Introduction
The association of chronic renal failure and anemia has been recognized since
the early 19th century; nowadays such a manifestation is regarded as one of the
many components of the vast array of signs and symptoms present in patients with
chronic renal failure. The introduction of dialysis brought new insights to this
complex subject, but also added new mechanisms for the development or
aggravation of such clinical picture.
The anemia of renal failure is usually characterized by normochromic and
normocytic blood cells. There is usually hypoplasia of the erythroid precursors
in the bone marrow with little or no interference with normal leucopoiesis and
megakaryocytopoiesis. On blood smears one may find typical, although not
exclusive, spiculed and deformed red cells (burr cells or echinocytes). The
anemia aggravates as the renal function further declines, and the hematocrit may
reach levels as low as 20% or 15%. As with any chronic anemia, compensatory
mechanisms come into play in order to maintain acceptable levels of tissue
oxygenation, and they consist mainly of increased levels of 2,3 DPG, lowered
peripheral vascular resistance and an elevated cardiac output (in the absence of
previous cardiac disease).
Pathophysiology
If the blood volume is constant, and blood loss is absent any case of anemia
can only be explained by decreased production of erythroid precursors or
increased destruction. Both processes seem to be operating in renal failure.
Increased destruction:
Many studies have shown an inverse correlation
between the red cell survival and serum blood urea nitrogen concentration. This
could be demonstrated by the classical study where red blood cells from uremic
individuals showed a normal life span when injected in normal individuals, the
inverse (shortened red cell life span) could be demonstrated when erythrocytes
from normal individuals were injected in uremic patients. The most convincing
demonstration that specific toxins (not necessarily urea) were the responsible
for the shortened red cell survival was obtained with the introduction of
dialysis.
Dialysis improved, to a limited extent, the anemia in chronic renal
failure patients , although this finding could not be ascribed to prolonged red
cell survival; rather, a better utilization of iron (not increased serum levels)
and red cell production seemed to be determinant. The patients showed diminished
transfusion requirements after initiation of a dialysis program.
Besides the mechanisms described above, the therapy itself (dialysis) can be
responsible for increased destruction of red blood cells, further aggravating
the anemia. Haemodialysis can worsen the anemia due to the procedure associated
blood losses and mild effect on oxygen transporting function. Hypersplenism may,
rarely, be associated with chronic dialysis leading to a sequestration of
erythrocytes and further destruction of circulating red cells. If hypersplenism
proves to be an important problem splenectomy may be considered, since it has
been shown to cause a decrease in transfusion requirements.
Decreased production:
Despite the mechanisms described above, the most
important determinant of the anemia is failure of production due to decreased
levels of circulating erythropoietin. Erythropoietin, a sialylglycoprotein
synthesized by the renal interstitial cells and to a lesser extent by the liver,
normally increases after specific stimuli , the most important being hypoxemia.
Under normal conditions; serum erythropoietin concentrations are increased by
bleeding and decreased after transfusion; actually in non-uremic patients it may
increase up to 100 times its normal value. In uremic patients the normal
response to hypoxemia (increased secretion of erythropoietin) is partially, but
not completely, blunted. These individuals show increased levels of the
glycoprotein after hemorrhage or hypoxic crisis, although the levels are not
even close to those of a normal individual. Therefore, the stimulus to
erythropoiesis is not sufficient in uremic patients.
Management of anemia
The mainstay of the treatment of anemic patients is the use of recombinant
human erythropoietin (rHuEPO). The response to treatment is impressive and the
need for transfusion is importantly decreased.
Upon initiation of therapy a
target hematocrit should be set as well as the iron stores should be completely
evaluated (since low stores may blunt the proliferative response to
erythropoietin).
The beginning of therapy should be gradual to avoid excessively
rapid increases in the red cell mass with its hyperviscosity consequences. A
total weekly dose of 110 to120 U/kg divided into two or three subcutaneous
injections is an adequate therapeutic regimen. Transfusions should be avoided as much as possible, not only because of the
well known infectious risks and the fluid overload in cardiac patients but also
to avoid inhibition of the low, although present, positive feedback on
erythropoietin secretion exerted by chronic hypoxemia.
Other possible
deficiencies should be assessed before therapy is started such as, vitamin B12
deficiency, folate deficiency or aluminum intoxication (this latter leading to
microcytic anemia). Throughout the course of therapy, iron stores (serum iron,
ferritin and TIBC) should be determined frequently, since the rapid
proliferative response may not be accompanied be an adequate availability of
iron. If the iron stores are proved insufficient during the course of therapy,
replacement should be started without delay.
Bernardo Boaventura Liberato
Adverse effects
Some adverse effects have been documented in patients receiving rHuEPO:
- Myalgia and influenza-like symptoms may occur.
- The occurrence of seizures remains an unsettled issue, with some defending a causal relationship
,while others argue against this hypothesis suggesting that these neurological
phenomena are due to imbalances in dialysis therapy.
- Thrombotic events are not
increased with the use of rHuEPO , although clotting within the dialyser may
occur.
- Hypertension is without any doubt the most important not only in terms of frequency but also
morbidity. Occurring in approximately 30% to 35%, hypertension usually occurs in
the first 4 months of treatment while the hematocrit is increasing. The exact
mechanism of hypertension is not defined yet but it may be so severe as to cause
hypertensive encephalopathy with headache, visual disturbances and seizures.
Uncontrolled hypertension is a contraindication to the initiation of therapy
with rHuEPO. Hypertension is not dependent on the dose of rHuEPO or the rate of
hematocrit increase.
Anemia in
Patients with Chronic Renal Failure and in Patients
undergoing Chronic Hemodialysis
Edmund G. Lowrie,
M.D.R. Garth Kirkwood, M.D.Martin R. Pollak, M.D
Anemia is defined as a reduction in the oxygen
carrying capacity of blood, measured in the
laboratory as a low hemoglobin concentration, or a
low hematocrit (the percentage of the blood volume
that is occupied by red blood cells or
erythrocytes). In a normal person, the hemoglobin is
approximately 13 grams per deciliter and the
hematocrit is approximately 40%.
Anemia is not a disease per se, but a reflection of
some other problem. It occurs when the balance
between the normal rates of blood loss and blood
production is disturbed. There are three basic
mechanisms by which this occurs: (1) blood loss, (2)
excessive destruction of red blood cells
(hemolysis), and (3) abnormally low production of
red blood cells by the bone marrow.
In a person with normal renal function, the finding
of anemia on routine blood analysis would prompt a
work-up to determine the ultimate cause. In chronic
renal failure, anemia is almost always present, and
can be a result of any of the mechanisms listed
above. However, the typical “anemia of chronic renal
insufficiency” is a result of a decreased production
of red blood cells by the bone marrow.
This defect in red blood cell production is largely
explained by the inability of the failing kidneys to
secrete the hormone erythropoietin. This hormone is
a necessary stimulus for normal bone marrow to
produce red blood cells. In addition, other factors
associated with renal failure, including the
accumulation of so-called uremic toxins, may play a
role in depressing bone marrow function. Excess
stores of aluminum may accumulate in the bone marrow
of long term dialysis patients and can contribute to
anemia as well.
Blood 1oss and red blood cell destruction also
frequently contribute to the anemia in patients with
renal failure. Platelets, which are small
constituents of blood which aid in blood clotting,
do not work normally in uremia. The defective blood
clotting seen in uremia makes bleeding more common.
Rapid bleeding—from an ulcer in the gastrointestinal
tract, for example—causes a rapid decrease in the
hematocrit and is a medical emergency. Very slow
loss of blood can also cause anemia by depleting the
body’s stores of iron, which the bone marrow uses to
produce blood cells.
Excessive destruction of red blood cells is also
seen in advanced renal failure. Normally, red blood
cells survive for about four months before being
destroyed. This life span is reduced in renal
failure, probably because of chemical effects of
uremia and decreased flexibility of the red blood
cells. This hemolysis is usually mild and a person
with a normal bone marrow could easily compensate
for it by increasing red blood cell production.
However, in renal failure, the bone marrow’s
capacity to compensate is diminished.
What is the role of hemodialysis in the anemia of
chronic renal failure? The effectiveness of dialysis
in reversing any complication of uremia depends on
the nature of that complication. Those disturbances
which are due to accumulation of a uremic toxin may
be reversible if that toxin is dialyzable and if the
removal rate by dialysis outstrips its generation
rate. Some improvement in red blood production is
seen with initiation of dialysis, probably by
decreasing the toxic effect of uremia on the marrow.
Dialysis, however, does not replace the hormone
producing functions of the kidney and therefore does
not by itself correct the main cause of anemia,
namely deficient production of erythropoietin.
Dialysis does correct the bleeding tendency seen in
uremia, but not to normal.
Dialysis itself may also contribute to the anemia.
Iron deficiency can result from unavoidable dialyzer
blood loss, clotted dialysis membranes, and frequent
blood sampling. Hemolysis may occur if there are
problems with the dialysate (temperature problems,
contamination with aluminum, fluoride, copper,
chlorine, or chloramine). Folate, a water soluble
vitamin necessary for normal red blood cell
production, is dialyzable. Generally, dialysis
patients are given oral supplementation with folic
acid in case their normal diet does not supply them
with sufficient folate to keep up with its loss
through dialysis.
Most patients tolerate chronic anemia fairly well.
In an otherwise healthy patient with chronic renal
failure, a hematocrit of approximately 25% is
typical. The presence of other medical problems,
particularly heart and lung disease, can decrease a
patient’s ability to tolerate a lower blood count.
Patients who have undergone bilateral kidney removal
(nephrectomies) often have hematocrits which are
significantly lower, probably because they cannot
make any erythropoietin at all. Patients whose
kidney failure is a result of polycystic kidney
disease generally do not have anemia.
The treatment of the anemia of chronic renal failure
has changed dramatically in recent years. Until
recently, the principal treatments were transfusion
of red blood cells and administration of the hormone
testosterone. Although transfusions will rapidly
correct a low blood count, repeated transfusions are
associated with some problems, including iron
overload, the development of certain antibodies, and
the possibility of viral infections. Testosterone
may stimulate red blood cell production by the bone
marrow, but the effect is generally small, and its
use is often associated with virilizing side effects
In 1983, the gene for erythropoietin was isolated,
then cloned. Subsequently this led to the mass
production of erythropoietin and finally to its use
in renal failure patients in 1990 (see Chapter 20).
It is administered either intravenously at dialysis
or subcutaneously. In anemic patients with chronic
renal failure, treatment with erythropoietin is now
standard practice and has dramatically reduced the
need for blood transfusions. The increase in
hematocrit seen with patients treated with
erythropoietin has generally resulted in improvement
in exercise tolerance and overall sense of
well-being. It is important to moniter the iron
status of treated patients, as iron deficient
patients will not respond appropriately to
administration of erythropoietin. The use of
erythropoietin is constrained by the extremely high
cost of this hormone and the reimbursement policies
of insurance companies and Medicare.
To summarize, anemia is a universal complication of
chronic renal failure. It has multiple causes, the
most important of which is decreased production of
erythropoietin by the kidney. The availability of
the recombinant form of this hormone is
revolutionizing treatment of this form of anemia.
References
1) The Kidney - Barry M. Brenner - 5th edition 2) Higgins MR, Grace
M, Ulan RA et al. - Anemia in haemodialysis patients - Arch Intern Med,
137:2,172-6-1977 3) Naets JP - Hematologic disorders in renal failure-
Nephron, 14:2,181-94:1975 4) Paganini EP - Overview of anemia associated with
chronic renal disease- Semin Nphrol,9:1Suppl 1, Mar3-8:1989
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