Prospective comparison of diagnostic tests for bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75-Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α-hydroxy-4-cholesten-3-one (C4) is inexpensive but lacks sensitivity. AIMS: To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT. METHODS: This diagnostic accuracy study was part of a randomised, placebo-controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient-reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation. RESULTS: Ninety-six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%-79%) sensitivity and 65% (47%-80%) specificity; C4 > 46 ng/mL had 47% (37%-57%) and 92% (87%-96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%-85%) sensitivity and 95% (83%-99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%-90%) sensitivity and 93% (80%-98%) specificity. CONCLUSIONS: Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4-based testing, offering potential widely available diagnostics. Further validation is warranted. CLINICALTRIALS: gov: NCT03876717.

Protective effect of sacubitril/valsartan (Entresto) on kidney function and filtration barrier injury in a porcine model of partial nephrectomy.

Kidney surgery often includes organ ischaemia with a risk of acute kidney injury. The present study tested if treatment with the combined angiotensin II-angiotensin II receptor type 1 and neprilysin blocker Entresto (LCZ696, sacubitril/valsartan) protects filtration barrier and kidney function after ischaemia and partial nephrectomy (PN) in pigs. Single kidney glomerular filtration rate (GFR) by technetium-99m diethylene-triamine-pentaacetate clearance was validated (n = 6). Next, four groups of pigs were followed for 15 days (n = 24) after PN (one-third right kidney, 60 min ischaemia) + Entresto (49/51 mg/day; n = 8), PN + vehicle (n = 8), sham + Entresto (49/51 mg/day; n = 4) and sham + vehicle (n = 4). GFR, diuresis and urinary albumin were measured at baseline and from each kidney after 15 days. The sum of single-kidney GFR (right 25 ± 6 mL/min, left 31 ± 7 mL/min) accounted for the total GFR (56 ± 14 mL/min). Entresto had no effect on baseline blood pressure, p-creatinine, mid-regional pro-atrial natriuretic peptide (MR-proANP), heart rate and diuresis. After 15 days, Entresto increased GFR in the uninjured kidney (+23 ± 6 mL/min, P < .05) and reduced albuminuria from both kidneys. In the sham group, plasma MR-proANP was not altered by Entresto; it increased to similar levels 2 h after surgery with and without Entresto. Fractional sodium excretion increased with Entresto. Kidney histology and kidney injury molecule-1 in cortex tissue were not different. In conclusion, Entresto protects the filtration barrier and increases the functional adaptive response of the uninjured kidney.

Comparison of nuclear imaging techniques and volumetric imaging for the prediction of postoperative mortality and liver failure in patients undergoing localized liver-directed treatments: a systematic review.

BACKGROUND/AIMS: Although volumetric imaging by computed tomography (CT) is the gold standard for preoperative assessment of the future liver remnant, nuclear imaging studies have shown promising data. This systematic review summarized the results from trials investigating volumetric and nuclear medicine imaging for the prediction of postoperative mortality and liver failure (LF). METHODS: MEDLINE and Web of Science were searched for papers investigating nuclear imaging methods for the prediction of postoperative clinical outcomes in patients undergoing local, liver-directed treatments. Only papers investigating both preoperative nuclear imaging and CT or magnetic resonance imaging (MR) for the prediction of postoperative mortality and/or LF were included. RESULTS: Twenty-five trials were qualified for this review. All trials but two used technetium-based tracers for the nuclear imaging examination. Four papers used MR imaging and the remaining used CT for the volumetric evaluation. Overall, the studies were heterogeneous both in terms of methodology and imaging technique. Of the thirteen studies reporting on postoperative mortality, most were descriptive without detailed diagnostic data. A few with detailed data found that nuclear imaging had better predictive value than volumetric imaging. Nineteen studies investigated the prediction of postoperative LF of which seven papers investigated the predictive value of both modalities in multivariable regression analysis. Two papers found that only nuclear imaging parameters were predictive of LF, one paper found that the CT parameter was predictive, and four papers found that combined nuclear and CT/MR imaging parameters were predictive of LF. CONCLUSION: Both methodologies were useful in the preoperative assessment of patients scheduled for liver interventions, especially in combination, but nuclear imaging demonstrated better predictive value for postoperative mortality and LF in a few trials. The overall technical and methodological heterogeneity of the included studies complicates the ability to directly compare the clinical utility of the two imaging techniques.

Accuracy of hepatobiliary scintigraphy and added value of SPECT/CT versus planar imaging for diagnosing biliary atresia.

OBJECTIVE: Hepatobiliary scintigraphy (HBS) is an important tool in diagnosing biliary atresia in infants. There is limited evidence on the use of single photon emission computed tomography/computed tomography (SPECT/CT) as an additional imaging method to planar imaging. We evaluated the value of SPECT/CT in unclear cases of planar HBS. SUBJECTS AND METHODS: Consecutive patients with suspected biliary atresia who underwent guideline-compliant HBS from January 2010 until March 2020 were reviewed, and cases with SPECT/CT were identified. Each step within the imaging procedure (dynamic, static [early and late], and SPECT/CT) was blindly reread in consensus by two observers and categorized based on a 5-point scale: 0, definitely no bowel excretion (i.e., atresia confirmed); 1, probably positive; 2,equivocal; 3, probably negative; and 4, definite negative (i.e., atresia not confirmed). In this analysis, categories were dichotomized as negative for biliary atresia (scores 3-4) or positive (scores 0-2, including equivocal scans). Available follow-up information constituted the standard of truth (SoT). RESULTS: Twenty-three infants had HBS, among which ten (4 boys and 6 girls; mean age 36 days; range 8-108) underwent SPECT/CT. Single photon emission computed tomography SPECT/CT was performed as early examination (<8h) in 3 subjects and late (8 to 24 h) in 7 infants. Reread SPECT/CT was categorized as positive for atresia in three infants and negative in seven infants. The SoT showed biliary atresia in one of ten patients. Single photon emission computed tomography/CT was true positive in one case, false positive in two, and true negative in seven. No false negative cases were noted. The diagnostic performance of SPECT/CT showed a sensitivity of 100%, specificity of 78%, positive predictive value (PPV) of 33%, negative predictive value (NPV) of 100%, and accuracy of 90%. For comparison, the diagnostic performance of planar HBS showed a sensitivity of 100%, specificity of 67%, PPV of 25%, NPV of 100%, and accuracy of 70%. In summary, the addition of SPECT/CT to planar HBS improved specificity andaccuracyand marginally improved PPV. Single photon emission computed tomography/CT provided more confidence in the final conclusion in 8/10 patients. In the remaining two cases, SPECT/CT did not improve the level of confidence (one remained equivocal, and one changed from probably no excretion to equivocal). CONCLUSION: These preliminary data demonstrated increased accuracy of add-on SPECT to planar HBS predominantly due to improved specificity. This finding is consistent with the existing but limited literature and supports the recommendation of routine use of SPECT/CT or SPECT.

Nuclear imaging methods for the prediction of postoperative morbidity and mortality in patients undergoing localized, liver-directed treatments: a systematic review.

BACKGROUND: Several nuclear imaging methods may predict postoperative liver function and outcome, but none has achieved recommendations in clinical guidelines. The purpose of this systematic review was to summarize the existing knowledge on this topic. METHODS: MEDLINE and Web of Science were searched for studies investigating nuclear medicine imaging methods for the prediction of postoperative liver function in patients undergoing localized, liver-directed treatments. The postoperative endpoints were clinical outcome (morbidity and mortality) as well as measures of postoperative liver function, e.g., liver function assessed by biochemical tests or nuclear imaging. RESULTS: A total of 1352 references were identified, of which 82 fulfilled the eligibility criteria and were included in the review. Most studies (n = 63) were retrospective studies. The vast majority of studies assessed [99mTc]Tc-galactosyl serum albumin (GSA) (n = 57) and [99mTc]Tc-mebrofenin (n = 19). Liver resection was entirely or partly major (involved at least three segments) in 78 reports. There were notable variations in the research methodology, e.g., image acquisition, imaging variables, and endpoints. Thirty-seven studies reported on postoperative mortality, of which most reported descriptive data at the patient level. Of the four reports that performed multivariate analyses, two showed significant predictive results of isotope-based preoperative tests. Fifty-two papers presented data on postoperative liver failure. Multivariate predictive analyses were performed in eighteen trials, of which fifteen showed the significant value of nuclear medicine tests. CONCLUSION: There is sparse evidence supporting the significant value of nuclear medicine imaging methods in predicting postoperative mortality. In contrast, a notable number of trials showed a significant prediction of liver failure in multivariate analyses. The research methodology was heterogeneous and exploratory in most trials. Documentation of nuclear medicine tests in this setting awaits the results of properly designed, prospective trials with the standardization of both the nuclear medicine test and endpoints.

Biochemical Diagnosis of Bile Acid Diarrhea: Prospective Comparison With the 75Seleno-Taurohomocholic Acid Test.

INTRODUCTION: The diagnosis of bile acid diarrhea is often missed because the availability of the seleno-taurohomocholic acid (SeHCAT) test is limited. We aimed to compare the biomarkers 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) with the SeHCAT test. METHODS: Patients with chronic diarrhea without intestinal resection referred for SeHCAT were prospectively recruited for this diagnostic accuracy study. Blood was sampled at fasting and after a stimulation meal with chenodeoxycholic acid. SeHCAT retention ≤10% defined bile acid diarrhea and >10% defined miscellaneous diarrhea. Receiver operating characteristics (ROC) were analyzed with SeHCAT as the gold standard. www.clinicaltrials.gov (NCT03059537). RESULTS: Patients with bile acid diarrhea (n = 26) had mean C4 of 30 ng/mL (95% confidence interval: 19-46) vs 8 (7-11; P < 0.001) in the miscellaneous diarrhea group (n = 45). Area under the ROC curve (ROCAUC) for C4 was 0.83 (0.72-0.93). C4 < 15 ng/mL had 85% (74%-96%) negative predictive value; C4 > 48 ng/mL had 82% (59%-100%) positive predictive value. Twenty patients had C4 values 15-48 ng/mL, of whom 11/20 had SeHCAT ≤10%. Median fasting FGF19 was 72 pg/mL (interquartile range: 53-146) vs 119 (84-240) (P = 0.004); ROCAUC was 0.71 (0.58-0.83). Stimulated FGF19 responses did not differ (P = 0.54). DISCUSSION: We identified C4 thresholds with clinically useful predictive values for the diagnosis of and screening for bile acid diarrhea in patients with chronic watery diarrhea. Further validation of the cutoff values with the placebo-controlled effect of sequestrant therapy is warranted (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B603).

Sedation practice for paediatric nuclear medicine procedures in Denmark related to EANM guidelines.

OBJECTIVE: The objective of this study was to examine sedation practices for paediatric nuclear medicine examinations. METHODS: A questionnaire was sent to all nuclear medicine departments in Denmark about sedation practices during 2012. RESULTS: The response rate was 100% (18 departments). Three departments did not examine children at all. The total number of paediatric examinations among the remaining 15 sites varied from 20 to 1,583 (median 191). Sedation practice showed that approximately 50% of the sites regularly (>50% of the patients) used pharmacological sedation for renography in children aged 6-12 months and 1-3 years. A minority of centres (∼15%) regularly used sedation in children aged 0-6 months, and no sites regularly used sedation in children aged and 4-6 years. Similar findings were found for renal scintigraphy. However, one large site used no sedation in children aged 1-3 years for renography but approximately 50% of patients used it in the same age group receiving renal scintigraphy with SPET. There was a trend for reduced use of sedation with increasing total number of paediatric medicine procedures. The most frequently used agents were benzodiazepines and barbiturates. The most common route of administration was rectal, oral, and intravenous. CONCLUSION: The sedation practices varied considerably among Danish nuclear medicine departments. The sedation of children in clinical practice seemed to be more prevalent than is recommended by guidelines.

Effect of recent contrast-enhanced CT and patient age on image quality of thyroid scintigraphy.

PURPOSE OF THE REPORT: When thyroid scintigraphy (TS) is performed after contrast-enhanced CT (CE-CT), tracer uptake of 99mTcO4 in the thyroid gland can be inhibited by free iodide. Currently, it is recommended to postpone TS until 4 to 8 weeks after CE-CT, but few data exist to support this recommendation. The purpose was to investigate the effect of CE-CT and other variables for the diagnostic quality of TS. PATIENTS AND METHODS: This retrospective study included 196 patients subjected to TS less than 3 months after a CE-CT (median, 66 days). Patients with elevated thyroid-stimulating hormone (>4.5 mIU/L) or suspected thyroiditis were excluded. Logistic regression was used to calculate the probability of a TS of diagnostic quality with the variables days since CE-CT, age, thyroid-stimulating hormone, and kidney function (eGFR). RESULTS: Days since CT and age were highly significant (P < 0.001) predictors for diagnostic TS. The probability of diagnostic quality TS after CE-CT increased with time and reached approximately 70% to 80% 6 to 8 weeks after CE-CT. Analysis of age-specific populations showed age to be a strong independent factor. CONCLUSIONS: Our findings are in consensus with the currently recommended interval of 6 to 8 weeks between CE-CT and TS. However, our results indicate that patient age should be taken into account, and we suggest the following delay from CE-CT to TS: 4 weeks for patients aged younger than 50 years, 6 weeks for patients aged 50 to 60 years, and 8 weeks for patients aged older than 60 years.

Detecting reduced renal function in children: comparison of GFR-models and serum markers.

BACKGROUND: The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR)-models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results. METHODS: Glomerular filtration rate was measured by plasma clearance of (51)Cr-EDTA (13.7-147.4 mL/min/1.73 m(2)) in 119 children (age range 2.3-14.9 years). Reduced renal function was defined as a GFR of <82 mL/min/1.73 m(2). SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone. RESULTS: The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629-637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221-230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50-57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other variables (P < 0.01), with the BCM-model performing the best (P < 0.05). The SCr-based Schwartz formula and SCr-ratio both performed better than SCr and SCysC. CONCLUSIONS: Among the 119 children enrolled in this study and the renal indicators tested, the BCM-model had the best diagnostic performance in terms of screening for normal or reduced renal function, and the SCr-ratio was a superior diagnostic tool to both SCr and SCysC.

Estimating renal function in children: a new GFR-model based on serum cystatin C and body cell mass.

This PhD thesis is based on four individual studies including 131 children aged 2-14 years with nephro-urologic disorders. The majority (72%) of children had a normal renal function (GFR > 82 ml/min/1.73 square metres), and only 8% had a renal function < 50% of the normal mean value. The present thesis´ main aims were: 1) to develop a more accurate GFR model based on a novel theory of body cell mass (BCM) and cystatin C (CysC); 2) to investigate the diagnostic performance in comparison to other models as well as serum CysC and creatinine; 3) to validate the new models precision and validity. The model´s diagnostic performance was investigated in study I as the ability to detect changes in renal function (total day-to-day variation), and in study IV as the ability to discriminate between normal and reduced function. The model´s precision and validity were indirectly evaluated in study II and III, and in study I accuracy was estimated by comparison to reference GFR. Several prediction models based on CysC or a combination of CysC and serum creatinine have been developed for predicting GFR in children. Despite these efforts to improve GFR estimates, no alternative to exogenous methods has been found and the Schwartz´s formula based on height, creatinine and an empirically derived constant is still recommended for GFR estimation in children. However, the inclusion of BCM as a possible variable in a CysC-based prediction model has not yet been explored. As CysC is produced at a constant rate from all nucleated cells we hypothesize that including BCM in a new prediction model will increase accuracy of the GFR estimate. Study I aimed at deriving the new GFR-prediction model based on the novel theory of CysC and BCM and comparing the performance to previously published models. The BCM-model took the form GFR (mL/min) = 10.2 × (BCM/CysC)E 0.40 × (height × body surface area/Crea)E 0.65. The model predicted 99% within ± 30% of reference GFR, and 67% within ±10%. This was higher than any other model. The present model also had the highest R E2 and the narrowest 95% limits of agreement. If replacing BCM with weight (Weight-model) the results were almost as convincing. The total day-to-day variation of the GFR-estimate (7.7%) was low. The two new models are, however, still not sufficiently accurate to replace exogenous markers when GFR must be determined with high accuracy. Study II aimed at determining biological variation and analytical precision of serum CysC and creatinine. The precision of CysC (1.7%), and creatinine (2.5%) was very good and the day-to-day variation of CysC and creatinine (within-subject variation between two days) also proved very low (6.4% for both analytes). Because of a relatively low ratio between within-subject variation and between-subject variation neither CysC nor creatinine seems qualified to discriminate between normal and reduced renal function, which was also confirmed in study IV. However, the relatively low total day-to-day variation of 6.6% (CysC) and 6.9% (creatinine) indicate that both are suitable for detecting changes in renal function over time. Study III aimed at determining biological variation and analytical precision of BCM and all other parameters given by measurement by bioimpedance spectroscopy (BIS). Depending on parameter the precision was 0.3-0.8% in children ≥ 6 years and 0.5-2.4% in children < 6 years with a statistically significant difference between the two age-groups (p < 0.001). Within-day variation was 1.1-2.8% and between-day variation 2.4-5.7%. The median value of three repeated measurements is recommended in order to avoid incorrect measurements. Study IV aimed at investigating the diagnostic performance of the BCM-model by: 1) Determining cut-off levels for a three-sided diagnostic procedure with the following outcomes: normal renal function, reduced renal function, indeterminable; 2) Calculating the diagnostic probabilities of reduced renal function for the indeterminable results. The lower the number of children in between cut-off levels, the better the diagnostic performance. The BCM-model resulted in the smallest percentage (39%) of indeterminate children in need for further investigation. In conclusion, with the models developed in the present thesis we are able to provide the clinician with both a reasonably accurate estimate of renal function and a probability of reduced renal function. Furthermore, the positive results from study II and III on precision and biological variation indicate that CysC, creatinine and BCM are very stable variables, which is an indirect validation of the BCM-model´s precision and validity. This is also reflected in the relatively low total day-to-day variation of the GFR-estimate.

GFR prediction from cystatin C and creatinine in children: effect of including body cell mass.

BACKGROUND: Aiming to develop a more accurate cystatin C-based model for estimation of glomerular filtration rate (GFR) in children, we hypothesized that inclusion of body cell mass (BCM) would increase the accuracy of the GFR estimate in comparison to a well-established GFR reference method. STUDY DESIGN: Diagnostic test accuracy study. SETTINGS & PARTICIPANTS: 119 children (mean age, 8.8; range, 2.3-14.9 years) referred for GFR measurement by chromium 51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) clearance (mean GFR, 98; range, 13.7-147.4 mL/min/1.73 m(2)). INDEX TEST: GFR estimations by the 2 prediction models resulting from theoretical considerations corroborated by forward stepwise variable selection: GFR (mL/min) = 0.542 × (BCM/SCysC)(0.40) × (height × BSA/SCr)(0.65) and GFR (mL/min) = 0.426 × (weight/SCysC)(0.39) × (height × BSA/SCr)(0.64), where SCysC is serum cystatin C level, BSA is body surface area, and SCr is serum creatinine level. The accuracy and precision of these models were compared with 7 previously published prediction models using random subsampling cross-validation. Local constants and coefficients were calculated for all models. Root mean square error, R(2), and percentage of predictions within ±10% and ±30% of the reference GFR were calculated for all models. Based on 1,000 runs of the cross-validation procedure, median values and 2.5th and 97.5th quantiles of the validation parameters were calculated. REFERENCE TEST: GFR measurement by (51)Cr-EDTA clearance. RESULTS: The BCM model predicted 98% within ±30% of reference GFR and 66% within ±10%, which was higher than for any other model. The weight model predicted 97.5% within ±30% of reference GFR and 62% within ±10%. The BCM model had the highest R(2) and the smallest root mean square error. LIMITATIONS: Included only 9 children with GFR <60 mL/min/1.73 m(2). Lack of independent validation cohort. CONCLUSIONS: The novel BCM model predicts GFR with higher accuracy than previously published models. The weight model is almost as accurate as the BCM model and allows for GFR estimation without knowledge of BCM. However, endogenous methods are still not sufficiently accurate to replace exogenous markers when GFR must be determined with high accuracy.

Measuring glomerular filtration rate in children; can cystatin C replace established methods? A review.

Our aim was to evaluate published methods that use serum cystatin C (s-CysC) for measuring glomerular filtration rate (GFR) in children and to discuss advantages and limitations of s-CysC and of established GFR methods. A comprehensive literature review of clinical studies in children evaluating s-CysC or CysC-based formulas and plasma creatinine or creatinine-based formulas against an exogenous reference method using receiver operating characteristics (ROC) curves or Bland-Altman plots is presented. The comparison of s-CysC with plasma creatinine indicated that s-CysC was superior to plasma creatinine in five of 13 studies; four studies showed no difference, and, in four studies, no statistical comparison was made. Comparison of s-CysC and the Schwartz formula showed that s-CysC was superior to the Schwartz formula in two of seven studies; two studies demonstrated no difference, and, in one study, the Schwartz formula was superior to s-CysC. In two studies no statistical comparison was made. The CysC-based prediction equations all had high accuracy but low agreement when compared with a reference GFR, in the range of 30-40% at best. S-CysC is most likely superior to plasma creatinine and at least equal to creatinine-based formulas. CysC-based prediction equations are at least as good as creatinine-based formulas but cannot replace exogenous methods.