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Estimated glomerular filtration rate and functional status among older people: A systematic review

Open AccessPublished:June 20, 2018DOI:https://doi.org/10.1016/j.ejim.2018.05.030

      Highlights

      • The association CKD-frailty/disability may be affected by the eGFR equation used.
      • Only few cross-sectional and longitudinal studies compared different equations.
      • Cystatin C- but not creatinine-eGFR may be associated with functional status.
      • Studies including recent eGFR equations developed for older people are lacking.
      • Evidence does not allow to prove which eGFR equation may better predict function.

      Abstract

      Background

      The association between chronic kidney disease (CKD) and functional status may change as a function of the equation used to estimate glomerular filtration rate (eGFR). We reviewed the predictive value of different eGFR equations in regard to frailty and disability outcomes.

      Methods

      We searched Pubmed from inception to March 2018 for studies investigating the association between eGFR and self-reported and/or objective measures of frailty or disability. Cross-sectional and longitudinal studies were separately analysed.

      Results

      We included 16 studies, one of which reporting both cross-sectional and longitudinal data. Three out of 7 cross-sectional studies compared different eGFR equations in regard to their association with functional status: two studies showed that cystatin C-based, but not creatinine-based eGFR may be associated with hand-grip strength or frailty; another study showed that two different creatinine-based eGFR equations may be similarly associated with disability. Four out of 10 longitudinal studies provided comparative data: two studies reported similar association with disability for different creatinine-based eGFR equations; one study showed that creatinine-based eGFR was not associated with frailty, but a not significant trend for association was observed with cystatin C-based eGFR; one study showed that cystatin C-based but not creatinine-based eGFR may predict incident mobility disability, while both methods may predict gait speed decline. High heterogeneity was observed in regard to confounders included in reviewed studies. None of them included the most recently published equations.

      Conclusion

      Available data do not support the superiority of one of the eGFR equations in terms of measuring or predicting functional decline.

      Keywords

      1. Introduction

      Progressive aging of the population in industrialized countries is accompanied by an increase in the prevalence of chronic kidney disease (CKD) [
      • Stevens P.E.
      • O'Donoghue D.J.
      • de Lusignan S.
      • Van Vlymen J.
      • Klebe B.
      • Middleton R.
      • et al.
      Chronic kidney disease management in the United Kingdom: NEOERICA project results.
      ]. Recently, it has been estimated that the residual lifetime incidence of CKD among US people aged 65 or more is 42%, while the prevalence of CKD among older adults is projected to increase from 13.2% currently to 14.4% in 2020 and 16.7% in 2030 [
      • Hoerger T.J.
      • Simpson S.A.
      • Yarnoff B.O.
      • Pavkov M.E.
      • Rios Burrows N.
      • Saydah S.H.
      • et al.
      The future burden of CKD in the United States: a simulation model for the CDC CKD initiative.
      ]. Thus, CKD has a relevant public health burden in the older population, resulting in an increased risk of end-stage renal disease (ESRD), morbidity and mortality [
      • Astor B.C.
      • Matsushita K.
      • Gansevoort R.T.
      • van der Velde M.
      • Woodward M.
      • Levey A.S.
      • et al.
      Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.
      ].
      Besides carrying negative prognostic implications in general and selected diseased populations, including older ones [
      • McAlister F.A.
      • Ezekowitz J.
      • Tonelli M.
      • Armstrong P.W.
      Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study.
      ,
      • Go A.S.
      • Chertow G.M.
      • Fan D.
      • McCulloch C.E.
      • Hsu C.Y.
      Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
      ,
      • Corsonello A.
      • Pedone C.
      • Lattanzio F.
      • Cherubini A.
      • Onder G.
      • Corica F.
      • et al.
      Chronic kidney disease and 1-year survival in elderly patients discharged from acute care hospitals: a comparison of three glomerular filtration rate equations.
      ,
      • Oh S.W.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • Chae D.W.
      • Chin H.J.
      Glomerular filtration rate and proteinuria: association with mortality and renal progression in a prospective cohort of a community-based elderly population.
      ,
      • Malmgren L.
      • McGuigan F.E.
      • Berglundh S.
      • Westman K.
      • Christensson A.
      • Akesson K.
      Declining estimated glomerular filtration rate and its association with mortality and comorbidity over 10 years in elderly women.
      ], CKD also has negative implications in terms of functional limitation and disability, including impaired physical function [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ,
      • Roshanravan B.
      • Khatri M.
      • Robinson-Cohen C.
      • Levin G.
      • Patel K.V.
      • de Boer I.H.
      • et al.
      A prospective study of frailty in nephrology-referred patients with CKD.
      ], frailty [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ], and sarcopenia [
      • Morley J.E.
      • Abbatecola A.M.
      • Argiles J.M.
      • Baracos V.
      • Bauer J.
      • Bhasin S.
      • et al.
      Sarcopenia with limited mobility: an international consensus.
      ,
      • Foley R.N.
      • Wang C.
      • Ishani A.
      • Collins A.J.
      • Murray A.M.
      Kidney function and sarcopenia in the United States general population: NHANES III.
      ]. Thus, early identification and management of CKD patients are paramount for planning interventions aimed at slowing the progression of kidney disease and associated comorbidities, but also to delay the onset of its functional complications.
      Currently available creatinine-based measures of kidney function are plagued by some degree of inaccuracy and may provide discrepant estimates [
      • Pedone C.
      • Corsonello A.
      • Incalzi R.A.
      • Investigators G.
      Estimating renal function in older people: a comparison of three formulas.
      ,
      • Corsonello A.
      • Pedone C.
      • Lattanzio F.
      • Semeraro R.
      • D'Andria F.
      • Gigante M.
      • et al.
      Agreement between equations estimating glomerular filtration rate in elderly nursing home residents and in hospitalised patients: implications for drug dosing.
      ]. Indeed, several studies showed the existence of a U-shaped relationship between creatinine-based eGFR and mortality in frail and older people [
      • Cox H.J.
      • Bhandari S.
      • Rigby A.S.
      • Kilpatrick E.S.
      Mortality at low and high estimated glomerular filtration rate values: a 'U' shaped curve.
      ,
      • Peters R.
      • Beckett N.
      • Poulter R.
      • Burch L.
      • Narkiewicz K.
      • Fagard R.
      • et al.
      Kidney function in the very elderly with hypertension: data from the hypertension in the very elderly (HYVET) trial.
      ,
      • Tonelli M.
      • Klarenbach S.W.
      • Lloyd A.M.
      • James M.T.
      • Bello A.K.
      • Manns B.J.
      • et al.
      Higher estimated glomerular filtration rates may be associated with increased risk of adverse outcomes, especially with concomitant proteinuria.
      ,
      • Shastri S.
      • Katz R.
      • Rifkin D.E.
      • Fried L.F.
      • Odden M.C.
      • Peralta C.A.
      • et al.
      Kidney function and mortality in octogenarians: cardiovascular health study all stars.
      ]. Additionally, creatinine-based eGFR may systematically underestimate measured GFR at higher levels of kidney function [
      • Stevens L.A.
      • Coresh J.
      • Feldman H.I.
      • Greene T.
      • Lash J.P.
      • Nelson R.G.
      • et al.
      Evaluation of the modification of diet in renal disease study equation in a large diverse population.
      ], leading to systematic over-diagnosis of CKD in clinically healthy older people.
      Efforts have been made to improve the estimating equations, especially in older patients. The Berlin Initiative Study (BIS) equations have been developed and tested in older people and have been proved to be accurate and precise in this population [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ]. Nevertheless, the creatinine-based CKD-EPI (CKD-EPIcre) remains the recommended equation also for older people [
      • Levey A.S.
      • Becker C.
      • Inker L.A.
      Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
      ], as the role and practical place of BIS equations have not been conclusively defined. Additionally, the potential usefulness of cystatin C-based equations is still to be clarified. Finally, given the mounting evidence about the disabling potential of CKD, individual equations should be tested not only as for their accuracy in predicting measured GFR as reference standard or traditional end-points (e.g. mortality and end-stage renal disease (ESRD)), but also for their ability in predicting functional outcomes.
      Therefore, greater focus should be on the comparison between the recommended CKD-EPIcre and other eGFR equations in predicting functional status. Improving knowledge on this issue may assist in designing CKD-related disability risk assessments and in tailoring interventions for older people. Thus, the purpose of this systematic literature review was to (i) identify all studies reporting on the relationship between eGFR and self-reported or objectively measured functional status among older people, and (ii) describe findings with regard to the difference between data obtained with CKD-EPIcre compared to other eGFR equations.

      2. Methods

      2.1 Data Sources and Searching

      We conducted a systematic literature review in MEDLINE (via PubMed) from inception to March 2018, using the following syntax:
      (Equation OR formula) AND (Berlin-Initiative-Study OR “CKD-EPI” OR “CKDEPI” OR Chronic Kidney Disease Epidemiology Collaboration OR Cockcroft-Gault OR MDRD4 OR (Modification of Diet in Renal Disease) OR (Cystatin C) OR “Cystatin C"[Mesh] OR “Glomerular Filtration Rate”[Mesh] OR Glomerular Filtration Rate OR BIS-1 OR “CKD-EPI” OR BIS-2 OR “Kidney Function Tests”[Mesh] OR Schwartz equation).
      Only English language studies were selected for further evaluation. A manual search of reference lists of relevant papers and reviews was performed to identify additional articles.

      2.2 Eligibility Criteria and Quality Assessment

      Three assessors (MDR, PF, AC) independently screened title and abstract of the records retrieved from the medical literature. The following eligibility criteria were used to retrieve studies to be included in the review:
      • -
        Study design: Either cross-sectional or cohort (retrospective and prospective) studies were included. All study settings and design (cross sectional/longitudinal cohort) were included in further evaluation.
      • -
        Participants: studies not including people older than 65 years were excluded, while studies including also people younger than 65 were included for further evaluation.
      • -
        Reference assessment of eGFR: Creatinine-based CKD-EPI equation was considered as the reference assessment of eGFR on the basis of current recommendations [
        • Levey A.S.
        • Becker C.
        • Inker L.A.
        Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
        ].
      • -
        Comparators: We searched for studies comparing creatinine-based CKD-EPI to other equations in regards to their association with functional status. However, in order to obtain a comprehensive review, we also included papers investigating only one eGFR equation.
      • -
        Outcomes: physical functional status outcomes were considered. Studies including self-reported and/or objectively measured functional status were gathered and analysed.
      • -
        Measures for cross-sectional studies: β coefficients for continuous outcomes and ORs for binary outcomes. Measures for longitudinal studies: HRs for survival analyses, β coefficients for continuous outcomes and ORs for binary outcomes. Relative risk for eGFR value <60 ml/min/1.73 m2 was also extracted or calculated from data reported in retrieved longitudinal studies.
      The full-text of the articles selected by at least one of the assessors was further evaluated. The same assessors extracted independently information from the selected studies, including study aims, population, eGFR equation(s) used, specification of outcomes and main findings. The list of confounders included in each study was also gathered. Additional details were collected as deemed necessary. Any disagreement was resolved through consensus building in the focus group. Data were grouped according to study design (cross-sectional and cohort studies).
      Quality assessment was carried out by the same assessors using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [
      • National Heart Lung and Blood Institute
      Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies - NHLBI.
      ], a 14-item tool designed to aid appraisal of internal validity (potential risk of selection, information, or measurement bias, or confounding). Any disagreement in quality assessment was resolved through consensus.

      3. Results

      Fig. 1 shows information about the process of literature review and the reasons for inclusion and exclusion of identified citations. The electronic search strategy identified a total number of 5796 citations. Of these, 55 were considered as potentially eligible during title/abstract evaluation and included in full-text assessment. Fourteen primary studies [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ,
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ,
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ,
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ,
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ,
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ] and one systematic review/meta-analysis [
      • Shen Z.
      • Ruan Q.
      • Yu Z.
      • Sun Z.
      Chronic kidney disease-related physical frailty and cognitive impairment: a systemic review.
      ] were selected. The five studies included in the systematic review by Shen et al. [
      • Shen Z.
      • Ruan Q.
      • Yu Z.
      • Sun Z.
      Chronic kidney disease-related physical frailty and cognitive impairment: a systemic review.
      ] were analysed: one study was excluded because it did not include older people, while two other studies were excluded because kidney function was not estimated by eGFR. The remaining two studies [
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ] were retrieved, leading to a total of 16 studies included in the analysis. One of the included studies reported both cross-sectional and prospective data [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. The overall number of subjects included in reviewed studies was 45,381.
      The equations used to calculate eGFR mentioned in this systematic review are reported in Table 1 [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ,
      • Cockcroft D.W.
      • Gault M.H.
      Prediction of creatinine clearance from serum creatinine.
      ,
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group.
      ,
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro 3rd, A.F.
      • Feldman H.I.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ,
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • Eckfeldt J.H.
      • Feldman H.I.
      • Greene T.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      ,
      • Pottel H.
      • Delanaye P.
      • Schaeffner E.
      • Dubourg L.
      • Eriksen B.O.
      • Melsom T.
      • et al.
      Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C.
      ,
      • Anderson A.H.
      • Yang W.
      • Hsu C.Y.
      • Joffe M.M.
      • Leonard M.B.
      • Xie D.
      • et al.
      Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study.
      ]. Study outcomes assessed in retrieved studies are described in Table 2 [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ,
      • Guralnik J.M.
      • Simonsick E.M.
      • Ferrucci L.
      • Glynn R.J.
      • Berkman L.F.
      • Blazer D.G.
      • et al.
      A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.
      ,
      • Simonsick E.M.
      • Newman A.B.
      • Nevitt M.C.
      • Kritchevsky S.B.
      • Ferrucci L.
      • Guralnik J.M.
      • et al.
      Measuring higher level physical function in well-functioning older adults: expanding familiar approaches in the Health ABC study.
      ,
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • Newman A.B.
      • Hirsch C.
      • Gottdiener J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      ,
      • Rankin J.
      Cerebral vascular accidents in patients over the age of 60. II. Prognosis.
      ,
      • Katz S.
      • Ford A.B.
      • Moskowitz R.W.
      • Jackson B.A.
      • Jaffe M.W.
      Studies of illness in the aged. The index of Adl: a standardized measure of biological and psychosocial function.
      ,
      • Lawton M.P.
      • Brody E.M.
      Assessment of older people: self-maintaining and instrumental activities of daily living.
      ,
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I Conceptual framework and item selection.
      ] [
      • Hamilton B.B.
      • Granger C.V.
      • Sherwin F.S.
      • Zeilezny M.
      • Tashman J.S.
      Uniform national data system for medical rehabilitation.
      ].
      Table 1Equations for estimating GFR used in reviewed studies.
      CG [
      • Cockcroft D.W.
      • Gault M.H.
      Prediction of creatinine clearance from serum creatinine.
      ]
      [(l40–age) × weight]/(72xScr) [×0.85 if female]
      MDRD [
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group.
      ]
      [186.3 × (Scr)-1.154 × (age)-0.203] [×0.742 if female] [×1.212 if black]
      6-variables MDRD [
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group.
      ]
      170 ∗ [Scr] − 0.999 × age−0.176 × BUN−0.170 × serum albumin0.318 [×0.762 in females] [×1.180 if black]
      CKD-EPIcre [
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro 3rd, A.F.
      • Feldman H.I.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ]
      Female (Scr ≤ 0.7) eGFR = 144 × (Scr/0.7)−0.329 × (0.993)Age
      (Scr > 0.7) eGFR = 144 × (Scr/0.7)−1.209 × (0.993)Age
      Male (Scr ≤ 0.9) eGFR = 141 × (Scr/0.9)−0.411 × (0.993)Age
      (Scr > 0.9) eGFR = 141 × (Scr/0.9)−1.209 × (0.993)Age
      CKD-EPIcys [
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • Eckfeldt J.H.
      • Feldman H.I.
      • Greene T.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      ]
      (Scys ≤ 0.8), eGFR = 133 × (Scys/0.8)−0.499× 0.996Age[×0.932 if female]
      (Scys > 0.8), eGFR = 133 × (Scys/0.8)−1.328 × 0.996Age[×0.932 if female]
      CRIC [
      • Anderson A.H.
      • Yang W.
      • Hsu C.Y.
      • Joffe M.M.
      • Leonard M.B.
      • Xie D.
      • et al.
      Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study.
      ]
      Study equation is only available for CRIC study internal use
      BIS1 [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ]
      3736 × creatinine- 0.87 × age- 0.95 [×0.82 if female]
      BIS2 [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ]
      767 × cystatin C–0.61 × creatinine- 0.40 × age- 0.57 [×0.87 if female]
      FAS [
      • Pottel H.
      • Delanaye P.
      • Schaeffner E.
      • Dubourg L.
      • Eriksen B.O.
      • Melsom T.
      • et al.
      Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C.
      ]
      107.3/(Scr/Q) for age = 2–40 years
      [107.3/(Scr/Q)] × 0.998(Age-40) for age > 40 years
      Q = mean or median Scr value for age−/sex-specific healthy populations
      Scr: serum creatinine; BUN: blood urea nitrogen; Scys: serum cystatin C; CG: Cockcroft-Gault; MDRD: Modification of Diet in Renal Disease; CKD-EPI: Chronic Kidney Disease Epidemiological Collaboration; CRIC, Chronic Renal Insufficiency Cohort; BIS: Berlin Initiative Study; FAS: Full Age Spectrum.
      Table 2Summary of outcomes reported in reviewed studies.
      Outcome(s)Description
      Self-reported
      Working, walking and cognitionSelf-reported limitation in listed tasks
      Leisure and social activitiesSelf-reported limitation in listed tasks
      Lower extremity mobilitySelf-reported limitation in listed tasks
      General physical activitySelf-reported limitation in listed tasks
      Walking or climbing stairsSelf-reported limitation in listed tasks
      Basic activities of daily living (BADL) [
      • Katz S.
      • Ford A.B.
      • Moskowitz R.W.
      • Jackson B.A.
      • Jaffe M.W.
      Studies of illness in the aged. The index of Adl: a standardized measure of biological and psychosocial function.
      ]
      Rating dependency in bathing, dressing, toileting, transferring, continence, eating
      Instrumental activities of daily living (IADL) [
      • Lawton M.P.
      • Brody E.M.
      Assessment of older people: self-maintaining and instrumental activities of daily living.
      ]
      Rating dependency in ability to use telephone, shopping, food preparation, housekeeping, laundry, mode of transportation, managing medications, managing money
      Short Form-36 (SF36) physical function scale (PFS) [
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I Conceptual framework and item selection.
      ]
      SF36 is a 36-item questionnaire which measures Quality of Life across eight domains, including: physical functioning; role limitations due to physical health; role limitations due to emotional problems; energy/fatigue; emotional well-being; social functioning; pain; general health. The Physical function scale is calculated as average score of items 3 to 12.
      Functional Independence Measurement (FIM) [
      • Hamilton B.B.
      • Granger C.V.
      • Sherwin F.S.
      • Zeilezny M.
      • Tashman J.S.
      Uniform national data system for medical rehabilitation.
      ]
      The FIM is an 18-item, 7-level functional assessment designed to evaluate the amount of assistance required by a person with a disability to perform basic life activities safely and effectively.
      Objectively measured or mixed
      400-m walk timeTime taken to walk a distance of 400 m
      Lower extremity performance score [
      • Guralnik J.M.
      • Simonsick E.M.
      • Ferrucci L.
      • Glynn R.J.
      • Berkman L.F.
      • Blazer D.G.
      • et al.
      A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.
      ,
      • Simonsick E.M.
      • Newman A.B.
      • Nevitt M.C.
      • Kritchevsky S.B.
      • Ferrucci L.
      • Guralnik J.M.
      • et al.
      Measuring higher level physical function in well-functioning older adults: expanding familiar approaches in the Health ABC study.
      ]
      Modified version of the lower extremity performance test used in the Established Populations for Epidemiologic Studies of the Elderly (EPESE), including five repeated chair stands, semi-tandem, full tandem, and single-leg standing balance tests, a 6-min walking test to determine usual gait speed, and a narrow walk test of balance.
      Hand grip strengthIsokinetic dynamometer
      Sarcopenic hand grip strength (HGS) [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ]
      Hand grip strength<29 kg when BMI < 24 kg/m2, <30 kg when BMI = 24.1–28 kg/m2, <32 kg when BMI > 28 kg/m2
      Knee extension strengthIsokinetic dynamometer
      Walking (gait) speedGait speed in m/s measured on a 4-or 6-m path at usual pace.
      SPPB [
      • Guralnik J.M.
      • Simonsick E.M.
      • Ferrucci L.
      • Glynn R.J.
      • Berkman L.F.
      • Blazer D.G.
      • et al.
      A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.
      ]
      The short physical performance battery (SPPB) is a group of measures that combines the results of walking speed, chair stand and balance tests.
      Frailty [
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • Newman A.B.
      • Hirsch C.
      • Gottdiener J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      ]
      Frailty if defined as a clinical syndrome in which three or more of the following criteria are present: unintentional weight loss, weakness (handgrip strength), self-reported exhaustion or poor endurance, slowness (walking speed), and low physical activity (kilocalories expended per week).
      Rankin scale [
      • Rankin J.
      Cerebral vascular accidents in patients over the age of 60. II. Prognosis.
      ]
      Measures the degree of disability or dependence in the daily activities of people with stroke or other neurological disabilities. The 6 levels of rating are: no symptoms; no significant disability despite symptoms; slight disability; moderate disability; moderately severe disability; severe disability; dead.

      3.1 Overview of Included cross-sectional studies

      Among the 7 cross-sectional studies retrieved (Table 3), only three studies provided a comparison between different eGFR equations in regards to their association with functional status: Plantinga et al. [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ] compared CKD-EPIcre and MDRD, while Tufan et al. [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ] compared CKD-EPIcre, CKD-EPIcys and MDRD, and Dalrymple et al. [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ] compared CKD-EPIcre and CKD-EPIcys. Other cross-sectional studies used only MDRD [
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ,
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ], CKD-EPIcre [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ], or CRIC [
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ] equations. Six studies involved community-dwelling individuals [
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ,
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ,
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ,
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ,
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ], while only one study included hospitalized patients [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ]. The study by Plantinga et al. [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ] also included people aged 18–65 years, but only results for subjects aged>65 were included in the present analysis. The outcomes were self-reported in two out of six studies [
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ,
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ], while one or more objective measures of functional status were used in the remaining five studies [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ,
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ,
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ,
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ].
      Table 3Summary of findings from retrieved cross-sectional studies.
      StudyNAgeDesign and settingOutcome(s)eGFR methodMain results
      Odden [
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ]
      304374Cross-sectional400-m walk timeMDRDAmong patients with eGFR<60 ml/min/1.73 m2

      • -
        400-m walking time: β = 19.7, 95%CI = 9.2–30.1
      • -
        Lower extremity performance: β = −0.18, 95%CI = −0.26- -0.10
      • -
        Grip strength: β = −1.9, 95%CI = −3.0- -0.7
      • -
        Knee extension: β = −10.2, 95%CI = −14.7- -5.6
      Among patients with eGFR≥60 ml/min/1.73 m2

      • -
        400-m walking time: β = −3.5, 95%CI = −7.0–0.0
      • -
        Lower extremity performance: β = 0.04, 95%CI = 0.02–0.07
      • -
        Grip strength: β = 0.9, 95%CI = 0.5–1.3
      • -
        Knee extension: β = 3.8, 95%CI = 2.2–5.5
      Lower extremity performance score
      Community-dwelling
      Grip strength
      Knee extension strength
      Lin [
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ]
      254467Cross-sectionalSF36 physical function scale (PFS)MDRDAssociation between former eGFR decline ≥25% and actual PFS

      • -
        Linear analysis: β = −3.5, 95%CI = −5.4, −1.5
      • -
        Logistic regression analysis considering PFS ≤ 65 as outcome variable: OR = 1.37, 95%CI = 1.04–1.81 (not significant after adjusting for BMI: OR 1.15; 95% CI 0.90–1.47).
      Community-dwelling
      Plantinga [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ]
      16,011≥65Cross-sectionalSelf-reported limitations in:

      • Working, walking, and cognition;
      • BADL;
      • IADL;
      • Leisure and social activities;
      • Lower extremity mobility;
      • General physical activity
      MDRDStage 3–4 CKD compared to no CKD Using MDRD:

      • -
        Adjusted prevalence of disability in type or amount of work performed (43.7 (95%CI = 39.0–48.4) vs 39.0 (95%CI = 35.5–42.4), p < .05)
      • -
        Adjusted prevalence of disability in leisure time activities (21.5 (95%CI = 18.5–24.6) vs 17.4 (95%CI = 15.5–19.3), p < .05)
      Using CKD-EPIcre:

      • -
        Adjusted prevalence of disability in leisure time activities (21.7 (95%CI = 18.5–24.9) vs 17.4 (95%CI = 15.5–19.2), p < .05)
      Community-dwellingCKD-EPIcre
      Lattanzio [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ]
      48680.1Cross-sectionalSPPB, either global score or its individual components (muscle strength, balance, and walking speed)CKD-EPIcreLinear association between eGFR and:

      • -
        SPPB total score (B = 0.49, 95%CI = 0.18–0.66)
      • -
        Balance (B = 0.30, 95%CI = 0.10–0.49)
      • -
        Muscle strength (B = 0.06, 95%CI = 0.01–0.10)
      • -
        Walking speed (B = −0.04, 95%CI = −0.09–0.11)
      Compared to patients with eGFR>60:

      • -
        eGFR = 30.0–44.9, adjusted mean difference − 1.28 (95%CI = −2.37- -0.18) for SPPB total score, and − 0.63 (95%CI = −1.12- -0.14) for balance score;
      • -
        eGFR<30, adjusted mean difference − 2.26 (95%CI = −3.60- -0.93) for total SPPB score, −0.76 (95%CI = −1.30- -0.22) for muscle strength score, and − 1.03 (95%CI = −1.63 to −0.43).
      Hospital
      Dalrymple [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]
      4150≥65Cross-sectionalFrailty (slow gait speed, muscle weakness, low physical activity, exhaustion and unintentional weight loss)CKD-EPIcreCKD-EPIcre ≥ 90: reference

      • -
        76–89 OR = 0.48 (95%CI 0.42–0.73)
      • -
        60–75 OR = 0.59 (95%CI 0.39–0.89)
      • -
        45–59 OR = 0.69 (95%CI 0.45–1.07)
      • -
        15–44 OR = 0.83 (95%CI 0.49–1.41)
      CKD-EPIcys ≥ 90: reference

      • -
        76–89 OR = 0.77 (95%CI 0.48–1.31)
      • -
        60–75 OR = 1.05 (95%CI 0.64–1.72)
      • -
        45–59 OR = 1.47 (95%CI 0.89–2.43)
      • -
        15–44 OR = 2.44 (95%CI 1.43–4.19)
      Community-dwellingCKD-EPIcys
      Reese [
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ]
      111165.0Cross-sectionalSPPB; Frailty (slow gait speed, muscle weakness, low physical activity, exhaustion and unintentional weight loss)CRICFor SPPB

      • -
        eGFR 30–59: β = −0.51, 95%CI = −0.80 - -0.22;
      • -
        eGFR 15–29: β = −0.61, 95%CI = −1.03 - -0.19;
      • -
        eGFR<15: β = −1.75, 95%CI = −2.33 - -1.16.
      For frailty

      • -
        eGFR 30–59: OR = 1.45, 95%CI = 1.05–1.99;
      • -
        eGFR 15–29: OR = 2.02, 95%CI = 1.29–3.16;
      • -
        eGFR <15: OR = 4.83, 95%CI = 2.60–8.98.
      Community-dwelling
      Tufan [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ]
      20967.8Cross-sectionalHand grip strength (HGS).MDRDOnly CKDEPIcys < 60 was significantly associated with sarcopenic HGS (OR = 2.40, 95%CI = 1.04–5.40).
      CKDEPIcre
      Community-dwellingSarcopenic HGS was defined as (<29 kg when BMI < 24 kg/m2, <30 when BMI = 24.1–28 kg/m2, and < 32 kg when BMI > 28 kg/m2)
      CKDEPIcys
      MDRD, Modification of Diet in Renal Disease; CKD-EPI, Chronic Kidney Disease Epidemiological Collaboration; CRIC, Chronic Renal Insufficiency Cohort.
      Among comparative studies, Plantinga et al. [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ] showed that MDRD-based stage 3-4 CKD is associated with higher prevalence of disability into ability to work, type or amount of work performed, walking or difficulties in basic activity of daily living (BADL), instrumental activities of living (IADL), leisure and social activities, lower extremity mobility, and general physical activity. However, after adjusting for potential confounders most of these associations were no longer significant, so that only disability in type or amount of work and leisure-time activities resulted to be more prevalent in CKD compared to no-CKD subjects. Similarly, a significantly increased adjusted prevalence of disability in leisure-time activities among patients with stage 3-4 CKD was observed when using CKD-EPIcre equation [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ]. On the other hand, Tufan et al. showed that CKD-EPIcys was significantly correlated to reduced hand grip strength, while MDRD and CKD-EPIcre were not [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ]. Finally, Dalrymple et al. [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ] showed that CKD-EPIcys < 45 ml/min/1.73 m2 was significantly associated with frailty, while CKD-EPIcre was not.
      Non comparative cross-sectional studies provided consistent results across different outcome measures [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ,
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ,
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ,
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ]: MDRD was found associated with 400-m walk time, lower extremity performance, grip strength, knee extension [
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ]; eGFR decline≥25% (based on MDRD equation) during the 10 years preceding functional assessment was found associated with impaired SF36™ physical performance scale [
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ]; CKD-EPIcre was found associated with Short Physical Performance Battery (SPPB) total score, balance and muscle strength sub-scores, but not walking speed [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ]; Chronic Renal Insufficiency Cohort (CRIC) equation was found associated with SPPB total score and frailty [
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ] (Table 3).
      Overall, the quality of cross-sectional studies was fair (Table S1). Sample size justification was reported by Lin et al. [
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ], while Lattanzio et al. [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ] and Plantinga et al. [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ] reported different levels of kidney function as related to the outcomes. Confounders included age, gender and comorbidities (especially cardiovascular disease, diabetes, cancer, and anemia) in the majority of studies [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ,
      • Lin J.
      • Curhan G.C.
      Kidney function decline and physical function in women.
      ,
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ,
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • Townsend R.R.
      • Gadegbeku C.A.
      • Anderson C.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      ]. Results obtained by Odden et al. [
      • Odden M.C.
      • Chertow G.M.
      • Fried L.F.
      • Newman A.B.
      • Connelly S.
      • Angleman S.
      • et al.
      Cystatin C and measures of physical function in elderly adults: the Health, Aging, and Body Composition (HABC) Study.
      ] and Tufan et al. [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ] were not adjusted for comorbidity, while the study by Lattanzio et al. [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ] also included cognitive status and cumulative comorbidity as potential confounders. Selected studies also adjusted their analysis by serum albumin [
      • Lattanzio F.
      • Corsonello A.
      • Abbatecola A.M.
      • Volpato S.
      • Pedone C.
      • Pranno L.
      • et al.
      Relationship between renal function and physical performance in elderly hospitalized patients.
      ,
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ].

      3.2 Overview of included cohort studies

      Among the 10 cohort studies (Table 4), only one study was retrospective, while the remaining nine had a prospective design. Pedone et al. [
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ] provided a comparison between Cockcroft-Gault (CG) and MDRD, while Bowling et al. [
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ] compared MDRD and CKD-EPIcre in regard to their association with functional status. Dalrymple et al. [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ] and Liu et al. [
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ] compared the ability of CKD-EPIcys and CKD-EPIcre in predicting incident frailty and mobility disability or change in gait speed, respectively. Among the remaining cohort studies, two used MDRD [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ], one used the 6-variables MDRD [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ], and three used CKD-EPIcre [
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ]. Seven out of ten studies involved community-dwelling individuals [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ,
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ,
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ], while the remaining three were carried out in the hospital setting [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ]. The outcomes were self-reported in five studies [
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ,
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ,
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ] and objectively measured or rated by study researchers in the remaining ones [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ].
      Table 4Summary of findings from retrieved cohort studies.
      StudyNAgeDesign and settingOutcome(s)eGFR methodMain results
      Fried [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ]
      213573.5ProspectiveDifficulty in walking 1/4 mile or climbing 10 steps on two consecutive reports 6 months apart.MDRDRelative risk not available
      F.U.: Up to 54 monthseGFR<60: HR = 1.30 (95%CI = 1.08–1.56)
      Community-dwelling
      Bowling [
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ]
      35777.4ProspectiveIADL declineMDRDUsing MDRD equation -

      • -
        Relative risk for eGFR<60 was 2.05, 95%CI = 1.80–2.30 for IADL decline and 2.89, 95%CI = 2.63–3.15 for BADL decline.
      • -
        eGFR<60: OR = 1.83 (95%CI = 1.06–3.17) for IADL decline; OR = 2.46 (95%CI = 1.19–5.12) for BADL decline.
      • -
        eGFR<45: OR = 3.12 (95%CI = 1.38–7.06) for IADL decline; OR = 3.78 (95%CI = 1.36–9.77) for BADL decline.
      Using CKD-EPIcre equation –

      • -
        Relative risk for eGFR<60 was 2.49, 95%CI = 2.30–2.68 for IADL decline and 2.42, 95%CI = 2.19–2.64 for BADL decline.
      • -
        eGFR<60 was significantly associated with IADL decline (unadjusted OR = 3.40, 95% CI = 2.00–5.77) and BADL decline (unadjusted OR = 2.56; 95% CI = 1.29–5.08). These associations were similar after multivariable adjustment (data not shown).
      BADL declineCKD-EPIcre
      F.U.: 2 yrs.

      Community-dwelling
      Adunsky [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ]
      49983.6Retrospective cohortFIM at discharge after hospital rehabilitation6-variables MDRDRelative risk not available
      eGFR was significantly associated with motor FIM (β = 0.028, p = .022) but not total FIM (β = 0.072, p = .101).
      Hospital
      Hip fracture patients
      Feng [
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ]
      118665.6ProspectiveIADL decline (total and cognitive)MDRDeGFR<60:

      IADL decline -

      • -
        Relative risk for eGFR<60 = 2.91, 95%CI = 2.60–3.22
      • -
        OR = 1.99, 95%CI = 1.16–3.41
      IADL cognitive decline -

      • -
        Relative risk not available
      • -
        OR = 2.06, 95%CI = 1.07–3.94 for cognitive IADL decline
      F.U.: 4 yrs.
      Community- dwelling
      Pedone [
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ]
      66673.1ProspectiveLoss of independency in ≥1 BADLCGeGFR<60:

      • -
        Relative risk for CG < 60 = 1.90 (95%CI = 1.11–3.26)
      • -
        HR = 4.40 (95%CI = 2.80–6.94) for CG
      • -
        Relative risk for MDRD<60 = 1.72 (95%CI = 1.09–2.70)
      • -
        HR = 3.19 (95%CI = 2.12–4.79) for MDRD
      F.U: 6 yrs.MDRD
      Community-dwelling
      Dalrymple [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]
      4150≥65ProspectiveFrailty (slow gait speed, muscle weakness, low physical activity, exhaustion and unintentional weight loss)CKD-EPIcreCKD-EPIcre ≥ 90: reference

      • -
        Relative risk for eGFRcre < 60 = 1.30, 95%CI = 1.07–1.53
      • -
        76–89 IRR = 0.60 (95%CI 0.37–0.97)
      • -
        60–75 IRR = 0.86 (95%CI 0.54–1.37)
      • -
        45–59 IRR = 0.67 (95%CI 0.40–1.12)
      • -
        15–44 IRR = 1.08 (95%CI 0.58–2.01)
      CKD-EPIcys ≥ 90: reference

      • -
        Relative risk for eGFRcys < 60 = 1.55, 95%CI = 1.39–1.71
      • -
        76–89 IRR = 1.51 (95%CI 0.80–2.86)
      • -
        60–75 IRR = 1.62 (95%CI 0.88–2.99)
      • -
        45–59 IRR = 1.77 (95%CI 0.89–3.13)
      • -
        15–44 IRR = 1.87 (95%CI 0.95–3.69)
      Community-dwelling
      CKD-EPIcys
      Chin [
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ]
      984≥65ProspectiveIADL declineCKD-EPIcreeGFR≥ 60: reference

      For IADL decline –

      • -
        Relative risk for eGFR<60 = 2.36, 95%CI = 1.63–3.09
      • -
        eGFR 45–59: OR = 1.41, 95%CI = 0.82–2.44
      • -
        eGFR<45: OR = 3.0, 95%CI = 1.57–5.74
      For BADL decline -

      • -
        Relative risk for eGFR<60 = 2.24, 95%CI = 1.81–2.67
      • -
        eGFR 45–59: OR = 0.64, 95%CI = 0.20–2.00
      • -
        eGFR<45: OR = 2.94, 95%CI = 0.99–8.73
      F.U.: 59.4 ± 6.9 monthsBADL decline
      Community-dwelling
      Liu [
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ]
      122668.0ProspectiveSelf-reported inability to walk 1/2 mile and/or climb a flight of stairsCKD-EPIcreeGFRcre < 60:
      F.U.: 6.6 yrs.For mobility disability

      • -
        Relative risk for eGFR<60 = 1.26, 95%CI = 0.86–1.67
      • -
        OR = 1.03, 95%CI = 0.64–1.62
      For gait speed decline -

      • -
        Relative risk not available
      • -
        β = 0.07, SE = 0.03, p = .0004
      eGFRcys < 60:

      For mobility disability -

      • -
        Relative risk for eGFR<60 = 2.08, 95%CI = 1.33–2.83
      • -
        OR = 1.55, 95%CI = 1.05–2.31
      For gait speed decline

      • -
        Relative risk not available
      • -
        β = 0.07, SE = 0.02, p = .0022
      Community-dwellingCKD-EPIcys
      Gait speed decline
      Wang [
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ]
      886569.5ProspectiveStroke disability (Rankin scale)CKD-EPIcreeGFR≥ 90: reference

      • -
        Relative risk for eGFR<60 = 1.49, 95%CI = 1.37–1.61
      • -
        eGFR<45: OR = 1.26, 95%CI = 0.95–1.67
      • -
        eGFR 45–59: OR = 1.00, 95%CI = 0.81–1.23
      • -
        eGFR 60–89: OR = 0.93, 95%CI = 0.83–1.05
      F.U.: 1 yr
      Hospital (stroke registry)
      Yang [
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ]
      190966.5ProspectiveStroke disability (Rankin scale)CKD-EPIcreeGFR≥ 90: reference

      • -
        Relative risk for eGFR<60 = 1.50, 95%CI = 1.31–1.68
      • -
        eGFR 15–44: OR = 1.35, 95%CI = 0.83–2.19
      • -
        eGFR 45–59: OR = 1.09, 95%CI = 0.75–1.59
      • -
        eGFR 60–89: OR = 0.87, 95%CI = 0.67–1.14
      F.U.: 90 days
      Hospital (stroke registry)
      F.U., follow-up; MDRD, Modification of Diet in Renal Disease; CKD-EPI, Chronic Kidney Disease Epidemiological Collaboration; CG, Cockcroft-Gault.
      The comparative study by Pedone et al. [
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ] showed that both CG and MDRD equations were able to predict the loss of at least 1 BADL during a 6-years follow-up period among community-dwelling older people. Bowling et al. [
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ] showed that both CKD-EPIcre and MDRD were similarly associated with incident BADL and IADL dependency during a 2-year follow-up. At variance, despite the observed increased relative risk for CKD-EPIcre < 60 ml/min/1.73 m2, creatinine-based eGFR did not predict incident frailty after adjusting for potential confounders in the study by Dalrymple et al., while a not significant trend for increased risk was observed with CKD-EPIcys [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. Finally, Liu et al. showed that CKD-EPIcys but not CKD-EPIcre may predict incident mobility disability, while both equations may predict gait speed decline [
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ].
      Non comparative studies showed that MDRD equation could predict IADL and BADL decline, as well as difficulty in walking or climbing stairs [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ]. The 6-variable MDRD equation could predict motor, but not total Functional Impairment Measurement (FIM) score at discharge among older patients with hip fracture in the only study with retrospective design [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ]. CKD-EPIcre was found associated with IADL and BADL decline, self-reported difficulty in walking or climbing stairs, and gait speed decline in community-dwelling individuals [
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ]. The relative risk for incident stroke disability was also increased among hospitalized patients with CKD-EPIcre eGFR<60 ml/min/1.73 m2, but such an association was no longer significant in multivariable analysis [
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ] (Table 4).
      None of the cohort studies reported sample size justification. The exposure variable was assessed more than once over time only in the studies by Adunsky et al. [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ] and Dalrymple et al. [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. Relative risk or data for its calculation were available for eight out of ten cohort studies reviewed. Subjects lost to follow up were not reported in five out of eight studies [
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ,
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ] (Table S1). Age, gender, cardiovascular comorbidities and diabetes were the most frequently included confounders in cohort studies [
      • Fried L.F.
      • Lee J.S.
      • Shlipak M.
      • Chertow G.M.
      • Green C.
      • Ding J.
      • et al.
      Chronic kidney disease and functional limitation in older people: health, aging and body composition study.
      ,
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. Other potential confounders considered in cohort studies were serum albumin [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ], hemoglobin [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ], lipids [
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ], smoking habits and alcohol consumption [
      • Chin H.J.
      • Ahn S.Y.
      • Ryu J.
      • Kim S.
      • Na K.Y.
      • Kim K.W.
      • et al.
      Renal function and decline in functional capacity in older adults.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ]. Few studies also included cognitive status [
      • Adunsky A.
      • Mizrahi E.H.
      • Kaplan A.
      • Purits E.
      • Waitzman A.
      • Arad M.
      Elevated blood urea, independent of glomerular filtration rate (GFR), confers increased risk of adverse functional outcome in elderly hip fracture patients.
      ,
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ,
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ], depression [
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ] and physical activity [
      • Feng L.
      • Yap K.B.
      • Yeoh L.Y.
      • Ng T.P.
      Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study.
      ,
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ] among potential confounders.

      4. Discussion

      Our systematic review shows that eGFR is associated with different phenotypes of functional impairment in most of the studies included in the analysis. However, selected differences among studies deserve mention. Indeed, two comparative cross-sectional studies showed that CKD-EPIcys, but not MDRD and/or CKD-EPIcre was associated with hand grip strength or frailty [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. Additionally, one comparative cohort study showed CKD-EPIcre may not predict incident frailty, while a not significant trend for increased risk could be observed with CKD-EPIcys [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. Finally, CKD-EPIcre was not associated with incident stroke disability [
      • Wang X.
      • Wang Y.
      • Wang C.
      • Zhao X.
      • Xian Y.
      • Wang D.
      • et al.
      Association between estimated glomerular filtration rate and clinical outcomes in patients with acute ischaemic stroke: Results from China National Stroke Registry.
      ,
      • Yang J.
      • Arima H.
      • Zhou J.
      • Zhao Y.
      • Li Q.
      • Wu G.
      • et al.
      Effects of low estimated glomerular filtration rate on outcomes after stroke: a hospital-based stroke registry in China.
      ]. Thus there is consistent uncertainty, if changes in kidney function estimated with different equations may predict phenotypes of functional decline with different accuracy.
      While the potential superiority of cystatin C-based equations in predicting functional status needs to be further investigated in comparative studies, the small evidence currently available suggests that sarcopenia may represent an important confounder in the association between eGFR and functional phenotypes. Indeed, normal or even high eGFR based on a calculation using serum creatinine may at least partly reflect inflammation, frailty and/or muscle loss with consequent reduced creatinine production rather than normal kidney function [
      • Shastri S.
      • Sarnak M.J.
      Chronic kidney disease: high eGFR and mortality: high true GFR or a marker of frailty?.
      ,
      • Montesanto A.
      • De Rango F.
      • Berardelli M.
      • et al.
      Glomerular filtration rate in the elderly and in the oldest old: correlation with frailty and mortality.
      ]. This incongruence affirms the need for new approaches to estimate kidney function in elderly individuals. Ideally, a new formula should not only extrapolate age-associated declining muscle mass but also reflect functional decline.
      eGFR has been considered a key prognostic and classificatory indicator in public health campaigns, whereas serum creatinine is an unreliable marker of renal function [
      • Stevens L.A.
      • Coresh J.
      • Greene T.
      • Levey A.S.
      Assessing kidney function—measured and estimated glomerular filtration rate.
      ]. Equations have been developed by incorporating demographic and clinical variables as surrogates for unmeasured physiological factors, such as creatine generation and tubular secretion, that contribute – apart from filtration function – to serum creatinine concentration [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ,
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group.
      ,
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro 3rd, A.F.
      • Feldman H.I.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ,
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • Eckfeldt J.H.
      • Feldman H.I.
      • Greene T.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      ]. Estimating equations seems to be reasonably accurate in detecting changes in kidney function over time [
      • Delanaye P.
      • Mariat C.
      The applicability of eGFR equations to different populations.
      ]. However, the distinctive lack of data comparing the predictive value of different eGFR equation in regard to functional status observed in the present study is a relevant issue because the accuracy in predicting outcomes may change as a function of the equation used. Indeed, disagreement between eGFR equations has been consistently reported [
      • Pedone C.
      • Corsonello A.
      • Incalzi R.A.
      • Investigators G.
      Estimating renal function in older people: a comparison of three formulas.
      ,
      • Corsonello A.
      • Pedone C.
      • Lattanzio F.
      • Semeraro R.
      • D'Andria F.
      • Gigante M.
      • et al.
      Agreement between equations estimating glomerular filtration rate in elderly nursing home residents and in hospitalised patients: implications for drug dosing.
      ,
      • Pattaro C.
      • Riegler P.
      • Stifter G.
      • Modenese M.
      • Minelli C.
      • Pramstaller P.P.
      Estimating the glomerular filtration rate in the general population using different equations: effects on classification and association.
      ,
      • Mandelli S.
      • Riva E.
      • Tettamanti M.
      • Detoma P.
      • Giacomin A.
      • Lucca U.
      Mortality prediction in the oldest old with five different equations to estimate glomerular filtration rate: the health and anemia population-based study.
      ,
      • Corsonello A.
      • Pedone C.
      • Bandinelli S.
      • Ferrucci L.
      • Antonelli Incalzi R.
      Agreement between chronic kidney disease epidemiological collaboration and berlin initiative study equations for estimating glomerular filtration rate in older people: the invecchiare in chianti (aging in chianti region) study.
      ,
      • Pedone C.
      • Semeraro R.
      • Chiurco D.
      • D'Andria F.
      • Gigante M.
      • Coppola A.
      • et al.
      Reliability of equations to estimate glomerular filtration rate in the very old.
      ], with age, gender, weight, and study setting representing important sources of discrepancy between equations [
      • Pedone C.
      • Corsonello A.
      • Incalzi R.A.
      • Investigators G.
      Estimating renal function in older people: a comparison of three formulas.
      ]. Thus, results obtained with different equations may be difficult to interpret. As an example, a U-shaped relationship between eGFR and mortality has been observed by using MDRD [
      • Cox H.J.
      • Bhandari S.
      • Rigby A.S.
      • Kilpatrick E.S.
      Mortality at low and high estimated glomerular filtration rate values: a 'U' shaped curve.
      ], CKD-EPIcre [
      • Peters R.
      • Beckett N.
      • Poulter R.
      • Burch L.
      • Narkiewicz K.
      • Fagard R.
      • et al.
      Kidney function in the very elderly with hypertension: data from the hypertension in the very elderly (HYVET) trial.
      ,
      • Shastri S.
      • Katz R.
      • Rifkin D.E.
      • Fried L.F.
      • Odden M.C.
      • Peralta C.A.
      • et al.
      Kidney function and mortality in octogenarians: cardiovascular health study all stars.
      ], and BIScre [
      • Montesanto A.
      • De Rango F.
      • Berardelli M.
      • Mari V.
      • Lattanzio F.
      • Passarino G.
      • et al.
      Glomerular filtration rate in the elderly and in the oldest old: correlation with frailty and mortality.
      ], but not with cystatin-C-based CKD-EPI equation [
      • Shastri S.
      • Katz R.
      • Rifkin D.E.
      • Fried L.F.
      • Odden M.C.
      • Peralta C.A.
      • et al.
      Kidney function and mortality in octogenarians: cardiovascular health study all stars.
      ]. This evidence further suggests that eGFR may not only reflect kidney function, but rather muscle loss, which may contribute to a low serum creatinine concentration [
      • Montesanto A.
      • De Rango F.
      • Berardelli M.
      • Mari V.
      • Lattanzio F.
      • Passarino G.
      • et al.
      Glomerular filtration rate in the elderly and in the oldest old: correlation with frailty and mortality.
      ]. Such hypothesis is also sustained by the observation that both low serum creatinine and low 24 h urine creatinine are associated with adverse outcomes [
      • Ix J.H.
      • de Boer I.H.
      • Wassel C.L.
      • Criqui M.H.
      • Shlipak M.G.
      • Whooley M.A.
      Urinary creatinine excretion rate and mortality in persons with coronary artery disease: the heart and soul study.
      ], while cystatin C is less influenced by body composition [
      • Ferguson T.W.
      • Komenda P.
      • Tangri N.
      Cystatin C as a biomarker for estimating glomerular filtration rate.
      ]. Nevertheless, only two longitudinal study [
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ] and two cross-sectional studies [
      • Tufan A.
      • Tufan F.
      • Akpinar T.S.
      • Ilhan B.
      • Bahat G.
      • Karan M.A.
      Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: Is creatinine or cystatin C-based estimation more relevant?.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ] compared the predictive value of creatinine- and cystatin C-based eGFR in regard to functional status.
      Current evidence suggests that filtration markers other than serum creatinine and not affected by muscle loss (i.e. cystatin C, beta-trace protein and beta2-microglobulin) [
      • Foster M.C.
      • Inker L.A.
      • Levey A.S.
      • Selvin E.
      • Eckfeldt J.
      • Juraschek S.P.
      • et al.
      Novel filtration markers as predictors of all-cause and cardiovascular mortality in US adults.
      ] may better predict negative outcomes, but their usefulness in predicting functional decline is still to be investigated. Despite CKD-EPIcre remains recommended as a reference equation [
      • Levey A.S.
      • Becker C.
      • Inker L.A.
      Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
      ], it may not perform better than other equations in predicting outcomes in older populations [
      • Mandelli S.
      • Riva E.
      • Tettamanti M.
      • Detoma P.
      • Giacomin A.
      • Lucca U.
      Mortality prediction in the oldest old with five different equations to estimate glomerular filtration rate: the health and anemia population-based study.
      ,
      • Corsonello A.
      • Pedone C.
      • Bandinelli S.
      • Ferrucci L.
      • Antonelli Incalzi R.
      Predicting survival of older community-dwelling individuals according to five estimated glomerular filtration rate equations: The InChianti study.
      ]. The cross-sectional association between MDRD or CKD-EPIcre and disabilities was no longer significant after adjusting for potential confounders [
      • Plantinga L.C.
      • Johansen K.
      • Crews D.C.
      • Shahinian V.B.
      • Robinson B.M.
      • Saran R.
      • et al.
      Association of CKD with disability in the United States.
      ]. On the other hand, CKD-EPIcys, but not CKD-EPIcre was found cross-sectionally associated with frailty [
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. In cohort studies, CG, MDRD and CKD-EPIcre showed similar associations with incident disability [
      • Pedone C.
      • Corsonello A.
      • Bandinelli S.
      • Pizzarelli F.
      • Ferrucci L.
      • Incalzi R.A.
      Relationship between renal function and functional decline: role of the estimating equation.
      ,
      • Bowling C.B.
      • Sawyer P.
      • Campbell R.C.
      • Ahmed A.
      • Allman R.M.
      Impact of chronic kidney disease on activities of daily living in community-dwelling older adults.
      ]. However, when comparing CKD-EPIcre and CKD-EPIcys in regard to their ability to predict incident frailty or mobility disability, only the latter equation showed a near significant trend for increased risk [
      • Liu C.K.
      • Lyass A.
      • Massaro J.M.
      • D'Agostino Sr., R.B.
      • Fox C.S.
      • Murabito J.M.
      Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: the Framingham Offspring Study.
      ,
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • Siscovick D.
      • Newman A.B.
      • Fried L.F.
      • et al.
      Kidney function and prevalent and incident frailty.
      ]. Thus, available studies are not sufficient to build a meta-analysis of comparative studies. Additionally, it is worth noting that we could not find any study including the most recent equations addressing the issue of estimating kidney function among older people. The BIS equations have been specifically developed in an older population and published in 2012 [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ]. It showed a reduced rate of misclassification of CKD stages [
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ,
      • Delanaye P.
      • Mariat C.
      The applicability of eGFR equations to different populations.
      ], which was confirmed in two external validation studies in older patients [
      • Koppe L.
      • Klich A.
      • Dubourg L.
      • Ecochard R.
      • Hadj-Aissa A.
      Performance of creatinine-based equations compared in older patients.
      ,
      • Alshaer I.M.
      • Kilbride H.S.
      • Stevens P.E.
      • Eaglestone G.
      • Knight S.
      • Carter J.L.
      • et al.
      External validation of the Berlin equations for estimation of GFR in the elderly.
      ]. In our review, three cross-sectional studies and five longitudinal studies were published after 2012, but none of them included BIS equation for kidney function assessment. Furthermore, the Full Age Spectrum (FAS) equation has been published in 2016, and it has been mathematically obtained by requiring continuity during the pediatric–adult and adult–old age transition to improve validity across the full age spectrum [
      • Pottel H.
      • Hoste L.
      • Dubourg L.
      • Ebert N.
      • Schaeffner E.
      • Eriksen B.O.
      • et al.
      An estimated glomerular filtration rate equation for the full age spectrum.
      ]. Thus, it seems sensible to suggest for including BIS and FAS equations in future studies investigating the relationship between kidney function and functional impairment.
      The major strengths of the present study are the careful study selection and the assessment of their quality, both of which contribute to provide a reliable overview of the evidence in this research field. Additionally, most of the retrieved studies involve community-dwelling older people, which likely enhance the generalizability of our results. As for limitations, more than one-third of reviewed studies are cross-sectional, which limits the exploration of the causal relationship between eGFR and functional status. Another important limitation is the frequent use of self-reported outcome measures. Indeed, the outcome was self-reported in two out of seven cross-sectional studies, and in five out of ten cohort studies. Finally, a high heterogeneity was observed in confounding variables included in retrieved studies. Future studies are expected to bridge these gaps by using both objective and subjective outcome measures in order to increase the strength of evidence. From this point of view, the Screening for Chronic Kidney Disease among Older People across Europe (SCOPE) project, a large prospective multicenter cohort study, represents an important ongoing effort towards achieving this goal (ClinicalTrial.govNCT02691546).

      5. Conclusions

      Low eGFR is significantly associated with impaired functional status among older people. However, our findings do not allow to draw a definitive conclusion on which eGFR equation may better predict self-reported and/or objectively measured functional decline. Further studies based on longitudinal design and including both self-reported and objective outcome measures, as well as eGFR assessment by equations specifically developed in older people, and cystatin-based ones may be very informative and helpful to define CKD-related disability risk assessment among older people.

      Acknowledgments

      The Authors are grateful to Drs Antonio Cherubini, Iosief Abraha and Carlos Chiatti for their skillful support.

      Declarations of Interest

      None.

      Competing Interests

      All Authors declare to have no competing interests with this manuscript.

      Funding

      The work reported in this publication was granted by the European Union Horizon 2020 program (Grant Agreement no 634869). Funder had no role in the systematic review.

      Authors' contributions

      Andrea Corsonello, Regina Roller-Wirnsberger and Fabrizia Lattanzio conceived the study and participated in manuscript writing and revising.
      Andrea Corsonello, Mirko Di Rosa and Paolo Fabbietti carried out literature search.
      Gerhard Wirnsberger, Tomasz Kostka, Agnieszka Guligowska, Francesco Mattace-Raso, Lisanne Tap, Pedro Gil, Lara Guardado Fuentes, Itshak Meltzer, Ilan Yehoshua, Francesc Formiga-Perez, Rafael Moreno-González, Christian Weingart, Ellen Freiberger, Johan Ärnlöv and Axel C. Carlsson participated in manuscript revision and approval.

      Appendix A. SCOPE study Investigators

      A.1 Coordinating Center

      Fabrizia Lattanzio, Italian National Research Center on Aging (INRCA), Ancona, Italy – Principal Investigator.
      Andrea Corsonello, Silvia Bustacchini, Silvia Bolognini, Paola D'Ascoli, Raffaella Moresi, Giuseppina Di Stefano, Laura Cassetta, Anna Rita Bonfigli, Roberta Galeazzi, Federica Lenci, Stefano Della Bella, Enrico Bordoni, Mauro Provinciali, Robertina Giacconi, Cinzia Giuli, Demetrio Postacchini, Sabrina Garasto, Annalisa Cozza - Italian National Research Center on Aging (INRCA), Ancona, Fermo and Cosenza, Italy – Coordinating staff.
      Romano Firmani, Moreno Nacciariti, Mirko Di Rosa, Paolo Fabbietti – Technical and statistical support.

      A.2 Participating Centers

      • -
        Department of Internal Medicine, Medical University of Graz, Austria: Gerhard Hubert Wirnsberger, Regina Elisabeth Roller-Wirnsberger.
      • -
        Section of Geriatric Medicine, Department of Internal Medicine, Erasmus University Medical Center Rotterdam, The Netherlands: Francesco Mattace-Raso, Lisanne Tap, Jeannette Goudzwaard, Gijsbertus Ziere.
      • -
        Department of Geriatrics, Healthy Aging Research Centre, Medical University of Lodz, Poland: Tomasz Kostka, Agnieszka Guligowska, Łukasz Kroc, Bartłomiej K Sołtysik, Katarzyna Smyj, Elizaveta Fife, Joanna Kostka, Małgorzata Pigłowska.
      • -
        The Recanati School for Community Health Professions at the faculty of Health Sciences at Ben-Gurion University of the Negev, Israel: Rada Artzi-Medvedik, Yehudit Melzer, Mark Clarfield, Itshak Melzer; and Maccabi Healthcare services southern region, Israel: Rada Artzi-Medvedik, Ilan Yehoshua, Yehudit Melzer.
      • -
        Geriatric Unit, Internal Medicine Department and Nephrology Department, Bellvitge University Hospital – IDIBELL - L'Hospitalet de Llobregat, Barcelona, Spain: Francesc Formiga-Perez, Rafael Moreno-González, Josep Maria Cruzado.
      • -
        Department of Geriatric Medicine, Hospital Clínico San Carlos, Madrid: Pedro Gil Gregorio, Jose A. Herrero-Calvo, Fernando Tornero Molina, Lara Guardado-Fuentes, Pamela Carrillo-García, María Mombiedro-Pérez.
      • -
        Department of General Internal Medicine and Geriatrics, Krankenhaus Barmherzige Brüder Regensburg and Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany: Christian Weingart, Ellen Freiberger, Cornel Sieber
      • -
        Department of Medical Sciences, Uppsala University, Sweden: Johan Ärnlöv, Axel Carlsson, Tobias Feldreich.

      A.3 Scientific Advisory Board (SAB)

      Roberto Bernabei, Catholic University of Sacred Heart, Rome, Italy.
      Christophe Bula, University of Lausanne, Switzerland.
      Hermann Haller, Hannover Medical School, Hannover, Germany.
      Carmine Zoccali, CNR-IBIM Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria, Italy.

      A.4 Data and Ethics Management Board (DEMB)

      Dr. Kitty Jager, University of Amsterdam, The Netherlands.
      Dr. Wim Van Biesen, University Hospital of Ghent, Belgium.
      Paul E. Stevens, East Kent Hospitals University NHS Foundation Trust, Canterbury, United Kingdom.

      Appendix B. Supplementary data

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