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Hepato-renal syndrome is a major complication of decompensated cirrhosis, entailing significant morbidity and mortality in the absence of liver transplant. It still remains a clinical diagnosis of exclusion due to lack of specific diagnostic markers. It is classified as either rapidly developing acute kidney injury (AKI) HRS type 1 or slowly developing chronic kidney disease (CKD) type 2. Both types of HRS are associated with significant decrease in renal blood flow and GFR. The median survival after diagnosis is roughly 1 month for HRS type 1 and 6.7 months for HRS type 2.(1)
History and Pathophysiology
The association of fulminant renal failure with the diseases of liver and biliary system has been known for more than a century and has been reported in Literature. In fact, it came to be known as Austin Flint or Heyd’s syndrome.(2) after the names of the surgeons who reported it in various case series.
HRS is a manifestation of extreme circulatory dysfunction in patients with cirrhosis. In compensated cirrhosis, the portal hypertension triggers an increase in production or activity of vasodilatory factors such as nitric oxide, carbon monoxide and endogenous cannabinoids leading to arterial vasodilation, particularly in the splanchnic bed. The resultant decrease in systemic vascular resistance is compensated by increased cardiac output in the initial stages of cirrhosis, permitting the effective arterial blood volume and pressure to remain within normal limits. In advanced stages of cirrhosis, the decrease in SVR becomes profound and an additional increase in cardiac output is not sufficient to maintain effective arterial volume. As a result, the renal Renin-angiotensin-aldosterone axis, the sympathetic system and in later stages, the non-osmotic hypersecretion of arginine vasopressin get activated. This leads to sodium and solute free water retention causing ascites and oedema and eventually to renal failure due to intense renal vasoconstriction.(3)
Renal cortical ischemia is the hall mark of HRS. Renal vasoconstriction in cirrhosis progresses from the main renal artery (hilum), toward the interlobar arteries (renal medulla), and finally the arcuate (junction of renal medulla and cortex) and interlobular arteries (renal cortex). Although patients without ascites and with diuretic-sensitive ascites preserve cortical renal blood flow, patients with diuretic refractory ascites and HRS have a substantial reduction in cortical renal blood flow.(4)
Diagnosis and new definitions
Classically, acute renal failure in cirrhosis was defined as an increase in serum creatinine (sCr) levels of ≥ 50% from baseline to a final level above 1.5 mg/dL (133μmol/L), and classical definition of HRS type-1 was doubling sCr levels over 2.5 mg/dL or 220 μmol/L within 2 wks. But cirrhotic patients are different than general population in that they have significant muscle wasting and reduced muscle mass and hence have decreased creatinine production. They also have increased tubular secretion of creatinine leading to overestimation of renal function by GFR. Furthermore, hyperbilirubinemia and haemolysis also interfere with accurate measurement of creatinine. Urine output is also not a reliable measurement of renal function in cirrhosis as many patients have low urine output due to hypersecretion of arginine vasopressin and may still have normal renal function. The studies on AKI in patients with cirrhosis have shown that AKI defined by an absolute increase in sCr P0.3 mg/dl (26.5 Umol/L) and/or P50% from baseline is associated with a higher probability of the patients being transferred to the intensive care unit, a longer hospital stay, and an increased in-hospital as well as 90-day and mid-term mortality. (5)
Combining the emerging evidence and consensus of the experts, the International club of ascites revised the criteria of AKI in patients with cirrhosis (type-1 HRS) in 2015. In the new definition, AKI was defined as a sCr increase of ≥ 0.3 mg/dL (26.5 umol/L) within 48 h or of ≥ 50% from baseline within 7 days. Three stages of AKI and responses to treatment were also defined. The use of urine output as one of the criteria was removed since it doesn’t apply to patients of cirrhosis. The implementation of the new criteria is to allow earlier treatment of patients with type-1 HRS, which may lead to a better outcome instead of having to wait until the sCr reaches ≥ 2.5 mg/dL. Other diagnostic criteria are the following: (1) diagnosis of cirrhosis and ascites; (2) diagnosis of AKI according to ICA-AKI criteria; (3) no response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g/kg of body weight); (4) absence of shock; (5) no current or recent use of nephrotoxic drugs (NSAIDS, aminoglycosides, iodinated contrast media, etc.); and (6) no macroscopic signs of structural kidney injury, defined as absence of proteinuria (> 500 mg/d), absence of microhematuria (> 50 RBC/HPF) and normal findings on renal ultrasound. (5)
The main change adopted in the new definition of HRS is the removal of a rigid and high cut-off value of sCr (2.5 mg/dL or 220 μmol/L) to start pharmacologic treatment. In this way, treatment can be administered early and potentially better results can be achieved. However, these clinical criteria do not allow differentiation between HRS and structural renal disease, which is extremely important because vasoconstrictors will not be effective in parenchymal renal disease and could even worsen the renal dysfunction. Thus, there is a huge interest in developing urinary biomarkers to help in the differential diagnosis of HRS.(5)
Novel Urinary biomarkers
Although several new blood and urinary AKI biomarkers have been identified recently, none is available to diagnose HRS superimposed on other AKI aetiologies (prerenal azotaemia, ATN etc.). Neutrophil gelatinase-associated lipocalcin (NGAL), Interleukin-18, Liver-type fatty acid binding protein (L-FABP), Kidney injury molecule-1, Toll-like receptor 4, π-glutathione S-transferase and α-glutathione S-transferase are a few which have been studied. Among all of them, current data show that NGAL is the most useful marker. It detects patients with acute tubular necrosis (ATN) but is not helpful to differentiate between pre-renal azotaemia and HRS. NGAL urinary levels are much higher in patients with ATN compared to patients with other causes of AKI. Going forward, incorporating NGAL into the clinical decision algorithm could be of benefit to rule out structural kidney injury and detecting a group of patients in whom treatment with vasoconstrictors wouldn’t be effective and could make the renal function worse.(6)
Vasoconstrictor Drug Treatment
Once the diagnosis of AKI–HRS is established, the vasopressin analogue Terlipressin is considered the first line vasoconstrictor drug in the treatment. It is administered initially at a dose of 0.5 to 1 mg IV bolus, every 4 to 6 hours; with maximum dose, up to 2 mg IV bolus every 4 to 6 hours if there is less than a 25% reduction in serum Cr level after 3 days and no side effects occur. Terlipressin should be discontinued after a maximum of 14 days of treatment if there is no improvement in renal function. (7, 8, 9 ,10)
Octreotide, a somatostatin analogue in combination with midodrine, an a-adrenergic agonist, is also recommended for the treatment of HRS type I. It is administered as 100 to 200 mcg s/c every 8 hours. Midodrine is administered as 7.5 mg orally 3 times a day up to 12.5 mg orally 3 times a day; the dose should be titrated to achieve an increase of 10-15 mm Hg in mean arterial pressure.
Noradrenaline, can also be used for the treatment of HRS type 1 especially in ICU setting where cardiac monitoring is available. It is administered at 0.5 to 3 mg/h continuous IV infusion, to achieve an increase of 10 mm Hg in mean arterial pressure.
Several meta-analyses have evaluated the effectiveness of vasoconstrictors for reversal of HRS. All of these studies showed that Terlipressin was significantly superior to placebo with or without albumin. Comparisons of Terlipressin with noradrenaline and noradrenaline with octreotide plus midodrine did not show any significant difference in reversing HRS although Terlipressin was significantly more efficacious in reversing HRS compared with octreotide plus midodrine. Albumin should be given in combination with any of the vasoconstrictor drug regimens. The recommended dose is 20 to 40 g IV once daily after the initial dose of 1 g/kg/d for 2 days. The additive effects provided by vasoconstrictors and albumin infusion improve outcome compared to monotherapy with either agent. A meta-analysis has demonstrated that increments of 100 g in cumulative albumin dose were associated with a significantly increased survival, which provides evidence on the important role of albumin dose in improving outcome of treating HRS.(11)
Many Meta-analyses have also evaluated drug therapies for mortality reduction without liver transplantation and have failed to show any survival benefits. Although meta-analyses have showed that there was no survival superiority of Terlipressin over noradrenaline, Terlipressin was shown to be more economical compared with noradrenaline in the treatment of HRS.
Renal Replacement Therapy and Trans- jugular Intrahepatic Portosystemic Shunt
Non-vasoconstrictor treatment of HRS includes renal replacement therapy and transjugular intrahepatic portosystemic shunting. Although randomized–controlled trials have failed to demonstrate a survival benefit of renal replacement therapy (RRT) for HRS-AKI and HRS type 2, continuous RRT use may, however, be advantageous in patients who are hemodynamically unstable or at risk of elevated intracranial pressure. It should also be considered in patients with irreversible HRS with no response to vasoconstrictor drugs, particularly in the presence of intractable fluid overload and acidosis, uremic symptoms, and electrolyte abnormalities. ( 12,13,14,15)
Although transjugular intrahepatic portosystemic shunting generally is contraindicated in patients with unresolved HRS type 1, it is shown to reduce the risk of HRS in patients with cirrhosis and diuretic-refractory ascites (HRS type -2). There are few small trials showing improvement on renal function and deactivation of vasoconstrictor system, i.e., reduction in levels of renin, aldosterone and noradrenaline after TIPS insertion. However, data is very limited to recommend the use of this risky procedure in clinical practice.(16)
Liver Transplantation Alone (LTA) Versus Simultaneous Liver–Kidney Transplantation (SLKT)
Liver transplantation, when available, is treatment of choice for HRS type 1. It reverses liver dysfunction and portal hypertension. Patients with HRS have high morbidity, longer ICU and hospital stay, longer RRT requirements and worse survival expectancy at one year. It is considered a factor of poor prognosis independently from MELD score. Furthermore, there is evidence that structural injury to the renal tubules occur early in the course of HRS-1 and the longer the patient is awaiting the transplant and suffering from HRS the higher the risk of not recovering their renal function or even requiring a renal transplant after LT. Currently, there is no general consensus about prioritization of patients with HRS awaiting a LT. Shortage of donor organs is also a significant problem. (17,18)
SLKT is the procedure of choice if native kidney recovery is not expected after LTA. Identifying patients who will require SLKT vs LTA remains a major challenge. The eligibility criteria have been revised in 2017. However, these criteria show large variations among liver transplant centres in terms of applicability in the United States. The percentage of adult SLKTs among all adult deceased donor liver transplants in the United States has increased by 150%; from 4% in 2002 to 10% in 2016. (19,20,21)
HRS can be prevented in different clinical scenarios. The first one is in the setting of Spontaneous Bacterial Peritonitis. HRS can be prevented with primary antibiotic prophylaxis and treatment of SBP. The deleterious effect on circulatory dysfunction produced by SBP can be prevented by early treatment with antibiotics and volume expansion with albumin. HRS can be prevented after large volume paracentesis (LVP) by administering albumin at a dose of 6-8 g per litre of ascites removed, to prevent worsening of circulatory dysfunction, and thus minimize the impact on electrolytes, creatinine and renin levels. Volume expansion with albumin also improves survival after LVP and it is recommended by international societies.
HRS is a major complication of decompensated liver cirrhosis. It carries a high short-term mortality rate. Current definition is based on clinical grounds and has been recently modified adopting AKI definition. Recent data on urinary NGAL show it is useful to differentiate acute tubular necrosis and should be incorporated in the diagnostic algorithm of HRS. Terlipressin and noradrenaline, both with albumin are the only effective treatment currently available and reversal rate is only 40%-50% of cases. Data on predictors of response to treatment suggest that treatment should be started as early as possible. In this sense, ICA new definition of HRS allows an early diagnosis. New treatments should be tested for this life-threatening condition. Liver Transplant is the only curative treatment and should be always considered though new data on SLKT is emerging.