SYSTEMIC DISEASE AND THE KIDNEY

Liver disease and renaldysfunctionPartha Das

Stephen Holt

AbstractRenal 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 asso-

ciated with this chronic liver damage. Chronic liver disease is implicated in

changes in vascular reactivity and tone, resulting in a systemic vasodila-

tation 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 impor-

tant 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

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.

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

Difficulties in measuring renal function

Using serum creatinine as a marker of renal function has many

shortcomings in normal individuals and is even more problem-

atic 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 per-

turbed 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 injurywith normal urine output or polyuria.5

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 knownwhether 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, espe-

cially IgA nephropathy, that are clearly associated with liver

disease.6

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 compen-

satory 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 sympa-

thetic 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 anti-

diuretic hormone (ADH). This combination of factors causes

� 2011 Elsevier Ltd. All rights reserved.

Mechanisms of haemodynamic changes affecting the renal vasculature in liver disease

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.

Endotoxin and other gut-derived toxins/cytokines

Systemic circulation

Vasodilatation

in systemic and splanchnic circulation

Non-osmotic AVP release

SVR ↓ Cardiac output ↑

Activation of RAAS/SNS

Renal vasoconstriction

Local vasoconstrictors, e.g. ET, Tx, IP

Sodium retention Failure to excrete a water load Reduced GFR

Liver

Portal veinPortosytemic shunts

NO, PGI2, SP, CGRP, glucagon

Hepatorenal reflex

Figure 1

SYSTEMIC DISEASE AND THE KIDNEY

sodium and water retention, leading to ascites and peripheral

oedema, hyponatraemia, oliguria, low urinary sodium (some-

times <10 mmol/litre) and often a low fractional excretion of

sodium (FENa; often as low as <1%).

Acute kidney injury (AKI) in liver disease

The classification of AKI into pre-renal, intrinsic renal and post-

renal 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 hep-

atorenal 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 39:8 493

Management of renal dysfunction

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 amino-

glycoside antibiotics.Ascites and/or oedemaare 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 collect-

ing 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

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

� 2011 Elsevier Ltd. All rights reserved.

Diagnostic criteria for the hepatorenal syndrome

C Cirrhosis with ascites

C Serum creatinine >133 mmol/litre (1.5 mg/dl)

C 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

C Absence of shock

C No current or recent treatment with nephrotoxic drugs

C 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

SYSTEMIC DISEASE AND THE KIDNEY

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 ofmany 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 malnutri-

tion 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 contro-

versial but may be required in severe hyponatraemia.

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 peri-

tonitis (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 inoc-

ulation 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

MEDICINE 39:8 494

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 associ-

ated 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 (encephalop-

athy or alcohol) and are therefore at risk of aspiration.9

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 sup-

porting 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 andmechanically

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 para-

centesis, 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 ofw8 g/litre of

ascites removed (e.g. roughly 100 ml of albumin 20% for every

2e3 litres drained).

Management of HRS

Several trials have evaluated the ability of medical therapies to

reverse the circulatory changes that generate HRS with varying

� 2011 Elsevier Ltd. All rights reserved.

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 (norepi-

nephrine) 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 adminis-

tration.16 Three small studies have examined the use of trans-

jugular 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.

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 replace-

ment 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 haemo-

filtration are tolerated better than short-hours, high pump speed,

intermittent haemodialysis. Bicarbonate- rather than lactate-

based 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 conven-

tional 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 hep-

atorenal syndrome as it reverses the underlying liver dysfunction

MEDICINE 39:8 495

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 allo-

cation of liver transplants.

There has recently been an increase in the number of end-stage

liver disease (ESLD) patients with renal failure receiving simulta-

neous liver kidney (SLK) transplants. Deciding which patients

should undergo SLK transplantation is difficult, but recent publi-

cations suggest patients who might benefit from SLK trans-

plantation 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

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� 2011 Elsevier Ltd. All rights reserved.

Practice points

C Most cirrhotic patients have subclinical renal dysfunction

C The commonest causes of acute renal dysfunction in cirrhosis

are related to infection and drugs

C Intravascular volume replacement with albumin is difficult but

essential

C 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

C The pathogenesis of renal dysfunction in the hepatorenal

syndrome involves systemic vasodilatation with vasocon-

striction in the renal bed. Systemic vasoconstrictor usage and

intravascular volume optimization can help to reverse these

changes

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

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18 National Institute For Health and Clinical Excellence. Extracorporeal

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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 39:8 496 � 2011 Elsevier Ltd. All rights reserved.