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Liver disease and renal dysfunction
SYSTEMIC DISEASE AND THE KIDNEY
Liver disease and renal dysfunction
Difficulties in measuring renal function Using serum creatinine as a marker of renal function has many shortcomings in normal individuals and is even more problematic in patients with cirrhosis as the concentration is frequently lower than expected if true glomerular filtration rate (GFR) is measured, falsely reassuring the unwary. Malnutrition, a reduced muscle mass, and impaired creatine synthesis by a failing liver result in low creatinine production rates, and tubular secretion of creatinine is increased in cirrhosis.2 Finally, the measurement of creatinine by photocolorimetric methods (e.g. the kinetic Jaffe reaction commonly used in UK laboratories) is erroneous in the presence of hyperbilirubinaemia.3 It follows that equations using creatinine to estimate renal function (e.g. Modification of Diet in Renal Disease (MDRD)) usually grossly overestimate the GFR (see Assessment of kidney function in adults in Medicine 2011; 39(6): 306e311). The use of newer biomarkers, such as cystatin C, may be more accurate but isotopic methods need to be used if a precise measure is needed.4 Urea kinetics are similarly perturbed and low serum urea values are common in cirrhosis, again reflecting hepatic underproduction and malnutrition. However, a relatively high urea suggests that a search for gastrointestinal blood loss from variceal bleeding or other sites may be appropriate. Bile acids may be directly involved in the renal dysfunction associated with obstructive jaundice. The mechanism is unclear but may involve direct renal tubular damage. This sometimes leads to acute kidney injury with normal urine output or polyuria.5
Partha Das Stephen Holt
Abstract Renal dysfunction frequently complicates liver disease and, when present, adversely affects prognosis. While a number of conditions can affect both the liver and the kidney acutely (e.g. paracetamol), many hepatotoxic insults (e.g. alcohol or viral hepatitis) cause more problems associated with cirrhosis. This review focuses mainly on the renal dysfunction associated with this chronic liver damage. Chronic liver disease is implicated in changes in vascular reactivity and tone, resulting in a systemic vasodilatation and renal vasoconstriction. In its extreme form it leads to the most feared of all renal complications of liver disease, the hepatorenal syndrome (HRS), which is frequently fatal. The recognition and early management of both the renal dysfunction and liver disease are important to survival. The key therapeutic issues revolve around optimizing the circulating volume, reversing the maladaptive haemodynamic changes, removal of other potential nephrotoxins and early treatment of infection.
Keywords hepatorenal syndrome; kidney diseases; liver cirrhosis; liver diseases
Immune events in cirrhosis Liver disease is accompanied by increased bacterial translocation from the gut to the portal and systemic circulation. Bacterial products activate the cellular immune system, increasing nitric oxide (NO) production and causing an increase, and probably phenotypic change, in circulating immunoglobulin (Ig) (especially IgA). It is not known whether this reflects an increase in production or a reduction in clearance, or both, but it may explain the link between cirrhosis and a number of glomerulonephritides, especially IgA nephropathy, that are clearly associated with liver disease.6
Four percent of the general population has abnormal liver function tests and up to 20% of those develop cirrhosis. Many experts are predicting a chronic liver disease epidemic in the next few decades, due largely to the impact of viral hepatitis, obesity and alcohol use. Patients with liver disease frequently have co-existent renal dysfunction, due to the liver disease itself, its treatment, or more often both. This is subclinical in its early stages, but when present, increases risk.1 In addition, 50% of patients with acute liver failure develop renal dysfunction. While there are a number of causes of renal dysfunction in liver disease, this article focuses on cirrhosis as a cause for renal dysfunction.
Haemodynamic events in cirrhosis The destruction of the architecture in the cirrhotic liver, and functional changes in hepatocytes and other hepatic cell lines (e.g. Ito cells) lead to an increase in the resistance to portal blood flow. There is an accompanying systemic vasodilatation, due to the action of NO and other mediators.7 This leads to a reduction in systemic vascular resistance (SVR) in most vascular beds, leading to a fall in mean arterial pressure (MAP) and a compensatory increase in cardiac output (CO) (Ohm’s law: CO ¼ MAP/ SVR). Therefore, these patients tend to have warm peripheries, a tachycardia with high-volume pulse and a low blood pressure. Homeostatic responses to the fall in SVR include activation of the renineangiotensinealdosterone system (RAAS) and the sympathetic nervous system (SNS). Together with locally produced vasoconstrictors and a neural reflex, renal vasoconstriction ensues (see Figure 1). There is also a non-osmotic release of antidiuretic hormone (ADH). This combination of factors causes
Partha Das MRCP is a Registrar in nephrology on the South Thames Specialist Renal Rotation currently at Guys Hospital, UK. Competing interests: none declared. Stephen Holt PhD FRCP is currently Associate Professor of Nephrology at the Department of Renal Medicine, Monash University, Melbourne, Australia. Formerly, Consultant Nephrologist and Honorary Senior Lecturer at Brighton and Sussex University Hospitals, UK. Qualified from the Middlesex Hospital and trained in nephrology mainly at the Royal Free Hospital, London. His research interests include renal dysfunction in liver disease. Competing interests: none declared.
MEDICINE 39:8
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
Mechanisms of haemodynamic changes affecting the renal vasculature in liver disease Endotoxin and other gut-derived toxins/cytokines Portosytemic shunts
Portal vein Liver
Systemic circulation
Hepatorenal reflex
Local vasoconstrictors, e.g. ET, Tx, IP
NO, PGI2, SP, CGRP, glucagon Vasodilatation in systemic and splanchnic circulation
SVR ↓ Cardiac output ↑ Activation of RAAS/SNS
Renal vasoconstriction
Non-osmotic AVP release
Sodium retention
Failure to excrete a water load
Reduced GFR
These changes result in systemic vasodilatation and renal vasoconstriction. The net result is sodium and water retention and reduced renal function. AVP, arginine vasopressin; CGRP, calcitonin gene related peptide; ET, endothelin; GFR, glomerular filtration rate; IP, isoprostanes; NO, nitric oxide; PGI2, prostacyclin; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system; SP, substance P; SVR, systemic vascular resistance; Tx, thromboxanes.
Figure 1
Management of renal dysfunction
sodium and water retention, leading to ascites and peripheral oedema, hyponatraemia, oliguria, low urinary sodium (sometimes <10 mmol/litre) and often a low fractional excretion of sodium (FENa; often as low as <1%).
Rationalization of drug treatment Removing all potential nephrotoxins is essential in minimizing further renal parenchymal damage. This includes non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and aminoglycoside antibiotics. Ascites and/or oedema are frequently treated with spironolactone (100e400 mg/day), which may provoke hyperkalaemia. Furosemide (40e160 mg/day) is often added if ascites proves resistant, but both drugs risk reducing intravascular volume, thereby exacerbating renal dysfunction and causing hyponatraemia. Withdrawal of diuretics is recommended for severe hyponatraemia (serum sodium <120 mmol/litre).9 Tolvaptan is a novel antagonist of arginine vasopressin (AVP) at its V2 receptor and blocks water reabsorption in the renal collecting ducts. It does not cause sodium excretion and, although not currently licensed for use in the UK, is of potential benefit in cirrhotic patients with ascites/oedema and hyponatraemia.10
Acute kidney injury (AKI) in liver disease The classification of AKI into pre-renal, intrinsic renal and postrenal causes is useful when evaluating renal failure in patients with liver disease. The causes of AKI are far more commonly intravascular volume depletion, sepsis and drugs than the hepatorenal syndrome (HRS), and early recognition and treatment can prevent significant morbidity and mortality. HRS is an extreme but potentially reversible form of functional renal failure that occurs in up to 40% of patients with advanced liver disease each year. There are generally no pathognomic histopathological changes on renal biopsy in HRS. It is a diagnosis of exclusion with the major diagnostic criteria outlined in Table 1. There are two main subtypes. Type 1 develops rapidly and is often precipitated by bacterial infection (especially SBP), variceal haemorrhage, major surgery or any acute hepatic insult to an already cirrhotic liver. It is associated with a poor prognosis, with a median survival of 2 weeks after diagnosis. Type 2 HRS develops more insidiously with slightly better survival (median survival 6 months), although mortality is still high as most patients will progress to a type 1 pattern following a metabolic or other insult. Overall, the prognosis is probably related to the cause of the renal dysfunction.8
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Fluid balance The combination of a hyperdynamic circulation and reduced effective arterial blood volume in patients with cirrhosis makes avoiding intravascular volume depletion critical. Central venous pressure (CVP) and other forms of invasive cardiac output/ systemic vascular resistance monitoring can be helpful as a guide to assessing volume status, but it is often difficult to expand intravascular volume in this cohort of patients without
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
5 days is recommended, together with fluconazole 50 mg daily for anti-fungal prophylaxis. Patients presenting with SBP even in the absence of septic shock have a high risk of developing severe hepatic insufficiency, encephalopathy and type 1 HRS. Intravenous albumin has been shown to improve survival in SBP. Recurrent infection occurs in 70% of SBP survivors and prophylactic oral norfloxacin 400 mg or ciprofloxacin 500 mg daily should be considered thereafter. Concomitant SBP or other bacterial infection in the context of gastrointestinal haemorrhage is a major problem and is associated with a higher risk of failure to control bleeding, a greater incidence of re-bleeding and increased mortality. Selective gut decontamination with either a quinolone (norfloxacin 400 mg twice daily for 7 days) or ceftriaxone (intravenous for high-risk patients or those having repeated luminal instrumentation) should be considered in patients presenting with cirrhosis and variceal bleeding. Treatment for chest infections in patients with liver disease should include cover for anaerobes, as patients are susceptible to periods of reduced conscious level (encephalopathy or alcohol) and are therefore at risk of aspiration.9
Diagnostic criteria for the hepatorenal syndrome C C C
C C C
Cirrhosis with ascites Serum creatinine >133 mmol/litre (1.5 mg/dl) No improvement of serum creatinine (decrease to a level of 133 mmol/litre or less) after at least 2 days with diuretic withdrawal and volume expansion with albumin Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, micro-haematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasonography
Note that although urinary sodium is frequently low it is not an essential criterion for diagnosis.
Table 1
worsening oedema, ascites and sodium overload because of rapid extravasation from the circulating compartment following administration of fluid. Whereas it has not been shown to be superior to crystalloids for volume expansion in most situations, albumin is recommended in this setting. It is frequently necessary to stop infusion of glucose 5% (beloved of many physicians in the setting of liver impairment) as this hardly expands intravascular volume and can worsen hyponatraemia. Albumin 4e5% can be given in 250e500 ml boluses until a sustained elevation of CVP has been achieved, especially when total body water depletion is thought to be the primary cause of renal impairment. Maintenance of intravascular volume can also be achieved with concentrated albumin (e.g. 20%; 100 ml containing 20 g of albumin), which has a lower concentration of sodium and thereby reduces the risk of sodium loading. The daily dose of albumin should not exceed 1 g/kg body weight. Diuretics can be given in addition, to promote a diuresis/ natriuresis if the patient is intravascularly volume replete. Harsh dietary salt restriction rarely leads to a negative salt balance (<20% of patients) and there is a real risk of malnutrition on such a diet, but a no-added-salt diet should be instituted. This provides adequate calories with 80e120 mmol sodium/day. Water restriction, which is routinely recommended, is controversial but may be required in severe hyponatraemia.
Treating underlying liver disease Treatment of liver disease can also improve renal function. Corticosteroids (prednisolone 40 mg/day) should be given for acute alcoholic hepatitis and there are encouraging studies supporting the use of anti-tumour necrosis factor agents including pentoxifylline (400 mg three times daily) and infliximab.12 Paracetamol overdose can cause acute tubular necrosis (ATN) even without severe hepatic dysfunction and the conventional acetylcysteine regimen should probably be extended for any patient with renal dysfunction. Some data suggest that acetylcysteine may be generally useful in liver disease (at w100 mg/kg/day) even outside the context of paracetamol overdose and is rarely toxic.13 Antiviral treatments can improve both hepatic and renal function where there is an immune complex glomerulonephritis secondary to viral hepatitis. In severe fulminant hepatitis, liver transplantation should be considered early. Managing ascites and fluid overload Ascites can cause an abdominal compartment syndrome (ACS), reducing perfusion to all intra-abdominal organs and mechanically increasing renal venous pressure, and can cause renal arterial vasoconstriction via SNS/RAAS activation. ACS is defined as an intra-abdominal pressure over 20 mmHg, as measured by an intravesicular pressure transducer (normal 5e7 mmHg).14 ACS should be considered in any patient with tense ascites and declining urine output. Paracentesis with complete drainage should be performed, but the catheter should be removed within 4 hours to reduce the risk of iatrogenic infection. During paracentesis, simultaneous albumin infusion is essential to avoid a catastrophic post-paracentesis circulatory collapse, which can cause rapid re-accumulation of ascitic fluid and precipitate HRS in 20% of patients. Albumin should be given at a rate of w8 g/litre of ascites removed (e.g. roughly 100 ml of albumin 20% for every 2e3 litres drained).
Infection Patients with liver disease are susceptible to infection and this is a frequent precipitant to renal dysfunction. Identification and empirical treatment of infection is vital since one rarely has time to await cultures. The incidence of spontaneous bacterial peritonitis (SBP) is approximately 10% in hospitalized patients with cirrhosis and mortality is 20%. Prognosis is related to the degree of renal dysfunction.11 An ascitic tap (with cell count and inoculation of culture bottles) should be performed in all patients with ascites with infection suggested by a fluid white cell count of >250 109 neutrophils/ml. Gram negative bacteria (usually Escherichia coli) and Gram positive cocci (streptococci and enterococci) are the commonest organisms. Cefotaxime 1e2 g twice daily or piperacillin/tazobactam 4.5 g three times daily for
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Management of HRS Several trials have evaluated the ability of medical therapies to reverse the circulatory changes that generate HRS with varying
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SYSTEMIC DISEASE AND THE KIDNEY
degrees of reproducibility and success. Renal vasodilators such as dopamine and prostaglandin E1 analogues do not lead to any improvement, and some treatments (endothelin antagonists) are detrimental to renal function. The greatest success has been with vasoconstrictor therapy, which attempts to improve renal perfusion by reversing the loss of vascular tone in the splanchnic vascular bed. Terlipressin has a selective action, with greater affinity for the systemic vasopressin 1 receptor than the renal vasopressin 2 receptors. It is generally well tolerated and may reverse type 1 HRS in 50% of cases.15 Noradrenaline (norepinephrine) is a cheaper alternative to terlipressin but requires a continuous infusion. Intravenous infusion of albumin is used with both vasopressors to maintain intravascular volume. Midodrine (7.5 mg orally three times daily titrating up to 15 mg three times daily) with octreotide (100 mg subcutaneously three times daily titrating to 200 mg three times daily) have also been advocated and have the benefit of oral/subcutaneous administration.16 Three small studies have examined the use of transjugular intrahepatic portosystemic shunt (TIPSS) in managing HRS, and have demonstrated a reduction in serum creatinine after insertion, but at a slower rate than when compared to vasoconstrictor plus albumin therapy; the risk of provoking hepatic encephalopathy (30%) means that this treatment is usually reserved as a last resort for such patients.
that leads to HRS. Patients with HRS undergoing orthotopic liver transplantation (OLT) have a higher perioperative mortality and morbidity compared to those without HRS. However, HRS is not a contraindication to transplantation, and renal function is one of the parameters included in the UKELD scoring system for allocation of liver transplants. There has recently been an increase in the number of end-stage liver disease (ESLD) patients with renal failure receiving simultaneous liver kidney (SLK) transplants. Deciding which patients should undergo SLK transplantation is difficult, but recent publications suggest patients who might benefit from SLK transplantation include ESLD patients who also have end-stage renal disease. An analysis of SLK registry survival data from the USA indicates that this cohort does better after SLK transplantation than those that receive a liver transplant but remain on dialysis. There is less evidence at present for performing SLK transplantation on ESLD patients with low-GFR CKD or those who have a prolonged AKI. Renal biopsy may be indicated in such patients, but carries a very high risk of bleeding complications.19 A
REFERENCES 1 Epstein M. The kidney in liver disease. 4th edn. Philadelphia: Hanley and Belfus, 1996. 2 Mackelaite L, Alsauskas ZC, Ranganna K. Renal failure in patients with cirrhosis. Med Clin North Am 2009 Jul; 93: 855e69. viii. 3 Bowers LD, Wong ET. Kinetic serum creatinine assays. II. A critical evaluation and review. Clin Chem 1980 Apr; 26: 555e61. 4 Randers E, Ivarsen P, Erlandsen EJ, et al. Plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Scand J Clin Lab Invest 2002; 62: 129e34. 5 Bomzon A, Holt S, Moore K. Bile acids, oxidative stress, and renal function in biliary obstruction. Semin Nephrol 1997 Nov; 17: 549e62. 6 Newell GC. Cirrhotic glomerulonephritis: incidence, morphology, clinical features, and pathogenesis. Am J Kidney Dis 1987 Mar; 9: 183e90. 7 Grange JD, Amiot X. Nitric oxide and renal function in cirrhotic patients with ascites: from physiopathology to practice. Eur J Gastroenterol Hepatol 2004 Jun; 16: 567e70. 8 Martı´n-Llahı´ M, Guevara M, Torre A, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011 Feb; 140: 488e96. 9 EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010 Sep; 53: 397e417. 10 Okita K, Sakaida I, Okada M, et al. A multicenter, open-label, doseranging study to exploratively evaluate the efficacy, safety, and doseresponse of tolvaptan in patients with decompensated liver cirrhosis. J Gastroenterol 2010 Sep; 45: 979e87. 11 Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2011 Mar; 9: 260e5. 12 Tilg H, Day CP. Management strategies in alcoholic liver disease. Nat Clin Pract Gastroenterol Hepatol 2007 Jan; 4: 24e34. 13 Holt S. The liver unit. In: Pusey C, Allen A, Glyne P, eds. Acute renal failure in practice. Imperial College Press, 2006; 465e488. 14 Tiwari A, Myint F, Hamilton G. Recognition and management of abdominal compartment syndrome in the United Kingdom. Intensive Care Med 2006 Jun; 32: 906e9.
Extra-corporeal therapies Renal support should be offered to patients with HRS where there is a realistic chance of liver transplantation or hepatic recovery. It can be tricky to identify those patients who will do well. Of several scoring systems, those that appear to predict mortality rely on assessing multiple organ disease severity (e.g. Sequential Organ Failure Assessment; SOFA score) rather than the degree of renal failure alone.17 Increasingly, a short trial of renal replacement therapy as a bridge to hepatic recovery or transplantation is offered. In such cases, it is important to set clear goals at the start of therapy for fear of merely delaying inevitable death. In general, slow intermittent haemodialysis or continuous haemofiltration are tolerated better than short-hours, high pump speed, intermittent haemodialysis. Bicarbonate- rather than lactatebased dialysate should be used as the latter may accumulate if the liver is functioning poorly. Extra-corporeal albumin dialysis is a system that dialyses blood across a membrane against an albumin-rich dialysate. Protein-bound toxins diffuse across the membrane and bind to the albumin in the dialysate. This dialysate is then passed over activated charcoal and an anion exchange resin to remove the albumin-bound toxins. The dialysate is then passed across a conventional haemodialysis filter to remove water-bound toxins. A meta-analysis has shown no difference in the survival of patients undergoing albumin dialysis compared to conventional treatment, though some smaller non-randomized trials have indicated a benefit in patients with alcohol-related cirrhotic liver disease.18 These treatments should probably be used only in the context of clinical trials as they are very expensive and their efficacy is as yet unproven. Liver transplantation Liver transplantation is the ultimate treatment of choice in hepatorenal syndrome as it reverses the underlying liver dysfunction
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SYSTEMIC DISEASE AND THE KIDNEY
15 Rajekar H, Chawla Y. Terlipressin in hepatorenal syndrome: Evidence for present indications. J Gastroenterol and Hepatol 2011 Jan; 26(Suppl 1): 109e14. 16 Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol 2009 Aug; 43: 680e5. 17 Das V, Boelle P, Galbois A, et al. Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival. Crit Care Med 2010 Nov; 38: 2108e16. 18 National Institute For Health and Clinical Excellence. Extracorporeal albumin dialysis for acute liver failure: N1995. London: National Institute for Health and Clinical Excellence, 2009. 19 Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant 2008 Nov; 8: 2243e51.
MEDICINE 39:8
Practice points C C
C
C
C
496
Most cirrhotic patients have subclinical renal dysfunction The commonest causes of acute renal dysfunction in cirrhosis are related to infection and drugs Intravascular volume replacement with albumin is difficult but essential Ascites should always be sampled to check for infection, but do not leave a cannula in for long and replace intravascular volume with albumin if a large paracentesis is planned The pathogenesis of renal dysfunction in the hepatorenal syndrome involves systemic vasodilatation with vasoconstriction in the renal bed. Systemic vasoconstrictor usage and intravascular volume optimization can help to reverse these changes
Ó 2011 Elsevier Ltd. All rights reserved.
Liver disease and renal dysfunction
Difficulties in measuring renal function Using serum creatinine as a marker of renal function has many shortcomings in normal individuals and is even more problematic in patients with cirrhosis as the concentration is frequently lower than expected if true glomerular filtration rate (GFR) is measured, falsely reassuring the unwary. Malnutrition, a reduced muscle mass, and impaired creatine synthesis by a failing liver result in low creatinine production rates, and tubular secretion of creatinine is increased in cirrhosis.2 Finally, the measurement of creatinine by photocolorimetric methods (e.g. the kinetic Jaffe reaction commonly used in UK laboratories) is erroneous in the presence of hyperbilirubinaemia.3 It follows that equations using creatinine to estimate renal function (e.g. Modification of Diet in Renal Disease (MDRD)) usually grossly overestimate the GFR (see Assessment of kidney function in adults in Medicine 2011; 39(6): 306e311). The use of newer biomarkers, such as cystatin C, may be more accurate but isotopic methods need to be used if a precise measure is needed.4 Urea kinetics are similarly perturbed and low serum urea values are common in cirrhosis, again reflecting hepatic underproduction and malnutrition. However, a relatively high urea suggests that a search for gastrointestinal blood loss from variceal bleeding or other sites may be appropriate. Bile acids may be directly involved in the renal dysfunction associated with obstructive jaundice. The mechanism is unclear but may involve direct renal tubular damage. This sometimes leads to acute kidney injury with normal urine output or polyuria.5
Partha Das Stephen Holt
Abstract Renal dysfunction frequently complicates liver disease and, when present, adversely affects prognosis. While a number of conditions can affect both the liver and the kidney acutely (e.g. paracetamol), many hepatotoxic insults (e.g. alcohol or viral hepatitis) cause more problems associated with cirrhosis. This review focuses mainly on the renal dysfunction associated with this chronic liver damage. Chronic liver disease is implicated in changes in vascular reactivity and tone, resulting in a systemic vasodilatation and renal vasoconstriction. In its extreme form it leads to the most feared of all renal complications of liver disease, the hepatorenal syndrome (HRS), which is frequently fatal. The recognition and early management of both the renal dysfunction and liver disease are important to survival. The key therapeutic issues revolve around optimizing the circulating volume, reversing the maladaptive haemodynamic changes, removal of other potential nephrotoxins and early treatment of infection.
Keywords hepatorenal syndrome; kidney diseases; liver cirrhosis; liver diseases
Immune events in cirrhosis Liver disease is accompanied by increased bacterial translocation from the gut to the portal and systemic circulation. Bacterial products activate the cellular immune system, increasing nitric oxide (NO) production and causing an increase, and probably phenotypic change, in circulating immunoglobulin (Ig) (especially IgA). It is not known whether this reflects an increase in production or a reduction in clearance, or both, but it may explain the link between cirrhosis and a number of glomerulonephritides, especially IgA nephropathy, that are clearly associated with liver disease.6
Four percent of the general population has abnormal liver function tests and up to 20% of those develop cirrhosis. Many experts are predicting a chronic liver disease epidemic in the next few decades, due largely to the impact of viral hepatitis, obesity and alcohol use. Patients with liver disease frequently have co-existent renal dysfunction, due to the liver disease itself, its treatment, or more often both. This is subclinical in its early stages, but when present, increases risk.1 In addition, 50% of patients with acute liver failure develop renal dysfunction. While there are a number of causes of renal dysfunction in liver disease, this article focuses on cirrhosis as a cause for renal dysfunction.
Haemodynamic events in cirrhosis The destruction of the architecture in the cirrhotic liver, and functional changes in hepatocytes and other hepatic cell lines (e.g. Ito cells) lead to an increase in the resistance to portal blood flow. There is an accompanying systemic vasodilatation, due to the action of NO and other mediators.7 This leads to a reduction in systemic vascular resistance (SVR) in most vascular beds, leading to a fall in mean arterial pressure (MAP) and a compensatory increase in cardiac output (CO) (Ohm’s law: CO ¼ MAP/ SVR). Therefore, these patients tend to have warm peripheries, a tachycardia with high-volume pulse and a low blood pressure. Homeostatic responses to the fall in SVR include activation of the renineangiotensinealdosterone system (RAAS) and the sympathetic nervous system (SNS). Together with locally produced vasoconstrictors and a neural reflex, renal vasoconstriction ensues (see Figure 1). There is also a non-osmotic release of antidiuretic hormone (ADH). This combination of factors causes
Partha Das MRCP is a Registrar in nephrology on the South Thames Specialist Renal Rotation currently at Guys Hospital, UK. Competing interests: none declared. Stephen Holt PhD FRCP is currently Associate Professor of Nephrology at the Department of Renal Medicine, Monash University, Melbourne, Australia. Formerly, Consultant Nephrologist and Honorary Senior Lecturer at Brighton and Sussex University Hospitals, UK. Qualified from the Middlesex Hospital and trained in nephrology mainly at the Royal Free Hospital, London. His research interests include renal dysfunction in liver disease. Competing interests: none declared.
MEDICINE 39:8
492
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
Mechanisms of haemodynamic changes affecting the renal vasculature in liver disease Endotoxin and other gut-derived toxins/cytokines Portosytemic shunts
Portal vein Liver
Systemic circulation
Hepatorenal reflex
Local vasoconstrictors, e.g. ET, Tx, IP
NO, PGI2, SP, CGRP, glucagon Vasodilatation in systemic and splanchnic circulation
SVR ↓ Cardiac output ↑ Activation of RAAS/SNS
Renal vasoconstriction
Non-osmotic AVP release
Sodium retention
Failure to excrete a water load
Reduced GFR
These changes result in systemic vasodilatation and renal vasoconstriction. The net result is sodium and water retention and reduced renal function. AVP, arginine vasopressin; CGRP, calcitonin gene related peptide; ET, endothelin; GFR, glomerular filtration rate; IP, isoprostanes; NO, nitric oxide; PGI2, prostacyclin; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system; SP, substance P; SVR, systemic vascular resistance; Tx, thromboxanes.
Figure 1
Management of renal dysfunction
sodium and water retention, leading to ascites and peripheral oedema, hyponatraemia, oliguria, low urinary sodium (sometimes <10 mmol/litre) and often a low fractional excretion of sodium (FENa; often as low as <1%).
Rationalization of drug treatment Removing all potential nephrotoxins is essential in minimizing further renal parenchymal damage. This includes non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and aminoglycoside antibiotics. Ascites and/or oedema are frequently treated with spironolactone (100e400 mg/day), which may provoke hyperkalaemia. Furosemide (40e160 mg/day) is often added if ascites proves resistant, but both drugs risk reducing intravascular volume, thereby exacerbating renal dysfunction and causing hyponatraemia. Withdrawal of diuretics is recommended for severe hyponatraemia (serum sodium <120 mmol/litre).9 Tolvaptan is a novel antagonist of arginine vasopressin (AVP) at its V2 receptor and blocks water reabsorption in the renal collecting ducts. It does not cause sodium excretion and, although not currently licensed for use in the UK, is of potential benefit in cirrhotic patients with ascites/oedema and hyponatraemia.10
Acute kidney injury (AKI) in liver disease The classification of AKI into pre-renal, intrinsic renal and postrenal causes is useful when evaluating renal failure in patients with liver disease. The causes of AKI are far more commonly intravascular volume depletion, sepsis and drugs than the hepatorenal syndrome (HRS), and early recognition and treatment can prevent significant morbidity and mortality. HRS is an extreme but potentially reversible form of functional renal failure that occurs in up to 40% of patients with advanced liver disease each year. There are generally no pathognomic histopathological changes on renal biopsy in HRS. It is a diagnosis of exclusion with the major diagnostic criteria outlined in Table 1. There are two main subtypes. Type 1 develops rapidly and is often precipitated by bacterial infection (especially SBP), variceal haemorrhage, major surgery or any acute hepatic insult to an already cirrhotic liver. It is associated with a poor prognosis, with a median survival of 2 weeks after diagnosis. Type 2 HRS develops more insidiously with slightly better survival (median survival 6 months), although mortality is still high as most patients will progress to a type 1 pattern following a metabolic or other insult. Overall, the prognosis is probably related to the cause of the renal dysfunction.8
MEDICINE 39:8
Fluid balance The combination of a hyperdynamic circulation and reduced effective arterial blood volume in patients with cirrhosis makes avoiding intravascular volume depletion critical. Central venous pressure (CVP) and other forms of invasive cardiac output/ systemic vascular resistance monitoring can be helpful as a guide to assessing volume status, but it is often difficult to expand intravascular volume in this cohort of patients without
493
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
5 days is recommended, together with fluconazole 50 mg daily for anti-fungal prophylaxis. Patients presenting with SBP even in the absence of septic shock have a high risk of developing severe hepatic insufficiency, encephalopathy and type 1 HRS. Intravenous albumin has been shown to improve survival in SBP. Recurrent infection occurs in 70% of SBP survivors and prophylactic oral norfloxacin 400 mg or ciprofloxacin 500 mg daily should be considered thereafter. Concomitant SBP or other bacterial infection in the context of gastrointestinal haemorrhage is a major problem and is associated with a higher risk of failure to control bleeding, a greater incidence of re-bleeding and increased mortality. Selective gut decontamination with either a quinolone (norfloxacin 400 mg twice daily for 7 days) or ceftriaxone (intravenous for high-risk patients or those having repeated luminal instrumentation) should be considered in patients presenting with cirrhosis and variceal bleeding. Treatment for chest infections in patients with liver disease should include cover for anaerobes, as patients are susceptible to periods of reduced conscious level (encephalopathy or alcohol) and are therefore at risk of aspiration.9
Diagnostic criteria for the hepatorenal syndrome C C C
C C C
Cirrhosis with ascites Serum creatinine >133 mmol/litre (1.5 mg/dl) No improvement of serum creatinine (decrease to a level of 133 mmol/litre or less) after at least 2 days with diuretic withdrawal and volume expansion with albumin Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, micro-haematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasonography
Note that although urinary sodium is frequently low it is not an essential criterion for diagnosis.
Table 1
worsening oedema, ascites and sodium overload because of rapid extravasation from the circulating compartment following administration of fluid. Whereas it has not been shown to be superior to crystalloids for volume expansion in most situations, albumin is recommended in this setting. It is frequently necessary to stop infusion of glucose 5% (beloved of many physicians in the setting of liver impairment) as this hardly expands intravascular volume and can worsen hyponatraemia. Albumin 4e5% can be given in 250e500 ml boluses until a sustained elevation of CVP has been achieved, especially when total body water depletion is thought to be the primary cause of renal impairment. Maintenance of intravascular volume can also be achieved with concentrated albumin (e.g. 20%; 100 ml containing 20 g of albumin), which has a lower concentration of sodium and thereby reduces the risk of sodium loading. The daily dose of albumin should not exceed 1 g/kg body weight. Diuretics can be given in addition, to promote a diuresis/ natriuresis if the patient is intravascularly volume replete. Harsh dietary salt restriction rarely leads to a negative salt balance (<20% of patients) and there is a real risk of malnutrition on such a diet, but a no-added-salt diet should be instituted. This provides adequate calories with 80e120 mmol sodium/day. Water restriction, which is routinely recommended, is controversial but may be required in severe hyponatraemia.
Treating underlying liver disease Treatment of liver disease can also improve renal function. Corticosteroids (prednisolone 40 mg/day) should be given for acute alcoholic hepatitis and there are encouraging studies supporting the use of anti-tumour necrosis factor agents including pentoxifylline (400 mg three times daily) and infliximab.12 Paracetamol overdose can cause acute tubular necrosis (ATN) even without severe hepatic dysfunction and the conventional acetylcysteine regimen should probably be extended for any patient with renal dysfunction. Some data suggest that acetylcysteine may be generally useful in liver disease (at w100 mg/kg/day) even outside the context of paracetamol overdose and is rarely toxic.13 Antiviral treatments can improve both hepatic and renal function where there is an immune complex glomerulonephritis secondary to viral hepatitis. In severe fulminant hepatitis, liver transplantation should be considered early. Managing ascites and fluid overload Ascites can cause an abdominal compartment syndrome (ACS), reducing perfusion to all intra-abdominal organs and mechanically increasing renal venous pressure, and can cause renal arterial vasoconstriction via SNS/RAAS activation. ACS is defined as an intra-abdominal pressure over 20 mmHg, as measured by an intravesicular pressure transducer (normal 5e7 mmHg).14 ACS should be considered in any patient with tense ascites and declining urine output. Paracentesis with complete drainage should be performed, but the catheter should be removed within 4 hours to reduce the risk of iatrogenic infection. During paracentesis, simultaneous albumin infusion is essential to avoid a catastrophic post-paracentesis circulatory collapse, which can cause rapid re-accumulation of ascitic fluid and precipitate HRS in 20% of patients. Albumin should be given at a rate of w8 g/litre of ascites removed (e.g. roughly 100 ml of albumin 20% for every 2e3 litres drained).
Infection Patients with liver disease are susceptible to infection and this is a frequent precipitant to renal dysfunction. Identification and empirical treatment of infection is vital since one rarely has time to await cultures. The incidence of spontaneous bacterial peritonitis (SBP) is approximately 10% in hospitalized patients with cirrhosis and mortality is 20%. Prognosis is related to the degree of renal dysfunction.11 An ascitic tap (with cell count and inoculation of culture bottles) should be performed in all patients with ascites with infection suggested by a fluid white cell count of >250 109 neutrophils/ml. Gram negative bacteria (usually Escherichia coli) and Gram positive cocci (streptococci and enterococci) are the commonest organisms. Cefotaxime 1e2 g twice daily or piperacillin/tazobactam 4.5 g three times daily for
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Management of HRS Several trials have evaluated the ability of medical therapies to reverse the circulatory changes that generate HRS with varying
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degrees of reproducibility and success. Renal vasodilators such as dopamine and prostaglandin E1 analogues do not lead to any improvement, and some treatments (endothelin antagonists) are detrimental to renal function. The greatest success has been with vasoconstrictor therapy, which attempts to improve renal perfusion by reversing the loss of vascular tone in the splanchnic vascular bed. Terlipressin has a selective action, with greater affinity for the systemic vasopressin 1 receptor than the renal vasopressin 2 receptors. It is generally well tolerated and may reverse type 1 HRS in 50% of cases.15 Noradrenaline (norepinephrine) is a cheaper alternative to terlipressin but requires a continuous infusion. Intravenous infusion of albumin is used with both vasopressors to maintain intravascular volume. Midodrine (7.5 mg orally three times daily titrating up to 15 mg three times daily) with octreotide (100 mg subcutaneously three times daily titrating to 200 mg three times daily) have also been advocated and have the benefit of oral/subcutaneous administration.16 Three small studies have examined the use of transjugular intrahepatic portosystemic shunt (TIPSS) in managing HRS, and have demonstrated a reduction in serum creatinine after insertion, but at a slower rate than when compared to vasoconstrictor plus albumin therapy; the risk of provoking hepatic encephalopathy (30%) means that this treatment is usually reserved as a last resort for such patients.
that leads to HRS. Patients with HRS undergoing orthotopic liver transplantation (OLT) have a higher perioperative mortality and morbidity compared to those without HRS. However, HRS is not a contraindication to transplantation, and renal function is one of the parameters included in the UKELD scoring system for allocation of liver transplants. There has recently been an increase in the number of end-stage liver disease (ESLD) patients with renal failure receiving simultaneous liver kidney (SLK) transplants. Deciding which patients should undergo SLK transplantation is difficult, but recent publications suggest patients who might benefit from SLK transplantation include ESLD patients who also have end-stage renal disease. An analysis of SLK registry survival data from the USA indicates that this cohort does better after SLK transplantation than those that receive a liver transplant but remain on dialysis. There is less evidence at present for performing SLK transplantation on ESLD patients with low-GFR CKD or those who have a prolonged AKI. Renal biopsy may be indicated in such patients, but carries a very high risk of bleeding complications.19 A
REFERENCES 1 Epstein M. The kidney in liver disease. 4th edn. Philadelphia: Hanley and Belfus, 1996. 2 Mackelaite L, Alsauskas ZC, Ranganna K. Renal failure in patients with cirrhosis. Med Clin North Am 2009 Jul; 93: 855e69. viii. 3 Bowers LD, Wong ET. Kinetic serum creatinine assays. II. A critical evaluation and review. Clin Chem 1980 Apr; 26: 555e61. 4 Randers E, Ivarsen P, Erlandsen EJ, et al. Plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Scand J Clin Lab Invest 2002; 62: 129e34. 5 Bomzon A, Holt S, Moore K. Bile acids, oxidative stress, and renal function in biliary obstruction. Semin Nephrol 1997 Nov; 17: 549e62. 6 Newell GC. Cirrhotic glomerulonephritis: incidence, morphology, clinical features, and pathogenesis. Am J Kidney Dis 1987 Mar; 9: 183e90. 7 Grange JD, Amiot X. Nitric oxide and renal function in cirrhotic patients with ascites: from physiopathology to practice. Eur J Gastroenterol Hepatol 2004 Jun; 16: 567e70. 8 Martı´n-Llahı´ M, Guevara M, Torre A, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011 Feb; 140: 488e96. 9 EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010 Sep; 53: 397e417. 10 Okita K, Sakaida I, Okada M, et al. A multicenter, open-label, doseranging study to exploratively evaluate the efficacy, safety, and doseresponse of tolvaptan in patients with decompensated liver cirrhosis. J Gastroenterol 2010 Sep; 45: 979e87. 11 Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2011 Mar; 9: 260e5. 12 Tilg H, Day CP. Management strategies in alcoholic liver disease. Nat Clin Pract Gastroenterol Hepatol 2007 Jan; 4: 24e34. 13 Holt S. The liver unit. In: Pusey C, Allen A, Glyne P, eds. Acute renal failure in practice. Imperial College Press, 2006; 465e488. 14 Tiwari A, Myint F, Hamilton G. Recognition and management of abdominal compartment syndrome in the United Kingdom. Intensive Care Med 2006 Jun; 32: 906e9.
Extra-corporeal therapies Renal support should be offered to patients with HRS where there is a realistic chance of liver transplantation or hepatic recovery. It can be tricky to identify those patients who will do well. Of several scoring systems, those that appear to predict mortality rely on assessing multiple organ disease severity (e.g. Sequential Organ Failure Assessment; SOFA score) rather than the degree of renal failure alone.17 Increasingly, a short trial of renal replacement therapy as a bridge to hepatic recovery or transplantation is offered. In such cases, it is important to set clear goals at the start of therapy for fear of merely delaying inevitable death. In general, slow intermittent haemodialysis or continuous haemofiltration are tolerated better than short-hours, high pump speed, intermittent haemodialysis. Bicarbonate- rather than lactatebased dialysate should be used as the latter may accumulate if the liver is functioning poorly. Extra-corporeal albumin dialysis is a system that dialyses blood across a membrane against an albumin-rich dialysate. Protein-bound toxins diffuse across the membrane and bind to the albumin in the dialysate. This dialysate is then passed over activated charcoal and an anion exchange resin to remove the albumin-bound toxins. The dialysate is then passed across a conventional haemodialysis filter to remove water-bound toxins. A meta-analysis has shown no difference in the survival of patients undergoing albumin dialysis compared to conventional treatment, though some smaller non-randomized trials have indicated a benefit in patients with alcohol-related cirrhotic liver disease.18 These treatments should probably be used only in the context of clinical trials as they are very expensive and their efficacy is as yet unproven. Liver transplantation Liver transplantation is the ultimate treatment of choice in hepatorenal syndrome as it reverses the underlying liver dysfunction
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15 Rajekar H, Chawla Y. Terlipressin in hepatorenal syndrome: Evidence for present indications. J Gastroenterol and Hepatol 2011 Jan; 26(Suppl 1): 109e14. 16 Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol 2009 Aug; 43: 680e5. 17 Das V, Boelle P, Galbois A, et al. Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival. Crit Care Med 2010 Nov; 38: 2108e16. 18 National Institute For Health and Clinical Excellence. Extracorporeal albumin dialysis for acute liver failure: N1995. London: National Institute for Health and Clinical Excellence, 2009. 19 Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant 2008 Nov; 8: 2243e51.
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Most cirrhotic patients have subclinical renal dysfunction The commonest causes of acute renal dysfunction in cirrhosis are related to infection and drugs Intravascular volume replacement with albumin is difficult but essential Ascites should always be sampled to check for infection, but do not leave a cannula in for long and replace intravascular volume with albumin if a large paracentesis is planned The pathogenesis of renal dysfunction in the hepatorenal syndrome involves systemic vasodilatation with vasoconstriction in the renal bed. Systemic vasoconstrictor usage and intravascular volume optimization can help to reverse these changes
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