CASE REPORT
Ascites Following Renal Transplantation B R U C E R. M A R C E L , MD, R A Y M O N D
S. K O F F , MD, F A C P , and S A N G I N C H O , MD
A small n u m b e r of uremic patients treated with maintenance peritoneal dialysis or hemodialysis have developed ascites (1-5). In some patients ascites has been attributed to the nephrotic s y n d r o m e , Circulatory overload, or inferior v e n a c a v a c o m p r e s sion (6). K n o w n c o m m o n causes of ascites, eg, cardiac, hepatic, pancreatic, and neoplastic diseases, have been excluded in m o s t dialysis patients b y a p propriate studies, and bacterial or tuberculous peritoneal infections have not been implicated. While the precise m e c h a n i s m responsible for the develo p m e n t of " i d i o p a t h i c " or unexplained ascites in this setting is uncertain, a role for uremic toxins has been postulated (2--4). Renal transplantation has been a d v o c a t e d in the m a n a g e m e n t of this disorder (3-4) since other t h e r a p y directed at control of ascites has been unsatisfactory. In this report we describe a patient who was free of ascites during a period of peritoneal dialysis and hemodialysis but, in w h o m , f o l l o w i n g s u c c e s s f u l r e n a l t r a n s plantation, unexplained ascites developed. This experience suggests that ascites in patients with endstage renal failure is not limited to the period of maintenance dialysis and that renal transplantation m a y paradoxically be followed by the d e v e l o p m e n t of ascites.
CASE REPORT The patient is a 59-year-old white man with insulin-dependent diabetes mellitus of 30 years duration. He was treated for pulmonary tuberculosis at age 35. Progressive azotemia due to diabetic nephropathy was recognized 10 years prior to this admission to the Boston VA Hospital. Peritoneal dialysis was begun at this time and two months later he was switched to a program of hemodialysis at inFrom the Medical and Surgical Services, Boston VA Hospital and the Department of Medicine, Boston University School of Medicine. Address for reprint requests: Dr. R.S. Koff, Medical Service, VA Hospital, 150 S. Huntington Ave., Boston, Massachusetts 02130. Digestive Diseases, Vol. 22, No. 2 (February 1977)
tervals of 4--5 days. During this period he had intermittent weight gain, pedal edema, and evidence of early congestive heart failure, all of which resolved completely with each dialysis. Ascites was absent. Five months after beginning hemodialysis, cadaver renal transplantation was performed. Ascites was not present at operation. A brief exacerbation of azotemia occurred postoperatively and subsided spontaneously, He was treated with insulin, prednisone, azathioprine, furosemide, isoniazid, and pyridoxine. Eighteen days after transplantation, while at home, he noted progressive abdominal, scrotal, and lower limb swelling. He had no history of previous ascites, liver or pancreatic disease, or excessive alcohol, fluid, or salt consumption, Examination disclosed an afebrile, noncachetic man with a blood pressure which did not exceed 160/60. The lungs were clear and signs of congestive heart failure were absent. Ascites was striking but there was neither abdominal tenderness nor palpable visceral enlargement. Scrotal edema and moderate edema from the groin to the toes were present. The hematocrit was 27%, and the white cell count was 6,400. The BUN was 68 mg/dl and serum creatinine was 3.8 mg/dl. Total serum protein was 5.4 g/dl with serum albumin of 3.0 g/dl. Serum sodium was 126; potassium 5.8, and chloride 90 mEq/Iiter. The serum bilirubin, serum alkaline phosphatase, amylase, SGOT, LDH, and prothrombin time were normal. Thyroid studies (T4 and T3 resin test) were normal. A 24-hr urine collection contained 460 mg of protein. Multiple urinary protein determinations, on other days, never exceeded this level. Abdominal paracentesis revealed clear straw-colored fluid containing 20 WBC/mm 3 and 52 RBC/mmL Ascitic fluid protein was 1.5 g/dl, and the amylase and LDH levels were within normal limits. Creatinine levels were similar to those obtained in serum. Cytological examination for malignant cells, and cultures of ascitic fluid and peritoneal tissue (obtained by biopsy) for tuberculosis and other bacteria, were negative. Radiologic studies of the chest, barium enema, UGI series, and an inferior vena cavagram were unrewarding, and a technetium liver-spleen scan was within normal limits. Intravenous pyelography revealed a normally functioning allograft kidney. Inferior vena cava pressure was 6 mm Hg, and wedged hepatic vein pressure was 10 mm Hg. A percutaneous needle biopsy of the liver disclosed normal hepatic tissue without fibrosis or cirrhosis. Peritoneal biopsy revealed "chronic inflammation" but granulomas were not seen.
137
MARCEL ET AL During the period of hospitalization the BUN rose to 100 mg/dl and the creatinine peaked at 5.5 mg/dl. Maintenance immunosuppressive therapy with prednisone and azathioprine was not changed. Serum proteins, bilirubin, and SGOT remained normal. Four weeks after admission spironolactone was added to the treatment regimen and the ascites diminished, accompanied by an 8-kg weight loss. At the time of discharge renal function had improved and serum creatinine was 2.0 mg/dl. He remained free of ascites dUring 6 months of follow-up but died suddenly of cardiovascular collapse at another hospital. Permission for post-mortem examination was not obtained. DISCUSSION Ascites following renal transplantation has been a rare manifestation of intraperitoneal leakage of urine from the new kidney and is treated by surgical repair (7). No evidence of a urinary contribution to the ascitic fluid was found in the present patient (ascitic fluid creatinine levels were nearly identical to plasma levels). The presence of both ascites and edema in this patient suggested avid renal retention of sodium and water as an underlying mechanism of fluid accumulation. While rejection of the allograft was considered a possible explanation, the absence of fever, hypertension, and proteinuria, and the imp r o v e m e n t noted without increasing immunosuppressive therapy did not support this concept. Furthermore, the preponderance of ascites led us to consider disorders which might have contributed to or initiated ascites formation. Other etiologic factors were sought but cardiac, hepatic, pancreatic, and neoplastic disease could not be demonstrated. "Chronic inflammation" of the peritoneum was found on biopsy but no bacterial or granulomatous etiology could be established. Although talc granulomata were not found, we considered the possibility of a chemical irritant as a cause of this transient effusion. We wondered whether our patient's ascites was related to his previous treatment by peritoneal and hemodialysis, since ascites has been described in patients with end-stage renal disease following peritoneal dialysis (5), hemodialysis, or hemodialysis preceded by peritoneal dialysis (6). In these circumstances ascites has been detected shortly after onset of dialysis (4, 5) but also has been noted as long as 6 years later (6). The frequency of ascites in the dialysis setting has varied from 2% to 13% (1, 3). No relationship of ascites to the duration or frequency of dialysis has been apparent. Ascitic fluid in previously reported patients has been variable in character (3-5, 8). Protein con-
138
tent has ranged from 1.2 to 6.3 g/dl with an albumin concentration of 1.8 to 3.3 g/dl. ,White cell counts of 30-1600/mm '~ have been reported. Differential counts have not been described. As many as 3000 red cells/mmz have been seen, although frequently only a few rbc have been noted. Analyses of ascitic fluid for amylase, LDH, malignant cells, and culture for bacteria have been negative. Hypoalbuminemia has been a characteristic feature in patients with dialysis-associated ascites, but primary liver disease does not appear to be responsible for fluid accumulation since liver tests have been normal and liver biopsy has revealed either normal tissue or mild hemosiderosis (4, 5). Important hepatic architectural damage has not been evident and wedged hepatic vein pressure has been normal (5). While the low serum albumin levels may contribute to the development or persistence of ascites, hypoalbuminemia has been occasionally seen in patients on maintenance dialysis without ascites and has not been considered an initiating factor. The pathophysiology of the ascites in these circumstances remains uncertain and treatment has been difficult. Fluid and sodium restriction, steroid administration, intensive dialysis, and hydrostatic ultrafiltration (3, 4t during dialysis have been ineffective, except to the extent that overhydration is present. Albumin infusion and surgical implantation of a peritoneo-a~rial shunt have failed to control fluid accumulation (1). Repeated paracenteses have led to protein depletion; reaccumulation of fluid has been usual. Bilateral nephrectomy has been reported to resolve the ascites associated with cachexia and hypertension in some patients on dialysis (8). Ascites has also resolved "spontaneously" and aft e r a b d o m i n a l s u r g e r y ( c o l e c t o m y or laparotomy) (5). Renal transplantation has been reported to be consistently effective in the resolution of dialysis-associated ascites and has been considered by some investigators to be the ideal treatment (3). The mechanism by which renal transplantation ameliorates ascites is not known. Several authors have hypothesized the presence of nondialyzable uremic toxins which might alter peritoneal membrane transport or capillary permeability (2-4). Such toxins might be excreted or detoxified by the viable kidney transplant. Our patient appears unusual since he was free of ascites during a 7-month period of maintenance dialysis and developed ascites only after renal transplantation. We are aware of one similar case (9) in which ascites occurred 21A Digestive Diseases, Vol. 22, No. 2 (February 1977)
ASCITES FOLLOWING RENAL TRANSPLANTATION years after renal transplantation when renal function was normal. Transudation of fluid from the transplanted kidney directly into the peritoneum was thought to be the mechanism of ascites formation. Whether transudation from the transplant played a role in our patient is uncertain. These two cases, taken together, might argue against the notion that a uremic toxin is responsible. Further study of this phenomenon seems warranted in these unusual patients. SUMMARY
Idiopathic ascites has been described in patients on maintenance peritoneal dialysis and hemodialysis. The mechanism responsible for ascites formation in these patients is unknown, and therapy has been generally unsuccessful. However, renal transplantation has been associated with resolution of this form of ascites. We describe a patient who was free of ascites during maintenance dialysis, in whom ascites developed following renal transplantation associated with transient impairment of renal function. No specific cause of the ascites was found. Resolution of ascites occurred as renal function improved. This experience extends the spec-
Digestive Diseases, Vol. 22, No. 2 (February 1977)
trum of idiopathic ascites in uremic patients to the transplant recipient. REFERENCES 1. Mahoney JF, Gutch CF, Holmes JH: Intractable ascites in chronic dialysis patients. Abstract of the 3rd Annual Meeting of the American Society for Nephrology. 1970, p 51. 2. Mahoney J, Pinggera W, Holmes J, et al.: Ascites during maintenance hemodialysis. Abstract of the 5th International Congress on Nephrology. 1972, p 21. 3. Wang F, Pillay VKG, Ing TS, et al.: Ascites in patients treated with maintenance hemodialysis. Nephron 12:105113, 1974 4. Singh S, Mitra S, Berman LB: Ascites in patients on maintenance hemodialysis. Nephron 12:114-120, 1974 5. Rodriguez H J, Walls J, Slatopolsky E, et al.: Recurrent ascites following peritoneal dialysis. Arch Int Med 134:283287, 1974 6. Arismendi GS, Izard MW, Hampton WR, et al.: Clinical spectrum of ascites associated with maintenance dialysis. Am J Med 60:46-51, 1976 7. Singh S, Aoki S, Mitra S, et al.: Ascites. An unusual manifestation of urinary leak in a renal allograft recipient. JAMA 226:777-778, 1973 8. Feingold LN, Gutman RA, Walsh FX, et al.: Control of cachexia and ascites in hemodialysis patients by binephrectomy. Arch Int Med 134:989-997, 1974 9. Clark WF, Sullivan SN, Lindsay RM, et al.: Ascites secondary to transudation from a renal cadaveric transplant. JAMA 235:635, 1976
139
Ascites Following Renal Transplantation B R U C E R. M A R C E L , MD, R A Y M O N D
S. K O F F , MD, F A C P , and S A N G I N C H O , MD
A small n u m b e r of uremic patients treated with maintenance peritoneal dialysis or hemodialysis have developed ascites (1-5). In some patients ascites has been attributed to the nephrotic s y n d r o m e , Circulatory overload, or inferior v e n a c a v a c o m p r e s sion (6). K n o w n c o m m o n causes of ascites, eg, cardiac, hepatic, pancreatic, and neoplastic diseases, have been excluded in m o s t dialysis patients b y a p propriate studies, and bacterial or tuberculous peritoneal infections have not been implicated. While the precise m e c h a n i s m responsible for the develo p m e n t of " i d i o p a t h i c " or unexplained ascites in this setting is uncertain, a role for uremic toxins has been postulated (2--4). Renal transplantation has been a d v o c a t e d in the m a n a g e m e n t of this disorder (3-4) since other t h e r a p y directed at control of ascites has been unsatisfactory. In this report we describe a patient who was free of ascites during a period of peritoneal dialysis and hemodialysis but, in w h o m , f o l l o w i n g s u c c e s s f u l r e n a l t r a n s plantation, unexplained ascites developed. This experience suggests that ascites in patients with endstage renal failure is not limited to the period of maintenance dialysis and that renal transplantation m a y paradoxically be followed by the d e v e l o p m e n t of ascites.
CASE REPORT The patient is a 59-year-old white man with insulin-dependent diabetes mellitus of 30 years duration. He was treated for pulmonary tuberculosis at age 35. Progressive azotemia due to diabetic nephropathy was recognized 10 years prior to this admission to the Boston VA Hospital. Peritoneal dialysis was begun at this time and two months later he was switched to a program of hemodialysis at inFrom the Medical and Surgical Services, Boston VA Hospital and the Department of Medicine, Boston University School of Medicine. Address for reprint requests: Dr. R.S. Koff, Medical Service, VA Hospital, 150 S. Huntington Ave., Boston, Massachusetts 02130. Digestive Diseases, Vol. 22, No. 2 (February 1977)
tervals of 4--5 days. During this period he had intermittent weight gain, pedal edema, and evidence of early congestive heart failure, all of which resolved completely with each dialysis. Ascites was absent. Five months after beginning hemodialysis, cadaver renal transplantation was performed. Ascites was not present at operation. A brief exacerbation of azotemia occurred postoperatively and subsided spontaneously, He was treated with insulin, prednisone, azathioprine, furosemide, isoniazid, and pyridoxine. Eighteen days after transplantation, while at home, he noted progressive abdominal, scrotal, and lower limb swelling. He had no history of previous ascites, liver or pancreatic disease, or excessive alcohol, fluid, or salt consumption, Examination disclosed an afebrile, noncachetic man with a blood pressure which did not exceed 160/60. The lungs were clear and signs of congestive heart failure were absent. Ascites was striking but there was neither abdominal tenderness nor palpable visceral enlargement. Scrotal edema and moderate edema from the groin to the toes were present. The hematocrit was 27%, and the white cell count was 6,400. The BUN was 68 mg/dl and serum creatinine was 3.8 mg/dl. Total serum protein was 5.4 g/dl with serum albumin of 3.0 g/dl. Serum sodium was 126; potassium 5.8, and chloride 90 mEq/Iiter. The serum bilirubin, serum alkaline phosphatase, amylase, SGOT, LDH, and prothrombin time were normal. Thyroid studies (T4 and T3 resin test) were normal. A 24-hr urine collection contained 460 mg of protein. Multiple urinary protein determinations, on other days, never exceeded this level. Abdominal paracentesis revealed clear straw-colored fluid containing 20 WBC/mm 3 and 52 RBC/mmL Ascitic fluid protein was 1.5 g/dl, and the amylase and LDH levels were within normal limits. Creatinine levels were similar to those obtained in serum. Cytological examination for malignant cells, and cultures of ascitic fluid and peritoneal tissue (obtained by biopsy) for tuberculosis and other bacteria, were negative. Radiologic studies of the chest, barium enema, UGI series, and an inferior vena cavagram were unrewarding, and a technetium liver-spleen scan was within normal limits. Intravenous pyelography revealed a normally functioning allograft kidney. Inferior vena cava pressure was 6 mm Hg, and wedged hepatic vein pressure was 10 mm Hg. A percutaneous needle biopsy of the liver disclosed normal hepatic tissue without fibrosis or cirrhosis. Peritoneal biopsy revealed "chronic inflammation" but granulomas were not seen.
137
MARCEL ET AL During the period of hospitalization the BUN rose to 100 mg/dl and the creatinine peaked at 5.5 mg/dl. Maintenance immunosuppressive therapy with prednisone and azathioprine was not changed. Serum proteins, bilirubin, and SGOT remained normal. Four weeks after admission spironolactone was added to the treatment regimen and the ascites diminished, accompanied by an 8-kg weight loss. At the time of discharge renal function had improved and serum creatinine was 2.0 mg/dl. He remained free of ascites dUring 6 months of follow-up but died suddenly of cardiovascular collapse at another hospital. Permission for post-mortem examination was not obtained. DISCUSSION Ascites following renal transplantation has been a rare manifestation of intraperitoneal leakage of urine from the new kidney and is treated by surgical repair (7). No evidence of a urinary contribution to the ascitic fluid was found in the present patient (ascitic fluid creatinine levels were nearly identical to plasma levels). The presence of both ascites and edema in this patient suggested avid renal retention of sodium and water as an underlying mechanism of fluid accumulation. While rejection of the allograft was considered a possible explanation, the absence of fever, hypertension, and proteinuria, and the imp r o v e m e n t noted without increasing immunosuppressive therapy did not support this concept. Furthermore, the preponderance of ascites led us to consider disorders which might have contributed to or initiated ascites formation. Other etiologic factors were sought but cardiac, hepatic, pancreatic, and neoplastic disease could not be demonstrated. "Chronic inflammation" of the peritoneum was found on biopsy but no bacterial or granulomatous etiology could be established. Although talc granulomata were not found, we considered the possibility of a chemical irritant as a cause of this transient effusion. We wondered whether our patient's ascites was related to his previous treatment by peritoneal and hemodialysis, since ascites has been described in patients with end-stage renal disease following peritoneal dialysis (5), hemodialysis, or hemodialysis preceded by peritoneal dialysis (6). In these circumstances ascites has been detected shortly after onset of dialysis (4, 5) but also has been noted as long as 6 years later (6). The frequency of ascites in the dialysis setting has varied from 2% to 13% (1, 3). No relationship of ascites to the duration or frequency of dialysis has been apparent. Ascitic fluid in previously reported patients has been variable in character (3-5, 8). Protein con-
138
tent has ranged from 1.2 to 6.3 g/dl with an albumin concentration of 1.8 to 3.3 g/dl. ,White cell counts of 30-1600/mm '~ have been reported. Differential counts have not been described. As many as 3000 red cells/mmz have been seen, although frequently only a few rbc have been noted. Analyses of ascitic fluid for amylase, LDH, malignant cells, and culture for bacteria have been negative. Hypoalbuminemia has been a characteristic feature in patients with dialysis-associated ascites, but primary liver disease does not appear to be responsible for fluid accumulation since liver tests have been normal and liver biopsy has revealed either normal tissue or mild hemosiderosis (4, 5). Important hepatic architectural damage has not been evident and wedged hepatic vein pressure has been normal (5). While the low serum albumin levels may contribute to the development or persistence of ascites, hypoalbuminemia has been occasionally seen in patients on maintenance dialysis without ascites and has not been considered an initiating factor. The pathophysiology of the ascites in these circumstances remains uncertain and treatment has been difficult. Fluid and sodium restriction, steroid administration, intensive dialysis, and hydrostatic ultrafiltration (3, 4t during dialysis have been ineffective, except to the extent that overhydration is present. Albumin infusion and surgical implantation of a peritoneo-a~rial shunt have failed to control fluid accumulation (1). Repeated paracenteses have led to protein depletion; reaccumulation of fluid has been usual. Bilateral nephrectomy has been reported to resolve the ascites associated with cachexia and hypertension in some patients on dialysis (8). Ascites has also resolved "spontaneously" and aft e r a b d o m i n a l s u r g e r y ( c o l e c t o m y or laparotomy) (5). Renal transplantation has been reported to be consistently effective in the resolution of dialysis-associated ascites and has been considered by some investigators to be the ideal treatment (3). The mechanism by which renal transplantation ameliorates ascites is not known. Several authors have hypothesized the presence of nondialyzable uremic toxins which might alter peritoneal membrane transport or capillary permeability (2-4). Such toxins might be excreted or detoxified by the viable kidney transplant. Our patient appears unusual since he was free of ascites during a 7-month period of maintenance dialysis and developed ascites only after renal transplantation. We are aware of one similar case (9) in which ascites occurred 21A Digestive Diseases, Vol. 22, No. 2 (February 1977)
ASCITES FOLLOWING RENAL TRANSPLANTATION years after renal transplantation when renal function was normal. Transudation of fluid from the transplanted kidney directly into the peritoneum was thought to be the mechanism of ascites formation. Whether transudation from the transplant played a role in our patient is uncertain. These two cases, taken together, might argue against the notion that a uremic toxin is responsible. Further study of this phenomenon seems warranted in these unusual patients. SUMMARY
Idiopathic ascites has been described in patients on maintenance peritoneal dialysis and hemodialysis. The mechanism responsible for ascites formation in these patients is unknown, and therapy has been generally unsuccessful. However, renal transplantation has been associated with resolution of this form of ascites. We describe a patient who was free of ascites during maintenance dialysis, in whom ascites developed following renal transplantation associated with transient impairment of renal function. No specific cause of the ascites was found. Resolution of ascites occurred as renal function improved. This experience extends the spec-
Digestive Diseases, Vol. 22, No. 2 (February 1977)
trum of idiopathic ascites in uremic patients to the transplant recipient. REFERENCES 1. Mahoney JF, Gutch CF, Holmes JH: Intractable ascites in chronic dialysis patients. Abstract of the 3rd Annual Meeting of the American Society for Nephrology. 1970, p 51. 2. Mahoney J, Pinggera W, Holmes J, et al.: Ascites during maintenance hemodialysis. Abstract of the 5th International Congress on Nephrology. 1972, p 21. 3. Wang F, Pillay VKG, Ing TS, et al.: Ascites in patients treated with maintenance hemodialysis. Nephron 12:105113, 1974 4. Singh S, Mitra S, Berman LB: Ascites in patients on maintenance hemodialysis. Nephron 12:114-120, 1974 5. Rodriguez H J, Walls J, Slatopolsky E, et al.: Recurrent ascites following peritoneal dialysis. Arch Int Med 134:283287, 1974 6. Arismendi GS, Izard MW, Hampton WR, et al.: Clinical spectrum of ascites associated with maintenance dialysis. Am J Med 60:46-51, 1976 7. Singh S, Aoki S, Mitra S, et al.: Ascites. An unusual manifestation of urinary leak in a renal allograft recipient. JAMA 226:777-778, 1973 8. Feingold LN, Gutman RA, Walsh FX, et al.: Control of cachexia and ascites in hemodialysis patients by binephrectomy. Arch Int Med 134:989-997, 1974 9. Clark WF, Sullivan SN, Lindsay RM, et al.: Ascites secondary to transudation from a renal cadaveric transplant. JAMA 235:635, 1976
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