Acute Kidney Injury in Hospitalized Patients With Exertional Rhabdomyolysis

Key Points Question What is the risk of acute kidney injury (AKI) in hospitalized patients with exertional rhabdomyolysis (ERM), and which factors are associated with its development? Findings In this cohort study of 200 hospitalized patients with ERM in Northern California, the AKI incidence was 8.5%. No association was observed between serum creatine kinase levels and AKI development; however, preadmission use of nonsteroidal anti-inflammatory drugs or dehydration was associated with a significantly increased risk of developing AKI. Meaning These findings suggest that an elevated creatine kinase level is not a reliable indicator of AKI in hospitalized patients with ERM, but preadmission use of nonsteroidal anti-inflammatory drugs or dehydration appear to be associated with AKI.


Introduction
Rhabdomyolysis, a condition characterized by muscle tissue breakdown, can result in severe complications, such as acute kidney injury (AKI) and chronic kidney disease (CKD), and can be fatal, with mortality rates up to 59%. 1,2Studies have shown that exertional rhabdomyolysis (ERM), caused by strenuous physical exertion, had a 10-fold increase in incidence in the US from 2000 to 2019 3 for unknown reasons, with incidence rates varying from 1 to 31.8 per 100 000 population across different populations. 4,5ncurrently, research on the outcomes of ERM, both AKI and CKD, and associated risk factors remains scarce.Elevated serum creatine kinase (CK) levels within the range of 5000 to 40 000 U/L (to convert to microkatals per liter, multiply by 0.0167) are reportedly associated with an increased risk of AKI. 2,6,7However, certain studies have reported no significant association between CK and creatinine levels in ERM. 8,9A previous study found that the risk of AKI in rhabdomyolysis can exceed 50% and varies by etiology. 2However, earlier investigations by Clarkson et al 9 have suggested a significantly lower risk of AKI in ERM.The risk factors that lead to AKI in association with ERM are largely unknown.In this study, we aim to bridge these gaps by examining both the short-term and long-term outcomes of ERM and identifying predisposing factors to AKI within a broad, diverse cohort in Northern California, with a focus on hospitalized patients who are at higher risk of severe complications.

Study Design
We used a retrospective cohort design for comparative analyses to identify factors that differentiate patients with AKI from those without AKI in a cohort of adult patients aged 18 years from multiethnic backgrounds 10 who, after presentation at an emergency department (ED), were subsequently admitted with ERM from January 1, 2009, to December 31, 2019, to 21 Kaiser Foundation Hospitals within Kaiser Permanente Northern California, a private, not-for-profit, integrated health system with 4.5 million members.Additional inclusion criteria included having engaged in strenuous physical activity, defined based on patient-reported information as any substantial physical activity occurring within 48 hours before hospitalization, which was verified with meticulous manual medical record review.The study was approved by the Kaiser Permanente Northern California Institutional Review Board with a waiver of the requirement for informed consent because risk was minimal.We adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Cases were identified using a combination of International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes to query electronic medical records.In our system, acute outpatient conditions are referred to the ED before hospital admission.We used regular expressions in SAS software, version 9.4 (SAS Institute Inc) and a natural language processing tool to identify clinical notes with key exercise-related phrases.Search terms combined exercise severity (eg, intense and extreme) and types (eg, running and weightlifting).We used ICD-9 and ICD-10 codes instead of CK levels to define ERM due to the lack of a universally accepted CK threshold, higher CK levels associated with AKI, and variability in CK levels by ethnicity.All cases identified for inclusion received manual medical record review and were verified for eligibility, history of dark urine, dehydration, and nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen exposure before hospitalization.Dark urine was defined based on the documentation of discolored urine, such as dark, brown, cola-colored, or red.Dehydration was defined based on the documentation of any findings, such as dehydration, nausea, vomiting, diarrhea, presyncope, and orthostatic hypotension, in the medical records, extracted through a manual review of all cases.Manual medical record reviews showed high interrater reliability (κ = 0.95; 95% CI, 0.84-1.00),indicating strong consensus among evaluators.We analyzed NSAID and illicit drug exposure within 48 hours before hospital Patients were also excluded if elevated CK levels could be attributed to trauma (defined as any recent physical injury to the body), significant hyperthermia (characterized by recorded body temperatures >38 °C), electrolyte imbalances, infections, or exposure to illicit drugs that could be myotoxic or nephrotoxic.

Statistical Analysis
Bivariate comparisons involving categorical variables were performed using χ 2 or Fisher exact tests.
Normally distributed continuous variables were compared using disease.Of the patients with stage 3 AKI, 4 did not require dialysis, whereas 5 did.Two of 200 patients (1.0%) were classified as not having a return to baseline creatinine levels (Table 2).
There were no significant differences between patients with ERM who developed AKI and those who did not regarding demographic or clinical variables, including patient's age, gender, race and ethnicity, baseline body mass index, presence of baseline diabetes, hypertension, smoking, year of disease onset, and season or month of disease occurrence (Table 1).We compared serum CK levels between patients with ERM who developed AKI during hospitalization and those who did not.No significant differences were observed in initial or peak CK levels (Table 1 and Figure 2).Given the reported increased AKI risk with NSAIDs, 12 we investigated the association between preadmission NSAID and acetaminophen use and AKI development in our cohort.We found a statistically significant association between a history of NSAID ).Further analysis revealed that dark urine was associated with significantly higher CK levels across the entire cohort and within both genders (eFigure, eTable 2, and eTable 3 in Supplement 1).We had limited data available for myoglobinuria analysis (15 of 200); however, within the first 24 hours of hospitalization, there was no significant association between dark urine discoloration and urine myoglobin levels, regardless of AKI development or differences in gender.
We did not find significant differences in the types of exercise leading to ERM between 183 patients with ERM who did not develop AKI vs the 17 patients who developed AKI (Table 1).
Additionally, we did not observe any significant difference in the length of hospital stay or the rate of daily intravenous fluid use during the index hospitalization between patients with ERM who developed AKI and those who did not, both in the initial 24 hours and in the mean daily intravenous fluid intake throughout the entire hospitalization period.All of the 17 patients with ERM who had AKI in this cohort presented with AKI from the initial laboratory results.There was no statistically significant difference in the intravenous fluid administered within the first 24 hours or during the entire hospitalization between patients with ERM who developed AKI and those who did not.
Patients with ERM who developed AKI were significantly more likely to receive mannitol (AKI: 2 U/L initially (with NSAID exposure) and 40 000 U/L on the second occurrence (without NSAIDs) (Table 2).No patient presented with anemia or thrombocytopenia or had evidence of disseminated intravascular coagulation.We identified only 1 patient with the sickle cell trait, who did not develop AKI.There was no significant difference in the incidence of AKI between patients with ERM admitted in the summer months compared with patients with ERM admitted in other months (Table 1).During our 10-year cohort study, 8 of the 200 patients (4%) were rehospitalized due to ERM but did not develop AKI during either the initial hospitalization or the subsequent episode.There was no difference in the initial or peak CK levels between the patients with ERM who were rehospitalized and those who were not.None of these patients reported a family history of rhabdomyolysis or hereditary myopathy.Genetic testing, encompassing whole exome sequencing and next-generation sequencing, was conducted on 5 of 200 patients with ERM (2.5%), including 3 rehospitalized individuals, to screen for hereditary myopathies; however, no pathogenic mutations were identified.

Discussion
In this study, we observed an annual ERM incidence of 0.63 per 100 000 individuals, with 8.5% developing AKI.We suggest the actual ERM incidence may be higher due to our focus on hospitalized patients, as subclinical cases go undetected.Conversely, the AKI incidence may be lower than 8.5% because individuals with highly elevated CK levels from strenuous exercise may not develop clinical ERM symptoms. 4,9,13Our study suggests that the risk of AKI in ERM is significantly lower compared with other common causes of rhabdomyolysis, such as trauma or sepsis. 2 These conditions may involve intravascular volume depletion and a plethora of cytokines, which could contribute to kidney injury in the setting of medullary hypoperfusion and elevated serum CK levels.Our findings suggest that elevated serum CK levels alone may not be a sufficient risk factor for AKI in patients with ERM.For example, cases with CK levels of 360 000 U/L did not result in AKI, whereas levels at 4180 U/L did (Table 2).This finding indicates that AKI development in ERM is influenced by a combination of elevated CK levels and additional risk factors, such as NSAID exposure.Dark urine was associated with male sex in our cohort; however, it was not associated with increased risk of AKI in the entire cohort or for either sex (eTables 1 and 2 in Supplement 1).However, it was associated with significantly higher CK levels across the entire cohort and within each sex (eFigure in Supplement 1).The observed phenomenon can be attributed to potential differences between genders in reporting bias, clearance rates, and symptom onset thresholds, which may be different across genders.Myoglobin, filtered by the kidneys, appears in the urine when plasma concentrations exceed 1.5 mg/dL. 14Given the lack of association between dark urine, which could be considered indicative of myoglobinuria, and AKI, this observation may suggest that, similar to serum CK, myoglobinuria alone may not suffice to cause AKI in patients with ERM.
Our study suggests that eliminating key risk factors, such as NSAID use and dehydration, may potentially reduce the incidence of AKI in patients with ERM.Animal studies offer a parallel perspective that elevated CK levels alone may be insufficient to cause AKI in ERM, emphasizing the crucial role of NSAIDs and dehydration. 15,16The association of prior dehydration with the development of AKI from rhabdomyolysis was also supported in these models. 15Interestingly, a previous study examined the effects of acetaminophen and ibuprofen on kidney function during exercise and dehydration.Ibuprofen was found to have a small but significant association with GFR in a sodium-depleted state, whereas acetaminophen had no such effect. 12These findings suggest the synergistic effects of NSAIDs and dehydration during strenuous exercise on kidney function and underscore the importance of choosing acetaminophen over NSAIDs for patients experiencing muscle pain.
The reduced GFR observed with NSAID use is primarily due to the inhibition of kidney prostaglandins, which regulate kidney hemodynamics.NSAIDs inhibit cyclooxygenase, reducing prostaglandin synthesis by 50% to 60%, affecting arteriole diameters and kidney filtration.CK levels in the rhabdomyolysis range after strenuous exercise, 9 underscoring the significant clinical relevance of our findings.
Finally, our study revealed that none of the patients with ERM who were without AKI at admission developed AKI subsequently; in other words, all patients with ERM diagnosed with AKI on admission exhibited laboratory findings consistent with this diagnosis in their initial evaluation.
Similar findings were reported elsewhere by Delaney and Vohra 18 that a normal first creatinine level was a strong indicator of a normal second creatinine level.The current literature lacks sufficient studies to inform clinicians about treating patients hospitalized for ERM, with minimal consensus on the appropriate timing for discharge. 19The median hospital stay for patients without AKI was 3 days, with all treated with fluids.Our findings suggest that hospitalization solely for hydration therapy and serum CK monitoring in most ERM cases may be unnecessary, potentially reducing hospitalizations.
Our study concurs with prior research suggesting a lack of a clear discharge CK level threshold for hospitalized patients with ERM and challenges the common practice of extended hospital stays solely for serum CK monitoring until reaching certain low-risk levels. 14,19Future studies should emphasize identifying patients at lower risk of developing AKI.
To our knowledge, our study represents the most extensive research to date on patients with ERM, and it has widespread implications across various disciplines.The findings have broad implications, from recreational activities to professional, institutional, and health care settings.These implications encompass physical health-oriented training activities, such as aerobic exercises and indoor cycling sessions.Moreover, these findings are relevant to multiple sectors and disciplines, including fire and police academies as well as military training.Importantly, this study's implications are broad within the medical field and applicable to multiple specialties.Lastly, the results of this study are crucial for public health educators, broadening our comprehension of the considerable effects that over-the-counter medications may exert on public health.

Strengths and Limitations
A major strength of our study is the focus on a community-based population with a diverse demographic and wide range of ethnic backgrounds, 10 in contrast to the predominantly homogenous cohorts featured in the existing literature.Distinguished by its longitudinal design, this study is a pioneer in exploring long-term ERM outcomes, offering insights into the progression of AKI to CKD and its implications.
Our retrospective study faced common challenges, including missing data on NSAID dosage 20 and urine myoglobin.A notable limitation is potential ascertainment bias, as patients with higher creatinine levels were more likely to be questioned about NSAID exposure and dehydration.Another limitation of our study is defining dehydration through patient-reported symptoms and health care professional examinations, and the lack of a thorough assessment of objective values, such as serum or urine osmolality, due to missing data.We also acknowledge the potential influence of nephrotoxic cofactors, environmental variables, and genetic factors such as sickle cell on AKI development in patients with ERM. 21We also acknowledge that because we did not include patients with ERM discharged from the ED in the study, the incidence of AKI-induced ERM may be overestimated.
Several questions remain unanswered, including the identification of additional risk factors for AKI in patients with ERM, such as environmental factors, patient behaviors, and genetic predispositions.
This study suggests that rhabdomyolysis, as a heterogeneous disease, likely has vastly different outcomes and prognoses, depending on its underlying cause, the target population, and environmental factors.Future research should aim to clarify outcomes related to ERM and focus on the etiologic factors specific to rhabdomyolysis rather than consolidating diverse groups into a single category. SUPPLEMENT Acute Kidney Injury in Hospitalized Patients With Exertional Rhabdomyolysis Acute kidney injury was defined according to KDIGO (Kidney Disease Improving Global Outcomes) guidelines, and CKD was identified by a glomerular filtration rate (GFR) below 60 mL/min/1.73m 2 .Patients with a history of AKI or end-stage kidney disease were excluded.
2-sample t tests.Comparisons of nonnormally distributed continuous variables were conducted using Wilcoxon rank sum tests.The small number of AKI cases made a multivariable analysis not feasible.Data analysis was performed

Table 2 )
11highlighting that CK levels alone may not determine AKI risk.We next examined the association between a history of preadmission dehydration and the risk of AKI development in the cohort.Our findings revealed a significant association between a history of preadmission dehydration and the risk of AKI development (9 of 17 [52.9%]vs9 of 183 [4.9%], P < .001)(Table1).The findings suggested that if NSAIDs are eliminated, the risk of AKI in patients with ERM could be significantly reduced, with a preventable fraction11of 81.3% (95% CI, 52.1%-92.7%).Furthermore, the elimination of dehydration could reduce the risk by 91.2% (95% CI, 80.0%-96.1%),and addressing both NSAIDs and dehydration could lead to a 92.6% (95% CI, 85.7%-96.1%)preventable fraction.Male patients exhibited a significantly higher prevalence of dark urine than female patients (87 of 145 [60.0%] vs 21 of 55 [38.2%];P = .007)(eTable 1 in Supplement 1 (Table1).We did not find a statistically significant association between the preadmission use of JAMA Network Open | Nephrology Acute Kidney Injury in Hospitalized Patients With Exertional Rhabdomyolysis JAMA Network Open.2024;7(8):e2427464.doi:10.1001/jamanetworkopen.2024.27464(Reprinted) August 13, 2024 3/12 Downloaded from jamanetwork.comby guest on 09/01/2024 acetaminophen and the development of AKI.One patient with AKI had a maximum CK level of 4180.0U/L, which is considered low.However, this patient was exposed to NSAIDs before hospitalization (

Table 1 .
Baseline Characteristics, Laboratory Values, Treatments, and Risks Associated With AKI in Hospitalized Patients With ERM 11.8%] vs no AKI: 1 [0.5%];P = .02)and bicarbonate (AKI: 12 [70.6%]vs no AKI: 77 [42.1%];P = .04),but not furosemide, compared with those who did not develop AKI.One patient (0.5%) with ERM Figure 1.Flow Diagram of Patients With Exertional Rhabdomyolysis (ERM) Eligible for Inclusion in This Study a Patients discharged from the emergency department were a heterogeneous group of individuals with rhabdomyolysis due to various causes, including ERM.They were treated according to usual protocols and deemed to have mild disease and be appropriate for discharge by the ED physician.JAMA Network Open.2024;7(8):e2427464.doi:10.1001/jamanetworkopen.2024.27464(Reprinted) August 13, 2024 5/13 Downloaded from jamanetwork.comby guest on 09/01/2024

Table 1 .
Baseline Characteristics, Laboratory Values, Treatments, and Risks Associated With AKI in Hospitalized Patients With ERM (continued) JAMA Network Open.2024;7(8):e2427464.doi:10.1001/jamanetworkopen.2024.27464(Reprinted) August 13, 2024 6/13 Downloaded from jamanetwork.comby guest on 09/01/2024 developed compartment syndrome and required fasciotomy; however, his kidney function remained normal.There were no fatalities associated with the ERM cases in our cohort.Among the 17 patients who developed AKI, 5 (29.4%) required hemodialysis.Characteristics of the 17 patients with AKI are summarized in Table 2. None of the 17 patients with AKI had prior ERM evaluations.One patient developed ERM without AKI after resuming exercise in 3 months, with a maximum CK level of 143 481

Table 1 .
Baseline Characteristics, Laboratory Values, Treatments, and Risks Associated With AKI in Hospitalized Patients With ERM (continued) a Two-sample t test.b Fisher exact test.c Includes American Indian or Alaska Native, declined to state, unknown, and any other race.d χ 2 test.e Two-sample Wilcoxon rank sum test.
2,17In 2 of 17 (11.8%) of our patients with ERM and AKI, no history of NSAID ingestion or dehydration was identified.This finding may be due to unreported NSAIDs, other nephrotoxic agents, dehydration, or unknown risk factors.Our findings suggest that straightforward interventions, such as avoiding NSAIDs and prioritizing hydration, may potentially lower AKI risk in those with intense exerciseinduced muscle pain.A previous study suggests that more than 50% of healthy volunteers exhibited a Not significant.JAMA Network Open | NephrologyJAMA Network Open.2024;7(8):e2427464.doi:10.1001/jamanetworkopen.2024.27464(Reprinted) August 13, 2024 9/12 Downloaded from jamanetwork.comby guest on 09/01/2024 1. eTable 1. Distribution of Dark Urine Based on Gender Among Patients Presenting With Exertional Rhabdomyolysis eFigure.Serum CK Levels Based on Gender and Dark Urine eTable 2. Association of Dark Urine With Serum CK Levels in Each Gender and the Total Cohort of Patients With Exertional Rhabdomyolysis eTable 3. Serum CK Levels Association With Dark Urine