The error of estimated GFR in predialysis care.

The error of estimated glomerular filtration rate (eGFR) and its consequences in predialysis are unknown. In this prospective multicentre study, 315 predialysis patients underwent measured GFR (mGFR) by the clearance of iohexol and eGFR by 52 formulas. Agreement between eGFR and mGFR was evaluated by concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). In a sub-analysis we assessed the impact of eGFR error on decision-making as (i) initiating dialysis, (ii) preparation for renal replacement therapy (RRT) and (iii) continuing clinical follow-up. For this sub-analysis, patients who started RRT due to clinical indications (uremia, fluid overload, etc.) were excluded. eGFR had scarce precision and accuracy in reflecting mGFR (average CCC 0.6, TDI 70% and cp 22%) both in creatinine- and cystatin-based formulas. Variations -larger than 10 ml/min- between mGFR and eGFR were frequent. The error of formulas would have suggested (a) premature preparation for RTT in 14% of stable patients evaluated by mGFR; (b) to continue clinical follow-up in 59% of subjects with indication for RTT preparation due to low GFRm and (c) to delay dialysis in all asymptomatic patients (n = 6) in whom RRT was indicated based on very low mGFR. The error of formulas in predialysis was frequent and large and may have consequences in clinical care.

ThyroidPrint®: clinical utility for indeterminate thyroid cytology.

Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in ITN. Post-validation studies are necessary to determine the real-world clinical benefit of ThyroidPrint® in patients with ITN. A single-center, prospective, noninterventional clinical utility study was performed, analyzing the impact of ThyroidPrint® in the physicians' clinical decisions for ITN. Demographics, nodule characteristics, benign call rates (BCRs), and surgical outcomes were measured. Histopathological data were collected from surgical biopsies of resected nodules. Of 1272 fine-needle aspirations, 109 (8.6%) were Bethesda III and 135 (10.6%) were Bethesda IV. Molecular testing was performed in 155 of 244 ITN (63.5%), of which 104 were classified as benign (BCR of 67.1%). After a median follow-up of 15 months, 103 of 104 (99.0%) patients with a benign ThyroidPrint® remained under surveillance and one patient underwent surgery which was a follicular adenoma. Surgery was performed in all 51 patients with a suspicious for malignancy as per ThyroidPrint® result and in 56 patients who did not undergo testing, with a rate of malignancy of 70.6% and 32.1%, respectively. A higher BCR was observed in follicular lesion of undetermined significance (87%) compared to atypia of undetermined significance (58%) (P < 0.05). False-positive cases included four benign follicular nodules and six follicular and four oncocytic adenomas. Our results show that, physicians chose active surveillance instead of diagnostic surgery in all patients with a benign ThyroidPrint® result, reducing the need for diagnostic surgery in 67% of patients with preoperative diagnosis of ITN.

Exercise and Prediabetes After Renal Transplantation (EXPRED-I): A Prospective Study.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) beyond 12 months (late PTDM) is a severe complication after renal transplantation. Late PTDM develops mostly in subjects with prediabetes. Although exercise may have a potential role in preventing late PTDM, there are no previous data on the effect of exercise in patients with prediabetes. MATERIAL AND METHODS: The design was a 12-month exploratory study to test the capacity of exercise in reverting prediabetes in order to prevent late-PTDM. The outcome was the reversibility of prediabetes, assessed every 3 months with oral glucose tolerance tests (OGTT). The protocol included an incremental plan of aerobic and/or strength training as well as an active plan for promoting adherence (telephone calls, digital technology, and visits). A priori, a sample size cannot be calculated which makes this an exploratory analysis. Based on previous studies, the spontaneous reversibility of prediabetes was 30% and the reversibility induced by exercise will account for another 30%, a total reversibility of 60% (p value < 0.05, assuming a potency of 85%). Ad interim analysis was performed during follow-up to test the certainty of this sample calculation. Patients beyond 12 months after renal transplantation with prediabetes were included. RESULTS: The study was interrupted early due to efficacy after the evaluation of the follow-up of 27 patients. At the end of follow-up, 16 (60%) patients reverted to normal glucose levels at fasting (from 102.13 mg/dL ± 11 to 86.75 ± 6.9, p = 0.006) and at 120 min after the OGTTs (154.44 mg/dL ± 30 to 113.0 ± 13.1, p = 0.002) and 11 patients had persistent prediabetes (40%). Also, insulin sensitivity improved with the reversibility of prediabetes, compared to those with persistent prediabetes: 0.09 [0.08-0.11] versus 0.04 [0.01-0.07], p = 0.001 (Stumvoll index). Most needed at least one increment in the prescription of exercise and compliance. Finally, measures aimed at the improvement of compliance were successful in 22 (80%) patients. CONCLUSION: Exercise training was effective to improve glucose metabolism in renal transplant patients with prediabetes. Exercise prescription must be conducted considering both the clinical characteristics of the patients and pre-defined strategy to promote adherence. The trial registration number of the study was NCT04489043.

Review on the management of cardiovascular risk factors in the elderly.

Cardiovascular risk factors (CVRF) are very prevalent in the elderly population and in addition to predisposing to cardiovascular disease they are related to functional decline, which limits the quality of life in this population. The objective of this work is to offer a review of the current evidence in the management of CVRF in the elderly population. The search strategy was executed in PubMed, Clinicalstrials.org and Embase, to search for clinical trials, observational cohort or cross-sectional studies, reviews, and clinical practice guidelines focused or including elderly population. The results provided were refined after reading the title and abstract, as well as elimination of duplicates, and were finally identified and assessed following the GRADE methodology. A total of 136 studies were obtained for all predefined risk factors, such as sedentary lifestyle, smoking, obesity and metabolic syndrome, hypertension, diabetes mellitus, dyslipidemia and alcohol. We described the results of the studies identified and assessed according to their methodological quality in different recommendation sections: diagnostic and prevention, intervention, or treatment in the elderly population. As the main limitation to the results of this review, there is the lack of quality studies whose target population is elderly patients. This issue limits the recommendations that can be made in this population. Due to this reason, comprehensive geriatric assessment seems the best tool currently available to implement the most appropriate treatment plans based on the baseline situation and comorbidity of each elderly patient.

Early glomerular filtration rate changes in living kidney donors and recipients: an example of renal plasticity.

Background: In living kidney transplantation there are two different individuals, a healthy donor and a renal transplant recipient. This is an excellent human model to study factors that influence kidney function in the context of reduced renal mass and the adaptation of two comparable kidneys to different metabolic demands. Methods: We analyzed the changes in measured glomerular filtration rate (GFR, iohexol) from pretransplantation to 12 months after transplantation in 30 donor-recipient pairs. Each donor was compared with his/her recipient. We defined a priori three different groups based on GFR differences at 12 months: donor > recipient (Group A; 78 ± 8 versus 57 ± 8 mL/min), donor < recipient (Group B; 65 ± 11 versus 79 ± 11 mL/min) and donor ≈ recipient (Group C; 66 ± 7 versus 67 ± 7 mL/min). Other factors like donor/recipient mismatches in body mass index (BMI), surface area and gender were evaluated. Results: In Group A donors were mostly male and recipients were female (75% each). Donors had a higher baseline weight than their recipients. During follow-up, weight remained stable in donors but increased 7% in recipients. In Group B donors were mostly female (60%) and recipients male. At baseline, donors had a lower weight than recipients. At 12 months, weight was stable in donors but increased in recipients. In Group C donors were mostly (75%) female and recipients male. At baseline, donors had a higher BMI than their recipients. At 12 months, BMI was stable in donors but increased 14% in recipients. In multivariable analysis, higher GFR at 12 months was associated with higher baseline weight and GFR in donors and with male gender and higher baseline weight in recipients. Conclusions: Kidneys from living donors are more 'plastic' than originally thought and respond to metabolic demands and weight changes of their new host. These changes should be taken into account when assessing GFR outcomes in this population.

Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1-4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed. METHODS: We evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment. RESULTS: No formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min. CONCLUSIONS: The evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.

Estimated GFR Slope in Kidney Transplant Patients: When the Error Is Random.

BACKGROUND: The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes. METHODS: We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y. RESULTS: Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%. CONCLUSIONS: Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.

Estimated glomerular filtration rate by formulas in patients with cirrhosis: An unreliable procedure.

BACKGROUND & AIMS: In cirrhosis, the reliability of formulas that estimate renal function, either those specifically developed in this population or the classic equations, has not been properly quantified. We studied the agreement between estimated (eGFR) and measured glomerular filtration rate (mGFR) in cirrhosis. METHODS: Renal function was estimated with 56 formulas including specific equations: Glomerular Filtration Rate Assessment in Liver Disease (GRAIL), Royal Free Hospital Cirrhosis (RFHC) and Mindikoglu-eGFR, and measured with a gold standard procedure; plasma clearance of iohexol using dried blood spots sampling in a group of cirrhotics. The agreement eGFR-mGFR was evaluated with specific tests: total deviation index (TDI), concordance correlation coefficient (CCC) and coverage probability (CP). We defined acceptable agreement as values: TDI < 10%, CCC ≥ 0.9 and CP > 90%. RESULTS: A total of 146 patients (age 65 ± 9 years, 81% male) were evaluated; 61 (42%) Child A, 67 (46%) Child B and 18 (12%) Child C. Median MELD-Na was 14 (9-15). The agreement between eGFR and mGFR was poor: TDI averaged was of 73% (90% of the estimations ranged from ±73% of mGFR); CCC averaged was 0.7 indicating low concordance and CP averaged 22% indicating that 78% of the estimations have an error > 10%. Specific formulas showed also poor agreement: TDI was 82%, 70% and 37% for the GRAIL, RFHC and Mindikoglu equations, respectively. CONCLUSIONS: Overall, formulas poorly estimated renal function in cirrhotic patients. Specific formulas designed for cirrhosis did not outperform classic equations. eGFR must be considered with caution in cirrhotic patients.

The Role of Vascular Lesions in Diabetes Across a Spectrum of Clinical Kidney Disease.

INTRODUCTION: The clinical-histologic correlation in diabetic nephropathy is not completely known. METHODS: We analyzed nephrectomy specimens from 90 patients with diabetes and diverse degrees of proteinuria and glomerular filtration rate (GFR). RESULTS: Thirty-six (40%) subjects had normoalbuminuria, 33 (37%) microalbuminuria, and 21 (23%) non-nephrotic proteinuria. Mean estimated GFR (eGFR) was 65±23 (40% <60 ml/min per 1.73 m2). About 170 glomeruli per patient were analyzed, and all samples included vascular tissue. Six subjects (7%) were classified in diabetic nephropathy class I, 61 (68%) in class II-a, 13 (14%) in class II-b, 9 (10%) class III, and 1 (1%) in class IV. Eighty percent to 90% of those with normoalbuminuria or microalbuminuria were classified in class II-a or II-b and <10% in class III; 52% of those with proteinuria were in class II-a, 15% in class II-b, and 19% in class III. Nodular sclerosis (57%) and mesangial expansion (15%) were more frequent in cases with proteinuria than in normoalbuminuria (28% and 8%; P = 0.028 and 0.017). About 20% to 30% of all cases, regardless the level of albuminuria or proteinuria or the histologic class had tubular atrophy, interstitial fibrosis, or inflammation in >10% to 20% of the sample. Moderate hyalinosis and arteriolar sclerosis were observed in 80% to 100% of cases with normoalbuminuria, microalbuminuria, proteinuria, as well as in class I, II, or III. CONCLUSIONS: Weak correspondence between analytical parameters and kidney histology was found. Thus, disease may progress undetected from the early clinical stages of the disease. Finally, vascular damage was a very common finding, which highlights the role of ischemic intrarenal disease in diabetes.

Exercise and Prediabetes after Renal Transplantation (EXPRED): Protocol Description.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a frequent and severe complication after renal transplantation. In fact, PTDM is a risk factor for both infection and cardiovascular diseases. The prevalence and incidence of PTDM have a bimodal evolution: early (up to 3 months) and late PTDM (beyond 12 months). The majority of late PTDM occurs in subjects with prediabetes after transplantation. So, treating patients with prediabetes, a potentially reversible condition, might help preventing PTDM. In the general population, exercise prevents the evolution from prediabetes to diabetes. However, in renal transplantation, not enough evidence is available in this field. OBJECTIVES: We designed an exploratory analysis to evaluate the feasibility of exercise to reverse prediabetes as a first step in the design of a trial to prevent PTDM. METHODS: Only patients with prediabetes beyond 12 months after transplantation with capacity to perform exercise will be included. Prediabetes will be diagnosed based on fasting glucose levels and oral glucose tolerance tests (OGTTs). Patients will be treated with a stepped training intervention, starting with aerobic exercise training (brisk walking, swimming, and cycling) 5 times per week and 30 min/day. Aerobic exercise training will be gradually increased to 60 min/day or eventually combined with anaerobic exercise training in case of persistent prediabetes. The reversibility/persistence of prediabetes will be measured with fasting glucose and OGTTs every 3 months. This study will last for 12 months.

Erratum: Impact of errors of creatinine and cystatin C equations in the selection of living kidney donors.

[This corrects the article DOI: 10.1093/ckj/sfz012.].

Renal Function Assessment Gap in Clinical Practice: An Awkward Truth.

INTRODUCTION: An accurate assessment of renal function is needed in the majority of clinical settings. Unfortunately, the most used estimated glomerular filtration rate (eGFR) formulas are affected by significant errors in comparison to gold standards methods of measured GFR (mGFR). OBJECTIVE: The objective of the study is to determine the extent of the error of eGFR formulas compared to the mGFR in different specific clinical settings. METHODS: A total retrospectively consecutive cohort of 1,320 patients (pts) enrolled in 2 different European Hospitals (Center 1: 470 pts; Center 2: 850 pts) was collected in order to compare the most common eGFR formulas used by physicians with the most widespread mGFR methods in daily clinical practice (Iohexol Plasma Clearance -Center 1 [mGFR-iox] and Renal Scintigraphy -Center 2 [mGFR-scnt]). The study cohort was composed by urological, oncological, and nephrological pts. The agreement between eGFR and mGFR was evaluated using bias (as median of difference), precision (as interquartile range of difference) accuracy (as P30), and total deviation index. RESULTS: The most accurate eGFR formula in the comparison with gold standard method (Iohexol plasma clearance) in Center 1 was represented by s-creatinine and cystatin C combined Chronic Kidney Disease-Epidemiology Collaboration-cr-cy, even though the P30 is reduced (84%) under the threshold of 60 mL/min/1.73 m2. Similar results were found in Center 2, with a wider discrepancy between mGFR-scnt and eGFR formulas due to the minor accuracy of the nuclear tool in respect to the mGFR-iox. CONCLUSIONS: The loss of accuracy observed for the formulas at lower values of GFR suggests the mandatory use of gold standards methods as Iohexol Plasma Clearance to assess the correct status of renal function for critical cases. The center 2 showed lower levels of agreement between mGFR and eGFR suggesting that the errors are partially accounted for the Renal Scintigraphy technique too. In particular, we suggest the use of mGFR-iox in oncological urological and nephrological pts with an eGFR lower than 60 mL/min/1.73 m2.

A Thyroid Genetic Classifier Correctly Predicts Benign Nodules with Indeterminate Cytology: Two Independent, Multicenter, Prospective Validation Trials.

Background: Although most thyroid nodules with indeterminate cytology are benign, in most of the world, surgery remains as the most frequent diagnostic approach. We have previously reported a 10-gene thyroid genetic classifier, which accurately predicts benign thyroid nodules. The assay is a prototype diagnostic kit suitable for reference laboratory testing and could potentially avoid unnecessary diagnostic surgery in patients with indeterminate thyroid cytology. Methods: Classifier performance was tested in two independent, ethnically diverse, prospective multicenter trials (TGCT-1/Chile and TGCT-2/USA). A total of 4061 fine-needle aspirations were collected from 15 institutions, of which 897 (22%) were called indeterminate. The clinical site was blind to the classifier score and the clinical laboratory blind to the pathology report. A matched surgical pathology and valid classifier score was available for 270 samples. Results: Cohorts showed significant differences, including (i) clinical site patient source (academic, 43% and 97% for TGCT-1 and -2, respectively); (ii) ethnic diversity, with a greater proportion of the Hispanic population (40% vs. 3%) for TGCT-1 and a greater proportion of African American (11% vs. 0%) and Asian (10% vs. 1%) populations for TGCT-2; and (iii) tumor size (mean of 1.7 and 2.5 cm for TGCT-1 and -2, respectively). Overall, there were no differences in the histopathological profile between cohorts. Forty-one of 155 and 45 of 115 nodules were malignant (cancer prevalence of 26% and 39% for TGCT-1 and -2, respectively). The classifier predicted 37 of 41 and 41 of 45 malignant nodules, yielding a sensitivity of 90% [95% confidence interval; CI 77-97] and 91% [95% CI 79-98] for TGCT-1 and -2, respectively. One hundred one of 114 and 61 of 70 nodules were correctly predicted as benign, yielding a specificity of 89% [95% CI 82-94] and 87% [95% CI 77-94], respectively. The negative predictive values for TGCT-1 and TGCT-2 were 96% and 94%, respectively, whereas the positive predictive values were 74% and 82%, respectively. The overall accuracy for both cohorts was 89%. Conclusions: Clinical validation of the classifier demonstrates equivalent performance in two independent and ethnically diverse cohorts, accurately predicting benign thyroid nodules that can undergo surveillance as an alternative to diagnostic surgery.

The estimation of GFR and the adjustment for BSA in overweight and obesity: a dreadful combination of two errors.

BACKGROUND: Obesity is an established risk factor for renal disease and for disease progression. Therefore, an accurate determination of renal function is necessary in this population. Renal function is currently evaluated by estimated glomerular filtration rate (GFR) by formulas, a procedure with a proven high variability. Moreover, the adjustment of GFR by body surface area (BSA) confounds the evaluation of renal function. However, the error of using estimated GFR adjusted by BSA has not been properly evaluated in overweight and obese subjects. METHODS: We evaluated the error of 56 creatinine- and/or cystatin-C-based equations and the adjustment of GFR by BSA in 944 subjects with overweight or obesity with or without chronic kidney disease (CKD). The error between estimated (eGFR) and measured GFR (mGFR) was evaluated with statistics of agreement: the total deviation index (TDI), the concordance correlation coefficient (CCC) and the coverage probability (cp). RESULTS: The error of eGFR by any equation was common and wide: TDI averaged 55%, meaning that 90% of estimations ranged from -55 to 55% of mGFR. CCC and cp averaged 0.8 and 26, respectively. This error was comparable between creatinine and cystatin-C-based formulas both in obese or overweight subjects. The error of eGFR was larger in formulas that included weight or height. The adjustment of mGFR or eGFR led to a relevant underestimation of renal function, reaching at least 10 mL/min in 25% of the cases. CONCLUSIONS: In overweight and obese patients, formulas failed in reflecting real renal function. In addition, the adjustment for BSA led to a relevant underestimation of GFR. Both errors may have important clinical consequences. Thus, whenever possible, the use of a gold standard method to measure renal function is recommended. Moreover, the sense of indexing for BSA should be re-considered and probably abandoned.

Impact of errors of creatinine and cystatin C equations in the selection of living kidney donors.

BACKGROUND: Reliable determination of glomerular filtration rate (GFR) is crucial in the evaluation of living kidney donors. Although some guidelines recommend the use of measured GFR (mGFR), many centres still rely on estimated GFR (eGFR) obtained through equations or 24-h creatinine clearance. However, eGFR is neither accurate nor precise in reflecting real renal function. We analysed the impact of eGFR errors on evaluation and decision making regarding potential donors. METHODS: We evaluated 103 consecutive living donors who underwent mGFR via iohexol plasma clearance and eGFR by 51 creatinine- and/or cystatin C-based equations. The cut-off for living donation in our centre is GFR > 80 mL/min for donors >35 years of age or 90 mL/min for those <35 years of age. We analysed the misclassification of donors based on the cut-off for donation-based eGFR. RESULTS: Ninety-three subjects (90.3%) had mGFR values above (donors) and 10 [9.7% (95% confidence interval 5.4-17)] below (non-donors) the cut-off. In non-donors, most of the equations gave eGFR values above the cut-off, so donation would have been allowed based on eGFR. All non-donors were female with reduced weight, height and body surface. In donors, up to 32 cases showed eGFR below the cut-off, while mGFR was actually higher. Therefore an important number of donors would not have donated based on eGFR alone. CONCLUSION: The misclassification of donors around the cut-off for donation is very common with eGFR, making eGFR unreliable for the evaluation of living kidney donors. Whenever possible, mGFR should be implemented in this setting.

The Error of Estimated GFR in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus represents 30-50% of the cases of end stage renal disease worldwide. Thus, a correct evaluation of renal function in patients with diabetes is crucial to prevent or ameliorate diabetes-associated kidney disease. The reliability of formulas to estimate renal function is still unclear, in particular, those new equations based on cystatin-C or the combination of creatinine and cystatin-C. We aimed to assess the error of the available formulas to estimate glomerular filtration rate in diabetic patients. We evaluated the error of creatinine and/or cystatin-C based formulas in reflecting real renal function over a wide range of glomerular filtration rate (from advanced chronic kidney disease to hyperfiltration). The error of estimated glomerular filtration rate by any equation was common and wide averaging 30% of real renal function, and larger in patients with measured glomerular filtration rate below 60 mL/min. This led to chronic kidney disease stages misclassification in about 30% of the individuals and failed to detect 25% of the cases with hyperfiltration. Cystatin-C based formulas did not outperform creatinine based equations, and the reliability of more modern algorithms proved to be as poor as older equations. Formulas failed in reflecting renal function in type 2 diabetes mellitus. Caution is needed with the use of these formulas in patients with diabetes, a population at high risk for kidney disease. Whenever possible, the use of a gold standard method to measure renal function is recommended.

Chronic kidney disease staging with cystatin C or creatinine-based formulas: flipping the coin.

Background: Chronic kidney disease (CKD) affects 10-13% of the population worldwide. CKD classification stratifies patients in five stages of risk for progressive renal disease based on estimated glomerular filtration rate (eGFR) by formulas and albuminuria. However, the reliability of formulas to reflect real renal function is a matter of debate. The effect of the error of formulas in the CKD classification is unclear, particularly for cystatin C-based equations. Methods: We evaluated the reliability of a large number of cystatin C and/or creatinine-based formulas in the definition of the stages of CKD in 882 subjects with different clinical situations over a wide range of glomerular filtration rates (GFRs) (4.2-173.7 mL/min). Results: Misclassification was a constant for all 61 formulas evaluated and averaged 50% for creatinine-based and 35% for cystatin C-based equations. Most of the cases were misclassified as one stage higher or lower. However, in 10% of the subjects, one stage was skipped and patients were classified two stages above or below their real stage. No clinically relevant improvement was observed with cystatin C-based formulas compared with those based on creatinine. Conclusions: The error in the classification of CKD stages by formulas was extremely common. Our study questions the reliability of both cystatin C and creatinine-based formulas to correctly classify CKD stages. Thus the correct classification of CKD stages based on estimated GFR is a matter of chance. This is a strong limitation in evaluating the severity of renal disease, the risk for progression and the evolution of renal dysfunction over time.

A Simple Method to Measure Renal Function in Swine by the Plasma Clearance of Iohexol.

There is no simple method to measure glomerular filtration rate (GFR) in swine, an established model for studying renal disease. We developed a protocol to measure GFR in conscious swine by using the plasma clearance of iohexol. We used two groups, test and validation, with eight animals each. Ten milliliters of iohexol (6.47 g) was injected into the marginal auricular vein and blood samples (3 mL) were collected from the orbital sinus at different points after injection. GFR was determined using two models: two-compartment (CL2: all samples) and one-compartment (CL1: the last six samples). In the test group, CL1 overestimated CL2 by ~30%: CL2 = 245 ± 93 and CL1 = 308 ± 123 mL/min. This error was corrected by a first-order polynomial quadratic equation to CL1, which was considered the simplified method: SM = -47.909 + (1.176xCL1) - (0.00063968xCL1²). The SM showed narrow limits of agreement with CL2, a concordance correlation of 0.97, and a total deviation index of 14.73%. Similar results were obtained for the validation group. This protocol is reliable, reproducible, can be performed in conscious animals, uses a single dose of the marker, and requires a reduced number of samples, and avoids urine collection. Finally, it presents a significant improvement in animal welfare conditions and handling necessities in experimental trials.

Iohexol plasma clearance simplified by dried blood spot testing.

Background: Renal function can be estimated with formulas, which are inaccurate, or measured with gold standard methods, which are reliable but unpractical. We propose to simplify the plasma clearance of iohexol, a gold standard method to measure renal function, by dried blood spot (DBS) testing. Methods: We compared glomerular filtration rate (GFR) values assessed by DBS and the reference plasma analysis technique. We tested in vitro the agreement between non-volumetric and volumetric DBS with the reference technique. Then, we performed a clinical validation in vivo between volumetric DBS and plasma analysis in 203 patients. The agreement was evaluated with the concordance correlation coefficient (CCC), the total deviation index (TDI) and the coverage probability. We defined acceptable agreement as a TDI <10%. Results: In the in vitro studies, the non-volumetric DBS showed moderate agreement, TDI = 26.0%, while the volumetric method showed better but insufficient agreement, TDI = 13.0%, with the reference method in plasma. The non-volumetric DBS was rejected. To improve the agreement of the volumetric DBS, iopamidol was used as an internal standard. This method showed acceptable agreement, TDI = 9.0% with the analysis in plasma, and was selected as the definitive DBS method. In the in vivo studies, the agreement between the final DBS method and the reference technique was acceptable: TDI = 9.5%. This indicates that 90% of the GFR values ranged from -9.5% to + 9.5% compared with the reference method. Conclusions: We simplified the plasma clearance of iohexol using DBS without losing accuracy and precision with respect to the reference technique. This may facilitate the use of a reliable determination of renal function to the medical community.

Genetic testing for indeterminate thyroid cytology: review and meta-analysis.

Thyroid cancer is the most frequent endocrine malignancy, and its incidence is increasing. A current limitation of cytological evaluation of thyroid nodules is that 20-25% are reported as indeterminate. Therefore, an important challenge for clinicians is to determine whether an indeterminate nodule is malignant, and should undergo surgery, or benign, and should be recommended to follow-up. The emergence of precision medicine has offered a valuable solution for this problem, with four tests currently available for the molecular diagnosis of indeterminate cytologies. However, efforts to critically analyze the quality of the accumulated evidence are scarce. This systematic review and meta-analysis is aimed to contribute to a better knowledge about the four available molecular tests, their technical characteristics, clinical performance, and ultimately to help clinicians to make better decisions to provide the best care options possible. For this purpose, we address three critical topics: (i) the proper theoretical accuracy, considering the intended clinical use of the test (rule-in vs rule-out) and the impact on clinical decisions; (ii) the quality of the evidence reported for each test (iii) and how accurate and effective have the tests proved to be after their clinical use. Together with the upcoming evidence, this work provides significant and useful information for healthcare system decision-makers to consider the use of molecular testing as a public health need, avoiding unnecessary surgical risks and costs.