Las bolsas domésticas y sus categorías funcionales

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he scientific aim of this dissertation was to provide clinical validation of the biomarker UCHI3L1 as early diagnostic or ‘predictive’ tool for emerging AKI in specific adult ICU settings.

I. Main results of this dissertation

In this dissertation we evaluated various biomarkers for early diagnosis or prediction of AKI in two different adult ICU settings. Our adult general ICU setting comprised patients who either underwent non-cardiac surgery or had a non-surgical reason for critical illness, and who had a respiratory SOFA score ≥ 2 or a cardiovascular SOFA score ≥ 1. In this cohort the UCHI3L1 concentration at ICU admission could predict occurrence of AKI stage ≥ 2 within the next 12 h with an AUC-ROC of 0.792 (95 % CI: 0.726-0.849). This performance was similar to that of UNGAL (P = 0.587), which had an AUC-ROC of 0.748 (95 % CI: 0.678-0.810). In our adult elective cardiac surgery ICU setting early post-operative measurements (i.e., within 4 h after ICU admission) of both UCHI3L1 and UNGAL could less satisfactorily predict occurrence of AKI stage ≥ 2 within 12 h after ICU admission. The highest AUC-ROC value for UCHI3L1 was 0.686 (95 % CI: 0.617-0.748) and for UNGAL 0.656 (95 % CI: 0.587-0.720). However, by using the CSA-NGAL score, we found that AKI was predominantly without acute tubular damage in this cohort, making us conclude that renal stress or damage biomarkers were not the most suited biomarkers to measure in these patients. On the other hand, also in this cohort renal stress or damage biomarkers were valuable tools as without UNGAL we would not have been able to identify the patients with subclinical AKI. As alternative, we demonstrated that more frequent assessment of the functional biomarker SCr in the early post-operative ICU period (first 4 h) was the best performing diagnostic tool in these patients. These key findings indicate that SCr assessment should be performed more frequently than in current routine clinical practice in order to detect CSA-AKI more early.

II. A unifying hypothesis explaining the findings in adult cardiac surgery patients In our adult elective cardiac surgery ICU setting, specific patient characteristics prompted the hypothesis that these patients had a lower RFR-G or a lower functioning nephron mass than the patients in our adult general ICU setting. When the exposure (i.e., the cardiac surgical procedure) caused hypoperfusion with ischemia, it also elicited acute tubular damage as defined by the CSA- NGAL score. We hypothesize that there was a lower risk of subclinical AKI, i.e. diagnostic rise in renal stress or damage biomarkers (e.g., UNGAL) without diagnostic rise in functional

biomarkers (e.g., SCr) (Figure 1, upper left graph). Further, we hypothesize that in most AKI patients with acute tubular damage, the diagnostic rise in functional biomarkers occurred before the diagnostic rise in renal stress or damage biomarkers due to early failure (i.e., before the development of ischemia) in maintaining a normal whole-organ baseline GFR (Figure 1, upper right graph, clinical scenario a-b). Patients with a higher RFR-G or a higher functioning nephron mass may in a timely matter benefit more from measuring renal stress or damage biomarkers, as these biomarkers can then diagnose subclinical AKI (Figure 1, upper left graph) or predict occurrence of AKI (Figure 1, upper right graph, clinical scenario c-d). The lower graphs in Figure 1 also show the correlation between functional biomarkers, renal stress or damage biomarkers, and RFR-G and functioning nephron mass in patients where the exposure caused hypoperfusion without ischemia. Note that in a patient with a normal RFR-G and a normal functioning nephron mass there is a lower probability of reaching the diagnostic threshold of the functional biomarker (Figure 1, lower left graph), whereas in a patient with a subnormal RFR-G or a subnormal functioning nephron mass there is a higher probability of reaching the diagnostic threshold of the functional biomarker (Figure 1, lower right graph).

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Figure 1 | Correlation between functional biomarkers (e.g., serum creatinine), renal stress or damage biomarkers (e.g., urinary neutrophil gelatinase-associated lipocalin), and renal functional reserve of the glomerular function and functioning nephron mass The 4 quadrants represent ‘no AKI and no acute tubular damage’ (lower left quadrant), ‘AKI without acute tubular damage’ (lower right quadrant), ‘subclinical AKI’ (upper left quadrant) and ‘AKI with acute tubular damage’ (upper right quadrant).

The letters indicate reaching of a diagnostic threshold. Note that 2 different clinical scenarios are possible in the upper right graph.

Upper graphs: The exposure (i.e., the cardiac surgical procedure) causes hypoperfusion with ischemia (indicated by the black colour of the kidneys)

Lower graphs: The exposure (i.e., the cardiac surgical procedure) causes hypoperfusion without ischemia (indicated by the white colour of the kidneys)

Left graphs: The patient has a normal RFR-G and a normal functioning nephron mass (indicated by the large kidneys)

Right graphs: The patient has a subnormal RFR-G or a subnormal functioning nephron mass (indicated by the small kidneys)

Abbreviations: AKI acute kidney injury, RFR-G renal functional reserve of the glomerular function c d a b a a

III. The long and uncertain path to biomarker utility for AKI diagnosis

A biomarker will not be widely used in the clinic unless all four steps in Table 1 have been successfully completed [203]. The decision that a biomarker is ‘reasonable and necessary’ (Table 1) indirectly influences coverage by private insurance carriers [204].

Table 1 | Roadmap to biomarker utility in the United States (based on [204]) Step 1 | Biomarker identification

File patent application on invention Step 2 | Biomarker application

Describe preferred embodiments of invention Granting of patent by USPTO No granting of patent by USPTO

No use of biomarker for patient care Step 3 | Analytical and clinical validation

Document, through use of specific laboratory investigations, that analytical performance characteristics of IVD method are suitable and reliable

Apply manufacturing controls that are adequate to ensure consistent manufacturing of finished IVD product

Document, by conducting clinical trials, that clinical performance characteristics of IVD product are suitable and reliable FDA approval: ‘safe and

effective’ No FDA approval

No use of biomarker for patient care