Thyroid Function With Continuous Kidney Replacement Therapy: A Prospective Study

Thyroid Function With Continuous Kidney Replacement Therapy: A Prospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Thyroid Function With Continuous Kidney Replacement Therapy: A Prospective Study Matthew Kennis, David Madison, North Foulon, Kayo Okamura, Zhibin He, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7394781/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 May, 2026 Read the published version in Kidney360 → Version 1 posted You are reading this latest preprint version Abstract Background: Acute kidney injury (AKI) and end stage kidney disease (ESKD) requiring continuous kidney replacement therapy (CKRT) are associated with high mortality. Solutes up to 40 kilodaltons (kDa) in size are amenable to CKRT clearance which includes thyroid stimulating hormone (TSH)(28 kDa), free thyroxine (fT4)(0.78 kDa), and free triiodothyronine (fT3)(0.68 kDa). The effect of CKRT on TSH and thyroid hormone clearance, thyroid function, and the hypothalamic-pituitary-thyroid (HPT) axis is unknown. Methods: This prospective, single-center observational study enrolled 50 ICU patients requiring CKRT and 50 control ICU patients. Serum TSH, fT4, fT3, and reverse T3 (rT3) were measured prior to and on days 1, 3, 8, and 14 after CKRT initiation; effluent TSH, fT4, and fT3 were measured on days 1, 3, 8, and 14. Thyroid function status was adjudicated on days 1, 3, 8, and 14. Statistical analyses included Fisher’s exact tests, unpaired t-tests, and Fisher’s Least Significant Difference tests to compare differences in thyroid hormones and Sequential Organ Failure Assessment (SOFA) scores. Results: Prior to and during CKRT, CKRT patients had reduced TSH, fT4, and fT3 levels compared to controls, with a higher proportion of values below the normal reference range. TSH and fT4 were present in the CKRT effluent, indicating clearance by CKRT. More severe and prolonged non-thyroidal illness syndrome (NTIS) was seen in the CKRT cohort compared to controls with similar severity of illness as judged by SOFA scores. No CKRT patient achieved euthyroid status during the study. Conclusions: This is the first study to assess thyroid function in CKRT patients. We demonstrate that patients requiring CKRT have a greater rate, severity, and duration of NTIS versus ICU controls, which may be affected by removal of TSH and fT4. These novel complications may contribute to the high mortality rate observed in patients with either AKI or ESKD who require CKRT. Trial Registration Not applicable Health sciences/Diseases Health sciences/Endocrinology Health sciences/Medical research Health sciences/Nephrology continuous kidney replacement therapy (CKRT) thyroid function non-thyroidal illness syndrome (NTIS) thyroid stimulating hormone (TSH) free thyroxine (fT4) free triiodothyronine (fT3) reverse T3 (rT3) critical illness Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 BACKGROUND Approximately 5–10% of patients with acute kidney injury (AKI) will require kidney replacement therapy (KRT), and for patients with severe AKI or end stage kidney disease (ESKD) requiring KRT in the ICU, estimated in-hospital mortality approaches 70% and 40%, respectively ( 1 – 4 ). For decades, it was hypothesized that mortality in patients with AKI requiring KRT could be reduced by optimizing KRT dose or duration; however, rigorously designed clinical studies have shown that neither increased dose nor earlier initiation conferred a mortality benefit ( 5 – 8 ). Solute removal during KRT is not selective and largely dependent on the dialysis filter size barrier resulting in the clearance of potentially harmful and beneficial solutes alike. ( 9 ) Thus, it is possible that there are competing benefits and harms of solute removal during KRT that explain the lack of mortality benefit with KRT optimization. Continuous kidney replacement therapy (CKRT) is a commonly employed modality of KRT for AKI or ESKD in the ICU, particularly with hemodynamic instability ( 10 ). Given the uninterrupted nature of CKRT, recipients may be particularly vulnerable to harm from indiscriminate solute removal ( 9 ). In particular, it is well known that CKRT leads to the substantial removal of amino acids, trace elements, vitamins, and certain medications ( 11 – 15 ). Whether CKRT removes other potentially beneficial substances including endocrine hormones such as thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) remains unexplored. TSH, free T4 (fT4), and free T3 (fT3) are low molecular weight hormones, with masses of 28, 0.78, and 0.68 kilodaltons (kDa), respectively. Modern high-flux dialysis membranes used in CKRT permit the filtration of molecules up to 40 kDa ( 16 ), making TSH, fT4, and fT3 all susceptible to CKRT removal. Case reports have described using CKRT in thyroid storm to lower the levels of fT4 and fT3 ( 17 – 19 ). However, these case reports did not directly measure thyroid hormone clearance, and other factors may have influenced hormone levels ( 17 – 19 ). Thus, while it is plausible that CKRT can clear TSH and thyroid hormones, CKRT clearance of these substances has not been directly investigated. The removal of thyroid hormones during CKRT may be especially problematic for patients in the ICU. Lower levels of fT3 and fT4 are common in critically ill patients as part of non-thyroidal illness syndrome (NTIS). In NTIS, the hypothalamic-pituitary-thyroid (HPT) axis is altered such that, instead of TSH rising in response to reduced thyroid levels (as happens normally with hypothyroidism), TSH remains normal or low; reverse T3 (rT3) levels also increase due to accelerated conversion of fT3 to the inactive isomer rT3 ( 20 – 22 ). The rates and severity of NTIS in patients with AKI or ESKD who require CKRT are unknown, as are the potential consequences of TSH and thyroid hormone removal on NTIS recovery. We conducted the present prospective study to address the knowledge gap regarding thyroid function in patients prior to and during CKRT. We hypothesized that TSH and thyroid hormones would be cleared during CKRT with resultant effects on the HPT axis. Since normal thyroid function may play a role in the recovery from critical illness, inadvertent removal of TSH and thyroid hormones during CKRT could represent a previously unrecognized adverse consequence of this commonly employed therapy in patients with kidney failure. METHODS Study Population and Design This prospective, single-center observational study was conducted at the University of Colorado Hospital, a quaternary care center in Aurora, Colorado. As no prior studies have evaluated CKRT-mediated clearance of TSH or thyroid hormones, no existing data were available to guide enrollment targets. Based on our prior experience (23, 24), we determined that 50 CKRT subjects would be sufficient for this pilot study. Fifty CKRT subjects were enrolled between March 2024 and July 2024. Subjects were eligible if they were ≥18 years of age, admitted to an ICU, and receiving CKRT as recommended by the nephrology consult service, which operated independently of the research team. Subjects with hypothyroidism on thyroid hormone supplementation were eligible for enrollment. Pregnant and incarcerated patients were excluded. Eligible patients were approached within 24 hours of CKRT initiation, and the day of enrollment was designated as day 1. Paired serum and effluent samples of TSH, fT4, fT3, and serum samples of rT3 were collected on days 1, 3, 8, and 14 between approximately 8:00 AM and 12:00 PM and were immediately transported to the hospital clinical laboratory for analysis. For pre-CKRT measurements, refrigerated serum samples drawn within 24 hours prior to CKRT initiation and stored in the hospital laboratory were used to assess TSH and fT4 levels (fT3 and rT3 could not be assessed in these stored samples). A control cohort of 50 ICU patients not receiving CKRT was enrolled between July 2024 and October 2024. Eligible patients were ≥18 years of age and receiving ICU care with mechanical ventilation and/or vasopressor or inotropic support, reflecting the clinical profile of most CKRT patients (25). Control subjects with hypothyroidism on thyroid hormone supplementation were eligible for enrollment. Exclusion criteria included pregnancy, incarceration, or receipt of KRT for AKI within five days prior to study inclusion. The day of study enrollment was considered day 1, and serum samples were collected on days 1, 3, 8, and 14 between 8:00 AM and 12:00 PM and immediately delivered to the hospital laboratory for analysis. To align with CKRT sampling methods, refrigerated serum samples drawn within 24 hours prior to enrollment were used to assess "pre" TSH and fT4 levels. Four control patients initiated CKRT during the study period; data collected after CKRT initiation in control subjects were excluded from analysis. Study approval was obtained locally from the Colorado Multiple Institutional Review Board (COMIRB), and informed consent was obtained from the subject directly when possible, or from an authorized representative if the subject was unable to provide informed consent. All experiments were performed in accordance with relevant guidelines and regulations as set forth by COMIRB. Demographic Data and Definitions Baseline creatinine was determined as previously described (24). AKI and stage were classified according to KDIGO serum creatinine criteria: Stage 1 was defined as an increase in serum creatinine >0.3 mg/dL from baseline and ≤2× baseline, Stage 2 as an increase ≥2× to ≤3× baseline, and Stage 3 as an increase ≥3× baseline or a serum creatinine ≥4.0 mg/dL (28). Although the need for dialysis is considered Stage 3 AKI, and all CKRT patients would meet this definition, we categorized patients based solely on creatinine criteria prior to KRT initiation to better reflect underlying AKI severity and offer a comparison to control patients that did not receive CKRT. Baseline estimated glomerular filtration rate (eGFR) was determined using baseline creatinine and the non-race corrected 2021 CKD-EPI formula (29). ESKD was defined as requiring hemodialysis or peritoneal dialysis for 90 days before enrollment. Sequential Organ Failure Assessment (SOFA) scores were calculated as per the published definition, excluding the renal sub-score (30), with missing sub-category values assigned a score of ‘0’. Norepinephrine equivalents were determined as described previously (31). If PaO2 values were unavailable to calculate PaO2/FiO2, a SpO2/FiO2 ratio was used (32). Nonsurvivors were defined as patients who died within 30 days of CKRT initiation (CKRT cohort) or study enrollment (control cohort).Demographic data, CKRT parameters, and lab values were collected from the electronic health record. The study team, unblinded to disposition status, classified patients as “Off CKRT” if they discontinued CKRT or were discharged prior to study completion, including one CKRT patient who transferred to another hospital on day 3 and one who declined further blood draws. Control patients were classified as discharged if this occurred prior to study completion. Death or transition to hospice was recorded as deceased for both cohorts. Measurement of TSH, fT4, fT3, and rT3 Serum and effluent TSH, fT4, and fT3 assays were performed by the University of Colorado Hospital Clinical Laboratory and serum rT3 assay was performed by ARUP Laboratories in Salt Lake City, Utah. TSH was quantified with a two-site immunoenzymatic assay (Beckman Coulter ACCESS, Loveland, CO, USA). fT4 and fT3 were quantified using a competitive chemiluminescent immunoassay (Siemens ADVIA Centaur, Malvern, PA, USA). rT3 was assessed using quantitative liquid chromatography-tandem mass spectrometry (ARUP Laboratories, Salt Lake City, UT, USA). Serum reference ranges were: TSH, 0.45–5.33 mIU/L; fT4, 0.89–1.76 ng/dL; fT3, 2.3–4.2 pg/mL; rT3, 9.0–27.0 ng/dL. Reference ranges for CKRT effluent have not been established. Interpretation of Thyroid Function Tests An endocrinologist (WHC), blinded to study cohort and disposition, interpreted thyroid function status based on serum TSH, fT4, fT3, and rT3 on days 1, 3, 8, and 14, as well as “pre” TSH and fT4 for all 100 subjects. Thyroid function status was first adjudicated at the day 1 time point and subsequent time points were adjudicated within the context of day 1 status. Day 1 NTIS was defined by: 1) ↓fT3 or ↓fT4 and normal/↓TSH; OR 2) normal fT3 and fT4 with normal/↓TSHand rT3 >36.68 ng/dL (lower quartile of all rT3 samples); OR 3) ↑TSH (up to 36.68 ng/dL with subsequent downward trends. These criteria are similar to those described by Mahashabde et al. (33). NTIS recovering was defined by initial evidence of NTIS with a subsequent consistent rise in TSH (≥50% increase from initial NTIS level) and further supported by a decreasing trend in rT3. Once a subject showed evidence of NTIS, they were presumed to have continued NTIS or NTIS recovering; however, a TSH rising to >20 mIU/L was considered hypothyroidism rather than NTIS recovering (34). Day 1 hypothyroidism was further distinguished from NTIS/NTIS recovering by↓fT3 or ↓fT4, ↑TSH, and rT3 <36.68 ng/dL, with no evidence of NTIS/NTIS recovering at subsequent time points. Subclinical hypothyroidism was defined as normal fT3/fT4, ↑TSH, and rT3 <36.68 ng/dL, with no evidence of NTIS/NTIS recovering at subsequent time points. Hyperthyroidism was defined as ↑fT4 or ↑fT3 and ↓TSH, with no evidence of NTIS/NTIS recovering at subsequent time points. Subclinical hyperthyroidism was defined as normal fT4/fT3 and ↓TSH, with no evidence of NTIS/NTIS recovering at subsequent time points. Euthyroid was defined as TSH, fT3, and fT4 all within the reference limit, with no evidence of NTIS/NTIS recovering at subsequent time points. These criteria are summarized in Table 1. CKRT Protocol CKRT was performed using the NxStage® System One™ S machines and NxStage Purema H filters, which are biocompatible polyethersulfone membranes. Of the 50 CKRT patients, 47 were initiated on continuous venovenous hemodialysis (CVVHD) and 3 on continuous venovenous hemofiltration (CVVH). The typical CKRT prescription at the University of Colorado Hospital included a blood flow rate of 300 mL/min and a dose of 20–25 mL/kg/hr (7). CKRT was generally initiated without anticoagulation, with anticoagulation added as needed based on filter clotting; no patients received citrate anticoagulation. Decisions regarding discontinuation or transition to intermittent KRT were made by the nephrology consult service, independent of the research team. CKRT data (time on CKRT, hourly effluent volume, and average CKRT dose per interval) were obtained from the electronic health record and calculated as previously described (24). Total effluent volume was determined by summing the hourly recorded therapy fluid volume and ultrafiltrate over the 24-hour period preceding thyroid hormone lab collection. Clearance and Sieving Coefficient Calculations The sieving coefficient (SC) and CKRT clearance were calculated using the following equations as previously described for the clearance of other solutes (35, 36): To quantify removal over 24 hours of CKRT, we calculated the median (IQR) amount removed from the 24-hour periods preceding days 3, 8, and 14, excluding day 1, as subjects had been on CKRT for an average of only 13 hours prior to this time point. Statistical Analysis Fisher’s exact test and unpaired t-tests were used for comparisons of demographics, baseline lab values, thyroid adjudication status, and the distribution of TSH, fT4, and fT3 values categorized as below, within, or above the reference range. Two strata were created: one including all control and CKRT patients, and another including only NTIS patients with SOFA scores of either ≤8 or 9–13 from both the control and CKRT cohorts. Unpaired Fisher’s Least Significant Difference tests were used to directly compare serum TSH, fT4, fT3, rT3, and SOFA between CKRT and control cohorts at pre, day 1, day 3, and day 8. Day 14 was not included in NTIS subgroup analyses due to substantial dropout in both cohorts. Data only from time points when patients remained hospitalized were included in statistical analyses, as these provided the appropriate basis for between-group comparisons. Due to clerical laboratory error, seven TSH, four fT4, one fT3, and eight rT3 values in total were unable to be assessed. Statistical significance was defined as a p-value <0.05. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. RESULTS Control and CKRT Cohort Characteristics As shown in Table 1 , the CKRT cohort had a younger median age and higher baseline serum creatinine (1.07 vs. 0.94 mg/dL; p = 0.0363) compared to controls. As expected, the CKRT cohort had patients with more advanced chronic kidney disease, including ESKD. Comorbidities such as hypertension, coronary artery disease, and heart failure were common and similar among both groups, except for chronic liver disease (more prevalent in CKRT patients) and solid malignancies (more prevalent in controls). Rates of hypothyroidism and thyroid hormone supplementation were similar between CKRT and control subjects. Use of mechanical ventilation was similar in both groups, while day 1 SOFA score and 30-day mortality were both higher in CKRT patients. Thyroid Hormones, Thyroid Function Status, and Disposition CKRT patients had significantly lower median TSH, fT4, and fT3 than controls at the pre and day 1 time points (Fig. 1a-c). For both CKRT patients and controls, the majority of TSH levels were within the normal reference range at the pre time point (CKRT 82% vs. Controls 62%; p = 0.04) and on day 1 (CKRT 66% vs. Controls 69%; p = 0.83) ( Table S1 ). The majority of fT4 levels at the pre and day 1 time points were below the reference range in CKRT patients and this finding was more common than in controls (CKRT 53% vs. Controls 19% for pre; p = < 0.001;CKRT 56% vs. Controls 34% for day 1; p = 0.04). Serum fT3 was below the reference range in the majority of both groups on day 1 and this finding was more common in CKRT patients (CKRT 94% vs. Control 68%; p = 0.002). Both serum rT3 and SOFA, indicators of NTIS and critical illness respectively, were increased in CKRT patients versus controls (Fig. 1d-e). Thyroid function assessment for all patients through the 14-day observation period is shown in Fig. 2 . On day 1, all categories of thyroid function status were evident in the overall ICU population, including euthyroid, hyperthyroid, and hypothyroid status. On day 1, CKRT patients were more likely to have NTIS versus controls (CKRT 88% vs. Controls 64%; p = 0.009), and none of the CKRT patients were euthyroid. CKRT patients also had indicators of more severe illness than controls, with no attainment of euthyroid status, lower rates of discharge from the hospital, and higher mortality over the observation period. CKRT Parameters; Effluent Levels, Sieving Coefficient, and CKRT Clearance of TSH CKRT parameters including dose, time on CKRT, and total effluent volume (for the preceding 24 hours) are reported in Table 2 . To determine if removal of TSH and thyroid hormones occurred during CKRT, effluent levels were assessed. Effluent is not an FDA-approved sample type for the TSH, fT4 and fT3 assays offered by our hospital laboratory. Therefore, any interfering effect from effluent matrix on measurement of these analytes is unknown. To assess the accuracy of the effluent measurements, effluent sampled from a mock CKRT circuit (i.e., not connected to a patient) was analyzed; samples analyzed included effluent collected directly from the dialysate bag, and then pre-filter and post-filter at 5, 20, and 25 minutes (n = 7 sample total). These “blank” effluent samples were assessed for TSH, fT4, and fT3 using the same clinical platform as serum. In all samples, TSH levels were below the detection limit (i.e., < 0.01 mIU/L); for fT4, levels were 0.12 ± 0.03 ng/dL; for fT3 levels were 2.24 ± 0.03 (Mean ± SD). Then, to quantify potential imprecision introduced by effluent matrix a “within-run” replicant study was performed utilizing a Clinical Laboratory and Standards Laboratory Institute protocol commonly employed in the clinical laboratory setting ( 37 ). Effluent from the post filter 25-minute sample was measured 10 consecutive times for TSH, fT4, and fT3. Replicant measurements for TSH were all undetectable. fT4 was 0.178 ± 0.048 ng/dL with a coefficient of variation (CV) % of 27.1%. fT3 was 2.13 ± 0.28 pg/mL with a CV % of 13.05%. Together, these data indicate that there was no matrix interference with the TSH assay and that these measurements can be considered reliable. For fT3, the mean values in the blank effluent (2.24) and replicant study (2.1) were greater than all of the effluent fT3 measurements from patients (1.26 ± 0.29 pg/mL, n = 111) indicating substantial matrix interference for the assay and an inability to determine the presence or absence of fT3 in the effluent. For fT4, the majority of values were greater than the mean of the blank effluent measurements and the replicant study (i.e., 92% were greater than 0.12; 52% were greater than 0.178; n = 109) indicating that fT4 is detectable in the effluent, however, the imprecision introduced by matrix interference indicates that levels cannot be accurately quantified. TSH clearance by CKRT was then assessed by calculating sieving coefficient and daily removal. The sieving coefficient of TSH was 0.15, 0.15, 0.16, and 0.16 on days 1, 3, 8, and 14, respectively ( Table 2 ), indicating that approximately 15% of plasma levels of TSH is continuously removed during CKRT; this equates to the removal of 12 mIU per 24 hours of CKRT. Thyroid Function Tests in CKRT and Control Patients with NTIS Having established that CKRT removes TSH and fT4, we next asked whether this clearance impacts HPT axis function; these analyses were limited to patients with NTIS to ensure comparison groups with similar baseline HPT pathophysiology and function. As shown in Fig. 3 , median fT4 and fT3 were significantly reduced in NTIS CKRT patients compared to NTIS controls at all time points except day 8, which approached statistical significance (P = 0.07 for fT3; P = 0.07 for fT4, CKRT versus control, day 8). TSH was similar between the groups. Serum rT3 and SOFA scores were significantly increased in NTIS CKRT patients versus NTIS controls at all time points. Thyroid Function Tests in CKRT and Control Patients with NTIS , Stratified by Survivorship and SOFA Scores Since severity of critical illness is associated with NTIS severity and SOFA scores were higher in NTIS CKRT patients versus NTIS controls, we stratified the NTIS cohorts using two methods: 1) by survivorship (i.e., survivors versus nonsurvivors) and 2) by SOFA score (i.e., SOFA score ≤ 8 or SOFA score 9–13) – in order to compare CKRT and control patients with similar levels of critical illness. TFTs in survivors and nonsurvivors with NTIS are shown in Fig. 4. Levels of fT4 and fT3 were similar between NTIS CKRT survivors versus and NTIS control survivors on all days. In contrast, fT4 was significantly decreased in nonsurvivor NTIS CKRT patients compared to nonsurvivor NTIS controls on all days assessed; fT3 was significantly decreased on day 3 and approached statistical significance on day 8 (P = 0.08) in nonsurvivors NTIS CKRT versus nonsurvivors NTIS control. rT3 was significantly increased on day 3 in NTIS CKRT nonsurvivors compared to NTIS control survivors. SOFA was significantly increased at all time points in NTIS CKRT nonsurvivors versus NTIS control nonsurvivors. TFTs by SOFA score groupings (≤ 8 or 9–13) is shown in Fig. 5 . Only the more severely ill subjects (SOFA 9–13) demonstrated lower fT4 and fT3 levels in NTIS CKRT subjects compared to controls (Fig. 5c-f). TSH was similar between NTIS CKRT and controls in both groups (Fig. 5a-b). Notably, rT3 levels were generally similar between NTIS CKRT subjects and controls who had either SOFA ≤ 8 or SOFA 9–13, suggesting that this categorization was effective in identifying similarly ill patients in the CKRT and control groups since increased levels of rT3 may reflect severity of illness (Fig. 5g-h). As shown in Fig. 6a-d , clinical thyroid status demonstrates a prolonged NTIS in the CKRT subjects, regardless of SOFA severity on day 1. Thus, in severely ill patients with SOFA scores from 9–13, CKRT subjects have lower levels of fT4, fT3, and prolonged NTIS than controls suggesting the severity of illness does not fully explain the thyroid derangements observed during CKRT. DISCUSSION This study addresses the knowledge gap regarding thyroid function before and during CKRT. The major findings are that: 1) patients requiring CKRT have a greater rate and severity of NTIS versus ICU controls; 2) both TSH and fT4 are removed by CKRT, 3) levels of fT4 and fT3 are lower in nonsurvivors requiring CKRT, and 4) patients requiring CKRT have prolonged NTIS. These novel complications may contribute to the high mortality rate observed in patients with either AKI or ESKD who require CKRT. Overall, the data in the present report demonstrate that a broad spectrum of thyroid function abnormalities exists in critically ill patients (with or without CKRT requirement), including hypothyroidism, hyperthyroidism, and NTIS. Of the 100 critically ill patients assessed, only 8 were euthyroid at study enrollment (all of whom were controls). NTIS was the predominant abnormality in CKRT patients, affecting a greater proportion at onset (88% vs. 64% in controls p = 0.009) and persisting throughout the course of CKRT. Notably, no CKRT patient – either in the full cohort or the NTIS subgroup – achieved euthyroid status during the two weeks of assessment. Furthermore, NTIS was more severe in CKRT patients with 59% having a fT4 level that was below the reference range; in contrast, only 28% of NTIS controls had reduced fT4 which is similar to the rate observed in other ICU studies ( 38 , 39 ). NTIS with low fT4 is an important subset of NTIS since it is associated with worse clinical outcomes including longer ICU stays, greater rates of mechanical ventilation, and increased mortality compared to those with normal fT4 ( 38 ) – findings known to occur in patients requiring CKRT. We demonstrate that fT4 and TSH are both removed by CKRT which may have adverse effects. The severe NTIS phenotype observed at study enrollment continued during CKRT treatment with persistently lower levels of fT4 and fT3 and prolonged NTIS versus controls. This trend was especially evident when comparing CKRT and control patients with a high severity of illness (i.e., SOFA scores 9–13). CKRT could contribute to these thyroid derangements through direct fT4 removal, maintaining lower levels of fT4 and diminishing a compensatory rise in TSH. Based on the quantities removed, however, we suspect that TSH removal could have the most significant clinical impact since the amount of TSH removed per day (approximately 12 mIU) equates to over 10% of normal daily TSH production ( 40 ). Despite lower fT4 and fT3, TSH was not at any point significantly elevated in CKRT patients compared to controls suggesting that critically ill CKRT patients are unable to centrally stimulate the HPT axis sufficiently (via TSH) to maintain thyroid hormone levels comparable to their non-CKRT counterparts. While severity of illness may contribute to this effect, our data suggest that the severity of thyroid function status may be exacerbated in the face of TSH removal. Regardless of the underpinning mechanisms of NTIS severity and duration, our findings have clinical significance for CKRT patients since NTIS with low fT4 and/or fT3 is associated with increased ICU mortality ( 38 , 41 – 44 ). While the adaptive versus maladaptive nature of NTIS early in critical illness remains debated ( 45 ), prolonged NTIS may exert harmful effects resembling hypothyroidism, including prolonged mechanical ventilation ( 39 ), cognitive impairment, myocardial dysfunction, muscle weakness ( 45 ), immune dysfunction ( 46 ), and fluid retention with generalized edema ( 47 ) – all of which may impair recovery from critical illness. Although previous studies of thyroid hormone supplementation in NTIS have shown mixed, but largely negative results for clinical outcomes ( 45 ), none focused on patients with the added stress of CKRT. Our data suggest that there may be a subset of severely ill CKRT patients who have an HPT axis that cannot adequately compensate for hormone losses and who might benefit from hormone replacement or thyrotropin-releasing hormone (TRH) analogs. This study has several strengths. Unlike many CKRT studies which estimate solute clearance using prescribed dose, modeling, or a short time frame, we quantified CKRT total effluent volume per 24 hours and examined paired serum and effluent samples over several days, allowing us to calculate sieving coefficient, clearance, and amount of TSH removed per day. Our cohort of 50 CKRT patients is large, and we included a contemporaneous control group. Lastly, the prospective design with daily thyroid status adjudication is novel in both the CKRT and NTIS literature. This study has several limitations. While an improvement over other CKRT studies which generally lack a control group, it is difficult to eliminate severity of critical illness as a confounder for the effects of CKRT on hormone levels. We believe that the SOFA score groupings successfully identified comparable cohorts, yet CKRT patients may still have been more critically ill due to factors not captured by SOFA score. While low fT3 and fT4 are predictors of ICU mortality ( 41 – 44 ) and were lower in CKRT nonsurvivors, assessing whether fT4 or fT3 were independent risk factors for mortality would require a larger, dedicated study. We did not study membrane adsorption, whereby solutes bind to the dialysis membrane and are not found in the effluent, which may have led to an underestimation of hormone clearance. Effluent fT3 could not be quantified with the clinical assay available and some amount of matrix interference with the fT4 assay was identified; thus, quantitative effluent levels of both hormones may be better assessed with different assays. However, our data do provide insight into the fact that a two-site immunoenzymatic or “sandwich” assay, as used in TSH measurement, does not display potential effluent matrix-related interference seen with a competitive chemiluminescent immunoassay methodology. The patient population was heterogeneous (e.g., included ESKD patients who have higher rates of thyroid disease ( 48 , 49 )) and our study was not designed to examine specific subpopulations. Finally, medications known to suppress the HPT axis (e.g., corticosteroids and dobutamine) ( 50 , 51 ) were used (although utilization rates were similar between groups). CONCLUSIONS In conclusion, this is the first study to assess thyroid function in CKRT patients. We demonstrate that patients with AKI or ESKD requiring CKRT have a greater rate, severity, and duration of NTIS versus ICU controls, which may be affected by removal TSH and fT4. These novel complications may contribute to the high mortality rate observed in patients with either AKI or ESKD who require CKRT. Abbreviations AKI Acute Kidney Injury CKRT Continuous Kidney Replacement Therapy TSH Thyroid-Stimulating Hormone fT4 Free Thyroxine fT3 Free Triiodothyronine rT3 Reverse Triiodothyronine NTIS Non-Thyroidal Illness Syndrome HPT Hypothalamic-Pituitary-Thyroid SOFA Sequential Organ Failure Assessment ESKD End-Stage Kidney Disease eGFR Estimated Glomerular Filtration Rate ICU Intensive Care Unit CVVHD Continuous Venovenous Hemodialysis CVVH Continuous Venovenous Hemofiltration BUN Blood Urea Nitrogen SC Sieving Coefficient. Declarations Ethics approval and consent to participate: Study approval was obtained locally from the Colorado Multiple Institutional Review Board, and consent was obtained from the subject directly when possible, or from an authorized representative if the subject was unable to consent. Consent for publication: Not applicable Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors have no competing interests to disclose. Funding: This study was funded by the Division of Renal Diseases and Hypertension at the University of Colorado School of Medicine Authors Contribution: MK: conceptualization, methodology, formal analysis, investigation, data curation, writing – original draft, visualization DM: investigation, data curation, writing – review & editing NF: investigation, data curation, writing – review & editing KO: investigation, resources, project administration ZH: investigation, resources, project administration IB: methodology, writing – review & editing MY: methodology, investigation, writing – review and editing BG: methodology, writing – review & editing BK: methodology, writing – review & editing MD: methodology, writing, investigation – review & editing WC: conceptualization, methodology, investigation, adjudication, writing – original draft, visualization, supervision SF: conceptualization, methodology, formal analysis, investigation, resources, data curation, writing – original draft, visualization, supervision, project administration, funding acquisition Acknowledgements : We gratefully acknowledge the University of Colorado Hospital Clinical Laboratory for their support in the analysis of research samples. 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Predictors of 15-Day Survival for the Intensive Care Unit Patient on Continuous Renal Replacement Therapy: A Retrospective Analysis. Cureus. 2020;12(5):e8175. Investigators S-A, Canadian Critical Care Trials G, Australian, New Zealand Intensive Care Society Clinical Trials G, United Kingdom Critical Care Research G, Canadian Nephrology Trials N, et al. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury. N Engl J Med. 2020;383(3):240-51. Graversen HV, Jensen SK, Vestergaard SV, Heide-Jorgensen U, Christiansen CF. Defining Baseline Creatinine for Identification of AKI in Population-Based Laboratory Databases: A Danish Nationwide Cohort Study. Kidney360. 2022;3(2):232-41. KDIGO. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int. 2012:1-138. Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49. Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med. 2009;37(5):1649-54. Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. 2019;23(1):374. Pandharipande PP, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, et al. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med. 2009;37(4):1317-21. Mahashabde ML, Kumar L, Bhimani YR, Reddy SK, Nitendra Saketh BV, Gharge SS. A Critical Investigation of Sick Euthyroid Syndrome in Chronic Heart Failure Patients: Addressing the Need for Accurate Thyroid Assessment. Cureus. 2024;16(8):e65985. Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim CF, Tuxen DV, et al. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness. J Clin Endocrinol Metab. 1986;62(4):717-22. Macedo E, Mehta RL. Continuous Dialysis Therapies: Core Curriculum 2016. Am J Kidney Dis. 2016;68(4):645-57. Foulon N, Haeger SM, Okamura K, He Z, Park BD, Budnick IM, et al. Procalcitonin levels in septic and nonseptic subjects with AKI and ESKD prior to and during continuous kidney replacement therapy (CKRT). Crit Care. 2025;29(1):171. Guideline. CaLSIEoPoQMPA, 3rd ed. CLSI document EP05-A3. Clinical and Laboratory Standards Institute W, PA; 2014. Plikat K, Langgartner J, Buettner R, Bollheimer LC, Woenckhaus U, Scholmerich J, et al. Frequency and outcome of patients with nonthyroidal illness syndrome in a medical intensive care unit. Metabolism. 2007;56(2):239-44. Bello G, Pennisi MA, Montini L, Silva S, Maviglia R, Cavallaro F, et al. Nonthyroidal illness syndrome and prolonged mechanical ventilation in patients admitted to the ICU. Chest. 2009;135(6):1448-54. Ridgway EC, Weintraub BD, Maloof F. Metabolic clearance and production rates of human thyrotropin. J Clin Invest. 1974;53(3):895-903. Wang F, Pan W, Wang H, Wang S, Pan S, Ge J. Relationship between thyroid function and ICU mortality: a prospective observation study. Crit Care. 2012;16(1):R11. Gutch M, Kumar S, Gupta KK. Prognostic Value of Thyroid Profile in Critical Care Condition. Indian J Endocrinol Metab. 2018;22(3):387-91. Yildizdas D, Onenli-Mungan N, Yapicioglu H, Topaloglu AK, Sertdemir Y, Yuksel B. Thyroid hormone levels and their relationship to survival in children with bacterial sepsis and septic shock. J Pediatr Endocrinol Metab. 2004;17(10):1435-42. Dai JJ, Du DF, Ma G, Jiang MJ. Association between serum-free thyroxine level and all-cause mortality in critically ill patients: a retrospective study from MIMIC-IV. Front Endocrinol (Lausanne). 2023;14:1164369. Fliers E, Bianco AC, Langouche L, Boelen A. Thyroid function in critically ill patients. Lancet Diabetes Endocrinol. 2015;3(10):816-25. Siampa VN, Abadi S, Aman AM, Bakri S, Halim R, Zainuddin AA. Association between severity of sepsis and thyroid function profile. Acta Biomed. 2023;94(6):e2023239. Sciacchitano S, De Vitis C, D'Ascanio M, Giovagnoli S, De Dominicis C, Laghi A, et al. Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies. J Transl Med. 2021;19(1):139. Schultheiss UT, Steinbrenner I, Nauck M, Schneider MP, Kotsis F, Baid-Agrawal S, et al. Thyroid function, renal events and mortality in chronic kidney disease patients: the German Chronic Kidney Disease study. Clin Kidney J. 2021;14(3):959-68. Cotoi L, Borcan F, Sporea I, Amzar D, Schiller O, Schiller A, et al. Thyroid Pathology in End-Stage Renal Disease Patients on Hemodialysis. Diagnostics (Basel). 2020;10(4). Davies PH, Franklyn JA. The effects of drugs on tests of thyroid function. Eur J Clin Pharmacol. 1991;40(5):439-51. Lee E, Chen P, Rao H, Lee J, Burmeister LA. Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH). Clin Endocrinol (Oxf). 1999;50(4):487-92. Tables Tables 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. 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5\u0026ndash;10% of patients with acute kidney injury (AKI) will require kidney replacement therapy (KRT), and for patients with severe AKI or end stage kidney disease (ESKD) requiring KRT in the ICU, estimated in-hospital mortality approaches 70% and 40%, respectively (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). For decades, it was hypothesized that mortality in patients with AKI requiring KRT could be reduced by optimizing KRT dose or duration; however, rigorously designed clinical studies have shown that neither increased dose nor earlier initiation conferred a mortality benefit (\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Solute removal during KRT is not selective and largely dependent on the dialysis filter size barrier resulting in the clearance of potentially harmful \u003cem\u003eand\u003c/em\u003e beneficial solutes alike. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Thus, it is possible that there are competing benefits and harms of solute removal during KRT that explain the lack of mortality benefit with KRT optimization.\u003c/p\u003e\u003cp\u003eContinuous kidney replacement therapy (CKRT) is a commonly employed modality of KRT for AKI or ESKD in the ICU, particularly with hemodynamic instability (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Given the uninterrupted nature of CKRT, recipients may be particularly vulnerable to harm from indiscriminate solute removal (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In particular, it is well known that CKRT leads to the substantial removal of amino acids, trace elements, vitamins, and certain medications (\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Whether CKRT removes other potentially beneficial substances including endocrine hormones such as thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) remains unexplored.\u003c/p\u003e\u003cp\u003eTSH, free T4 (fT4), and free T3 (fT3) are low molecular weight hormones, with masses of 28, 0.78, and 0.68 kilodaltons (kDa), respectively. Modern high-flux dialysis membranes used in CKRT permit the filtration of molecules up to 40 kDa (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), making TSH, fT4, and fT3 all susceptible to CKRT removal. Case reports have described using CKRT in thyroid storm to lower the levels of fT4 and fT3 (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). However, these case reports did not directly measure thyroid hormone clearance, and other factors may have influenced hormone levels (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Thus, while it is plausible that CKRT can clear TSH and thyroid hormones, CKRT clearance of these substances has not been directly investigated.\u003c/p\u003e\u003cp\u003eThe removal of thyroid hormones during CKRT may be especially problematic for patients in the ICU. Lower levels of fT3 and fT4 are common in critically ill patients as part of non-thyroidal illness syndrome (NTIS). In NTIS, the hypothalamic-pituitary-thyroid (HPT) axis is altered such that, instead of TSH rising in response to reduced thyroid levels (as happens normally with hypothyroidism), TSH remains normal or low; reverse T3 (rT3) levels also increase due to accelerated conversion of fT3 to the inactive isomer rT3 (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The rates and severity of NTIS in patients with AKI or ESKD who require CKRT are unknown, as are the potential consequences of TSH and thyroid hormone removal on NTIS recovery.\u003c/p\u003e\u003cp\u003eWe conducted the present prospective study to address the knowledge gap regarding thyroid function in patients prior to and during CKRT. We hypothesized that TSH and thyroid hormones would be cleared during CKRT with resultant effects on the HPT axis. Since normal thyroid function may play a role in the recovery from critical illness, inadvertent removal of TSH and thyroid hormones during CKRT could represent a previously unrecognized adverse consequence of this commonly employed therapy in patients with kidney failure.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cem\u003eStudy Population and Design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective, single-center observational study was conducted at the University of Colorado Hospital, a quaternary care center in Aurora, Colorado. \u0026nbsp;As no prior studies have evaluated CKRT-mediated clearance of TSH or thyroid hormones, no existing data were available to guide enrollment targets. Based on our prior experience (23, 24), we determined that 50 CKRT subjects would be sufficient for this pilot study.\u003c/p\u003e\n\u003cp\u003eFifty CKRT subjects were enrolled between March 2024 and July 2024. Subjects were eligible if they were \u0026ge;18 years of age, admitted to an ICU, and receiving CKRT as recommended by the nephrology consult service, which operated independently of the research team. Subjects with hypothyroidism on thyroid hormone supplementation were eligible for enrollment. Pregnant and incarcerated patients were excluded. Eligible patients were approached within 24 hours of CKRT initiation, and the day of enrollment was designated as day 1. Paired serum and effluent samples of TSH, fT4, fT3, and serum samples of rT3 were collected on days 1, 3, 8, and 14 between approximately 8:00 AM and 12:00 PM and were immediately transported to the hospital clinical laboratory for analysis. For pre-CKRT measurements, refrigerated serum samples drawn within 24 hours prior to CKRT initiation and stored in the hospital laboratory were used to assess TSH and fT4 levels (fT3 and rT3 could not be assessed in these stored samples).\u003c/p\u003e\n\u003cp\u003eA control cohort of 50 ICU patients not receiving CKRT was enrolled between July 2024 and October 2024. Eligible patients were \u0026ge;18 years of age and receiving ICU care with mechanical ventilation and/or vasopressor or inotropic support, reflecting the clinical profile of most CKRT patients (25). Control subjects with hypothyroidism on thyroid hormone supplementation were eligible for enrollment. Exclusion criteria included pregnancy, incarceration, or receipt of KRT for AKI within five days prior to study inclusion.\u0026nbsp;The day of study enrollment was considered day 1, and serum samples were collected on days 1, 3, 8, and 14 between 8:00 AM and 12:00 PM and immediately delivered to the hospital laboratory for analysis. To align with CKRT sampling methods, refrigerated serum samples drawn within 24 hours prior to enrollment were used to assess \u0026quot;pre\u0026quot; TSH and fT4 levels. Four control patients initiated CKRT during the study period; data collected after CKRT initiation in control subjects were excluded from analysis.\u003c/p\u003e\n\u003cp\u003eStudy approval was obtained locally from the Colorado Multiple Institutional Review Board (COMIRB), and informed consent was obtained from the subject directly when possible, or from an authorized representative if the subject was unable to provide informed consent. All experiments were performed in accordance with relevant guidelines and regulations as set forth by COMIRB.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDemographic Data and Definitions\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBaseline creatinine\u003c/em\u003e was determined as previously described (24). \u003cem\u003eAKI\u003c/em\u003e and \u003cem\u003estage\u003c/em\u003e were classified according to KDIGO serum creatinine criteria: Stage 1 was defined as an increase in serum creatinine \u0026gt;0.3 mg/dL from baseline and \u0026le;2\u0026times; baseline, Stage 2 as an increase \u0026ge;2\u0026times; to \u0026le;3\u0026times; baseline, and Stage 3 as an increase \u0026ge;3\u0026times; baseline or a serum creatinine \u0026ge;4.0 mg/dL (28). Although the need for dialysis is considered Stage 3 AKI, and all CKRT patients would meet this definition, we categorized patients based solely on creatinine criteria prior to KRT initiation to better reflect underlying AKI severity and offer a comparison to control patients that did not receive CKRT. \u003cem\u003eBaseline estimated glomerular filtration rate\u0026nbsp;\u003c/em\u003e(eGFR) was determined using baseline creatinine and the non-race corrected 2021 CKD-EPI formula (29). \u003cem\u003eESKD\u003c/em\u003e was defined as requiring hemodialysis or peritoneal dialysis for 90 days before enrollment. \u003cem\u003eSequential Organ Failure Assessment\u003c/em\u003e (SOFA) scores were calculated as per the published definition, excluding the renal sub-score (30), with missing sub-category values assigned a score of \u0026lsquo;0\u0026rsquo;. Norepinephrine equivalents were determined as described previously (31). If PaO2 values were unavailable to calculate PaO2/FiO2, a SpO2/FiO2 ratio was used (32). \u003cem\u003eNonsurvivors\u0026nbsp;\u003c/em\u003ewere defined as patients who died within 30 days of CKRT initiation (CKRT cohort) or study enrollment (control cohort).Demographic data, CKRT parameters, and lab values were collected from the electronic health record.\u003c/p\u003e\n\u003cp\u003eThe study team, unblinded to disposition status, classified patients as \u0026ldquo;Off CKRT\u0026rdquo; if they discontinued CKRT or were discharged prior to study completion, including one CKRT patient who transferred to another hospital on day 3 and one who declined further blood draws. Control patients were classified as discharged if this occurred prior to study completion. Death or transition to hospice was recorded as deceased for both cohorts.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMeasurement of TSH, fT4, fT3, and rT3\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Serum and effluent TSH, fT4, and fT3 assays were performed by the University of Colorado Hospital Clinical Laboratory and serum rT3 assay was performed by ARUP Laboratories in Salt Lake City, Utah. TSH was quantified with a two-site immunoenzymatic assay (Beckman Coulter ACCESS, Loveland, CO, USA). fT4 and fT3 were quantified using a competitive chemiluminescent immunoassay (Siemens ADVIA Centaur, Malvern, PA, USA). \u0026nbsp;rT3 was assessed using quantitative liquid chromatography-tandem mass spectrometry (ARUP Laboratories, Salt Lake City, UT, USA). Serum reference ranges were: TSH, 0.45\u0026ndash;5.33 mIU/L; fT4, 0.89\u0026ndash;1.76 ng/dL; fT3, 2.3\u0026ndash;4.2 pg/mL; rT3, 9.0\u0026ndash;27.0 ng/dL. Reference ranges for CKRT effluent have not been established.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInterpretation of Thyroid Function Tests\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn endocrinologist (WHC), blinded to study cohort and disposition, interpreted thyroid function status based on serum TSH, fT4, fT3, and rT3 on days 1, 3, 8, and 14, as well as \u0026ldquo;pre\u0026rdquo; TSH and fT4 for all 100 subjects. Thyroid function status was first adjudicated at the day 1 time point and subsequent time points were adjudicated within the context of day 1 status. Day 1 \u003cstrong\u003eNTIS\u003c/strong\u003e was defined by: \u003cstrong\u003e1)\u003c/strong\u003e \u0026darr;fT3 or \u0026darr;fT4 and normal/\u0026darr;TSH; \u003cstrong\u003eOR 2)\u0026nbsp;\u003c/strong\u003enormal fT3 and fT4 with normal/\u0026darr;TSHand rT3 \u0026gt;36.68 ng/dL (lower quartile of all rT3 samples); \u003cstrong\u003eOR 3)\u003c/strong\u003e \u0026uarr;TSH (up to \u0026lt;20mIU/L) and rT3 \u0026gt;36.68 ng/dL with subsequent downward trends. These criteria are similar to those described by Mahashabde et al. (33). \u003cstrong\u003eNTIS recovering\u003c/strong\u003e was defined by initial evidence of NTIS with a subsequent consistent rise in TSH (\u0026ge;50% increase from initial NTIS level) and further supported by a decreasing trend in rT3. Once a subject showed evidence of NTIS, they were presumed to have continued NTIS or NTIS recovering; however, a TSH rising to \u0026gt;20 mIU/L was considered hypothyroidism rather than NTIS recovering (34). Day 1 \u003cstrong\u003ehypothyroidism\u003c/strong\u003e was further distinguished from NTIS/NTIS recovering by\u0026darr;fT3 or \u0026darr;fT4, \u0026uarr;TSH, and rT3 \u0026lt;36.68 ng/dL, with no evidence of NTIS/NTIS recovering at subsequent time points. \u003cstrong\u003eSubclinical hypothyroidism\u003c/strong\u003e was defined as normal fT3/fT4, \u0026uarr;TSH, and rT3 \u0026lt;36.68 ng/dL, with no evidence of NTIS/NTIS recovering at subsequent time points. \u003cstrong\u003eHyperthyroidism\u003c/strong\u003e was defined as \u0026uarr;fT4 or \u0026uarr;fT3 and \u0026darr;TSH, with no evidence of NTIS/NTIS recovering at subsequent time points. \u003cstrong\u003eSubclinical hyperthyroidism\u003c/strong\u003e was defined as normal fT4/fT3 and \u0026darr;TSH, with no evidence of NTIS/NTIS recovering at subsequent time points. \u003cstrong\u003eEuthyroid\u003c/strong\u003e was defined as TSH, fT3, and fT4 all within the reference limit, with no evidence of NTIS/NTIS recovering at subsequent time points. These criteria are summarized in \u003cstrong\u003eTable 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCKRT Protocol\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCKRT was performed using the NxStage\u0026reg; System One\u0026trade; S machines and NxStage Purema H filters, which are biocompatible polyethersulfone membranes. Of the 50 CKRT patients, 47 were initiated on continuous venovenous hemodialysis (CVVHD) and 3 on continuous venovenous hemofiltration (CVVH). The typical CKRT prescription at the University of Colorado Hospital included a blood flow rate of 300 mL/min and a dose of 20\u0026ndash;25 mL/kg/hr (7). CKRT was generally initiated without anticoagulation, with anticoagulation added as needed based on filter clotting; no patients received citrate anticoagulation. Decisions regarding discontinuation or transition to intermittent KRT were made by the nephrology consult service, independent of the research team. CKRT data (time on CKRT, hourly effluent volume, and average CKRT dose per interval) were obtained from the electronic health record and calculated as previously described\u0026nbsp;(24). Total effluent volume was determined by summing the hourly recorded therapy fluid volume and ultrafiltrate over the 24-hour period preceding thyroid hormone lab collection.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClearance and Sieving Coefficient Calculations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe sieving coefficient (SC) and CKRT clearance were calculated using the following equations as previously described for the clearance of other solutes (35, 36):\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cp\u003eTo quantify removal over 24 hours of CKRT, we calculated the median (IQR) amount removed from the 24-hour periods preceding days 3, 8, and 14, excluding day 1, as subjects had been on CKRT for an average of only 13 hours prior to this time point.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFisher\u0026rsquo;s exact test and unpaired t-tests were used for comparisons of demographics, baseline lab values, thyroid adjudication status, and the distribution of TSH, fT4, and fT3 values categorized as below, within, or above the reference range. Two strata were created: one including all control and CKRT patients, and another including only NTIS patients with SOFA scores of either \u0026le;8 or 9\u0026ndash;13 from both the control and CKRT cohorts. Unpaired Fisher\u0026rsquo;s Least Significant Difference tests were used to directly compare serum TSH, fT4, fT3, rT3, and SOFA between CKRT and control cohorts at pre, day 1, day 3, and day 8. Day 14 was not included in NTIS subgroup analyses due to substantial dropout in both cohorts. Data only from time points when patients remained hospitalized were included in statistical analyses, as these provided the appropriate basis for between-group comparisons. Due to clerical laboratory error, seven TSH, four fT4, one fT3, and eight rT3 values in total were unable to be assessed. Statistical significance was defined as a p-value \u0026lt;0.05. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eControl and CKRT Cohort Characteristics\u003c/h2\u003e\u003cp\u003eAs shown in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e, the CKRT cohort had a younger median age and higher baseline serum creatinine (1.07 vs. 0.94 mg/dL; p\u0026thinsp;=\u0026thinsp;0.0363) compared to controls. As expected, the CKRT cohort had patients with more advanced chronic kidney disease, including ESKD. Comorbidities such as hypertension, coronary artery disease, and heart failure were common and similar among both groups, except for chronic liver disease (more prevalent in CKRT patients) and solid malignancies (more prevalent in controls). Rates of hypothyroidism and thyroid hormone supplementation were similar between CKRT and control subjects. Use of mechanical ventilation was similar in both groups, while day 1 SOFA score and 30-day mortality were both higher in CKRT patients.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eThyroid Hormones, Thyroid Function Status, and Disposition\u003c/h2\u003e\u003cp\u003eCKRT patients had significantly lower median TSH, fT4, and fT3 than controls at the pre and day 1 time points (Fig.\u0026nbsp;1a-c). For both CKRT patients and controls, the majority of TSH levels were within the normal reference range at the pre time point (CKRT 82% vs. Controls 62%; p\u0026thinsp;=\u0026thinsp;0.04) and on day 1 (CKRT 66% vs. Controls 69%; p\u0026thinsp;=\u0026thinsp;0.83) (\u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). The majority of fT4 levels at the pre and day 1 time points were below the reference range in CKRT patients and this finding was more common than in controls (CKRT 53% vs. Controls 19% for pre; p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001;CKRT 56% vs. Controls 34% for day 1; p\u0026thinsp;=\u0026thinsp;0.04). Serum fT3 was below the reference range in the majority of both groups on day 1 and this finding was more common in CKRT patients (CKRT 94% vs. Control 68%; p\u0026thinsp;=\u0026thinsp;0.002). Both serum rT3 and SOFA, indicators of NTIS and critical illness respectively, were increased in CKRT patients versus controls (Fig.\u0026nbsp;1d-e).\u003c/p\u003e\u003cp\u003eThyroid function assessment for all patients through the 14-day observation period is shown in \u003cb\u003eFig.\u0026nbsp;2\u003c/b\u003e. On day 1, all categories of thyroid function status were evident in the overall ICU population, including euthyroid, hyperthyroid, and hypothyroid status. On day 1, CKRT patients were more likely to have NTIS versus controls (CKRT 88% vs. Controls 64%; p\u0026thinsp;=\u0026thinsp;0.009), and none of the CKRT patients were euthyroid. CKRT patients also had indicators of more severe illness than controls, with no attainment of euthyroid status, lower rates of discharge from the hospital, and higher mortality over the observation period.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eCKRT Parameters; Effluent Levels, Sieving Coefficient, and CKRT Clearance of TSH\u003c/h2\u003e\u003cp\u003eCKRT parameters including dose, time on CKRT, and total effluent volume (for the preceding 24 hours) are reported in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eTo determine if removal of TSH and thyroid hormones occurred during CKRT, effluent levels were assessed. Effluent is not an FDA-approved sample type for the TSH, fT4 and fT3 assays offered by our hospital laboratory. Therefore, any interfering effect from effluent matrix on measurement of these analytes is unknown. To assess the accuracy of the effluent measurements, effluent sampled from a mock CKRT circuit (i.e., not connected to a patient) was analyzed; samples analyzed included effluent collected directly from the dialysate bag, and then pre-filter and post-filter at 5, 20, and 25 minutes (n\u0026thinsp;=\u0026thinsp;7 sample total). These \u0026ldquo;blank\u0026rdquo; effluent samples were assessed for TSH, fT4, and fT3 using the same clinical platform as serum. In all samples, TSH levels were below the detection limit (i.e., \u0026lt; 0.01 mIU/L); for fT4, levels were 0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03 ng/dL; for fT3 levels were 2.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03 (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD). Then, to quantify potential imprecision introduced by effluent matrix a \u0026ldquo;within-run\u0026rdquo; replicant study was performed utilizing a Clinical Laboratory and Standards Laboratory Institute protocol commonly employed in the clinical laboratory setting (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Effluent from the post filter 25-minute sample was measured 10 consecutive times for TSH, fT4, and fT3. Replicant measurements for TSH were all undetectable. fT4 was 0.178\u0026thinsp;\u0026plusmn;\u0026thinsp;0.048 ng/dL with a coefficient of variation (CV) % of 27.1%. fT3 was 2.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 pg/mL with a CV % of 13.05%. Together, these data indicate that there was no matrix interference with the TSH assay and that these measurements can be considered reliable. For fT3, the mean values in the blank effluent (2.24) and replicant study (2.1) were greater than all of the effluent fT3 measurements from patients (1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29 pg/mL, n\u0026thinsp;=\u0026thinsp;111) indicating substantial matrix interference for the assay and an inability to determine the presence or absence of fT3 in the effluent. For fT4, the majority of values were greater than the mean of the blank effluent measurements and the replicant study (i.e., 92% were greater than 0.12; 52% were greater than 0.178; n\u0026thinsp;=\u0026thinsp;109) indicating that fT4 is detectable in the effluent, however, the imprecision introduced by matrix interference indicates that levels cannot be accurately quantified.\u003c/p\u003e\u003cp\u003eTSH clearance by CKRT was then assessed by calculating sieving coefficient and daily removal. The sieving coefficient of TSH was 0.15, 0.15, 0.16, and 0.16 on days 1, 3, 8, and 14, respectively (\u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e), indicating that approximately 15% of plasma levels of TSH is continuously removed during CKRT; this equates to the removal of 12 mIU per 24 hours of CKRT.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eThyroid Function Tests in CKRT and Control Patients with NTIS\u003c/h2\u003e\u003cp\u003eHaving established that CKRT removes TSH and fT4, we next asked whether this clearance impacts HPT axis function; these analyses were limited to patients with NTIS to ensure comparison groups with similar baseline HPT pathophysiology and function. As shown in \u003cb\u003eFig.\u0026nbsp;3\u003c/b\u003e, median fT4 and fT3 were significantly reduced in NTIS CKRT patients compared to NTIS controls at all time points except day 8, which approached statistical significance (P\u0026thinsp;=\u0026thinsp;0.07 for fT3; P\u0026thinsp;=\u0026thinsp;0.07 for fT4, CKRT versus control, day 8). TSH was similar between the groups. Serum rT3 and SOFA scores were significantly increased in NTIS CKRT patients versus NTIS controls at all time points.\u003c/p\u003e\u003cp\u003e\u003cb\u003eThyroid Function Tests in CKRT and Control Patients with NTIS\u003c/b\u003e, \u003cb\u003eStratified by Survivorship and SOFA Scores\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSince severity of critical illness is associated with NTIS severity and SOFA scores were higher in NTIS CKRT patients versus NTIS controls, we stratified the NTIS cohorts using two methods: 1) by survivorship (i.e., survivors versus nonsurvivors) and 2) by SOFA score (i.e., SOFA score\u0026thinsp;\u0026le;\u0026thinsp;8 or SOFA score 9\u0026ndash;13) \u0026ndash; in order to compare CKRT and control patients with similar levels of critical illness.\u003c/p\u003e\u003cp\u003eTFTs in survivors and nonsurvivors with NTIS are shown in Fig.\u0026nbsp;4. Levels of fT4 and fT3 were similar between NTIS CKRT survivors versus and NTIS control survivors on all days. In contrast, fT4 was significantly decreased in nonsurvivor NTIS CKRT patients compared to nonsurvivor NTIS controls on all days assessed; fT3 was significantly decreased on day 3 and approached statistical significance on day 8 (P\u0026thinsp;=\u0026thinsp;0.08) in nonsurvivors NTIS CKRT versus nonsurvivors NTIS control. rT3 was significantly increased on day 3 in NTIS CKRT nonsurvivors compared to NTIS control survivors. SOFA was significantly increased at all time points in NTIS CKRT nonsurvivors versus NTIS control nonsurvivors.\u003c/p\u003e\u003cp\u003eTFTs by SOFA score groupings (\u0026le;\u0026thinsp;8 or 9\u0026ndash;13) is shown in \u003cb\u003eFig.\u0026nbsp;5\u003c/b\u003e. Only the more severely ill subjects (SOFA 9\u0026ndash;13) demonstrated lower fT4 and fT3 levels in NTIS CKRT subjects compared to controls (Fig.\u0026nbsp;5c-f). TSH was similar between NTIS CKRT and controls in both groups (Fig.\u0026nbsp;5a-b). Notably, rT3 levels were generally similar between NTIS CKRT subjects and controls who had either SOFA\u0026thinsp;\u0026le;\u0026thinsp;8 or SOFA 9\u0026ndash;13, suggesting that this categorization was effective in identifying similarly ill patients in the CKRT and control groups since increased levels of rT3 may reflect severity of illness (Fig.\u0026nbsp;5g-h). As shown in \u003cb\u003eFig.\u0026nbsp;6a-d\u003c/b\u003e, clinical thyroid status demonstrates a prolonged NTIS in the CKRT subjects, regardless of SOFA severity on day 1. Thus, in severely ill patients with SOFA scores from 9\u0026ndash;13, CKRT subjects have lower levels of fT4, fT3, and prolonged NTIS than controls suggesting the severity of illness does not fully explain the thyroid derangements observed during CKRT.\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study addresses the knowledge gap regarding thyroid function before and during CKRT. The major findings are that: 1) patients requiring CKRT have a greater rate and severity of NTIS versus ICU controls; 2) both TSH and fT4 are removed by CKRT, 3) levels of fT4 and fT3 are lower in nonsurvivors requiring CKRT, and 4) patients requiring CKRT have prolonged NTIS. These novel complications may contribute to the high mortality rate observed in patients with either AKI or ESKD who require CKRT.\u003c/p\u003e\u003cp\u003eOverall, the data in the present report demonstrate that a broad spectrum of thyroid function abnormalities exists in critically ill patients (with or without CKRT requirement), including hypothyroidism, hyperthyroidism, and NTIS. Of the 100 critically ill patients assessed, only 8 were euthyroid at study enrollment (all of whom were controls). NTIS was the predominant abnormality in CKRT patients, affecting a greater proportion at onset (88% vs. 64% in controls p\u0026thinsp;=\u0026thinsp;0.009) and persisting throughout the course of CKRT. Notably, no CKRT patient \u0026ndash; either in the full cohort or the NTIS subgroup \u0026ndash; achieved euthyroid status during the two weeks of assessment. Furthermore, NTIS was more severe in CKRT patients with 59% having a fT4 level that was below the reference range; in contrast, only 28% of NTIS controls had reduced fT4 which is similar to the rate observed in other ICU studies (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). NTIS with low fT4 is an important subset of NTIS since it is associated with worse clinical outcomes including longer ICU stays, greater rates of mechanical ventilation, and increased mortality compared to those with normal fT4 (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) \u0026ndash; findings known to occur in patients requiring CKRT.\u003c/p\u003e\u003cp\u003eWe demonstrate that fT4 and TSH are both removed by CKRT which may have adverse effects. The severe NTIS phenotype observed at study enrollment continued during CKRT treatment with persistently lower levels of fT4 and fT3 and prolonged NTIS versus controls. This trend was especially evident when comparing CKRT and control patients with a high severity of illness (i.e., SOFA scores 9\u0026ndash;13). CKRT could contribute to these thyroid derangements through direct fT4 removal, maintaining lower levels of fT4 and diminishing a compensatory rise in TSH. Based on the quantities removed, however, we suspect that TSH removal could have the most significant clinical impact since the amount of TSH removed per day (approximately 12 mIU) equates to over 10% of normal daily TSH production (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Despite lower fT4 and fT3, TSH was not at any point significantly elevated in CKRT patients compared to controls suggesting that critically ill CKRT patients are unable to centrally stimulate the HPT axis sufficiently (via TSH) to maintain thyroid hormone levels comparable to their non-CKRT counterparts. While severity of illness may contribute to this effect, our data suggest that the severity of thyroid function status may be exacerbated in the face of TSH removal.\u003c/p\u003e\u003cp\u003eRegardless of the underpinning mechanisms of NTIS severity and duration, our findings have clinical significance for CKRT patients since NTIS with low fT4 and/or fT3 is associated with increased ICU mortality (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). While the adaptive versus maladaptive nature of NTIS early in critical illness remains debated (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), prolonged NTIS may exert harmful effects resembling hypothyroidism, including prolonged mechanical ventilation (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), cognitive impairment, myocardial dysfunction, muscle weakness (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), immune dysfunction (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e), and fluid retention with generalized edema (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e) \u0026ndash; all of which may impair recovery from critical illness. Although previous studies of thyroid hormone supplementation in NTIS have shown mixed, but largely negative results for clinical outcomes (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), none focused on patients with the added stress of CKRT. Our data suggest that there may be a subset of severely ill CKRT patients who have an HPT axis that cannot adequately compensate for hormone losses and who might benefit from hormone replacement or thyrotropin-releasing hormone (TRH) analogs.\u003c/p\u003e\u003cp\u003eThis study has several strengths. Unlike many CKRT studies which estimate solute clearance using prescribed dose, modeling, or a short time frame, we quantified CKRT total effluent volume per 24 hours and examined paired serum and effluent samples over several days, allowing us to calculate sieving coefficient, clearance, and amount of TSH removed per day. Our cohort of 50 CKRT patients is large, and we included a contemporaneous control group. Lastly, the prospective design with daily thyroid status adjudication is novel in both the CKRT and NTIS literature.\u003c/p\u003e\u003cp\u003eThis study has several limitations. While an improvement over other CKRT studies which generally lack a control group, it is difficult to eliminate severity of critical illness as a confounder for the effects of CKRT on hormone levels. We believe that the SOFA score groupings successfully identified comparable cohorts, yet CKRT patients may still have been more critically ill due to factors not captured by SOFA score. While low fT3 and fT4 are predictors of ICU mortality (\u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e) and were lower in CKRT nonsurvivors, assessing whether fT4 or fT3 were independent risk factors for mortality would require a larger, dedicated study. We did not study membrane adsorption, whereby solutes bind to the dialysis membrane and are not found in the effluent, which may have led to an underestimation of hormone clearance. Effluent fT3 could not be quantified with the clinical assay available and some amount of matrix interference with the fT4 assay was identified; thus, quantitative effluent levels of both hormones may be better assessed with different assays. However, our data do provide insight into the fact that a two-site immunoenzymatic or \u0026ldquo;sandwich\u0026rdquo; assay, as used in TSH measurement, does not display potential effluent matrix-related interference seen with a competitive chemiluminescent immunoassay methodology. The patient population was heterogeneous (e.g., included ESKD patients who have higher rates of thyroid disease (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e)) and our study was not designed to examine specific subpopulations. Finally, medications known to suppress the HPT axis (e.g., corticosteroids and dobutamine) (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e) were used (although utilization rates were similar between groups).\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn conclusion, this is the first study to assess thyroid function in CKRT patients. We demonstrate that patients with AKI or ESKD requiring CKRT have a greater rate, severity, and duration of NTIS versus ICU controls, which may be affected by removal TSH and fT4. These novel complications may contribute to the high mortality rate observed in patients with either AKI or ESKD who require CKRT.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAKI\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcute Kidney Injury\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCKRT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eContinuous Kidney Replacement Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eTSH\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eThyroid-Stimulating Hormone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003efT4\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFree Thyroxine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003efT3\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFree Triiodothyronine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003erT3\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eReverse Triiodothyronine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eNTIS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNon-Thyroidal Illness Syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eHPT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypothalamic-Pituitary-Thyroid\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eSOFA\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSequential Organ Failure Assessment\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eESKD\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEnd-Stage Kidney Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eeGFR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEstimated Glomerular Filtration Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eICU\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntensive Care Unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCVVHD\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eContinuous Venovenous Hemodialysis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCVVH\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eContinuous Venovenous Hemofiltration\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eBUN\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBlood Urea Nitrogen\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eSC\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSieving Coefficient.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eStudy approval was obtained locally from the Colorado Multiple Institutional Review Board, and consent was obtained from the subject directly when possible, or from an authorized representative if the subject was unable to consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors have no competing interests to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was funded by the Division of Renal Diseases and Hypertension at the University of Colorado School of Medicine\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMK: conceptualization, methodology, formal analysis, investigation, data curation, writing – original draft, visualization\u003c/p\u003e\n\u003cp\u003eDM: investigation, data curation, writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eNF: investigation, data curation, writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eKO: investigation, resources, project administration\u003c/p\u003e\n\u003cp\u003eZH: investigation, resources, project administration\u003c/p\u003e\n\u003cp\u003eIB: methodology, writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eMY: methodology, investigation, writing – review and editing\u003c/p\u003e\n\u003cp\u003eBG: methodology, writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eBK: methodology, writing – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eMD: methodology, writing, investigation – review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eWC: conceptualization, methodology, investigation, adjudication, writing – original draft, visualization, supervision\u003c/p\u003e\n\u003cp\u003eSF: conceptualization, methodology, formal analysis, investigation, resources, data curation, writing – original draft, visualization, supervision, project administration, funding acquisition\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We gratefully acknowledge the University of Colorado Hospital Clinical Laboratory for their support in the analysis of research samples.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eRewa O, Bagshaw SM. Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol. 2014;10(4):193-207.\u003c/li\u003e\n \u003cli\u003eBagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH, Mucenski M, et al. Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care. 2005;9(6):R700-9.\u003c/li\u003e\n \u003cli\u003eUchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813-8.\u003c/li\u003e\n \u003cli\u003eWalcher A, Faubel S, Keniston A, Dennen P. In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD. Ren Fail. 2011;33(10):935-42.\u003c/li\u003e\n \u003cli\u003eInvestigators RRTS, Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, et al. Intensity of continuous renal-replacement therapy in critically ill patients. 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Association between severity of sepsis and thyroid function profile. Acta Biomed. 2023;94(6):e2023239.\u003c/li\u003e\n \u003cli\u003eSciacchitano S, De Vitis C, D\u0026apos;Ascanio M, Giovagnoli S, De Dominicis C, Laghi A, et al. Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies. J Transl Med. 2021;19(1):139.\u003c/li\u003e\n \u003cli\u003eSchultheiss UT, Steinbrenner I, Nauck M, Schneider MP, Kotsis F, Baid-Agrawal S, et al. Thyroid function, renal events and mortality in chronic kidney disease patients: the German Chronic Kidney Disease study. Clin Kidney J. 2021;14(3):959-68.\u003c/li\u003e\n \u003cli\u003eCotoi L, Borcan F, Sporea I, Amzar D, Schiller O, Schiller A, et al. Thyroid Pathology in End-Stage Renal Disease Patients on Hemodialysis. Diagnostics (Basel). 2020;10(4).\u003c/li\u003e\n \u003cli\u003eDavies PH, Franklyn JA. The effects of drugs on tests of thyroid function. Eur J Clin Pharmacol. 1991;40(5):439-51.\u003c/li\u003e\n \u003cli\u003eLee E, Chen P, Rao H, Lee J, Burmeister LA. Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH). Clin Endocrinol (Oxf). 1999;50(4):487-92.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"continuous kidney replacement therapy (CKRT), thyroid function, non-thyroidal illness syndrome (NTIS), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), reverse T3 (rT3), critical illness","lastPublishedDoi":"10.21203/rs.3.rs-7394781/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7394781/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eAcute kidney injury (AKI) and end stage kidney disease (ESKD) requiring continuous kidney replacement therapy (CKRT) are associated with high mortality. Solutes up to 40 kilodaltons (kDa) in size are amenable to CKRT clearance which includes thyroid stimulating hormone (TSH)(28 kDa), free thyroxine (fT4)(0.78 kDa), and free triiodothyronine (fT3)(0.68 kDa). The effect of CKRT on TSH and thyroid hormone clearance, thyroid function, and the hypothalamic-pituitary-thyroid (HPT) axis is unknown.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eThis prospective, single-center observational study enrolled 50 ICU patients requiring CKRT and 50 control ICU patients. Serum TSH, fT4, fT3, and reverse T3 (rT3) were measured prior to and on days 1, 3, 8, and 14 after CKRT initiation; effluent TSH, fT4, and fT3 were measured on days 1, 3, 8, and 14. Thyroid function status was adjudicated on days 1, 3, 8, and 14. Statistical analyses included Fisher\u0026rsquo;s exact tests, unpaired t-tests, and Fisher\u0026rsquo;s Least Significant Difference tests to compare differences in thyroid hormones and Sequential Organ Failure Assessment (SOFA) scores.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003ePrior to and during CKRT, CKRT patients had reduced TSH, fT4, and fT3 levels compared to controls, with a higher proportion of values below the normal reference range. TSH and fT4 were present in the CKRT effluent, indicating clearance by CKRT. More severe and prolonged non-thyroidal illness syndrome (NTIS) was seen in the CKRT cohort compared to controls with similar severity of illness as judged by SOFA scores. No CKRT patient achieved euthyroid status during the study.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e\u003cp\u003eThis is the first study to assess thyroid function in CKRT patients. We demonstrate that patients requiring CKRT have a greater rate, severity, and duration of NTIS versus ICU controls, which may be affected by removal of TSH and fT4. These novel complications may contribute to the high mortality rate observed in patients with either AKI or ESKD who require CKRT.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e","manuscriptTitle":"Thyroid Function With Continuous Kidney Replacement Therapy: A Prospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-25 13:41:04","doi":"10.21203/rs.3.rs-7394781/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fd96b35f-c37b-4946-8a46-a4abcce471f9","owner":[],"postedDate":"September 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55304627,"name":"Health sciences/Diseases"},{"id":55304628,"name":"Health sciences/Endocrinology"},{"id":55304629,"name":"Health sciences/Medical research"},{"id":55304630,"name":"Health sciences/Nephrology"}],"tags":[],"updatedAt":"2026-05-19T18:55:00+00:00","versionOfRecord":{"articleIdentity":"rs-7394781","link":"https://doi.org/10.34067/KID.0000001220","journal":{"identity":"kidney360","isVorOnly":true,"title":"Kidney360"},"publishedOn":"2026-05-04 00:00:00","publishedOnDateReadable":"May 4th, 2026"},"versionCreatedAt":"2025-09-25 13:41:04","video":"","vorDoi":"10.34067/KID.0000001220","vorDoiUrl":"https://doi.org/10.34067/KID.0000001220","workflowStages":[]},"version":"v1","identity":"rs-7394781","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7394781","identity":"rs-7394781","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}