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 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.

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.

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.

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.

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.

Impact and consequences of the error of estimated GFR in patients with heart failure.

Heart failure is a highly prevalent disease, which courses with frequent readmissions, mainly by Acute Heart Failure (AHF). Reduced renal function is associated with increased mortality in patients with HF. Therefore, an accurate and precise evaluation of renal function in patients with HF is crucial. The error of estimated GFR (eGFR) is wide and common, showing a ± 30% variability compared to measured GFR (mGFR). However, there is no evidence on the error of formulas in reflecting real renal function and particularly the consequences of this error in patients with AHF. This is a prospective study comparing the impact of mGFR versus eGFR in the onset of cardiovascular (CV) outcomes in patients with AHF. This was tested with cox survival analysis. Measured GFR was determined by the plasma clearance of iohexol-dbs and eGFR by Cockroft-Gould, MDRD, CKD-EPI creatinine, CKD-EPI cystatin-C and CKD-EPI creatinine + cystatin-C equations formulas. Also the agreement between mGFR and eGFR was analyzed. A total of 90 patients were included. Average age was 66 (± 12 years) and 52 (58%) were male. Of them 53 patients (59%) had a cardiovascular event during follow-up, 22 fatal (41%). The agreement between mGFR and eGFR indicated moderate precision and accuracy (concordance correlation coefficient of 0.77; CI = 0.73-0.82). In multiple cox survival analysis, mGFR was significantly associated with cardiovascular events together with NTproBNP, BMI, LVEF and previous coronary artery disease (p = 0.037; HR = 0.98, 95% CI = 0.95-0.99). Estimated GFR by formulas was not significant. In patients with AHF the error of formulas is large, frequent and random, also, mGFR and not eGFR predicted future CV events. The error of eGFR may have clinical consequences in specific subpopulations.

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.

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.

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.

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.

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.

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.].

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.

Estimated Glomerular Filtration Rate in Renal Transplantation: The Nephrologist in the Mist.

BACKGROUND: Formulas do not estimate renal function with acceptable precision and accuracy. METHODS: We compared 51 creatinine-based and/or cystatin c-based formulas with a gold standard (iohexol plasma clearance) in 193 renal transplant recipients using concordance correlation coefficient, total deviation index, coverage probability and the error in chronic kidney disease (CKD) stage classification. RESULTS: No formula showed a concordance correlation coefficient greater than 0.90 (average for creatinine-based formulas: ∼0.70 and for cystatin c-based formulas: ∼0.85). A wide total deviation index was observed: approximately 70% (creatinine-based) and approximately 50% (cystatin c-based), indicating that 90% of the estimations showed bounds of error of ±70% or ±50%, respectively, compared with the gold standard. No formula included 90% of the estimations within a coverage probability of ±10%. Half the CKD stages classified by creatinine-based formulas were incorrect, mainly due to overestimation of renal function. One of 3 CKD stages diagnosed by cystatin c-based formulas was incorrect, with both overestimation and underestimation. Overall, the formulas showed very low precision and accuracy and a high degree of error in reflecting real renal function. CONCLUSIONS: In conclusion, formulas do not properly reflect renal function in kidney transplantation, which makes their use in clinical practice unreliable. Moreover, their use in clinical trials should be avoided.