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Inflammation in patients on peritoneal dialysis is associated with increased extracellular fluid volume
Archives of Medical Research 35 (2004) 220–224
ORIGINAL ARTICLE
Inflammation in Patients on Peritoneal Dialysis Is Associated with Increased Extracellular Fluid Volume Marlen Vicente´-Martı´nez,a Leonel Martı´nez-Ramı´rez,b Rodrigo Mun˜oz,c Marcela Avila,d Marı´a-de-Jesu´s Ventura,d Ernesto Rodrı´guez,d Dante Amatod and Ramo´n Paniaguad Departamentos de aMedicina Interna y, bCardiologı´a, Hospital General 47 Vicente Guerrero, Mexico City, Mexico Departamento de Medicina Nuclear y, dUnidad de Investigacio´n Me´dica en Enfermedades Nefrolo´gicas, Hospital de Especialidades, Centro Me´dico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
c
Received for publication July 11, 2003; accepted January 9, 2004 (03/115).
Background. Cardiovascular disorders (CD) are the most frequent cause of death in patients on dialysis. CD have been related to increased extracellular fluid volume, peritoneal transport type (PTT), hypertension, and inflammation. Inflammation is in itself a risk factor for mortality. The aim of this study was to assess the relationship of increased extracellular fluid volume, inflammation, and PTT in patients on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD). Methods. A cross-sectional study was carried out with 20 healthy controls (C), 21 patients on CAPD, and nine patients on APD. Clinical and demographic variables were measured and registered. Peritoneal equilibrium test (PET) was done. Blood volume (BV), total body water (TBW), inferior vena cava diameter during inspiration (IVCDi) and expiration (IVCDe), serum albumin, and serum C-reactive protein (CRP) were measured. Results. All patients on peritoneal dialysis (PD) had at least one sign or symptom of increased extracellular fluid volume, hypertension being the most common. Patients also had higher TBW (C, 60.7 ⫾ 7.2; APD, 62.6 ⫾ 8.7; CAPD, 66.1 ⫾ 8.3, as percentage of body weight, p ⬍0.02), higher BV (C, 7.9 ⫾ 1.6; APD, 9.8 ⫾ 2.3; CAPD, 9.6 ⫾ 2.3, as percentage of body weight, p ⬍0.02), higher DIVCi (C, 2.9⫾1.2; APD, 4.6 ⫾ 2.5; CAPD, 4.5 ⫾ 2.4 mm/m2 BSA, p ⬍0.02), and higher DIVCe (C, 6.2 ⫾ 1.7; APD, 8.3 ⫾ 3.4; CAPD, 8.0 ⫾ 2.8 mm/m2 BSA, p ⬍0.05). PD patients also had hypoalbuminemia and higher CRP levels. There was significant positive correlation between CRP and DIVCi (r ⫽ 0.43, p ⬍0.05) and IVCe (r ⫽ 0.45, p ⬍0.05) and between serum albumin and creatinine dialysate-to-plasma ratio (D/P Cr, r ⫽ 0.57, p ⬍0.01). Serum albumin and CRP were negatively correlated (r ⫽ ⫺0.54, p ⬍0.02). Conclusions. Patients on PD have increased extracellular fluid volume as compared with healthy controls. Hyperhydration is related to inflammation and to higher peritoneal transport types. 쑖 2004 IMSS. Published by Elsevier Inc. Key Words: C-reactive protein, Fluid overload, Increased extracellular fluid volume, Inflammation, Peritoneal dialysis, Peritoneal transport.
Introduction Cardiovascular disorders (CD) are the most frequent causes of morbidity and mortality in patients on continuous ambula-
Address reprint requests to: Ramo´n Paniagua, Coordinacio´n de Investigacio´n en Salud, Unidad de Congresos, Bloque B, 4o piso, CMN-SXXI, IMSS, Av. Cuauhte´moc 330, Col. Doctores, 06725 Me´xico, D.F., Me´xico. Phone: (⫹52) (55) 5627-6967; FAX: (⫹52) (55) 5761-0952; E-mail: [email protected]
0188-4409/04 $–see front matter. Copyright d o i : 10 .1 0 1 6/ j.ar c med .2 0 04 .0 1 .0 0 3
tory peritoneal dialysis (CAPD) (1). Cardiovascular morbidity, hypertension, and extracellular volume control are closely related to patient survival. Of these, extracellular volume appears to be the most important issue. It was described that fluid overload was the origin of hypertension in 85% of patients with chronic kidney disease (CKD) and that adequate control of sodium intake (2) and of extracellular volume (3) renders use of antihypertensive medication unnecessary. It was also found that adequate control of extracellular volume and therefore of hypertension prevented loss
쑖 2004 IMSS. Published by Elsevier Inc.
Fluid Overload and Inflammation in Peritoneal Dialysis
of residual renal function and reduced cardiovascular mortality and morbidity (4). Extracellular fluid volume control is not an easy goal to achieve in patients on CAPD. This is partly because a reliable and practical extracellular volume measurement technique is lacking, as well as definitions for dry weight and optimal dimension of extracellular volume for patients on peritoneal dialysis (PD) (5). Among currently used methods, electrical bioimpedance (6), biochemical markers (7,8), and inferior vena cava diameter and compliance (9) appear to be the most suitable techniques. Some characteristics of therapy and patient conditions may interfere with extracellular fluid volume control. The main limiting characteristic of the therapeutic modality is its use of glucose in dialysate as osmotic agent. To achieve effective ultrafiltration, hypertonic glucose solutions are required. This kind of solution may cause hyperglycemia, hyperinsulinemia, and obesity. Other problems related to dialysate were bioincompatibility, advanced glycosylation end-product generation, direct peritoneal damage and in the long term, loss of peritoneal ultrafiltration capability (10). Regarding patient characteristics, glucose as osmotic agent had little value in high or high-average transporters (11,12) because it diffused rapidly from peritoneal cavity to intravascular space, causing loss of osmotic gradient. Additionally, diabetic patients frequently were high transporters (12); therefore, inconveniences of glucose were even worse for this group of patients. On the other hand, inflammation is recognized as a key factor for development of atherosclerosis. As a risk factor for cardiovascular death, inflammation had relative importance even higher than traditionally acknowledged markers (13). Presence of dialysate and hydraulic intraperitoneal (i.p.) pressure that it exerts may cause inflammation. Extracellular fluid volume expansion and inflammation are closely related. Hypervolemia was reported as a cause of inflammation (14), and in turn inflammation was associated with high peritoneal permeability and with incapacity for achieving adequate ultrafiltration due to osmotic gradient loss (15). Anatomic and functional loss of peritoneal surface occurred later and was due to mesothelial cell damage secondary to local chronic inflammatory stimulus (16). The objective of the present study was to assess association of fluid overload, peritoneal transport type, and inflammation in patients on PD.
Subjects and Methods A cross-sectional study was carried out that included 30 prevalent adult patients from a single PD center. The sample was randomly selected from the outpatient clinic of ca. 300 patients. Of these patients, 21 received CAPD and 9, APD. No selection criteria by age, gender, or cause of CKD were applied. No patient had peritonitis (during the month prior
221
to recruitment), cancer, hepatitis B, and AIDS, and none received immunosuppressant drugs. All patients gave informed consent to participate in the study. An additional group of 20 healthy controls of similar age and gender was also studied. Demographic and cardiovascular comorbidity data were obtained and registered. Short peritoneal equilibrium test (PET) (17) was carried out to classify peritoneal transport type (PTT). Residual renal function was measured as average of endogenous urea and creatinine clearances and was registered. Total body water (TBW) was measured by electric bioimpedance (6), blood volume (BV) by measuring 99TCalbumin space (18), and inferior vena cava diameters during inspiration (IVCDi) and expiration (IVCDe) were measured by echocardiography (ATL Ultrasound HDI 3500, ATL Philips, Andover, MA, USA). Serum albumin (Synchron CX5, Beckman Instruments, Brea, CA, USA), and quantitative C-reactive protein (CRP) levels by nephelometry (Array, Beckman Instruments) were also measured. TBW and BV are expressed as percentage of body weight. Distensibility of IVC was calculated as [(IVCDe-IVCDi)/IVCDi]*100. CRP was considered positive when ⱖ10 mg/L. Statistical methods. Data were shown as means and standard deviations (SDs) for continuous variables and as absolute frequencies for discontinuous variables. Differences among groups were assessed by parametric one-way ANOVA or chi-squared according to variable characteristics. Multiple Pearson linear correlation was used for multivariate analysis. All analyses were done with the software package SPSSw, version 9.0 (SPSS, Chicago, IL, USA).
Results Most relevant demographic and clinical data are shown in Table 1. All patients had at least one sign or symptom of extracellular fluid volume expansion; the most common of these was hypertension. Twenty four patients were on antihypertensive therapy and 18 had blood pressure ⱖ140/90 despite treatment. Other clinical parameters of fluid expansion such as edema and functional class of congestive heart failure according to New York Heart Association (NYHA) guidelines are also presented in Table 1. Edema was present in 14 patients, 5 in APD, and 9 in CAPD. PD patients had significantly higher percentage of TBW and higher BV, IVCDi, and IVCDe than controls (Table 2). Distensibility of IVC was lower in patients than in controls, but no difference was noted between PD groups. Data regarding residual renal function, urine volume, serum albumin, and CRP are shown in Table 3. The majority of patients were anuric, defined as having urine output ⬍500 mL/24 h, while the remainder had very low residual renal function. Twenty percent of patients were classified as high transporters according to PET. All patients were anemic, 25.5 ⫾ 5.4% the
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Table 1. Demographic and clinical data of studied patients Peritoneal dialysis
n Age (years) Gender (male/female) Diabetes mellitus (yes/no) Time on PD (months) Height (cm) Weight (kg) Body surface area (m2) Systolic BP (mmHg) Diastolic BP (mmHg) Blood pressure ⬎140/90 Antihypertensive therapy Edema Heart failure NYHA stage I II III IV a
Control
APD ⫹ CAPD
APD
CAPD
20 29.1 ⫾ 10.3 10/10 0/20
30 33.7 ⫾ 11.4 17/13 8/22a 22.1 ⫾ 16.2 158.2 ⫾ 9.8 60.1 ⫾ 12.8 1.605 ⫾ 0.199 134.5 ⫾ 20.2b 82.4 ⫾ 14.0b 18b 24 14b
9 36.1 ⫾ 10.8 5/4 1/8 24.8 ⫾ 21.6 159.2 ⫾ 10.1 60.3 ⫾ 14.5 1.613 ⫾ 0.223 120.6 ⫾ 13.3 74.2 ⫾ 16.3 3 5 5
21 32.7 ⫾ 11.7 12/9 7/14a 20.9 ⫾ 14.4 157.7 ⫾ 10.0 60.0 ⫾ 12.3 1.601 ⫾ 0.193 140.5 ⫾ 19.9b,c 86.0 ⫾ 11.6b,c 15c 19 9
5 7 7 7
2 2 2
3 3 5 7
160.9 ⫾ 7.9 64.3 ⫾ 12.9 1.670 ⫾ 0.170 114.9 ⫾ 6.8 71.2 ⫾ 7.6 0 0 0
p ⬍0.05 vs. control; bp ⬍0.01 vs. control; cp ⬍0.05 vs. APD.
average hematocrit. Mean serum albumin level was 3.25 ⫾ 0.49 g/dL. Mean CRP levels were higher in PD patients than in controls. Twenty seven percent of patients had high CRP, defined as CRP level ⬎10 mg/L. Multivariate correlation of TBW, BV, IVCDi, IVCDe, serum albumin, and CRP controlling by age, sex, and body surface area are shown in Table 4. There were significant positive correlations of IVCDi with BV and also of IVCDi and IVCDe with CRP. IVCDi and CRP had significant negative correlation with serum albumin. In univariate analysis, serum albumin level had significant negative correlation with PTT, expressed as creatinine D/P ratio (r ⫽ ⫺0.57, p ⬍0.05). On the other hand, there was a significant difference in blood volume ( p ⬍0.001), IVCDi ( p ⬍0.001), and IVCDe ( p ⬍0.001) among different NYHA functional classes of heart failure disclosed by ANOVA.
Discussion In our studied group, fluid overload, PTT, and inflammation were associated. Furthermore, higher functional class of heart failure according to NYHA was associated with fluid overload assessed by blood volume and IVC diameters. Recently, extracellular fluid volume control and accurate determination of dry weight have been causes of concern. Consequently, methods to measure these variables were revised and compared (5). There is no optimal method. Some methods have been complex and unsuitable for routine clinical use, such as isotopic dilution. Others such as electric bioimpedance required use of equations derived from other methods from normal subjects (6). Biochemical markers such as plasmatic levels of ANP and cGMP were indirect markers (7,8). On the other hand, measurement of inferior
Table 2. Body composition, inferior vena cava diameter, and inferior vena cava distensibility Peritoneal dialysis
n Total body water (% of BW) Blood volume (% of BW) Inferior vena cava diameter inspiration (mm/m2 BSA) Inferior vena cava diameter expiration (mm/m2 BSA) Inferior vena cava distensibility (%) a
p ⬍0.05 vs. control; bp ⬍0.01 vs. control.
Control
APD ⫹ CAPD
APD
CAPD
20 60.7 ⫾ 7.2 7.8 ⫾ 1.6 2.98 ⫾ 1.19 6.22 ⫾ 1.67 122 ⫾ 58
30 64.9 ⫾ 8.4a 9.7 ⫾ 2.5b 4.55 ⫾ 2.42b 8.06 ⫾ 2.93b 95 ⫾ 58a
9 62.6 ⫾ 8.7a 9.8 ⫾ 2.3a 4.60 ⫾ 2.53a 8.28 ⫾ 3.42a 95 ⫾ 62
21 66.1 ⫾ 8.3a 9.7 ⫾ 2.6a 4.53 ⫾ 2.43a 7.97 ⫾ 2.78a 94 ⫾ 57
Fluid Overload and Inflammation in Peritoneal Dialysis
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Table 3. Extracellular fluid volume markers (serum albumin and hematocrit), creatinine D/P ratio, residual renal function, number of anuric patients, and number of subjects with positive C-reactive protein in controls and patients on APD and CAPD Peritoneal dialysis
n Serum albumin (g/dL) Hematocrit (%) Creatinine D/P ratio Urinary volume (mL/24 h) CrCl renal (mL/min) Anuric pts (⬍500 mL/24 h) C-reactive protein (mg/L) C-reactive protein ⬎10 mg/L (n) a
Control
APD ⫹ CAPD
APD
CAPD
20 4.3 ⫾ 0.50 42.0 ⫾ 4.1
30 3.25 ⫾ 0.49b 25.5 ⫾ 5.4b 0.55 ⫾ 0.16 313 ⫾ 294b 0.72 ⫾ 1.1b 26b 0.93 ⫾ 1.77a 8b
9 3.36 ⫾ 0.46b 28.1 ⫾ 6.1b 0.57 ⫾ 0.16 396 ⫾ 505b 1.1 ⫾ 1.2b 7b 1.51 ⫾ 2.4 4b
21 3.19 ⫾ 0.52b 24.4 ⫾ 4.9b 0.53 ⫾ 0.17 240 ⫾ 276b 0.45 ⫾ 0.83b 19b 0.66 ⫾ 1.40 4a
1,422 ⫾ 367 125 ⫾ 24 0 0.38 ⫾ 0.32 1
p ⬍0.05 vs. control; bp ⬍0.01 vs. control.
vena cava diameter was a noninvasive, practical, and easy measurement that showed good correlation with other markers of extracellular fluid volume (9). In the present work we used three different methods to assess extracellular fluid volume; method results were consistent because fluid overload was demonstrated by all three methods. Imbalance between sodium intake and capability to excrete sodium loads appears to be the central issue of the problem. Anuric patients are at higher risk for developing fluid overload. It is widely acknowledged that residual renal function and thus the capability for excreting sodium and water are directly related to patient survival. There was also recent evidence that fluid and sodium removal predicted relevant clinical outcomes such as mortality in PD patients (19). Although icodextrin-based solutions were more effective than glucose-based solutions for achieving negative sodium balance, cost and availability issues limited their widespread use (20). Conventional 1.5% glucose dialysis solutions allowed neutral or slightly negative sodium balance. Hypertonic glucose solutions increased convective sodium extraction, but the sieving effect may have limited results (19,21). On the other hand, the therapeutic value of dietary sodium intake restriction has received less attention than it deserves. Current diet guidelines are quite permissive regarding sodium intake. For patients on PD, from 2 to 4 g
of sodium per day are generally accepted, exceeding dialysisextracting capability that ranges from 0 to 70 mEq per day when 4.25% glucose solutions were used (21). Mechanisms explaining why extracellular fluid volume expansion induces inflammation are not clear. Heart failure may be involved. Recently, relationships between functional status and inflammation marker levels and between inflammation severity and survival in patients with heart failure were reported (22). In patients on PD, PTT, inflammation, and fluid removal had significant effects on nutritional status and clinical outcomes (23–25). Our results are in line with these reports because PCR levels and PTT had negative correlation with serum albumin. Fluid overload was also positively correlated with PCR and inversely correlated with serum albumin. Cross-sectional studies do not allow a cause-effect relationship to be established. However, they contribute to the body of knowledge on the subject and may generate hypotheses for more complex studies.
Acknowledgments The authors wish to thank the Coordinacio´n de Investigacio´n en Salud of the Instituto Mexicano del Seguro Social (IMSS) for financial support of this work.
Table 4. Multivariate correlation of total body water, blood volume, inferior vena cava diameter during inspiration, inferior vena cava diameter during expiration, serum albumin, and C-reactive protein Blood volume (% BW) Total body water (% BW) IVC diameter inspiration (mm) IVC diameter expiration (mm) Albumin (g/dL) C-reactive protein (mg/dL)
0.008 ns 0.536 ⬍0.02 0.233 ns ⫺0.398 ns 0.405 ns
Total body water (% BW)
0.267 0.297 ⫺0.402 0.079
ns ns ns ns
IVC diameter inspiration (mm)
IVC diameter expiration (mm)
Albumin (g/dL)
0.847 ⬍0.01 ⫺0.544 ⬍0.02 0.430 ⬍0.05
⫺0.425 ns 0.450 ⬍0.05
⫺0.540 ⬍0.02
Multivariate correlation analysis was controlled by age, sex, and body surface area; ns ⫽ not significant.
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References 1. Collins AJ, Hao W, Xia H, Ebben JP, Everson SE, Constantini EG, Ma JZ. Mortality risks of peritoneal dialysis and hemodialysis. Am J Kidney Dis 1999;34:1065–1074. 2. Shaldon S. Dietary salt restriction and drug-free treatment of hypertension in ESRD patients: a largely abandoned therapy. Nephrol Dial Transplant 2002;17:1163–1165. 3. Cocchi R, Esposti ED, Fabbri A, Lucatello A, Sturani A, Quarello F, Boero R, Bruno M, Dadone C, Favazza A, Scanziani R, Tommasi A, Giangrande A. Prevalence of hypertension in patients on peritoneal dialysis: results of an Italian multicentre study. Nephrol Dial Transplant 1999;14:1536–1540. ¨ zkahya M, Ok E, Cirit M, Aydin S, Akcicek F, Basci A, Dorhout 4. O Mees EJ. Regression of left ventricular hypertrophy in haemodialysis patients by ultrafiltration and reduced salt intake without antihypertensive drugs. Nephrol Dial Transplant 1998;13:1489–1493. 5. Jaeger JQ, Mehta RL. Assessment of dry weight in hemodialysis. J Am Soc Nephrol 1999;10:392–403. 6. Lukaski HC. Methods for the assessment of human body composition: traditional and new. Am J Clin Nutr 1987;46:537–556. 7. De Zeeuw D, Janssen WM, de Jong PE. Atrial natriuretic factor: its (patho) physiological significance in humans. Kidney Int 1992;41: 1115–1133. 8. Lauster F, Heim JM, Drummer C, Fulle HJ, Gerzer R, Schiffl H. Plasma cGMP level as a marker of the hydration state in renal replacement therapy. Kidney Int 1993;41:57–59. 9. Krause I, Birk E, Davidovits M, Cleper R, Blieden L, Pinhas L, Gamzo Z, Eisenstein B. Inferior vena cava diameter: a useful method for estimation of fluid status in children on haemodialysis. Nephrol Dial Transplant 2001;16:1203–1206. 10. Hain H, Kessel M. Aspect of new solutions for peritoneal dialysis. Nephrol Dial Transplant 1987;2:67–72. 11. Wang T, Heimbu¨rger O, Waniewski J, Bergstro¨m J, Lindholm B. Increased peritoneal permeability is associated with decreased fluid and small-solute removal and higher mortality in CAPD patients. Nephrol Dial Transplant 1998;13:1242–1249. 12. Cueto-Manzano AM, Correa-Rotter R. Is high peritoneal transport rate an independent risk factor for CAPD mortality? Kidney Int 2000; 57:314–320. 13. Qureshi AR, Alvestrand A, Divino-Filho JC, Gutie´rrez A, Heimburger O, Lindholm B, Bergstrom J. Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol 2002;13(Suppl):S28–S36.
14. Chung SH, Heimbu¨rger O, Stenvinkel P, Bergstrom J, Lindholm B. Association between inflammation and changes in residual renal function and peritoneal transport rate during the first year of dialysis. Nephrol Dial Transplant 2001;11:2240–2245. 15. Pecoits-Filho R, Arau´jo MRT, Lindholm B, Stenvinkel P, Abensur H, Romao JE Jr, Marcondes M, De Oliveira AH, Noronha IL. Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate. Nephrol Dial Transplant 2002;17: 1480–1486. 16. Krediet RT, Ho-dac-Pannekett MM, Struijk DG. Preservation of peritoneal membrane function. Kidney Int 1996;76(Suppl 56):S62–S68. 17. Twardowski ZJ. The fast peritoneal equilibration test. Semin Dial 1990;3:141–142. 18. du Raan H, Lotter MG, Harris GW, vas Aswegen A, Otto AC, Nel MG, Badenhorst PN, Verbeke KA, Verbruggen AM. Measurement of plasma volume using 99Tc(m)-labelled DMP-HSA. Nucl Med Commun 2000;21:539–544. 19. Ates K, Nergizoglu G, Keven K, Sen A, Kutlay S, Erturk S, Duman N, Ertug AE. Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int 2001;60:767–776. 20. Mistry CD, Mallick NP, Gokal R. Ultrafiltration with isosmotic solution during long peritoneal dialysis exchanges. Lancet 1987;ii:178–182. 21. Wang T, Waniewski J, Heimburger O, Werynski A, Lindholm B. A quantitative analysis of sodium transport and removal during peritoneal dialysis. Kidney Int 1997;52:1609–1616. 22. Cicoira M, Bolger AP, Doehner W, Rauchhaus M, Davos C, Sharma R, Al-Nasser FO, Coats AJ, Anker SD. High tumour necrosis factoralpha levels are associated with exercise intolerance and neurohormonal activation in chronic heart failure patients. Cytokine 2001;15:80–86. 23. Paniagua R, Frı´as Y, Ventura MJ, Rodrı´guez E, Hurtado ME, Alca´ntara G, Va´zquez R, Ortiz R, Salcedo M, Rı´os ME, Kaji J, Amato D. Creactive protein and anti-Chlamydia pneumoniae antibodies as risk factors of cardiovascular death in incident patients on peritoneal dialysis. Perit Dial Int 2003;23:132–137. 24. Chung SH, Heimburger O, Stenvinkel P, Wang T, Lindholm B. Influence of peritoneal transport rate, inflammation, and fluid removal on nutritional status and clinical outcome in prevalent peritoneal dialysis patients. Perit Dial Int 2003;23:174–183. 25. Chung SH, Heimburger O, Stenvinkel P, Qureshi AR, Lindholm B. Association between residual renal function, inflammation and patient survival in new peritoneal dialysis patients. Nephrol Dial Transplant 2003;18:590–597.
ORIGINAL ARTICLE
Inflammation in Patients on Peritoneal Dialysis Is Associated with Increased Extracellular Fluid Volume Marlen Vicente´-Martı´nez,a Leonel Martı´nez-Ramı´rez,b Rodrigo Mun˜oz,c Marcela Avila,d Marı´a-de-Jesu´s Ventura,d Ernesto Rodrı´guez,d Dante Amatod and Ramo´n Paniaguad Departamentos de aMedicina Interna y, bCardiologı´a, Hospital General 47 Vicente Guerrero, Mexico City, Mexico Departamento de Medicina Nuclear y, dUnidad de Investigacio´n Me´dica en Enfermedades Nefrolo´gicas, Hospital de Especialidades, Centro Me´dico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
c
Received for publication July 11, 2003; accepted January 9, 2004 (03/115).
Background. Cardiovascular disorders (CD) are the most frequent cause of death in patients on dialysis. CD have been related to increased extracellular fluid volume, peritoneal transport type (PTT), hypertension, and inflammation. Inflammation is in itself a risk factor for mortality. The aim of this study was to assess the relationship of increased extracellular fluid volume, inflammation, and PTT in patients on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD). Methods. A cross-sectional study was carried out with 20 healthy controls (C), 21 patients on CAPD, and nine patients on APD. Clinical and demographic variables were measured and registered. Peritoneal equilibrium test (PET) was done. Blood volume (BV), total body water (TBW), inferior vena cava diameter during inspiration (IVCDi) and expiration (IVCDe), serum albumin, and serum C-reactive protein (CRP) were measured. Results. All patients on peritoneal dialysis (PD) had at least one sign or symptom of increased extracellular fluid volume, hypertension being the most common. Patients also had higher TBW (C, 60.7 ⫾ 7.2; APD, 62.6 ⫾ 8.7; CAPD, 66.1 ⫾ 8.3, as percentage of body weight, p ⬍0.02), higher BV (C, 7.9 ⫾ 1.6; APD, 9.8 ⫾ 2.3; CAPD, 9.6 ⫾ 2.3, as percentage of body weight, p ⬍0.02), higher DIVCi (C, 2.9⫾1.2; APD, 4.6 ⫾ 2.5; CAPD, 4.5 ⫾ 2.4 mm/m2 BSA, p ⬍0.02), and higher DIVCe (C, 6.2 ⫾ 1.7; APD, 8.3 ⫾ 3.4; CAPD, 8.0 ⫾ 2.8 mm/m2 BSA, p ⬍0.05). PD patients also had hypoalbuminemia and higher CRP levels. There was significant positive correlation between CRP and DIVCi (r ⫽ 0.43, p ⬍0.05) and IVCe (r ⫽ 0.45, p ⬍0.05) and between serum albumin and creatinine dialysate-to-plasma ratio (D/P Cr, r ⫽ 0.57, p ⬍0.01). Serum albumin and CRP were negatively correlated (r ⫽ ⫺0.54, p ⬍0.02). Conclusions. Patients on PD have increased extracellular fluid volume as compared with healthy controls. Hyperhydration is related to inflammation and to higher peritoneal transport types. 쑖 2004 IMSS. Published by Elsevier Inc. Key Words: C-reactive protein, Fluid overload, Increased extracellular fluid volume, Inflammation, Peritoneal dialysis, Peritoneal transport.
Introduction Cardiovascular disorders (CD) are the most frequent causes of morbidity and mortality in patients on continuous ambula-
Address reprint requests to: Ramo´n Paniagua, Coordinacio´n de Investigacio´n en Salud, Unidad de Congresos, Bloque B, 4o piso, CMN-SXXI, IMSS, Av. Cuauhte´moc 330, Col. Doctores, 06725 Me´xico, D.F., Me´xico. Phone: (⫹52) (55) 5627-6967; FAX: (⫹52) (55) 5761-0952; E-mail: [email protected]
0188-4409/04 $–see front matter. Copyright d o i : 10 .1 0 1 6/ j.ar c med .2 0 04 .0 1 .0 0 3
tory peritoneal dialysis (CAPD) (1). Cardiovascular morbidity, hypertension, and extracellular volume control are closely related to patient survival. Of these, extracellular volume appears to be the most important issue. It was described that fluid overload was the origin of hypertension in 85% of patients with chronic kidney disease (CKD) and that adequate control of sodium intake (2) and of extracellular volume (3) renders use of antihypertensive medication unnecessary. It was also found that adequate control of extracellular volume and therefore of hypertension prevented loss
쑖 2004 IMSS. Published by Elsevier Inc.
Fluid Overload and Inflammation in Peritoneal Dialysis
of residual renal function and reduced cardiovascular mortality and morbidity (4). Extracellular fluid volume control is not an easy goal to achieve in patients on CAPD. This is partly because a reliable and practical extracellular volume measurement technique is lacking, as well as definitions for dry weight and optimal dimension of extracellular volume for patients on peritoneal dialysis (PD) (5). Among currently used methods, electrical bioimpedance (6), biochemical markers (7,8), and inferior vena cava diameter and compliance (9) appear to be the most suitable techniques. Some characteristics of therapy and patient conditions may interfere with extracellular fluid volume control. The main limiting characteristic of the therapeutic modality is its use of glucose in dialysate as osmotic agent. To achieve effective ultrafiltration, hypertonic glucose solutions are required. This kind of solution may cause hyperglycemia, hyperinsulinemia, and obesity. Other problems related to dialysate were bioincompatibility, advanced glycosylation end-product generation, direct peritoneal damage and in the long term, loss of peritoneal ultrafiltration capability (10). Regarding patient characteristics, glucose as osmotic agent had little value in high or high-average transporters (11,12) because it diffused rapidly from peritoneal cavity to intravascular space, causing loss of osmotic gradient. Additionally, diabetic patients frequently were high transporters (12); therefore, inconveniences of glucose were even worse for this group of patients. On the other hand, inflammation is recognized as a key factor for development of atherosclerosis. As a risk factor for cardiovascular death, inflammation had relative importance even higher than traditionally acknowledged markers (13). Presence of dialysate and hydraulic intraperitoneal (i.p.) pressure that it exerts may cause inflammation. Extracellular fluid volume expansion and inflammation are closely related. Hypervolemia was reported as a cause of inflammation (14), and in turn inflammation was associated with high peritoneal permeability and with incapacity for achieving adequate ultrafiltration due to osmotic gradient loss (15). Anatomic and functional loss of peritoneal surface occurred later and was due to mesothelial cell damage secondary to local chronic inflammatory stimulus (16). The objective of the present study was to assess association of fluid overload, peritoneal transport type, and inflammation in patients on PD.
Subjects and Methods A cross-sectional study was carried out that included 30 prevalent adult patients from a single PD center. The sample was randomly selected from the outpatient clinic of ca. 300 patients. Of these patients, 21 received CAPD and 9, APD. No selection criteria by age, gender, or cause of CKD were applied. No patient had peritonitis (during the month prior
221
to recruitment), cancer, hepatitis B, and AIDS, and none received immunosuppressant drugs. All patients gave informed consent to participate in the study. An additional group of 20 healthy controls of similar age and gender was also studied. Demographic and cardiovascular comorbidity data were obtained and registered. Short peritoneal equilibrium test (PET) (17) was carried out to classify peritoneal transport type (PTT). Residual renal function was measured as average of endogenous urea and creatinine clearances and was registered. Total body water (TBW) was measured by electric bioimpedance (6), blood volume (BV) by measuring 99TCalbumin space (18), and inferior vena cava diameters during inspiration (IVCDi) and expiration (IVCDe) were measured by echocardiography (ATL Ultrasound HDI 3500, ATL Philips, Andover, MA, USA). Serum albumin (Synchron CX5, Beckman Instruments, Brea, CA, USA), and quantitative C-reactive protein (CRP) levels by nephelometry (Array, Beckman Instruments) were also measured. TBW and BV are expressed as percentage of body weight. Distensibility of IVC was calculated as [(IVCDe-IVCDi)/IVCDi]*100. CRP was considered positive when ⱖ10 mg/L. Statistical methods. Data were shown as means and standard deviations (SDs) for continuous variables and as absolute frequencies for discontinuous variables. Differences among groups were assessed by parametric one-way ANOVA or chi-squared according to variable characteristics. Multiple Pearson linear correlation was used for multivariate analysis. All analyses were done with the software package SPSSw, version 9.0 (SPSS, Chicago, IL, USA).
Results Most relevant demographic and clinical data are shown in Table 1. All patients had at least one sign or symptom of extracellular fluid volume expansion; the most common of these was hypertension. Twenty four patients were on antihypertensive therapy and 18 had blood pressure ⱖ140/90 despite treatment. Other clinical parameters of fluid expansion such as edema and functional class of congestive heart failure according to New York Heart Association (NYHA) guidelines are also presented in Table 1. Edema was present in 14 patients, 5 in APD, and 9 in CAPD. PD patients had significantly higher percentage of TBW and higher BV, IVCDi, and IVCDe than controls (Table 2). Distensibility of IVC was lower in patients than in controls, but no difference was noted between PD groups. Data regarding residual renal function, urine volume, serum albumin, and CRP are shown in Table 3. The majority of patients were anuric, defined as having urine output ⬍500 mL/24 h, while the remainder had very low residual renal function. Twenty percent of patients were classified as high transporters according to PET. All patients were anemic, 25.5 ⫾ 5.4% the
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Table 1. Demographic and clinical data of studied patients Peritoneal dialysis
n Age (years) Gender (male/female) Diabetes mellitus (yes/no) Time on PD (months) Height (cm) Weight (kg) Body surface area (m2) Systolic BP (mmHg) Diastolic BP (mmHg) Blood pressure ⬎140/90 Antihypertensive therapy Edema Heart failure NYHA stage I II III IV a
Control
APD ⫹ CAPD
APD
CAPD
20 29.1 ⫾ 10.3 10/10 0/20
30 33.7 ⫾ 11.4 17/13 8/22a 22.1 ⫾ 16.2 158.2 ⫾ 9.8 60.1 ⫾ 12.8 1.605 ⫾ 0.199 134.5 ⫾ 20.2b 82.4 ⫾ 14.0b 18b 24 14b
9 36.1 ⫾ 10.8 5/4 1/8 24.8 ⫾ 21.6 159.2 ⫾ 10.1 60.3 ⫾ 14.5 1.613 ⫾ 0.223 120.6 ⫾ 13.3 74.2 ⫾ 16.3 3 5 5
21 32.7 ⫾ 11.7 12/9 7/14a 20.9 ⫾ 14.4 157.7 ⫾ 10.0 60.0 ⫾ 12.3 1.601 ⫾ 0.193 140.5 ⫾ 19.9b,c 86.0 ⫾ 11.6b,c 15c 19 9
5 7 7 7
2 2 2
3 3 5 7
160.9 ⫾ 7.9 64.3 ⫾ 12.9 1.670 ⫾ 0.170 114.9 ⫾ 6.8 71.2 ⫾ 7.6 0 0 0
p ⬍0.05 vs. control; bp ⬍0.01 vs. control; cp ⬍0.05 vs. APD.
average hematocrit. Mean serum albumin level was 3.25 ⫾ 0.49 g/dL. Mean CRP levels were higher in PD patients than in controls. Twenty seven percent of patients had high CRP, defined as CRP level ⬎10 mg/L. Multivariate correlation of TBW, BV, IVCDi, IVCDe, serum albumin, and CRP controlling by age, sex, and body surface area are shown in Table 4. There were significant positive correlations of IVCDi with BV and also of IVCDi and IVCDe with CRP. IVCDi and CRP had significant negative correlation with serum albumin. In univariate analysis, serum albumin level had significant negative correlation with PTT, expressed as creatinine D/P ratio (r ⫽ ⫺0.57, p ⬍0.05). On the other hand, there was a significant difference in blood volume ( p ⬍0.001), IVCDi ( p ⬍0.001), and IVCDe ( p ⬍0.001) among different NYHA functional classes of heart failure disclosed by ANOVA.
Discussion In our studied group, fluid overload, PTT, and inflammation were associated. Furthermore, higher functional class of heart failure according to NYHA was associated with fluid overload assessed by blood volume and IVC diameters. Recently, extracellular fluid volume control and accurate determination of dry weight have been causes of concern. Consequently, methods to measure these variables were revised and compared (5). There is no optimal method. Some methods have been complex and unsuitable for routine clinical use, such as isotopic dilution. Others such as electric bioimpedance required use of equations derived from other methods from normal subjects (6). Biochemical markers such as plasmatic levels of ANP and cGMP were indirect markers (7,8). On the other hand, measurement of inferior
Table 2. Body composition, inferior vena cava diameter, and inferior vena cava distensibility Peritoneal dialysis
n Total body water (% of BW) Blood volume (% of BW) Inferior vena cava diameter inspiration (mm/m2 BSA) Inferior vena cava diameter expiration (mm/m2 BSA) Inferior vena cava distensibility (%) a
p ⬍0.05 vs. control; bp ⬍0.01 vs. control.
Control
APD ⫹ CAPD
APD
CAPD
20 60.7 ⫾ 7.2 7.8 ⫾ 1.6 2.98 ⫾ 1.19 6.22 ⫾ 1.67 122 ⫾ 58
30 64.9 ⫾ 8.4a 9.7 ⫾ 2.5b 4.55 ⫾ 2.42b 8.06 ⫾ 2.93b 95 ⫾ 58a
9 62.6 ⫾ 8.7a 9.8 ⫾ 2.3a 4.60 ⫾ 2.53a 8.28 ⫾ 3.42a 95 ⫾ 62
21 66.1 ⫾ 8.3a 9.7 ⫾ 2.6a 4.53 ⫾ 2.43a 7.97 ⫾ 2.78a 94 ⫾ 57
Fluid Overload and Inflammation in Peritoneal Dialysis
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Table 3. Extracellular fluid volume markers (serum albumin and hematocrit), creatinine D/P ratio, residual renal function, number of anuric patients, and number of subjects with positive C-reactive protein in controls and patients on APD and CAPD Peritoneal dialysis
n Serum albumin (g/dL) Hematocrit (%) Creatinine D/P ratio Urinary volume (mL/24 h) CrCl renal (mL/min) Anuric pts (⬍500 mL/24 h) C-reactive protein (mg/L) C-reactive protein ⬎10 mg/L (n) a
Control
APD ⫹ CAPD
APD
CAPD
20 4.3 ⫾ 0.50 42.0 ⫾ 4.1
30 3.25 ⫾ 0.49b 25.5 ⫾ 5.4b 0.55 ⫾ 0.16 313 ⫾ 294b 0.72 ⫾ 1.1b 26b 0.93 ⫾ 1.77a 8b
9 3.36 ⫾ 0.46b 28.1 ⫾ 6.1b 0.57 ⫾ 0.16 396 ⫾ 505b 1.1 ⫾ 1.2b 7b 1.51 ⫾ 2.4 4b
21 3.19 ⫾ 0.52b 24.4 ⫾ 4.9b 0.53 ⫾ 0.17 240 ⫾ 276b 0.45 ⫾ 0.83b 19b 0.66 ⫾ 1.40 4a
1,422 ⫾ 367 125 ⫾ 24 0 0.38 ⫾ 0.32 1
p ⬍0.05 vs. control; bp ⬍0.01 vs. control.
vena cava diameter was a noninvasive, practical, and easy measurement that showed good correlation with other markers of extracellular fluid volume (9). In the present work we used three different methods to assess extracellular fluid volume; method results were consistent because fluid overload was demonstrated by all three methods. Imbalance between sodium intake and capability to excrete sodium loads appears to be the central issue of the problem. Anuric patients are at higher risk for developing fluid overload. It is widely acknowledged that residual renal function and thus the capability for excreting sodium and water are directly related to patient survival. There was also recent evidence that fluid and sodium removal predicted relevant clinical outcomes such as mortality in PD patients (19). Although icodextrin-based solutions were more effective than glucose-based solutions for achieving negative sodium balance, cost and availability issues limited their widespread use (20). Conventional 1.5% glucose dialysis solutions allowed neutral or slightly negative sodium balance. Hypertonic glucose solutions increased convective sodium extraction, but the sieving effect may have limited results (19,21). On the other hand, the therapeutic value of dietary sodium intake restriction has received less attention than it deserves. Current diet guidelines are quite permissive regarding sodium intake. For patients on PD, from 2 to 4 g
of sodium per day are generally accepted, exceeding dialysisextracting capability that ranges from 0 to 70 mEq per day when 4.25% glucose solutions were used (21). Mechanisms explaining why extracellular fluid volume expansion induces inflammation are not clear. Heart failure may be involved. Recently, relationships between functional status and inflammation marker levels and between inflammation severity and survival in patients with heart failure were reported (22). In patients on PD, PTT, inflammation, and fluid removal had significant effects on nutritional status and clinical outcomes (23–25). Our results are in line with these reports because PCR levels and PTT had negative correlation with serum albumin. Fluid overload was also positively correlated with PCR and inversely correlated with serum albumin. Cross-sectional studies do not allow a cause-effect relationship to be established. However, they contribute to the body of knowledge on the subject and may generate hypotheses for more complex studies.
Acknowledgments The authors wish to thank the Coordinacio´n de Investigacio´n en Salud of the Instituto Mexicano del Seguro Social (IMSS) for financial support of this work.
Table 4. Multivariate correlation of total body water, blood volume, inferior vena cava diameter during inspiration, inferior vena cava diameter during expiration, serum albumin, and C-reactive protein Blood volume (% BW) Total body water (% BW) IVC diameter inspiration (mm) IVC diameter expiration (mm) Albumin (g/dL) C-reactive protein (mg/dL)
0.008 ns 0.536 ⬍0.02 0.233 ns ⫺0.398 ns 0.405 ns
Total body water (% BW)
0.267 0.297 ⫺0.402 0.079
ns ns ns ns
IVC diameter inspiration (mm)
IVC diameter expiration (mm)
Albumin (g/dL)
0.847 ⬍0.01 ⫺0.544 ⬍0.02 0.430 ⬍0.05
⫺0.425 ns 0.450 ⬍0.05
⫺0.540 ⬍0.02
Multivariate correlation analysis was controlled by age, sex, and body surface area; ns ⫽ not significant.
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