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Abaterusso, Cataldo (2009) Formule di stima del GFR e composizione della massa corporea: potenzialità e limiti. [Tesi di dottorato]

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Abstract (inglese)

Background
Prevalence of chronic kidney diseases is increasing as well as projections in terms of prevalence, incidence and dedicated economical budget. An accurate determination of renal function is a central tool in the early diagnosis of the renal damage and its progression, as well as in customizing drug regimens.
Further to morphological and functional modifications in a number of organs and apparatus, the ageing process is associated with the progressive decline in renal function. Determination of the glomerular filtration rate (GFR) is the most accurate test to disclose a renal dysfunction; however, due to its complexity and costs, this technique cannot be used routinely. International guidelines recommend the use of formulae (mostly serum creatinine-based) for GFR estimation (eGFR) and for stratification of the cardiovascular risk in patients with Chronic Kidney Disease (CKD).
That "creatinine-based" eGFR formulae are not accurate in elderly people, in females, malnurished, or obese, or sarcopenic-obese patients is well known. This is due to the lack of sensibility of serum creatinine in the very initial reduction of GFR, in the rough estimation of the lean body mass by formulae in some categories of individuals and eventually in the lack of standardization of the assay for serum creatinine. The interest in using of Cystatin C as and endogenous marker of GFR has much increased recently.

Aim
The present manuscript reports results from a prospective study and a cross-sectional investigation.
Prospective study. In a cohort of elderly, healthy people the relationship between renal function and modifications in body composition was evaluated. Renal function was estimated by two endogenous markers (serum creatinine and Cystatin C) and applying more or less common formulae for estimating GFR.

Cross-sectional study: the effect of body composition on the performance of formulae in predicting the early decline of GFR in a cohort of adults was investigated. The implementation of the analysis with other parameters to improve the performance was also investigated.

Subjects and Methods
Elderly (prospective study) and adult (cross-sectional study) people of both genders have been enrolled after obtaining informed consent. Both studies were approved by the Institutional Ethical Committee. Inclusion and exclusion criteria are shortly reported below. In all the following determinations were performed: anthropometric measurements, body composition by Dual energy X-ray Absorptiometry (DXA), bioimpedence, routine biochemistry, serum Cystatin C concentration (CyC).
Prospective study: Elderly, healthy and non-istitutionalized subjects of both genders were recruited. Individuals with renal failure (serum creatinine >1.4 mg/dl in males, >1.2 mg/dl in females) were ruled out. Anthropometric measurements, body composition, nutritional enquiry and routine biochemistry were performed yearly during a 5 yrs follow-up. Estimated GFR was determined by 5 different formulae (Cockcroft-Gault, Virga, MDRD, Taylor, Hoek), either creatinine- or Cystatin C-based.
Cross-sectional study: CKD 1 and 2 adult patients of both genders were enrolled consecutively. Serum creatinine had to be <2mg/dl in males and <1.8mg/dl in females. All patients underwent GFR measurement (mGFR) by the Iohexol plasmatic clearance. Using the same formulae of above, eGFR was also estimated.
Results
Prospective study: 91 females who at the beginning of the study were 71.9 ± 2.4 yrs old, and had BMI 26.34 ± 4.44 Kg/m² and 62 males (72.5± 2.29 yrs and BMI 27.01± 3.39 Kg/ m²) were followed-up. After 5 yrs follow-up, a decrease in the lean body mass (total and appendicular) was observed in both genders, but particularly in males, without any modification of the nutritional state. At the end of follow-up serum creatinine was reduced proportionally reduced more than the decrease of lean body mass (percent variation of serum creatinine and lean mass was -1.4% vs -0.5% per year, respectively).
On the contrary, Cystatin C increased in both genders. Variations in serum Cystatin C were independent from lean mass changes and age. Only the Hoek’s formula (Cystatin C-based), at odds with the other formulae (all creatinine-based), disclosed the physiological decrease of GFR awaited with ageing.
Cross sectional study: It was carried out in a cohort of 83 subjects (34 females). Serum creatinine was on average (mean±SD) 1.19±0.39 mg/dL,. (serum creatinine 1.27±0.39 and 1.08±0.37 mg/dL, male and female, respectively). BMI was almost uniformly distributed among normal, overweight and obese (approx. 30% each). Measured GFR was 73.9±25.9 ml/min/1.73m2 (range 23-137.7 ml/min/1.73m2). The accuracy of different formulae, calculated by the prevalence of subjects having a percent difference between eGFR and mGFR (100 x [eGFR-mGFR]/mGFR) in 15% of the true GFR, disclosed a good predictive value in reference to the Virga (52% ). The accuracy of C-G and MDRD formulae were better than other for predicting eGFR <30% of true value (80 and 89%, respectively), confirming previous reports.
By the use of mathematical models of multiple linear regression it was possible to estimate the individual creatinine production rate (CrPROD in mg/min), which was 0.89±0.31 mg/min (Cr-PROD: 1.04±0.28 and 0.67±.0.21 mg/min, in male and female gender, respectively).. In particular, CrPROD was estimated considering LBM, or anthropometric measurements only as variables by the following equations:
1) Cr-prod = 0.9821 + 0.03842 * (Lean-app in Kg -25).
Intercept (±SE) 0.9821±0.04, coefficient (±SE) per (Lean-app in Kg-25): 0.03842, (p<0.0001). In other words, as an example, an normal individuals with an appendicular lean mass of 25 Kg should produce approx. 1mg/min creatinine, that is 1.44 g/24 hrs.
2) Cr-PROD = -0.366115 + (0.28081 if male) – (0.00275 * Circ-abdomen in cm) + 0.042854 * Circ-arm (in cm)
Male gender: coefficient(±SE) 0.280811±0.04, (p<0.0001); Circ-abd: coefficient(±SE) -0.00275±0.002, (p=0.05); Circ-arm: coefficient(±SE) 0.042854±0.008, (p<0.0001).
Conclusions
Perspective study
During the aging process, serum creatinine looses its ability to predict renal function partly because of the lean body mass reduction. Thus, creatinine-based eGFR formulae are less accurate in the elder, and may lead to a paradoxical, apparent increase in GFR. Lean mass reduction, earlier in males, is associated with a proportionally higher decrease in the synthetical and metabolical muscle activity.
Our findings sugget that Cystatin C is particularly useful in the evaluation of renal function in elderly people because it is independent on age-related modifications in body composition.
Cross sectional study
Serum creatinine alone is not capable to disclose in a sufficient accurate way the early renal damage in CKD. The present study confirms the large variability and low accuracy of the more frequently used formulae for GFR estimation, particularly in patients with initial reduction in GFR, in obesity and in the feminine gender. The recently proposed Virga’s formula, although not yet validated in large case populations, has shown a good performance in detecting mild, initial reduction of GFR with an error <15% of the true value of measured GFR. The estimation of the creatinine production rate seems to be possible by the use of simple, and repeatable direct anthropometric measurements that do not need any expensive diagnostic method.

Albeit the relatively modest number of investigated subjects in both studies, present data suggest that uncertainty in the quantitative and quali-quantitative estimation of lean mass in adults (cross-sectional study) and in elderlies (perspective study), respectively, is the major biasing factor in the estimation of GFR. The hypothesis raised by the Prospective study, if experimentally confirmed, suggests that elderly-dedicated formulae for GFR estimation needs to be developed, similarly to those used in children.

Abstract (italiano)

Premessa
Le malattie renali sono in crescente aumento e le previsioni per il futuro in termini di prevalenza, incidenza e costi sanitari sono allarmanti. L'accurata determinazione della funzione renale rappresenta un indispensabile strumento per l'identificazione precoce del danno e della progressione delle malattie renali e per nonchè© per l'adeguamento della posologia di molti farmaci. L'invecchiamento, inoltre, insieme alle modificazioni morfo-funzionali di organi ed apparati, si accompagna anche ad un progressivo declino della funzione renale. La misura della velocitè di filtrazione glomerulare (GFR) è¨ il test piè¹ accurato per evidenziare una disfunzione renale, tuttavia la complessitè dei metodi ed i costi rendono non proponibili tali metodiche nella pratica clinica. Le linee guida internazionali raccomandano l'impiego di formule, generalmente basate sull'impiego della creatinina sierica, per la stima del GFR (eGFR) e la stratificazione del rischio cardiovascolare nei pazienti con malattie renali croniche (Chronic Kidney Disease, CKD) E' noto che le formule di eGFR '€œcreatinine-based'€ risultano spesso poco accurate specialmente in determinate categorie di soggetti: anziani, donne, malnutriti, obesi, obesi-sarcopenici. I limiti sono da ricercare nella scarsa sensibilitè della creatinina a segnalare l'iniziale declino del GFR, nella inesatta stima della massa magra in alcune categorie di soggetti e, infine, nei problemi analitici legati alla standardizzazione, non ancora ottimale, del dosaggio della creatininemia.
Da alcuni anni crescente interesse ha suscitato l'utilizzo della la Cistatina C come marker endogeno di GFR.

Scopo.
In questo lavoro sono presentati i risultati di due Studi, il primo prospettico e il secondo trasversale.
Studio I (prospettico): lo scopo è¨ stato quello di valutare prospetticamente, in una coorte di anziani sani, le relazioni tra la funzionalitè renale, determinata attraverso l'impiego di due marcatori endogeni come creatininemia e cistatina C e l'applicazione di alcune comuni e meno comuni formule di stima del GFR, e le modificazioni della composizione corporea.
Studio II (trasversale): scopo del secondo studio è¨ stato quello di valutare l'impatto della composizione corporea sulla capacitè delle formule di predire l'iniziale declino del GFR in una coorte di soggetti adulti e di valutare possibili regressori in grado di implementare l'accuratezza delle stesse. Inoltre valutare il miglior metodo di indicizzazione del GFR misurato (mGFR).

Soggetti e Metodi
Sono stati arruolati soggetti anziani (Studio I) e adulti (Studio II) di ambo i sessi previo consenso informato scritto. Entrambi gli Studi hanno ottenuto l'approvazione del Comitato Etico di Verona. I criteri di inclusione ed esclusione sono in sintesi riportate di seguito, Tutti i soggetti sono stati sottoposti a determinazione delle misure antropometriche, della composizione corporea mediante Dual energy X-ray Absorptiometry (DXA), esame di bioimpedenza, esami bioumorali di routine, misura del valore plasmatico di Cistatina C (CyC).

Studio I: Sono stati arruolati e seguiti prospetticamente soggetti anziani di ambo i sessi in buone condizioni di salute, non istituzionalizzati e in assenza di patologie croniche debilitanti. Erano esclusi dallo studio soggetti con insufficienza renale (creatininemia >1.4 mg/dl per i maschi, >1.2 mg/dl per le femmine). I parametri antropometrici, la composizione corporea, l'anamnesi alimentare ed esami bioumorali di routine sono stati determinati annualmente per un follow-up mediano di 5 anni. L'eGFR è¨ stato determinato mediante l'applicazione di cinque formule (Cockcroft-Gault, Virga, MDRD, Taylor, Hoek) che utilizzano la creatininemia o la cistatina C come marcatori endogeni di GFR.

Studio II: Sono stati arruolati, consecutivamente, soggetti adulti con malattia renale cronica CKD I-II stadio e creatininemia <2mg/dl nel maschio e <1,8mg/dl nella femmina. Tutti i pazienti sono stati sottoposti, inoltre, alla misurazione del filtrato glomerulare (mGFR) con la tecnica della clearance plasmatica dello Ioexolo. L'eGFR è¨ stato ricavato con le stesse formule usate nello Studio I.

Risultati
Studio I: Lo studio I è¨ stato condotto in una coorte di 91 donne con etè all'inizio dello studio di 71.9 '± 2.4 anni e BMI di 26.34 '± 4.44 Kg/m'² e 62 uomini di etè di 72.5'± 2.29 anni e BMI di 27.01'± 3.39 Kg/ m'². Al termine dei 5 anni di follow-up si è¨ osservata in entrambi i sessi, fatto perè² piè¹ evidente nei maschi, una riduzione della massa magra totale ed appendicolare in assenza di significative modificazioni dello stato nutrizionale. I valori di creatininemia sono risultati ridotti in proporzione maggiore rispetto alla variazione di composizione corporea (variazione percentuale media annua di creatinina e massa magra: -1.4% vs -0.5%, rispettivamente). Al contrario la cistatina C è¨ risultata in aumento in entrambi i sessi. La variazione del valore della cistatina C è¨ risultata indipendente dalla variazione di massa magra ed etè . Soltanto la formula di Hoek (cistatin C-based) rispetto alle altre formule (creatinine-based) analizzate, ha decritto il declino del GFR come atteso nel fisiologico processo di invecchiamento di un soggetto sano

Studio II: Lo Studio II è¨ stato condotto in una coorte di 83 soggetti (34 femmine). Il valore della creatininemia risultava (media'±SD) 1.19'±0.39 mg/dL (creatininemia 1.27'±0.39 e 1.08'±0.37, rispettivamente nei maschi e nelle femmine). Il BMI era distribuito uniformemente (circa 30%) per normopeso, sovrappeso e obesitè . Il GFR misurato è¨ risultato in media 73.9'±25.9 ml/min/1.73m2 con range compreso tra 23-137.7 ml/min per 1.73m2.
L'accuratezza delle varie formule è¨ stata definita come prevalenza dei soggetti con differenza percentuale tra eGFR e mGFR (100 x [eGFR-mGFR]/mGFR) entro il 15% e 30% del GFR reale. La formula di Virga si mostra leggermente superiore alle altre nella previsione di eGFR <15% del valore reale in una maggiore percentuale di soggetti (52% vs 46% vs 42% vs 35% vs 45%, rispettivamente Vir vs CG vs MDRD vs MCQ vs Tay). Invece sia CG che MDRD risultano superiori alle altre riuscendo a prevedere il valore di eGFR <30% rispetto al reale, nel 80 e 89% dei pazienti, rispettivamente.
Utilizzando modelli matematici di regressione lineare multipla è¨ stato possibile dedurre quota di produzione di creatinina individuale (CrPROD in mg/min), determinata attraverso un modello matematico è¨ risultato: Cr-PROD: 0.89'±0.31 mg/min (Cr-PROD: 1.04'±0.28 e 0.67'±.0.21 mg/min, rispettivamente nel sesso maschile e nel sesso femminile). Attraverso l'analisi di regressione lineare a variabili multiple è¨ stato possibile stimare CrPROD essendo nota la LBM ovvero le sole misure antropometriche con le seguenti funzioni:
1) Cr-prod = 0.9821 + 0.03842 * (Lean-app in Kg -25).
Intercetta ('±SE) 0.9821'±0.04, coefficiente ('±SE) per (Lean-app in Kg-25) 0.03842; p<0.0001. In altri termini, ad esempio, un soggetto medio con 25 kg di massa magra appendicolare dovrebbe produrre ca. 1mg/min di creatinina pari a circa 1.44 g/die.
2) Cr-PROD = -0.366115 + (0.28081 se maschio) (0.00275 * Circ-addome in cm) + 0.042854 * Circ-braccio (in cm)
Sesso maschile: coefficiente('±SE) 0. 280811'±0.04, p<0.0001; Circ-add: coefficiente('±SE) -0.00275'±0.002, p=0.05; Circ-braccio: coefficiente('±SE) 0.042854'±0.008, p<0.0001.

Conclusioni
Il semplice dosaggio della creatininemia non è¨ in grado di individuare con sufficiente accuratezza lo stadio funzionale CKD in un ampissima quota della popolazione. Questo studio conferma la grande variabilitè e la scarsa accuratezza delle principali formule per la stima del GFR, soprattutto nei pazienti con iniziale decurtazione della funzionale renale, obesitè e sesso femminile. La recente formula di Virga, non ancora validata in ampie casistiche, ha mostrato una buona accuratezza, paragonabile alla formula MDRD, anche per GFR intorno alla normalitè e con buona performance per la predizione di eGFR <15% di errore rispetto al valore reale.
La valutazione attraverso misurazioni dirette della LBM e la correzione del GFR per questo dato hanno evidenziato una relazione molto superiore rispetto ai parametri surrogati di composizione corporea, come l'età , il peso, l'altezza. La stima della quota di produzione della creatinina è¨ possibile, sebbene i dati siano ancora preliminari, attraverso semplici e ripetibili determinazioni antropometriche dirette che non richiedono il ricorso a costose tecniche diagnostiche.
Nonostante la popolazione esaminata sia esigua, l'ipotesi che l'incertezza nella corretta definizione quantitativa della massa magra, da cui origina la creatinina di ogni soggetto, sia il principale determinante del bias delle formule è¨ stato confermato in questo studio.
Sarà necessario verificare con ulteriori studi se l'espansione del numero e della complessitè clinica dei soggetti studiati possa consentire l'elaborazione di un modello matematico piè¹ preciso ed affidabile per la stima del GFR nelle fasi iniziali delle nefropatie.

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Tipo di EPrint:Tesi di dottorato
Relatore:Gambaro, Giovanni
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE NEFROLOGICHE
Data di deposito della tesi:31 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):GFR, eGFR, body composition, cystatin C, iohexol
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/14 Nefrologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Mediche e Chirurgiche
Codice ID:1722
Depositato il:31 Gen 2009
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