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

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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