Maria Burniston

Utility and limitations of 3,3-diphosphono-1, 2-propanodicarboxylic acid scintigraphy in systemic amyloidosis

AIMS Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) is a sensitive method for imaging cardiac transthyretin (ATTR) amyloid. We report utility and limitations of (99m)Tc-DPD scintigraphy in 321 patients with suspected cardiac amyloidosis. METHODS AND RESULTS The cohort included wild-type ATTR (ATTRwt) amyloidosis in 94 (29%), ATTR-Val122Ile amyloidosis in 38 (12%), hereditary ATTR (ATTRmt) amyloidosis in 46 (14%), primary light-chain (AL) amyloidosis in 44 (14%), secondary (AA) amyloidosis in three (1%), other hereditary amyloidosis types in nine (3%), undetermined types in two (0.5%), and 85 (26.5%) patients in whom systemic amyloidosis was ultimately excluded. All 158 patients with ATTR amyloidosis with clinical cardiac involvement had cardiac (99m)Tc-DPD uptake, with median Grade 2 intensity. Thirteen further ATTR amyloidosis patients without clinical evidence of cardiac involvement also demonstrated (99m)Tc-DPD cardiac uptake. Eighteen of 35 (51%) AL patients with cardiac involvement had (99m)Tc-DPD cardiac uptake (median Grade 1 intensity). SPECT imaging indicates that the apparent reciprocal reduction in bone uptake is due to masking of bone uptake by extensive soft-tissue uptake in ATTR amyloidosis, especially ATTRwt, and ATTR-Val122Ile types. CONCLUSION (99m)Tc-DPD scintigraphy is a highly sensitive technique for imaging cardiac ATTR amyloidosis and is an important investigation in the diagnostic pathway of patients with cardiac amyloidosis. It is not specific for ATTR in isolation but must be interpreted in a broad clinical context to avoid dangerous diagnostic errors. Diffuse skeletal muscle uptake identifies muscle as a hitherto unrecognized site that merits investigation as a target organ in ATTR amyloidosis.

Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid

Aims High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99mTc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. Methods and results Patient survival from time of 99mTc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR (ATTRwt) and 225 with mutant ATTR (ATTRm) amyloidosis. Patients were stratified according to Perugini grade (0-3) on 99mTc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99mTc-DPD scan (n = 28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n = 28), 2 (n = 436) or 3 (n = 110) 99mTc-DPD scan (P < 0.005). There were no differences in survival between patients with a grade 1, grade 2 or grade 3 99mTc-DPD scan in ATTRwt (n = 369), V122I-associated ATTRm (n = 92) or T60A-associated ATTRm (n = 59) amyloidosis. Cardiac amyloid burden, determined by equilibrium contrast cardiac magnetic resonance imaging, was similar between patients with Perugini grade 2 and Perugini grade 3 99mTc-DPD scans but skeletal muscle/soft tissue to femur ratio was substantially higher in the latter group (P < 0.001). Conclusion 99mTc-DPD scintigraphy is exquisitely sensitive for identification of cardiac ATTR amyloid, but stratification by Perugini grade of positivity at diagnosis has no prognostic significance.

Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate.

Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between “true” and calculated glomerular filtration rate (GFR). We compared the performance of the four‐variable and six‐variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with “true,” or measured, GFR (mGFR) and the impact of this difference on Model for End‐Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≥3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine–0·836) × (urea–0·229) × (international normalized ratio–0·113) × (age−0.129 [Corrected November 29, 2016: originally written as “age‐129.”]) × (sodium0·972) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. Conclusion: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582‐591).

Validation of Tikhonov adaptively regularized gamma variate fitting with 24-h plasma clearance in cirrhotic patients with ascites

PurposeThe aim was to compare late-time extrapolation of plasma clearance (CL) from Tikhonov adaptively regularized gamma variate fitting (Tk-GV) and from mono-exponential (E1) fitting.MethodsTen 51Cr-ethylenediaminetetraacetic acid bolus IV studies in adults—8 with ascites—assessed for liver transplantation, with 12–16 plasma samples drawn from 5-min to 24-h, were fit with Tk-GV and E1 models and CL results were compared using Passing-Bablok fitting.ResultsThe 24-h CL(Tk-GV) values ranged from 11.4 to 79.7 ml/min. Linear regression of 4- versus 24-h CL(Tk-GV) yielded no significant departure from a slope of 1, whereas the 4- versus 24-h CL(E1) slope, 1.56, was significantly increased. For CL(Tk-GV-24-h) versus CL(E1-24-h), there was a biased slope and intercept (0.85, 5.97 ml/min). Moreover, the quality of fitting of 24-h data was significantly better for Tk-GV than for E1, as follows. For 10 logarithm of concentration curves, higher r values were obtained for each Tk-GV fit (median 0.998) than for its corresponding E1 fit (median 0.965), with p < 0.0001 (paired t-test of z-statistics from Fisher r-z transformations). The E1 fit quality degraded with increasing V/W [volume of distribution (l) per kg body weight, p = 0.003]. However, Tk-GV fit quality versus V/W was uncorrelated (p = 0.8).ConclusionCL(E1) values were dependent on sample time and the quality of fit was poor and degraded with increasing ascites, consistent with current opinion that CL(E1) is contraindicated in ascitic patients. CL(Tk-GV) was relatively more accurate and the good quality of fit was unaffected by ascites. CL(Tk-GV) was the preferred method for the accurate calculation of CL and was useful despite liver failure and ascites.

Development of a modified sampling and calculation method for isotope plasma clearance assessment of the glomerular filtration rate in patients with cirrhosis and ascites.

AimThe aim of this study was to identify a practical sampling regimen and calculation method that could be used to measure the glomerular filtration rate in patients with ascites using plasma sampling. Patients and methodsThirteen potential liver transplant patients with cirrhosis and ascites were injected with Cr-51 ethylenediaminetetraacetic acid, and plasma samples were obtained at up to 16 time points for each patient. Reference clearance values were calculated using the area under the plasma clearance curve, which was calculated using all the available data points. Clearance calculations were then performed using three and four data points from each patient and three different calculation methods to identify a sampling regimen and calculation method that yielded good agreement with the reference values. ResultsThe reference clearances ranged from 6 to 80 ml/min. Sampling at 2, 4, 8 and 24 h and calculation of the area under the plasma clearance curve using a log–linear trapezoidal rule with extrapolation to zero and infinity yielded a relative root mean square difference from the reference of less than 7%. ConclusionThis method for measuring glomerular filtration rate in patients with cirrhosis and ascites was found to be more accurate than the slope–intercept technique and is a practical alternative to urine collection.

Cystatin C in assessment of glomerular filtration rate in children and young adults suffering from cancer.

The study objective was to establish the diagnostic efficacy of cystatin C in the assessment of glomerular filtration rate (GFR) in paediatric oncology patients by investigating the relationships between serum cystatin C, serum creatinine and isotope clearance and determining whether these relationships are different from those seen in a group of patients of similar age with renal disease. This was a cohort study in which patients were divided into two groups: group A comprised renal patients and group B comprised oncology patients. All patients were referred for isotopic GFR assessment as part of routine clinical management and concurrently also had assessments made of their serum creatinine and cystatin C levels, together with height and weight measurements. Reciprocals of cystatin C correlate well with isotopic GFR; correlation coefficients from linear regression were 0.83 and 0.66 for the renal and oncology groups, respectively. However, when GFR was assessed from serum creatinine and cystatin C, levels of agreement were still very high (95% levels of agreement: −33 and 31 ml/min/1.73 m2 for cystatin C and −46 and 30 ml/min/1.73 m2 for the Counahan serum creatinine estimate). Receiver–operator characteristic curve analysis demonstrated that cystatin C has improved diagnostic utility for identifying patients with GFRs both below normal (90 ml/min/1.73 m2) and below the point at which chemotherapy dose reduction may be considered (60 ml/min/1.73 m2). Levels of intrapatient variability were similar for both tracers. Cystatin C was shown to be a better indicator of renal function compared with serum creatinine in oncology patients as demonstrated by receiver–operator characteristic curve and Bland–Altman analyses; however, sensitivity of the tracer to mild reductions in GFR is still low.

A national survey of computed tomography doses in hybrid Pet-ct and Spect-ct examinations in the Uk

Objectives The aim of this study was to conduct a nationwide survey of computed tomography (CT) doses for a wide range of PET-CT and single photon emission computed tomography-computed tomography (SPECT-CT) imaging procedures, with the aim of generating proposed UK national diagnostic reference levels (NDRLs). Methods CT protocol and dosimetry data for three PET-CT and seven SPECT-CT examinations were gathered from centres across the UK. Data were divided according to CT purpose (attenuation correction, localization or diagnostic) and third quartile values of scanner average dose metrics were used to generate suggested NDRLs for a range of examination and CT purpose combinations. Achievable doses were also established from the median of the dose distributions. Results Data were obtained from 47 centres, allowing suggested NDRLs to be produced for fluorine-18-fluorodeoxyglucose half-body PET-CT, and parathyroid, post-thyroid ablation, meta-iodobenzylguanidine/octreotide, cardiac and bone SPECT-CT examinations. Variations in dose of up to a factor of 35 were observed for a given examination/CT purpose combination. For fluorine-18-fluorodeoxyglucose half-body PET-CT examination dose levels for the three CT purposes overlapped, which highlights the variability in the way in which CT purposes are interpreted across the UK. This lack of standardization is believed to be the largest contributor to the dose variations that were observed. The survey highlighted the need for targeted optimization work in many centres. Conclusion Suggested UK NDRLs and achievable doses for six common PET-CT and SPECT-CT examinations have been established as a result of this study.

The early plasma concentration of 51Cr-EDTA in patients with cirrhosis and ascites: a comparison of three models.

Objectives The aim of the study was to determine which of three two-parameter fitting functions (exponential, linear-log, and negative-power function of time) most accurately models early chromium-51-EDTA (51Cr-EDTA) plasma concentration data prior to 120 min in patients with cirrhosis and ascites and understand how these fitting functions affect the calculation of the area under the plasma concentration curve (AUC). Methods A bolus, antecubital intravenous injection of 2.6 MBq of 51Cr-EDTA was given to 13 patients with cirrhosis and ascites. Up to 16 blood samples were drawn at time points ranging from 5 to 1440 min following injection. The concentration data prior to 120 min were used as reference data. Early time concentration values, estimated by fitting exponential, linear-log, and negative-power functions of time to the time samples at 120, 180, and 240 min, were then compared with reference data. The AUC was calculated for each patient using the exponential, Bröchner-Mortensen-corrected exponential, and linear-log functions, and these values were compared. Results The withheld, observed plasma concentrations were (a) most accurately estimated by linear-log functions (Wilcoxon P=0.4548), (b) significantly underestimated by exponential functions (Wilcoxon P=0.0002), and (c) significantly overestimated by negative-power functions (Wilcoxon P=0.0034). The relative errors when ranked from best to worst were those for the linear-log (12.0%, 9.0%), exponential (22.9%, 14.2%), and negative-power (31.9%, 48.4%) functions of time, respectively (median, interquartile range). For each patient, the values for AUC calculated by the exponential function differed significantly (range=3.4–15.3%, median=8.3%) from those calculated by the corrected Bröchner-Mortensen exponential, as to a lesser extent did those values calculated using linear-log functions (range=0.4–8.0%, median=3.0%). Conclusion In patients with cirrhosis, linear-log functions were significantly more accurate than exponential or power functions in estimating early time plasma concentrations (<120 min). However, the improved linear-log early time plasma concentration model does not provide as much correction to the total AUC as does the corrected Bröchner-Mortensen exponential method. This is likely because of the large contribution of late time data to the AUC, and future work is suggested to explore the late time fit problem.

A systematic review of single-sample glomerular filtration rate measurement techniques and demonstration of equal accuracy to slope-intercept methods.

PurposeWe aimed to identify the most accurate single-sample glomerular filtration rate (SS-GFR) technique for all patient ages. Materials and methodsWe performed a systematic review of all published SS-GFR measurement techniques and compared the results from each test with a gold-standard nine-point ‘area-under-curve’ measurement of GFR as well as slope-intercept (SI-GFR) methods for 412 GFR tests. ResultsWe have shown that for patients of all ages the SS-GFR technique developed by Fleming and colleagues delivers the best accuracy and precision, with results equivalent to those calculated by SI-GFR. The median percentage difference from the gold-standard GFR for the Fleming technique is 4.8% (95% confidence interval 3.9–5.7%) and that for the three-point SI-GFR is 5.6% (95% confidence interval 4.9–6.3%). The interquartile range of the distribution of percentage difference from the gold standard is −0.23 to 11% for the Fleming method and 1.6–11% for the three-point SI-GFR. ConclusionThe Fleming technique outperforms the method currently recommended by the international guidelines, and is simpler as only one equation is required for all patients instead of separate equations for adults and children. We propose that the SS-GFR technique of Fleming replace the methods currently recommended by the international and BNMS guidelines for routine measurement of GFR for expected results greater than 30 ml/min/1.73 m2. A thorough system of measurement checks should be implemented for all methods of GFR assessment; the perceived lack of opportunity for quality control checks to be performed on the result of a single-sample measurement is addressed in the companion paper of this study.

Validation and impact of a new technique for assessment of glomerular filtration rate in patients with liver disease.

Objectives Previously we have proposed a technique for the measurement of plasma clearance in patients with ascites. The impact of using the technique was assessed and the results compared with those from a reference technique in 111 patients having glomerular filtration rate measurements as part of their workup for liver transplantation. Methods Results of calculations using the new technique were compared with plasma clearance measurements obtained using a conventional slope–intercept technique and with clearance measurements based on urine collection. Discrepancies between the results of plasma clearance and urinary clearance assessments were investigated by using an uncollimated gamma camera to measure the total retention of the tracer. Results Conventional slope–intercept calculations overestimated clearance compared with the new technique by more than 20% in 21% of the patients. Significant differences between the results of the two methods were more likely in patients with more severe ascites. Results of urine collection-based measurements of Cr-51 EDTA clearance were frequently significantly lower than measurements using the new technique, whereas measurements of urinary clearance of creatinine were higher. Gamma camera measurements suggest that discrepancies between total and urinary clearance of Cr-51 EDTA are due to incomplete urine collection. Conclusion The new technique is a practical method for assessment of kidney function and should be used in patients with liver disease who have or may have ascites.