1. XV CONVEGNO NAZIONALE GRUPPO DI STUDIO DIALISI PERITONEALE BARI 18-20 MARZO 2010 Paolo Lentini Struttura Complessa di Nefrologia e Dialisi Ospedale San Bassiano Bassano Del Grappa LA BIOIMPEDENZA E’ UN UTILE STRUMENTO CLINICO ?

2. From PD gudelines (ISPD) Biocompatible PD solutions - normal pH, low concentration of glucose Insertion of PD catheter – 10 days-6 weeks before RRT urea / creatinine clearance measured every 6 months PET: 6 weeks after commencing treatment + annually Avoid routine use of high glucose concentrations )use of icodextrin, aminoacids instead) Preserve residual diuresis, obtain UF above 750 ml/day [hydration status] Peritonitis and exit-site infection rates, regular revision of technique Invasive procedures cover by ATB prophylaxis Topical ATB administration if needed (S.aureus, Ps. aeruginosa) Beware central obesity and malnutrition ISPD GUIDELINES/RECOMMENDATIONS Perit Dial Int 2006; 26:520–522

3. I. CLINICAL PRACTICE GUIDELINES FOR PERITONEAL DIALYSIS ADEQUACY GUIDELINE 3: PRESERVATION OF RESIDUAL KIDNEY FUNCTION Prospective randomized trials of dialysis adequacy and many observational studies have confirmed a strong association between the presence of RKF and reduction of mortality in patients on PD therapy. It is important to monitor and preserve RKF. (A) GUIDELINE 4. MAINTENANCE OF EUVOLEMIA Volume overload is associated with CHF, left ventricular hypertrophy (LVH), and hypertension; therefore, it is important to monitor ultrafiltration volume, dry weight, sodium intake, and other clinical assessments of volume status.

4. Guideline B. Assessment of nutritional status For PD patients should be routinely assessed using a panel of measures. The frequency of using these measures has not been verified, but a 6 monthly review is desirable. Serum albumin, prealbumin, creatinine and creatinine index, dietary interviews and diaries, protein equivalent of nitrogen appearance (nPNA), subjective global Assessment (SGA), anthropometry and dual-energy X- ray photon absorptiometry (DEXA) are all measures utilized to assess nutritional status and their evidence for use will be substantiated. CLINICAL PRACTICE GUIDELINES FOR PERITONEAL DIALYSIS NUTRITION EBPG Nutrition Nephrol Dial Transplant (2005) 20 [Suppl 9]

5. Methods for Body Composition Assessment Diluition Techniques – Reference method – 2 H, 3 H, 18 O, NaBr; Dual Energy X-ray Absorptiometry (DEXA)- Reference method Computed Tomography and Magnetic Resonance Imaging –Site Specific images - IAAT Densitometry – –Hydrostatic Weighing, BodPod Electrical Impedance Techniques –BIA (single & multi- frequency) –BIS – Cole-Cole Model Skinfolds & Anthropometric Body Mass or Weight

6. References Methods Dilution Techniques Deuterium ( 2 H) exchanges with H 2 O – reference method for Total Body Water NaBr (sodium-bromide) dilution doesn’t cross cell membrane – ECF space Requires pre- and post- dilution specimen (serum, urine) and mass spectrometer Dual Energy X-ray Absortiometry (DXA) X-ray Measures Bone Mineral Content (BMC) Bone Free Soft Tissue (BFST) BMC + BFST = FFM Distribution of Fat and Lean Tissue

7. PRINCIPLES OF BIA The resistance (R) of an of homogeneous material of uniform cross-sectional area is proportional to its length (L) and inversely proportional to its cross sectional area (A). The body offers two types of R to an electrical current: capacitative R (Reactance), and resistive R (simply called Resistance). Reactance (Re or X): Capacitative R CELL MEMBRANES Reactance (R): Extra and Intracellular FLUIDS Impedance (Z): Relation between X and R Phase Angle (PA): Lower phase angles: decreased cell integrity A basic assumption of BIA is that the sum of the arm, trunk and leg volumes can be modeled as a cylinder with uniform conductivity.

8. CLASSIFICATION BIA: Bioelectrical Impedance Analysis SF-BIA: Single Frequency Bioelectrical Impedance Analysis MF-BIA: Multi Frequency Bioelectrical Impedance Analysis BIS: Bioelectrical Impedance Spectroscopy BIVA: Bioelectrical Impedance Vector Analysis W-BIA: Whole Body Bioelectrical Impedance Analysis S-BIA: Segmental Bioelectrical Impedance analysis

9. CLINICAL USE OF BIA IN PD BODY COMPOSITION ASSESSMENT MANAGEMENT OF EXTRACELLULAR FLUID (DRY WEIGHT) ASSESSMENT OF NUTRITIONAL STATUS Nearly 2000 papers about BIA are found in English medical literature 1990-2010, 1200 being pubblished in the last 7 years.

10. MACHINES FOR BIOIMPEDANCE ANALYSIS Quantum II (RLJ System) SC-331 S (Tanita Corporation) ElectroFluidGraph (Akern s.r.l.) SFB7 (Impedimed Ltd.) Bioscan 916S (Maltron Ltd. Body Composition Monitor (Fresenius Medical Care)

11. CLINICAL USE OF BIA BODY COMPOSITION ASSESSMENT FAT MASS FAT-FREE MASS Mineral Protein Water

12. BODY COMPARTMENTS TBW: Total Body Water ECW: Extracellular Water ICW: Intracellular Water BF: Body Fat FFM: Fat-free Mass FM: Fat Mass

14. CLINICAL USE OF BIA MANAGEMENT OF EXTRACELLULAR FLUID (DRY WEIGHT)

15. “The lowest [post-dialysis] weight a patient can tolerate without intradialytic symptoms and/or hypotension and in the absence of overt fluid overload” Henderson KI 17: 571-576; 1980 Dry weight “ The post-dialysis weight at which the patient is and remains normotensive until the next dialysis in spite of interdialytic fluid retention and without antihypertensive medication” Charra 1996

16. EXCESS FLUID WEIGHT CONCEPT OF DRY WEIGHT DRY WEIGHT Clinical assessment of dry weight is a difficult task in PD patients by the lack of treatment associated signs indicative of dehydration as may be observed in HD patients such as intradialytic hypotension or cramps. Useful monitoring tools for fluid status estimation during HD like as on line blood volume and blood pressure measurement are not availble for application in PD patients

17. Physical examination should always be the basis for assessment dry weight in dialysis patients. However, as sometimes physical examination allows no definite conclusion, several non-invasive methods have been developed.

18. –Body Weight –Blood Pressure –Edema –Diuresis –Skin and Mucous hydration –Hematocrit –Electrolites Disorders –Chest X-Ray VOLUME

19. NO INVASIVE U.S. Inferior vena caval diameter Bio Impedance Analysis (BIA) Natriuretic Peptides (ANP, BNP,CNP) INVASIVE Central Venous Pressure (CVP) Pulmunary Artery Occlusion Pressure (PAOP) Cardiac Output ( SVV, SVO2) VOLUME EVALUATION

20. Overhydration: VCD > 11, CI < 40% Ideally measured 2hrs post dialysis Limitations: Operator variability, heart failure Timing of measurements is of pivotal importance for VCD, reference value of 8mm/m2 obtained 2 h after dialysis. INFERIOR VENA CAVAL DIAMETER

21. BNP correlates well with cardiac function, and is a good prognosticator for risk stratification ANP is sensitive to volume changes during dialysis, but changes in concentration do not predict achievement of euvolemia. Natriuretic peptides and the dialysis patient Suresh et al. Seminars in Dialysis 2005

22. SF-BIA SF-BIA, injecting 800 µA and 50 kHz alternating sinusoidal current is passed between surface electrodes placed on hand and foot. At 50 kHz, the current passes through both intra and extracellular fluid; LIMITS SF-BIA permits to estimate TBW from equations derived from healthy subjects; Fat-free mass is estimated by assuming TBW content is 73%, and fat is derived as weight minus FFM. Thus, both of these are potentially unreliable in situations with abnormal FFM hydration. Accuracy is not enough for clinical use due to the individual variation in Body composition

23. Frequencies vary from 5 kHz – 1MHz In biological tissues lower frequency currents travel preferentially in the extracellular space,whereas high frequency currents traverse both ECV and ICV. Use of prediction equations - not independent of TBW Cole-Cole model is applying to calculate extracellular and intracellular resistance MF-BIA and BIS

24. MF-BIA AND BIS At low frequency (below 30 kHz) the current travels through the ECF At high frequency the current travels through both the ECF and ICF

25. Bioimpedance Spectroscopy (BIS) BIS Scans from low (4 kHz) to high (1000 kHz) frequencies 400-500 discrete data points Ri (Impedance Intracellular) Determined mathematically by parallel subtraction of Rinf and R0 R0 Impedance at 0 kHz (Impedance ECF) Rinf Impedance at infinite KHz (Impedance TBW)

26. Transformation Ri (ohm) Impedance intracellular R0 (ohm) Impedance extracellular (Hanni mixture theory) Transformation (Hanni mixture theory) Transformation ICF (Litres) 14.2 L ECF (Litres) 22.2 L TBW (Litres) 36.4 L (14.2 + 22.2) Key Points Height of the patient must be known to calculate volumes from the raw data (R0 and Ri). If calculating Fat Mass in addition to fluid volumes the body weight of the patient must be known.

27. Assumptions of the Hanni Mixture theory Assumption 1 Body is made up of 5 cylinders (2 arms, 2 legs and the chest/abdomen) Assumption 2 These are filled with fluid and suspended cells of a homogenous type and density Assumption 3 The cylinders have a homogenous conductive properties (resistivities)

28. To assess abnormalities in body composition in 40 PD patients and in fluid status between 1.MF-BIA 2.Segmental BIA 3.Watson formula 4.Diluition methods (deuterium oxide [D02] for TBW and Bromide Diluition [NaBr]for ECW and DEXA for for body composition)

29. RESULTS MF-BIA tended to underestimate TBW according to D2O Whereas the Watson formula tended to overstimate TBW according to D2O

30. TBW: (D20 vs MF-BIA) 2.0 ± 3.9 L ECW: (NaBr vs MF-BIA) -2.8 ± 3.9 L BIA techniques did not appear to have significant advantages over the Watson formula to predicting TBW

31. MF-BIA AND BIS Limits MF-BIA was unable to detect changes in the distribution of fluid between extracellular and intracellular spaces in OVERHYDRATED patients; BIS: Modeling for body cell mass derived from spherical model (Cole-Cole Plot); muscle mass are non-spherical, but rather cylindrical. This difference in geometry may account for the understimation of R; Standard error by BIS for ECV measurement in healthy subjects is> ±1 L and that of ICV is > ±1.5 L limiting their clinical utility to dry weight determination;

32. BIVA The BIVA approach developed by Piccoli permits patient evaluation from the direct measurement of the impedance vector and does not depend on equations or models. In BIVA, R and reactance (Xc), standardized for height, are plotted as point vectors in the R-Xc plane. An individual vector can then be compared with the reference 50%, 75%, and 95% tolerance ellipses calculated in the healthy population of the same gender and race (R Xc graph method)

33. Cross-Sectional Study: 200 CAPD adults patients (149 without edema and 51 with edema). SF-BIA Rxc Graph (BIVA) was performed and measured TBW compared with: 1.726 Healthy subjects 2.1116 Hemodialysis patients 3.50 Nephrotic patients

34. The mean impedance vector of CAPD patients without edema was half way between the mean vectors of the healthy population and the HD population before the hemodialysis session.

35. BIVA: Limits An individual vector can be compared with the reference 50%, 75%, and 95% tolerance ellipses calculated in the healthy population of the same gender and race

36. SEG-BIA Segmental-BIA is performed by either placing two additional electrode on wrist and foot on the opposite side, or by placing sensor electrodes on wrist, shoulder (acromion), upper iliac spine and ankle. The trunk of the body contributes only as 10% to whole bodyimpedance; This implies three aspects : (1)Changes of the impedance are closely related to changes of the FFM (or muscle mass or body cell mass (BCM)) of the limbs; (2) Changes of the FFM of the trunk are probably not adequately described by whole body impedance measurements; (3) Segmental BIA must be used to determine fluid shifts and fluid distribution in some diseases (ascites, renal failure, surgery), and may be helpful in providing information on fluid accumulation in the pulmonary or abdominal region of the trunk (PD?) Composition of the ESPEN Working Group; Clinical Nutrition (2004) 23, 1226–1243

37. AIM:Using Segmental BIA to determine the characteristics of fluid shift of each body segment in 13 CAPD patients before and after PD solution exchange Method: Seg-BIA Trunk, arms and legs 1 h before and 1 and 2 hors later PD solution exchange

38. ARMs LEGs TRUNK RESULTS IMPEDANCE (ω) ARMS: Increased 1 h after drainage; LEGS: Decrease after exchange; TRUNK: Increase 1 h after drainage; TBW (L) ARMS: - 0.25 L LEGS: + 0.47 L TRUNK: -0. 25 L The change in body weight significantly correlated with total net calculated water volume change (p = 0.009)

39. 14 CAPD patients during standard exchange with fluids of known conductivity. Bioimpedance was continuously measured in the arm, trunk, and leg and from wrist to ankle. Volume changes were calculated using both segmental BIA (SBIA) and wrist-to-ankle BIA (WBIA) and were compared with volume changes measured gravimetrically.

40. When 2.19 ± 0.48 L were removed from the peritoneal cavity during draining, 95.2 ± 3.8% of this volume was detected by SBIA compared with 12.5 ± 24.3% detected by WBIA. When 2.11 ± 0.20 L of fresh dialysate was infused into the peritoneal cavity, 91.1 ± 19.6% of this volume was detected by SFBIA compared with only 8.86 ± 21.1% detected by WBIA.

41. SEGMENTAL BIA LIMITS Segmental-BIA requires prior standardization, particularly when different approaches and different BIA devices are employed; Standardization of the type of electrodes used and their placement; In literature we found very high relative errors with segmental-BIA for arms and legs FFM: 13– 17% for arm FFM and 10–13% for leg FFM.

42. CLINICAL USE OF BIA ASSESSMENT OF NUTRITIONAL STATUS

43. NUTRITIONAL STATUS MF-BIA: Body cell mass are derived from from DEXA in healthy as well as TBW are derived from D2O diluition in healthy:in conditions of abnormal fluid distribution can affect resistance and the error must be significant for FFM SF-BIA and FFM: BIA measure primarly TBW when the high correlations with FFM assume that the hydration costant is stable at 73%. In overhydrated patient the use of SF-BIA or MF-BIA or BIS to estimate FFM for nutritional assessment may lead to erroneous results

44. PHASE ANGLE PhA has been correlated with the disease prognosis in HIV- Infection, hemodialysis, peritoneal dialysis, chronic renal failure and Liver cirrhosis patients: these study suggest that PhA may be useful in determining increased risk of morbidity and that PhA decreased with age

45. This study prospectively examined the relationship of bioimpedance indexes to the nutrition status and survival of 45 PD patients who were followed for more than 1°year.

46. The cumulative observed survival of PD patients with an enrollment phase angle >6 degrees was significantly (p= 0.01) Higher than that of patients with an Enrollment phase angle <6 degrees. The BIA indices reflect nutrition status in PD patients, and may be useful in Monitoring Nutrition Fein PA, Advances in Peritoneal Dialysis, Vol. 18, 2002

47. OTHERS APPLICATIONS OF BIA TO PD Outflow Failure Dialysis Adequacy (Mendley et al ): Kt/V urea in pediatric PD patients utilizing TBW for volume (by SF-BIA) and compared with deuterium diluition.(mean difference 0.33± 1.44 L ns) Blood Pressure Control and fluid status in PD (Wang et al): ECV higher in uncontrolled hypertension

48. SEGMENTAL BIA IN PD Outflow failure, defined by the incomplete recovery of instilled fluid, is observed frequently in PD patients. Kinking of the catheter, malpositioning, omental occlusion and constipation are commonly observed, but it is important to exclude dialysate leakage as the underlying cause. The initial manifestations of dialysate leakage may be subtle. Intra-abdominal fluid volume determined by segmental BIA could aid differential diagnosis of outflow failure (catheter problem versus leakage) and reduce the need for imaging studies.

49. BIA UNSOLVED PROBLEMS Limitations of BIA equations Limitations of Reference Methods Limitations with reference study population (Ethins specificity differences) Limitations imposed by uremia and dialytic process on BIA measurement Common errors in BIA application

50. LIMITATIONS OF BIA EQUATIONS (1) Regression Functions (for SF-BIA): Based on experimental data derived from healthy population; Model that used equations based on the knowledge of extra- and intracellular volume space distribution (for MF-BIA and BIS) for bicompartimental model; The trunk contributes only a small proportion to whole body impedance;

51. TBW ERRORS Composition of the ESPEN Working Group; Clinical Nutrition (2004) 23, 1226–1243

52. FAT-FREE MASS Errors Composition of the ESPEN Working Group; Clinical Nutrition (2004) 23, 1226–1243

53. REFERENCE METHODS Each of these reference methods has limitations and makes assumptions that are not valid in all situations Isotope Diluition is not valid for multi- compartment model DEXA limitations is that results by different manufacturers do not agree. TBK is a reference method for body cell mass (BCM) but is limited in the determination of FFM because TBK content varies with sex and age.

54. STUDY POPULATON SUBJECTS Ethnic-specific equations for body composition are justified because of differences in body build among ethnic groups. Relative leg lengths, frame size and body buildt are factors responsible for ethnic differences in the body mass index (BMI); Failing to adjust for differences in FFM density in ethnic groups may result in systematic biases 3- 10%.

55. BIA MEASUREMENT CONDITIONS (1) Subject must be measured for height and weight at the time of BIA Body Position: Supine, arms separeted from trunk by about 30° and les separeted by about 45° Previous Exercise: No excercise from about 8 hours; Dietary Intake: Stop Food 2-4 hours before; Skin Temperature: Integrity, Clean with alcohol Electrode Position: Min. 5 cm of distance between electrodes; Ethnic Group: Note Race, USE SPECIFIC EQUATION IF AVAILABLE Time Measurement: For Hemodialysis: 20-30 minute after session results show not difference against 2 hours after session;

57. BIA MEASUREMENT CONDITIONS (2) Severely malnourished (BMI 34 Kg/m²) BIA results are affected by variable tissue hydration and should be interpreted with caution Body Abnormalities: Amputation-Orthopedic prosthesis,Atrophy, Hemiplegia,dystrophy (Duchenne, Cushing’s syndrome etc), Pachydermia (May invalidated meausre for high skin resistance; Special Conditions: Ascites with or without Liver Failure, Hemodialysis : No vascular access side; Peritoneal Dialysis: No difference between empty of full abdomen, consider Seg-BIa Treatments: Electrolite infusions and diuretics can interferes with BIA results Pacemaker-Defibrillator: No interference with measurement

58. Limitations imposed by dialysis on BIA measurement Underlying equations derived from non-uraemic control groups. Fluids, Electrolyte and hematocrit: An increase in Eletr or hematocrit concentrations will result in a reduction in R Error of method vs fluid removal in HD and PD: SEE for linear-regression for BIA equations is 2 L, the usual amount of ultrafiltrate removed ranges from 1-4 L Arms and Legs contribute 90% of whole-body impedance: abdomen fluids are under-estimated respect to Seg-BIA

59. CONCLUSIONS Visible Edema: Hand-to foot SF-BIA is not valid Significantly altered hydration states (Diuretic, ascites, liver and heart failure): the application of SF and MF-BIA are not appropriate to assess ICW and ECW; HD/DP: MF-BIA and BIS do not appear accurate to determine dialysis volume and intraperitoneal fluid changes Segmental BIA may prove to be best to determining abnormal hydration in trunk and ouflow failure: however this method is has not yet been sufficiently standardized to be used as a bedside technique BIVA method is able to detect altered tissue electric property in ill subjects; Low PhA have been shown to be of prognostic relevance in HD and PD patients

60. CONCLUSIONS We have to use different tecniques for different patients for different aims; We need standardization of the current Techniques and reference equations for specials kidney related populations (CKD, HD, PD).

61. GRAZIE