Sclerostin is a small 24-kDa glycoprotein expressed and secreted by osteocytes to inhibit the Wingless-type mouse mammary tumor virus integration site (Wnt) pathway. By antagonizing Wnt, sclerostin inhibits osteogenesis.1 The earliest report of sclerostin in CKD patients was in dialysis patients. Elevated level in these patients was negatively correlating with osteoblast number.2 Sclerostin was negatively correlating with glomerular filtration rate among pre-dialysis CKD patients.3 Pelletier et al. 2013 demonstrated elevated level of sclerostin in stage 3 CKD.4 Low serum sclerostin was associated with better patient survival and lower prevalence of cardiovascular events in CKD patients maintained on peritoneal dialysis, but no similar relationships in hemodialysis patients. Serum sclerostin level did not correlate with coronary artery calcification.5 However, previous studies reported conflicting results. Some disclosed significant positive correlation between serum sclerostin and calcification of coronary artery and abdominal aorta in CKD patients.6,7 On the other hand, another study disclosed that high serum sclerostin is associated with lower aortic calcification scores.8 Serum sclerostin was associated with decreased flow mediated vasodilation, fatal and nonfatal cardiovascular events in pre-dialysis CKD patients.9 Nevertheless, it failed to show significant correlation with brachial artery flow mediated vasodilatation in rheumatoid arthritis patients.10 In CKD patients treated with kidney transplantation, sclerostin was associated with increased overall mortality.11

No studies have looked for impact of increased serum sclerostin on insulin resistance in CKD patients. In women with polycystic ovary, serum sclerostin was associated with increased insulin resistance.12

In spite of the plethora of data about sclerostin in CKD Patients before dialysis, during dialysis and after kidney transplantation, the literature lacks any studies in AKI patients.

The aim of this work is the study of serum sclerostin level in AKI patients and its association with endothelial function, insulin resistance and mortality among these patients.

This is a cross sectional case control observational study that took place in the intensive care units of Cairo University and Theodor Bilharz research Institute Located in Guiza governerate, Egypt between June 2016 and July 2020. During this period, there were 418 cases suffering AKI as a consequence of severe sepsis, 219 of them were included in this study after obtaining a written consent from each patient or his next of kin (group I). Diagnosis of AKI was according to the Acute Dialysis Quality Initiative first proposed the Risk, Injury, Failure, Loss and End-Stage Renal Disease (RIFLE) criteria for diagnosis and classification of acute impairments in kidney function13 and acute on chronic CKD was settled when a patient has an increase of inpatient serum creatinine greater than the last preadmission serum creatinine by ≥50% or if the patient needs dialysis during hospitalization.14 According to RIFLE criteria, 60 (27.4%) of patients were in class R, 96 (43.8%) were in class I, and 63 (28.8%) were in class F. In addition, 219 age-matched normal medical and paramedical personnel were included as control group (group II). After initial clinical assessment and getting consent, all subjects were investigated for body mass index (BMI), complete blood count (CBC), serum alanine transaminase (ALT), aspartate transaminase (AST), creatinine, urea, uric acid, calcium, phosphorus, fasting blood sugar level, insulin level, CRP, IL6, PTH, 25 OH vit D, FGF23, beside serum sclerostin and FMD. In addition follow up of the outcome of group I patients till they recover or get lost was done. Group I patients were divided into two subgroups according to absence or presence of underlying CKD into group Ia and group Ib respectively. Group Ia patients had multiple comorbid conditions including acute leukemia, bronchopneumonia, aspiration pneumonia, chronic obstructive airway disease, liver cirrhosis, hepatocellular carcinoma, diabetic ketoacidosis, non-Hodgkin lymphoma, post cardiopulmonary resuscitation, tumor lysis syndrome, cardiogenic shock, puerperal sepsis, severe vaginal bleeding, ischemic heart disease, heart failure, infective endocarditis, septic shock, and hypovolemic shock. Comorbid conditions in group Ib include lobar pneumonia, bronchopneumonia, respiratory failure, infective endocarditis, diabetic ketoacidosis, lupus encephalitis, heart failure, acute coronary insufficiency, lupus nephritis, severe sepsis, cerebrovascular stroke, post cardiopulmonary resuscitation, ventricular arrhythmias, and acute gastrointestinal bleeding.

Serum sclerostin was assayed using Quantikine ELIZA according to the manufacturer's instructions. Enzyme amplified sensitivity immunoassay was used to estimate iPTH (Roche Diagnostics, Indianapolis, IN). Serum 25 OH vit D was measured using high-performance liquid chromatography (HPLC). Serum FGF23 was assayed using a two-site (NH2-terminal/C-terminal) enzyme-linked immunosorbent assay (ELISA) (Immutopics, San Clemente, CA). Serum IL-6 levels were identified immediately after blood sampling, using ELISA (eBioscience, ESP). FMD was estimated bedside for group 1 patients and in the Doppler lab for group II cases by an expert sonographer using B-mode SIEMENS ACUSON X300 ultrasonographer.

Tables 1–3 and Fig. 1 summarize the results of this study. Serum sclerostin, FGF23, PTH, CRP, IL6, serum creatinine, urea, uric acid, phosphorus, WBC, and Homa IR are significantly higher while serum calcium, 25 OH vit D, hemoglobin concentration (Hb), platelet count, and FMD are significantly lower in AKI cases in comparison to the normal control group (P<0.001 in all, Table 1). The patients that developed acute on chronic renal failure are significantly younger than those with de novo AKI (P=0.0012). De novo AKI had significantly higher serum ALT, AST, uric acid, Hb (P<0.001 in all), and WBC (P=0.034), significantly lower serum urea (P=0.0024), creatinine (P<0.001), and phosphorus (P=0.0168) compared to cases of acute on chronic renal failure, while there was no significant difference in serum sclerostin, PTH, FGF23, 25 OH vit D, serum calcium, CRP, IL6, platelet count, Homa IR, and FMD between the two groups (Table 2). Moreover, Patients that recovered have younger age (P<0.04), had higher platelet count (P<0.005), and lower AST (<0.0001), otherwise, there was no significant difference in serum sclerostin, FGF23, PTH, 25 OH vit D, CRP, IL6, urea, creatinine, uric acid, calcium, phosphorus, Hb, WBC, Homa IR, or FMD between survivors and non survivors. Out of 133 cases in group Ia, 69 (52%) recovered and left the ICU while 64 (48%) were lost while in group Ib, out of 86 cases, 53 (61.6%) survived and 33 (38.4%) were lost, 95% confidence interval (CI) of mortality is −3.7% to 22.5%, P=0.157.

Fig. 1.

Correlation of sclerostin with FGF23 in control group (1), and in AKI group (2). Correlation between Homa IR with sclerostin (3) and FGF23 (4).

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This is the first study of sclerostin in AKI. It proved that serum sclerostin level increases in parallel to FGF23 in AKI patient to levels comparable to CKD patients. Apart from the week association with insulin resistance, neither sclerostin nor FGF23 had an impact on endothelial function or survival of AKI patients. Previous studies have shown strong association of FGF23 with insulin resistance among CKD patients.15,16 The variation of this association between CKD and AKI cases is likely related to disease duration. Similar studies on sclerostin in CKD patients are lacking, but it was found associated with insulin resistance in women with polycystic ovary.12 The present study failed to disclose significant association of sclerostin with FMD as an index of endothelial function, there is no significant difference in serum sclerosin between AKI patients that recovered and those that were lost. The only study that looked on endothelial function in association with high serum sclerostin in CKD patients showed different effect. They also disclosed a significant association of sclerostin with mortality.9 This last association was found in another study in peritoneal dialysis patients but failed to show similar association among hemodialysis cases.5

The main drawbacks of this study include the cross-sectional nature; longitudinal research is more suitable for the study of biomarkers. The fluctuations in serum biomarkers in relation to the state of disease activity can be best evaluated in longitudinal studies; that are therefore more capable of identifying differences in the levels of biomarkers according to various circumstances. Another limitation that faced this work was the multiple comorbid conditions affecting individual AKI patients and may explain the increased mortality among these patients.

All authors have contributed significantly and equally in the design of this work, data acquisition, analysis, and interpretation. In addition to the writing and revising of this manuscript, all authors approved the final version before submission.

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

The authors have declared that no conflict of interest exists.