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Summary

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

The United Network for Organ Sharing database revealed that over the last 4–5 years, an average of 1800 patients were removed from the cadaveric waiting list annually because of patients’ death and an additional 400–500 were removed from the list because of the severity of their illnesses.1 The pre-transplant evaluation process, therefore, requires careful and continued assessment of the patient's pulmonary, cardiac and renal function among others.

This article describes a systematic approach to the evaluation and management of renal dysfunction complicating the course of advanced liver disease, the pathogenic mechanisms and current recommendations for the treatment of hepatorenal syndrome, and the indications for combined liver–kidney transplantation.


Assessment of renal function in end-stage liver disease patients awaiting liver transplantation

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

The management of end stage liver disease (ESLD) patients is often complicated by concomitant renal disease. The initial challenge for the clinician is not to make the diagnosis, but to recognize early renal dysfunction. Routine measurement of the serum creatinine (SCr) level or estimating creatinine clearance (CCr) or glomerular filtration rate (GFR) using creatinine-based equations (e.g. Cockcroft-Gault formula) is an insensitive method for assessing renal function in ESLD patients. Reduced muscle mass, protein-poor diet, severe hyperbilirubinaemia, and diminished hepatic biosynthesis of creatine, a substrate for skeletal muscle production of creatinine, and/or overly aggressive fluid administration can all contribute to a falsely low SCr level,2 hence, an overestimation of GFR and/or CCr. In a study to assess renal function in cirrhotic patients using inulin clearance (Cin) as the gold standard for GFR evaluation, Caregaro et al. demonstrated that SCr, predicted GFR (based on Cockcroft-Gault formula), and CCr had a sensitivity of 18.5%, 51%, and 74%, respectively, in detecting renal failure among 55 consecutive stable cirrhotic patients.3 Independent investigators have shown that the discrepancy between CCr and Cin is greater in patients with impaired compared to those with normal renal function.4 Ideally, the GFR in ESLD patients should be measured with inulin or studies using radioisotopes such as [125I]-iothalamate or chromium S1-ethylene diaminetetraacetic acid or (51Cr-EDTA) clearance.

The second challenge in the management of renal failure in ESLD patients is identifying the aetiology of the renal dysfunction. Beside the subset of patients with simultaneous kidney–liver diseases, most ESLD patients are exposed to therapies and clinical circumstances that place them at risk for developing renal failure including invasive diagnostic procedures, imaging studies requiring nephrotoxic contrast dyes, nephrotoxic medications, urinary tract manipulations with resultant recurrent urinary tract infection and obstruction, and therapies leading to volume depletion. The differential diagnosis of renal failure in ESLD patients is not infrequently made more complicated by the potential development of hepatorenal syndrome (HRS). Despite the challenges involved, determination of the cause of renal failure in ESLD patients is necessary for short-term management, determination of renal prognosis, and evaluation for combined liver–kidney transplantation.

The following section discusses the various causes of renal dysfunction in the cirrhotic patients. Suggested medical management and preventive measures are also presented.

Renal failure as an entity independent of the cause of ESLD

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

Similar to patients without liver disease, the causes of renal failure in ESLD patients can be classified as pre-, intrinsic- and post-renal failure. 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 and possible urinary tract obstruction. Laboratory examination should include a routine urinalysis, urine electrolytes, a urine eosinophil count, a complete serum electrolyte panel and a renal ultrasound (Figure 1).2 Although pre- and post-renal failure can often be diagnosed based on clinical grounds and/or imaging studies, intrinsic renal failure may require a kidney biopsy. For those patients with a severe coagulopathy, either a transjugular venous approach or an open kidney biopsy may be considered.

Prerenal failure

Prerenal failure in ESLD patients is frequently multifactorial and may be due to true volume depletion, drug-induced renovasoconstriction, decreased effective circulating blood volume and/or sustained severe hypotension. Examples of common causes include variceal bleeding, severe ascites induced early satiety and poor oral intake, excessive use of diuretics, and lactulose-induced diarrhoea. Commonly prescribed medications that may potentially precipitate acute preglomerular type renal dysfunction include angiotensin-converting enzyme inhibitors, angiotensin receptor-blockers, non-steroidal anti-inflammatory drugs (NSAIDs) and contrast dye. Although selective cyclo-oxygenase (COX)-2 inhibitors such as celecoxib or rofecoxib were initially thought to be less nephrotoxic than that of non-selective NSAIDs, there has been increasing evidence suggesting that COX-2 inhibitors are as nephrotoxic as non-selective NSAIDs. Both classes of drugs can cause acute renal failure, particularly in patients in whom preservation of adequate renal perfusion is ‘prostaglandin-dependent’. Administration of COX-2 inhibitors has been reported to result in a marked reduction in the GFR in salt-depleted elderly subjects and in patients with cirrhosis and ascites.5, 6

Other potential causes of prerenal failure in ESLD patients include severe sepsis and HRS presumably because of decreased effective arterial blood volume and/or decreased arterial pressure. Spontaneous bacterial peritonitis has also been suggested to predispose ESLD patients to develop acute renal failure in the presence or absence of septic shock.7 Whether these patients have preglomerular type renal dysfunction alone is speculative. Finally, increased intra-abdominal pressure with resulting compromise of renal perfusion has been implicated in some patients with tense ascites.

Intrinsic renal failure

Intrinsic causes of acute renal failure may be classified according to the primary site of injury including the tubules, interstitium, glomerulus and intrarenal vessels. Although there are minimal data on the incidence of the different types of acute intrinsic renal failure in ESLD patients, small-vessel vascular causes of acute renal failure are uncommon. The United Network for Organ Sharing (UNOS) database revealed that over a nearly 4-year period of observation (05/01/1999–03/31/2003), only one of 595 combined kidney–liver transplants (0.17%) was performed for the renal diagnosis of haemolytic uraemic syndrome, and one for the renal diagnosis of progressive systemic sclerosis (0.17%).

Acute injury to the renal tubules leading to acute tubular necrosis (ATN) may be ischaemic and/or toxic in origin. In critically ill patients such as those with septic shock, ATN is commonly due to a combination of ischaemic injury and the use of nephrotoxins such as amphotericin B or aminoglycoside antibiotics. It has been suggested that the risk of developing aminoglycoside nephrotoxicity is 10-fold higher among cirrhotic patients compared with the general population.8

Acute renal failure because of interstitial nephritis is often due to drug-induced hypersensitivity reactions. Potential and common offending agents include sulpha drugs, oxacillin, nafcillin, ciprofloxacin, levofloxacin, cephalosporins, NSAIDs, and diuretics including hydrochlorothiazide, furosemide, triamterene and ethacrynic acid.

The incidence of glomerulonephritis causing acute renal failure or chronic kidney disease 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 to >130 μm, or proteinuria >0.5 g/day, glomerular lesions were identified in 41 of 55 patients (74.5%), interstitial in seven (12.7%), end-stage renal failure in two (3.6%) and normal biopsy in five (9.09%).9 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 pathology was found in 15 of 28 (53.5%), tubular in six of 28 (21.4%), end-stage renal failure in two of 28 (7.1%) and normal renal biopsy in four of 28 (14.2%). The glomerular lesions included membranoproliferative glomerulonephritis (MPGN) in five, nephrosclerosis in three, diabetic nephropathy in two, IgA nephropathy in two, minimal change disease in two, and early glomerulosclerosis in one.10

Renal failure as part of the disease entity associated with end-stage liver disease

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

Renal failure 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. Broad categories of conditions or diseases affecting both liver and kidney include infections, toxins, autoimmune or collagen vascular diseases, generalized vascular dysfunction, adult polycystic kidney disease, congenital diseases, neoplasms and metabolic disorders.2

Viral hepatitis and associated glomerular diseases

Viral infections such as hepatitis B and C are well-known to induce concomitant severe hepatic and renal injuries. The mechanisms whereby different viral infections induce distinct glomerular lesions and/or systemic complications have not been fully elucidated. Circulating and most likely in situ immune complexes involving viral antigens and host anti-viral antibodies have been implicated in hepatitis B- associated membranous glomerulonephropathy (MGN). The hepatitis B e antigen (HBeAg) has been reported to be prevalent in MGN and presumably because of its size, has been found to localize in the subepithelial spaces in MGN.11 The presence of HbsAg has also been reported to be associated with membranoproliferative glomerulonephropathy and IgA nephropathy.12

Hepatitis C is most commonly associated with membranoproliferative glomerulonephropathy with or without mixed cryoglobulinaemia. Mixed cryoglobulinaemia may be classified as type II [monoclonal rheumatoid factor (RF) and polyclonal immunoglobulin] or type III (both RF and immunoglobulin are polyclonal). While the prevalence of cryoglobulinaemia in patients with hepatitis C has been reported to range from 18% to over 50% (reviewed in Ref.13), up to 90% of unselected patients with cryoglobulinaemia has been shown to have anti-HCV. Type II mixed cryoglobulinaemia observed in patients with hepatitis C appears to reflect the chronic HCV-induced benign monoclonal proliferation of B cells expressing the RF with specific cross-reactive idiotype known as WA that may recognize an antigen of hepatitis C virus (HCV). Accordingly, cryoprecipitates in patients with hepatitis C have been reported to comprises HCV virions, HCV antigen–antibody complexes, most commonly in association with the WA type of RF.14

Glomerular involvement observed with HCV is typically MPGN type I with or without associated cryoglobulinaemia. Clinical manifestations include proteinuria, non-nephrotic to nephrotic range, microscopic haematuria, renal insufficiency presenting as either a chronically progressive or rapidly progressive glomerulonephritis. The pathogenesis of MPGN type I is believed to result from glomerular deposition of circulating immune complexes preferentially in the mesangium and subendothelial space, with subsequent activation of complements via the classical pathway and associated inflammatory response.15 Other glomerular lesions observed in patients with HCV include MGN, IgA nephropathy, postinfectious glomerulonephritis, focal segmental glomerulosclerosis, fibrillary glomerulonephritis and immunotactoid glomerulopathy.16

Therapy in HCV-related cryoglobulinaemia and renal disease is targeted at suppressing the immune response as well as viral replication. In severe cases of cryoglobulinaemia with glomerulonephritis or vasculitis, immunosuppressive therapy with corticosteroids with or without cyclophosphamide and plasmapheresis with the addition of combination anti-viral therapy using peginterferon and ribavirin for 48 weeks have been advocated.16 It should be noted, however, that the use of immunosuppressive therapy in these patients may increase viral titres and potential worsening of the underlying hepatic disease and the use of ribavirin may be limited in cases of significant renal insufficiency. More recently, the use of monoclonal antibody to B cells CD-20 (rituximab) has also been suggested to be beneficial in refractory cases.17

In addition, active hepatitis B18, 19 and in rare case reports, hepatitis C20 have also been implicated in the development of polyarteritis nodosa, presumably via deposition of immune complexes and resultant systemic necrotizing inflammation in small- and medium-sized arteries. Multiple organs including the skin, peripheral nerve, gut, kidney and heart may be affected. Renal involvement may present clinically with proteinuria, micro- and macro-scopic haematuria, renal failure and hypertension. Medical management in the acute inflammatory phase in hepatitis B-associated polyarteritis nodosa (PAN) may include short-term prednisone at 1 mg/kg/day (tapered by 2 weeks) followed by plasmapheresis (tapered by 6 weeks) and anti-viral therapy with lamivudine 100 mg/day or less (as dictated by renal function over a maximum of 6 months) to avoid the development of a chronic hepatitis carrier state and subsequent cirrhosis in survivors.21

Renal failure in alcoholic hepatitis

Renal failure in alcoholics may also be associated with IgA nephropathy,22, 23 recurrent myoglobin-induced renal failure from rhabdomyolysis,24 associated with severe electrolyte abnormalities, particularly hypophosphataemia and alcoholic myopathy, ingestion of ethylene glycol with resultant urinary calcium oxalate precipitation, or high-dose acetaminophen/paracetamol25 and ATN. The latter may also result from volume depletion or severe renal vasoconstriction by systemic endotoxaemia because of impaired hepatic toxin clearance and potential exacerbation by thiamine deficiency.26

Despite the common occurrence of alcoholic hepatitis and its grave complications, therapeutic options remain limited. Besides abstinence and non-specific therapy with corticosteroids in selected cases, targeted therapy with the tumour necrosis factor –α inhibitor, pentoxifylline has been advocated in recent years. In a 4-week double-blind randomized study, Akriviadis et al. reported improvement in short-term survival in patients with severe alcoholic hepatitis treated with pentoxifylline 400 mg orally three times a day compared with placebo. The survival benefit was felt to be related to a significant decrease in the risk of developing HRS.27

Other disease processes that may involve both the liver and kidney at varying degrees include haemochromatosis, acute fatty liver of pregnancy, sickle cell disease, ulcerative colitis and toxaemia of pregnancy.28 Typically mild, renal injury in association with haemochromatosis has been suggested to result from iron overload induced tubular dysfunction and increased susceptibility to ischaemic injuries.29, 30 Although the pathogenesis of acute renal failure (ARF) in acute fatty liver of pregnancy is not understood, its incidence has been reported to be over 60% in the USA.31Table 1 lists the diseases or conditions known to affect both the liver and kidney that are commonly encountered in orthotopic liver transplantation (OLT) and combined kidney liver transplant (CKLT) candidates. For a more extensive review of the glomerular and interstitial diseases associated with liver disease readers are referred to reference.28

Table 1.  Conditions known to affect both liver and kidney
Liver diseaseAssociated renal disease
  1. MGN, membranous glomerulonephropathy; MPGN, membranoproliferative glomerulonephritis; IgA, immunoglobulin A; RTA, renal tubular acidosis; ANCA, antineutrophil cystoplasmic antibodies; GBM, glomerular basement membrane.

Chronic liver cirrhosis
 Parenchymal liver disease
  Hepatitis BMGN, MPGN, PAN
  Hepatitis CMPGN ± cryoglobulinaemia, MGN, fibrillary GN, immunotactoid GN, IgA, postinfectious GN
  Alcoholic cirrhosisIgA, hepatic sclerosis
  Autoimmune hepatitisImmune complex GN, RTA
 Primary cholestatic disease
  Primary biliary cirrhosisMGN, ANCA (+) vasculitis, RTA
  Cryptogenic cirrhosisIgA, hepatic sclerosis
 Vascular disease
  Budd-Chiari syndromeMetastatic renal cell carcinoma
Acute fulminant hepatic failure
 Drug induced (acetaminophen, halothane) 
 Metabolic liver disease (Reyes’ syndrome) 
Inborn error of metabolism
 Glycogen storage disease type 1Focal glomerulosclerosis
 α1-Antitrypsinogen deficiencyMPGN, anti-GBM disease
 Wilson's diseaseFanconi's syndrome
Miscellaneous
 Polycystic liver diseasePolycystic kidney disease
 Primary hyperoxaluria type IInterstitial fibrosis

Renal failure as a consequence of end-stage liver disease

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

Hepatorenal syndrome

Also known as functional renal failure secondary to ESLD, HRS was first described by Austin Flint in 1863 in a clinical analysis of 46 cases.32 Although its pathogenesis is complex, HRS has long been recognized to be reversible with a well-functioning OLT. Depending on the duration and severity of HRS, however, the reversibility of HRS following liver transplantation is usually delayed and incomplete. The probability of HRS occurrence among non-azotaemic cirrhotic patients with ascites at 1, 2 and 5 years has been reported to be 18%, 32%, and 39–41%, respectively.33, 34

Definition, clinical features and diagnosis of HRS

The HRS can be loosely defined as impaired renal function that occurs in patients with chronic advanced or acute liver failure because of marked renal vasoconstriction and concomitant extrarenal vasodilatation. In 1990, the International Ascites Club (IAC) met in Florence, Italy to focus on research involving the mechanisms of circulatory and renal dysfunction in liver diseases and set forth major and minor diagnostic criteria of HRS that are now widely used (Table 2).35 Based on the IAC definition, the HRS ‘…is 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’.

Table 2.  Criteria proposed by the International Ascites Club (IAC) for the diagnosis of hepatorenal syndrome (HRS)
Major criteria
 Chronic or acute liver disease with advanced hepatic failure and portal hypertension
 Low glomerular filtration rate (serum creatinine > 1.5 mg/dL or 24-h creatinine clearance <40 mL/min)
 Absence of shock, ongoing bacterial infection, current or recent treatment with nephrotoxic drugs, excessive gastrointestinal or renal fluid losses
 No sustained improvement in renal function following diuretic withdrawal and plasma volume expansion with 1.5 L isotonic saline
 Proteinuria <500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal disease
Minor criteria
 Urine volume <500 mL/day
 Urine sodium <10 mm
 Urine osmolality greater than plasma osmolality
 Urine red blood cells <50 per high power field
 Serum sodium concentration <130 mm

Predictors for the development of HRS have been suggested to include liver size, serum sodium concentration <133 mm, elevated plasma renin >3.5 ng/mL/h, and increased resistive index of renal arcuate and interlobar arteries >0.7 by Doppler ultrasound studies.36, 37 It should be noted that while Gines et al. found that neither the aetiology of liver failure nor the Child-Pugh score had any positive predictive value for the development of HRS36 Platt et al. reported that two major determinants of the Child-Pugh score including total bilirubin (P < 0.05) and prothrombin time (PT) (P < 0.05) are independent predictive indicators for HRS.37

The IAC further subtyped HRS into types I and II to facilitate successful multicentre trials. Whereas the former includes patients with rapidly progressive renal failure with doubling of the SCr to a level >2.5 mg/dL or CCr reduction of >50% within 2 weeks, the latter includes patients with a more moderate or stable reduction in renal function. Once patients develop HRS, spontaneous recovery of renal function is rare (3.5%) and the median survival is <2 weeks without therapeutic intervention.

Pathogenesis of HRS

Although the pathogenesis of HRS is not completely understood, it has been suggested to represent the decompensated renal state in response to, or responsible for, ascites formation in cirrhotic patients. Three major hypotheses linking the alterations of renal haemodynamics and ascites formation have been proposed. The pathogenesis of ascites formation and HRS is not clearly understood. Nevertheless, several hypotheses have been proposed. The overflow hypothesis is based on a primary increase in portal vascular resistance, in which intrahepatic mechanoreceptors sense decreased hepatocyte perfusion and activate a hepatorenal reflex that causes severe renovasoconstriction with associated water and sodium retention, increased circulating blood volume, and eventually, overflow of fluid into the peritoneal cavity.38 The underfilling hypothesis suggests that accumulation of blood in the splanchnic circulation and increased splanchnic lymph production are primary defects contributing to a decreased effective intravascular volume and associated stimulation of the rennin-angiotensin system.39 The theory of peripheral arterial vasodilatation proposes a primary fall in peripheral vascular resistance with resulting arterial underfilling and associated hyperdynamic circulation and compensatory activation of various vasoconstrictor systems including renal vasoconstriction with sodium and water retention.40 While the peripheral vascular resistance may be further decreased and renal vasoconstriction further increased with relative normal renal function in the compensated state, severe renal vasoconstriction with excess sodium and water retention in the decompensated state results in ascites formation and the development of HRS. Although the last hypothesis is more popular, all three hypotheses have been challenged by experts in the field.

Management of HRS

Before the availability of liver transplantation, HRS was regarded as universally fatal. Survival following the development of HRS (type I) without renal replacement therapy and OLT is generally 2–3 weeks.33, 41 Spontaneous recovery from HRS is rare unless there is an improvement in liver function.42, 43 Ideally OLT is the treatment of choice for patients with HRS and ESLD. However, due to the limited supply of deceased donor organs, management of HRS in OLT candidates is often restricted to preventive measures and supportive care.

As HRS may be precipitated by therapies directed at the complications of cirrhosis, any such therapy has to be closely monitored. The potential benefits of diuretics, lactulose, contrast dye exposure, nephrotoxic medications, NSAIDs and selective COX-2 inhibitors have to be carefully balanced against the risk of precipitating HRS. Large volume paracentesis in patients with severe hypoalbuminaemia or ascites without peripheral oedema are thought to be at increased risk for the development of acute volume depletion and potential HRS.44 In these cases, the use of plasma expanders has been advocated. In general, albumin is felt to be more effective than artificial plasma expanders in the prevention of circulatory dysfunction. Nevertheless, not all investigators agree that plasma expansion is necessary during large volume paracentesis or that paracentesis can precipitate HRS.44–47 The use of albumin infusion among cirrhotic patients with SBP, on the other hand, has been more recently suggested to reduce the risk of renal failure and mortality, especially among those who present with renal insufficiency and hyperbilirubinaemia at the time of diagnosis.48, 49

Non-transplant management of HRS may be dictated by the severity of liver failure and the availability of different treatment modalities.

Transjugular intrahepatic shunt placement (TIPS) has been designed to divert portal blood flow to the hepatic vein, thereby redistributing splanchnic and portal blood centrally and effectively improving both variceal bleed and renal perfusion.50 Clinically, TIPS has been shown to increase urinary sodium excretion51–53 and in some studies52 improvement of renal function and reduction in the de novo development of HRS or conversion from type II to type I.54 The limitations of TIPS placement, however, include worsening of liver function and hepatic encephalopathy.50 For these reasons, TIPS is generally reserved for patients with Child-Pugh class B or early C. Survival improvement with TIPS has only been reported in selected patients.

For patients with more advanced liver disease, medical therapies with various vasoactive agents have resulted in different degrees of success. Vasoactive agents used in the treatment of HRS include renal vasodilators such as saralasine, dopamine, misoprostol and endothelin (ET)-A antagonists and/or splanchnic vasoconstrictors such as octapressin, ornipressin, terlipressin and octreotide.

An early study involving saralasine, an angiotensinogen antagonist, only led to worsening of systemic hypotension and did not improve renal function.55 Renal dose dopamine previously used for acute renal failure in critically ill patients failed to significantly improve renal function in patients with HRS.56, 57 Reports on the benefit of combination administration of dopamine and vasopressors in HRS have been inconsistent.57 As ET-1 has been proposed to play a role in both renal and hepatic vasoconstriction in HRS, the use of ET antagonist has also been suggested to ameliorate HRS. In an anecdotal report involving three patients, Soper et al. documented a dose-dependent renal improvement during treatment with the ET-A antagonist BQ123, but unfortunately, all patients subsequently died.58 Low doses of misoprostol, a synthetic prostaglandin E1 analogue, are vasodilatory, natriuretic and diuretic, and are therefore, potentially beneficial in HRS. Nevertheless, none of the HRS studies involving misoprostol therapy revealed substantial and/or conclusive benefit.59–62

The rationale for the use of splanchnic vasoconstrictors is the reduction in splanchnic organ blood flow and resultant reduction of portal blood flow and pressure. Splanchnic vasoconstrictors used in the management of HRS include the vasopressin synthetic analogues octapressin, ornipressin and terlipressin. Octapressin, when infused at low doses (0.004–0.002 units/min) produced an increase in renal blood flow with an associated decrease in renal vascular resistance. At higher doses, however, renal vascular resistance increased significantly, and changes in renal blood flow diminished. In an earlier study involving 11 patients, only four of five patients who had a systemic improvement in blood pressure >5 mmHg, had improvement of renal perfusion. The drug only appeared to work for hypotensive patients who responded with increased blood pressure. Despite temporary improvement in renal haemodynamics and function, all patients eventually died.63

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. Unfortunately, with prolonged infusion, complications including intestinal and tongue infarctions and arrhythmias were reported.64–66

To date, the most widely studied splanchnic vasoconstrictor and perhaps most promising medical therapy in the treatment of HRS is terlipressin with or without albumin infusion. Unlike ornipressin, terlipressin has a longer biological half-life, which allows for administration as a 4 h bolus. In 1995, 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 q 12 h over a 48-h period.67 In 1996, Ganne-Carrie et al. reported the successful use of long-term treatment with terlipressin as a bridge to liver transplantation.68 Based on the favourable outcomes of these reports, a series of studies on the effect of terlipressin in patients with HRS were performed using different protocols including variations in dosages, duration of terlipressin infusion and addition of albumin. Most of these studies were prospective open studies involving mostly type I HRS patients. Overall, there was an improvement in renal function and a significant improvement in survival compared with that reported by Gines et al.69–74 Unlike previous vasopressin analogues, side-effects of terlipressin have been reported to be minimal and reversible with dose reduction or discontinuation. More recently, a randomized placebo-controlled clinical trial similarly confirmed that terlipressin administered at 1 mg intravenously at 12-h intervals over a study period of 15 days significantly improved renal function and systemic haemodynamics, and a trend towards better clinical outcome.75 Another potentially beneficial approach to the use of terlipressin is the addition of albumin infusion. Although inconclusive, available data appear to suggest that the addition of albumin may be beneficial in terms of better response rates and greater reduction in SCr.69, 74

Anecdotal reports and smaller studies of therapies that may benefit patients with HRS include noradrenaline plus albumin,76N-acetylcysteine77 and the combination of octreotide, midodrine and albumin.78

In patients with complete renal failure, various renal replacement therapies including intermittent haemodialysis (HD), continuous renal replacement therapy and molecular adsorbent recirculating system (MARS; Teraklin, AG, Rostock, Germany) may be performed as a bridge to liver transplantation. The choice of intermittent HD vs. continuous renal replacement therapy is often based on the clinical condition of the patient. In patients with severe liver disease and significant hypotension, intermittent HD may worsen the haemodynamic status.79 Slow continuous correction of volumes and solutes with continuous renal replacement therapy (CRRT) [preferably in the form of continuous venovenous haemodialysis (CVVHD)] is preferred. It is speculated that the removal of inflammatory cytokines such as tumour necrosis factor, interleukin (IL)-6, IL-8 and IL-10 may partly explain the better cardiovascular stability seen in patients treated with CRRT compared to those treated with intermittent HD.80 More recently it has been suggested that the MARS might offer survival advantage over dialysis therapy in type I HRS patients awaiting liver transplantation. MARS is based on the concept that kidney dialysis removes only water-soluble toxins, while the liver removes albumin-bound toxins. In Teraklin's MARS system, blood is cleansed in an extracorporeal circuit designed as a combination of both kidney and ‘liver dialysis’. For this reason, in addition to a conventional kidney dialysis, MARS uses human albumin in a second closed loop circuit to cleanse the blood of albumin-bound toxins, hence mimicking the detoxification function of the liver. Additional toxins that may be dialysed by the Teraklin's MARS system include bilirubin, bile acids, phenols, mercaptans, dioxin-like substances, tryptophan, ammonia, copper and iron. Although MARS has shown promising results in some reports,81,82 its use is not without criticisms. In addition to its limited availability and data involving large randomized-controlled trials and costs, MARS has been reported to induce coagulopathy,83 non-cardiogenic pulmonary oedema84 and hypoglycaemia in non-diabetic patients.85

Although liver transplantation is the ultimate life-saving procedure, bridging therapies including TIPS, the use of vasoconstrictors, and MARS have been shown to have marginal to moderate improvement in short-term survival. A recent review of pooled data to evaluate the impact of TIPS and vasoconstrictors on survival in patients with HRS suggests that both TIPS and vasoconstrictors do improve short-term survival compared to the traditional treatment with paracentesis with or without the addition of dopamine.86 Nevertheless, it should be noted that TIPS placement is only appropriate in selected patients with lower Child-Pugh scores while vasopressors may be used in patients with more advanced liver disease. Finally, MARS remains to be proven a viable option for patients with the most advanced liver failure.

Orthotopic liver transplantation: treatment of choice for HRS

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

Ideally, all suitable candidates with HRS should be considered for OLT. While the advent of TIPS, vasoconstrictors, and/or MARS variably improve short-term survival in selected patients with HRS, OLT is currently still believed to be the only curative treatment. In an early series of 56 patients with HRS undergoing OLT at Baylor University Medical Center, actuarial patient and graft survival at 5-years were 60% and 51%, respectively.87 It should be noted that the 5-year patient survival rate of 60% is far superior to any non-transplant treatment modalities currently available for this disease.

Outcome in patients with HRS following liver alone transplantation

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

The functional nature of HRS was first suggested by Koppel et al. in 1969 who noted reversal of renal dysfunction following transplantation of cadaveric kidneys from patients with HRS into patients with a normal liver.88 This reversal was later confirmed by Iwatsuki et al. in 1973 who demonstrated recovery from HRS after OLT.89 There is now ample literature documenting the potential for recovery of HRS following OLT.2 Liver only transplantation rather than CKLT should, therefore, be the initial consideration in patients with ESLD and associated HRS.

Compared with non-HRS patients, patients with HRS have been shown to be more likely to require dialysis in the pre- and post-transplant period.87, 90 Management of HRS in the post-transplant period includes dialysis support and judicious use of calcineurin inhibitors (CNI) or CNI-sparing protocol at the discretion of the transplant doctor. Early reports from our centre revealed that in patients with HRS, modification of the immunosuppressive protocol resulted in a 20% decrease in the requirement for post-operative dialysis.91 Following a successful OLT, renal function invariably improved over time although at long-term follow-up renal function in patients with HRS remained inferior to that of non-HRS patients.87, 90 In a retrospective study consisting of 834 recipients of OLT who survived 6 months after transplant, Gonwa and Wilkinson91 have shown that patients with HRS, particularly those requiring dialysis the first 3 months after transplant had the greatest risk for developing chronic renal failure (defined as sustained SCr > 2.5 mg/dL) and end-stage renal disease (ESRD). Among those with HRS, 7.9% developed chronic renal failure (CRF) and 11.4% developed ESRD at 13 years follow-up compared with 4.4% and 4.4%, respectively for those without HRS (P = 0.04).92

In a large retrospective study conducted to evaluate the incidence of CRF in recipients of non-renal organ transplants that included intestine, liver, heart and heart–lung transplants, the 5-year risk of CRF [defined as GFR < 29 mL/min/1.73 m2 bovine serum albumin (BSA) or ESRD] has been shown to vary from 6.9% among recipients of heart–lung transplants to 21.3% among recipients of intestine transplants.93 Hence, despite an increased incidence of CRF/ESRD in OLT recipients with HRS compared to those without HRS, it should be noted that the 7.9% risk of CRF and 11.4% risk of ESRD at 13 years were less than or comparable with the risk of developing CRF among recipients of other non-renal solid organ transplants, re-emphasizing that patients with renal dysfunction because of HRS should receive a liver-only transplant; however, when patients with presumed HRS or ATN require dialysis for more than 4–6 weeks before transplantation, renal cortical fibrosis may develop and renal function may not recover. Under these circumstances, simultaneous liver–kidney transplantation is recommended. However, it should also be noted that recovery of renal function following OLT has been reported to occur in patients who require pre-OLT dialysis for over 2-month duration. Although there have been no well-defined clinical criteria to determine the potential for renal function recovery in those patients who remain dialysis-dependent for a prolonged period of time, evaluation of renal cortical blood flow by means of renal Doppler ultrasound, renal scan, and/or gadolinium-enhanced magnetic resonance imaging (MRI) may be helpful adjunct(s) to clinical assessment. A markedly decreased or absence of cortical blood flow suggests irreversible renal failure and CKLT should be considered.

Indications for combined kidney–liver transplantation

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

The UNOS database on the renal indications for CKLT

Between January 1988 and 30 April 1999 the most common renal indications for CKLT reported to the UNOS organ procurement transplant network (OPTN) Scientific registry database were polycystic kidney disease (7.3%), followed by oxalate nephropathy (6.3%), unspecified chronic glomerulonephritis (5.2%), ciclosporin nephrotoxicity (4.3%) and kidney retransplant/graft failure (3.6%).2

More recent UNOS OPTN data collected between 1 May 1999 and 31 March 2003 indicates that polycystic kidney disease (PCKD) remains a common renal diagnosis in recipients of CKLT (7.39%).94 During that time period, however, CKLT was performed with an increasing frequency in patients with renal failure because of diabetic nephropathy (type II insulin-dependent and non-insulin-dependent, adult onset) and ciclosporin nephrotoxicity (10.58% and 6.22%, respectively).95 It is conceivable that early or unrecognized diabetic nephropathy and/or ciclosporin nephrotoxicity progressed with time after transplantation and the incidence of severe chronic kidney disease increased over time among long-term survivors of OLT recipients.

With the introduction of the model for end-stage liver disease (MELD) score for the allocation of OLT in February 2002, an abrupt increase in the number of CKLT was observed at the UCLA Kidney and Liver transplant program during an 8-month study period from March 2002 to 1 October 2002 (average number of CKLT performed before and after the adoption of MELD score: 4–6 vs. 8, respectively).

Analysis of the UNOS database revealed a nearly 84% increase in the number of CKLT performed between 27 February 2002 and 30 June 2003 compared with the immediate previous 16-month period (between 1 November 2000 to 26 February 2002). During a 16-month period, the total number of CKLT performed before and after the adoption of MELD score were 161 vs. 287, respectively. As the MELD score-based allocation of OLTs prioritizes patients with renal dysfunction, the prevalence of various renal indications for double organ transplantation has changed over time. During the study period, CKLT was increasingly performed for the renal diagnosis of ciclosporin nephrotoxicity [before and after the MELD era: 1.86% vs. 6.97%, respectively (UNOS database as of June 2003)].94

Indications for CKLT: current views

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

For OLT candidates with simultaneous end-stage kidney failure, CKLT is a well-established effective therapeutic option for virtually all suitable candidates. However, there have been no well-defined guidelines to determine whether a kidney transplant should be offered to OLT candidates who have chronic kidney disease or who have prolonged HRS or ATN while awaiting a liver transplant. Accurate assessment of the degree of renal dysfunction may be difficult in the former and predicting the extent of renal function recovery in the latter may be equally challenging. However, when patients with presumed HRS or ATN require dialysis for more than 4–6 weeks, CKLT is recommended. In patients with mild to moderate chronic kidney disease (SCr > 2 mg/dL), more accurate determination of GFR by nuclear studies should be performed. Kidney biopsy may be required to resolve any diagnostic or therapeutic dilemma. End-stage liver disease patients with severe chronic kidney disease (GFR, 20–30 mL/min) may benefit from pre-emptive kidney transplantation immediately following OLT in anticipation of further worsening of renal failure in the post-transplantation period with the introduction of ciclosporin or tacrolimus. A well-functioning kidney facilitates post-operative management and avoids severe complications associated with renal failure. In diseases that involve both the liver and the kidney such as polycystic kidney and liver disease and primary hyperoxaluria type I, CKLT is not necessarily performed as a result of end-stage failure of both organs (for a more extensive review of the indications for CKLT in polycystic kidney and polycystic liver disease and primary hyperoxaluria type I, readers are referred to Ref. 95).

Conclusion

  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References

Early recognition and determination of the cause of renal dysfunction in ESLD patients can be difficult because of the potential interplay among various factors and the wide array of differential diagnoses. Nonetheless, a systematic approach can assist clinicians to identify common and potentially reversible causes of acute renal failure. Distinguishing patients with functional renal failure such as HRS from those with advanced irreversible disease can have important prognostic and therapeutic implications. Isolated liver transplantation is the treatment of choice for the former, whereas CKLT may be an option for the latter. Non-transplant management of HRS including TIPS, vasoconstrictors and/or MARS have been reported to result in marginal to moderate improvement in short-term survival in selected candidates and may be performed as a bridge to liver transplantation. Following OLT, despite an increased incidence of CRF/ESRD in patients with HRS compared with their non-HRS counterpart, it should be noted that in most patients with HRS, renal function recovers to an acceptable level and these patients should receive a liver only transplant. However, in patients with HRS requiring prolonged dialysis (>4–6 weeks), irreversible renal failure may develop and CKLT is justifiable. With the ever-increasing disparity between demand and supply of deceased donor organs, CKLT should be used judiciously. A renal biopsy may be required in the evaluation process. Although timely referral of patients for OLT may avoid potential severe renal complications and obviate the need for double organ transplantation, the growing shortage of donor organs is emerging as an obstacle to early transplantation despite the current effort to expand the donor pool by using marginal donor organs, split liver transplants and living donor transplants. Hence, management of OLT candidates requires continued assessment of their overall medical condition in general and in particular, their renal complications.

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  1. Top of page
  2. Summary
  3. Assessment of renal function in end-stage liver disease patients awaiting liver transplantation
  4. Renal failure as an entity independent of the cause of ESLD
  5. Renal failure as part of the disease entity associated with end-stage liver disease
  6. Renal failure as a consequence of end-stage liver disease
  7. Orthotopic liver transplantation: treatment of choice for HRS
  8. Outcome in patients with HRS following liver alone transplantation
  9. Indications for combined kidney–liver transplantation
  10. Indications for CKLT: current views
  11. Conclusion
  12. Acknowledgement
  13. References
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