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Novel therapeutic option for refractory heart failure in elderly patients with chronic kidney disease by incremental peritoneal dialysis
Journal of Cardiology (2010) 55, 49—54
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jjcc
ORIGINAL ARTICLE
Novel therapeutic option for refractory heart failure in elderly patients with chronic kidney disease by incremental peritoneal dialysis Masaru Nakayama (MD) a,∗, Hirofumi Nakano (MD) b, Masaaki Nakayama (MD) c a
Division of Cardiology, Kashima Hospital, 22-1 Kashimamachi, Shimokuramochi, Aza-Nakasawame, Iwaki, Fukushima 971-8143, Japan b Division of Nephrology, Kashima Hospital, Fukushima, Japan c Tohoku University Graduate School of Medicine, Miyagi, Japan Received 1 May 2009; received in revised form 3 August 2009; accepted 7 August 2009 Available online 26 September 2009
KEYWORDS Aging; Chronic kidney disease (CKD); Heart failure; Peritoneal dialysis; Renal function
∗
Summary Background: Heart failure (HF) often accompanies chronic kidney disease (CKD) in the elderly. This clinical condition is a critical socio-medical issue, because high-dose diuretic therapy stimulates the renin—angiotensin—aldosterone axis and sympathetic nervous system outflow, and may thus result in vicious cycles of cardio-renal deterioration, leading to excess hospitalization and death. Peritoneal dialysis (PD) is a renal replacement therapy used for maintenance dialysis, and is characterized by the continuous removal of fluid. The present study examined the clinical feasibility and effects of a novel style of PD for elderly CKD patients with refractory HF. Methods: Twelve elderly CKD patients (stages 3—5) with refractory HF [New York Heart Association (NYHA) class III, n = 9; IV, n = 3; mean age, 81 ± 6 years] received PD treatment. Patients had episodes of >3 hospitalizations in the previous year, and were initially treated with ≤19 sessions of sequential hemofiltration, followed by incremental PD, with 3 PD sessions/week (8 h each) at the start, increasing in frequency and dwelling time as clinically indicated. Results: During follow-up (median, 26.5 months), PD was well tolerated by all patients, and no patients required hospitalization for HF. Three patients died due to non-HF-related events. All patients showed improvements in NYHA functional class (class I, n = 9; class II, n = 3) and significant decreases in the dose of diuretics prescribed (P < 0.05). Kidney function stabilized, while significant improvements in end-diastolic left ventricular diameter (−5%, P < 0.05) and hemoglobin count (+15%, P < 0.05) were achieved. Brain natriuretic peptide (−46%) and aldosterone (−13%) levels tended to decrease. Conclusions: Incremental PD could represent a novel therapeutic option for elderly patients with refractory HF. In addition to fluid removal by PD, correction of renal anemia, preservation
Corresponding author. Tel.: +81 246 58 5010; fax: +81 246 58 8088. E-mail address: [email protected] (M. Nakayama).
0914-5087/$ — see front matter © 2009 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2009.08.003
50
M. Nakayama et al. of kidney function, and avoidance of high-dose diuretic therapy may play a role in maximizing clinical benefits. © 2009 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction To date, the pathophysiology and treatment options for heart failure (HF) have been well investigated [1—5]. However, some HF patients, particularly among the elderly, remain refractory to conventional therapies and require frequent hospitalization [6]. Furthermore, the prevalence of HF in the population over 65 years old has been consistently increasing in recent years [5,6]. Very few studies regarding established, evidence-based HF management [e.g. renin—angiotensin—aldosterone system (RAAS) modulation, beta blockers, and aldosterone antagonists] have included elderly subjects [1—5]. Geriatric-specific issues such as renal insufficiency, anemia, and hypoalbuminemia generate numerous clinical difficulties in the treatment of elderly HF patients, preventing or limiting the prescription of conventional medications, and the presence of dementia can lead to difficulties in restricting sodium intake, patient compliance, and exclusion from invasive strategy options (surgery, transplant, device therapy). These problems result in a tendency toward treatment using high-dose diuretics [6—8]. High-dose diuretics may increase the risk of adverse renal effects, such as exaggerating renal perfusion (azotemia), and stimulating RAAS and sympathetic nervous system (SNS) activity [7]. Alternative management strategies are thus required. Extra- and/or intracorporeal ultrafiltrations have generated clinical improvement and represent potential therapeutic options for HF [8—12], but the intermittent mode of therapy has limited the clinical potential. Peritoneal dialysis (PD) is a renal replacement therapy used for maintenance dialysis, and is characterized by the continuous correction of the uremic milieu, including excess fluid in the body. PD is thus reasonably expected to benefit patients with HF. In fact, favorable clinical results have recently been reported for dialysis patients with refractory HF following the application of PD [8,10—12]. Incremental PD was first proposed by Mehrotra et al. [13]. The therapeutic concept involves prescribing the PD regimen according to the level of residual renal function. Patients thus start PD with exchange of at least one bag, and increase PD dose in proportion to the declining urinary excretion of solutes and fluid. This therapeutic approach to chronic kidney disease (CKD) patients with HF may reasonably be expected to exert cardio-renal-protective effects [14]. The present study therefore examined the clinical efficacy and feasibility of therapeutic PD application in elderly CKD patients with HF refractory to conventional therapy.
Methods Patients Data from 12 consecutive patients who underwent incremental PD between April 2002 and May 2008 were evaluated.
Patients were enrolled in this study based on the following inclusion criteria: (1) age ≥70 years; (2) stages 3—5 CKD; and (3) frequent HF hospitalization (≥3 times/year) despite conventional outpatient therapy (defined as refractory HF). Glomerular filtration rate (GFR) was calculated using the modified Modification of Diet in Renal Disease equation. Etiologies of CKD for these study subjects were not well evaluated, but subjects included at least two cases with diabetic nephropathy. The major cause of CKD in the other study subjects was thought to be renal sclerosis, based on the clinical course. Diagnosis of HF was based on the Framingham or Massachusetts General Hospital criteria. The study population included three patients with mild left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) <50%], and nine patients with preserved LVEF. All patients were evaluated for suitability and initiated on PD treatment by an attending nephrologist. All patients provided written informed consent to participate in this study prior to enrolment. All protocols were approved by the ethics committee of our hospital.
Ultrafiltration and induction of PD Patients were initially treated with 0—19 sessions of sequential hemofiltration for acute decompensated HF, followed by incremental PD. A Tenckhoff catheter was surgically implanted, and the optimal PD solution was determined. Typical PD solution consisted of 1.5—2.0 L of 1.5% dextrose (Dianeal® ; Baxter, Deerfield, IL, USA) based on the peritoneal equivalent test result and body mass. Following completion of sequential hemofiltration treatments, patients were initiated on three PD sessions/week (8 h each). Dwell time, frequency, dextrose concentration (1.5%, 2.5%, and 4.25%), and PD solution (to icodextrin, Extraneal® ; Baxter) were changed as needed to optimize efficiency of ultrafiltration rate.
Observations Time points for data analysis included the time at which dry weight was attained (baseline), at the end of follow-up (May 2008), and/or just prior to any clinical events. Five endpoints were examined: all-cause mortality; cardiovascular mortality; all-cause hospitalization; HF hospitalization; and PD-related hospitalization. Data collected included resting systolic and diastolic blood pressures, heart rate (STBP-780; Omron Colin, Tokyo, Japan), body weight, New York Heart Association (NYHA) functional class, echocardiographic determinants of cardiac function, and loading conditions (EUB-8500; Hitachi Medical, Tokyo, Japan), such as left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), Doppler measurement at left ventricular inflow (E/A), left ventricular ejection fraction (LVEF), renal function [serum creatinine (Cr) and GFR], hemoglobin (Hb) level, and
Incremental PD for HF with CKD Table 1
51
Statistical analysis
Baseline patient characteristics.
Variables Age (years) Sex (male:female) Diabetes mellitus (n)
81 ± 6 7:5 3
Etiology of HF (n) Hypertensive heart disease Valvular heart disease Ischemic cardiomyopathy Dilated phase hypertrophic cardiomyopathy
6 3 2 1
Medications (n) Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers Beta blockers Calcium channel blockers Digoxin Nitrate
6 6 3 7 2 6
New York Heart Association functional class (n) III IV
9 3
Data are presented as mean ± standard deviation (SD) or number. HF, heart failure.
neurohumoral factors [brain natriuretic peptide (BNP), plasma rennin activity (PRA) and aldosterone (ALD)]. Changes in diuretic dosages (furosemide and trichlomethiazide) were also recorded. An azosemide dose of 30 mg was regarded as equivalent to a furosemide dose of 20 mg. HF drugs were changed as clinically indicated. Patients with anemia (Hb <11 g/dL) received subcutaneous epoetin- once a week at a dose of 6000 IU and/or intravenous iron, if appropriate.
Table 2
Statistical analysis was performed using StatView software (SAS Institute, Cary, NC, USA). Results are presented as mean ± standard deviation (SD). Student’s paired t-test was used to compare data between baseline and the end of follow-up.
Results Patient characteristics at the initiation of PD are summarized in Table 1. The study population comprised elderly patients with mild anemia and severe renal insufficiency. Functional capabilities were characterized defined as class III (n = 9) or IV (n = 3). All patients were being prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Median follow-up was 26.5 months (range, 6—62 months). Finally, mean frequency of PD sessions was 14.6 ± 4.7 times/week. At the end of follow-up, one patient required hemodialysis secondary to ultrafiltration failure of PD. None of the patients required hospitalization due to HF, but one patient was hospitalized due to non-HF-related disease (colon cancer), and two patients were hospitalized due to uremia-related malnutritional cachexia and catheterrelated peritonitis. All three of these hospitalized patients died (Table 2). Compared with baseline values, diuretics had been withdrawn or reduced in all patients by the end of follow-up (Table 3; Fig. 1A). No change in body weight was seen between baseline and final data (Table 3). No changes in systolic or diastolic blood pressure, heart rate, or laboratory findings were seen regarding Cr or GFR when comparing baseline and final data. However, a significant increase in Hb (Fig. 1B) indicated a correction of renal anemia. In terms of echocardiographic parameters, no changes in LVEF, LVDs, or E/A were seen, but LVDd was
Status at final dose of PD and status and major events during follow-up.
Age/sex
Etiology of HF
PD (sessions/week)
Follow-up (months)
Event
89/F 82/M 85/F 84/F 79/M 86/M 78/M 72/M 71/F 79/M 79/F 76/M
HHD HHD DHCM/Pacing MVR/Af/DM MR/Af HHD HHD ICM ICM/DM HHD/DM AR HHD
14 14 14 14 14 7 14 14 7 21 21 21
6 6 15 21 22 26 27 33.5 33.5 37 43 62
— — Colon cancera — MIA syndromea — — — Catheter-related peritonitisa — — UF failure
14.6 ± 4.7
27.7 ± 15.8
Mean ± SD
HF, heart failure; PD, peritoneal dialysis; HHD, hypertensive heart disease; DHCM, dilated-phase hypertrophic cardiomyopathy; MVR, mitral valve replacement; Af, atrial fibrillation; DM, diabetes mellitus; MR, mitral valve regurgitation; ICM, ischemic cardiomyopathy; AR, aortic valve regurgitation; MIA, malnutrition—inflammation—atherosclerosis; UF, ultrafiltration. a Patients who died.
52 Table 3
M. Nakayama et al. Clinical variables at baseline and on PD.
Variables
Baseline
Body weight (kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) LV diastolic diameter (mm) LV systolic diameter (mm) LV ejection fraction (%) E/Aa Brain natriuretic peptide (pg/mL) Aldosterone (pg/mL) Plasma renin activity (ng/mL/h) Blood urea nitrogen (mg/dL) Creatinine (mg/dl) Calcium (mequiv./L) Phosphate (mequiv./L) Albumin (g/dL) Total cholesterol (mg/dL) Hemoglobin (g/dL) Estimated GFR (mL/min/1.73 m2 ) Furosemide dosage (mg) Trichlomethiazide dosage (mg)
52.1 132 69 72 52.6 35.0 56 0.60 813.3 102.3 6.7 50.0 4.6 8.6 4.9 2.9 163 9.8 10.5 56.7 2.3
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
On PD 10.9 25 13 12 5.2 6.3 10 0.12 1248.5 52.4 7.0 20.0 2.1 0.8 1.1 0.5 57 1.7 8.2 30.6 1.9
51.7 133 69 70 48.5 31.6 58 0.59 362.3 87.4 4.5 51.6 5.2 8.3 3.8 2.6 157 11.0 9.5 20.0 0.8
P ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
12.5 22 13 7 4.4 3.8 6 0.11 454.2 41.5 4.9 16.2 2.4 0.7 1.2 0.5 35 1.3 7.5 19.1 1.3
0.5803 0.8535 0.7513 0.4472 0.0138 0.0717 0.4993 0.7879 0.0996 0.0861 0.1644 0.8276 0.2073 0.2742 0.3106 0.0566 0.7116 0.0364 0.2476 0.0056 0.0121
Data are presented as mean ± SD. PD, peritoneal dialysis; LV, left ventricular; GFR, glomerular filtration rate; E/A, Doppler measurement at left ventricular inflow. a n = 9 (not available for three cases; two cases of atrial fibrillation; one case of right ventricular apical pacing).
significantly decreased (Fig. 1C). Decreases in BNP, PRA, and ALD were identified, but did not reach the level of statistical significance. Summarized data are presented in Table 3. Final NYHA functional class improved in all cases (class I, n = 9; class II, n = 3; Fig. 1D).
Discussion PD was used to treat 12 elderly patients with CKD and refractory HF. PD was well tolerated by all patients during the observation period and produced clinical benefits as demonstrated by (1) improved NYHA functional class; (2) no hospitalization related to HF; (3) reduced dosages of diuretics; (4) increased Hb level; (5) decreased LV diastolic diameter; (6) no worsening in neurohumoral factor levels; and (7) maintenance of cardiac and renal function. PD may exert therapeutic effects in the context of HF via several mechanisms, such as removing excess water and sodium [8,10—12]. The sodium excretion efficiency of PD is known to be nearly 1.5-fold higher than that of the same volume of urine [15]. In this study, median removal of excess water and sodium per PD session was 213 mL and 134 mequiv./L, respectively (data not shown). This is equivalent to a 1.4 g reduction in sodium per PD session, without the need for high-dose diuretics. Although extracorporeal ultrafiltration is superior to PD in terms of the prompt removal of excess water and sodium, the property of continuous and slow removal of excess water and sodium by PD could contribute to the maintenance of renal function and avoidance of adverse renal effects [7]. Furthermore, PD does not require
hospitalization, contrasting sharply with the extracorporeal ultrafiltration method. This may also benefit elderly patients. Regarding the therapeutic benefits of increased ultrafiltration volume in patients with HF, the pathophysiological HF process could be at least partially reversed by inhibition of inflammatory cytokine release, normalization of neurohormonal pathways, and restoration of diuretic responsiveness [16—20]. As ultrafiltration-mediated convective clearance of cytokines is nonspecific, beneficial cytokines are lost along with harmful ones. Furthermore, although the mass clearance of cytokine compounds with PD is low, PD can remove the molecular weight of myocardial depressant factors, which range between 0.5 and 20 to 30 kDa (e.g. tumor necrosis factor-␣). In this and previous studies, the observation that PD resulted in decreased BNP (3.5 kDa) levels [17] was very important from a clinical perspective, although this decreasing tendency was not significant. The decrease in BNP might also be due to a reduction in cardiac preload and may affect changes in cognitive function, warranting further investigation. Anemia is prevalent in both HF and CKD. In fact, these three conditions form a vicious cycle, with each condition capable of causing or being caused by the others. This phenomenon has been referred to as cardio-renal anemia syndrome by Silverberg et al. [20—23]. While several studies have suggested that erythropoietin therapy might be beneficial in CKD patients with HF, this remains controversial, as many patients appear unresponsive. The present study revealed significant increases in hemoglobin levels following PD induction (Table 3). With no change in inflammatory conditions, increased responsiveness to ery-
Incremental PD for HF with CKD
53
Figure 1 Changes in furosemide dosage (A), hemoglobin (Hb) level (B), and left ventricular diastolic diameter (LVDd) (C). Lines within boxes represent median values, with top and bottom lines of boxes representing the 75th and 25th percentiles, respectively, and top and bottom bars outside of boxes representing the 90th and 10th percentiles, respectively. Incremental PD resulted in reduced furosemide dosing, reduced LVDd, higher Hb, and better New York Heart Association functional class (D). Data are presented as mean ± SD. PD, peritoneal dialysis; NYHA, New York Heart Association.
thropoietin administration as well as glucose-calorie load by PD solution may be involved in these improvements. In the present study, two cases were lost to PD-related complications. One patient died due to uremia-related malnutritional cachexia, which is common among elderly patients on chronic dialysis. This characteristic clinical feature has recently been defined as malnutrition— inflammation—atherosclerosis (MIA) syndrome, and accumulated evidence has revealed the worst outcomes in patients with this syndrome [24]. In this patient, the cause of death was diagnosed as malnutrition and cachexia due to pathology-related uremic condition. The other patient died due to catheter-related peritonitis. Complications of PD include catheter-related infections such as exit-site infection, skin-tunnel (subcutaneous) infection and peritonitis, and mechanical stress-related events involving the PD solution, such as herniation of the esophagus, abdominal wall, or inguinal region. Among these, catheter-related infection is the most common complication according to recent reports [24]. The peritonitis rate in Japan is low compared with other countries, at one episode per 37.0—58.8 patient—months. As a reason for dropout from PD, peritonitis accounts for only 14% of dropouts in Japan [25]. The case in our study was well managed by PD for 33.5 months, and was free from peritonitis before the final episode. In addition, catheter-related peritonitis is usually curable, and
management is well established using standard antibiotic regimens. However, in the case of an elderly patient with MIA syndrome, episodes of peritonitis can sometimes become lethal. The case in the present study should be the same clinical conditions as mentioned above. We think that this novel approach of incremental PD could be beneficial, since no subjects needed hospitalization due to HF during the study, in striking contrast to the pre-PD period for all subjects. However, some limitations in this study must be considered when interpreting the results. First, the number of patients was limited, and the study design was observational and not randomized or compared to untreated controls. These are issues that need to be addressed in future studies. In conclusion, incremental PD could represent a novel therapeutic option for elderly patients with refractory HF. In addition to fluid removal by PD, correction of renal anemia, preservation of kidney function, and avoidance of high-dose diuretic therapy may play roles in maximizing the clinical benefits of therapy. Further investigations are needed to determine whether these results apply to all types of HF.
References [1] The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection frac-
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M. Nakayama et al. tions and congestive heart failure. N Engl J Med 1991;325: 293—302. Kjekshus J, Swedberg K, Snapinn S. Effects of enalapril on longterm mortality in severe congestive heart failure. CONSENSUS Trial Group. Am J Cardiol 1992;69:103—7. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709—17. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996;94:2807—16. Gottdiener JS, McClelland RL, Marshall R, Shemanski L, Furberg CD, Kitzman DW, Cushman M, Polak J, Gardin JM, Gersh BJ, Aurigemma GP, Manolio TA. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002;137:631—9. Tehrani F, Phan A, Chien CV, Morrissey RP, Rafique AM, Schwarz ER. Value of medical therapy in patients >80 years of age with heart failure and preserved ejection fraction. Am J Cardiol 2009;103:829—33. Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001;96:132—43. Gotloib L, Fudin R, Yakubovich M, Vienken J. Peritoneal dialysis in refractory end-stage congestive heart failure: a challenge facing a no-win situation. Nephrol Dial Transplant 2005;20:32—6. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, Jaski BE, Fang JC, Feller ED, Haas GJ, Anderson AS, Schollmeyer MP, Sobotka PA, UNLOAD Trial Investigators. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675—83. Basile C, Chimienti D, Bruno A, Cocola S, Libutti P, Teutonico A, Cazzato F. Efficacy of peritoneal dialysis with icodextrin in the long-term treatment of refractory congestive heart failure. Perit Dial Int 2009;29:116—8. Kagan A, Rapoport J. The role of peritoneal dialysis in the treatment of refractory heart failure. Nephrol Dial Transplant 2005;20:28—31. Kazory A, Ross EA. Contemporary trends in the pharmacological and extracorporeal management of heart failure: a nephrologic perspective. Circulation 2008;117:975—83.
[13] Mehrotra R, Nolph KD, Gotch F. Early initiation of chronic dialysis: role of incremental dialysis. Perit Dial Int 1997;17:426—30. [14] Viglino G, Neri L, Barbieri S. Incremental peritoneal dialysis: effects on the choice of dialysis modality, residual renal function and adequacy. Kidney Int Suppl 2008;108:S52—5. [15] Nakayama M. Studies on the sodium concentration of dialysate solution for continuous ambulatory peritoneal dialysis. Nippon Jinzo Gakkai Shi 1992;34:913—20 (in Japanese). [16] Agostoni PG, Marenzi GC. Sustained benefit from ultrafiltration in moderate congestive heart failure. Cardiology 2001; 96:183—9. [17] Kazory A, Ejaz AA. Removal of BNP and inflammatory cytokines by haemodiafiltration in refractory heart failure. Nephrol Dial Transplant 2007;22:2093—4. [18] Hörl WH, Riegel W. Cardiac depressant factors in renal disease. Circulation 1993;87:77—82. [19] Zemel D, Imholz AL, de Waart DR, Dinkla C, Struijk DG, Krediet RT. Appearance of tumor necrosis factor-alpha and soluble TNFreceptors I and II in peritoneal effluent of CAPD. Kidney Int 1994;46:1422—30. [20] Fincher ME, Campbell HT, Sklar AH, Caruana RJ, Lightfoot BO, Cheek PL, Smith KL, Hess CP. Atrial natriuretic peptide (ANP) is removed by peritoneal dialysis in humans. Adv Perit Dial 1989;5:16—9. [21] Silverberg DS, Wexler D, Iaina A. The role of anemia in congestive heart failure and chronic kidney insufficiency: the cardio renal anemia syndrome. Perspect Biol Med 2004;47: 575—89. [22] Silverberg DS, Wexler D, Blum M, Iaina A, Sheps D, Keren G, Scherhag A, Schwartz D. Effects of treatment with epoetin beta on outcomes in patients with anaemia and chronic heart failure. Kidney Blood Press Res 2005;28: 41—7. [23] Palazzuoli A, Silverberg DS, Iovine F, Calabrò A, Campagna MS, Gallotta M, Nuti R. Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome. Am Heart J 2007;154: e9—15. [24] Akdag I, Yilmaz Y, Kahvecioglu S, Bolca N, Ercan I, Ersoy A, Gullulu M. Clinical value of the malnutritioninflammation-atherosclerosis syndrome for long-term prediction of cardiovascular mortality in patients with end-stage renal disease: a 5-year prospective study. Nephron Clin Pract 2008;108:c99—105. [25] Nakamoto H, Kawaguchi Y, Suzuki H. Is technique survival on peritoneal dialysis better in Japan? Perit Dial Int 2006;26:136—43.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jjcc
ORIGINAL ARTICLE
Novel therapeutic option for refractory heart failure in elderly patients with chronic kidney disease by incremental peritoneal dialysis Masaru Nakayama (MD) a,∗, Hirofumi Nakano (MD) b, Masaaki Nakayama (MD) c a
Division of Cardiology, Kashima Hospital, 22-1 Kashimamachi, Shimokuramochi, Aza-Nakasawame, Iwaki, Fukushima 971-8143, Japan b Division of Nephrology, Kashima Hospital, Fukushima, Japan c Tohoku University Graduate School of Medicine, Miyagi, Japan Received 1 May 2009; received in revised form 3 August 2009; accepted 7 August 2009 Available online 26 September 2009
KEYWORDS Aging; Chronic kidney disease (CKD); Heart failure; Peritoneal dialysis; Renal function
∗
Summary Background: Heart failure (HF) often accompanies chronic kidney disease (CKD) in the elderly. This clinical condition is a critical socio-medical issue, because high-dose diuretic therapy stimulates the renin—angiotensin—aldosterone axis and sympathetic nervous system outflow, and may thus result in vicious cycles of cardio-renal deterioration, leading to excess hospitalization and death. Peritoneal dialysis (PD) is a renal replacement therapy used for maintenance dialysis, and is characterized by the continuous removal of fluid. The present study examined the clinical feasibility and effects of a novel style of PD for elderly CKD patients with refractory HF. Methods: Twelve elderly CKD patients (stages 3—5) with refractory HF [New York Heart Association (NYHA) class III, n = 9; IV, n = 3; mean age, 81 ± 6 years] received PD treatment. Patients had episodes of >3 hospitalizations in the previous year, and were initially treated with ≤19 sessions of sequential hemofiltration, followed by incremental PD, with 3 PD sessions/week (8 h each) at the start, increasing in frequency and dwelling time as clinically indicated. Results: During follow-up (median, 26.5 months), PD was well tolerated by all patients, and no patients required hospitalization for HF. Three patients died due to non-HF-related events. All patients showed improvements in NYHA functional class (class I, n = 9; class II, n = 3) and significant decreases in the dose of diuretics prescribed (P < 0.05). Kidney function stabilized, while significant improvements in end-diastolic left ventricular diameter (−5%, P < 0.05) and hemoglobin count (+15%, P < 0.05) were achieved. Brain natriuretic peptide (−46%) and aldosterone (−13%) levels tended to decrease. Conclusions: Incremental PD could represent a novel therapeutic option for elderly patients with refractory HF. In addition to fluid removal by PD, correction of renal anemia, preservation
Corresponding author. Tel.: +81 246 58 5010; fax: +81 246 58 8088. E-mail address: [email protected] (M. Nakayama).
0914-5087/$ — see front matter © 2009 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2009.08.003
50
M. Nakayama et al. of kidney function, and avoidance of high-dose diuretic therapy may play a role in maximizing clinical benefits. © 2009 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction To date, the pathophysiology and treatment options for heart failure (HF) have been well investigated [1—5]. However, some HF patients, particularly among the elderly, remain refractory to conventional therapies and require frequent hospitalization [6]. Furthermore, the prevalence of HF in the population over 65 years old has been consistently increasing in recent years [5,6]. Very few studies regarding established, evidence-based HF management [e.g. renin—angiotensin—aldosterone system (RAAS) modulation, beta blockers, and aldosterone antagonists] have included elderly subjects [1—5]. Geriatric-specific issues such as renal insufficiency, anemia, and hypoalbuminemia generate numerous clinical difficulties in the treatment of elderly HF patients, preventing or limiting the prescription of conventional medications, and the presence of dementia can lead to difficulties in restricting sodium intake, patient compliance, and exclusion from invasive strategy options (surgery, transplant, device therapy). These problems result in a tendency toward treatment using high-dose diuretics [6—8]. High-dose diuretics may increase the risk of adverse renal effects, such as exaggerating renal perfusion (azotemia), and stimulating RAAS and sympathetic nervous system (SNS) activity [7]. Alternative management strategies are thus required. Extra- and/or intracorporeal ultrafiltrations have generated clinical improvement and represent potential therapeutic options for HF [8—12], but the intermittent mode of therapy has limited the clinical potential. Peritoneal dialysis (PD) is a renal replacement therapy used for maintenance dialysis, and is characterized by the continuous correction of the uremic milieu, including excess fluid in the body. PD is thus reasonably expected to benefit patients with HF. In fact, favorable clinical results have recently been reported for dialysis patients with refractory HF following the application of PD [8,10—12]. Incremental PD was first proposed by Mehrotra et al. [13]. The therapeutic concept involves prescribing the PD regimen according to the level of residual renal function. Patients thus start PD with exchange of at least one bag, and increase PD dose in proportion to the declining urinary excretion of solutes and fluid. This therapeutic approach to chronic kidney disease (CKD) patients with HF may reasonably be expected to exert cardio-renal-protective effects [14]. The present study therefore examined the clinical efficacy and feasibility of therapeutic PD application in elderly CKD patients with HF refractory to conventional therapy.
Methods Patients Data from 12 consecutive patients who underwent incremental PD between April 2002 and May 2008 were evaluated.
Patients were enrolled in this study based on the following inclusion criteria: (1) age ≥70 years; (2) stages 3—5 CKD; and (3) frequent HF hospitalization (≥3 times/year) despite conventional outpatient therapy (defined as refractory HF). Glomerular filtration rate (GFR) was calculated using the modified Modification of Diet in Renal Disease equation. Etiologies of CKD for these study subjects were not well evaluated, but subjects included at least two cases with diabetic nephropathy. The major cause of CKD in the other study subjects was thought to be renal sclerosis, based on the clinical course. Diagnosis of HF was based on the Framingham or Massachusetts General Hospital criteria. The study population included three patients with mild left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) <50%], and nine patients with preserved LVEF. All patients were evaluated for suitability and initiated on PD treatment by an attending nephrologist. All patients provided written informed consent to participate in this study prior to enrolment. All protocols were approved by the ethics committee of our hospital.
Ultrafiltration and induction of PD Patients were initially treated with 0—19 sessions of sequential hemofiltration for acute decompensated HF, followed by incremental PD. A Tenckhoff catheter was surgically implanted, and the optimal PD solution was determined. Typical PD solution consisted of 1.5—2.0 L of 1.5% dextrose (Dianeal® ; Baxter, Deerfield, IL, USA) based on the peritoneal equivalent test result and body mass. Following completion of sequential hemofiltration treatments, patients were initiated on three PD sessions/week (8 h each). Dwell time, frequency, dextrose concentration (1.5%, 2.5%, and 4.25%), and PD solution (to icodextrin, Extraneal® ; Baxter) were changed as needed to optimize efficiency of ultrafiltration rate.
Observations Time points for data analysis included the time at which dry weight was attained (baseline), at the end of follow-up (May 2008), and/or just prior to any clinical events. Five endpoints were examined: all-cause mortality; cardiovascular mortality; all-cause hospitalization; HF hospitalization; and PD-related hospitalization. Data collected included resting systolic and diastolic blood pressures, heart rate (STBP-780; Omron Colin, Tokyo, Japan), body weight, New York Heart Association (NYHA) functional class, echocardiographic determinants of cardiac function, and loading conditions (EUB-8500; Hitachi Medical, Tokyo, Japan), such as left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), Doppler measurement at left ventricular inflow (E/A), left ventricular ejection fraction (LVEF), renal function [serum creatinine (Cr) and GFR], hemoglobin (Hb) level, and
Incremental PD for HF with CKD Table 1
51
Statistical analysis
Baseline patient characteristics.
Variables Age (years) Sex (male:female) Diabetes mellitus (n)
81 ± 6 7:5 3
Etiology of HF (n) Hypertensive heart disease Valvular heart disease Ischemic cardiomyopathy Dilated phase hypertrophic cardiomyopathy
6 3 2 1
Medications (n) Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers Beta blockers Calcium channel blockers Digoxin Nitrate
6 6 3 7 2 6
New York Heart Association functional class (n) III IV
9 3
Data are presented as mean ± standard deviation (SD) or number. HF, heart failure.
neurohumoral factors [brain natriuretic peptide (BNP), plasma rennin activity (PRA) and aldosterone (ALD)]. Changes in diuretic dosages (furosemide and trichlomethiazide) were also recorded. An azosemide dose of 30 mg was regarded as equivalent to a furosemide dose of 20 mg. HF drugs were changed as clinically indicated. Patients with anemia (Hb <11 g/dL) received subcutaneous epoetin- once a week at a dose of 6000 IU and/or intravenous iron, if appropriate.
Table 2
Statistical analysis was performed using StatView software (SAS Institute, Cary, NC, USA). Results are presented as mean ± standard deviation (SD). Student’s paired t-test was used to compare data between baseline and the end of follow-up.
Results Patient characteristics at the initiation of PD are summarized in Table 1. The study population comprised elderly patients with mild anemia and severe renal insufficiency. Functional capabilities were characterized defined as class III (n = 9) or IV (n = 3). All patients were being prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Median follow-up was 26.5 months (range, 6—62 months). Finally, mean frequency of PD sessions was 14.6 ± 4.7 times/week. At the end of follow-up, one patient required hemodialysis secondary to ultrafiltration failure of PD. None of the patients required hospitalization due to HF, but one patient was hospitalized due to non-HF-related disease (colon cancer), and two patients were hospitalized due to uremia-related malnutritional cachexia and catheterrelated peritonitis. All three of these hospitalized patients died (Table 2). Compared with baseline values, diuretics had been withdrawn or reduced in all patients by the end of follow-up (Table 3; Fig. 1A). No change in body weight was seen between baseline and final data (Table 3). No changes in systolic or diastolic blood pressure, heart rate, or laboratory findings were seen regarding Cr or GFR when comparing baseline and final data. However, a significant increase in Hb (Fig. 1B) indicated a correction of renal anemia. In terms of echocardiographic parameters, no changes in LVEF, LVDs, or E/A were seen, but LVDd was
Status at final dose of PD and status and major events during follow-up.
Age/sex
Etiology of HF
PD (sessions/week)
Follow-up (months)
Event
89/F 82/M 85/F 84/F 79/M 86/M 78/M 72/M 71/F 79/M 79/F 76/M
HHD HHD DHCM/Pacing MVR/Af/DM MR/Af HHD HHD ICM ICM/DM HHD/DM AR HHD
14 14 14 14 14 7 14 14 7 21 21 21
6 6 15 21 22 26 27 33.5 33.5 37 43 62
— — Colon cancera — MIA syndromea — — — Catheter-related peritonitisa — — UF failure
14.6 ± 4.7
27.7 ± 15.8
Mean ± SD
HF, heart failure; PD, peritoneal dialysis; HHD, hypertensive heart disease; DHCM, dilated-phase hypertrophic cardiomyopathy; MVR, mitral valve replacement; Af, atrial fibrillation; DM, diabetes mellitus; MR, mitral valve regurgitation; ICM, ischemic cardiomyopathy; AR, aortic valve regurgitation; MIA, malnutrition—inflammation—atherosclerosis; UF, ultrafiltration. a Patients who died.
52 Table 3
M. Nakayama et al. Clinical variables at baseline and on PD.
Variables
Baseline
Body weight (kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) LV diastolic diameter (mm) LV systolic diameter (mm) LV ejection fraction (%) E/Aa Brain natriuretic peptide (pg/mL) Aldosterone (pg/mL) Plasma renin activity (ng/mL/h) Blood urea nitrogen (mg/dL) Creatinine (mg/dl) Calcium (mequiv./L) Phosphate (mequiv./L) Albumin (g/dL) Total cholesterol (mg/dL) Hemoglobin (g/dL) Estimated GFR (mL/min/1.73 m2 ) Furosemide dosage (mg) Trichlomethiazide dosage (mg)
52.1 132 69 72 52.6 35.0 56 0.60 813.3 102.3 6.7 50.0 4.6 8.6 4.9 2.9 163 9.8 10.5 56.7 2.3
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
On PD 10.9 25 13 12 5.2 6.3 10 0.12 1248.5 52.4 7.0 20.0 2.1 0.8 1.1 0.5 57 1.7 8.2 30.6 1.9
51.7 133 69 70 48.5 31.6 58 0.59 362.3 87.4 4.5 51.6 5.2 8.3 3.8 2.6 157 11.0 9.5 20.0 0.8
P ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
12.5 22 13 7 4.4 3.8 6 0.11 454.2 41.5 4.9 16.2 2.4 0.7 1.2 0.5 35 1.3 7.5 19.1 1.3
0.5803 0.8535 0.7513 0.4472 0.0138 0.0717 0.4993 0.7879 0.0996 0.0861 0.1644 0.8276 0.2073 0.2742 0.3106 0.0566 0.7116 0.0364 0.2476 0.0056 0.0121
Data are presented as mean ± SD. PD, peritoneal dialysis; LV, left ventricular; GFR, glomerular filtration rate; E/A, Doppler measurement at left ventricular inflow. a n = 9 (not available for three cases; two cases of atrial fibrillation; one case of right ventricular apical pacing).
significantly decreased (Fig. 1C). Decreases in BNP, PRA, and ALD were identified, but did not reach the level of statistical significance. Summarized data are presented in Table 3. Final NYHA functional class improved in all cases (class I, n = 9; class II, n = 3; Fig. 1D).
Discussion PD was used to treat 12 elderly patients with CKD and refractory HF. PD was well tolerated by all patients during the observation period and produced clinical benefits as demonstrated by (1) improved NYHA functional class; (2) no hospitalization related to HF; (3) reduced dosages of diuretics; (4) increased Hb level; (5) decreased LV diastolic diameter; (6) no worsening in neurohumoral factor levels; and (7) maintenance of cardiac and renal function. PD may exert therapeutic effects in the context of HF via several mechanisms, such as removing excess water and sodium [8,10—12]. The sodium excretion efficiency of PD is known to be nearly 1.5-fold higher than that of the same volume of urine [15]. In this study, median removal of excess water and sodium per PD session was 213 mL and 134 mequiv./L, respectively (data not shown). This is equivalent to a 1.4 g reduction in sodium per PD session, without the need for high-dose diuretics. Although extracorporeal ultrafiltration is superior to PD in terms of the prompt removal of excess water and sodium, the property of continuous and slow removal of excess water and sodium by PD could contribute to the maintenance of renal function and avoidance of adverse renal effects [7]. Furthermore, PD does not require
hospitalization, contrasting sharply with the extracorporeal ultrafiltration method. This may also benefit elderly patients. Regarding the therapeutic benefits of increased ultrafiltration volume in patients with HF, the pathophysiological HF process could be at least partially reversed by inhibition of inflammatory cytokine release, normalization of neurohormonal pathways, and restoration of diuretic responsiveness [16—20]. As ultrafiltration-mediated convective clearance of cytokines is nonspecific, beneficial cytokines are lost along with harmful ones. Furthermore, although the mass clearance of cytokine compounds with PD is low, PD can remove the molecular weight of myocardial depressant factors, which range between 0.5 and 20 to 30 kDa (e.g. tumor necrosis factor-␣). In this and previous studies, the observation that PD resulted in decreased BNP (3.5 kDa) levels [17] was very important from a clinical perspective, although this decreasing tendency was not significant. The decrease in BNP might also be due to a reduction in cardiac preload and may affect changes in cognitive function, warranting further investigation. Anemia is prevalent in both HF and CKD. In fact, these three conditions form a vicious cycle, with each condition capable of causing or being caused by the others. This phenomenon has been referred to as cardio-renal anemia syndrome by Silverberg et al. [20—23]. While several studies have suggested that erythropoietin therapy might be beneficial in CKD patients with HF, this remains controversial, as many patients appear unresponsive. The present study revealed significant increases in hemoglobin levels following PD induction (Table 3). With no change in inflammatory conditions, increased responsiveness to ery-
Incremental PD for HF with CKD
53
Figure 1 Changes in furosemide dosage (A), hemoglobin (Hb) level (B), and left ventricular diastolic diameter (LVDd) (C). Lines within boxes represent median values, with top and bottom lines of boxes representing the 75th and 25th percentiles, respectively, and top and bottom bars outside of boxes representing the 90th and 10th percentiles, respectively. Incremental PD resulted in reduced furosemide dosing, reduced LVDd, higher Hb, and better New York Heart Association functional class (D). Data are presented as mean ± SD. PD, peritoneal dialysis; NYHA, New York Heart Association.
thropoietin administration as well as glucose-calorie load by PD solution may be involved in these improvements. In the present study, two cases were lost to PD-related complications. One patient died due to uremia-related malnutritional cachexia, which is common among elderly patients on chronic dialysis. This characteristic clinical feature has recently been defined as malnutrition— inflammation—atherosclerosis (MIA) syndrome, and accumulated evidence has revealed the worst outcomes in patients with this syndrome [24]. In this patient, the cause of death was diagnosed as malnutrition and cachexia due to pathology-related uremic condition. The other patient died due to catheter-related peritonitis. Complications of PD include catheter-related infections such as exit-site infection, skin-tunnel (subcutaneous) infection and peritonitis, and mechanical stress-related events involving the PD solution, such as herniation of the esophagus, abdominal wall, or inguinal region. Among these, catheter-related infection is the most common complication according to recent reports [24]. The peritonitis rate in Japan is low compared with other countries, at one episode per 37.0—58.8 patient—months. As a reason for dropout from PD, peritonitis accounts for only 14% of dropouts in Japan [25]. The case in our study was well managed by PD for 33.5 months, and was free from peritonitis before the final episode. In addition, catheter-related peritonitis is usually curable, and
management is well established using standard antibiotic regimens. However, in the case of an elderly patient with MIA syndrome, episodes of peritonitis can sometimes become lethal. The case in the present study should be the same clinical conditions as mentioned above. We think that this novel approach of incremental PD could be beneficial, since no subjects needed hospitalization due to HF during the study, in striking contrast to the pre-PD period for all subjects. However, some limitations in this study must be considered when interpreting the results. First, the number of patients was limited, and the study design was observational and not randomized or compared to untreated controls. These are issues that need to be addressed in future studies. In conclusion, incremental PD could represent a novel therapeutic option for elderly patients with refractory HF. In addition to fluid removal by PD, correction of renal anemia, preservation of kidney function, and avoidance of high-dose diuretic therapy may play roles in maximizing the clinical benefits of therapy. Further investigations are needed to determine whether these results apply to all types of HF.
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