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Renal Failure in Adults
Orthotopic liver transplantation (OLT) is a well-established definitive treatment for patients with chronic advanced cirrhosis or acute fulminant hepatic failure and a viable therapeutic option for those with primary resectable hepatic malignancies with or without cirrhosis. Over the past decade more than 6000 such transplants were performed in the United States annually. Whereas the demand for liver transplantation has steadily increased, the supply of deceased donor organs has remained relatively constant. As a result, an increasing percentage of wait-listed patients either died or developed various complications while awaiting transplantation. The pretransplant evaluation process therefore requires careful and continued assessment of the patient’s pulmonary, cardiac, and renal function. This chapter describes a systematic approach to the evaluation of renal dysfunction and electrolyte and acid-base disturbances complicating the course of advanced liver disease, the pathogenic mechanisms and current recommendations for the treatment of hepatorenal syndrome (HRS), and the indications for combined liver and kidney transplantation. Acute kidney injury (AKI) and chronic kidney disease (CKD) of diverse causes continue to be important sources of morbidity and mortality both in the immediate and long-term postoperative period. The potential intraoperative and perioperative factors contributing to postoperative AKI, the long-term consequences of AKI or CKD after transplantation, and the impact of AKI or CKD on ultimate allograft and patient survival are also reviewed.
Assessment of Renal Function in End-Stage Liver Disease Patients Awaiting Liver Transplantation
Early recognition of renal dysfunction in patients with end-stage liver disease (ESLD) can be challenging because assessment of renal function based on serum creatinine (SCr) level or estimating glomerular filtration rate (GFR) using creatinine-based equations (e.g., Cockcroft-Gault formula) has been shown to overestimate true GFR to variable degrees in this patient population. Reduced muscle mass, protein-poor diet, severe hyperbilirubinemia, and diminished hepatic biosynthesis of creatine, a substrate for skeletal muscle production of creatinine, can all contribute to a falsely low SCr level. In addition, volume overload from aggressive fluid administration in hypotensive patients may cause a dilutional effect, normalizing the measured SCr concentration. Similar to patients with CKD of other causes, cirrhotic patients with renal insufficiency have a relatively increased fraction of tubular creatinine secretion to filtration compared to those with normal renal function. Consequently, the SCr level is falsely low in the setting of renal impairment, and assessment of renal function using creatinine-based equations leads to overestimation of GFR. Although the Modification of Diet in Renal Disease (MDRD) formula has been suggested to have better precision than other currently available formulas (e.g., Cockcroft-Gault formula or the Nankivell equation) in estimating GFR in liver transplant recipients, the MDRD equation has been shown to underestimate GFR measured by the gold standard of iothalamate clearance. More recently cystatin C has been suggested to be a better marker for renal function in cirrhotic patients because it is independent of muscle mass. However, cystatin C has been shown to vary with age, ethnicity, gender, inflammation, sepsis, steroids, and thyroid disease and is not yet readily available in many centers. Although more costly and complicated, traditional studies evaluating the renal clearance of inulin or radioisotopes such as iothalamate sodium I 125 or chromium Cr 51 ethylenediaminetetraacetic acid remain the gold standard for evaluating renal function in liver patients.
The second challenge in the management of AKI in ESLD patients is diagnosing the cause of the renal dysfunction. Besides the subset of patients with simultaneous kidney-liver diseases, almost all ESLD patients are commonly exposed to therapies and clinical circumstances that place them at high risk for developing AKI. ESLD patients are commonly exposed to multiple renal insults, including invasive diagnostic procedures, multiple imaging studies requiring nephrotoxic dyes, nephrotoxic medications, urinary tract manipulations causing recurrent urinary tract infection and obstruction, and therapies leading to volume depletion and subsequent prerenal AKI. The differential diagnosis of AKI in ESLD patients is not infrequently made more complicated by the potential development of the well-described hepatorenal syndrome. Despite the challenge involved, determination of the cause of AKI is necessary for short-term management, determination of prognosis and long-term survival, and evaluation for combined kidney and liver transplantation (CKLT).
Causes of Acute Kidney Injury before Orthotopic Liver Transplantation
Acute Kidney Injury as an Entity Independent of the Cause of End-Stage Liver Disease
As in patients without liver disease, the causes of AKI in ESLD patients can be classified as prerenal, intrinsic renal, and postrenal AKI. The initial evaluation should include a complete history and thorough chart review focusing on the recent use of nephrotoxic medications, imaging studies using contrast agents, excessive use of diuretics or large-volume paracentesis, and evidence for renal or gastrointestinal fluid losses. Physical examination should focus on volume status; sources of fluid losses, including insensible fluid losses; possible urinary tract obstruction; and Foley catheter patency. Laboratory examination should include a routine urinalysis, measurement of urine electrolyte levels, a urine eosinophil count, a complete serum electrolyte panel, and a renal ultrasound examination ( Fig. 74-1 ). Although prerenal and postrenal AKI can often be diagnosed based on clinical grounds or imaging studies or both, intrinsic kidney injury can be difficult to diagnose clinically. A kidney biopsy may be recommended when the renal diagnosis is obscure or when the degree of irreversibility of kidney injury cannot be determined based on clinical and laboratory evidence. For those patients in whom a severe coagulopathy makes a percutaneous core needle biopsy unsafe, either a transjugular venous approach or an open kidney biopsy may be considered.
Prerenal Acute Kidney Injury
Prerenal AKI in ESLD patients is frequently multifactorial and may be due to true volume depletion, drug-associated preglomerular-type of renal dysfunction, or decreased effective arterial blood volume and sustained hypotension. Examples of true volume depletion include variceal bleeding, decreased food or fluid intake due to early satiety caused by distended ascites, excessive use of diuretics, and diarrhea caused by lactulose. Commonly used drugs that may potentially precipitate acute preglomerular-type renal dysfunction include contrast dye, nonsteroidal antiinflammatory drugs (NSAIDS) and selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Decreased effective arterial blood volume and decreased arterial pressure may be seen in severe sepsis or in HRS. The proposed pathogenic mechanism(s) of HRS and its treatment options are discussed in a later section.
Intrinsic Causes of Acute Kidney Injury
Intrinsic causes of AKI may be classified according to the primary site of injury, including the tubules, interstitium, glomerulus, and small intrarenal vessels. Although data on the incidence of the different types of AKI in ESLD patients are limited, small-vessel vascular causes of AKI are uncommon. The United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database revealed that acute tubular necrosis (ATN) is the most common cause of intrinsic AKI requiring CKLT both in the pre– and post–Model for End-Stage Liver Disease (MELD) eras (2.10% and 3.4% of CKLTs were performed over a 9-year period in the pre-and post-MELD eras, respectively), followed by malignant hypertension (0.95% and 0.69% in the pre- and post-MELD eras, respectively), and drug-related interstitial nephritis (0.38% and 0.72%, in the pre- and post-MELD eras, respectively).
Acute injury to the renal tubules leading to ATN may be ischemic or toxic in origin. The former is frequently due to sustained prerenal AKI, and the latter is due to the use of nephrotoxic drugs such as amphotericin B or aminoglycoside antibiotics. In a multivariate logistic regression analysis Hampel et al have shown that in hospitalized cirrhotic patients, aminoglycoside treatment was a strong risk factor for renal dysfunction, independent of the severity of liver disease or peritonitis. However, in critically ill patients such as those with septic shock, ATN is commonly due to a combination of ischemic injury and the use of nephrotoxins.
AKI due to acute interstitial nephritis is often due to drug-induced hypersensitivity reactions. Potential and common offending agents include sulfa drugs, oxacillin, nafcillin, ciprofloxacin, levofloxacin, cephalosporins, NSAIDS, and diuretics, including hydrochlorothiazide, furosemide, triamterene, and ethacrynic acid.
The incidence of glomerulonephritis (GN) causing AKI or CKD in ESLD is unknown. In a series of 55 patients with liver cirrhosis and coagulopathy who underwent successful transjugular renal biopsy for evaluation of elevated SCr level above 130 μmol/L or proteinuria greater than 0.5 g/day, glomerular lesions were identified in 41 out of 55 patients (74.5%), interstitial in 7 (12.7%), end-stage renal failure in 2 (3.6%), and normal biopsy findings in 5 (9.1%). In a small series consisting of 28 patients with both liver disease and renal abnormalities who underwent successful transjugular renal biopsy (with or without simultaneous liver biopsy), glomerular pathologic conditions were found in 15 (53.6%), tubular in 6 (21.4%), end-stage renal failure in 2 (7.1%), nonspecific changes in 1 (3.6%), and normal renal biopsy findings in 4 (14.3%). The glomerular lesions included membranoproliferative GN in 5, nephrosclerosis in 3, diabetic nephropathy in 2, immunoglobulin A (IgA) nephropathy in 2, minimal change disease in 2, and early glomerulosclerosis in 1.
For recipients of CKLT, the glomerular diagnoses reported to the UNOS/OPTN for transplants performed between February 26, 1993, and February 27, 2011, in order of decreasing frequency included diabetic nephropathy type 2, unspecified chronic GN, membranous glomerulonephropathy, diabetes mellitus type 1, IgA nephropathy, unspecified chronic glomerulosclerosis, focal segmental glomerulosclerosis, amyloidosis, sarcoidosis, systemic lupus erythematosus, postinfectious crescentic GN, membranoproliferative glomerulonephritis type 1, membranoproliferative glomerulonephritis type 2, Alport’s syndrome, rapidly progressive GN, and Goodpasture’s syndrome ( Table 74-1 ).
TABLE 74-1
Glomerular Diagnoses for Transplants Performed Between February 26, 1993, and February 27, 2011
| Kidney Primary Diagnoses | No. of Transplants | % of Transplants |
|---|---|---|
| Diabetes mellitus type 2 | 481 | 12.13 |
| Unspecified chronic GN | 151 | 3.83 |
| Membranous GN | 118 | 2.97 |
| Diabetes mellitus type 1 | 105 | 2.49 |
| IgA nephropathy | 80 | 2.2 |
| Unspecified chronic glomerulosclerosis | 57 | 1.43 |
| Focal segmental glomerulosclerosis | 46 | 1.16 |
| Amyloidosis | 17 | 0.43 |
| Sarcoidosis | 16 | 0.40 |
| SLE | 10 | 0.26 |
| Postinfectious crescentic GN | 10 | 0.26 |
| MPGN type 1 | 8 | 0.20 |
| MPGN type 2 | 3 | 0.08 |
| Alport’s syndrome | 3 | 0.08 |
| Rapidly progressive GN | 2 | 0.06 |
| Goodpasture’s syndrome | 1 | 0.03 |
GN , Glomerulonephritis; IgA , immunoglobulin A; MPGN , membranoproliferative GN; SLE , systemic lupus erythematosus.
Postrenal Acute Kidney Injury
Postrenal AKI among ESLD patients is not commonly recognized. Despite its low occurrence, ESLD patients are at least at similar risk for the development of obstructive uropathy as the general population, and it may be functional or anatomical in nature. The former can be caused by a neurogenic bladder or anticholinergic drugs, whereas the latter can be due to recurrent urinary tract instrumentation with associated blood clots, kidney stones, prostatic hypertrophy, or even papillary necrosis. Bladder catheterization and renal ultrasonography are readily available and should be performed in all patients with AKI. Prompt diagnosis and management of obstructive uropathy is of prognostic significance because the likelihood for recovery of renal function decreases with the duration of obstruction.
Acute or Chronic Kidney Injury as Part of the Disease Entity Associated with End-Stage Liver Disease
Acute or chronic kidney injury may present as a manifestation of the same systemic disease responsible for the liver disease, or it may be develop as a direct complication of the disease affecting the liver. In addition, there are different glomerulopathies that are secondarily associated with specific types of liver disease through either immunological or undetermined causes. Broad categories of conditions or diseases affecting both liver and kidney include infections, toxins, collagen vascular diseases, generalized vascular dysfunction, adult polycystic kidney disease, congenital diseases, neoplasms, and metabolic disorders. Other disease processes that may involve both the liver and kidney include hemochromatosis, ulcerative colitis, and toxemia of pregnancy. Table 74-2 lists the diseases or conditions known to affect both the liver and kidney that are commonly encountered in OLT and CKLT candidates. For a more extensive review of the glomerular and interstitial diseases associated with liver disease, see the article by Davis et al.
TABLE 74-2
Diseases or Conditions Commonly Encountered in Orthotopic Liver Transplantation and Combined Kidney and Liver Transplantation Candidates That Are Known to Affect Both the Liver and the Kidney
| Chronic Liver Cirrhosis | Associated Kidney Disease |
|---|---|
| Parenchymal Liver Disease | |
| Hepatitis B Hepatitis C Alcoholic cirrhosis |
MGN, MPGN, PAN MPGN, MGN, fibrillary GN, immunotactoid GN, IgA nephropathy, postinfectious GN IgA nephropathy, hepatic sclerosis Immune complex GN, RTA |
| Primary Cholestatic Disease | |
| Primary biliary cirrhosis Cryptogenic cirrhosis |
MGN, ANCA-positive vasculitis, RTA IgA nephropathy, hepatic sclerosis |
| Vascular Disease | |
| Budd-Chiari syndrome | Metastatic renal cell carcinoma |
| Acute Fulminant Hepatic Failure | |
| Viral hepatitis (HBV, HCV) Drug-induced (acetaminophen, halothane) Metabolic liver disease (Reye’s syndrome) |
|
| Inborn Error of Metabolism | |
| Glycogen storage disease type 1 α-Antitrypsin deficiency Wilson’s disease |
Focal glomerulosclerosis MPGN, anti-GBM disease Fanconi syndrome |
| Miscellaneous | |
| Polycystic liver disease Primary hyperoxaluria type 1 |
Polycystic kidney disease Interstitial fibrosis |
ANCA , Antineutrophil cytoplasmic antibody; GBM , glomerular basement membrane; GN , glomerulonephritis; HBV , hepatitis B virus; HCV , hepatitis C virus; IgA , immunoglobulin A; MGN , membranous GN; MPGN , membranoproliferative GN; PAN , polyarteritis nodosa; RTA , renal tubular acidosis.
Acute Kidney Injury as a Consequence of End-Stage Liver Disease
Hepatorenal Syndrome
The International Club of Ascites (ICA) defines HRS as “a clinical condition that occurs in patients with chronic liver disease, advanced hepatic failure, and portal hypertension characterized by impaired renal function and marked abnormalities in the arterial circulation and activity of the endogenous vasoactive systems. In the kidney, there is marked renal vasoconstriction that results in a low GFR. In the extrarenal circulation there is predominance of arterial vasodilation that results in reduction of total systemic vascular resistance and arterial hypotension.” The most recent ICA criteria for the diagnosis of HRS include the following: (1) cirrhosis with ascites; (2) SCr level greater than 1.5 mg/dL; (3) no improvement in SCr level after at least 2 days following diuretic withdrawal and volume expansion with albumin (recommended dose of 1 g/kg body weight per day up to 100 g/day); (4) absence of shock; (5) no current or recent nephrotoxic drugs; (6) absence of parenchymal kidney disease as indicated by proteinuria greater than 500 mg/day, microhematuria greater than 50 red blood cells per high-power field, and/or abnormal renal ultrasound examination results ( Table 74-3 ). Two types of HRS have been described. Type 1 is characterized by rapidly progressive reduction in renal function defined by a doubling of the initial SCr level to greater than 2.5 mg/dL or a 50% reduction in the initial 24-hour creatinine clearance to a level of less than 20 mL/min in less than 2 weeks. Type 2 does not have a rapidly progressive course ( Table 74-4 ).
TABLE 74-3
Hepatorenal Syndrome: International Club of Ascites Diagnostic Criteria
|
HPF , High-power field; RBC , red blood cell; SCr , serum creatinine.
TABLE 74-4
Subtypes of Hepatorenal Syndrome
| Type 1 | Type 2 |
|---|---|
|
|
CrCl , Creatinine clearance; GFR , glomerular filtration rate; GI , gastrointestinal; SCr , serum creatinine.
Earlier data have reported the probability of developing HRS among cirrhotic patients at 1, 2, and 5 years to be 18%, 32%, and 40%, respectively. In a cross-sectional study involving 240 patients admitted for chronic liver disease and ascites, HRS as defined by the ICA criteria developed in 47.4%. Risk factors include bacterial infections such as spontaneous bacterial peritonitis (SBP) or sepsis, acute alcoholic hepatitis, or large-volume paracentesis without albumin expansion.
Pathogenesis
HRS is a functional renal dysfunction that is caused by marked intrarenal arteriolar vasoconstriction. As previously discussed, the key underlying abnormality in HRS is the extrarenal arterial vasodilatation that occurs in the splanchnic bed and peripheral arterial system. The compensatory activation of the renin angiotensin aldosterone system and sympathetic nervous system lead to severe vasoconstriction and hence hypoperfusion in other organs, including the kidneys, liver, and brain. In addition, renal perfusion may be compromised by insufficient cardiac compensation to counteract the reduced peripheral vascular resistance. Reduced cardiac preload, impaired chronotropic function, and impaired left ventricular function have been described in patients with advanced liver disease independent of any other underlying cardiac conditions. Vasoconstriction in the brain has been attributed to hepatic encephalopathy in advanced liver patients.
Fluid Management
In liver patients who present with AKI of unclear cause, the ICA recommends diuretic withdrawal, where applicable, and a trial of volume expansion with albumin at a recommended dose of 1 g/kg body weight per day up to 100 g/day. Failure to improve renal function within 2 days suggests HRS or other intrinsic kidney disease.
In patients with stable renal function and no ongoing fluid loss, fluid administration should be in accordance with the routine recommendation of daily sodium restriction of 88 mmol. In patients who cannot have or tolerate oral intake, intravenous saline infusion should be limited to 0.6 to 0.75 L of normal saline or 1.2 to 1.5 L of half normal saline per day. This is equivalent to 92 to 116 mmol of daily sodium intake. Normal saline is preferred over half normal saline in patients with hyponatremia. In patients with excessive body fluid loss, matching volume of half or normal saline may be used to prevent intravascular volume depletion. Selection of half versus normal saline depends on the type of fluid loss and current serum sodium concentration. Whole blood loss or any type of fluid loss with concurrent hyponatremia may require normal saline, whereas hypotonic insensible fluid loss may only require half normal saline. In stable liver patients with hyponatremia, free water restriction should be enforced because hyponatremia has been shown to be associated with higher mortality even after MELD score adjustments. In our opinion, free water restriction at 10 to 20 mL/kg/day should be enforced in patients with serum sodium level of less than 136 mmol/L and not delayed until the manifestation of neurological symptoms. The degree of fluid restriction should be titrated to patients’ volume status and severity of hyponatremia. In patients with hyponatremia who also have severe hypoalbuminemia (<2 g/dL) or anemia, the addition of albumin and blood products to improve intravascular oncotic pressure may be preferred over normal saline alone. High volume of hypotonic saline (e.g., >1.5 L of half normal saline per day) should be avoided in patients with existing hyponatremia who have no ongoing hypotonic fluid loss. Although sodium and water restriction are often necessary in liver patients, close monitoring for signs and symptoms of volume depletion and hemodynamic compromise due to excessive restrictions is required.
Prognosis
The prognosis for HRS is very poor. Among those patients with a 50% or more reduction in renal function over a 2-week period (type 1 HRS), mortality is essentially 100% within 3 months from onset. Even among those with type 2 HRS, where there is a moderate, but stable reduction in creatinine clearance, the median survival has been reported to be only 6 months without liver transplantation.
Predictive and Precipitating Factors
Predictive and precipitating factors for the development of HRS are given in Table 74-5 and include hyponatremia below 133 mmol/L, high MELD score, marked arterial hypotension (mean arterial blood pressure < 85 mm Hg), elevated neurohormone levels, cardiac output below 6.0 L/min, and elevated intrarenal resistive index. The single most common trigger for the development of HRS type 1 is bacterial infection, predominantly SBP.
Table 74-5
Hepatorenal Syndrome: Predictive and Precipitating Factors
Predictive Factors
Precipitating Factors
|
Suggested Preventive Measures
|
GI , gastrointestinal; MELD , Model for End-Stage Liver Disease; SBP , spontaneous bacterial peritonitis.
Management
Preventive Therapy
Measures to prevent the development of HRS may be considered in patients with SBP and acute alcoholic hepatitis. In the former condition the infusion of albumin at 1.5 g/kg body weight at diagnosis and 1 g/kg body weight 48 hours later in addition to antimicrobial therapy has been shown to prevent circulatory dysfunction and subsequent development of HRS (10% versus 33%) as well as increasing survival (10% versus 29%). The beneficial effect of albumin has been attributed to its role in minimizing the fall in systemic arterial pressure and subsequent activation of the vasoconstricting systems associated with bacterial infections. Of note, hydroxyethyl starch has not been shown to be similarly effective.
The use of pentoxifylline, an inhibitor of hepatic synthesis of tumor necrosis factor in alcoholic hepatitis has been suggested in a Cochrane systematic review to have a “possible positive intervention effect on all-cause mortality and mortality due to HRS” compared to controls. The evidence, however, was felt to be weak. Although the exact protective mechanism is unknown, it is conceivable that pentoxifylline reduces tumor necrosis factor–induced hepatic injury and enhances hepatic blood flow.
Pharmacological Therapy
The pharmacological management of HRS involves four theoretically beneficial interventions: portal hypertension decompression, renal vasodilation, splanchnic bed vasoconstriction, and systemic vasoconstriction. Although decompression of portal hypertension may be achieved with transjugular intrahepatic portosystemic shunt (TIPS), it is an invasive procedure that is limited to selected patients with relatively preserved liver function.
The use of intrarenal vasodilators including saralasin (angiotensinogen antagonist), dopamine, and misoprostol (synthetic prostaglandin E analogue) have resulted in disappointing outcomes, worse side effect profiles, or both. Although the use of endothelin-A antagonist has reportedly resulted in a dose-dependent improvement of renal function, data are severely lacking and survival benefit has never been noted.
Two remaining therapeutic options that may be feasible to the majority of patients with HRS thus include the use of splanchnic vasoconstrictors and systemic vasoconstrictors:
Splanchnic Vasoconstrictors
The rationale for the use of splanchnic vasoconstrictors is the reduction in splanchnic organ blood flow and resultant reduction in portal blood flow and pressure. Splanchnic vasoconstrictors evaluated in the management of HRS include synthetic analogues of vasopressin with decreased antidiuretic properties, including octapressin, ornipressin, and terlipressin, and a synthetic analogue of the pancreatic hormone somatostatin, octreotide.
Synthetic Analogues of Vasopressin
Ornipressin has been shown to confer minimal improvement in renal function with or without the addition of dopamine unless the medication was administered as a continuous and prolonged infusion. Its use, however, has been abandoned because of high rates of complications, including intestinal and tongue infarctions and arrhythmias.
In 1998 Hadengue et al first reported the success of 10 patients who had improvement in renal function and diuresis following a low-dose administration of terlipressin at 1 mg every 12 hours over a 48-hour period. Subsequent studies using different protocols, including variations in dosages, duration of terlipressin infusion, and addition of albumin, have resulted in similar favorable outcomes. In a recent pooled analysis consisting of 21 studies (n = 501 patients), an increase in mean arterial pressure during vasoconstrictor therapy in patients with HRS was associated with improvement in kidney function across the spectrum of drugs tested. Furthermore, a decrease in plasma renin activity correlated with renal function improvement. In most studies terlipressin was tested as a vasoconstrictor. Other less frequently used vasoconstrictors included ornipressin, midodrine, octreotide, and norepinephrine.
Although terlipressin has been shown to have a beneficial effect on HRS reversal, its use appears to have no impact on posttransplant survival. In a multicenter, double-blind trial consisting of 112 patients with HRS who were randomized in a 1:1 ratio to receive either terlipressin plus albumin or placebo plus albumin, reversal of HRS occurred in 34% and 13% of the terlipressin and placebo groups, respectively ( P = .008). However, the overall and transplantation-free survival was comparable between the two treatment groups ( P = .84). In one single-center study consisting of 46 patients with HRS (type 1 or type 2) who were randomized to receive either terlipressin and albumin or albumin alone, reversal of HRS occurred in 44% in the terlipressin and albumin group compared with 8.7% in the albumin alone group (P = .017). However, there was no difference in 3-month survival between the two treatment groups (27% and 19% in the terlipressin and control groups, respectively; P = .017).
Currently, terlipressin is the only synthetic vasopressin analogue available for clinical use. A lower baseline SCr level at initiation of therapy has been suggested to be the most consistent predictor of response to terlipressin, whereas a sustained rise in mean arterial pressure is required for HRS reversal. Young age and a Child-Turcotte-Pugh score of less than 13 have also been suggested to be important predictors of favorable response to terlipressin. Despite its potential beneficial effect in HRS reversal and its minimal side effect profile, terlipressin is available only in Europe but not in the United States due to insufficient survival benefit data.
Synthetic Analogue of the Pancreatic Hormone Somatostatin: Octreotide
The splanchnic vasoconstrictive effect of octreotide is thought to occur via the inhibition of glucagon and other vasodilating peptides. As a single agent, however, octreotide has not been found to be effective. Generally improvement in renal function is observed when octreotide is used in combination with midodrine, an α 1 -adrenergic agonist and systemic vasoconstrictor, with or without the addition of albumin infusion. The American Association for the Study of Liver Diseases currently recommends albumin infusion plus administration of vasoactive drugs such as octreotide and midodrine in the treatment of type 1 HRS.
Miscellaneous
Other reportedly beneficial therapeutic options include N -acetylcysteine and noradrenaline. N -acetylcysteine is a free radical scavenger that has been proposed to improve medullary perfusion. Noradrenaline, a catecholamine with predominantly α-adrenergic activity, has also been tested in the management of HRS given its theoretical ability to counteract the fall in systemic vascular resistance that leads to HRS. The use of N -acetylcysteine and noradrenaline, however, cannot be routinely recommended because data regarding their efficacy are scant.
Transjugular Intrahepatic Portosystemic Shunt
TIPS has been used for more than 20 years to treat complications of portal hypertension by diverting portal blood flow to the hepatic vein, resulting in reduction in portal venous pressure. The latter has been shown to be associated with favorable changes in neurohumoral factors, natriuresis, and renal function. Limited pilot studies suggested that TIPS provides sustained improvement in kidney function and improved survival in cirrhotic patients with HRS.
In a small single-center prospective study to evaluate the effects of TIPS on renal function and vasoconstrictive systems in patients with type 1 HRS, Guevera et al demonstrated that TIPS improves renal function concomitant with improvement in renal hemodynamics and reduction in the activity of the renin-angiotensin and sympathetic nervous systems. The study consisted of seven cirrhotic patients with type 1 HRS. Successful TIPS resulted in a marked decrease in the portal pressure gradient in all patients (pre-TIPS and post-TIPS, P < .001). A significant reduction in blood urea nitrogen (BUN) and SCr levels and a twofold to threefold increase in GFR were observed 30 days after TIPS insertion (BUN and SCr at baseline versus 30 days after TIPS were 109 ± 7 mg/dL and 5.0 ± 0.8 mg/dL, respectively, versus 56 ± 11 mg/dL and 1.8 ± 0.4 mg/dL, respectively; P < .05); GFR at baseline and 30 days after TIPS was 9 ± 4 mL/min and 27 ± 7 mL/min, respectively; P = 0.04). Mean survival was 4.7 ± 2 months (0.3 to 17 months).The incidence of hepatic encephalopathy after TIPS was similar to that reported in a series of patients treated with TIPS for indications other than HRS. The results of the study suggested that TIPS improves renal function and reduces the activity of the renin-angiotensin and sympathetic nervous systems in cirrhotic patients with type 1 HRS. Nonetheless, the authors acknowledged that definitive conclusions about the efficacy and safety of TIPS in the management of type 1 HRS could not be obtained because of the small number of patients studied and the lack of a control group.
In a series consisting of 31 nontransplantable cirrhotic patients with HRS who underwent TIPS insertion (type 1 HRS, n = 17, and type 2, n = 14), Brensing et al similarly demonstrated that the procedure had a favorable effect on renal function. A significant improvement in SCr level, creatinine clearance, and serum urea level were observed 4 weeks after TIPS (after TIPS compared with baseline; P < .001). Of the seven dialysis-dependent patients, four discontinued dialysis, and liver transplantation was performed in two patients 7 and 24 months after TIPS when the initial medical condition that precluded transplantation had improved. In contrast, in patients who were not candidates for TIPS due to advanced liver failure (non-TIPS, n = 10), renal function progressively worsened in all but one patient. Three-, 6-, and 12-month survival rates in patients with type 1 HRS who underwent TIPS procedure (n = 14) were 64%, 50%, and 20%, respectively, and were significantly better than their non-TIPS counterparts (n = 7) with similar renal dysfunction at baseline ( P < .01). On the basis of the study results the authors concluded that TIPS represents a promising new option for treating selected HRS patients with sustained efficacy, even without liver transplantation.
Sequential Treatment with Vasoconstrictors Followed by Transjugular Intrahepatic Portosystemic Shunt
In a study to evaluate the efficacy of TIPS in cirrhotic patients with refractory ascites who responded to vasoconstrictor therapy, Wong et al demonstrated that combination therapy with midodrine, albumin, and octreotide followed by TIPS in suitable candidates resulted in further improvement in renal function and urinary sodium excretion concomitant with normalization of plasma renin and aldosterone levels. The study consisted of 14 cirrhotic patients with type 1 HRS. Ten patients (71%) responded to vasoconstrictive therapy defined as a decline in serum creatinine level to less than 1.53 mg/dL for 3 consecutive days. In an attempt to further improve renal function, TIPS was inserted in five patients who were at low risk for hepatic encephalopathy. At 12-month post-TIPS follow-up, significant improvement in GFR (versus pre-TIPS; P < .01) and renal hemodynamics (versus pre-TIPS; P < .05), increased natriuresis, and normalization of plasma renin and aldosterone levels were observed. Of the five patients who underwent TIPS, four were alive 6 to 30 months without a liver transplant and with minimal ascites, whereas one received a living related liver transplantation at 13 months. In contrast, among five responders to vasoconstrictors who did not undergo TIPS insertion, three died and two required liver transplantation.
Although results of small pilot studies suggested that TIPS may have a beneficial effect on renal function and short-term survival in patients with HRS, it should be noted that patients with poor prognostic factors were inherently not candidates for TIPS. The use of TIPS for the treatment of HRS is currently not recommended and should be considered investigational. Large randomized controlled trials are needed.
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