review

Organogenesis 7:1, 2-12; January/February/March 2011; © 2011 Landes Bioscience

Renal replacement therapy review

Past, present and future
Geoffrey M. Fleming
Department of Pediatrics; Vanderbilt University Medical Center; Nashville, TN USA

Key words: dialysis, peritoneal dialysis, hemodialysis, renal replacement therapy, artificial kidney

Introduction modern dialysis today is performed using the work of Dr. Nils
Alwall. The Alwall dialyzer compressed blood-filled cellophane
Support of renal function in modern times encompasses a wide tubing between an inner and outer cylinder. Dialysate was passed
array of methods and clinical scenarios, from the ambulatory in the countercurrent direction to blood between the cylinders.4
patient to the critically ill. The ability to safely and routinely The authors describe dialysis in eight patients, including changes
deliver ongoing organ support in the outpatient setting has, until in levels of non-protein nitrogen (N.P.N.), using countercur-
recently, separated renal replacement therapy from other organ rent exchange between blood and dialysis fluid that is still in use
support. Renal replacement therapy (RRT) can be applied inter- today in RRT.
mittently or continuously using extracorporeal (hemodialysis) The peritoneum was noted to be a “living dialyzer” by
or paracorporeal (peritoneal dialysis) methods. The purpose of Dr. Tracey J. Putnam in 1923 in a series of experiments with
this article is to familiarize the reader with the history, physi- cats receiving peritoneal dialysis.5 He, unlike his predecessors,
ology, mode, dose, equipment and future of renal replacement made a complete evaluation of the spent dialysate and remarked
therapy and not to detail the technical methods employed for upon the ability of the peritoneal membrane to exchange fluid
blood purification. and solute in the living animal. However, despite this early suc-
cess, clinical peritoneal dialysis was delayed until the 1940s with
History the presentation of four cases by Dr. Jacob Fine and colleagues
at the American Surgical Association.6 Widespread use of perito-
Artificial support of the functions of failing organs has a his- neal dialysis required improvement in the dialysis catheter used,
tory deeply rooted in the beginning of the last century. Although and was accomplished with the work of Dr. Quinton7 and Dr.
artificial respiration may have been used as early as Roman times Tenckhoff.8 Today, the methods and catheter designs of these
by the physician Galen, and as late as 1908 by George Poe, sup- pioneers are still evident in clinical practice around the world.
port of the failing kidney began as early as 1913. Two scholars Continuous therapies of today have their origins in the 1960s,
are credited repeatedly in the literature, Dr. John J. Abel and with early descriptions of pump-assisted continuous arterio-
Dr. W. J. Kolff, as the forefathers of modern dialysis. “Vivi- venous hemofiltration (CAVH) by Dr. Scribner.9,10 Dr. Scribner
diffusion” was coined in a paper given before the Association of found that the resistance of the hemofilter varied by design
American Physicians in 1913 in which the blood of animals was and hand manufacturing techniques, which made predictable
cleansed of intermediaries of metabolism.1 This “vivi-diffusion” response to therapy difficult. Additionally, dialysate was cooled
was achieved using arterial cannulation and hirudin anticoagula- for aseptic technique but re-warming blood prior to return to the
tion in a dog with blood directed through branching glass tubing patient resulted in bubble formation and clinical symptoms in
to reach a series of cellodin dialysis membranes and then back to the patient. Finally, a predictable method of delivering heparin
a venous cannula. This concept was concomitantly developed by for anticoagulation was required, as the standard IV pump of
Dr. Kolff in the Netherlands and led to the first apparatus avail- today was not available. Dr. Robert Bartlett utilized this therapy
able for clinical use.2 Dr. Kolff’s drum dialyzer fed blood through in the management of patients on extracorporeal membrane
cellophane tubing wrapped around a rotating drum sitting in a oxygenation (ECMO) and was among the early authors in the
bath of dialysate. The rotation of the drum moved blood through literature.11-13 These pump-assisted therapies required arterial
the dialysis bath, and then blood flow return to the patient was cannulation, and the success of veno-venous circulation using a
controlled using a burette. Although Dr. Kolff’s apparatus was pump for continuous ultrafiltration helped reduce the morbidity
used prominently as late as the 1950s during the Korean war,3 of the therapy. Dr. Canaud described continuous veno-venous
hemofiltration for adults in 1988,14 and Dr. Yorgin described
Correspondence to: Geoffrey M. Fleming; the therapy applied to children in 1990.15 To date, we delivery
Email: geoffrey.fleming@vanderbilt.edu therapy in fundamentally the same fashion as described in the
Submitted: 08/01/10; Accepted: 10/21/10 preceding paragraphs with some modification and refinement of
DOI: 10.4161/org.7.1.13997
technique over time.

2 Organogenesis Volume 7 Issue 1

 review REVIEW

Indications the shock state in normal pigs.37 Subsequent work has suggested
cytokines to be the target of hemofiltration during the systemic
The primary indication for RRT is acute or chronic renal failure. inflammatory response syndrome (SIRS) of sepsis.38 Human
However, much debate exists today regarding the optimal defini- trials of hemofiltration during sepsis have had mixed results on
tion of renal failure, especially with acute renal disease. As many despite documentation of removal of cytokines.39-43 Success or
as 30 definitions of renal failure exist in the literature, yet recent failure to show clinical improvement has been hypothesized by
consensus definitions and guidelines are becoming more wide- some to be related to frequency of filter change, mode of clear-
spread. The Kidney Dialysis Outcomes Initiative’s(K/DOQI) ance and dose of clearance.44 Recent data are the first to sug-
clinical practice guidelines for chronic kidney disease16 define gest that early hemofiltration during sepsis may associated with
end stage kidney failure as Stage 5 with glomerular filtration rate increased mortality.45 Investigators continue to examine hemofil-
(GFR) of <15 ml/min/1.73 m2 or the use of dialysis. GFR is esti- tration to control the cytokine storm and hemodynamic instabil-
mated using serum creatinine measurement in conjunction with ity of severe sepsis; however, the most recent sepsis guidelines do
the Modification of Diet in Renal Disease (MDRD), Crockcroft- not include hemofiltration in the recommendations beyond renal
Gault or Schwartz equations.17-19 The Acute Dialysis Quality support.46,47 Certain subgroups with hypercytokinemia, such as
Initiative (ADQI) group published a consensus definition of patients with severe pancreatitis, may benefit from RRT for cyto-
acute renal failure for adults,20 with a graded severity Risk Injury kine removal.48
Failure Loss and ESKD (RIFLE) and the recent publication of Current indications for RRT in the hospitalized patient include
a modification for use in pediatric patients.21 Classification is renal failure, severe acidosis, hyperkalemia or other electrolyte
based on a change in GFR or urine output in the previous hours abnormalities, and toxin/poisonings. Fluid overload >10% in the
rather than absolute values individualizing it to the patient. Both critically ill patient is gaining support as an indication for RRT.
the K/DOQI and RIFLE definitions of renal failure rely upon Cytokine modulation during SIRS remains a popular topic in
serum creatinine measurements, which are known to overes- the literature, yet no current data support universal application.
timate GFR.22-25 Additionally, in acute renal injury, the rise in RRT indications for chronic renal failure are currently targeted
serum creatinine used to define organ failure is delayed approxi- at patients with GFR <10 ml/min/1.73 m2.
mately 24–48 hours from the insult. Although not an issue in
chronic kidney disease and failure, it affects timing of definition Physiology
and organ support in the acute setting. Consequently, current
research is focused on an appropriate biomarker(s) that would RRT employs only two physiologies for solute and fluid move-
aid in the diagnosis of acute renal failure, especially in the criti- ment.49 Both methods require sequestration of blood on one side
cally ill patient. Multiple markers are under study, some of which of a semi-permeable membrane. In diffusive clearance (Dialysis),
have performed well in select patient populations to date, and the solute moves down its concentration gradient, from areas of
reader is directed to comprehensive reviews of the subject.26,27 In high concentration to low concentration. The solute must be of
the future, the definition of acute renal failure will be driven by a appropriate size and charge to pass through a semi-permeable
combination of markers of organ function, including biomarkers, membrane. By passing fluid across the membrane countercurrent
as is the case for myocardial infarction. to blood flow, equilibration of plasma and dialysate solute con-
Other indications for RRT exist beyond renal failure and clas- centrations occur. This process may remove or add solute to the
sically have included electrolyte or acid-base abnormalities and plasma water space depending upon the relative concentrations
toxins removable by dialysis. The critically ill pediatric popula- in dialysate and plasma. Water will also move along a gradient,
tion has been the primary study ground for fluid overload as an in this case the osmolar or osmotic gradient, in effect “follow-
indication for RRT. This idea arose from adult studies of criti- ing” the solute. Diffusive clearance is more effective at removal of
cally ill patients in whom a mortality benefit was noted, reversal small solute, such as serum ions and urea, than for larger solute.
of fluid overload in the first days of illness.28,29 Numerous obser- Convective clearance (hemofiltration or ultrafiltration) uti-
vational studies of pediatric patients demonstrated fluid overload lizes a pressure gradient rather than concentration gradient and
was associated with higher mortality.30-33 In these studies, fluid has its main effect on water movement with solute movement
overload >10% was associated with higher mortality when con- in conjunction with water. The transmembrane pressure differ-
trolling for severity of illness. Data from the Prospective Pediatric ence is increased as needed to “push” water through the mem-
CRRT Registry Group demonstrated again that % fluid overload brane down a pressure gradient. This bulk flow of plasma water
was associated with mortality, and that survival was improved “drags” solute with it (convective mass transfer) in the forma-
(76%) if dry weight was attained during CRRT as compared to tion of ultrafiltrate. Small solute removal is nearly the same as
those who did not attain dry weight (36%).34 with diffusion, but fluid removal is far superior with convective
Since the earliest animal studies of sepsis, a soluble myocar- clearance. Additionally, clearance of small solute is equivalent to
dial depressant factor has been postulated to exist and is later diffusion, but convection demonstrates increased middle mol-
suggested as removable from the plasma. Hemofiltration in a ecule (500–5,000 Dalton) clearance and is limited by membrane
canine sepsis model reversed left ventricular dysfunction35 as well characteristics. Simply removing isotonic plasma water is con-
as right ventricular dysfunction in porcine sepsis.36 Re-infusion sidered slow continuous ultrafiltration (SCUF) but may lead to
of the ultrafiltrate from hemofiltration in porcine sepsis induced large volume shifts during therapy. To offset the large fluid shifts

www.landesbioscience.com Organogenesis 3
of hemofiltration, convective therapies usually include a filter with significant resources; however, intermittent therapy is often
replacement fluid (FRF) that is administered into the patient. employed in these circumstances.
Fluid given is removed in equal quantities for isovolemic hemofil- Data regarding the modality used for RRT comes predomi-
tration, yet the plasma composition will eventually resemble the nantly from survey results, with few publications of worldwide
FRF, allowing for solute management. usage. In a 2005 survey using the Fresenius medical care network,
Although these two models suggest very simple and pre- it was estimated 1.3 million patients received RRT worldwide, of
dictable solute and fluid movement, these processes are in real- which 89% received hemodialysis and 11% received peritoneal
ity quite complex. Diffusion gradients change depending upon dialysis.51 In an international sampling of ICUs, the most fre-
blood flow rates, dialysate flow rates and starting concentration quently employed continuous modality was CVVH,52 as was also
gradients. Additionally, convection allows for larger solute to be true for patients in the United Kingdom.53 In surveys of specific
pushed/ pulled through the membrane with fluid transfer, con- countries and regions, peritoneal dialysis remains the predomi-
ferring additional solute clearance properties. Flow characteris- nant therapy due to its relative ease and lower cost as compared
tics at the membrane surface also affect diffusion and are termed to IHD.54-56 Peritoneal dialysis is preferred in the pediatric pop-
boundary layers. Proteins affect equilibrium of ions due to ulation after surgery for repair of congenital cardiac disease57,58
sequestration of charged proteins on one side of the membrane, and possibly for adult cardiac transplant patients.59 Yet, among
termed the Gibbs-Donnan Equilibrium.50 Finally, the combina- other pediatric patients with kidney failure, PD is employed less
tion of diffusion and convection across the membrane alter the frequently in favor of hemo-based CRRT.60 In some instances,
properties of individual methods in a complex manner. A great the modality of choice is driven by practice guidelines based on
deal of literature examines these complexities and is beyond the patient and disease characteristics such as hemodynamic stability
scope of this article to review. and other organ failures.61 Furthermore, cost of therapy may be a
significant driving force in the choice of modality.
Modalities For critically ill inpatients with acute kidney failure, debate
exists over the choice of intermittent versus continuous thera-
The previous sections are a prelude to the modalities available pies.62 Single center data and meta-analysis demonstrate conflict-
for RRT. Blood may be passed through tubing and across arti- ing results,63-65 possibly due to difficulties such as sicker patients
ficial membranes (hemodialysis or hemofiltration), or dialysate crossing over from intermittent to continuous therapies,63 signifi-
may be instilled adjacent to the peritoneal membrane (perito- cant interruption time in continuous therapies63 and effect of era
neal dialysis). Peritoneal or hemo-based modalities may either of study.64 As such, no definitive data exist to support one therapy
be intermittent or continuous therapies. Finally, the method of over the other, and the two most recent large adult trials failed
clearance is also included in the description. Hence, RRT has to show benefit of continuous therapy over intermittent.66,67 One
been plagued with a confusing array of nomenclature in the liter- recurring concern with this comparison is the hemodynamic
ature, but includes peritoneal dialysis (PD), intermittent hemodi- stability of patients and tolerance of intermittent therapy. Two
alysis (IHD), sustained low-efficiency dialysis (SLED), extended studies have compared hemodynamic stability between IHD
daily dialysis (EDD) and continuous renal replacement therapy and CVVH, both demonstrating lower mean blood pressure in
(CRRT). CRRT is comprised of slow continuous ultrafiltra- the IHD group, presumably due to lower blood flows and slower
tion (SCUF), continuous veno-venous hemofiltration (CVVH), fluid removal during CVVH.68,69 Newer hybrids such as extended
continuous veno-venous hemodialysis (CVVHD) or a combi- daily dialysis had no hemodynamic instability as compared to
nation of convective and diffusive therapies, continuous veno- CVVH in a more recent study, suggesting blood flow rate and
venous hemodiafiltration (CVVHDF). PD includes Automated fluid removal rates may be the limiting factor.70 Hemodynamic
Peritoneal Dialysis (APD), with ~3–6 nocturnal cycles of dialy- instability is often the cited reason for CRRT use in critically ill
sis fill and drain and a small residual dwell during the day, and children as compared to IHD, especially children <10 kg.71 At
Continuous Ambulatory Peritoneal Dialysis (CAPD), with fre- least one study has suggested improved return of renal function
quent exchanges during the waking hours and one long dwell in the continuous therapy group, although this is not a consistent
during the night. Hence, peritoneal dialysis may be considered finding.63
CRRT in the sense it is continuous and is renal replacement Cost. The cost of continuous therapy in the intensive care unit
therapy, although most connote hemo-based therapy when using is generally felt to be greater than the cost of intermittent therapy,
the term CRRT. The selection of peritoneal based versus hemo- predominantly due to fluid expenditures.72-74 Cost comparisons
based RRT is decided using patient characteristics (age, severity of therapy are difficult due to the complexity of the analysis,
of illness, comorbid illness), indication for RRT (ion removal, including personnel time use and costs, equipment depreciation
middle molecule clearance, fluid removal), location (inpatient, costs, total hospital charges and country of study. Other hidden
ICU, outpatient) and resources (financial, equipment, training). costs may not be included in analysis of intermittent therapy such
Although PD may be the correct choice for an outpatient with as water purification system costs and maintenance. In developed
stable chronic renal dysfunction, it is also used for critically ill countries, intermittent therapy is felt to be more costly than peri-
children in ICU after surgery for congenital cardiac disease sur- toneal dialysis, yet in developing countries, IHD may be more
gery in developed countries. Conversely, CRRT is almost exclu- cost effective than PD.75 These differences are felt to be due to
sively restrained to the intensive care unit in a developed country costs of fluids and personnel time associated with the therapy. As

4 Organogenesis Volume 7 Issue 1

hybrid therapies gain in popularity, cost comparisons will emerge clearance in intermittent and continuous therapies with vary-
but initial studies suggest SLED is less costly than CRRT in ing degrees of urea generation, and suggested IHD had to occur
North America and New Zealand.76-78 6–7 times per week to achieve and maintain equivalent time aver-
aged urea control.81 The optimal dose delivery in continuous con-
Dose vective therapies was suggested to be 35 ml/kg/hr (Kt/V ~ 1.4/70
kg) of ultrafiltration (the SC of urea is 1, hence K is approximated
An important comparison between intermittent and continuous by Quf for urea in convective clearance), which showed benefit
therapies is the total dose of therapy given, usually represented over 20 ml/kg/hr.82 However, others have failed to reproduce
as a urea clearance. Although creatinine clearance is the mea- these results.33,67,83,84 It is now felt that there is a threshold of dose
surement of native renal function in clinical practice, most dia- for both intermittent and continuous therapies in critically ill
lytic therapies are measured by urea clearance. During diffusive patients above which no further benefit is seen,85 which appears
clearance (K), solute rapidly equilibrates across the membrane to be between 20 and 35 ml/kg/hour based on previous stud-
and its instantaneous clearance is described using the equation ies.67,82,84 The effects of RRT on the critically ill patient has been
K = (Qb) (Ci-Co)/Ci where Qb is blood flow in ml/min and C is studied using a variety of biomarkers from urea to b2 microglob-
the concentration of solute in inlet and outlet blood. This simple ulin to cytokines, yet Kt/V for urea is the most consistently stud-
instantaneous clearance formula is true for situations of single ied in large populations. However, it is unknown whether this
pass hemodialysis with dialysate in countercurrent exchange with is an adequate surrogate marker for the overall effects of blood
blood. The equation is further simplified for urea, which is not purification that occurs during RRT in the critically ill.85
present in “fresh” dialysate, with K = (Qd) (Cd/Ci) where Qd is The instantaneous clearance (K) for intermittent therapy is
dialysate flow rate and C is the concentration of urea in dialysate much higher than continuous therapy due to operational char-
effluent and inlet plasma. If the Qd/Qb ratio is <0.3, dialysate is acteristics (Qb, Qd and Qf rates), yet the efficacy of continuous
considered to be fully saturated at the effluent port, whereas with therapies is greater due to the duration. This is true only if the
a ratio >0.3 the actual K may be significantly less than calculated prescribed dose is delivered and not interrupted. In the intensive
by the above equation. Similar formulae may be written for con- care unit setting, therapy is often interrupted due to circuit mal-
vective clearances of solute with K = (Qf) (Cf/Cp), where Qf is function or traveling outside the ICU for procedures or imag-
the rate of ultrafiltrate production and C is the concentration of ing. Hence the daily dose actually delivered may be substantially
solute in ultrafiltrate and plasma. The ratio of solute in ultrafil- below the prescribed dose, with approximately 8 hours of “down-
trate to plasma is termed the sieving coefficient and is specific for time” per day in continuous therapies.63,86,87
a membrane/solute combination. Risk of excessive hemoconcen- These difficulties have given rise to hybrid techniques com-
tration exists with Qf/Qb ratios >0.2 and may be associated with bining a portion of the instantaneous clearance (K) of IHD with
filter clotting. In both diffusive and convective clearance, K is the longer duration of therapy and slower fluid shifts of CRRT.
affected by solute size, charge of the membrane and solute, and These include Sustained Low Efficiency Daily Dialysis (SLEDD)
pore size in the membrane, with characteristics specific to a solute and Extended Daily Dialysis (EDD).88 Hybrid techniques uti-
+ membrane combination. Additionally, recirculation of blood in lize a lower Qb and Qd than IHD, with Qb 200 ml/min and
double lumen access may affect clearance because blood in the Qd 100–200 ml/min as compared to 500–800 ml/min during
inflow limb of the circuit may have lower solute concentration IHD. An early publication in 2000 described EDD with a Qb
than plasma, which reduces the efficiency and efficacy of dialytic 200 ml/min, Qd 300 ml/min over 6–8 hours with improved urea
therapies. clearance as compared to continuous hemofiltration.89 Although
These formulae are useful for calculating the instantaneous not published until 2001, SLED experience began in 1998 at a
clearance (efficiency) of a molecule, but to describe the total single institution and demonstrated a Kt/V 1.36 delivered over 10
clearance over an entire therapy (efficacy) the formula for Kt/V hours with Qb 200 ml/min and Qd 100 ml/min.90 In both these
has been utilized. K is the instantaneous clearance of solute, t is publications, the therapy was hemodynamically tolerated, and an
the duration (time); this clearance is applied to a volume of dis- adequate dose of therapy was delivered. In a single institution
tribution (V) of the solute in question. Kt/V values of >1 have study, SLEDD was not associated with an increased patient mor-
been extracted from large observational studies and suggest that tality compared to mortality predicted by acute physiology and
increased total dose is associated with survival; however, this chronic health evaluation scores (APACHE II).90 The addition
has not been well documented in randomized controlled trials. of convective clearance (hemofiltration) to the therapy has been
The National Kidney Foundation practice guidelines recom- termed Sustained Low Efficiency Diafiltration (SLEDD-f) and
mend a minimum Kt/V of 1.2 per treatment three times a week has the goal of improving middle molecule clearance.91 Although
in chronic hemodialysis; however, this is in a stable outpatient some centers have migrated from CRRT to a hybrid therapy, this
population and has not been rigorously studied in the acute renal is not yet universal. In the recent, large adult study to investigate
failure population.79 The minimal adequate dose for peritoneal effects of dose intensity, only 2.5% of 11,602 total RRT thera-
dialysis has recently been modified from weekly Kt/V = 2 to 1.7.80 pies were a hybrid technique in the Veterans Administration sys-
For patients on continuous therapy in the intensive care unit, the tem in the United States.67 However, in three ICUs in Australia,
minimum dose was initially extrapolated from the IHD literature New Zealand and Italy, hybrid techniques have come to repre-
with a goal Kt/V of ≥1.2 per day. This lead to modeling of urea sent 50–100% of RRT delivered to adult patients over the past

www.landesbioscience.com Organogenesis 5
decade.92 Additionally, anecdotal experience shows this to be the The ultimate goal for fluid composition during RRT is pre-
treatment of choice in practices outside of academic centers in the cise management of the solute composition of the plasma. This
United States. may be achieved through creation of concentration gradients in
The approach to RRT modality in the intensive care unit is dialysate for effective transfer of solute to and from the patient
still under debate. No study has clearly shown unbiased results or composition of FRF to mimic goal plasma solute concen-
that support one therapy over another at equivalent dose. trations. Within this framework, the standard cations remain
Adjustment of the technique to facilitate patient stability was the sodium, potassium, magnesium and calcium, with standard
driving force of the expansion of CRRT, and further work with anions chloride, bicarbonate and occasionally phosphorus. The
hybrid techniques may provide further benefits in terms of cost base included in the solution has undergone a great deal of study,
and personnel. Whichever modality is employed, it can only be mostly in continuous therapies, with extensive comparisons
described in a few categories as intermittent or continuous, blood between lactate and bicarbonate. Acidosis during CVVH occurs
or peritoneal-based, using convective and/or diffusive clearances. as a consequence of fluid composition with lower pH, as seen
with acetate >lactate>bicarbonate based solutions.94-96 Failure to
Equipment and Fluids resolve acidosis during RRT is associated with increased mortal-
ity, hence this choice is important.96-98 Lactate is noted to rise
The most significant changes in RRT delivery have centered during lactate-based RRT and may have deleterious cardiovascu-
around equipment technology. Although roller pump technology lar side effects and is associated with poor outcomes.95,96,98-101 It
has changed little, machine safety and therapy monitoring con- is unclear whether lactate induces injury or is simply a marker of
tinue to improve. With microprocessor technologies advancing, dysoxia and abnormal liver metabolism of lactate during critical
user interface has changed dramatically, now automating therapy illness hence its association with mortality. Although some fluids
after a few input variables. Additionally, synthetic membranes still contain minimal lactate (~3 mEq), most fluids are bicarbon-
have been developed and nearly universally adopted into practice. ate (20–24 mEq/L) based. For on-line IHD fluid generation,
Tubing is exclusively polyvinylchloride (PVC) and designed for bicarbonate is used exclusively as the base with a small amount of
single use only. Fluids for continuous therapies have been devel- acidifying acetate added for solution stability.102
oped for mass production, eliminating the need for on-site fluid On-line dialysate production allows for alteration of the com-
preparation. However, for IHD and hybrid therapies, on-line position, which may improve patient outcomes. Data regarding
dialysate production remains the standard. sodium concentration has been associated with interdialytic vol-
Machines. The differences between individual machines by ume status and potassium concentration with arrhythmias dur-
various makers are vast and at the same time limited. Operational ing therapy. Additionally, glucose-based dialysis solutions have
characteristics are altered by adjusting fluid rates to achieve the undergone much investigation, with recent data suggesting that
desired effect. Blood flow is driven and adjusted using a single a minimal amount of glucose limits extensive glucose losses with
roller pump. Dialysate flow is driven by a pump on the inlet port, nutritional consequences without creating hyperglycemia and
and ultrafiltrate is generated by creating relative negative pressure hyperinsulinemia associated with high glucose dialysate concen-
at the outlet port by a third pump spinning faster than the inlet trations.103,104 Hence, individualization of dialysate composition
pump. Alternatively, dialysate and ultrafiltrate flow rates may be may improve individual patient outcomes and is recommended
adjusted using a series of valves. Some form of adjusting the oper- for on-line dialysate production.103,105,106 Commercial fluid com-
ational characteristics are universally shared by machines used positions for CRRT also vary the amount of potassium, glucose
for blood purification (peritoneal dialysis cyclers only adjust the and calcium but with less flexibility of choice, however, as com-
dialysate influx and efflux rates), and it is the user interface and pared to on-line fluid production.107 Calcium and bicarbon-
machine programming that differs between manufacturers. The ate content becomes important for patients on regional citrate
two major categories of machines are those used for continuous anticoagulation (see section on anticoagulation), as calcium in
therapies and those for intermittent therapies. These differences dialysate counteracts the effects of citrate at the membrane and
will not be reviewed here due to scope of the article and to avoid alkalosis may develop due to citrate metabolism and increased
industry bias; however, numerous companies exist worldwide bicarbonate load. The variety of solutions available commercially
with excellent products.93 are too extensive to list here, and the choice of fluids for CRRT
Fluids. Intermittent therapy (IHD and SLEDD) uses an on- is individualized to an institution with consideration of method
line dialysate and FRF production system, whereas continuous of anticoagulation, degree of flexibility required, cost of stocking
therapies use pre-prepared fluids. On-line dialysate and FRF multiple fluids, solute composition and regulatory body approval
production allows for instantaneous adjustment of solute control status.
without wasting or changing large bags of fluid. For continuous Water purity. For intermittent therapies using on-line fluid
therapies, industry manufactured solutions are available with a generation, water purity is an issue of paramount importance.
variety of solute compositions. These fluids are regulated differ- Dialysate production in the earliest days utilized tap water as
ently in the United States, with FRF categorized as a medica- the basic ingredient; however, water quality varies based on local
tion and dialysate as a device. Because of industry and regulatory regulations and facilities. An average adult patient on IHD is
standards, the composition, quality and sterility of these fluids is exposed to ~24,000 liters of water per year in dialysate, hence
ensured; however, this comes at significant cost. minute impurities become magnified, and it is now understood

6 Organogenesis Volume 7 Issue 1

that the purity or quality of dialysate is associated with patient and hyperinsulinemia in patients requiring long dwell times
outcomes.102,103,108-110 The addition of reverse osmosis technol- for chronic renal support. It is a large molecular weight glu-
ogy greatly improved water purity for hemodialysis and has cose polymer that exerts its effects as an oncotic gradient rather
been the standard for sometime. This process uses pressure to than osmotic agent with few side effects.121 A minimal amount
filter water through highly selective membranes that limit sol- is absorbed via the lymphatics and metabolized by amylases to
ute transfer, resulting in water with minimal impurities. Using metabolites with renal clearance of parent and intermediate com-
this technology, the standard for hemodialysis water quality, pounds.122-124 Machines used for peritoneal dialysis are relatively
including metals, micronutrients and bacteria, has been set in simple, yet may be automated with a series of valves that allow
the United States by the Association for the Advancement of for filling and emptying through the same catheter while keep-
Medical Instrumentation (AAMI).111 These standards allowed ing fresh and spent dialysate separate as during APD. Again,
for <100 colony forming units of (CFU) of microorganisms per the choices of manufacturers are too varied to review in this
milliliter (ml) of fluid and <2 endotoxin units (EU) per millili- manuscript.
ter and remain in force in the United States. Recent data have Membranes. The membrane used during hemodialysis/
given rise to more stringent standards in Europe of <0.1 CFU/ ml hemofiltration has evolved significantly since the earliest reports.
and <0.03 EU/ml for dialysate fluids that are associated with Initial membranes were natural materials, such as cellulose, or
improved patient outcomes.112 Chronic exposure to bacteria and simple synthetic compositions, such as polysulfone, with symmet-
bacterial byproducts (such as endotoxins) increases the inflam- ric structures and good performance for small solute passage.125
matory response and leads to chronic inflammatory processes However, these membranes include significant interactions with
as well as ongoing oxidative stress.108-110,112,113 Hence, more strin- the complement pathway and immune response. Modifying the
gent standards have been incorporated into the International hydroxyl groups on cellulose membranes gives similar perfor-
Organization for Standardization publications regarding water mance characteristics and less bioactivity and includes cellulose
quality and water treatment devices/equipment114-116 and are diacetate and hemophan membranes. With improvements in
being adopted by other agencies as standards for dialysate fluid chemical engineering and manufacturing, cellulose-based mem-
as data emerges regarding patient outcomes.108 To achieve these branes have yielded to synthetic membranes. The most popu-
standards it is necessary to include filtration of endotoxins and lar membranes in use today are polyacrylonitrile (AN69) and
routine decontamination of the system.108,109,112,113 The technical polysulfone; however, polyamide, polycarbonate and polymeth-
aspects of decontamination will not be reviewed here; however, ylmethacrylate are available. These materials have improved bio-
this does include the eradication of biofilms that develop in the compatibility and reduce complement activation; however, they
transport and circulation systems of water treatment equipment. may enhance protein adsorption to the membrane in the absence
Hence, although ultrapure water is generated through a series of of further modification. Despite the improved compatibility
filtrations, stagnation within the system may lead to the forma- of synthetic membranes, the most recent large review does not
tion of microbe-releasing biofilms. A variety of approaches have demonstrate benefits conveyed by bio-compatibility.126 The ultra-
been recommended, including chemical, heat and ultraviolet structure of membranes is predominantly the capillary design, or
treatment of water purifying equipment. Of utmost importance hollow fiber structure, in which blood flows through a series of
is a regular decontamination schedule and frequent monitoring. small tubes held together in a bundle. This allows for a low resis-
Of note, the monitoring of such systems is also complicated by tance, high surface area membrane. Membrane properties such as
differing results of CFU counts dependent upon isolation tech- charge, wall thickness and pore size affect function. The radius of
nique, which will require appropriate techniques for evaluation of the pore is related to the ultrafiltrate flow through the membrane,
maintenance of published standards.112,117 but overall fluid transfer is a function of the mean pore size. The
Peritoneal dialysis equipment. The equipment and flu- number or density of pores and the radius of the pore affects
ids necessary for peritoneal dialysis require specific mention. solute transfer in diffusive clearances. Membrane characteristics
Fluid for peritoneal dialysis must dwell for an extended period such as flux (range and efficiency of solute transfer) and perme-
of time and hence requires more pronounced osmotic gradients ability to water are determinants of pore characteristics and wall
to produce adequate fluid shift from the patient. This require- thickness. The reader is directed to an excellent brief review for
ment has been partially altered by continuous flow peritoneal further study.127
dialysis, which increases total clearance due to frequent dialy- Reuse of dialysis membranes has been commonplace in main-
sate replenishment. Glucose has traditionally been the agent of tenance IHD since the inception of the therapy.128 Initially it was
choice; however, hyperglycemia remains a concern, as well as driven by the time consuming process of assembling a circuit and
accelerated changes of the peritoneal membrane. Additionally, later by the cost of industry produced equipment. Multiple meth-
the heat sterilization process for PD fluids produces glucose ods have been used to sterilize the dialyzers, including heat, cold
degradation products that enhance detrimental changes to the and chemicals as well as the invention of machines that automate
peritoneal membrane. Newer approaches have included amino the sterilization process. This process, originally driven by cost
acids as the osmotic agent. Despite improving nitrogen balance, and convenienc,e was thought by some to improve intra-dialytic
this may increase azotemia and acidosis in the patient and affect symptoms such as nausea, back pain, cramping, headaches, chest
changes to the peritoneum.118-120 Other agents have been studied, pain, dyspnea and headaches. No consistent evidence exists to
and icodextrin appears to improve glucose-related dyslipidemia support claims of improved morbidity by the reuse of dialyzers

www.landesbioscience.com Organogenesis 7
nor is there any concomitant increase in mortality.129-132 A recent required by the wearer that would deliver safe and highly effec-
study suggests reuse of dialyzers may convey a reduced mortality tive renal replacement therapy including metabolic and endo-
risk; however, this was a short study in a single center and caution crine functions.
is warranted regarding generalization of results.133 Dialyzer reuse Fluid reclamation has been addressed using sorbent technol-
continues worldwide using predominantly chemical processing, ogy to remove waste products from ultrafiltrate or dialysate. The
most commonly peracetic acid and formaldehyde.128 earliest of these systems was the Recycled Dialysis (REDY) sys-
Anticoagulation. Anticoagulation of the CRRT circuit varies tem,142-144 and the next iteration was the Alliant Hemodialysis
by modality and local practice. Systemic heparinization remains System.145 These cartridges use a series of layers to process flu-
the mainstay of anticoagulation for IHD and is still used by many ids, first filtering through a layer of activated charcoal for initial
for anticoagulation of RRT circuits. Citrate regional anticoagula- purification and removal of organic molecules and heavy metals.
tion has gained significant popularity over the previous decade The next layer contains urease to convert urea to ammonium,
and is used exclusively in some centers for CRRT.134-136 Two stud- which is adsorbed in the subsequent zirconium phosphate layer.
ies document the safety of citrate, avoiding anticoagulation and This layer is also responsible for the majority of active ion adsorp-
bleeding, with improved circuit survival compared to heparin in tion. The final zirconium oxide layer adsorbs phosphate and
adults.135,136 Citrate is delivered pre-filter as tri-sodium citrate, residual heavy metal and generates bicarbonate and acetate in a
which chelates calcium in the circuit with the goal of 0.4 mmol/l pH dependent reaction.146 Miniaturization of the cartridges and
ionized calcium at the filter, and calcium is re-infused to the placement in series allows reclamation cartridges to be included
patient to prevent systemic hypocalcaemia. Citrate is metabolized in smaller devices than previously marketed.
by the liver to ~3 moles of bicarbonate, and hence, the infusion Reclamation technology has been applied to the Wearable
may induce hypernatremic alkalosis. Low concentration citrate Artificial Kidney for Peritoneal Dialysis (ViWAK PD)147 and the
protocols have been developed to prevent these complications137 Wearable Artificial Kidney (WAK).148 The WAK has performed
as have protocols for other modalities, such as high-flux hemodi- well in eight patients for a short term pilot study, with low but
alysis and SLED.138-140 In patients with liver disease, citrate may adequate urea clearance during continuous ambulatory hemodi-
accumulate if citrate infusion is greater than total clearance (filter alysis. Low urea clearances were felt to be due to Qb and Qd rates
and liver combined), and this complication may have significant achievable with a 9 volt miniaturized pump. Further modifica-
effects in pediatric patients who often experience hypotension tions have improved this design, and the WAK V1.1 uses pulsatile
with hypocalcaemia. Hypocalcaemic Citrate Toxicity (HCCT) blood and dialysate flows half a cycle apart such that blood flow
occurred in up to 17% of pediatric CRRT treatments without peaks as dialysate flow ebbs and vice versa in a device weighing
increased mortality risk.141 However, citrate remains the preferred <1 kg. This, which the authors term “pulsatile push-pull internal
agent of anticoagulation even in liver disease and requires atten- hemodiafiltration,” creates very high instantaneous Qb and Qd,
tion to infusion and clearance rates of citrate. From both adult allowing for improved hemodiafiltration achieving Kurea 55 ml/
and pediatric studies it is evident that heparin or citrate use pro- min.149 Currently, the WAK technology utilizes established dialy-
longs filter life compared to no anticoagulation in CRRT. sis techniques with miniaturized components and sorbent-based
fluid reclamation.
Future Trends Although adequately replacing the filtration and waste elimi-
nation, functions of the kidney, endocrine and metabolic activi-
Renal transplantation is the ultimate step for end stage renal fail- ties are not replaced. Specifically glutathione (antioxidant effects)
ure management, as it replaces native renal function completely, and vitamin D (bone mineralization) replacement is felt to be
yet availability of organs limits the widespread use of transplan- important. Proximal renal tubule cells are the primary source
tation for the millions of patients worldwide on RRT. Although for these functions in the native kidney and have been incor-
current RRT is able to mimic or exceed the bulk solute clear- porated into the bioengineering solution of renal support. Two
ance of the native kidney, it does so using significant volumes of primary sources of cells have been reported, including harvesting
fluids that require tethering to static water and power sources. from whole organs and cultured cell lines. Whole organ procure-
Although the native kidney produces ~140 liters per day of ultra- ment in the lab setting is reported from porcine kidneys150 and
filtrate, it excretes only 1–2 liters per day of urine, reclaiming human kidneys procured but unsuitable for transplantation.151
>98% of ultrafiltrate produced. This type of fluid reclamation is Investigational cell lines have been utilized, specifically Madin-
prominent in artificial kidney research, which would un-tether Darby canine kidney (MDCK) cells and Lewis lung cancer-
the patient from a fluid source. Additionally, the kidney is able porcine kidney 1 (LLC-PK1) cells.152,153 Renal tubule cells are
to modulate the solute concentration during the fluid reclama- cultured on an ultrastructure, typically an existing hollow fiber
tion process, another trend in artificial kidney research. Finally, membrane or a newer engineered membrane. The Renal Assist
the native kidney has metabolic and endocrine functions beyond Device (RAD) utilizes human tubule cells, which are attached
simple filtration, with the production of the antioxidant glu- to a polysulfone high-flux membrane coated with pronectin-L.150
tathione and formation of active 1–25 OH-Vitamin D as well Others have used nanopore silicone membranes with collagen
as epoprotein. Current trends in artificial kidney research are coating to attach human renal tubule cells.154 The membrane
addressing each of these issues with the lofty goal of a small serves both structural and protective functions as humoral and
device, preferably implanted with little or no maintenance cellular immune components are excluded from the cultured

8 Organogenesis Volume 7 Issue 1

tissue environment by the membrane allowing cultured xeno- dual membrane system has been designed using nanotechnology
graft-allograft cells to survive. that has incorporated hydrophobicity into the pore design.157 This
The RAD system has been the most extensively studied with allows for selection of ion passage based on molecular weight and
evidence of both glutathione and Vitamin D metabolism in the “hydration shell,” the molecular arrangement of water around
artificial organ.150,155 This more “complete” renal replacement was the ion. Hence, membranes with engineered specificity may be
felt to be safe151 and to convey 180 day survival and return of renal designed and miniaturized.
function benefits to a small group of ICU patients enrolled in an The complete artificial kidney has not been created, but work
open-label trial for CVVH with RAD augmentation.156 Phase III in this area looks promising for the future. Efficient fluid man-
trials have not been published but are planned according to the agement with reclamation and selective membranes in conjunc-
authors. However, the RAD is a long way from the criteria for tion with metabolic and endocrine function replacement in a
ultimate renal replacement support, as it is used in conjunction miniaturized package is a possibility.
with standard, machine-based hemofiltration whereby the ultra-
filtrate is shuttled through the RAD with reclamation of approxi- Conclusion
mately 25% of solute and fluid prior to return to the patient.
Unlike the sorbent reclamation system of the WAK, the RAD Renal replacement therapy continues to evolve. Although some
uses cellular-based fluid reclamation. A biofilm of renal tubule indications for therapy in the acute setting are well established,
cells attached to a semi-permeable membrane has beneficial fluid other indications emerge as we care for critically ill patients. The
transport properties, and a small osmotic gradient creates suf- choice of RRT for both inpatients and outpatients should best
ficient transfer of isosmotic fluid across the tubule cells.153 This meet the needs of the patient, adequate clearance at minimal
reclamation process allows therapy to be delivered without large inconvenience as well as fit the financial and resource allocations
volume fluid replacement, freeing the patient from water sources. of the region. Although filtration functions have been adequately
Membrane characteristics have also been altered to alter solute mimicked in current RRT, the replacement of endocrine and
transfer properties, thus allowing for selective hemofiltration. metabolic functions are not yet mainstream. Current fluid rec-
Microelectromechanical systems (MEMS) allow the creation of lamation and nanotechnology continue to evolve, making the
nanopore silicone membranes. These membranes contain pores implantable artificial kidney a possibility for the future.
with highly controlled pore size, within 1 nanometer over a wide
range of pore sizes from 8–90 nanometers.154 Pore size and density Acknowledgements
control selectivity of solute transfer and water permeability, hence I would like to thank Dr. Thomas Golper for his role as mentor
desirable characteristics can be engineered into small devices. A and editor in the preparation of this manuscript.
13. Heiss KF, Pettite B, Hirschl RB, Cilley RE, Chapman 23. Shermesh O, Golbetz H, Kriss JP, Myers BD.
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