Journal of Cardiac Failure Vol. 18 No.

12 2012

Review Article
Congestive Renal Failure: The Pathophysiology and Treatment
of Renal Venous Hypertension
EDWARD A. ROSS, MD
Gainesville, Florida

ABSTRACT
Longstanding experimental evidence supports the role of renal venous hypertension in causing kidney dys-
function and ‘‘congestive renal failure.’’ A focus has been heart failure, in which the cardiorenal syndrome
may partly be due to high venous pressure, rather than traditional mechanisms involving low cardiac output.
Analogous diseases are intra-abdominal hypertension and renal vein thrombosis. Proposed pathophysiologic
mechanisms include reduced transglomerular pressure, elevated renal interstitial pressure, myogenic and
neural reflexes, baroreceptor stimulation, activation of sympathetic nervous and renin angiotensin aldoste-
rone systems, and enhanced proinflammatory pathways. Most clinical trials have addressed the underlying
condition rather than venous hypertension per se. Interpreting the effects of therapeutic interventions on renal
venous congestion are therefore problematic because of such confounders as changes in left ventricular func-
tion, cardiac output, and blood pressure. Nevertheless, there is preliminary evidence from small studies of
intense medical therapy or extracorporeal ultrafiltration for heart failure that there can be changes to central
venous pressure that correlate inversely with renal function, independently from the cardiac index. Larger
more rigorous trials are needed to definitively establish under what circumstances conventional pharmaco-
logic or ultrafiltration goals might best be directed toward central venous pressures rather than left ventric-
ular or cardiac output parameters. (J Cardiac Fail 2012;18:930e938)
Key Words: Renal venous hypertension, congestive heart failure, cardiorenal syndrome, intra-abdominal
hypertension.

There is accumulating evidence from studies of decompen- interest in the 1980s with hypotheses exploring venous hyper-
sated heart failure (HF) that there may be a component of the tension as a direct cause of sodium retention and edema.3
cardiorenal syndrome due to renal venous hypertension. The More detailed studies were then facilitated by recent technol-
concept of passive renal congestion leading to depressed ogies that permitted the measurement of hormone levels for
kidney function is not new and may have additional noncar- the renin-angiotensin-aldosterone system (RAAS), sympa-
diac causes. In the 1930s, investigators reported1 a dog model thetic nervous system (SNS), and cytokine pathways, vascu-
in which acute renal vein obstruction was associated with lar pressures, blood flow, baroreceptor and neural activity, and
kidney dysfunction, reduced renal blood flow, and sodium the effects of denervation (eg, sympathectomy) or antagonists
retention. By the 1960s it was recognized that renal venous to adrenergic vasoconstriction. The purpose of the present re-
hypertension occurred in chronic HF.2 There was renewed view is to examine the evidence for the proposed mechanisms
by which venous hypertension might cause kidney dysfunc-
tion, and whether there are renal benefits from decongestion
From the Division of Nephrology, Hypertension and Renal Transplanta- by pharmacologic or ultrafiltration (UF) therapies.
tion, University of Florida, Gainesville, Florida.
Manuscript received July 15, 2012; revised manuscript received October
1, 2012; revised manuscript accepted October 4, 2012. Pathophysiology of Renal Venous Hypertension
Reprint requests: Edward A. Ross, MD, Division of Nephrology, Hyper- and Renal Dysfunction (Table 1, Fig. 1)
tension, and Renal Transplantation, University of Florida, Box 100224,
Gainesville, FL 32610-0224. Tel: 352-273-8821; Fax: 352-392-3581. Pressure-Related Effects
E-mail: [email protected]
See page 936 for disclosure information. Much research has turned from pressure-related and re-
1071-9164/$ - see front matter
Ó 2012 Elsevier Inc. All rights reserved. ceptor pathways resulting from ‘‘forward’’ HF to those
http://dx.doi.org/10.1016/j.cardfail.2012.10.010 originating from ‘‘backward’’ HF. An isolated rise in renal

930
 Congestive Renal Failure and Venous Hypertension
Ross 931

Table 1. Proposed Pathophysiology of the Effect of Renal known since animal investigations in the 1950s.5 Based
Venous Hypertension on Kidney Function on dog studies, it appears that rises in renal venous pressure
Decreased transglomerular pressure gradient to the 10e20 mm Hg range are associated with an increase
Increased renal interstitial pressure in interstitial pressure of w6 mm Hg.6 It is important to
Renal arterial vasculature myogenic response: appreciate that a rise in renal interstitial pressure due to
Vasodilatation then vasoconstriction
Neural vasoconstrictive reflexes: venous congestion is physiologically different than that
Intra- and extrarenal (eg, spinal) caused by elevations in arterial pressured which is associ-
Renal parenchymal hypoxia ated with a natriuresis. The renal effects of rises in renal
Baroreceptor activation:
Right atrium and other (venous) vasculature venous pressure to very high levels (ie, supraphysiologic,
Atrial natriuretic peptide release O30 mm Hg) have not been well studied in humans, but
Renin-angiotensin-aldosterone system activation may be quite different based on animal investigations.6
Sympathetic nervous system activation
Decreased splanchnic venous blood capacitance Neural and Myogenic Mechanisms
Endothelin release
Proinflammation cytokines and reactive oxygen species release
Renal arterial vascular smooth muscle hypertrophy
The effects of renal venous hypertension have been chal-
Glomerular hyperemia and sclerosis lenging to elucidate in that there is added complexity due to
secondary changes in filtration fraction and flow from baro-
receptor, tubuloglomerular feedback (TGF), RAAS, SNS,
venous pressure would lower the arteriovenous pressure and intrinsic vascular reflex pathways.7 Regarding the lat-
gradient across the kidney, decrease the renal blood flow, ter, there is strong evidence that there are vascular ‘‘myo-
and lower the transglomerular pressure gradients; however, genic’’ responses to venous congestion that control the
the importance of intrarenal compensatory mechanisms arterial microcirculation via neural reflexes. Abildgaard
were highlighted when blood flow was experimentally et al described how partially obstructed renal veins caused
maintained by changes in arterial perfusion or pressure.4 vasoconstriction and studied the effects of denervation or
The renal venous hypertension, however, could also sec- local instillation of an alpha-adrenoreceptor blocker.8 In
ondarily lead to parenchymal congestion within the con- their model, the initial mild venous congestion raised inter-
fines of the nondistensible kidney capsule. Thus, there stitial tissue pressure, but perfusion was maintained by
would be a rise in renal interstitial pressure that would what was viewed as an adaptive intrinsic myogenic vasodi-
affect the entire capillary bed and the tubules, possibly latory response. Further rises in venous hypertension,
also involving local hypoxia. Compression of the tubules however, triggered maladaptive sympathetic vasoconstric-
raises the luminal pressure, further attenuates the transglo- tive neural reflexes that were both extrarenal (spinal cord
merular pressure gradient, and lowers the glomerular filtra- via mechanoreceptors in the renal capsule) and intrarenal
tion rate (GFR). These effects on the tubules and capillaries (receptors within the renal parenchyma). Surgical or phar-
occur with venous pressure O15 mm Hg and have been macologic sympathectomy was partially effective in

Fig. 1. Proposed pathophysiology of renal venous hypertension, congestion, and dysfunction. ANP, atrial natriuretic peptide; GFR, glomer-
ular filtration rate; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SNS, sympathetic nervous system.
932 Journal of Cardiac Failure Vol. 18 No. 12 December 2012

preventing the adverse effects from the venous congestion. renal blood flow and GFR as well as increases in plasma
In other models of abdominal venous obstruction or cirrho- renin activity and aldosterone.18 These acute changes oc-
sis, the activation of hepatic,9 intestinal, and splenic10 affer- curred after 2 hours of venous hypertension to 30 mm Hg
ent neural pathways has been proposed to be associated and were reversible. The authors thought that this was anal-
with altered sympathetic outflow,11 renin release, and de- ogous to renal dysfunction in the abdominal compartment
creased renal blood flow. Whether there is a similar syndrome and then improvement upon decompression.
intestinal-renal neural reflex remains controversial. Surgical The situation appears, however, to be more complex in
or pharmacologic denervation in some renal and splenic ve- that there may be differences across the various abdominal
nous hypertension models greatly attenuated the reduction venous structures. For example, there may be increased
in renal blood flow10; however, the literature is controver- adrenergic tone affecting renal perfusion and renin secre-
sial in that in other models of renal interstitial hypertension, tion resulting from portal hypertension and not from
renal blood flow decreased despite kidney decapsulation thoracic inferior vena cava constriction.19
and blockade of TGF and SNS pathways.12 Reports of elevated renal and systemic levels of angio-
tensin II6,20 are consistent with not only increases in renin,
Baroreceptor Mechanisms
but they may also be due to heightened SNS activity. It is
Activation of mechanical baroreceptors would help not clear whether these pathways are involved locally
explain renal dysfunction due to a variety of disorders re- when renal tissue hypoxia (perhaps exacerbated by intersti-
sulting in renal venous hypertension: HF with high CVP; tial edema) is proposed to trigger a decrease in GFR.20
cirrhosis with portal hypertension and hepatorenal and sple- Venous Capacitance Mechanism
norenal venous congestion; other mesenteric venous throm-
botic conditions with intestinal-renal venous hypertension; Pathophysiology that involves neural and sympathetic
intra-abdominal hypertension (IAH); direct pressure on nervous system pathways is particularly relevant regarding
the renal parenchyma; and obstruction at the renal veins a recently advocated mechanism that involves splanchnic
by thrombi, tumors, trauma, or in experimental animal venous capacitance. Fallick et al21 hypothesized that acute
models. Stretch receptors in the atrium are of special inter- HF can result from increases in venous tone that cause
est. High atrial natriuretic peptide levels not only would be decreased capacitance, increased venous return, higher
a marker of venous congestion, but there is also evidence effective blood volume, and thence cardiac decompensa-
that its beneficial natriuretic effects are attenuated in HF. tion. Short-term regulation of the splanchnic venous vol-
High renal interstitial pressure due to venous congestion ume would thereby be regulated by sympathetic activity,
may impair preservation of GFR by loss of atrial natriuretic predominantly alpha-adrenergic. Thus HF exacerbations
peptide’s effects modulating TGF.13 These proposed vascu- or remissions occur with redistribution of the intravascular
lar baroreceptor neural networks would thus be extensive blood volume rather than from changes in total body salt
and complex, and there is no evidence that there would or water. This model would lead to parallel changes in renal
be a therapeutic role in HF by their ablation with surgical venous hypertension and kidney congestion. If this pathway
or the recently developed cryo- or radiofrequency is shown to be clinically relevant it could guide pharmaco-
techniques. logic therapy, such as a greater focus on the use of
SNS and RAAS Mechanisms
alpha-adrenergic blockade, beta-blocker formulations with
intrinsic alpha effects, and possibly sympatholytic interven-
In addition to the baroreceptor-associated, neural reflex, tional therapies involving radiofrequency or other ablative
and natriuretic peptide pathways, there is longstanding technologies.
evidence that renal venous congestion influences the sym-
Inflammation, Cytokine, and Other Mechanisms
pathetic nervous system and RAAS systems. Early observa-
tions of sodium retention in models of venous obstruction In addition to the traditional renal venous hypertension
were confounded by other hemodynamic changes present effects on intra- and extrarenal hemodynamics, pressure
in HF. In a 1940s dog model of unilateral renal vein con- profiles, and neurohumoral pathways, there has been
striction, there was rapid ipsilateral retention of sodium a growing interest in inflammatory and endothelial cell
and water that was independent of blood pressure, renal activation. It has been proposed that in HF the endothelium
blood flow, or GFR.14 Reports since the 1960s also showed changes from a quiescent redox profile to an activated
that there was impaired salt excretion associated with dec- proinflammatory, prooxidant, and provasoconstrictive
rements in GFR after renal venous constriction.15,16 state.22 Deleterious effects on the heart and kidneys would
Although animal models such as these demonstrated that then exacerbate this congestive pathophysiology, initiating
even mildly elevated renal venous pressure17 can cause a vicious cycle. It was theorized that venous congestion
a rapid rise in plasma renin activity and aldosterone levels, causes a biochemical signal to endothelial cells that
it was difficult to exclude effects from changes in systemic changes their redox phenotype of reactive oxygen species,
hemodynamics. Subsequently, in a swine model of renal ve- endothelin,23 interleukin-6, tumor necrosis factor alpha,
nous constriction in which there were no changes in cardiac and nitric oxide bioavailability. These markers were in-
index or systemic blood pressure, there still was a decline in creased in a dog model of acute fluid overload and venous
 Congestive Renal Failure and Venous Hypertension
Ross 933

congestion.24 The authors also provided preliminary evi- The use of right atrial parameters (by direct measurement
dence for proinflammatory endothelial cell changes after or by imaging) as markers for venous congestioneinduced
acute venous congestion of the forearm in humans.22 renal dysfunction is appealing, and there have been studies
supporting that approach. For example, in Maeder et al’s re-
Effects on CKD
port of HF patients, the echocardiographic severity of tri-
Beyond the diverse mechanisms for renal dysfunction cuspid regurgitation was independently associated with
due to acute renal venous congestion, there is also the im- the degree of renal dysfunction.31 Nevertheless, a prepon-
portant concern for the development of chronic injury that derance of studies analyzing right atrial pressures have
could cause or contribute to advancing CKD. In a canine demonstrated 2 major confounding factors that make it dif-
model of renal venous hypertension induced by varying ficult to interpret these findings in HF: the extent of coex-
degrees of right-sided heart overload, there was glomerular istent primary parenchymal renal disease, and the degree
hyperemia and sclerosis.25 The investigators proposed that to which cardiac index is depressed. It has been suggested
this injury was attenuated in animals that developed an that elevations in right atrial pressure become clinically rel-
adaptive increase in renal artery tone and hypertrophy of evant only in states in which cardiac output is depressed. In
the vascular smooth musculature. a canine model of acute renal venous congestion (13 cm
H2O) the renal dysfunction (reduced blood flow, GFR,
Renal Venous Hypertension in Human Disease and sodium and water clearance) was ameliorated when
transfusions normalized systemic hemodynamics.32 In an
HF and the Cardiorenal Syndrome
important human study of cardiac dysfunction due to pul-
Although the renal dysfunction associated with HF has monary hypertension, right atrial pressure (RAP) and renal
traditionally been attributed to impaired cardiac output blood flow independently correlated with iothalamate-
and kidney hypoperfusion, this relationship may not hold measured GFR; however, the association with RAP and
true across large cohorts of patients. For example, using therefore venous congestion was most apparent in the
the ADHERE (Acute Decompensated Heart Failure Na- low-renal-flow subjects.20 In a series of 140 patients with
tional Registry) database of 118,465 decompensated HF acute HF it was only in those with hypotension that
admissions, Heywood et al were not able to show an asso- a high CVP on admission and discharge that there was a cor-
ciation between left ventricular systolic dysfunction and re- relation with lower eGFR.33 Low cardiac index might thus
nal impairment.26 Many recent trials have raised the identify a population of patients who could potentially ben-
possibility of alternative pathophysiologic mechanisms, efit from decongestive therapies guided by measurement of
with a growing interest in the effects of high right atrial venous pressures. It has been suggested20 that this stratifica-
pressures on renal venous congestion and hypertension. tion of patients at risk could explain the subset in the
This was highlighted in the ESCAPE (Evaluation Study ESCAPE trial34 whose renal function did not worsen
of Congestive Heart Failure and Pulmonary Artery Cathe- when therapy was guided by RAP as opposed to clinical
terization Effectiveness) trial involving hospitalized decom- assessments.35 A primary renal function dependence on
pensated HF patients in which kidney function did not cardiac output would suggest that venous congestion is
correlate with cardiac index, pulmonary capillary wedge of concern when ‘‘warm’’ HF patients move to ‘‘cold’’
pressure, or systemic vascular resistance, but rather was (eg, with lower renal perfusion), with manifestations of el-
(weakly) associated with right atrial pressure.27 In Damman evated jugular venous pressure on physical exam and asso-
et al’s retrospective analysis of 2,557 patients undergoing ciated higher rates of hospitalization, HF progression, and
right heart catheterization, elevated central venous pressure mortality.36,37 Therefore, the design of clinical trials study-
(CVP) was associated with low estimated glomerular filtra- ing the effects of lowering renal venous pressure would be
tion rate (eGFR) independently from cardiac index, and it challenging, because the results would be confounded if the
predicted mortality.28 These investigators reported support- intervention independently improved cardiac output.
ive findings in a study of 2,647 patients with systolic heart Although studies of patients with varying degrees of
failure, in which depressed eGFR and mortality were asso- reduced-EF HF have thus provided valuable lessons, the
ciated with congestive findings such as ascites and elevated physiology and care of individuals with preserved-EF HF
jugular venous pressure.29 Similarly, Guglin et al30 de- remains very challenging. In some HF populations, approx-
scribed catheterization findings in 178 HF patients wherein imately one-half the patients have preserved EF and the
low eGFR correlated with high CVP and low renal perfu- diastolic dysfunction causes complex changes across the
sion pressure (mean arterial pressure  CVP), but not the pulmonary vascular bed and right-sided cardiac structures.
cardiac index or left ventricular ejection fraction (LVEF). Right-sided heart failure would then be associated with re-
Echocardiogram data showed an association of renal im- duced left ventricular end-diastolic and stroke volumes,
pairment with peak tricuspid regurgitation velocity but thereby making the patients preload dependent.38 In this
not LVEF. Further complicating patient presentations are situation, fluid removal protocols based on high CVP levels
those with low cardiac index and HF in the setting of pre- could be confounded by unintended deterioration in cardiac
served ejection fraction, as well as having a range of vascu- output. Complexities such as these highlight the potential
lar tone and perfusion across different various tissue beds. therapeutic equipoise between treating the high CVP and
934 Journal of Cardiac Failure Vol. 18 No. 12 December 2012

renal venous pressure while simultaneously maintaining collapse during inspiration. These findings are particularly
preload, cardiac output, and renal perfusion. relevant for patients with predominant or primary right ven-
tricular failure in that therapies (eg, sildenafil) prescribed to
Renal Venous Hypertension and Congestion in
improve outflow dynamics may have previously underap-
Noncardiac Diseases
preciated secondary benefits from lowering renal venous
Many of the concepts proposed for the renal dysfunction pressure. Clinicians need to be mindful that with patho-
in HF are analogous to those for IAH: renal venous conges- physiology being different between acute and chronic ve-
tion with or without low cardiac output. In the 1940s, Brad- nous hypertension, it is anticipated that there are also
ley and Bradley studied the effects of abdominal differences in the respective therapies.
compression devices in humans and induced IAH levels
Pharmacologic Treatment: Diuretic Therapy
of up to 80 mm Hg.39 At 20 mm Hg there was decreased
renal plasma flow (from 621 mL/min to 488 mL/min), de- The potential disadvantages of choosing diuretics to treat
creased GFR (from 117 mL/min to 88 mL/min), unchanged acute HF have been well studied and described in the liter-
filtration fraction, increased water reabsorption, and de- ature.45 These include maladaptive activation of TGF, acti-
creased urine flow, changes which they hypothesized were vation of SNS and RAAS, and increased afterload.46
due to renal venous hypertension. Those findings are con- Francis et al47 have demonstrated that when chronic HF pa-
sistent with reports of elevated plasma renin activity and tients are given intravenous furosemide, there is a rise in
aldosterone levels.40 There has been a concern that some systemic vascular resistance, plasma renin activity, and
of the renal dysfunction with IAH is due to hypotension plasma levels of norepinephrine and arginine vasopressin.
and low cardiac output. Nevertheless, when cardiac output Nevertheless, diuretics have been the mainstay of HF treat-
is corrected by volume expansion in IAH dogs, renal blood ment and are effective in many patients, which is consistent
flow and GFR were still !25% of normal.41 Similarly, with a paradigm of decongestion that includes attenuating
others have shown that with carefully maintained cardiac renal venous hypertension and kidney congestion. It is pos-
output there is still renal dysfunction with IAH as low as sible that the latter is due at least in part to the effects of
15 mm Hg.42 Nevertheless animal models with dramatic loop diuretics on pathways distinct from a direct receptor-
falls in cardiac output (eg, to 37% of normal with GFR mediated natriuresis. These medications reportedly enhance
down to 7%41) highlight why potentially profound systemic the synthesis of prostaglandins which cause relaxation of
changes in severe IAH limit the utility of this model for smooth muscles and thence renal vasodilatation.48,49 Simi-
studying kidney dysfunction in HF. larly, the benefits of spironolactone therapy for advanced
chronic HF (as reported by the Randomized Aldactone
Treatment of Renal Venous Hypertension and Evaluation Study) may not have been from its diuretic ef-
Congestion fect but rather neurohumoral from blockade of the
RAAS.50 This hypothesis was extended by the investigators
In light of the complex pathophysiology, crafting patient in their report of the improved outcomes from eplerenone
care guidelines that incorporate measures of both renal ve- treatment being beyond that from diuretic or potassium
nous hypertension and left ventricular function is difficult effects and instead possibly due to other mechanisms
and remains controversial. The frequent discordance be- from mineralocorticoid receptor antagonism.51
tween the cardiac index and right-sided pressures across As in any diuretic regimen, future protocols designed to
the various cardiac disease entities (eg, with right, left, or use diuretics to lower renal venous pressure would need to
biventricular dysfunction) might explain why in Mullins address the enhanced sodium reabsorption that can occur in
et al’s series43 the elevation in right atrial pressure at the the time intervals between short-acting loop diuretic doses.
time of acutely decompensated HF presentation did not cor- As shown by Wilcox et al,52 a moderate salt intake
relate with renal dysfunction. Nevertheless, with treatment, (270 mEq/d) coupled with rebound salt hyperabsorption
those patients who did not have a fall in RAP were more in the interdiuretic interval can negate any net natriuretic
likely to have worsened renal function and adverse clinical benefit from loop agents. Therefore, effective decongestion
outcomes. Kidney dysfunction occurred less frequently and potential decreases in renal venous hypertension would
when the CVP decreased to !8 mm Hg, and therefore its necessitate optimal salt restriction and/or longer-acting
measurement was proposed as a way to stratify risk for diuretics. A renal venous hypertensionedirected approach
renal impairment. This also has important implications using diuretics has yet to be investigated.
for therapeutic interventions, such as extracorporeal UF,
Pharmacologic and Interventional Treatments:
in which fluid removal could potentially be guided by mon- Sympatholytic Therapies
itoring of RAP. A report by Testani et al44 described an as-
sociation of venous congestion and right ventricular The success of beta- and alpha-adrenergic blockade in
dysfunction with improved renal outcomes after UF. They the treatment of low cardiac output in HF could theoreti-
theorized that kidney function improves in the subset of cally have benefits from lowering renal venous pressure,
patients in whom decongestive therapy improves echocar- but these have not been independently rigorously investi-
diographic volume parameters, such as with vena cava gated. However, alpha-adrenergic inhibition in particular
 Congestive Renal Failure and Venous Hypertension
Ross 935

has additional appeal based on Fallick et al’s21 proposed approaches to reduce IAH there are little data to support
splanchnic venous capacitance mechanism. If this pathway the use of extracorporeal fluid removal modalities. Never-
is shown to be of clinical magnitude, then, as described theless, a report by Bonfim et al supports a role for extra-
above, there might be pharmacologic or interventional corporeal UF in IAH. They described 5 patients who
treatments to ameliorate acute-on-chronic redistribution of underwent intermittent or extended HD treatments.55
splanchnic blood into the effective blood circulatory vol- A mean of 14 kg was removed and the decrease in intra-
ume. Consistent with this paradigm are recent preliminary abdominal pressures of w8 mm Hg correlated with the
findings from Taborsky et al.53 Following radiofrequency ‘‘hydric balance.’’ Similarly to IAH, there have yet to be
renal denervation, patients (n 5 26) had higher ejection rigorous studies addressing the effects on renal congestion
fraction (31% vs 25% in the control group; n 5 25) and and function after surgical or shunting procedures to relieve
fewer HF hospitalizations (8 vs 18). venous, portal, or mesenteric hypertension or thromboses.
Mechanical Interventions Fluid Removal and ‘‘Decongestion’’ by Extracorporeal
Ultrafiltration
Analogous to there being unquantified benefits of phar-
macologic HF therapy on relieving renal congestion, there Despite the above-described evidence for adverse renal
are similar possible benefits from correcting valvular or effects from renal venous hypertension, it has been difficult
other structural cardiac abnormalities that decrease cardiac to quantify benefits from its treatment in light of the thera-
output. This includes left-to-right shunts, such as acute rup- pies typically being confounded by other systemic effects.
tures of sinuses of Valsalva, which can acutely raise right- In the case of HF, eg, the heart and renal benefits from
sided pressures and cause renal congestion. UF are associated not only with reduced RAP but also
Interventions for Intra-abdominal Hypertension
with improved cardiac output. A report by Marenzi et al56
characterized hemodynamics during and after extracorpo-
For IAH and the abdominal compartment syndrome, real UF in 24 patients with refractory HF. With fluid re-
therapy has primarily involved procedures that directly moval up to w5 L, there was progressive reduction in
lower pressure: paracentesis, gastrointestinal decompres- right atrial, pulmonary artery, and capillary wedge pres-
sion, wall musculature paralytics, and of course decompres- sures, as well as increased cardiac output with improved
sive abdominal wall surgery. Resolution of IAH is New York Heart Association functional classification stage
associated with rapid improvements in renal function, but of HF. Notably, the subjects became more responsive to di-
effects on renal venous hypertension can not be dissociated uretics, which permitted a two-thirds reduction in furose-
from a wide range of other dramatic improvements, includ- mide dose. In that the vast majority of UF studies for HF
ing cardiac output and blood pressure. It is possible that pa- were based on volume removed rather than venous hyper-
tients with decompensated HF develop enough ascites or tension parameters, this investigative group has provided
interstitial tissue edema so as to raise intra-abdominal pres- a valuable approach with their protocols guided by RAP.
sure, thereby developing a component of IAH in addition to For example, in the exercise capacity study of 26 patients
other causes of the cardiorenal syndrome. Mullens et al54 with stable moderate HF, UF was adjusted based on right
raised this hypothesis in a report of 40 decompensated atrial measurements.57 Fluid was removed in a single ses-
HF patients treated with intense pharmacologic manage- sion until RAP decreased to 50% of baseline, and this re-
ment. At baseline there was a mean intra-abdominal pres- sulted in w600 mL/h for the 2 L of ultrafiltrate. In
sure of 8 6 4 mm Hg, and 60% of the subjects had what subsequent studies involving pulmonary function, this
were considered to be elevated intra-abdominal pressures pressure-driven approach to UF protocols58 explains the
at $8 mm Hg (well below the 12 mm Hg threshold for wide variation in UF volume: 1,250e2,600 mL.
IAH or 20 mm Hg for abdominal compartment syndrome). Although the few studies that were guided by RAP pro-
For the latter subset, after treatment there were significant vide some insights into the design of future trials for UF, the
declines in abdominal pressure (from a mean of 10 mm purported benefits from fluid removal have come mostly
Hg to 6 mm Hg) in some but not all patients. Only 10% from investigations using other therapeutic targets. There
of the subjects had the higher pressures typical of IAH, are reports of protocols that have adjusted UF based on he-
and those decreased from a mean of 15 mm Hg to 7 mm moconcentration, assessed by red packed cell volume,56 but
Hg. With treatment there were significant declines in this is problematic for rigorous trials in that there is large
CVP and wedge pressure as well as increased cardiac index variation of plasma refill rates across patient populations.
and eGFR. Improvement in renal function, however, corre- Vascular refill rates may also vary during the course of a sin-
lated only with decreases in the intra-abdominal pressure, gle UF session, declining as volume overload is amelio-
not the hemodynamic variables. Beneficial renal effects rated. This approach does not address hemodynamics
from relieving these relatively low levels of ‘‘IAH’’ after fluid shifts reach equilibrium, nor their ultimate effects
(especially in light of the multiple simultaneous confound- on right atrial or renal venous hypertension.
ing changes in central hemodynamics) would need to The majority of studies purporting the HF benefits
be rigorously confirmed. In that there are well establi- of ultrafiltration adopted protocol-driven UF rates
shed interventional (eg, paracentesis) and pharmacologic rather than adjusting fluid removal by either RAP or
936 Journal of Cardiac Failure Vol. 18 No. 12 December 2012

hemoconcentration, thereby being unable to dissociate ve- and intra-abdominal hypertension. Renal congestion may
nous pressure effects from other hemodynamic changes. also be an integral consequence of acute redistributions of
Most of these investigations were facilitated by the devel- blood volume, such as from changes in splanchnic venous
opment of a small simple portable device dedicated to iso- capacity. Although the kidney improvements observed in
lated ultrafiltration, and data have been generated from trials using traditional pharmacologic strategies or UF
inpatient and outpatient ‘‘aquapheresis’’ clinic experiences. have been attributed to improvement in cardiac output
In early small trials some subjects experienced worsening and renal perfusion, based on the physiology there is reason
of their renal function with UF, which occurred in 45% to hypothesize that there were benefits from reducing
of the 11 patients reported by Liang et al, 5 of whom ulti- venous hypertension. The degree to which kidney function
mately needed dialysis.59 Bartone et al60 described serum improves with relief of congestion by UF may depend on
creatinine rising from 1.9 mg/dL to 22 mg/dL, with levels the preprocedure intrarenal hemodynamics driven by
increasing O0.5 mg/dL in 44% of the patients undergoing cardiac output and renal arterial perfusion. It is hoped
UF. These investigations highlight that potential kidney that, by including measurements of RAP or other venous
benefits from decongestion may be outweighed by overly pressure parameters, future studies will be able to
aggressive UF rates and the induction of acute prerenal azo- elucidate the extent and circumstances in which relief of
temia. The few single-center small series were followed by venous hypertension by pharmaceutical or extracorporeal
a multicenter randomized controlled trial (UNLOAD) of therapies will have clinically relevant benefits to kidney
early inpatient treatment of acutely decompensated HF function.
with the UF device compared with conventional care with
intravenous diuretics.61 Although perhaps owing in part to Disclosures
the highly protocolized medication dosing, the UF patients
did have more weight loss over the first 2 days, but without None.
better renal function, dyspnea scores, or length of hospital
stay. Nevertheless, at 90 days after discharge UF was asso- References
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uted to relief of renal venous hypertension. lian kidney. J Physiol 1931;72:49e61.
2. Maxwell MH, Breed ES, Schwartz IL. Renal venous pressure in
Peritoneal Dialysis Ultrafiltration chronic congestive heart failure. J Clin Invest 1950;29:342e8.
3. Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct
The literature regarding UF with the use of peritoneal cause of renal sodium retention in oedema? Lancet 1988;1:1033e5.
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