Performance and pitfalls of the tools for measuring glomerular filtration rate to guide chronic kidney disease diagnosis and assessment.

Accurate diagnosis, classification and risk stratification for chronic kidney disease (CKD) allow for early recognition and delivering optimal care. Creatinine-based glomerular filtration rate (GFR), urinary albumin: creatinine ratio (UACR) and the kidney failure risk equation (KFRE) are important tools to achieve this, but understanding their limitations is important for optimal implementation.When accurate GFR is required (eg, chemotherapy dosing), GFR is measured using an exogenous filtration marker. In routine clinical practice, in contrast, estimated GFR (eGFR) from serum creatinine (SCr), calculated using the enzymatic method±UACR, is recommended. Limitations of SCr include non-GFR determinants such as muscle mass, diet and tubular handling. An alternative or additional endogenous filtration marker is cystatin C, which can be used alongside SCr for confirmatory testing of CKD. However, its role in the UK is more limited due to concerns regarding false positive results.The recommended creatinine-based eGFR equation in the UK is the CKD Epidemiology Collaboration 2009 equation. This was recently updated to a race-neutral 2021 version and demonstrated reduced bias in people of Black ethnicity, but has not been validated in the UK. Limitations are extremes of age, inaccuracy at greater GFRs and reduced generalisability to under-represented ethnicity groups.The KFRE (based on age, sex, SCr and UACR) has recently been developed to help determine 2-year and 5-year risk of progression to end-stage kidney disease. It has been validated in over 30 countries and provides meaningful quantitative information to patients. However, supporting evidence for their performance in ethnic minority groups and kidney diseases such as glomerulonephritis remains modest.In conclusion, early identification, risk stratification of kidney disease and timely intervention are important to impact kidney disease progression. However, clinician awareness of the limitations and variability of creatinine, cystatin C and the eGFR equations, is key to appropriate interpretation of results.

75SeHCAT whole body retention for unexplained chronic diarrhoea based on early first whole body counting.

BACKGROUND: There are many protocol variations in the whole-body 75SeHCAT retention test [whole-body retention (WBR)] for investigation of bile acid diarrhoea. The time between capsule consumption and first count, however, is widely taken, without debate, to be 3 h. In the Covid-19 era, it is desirable to limit the time patients spend in the department. We, therefore, questioned the need for a 3 h interval between capsule administration and the initial count. METHODS: Using an uncollimated gamma camera, whole-body counting was performed at 5, 30 and 180 min after capsule ingestion in 24 patients with chronic diarrhoea. Geometric mean was taken of counts acquired from posterior and anterior projections. WBR was expressed as the ratio of 7 day-to-initial whole-body counts (%) to give WBR5, WBR30 and WBR180. A small meal was given at 60 min after capsule ingestion. RESULTS: There was a close correlation between WBR30 and WBR180 (y = 1.0x - 0.29%; r = 0.99). For WBR180 values of <15% (lower limit of normal), there was close agreement between WBR30 and WBR180 (bias 0.03%; precision 0.7%). WBR5 overestimated WBR180. However, cWBR5, obtained by multiplication of WBR5 by 0.75, also correlated closely with WBR180 (y = 1.2x - 4.5%; r = 0.97), and there was close agreement between cWBR5 and WBR180 for WBR180 values <15% (bias 0.08%, precision 1.3%). CONCLUSION: The first whole-body count in the 75SeHCAT test can be undertaken at 30 min postcapsule without loss of accuracy, or even 5 min if only subnormal values are considered relevant. No food is required after capsule consumption.

Hepato-splenic axis: hepatic and splenic metabolic activities are linked.

The concept of a hepato-splenic axis has recently been put forward. We aimed to investigate whether hepatic and splenic metabolic activities are linked, and if splenic metabolic activity is increased in non-alcoholic fatty liver disease (NAFLD). Blood clearance rates of phosphorylated 18F-fluorodeoxyglucose were measured in the spleen and liver from dynamic PET using Gjedde-Patlak-Rutland graphical analysis and abdominal aorta for input function in 59 patients undergoing routine PET/CT. Plot gradient (Ki), which represents blood clearance, was divided by intercept (V(0)), which represents tissue FDG distribution volume, and multiplied by blood glucose to give glucose uptake rate per unit tracer distribution volume (MRglu). In addition, liver-to-spleen raw count rate ratio was plotted against time, and gradient (b) divided by intercept (A) to obtain hepatic-to-splenic blood clearance ratio independent of aortic input function. Hepatic steatosis was inferred when hepatic CT density was ≤40 HU. There was no difference in splenic MRglu between 8 patients with inactive lympho-proliferative disease (LPD) as identified by negative PET/CT, 25 with non-haematological malignancy and 13 with normal PET/CT. It was significantly increased in 13 with active LPD, who were therefore excluded, along with 3 more with type-2 diabetes mellitus. Splenic MRglu was higher in patients with hepatic steatosis (4.0±1.6; n = 12) than without (2.6±1.7 µmol/min/100 ml; P = 0.02) and correlated inversely with hepatic CT density (r = -0.49; P<0.001). Hepatic and splenic Ki/V(0) correlated (r = 0.52; P<0.01) in 22 patients in whom the correlation coefficient between b/A and hepatic-to-splenic Ki/V(0) ratio was 0.99 and in whom, therefore, input function errors in graphical analysis could be discounted. In men, splenic longitudinal diameter correlated significantly with hepatic CT density (r = -0.35; P = 0.046), hepatic MRglu (r = 0.44; P = 0.005) and splenic MRglu (r = 0.35; P = 0.046). Splenic Ki/V(0) correlated positively with blood glucose, suggesting sensitivity to insulin. We conclude that hepatic and splenic metabolic activities are linked and that a speculative mechanism, which deserves further investigation, is shared insulin sensitivity. Splenic MRglu and spleen size are increased in NAFLD.

Hepatic glucose utilization in hepatic steatosis and obesity.

Hepatic steatosis is associated with obesity and insulin resistance. Whether hepatic glucose utilization rate (glucose phosphorylation rate; MRglu) is increased in steatosis and/or obesity is uncertain. Our aim was to determine the separate relationships of steatosis and obesity with MRglu. Sixty patients referred for routine PET/CT had dynamic PET imaging over the abdomen for 30 min post-injection of F-18-fluorodeoxyglucose (FDG), followed by Patlak-Rutland graphical analysis of the liver using abdominal aorta for arterial input signal. The plot gradient was divided by the intercept to give hepatic FDG clearance normalized to hepatic FDG distribution volume (ml/min per 100 ml) and multiplied by blood glucose to give hepatic MRglu (µmol/min per 100 ml). Hepatic steatosis was defined as CT density of ≤40 HU measured from the 60 min whole body routine PET/CT and obesity as body mass index of ≥30 kg/m2 Hepatic MRglu was higher in patients with steatosis (3.3±1.3 µmol/min per 100 ml) than those without (1.7±1.2 µmol/min per 100 ml; P<0.001) but there was no significant difference between obese (2.5±1.6 µmol/min per 100 ml) and non-obese patients (2.1±1.3 µmol/min per 100 ml). MRglu was increased in obese patients only if they had steatosis. Non-obese patients with steatosis still had increased MRglu. There was no association between MRglu and chemotherapy history. We conclude that MRglu is increased in hepatic steatosis probably through insulin resistance, hyperinsulinaemia and up-regulation of hepatic hexokinase, irrespective of obesity.

Lymph proteins may access peripheral blood without entering thoracic duct in patients with lymphatic dysfunction.

OBJECTIVE: The objective was to investigate the hypothesis that lymphovenous communications, which allow lymph proteins to access peripheral blood without first entering the thoracic duct, open in patients with abnormal lymphatic function. METHODS: Routine lymphoscintigraphy of 182 patients, including 27 without clinical evidence of lymphedema (controls), was performed immediately and 45 and 150 minutes after subcutaneous injection of technetium Tc 99m nanocolloid into both feet. Counts per pixel in a region of interest over the liver (L) were divided by total counts in bilateral ilioinguinal nodes (N) at 45 minutes (L/N45) and 150 minutes (L/N150). If all activity leaving ilioinguinal lymph nodes entered the thoracic duct, these L/N ratios would be similar from patient to patient. RESULTS: Eight patients were excluded because of immediate liver activity suggesting inadvertent intravascular injection of tracer. In controls (group 1), L/N150 displayed a normal distribution with mean (± standard deviation) of 0.16 (0.09) × 10(-4) pixels(-1). Patients with L/N150 >0.34 × 10(-4) pixels(-1) (ie, 0.16 + 2 standard deviations) were assumed to have lymphovenous communications. Of 34 patients with clinical evidence of lymphedema but with normal findings on lymphoscintigraphy (group 2), 3 (9%) had lymphovenous communications; of 114 with abnormalities on lymphoscintigraphy (group 3), 43 (38%) had lymphovenous communications (P = .001). N45/150 was significantly higher than L45/150 in all four groups, indicating arrival of activity in nodes before the liver. Abnormal features of lymphoscintigraphy-lymph transport delay, popliteal node visualization, and diversion of lymph through the skin-showed no association with L/N ratios. CONCLUSIONS: Lymphovenous communications exist in about one-third of patients with abnormalities detected on lymphoscintigraphy. The timings of tracer arrival in the liver and lymph nodes is consistent with lymphovenous communication within lymph nodes themselves.

Pitfalls and Limitations of Radionuclide Renal Imaging in Adults.

To understand pitfalls and limitations in adult renography, it is necessary to understand firstly the physiology of the kidney, especially the magnitude and control of renal blood flow, glomerular filtration rate and tubular fluid flow rate, and secondly the pharmacokinetics and renal handling of the three most often used tracers, Tc-99m-mercaptoacetyltriglycine (MAG3), Tc-99m-diethylene triamine pentaacetic acid (DTPA) and Tc-99m-dimercaptosuccinic acid (DMSA). The kidneys may be imaged dynamically with Tc-99m-MAG3 or Tc-99m-DTPA, with or without diuretic challenge, or by static imaging with Tc-99m-DMSA. Protocols are different according to whether the kidney is native or transplanted. Quantitative analysis of dynamic data includes measurement of renal vascularity (important for the transplanted kidney), absolute tracer clearance rates, differential renal function (DRF) and response to diuretic challenge. Static image reveals functional renal parenchymal damage, both focal and global, is useful in the clinical management of obstructive uropathy, renal stone disease and hypertension (under angiotensin converting enzyme inhibition), and is the preferred technique for determining DRF. Diagnosis based on morphological appearances is important in transplant management. Even though nuclear medicine is now in the era of hybrid imaging, renal imaging remains an important subspecialty in nuclear medicine and requires a sound basing in applied physiology, the classical supporting discipline of nuclear medicine.

Peripheral lymphovenous communication in lymphoedema.

AIM: To investigate whether in lower extremity lymphoedema, lymph proteins enter blood before they do the thoracic duct. METHODS: Retrospective analysis of routine lymphoscintigraphy in 69 adults imaged at 5, 45 and 150 min following bilateral subcutaneous web space injection of Tc-nanocolloid was carried out. Regions of interest were placed over the liver and ilioinguinal lymph nodes bilaterally on the anterior images at 45 and 150 min. Individual minor (0.5 point for each) and major (1 point for each) criteria of abnormal scintigraphy were applied to each limb and summed to give a lymphoscintigraphic abnormality score. An abnormal limb had a score ≥1. RESULTS: The ratio of hepatic counts per pixel to total bilateral ilioinguinal counts (L/N ratio) was higher in patients with abnormal results on lymphoscintigraphy (median 6.2; interquartile range 4.0-15.6 pixels×10; n=48) compared with that in patients with normal lymphoscintigraphic results (2.5 [1.5-5.0] pixels×10; n=21; P<0.0002). In the abnormal group, the lymphoscintigraphic score (two limbs summed) correlated with the 150-min L/N ratio (r s=0.42; P<0.005). L/N ratios at 45 and 150 min correlated in the abnormal group (r s=0.44; P<0.005) but not in the normal group (r s=0.3; P>0.05). The 45-min activity, as a percentage of the 150-min activity, was higher in lymph nodes than in the liver in both the abnormal (35.0 [8.2-50.0] vs. 10.6 [5.8-30.0]%; P<0.0001]) and normal groups (38.3 [18.4-63.5] vs. 23.3 [12.4-33.1]%; P<0.05), and, with respect to the liver, was higher in the normal group (P<0.01). CONCLUSION: In lymphoedema, more lymph proteins enter blood proximal to the thoracic duct. The time courses of nodal and hepatic activities suggest that access may occur within nodes themselves.

Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling.

PURPOSE: To determine how often lymphatic dysfunction is bilateral when, clinically, lymphedema appears unilateral. METHODS: Lymphoscintigraphy was performed after subcutaneous Tc-99m-nanocolloid injection in the first webspaces of both feet. The percentage of injected radioactivity accumulating in the ilioinguinal regions was recorded in dedicated images separately acquired at 60 and 180 minutes after injection. RESULTS: Within a consecutive series of 204 patients, 74 had unilateral clinical lymphedema of whom 68 had abnormal scintigraphy. Of these 68 patients, 46 had unilateral abnormal scintigraphy affecting the clinically abnormal limb, but 20 patients had bilateral abnormal scintigraphy and 2 had unilateral abnormal scintigraphy in the clinically unaffected limb. Thus, 32% (22/68) of patients in whom clinical lymphedema appeared to be unilateral, nevertheless, had abnormal scintigraphy in the clinically normal limb. Twenty-nine patients had no clinical evidence of lymphedema in either limb and were scintigraphically normal bilaterally. Mean ilioinguinal nodal accumulation at 180 minutes in the 44 limbs of 22 of these clinically and scintigraphically normal patients (dedicated ilioinguinal imaging was not performed in all patients) was 13.1% (standard deviation, 8.8%), higher (P = 0.02) than the mean value of 9.3% (standard deviation, 5.0%) in the clinically and scintigraphically normal contralateral limbs of 39 patients with unilateral clinical lymphedema. CONCLUSIONS: In the presence of unilateral lymphedema, the contralateral limb is often also abnormal. On lymphoscintigraphy, therefore, care should be taken before diagnosing unilateral lymphatic dysfunction. Quantification should be included in routine lymphoscintigraphy, as reduced ilioinguinal nodal accumulation may be the only apparent abnormality.

Effect of extracellular fluid volume on single-sample measurement of glomerular filtration rate.

UNLABELLED: Objective. The objective of our study was to evaluate the effect of extracellular fluid volume (ECV) on the accuracy of measurement of glomerular filtration rate from a single sample (GFR1). METHODS: Multi-sample GFR (GFR6) and ECV (per 1.73 m(2)) were measured with both Cr-51-EDTA and iohexol, injected into opposite arms (110 studies in 80 subjects). Six plasma samples were obtained bilaterally 20- 240 min post-injection to measure GFR6/1.73 m(2). GFR1/1.73 m(2) was calculated from 2-, 3- and 4-h samples using Jacobsson's formula for iohexol and the Christensen and Groth formula for Cr-51-EDTA. The quotient, GFR1/GFR6, was taken to indicate the accuracy of GFR1. RESULTS: When GFR6 was <60 ml/min/1.73 m(2), GFR1/ GFR6 correlated positively with ECV at all single-sample times. When GFR6 was 60-90 ml/min/1.73 m(2) or >90 ml/min/1.73 m(2), GFR1/GFR6 correlated positively with ECV at 2 h, but negatively at 4 h, indicating that at some time between 2 and 4 h, GFR1/GFR6 was transiently independent of ECV. A plot of the regression gradient of GFR1/GFR6 on ECV against sample time indicated that the time of transient independence, at which time GFR1 depends exclusively on GFR6, was 3.2-3.9 h (depending on indicator combination used) when GFR6 was 60-90 ml/min/1.73 m(2) and 2.4-2.9 h when GFR was >90 ml/min/1.73 m(2). Transient independence when GFR6 was <60 ml/min/1.73 m(2) was not reached by 4 h and estimated to be 5-7 h. CONCLUSION: The accuracy of GFR1 depends on ECV, overestimation or underestimation respectively depending on sample time and GFR. The time at which GFR1 is independent of ECV increases with decreasing GFR. If sampling time is too early, GFR1 overestimates GFR, but the reverse occurs when sampling is too late, even if GFR is abnormally low.