Asymptomatic Pulmonary Congestion and Physical Functioning in Hemodialysis Patients

Article

Asymptomatic Pulmonary Congestion and PhysicalFunctioning in Hemodialysis Patients

Giuseppe Enia,*† Claudia Torino,† Vincenzo Panuccio,*† Rocco Tripepi,† Maurizio Postorino,*† Roberta Aliotta,*†

Marianna Bellantoni,*† Giovanni Tripepi,† Francesca Mallamaci,*† and Carmine Zoccali,*† on behalf of the Lung CometsCohort Working Group

SummaryBackground and objectives Poor physical performance is common in patients with kidney failure on dialysis (CKD-5D).Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute tothe low physical performance of CKD-5D patients has not been investigated in hemodialysis patients.

Design, setting, participants, & measurements This study investigated the relationship between the physicalfunctioning scale of the Kidney Disease Quality of Life Short Form and a validated ultrasonographic measure oflung water in a multicenter survey of 270 hemodialysis patients studied between 2009 and 2010.

ResultsModerate to severe lung congestion by lung ultrasonography was observed in 156 (58%) patients; amongthese, 60 (38%) were asymptomatic (New York Heart Association [NYHA] class I). On univariate analysis,physical functioning was inversely associated with lung water in the whole group (r=20.22; P,0.001) and in thesubgroup of asymptomatic patients (r=20.40; P=0.002). Age (r=20.45; P,0.001) and past cardiovascular events(r=20.22; P=0.002) were also inversely associated with physical functioning, whereas albumin (r=0.23; P,0.001)was directly associated with the same parameter. NYHA class correlated strongly with physical functioning(r=20.52; P,0.001). In a multiple regression analysis, both NYHA class and lung water maintained an inde-pendent associationwith physical functioning, whereas albumin and background cardiovascular events failed toindependently relate with the same outcome.

Conclusions Symptomatic and asymptomatic lung congestion is associated with poor physical functioning inhemodialysis patients. This association is independent of NYHA, suggesting that this measurement and NYHAmay have complementary value to explain the variability in physical performance in hemodialysis patients.

Clin J Am Soc Nephrol 8: 1343–1348, 2013. doi: 10.2215/CJN.11111012

IntroductionPhysical functioning, one of the most important dimen-sions of quality of life, is markedly compromised inpatients with kidney failure on dialysis (stage CKD-5D)(1–3). Anemia, mineral and bone disorders, the inflam-mation-muscular-wasting complex, cardiomyopathy,neuropathy, and depression, all disturbances that fre-quently coexist in CKD-5D, may be involved in thepoor physical functioning of this population (3–6). Pul-monary congestion detected and quantified by lungultrasonography recently emerged as a powerful corre-late of poor physical functioning in a multicenter studyin peritoneal dialysis (PD) patients (7), a populationwith an exceedingly high prevalence of fluid overloadand left ventricular dysfunction (8–10), suggesting thatvolume expansion and cardiomyopathy, two poten-tially reversible risk factors, play a major role in thepoor physical performance of this population.

The dynamics of fluid removal (continuous versus in-termittent) and the equilibriumbetween cardiopulmonaryfluid compartments (stable versus variable) differ inhemodialysis and in PD; therefore, observations in PD

patients do not necessarily apply to hemodialysispatients. To further explore this issue, we investigatedthe relationship between pulmonary congestion andphysical functioning in a large multicenter survey inhemodialysis patients. Because fluid accumulation inthe lung, per se or as an expression of cardiomyopathy,may lead to dyspnea, the association between pulmo-nary congestion and physical functioning was analyzedalso considering the New York Heart Association(NYHA) classification, a scoring system of heart failurein which dyspnea represents a dominant component.

Materials and MethodsThe study protocol was in conformity with the Dec-

laration of Helsinki and was approved by the localethics committee. Informed consent was obtained byall participants.

Study PopulationAll prevalent and incident patients on regular hemo-

dialysis treatment between 2009 and 2010 in the dialysis

*Nephrology,Dialysis,Hypertension, andRenal TransplantationUnit, AziendaOspedaliera, ReggioCalabria, Italy; and†CNR-IBIM, ClinicalEpidemiology, andPhysiopathology ofRenal Diseases andHypertension, ReggioCalabria

Correspondence:Dr. Giuseppe Enia,Nephrology, Dialysis,Hypertension, andRenal TransplantationUnit, AziendaOspedaliera andCNR-IBIM, via vallonePetrara, 89124 ReggioCalabria, Italy. Email:[email protected]

www.cjasn.org Vol 8 August, 2013 Copyright © 2013 by the American Society of Nephrology 1343

units participating in this study were invited to enter intothis survey. After exclusion of patients unable to completethe Kidney Disease Quality of Life Short Form (KDQOL-SF)(Rand Corporation, Santa Monica, CA) and those with pre-vious amputations, severe neurologic deficit or orthopedicdisease impairing physical activity, 270 patients, treated in 10renal units (105 women, 165 men), were enrolled (Figure 1).

Physical Functioning MeasurementWe used the subscale physical functioning of the

KDQOL-SF, which was specifically validated on CKDpatients in the Italian translation (11). This is a 10-questionscale (items 3–12) that captures self-reported abilities todeal with the physical requirements of life, such as attend-ing to personal needs and walking. The score of this scalecan range from 100 (no limitation at all in activities) to0 (limited a lot in activities). The median value of physicalfunctioning (SF-36) in normative data of the Italian popu-lation, of age similar to that of our study sample, was 95.We adopted the cut-off value of 70 (corresponding to the75th percentile of the physical functioning distribution inour study population) because this value approaches the25th percentile of the same score in the healthy, Italiangeneral population (12).

Lung UltrasonographyLung water was estimated by chest ultrasonography (13)

before hemodialysis. We described in detail the techniqueand tested its validity in hemodialysis and PD patients(14,15). The rationale of the method is that in the presenceof extravascular lung water, the ultrasound beam is re-flected by subpleural interlobular septa thickened bylung edema. The reflection of the beam generates comet-tail reverberation artifacts, called ultrasound B lines (16).The sum of ultrasound B lines observed in well identifiedchest areas (see below) produces a score reflecting the ex-tent of lung water accumulation (zero being no detectableultrasound B lines).As described (14), ultrasound scanning of the anterior

and lateral chest was performed on the right and left hemi-thorax, from the second to the fourth (on the right side to

the fifth) intercostal spaces, and from the parasternal to theaxillary line. The severity of lung congestion was catego-rized in three classes, as described elsewhere (14), and pa-tients with an ultrasound B line score between 15 and 30 andthose with a score .30 were considered as having moderateand severe lung congestion, respectively. A detailed de-scription of the technique is given in a YouTube film (http://www.youtube.com/watch?v=7y_hUFBHStM).One operator was responsible for lung ultrasonography

in each center. As described in detail elsewhere, theinteroperator reproducibility of ultrasound B line determi-nation in kidney failure patients on dialysis is excellent (14).All sonographers of participating units in this study werepreliminarily trained at CNR-IBIM, Reggio Calabria, andthe agreement of ultrasound B line measurements betweenthem and the trainer sonographer was confirmed to beexcellent (i.e., 610% the reference measurements madeby the sonographer-trainer). Ultrasound B lines and phys-ical functioning were assessed in the same day and allsonographers were blinded to the clinical and laboratorydata.

NYHA ScoresNYHA assessors were blind to detailed clinical infor-

mation and were unaware of the ultrasound B line results.Categories of increasing severity in the NYHA classifica-tion show a progressively higher mortality risk in dialysispatients (17) and we documented a fairly good agreementbetween independent NYHA assessors in these patients (17).

Other Covariates StudiedWe collected data on demographics (age, sex), treatment

parameters [dialysis vintage, Kt/V estimated by the Dau-girdas equation (18)], laboratory parameters (serum creat-inine, calcium, phosphate, albumin, hemoglobin), bodysize as body mass index (BMI) (kg/m2), predialysis BP,and comorbidities including diabetes, chronic obstructivepulmonary disease, and previous cardiovascular events(electrocardiography-documented angina and myocardialinfarction, stroke, transient ischemic attacks, heart failure,arrhythmias, or peripheral vascular disease). Treatment withantihypertensive and erythropoiesis-stimulating agents(ESAs) was also recorded. We also evaluated patients bythe subscale mental health of the KDQOL-SF validated inthe Italian translation (11). This five-question scale (items24–26, 28, and 30) scores feelings pertaining to anxiety anddepression and is considered as a useful screening instru-ment for depressive symptoms in dialysis patients (19). Ascore of 100 represents the best state, whereas 0 is the worst.Laboratory variables were measured by routine auto-analyzer methods at laboratories linked to each renal unit.

Statistical AnalysesData are presented as the mean 6 SD, median (inter-

quartile range), or percent frequency and comparison be-tween groups were made by t test, Mann–Whitney test, orchi-squared test, as appropriate. Variables that were notnormally distributed were log transformed.The independent association between ultrasound B lines

and physical functioning by the KDQOL-SF was analyzedby simple and multiple linear regression analyses adjusting

Figure 1. | Flow-diagram showing enrollment of hemodialysis pa-tients. KDQOL-SF, Kidney Disease Quality of Life Short Form.

1344 Clinical Journal of the American Society of Nephrology

for covariates that were associated (P#0.10) with physicalfunctioning and/or ultrasound B lines at univariate anal-ysis. In multiple linear regression analysis, multicollinear-ity was tested by investigating the variance inflation factorand tolerance. To further explore the risk for poor physicalfunctioning (score ,75 percentile) in relationship to lungcongestion, we performed a logistic regression based onthe same variables included in the multiple regressionmodel of the same outcome variable. Data were expressedas standardized regression coefficients (b) and P values inthe multiple linear regression analysis and as odds ratios,95% confidence intervals, and P values in the multiple lo-gistic regression analysis. All calculations were madeusing a standard statistical package (SPSS for Windows,version 9; SPSS Inc, Chicago, IL).

ResultsThe mean age of the study population was 65.9 years (SD

14.9), and median dialysis vintage was 51.2 months(interquartile range, 24–101). There were 235 patients onbicarbonate dialysis with standard or high-flux mem-branes, whereas 35 were being treated with hemodiafiltra-tion. Of the patients, 248 were dialyzed thrice weekly, 19were dialyzed four times per week, and 3 were dialyzedtwice weekly. The cause of chronic renal disease wasnephroangiosclerosis in 80, polycystic kidneys in 27, GNin 26, tubulointerstitial nephritis in 20, vasculitis in 3,hemolytic-uremic syndrome in 2, other diseases in 10,and unknown causes in 53 patients. Forty-nine patients haddiabetic nephropathy but diabetes as a comorbidity waspresent in 25 additional patients.The median KDQOL-SF physical functioning score was

40 (interquartile range, 15–70) and the vast majority ofpatients (Figure 2) scored ,25th percentile of the distribu-tion of the same score in the normal Italian population ofsimilar age (12). Table 1 shows the main baseline charac-teristics of the patients divided into three groups on thebasis of physical functioning tertiles. Patients in lowerfunctional categories were older and more frequentlywere women; they had lower serum albumin, diastolicpressure, phosphate, and creatinine levels and more fre-quently had a history of diabetes, cardiovascular events,and chronic obstructive pulmonary disease.

Correlates of Physical FunctioningThe number of ultrasound B lines was higher in patients

with lower physical performance and this score correlatedinversely (r=20.22; P,0.001) with the same parameter(Table 1) and tended to be directly related to interdialysisweight gain (r=0.11; P=0.06). The association was evenstronger (r=20.40; P=0.002) in the subgroup of 60 asymp-tomatic patients (i.e., classified in NYHA class I) (Figure 3).Physical functioning was also inversely associated withage (r=20.45; P,0.001), diabetes (r=20.17; P=0.01), andbackground cardiovascular events (r=20.22; P=0.002)and was directly associated with serum albumin (r=0.23;P,0.001), creatinine (r=0.29; P,0.001), phosphate (r=0.19;P=0.002), and diastolic BP (r=0.13; P=0.03) (Table 1).NYHA class (r=20.52; P,0.001) and mental health(r=0.38; P,0.001) were strongly associated with physicalfunctioning (Figure 4).

Multivariate Analyses of Physical FunctioningTo define the factors that explain the variability in

physical functioning, we built a multiple regression modelincluding all variables that were associated with physicalfunctioning and/or with ultrasound B lines at univariateanalysis. In this model, NYHA ranked as the strongestindependent correlate of the outcome variable followed bymental health, age, and ultrasound B lines (Table 2). Forc-ing BMI into the model, as well as the full set of variableslisted in Table 1, did not materially affect the strength ofthe relationship between ultrasound B lines and physicalfunctioning. In the same model, BMI failed to be indepen-dently related to physical performance (P=0.42).Multivariate logistic regression analysis showed that for

each 10-unit increase in ultrasound B lines, the probabilityof poor physical performance increased by 23% (odds ratio,1.23; 95% confidence interval, 1.03 to 1.48; P=0.03) and theexcess risk was again independent of NYHA class (Table 3).

DiscussionThis survey documents that lung water by chest ultra-

sonography (13–15) is associated with physical functioningin stage 5 CKD patients on hemodialysis treatment. Suchan association is largely independent of other risk factors,including the severity of heart failure as assessed byNYHA, traditional, and CKD-related risk factors.In keeping with previous surveys (1–3), we found that

physical functioning is impaired in hemodialysis patientsand that age, diabetes, and cardiovascular comorbiditiesrepresent the strongest correlates of poor physical func-tioning in this population. We also observed that nutritionbiomarkers (namely, serum albumin, creatinine, and phos-phate) were closely associated with physical functioning atunivariate analysis but these parameters were no longersignificantly related to this outcome variable in multipleregression analyses. Selective multivariate modelingshowed that data adjustment by age was the critical factorabrogating the link between nutritional biomarkers andphysical functioning, suggesting that this link is large-ly attributable to confounding by the aging process.

Figure 2. | Bar graph of the physical functioning score distribution.The vertical arrow indicates the 75th percentile (corresponding to the25th percentile of the distribution of the same score in the Italiangeneral population) [see Apolone and Mosconi (12)].

Clin J Am Soc Nephrol 8: 1343–1348, August, 2013 Pulmonary Congestion and Physical Functioning, Enia et al. 1345

Confirming observations in PD patients (7), physical per-formance was independent of hemoglobin, a parameterconsidered as a fundamental determinant of physicalhealth. Such a lack of association most likely depends on

the fact that anemia was adequately treated in most pa-tients (81% of hemodialysis patients had hemoglobin$10.5 g/dl). NYHA classification was the strongest pre-dictor of physical functioning score explaining more than aquarter (27%) of the variance in this parameter.Pulmonary congestion frequently occurs in hemodialysis

patients (14). This phenomenon more likely reflects im-paired cardiac function than true volume overloadbecause a previous study has demonstrated stronger cor-relations between ultrasound B lines and left ventricularsystolic function than total body water as measured bybody impedance analysis (14). The novel key finding ofthis study in hemodialysis patients is the independent as-sociation between physical functioning and pulmonarycongestion as assessed by lung ultrasonography. Notably,this association was particularly strong in the subgroup ofasymptomatic patients (classified as NYHA class I). In-deed, in this subgroup, 16% of the variance in physicalfunctioning was explained by the simultaneous variabilityin lung water, suggesting that lung congestion contributesto physical impairment in apparently asymptomatic he-modialysis patients. Multivariate analysis attenuated butdid not abolish the relationship between lung water and

Figure 3. | Relationship between ultrasound B line score and phys-ical functioning in patients scored asNYHAclass I. NYHA,NewYorkHeart Association; KDQOL-SF, Kidney Disease Quality of Life ShortForm; USB, ultrasound B line.

Table 1. Main demographic, clinical, and biochemical data of hemodialysis patients

Variable

KDQOL-SF Score (Physical Functioning)

I tertile ,20(n=91)

II tertile 20–55(n=90)

III tertile .55(n=89) P r (P)

Age (yr) 72612 69611 57617 ,0.001a 20.45 (,0.001)a

Male sex (%) 46 71 66 0.001a 0.15 (0.02)a

Diabetes (%) 37 28 19 0.02a 20.17 (0.01)a

Previous cardiovascular events (%)b 57 40 32 0.002a 20.22 (0.002)a

Dialysis vintage (mo) 57 (24–108) 51 (27–109) 41 (20–82) 0.18 20.06 (0.31)COPD 19 17 6 0.05a 20.13 (0.04)a

Antihypertensive treatment (%) 53 49 58 0.44 0.03 (0.67)ESA treatment 85 74 73 0.09 20.05 (0.41)Predialysis systolic BP (mmHg) 136626 139621 131620 0.12 20.10 (0.12)Predialysis diastolic BP (mmHg) 69612 75611 73613 0.04a 0.13 (0.03)a

Body mass index (kg/m2) 24.965.0 25.065.0 24.864.8 0.91 20.01 (0.93)Serum creatinine (mg/dl) 8.262.6 9.362.5 10.163.1 ,0.001a 0.29 (,0.001)a

Hemoglobin (g/dl) 11.161.2 11.561.4 11.361.4 0.19 0.03 (0.63)Calcium (mg/dl) 9.060.8 9.060.9 9.060.8 0.83 0.01 (0.84)Phosphate (mg/dl) 4.561.4 4.961.6 5.261.7 0.003a 0.19 (0.002)a

Serum albumin (g/dl) 3.860.4 4.060.3 4.060.4 0.001a 0.23 (,0.001)a

Kt/V 1.4460.32 1.4060.37 1.3860.25 0.33 20.07 (0.36)Predialysis ultrasound B lines (n) 25 (13–55) 18 (10–36) 16 (8–30) 0.10a 20.22 (,0.001)a

NYHA class ,0.001a 20.52 (,0.001)a

I 15 8 46II 28 62 48III 36 27 6IV 21 3 0

Mental health score 46619 54618 62619 ,0.001a 0.38 (,0.001)a

Data are expressed as mean6 SD,median (interquartile range), or as percent frequency, as appropriate. Patients are divided into threegroups on the basis of tertiles of KDQOL-SF physical functioning score. P tests the differences among the groups. r is the Pearsoncoefficient of correlation between KDQOL-SF physical functioning score and the variables. KDQOL-SF, Kidney Disease Quality of LifeShort Form; COPD, chronic obstructive pulmonary disease; ESA, erythropoiesis-stimulating agent.aIndicates significant differences between groups and significant correlations.bPrevious cardiovascular events such as electrocardiography-documented angina andmyocardial infarction, stroke, transient ischemicattacks, heart failure, arrhythmias, or peripheral vascular disease.

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physical functioning and both lung water and NYHA classremained independent predictors of physical functioning,suggesting that the two scoring systems have complemen-tary value to explain physical functioning in hemodialysispatients. Ultrasound B lines are tightly associated withfundamental functional parameters of the left ventriclesuch as ejection fraction, left atrial volume, and pulmonarypressure (13–15); therefore, the additional explanatorypower of ultrasound B lines over and above the severityof dyspnea by NYHA likely depends on the fact that pul-monary congestion by this technique captures explanatorypower conveyed by low ejection fraction and other leftventricular disorders underlying water accumulation inthe lungs.This study has several limitations. The main limitation

depends on the cross-sectional design, which prevents usfrom making a causal interpretation of our findings.

Another limitation is the lack of an objective indicator ofmuscular strength and physical performance. We used awell validated but self-reported scale of physical function-ing. However, the subjective perception by patients of theirphysical functioning is one of the most important aspects ofquality of life; in a previous study in CKD patients, wedocumented that physical functioning by the KDQOL-SFhas a fairly good agreement with actual physical activity as

Table 2. Multiple regression analysis of physical functioning

Variable b P

NYHA class 20.30 ,0.001Mental health 0.26 ,0.001Age 20.23 ,0.001Predialysis ultrasound B lines 20.11 0.03Male sex 0.08 0.15Serum albumin 0.05 0.34Phosphate 0.05 0.35Diabetes 20.04 0.44Serum creatinine 0.04 0.45COPD 20.02 0.63Predialysis diastolic BP 20.02 0.78Hemoglobin 20.01 0.81ESA treatment 20.01 0.91Previous cardiovascular events 20.01 0.91

Data are expressed as standardized regression coefficient (b)and P value. NYHA, New York Heart Association; COPD,chronic obstructive pulmonary disease; ESA, erythropoiesis-stimulating agent.

Figure 4. | Median and interquartile range of physical functioning according toNYHA class andmental health score tertiles. The relationshipbetween variables is also expressed as the correlation coefficient and P value.NYHA,NewYorkHeart Association; KDQOL-SF, KidneyDiseaseQuality of Life Short Form.

Table 3. Logistic regression analysis of physical functioning<75th percentile as the dependent variable

Variable (Unitsof Increase)

OddsRatio

95%ConfidenceInterval

P

NYHA class (1 unit) 2.76 1.48 to 5.13 0.001Age (1 yr) 1.05 1.01 to 1.08 0.004PredialysisultrasoundB lines (10 units)

1.23 1.03 to 1.48 0.03

Mental health (1 unit) 0.98 0.96 to 1.00 0.05Male sex 0.46 0.19 to 1.09 0.08Predialysis diastolicBP (1 mmHg)

1.03 0.99 to 1.07 0.09

ESA treatmenta 0.49 0.18 to 1.30 0.15COPDa 2.55 0.53 to 12.21 0.24Phosphate (1 mg/dl) 0.88 0.67 to 1.17 0.39Previouscardiovasculareventsa

1.32 0.57 to 3.04 0.51

Diabetesa 1.14 0.56 to 2.87 0.78Serum albumin(1 g/dl)

0.87 0.29 to 2.62 0.81

Hemoglobin (1 g/dl) 1.01 0.75 to 1.36 0.94Serum creatinine(1 mg/dl)

1.00 0.87 to 1.16 0.95

NYHA, New York Heart Association; ESA, erythropoiesis-stimulating agent; COPD, chronic obstructive pulmonary dis-ease.a0 = no; 1 = yes.

Clin J Am Soc Nephrol 8: 1343–1348, August, 2013 Pulmonary Congestion and Physical Functioning, Enia et al. 1347

measured by a step counter (7). A proportion of screenedpatients did not qualify for inclusion and our study pop-ulation was racially and ethnically homogenous, with aproportion of patients with diabetes less than in the USRenal Data System. Ours was a typical sample of patientsbeing treated in European centers. Indeed, patients consid-ered into the study are fully comparable with those in-cluded in the European Renal Association – EuropeanDialysis and Transplant Association registry for relevantprognostic factors such as age (66 years versus 64 years),sex (61% versus 64%), and diabetes (28% versus 27%).In conclusion, our study generates the hypothesis that

symptomatic as well as asymptomatic lung congestioncontributes to poor physical performance in stage 5 CKDpatients on hemodialysis. Because lung congestion is amodifiable risk factor, intervention studies are warrantedto test whether treating asymptomatic pulmonary conges-tion may translate into improved physical functioning inhemodialysis patients.

AcknowledgmentsCollaborators of the Lung Comets Cohort Working Group are as

follows: Giovanni Alati, Rosalia Boito, Graziella Bonanno, Simo-netta Cassani, Antonio Chippari, Teresa Cicchetti, Anna Clementi,Maurizio Garozzo, Domenico Logozzo, Rosita Lucà, DomenicoMancuso, Francesco Mollica, Giuseppe Natale, and ArcangeloSellaro.

DisclosuresNone.

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Received: October 29, 2012 Accepted: March 5, 2013

Published online ahead of print. Publication date available at www.cjasn.org.

See related editorial, “Pulmonary Congestion in Hemodialysis: AnOld Chestnut Worth Screening For?,” on pages 1279–1281.

1348 Clinical Journal of the American Society of Nephrology