A 58-Year-Old Man With Worsening Symptoms of Cirrhosis and Renal Function

ANSWER: C. Initiate 25% albumin infusions, 1 gm/kg per 24 hours in divided doses.

Discussion. The patient presented with an advanced cirrhosis with ascites. He not only seems to be clinically deteriorating due to his liver disease, but he also shows a deterioration in his renal function. Previously, this constellation of findings would be termed "hepatorenal syndrome" (HRS), a dreaded complication most often ending in death. Currently, a rapid deterioration in renal function is termed "acute kidney injury" (AKI), which still has the traditional differential diagnosis of renal hypoperfusion (prerenal), intrinsic kidney injury, and postrenal or obstructive renal failure. In recent years, the finding of AKI in the subset of patients with cirrhosis has been given its own set of definitions: an acute form, where a previously normal creatinine rather quickly worsens within a series of days is termed HRS Type I, and a more chronic deterioration of renal function in a cirrhotic over the course of several months is termed HRS Type II.¹ Specific parameters for HRS Type I are an absolute rise in creatinine of more than 0.3 mg/dL within 48 hours or an increase in creatinine by 1.5X baseline level or urinary output of less than 0.5 ml/kg for 6 hours.² The presented patient's last known creatinine was 0.6 mg/kg, but on current admission his creatinine is 1.9 mg/kg, which fulfills the new definition of HRS Type I.

The initial creatinine change suggests AKI. Appropriate workup needs be performed for what are hopefully reversible causes, such as infection/sepsis, bleeding. The history does not suggest any of these were present. There was no melena/hematemesis, no fever, the ascites cell count was low, there had been no changes or increase in diuretics nor introduction of nephrotoxic antibiotics or NSAIDs. Thus, it is quite reasonable to assume that we are dealing with the onset of HRS Type I. A helpful finding would be demonstrating fractional excretion of sodium less than 1% (usually even less so) showing intense sodium retention, which can be quickly performed early on.² And within the initial 24 hours, accurate urinary output and serial creatinine levels should demonstrate and confirm the diagnosis of HRS Type I.

Managing this patient population is challenging because the therapeutics in patients with AKI-I HRS are somewhat limited with inconsistent effectiveness. The best treatment option for AKI-I HRS is volume expansion, despite the presence of ascites, which needs be pushed to the point of pulmonary congestion even though the total body sodium and water overload often manifest at presentation. Despite the presence of ascites and even edema, there is decreased effective circulating blood volume due to the vasodilation in the splanchnic circulation. Any volume depleting maneuver is thus contraindicated, which makes answers A (large volume paracentesis) and B (more aggressive diuresis) incorrect.

The standard of care currently involves volume expansion using 20% to 25% albumin, 1 gm/kg (100 gm/day max) in divided doses looking for decreasing creatinine and increase urine volumes as markers of response.³ The use of vasoconstrictor drugs in the vasopressin family, like octreotide, have been used and there is encouraging data on another agent, terlipressin, which is not yet FDA approved or available in the United States.^4,5 For now, vasopressin analogues seem to acutely improve numbers when combined with volume expansion, but no long-term survival benefit has been shown as yet.^4,5 As to the role of renal replacement therapy, these patients are essentially too fragile and unstable for standard dialysis. Additionally, dialysis does not change the outcome unless as a bridge to hepatic transplantation. Techniques of "life supportive treatments for renal failure" include continuous hemofiltration and intermittent hemodialysis, which are used as a bridge to the one therapy in AKI-I HRS that is effective: hepatic transplantation.^1,2 The precise role and timing belong to attending nephrologists ,but to initiate them so early in the therapeutic protocol, makes Answer D incorrect. The best answer here is C: volume expansion with albumin infusions.

The pathophysiology of hepatorenal syndrome, as with so many things in nephrology, is elegant and complex. We can try to concentrate the basic facts into a concise and understandable digest. The baseline underlying HRS is portal hypertension due to cirrhosis. The hepatic circulation is placed under increased pressure due to intrahepatic fibrosis with subsequent obstruction to portal flow. 

A key landmark finding in patients with liver disease is the onset of ascites, which is related to the increased splanchnic pressures and the resulting vasodilation. Secondary to these pressure changes is the activation of vasodilators involving not only the splanchnic circuits but also the systemic circulation. An imbalance occurs between the capacitance and blood volume such that effective circulating blood volume is inadequate to sustain a good pressure in the systemic circulation. Then, further responses to this pathophysiology become even more counterproductive. The body senses diminished circulating blood volume and glomerular filtration rate (GFR) falls triggering activation of the renin-angiotensin system (with diminished renal glomerular blood flow resulting), profound sodium and water retention with the clinical correlates of worsening/refractory ascites and pre-renal injury-in short AKI Type I or HRS.

This diagnosis requires changes in renal function (decreasing GFR, rising creatinine, scant urine output and profound sodium retention) and is often clinically obvious once the HRS process has started. As with all AKI situations the usual other suspects and complicating insults must be excluded. So, traditional pre-renal causes of inadequate volume such as overuse of diuretics, GI bleeding, or a systemic inflammatory response as with infection such as spontaneous peritonitis in these ascites patients must be excluded or addressed. Intrarenal pathology from drugs such as antibiotics and NSAIDs is another reversible cause for renal deterioration in any patient with renal failure. Finally, obstructive uropathy is an easily excludable situation. Finding and reversing one of the above is the best hope for a good outcome in this patient population.

What’s The Take Home? A rapidly deteriorating renal function is now referred to as acute renal injury-AKI. Always a most worrisome event, the finding of AKI in a patient with advanced cirrhosis is an extremely dangerous and life-threatening situation, which is often compounded by the difficulty in management due to the variety of additive and conflicting multiorgan pathophysiologies. The current definition of AKI in a patient with cirrhosis and ascites involves an increase in creatinine of more than 1.5X baseline level or urine output less than 0.5 ml/kg for 6 hours. A still useful term for such patients by generalists is "hepatorenal syndrome” although nephrologists have subclassified variants of the syndrome. 

The core and net result of pathogenesis is a vasodilation within the splanchnic circulation resulting in reduction of effective blood volume systemically. A renal response to the diminished perfusion is a profound sodium and water retention and decreased GFR. hepatorenal syndrome is still a default diagnosis of exclusion and reversible alternative or additive causations must be entertained and excluded. These include sepsis/infection, nephrotoxic medications, IV contrast, and actual hypovolemia as with GI bleeding. Once HRS has been determined as the primary diagnosis, the core therapeutic is volume expansion, 25% albumin dosed at 1 gm/kg per 24 hours in divided doses. Recent studies indicate that careful use of vasoconstrictor drugs from the vasopressin family are effective and additive in HRS, at least acutely. However, HRS remains a very dangerous and difficult complication with high mortality. Very often the only meaningful long-term solution in these patients is liver transplantation. An example mortality figure in the literature is median survival 1.7 weeks and 90% mortality at 10 weeks.⁵

Patient follow-up. The patient was admitted to the ICU for ongoing monitoring and care. He received albumin infusions for the initial 24 hours and tolerated them with experiencing signs or symptoms of CHF. Blood and ascites cultures were negative. However, urine out remained sparse. Fractional excretion of sodium was less than 0.1% and creatinine level increased again to 2.8 mg /dL. His blood pressure remained in the 95/70 range. On day 3, more albumin infusions were administered and so we started with octreotide. Again, no signs or symptoms of chronic heart failure/pulmonary congestion were found but mental confusion and asterixis were noted. Urine output was less than 500cc/24 hours and creatinine rose to 4.1 mg/dL. Discussions of hepatic transplantation occurred but his recent and ongoing alcohol use rendered him a non-candidate for the procedure. Despite ongoing supportive measures, the clinical course was progressively downhill with daily worsening of mental function and creatinine. The patient died on day 11 of hospitalization.

AFFILIATIONS:
¹Lewis Katz School of Medicine at Temple University, Philadelphia, PA
²Department of Medicine, Temple University Hospital, Philadelphia, PA
³Watertown Nephrology Associates, Watertown, NY

CITATION:
Rubin RN, Rubin AM. A 58-Year-Old Man With Worsening Symptoms Of Cirrhosis And Renal Function. Consultant. 2023;63(8):eX. doi:10.25270/con.2023.08.000008.

DISCLOSURES:
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)