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Serum myo-inositol oxygenase levels at hospital discharge predict progression to chronic kidney disease in community-acquired acute kidney injury

A total of 1,453 patients with a diagnosis of AKI were screened between February 2017 and January 2020. After excluding 1203 patients, 250 patients were enrolled. A total of 124 patients died or were lost to follow-up, leaving 126 patients for the final analysis (Fig. 1). The mean age of study participants was 37.23 ± 15.20 years and 43.7% were females. 93.7% of patients were in stage 3 of AKI. The main cause of CA-AKI was infection (47%) followed by obstetric (16%), envenomation (14%), over the counter or indigenous drug related (7%), and other causes (16%). Infections included acute gastroenteritis (37%), undifferentiated acute febrile illness (27%), urinary tract infection (10%), scrub typhus (9%), leptospirosis (5%), malaria (5%) and others (7%) . Out of 126 patients, progression to CKD at 4 months was observed in 19.84% (n = 25).

Figure 1

The patient characteristics including laboratory investigations are shown in Tables 1 and 2. Patients who progressed to CKD were older (44.40 ± 15.32 vs 35.46 ± 14.72 years, p = 0.008), had longer duration of hospitalization (16.40 ± 9.02 vs 12.29 ± 9.45 days , p = 0.052), and had higher serum creatinine (p < 0.001), and lower serum albumin at discharge (p = 0.001). Further, uPCR at the time of hospital was higher in these patients discharge as compared to recovered patients [896 (317, 2128) vs 232 (131, 588) mg/gm, p < 0.001].

Table 1 Baseline patient characteristics in the study participants.
Table 2 Clinical characteristics, serum and urine biomarkers at the time of discharge in study subjects.

Biomarkers and recovery from CA-AKI

The serum and urine biomarkers at the time of hospital discharge have been tabulated in Table 2 and Fig. 2. Urine biomarker values ​​were normalized using spot urine creatinine concentration. Serum MIOX was higher in patient who progressed to CKD [4995 (3280, 6107) vs 3005 (2221, 3807) pg/ml, p < 0.001]. High level of urine NGAL/creatinine [159.75 (51.26, 357.69) vs 44.93 (15.32, 116.14) ng/g, p < 0.001] and uPCR [896 (317, 2128) vs 232 (131, 588) mg/g, p < 0.001] whereas low urine LFABP/creatinine [10.98 (5.24, 287.11) vs 274.79 (7.50, 911.97) ng/g, p = 0.035] was also noted in these subjects as compared to a patient who recovered from AKI. There was no statistically significant difference between groups with regards to urinary MIOX level, serum and urinary YAP levels, urine KIM-1 and quinolinate to tryptophan ratio (uQ/T) (Table 2).

Figure 2
figure 2

Box and whisker plot showing the levels of serum and urine biomarkers in recovered patients and those who progressed to CKD from CA-AKI. sMIOX serum myo-inositol oxygenase, uMIOX urine myo-inositol oxygenase, SYAP serum Yes-associated protein, uYAP urine Yes-associated protein, uKIM-1 urine kidney injury molecule-1, UNGAL urine neutrophil gelatinase-associated lipocalin, uL-FABP urine liver-type fatty acid binding protein, uPCR urine protein creatinine ratio, scr serum creatinine, Cr; creatinine.

Unadjusted logistic regression analysis showed that a 10% increase in standardized serum MIOX level increased the odds of progression to CKD by 12.8% [OR 3.58, 95% CI (1.84, 6.96), p < 0.001]. With every 10% increase in standardized urine NGAL [OR 2.69, 95% CI (1.56, 4.63), p < 0.001]and standardized serum creatinine [OR 2.69 95% CI (1.54, 4.69), p < 0.001], the odds of progression to CKD increased by 9.8%. For 10% increase in standardized uPCR [OR 2.61 95% CI (1.61, 4.23), p < 0.001] level, odds of progression to CKD rose by 9.5%. (Table 3).

Table 3 Unadjusted logistic regression of clinical parameters, serum and urine biomarkers at hospital discharge and for the association of renal outcome (progression to CKD from CA-AKI).

After adjusting with age, sex, hypertension, diabetes, requirement of kidney replacement therapy (KRT), quick sequential organ failure assessment (qSOFA) score, and duration of hospitalization; serum MIOX, urinary NGAL, serum creatinine and uPCR were independently associated with progression to CKD (Table 4). 10% increase in standardized serum MIOX level increased the odds of progression to CKD by 13.5% [OR 3.81, 95% CI (1.66, 8.73)]. With 10% increase in standardized urine NGAL level [OR 2.88, 95% CI (1.39, 5.99)]and standardized serum creatinine level [OR 2.63, 95% CI (1.30, 5.31)], increase in the odds of progression to CKD was 10.5% and 9.6%, respectively. For standardized uPCR [OR 2.27, 95% CI (1.29, 3.98)]10% increase in its level would rise odds of progression to CKD by 8%.

Table 4 Adjusted logistic regression of serum and urine biomarkers at hospital discharge for the association of renal outcome (progression to CKD from CA-AKI).

Penalized LASSO logistic regression with AKI to CKD progression as the outcome and all serum and urine biomarkers plus other parameters including age, sex, diabetes, hypertension, qSOFA score, requirement of KRT, and hospital duration as potential predictors resulted in a final model containing age , sex, hypertension, hospital duration, serum MIOX, discharge uPCR, and discharge serum creatinine. Linear predictor values ​​for all study subjects were calculated using the intercept and coefficients from the multivariable model (shown in Supplementary Table 1). Finally, the logistic regression model was fit for only the select variables obtained from penalized LASSO regression to assess the association with progression to CKD. The ROC-AUC of the multivariable logistic model with selected parameters was 0.88; (95% CI 0.81, 0.95) and was significantly greater than those of any of the 3 variables analyzed individually; serum MIOX (AUC 0.85; 95% CI 0.78, 0.93), discharge serum creatinine (AUC = 0.85; 95% CI = 0.87, 0.92) and discharge uPCR (AUC 0.83; 95% CI 0.74, 0.91) (Fig. 3).

Figure 3
figure 3

Receiver operating characteristic curves (ROC) for the multivariate model and its individual constituents. AUC area under the curve.

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