salient features of the pathophysiology of HRS, and to discuss the management of thissyndrome with emphasis upon extracorporeal blood purification. Fig. 1. (A) A selective renal arteriogram performed in a patient with oliguric renal failure and cirrhosis (T.L.). Note the extreme abnormality of the intrarenal vessels,including primary branches off of the main renal artery and the interlobar arteries. Thearcuate and cortical arterial system is not recognizable, nor is a distinct corticalnephrogram present. The arrow indicates the edge of the kidney. (B) Angiogram of thesame kidney performed postmortem with the intra-arterial injection of micropaque ingelatin as the contrast agent. Note filling of the renal arterial system throughout thevascular bed to the periphery of the cortex. The peripheral arterial tree that did notopacify in vivo now fills completely. The vascular attenuation and tortuosity are nolonger present. The vessels were also histologically normal. (From Epstein M.Hepatorenal syndrome: emerging perspectives. Semin Nephrol 1997;17:563–575;with permission.)DiagnosisTwo different forms of HRS have been described. Type I HRS is characterized by rapidimpairment of renal function and either doubling of the serum creatinine to aconcentration >2.5 mg/dL or a 50% reduction in creatinine clearance to <20 ml/min inless than 2 weeks  . Type II HRS is characterized by a more gradual decrement inrenal function   . The International Ascites Club has provided diagnostic criteria forHRS (Table 1)  . Causes for acute renal failure in the setting of liver disease aremanifold (Table 2)    ; therefore, the diagnosis of HRS rests upon theidentification of clinical and laboratory features. In general, HRS is characterized by: 1)urine that is relatively hyperosmolar to plasma, 2) a high urine:plasma creatinine ratio(typically >30), and 3) very low urinary sodium concentration (<10 mEq/L) andfractional excretion of sodium (FENa <1%) even in the presence of diuretics    .Low urinary sodium excretion is not specific for HUS, since acute glomerulonephritis,contrast nephropathy, and myoglobinuric renal failure can be accompanied by lowurinary sodium concentration [UNa]  . Although a reduced urinary sodiumconcentration [UNa] is considered to be pathognomonic for HRS, the syndrome can beassociated with elevated [UNa]   . Both urinary sodium and chloride should bemeasured, since the former may increase with urinary excretion of nonreabsorbedanions (penicillin derivatives, ketones, diatrizoate) or excretion of bicarbonate(resolving metabolic or developing respiratory alkalosis and resolving respiratoryacidosis)   . Because of malnutrition, muscle wasting, and reduced creatinineproduction in patients with cirrhosis, a normal serum creatinine may be present despitesevere renal dysfunction  . In addition, serum creatinine may be underestimated bysome analyzers due to interference by bilirubin. Bile constituents (bile acids, bilirubin,cholesterol) probably do not produce direct nephrotoxicity but may contribute to renaldysfunction in HRS by producing pre-renal hypoperfusion via extrarenal factors such asreduced systemic vascular resistance   . Other plausible mechanisms of renaldysfunction in cholemia include: 1) impaired tubular function via inhibition of theNa+/H+-antiporter and Na+/K+-ATPase   ; 2) tubular damage via oxidative stress(e.g., increased F2-isoprostane synthesis)  ; and 3) complex interplay with othermediators including endothelin-1, leukotrienes, and endotoxin   .Hyperbilirubinemia in patients with hypoalbuminemia has been associated with
decreased urinary sodium excretion, free water clearance, creatinine clearance, andrenal blood flow  .Table 1. International Ascites Clubs diagnostic criteria of hepatorenalsyndromeFrom Arroyo V, Gines P, Gerbes AL, et al: Definition and diagnostic criteria ofrefractory ascites and hepatorenal syndrome in cirrhosis: International Ascites Club.Hepatology 1996;23:164–176; with permission.Major criteria Chronic or acute liver disease with advanced hepatic failure and portal hypertension Low glomerular filtration rate as indicated by serum creatinine of >1.5 mg/dL or 24-hcreatinine clearance <40 mL/min Absence of shock, ongoing bacterial infection, and current or recent treatment withnephrotoxic drugs; absence of gastrointestinal fluid losses (repeated vomiting orintense diarrhea) or renal fluid losses (weight loss >500 g/d for several days in patientswith ascites without peripheral edema or 1000 g/d in patients with peripheral edema) No sustained improvement in renal function (decrease in serum creatinine to ≤1.5mg/dL or increase in creatinine clearance to ≥40 mL/min) following diuretic withdrawaland expansion of plasma volume with 1.5 L of isotonic saline Proteinuria <500 mg/dL and no ultrasonographic evidence of obstructive uropathyor parenchymal renal diseaseAdditional criteria Urine volume <500 mL/d Urine sodium <10 mEq/L Urine osmolality greater than plasma osmolality Urine red blood cells <50 per high power field Serum sodium concentration <130 mEq/LTable 2. Conditions causing simultaneous liver and renal failureData from references    .Infections Sepsis Leptospirosis Reyes syndrome Malaria CytomegalovirusToxins Methoxyflurane Carbon tetrachloride
Table 2. Conditions causing simultaneous liver and renal failure Tetracyclines (especially in third trimester of pregnancy) Acetaminophen Elemental phosphorus (contained in some rodent poisons)Circulatory Congestive heart failure ShockNeoplasms Metastatic HypernephromaCollagen vascular disease Systemic lupus erythematosus Polyarteritis nodosaGenetic Polycystic kidney disease Sickle cell anemiaMiscellaneous Amyloidosis Glomerulonephritis associated with hepatitis B, and IgA nephropathy associatedwith alcoholic cirrhosis Hepatorenal syndromeIn patients with hepatic cirrhosis, ascites, renal dysfunction and low fractional sodiumexcretion (FENa <1%), administration of volume expanders (100 grams albumin in 500mL normal saline) is recommended to distinguish between pre-renal azotemia andHRS  . However, because cirrhotic patients may require massive amounts of colloidand crystalloid solutions to replete intravascular volume, central hemodynamics andother clinical parameters (e.g., urine flow rate, creatinine clearance) should bemonitored   . In patients with HRS, a sustained response to intravascular volumeexpansion is unlikely, and other measures such as transjugular intrahepaticportosystemic shunting [TIPS], peritoneovenous shunting [PVS], dialysis, or orthotopicliver transplantation [OLT] may become necessary (see later).PathophysiologySeveral theories have been advanced to explain the development of ascites and renaldysfunction in HRS (Fig. 2)  . The overflow hypothesis postulates that a primaryincrease in renal sodium retention leads to expansion of the extracellular fluid and,subsequently, ascites formation  . The hepatic sinusoids, which are ordinarily freelypermeable to albumin, rely on low hydrostatic pressure to maintain fluid within thevascular space  . Portal venous hypertension increases the intrasinusoidalhydrostatic pressure, leading to translocation of fluid (lymph) from the sinusoids to thehepatic interstitium  . On the other hand, the underfill concept, that proposesaberrations in Starling forces within the hepatic sinusoids and splanchnic capillaries areresponsible for ascites formation rather than primary renal sodium retention alone  .As lymph fluid accumulates in the peritoneal space, plasma volume is decreased. This
reduction in effective circulating volume, in turn, leads to increased renal sodium andwater retention, a failure to escape from the sodium-retaining effect of aldosterone, andrenal resistance to atrial natriuretic peptide   . The revised underfill theorypostulates that peripheral arterial vasodilation is the primary event that spawns renalsodium and water retention    . The stimulus for the peripheral vasodilation,which is most pronounced in the splanchnic circulation, is incompletely understood  .The ensuing decrease in effective arterial blood volume is sensed by arteriolarbaroreceptors. Fig. 2. Presumed sequence of events culminating in ascites formation, according to three alternative theories. Refer to text for explanation. From Epstein M.Hepatorenal syndrome, in Epstein M, editor. The kidney in liver disease, chap 1.Philadelphia:Lippincott, 1996, pp 75–108; with permission.)The presence of decreased effective arterial blood volume appears to be an importantfeature of HRS, as head out water immersion, which increases central blood volume,corrects renal sodium and water retention in these patients   . Three majorvasoconstrictive mechanisms are stimulated: 1) the renin-angiotension-aldosteronesystem (RAAS), 2) the sympathetic nervous system (SNS), and 3) the nonosmoticrelease of vasopressin  . In addition, an increase in other vasoconstrictors (e.g.,leukotrienes, thromboxanes) or a decrease in renal vasodilatory eicosanoids (e.g.,PGE2 and PGI2) may partially explain renal vasoconstriction in decompensatedcirrhosis with ascites  . The observations that nonsteroidal antiinflammatory drugs(NSAIDs) decrease renal blood flow and glomerular filtration rate (GFR)   andthat a prostaglandin E analog (misoprostol 0.4 mg QID) may improve renal function inpatients with alcoholic cirrhosis support the peripheral vasodilation theory   . Themost severe manifestation of the peripheral vasodilatory state is HRS, a hyperdynamicstate with reduced SVR, increased cardiac output, low mean arterial pressure,hyperreninism, and renal vasoconstriction that varies independently of changes incardiac output    . Other neurohormonal mediators contributing to renal ischemiainclude elevated plasma endothelin levels, endotoxemia, enhanced nitric oxideproduction, and impaired renal kallikrein production  . The discovery that infusion ofglutamine into the portal-venous system leads to reduced GFR, renal plasma flow, andurine output has ignited interest in the existence of a hepatorenal depressor reflex  .InterventionBecause no single therapeutic maneuver for HRS is fully effective aside from livertransplantation, prevention and eradication of precipitating factors remain vital. In thisregard, avoidance of intravascular volume contraction and nephrotoxic agents isparamount. Overusage of diuretics and lactulose should be discouraged to avoidintravascular volume contraction   . Prostaglandin synthetase inhibitors (e.g.,NSAIDs) and demeclocycline (used to treat hyponatremia in the syndrome ofinappropriate antidiuretic hormone secretion) may induce azotemia in patients withcirrhosis and ascites    . NSAIDs also blunt the natriuretic and diuretic responseto diuretics in patients with cirrhosis  . Aminoglycosides may produce nephrotoxicityin hepatic disease either through interference with a vasodilatory prostaglandin  or through enhanced renal uptake of gentamicin in the presence of endotoxemia   . Beta-adrenergic antagonists (e.g., propranolol), which can reduce renal plasma
flow and GFR in hypertensive patients, do not appear to produce renal failure incirrhotic patients    .AscitesThe goal of ascites management is attainment of negative sodium and water balance  . Initial measures include bed rest, which increases central volume and reducesSNS and RAAS activity, as well as dietary sodium (90 mEq or approximately 2 gramsper day) and fluid (1000–1500 mL per day) restriction   . However, most patientswith ascites require diuretics      . A recent review advocates use ofspironolactone alone in patients with initial urinary sodium excretion >30 mEq/L and acombination of spironolactone and furosemide when urinary sodium excretion is 10–30mEq/L. The usual ratio of spironolactone to furosemide is 100 mg: 40 mg once daily inthe morning  . The natriuretic activity of spironolactone and its metabolites (e.g.,canrenone) depends upon the degree of hyperaldosteronism; therefore, doses of 400–600 mg daily may be required in patients with HRS. Similarly, high doses of furosemide(up to 160 mg daily) may be required, as this agent depends on plasma protein bindingin order to be secreted into the tubular lumen and reach its site of action  . Largevolume paracentesis with volume expanders (6–8 grams albumin per liter of asciticfluid) is recommended for patients with diuretic-resistant ascites, or patients in whomdiuretic therapy has been complicated by hyponatremia, encephalopathy, or azotemia  . Patients who require frequent paracentesis (more than once every 2 weeks)may be candidates for TIPS or PVS (see later)  . Combined ascitic fluid andfurosemide infusion has been found to create greater increases in GFR, urine volume,and urinary sodium excretion than either therapy alone  . Other authors havedescribed spontaneous ascites filtration and reinfusion (SAFR) as a means ofconcentrating ascitic fluid via a polyamide dialysis filter  . The concentrate is thenreinfused into an antecubital vein   or the peritoneal cavity       .While this method has been shown to increase urine output and natriuresis   andmay provide more favorable hemodynamic effects  and safer solute removal thanhemodialysis  , it is rarely, if ever, used in clinical practice.Pharmacologic manipulation of hemodynamic perturbations in HRSNitric oxide causes systemic vasodilation in cirrhotic patients with endotoxemia, whichappears to induce one form of nitric oxide synthase   . Use of nitric oxide synthaseinhibitors (e.g., N-monomethyl-L-arginine) in patients with cirrhosis has receivedattention recently; however, the use of these agents is currently restricted toinvestigational settings   . Demonstrations of elevated circulating levels ofendothelin-1 and endothelin-3 in patients with HRS  have provided the rationale forthe use of a selective endothelin receptor antagonist (BQ123) to ameliorate renaldysfunction in this syndrome. Dose-related improvements in renal inulin clearance withBQ123 were seen in a small number of patients  . Whether endothelin accumulatesas an effect of HRS or as a consequence of reduced renal clearance is uncertain  N-acetylcysteine (NAC) administration was associated with increased creatinineclearance, urine output, and sodium excretion in 12 patients with HRS. The 1-monthand 3-month survival rates of the patients were 67% and 58%, respectively, and two ofthe patients underwent orthotopic liver transplantation after improvement in renalfunction  . While initial studies on the effect of pressor amines such as metaraminoldemonstrated improvement in urine volume, urinary sodium excretion, and attenuationof the hyperdynamic state in patients with HRS    , dopamine infusion alone inpatients with HRS revealed inconsistent improvement in urine output and glomerular
filtration rate (GFR)   . However, combined intravenous dopamine (3.0mcg/kg/min) and norepinephrine (titrated to maintain SVR ∼800 dyne-sec/cm3)infusions have been found to have favorable effects on urine output, sodium excretion,and systemic hemodynamics. These changes have been attributed to vasodilation ofrenal afferent arterioles and vasoconstriction of peripheral and splanchnic vesselsleading to reversal of renal ischemia  . More recent literature has focused upon useof vasopressin analogs, such as 8-ornithin vasopressin (Ornipressin). These agentshave preferential affinity for the V1 rather than V2 receptor and, therefore, havevasoconstrictive potency similar to vasopressin but approximately 20% less antidiureticeffect   . Increased urine volume, sodium excretion, and creatinine clearance   as well as reversal of the hyperdynamic circulatory state (e.g., increased SVR andrenal blood flow, and decreased norepinephrine and renin activity)  have beenreported utilizing a continuous infusion of ornipressin (6 IU/hr) at a dose of 6 IU/hr.Improvement in renal function has also been demonstrated by combining ornipressin(6I U/hr) with dopamine (2–3 μg/kg/min)  . Lower infusion rates (2 IU/hr) have beenused successfully for longer periods of time (15 days) in combination with albumin-based plasma volume expansion  . While reductions in plasma aldosterone andnorepinephrine concentration and increased atrial natriuretic peptide levels have beenobserved with ornipressin, plasma endothelin levels do not appear to be affected  . In addition, evidence of gastrointestinal, cardiac, and tongue ischemia as well aslimited cutaneous necrosis have rarely been associated with this therapy    .Other vasopressin analogs such as PLV-2 (Octapressin 0.004–0.5 units/min) andterlipressin (2–6 mg/day) have been used successfully in HRS     . Midodrinehydrochloride, an oral α-mimetic agent, has been used in Type II HRS with no effectson renal hemodynamics or renal function  . Another study reported use of oralmidodrine (7.5–12.5 mg three times daily) combined with octreotide (100–200 μgsubcutaneously three times daily) and human albumin (50–100 mL of 20% daily for 20days) in five of thirteen patients with Type I HRS  . These authors found thatcombining midodrine, a vasoconstrictive agent, with octreotide, an inhibitor ofendogenous vasodilators, led to improvement in renal plasma flow, GFR, and urinarysodium excretion  . Inhibitors of thromboxane synthesis (e.g., dazoxiben and OKY046) have been studied as a method of reducing circulating levels of thromboxanes A2and B2 while allowing continued production of vasodilatory prostaglandins    .However, these agents allow for accumulation of the endoperoxides PGG2 and PGH2,which mimic thromboxane A2 via similar receptor interaction. A thromboxane receptorantagonist (ONO-3708) has been evaluated and found to have a favorable renalhemodynamic profile  , and initial research involving an adenosine-1 receptorantagonist has also suggested salutary renal effects   . Calcium antagonists havebeen postulated to have a similarly favorable renal hemodynamic profile because oftheir ability to reduce afferent arteriolar resistance and, possibly, attenuate renalischemia in HRS   . Calcium antagonists may also offer protection against theintrarenal effects of endothelin-1  .Although several of these pharmacologic agents appear to offer hemodynamic benefitin HRS, most of the studies involved small numbers of patients and had surrogaterather than hard outcome measures. At present, there is not a standard pharmacologicapproach to HRS.Peritoneovenous shunts and liver transplantationIn 1974, LeVeen and colleagues developed an extracorporeal device, which reinfusesascitic fluid into the systemic circulation  . The peritoneovenous or LeVeen shuntoperates on the principle of a pressure difference between the peritoneal cavity and thesuperior vena cava. Since their intital report, a number of competing shunts became
available (such as the Denver and the Minnesota shunts). All of these act on the sameprinciple, but with modifications. The insertion of peritoneovenous shunts with cirrhosisand ascites results in an expansion of the intravascular volume, an increase innatriuresis, creatinine clearance, renal blood flow, and a decrease in plasma reninactivity and aldosterone levels. Before the advent of TIPS, which produces the samealterations in circulatory physiology, the peritoneovenous shunt was offered to cirrhoticpatients and patients with refractory ascites, malignant ascites, and hepatichydrothorax. This shunt has been used in patients with hepatorenal syndrome, butcontrolled studies have not convincingly shown benefit.The peritoneovenous shunt should not be offered to patients with ascites infection,congestive heart failure, or severe coagulopathy. This type of shunt is fraught withnumerous complications including early shunt occlusion, disseminated intravascularcoagulation, sepsis, and late complications including these as well as thrombosis ofjugular or superior vena cava, emboli from the catheter tip, intestinal obstruction, andabdominal abscess  . In general, the use of such shunts has no role in the treatmentof refractory ascites or hepatorenal syndrome in patients awaiting livertransplantation. The use of large volume paracentesis and TIPS has proved to be saferfor these complications of cirrhosis and has served as a more effective bridge to livertransplantation.Transjugular intrahepatic portosystemic shuntThe advent of the transjugular intrahepatic portosystemic (TIPS) shunt has aidedpatients with end-stage liver disease who have refractory ascites and hepatopleuraleffusions. In general, TIPS may serve as a bridge to liver transplantation. Its impacthas been reviewed in the liver transplantation literature  . A TIPS is used to reduceportal hypertension, believed to be one of the major factors responsible for HRS. Theplacement of a TIPS requires creation of a parenchymal tract between the portal andhepatic veins followed by reinforcement of the tract with a metallic stent underfluoroscopic guidance. Absolute contraindications to TIPS placement include right-sided heart failure with elevated central venous pressure, polycystic liver disease, andsevere, or decompensated, hepatic failure. Relative contraindications include activeintrahepatic or systemic infection, severe hepatic encephalopathy poorly controlled bymedical therapy, and portal vein thrombosis. Acute complications includehemoperitoneum, hemobilia, acute hepatic ischemia, cardiac puncture, pulmonaryedema, septicemia, hematoma, hemolytic anemia, fever, and reactions to contrastagents. Chronic complications include portal or splenic vein thrombosis, chronichemolysis, worsening hepatic function, shunt stenosis, and chronic refractory hepaticencephalopathy. Of interest, a transient increase in serum creatinine is commonlyobserved following TIPS insertion. This may be related to the large radiocontrast dyeload given during the procedure. Thus, careful attention to intravascular volumereplacement before and after the procedure is recommended to minimize this risk.The use of TIPS in HRSDespite the evidence of isolated reports of improvement of renal function in patientswith HRS after portacaval shunts during the 1970s, neither this procedure norplacement of a LeVeen peritoneal shunt is recommended for the treatment of HRSbecause of the trend toward higher morbidity and mortality. The introduction of TIPShas led to reconsideration of the utility of portal decompression  . Patients withrefractory ascites who are at high risk of HRS can be effectively treated by TIPS.
However, data on recovery of renal function after TIPS placement in such patients arecontroversial and limited. One study reported an increase in glomerular filtration rate(GFR) in 6-month survivors  . In another small randomized trial comparing TIPS withlarge volume paracentesis for refractory ascites, GFR improved only marginally afterTIPS while natriuresis increased significantly  . As refractory ascites and HRS sharea similar pathophysiology  , TIPS has been tried as a rescue measure in patients withadvanced HRS. So far, preliminary short-term data are favorable. However, theseseries are small (1–7 severe HRS patients) and often lack follow-up data beyond threemonths         . Furthermore, these studies use a variety ofdefinitions of HRS and include patients who are candidates for transplant rescue    , limiting, to some extent, outcome interpretation especially for those patientswho are not transplant candidates at the time of HRS diagnosis.In a recent phase II clinical investigation 41 non-transplantable cirrhotics wereprospectively studied following TIPS placement to evaluate feasibility, safety, efficacy,and outcomes  . HRS was diagnosed using current criteria [severe (type I) HRS andmoderate (type II) HRS]. Thirty-one patients (14 type I, 17 type II) received TIPS; in 10patients advanced liver failure precluded shunting. The median time for follow-up was24 months and renal function, complications, and survival by Kaplan-Meier plots werereported. TIPS markedly reduced the portal pressure gradient from 21 ± 5 to 13 ± 4mmHg (P<0.001) with one procedure-related death (3.2%). Renal function deterioratedwithout TIPS but improved within two weeks after TIPS with creatinine clearanceincreasing from 18 ± 15 to 48 ± 42 ml/min (P<0.001), with stabilization thereafter.Following TIPS, 3-, 6-, 12-, and 18-month survival rates were 81%, 71%, 48%, and35%, respectively. Only 10% of non-TIPS patients survived 3 months, and the totalsurvival rates were 63%, 56%, 39%, and 29%, respectively  . The important point tonote in this study, however, is that multivariate Cox regression analysis demonstratestwo independent predictors of survival after TIPS placement: serum bilirubin and HRStype. These predictors imply that patients with severe end-stage liver failureaccompanied by HRS, who are unlikely to survive with or without a liver transplant, willnot have improved morbidity or mortality rates by the placement of TIPS for HRS.These data, however, are limited, and larger, prospective studies will need to clarifywhether benefits from TIPS in HRS are lacking. In summary, some published studiesindicate that TIPS improves renal perfusion and glomerular filtration rates and reducesthe activity of vasoconstrictor systems    . It is clear that any improvement seenwith the placement of TIPS for HRS has been on a case by case basis. At this time therole of TIPS in the management of HRS needs to be established by rigorousrandomized controlled clinical trials.Extracorporeal blood purificationDialysis has traditionally been considered to be ineffective in patients with HRSbecause of the high mortality rate (86.5–92%) despite institution of dialytic therapy   . Indeed, some advocate a limited trial of hemodialysis solely as a bridge tohepatic transplantation, since dialytic support beyond 2 weeks is associated with poorsurvival in those who undergo transplantation beyond this time frame   . Othersbelieve that dialysis is warranted in HRS patients and those with concomitant renalfailure and a reversible hepatic insult   . One must consider the observation thatrecovery of renal failure depends on the severity of liver damage and that the outcomeof HRS is generally fatal if orthotopic liver transplantation (OLT) is not offered  . Forthese reasons, withholding renal replacement therapy may be justified for patients withHRS who are not candidates for OLT   . In addition, there continues to becontroversy over the time at which to commence renal replacement therapy as well asthe best modality  .
The indications for initiating renal replacement therapy include correction of solutedisturbances (acidemia, hyperkalemia, uremia, hyperphosphatemia) and volumeoverload (pulmonary edema, parenteral administration of hyperalimentation, bloodproducts, and medications)     . Furthermore, there is an emerging role forextracorporeal blood purification methodologies in addition to hemodialysis as supportmeasures for patients with hepatic failure (Table 3)  .Table 3. Extracorporeal blood purification for hepatic failureFrom Kaplan AA, Epstein M: Extracorporeal blood purification in the management ofpatients with hepatic failure. Semin Nephrol 1997;17:576–58; with permission.Systems Hemodialysis Continuous renal replacement therapy (e.g., CAVH, CAVHD, CVVHD) Therapeutic plasma exchange Sorbent systems Hemoperfusion Combined filter-sorbent systems Hybrid organ systems Hepatocyte-lined filters Extracorporeal liver perfusionIndications Temporary support for fulminant, reversible liver failure Reversal of hepatic coma Treatment for intracranial hypertension Intraoperative fluid management during hepatic transplantation Reversal of hepatorenal syndrome Bridge to hepatic transplantationChoice of extracorporeal modalityNo single extracorporeal modality can adequately remove all of the toxins associatedwith hepatic failure, due mainly to the range in their molecular weights (Table 4)  .Moreover, currently available toxin removal systems do not replace the synthetic (e.g.,clotting factors, albumin) and metabolic (e.g., maintenance of serum glucose) functionsof the liver and may, in fact, remove potentially regenerative substances  . Of themajor modalities, hemodialysis is capable of removing small molecular weightsubstances with large volumes of distribution, while larger “middle molecules” (MW15,000–20,000 daltons) are better removed by hemofiltration. Still, other modalitiessuch as therapeutic plasma exchange (TPE) are needed to remove endotoxin andalbumin-bound substances  .
Table 4. Toxins associated with hepatic failure: relation to blood purificationtechniques b Phenolic acids, fatty acids, and mercaptans have been shown to inhibit Na+/K+-ATPase activity and may contribute to the cerebral edema associated with severehepatic encephalopathy. a Albumin-bound.From Kaplan AA, Epstein M: Extracorporeal blood purification in the management ofpatients with hepatic failure. Semin Nephrol 1997;17:576–582; with permission.Small–molecular-weight toxins removable by hemodialysis Ammonia False neurotransmitters γ-Aminobutyric acid (GABA) Octopamine (false neurotransmitter)Middle–molecular-weight substances removable by hemofiltration Cytokines (IL-6, IL-1, TNF-α) Middle moleculesbAlbumin-bound or large–molecular-weight toxins removable by plasma exchange Aromatic amino acidsa Bile acidsa Bilirubina Endotoxin Endotoxin-induced substances: nitrous oxide, cytokines (IL-6, IL-1, TNF-α) Indolsa Mercaptansa,b Phenolsa,b Short chain fatty acids†Substances removable by hemoperfusion Bile Acidsa Bilirubin (conjugated and unconjugated)a Cytokines (IL-6, IL-1, TNF-α) Mercaptansa,b Phenolsa,bHemodialysis (HD) and peritoneal dialysis (PD) have been utilized in patients withhepatic cirrhosis. Some authors have described the successful application of PD inpatients with chronic renal failure and liver disease  , and others have described useof this modality in patients with fulminant hepatic failure  . However, in a series offour studies compiled by Perez et al., patients with fulminant hepatic failure and HRSdemonstrated poor outcome with PD  . These authors have illustrated similar resultswith HD, underscoring the overall dismal prognosis of HRS despite dialytic therapy  .PD may offer a more favorable hemodynamic profile than HD, allow for control ofascites formation, and be performed without anticoagulation  . However, argumentsposed against the use of PD in this situation include diminution of solute clearanceimposed by the presence of ascites    and augmentation of protein losses  .
Ultimately, the decision to use PD versus intermittent HD may be based upon theexperience of the institution.Continuous renal replacement therapy (CRRT) is the preferred approach in patientswith combined hepatic and renal failure  . Because of increased cardiac output andreduced systemic vascular resistance, patients with hepatic failure are particularlyprone to hypotension during intermittent HD. Intradialytic hypotension normally occursin 20–50%    of patients despite using cooled (35.5°C) dialysate with variablesodium concentration, priming the lines with albumin, and monitoring intradialyticplasma volume  . CRRTs have been shown to confer greater hemodynamic andcerebrovascular stability than either intermittent HD or intermittent hemofiltration (HF)     . One study demonstrated that intermittent hemofiltration (3.5–4.5 hoursand average fluid exchange 17 L per treatment) created greater reductions in cerebralperfusion pressure and MAP and, hence, greater increases in intracranial pressure(ICP) than either continuous arteriovenous or venovenous hemodialysis (CAVHD orCVVHD, respectively)  . These changes were most pronounced within the first hourof treatment, when significant changes in serum osmolality had not yet occurred, andwere independent of changes in plasma volume (as evidenced by stable hematocrit)and SVR (which remained unchanged from already reduced baseline levels)  . Thesefindings are particularly relevant to patients with hepatic failure since such patients areat risk for cerebral edema  . These individuals may experience paradoxical acidemiaof the cerebrospinal fluid (CSF) due to the loss of CSF bicarbonate during dialysis.This, in turn, is accompanied by an increase in brain osmole content due toaccumulation of idiogenic osmoles and, ultimately, cerebral edema  . Importantly,increased intracranial pressure is likely the result of decreased cerebral perfusionpressure, which leads to rebound vasodilatation. This acute ischemic insult, which issuperimposed on already impaired cerebral autoregulation in fulminant hepatic failure,is believed to be the most plausible explanation for increased ICP  . In addition to itsability to mitigate changes in ICP, CRRT is also postulated to improve cerebral stabilityby removing a cardiodepressant or vascular endothelial vasodilatory factor  .Moreover, CRRT provides improved solute clearance over PD and has the potential toprovide more efficient urea transfer than intermittent HD over a long period of time  .The nomenclature for CRRTs is based upon the blood access used to drive theextracorporeal circuit (AV: arteriovenous; VV: venovenous) as well as the method ofsolute removal (diffusion, convection, or both)   . A detailed description of CRRTsis provided elsewhere in this volume. A comparison of extracorporeal modalities inHRS is made difficult by the small numbers of patients in these trials and by the lack ofuniform etiology of combined hepatic and renal disease in these subjects. CRRTs havebeen utilized intraoperatively during the anhepatic phase of orthotopic livertransplantation, and CRRT in combination with other modalities such as therapeuticplasma exchange (TPE) and charcoal hemoperfusion has also been described (seelater)      . Continuous arteriovenous hemofiltration (CAVH) has beenfavored as the leading extracorporeal support modality because it allows for removal offluid, electrolytes, and medium-size molecules (MW<50,000 D) by convection and isdriven by the patients mean arterial pressure (MAP)      . Slow continuousultrafiltration (SCUF) using either arteriovenous or venovenous blood access may beapplied to patients with liver disease who require fluid removal only. Continuousarteriovenous ultrafiltration (CAVU) is one form of this methodology   . Because thetechnique requires central venous access for blood return, insertion of a catheter intoeither the femoral, subclavian, or internal jugular vein is necessary. If the technique isto be used intraoperatively, the preferred site of venous access may be the latter sinceclamping of the inferior vena cava during OLT increases femoral venous pressure andreduces MAP, thus reducing the arterial-to-venous pressure gradient that drives the
circuit  . Pump-assisted CAVH has been described as a means of circumventing thisproblem  . The hemorrhagic and ischemic risks imposed by CAVH and CAVU stemmainly from the arteriotomy required for temporary access and the potential need foranticoagulation of the circuit  . In contrast, continuous venovenous hemofiltration(CVVH) requires insertion of one dual lumen catheter into a central vein  , butrequires a blood pump in order to maintain the transmembrane pressure gradientnecessary for convection. With any form of hemofiltration, replacement fluid can begiven in the form of Ringers lactate solution and/or saline or Plasmalyte (Baxter). Thesolution may be administered postfilter, in which case urea clearance approximatesultrafiltrate removal,   or prefilter, which potentially reduces anticoagulationrequirements  but increases ultrafiltration requirements by ∼15%  . Bicarbonate-based replacement fluid and dialysate are favored over lactate- or acetate-basedsolutions due to the potential for impaired hepatic conversion of these substances tobicarbonate in the presence of hepatic disease    . Moreover, accumulation oflactate may be associated with vasodilation   , potentially contributing to thehemodynamic instability in these patients. Because of clotting factor deficiencies andthrombocytopenia in hepatic failure, anticoagulation may not be needed to maintain theCRRT circuit   . However, in some patients with liver failure, clotting of the CRRTcircuit may occur because of activation of the intrinsic pathway (factor VII) andgeneration of thrombin. These aberrations may occur as a consequence of decreasedlevels of natural anticoagulants and perturbations within the tissue factor pathway  .Moreover, reduced circulating levels of antithrombin III and heparin cofactor II mayrender heparin ineffective  . Trisodium citrate, a widely used anticoagulant, mayproduce hypernatremia and has been known to create metabolic alkalosis in patientswith hepatic dysfunction  . Hypocalcemia is a known complication of trisodium citrateanticoagulation; however, hypercalcemia associated with low ionized calciumconcentration and calcium-citrate complexing has been reported in a patient withcombined hepatic and renal failure  . Recently, attention has focused on otheranticoagulation strategies including prostacyclin, which may increase cerebral oxygenuptake,   and the serine protease inhibitors nafamostat mesilate and gabexatemesilate  .The characteristics of the dialyzer membrane impact substrate removal and may affectcognitive function in patients with HRS. Dialyzer membranes used for hemofiltrationand hemodialysis can be described in terms of their biocompatibility, or their ability toactivate peripheral blood cells and plasma proteins upon contact with plasma in theextracorporeal circuit   . The prototype of bioincompatible membranes isCuprophane, which is a cellulosic material that has been found to cause neutropeniaas a result of neutrophil sequestration within the pulmonary microcirculation. This eventis believed to be mediated by activation of complement proteins  , such as theanaphylatoxins C3a and C5a, which can be measured by commercial C3a(desArg) andC5a(desArg) radioimmunoassay. In addition to sequestration, neutrophils releaseproinflammatory mediators (e.g., reactive oxygen species and intragranular proteases)on contact with the dialyzer membrane. In contrast, biocompatible membranes, whichare composed of synthetic materials such as polysulfone, polyamide, andpolyacrylonitrile [PAN], possess properties which attenuate complement activation.AN69 membranes, which are composed of PAN and sodium methallyl sulfonate, areknown to adsorb cationic peptides and allow binding and activation of factor XII, whichresults in conversion of kininogen to kinin. Angiotensin converting enzyme (ACE), akininase, can catalyze this reaction. Therefore, the potential for bradykininaccumulation and anaphylactoid reactions exists when AN69 membranes and ACE-inhibitors are used concurrently     . While there is evidence to suggestgreater survival, increased recovery of renal function, and need for fewer dialysissessions with synthetic versus celluosic membranes   , some controversy stillexists  over the benefit of dialyzer membrane composition. Recent literature favors
the use of synthetic membranes, however          .Polyacrylonitrile membranes, in particular, have been touted for use in hemodialysisand hemofiltration in combined renal and hepatic failure, because they are highlypermeable and, thus, allow for the filtration of large molecular weight substances (limit35,000–40,000 Daltons)     . One study found that PAN membranesproduced no leukopenia and reduced cerebral perfusion pressure less than polyamidemembranes despite similar hemofiltration prescriptions  . Patients who underwenthemofiltration with polyamide membranes, on the other hand, experienced significantreductions in cardiac output, pulmonary artery occlusive pressure, tissue oxygendelivery, and mean arterial pressure  . Importantly, while biocompatible membranesmay produce less monocyte activation and release of proinflammatory cytokines (IL-1β, IL-6, TNF-α), they may be permeable enough to allow backdiffusion or backfiltrationof “toxic” substances from the dialysate into the plasma space   .Substrate removal in renal replacement therapy is dependent upon several factorsincluding plasma concentration, dialyzer membrane porosity, modality (CRRT versusintermittent therapy), dialysate and ultrafiltration rate, and blood flow. In general,hemodialysis and hemofiltration effectively remove water-soluble substances,particularly lower molecular weight toxins such as urea, ammonia, gamma-aminobutyric acid (GABA), and octopamine (a false neurotransmitter). However, theactual daily removal of toxins such as ammonia and GABA is small compared with thetotal body pool and overall rates of generation   . One study combined CVVH withplasma exchange in sixteen patients with acute hepatic failure and ≥ grade IIencephalopathy. These authors demonstrated removal of “middle molecular weight”substances (>600–4500 <15,000 D) with a polysulfone (synthetic, high permeability)dialyzer membrane  . These middle molecules have been shown to inhibit brainNa+/K+-ATPase, leading to coma and cerebral edema   . Other toxins which maybe able to inhibit Na+/K+-ATPase include bile constituents, free fatty acids, digoxin-likeimmunoreactive substances, mercaptans, and phenols  . Changes in serum highperformance liquid chromatography (HPLC) profile and coma grade for one patient areshown.  . The HPLC spikes produced by middle molecules were gradually removedby continuous hemofiltration  . Similar middle molecule removal was not achieved byplasma exchange alone. Of this cohort, 50% (8/16) showed improved level ofconsciousness, 3/16 survived the acute illness, and 5/16 survived > 3 weeks  .Another study demonstrated similar recovery of consciousness in 59% (13/22) ofpatients  . Removal of proinflammatory cytokines (IL-1β, IL-6, TNF-α) has recentlyreceived attention. Some researchers suggest removal of both proinflammatory andantiinflammatory cytokines (IL-10, soluble TNF receptors I and II, IL-1 receptorantagonist) with CVVH  , while others suggest no significant removal  . There isadditional evidence for cytokine removal via adsorption to an AN69 dialyzer membrane.The greatest reductions in cytokine levels occurred within the first hour of initiatingCVVH and immediately after changing the membrane  . Greater adsorption was alsonoted when blood flows were increased from 100 to 200 ml/min, which may increasethe membrane hydrogel surface area available for adsorption  . Other researchersprovide evidence for hemofiltration of immunomodulatory substances, which arecapable of stimulating peripheral blood monocyte TNF-α release  , and clearance ofhepatotoxic substances which suppress proliferation of in vitro hepatic cells (HepG2)and are capable of stimulating an acute phase response  . Hepatocyte growth factor(MW 35,000–70,000 Daltons), which is not likely to be filtered, also possesses anantiproliferative effect on HepG2 cells  . Daily change in the HPLC profile of sera, coma grade, and prothrombin time (PT) during continuous hemofiltration in a patient with fulminant hepatic failure. (FromMatsubara S, Okabe K, Ouchi K, Miyazaki Y, Yajima Y, Suzuki H, Otsuki M, Matsuno
S. Continuous removal of middle molecules by hemofiltration in patients with acute liverfailure. Crit Care Med 1990;18:1331–1338; with permission.)Nutrient and drug removal with CRRTRemoval of amino acids tends to be greater with continuous hemodialysis (6–16grams/day) than with CVVH (5–8 grams/day) or intermittent dialysis (5–13grams/treatment)  . Amino acid clearances depend upon dialysate flow rate (Qd) andcan represent from 8.9 ± 1.2% (Qd = 1 L/hr) to 12.1 ± 2.2% (Qd = 2 L/hr) of the dailyprotein input  . General recommendations for amino acid supplementation includeprovision of 500 mg per liter filtrate/dialysate or an additional 0.2 gm/kg/day of aminoacids in patients on continuous therapies   . Infusion of essential and nonessentialamino acids in addition to glucose has been proposed to maintain serum levels ofthese compounds in individuals receiving standard hemodialysis  . Exact removal ofspecific amino acids varies according to study       ; however, of theessential amino acids, valine, isoleucine, and leucine (all branched) do not appear tobe significantly removed by PAN hemodialysis, whereas significant decreases inplasma levels of methionine and phenylalanine (branched) as well as lysine andthreonine have been observed   . Trace amounts of cholesterol and/ortriglycerides have been detected in the ultrafiltrate from patients receiving continuoushemodiafiltration   . Use of dextrose-containing replacement solutions may resultin large net uptake of glucose during continuous hemofiltration and hemodiafiltration(11.9 ± 3.1 g/hr and 8.1 ± 2.1 mg/kg/min, respectively)   . Dextrose-free solutions,on the other hand, are associated with a small, but predictable, glucose loss duringCRRT  . The pharmacokinetics of drug dosing with CRRT is described elsewhere    .Therapeutic plasma exchange (TPE)/hemoperfusion/filter-sorbentsystems/hybrid bioartificial liverTherapeutic plasma exchange (TPE) has been utilized for its ability to remove albumin-bound, macromolecular substances that are confined to the intravascular space, suchas endotoxin, aromatic amino acids, and certain bile constituents (Table 4)   . Thisis distinctly different from hemofiltration, which removes substances that are notprotein-bound and have large volumes of distribution. TPE was initially described as ameans of removing putative nondialyzable substances responsible for hepatic coma . Later experience revealed little impact of TPE alone on survival   ; however,improved neurologic status and survival have been described with combined TPE andcontinuous hemofiltration or hemodiafiltration     . It is possible that use ofplasmapheresis may supplement ordinary hemodialysis and hemofiltration by allowingreplacement of plasma components that are depleted in hepatic failure, particularlyclotting factors  .Hemoperfusion (HP) is a sorbent-based technique which utilizes either activatedcharcoal (e.g., DHP-1 from Kuraray Co. Ltd., Osaka, Japan and Adsorba 150C fromGambro Ltd., Sidcup, Kent, UK) or an albumin-coated ion exchange resin such asAmberlite XAD-7 (Rohm and Haas Ltd., Croydon, Surey, UK)    . The formereffectively removes water-soluble substances (e.g., GABA, inhibitors of Na+/K+-ATPase, mercaptans) while the latter removes protein-bound (e.g., bile acids, aromaticamino acids) and lipid-soluble substances       . The largest study of
hemoperfusion evaluated patients with fulminant hepatic failure from several etiologies(viral hepatitis, acetominophen overdose, halothane / other drug exposure) and foundno survival benefit with daily HP regardless of treatment time (grade IIIencephalopathy: 5 hrs = 51%: 10 hrs = 50%:: grade IV encephalopathy: no HP =39.3%: 10 hrs = 34.5%)  . In addition, hemoperfusion has been associated withplatelet losses, platelet aggregation within the extracorporeal circuit   , and loss ofcoagulation factors  . A smaller, more recent trial involving 31 patients with acutehepatic failure reported a 50% survival rate in only four patients undergoing HPcompared with hemofiltration (6/9: 67% survival), TPE (3/8: 37%), and hemodialysis(3/10: 30%)  .Combination filter-sorbent systems provide another form of extracorporeal bloodpurification for patients awaiting liver transplantation. One such system is the Biologic-DT (HemoCleanse, Inc., West Lafayette, IN), which combines a sorbent-based systemwith standard hemodialysis   . Similar to the Biologic-HD system (Ash MedicalSystems, West Lafayette, IN), which utilizes a sorbent column to regenerate dialysate , the Biologic-DT system performs dialysis with a cellulosic plate dialyzer and adialysate solution containing both powdered activated charcoal (300,000 m2 surfacearea) and a cation exchanger. This allows removal of middle molecules (100–5000Daltons) as well as cations such as ammonium  . A study which used this systemevaluated 15 patients with acute hepatic failure, 11 of whom had concomintant renalfailure. All but two experienced neurologic improvement. Four patients recovered liverfunction without transplantation (two survived), and four received liver transplantation(two survived) with 1–12 daily treatments of 8–12 hours duration  . Less favorableresults were found in a prospective evaluation of 10 patients with fulminant hepaticfailure, in which one of five patients treated with sorbent-based dialysis survived  .The Molecular Adsorbent Recirculating System (MARS) has also been recentlydescribed   . This liver support system utilizes either intermittent (6–8 hours daily)or continuous hemodialysis with dialysate enriched with 20% human serum albumin asa means to remove albumin-bound toxins (bilirubin, bile acids, fatty acids, tryptophan,aromatic amino acids, and copper)  . Improvement in hepatic encephalopathy,decreases in serum creatinine and bilirubin concentration, and increases in serumsodium concentration and prothrombin activity were observed with MARS therapy inpatients with hepatic cirrhosis and Type I HRS  . In HRS, MARS may facilitateremoval of nitric oxide, albumin-bound uremic toxins, bile components, and vasoactivehormones (e.g., renin, angiotensin)  .The hybrid bioartificial liver (BAL) is a novel liver assist strategy that utilizes primaryhepatocytes derived from either human or animal sources  . One group has used aclonally derived human liver cell line (C3A) and cultured them by inoculating 5–10grams of cells into a dialyzer membrane. The cells exhibit many properties of hepaticcells in vivo such as conversion of ammonia to urea and glutamine, metabolism ofaromatic amino acids (phenylalanine, tyrosine), synthesis of clotting factors, expressionof P-450 enzymes, and proliferation in glucose-free medium (indicative ofgluconeogenesis). Moreover, these cells exhibit contact inhibition. Each dialyzer carriesapproximately 2 × 1011 cells (metabolic equivalent 200 grams hepatocytes)  . Liverregeneration, as documented by increasing organ size and increasing α-fetoprotein,has been observed with this technique  . Others have combined hybridextracorporeal liver support with hemoperfusion and plasmapheresis in an effort tomitigate the risk of bleeding associated with hemoperfusion-induced platelet losses . A similar approach using sequential total plasma volume exchange and artificial livertreatment (7 hr per treatment) has been used successfully to control intracranialpressure in a patient during the transition period (14 hr) from total hepatectomy to OLT . While xenogenically derived hepatocytes are readily available, disadvantagesimposed by their use include effects of animal proteins in human circulation (e.g.,
antibody formation, complement activation, and induction of proinflammatory cytokines)as well as viral transfer   . In addition, the hepatocyte cell mass required tosustain metabolic support and life in humans remains uncertain, but has been targetedat 20%  . Other researchers have described extracorporeal liver perfuson (ECLP) inpatients with terminal hepatic disease and advanced (stage III or IV) hepatic coma  .This methodology involves perfusion of the patients blood through a donor liver whichotherwise would be considered unacceptable for transplantation. A report on threepatients demonstrated decrements in serum bilirubin and arterial ammonia towardnormal and clear neurologic improvement in two of the three subjects. Trends towardimproved prothrombin time were also noted  .Orthotopic liver transplantation (OLT)OLT remains the ultimate treatment for hepatorenal syndrome. Delaying livertransplantation, whether intentionally or as an unintended consequence of the liverorgan donor shortage, with the onset of HRS imposes great risk to the patient and anychance for survival even with transplantation. OLT recipients with HRS have asignificantly decreased survival at 5 years compared with those without HRS (60% vs.68%)  . In addition, both pre- and post-transplantation liver patients with HRS havelonger hospitalizations including prolonged intensive care unit stays. Clearly, anincrease in liver organ donation and early transplantation in patients with advancedliver disease that do not yet have HRS or significant renal insufficiency is the best life-saving and cost-effective course.SummaryHepatorenal syndrome is a well characterized entity in which vasodilation ofsplanchnic vessels and intense constriction of the renal cortical vasculature occur inconcert. The condition is often fatal unless orthotopic liver transplantation (OLT) isperformed. Many extracorporeal blood purification techniques exist which can beoffered to patients awaiting OLT. Continuous hemofiltration, with or without othermodalities such as therapeutic plasma exchange and hemoperfusion, may be helpful inimproving the level of consciousness of these patients. Unfortunately, mortality andhepatic regeneration do not appear to be affected by such interventions. Thedevelopment of a hybrid bioartifical liver support system and pharmacologicmanipulation of the hemodynamic perturbations that occur in HRS provide particularlyappealing prospects as a means of providing a bridge to liver transplantation in thefuture.
I was so high I did not recognizeThe fire burning in her eyesThe chaos that controlled my mindWhispered goodbye and she got on a planeNever to return againBut always in my heartThis love has taken its toll on meShe said Goodbye too many times beforeAnd her heart is breaking in front of meI have no choice cause I wont say goodbye anymoreI tried my best to feed her appetiteKeep her coming every nightSo hard to keep her satisfiedKept playing love like it was just a gamePretending to feel the sameThen turn around and leave againThis love has taken its toll on meShe said Goodbye too many times beforeAnd her heart is breaking in front of meI have no choice cause I wont say goodbye anymoreIll fix these broken thingsRepair your broken wingsAnd make sure everythings alrightMy pressure on your hipsSinking my fingertipsInto every inch of youCause I know thats what you want me to do