Chronic renal failure

Haemodialysis

of the benefits of increased frequency, there are considerable

practical and economic barriers.

Murugan Sivalingam

Principles of haemodialysis

Ken Farrington

Dialysis involves movement of solutes and water across semipermeable membranes by diffusion and convection. Diffusion
is the movement of solutes across a semi-permeable membrane
down a concentration gradient. Diffusive clearance of a solute
depends on its molecular weight, electrical charge, the blood
dialysis fluid concentration gradient, blood and dialysis flow
rates and on membrane characteristics (diffusion coefficient).
Smaller molecules, such as urea (60Da), are cleared well whilst
larger molecules, such as albumin (60,000Da), cannot pass
through the membrane. The clearance of middle molecules such
as 2-microglobulin (11,800Da) can be improved using high-flux
membranes, which have pores of sufficient size to allow the passage of such molecules. Convection refers to the movement of solvent and dissolved solutes across a semi-permeable membrane,
down a hydrostatic pressure gradient. Convection improves middle molecule clearance. Ultrafiltration is the convective movement
of water across the membrane. The ultrafiltration rate depends on
the hydrostatic pressure difference across the membrane and on
its permeability to water (ultrafiltration coefficient).

Abstract
The haemodialysis population continues to increase rapidly and is
becoming more elderly and dependent. Despite major advances in
technology, long-term clinical outcomes are disappointing, even in lowrisk patients. Current definitions of dialysis adequacy, based on urea
clearance, need to be broadened to encompass parameters such as
2-microglobulin clearance, salt and water balance, and phosphate
control. More frequent treatments may be necessary to adequately control
uraemia and to improve survival. Haemodiafiltration provides improved
2-microglobulin clearance over haemodialysis, and may improve outcomes. Failures in access provision, particularly over-dependence on
tunnelled lines, contribute significantly to morbidity and excess mortality.

Keywords adequacy; convection; diffusion; dry weight; haemodialysis;

The dialysis system: technical considerations

Dialysers consist of semi-permeable membranes arranged to
form separate adjacent paths for blood and dialysis fluid, which
flow on opposite sides of the membrane in opposite directions
to maximize diffusion gradients. Dialysers are classified by their
design geometry, membrane composition, surface area, permeability characteristics (diffusion and ultrafiltration coefficient)
and biocompatibility characteristics. Hollow-fibre dialysers are
most commonly used.

haemodiafiltration; HEMO study; 2-microglobulin; uraemia

Haemodialysis (HD) is a highly successful life-saving and lifesustaining therapy. With its complementary treatments, peritoneal dialysis and renal transplantation, it has revolutionized the
outlook for patients with end-stage renal failure (ESRF). Evolution of the technique from experimental studies in dogs (Abel,
1913) to its successful use in humans with acute renal failure
(Kolff, 1945) followed in the wake of technical advances in the
development of semi-permeable membranes and anticoagulants.
Its application to the treatment of ESRF required further technical developments in the 1960s to allow reliable and repeated
access to the circulation the Scribner shunt and the CiminoBrescia arteriovenous fistula.1 Since then, the number of patients
receiving chronic HD worldwide has risen dramatically and now
many hundreds of thousands are maintained on the treatment.
Haemodialysis treatment is now widely available in developed
countries and as a consequence the age, comorbid load2 and
dependency of the HD population has increased and the technique has become the default modality for the treatment of ESRF.
However, the technique only partially replaces an aspect of renal
function, and life expectancy of HD patients remains far below
that of the age-matched general population. Thrice-weekly treatment is the standard and though there is emerging evidence

Extracorporeal circuit (Figure 1): blood is withdrawn from

the patient via the A needle by a peristaltic pump, circulated
through the dialyser and returned to the patient through the V
needle. The circuit is anti-coagulated by heparin, which is infused
downstream from the blood pump. The arterial pressure monitor protects the fistula by detecting excessive negative pressure.
The venous pressure monitor provides some protection against
blood loss from the circuit to the environment though leaks arising from dislodgement of the V needle from the fistula that are
not detected. The bubble trap level detector protects against air
embolus. The blood flow rate, dialysate flow rate, fluid removal
rate (ultrafiltration rate) and duration of dialysis are all set at the
time of dialysis and individualized for each patient.
Dialysis machine
The dialysis machine supplies dialysis fluid at the prescribed
flow rate, temperature and chemical composition. The machine
also monitors the extracorporeal circuit and in fail-safe mode
activates the venous clamp and switches off the blood pump.
Modern machines use volumetric methods, comprising a balancing system that regulates dialysis fluid flow rates to and from
the dialyser, allowing removal of required ultrafiltration volumes preset by the operator. Other technical advances include
blood temperature monitors, allowing control of thermal balance

Murugan Sivalingam MRCP is a Dialysis Research Fellow at the Renal

Unit in Lister Hospital, Stevenage, UK. Competing interests: none
declared.
Ken Farrington MD FRCP is a Consultant Nephrologist at the Renal Unit in
Lister Hospital, Stevenage, UK. Competing interests: none declared.

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Chronic renal failure

The extracorporeal blood circuit

Arterial
needle

Arterial pressure
monitor

Heparin
infusion

Blood pump
Dialyser
Venous
pressure monitor

Ultrasonic
level detector

Venous
needle

Venous
clamp

Blood flow = 300500 ml/minute

Dialysis fluid flow = 300800 ml/minute
Figure 1

significant health risks. Aluminium contamination causes adynamic bone disease, fatal encephalopathy and anaemia. Contamination with chloramines causes haemolytic anaemia and the
endotoxins and bacteria cause febrile reactions and septicaemia.
Water is purified using a combination of techniques including
softening and de-ionization, carbon adsorption, reverse osmosis
and ultraviolet irradiation.

uring dialysis to improve haemodynamic stability and measured

ment of access recirculation, and blood volume monitors, which
detect changes in haematocrit during dialysis and are potentially
useful in predicting hypotensive episodes.
Water and dialysis fluid
The dialysis machine mixes prepared concentrates of electrolytes
with treated water to produce dialysis fluid. Typical concentrations
of electrolytes in dialysis fluid are shown in Figure 2. HD patients
are exposed to over 300 litres of water each week. Contamination
of water with chemical impurities and microorganisms carry

Haemodialysis techniques
Conventional haemodialysis uses low-flux (low ultrafiltration
coefficient) membranes, which allow diffusive but little convective

Diffusive blood purification within the dialyser

Blood flow = 300500 ml/minute

Urea
Creatinine

K+

Ca2+

HCO3

Na+

1.5
mmol/litre

1.25
mmol/litre

37
mmol/litre

140
mmol/litre

Plasma
Water

Dialysis fluid flow = 500/700/800 ml/minute

The concentrations given are typical values for dialysis fluid

Figure 2

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Chronic renal failure

Haemodiafiltration (HDF) is the addition of a prescribed convective component (haemofiltration) to the technique of highflux HD. Each high-flux session, 12 to 25 litres of ultrafiltrate is
removed and replaced by substitution fluid. The cheap on-line
production by the dialysis machine of ultra-pure substitution
fluid from dialysis fluid has allowed HDF to become established
as a viable routine therapy of ESRF (Figure 4). Fluid is removed
from the constant-volume loop D by a haemodiafiltration pump
(HDF), passed through an ultrafilter (F2) and infused in to the
V line (post-dilution) or the A line (pre-dilution [not shown]).
To maintain the volume in loop D, an equal volume of fluid is
drawn from the blood across the dialysis membrane. The added
convective component in HDF produces a small improvement in
small-solute clearance over that seen in high-flux dialysis, with
a significant improvement in middle molecule clearance. Serum
2-microglobulin levels are reduced, and dialysis-related amyloidosis may be delayed. Haemodynamic stability and survival may
be improved.3

solute removal. Smaller molecules such as urea are cleared efficiently, but middle molecule clearance is poor. The prescribed
fluid is volumetrically removed by means of an ultrafiltration
pump (UF in Figure 3) placed in a loop D of the dialysis fluid flow
path. Fluid removal from the loop will result in an equal volume
being removed from the blood across the dialysis membrane.
Haemofiltration is a purely convective treatment. Highly
permeable membranes are used, permitting high-volume ultrafiltration of 2050 litres per session. Dissolved solutes are also
removed. High-volume replacement is also required with substitution fluid, from commercially prepared bags, being delivered
either on the arterial side of the filter (pre-dilution) or into the
venous bubble trap (post-dilution). Middle molecule clearance is
excellent but small molecule clearance is poor. For this reason
intermittent haemofiltration has not been a successful long-term
treatment for ESRF. However, the technique is used very successfully in continuous mode for the treatment of acute renal
failure in the critical care setting. There are number of variants. Continuous arteriovenous haemofiltration (CAVH), which
required femoral artery cannulation, has given way to continuous
venovenous haemofiltration (CVVH), which requires a pumped
venous supply. Continuous venovenous haemodialysis (CVVHD)
is a further variant. CVVH is usually the preferred mode of renal
replacement therapy for unstable patients with multi-organ failure in the intensive care setting. It is well tolerated haemodynamically, avoids the peaks and troughs in metabolic, electrolyte,
acidbase and volume control which are a feature of intermittent
treatments, and allows proper attention to nutrition.
High-flux haemodialysis uses highly permeable, usually
biocompatible, membranes. These membranes provide good
diffusive clearance of small solutes combined with much better
diffusive removal of middle molecules than conventional dialysis. This is augmented by a convective contribution to middle
molecule clearance resulting from a degree of obligate backfiltration within the dialyser.

Managing dialysis
Adequate dialysis and duration: the assessment of how much
dialysis is required to maintain health is still controversial. Blood
levels of urea and creatinine can be misleading as indicators of
the adequacy of dialysis. Low levels are just as likely to indicate malnutrition and muscle wasting as good dialysis. Instead,
dialysis dose is normally defined in relation to small solute clearance, either by the urea reduction ratio (percentage reduction in
blood urea during dialysis) or, more commonly, by urea kinetic
modelling in terms of normalized urea clearance (Kt/V where
K is the dialyser urea clearance, t is the duration of dialysis in
minutes and V is the urea distribution volume estimated as total
body water from anthropomorphic data). Dialyser clearance is

Dialysis fluid pathway in post-dilution

haemodiafiltration

Dialysis fluid pathway in haemodialysis

A

V
Haemodiafiltration
Haemodialysis

F2

UF

UF

HDF
Balancing
chamber

Balancing
chamber

F1
F1

F1 and F2, filters; A, arterial line; V, venous line; HDF, haemodiafiltration pump;
UF, ultrafiltration pump; D, constant-volume loop.

F1, filter; A, arterial line; V, venous line; UF, ultrafiltrate;

D, constant-volume loop.

Figure 3

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Chronic renal failure

dependent on membrane characteristics (permeability and area)

and blood and dialysis fluid flow rates.
Lower Kt/V doses are associated with increased short-term
morbidity and mortality, and observational data suggest improved
outcomes at higher doses. However, the HEMO study,4 a randomized controlled trial, showed no additional benefit of high
compared to standard doses (mean delivered 2-pool Kt/V 1.53 v
1.16) except perhaps in women. The UK Renal Association and
the US National Kidney Foundation Kidney Disease Outcomes
Quality Initiative (KDOQI) recommend a minimum Kt/V of 1.2.
Adequate dialysis, as judged by Kt/V, can be delivered in
short sessions using high blood flows and large dialysers to augment clearance, but it is difficult to control other parameters such
as phosphate and blood pressure, which affect morbidity and
mortality. More frequent dialysis, up to 6 times a week, either
overnight or daily not only enhances urea clearance to a degree
which is not possible by extended thrice-weekly sessions but
also provides excellent control of these other parameters, and
may improve survival.5 Clearance is just one measure of the
adequacy of dialysis. Broader concepts of adequacy are required
which encompass other factors impacting on the patients overall
well-being.

in which dialysed blood returning to the fistula through the

venous needle is drawn by the blood pump directly to the arterial needle resulting in under-delivery of prescribed dialysis dose.
Access monitoring may help to avoid such problems, facilitating
early diagnosis and pre-emptive radiological or surgical intervention. Fistula flow assessment by ultrasound dilution is probably
the monitoring mode of choice. Tunnelled central venous catheters have a high risk of infection, are prone to clotting, and
provide much lower blood flow rates than the AVF. Limiting the
use of lines to the 15% or so of HD patients with no other option
is an important quality target.

Intradialytic complications7
Dialysis disequilibrium syndrome is a rare complication, which
occurs in severely uraemic patients, often those presenting late,
who have been subjected to aggressive dialysis initiation.8 This
causes rapid reductions in serum osmolality and paradoxical
cerebrospinal fluid (CSF) acidosis, leading to cerebral oedema.
Restlessness, headache, tremors and, occasionally, fits and coma
occurring during or after dialysis are the hallmarks. Short initial
treatment using dialysers of small surface area and low blood
pump settings prevent the problem.
Hypotension is common during dialysis and is associated with
cramps, nausea, vomiting, dizziness and syncope. It results from
excessive ultrafiltration and is common in patients with cardiovascular compromise, autonomic dysfunction, those on hypotensive medications, those with excessive interdialytic fluid gains,
and in those whose dry weight has increased due to improved
nutrition. Ultrafiltration depletes the blood volume, which is
replenished by rapid refilling from surrounding tissue spaces.
Failure of this process, for whatever reason, results in hypotension. Accurate dry weight assessment, sodium restriction to limit
interdialytic fluid gain, restricted use of antihypertensive drugs,
low ultrafiltration rates and longer treatment duration are useful
strategies to reduce hypotensive episodes.
Cardiac arrhythmias are common especially in patients with
left ventricular hypertrophy and coronary artery disease. Rapid
intradialytic electrolyte fluxes, especially changes in serum
potassium levels and in acidbase balance, predispose.
Dialyser reactions are rare with the use of biocompatible
membranes. Ethylene oxide, a device sterilant, and other leachable materials have been implicated. Type A reactions are anaphylactoid. They are rare but life-threatening. Symptoms usually
begin in the first few minutes of dialysis but can be delayed for
20 minutes or more. Dialysis must be stopped, the lines clamped
and discarded, and corticosteroids and antihistamines (adrenaline in very severe cases) administered. Type B reactions are
less severe but more common. They are seen 30 to 60 minutes
after starting dialysis. Dialysis can be continued and patients are
managed with supportive treatment.
Pyrexial reactions can occasionally occur during dialysis. These
days, with the increasing use of ultrapure water, such reactions
are much more likely to be due to infection related to the use of
tunnelled lines for access than to contaminated dialysis fluid.
Circuit clotting due to under-anticoagulation, and prolonged bleeding from the fistula after needle removal, due to
over-anticoagulation may occur. More serious problems with
anticoagulation are rare.

Dry weight and hypertension

The removal of the excess fluid accumulated between dialysis
sessions is a vital function of dialysis. The dry weight concept
assumes that there are two components of body weight a dry
or target weight, at which body fluid compartments are normal,
and excess weight which consists of accumulated fluid which
expands fluid compartments, elevates blood pressure, and contributes to excess cardiovascular morbidity and mortality. Dry
weight is the weight at which the patient is oedema free and
below which hypotension occurs on further fluid removal.6 The
concept is difficult to apply rigorously to the increasing proportion of the dialysis population with cardiac dysfunction, and
compromises are frequently necessary. Shorter treatment times
and less rigorous salt restriction have increased these difficulties.
Dry weight changes over time, falling during periods of intercurrent illness and poor nutrition and increasing during recovery
from such episodes. It is set by clinical evaluation and requires
regular review.
Vascular access
Securing and maintaining reliable access to the circulation is vital
for the continued well-being of chronic HD patients. The options
include arteriovenous fistula (AVF), arteriovenous polytetrafluoroethylene (PTFE) grafts and cuffed, tunnelled internal jugular
venous catheters. AVF are preferred because they have the lowest
complication rate and the longest lifespan. They are created by
end-to-side or side-to-side anastamosis, preferably of the radial
artery and cephalic vein in the non-dominant forearm, though
use of other sites, such as the brachial artery and cephalic vein
is common. After anastamosis, venous distension and arterialization occur, and needling is usually possible after about 6 weeks.
Primary non-function is, unfortunately, common and attention to
the preservation of these vessels in pre-dialysis patients is important. Distal steal may occur with large brachiocephalic fistulae.
Stenosis and thrombosis may occur, which in addition to predisposing to premature fistula loss, may lead to access recirculation

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Chronic renal failure

Other complications such as air embolism and circuit

disconnection are very rare with modern fail-safe machines.

2 Feest TG, Rajamahesh J, Byrne C, et al. Trends in adult renal

replacement therapy in the UK: 19822002. QJM 2005; 98: 2128.
3 Canaud B, Bragg-Gresham JL, Marshall MR, et al. Mortality risk for
patients receiving hemodiafiltration versus hemodialysis: European
results from the DOPPS. Kidney Int 2006; 69: 208793.
4 Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and
membrane flux in maintenance hemodialysis. N Engl J Med 2002;
347: 201019.
5 Pierratos A, McFarlane P, Chan CT. Quotidian dialysisupdate 2005.
Curr Opin Nephrol Hypertens 2005; 14: 11924.
6 Jaeger JQ, Mehta RL. Assessment of dry weight in hemodialysis:
an overview. J Am Soc Nephrol 1999; 10: 392403.
7 Davenport A. Intradialytic complications during hemodialysis.
Hemodial Int 2006; 10: 16267.
8 Arieff AI. Dialysis disequilibrium syndrome: current concepts on
pathogenesis and prevention. Kidney Int 1994; 45: 62935.
9 Dember LM, Jaber BL. Dialysis-related amyloidosis: late finding or
hidden epidemic? Semin Dial 2006; 19: 10509.
10 Chandna SM, Schulz J, Lawrence C, Greenwood RN, Farrington K.
Is there a rationale for rationing chronic dialysis? A hospital based
cohort study of factors affecting survival and morbidity. BMJ 1999;
318: 21723.

Chronic complications
Cardiovascular disease is common in patients on HD, and plays
a major role in the high mortality. Its pathogenesis is complex:
accelerated atheroma, hypertension, left ventricular hypertrophy,
vascular calcification and anaemia all contribute.
Dialysis-related amyloidosis9 is a disabling complication
in patients on long-term HD. Amyloid deposits contain
2-microglobulin, a normal component of human class 1 HLA
complex. It has a molecular weight of 11.8 kDa and is renally
excreted but not cleared by low-flux dialysis. Hence it accumulates and is deposited in many tissues as amyloid fibrils. Patients
present with carpal tunnel syndrome and destructive arthropathy. High-flux HD and HDF greatly improve the clearance of
2-microglobulin and may delay the onset of amyloidosis, as
may use of ultrapure water.
Renal osteodystrophy and renal anaemia are discussed
elsewhere (see pages 45052 and 45760).

Outcome
Age, non-renal comorbidity and dependency are strong predictors of survival, and patients can be risk-stratified using these
factors.10 However, it is apparent that even in low-risk patients,
mortality is substantially greater than that in age-matched controls without renal failure. This relates to the failure of current
thrice-weekly based treatment to adequately control uraemia in
all its facets (solute removal, blood pressure control, mineral
metabolism, anaemia). Improved survival must be the aim in
those low-risk patients unsuitable for transplantation. Daily short
or nocturnal home-based dialysis may be required to achieve this.
On the contrary, in some high-risk patients, dialysis may achieve
little more than prolonging the process of dying. It is perhaps not
surprising that withdrawal of dialysis accounts for almost 20%
of the mortality amongst dialysis patients in the USA. Indeed,
conservative management of end-stage renal failure is becoming
widely accepted as an alternative option for highly dependent
patients with multiple comorbidities.

Practice points
The haemodialysis population continues to increase rapidly
and is becoming more elderly and dependent
Despite major advances in technology, long-term clinical
outcomes are disappointing, even in low-risk patients
Current definitions of dialysis adequacy, based on urea
clearance, need to be broadened to encompass parameters
such as 2-microglobulin clearance, salt and water balance,
and phosphate control
The HEMO study has defined the limits of thrice weekly
treatment. More frequent treatments may be necessary to
adequately control uraemia and to improve survival. These
treatments will need to be home-based
Haemodiafiltration provides improved 2-microglobulin
clearance, and may improve outcomes
Failures in access provision, particularly over-dependence on
tunnelled lines, contributes to morbidity and excess mortality

References
1 Scribner BH. Lasker Clinical Medicine Research Award. Medical
dilemmas: the old is new. Nat Med 2002; 8: 106667.

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