Analysis of Crush Syndrome Patients With and Without Acute Kidney Injury during the 2023 Kahramanmaraş Earthquake: Experience of a Tertiary Referral Center from Türkiye

Background: Early recognition and practical approaches for prevention and rapid treatment of acute kidney injury (AKI) is crucial for decreasing morbidity and mortality in earthquake victims. This study aims to determine various features of hospitalized crush syndrome patients with or without AKI after the Kahramanmaraş (Türkiye) earthquake in February 2023 and provides the knowledge of a tertiary referral center. Methods: Crush syndrome was described as the existence of crush injury and systemic manifestations. Patients without preexisting chronic kidney disease were diagnosed to have AKI in the presence of azotemia and/or increased creatinine levels ( > 2 mg/dl) with or without oliguria and hyperkalemia. Patients with crush syndrome were separated into 2 groups: group 1, AKI (+); group 2, AKI ( − ). Results: A total of 2300 earthquake wictims were admitted and compared with regards to the outcomes. After excluding 2147 patients, the final evaluation was performed in 153 patients (group 1, n = 56; and group 2, n = 97). Sepsis, hypovolemic shock, need for intensive care unit (ICU), and mortality rates were higher in AKI (+) patients than AKI ( − ). Thirty-four patients (22.2%) were admitted to the ICU, and 6 were non-survivors. One hundred forty-seven patients were discharged. Amputation, C-reactive protein (CRP), and each 50000 IU/L increase in creatine phosphokinase (CK) levels were risk factors for the development of AKI ( P < .05). Conclusion: Acute kidney injury in crush syndrome contributes to morbidity and mortality. Clinicians should be careful about AKI development in patients with amputation, high CRP, and CK levels > 50000.


INTRODUCTION
On February 6, 2023, 2 major earthquakes occurred in Türkiye, with the epicenters in Pazarcık [moment magnitude (M w ) 7.7; focal depth: 8.6 km] and Elbistan (M w 7.6; focal depth: 7 km) districts of Kahramanmaraş, at 4:17 am and 1:24 pm local time, respectively (Figure 1).These earthquakes, both of which are unprecedented in recent history in terms of magnitude and covered area, caused great destruction in a total of 11 provinces.Fourteen million people, namely, approximately 16% of the population of Türkiye, were affected.As of June 2023, there are 50 783 non-survivors and 115 353 injured. 1 The earthquake victims were transferred to the closest hospitals in Adana and Mersin provinces due to the damaged or destroyed hospitals in the earthquake zone.
Mersin University Faculty of Medicine was among the hospitals that accepted and treated most of the earthquake victims.
Crush syndrome is the second leading cause of mortality, following the direct traumatic effects caused by the earthquake. 2 Permanent disabilities and loss of organ function may also occur in many patients with crush syndrome.Clinical and laboratory findings at admission in these patients are associated with mortality and morbidity. 3,4Acute kidney injury (AKI) due to crush syndrome has been reported to be related to increased morbidity and mortality compared to victims with crush syndrome without AKI. 5So, early recognition and practical approaches for prevention and rapid treatment of AKI are crucial.
This study aims to determine the features of hospitalized crush syndrome patients with or without AKI after the Kahramanmaraş (Türkiye) earthquake in February 2023 and provides knowledge of a tertiary referral center.

Study Design and Subjects
This study was authorized by the Mersin University Ethics Committee with an ethics committee approval number of 29-03-2023/199.This was a retrospective, single center, observational study.Data were collected in Mersin University nephrology clinic in Türkiye between March 6 and 12, 2023.The data were received from the hospital's electronic software system.

MAIN POINTS
• AKI in crush syndrome contributes to morbidity and mortality.
• Early recognition and rapid treatment of crush syndrome and practical approaches to prevent the occurrence of acute kidney injury are crucial for decreasing the rate of morbidity and mortality in earthquake victims.• Amputation, C-reactive protein, and each 50000 IU/L increase in CK levels were risk factors for the development of AKI.

Inclusion and Exclusion Criteria
The study included earthquake victims diagnosed with crush syndrome.Among these patients, those who were younger than 18 years of age, discharged from the hospital at the time of data collection, or lacked hospital discharge and were still hospitalized during data collection, referred from other hospitals, or referred to other centers were excluded from the study.
Earthquake victims with crush syndrome were divided into groups as AKI (+) and AKI (−) according to the findings at the time of admission.

Crush Injury
Crush injury is damage to the muscle cell as a result of a direct and local injury to the muscles.If patients had a creatine phosphokinase (CK) level higher than at least 5 times the normal level, this was accepted as crush injury (CK >725 U/L). 6

Crush Syndrome
Crush syndrome was described as the systemic manifestation of crush injury, including AKI and/or acute respiratory distress syndrome (ARDS), dyselectrolytemia, disseminated intravascular coagulation (DIC), hypovolemic shock, arrhythmias, and surgical interventions. 7

Compartment Syndrome
A localized quick increase of tension within a muscle compartment is defined as compartment syndrome. 7,8

Acute Kidney Injury
Patients with crush injuries and without known preexisting chronic kidney disease who presented with azotemia (urea >85 mg/dL) and/or increased creatinine levels (>2 mg/dL) with or without oliguria and hyperkalemia were considered to be AKI cases as a result of crush injury. 9

Biochemical, Clinical, and Demographic Data at the Time of Admission
Baseline data at the time of admission included comorbidities, initial laboratory assessments such as serum CK (<145 U/L), myoglobin (25-72 ng/mL), and creatinine.Patients' requirement for intensive care unit (ICU), injury types [compartment syndrome, extremity fracture, limb trauma, cranial trauma, thoracic trauma (hemothorax, pneumothorax), abdominal trauma], surgical interventions (fasciotomy, splint, external fixation of fractures, amputation of extremities), empirical antibiotic therapy given at admission, length of hospital stay, sepsis, microorganisms obtained from blood, wound or urine cultures, number of patients coming from the city of the earthquake, time under the rubble, time from earthquake zone to hospital arrival (hours), and follow-up parameters were also noted.
Crush syndrome-related abnormalities in all included patients during hospitalization were observed.
Hemodialysis (HD) indications were accepted as blood urea nitrogen ≥100 mg/dL or serum creatinine level exceeding 8 mg/dL, serum potassium ≥7 mEq/L, arterial bicarbonate level <10 mEq/L and pH <7.1, hypervolemia, pulmonary edema, and/or any severe uremic symptoms (uremic pericarditis, confusion due to uremia, persistent nausea and vomiting, etc.).Prophylactic dialysis was applied in hypercatabolic cases if this was deemed necessary, e.g., when potassium increased very rapidly, even without hyperkalemia. 10,11Hemodialysis treatment was scheduled as per the clinical and laboratory parameters necessitated.

Intensive Care Unit Admission Criteria for Patients
Patients with respiratory failure and requiring or likely to require respiratory support, multiorgan dysfunction syndrome, patients at major risk of morbidity and mortality following surgery, patients with cardiopulmonary arrest, life-threatening arrhythmia, DIC, hypovolemic shock, severe head trauma, and the requirement for hemodialysis in an unstable patient were followed in the ICU. 12 Follow-up Patients were followed from the date of hospitalization to the time of reaching any of the outcomes, namely, discharge from the hospital or death.
Patients with and without AKI were compared regarding demographic, clinical, and laboratory data.These comparisons were also applied to subgroups of AKI (+) patients who did or did not require HD.
Patients were assessed for the predicting factors of AKI development and HD requirement.

Statistical Analysis
The frequency counts and percentages were used in categorical variables, while quantitative variables were summarized using means and standard deviations, or Results were noted as statistically significant when P-values were equal to or less than .05.

RESULTS
A total of 2300 earthquake victims were admitted.After excluding 2147 patients who had at least one of the exclusion criteria, the final evaluation was performed in 153 patients (AKI (+) group 1, n = 56 and group 2, n = 97) as shown in Figure 2.
The median time period for transfer from the earthquake zone to our hospital was 72.0 (50.3-86.0)hours.

Baseline Clinical Features and Laboratory Values of the Groups at Admission
Table 1 shows the groups' baseline clinical features, laboratory values, and follow-up parameters.Surgical interventions such as amputation, splint, and fixator rates were higher in AKI (+) patients than in AKI (−) patients (P < .05).

Follow-up Parameters
All patients received isotonic saline and glucose 5% + 100 mEq bicarbonate as fluids.An average of 300 mL/h of fluid was given to both groups on the first day of hospitalization.On the following days, 3-6 L of fluid was administered per day, depending on the urine output.
Thirty-four (22.2%) of all crush syndrome patients were admitted to the ICU.Of a total of 6 non-survivors (3.9%), all of them had AKI (+) crush syndrome, and all required HD.One hundred forty seven patients were discharged.In both groups, serum creatinine levels and electrolytes returned to the normal biochemical range at discharge.
Crush syndrome-related abnormalities in all included patients during hospitalization are shown in Table 2.

Acute Kidney Injury Patients Who Required Hemodialysis and Who Did Not Require Hemodialysis
Of the 153 patients with crush syndrome, AKI was detected in 56 (36.6%), 32 of whom required dialysis support.However, 24 of them did not.The most common HD indications were hyperkalemia (71.9%), hypercatabolic states (21.9%), and hypervolemia (6.3%).
The mean number of HD sessions was 5.2 ± 4.8.
Demographic, laboratory, and follow-up parameters of HD requirement and no HD requirement in AKI patients are shown in Table 3.

Predicting Factors of Acute Kidney Injury Development and Hemodialysis Requirement
In the univariate logistic regression analysis, amputation, each 50000 IU/L increase in CK levels, blood glucose level, C-reactive protein (CRP), albumin, ICU requirement, and hemoglobin were the factors predicting for AKI development (Table 4).However, in multivariate analyses, CRP, amputation, and each 50000 IU/L increase in CK levels were risk factors for the development of AKI.
In the univariate logistic regression analysis, each 50000 IU/L increase in CK levels, hemoglobin, and age was a predicting factor for HD requirement (Table 5).But there were no predictive parameters in multivariate analyses.

The Most Important Baseline Demographic, Clinical Characteristics, and Biochemical Features of Non-survivor Earthquake Victims
The number of non-survivors was 6 (4 males and 2 females).The mean age was 50.7 ± 11.4 years.
There was no statistical difference for median time under the rubble between survivors and non-survivors (9 hours versus 6 hours, P = .77).
Five patients were hospitalized in the ICU, and 1 patient was admitted to the ward.The mean length of hospital stay was 7.8 ± 7.4 days.At the time of death, 2 patients had ARDS, 2 patients had ARDS + sepsis, 2 patients had sepsis, and 2 patients had DIC.
Cranial, thoracic, or abdominal trauma were not detected in patients who were non-survivors.Compartment syndrome was diagnosed in 3 patients.Fasciotomy was performed in 1 patient while amputation in 3 patients.
The predictive cutoff value of CK for crush injuries was found to be 6967 IU/L.The sensitivity and specificity of these CK levels were found to be 75% and 76.2%, respectively.
Kaplan-Meier plots of patient survival are presented in Figure 3.
Of note, the in-hospital mortality rate was significantly different between the AKI (+) and AKI (−) (log-rank P = .005).
Figure 4 shows that there was a negative relationship between age and time under rubble (r = −0.156,P = .042).A significant negative correlation was found between age and CK levels (r = −0.233,P < .001)(Figure 5).

DISCUSSION
This study evaluates biochemical, clinical, and demographical data in Kahramanmaraş earthqauke victims who have crush syndrome with or without AKI.According to the results of our study presenting the experience of a tertiary referral center, intravenous fluid treatment does not cause any adverse results, such as development of prerenal AKI or hypervolemia, when administered under close monitoring.The major predictors for the development of AKI were detected to be a 50000 IU/L increase in CK levels, CRP levels, and amputation.
It's known that the mortality rate is higher in AKI (+) crush syndrome patients than in AKI (−). 13In the current study, we could not compare the mortality rates in the study groups.
Mortality among the patients with crush syndrome following the Marmara earthquake was reported to be 15.2%, 9 whereas, in our study, it was 10.7% (6/56) in AKI (+) crush syndrome patients.None of the patients with AKI (−) crush syndrome died.More seriously injured victims may have been admitted  to the city hospitals that were closer to the epicenter, and/ or most of the patients may have been non-survivors under the rubble.Additionally, Marmara earthquake experiences were applied in our center.These factors may probably be the reasons for the lower mortality rate in our study.Sever et al 3 declared that the mortality percentage of the dialyzed Marmara earthquake victims was 17.2%, significantly higher than that of non-dialyzed patients with kidney problems.This mortality rate in AKI patients that required HD was similar to our study (18.8%).
Two thousand three hundred earthquake victims were admitted to our hospital within a week.Our study included a total of 153 crush syndrome (6%) patients, of whom 56 were AKI (+) patients, 32 of whom required dialysis support, and 97 patients were AKI (−).The incidence of crush syndrome following major earthquakes has not been well described, and 2-5% of the earthquake victims presented with crush syndrome. 10Also, information regarding the incidence of AKI caused by crush syndrome is scarce.Of the 2702 traumatized victims during the Kobe earthquake, 372 (13.8%) were detected to have crush syndrome, and 202 (7.5%) suffered from AKI. 14 The optimal fluid management has prime importance to prevent either hypervolemia or prerenal AKI.The Marmara earthquake experience of the investigators has helped us with early, suitable fluid therapy after admission. 14Due to the damaged or destroyed hospitals in the earthquake zone and the chaotic conditions, it was not known exactly how much fluid was given after the event until their admission to our hospital.Additionally, aggressive fluid treatment was not administered at admission because of the relatively long period of time for arrival at our hospital.Intravenous fluid (isotonic saline and glucose 5% + 100 mEq bicarbonate) was administered to the patients under close monitoring, namely, 300 mL/h on the first day of hospitalization, followed by 3-6 L/day in the following days depending on the volume status and urine output.Hypervolemia constituted 6% of HD indications at the time of hospitalization.During hospital stay, none of the AKI (−) crush syndrome patients developed prerenal AKI and hypervolemia.Although hypovolemic shock was detected in 7 patients at the time of hospitalization, none of our patients developed hypovolemic shock during their hospitalization.None of our patients, who were non-survivors, had hypovolemic shock at the time of mortality.Thus, we believe that controlled fluid treatment can prevent both the development of prerenal AKI and hypervolemia during hospitalization.
Hyperkalemia and hyperphosphatemia due to the release of potassium and phosphorus from injured muscle cells, 15 hypercatabolic situations, and hypervolemia are the major causes for the requirement of HD in patients with crush syndrome. 16In the present study, the requirement of HD among AKI patients was 57.14% (32/56) while it was 61% (123/202) in the Hanshin-Awaji (Kobe) earthquake 4 and 74.6% (477/639) in the Marmara earthquake study. 3It was reported in the study by Sever et al that the most important and fatal medical complication in crush syndrome patients is hyperkalemia.They found that in hospitalized patients within the first 3 days of the Marmara earthquake, the mean serum potassium level was 5.4±1.3mEq/L. 17n our study, we found that median serum potassium levels were higher in AKI (+) compared to AKI (−) patients (5.2 versus 4.0 mEq/L).Serum potassium levels in 2 patients were above 7 mEq/L, while it was 6-7 mEq/L in 18 patients and below 3.5 mEq/L in 14 patients.In earthquake victims, serum potassium levels may vary depending on the trauma severity.However,  the hyperkalemia risk may persist throughout hospitalization, even if patients are normokalemic at presentation.
In the Kahramanmaraş earthquake, the median time under rubble [8.5 (5.0-24.0)hours] was shorter than the Marmara (11.7 ± 14.3 hours), Kobe (9 ± 13 hours), and Erzincan (9 ± 5 hours) earthquakes. 9,13,14It was emphasized that a minimum four hours of compression of muscles is necessary for crush injury to develop. 18Sever et al reported in their article that time under the rubble is not a prognostic factor of mortality or AKI for patients with crush syndrome, probably because only earthquake victims with minimal or modest injuries can survive under the rubble for a longer time.We found that the median time under the rubble was 12 hours in AKI (+) and 9.0 hours in AKI (−) patients.We detected that the shortest period that the patients remained under the rubble was 1 hour, and the longest period was 96 hours.However, the time under the rubble is not a prognostic indicator for AKI and mortality.In the current study, there was no statistical difference in the median time under rubble between survivors and non-survivors.
Bacterial infection and sepsis are common in earthquake victims and are associated with increased mortality.We detected    sepsis in 36 (23.5%) patients.This rate was similar to that reported with Marmara earthquake victims (18.9%). 19The Marmara earthquake study found that sepsis was associated with increased mortality. 19However, sepsis was present in 3 out of 6 of our earthquake victims who were non-survivors.Sepsis rate and CRP levels were quite higher in our AKI (+) crush syndrome patients than in AKI (−) patients.This study found that CRP levels are a major risk factor for AKI.
In the present series, low serum albumin reflects a poor prognosis for kidney function.Serum albumin levels were lower in AKI (+) crush syndrome patients than in AKI (−) patients.Furthermore, hypoalbuminemia was a risk factor for AKI development (Table 4).The most common reason for reduced plasma albumin levels is an acute-phase response.Hemodilution, loss of extravascular area, increased consumption by injured muscle cells, malnutrition, capillary leakage, and decreased synthesis are among the other causes of hypoalbuminemia. 20 the Marmara earthquake, the mean age of victims with AKI was 33 ± 14 and 31 ± 15 years for male and females, respectively. 21Like the victims of the Marmara earthquake, both our AKI (−) and AKI (+) patients were young (40.0 vs. 39.0 years).The median age of AKI patients that required HD was significantly lower than that of AKI patients that did not require HD.The univariate analysis showed that the HD requirement increased with decreased age (OR, 95% CI, 0.932-0.993,P = .016).In our study, we found the sensitivity and specificity of CK levels (6967 IU/L) for crush injury were 75% and 76.2%, respectively.A negative correlation was found between age and time spent under rubble.Most of our patients with both AKI (+) and AKI (−) crush syndrome did not have comorbidities (73.2% vs. 64.9%),and the patients were relatively young.It may be commented that    many elderly patients may have been non-survivors under the rubble, while younger patients remained longer under the rubble and were more affected by the intensity of the earthquake.These results may explain why young age is a risk factor for HD requirements.
In earthquakes, most hospital admissions happen within the first 3 days after the event. 22Compatible with this conjecture, only 2.4% of the 902 patients were admitted 7 days or more after the Armenian earthquake. 23In the Marmara earthquake study, a similar result was observed: earthquake patients were admitted the 3-7 days after the earthquake. 24In our series, a similar trend was observed.The median time from the earthquake zone to hospital arrival of all included study patients was found to be 72.0 (50.3-86.0)hours.Patients with AKI came to the hospital from the earthquake zone in a shorter time than AKI (−) patients (62.36 ± 27.1 vs. 75.68± 34.1 hours; P < .05).Due to the violence of the trauma, AKI (+) patients may have been brought to the hospital in a shorter time than AKI (−) patients by their relatives or 112 emergency services.
Amputation has some additional risks for AKI, such as hypotension and bleeding during surgery.Amputation was performed on 20 patients (20/153, 13%) in our hospital, and it was more frequent in patients with AKI.We found that amputation was a risk factor for AKI.
Low values of hemoglobin may indicate either blood loss or hemodilution in patients who received large amounts of fluid.In contrast, a high hemoglobin value in crush syndrome victims showed severe dehydration. 25In our AKI (+) patients, hemoglobin values were higher than in AKI (−) patients at the time of hospitalization.The hemoglobin value was a risk factor for AKI development in our study.
Median CK levels were quite high in both AKI (+) and AKI (−) patients, probably related to the severity of the trauma.In most of our patients, blood glucose level was found to be above the normal value.In these patients, that may be related to the stress due to trauma.CK > 50000 IU/L levels, ICU requirement, and blood glucose level were independent risk factors for AKI.

Limitations
First, our study was conducted at a single center.Second, we were unable to perform a mortality analysis due to our mortality rate.
Acute kidney injury in crush syndrome contributes to morbidity and mortality.Clinicians should be careful about the development of AKI in patients with amputation, high CRP, and CK level > 50000 IU/L.Patients should be closely followed for controlled fluid administration at the time of hospitalization.This approach can prevent both the development of prerenal AKI and hypervolemia.

Figure 2 .
Figure 2. Flowchart illustrating the selection of the study population.

Figure 4 .
Figure 4. Correlation between age and time under rubble.

Figure 5 .
Figure 5. Correlation between age and CK levels.

Table 1 .
Demographic, Laboratory, and Follow-up Parameters of Patients

Table 2 .
Crush Syndrome-Related Abnormalities in all Included Patients During Hospitalization

Table 3 .
Demographic, Laboratory, and Follow-up Parameters of Hemodialysis Requirement and No Hemodialysis Requirement in Acute Kidney Injury patients

Table 4 .
Logistic Regression Analysis for Parameters Predicting Acute Kidney Injury Development , creatine phosphokinase; CRP, C-reactive protein; BGL, blood glucose level; ICU, intensive care unit; SBP, systolic blood pressure. CK

Table 3 .
Demographic, Laboratory, and Follow-up Parameters of Hemodialysis Requirement and No Hemodialysis Requirement in Acute Kidney Injury patients (Continued)

Table 5 .
Logistic Regression Analysis for Parameters Predicting Hemodialysis Requirement CK, creatine phosphokinase; ICU, intensive care unit.