I Have Been Increasing the Dose of Diuretics in My Patient With Ascites Over Several Weeks. He Still Has Ascites but Has Now Developed an Elevation in Serum Creatinine to 2.0 mg/dL. What Should I Do?
Rising creatinine in the cirrhotic patient with ascites is a potentially ominous finding. It requires immediate attention to identify and address the underlying cause. Six possible explanations should be considered in this situation.
First, azotemia may simply reflect overaggressive diuresis of cirrhotic ascites. Studies in the 1960s by Gabuzda and colleagues demonstrated that the maximum rate of absorption of ascites from the peritoneum is on the order of 500 mL per day.1 While peripheral edema is present, diuresis can proceed rapidly, since tissue fluid can be mobilized quickly. Once edema has cleared, however, continued aggressive diuresis may lead to significant contraction of the circulating volume with reduced renal perfusion and prerenal azotemia. Cessation of diuretics, perhaps with a brief infusion of saline or albumin, usually will reverse the azotemia, after which diuretics can be resumed at a lower dose.
Second, the patient’s ascites may not be due to cirrhosis. Not all ascites in the cirrhotic patient is cirrhotic ascites. Patients with cirrhosis may develop ascites for other reasons, including nephrotic syndrome, congestive heart failure, hypothyroidism, chronic pancreatitis, tuberculosis, or malignancy. Current guidelines recommend that a diagnostic paracentesis be performed at the time that ascites first becomes manifest.2 Cirrhotic ascites is characterized by a low total protein concentration with serum-ascites albumin gradient (SAAG) greater than 1.1 g/dL; if paracentesis confirms this picture, then further diagnostic evaluation usually is unnecessary. Ascites fluids with high protein content and low SAAG reflect exudative processes such as cancer or infection; ascites in these conditions typically does not resolve with diuretic therapy. Treatment should be addressed at the underlying disease, with palliative large volume paracentesis as needed.
Third, a renal insult may have occurred. Cirrhotics are particularly susceptible to nephrotoxicity of nonsteroidal antiinflammatory drugs; these should be sought out and discontinued. Oral neomycin given for suppression of encephalopathy can be absorbed across the cirrhotic gut in sufficient quantities to cause renal failure. Intravenous contrast given for liver imaging studies (computed tomography, angiography) may contribute. Cirrhotics may also have intrinsic renal disease, either related to the cause of their liver disease (immune complex glomerulonephritis in hepatitis B or C, diabetic nephropathy in nonalcoholic steatohepatitis) or due to unrelated conditions such as multiple myeloma. The possibility of obstructive nephropathy from nephrolithiasis, prostatic hypertrophy, or urinary tract cancers also should be considered. Indicators suggestive of intrinsic renal disease include a high fractional excretion of sodium or the finding of leukocytes, blood, or protein on urinalysis. Imaging of the kidneys, ureters, and bladder with ultrasound or computed tomography (CT) and measurement of a postvoid residual may be indicated if obstruction is suspected.
Fourth, the patient’s renal perfusion may be compromised by hypotension resulting from infection or hemorrhage. In particular, spontaneous bacterial peritonitis may present insidiously as deterioration of renal function in the cirrhotic patient. Absorption of endotoxin aggravates the generalized vasodilatation of cirrhosis and leads to reduced renal perfusion. Other findings supporting a diagnosis of infection include fever, abdominal pain, deterioration of liver function, and elevation of circulating white blood cells above the patient’s baseline. If there is any question of infection, the patient should undergo diagnostic paracentesis, as well as culture of blood and urine, and antibiotic therapy should be initiated. The patient should also be given albumin to expand the circulating volume; this measure is effective in preventing progressive renal failure in patients with spontaneous bacterial peritonitis.3
Fifth, the patient’s ascites may have become refractory to medical therapy. The term refractory ascites is reserved for cases in which either (a) ascites persists despite maximal therapy with diuretics and salt restriction, or (b) ascites persists because patients cannot tolerate maximal diuretic therapy secondary to development of azotemia or hyponatremia.4 Refractory ascites occurs in 5% to 10% of all patients with cirrhosis and is a poor prognostic sign, indicative of impending terminal decompensation; at least 50% will die within 1 year. If accompanied by hyponatremia or azotemia, the prognosis is even worse. Management options include liver transplantation, serial large volume paracentesis (LVP), transjugular intrahepatic portasystemic shunt (TIPS), or peritoneovenous shunt.5 Of these, only liver transplantation has been shown to improve survival. TIPS may be useful for mobilizing ascites in patients with well-preserved hepatic function but risks aggravating hepatic encephalopathy.6 Large volume paracentesis provides palliative benefit and usually will not aggravate azotemia, provided that the patient receives intravenous albumin concurrently (see Question 42).
Sixth and finally, the patient may be developing hepatorenal syndrome. This serious complication of end-stage liver disease occurs almost exclusively in patients with ascites. It is characterized by renal cortical vasospasm and reduced glomerular filtration rate with elevated serum creatinine. Fractional excretion of sodium is low. The condition fails to normalize with volume expansion. The underlying trigger appears to be an extreme renal cortical vasospasm in response to systemic vasodilatation with hypotension, as well as unknown circulating vasoactive toxins. Two general patterns are recognized. Type II hepatorenal syndrome is characterized by persistent stable creatinine elevation that may persist for many months; creatinine clearance may fluctuate with changes in circulating volume but does not normalize. Type I hepatorenal syndrome is characterized by hypotension and rapidly progressive azotemia with oliguria, leading to uremia; unless it can be reversed immediately, patients usually die within weeks. Type II hepatorenal syndrome is managed as refractory ascites. Type I hepatorenal syndrome can sometimes be corrected by aggressive intervention with volume expansion (typically albumin), vasoconstrictors (midodrine plus octreotide, terlipressin, norepinephrine drip), as well as antibiotics. If these measures fail, urgent liver transplantation is required. Hemodialysis may be useful as a bridge to transplantation.
In a case such as the one described, we would discontinue diuretics. We would send urine for sodium, creatinine, and urinalysis and would also send blood for liver tests, electrolytes, complete blood count, and coagulation studies. We might give an intravenous infusion of saline or albumin. If history and physical showed no sign of infection or deteriorating liver function, we would consider outpatient management with frequent follow-up (generally at daily intervals until clear improvement is seen). However, if there is evidence of infection or deteriorating liver function, or if the patient’s renal function fails to respond immediately to these conservative measures, we would hospitalize for further diagnostic evaluation and therapy.
Any patient with cirrhotic ascites, particularly one who has experienced azotemia, should be evaluated for liver transplantation.7 If no contraindication to transplantation is identified, the patient should be referred to a transplant center for listing. Creatinine is one of the components of the model for end-stage liver disease (MELD), the prognostic model used to allocate organs for liver transplantation in the United States.8 Cirrhotic patients with significant azotemia usually have high MELD scores and receive high priority for transplantation.
1. Shear L, Ching S, Gabuzda GJ. Compartmentalization of ascites and edema in patients with hepatic cirrhosis. N Engl J Med. 1970;282:1391-1396.
2. Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology. 2004;39:841-856.
3. Bass NM. Intravenous albumin for spontaneous bacterial peritonitis in patients with cirrhosis. N Engl J Med. 1999;341:443-444.
4. Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology. 1996;23:164-176.
5. Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology. 2003;38:258-266.
6. Sanyal AJ, Genning C, Reddy KR, et al. The North American Study for the Treatment of Refractory Ascites. Gastroenterology. 2003;124:634-641.
7. Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005;41:1407-1432.
8. Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology. 2007;45:797-805.