, 11]. While this is a plausible hypothesis, further research is needed to confirm it, especially as detailed muscle function data was not available in their large database study. Instead, they analyzed the impact of serum creatinine across different BMI groups and found that the association between low creatinine and mortality was independent of BMI. However, it is well-recognized that BMI is an imperfect measure of muscle mass [11].
Practical Implications for Clinicians
The study by Udy et al., drawing on data from over a million ICU patients representing a diverse population, possesses strong external validity. While further research is warranted, particularly to elucidate the underlying mechanisms and explore potential therapeutic interventions, the current evidence has immediate practical implications. The finding of a low baseline serum creatinine level should serve as a “red flag,” alerting clinicians to the potential for higher risk in individual patients.
Interestingly, the APACHE II score, a widely used severity-of-illness scoring system, already incorporates low creatinine as a risk factor, assigning two points if the lowest serum creatinine level in the first 24 hours is below 0.6 mg/dL (53 µmol/L). However, other prominent risk prediction scores such as the Simplified Acute Physiology Score II (SAPS II) and the Sequential Organ Failure Assessment (SOFA) score do not currently account for low creatinine levels. We have long recognized high creatinine levels as indicators of poor prognosis, and now, accumulating evidence suggests that low creatinine levels may be equally concerning, regardless of the precise underlying cause. This underscores the importance of considering the full spectrum of creatinine values, not just elevated levels, in assessing patient risk and guiding clinical decision-making.
References
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