Assessment of renal function in persons with motor complete spinal cord injury-cystatin C as an accurate single marker.

STUDY DESIGN: Observational cohort. AIM: To show that Cystatin C is an accurate single marker to estimate GFR in motor complete persons with SCI. OBJECTIVES: To assess if Cystatin C is an accurate for estimating GFR in persons with SCI with no preserved motor power. To study if use of Serum creatinine for estimation of GFR in this population significantly overestimates GFR, thereby inaccurate. SETTING: Tertiary care hospital and Medical College, Vellore, South India. METHODS: 30 persons with SCI (ASIA A and B) fulfilling the inclusion criteria were recruited. Serum Creatinine and Serum Cystatin C values were obtained, and eGFR was calculated based on available formulae. 24-h urine for urine creatinine clearance-based eGFR was used as a reference value. RESULTS: Analysis with a Bland-Atman plot showed that eGFR estimated with Serum Cystatin C was more accurate than Serum Creatinine, using 24-h urine creatinine as a reference value. eGFR using Serum Creatinine significantly overestimated GFR by over 50.6%. Estimated GFR using Serum Cystatin C showed a meager mean difference of 0.5% from the reference 24-h urine creatinine clearance (mean difference of -2.56%). CONCLUSION: Serum Cystatin C is a much more accurate marker for estimating GFR in SCI, compared to serum Creatinine which overestimates GFR.

Comparison of Cystatin C and Creatinine in the Assessment of Measured Kidney Function during Critical Illness.

BACKGROUND: Incomplete recovery of kidney function is an important adverse outcome in survivors of critical illness. However, unlike eGFR creatinine, eGFR cystatin C is not confounded by muscle loss and may improve identification of persistent kidney dysfunction. METHODS: To assess kidney function during prolonged critical illness, we enrolled 38 mechanically ventilated patients with an expected length of stay of >72 hours near admission to intensive care unit (ICU) in a single academic medical center. We assessed sequential kidney function using creatinine, cystatin C, and iohexol clearance measurements. The primary outcome was difference between eGFR creatinine and eGFR cystatin C at ICU discharge using Bayesian regression modeling. We simultaneously measured muscle mass by ultrasound of the rectus femoris to assess the confounding effect on serum creatinine generation. RESULTS: Longer length of ICU stay was associated with greater difference between eGFR creatinine and eGFR cystatin C at a predicted rate of 2 ml/min per 1.73 m 2 per day (95% confidence interval [CI], 1 to 2). By ICU discharge, the posterior mean difference between creatinine and cystatin C eGFR was 33 ml/min per 1.73 m 2 (95% credible interval [CrI], 24 to 42). In 27 patients with iohexol clearance measured close to ICU discharge, eGFR creatinine was on average two-fold greater than the iohexol gold standard, and posterior mean difference was 59 ml/min per 1.73 m 2 (95% CrI, 49 to 69). The posterior mean for eGFR cystatin C suggested a 22 ml/min per 1.73 m 2 (95% CrI, 13 to 31) overestimation of measured GFR. Each day in ICU resulted in a predicted 2% (95% CI, 1% to 3%) decrease in muscle area. Change in creatinine-to-cystatin C ratio showed good longitudinal, repeated measures correlation with muscle loss, R =0.61 (95% CI, 0.50 to 0.72). CONCLUSIONS: eGFR creatinine systematically overestimated kidney function after prolonged critical illness. Cystatin C better estimated true kidney function because it seemed unaffected by the muscle loss from prolonged critical illness. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Skeletal Muscle Wasting and Renal Dysfunction After Critical Illness Trauma - Outcomes Study (KRATOS), NCT03736005 .

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.

Proteomic cardiovascular risk assessment in chronic kidney disease.

AIMS: Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models. METHODS AND RESULTS: Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis. CONCLUSION: In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.

Impact of race-independent equations on estimating glomerular filtration rate for the assessment of kidney dysfunction in liver disease.

BACKGROUND: Altered hemodynamics in liver disease often results in overestimation of glomerular filtration rate (GFR) by creatinine-based GFR estimating (eGFR) equations. Recently, we have validated a novel eGFR equation based on serum myo-inositol, valine, and creatinine quantified by nuclear magnetic resonance spectroscopy in combination with cystatin C, age and sex (GFRNMR). We hypothesized that GFRNMR could improve chronic kidney disease (CKD) classification in the setting of liver disease. RESULTS: We conducted a retrospective multicenter study in 205 patients with chronic liver disease (CLD), comparing the performance of GFRNMR to that of validated CKD-EPI eGFR equations, including eGFRcr (based on creatinine) and eGFRcr-cys (based on both creatinine and cystatin C), using measured GFR as reference standard. GFRNMR outperformed all other equations with a low overall median bias (-1 vs. -6 to 4 ml/min/1.73 m2 for the other equations; p < 0.05) and the lowest difference in bias between reduced and preserved liver function (-3 vs. -16 to -8 ml/min/1.73 m2 for other equations). Concordant classification by CKD stage was highest for GFRNMR (59% vs. 48% to 53%) and less biased in estimating CKD severity compared to the other equations. GFRNMR P30 accuracy (83%) was higher than that of eGFRcr (75%; p = 0.019) and comparable to that of eGFRcr-cys (86%; p = 0.578). CONCLUSIONS: Addition of myo-inositol and valine to creatinine and cystatin C in GFRNMR further improved GFR estimation in CLD patients and accurately stratified liver disease patients into CKD stages.

The assessment of cortical hemodynamic responses induced by tubuloglomerular feedback using in vivo imaging.

The tubuloglomerular feedback (TGF) mechanism modulates renal hemodynamics and glomerular filtration rate in individual nephrons. Our study aimed to evaluate the TGF-induced vascular responses by inhibiting Na-K-2Cl co-transporters and sodium-glucose co-transporters in rats. We assessed cortical hemodynamics with high-resolution laser speckle contrast imaging, which enabled the evaluation of blood flow in individual microvessels and analysis of their dynamical patterns in the time-frequency domain. We demonstrated that a systemic administration of furosemide abolishes TGF-mediated hemodynamic responses. Furthermore, we showed that the local microcirculatory blood flow decreased, and the TGF-induced hemodynamic oscillations were sustained but weakened after inhibiting sodium-glucose co-transporters in Sprague-Dawley rats.

The paradoxical relationship between severity of cerebral palsy and renal function in middle-aged adults: better renal function or inappropriate clinical assessment?

PURPOSE: To determine the association between severity of cerebral palsy with serum creatinine (sCr) and sCr-based equations to estimate glomerular filtration rate (eGFR), a marker of renal function. METHODS: A clinic-based sample of 30-64 year-olds with cerebral palsy was examined and stratified by motor impairment: gross motor function classification system (GMFCS) I/II (n = 79), GMFCS III (n = 78), and GMFCS IV/V (n = 137). sCr, which is influenced by muscle mass, was obtained and sCr-based eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. RESULTS: sCr was lower with increasing GMFCS. The opposite pattern was observed for eGFR: GMFCS IV/V had significantly higher eGFR derived from MDRD compared to other GMFCS groups; GMFCS III had significantly higher eGFR compared to GMFCS I/II. The pattern was similar for CKD-EPI derived eGFR. CONCLUSIONS: According to widely used clinical assessment methods for renal function, higher severity of cerebral palsy among adults is associated with better renal function, which is incongruent with their other biological systems. This paradoxical relationship is likely driven by lower muscle rather than true renal function, and thus, sCr-based eGFR may overestimate renal function, especially for GMFCS IV/V. Further prospective studies are needed.Implications for rehabilitationCommon methods of clinical assessment may over-estimate renal function for adults with cerebral palsy (CP), potentially giving a false positive for normal renal health due to their reliance on muscle mass.This study of a clinic-based sample of middle-aged adults with CP highlights the paradoxical relationship between severity of CP and renal function, which is likely driven by methodological limitations in the presence of low muscle mass rather than actual better renal function.It is recommended that clinicians have a high suspicion of abnormal renal function and the need for a nephrology consultation, especially with changes in creatinine levels, even within the normal range.Rehabilitation for adults with CP must have a strong focus on muscle and kidney health, especially for patients with more severe forms of CP.

Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

PURPOSE: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. METHODS: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. RESULTS: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05-0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20-60 mL/min and aged 65-95 years were calculated as 200-500 mg q24h. CONCLUSION: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

Assessment of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker on the split renal function in the patients with primary hypertension.

ABSTRACT: Bilateral kidney damage in hypertensive patients is not parallel. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), as a commonly used antihypertensive drug, could protect kidney function and delay its deterioration. Most studies focused on overall renal function, but the researches on split renal function (SRF) are rare. We investigated the effects of ACEI/ARB on the SRF in patients with primary hypertension.Patients with primary hypertension (n = 429; male: 213; female: 216) admitted to our department between January 2014 and December 2016 were included in this study. The glomerular filtration rate (GFR) of split and total renal function were determined using diethylenetriaminepentaacetic acid tagged with 99mTc renal dynamic imaging method. For the same patient, the side with high GFR was considered as higher GFR kidney, whereas that with a low GFR was considered as lower GFR kidney. The split function score (Q value) was utilized to evaluate the differences of bilateral renal function. The patients were divided into 3 groups based on the Q values (Group 1, Q value <5%; Group 2, Q value of 5%-10%; Group 3, Q value ≥10%). All the patients received antihypertensive therapy based on ACEI/ARB. The renal dynamic imaging was performed in the 1-year follow-up to investigate the changes of the SRF.Compared with the baseline level, significant decline was noticed in the serum creatinine (Scr) in Group 2 and Group 3 (P < .05). The cystatin C in Group 3 showed significant decline (P < .05). Compared with the baseline, there was significant decline in the Q value in Group 2, whereas the GFR of lower GFR kidney showed significant increase (P < .05). No statistical differences were noticed in the Q value and split GFR in Group 1 and Group 3 (P > .05).In primary hypertension patients, ACEI/ARB therapy could improve the SRF of lower GFR kidney in the presence of certain differences between the SRF. As a result, the SRF difference was reduced. In case of Q value in a range of 5% to 10%, ACEI/ARB could improve the renal function effectively. It may be significant for the design of antihypertensive drugs.

Assessment of chronic allograft injury in renal transplantation using diffusional kurtosis imaging.

BACKGROUND: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. METHODS: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m2) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30-60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI. RESULTS: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = - 0.49, - 0.44, - 0.57, - 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis. CONCLUSION: The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.

Volumetric absorptive microsampling as alternative sampling technique for renal function assessment in the paediatric population using iohexol.

The glomerular filtration rate (GFR) is considered the best overall index for the renal function. Currently, one of the most promising exogenous markers for GFR assessment is iohexol. In this study, the suitability of volumetric absorptive microsampling (VAMS) as alternative for the conventional blood sampling and quantification of iohexol in paediatric plasma was assessed. Therefore, a new, fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed. Subsequently, the clinical suitability was evaluated in 20 paediatric patients by comparing plasma iohexol concentrations and associated GFR values obtained by the VAMS method with those obtained by conventional blood sampling and quantification of iohexol in plasma. The developed, simple and cost-effective LC-MS/MS-method fulfilled all pre-set validation acceptance criteria. Iohexol could be accurately quantified within a haematocrit range of 20-60% and long-term stability of iohexol in VAMS was demonstrated up to 245 days under different storage temperatures. Both iohexol plasma concentrations (r = 0.98, mean bias: -4.20%) and derived GFR values (r = 0.99; mean bias: 1.31%), obtained by a conventional plasma and the VAMS method, demonstrated good correlation and acceptable bias. The agreement between the two methods was especially good for GFR values higher than 60 mL/min/1.73 m2. Nevertheless, for GFR values <60 mL/min/1.73 m2 the accuracy compared to the plasma method was lower. However, small adjustments to the sampling protocol could probably solve this problem.

Usefulness of atherogenic index of plasma for estimating reduced eGFR risk: insights from the national health and nutrition examination survey.

AIMS: Previous studies have identified Atherogenic index of plasma (AIP) as a simple measure of atherosclerosis. Because atherosclerosis plays a role in the development of renal damage, our study aims to evaluate the effect of AIP on the risk of reduced eGFR and assess its usefulness to refine the risk stratification of reduced estimated glomerular filtration rate (eGFR). METHODS: Our study included 15,836 participants from the National Health and Nutritional Survey (NHANES) 2009-2016. Association was investigated by logistic regression. AIP was calculated as log (triglycerides/high-density lipoprotein cholesterol). Reduced eGFR was determined as eGFR < 60 ml/min per 1.73 m*2. RESULTS: The prevalence of reduced eGFR was 8.01%. In the full model, each SD increase of AIP leaded to 27.4% additional risk for reduced eGFR. After dividing AIP into quartiles, the fourth quartile had a 1.649 times risk than the first quartile. Moreover, smooth curve fitting suggested that the risk of reduced eGFR elevated linearly with the increase of AIP. Subgroup analysis demonstrated that the association between AIP and reduced eGFR was robust in sex, body mass index, hypertension, and diabetes subpopulation, but the association was significantly stronger in black race and people aged less than 50 years old. Additionally, AUC displayed an advancement when introducing AIP into established risk factors (0.875 cs. 0.897, P < 0.001), category-free net reclassification index (0.249, 95% CI: 0.192-0.306, P < 0.001) and integrated discrimination index (0.007, 95% CI: 0.004-0.009, P < 0.001) also suggested the improvement from AIP. CONCLUSION: The present work suggested a linear association between AIP and reduced eGFR. Furthermore, the results showed that the association was stronger in black race and people aged less than 50 years old. Most importantly, our work implicated the usefulness of AIP to refine the risk stratification of reduced eGFR.

Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m2 was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary.

Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review.

OBJECTIVES: To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity. DATA SOURCES: PubMed (1976 to mid-May 2020) was used, with bibliographies of retrieved articles searched for additional articles. STUDY SELECTION AND DATA EXTRACTION: Articles using gold standard mGFR to evaluate eClCr, mClCr, and eGFR assessments of kidney function in patients with more extreme forms of obesity were included. DATA SYNTHESIS: The overestimation of GFR by mClCr is well established, but mClCr is an alternative to mGFR assessments for determining medication dosing in patients with extremes of body size or muscle mass, or in patients receiving narrow therapeutic index medications when eGFR is likely to be inaccurate. The vast majority of studies comparing eGFR assessments with gold standard indicators of kidney function were attempts to validate eGFR equations for diagnosing and staging chronic kidney disease (CKD). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: For dosing medications in patients with stable kidney function and extreme obesity, a deindexed 4-variable Modification of Diet in Renal Disease or CKD Epidemiology Collaboration equation is an alternative to Cockcroft-Gault. Consistent use of the same equation by provider and between providers within any given setting is of paramount importance. CONCLUSIONS: In patients with extreme obesity and stable kidney function, eClCr or eGFR using deindexed values provides estimates of function for dosing adjustments of medications with elimination by the kidneys, but more research is needed with respect to the best size descriptor to use with estimating equations.

Simple Nephrectomy in a Tertiary Care Safety Net Hospital-Patient Characteristics, Causes, Cost, and Renal Function Implications.

OBJECTIVE: To evaluate factors associated with simple nephrectomy at a safety net hospital with a diverse patient population and large catchment area. Simple nephrectomy is an underreported surgery. Performance of simple nephrectomy may represent a failure of management of underlying causes. METHODS: We performed a retrospective review of simple nephrectomies performed at a major urban safety net hospital from 2014 to 2019. Detailed demographic, surgical, and renal functional outcomes were abstracted. We assessed the medical and social factors leading to performance of simple nephrectomy and report contemporaneous perception of preventability of the simple nephrectomy by the surgeon. RESULTS: Eighty-five patients underwent simple nephrectomy during the study period; 55% were non-white, 77% were women, and the median age at time of surgery was 46 years. The most common medical factors contributing to simple nephrectomy were stone disease in 55.3%, followed by retained ureteral stent (30.6%) and stricture (30.6%). The most common social factors were lack of insurance (58.5%), substance abuse issues (32.3%), mental health issues (24.6%), and immigration status (18.5%). In 38.8% of cases, the provider felt the surgery was preventable if medical factors leading to simple nephrectomy were properly addressed. CONCLUSIONS: Simple nephrectomy is a common surgery in the safety net hospital setting. Both medical and sociologic factors can lead to simple nephrectomy, and awareness of these factors can lead efforts to mitigate them. This review has led to the implementation of strategies to minimize occurrences of retained stents in our patients.

Use of mechanistic information to derive chemical-specific adjustment factors - Refinement of risk assessment.

When extrapolating data from animal toxicological studies a default factor (dUF) of 100 is applied to derive a heath based guidance value. The UF takes into account the interspecies differences (ID) and the intraspecies variability (IV). When re-evaluating the safety of phosphates used as food additives nephrocalcinosis was identified as the critical endpoint. The underlying mechanism for nephrocalcinosis was attributed to the precipitation of calcium phosphate in the kidney, depending on its solubility, irrespective of the species and the population. Based on the mechanism, the volume of primary urine, for which the glomerular filtration rate (GFR) was used as a proxy, was considered to be the only parameter relevant for ID and IV. Median value of GFR in rats was 4.0 ml/min/kg bw. In humans it was 1.6 ml/min/kg bw in healthy adults and 0.9 in elderly. These values were calculated from the distribution of the GFR data from 8 studies in rats (n = 191), 16 studies in adults (n = 1540) and 5 studies in elderly (n = 2608). Multiplying the distribution of the ratio rat/healthy humans (ID) with the distribution of the ratio healthy humans/elderly human (IV) resulted in a phosphate specific factor of 4.5 (3.3-6.7) (median; 25th - 75th percentile).

Point-of-care creatinine tests to assess kidney function for outpatients requiring contrast-enhanced CT imaging: systematic reviews and economic evaluation.

BACKGROUND: Patients with low estimated glomerular filtration rates may be at higher risk of post-contrast acute kidney injury following contrast-enhanced computed tomography imaging. Point-of-care devices allow rapid measurement of estimated glomerular filtration rates for patients referred without a recent estimated glomerular filtration rate result. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of point-of-care creatinine tests for outpatients without a recent estimated glomerular filtration rate measurement who need contrast-enhanced computed tomography imaging. METHODS: Three systematic reviews of test accuracy, implementation and clinical outcomes, and economic analyses were carried out. Bibliographic databases were searched from inception to November 2018. Studies comparing the accuracy of point-of-care creatinine tests with laboratory reference tests to assess kidney function in adults in a non-emergency setting and studies reporting implementation and clinical outcomes were included. Risk of bias of diagnostic accuracy studies was assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Probabilities of individuals having their estimated glomerular filtration rates correctly classified were estimated within a Bayesian framework and pooled using a fixed-effects model. A de novo probabilistic decision tree cohort model was developed to characterise the decision problem from an NHS and a Personal Social Services perspective. A range of alternative point-of-care testing approaches were considered. Scenario analyses were conducted. RESULTS: Fifty-four studies were included in the clinical reviews. Twelve studies reported diagnostic accuracy for estimated glomerular filtration rates; half were rated as being at low risk of bias, but there were applicability concerns for most. i-STAT (Abbott Point of Care, Inc., Princeton, NJ, USA) and ABL (Radiometer Ltd, Crawley, UK) devices had higher probabilities of correctly classifying individuals in the same estimated glomerular filtration rate categories as the reference laboratory test than StatSensor® devices (Nova Biomedical, Runcorn, UK). There was limited evidence for epoc® (Siemens Healthineers AG, Erlangen, Germany) and Piccolo Xpress® (Abaxis, Inc., Union City, CA, USA) devices and no studies of DRI-CHEM NX 500 (Fujifilm Corporation, Tokyo, Japan). The review of implementation and clinical outcomes included six studies showing practice variation in the management decisions when a point-of-care device indicated an abnormal estimated glomerular filtration rate. The review of cost-effectiveness evidence identified no relevant studies. The de novo decision model that was developed included a total of 14 strategies. Owing to limited data, the model included only i-STAT, ABL800 FLEX and StatSensor. In the base-case analysis, the cost-effective strategy appeared to be a three-step testing sequence involving initially screening all individuals for risk factors, point-of-care testing for those individuals with at least one risk factor, and including a final confirmatory laboratory test for individuals with a point-of-care-positive test result. Within this testing approach, the specific point-of-care device with the highest net benefit was i-STAT, although differences in net benefit with StatSensor were very small. LIMITATIONS: There was insufficient evidence for patients with estimated glomerular filtration rates < 30 ml/minute/1.73 m2, and on the full potential health impact of delayed or rescheduled computed tomography scans or the use of alternative imaging modalities. CONCLUSIONS: A three-step testing sequence combining a risk factor questionnaire with a point-of-care test and confirmatory laboratory testing appears to be a cost-effective use of NHS resources compared with current practice. The risk of contrast causing acute kidney injury to patients with an estimated glomerular filtration rate of < 30 ml/minute/1.73 m2 is uncertain. Cost-effectiveness of point-of-care testing appears largely driven by the potential of point-of-care tests to minimise delays within the current computed tomography pathway. FUTURE WORK: Studies evaluating the impact of risk-stratifying questionnaires on workflow outcomes in computed tomography patients without recent estimated glomerular filtration rate results are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018115818. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 39. See the NIHR Journals Library website for further project information.

Before computed tomography scans are done, a contrast agent is usually needed to improve the visibility of internal body structures. After receiving a contrast agent (through a vein), some patients' kidneys may be affected, especially if their kidneys already do not work well. A blood test can identify these patients before a computed tomography scan, to reduce the risk of kidney harm. The blood test measures creatinine, which is a marker of how well the kidneys work. Before a contrast-enhanced computed tomography scan, some patients have a recent creatinine result from an earlier blood test. Blood tests are normally done in a central laboratory, and usually take at least 1 hour. Other patients do not have a recent creatinine result, so their computed tomography scan may be delayed or rearranged. Sometimes, to avoid risking kidney harm, patients may have scans without contrast. 'Point-of-care' (handheld, tabletop or portable) devices can quickly measure creatinine (usually in patients with risk factors), often from a finger-prick blood sample. Many point-of-care devices are available but they may not be as exact as laboratory tests, so their benefit is unclear. This study reviewed all available evidence on the benefits and harms of point-of-care creatinine tests before computed tomography scans and assessed whether or not they are a cost-effective use of NHS resources. The study found that some devices [i.e. i-STAT (Abbott Point of Care, Inc., Princeton, NJ, USA) and ABL (Radiometer Ltd, Crawley, UK)] were more accurate than others [i.e. StatSensor^® (Nova Biomedical, Runcorn, UK)]. There was insufficient evidence for other devices. The study found that, for outpatients, doing a point-of-care test in patients who are at a higher risk of kidney harm (according to a questionnaire) and then confirming this with a laboratory test appeared to be a cost-effective use of NHS resources. The study found that the risk of kidney harm as a result of contrast agents appears very low. The main benefit of point-of-care testing may be to reduce needless delays or rearranged computed tomography scan appointments.