Uremic Toxicity

Kopple J. D. and Massry S. D. :Nutritional

Management of Renal Disease, p97-190

:
:92.08.15
 Uremia-1
Greek words : urine + blood = uremia
Uremia is the retention of excessive by
products of protein metabolism in the blood
and the toxic condition produced thereby.
 Uremia-2
Uremia is a toxic syndrome caused by
severe glomerular insufficiency, associated
with disturbances in tubular and endocrine
functions of the kidney. It is characterized
by retention of toxic metabolites, associated
with changes in volume and electrolyte
composition of the body fluids and excess
or deficiency of various hormones.
 Uremic symptoms and signs
Table 5.1.

Central nervous system

Peripheral nerves
Gastrointestinal tract
Hematologic and immunologic
Cardiovascular system
Respiratory system
Skin
Musculoskeletal system
Endocrine and metabolic changes
 Toxic effects of uremic plasma
There is evidence that a variety of
disturbances, such as anemia, immunologic
deficiency, bleeding tendency, disorders of
carbohydrate and lipid metabolism, and
various membrane transport disturbances.
 Definition of a uremic toxin
Plasma and /or tissue concentration of the compound
should be higher in uremic patients.
High concentrations The compound should be chemical
identified, specific and accurate quantitative analysis
should be related to specific uremic symptoms and
disappear when the concentration is reduced.
Studying toxicity of the compound , the concentration
shoul be compartable to those found in the body fluids
and/or tissues of uremic patients.
Factors that influence uremic toxicity

Dialysis treatment
Small, middle-sized, and large moleules
 Factors that influence uremic toxicity-1

Dialysis treatment

The aim of dialysis treatment is to

normalize the volume and composition of
the body fluids.
Efficacy of dialysis: molecular size, degree
of plasma protein binding
 Factors that influence uremic toxicity-2

Small, middle-sized, and large

moleules

Size: Small : < 500 ( or 350 ) Da

Middle : 500 ~ 5,000 Da
Large : > 5,000 Da
Protein binding
Protein intake
Intestinal bacterial flora
 Toxicity of inorganic substances in
uremia
Water
Sodium
Potassium
Hydrogen ions
Magnesium
Phosphate
Sulfate
Trace elements
 Toxicity of inorganic substances in uremia

Water
Water overload: isotonic (edematous
conditions), hypotonic (water intoxication)
Cause: inappropriate thirst or iatrogenic
influsion of excess fluid.
Water excess: edema and heart failure.
Water intoxication: mental confusion,
restlessness, twitching, muscle cramps,
convulsions, coma.
 Toxicity of inorganic substances in uremia

Sodium
Sodium retention
Hypertension
Pulmonary edema
Heart failure
Peripheral edema
 Toxicity of inorganic substances in uremia

Potassium
Hyperkalemia : oral intake
parental administration
endogenous catabolism
Metabolic acidosis : K moves out of the
cells as pH decreases.
Cardiovascular : ECG change
ventricular fibrillation
cardiac arrest
 Toxicity of inorganic substances in uremia

Hydrogen ions
Metabolic acidosis (common feature of
renal failure) presented with elevated
concentration of hydrogen ions.
Central nervous system disorder,
hyperventilation, hyperkalemia,
abnormality in energy metabolism, and
dissolution of bone.
 Toxicity of inorganic substances in uremia

Magnesium
Hyper~
Vomiting
Malaise
Hypotension
Decreased reflexes
Arrhythmias
Cardiac arrest be observed after Mg salt
 Toxicity of inorganic substances in uremia

Phosphate
Hyper~
When the GFR falls below 25% of normal
Calcium phosphate deposits in organs and
tissues ( renal calcification )
Treatment : oral calcium carbonate
( low protein diet )
 Toxicity of inorganic substances in uremia

Sulfate
Unstable calcium sulfate complexes
deposited in the skin could be a significant
factor in dialysis related pruritus.
 Toxicity of inorganic substances in uremia

Trace elements
Heavy metals and other trace elements.
Accumulation in uremic patients: reduce
renal excretion, excess uptake from dialysis
fluid,dialysis equipment,or oral medication.
High concentration of aluminum, arsenic,
chromium, copper, cobalt, silicon ..etc.
 Organic compounds of Low
molecular weight
Urea
Creatinine
Guanidines (other than creatinine)
Methylguanidine
Guanidinosuccinic Acid (GSA)
Methylated Arginine Metabolites
Other guanidines
Products of Nucleic Acid Metabolism
 Organic compounds of Low molecular weight

Urea (1)
The most important end product of nitrogen
metabolism in mammals and acount for
85% of the urinary nitrogen excretion.
Blood concentration: glomerular filtration
rate, nitrogen intake, balance between
endogenous protein synthesis and
breakdown.
 Organic compounds of Low molecular weight

Urea(2)
In hemodialysis patients: low serum urea
nitrogen level (low protein intake), increase
risk of death; Excess high of serum urea
nitrogen level (underdialysis), increase
mortality.
Estimate adequacy of dialysis (small
molecular) : Urea clearance length of
dialysis distribution volume of urea.
 Organic compounds of Low molecular weight

Urea(3)
High concentration: headache, fatigue,
nausea, vomiting, glucose intolerance, and
bleeding.
The most severe uremic GI, CV, mental and
neurologic changes were not seen.
Considered mild uremic toxin .
Role in the pathophysiology of uremia is
not well defined.
 Organic compounds of Low molecular weight

Creatine(1)
The major guanidine compound retained in
patients with diminished glomerular
filtration rate.
Produce from the creatine pool in skeletal
muscle and some extent from exogenous
creatine present in meat.
Routinely determined in plasma or serum as
a measure of impairment of renal function.
 Organic compounds of Low molecular weight

Creatinine(2)
In general , toxic effects in vitro of
creatininee only been observed at
concentration much higher than those found
in uremic patients.
 Organic compounds of Low molecular weight

Other guanidines
The concentrations of various guanidine
compounds are higher in uremic patients.
Some toxic in vitro effects seem to have been
obtained at concentrations similar to those in
uremic body fluids.
Most in vitro and in vivo toxis effects have been
observed at much higher concentrations than are
found in uremic patients
The role of guanidines as uremic toxins is stillm
not well defined.
Product of Nucleic Acid Metabolism
Uric acid and other purine derivatives
Cyclic AMP
Pyridine derivatives
Amino acids, dipeptides, and tripeptides
Sulfur amino acids
Aliphatic amines
Aromatic amines
Polyamines
Indoles
Phenols
Carbonhyrate derivatives
 Middle molecules as uremic toxins

The middle molecule hypothesis:

Peritoneal membrane was more leaky and thus
more effective at removing middle molecules than
the hemodialysis membranes.
It is well established that CAPD patients may
survive and thrive as well as HD patients do, even
though their average weekly clearance of urea is
considerably lower than that for HD patients.
 Determination and characterization
of MMs
Many methods were applied to isolate or separate
MMs from plasma, serum, dialysate, ultrafiltrate,
and urine: gel permeation chromatography, ion
exchange chromography, electrohporetic method,
paper or thin layer chromography
MM fractions contains peptides or conjugated
amino acids but only some of them have been
isolated in pure form and their molecular strctured
idertified
Carbohydrate with neurotoxic property was also
identified
Toxic effects of crude MM fractions
Inhibition of proliferation of undifferentiated cell
lines and hematopoietic cell lines, depression of
several immmune function, increase hemolysis,
cardiotoxicity, inhibition of platelet aggregation,
inhibition of glucose utilization, inhibit protein
synthesis and amino acid transport, inhibition of
mitochondrial respiration
Inhibit osteoclast mitogenesis
Some enzyme activities are also inhibited
 Clinical studies of MMs
sick uremic patients tend to have higher MMs in plasma
than patients free of complications
Some studies support MMs involve in uremic
neurotoxicity
Correlation have been found between plasma levels of
immunoreactive parathyroid hormone and MMs
Patients on CAPD have been shown to have lower plasma
MM levels than patients on intermittent hemodialysis
There is strong indirect evidence that compounds in the
MM weight range, which accumulate in uremia, are toxic.
Most of these compounds are still not fully identified, their
role as uremic toxins remains unidentified.
 The trade-off hypothesis
Certain humoral factors may exert toxic
effects accumulate in uremia, not as a
consequence of reduced renal excretion but
due to homeostatic adaption to the reduced
glomerular filtration rate
Natriuretic factors, parathyroid hormone
 Natriuretic factors
Stimulate by volume expansion
Accounts for decreased fractional
absorption of sodium in chronic uremia
when the glomerular filtration falls
Elavated plasma concentrations showed
digoxinlike activity and inhibit Na-K-
ATPase
 Parathyroid hormone
Incresed in uremic patients as consequence of
phosphate retention, decreasing ionized calcium
stimulate parathyroid glands to increase PTH
secretion
PTH hypersecretiopn in uremic patients :
encephalopathy, neuropathy, dementia, bone
disease, soft tissue calcification, hypertension,
cardiomegaly, carbohydrate intolerance, anemia,
sextual dysfunction
High-molecular-weight peptides and
proteins
Ribonuclease
Granulocyte-inhiting proteins
Complement factors
Beta2-Microglobulin and Dialysis-related
amyloidosis