US Pharm. 2013;38(8):HS11-HS16.
syndrome involves the impairment of several biochemical and
physiological functions associated with deteriorating renal function.
Uremia presents as a broad array of symptoms and is characterized by an
accumulation of toxins, which are classified based on size and protein
binding. Dialysis is the mainstay of toxin removal, although kidney
transplantation may be necessary in severe cases. Clinical effects of
uremic toxins are proposed based on surrogate mechanisms of oxidative,
endothelial, and erythrocyte damage. Currently, drug therapy targeting
uremic symptoms is anecdotal. Uremic bleeding is the most well-described
symptom in the literature, and viable therapeutic options for
management are available.
Uremic patients present with various signs and symptoms collectively referred to as uremic syndrome.
This syndrome involves the impairment of several biochemical and
physiological func-tions associated with deteriorating renal function.
Symptoms are nonspecific and difficult to identify in early disease (TABLE 1).1
Cardinal signs and symptoms of advanced disease include anorexia and
eventual weight loss, confusion, lethargy, bleeding, coma, and death.2
Treatment of uremia primarily involves dialysis
(hemodialysis and peritoneal) and ultimately kidney transplantation for
eligible candi-dates. Inadequate removal of uremic toxins through
conventional dialysis may result in a phenomenon known as residual syndrome. Patients with this syndrome may experience subtle signs of malnutrition, mild lethargy, infection, and serositis.2
Complete symptom reversal usually requires kidney transplantation.
Although transplantation is the most effective method of treatment, it
is increasingly difficult due to the limited number of donor kidneys.3
Uremia is characterized by an accumulation of toxins in
chronic kidney disease (CKD) and end-stage renal disease that leads to
illness. Generally, uremic symptoms cannot be attributed to changes in
volume status, electrolyte disturbances, or absence of renal
Although predominant, urea is only one of many toxins that
accumulate in CKD. Other toxic solutes include peptides and small
proteins, guanidines, phenols, indoles, aliphatic amines, furans,
polyols, nucleosides, dicarboxylic acids, and carbonyls.1,4
Classification of uremic toxins is based on several criteria, one being
that removal of the toxin demonstrates a reduction in symptoms.
Inability to effectively remove certain solutes to demonstrate
resolution of symptoms can make toxin assignment difficult. Data linking
toxic effects and disturbances of various biological and biochemical
functions associated with specific uremic solutes are limited.
The European Uremic Toxin Work Group has identified over 100 uremic toxins and has classified them by structure.4,5
Uremic compounds are categorized into three groups: 1) small,
water-soluble, nonprotein-bound compounds (<500 D); 2) small,
lipid-soluble and/or protein-bound compounds; and 3) large “middle”
molecules.5 Accumulated toxic solutes in uremia produced by
gut bacteria and mammalian cells are positively charged compounds with
preferential intracellular distribution, making removal by dialysis
difficult.1,2 Protein-bound molecules and large middle
molecules are also inadequately removed by current dialysis methods.
Continued strides to improve dialysis strategies and develop novel
approaches to inhibit toxin production may lead to greater symptomatic
relief and survival benefits in CKD.
Small, Water-Soluble Compounds: In kidney failure, urea was the first organic compound to be identified in high concentrations systemically.1 Urea is a water-soluble 60-D solute that is minimally toxic and only partially accounts for some uremic symptoms.6 Studies show mixed results and poor correlation of symptom resolution and improved survival with urea removal through dialysis.1,6
Additionally, urea, which used to be the prototype of small,
water-soluble compound retention and dialysis removal, does not appear
to adequately represent the behavior exhibited by similar compounds
Guanidines are water-soluble uremic compounds structurally similar to urea with pleiotropic effects, including neurotoxicity.5,6
Recently, guanidines have been investigated for having potential
cardiovascular effects in uremic patients. High concentrations of
guanidines are believed to activate leukocyte function, leading to
proinflammatory production of tumor necrosis factor alpha (TNF-α) and
interleukin-6 (IL-6).6 The impact of guanidines on albumin
may also increase unbound levels of homocysteine, a protein-bound
compound linked to cardiovascular damage through macrophage activation,
resulting in high superoxide anion levels.7 Folic acid can counteract homocysteine elevation to some degree.7
Guanidines exhibit large volumes of distribution, hindering their
removal via hemodialysis, but longer durations or increasing frequency
of hemodialysis sessions can potentially improve their removal.6
Protein-Bound Molecules: P-cresol is a 108-D lipophilic phenol prototype of protein-bound molecules produced by intestinal bacteria.4,5
High concentrations of p-cresol have been associated with increased
hospitalization due to infections, uremic symptoms, mortality, and
cardiovascular disease.6 However, p-cresol is now known to be
absent in the body, and its appearance in uremic samples is a result of
artifact from hydrolysis of conjugates, such as p-cresyl sulfate (PCS),
a compound present in vivo.5 P-cresol attenuates leukocyte activity, whereas PCS improves leukocyte activity.5
Recent studies with PCS produced findings of increased cardiovascular
disease and mortality similar to those of p-cresol despite having
opposing effects.6 Removal of p-cresol is no better with high-flux than with low-flux dialysis.5
Fractionated plasma separation adsorption could enhance p-cresol
removal; however, studies show evidence of severe coagulation
Indols are protein-bound molecules also linked to various mechanisms of endothelial damage.5
They may interfere with protein binding of acidic drugs and inhibit
tubular secretion of highly protein-bound drugs, increasing the risk of
drug toxicity.6 Appearance of indols requires intestinal
bacteria metabolism; thus, administration of oral prebiotics such as
bifidobacteria in gastro-resistant capsules may reduce indoxyl sulfate
levels.6 Dialysis is usually a poor strategy for removal of protein-bound indols.
Large “Middle” Molecules: Middle
molecules are arbitrarily assigned as compounds >500 D in molecular
weight and include toxins such as TNF-α and IL-6. Middle molecules are
believed to be involved in inflammation, endothelial destruction,
smooth-muscle cell proliferation, and coagulation, although studies
determining the nature of their effect in uremic processes are lacking.6
Beta2-microglobulin is 12,000 D and the
prototype for middle-molecule uremic toxins. It is used as a marker in
peripheral vascular disease and may play a role in arterial stiffness
and bone disease.6 Beta2-microglobulin is more
readily cleared by high-flux hemodialysis, which incorporates greater
permeability and larger pore size for more effective solute removal.1 Removal of beta2-microglobulin in CKD has been associated with good outcomes and improved mortality related to infection.6
Leptin is a large, protein-bound, 16-KD molecule that may provoke vascular damage.4,7 It increases tissue factor expression linked to clotting and inflammation and may enhance atherosclerosis in CKD.7
Pharmacologic Therapy of Uremic Toxins
Current cardiovascular therapies proportionally prevent
more cardiovascular death in patients without CKD versus those with
renal failure. Determining adverse biological effects caused by toxins
that accumulate in uremia can provide strategies to improve quality of
life and reduce mortality in patients with CKD. Currently, what is known
is that many of these designated toxins impair functions in leukocytes,
endothelium, and smooth muscle cells, which can subsequently contribute
to immune deficiency, inflammation, atherosclerosis, and cardiovascular
The esoteric effects of uremia on vasculature and immunity
make it difficult to isolate mechanisms by which drugs may improve
uremic symptoms. However, drugs that have been used empirically to
counteract toxic effects of uremia include aspirin for antiplatelet and
anti-inflammatory properties; antihypertensives such as
angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic
blockers, and diuretics to normalize blood pressure; statins to lower
atherosclerotic cholesterol; phosphate binders to lower phosphorous
levels; and folic acid to reduce homocysteine levels.7 Future
targets indicate a role for drugs that inhibit culprit receptors,
calcium transporters, transcription factors, and promoters of oxidative
stress that are specific to the detrimental effects of uremia.7
Among the numerous symptoms of uremia in CKD, uremic bleeding is perhaps the most well-documented complication.8-10
Although its exact pathophysiology is unknown, platelet dysfunction
seems to play the largest role and involves impairment of both platelet
aggregation and adhesive-ness.8,11,12 Uremic toxins, elevated prostaglandin I2 (PGI2)
levels, increased nitric oxide (NO) production, von Willebrand factor
(vWF) abnormalities, and anemia are among the leading causes of
hemostatic disturbance in uremic patients.8-12
With regard to urea, there does not seem to be a clear
relationship between blood urea nitrogen (BUN) levels and abnormal
bleeding time in renal failure patients.13 However, excess
levels of urea can ultimately result in greater formation of
guanidinosuccinic acid (GSA), which may inhibit adenosine diphosphate
(ADP)–induced platelet aggregation. Phenolic acids also inhibit this
aggregation, contributing to the platelet dysfunction.14,15
Elevated levels of GSA and methylguanidine have been
implicated in the stimulation of NO production, resulting in platelet
adhesion and aggregation dysfunction.9,16,17 Elevated NO
levels stimulate guanylyl cyclase and result in excess cyclic guanosine
monophosphate (cGMP). This leads to a reduction in thromboxane A2 and ADP levels, further contributing to abnormal platelet aggregation.10,14,15-17 An elevation of PGI2 may also be seen in chronic renal failure patients (with abnormal bleeding times) due to reduced levels of thromboxane A2 and ADP, which result from adenylyl cyclase stimulating the production of cyclic adenosine monophosphate (cAMP).8,18,19 PGI2 may also play a role in the inhibition of platelet spreading, thereby reducing adhesion and thrombus formation.20
An abnormal interaction between vWF and glycoprotein (GP) Ib/IX may also lead to platelet dysfunction in uremic patients.10,21 Without appropriate binding of vWF to these receptors, levels of thromboxane A2 and ADP are ultimately reduced and GPIIb/IIIa receptors are not activated, leading to additional platelet aggregation issues.22,23
In patients with anemia associated with chronic renal
failure, decreased levels of erythropoietin and red blood cells may also
result in abnormal platelet aggregation.11 At normal levels, red blood cells release thromboxane A2 and ADP and allow platelets to adhere to endothelial surfaces and form platelet plugs in response to injury.11,24,25 Low levels of hemoglobin can remove and inactivate NO and may also contribute to platelet dysfunction.26
Management of Uremic Bleeding
Patients with uremic bleeding may present with various
symptoms of bleeding (e.g., epistaxis, ecchymosis), as well as mild
thrombocytopenia.10 Other causes of bleeding must be ruled
out prior to formulating a therapeutic plan for uremic patients.
Bleeding time is considered to be the preferred test for assessing
Dialysis: In patients with advanced
renal impairment, dialysis may be necessary to remove by-products and
uremic toxins. Approximately two-thirds of uremic patients with bleeding
may exhibit partial bleeding-time correction with hemodialysis or
peritoneal dialysis.27-29 In one study, bleeding time was normalized during 30% of dialysis sessions.28 Hemodialysis without anticoagulation is recommended in patients with active bleeding.30
In addition, certain small, water-soluble guanidino compounds may
require longer or more frequent dialysis sessions for their removal (due
to their higher distribution volumes as compared to urea).31
Desmopressin: This vasopressin analogue
stimulates the release of vWF from endothelial cells, as well as the
release of factor VIII (a protein essential for blood clotting) from
other storage sites.32-34 It may also aid in the expression of glycoprotein on platelet membranes.34
Improvement in bleeding time can be seen within 1 hour of
administration, and duration is approximately 4 to 8 hours, with
bleeding time generally returning to baseline within 24 hours.10,35
Although not approved for uremic bleeding, studies have
demonstrated a normalization or reduction in bleeding time with
desmopressin. Doses of desmopressin in these studies ranged from 0.3
mcg/kg to 0.4 mcg/kg IV or SC.35-38 Adverse events included
headache, flushing, and rare thrombotic events. Hyponatremia and reduced
urine volume may also occur. In addition, tachyphylaxis after one or
two doses may develop and is believed to be a result of vWF or factor
VIII storage depletion.8,35-38
Cryoprecipitate: Cryoprecipitate is a
blood product containing factor VIII, vWF, and fibrinogen, which may
contribute to platelet aggregation in patients with uremic bleeding.10,39,40
Ten units/bags of American Red Cross–prepared cryoprecipitate
administered IV over 30 minutes have resulted in decreased bleeding
times within 4 to 12 hours of infusion, with an onset of approximately 1
hour.10,39,41 However, this product is generally used in
patients who do not respond to desmopressin or have a contraindication
to desmopressin therapy due to the potential risks of infection
transmission, allergic or anaphylactic reactions, and potential
serologic incompatibilities associated with cryoprecipitate.10,40,41
Erythropoietin: Elevations in hemoglobin ≥10 g/dL may improve platelet function and reduce bleeding times in patients with anemia of CKD.42,43
Recombinant erythropoietin-stimulating agents (ESAs) have been seen to
decrease or normalize bleeding time in uremic patients with a target
hematocrit of >30%, which can take up to 9 weeks in uremic patients.10,42,44,45 However, an increase in reticulated platelets can be observed within 7 days of ESA initiation.42,45 In addition, ESAs may aid with platelet adhesion and aggregation in the acute setting.46
Transfusion of packed red blood cells is also commonly used acutely to
correct anemia and for patients with active bleeding complications.40,43
Conjugated Estrogens: Conjugated estrogens are believed to decrease the production of NO47
and have yielded beneficial effects (i.e., bleeding-time and clinical
bleeding improvements) in the chronic management of bleeding in uremic
patients.10,40,48-51 Although oral and transdermal therapies
have been shown to aid in the control of bleeding, the majority of
evidence supports 0.6 mg/kg of IV-administered conjugated estrogens once
daily for 5 days. The onset of action is approximately 6 hours, with a
total duration of about 14 to 21 days.48-50 However, long-term use of conjugated estrogen therapy is limited due to estrogen-associated adverse effects.10,40
Uremia presents as a broad scope of symptoms appearing in
CKD caused by an accumulation of toxins. Removal of larger and highly
protein-bound molecules is difficult, even with improving methods of
dialysis. From available reviews, detrimental clinical effects of uremic
compounds can be assumed based on surrogate mechanisms of damage to
leukocytes, endothelium, and erythrocytes exhibited by these solutes.
Currently, there are no useful drugs to treat uremic symptoms aimed at
specific toxins. The armamentarium of drugs used in CKD is similar to
drugs used to prevent cardiovascular disease in the general population.
Among the symptoms seen in uremia, uremic bleeding is the most well
described in the literature, and viable therapeutic options for
management have been elucidated.
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