Creatinine, Lactate Dehydrogenase, and C-Reactive Protein As Indicators of Acute Vaso-Occlusive Crisis and Sickle Cell Disease Severity in the Emergency Department
Authors: James Elena M , Sturgis LaShon C , Kutlar Abdullah , Gibson Robert , Lyon Matthew L 
Published: October 2019

Abstract
Sickle cell disease (SCD) patients often seek care in the Emergency Department (ED) due to vaso-occlusive crisis (VOC), the most common complication of SCD. Currently, no diagnostic test can determine if a SCD patient is having an acute VOC. This study analyzed the utility of creatinine (Cr), C-reactive protein (CRP), and lactate dehydrogenase (LDH) as indicators of acute VOC and increased disease severity. We hypothesized that increased levels of these markers correlated with acute VOC and increased SCD severity because they are suggestive of renal injury, accelerated hemolysis, and inflammation with VOC onset.
Data was collected from a cohort of 171 patients followed at an adult sickle cell clinic from 2005 to 2012. Eligibility criteria included a minimum age of 18 with SCD genotypes Hb S/S, Hb S/C, Hb S/B+, or Hb S/B0. Marker values were collected prospectively, with baseline values obtained during non-crisis visits to the sickle cell clinic, and crisis values obtained during treatment for VOC in the ED. Patients were categorized as high or low ED users to approximate disease severity using two methods. Aggregate (AG) analysis assigned patients to the high user group, 65 patients (38%), if they had >3 VOC ED visits in any year. The low user group, 106 patients (62%), had 3 or less VOC ED visits in any year. Since disease severity fluctuates in individual patients over time, a second analysis divided the groups using an individual (IN) analysis where high user-years were defined as >3 VOC ED visits/year. IN analysis resulted in 226 (47%) high user-years and 259 (53%) low user-years. Statistical analysis using R Version 3.1.0 compared overall average baseline and crisis values to determine if biomarker levels increased in acute VOC. High and low user values were compared with respect to baseline and crisis averages to determine if biomarker levels correlated with SCD severity. Analysis of baseline and crisis values over the study period evaluated changes with age. Statistical significance was set to p<0.05.
Table 1 summarizes the significant results of the statistical analysis. Changes in Cr and LDH between high and low users with respect to baseline, crisis, and difference between baseline and crisis were not statistically significant in both analyses. However, crisis CRP values between high and low user-years differed significantly. In both analyses, overall baseline and crisis Cr and LDH differed significantly. Crisis Cr and baseline LDH increased significantly over the 7-year time span.
Table 1 Marker Variable Mean SD P-value Cr (mg/dL) AG overall baseline 0.80 0.687 0.0053 AG overall crisis 1.08 1.55 IN overall baseline 0.817 0.931 0.0178 IN overall crisis 1.00 1.48 Overall crisis start 1.02 1.59 0.0087 Overall crisis end 1.10 1.76 LDH (U/L) AG overall baseline 387 196 7.90E-5 AG overall crisis 463 227 IN overall baseline 395 228 0.0194 IN overall crisis 445 269 Overall baseline start 373 181 0.0015 Overall baseline end 417 234 CRP (mg/dL) IN high user crisis 2.61 4.31 0.0247 IN low user crisis 1.05 1.02
Creatinine, a urinary muscle metabolite, is a marker of kidney function. Dehydration, a potential cause of VOC, may explain the rise in Cr during crisis. LDH increase in crisis reflects increased intravascular hemolysis during VOC. The results support the utility of Cr and LDH as indicators of acute VOC in the ED. However, both AG and IN analyses reveal no distinction between high and low users of the ED. LDH and Cr increase with age, suggesting potential for monitoring SCD disease progression. Increased Cr crisis levels with age may reflect kidney dysfunction due to medullary ischemia from multiple VOCs. Increased non-crisis LDH levels with age suggest increased disease severity, progressive organ damage, and steady state pro-inflammatory conditions.
CRP, an acute phase reactant indicative of systemic inflammation, was higher during crisis in high user-years than in low user-years. The correlation of increased crisis CRP to increased ED usage may represent a higher inflammatory state in these patients. Further studies are needed to determine the cause and effect relationship of this correlation.
The data supports the utility of Cr and LDH as markers for acute VOC. LDH and Cr also demonstrate potential as indicators of SCD disease severity in a long-term context, while CRP demonstrates potential to monitor for short-term inflammatory states leading to increased severity in frequency and possibly intensity of VOC.

Disclosures
No relevant conflicts of interest to declare.