PATIENTS AND METHODS. KEY WORDS: Albumin; ascites; hemodialysis; nutrition; survival.

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1 Peritoneal Dialysis International, Vol. 17, pp /97 $ Printed in Canada All rights reserved Copyright 1997 International Society for Peritoneal Dialysis SYMPTOMATIC ASCITES AFTER DISCONTINUATION OF CONTINUOUS PERITONEAL DIAL YSIS Muhammad z. Haq, Antonios H. Tzamaloukas, Deepak Malhotra, and Lawrence J. Gibel Medical Service and Urology Section, Albuquerque Veterans Affairs Medical Center, and University of New Mexico School of Medicine, Albuquerque, New Mexico, U.S.A..Objective: To analyze pathogenetic associations, clinical features, management, and outcome of ascites following discontinuation of continuous peritoneal dialysis (CPD)..Design: Retrospective analysis of symptomatic ascites, defined as ascites requiring at least one therapeutic paracentesis, developing in patients who discontinued CPD..Setting: Dialysis unit of one tertiary care center..participants:twelve patients with 13 episodes of symptomatic ascites diagnosed soon after (a few days to 2 months) discontinuation of CPD..Interventions: Diagnostic tests to characterize the pathogenesis of ascites; management of ascites by hemodialysis or CPD..Main Outcome Measures: Evolution of clinical features and nutritional parameters, survival..results: Ascites was infectious in 3 episodes (nontuberculous mycobacterial peritonitis) and noninfectious in the remaining 10 episodes. Serum-to-ascites albumin concentration gradient (AG) was 6.3 ± 1.5 g/l in infectious ascites and 17.3 ± 2.7 g/l ( >11 g/l in every episode) in noninfectious ascites. Infectious ascites was managed with hemodialysis, prolonged courses of antimicrobial agents, and repeated paracentesis. Paracentesis ceased after 3 9 months. The patients were alive after 52 ± 19 months. Seven episodes of noninfectious ascites were managed by hemodialysis and repeated paracentesis. Five patients died within 6 months from cardiac causes or sepsis. The remaining 2 patients died after 14 and 16 months from cardiac causes. Three episodes of noninfectious ascites in 2 patients were treated by restarting CPD within 2-5 months. Patients were alive at 16.9 ± 13.2 months. They were asymptomatic and achieved fluid control. On the same CPD schedule, peritoneal clearances of urea and creatinine and normalized protein nitrogen appearance were unchanged between the initial and restarted CPD. Serum albumin was 33.3 ± 2.5 g/l at the end of the first CPD period, 23.6 ± 2.5 g/l soon after restarting CPD, and 31.3 ± 5.5 g/l 4 months after restarting CPD. Correspondence to: A.H. Tzamaloukas, Renal Section (lllc), Veterans Affairs Medical Center, 2100 Ridgecrest Dr., SE, Albuquerque, New Mexico, U.S.A. Received 25 March 1997; accepted 28 August Conclusions: Noninfectious ascites after discontinuation of CPD is often characterized by an AG > 11 g/l, suggesting portal hypertension. Restarting CPD in noninfectious ascites may be associated with improvement in ascites symptomatology and nutritional parameters and with satisfactory survival. KEY WORDS: Albumin; ascites; hemodialysis; nutrition; survival. A scites may complicate the course of chronic dialysis. In the review by Gluck and Nolph (1), the incidence of dialysis ascites was reported to vary between 0.7% and 20% and appeared to have decreased with time. The pathogenesis of dialysis ascites is multifactorial (1). Continuous peritoneal dialysis (CPD) has been successfully employed in the management of ascites in congestive heart failure (2), cirrhosis (2-5), and ascites complicating hemodialysis (HD) (6-9). In this report, we analyzed episodes of symptomatic ascites diagnosed soon after discontinuation of CPD. We used the serum-to-ascitic fluid albumin gradient (AG) to characterize the ascites as hydrostatic (secondary to portal hypertension) or inflammatory (10). We also analyzed management and outcome of ascites. Emphasis was placed in the reinstitution of CPD as a means of managing the ascites. PATIENTS AND METHODS Over a period of 11 years (1986 to 1996), 12 patients, 1 woman and 11 men, aged 56.4± 13.2 years, on CPD for 33.8 ± 27.6 months developed 13 episodes of symptomatic ascites within a few days to 2 months after discontinuation of CPD. Ascites was defined as symptomatic if it required at least one therapeutic paracentesis. End-stage renal disease was caused by diabetes mellitus in 4 patients, hypertensive vascular disease in 3, glomerulopathies in 2, unknown conditions in 2, and autosomal dominant

2 polycystic kidney disease (ADPKD) in 1 patient who had two distinct episodes of ascites. Continuous peritoneal dialysis was discontinued because of nontuberculous mycobacterial peritonitis in 3 episodes, staphylococcal peritonitis in 2 (one due to Staphylacoccus aureus and the other due to Staph. epidermidis ), renal transplant in 2 (both transplants failed within 5 months), uncontrolled fluid gains in 2, patient preference in 2, and management decision in 2 episodes. Clinical features related to ascites were tabulated. Regardless of the cause of CPD discontinuation, the ascites was characterized as infectious when ascitic fluid neutrophil count exceeded 250/mm3 (10) or ascitic fluid cultures were positive, or noninfectious when ascitic fluid neutrophil count was less than 250/mm3 and ascitic fluid cultures were negative. The ascitic fluid was further characterized by the AG. An AG greater than 11 g/l is considered diagnostic of portal hypertension (10). Potential causes of portal hypertension were analyzed in all patients with AG > 11 g/l. The management, course, and outcome of ascites were analyzed. We also analyzed selective parameters reflecting nutrition (dry weight, serum albumin, serum urea, hematocrit) and, in patients who restarted CPD, clearance indices. For the nutritional parameters, a comparison was carried out between the average value of the three last measurements prior to the discontinuation ofcpd (pre), the lowest value right after discontinuation ofcpd (nadir), and a recovery value 3 or 4 months after restoration of CPD (post). RESULTS Table 1 shows the clinical features related to ascites. Dyspnea was universal and improved with each therapeutic paracentesis. Severe anorexia was common. Although the assessment of dry weight was complicated by the presence of ascites, large losses in dry weight were noted in more than 50% of the patients. Only the 3 patients with mycobacterial peritonitis continued to have positive cultures and elevated white cell counts in the ascitic fluid after discontinuation of CPD. All other patients had noninfectious ascites. Table 2 shows some characteristics of the infectious and noninfectious groups. In both groups, blood hematocrit and serum albumin decreased soon after discontinuation ofcpd from their respective average levels before stopping CPD (p 0.05). The percent decrease in dry weight was large in the infectious episodes (15 ± 9%) and modest in the noninfectious episodes (2.8 ± 4.2%). The AG was < 11 g/l in all episodes of infectious ascites and > 11 g/l in all episodes of noninfectious ascites (Figure 1). Among the 9 patients with noninfectious ascites, 5 (56% ) had clinical conditions known to cause portal hypertension (3 severe heart failure, 1 autopsy-proven cirrhosis, and 1 biopsy-proven cirrhosis and advanced heart failure). Another 2 patients (22%) had liver pathology that may rarely be associated with portal hypertension (1 patient with ADPKD and multiple, large liver cysts and 1 patient with a large, benign hepatic tumor). Finally, 2 patients (22%) had no clinically recognizable condition associated with portal hypertension. Liver function tests were mildly abnormal in 7 patients with noninfectious ascites (78%), while 1 patient (33%) with infectious ascites had an episode of prolonged jaundice secondary to parenteral nutrition. Serum amylase and lipase were normal in the 7 episodes (3 with infectious ascites) in which they were measured.

3 In the infectious group, ascites was managed by prolonged (6 12 months) use of antimycobacterial antibiotics plus repeated therapeutic paracentesis, while the patients were maintained on HD. Hemo dialysis was complicated by hypotension in 2 subjects. Ascites disappeared after 4 9 months oftreatment and the patients were alive 52 ± 19 months after discontinuation of CPD. Nutritional parameters, including body weight, returned to baseline levels within 16 months. One patient received a cadaveric renal transplant 31 months after discontinuation of CPD. The noninfectious ascites group was subdivided into the group that was maintained on HD (7 patients) and the group that returned to CPD after 2 5 months of HD (3 episodes, 2 patients). In the HD subgroup, ascites was managed by HD 3-5 times weekly, ultrafiltration attempting to remove 1-3 kg of fluid, and abdominal taps every 3-8 days with removal of L per tap. Five subjects with severe heart failure and cirrhosis exhibited profound hypotension during HD. All five died within 6 months of CPD discontinuation from cardiac causes (4 patients) or sepsis (1 patient). Control of ascites and fluid balance was achieved without serious side effects in the remaining 2 patients, who died from sudden cardiac events 14 and 16 months, respectively, after discontinuation of CPD. In these patients, the rate of ascites formation had decreased greatly. Paracentesis had not been required for the last 4 and 8 months respectively and serum albumin had returned to baseline levels. Both patients in the CPD subgroup had experienced severe hypotension while on HD. In addition, the subject with 2 ascites episodes reaccumulated ascites at a fast rate during the period ofhd: abdomi nal taps were required every 3-8 days with removal of 2-5 L per tap. The rate of ascitic fluid removal was 1.1 L daily for 32 days in the first episode and 0.85 L daily for 45 days in the second. Both patients were alive on CPD at the end of observation. Followup was 17.0 ± 13.2 months after restarting CPD. The patients had no problems with fluid control or hypotension. Dyspnea and anorexia disappeared and weakness improved greatly. In the CPD subgroup, clearance studies and peritoneal equilibration tests were performed prior to the discontinuation ofcpd (within 6 months) and 1 month after reinstitution of CPD (twice in the second patient). On the same CPD schedule, weekly peritoneal KtN urea was 1.66 ± 0.24 before stopping CPD and 1.65 ± 0.24 after restarting it. Correspondinglevels were 51.7 ± 5.0 L/l.73 m2 and 50.9 ± 5.4 L/ 1.73 m2, respectively, for weekly peritoneal creatinine clearance and 1.12± 0.13 and 1.08 ±0.09g/(kgstandard weight x 24 hr) respectively for normalized protein nitrogen appearance (npna). Peritoneal solute transport type was characterized by the 4-hour dialysate-to-plasma creatinine concentration ratio (D/P cr) in peritoneal equilibration tests performed both before discontinuing CPD and after restarting it. Peritoneal transport decreased in 1 subject [from low avera g e (D/P of cr 0.63) c to low (D/P of 0.47)], did not change in the first ascites episode of the second r subject [high average (D/P cr 0.68 and 0.71)], and increased in the second episode of the second subject [from high average (D/P cr of 0.71) to high (D/P cr of 0.86)]. In this last ascites episode, daily losses in the dialysate, measured 2 months after reinstitution of CPD, amounted to 8.4 g for albumin and 15.6 g for total protein. Figure 2 shows serum albumin and urea concentration and blood hematocrit prior to the discontinuation ofcpd (pre), soon after restarting CPD (nadir), and 3-4 months after the reinstitution of CPD (post). For all three parameters, the measurement at nadir was lower than the pre or post measurements. The patient with high transport maintained a serum albumin between 28 g/l and 33 g/l. His npna was between 1.42 and 1.89 g/(kg standard weight x 24 hr), suggesting large dietary protein intake. DISCUSSION General causes of ascites include increased net ultrafiltration pressure in the peritoneal capillaries, increased permeability of the peritoneal membrane to macromolecules, and decreased peritoneal lymphatic absorption. Specific factors invoked in the pathogenesis of dialysis ascites include fluid overload, functional or structural changes in the peritoneal membrane, impaired lymphatic drainage, heart

4 failure, constrictive pericarditis, hypoalbuminemia, hyperparathyroidism, pancreatitis, and hepatitis ( 1). Rodriguez et al. (11) described 4 patients who developed ascites after acute peritoneal dialysis with hypertonic dextrose solutions. In the review by Gluck and Nolph (1), 69% of the cases of dialysis ascites developed in patients who had been on peritoneal dialysis. These observations, coupled with the close temporal relationship between the discontinuation of CPD and the diagnosis of ascites in our study, suggest that peritoneal dialysis plays a role in the pathogenesis of ascites. Classification of ascites by the AG is superior to its characterization as transudate or exudate by older criteria (10). TheAGexceeds 11 g/linascites caused by portal hypertension and is less than 11 g/l in ascites caused by peritonitis (Figure 1), inflammatory processes, or malignancy (10). Using the AG as criterion, elevated net ultrafiltration pressure in the peritoneal capillaries was a factor in the development of ascites in all cases with noninfectious ascites in our study. Two lines of evidence in the review by Gluck and Nolph (1) suggest that altered peritoneal permeability to macromolecules may also playa role, at least in some cases of dialysis ascites: (1) The calculated AG was less than 9 g/l in 11 of22 cases. (2) Structural changes (inflammation and fibrosis) were detected in 45% of the peritoneal biopsies in patients with dialysis ascites. Therefore, the pathogenesis of dialysis ascites involves at least two processes, increased net peritoneal ultrafiltration pres sure and increased peritoneal permeability. Whether abnormalities of the peritoneal lymphatic drainage are also involved is not clear. Gluck and Nolph (1) suggested that the term dialysis (or end-stage renal disease) ascites should be reserved for subjects who do not have a recognizable condition causing ascites. In the present study, 80% of the subjects with noninfectious ascites had clinical conditions either definitely (heart failure, cirrhosis) or potentially (ADPKD, benign hepatic tumor) associated with portal hypertension. The recessive (infantile) form of polycystic kidney disease is associated with severe hepatic disease and portal hypertension. Although 40% -50% of the patients with ADPKD have cysts in the liver, liver abnormalities are rare in this condition (12). Few cases of portal hypertension have been reported in patients with ADPKD (13-15). Albumin concentration gradient was the only finding suggesting portal hypertension in our patient. Sulfur colloid scan did not show increased splenic uptake and liver function tests were normal. Thus the association between ADPKD and ascites was rather tenuous. A single benign hepatic tumor is an even more questionable cause of portal hypertension. Renal transplantation is probably the most effective method of managing dialysis ascites (1). Other methods used to treat dialysis ascites include HD performed with increased frequency and coupled with fluid restriction and isolated ultrafiltration, intraperitoneal instillation of corticosteroids, peritoneo-jugular shunts, reinfusion of the ultrafiltered ascitic fluid, bilateral nephrec.tomy, peritoneal dialy sis, and laparotomy (1). In this study we employed HD and reinstitution of CPD. Hemodialysis was performed with increased frequency and in conjunction with isolated ultrafiltra tion. Its effectiveness was limited by severe hypotension. Hypotension is a frequent complication ofhd in patients with dialysis ascites (1,6,7,11). Mortality was high in patients with noninfectious ascites treated by HD. However, all early deaths occurred in patients with terminal heart or liver disease. The 2 subjects who survived longer than 1 year had shown signs of both slowing formation of ascites and improving nutrition. Thus HD may be effective in the management of dialysis ascites in patients who do not have advanced cardiac or hepatic disease and do not develop severe hypotension during treatment. In this study, the patients treated with restoration of CPD had exhibited severe anorexia, hypoalbuminemia, weakness, and hypotension during the initial period after CPD discontinuation, when they were on HD. Clinical manifestations improved dra matically after restarting CPD. Clearance indices and nutritional parameters returned to the baseline

5 levels. After an average follow-up exceeding 1 year, the subjects were alive and feeling well. More clinical observations will be needed to validate restarting CPD as a method of managing ascites after previous CPD discontinuation. However, based on this study, we suggest that continuous peritoneal dialysis may provide satisfactory results in dialysis ascites, especially in subjects who had severe hypotension during hemodialysis. ACKNOWLEDGMENT Supported by the Albuquerque Veterans Affairs Medical Center. This work was presented in a poster session at the 17th Annual Conference on Peritoneal Dialysis. REFERENCES 1. Gluck Z, Nolph KD. Ascites associated with end-stage renal disease. Am J Kidney Dis 1987; 10: Van Loo A, Vanholder R, Lameire N, Ringoir S. CAPD for refractory ascites in heart and liver failure (Ab stract). Perit Dial Int 1996; 16: Marcus RG, Messana J, Swartz R. Peritoneal dialysis in endstage renal disease patients with preexisting chronic liver disease and ascites. Am J Med 1992; 93: Poulos AM, Howard L, Eisele G, Rodgers JP. Peritoneal dialysis therapy for patients with liver and renal failure with ascites. Am J Gastroenterol 1993; 88: Bajo MA, Selgas R, Jimenez C, Del Paso G, Fernandez Reyes MJ, Dapena F, et al. CAPD for treatment of ESRD patients with ascites secondary to liver cirrhosis. In: Khanna R, ed. Advances in peritoneal dialysis. Toronto: Peritoneal Dialysis Publications, 1994; 10: IngTS, DaugirdasJT, Popli S,KheirbekAO, Humayun HM, Gandhi VC, et al. Treatment of refractory hemodialysis ascites with maintenance peritoneal dialysis. Clin Nephrol1981; 15: Rubin J, Kiley J, Ray R, McFarland S, Bower J. Continuous ambulatory peritoneal dialysis: treatment of dialysis-related ascites. Arch Intern Med 1981; 141: Bennett RR, Moore J. Dialysis-induced ascites treated with peritoneal dialysis.southmed J 1987; 80: Duranay M, Erbilen M, Bali M, Sahin M, Ates K, Hasanoghe A, et al. Treatment of hemodialysis ascites with continuous ambulatory peritoneal dialysis. Nephron 1996; 73: Runyon BA. Care of patients with ascites. N Engl J Med 1994; 330: Rodriguez HJ, Walls J, Slatopolsky E, Klahr S. Recur rent ascites following peritoneal dialysis. A new syn drome? Arch Intern Med 1974; 184: Oreopoulos DG, Bell TK, McGeown MG. Liver function and the liver scan in patients with polycystic kidney disease. Br J Urol1971; 43: Katzen NG. Fatal hepatic polycystic disease. Br Med J 1964; i: DelGuercio E, Greco J, Kim KE, Chinitz J. Swartz C. Esophageal varices in adult patients with polycystic kidney and liver disease.n Engl J Med 1973;289: RatcliffePJ,ReedersS, TheakerJM.Bleedingoesopha geal varices and hepatic dysfunction in adult polycystic kidney disease. Br Med J 1984; 288: