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Review: Diagnosis, Pathogenesis, and Treatment of Hepatorenal Syndrome in Patients With Cirrhosis

Hepatorenal syndrome (HRS), a frequently fatal complication of decompensated cirrhosis, is difficult to evaluate due to challenges in assessment of glomerular filtration rate and level of renal dysfunction. In the February issue of Clinical Gastroenterology and Hepatology Ayse L. Mindikoglu and Stephen C. Pappas review strategies for diagnosis and assessment of renal function in patients with cirrhosis. They summarize new concepts and developments in the diagnosis, epidemiology, pathophysiology, and treatment of HRS, focusing on HRS type 1.

In patients with cirrhosis, renal vasoconstriction progresses from the main renal artery (hilum), toward the interlobar arteries (renal medulla), and finally affects the arcuate (junction of renal medulla and cortex) and interlobular arteries (renal cortex). There is an inverse relationship between renal blood flow (RBF) and the renal resistive index (RI). When RBF decreases, the renal RI increases. Although patients without ascites and with diuretic-sensitive ascites preserve cortical renal blood, patients with diuretic-refractory ascites have a substantial reduction in cortical renal blood flow. So, although there is a renal RI gap between interlobar and cortical arteries in patients with cirrhosis without ascites and with diuretic-sensitive ascites, this RI gap disappears, due to an increase in interlobar and cortical RIs in patients with cirrhosis and diuretic-refractory ascites. Cortical ischemia is an important feature of cirrhosis and diuretic-refractory ascites and HRS.

HRS is characterized as renal dysfunction secondary to a reduction in renal blood flow in patients with cirrhosis and portal hypertension, and associated with a decrease in glomerular filtration rate (GFR). HRS can be classified as either rapidly developing acute kidney injury (HRS type 1; median survival time, 1 month), or slowly progressive chronic kidney disease (HRS type 2; median survival, 6.7 months). 

Mindikoglu and Pappas explain that it has been a challenge to establish when renal dysfunction occurs in patients with cirrhosis, the utility of serum level of creatinine and other renal biomarkers, the most accurate criteria for diagnosis, and the efficacies of pharmacologic and other therapies.

Although serum levels of creatinine are lower in patients with cirrhosis, the authors explain that this is not an accurate marker of renal dysfunction in these patients. They discuss other methods to assess renal function, such as by measuring GFR, which is expensive, time consuming, and labor intensive, or directly measuring creatinine clearance, which is prone to logistical errors and impractical for critically ill patients with end-stage liver disease. Recently developed GFR equations include measurements of the renal biomarker cystatin C.

Increased renal resistive indices in hilar, medullary, and cortical areas on duplex Doppler ultrasonography and disappearance of the gap between interlobar and cortical resistive indices can indicate a reduction in renal blood flow and serve as a marker of HRS type 1 or HRS type 2 (see figure).

Mindikoglu and Pappas review urinary markers of acute kidney injury and blood biomarkers of renal function that have been evaluated in patients with cirrhosis to estimate GFR, renal plasma flow, and renal resistive indices. Staging systems have been developed to evaluate acute kidney injury in patients with cirrhosis. Biomarkers detected by metabolomic profiling analyses might be used to detect renal dysfunction in patients with cirrhosis, allowing early diagnosis of HRS, prediction of response to HRS treatment, or native kidney recovery after liver transplantation.

In patients with cirrhosis, reduced renal blood flow has been attributed to alterations in production of nitric oxide. HRS has also been associated with infections, systemic inflammatory response syndrome, bile cast nephropathy, and proximal tubulopathy.

Treatment of HRS with vasopressors, such as terlipressin and norepinephrine, are effective in improving renal function, although more effective strategies to reduce HRS are needed. By decreasing portal venous pressure,  terlipressin improved renal function and reversed HRS in a higher proportion of patients with HRS type 1 than albumin plus placebo.

Mindikoglu and Pappas provide a table of meta-analyses that have evaluated the effectiveness of vasoconstrictors in patients with HRS and their effects on mortality. Their review also provides a treatment algorithm. They also discuss renal replacement therapy, transjugular intrahepatic portosystemic shunts, and molecular adsorbent recirculating system.

Liver transplantation is the definitive treatment for HRS; the challenge is to identify patients who require simultaneous liver–kidney transplantation vs only liver transplantation. The authors conclude that practical, robust, evidence-based algorithms to predict native kidney recovery after liver transplantation are an important yet unmet medical need.


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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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