Williams Hematology



Etiology and Pathogenesis

Renal Excretory Failure

Failure of Renal Endocrine Function
Clinical and Laboratory Features
Therapy, Course, and Prognosis
Chapter References

Current use of recombinant human erythropoietin (EPO) to ameliorate the anemia in patients with chronic renal disease has been spectacularly successful and has shown that the primary cause of the anemia found in almost all patients with renal failure is due to a deficiency in the production of EPO. The accumulation of a number of toxic metabolic end products may also play a role in the pathogenesis of the anemia. This chapter analyzes the anemia of chronic renal disease as being caused by a failure of both renal excretory and endocrine function.

Acronyms and abbreviations that appear in this chapter include: EPO, erythropoietin.

Failure of the renal excretory function causes a moderate reduction of red cell life span, the impairment of the function of blood platelets, and suppression of marrow activity. Intensive dialysis is the most effective treatment for these changes. The failure of renal endocrine function is managed by replacement treatment with EPO. If enough iron is provided, a hematocrit of 33 to 36 percent can be maintained by subcutaneous injections two to three times a week, and about 95 percent of the patients will be responsive without significant side effects.
Anemia is one of the most characteristic and visible manifestations of chronic renal failure. In 1836, Richard Bright first commented on the pallor of patients with renal disease,1 and since then numerous observers have described and attempted to explain the underlying anemia. The degree of anemia appears to be roughly proportional to the severity of renal failure,2 but a strict linear relationship between hematocrit and creatinine clearance does not exist. At creatinine clearances less than 20 mL/min, however, the hematocrit is almost always below 30 percent (Fig. 33-1). Infectious, neoplastic, immunologic, or metabolic disorders that may accompany renal failure may also affect the degree of anemia.

FIGURE 33-1 Relationship between hematocrit and creatinine clearance in patients with chronic renal disease. (Redrawn from Radtke et al.2)

Experimental and clinical observations on the effect of intensive dialysis, bilateral nephrectomy, and EPO have clarified some of the pathophysiologic mechanisms responsible for the anemia. The main cause of the anemia of chronic renal failure is a decreased production of EPO by the failing kidney. Nevertheless, a diminished capacity to excrete potentially toxic metabolic end products aggravates the anemia by shortening the red cell life span and causing blood loss and marrow suppression.
The life span of red cells in patients with chronic renal disease is usually shorter than normal. Since the red cells survive normally when injected into healthy recipients and since normal red cells may have a shortened life span in uremic recipients,3,4 it appears that the metabolic or mechanical environment in uremic patients is unfavorable for normal survival of red cells.
The presence of an erythrocyte metabolic defect is suggested by the inverse relationship that has sometimes been noted between blood urea nitrogen and red cell life span5,6 and 7 and by the occasional normalization of the red cell life span after intensive dialysis.7 However, most red cell enzymes show normal or increased activity in uremia, and the intracellular level of ATP is high, possibly due to a high serum phosphate concentration.8
The intracellular concentration of 2,3-bisphosphoglycerate is also appropriately increased in response to anemia and hyperphosphatemia,9 with a moderate decrease in the affinity of hemoglobin for oxygen.10 In the presence of uremic acidosis, this decrease in oxygen affinity is augmented by a shift to the right in the oxygen dissociation curve (Bohr effect). However, acidosis will also tend to decrease the concentration of intracellular organic phosphates, establishing a condition of opposing effects on the oxygen affinity of hemoglobin.11 Intensive dialysis may initially cause a reduction in the concentration of intracellular organic phosphate compounds, possibly because of hypophosphatemia.12 This results in increased oxygen affinity of hemoglobin and a temporary aggravation of tissue hypoxia, and may play a role in the so-called dialysis disequilibrium syndrome.13
Only the activity of transketolase, a hexose monophosphate shunt enzyme (see Chap. 26),14 and ATPase, powering the Na+-K+ membrane pumps,15 are decreased in uremia. The decreased response of the hexose monophosphate shunt renders the hemoglobin and red cell membrane excessively sensitive to oxidant drugs or chemicals.16,17 For example, tap water used for hemodialysis and purified with chloramine can cause the formation of Heinz bodies and hemolytic anemia.18 The decreased activity of the Na+-K+ pumps could cause changes in red cell shape and rigidity and, in turn, in red cell life span. The toxic substances responsible for these metabolic impairments are presumably dialyzable but have not been identified. Other exogenous toxins introduced by dialysis fluids, such as copper, nitrates, and formaldehyde, can also contribute to hemolysis and on occasion produce severe, even fatal, hemolytic episodes.19 Parathyroid hormone, often increased in renal failure,20 may also contribute to hemolysis by increasing red cell osmotic fragility.21
Despite these data on a metabolic basis for hemolysis, a considerable number of investigators have failed to find a clear-cut correlation between red cell life span and degree of renal failure.2 It has been suggested that red cell injury and premature destruction may be caused by mechanical trauma rather than by metabolic alterations.22 Normal red cells exposed to strong shearing stress, especially at a fibrin interphase, will become deformed and vulnerable to monocyte-macrophage sequestration. In some cases of malignant hypertension, extensive red cell fragmentation occurs with severe hemolytic anemia,23 but in most cases of chronic renal disease the hemolysis as well as the morphologic changes are moderate. At the present, it appears reasonable to relate premature destruction of red cells in uremia to mechanical disruption of metabolically impaired cells.
The hemolytic uremic syndrome is probably a distinct entity,24 although many of its manifestations are similar to those found in patients with microangiopathic disorders (see Chap. 51) or consumptive coagulopathies (see Chap. 126). It was first described in 1955 by Gasser and coworkers,25 who found hemolysis and uremia in infants and young children subsequent to episodes of gastrointestinal or upper respiratory infections. Since then the syndrome has been recognized in patients of all ages and associated with a variety of exogenous agents.26 It appears to be initiated by damage to the endothelium of glomerular capillaries and renal arterioles.27 This leads to local platelet deposition, intravascular coagulation, and ischemic renal cortical necrosis.27 The clinical manifestations are pallor, purpura, jaundice, and oliguria, and laboratory tests reveal anemia with a blood film displaying many deformed and fragmented red cells (Fig. 33-2), increased number of reticulocytes, and occasional nucleated red cells.26,28 EPO levels are increased despite an elevated serum creatinine concentration.29 There is thrombocytopenia and a compensatory increase in marrow megakaryocytes. In many cases it may be difficult to distinguish the hemolytic uremic syndrome from the syndrome of thrombotic thrombocytopenic purpura (see Chap. 51 and Chap. 117). However, despite the similarity of clinical and laboratory data between these two syndromes, a basic biochemical difference has been demonstrated without, unfortunately, clarifying the pathogenesis of the hemolytic uremic syndrome. The normal cleaving of von Willebrand multimers is impaired in thrombotic thrombocytopenic purpura either due to a congenital absence of a multimer-cleaving protease or because of immunologic inactivation of this protease.30,31 This is associated with unrestricted multimer-induced aggregation of platelets and, in turn, thrombosis and consumption of coagulation proteins. In the hemolytic uremic syndrome, however, there is no lack of this protective protease and no excessive accumulation of von Willebrand factor multimers.30 Consequently, plasma infusions and plasmapheresis, so effective in thrombotic thrombocytopenic purpura, have been of little avail in treating patients with the hemolytic uremic syndrome. Fortunately, most milder cases of this syndrome clear spontaneously, but severe cases may cause life-threatening renal failure.

FIGURE 33-2 Blood film from a patient with the hemolytic uremic syndrome, showing fragmentation and distortion of red blood cells.

Purpura and gastrointestinal and gynecologic bleeding occur in one-third to one-half of all patients with chronic renal failure.32 In addition, blood and iron are lost in laboratory testing and in discarded dialysis tubing. All this constitutes a significant loss of iron and may contribute to the development of anemia. The pathogenesis of the bleeding tendency is poorly understood. Thrombocytopenia, when present, is rarely of sufficient magnitude to explain spontaneous blood loss.33 However, platelet or vascular function, as judged from bleeding time, platelet adhesiveness and aggregation, clot retraction, thromboxane formation, or prostacyclin production by vessel walls, is abnormal in the majority of cases and may, alone or together, account for the bleeding tendency (see Chap. 120). Dialysis has been found to correct or ameliorate both the laboratory and clinical manifestations of abnormal platelet function,33 but the dialyzable agent responsible has not been identified. Urea or creatinine is probably not involved, but certain guanidine compounds are suspected.34
Although a deficiency of EPO (see “Failure of Renal Endocrine Function”) could in itself explain the development of anemia, it has been suggested that, in addition, uremic toxins may impair erythroid activity and in part be responsible for the development of anemia.35 Older studies36 have suggested that such uremic toxins exist, but all attempts to identify and isolate them have been unsuccessful. Spermine, an attractive candidate,37 was found to suppress all cellular elements, and not only the erythroid tissue, when administered in toxic doses.38 Parathyroid hormone,39 another contender, causes general marrow suppression by inducing marrow fibrosis.20 Exogenous EPO has been shown to be equally effective when administered to patients before and after successful kidney transplantation.40 These observations would suggest that uremia per se does not affect normal erythroid metabolism in vivo. Nevertheless, it has also been reported41 that the response to EPO in stable, well-dialyzed patients is about half of that in normal individuals (Fig. 33-3). Whether this decreased responsiveness is due to uremic toxins, to associated diseases, or to relative iron deficiency is not clear.

FIGURE 33-3 Rate of red cell production as related to plasma concentrations of EPO in 22 stable uremic patients (open circles). Due to their stable hematocrits, the rate of red cell production must equal the rate of red cell destruction, which was calculated by dividing red cell mass by red cell life span. The square denotes the rate of red cell production in normal individuals at normal EPO levels.41

Iron may be in short supply in most patients with renal failure due to excessive blood loss (see above),42 and iron supplementation in patients receiving EPO has been found to be of great importance (see below). Aluminum in dialysis water may interfere with iron incorporation in erythroid cells and cause a microcytic anemia and occasionally osteomalacia and encephalopathy.43 In a rare case of nephrosis, the urinary loss of transferrin has been reported to cause low iron-binding capacity, with impairment in the metabolic cycling of iron.44 Folic acid deficiency should always be suspected and prevented in patients undergoing intensive dialysis, since folic acid is dialyzable and may be lost in the dialysis bath.45
Erythropoietin is a 34-kDa glycoprotein hematopoietic growth factor capable of controlling the rate of red cell production (see Chap. 29). In 1957, Jacobson and coworkers46 reported that nephrectomized and uremic rats failed to respond to blood loss by releasing EPO, while ureter-ligated and equally uremic rats responded in an almost normal manner. This important observation led to the hypothesis that the kidney produces EPO. Although the role of the kidney in EPO production has not been seriously challenged, various mechanisms have been proposed, for example, that the kidney synthesizes activating enzymes or inactive precursors that, after exposure to circulating plasma proteins, produce EPO molecules.47 In the 1970s, studies on isolated perfused kidneys supported a direct role of the kidney in EPO production.48 However, it was not until the demonstration of EPO mRNA in renal tissue that it was finally established that the kidney is an EPO-producing organ.49,50 and 51
In situ hybridization studies have localized the EPO-producing cells to the cortical interstitium of mouse and rat kidneys.52,53 These immunoelectron microscopic techniques showed that EPO-expressing cells also express the surface enzyme ecto-5′-nucleotidase,54,55 a marker restricted to fibroblastic cells. An intriguing observation is that a number of EPO-producing cells appear to be recruited to express the gene in an all-or-none fashion, with recruitment spreading outward from the corticomedullary boundary.56
Hypoxia is followed within 1 h by a measurable accumulation of EPO mRNA in the kidneys and shortly afterward by an increase in circulating EPO.51,57 The mechanism, however, by which renal hypoxia causes an activation of the EPO gene is still not clear (see Chap. 29). Extrarenal sites of EPO production exist and in adult rodents account for about 15 to 20 percent of total EPO secretion.58 In humans, very low but still detectable levels of EPO are found in severely anemic anephric individuals (Fig. 33-4).59 In fetal life, extrarenal production of EPO by the liver predominates, with a gradual change to renal production at time of birth.60 In the liver, two types of cells express the EPO gene, hepatocytes and intermedullary cells,61,62 the nonparenchymal Ito cells that are morphologically and functionally very similar to the interstitial fibroblasts in the kidneys.63 The genomic EPO sequences that determine expression are somewhat different, with the kidney requiring a 14-kb upstream fragment not needed by the liver.64 The inappropriate production of EPO by renal and extrarenal cysts and tumors appears to be accomplished by cells different from those responsible for normal, regulated synthesis of EPO.54

FIGURE 33-4 EPO levels in nephric and anephric uremic patients as compared to individuals with intact kidneys. Values for normal subjects and patients with simple anemia,
; anephric patients,
; nephric patients,
. All determinations were made by bioassay of plasma concentrates in hypertransfused mice.

In patients with renal disease, the reduction in EPO production is roughly proportional to the degree of excretory impairment. However, even nonfunctioning kidneys produce some EPO and are capable of maintaining higher hemoglobin levels than those found in anephric patients (see Fig. 33-4).59 This remaining capacity of remnant kidneys to produce EPO appears to be responsible for the polycythemia that occurs in 10 to 15 percent of patients following kidney transplantation.65 It is also responsible for the brief but significant increase in EPO levels seen in end-stage uremic patients following episodes of acute hypoxia or blood loss.66,67
The symptoms and physical manifestations of renal failure depend primarily on the underlying disorder. However, pallor and anemia are almost invariably present and may become of major clinical concern.
The anemia is characteristically normocytic and normochromic and is associated with a normal or slightly decreased number of reticulocytes. A few red cells appear deformed on blood films, some with multiple tiny spicules and others with grossly abnormal contour and loss of volume. The former cells, echinocytes or burr cells, were thought to be quite characteristic of chronic renal failure.68 However, even normal cells will undergo a reversible transformation to burr-cell–like echinocytes when exposed to a glass surface or suspended in incubated plasma.69
Grossly deformed cells, however, such as acanthocytes with a few large spicules or fragmented schistocytes, are undoubtedly formed in the microcirculation in vivo.70 They are found most abundantly in the hemolytic uremic syndrome (see Fig. 33-2) but in small numbers can be recognized on blood films from most uremic patients.
The total and differential leukocyte count and the platelet count are usually normal, but, as with all other hematologic parameters, the underlying disorder plays a modifying role. Uremia and dialysis may have an effect on both leukocytes and platelets. The phagocytic activity of granulocytes may be reduced,71 and complement activation by the hemodialysis membrane may cause pulmonary leukostasis with temporary granulocytopenia.72 Cell-mediated immunity is also depressed, resulting in both an increased incidence of infections but also favoring prolonged graft survival.71 Platelet function is abnormal and related to the degree of uremia and dialysis (see “Blood Loss”).73,74 and 75 The marrow is usually normal in appearance and in the maturation sequence of all cellular elements, including the nucleated red cells. However, normal marrow morphology is inappropriate when considered in the context of a reduced hemoglobin concentration, since a compensatory increase in erythroid activity would be expected. The marrow may, however, be somewhat hypoplastic, and in acute renal failure severe erythroid hypoplasia has been described. The level of circulating EPO and the iron turnover are within the “normal range,” which is also inappropriate for the degree of anemia. Iron utilization is regularly decreased in renal insufficiency. Again, these “normal” levels contrast with the increased levels found at similar degrees of anemia but with normal kidney function, as shown in Fig. 33-4. In many cases the underlying disease will cause specific changes in iron kinetics and in the serum concentration of folic acid, iron, and transferrin. These changes may modify and aggravate the relative marrow failure that characterizes the anemia of chronic renal disease.
In the past, anemia was often considered a relatively minor problem for patients suffering from the many metabolic consequences of failing kidneys. The development of efficient hospital and home dialysis, however, provided partial relief for many of these metabolic problems but left the anemia unchanged. Until the availability of EPO, therapy for the anemia consisted of providing elements necessary for red cell production, such as iron and folic acid, attempting to stimulate endogenous EPO production by the administration of androgens but relying largely on the use of red cell transfusions.
Dialysis per se has very little effect in correcting the anemia, although a mild increase in hemoglobin concentration may occur75 due to a decrease in bleeding tendency. For still unexplained reasons, ambulatory peritoneal dialysis tends to ameliorate and, on occasion, completely correct the anemia.76
Although there may be no evidence of overt folic acid or iron deficiency, these compounds are given routinely to most patients with renal disease. It is important to maintain a serum ferritin level of 100 ng/ml, since effective treatment will demand an adequate iron supply to the erythroid cells. Androgens have been widely used in the past to stimulate EPO production and action. Even with the advent of appropriate treatment with EPO, androgens are used occasionally in apparently resistant patients. Of the many preparations available, nandrolone decanoate77 and fluoxymesterone78 are usually quite effective. However, there are minor and major side effects, and, with the availability of EPO, the use of androgens is rarely justified.
Transfusions with packed red cells are necessary to counteract the effects of acute blood loss and may occasionally be needed to maintain an acceptable hemoglobin concentration in patients who do not respond adequately to EPO. The effect of transfusion on the course of renal transplantation is discussed in Chap. 140.
Replacement therapy with EPO, the most rational approach to the treatment of the anemia of renal disease, became a reality in 1987 with the introduction of mass-produced recombinant human EPO.79,80 The recombinant product has the same amino acid composition as natural human EPO81 as well as an almost identical carbohydrate composition,82 and thus antibodies against the recombinant product have not been found in any treated patient. The results have been dramatic, and the administration of EPO has been capable of ameliorating the anemia in almost every patient treated, irrespective of the underlying cause of the renal disorder (Fig. 33-5).80

FIGURE 33-5 The slopes of hematocrit increase in uremic patients after the weekly administration of various doses of recombinant EPO. —, 500 units/kg; – · –, 150 units/kg; — — —, 50 units/kg; – ·· –, 15 units/kg. (From Eschbach et al, with permission.80)

The National Kidney Foundation has recently published detailed guidelines for the administration of EPO to patients with the anemia of chronic renal diseases.83 In short, the presence of an anemia with hematocrits of less than 33 percent or hemoglobins of less than 11 g/dl should first initiate a thorough search for conditions unrelated to decreased EPO production or action. Measurements of folic acid and B12 levels should be carried out, and it is especially important to measure iron, iron binding capacity, and ferritin levels. Determination of EPO levels is not necessary. It is important to rule out complicating chronic illnesses that, through cytokine action, can aggravate the anemia. Although the anemia of renal disease is roughly proportional to the severity of the renal failure, renal anemia can occur with serum creatinine levels as low as 2 mg/dl.
Because of the availability of venous access in dialysis patients, EPO has been given primarily by the intravenous route. Pharmacokinetic studies in normal volunteers and in chronic renal disease patients, however, have shown that subcutaneous administration may be equally effective.84,85 The half-life of intravenous EPO is between 6 and 9 h, with a volume of distribution slightly larger than that of the plasma volume (Fig. 33-6a).86,87 When the subcutaneous route is employed, there are no peaks and lower plasma levels are observed, but the lower levels are more sustained throughout the course (Fig. 33-6b).87,88 However, it appears that bioavailability after subcutaneous injections is less predictable, possibly due to erratic tissue absorption. Subcutaneous EPO administration can maintain a target hematocrit value of 30 to 33 percent with the use of about 30 percent lower doses of EPO.89

FIGURE 33-6 Pharmacokinetics of plasma EPO in normal volunteers. (a) Intravenous administration. (b) Subcutaneous administration.

Based on the initial clinical trials, the U.S. Food and Drug Administration approved the clinical use of EPO in June 1989, setting the target hematocrit at 30 to 33 percent.90 In its 1997 guidelines,83 the National Kidney Foundation recommended an increase in the target hematocrit to 33 to 36 percent and target hemoglobin to 11 to 12 g/dl. Furthermore, they recommended that the preferred route of EPO administration be subcutaneous and that routine iron supplementation be given intravenously, rather than orally, to optimize the response. Some have advocated higher target hematocrits, close to the normal range. However, a disappointing number of complications occur in the near-normal hematocrit group.91
In order to achieve the target hematocrit within 3 to 4 months of therapy,83,92 the initial dose of EPO in adult patients should be 80 to 120 units/kg/week divided into two or three subcutaneous injections or 120 to 180 units/kg/week given as three intravenous injections. The response should be monitored by measuring the hematocrit and hemoglobin at least once every 2 weeks. Once the target hematocrit has been reached, most adult patients can be maintained by administering 50 to 100 units/kg/week in divided doses. Pediatric patients (<5 years of age) usually require higher initial and maintenance doses.
Anemia in predialysis patients can also be corrected with exogenous EPO. Such corrections will not jeopardize renal function93,94 and may prevent the development of cardiac hypertrophy.
It is, of course, essential to maintain adequate iron stores. Although the National Kidney Foundation has expressed a preference for the use of intravenous iron, many physicians, especially when using EPO subcutaneously, will prefer the use of an oral iron preparation providing at least 100 mg of elemental iron a day.95
By now, large multicenter studies have shown that more than 95 percent of patients respond to EPO therapy.83 Nevertheless, there is a small group of patients who either do not respond or first respond when larger doses are administered. The most common causes of a poor response are inadequate iron supply, intercurrent infections, or excessive splenic hemolysis.96 Aluminum toxicity may be responsible for resistance to treatment and should be suspected in patients with microcytic red cell indices.97
During the initial clinical trials, most of which were uncontrolled, a number of adverse effects were reported.98,99 Some of these have not been observed in subsequent trials, probably because of the more judicious use of the hormone.83 However, of considerable and sustained concern have been hypertension, seizures, thrombosis of arteriovenous fistulas, and high potassium levels in treated patients.99 Hypertension has been the most common complication. It usually represents exaggeration of a previously existing condition, but it can occur de novo. Blood pressure should be carefully monitored throughout the treatment.83 Initiation or adjustment of antihypertensive medication and reduction of EPO dosage may be required. Also noted in the initial trials was an increased incidence of seizures. In several subsequent studies, the incidence of seizures in patients started on EPO was found to be 3 percent, with a range of 0 to 13 percent.100 Such an incidence, however, is about the same in EPO-untreated patients.101 It is now believed that EPO treatment is not contraindicated in patients with a previous history of seizures.
A widespread concern with the use of EPO in hemodialyzed patients is the possible effect of higher hematocrits on the native fistulas or synthetic shunts. In a review of 26 studies in which 4100 patients were enrolled, the average incidence of thrombosis of the access routes in patients on EPO was 7.5 percent.102 This value is well within the accepted values for thrombotic episodes in dialyzed patients not receiving EPO.
Amelioration of the anemia has resulted in a variety of beneficial changes103,104 and 105 in various systems and in general has greatly improved the quality of life of these unfortunate patients.106,107

Bright R: Cases and observations, illustrative of renal disease accompanied with the secretion of albuminous urine. Guys Hosp Rep 1:340, 1836.

Radtke HW, Claussner A, Erbes PM, et al: Serum erythropoietin concentration in chronic renal failure: Relationship to degree of anemia and excretory function. Blood 54:877, 1979.

Ragen PA, Hagedorn AB, Owen CA: Radioisotope study of anemia in chronic renal disease. Arch Intern Med 105:518, 1960.

Desforges JF, Dawson JP: The anemia of renal failure. Arch Intern Med 101:326, 1958.

Joske RA, McAllister JM, Prankerd TAJ: Isotope investigations of red cell production and destruction in chronic renal disease. Clin Sci 15:511, 1956.

Adamson JW, Eschbach J, Finch CA: The kidney and erythropoiesis. Am J Med 44:725, 1968.

Berry ER, Rambach WA, Alt HL, Del Greco G: Effect of peritoneal dialysis on erythrokinetics and ferrokinetics of azotemic anemia. Trans Am Soc Artif Intern Organs 10:415, 1965.

Mansell M, Grimes AJ: Red and white cell abnormalities in chronic renal failure. Br J Haematol 42:168, 1979.

Chillar RK, Desforges JF: Red cell organic phosphates in patients with chronic renal failure on maintenance haemodialysis. Br J Haematol 26:549, 1974.

Mitchell TR, Pegrum GD: The oxygen affinity of haemoglobin in chronic renal failure. Br J Haematol 21:463, 1971.

Lichtman MA, Murphy MS, Whitbeck AA, Kearney EA: Oxygen binding to haemoglobin in subjects with hypoproliferative anaemia, with and without chronic renal disease: Role of pH. Br J Haematol 27:439, 1974.

Lichtman MA, Miller OR, Freeman RB: Erythrocyte adenosine triphosphate depletion during hypophosphatemia in a uremic subject. N Engl J Med 280:240, 1969.

Torrance JD, Milne FJ, Hurwitz S, et al: Changes in oxygen delivery during hemodialysis. Clin Nephrol 3:53, 1975.

Lonergan ET, Semar M, Sterzel RB, et al: Erythrocyte transketolase activity in dialyzed patients: A reversible metabolic lesion of uremia. N Engl J Med 284:1399, 1971.

Cole CH: Decreased ouabain-sensitive adenine triphosphatase activity in the erythrocyte membrane of patients with chronic renal disease. Clin Sci 45:775, 1973.

Yawata Y, Howe R, Jacob HS: Abnormal red cell metabolism causing hemolysis in uremia: A defect potentiated by tap water hemodialysis. Ann Intern Med 79:362, 1973.

Rosenwund A, Binswanger U, Straub PW: Oxidative injury to erythrocytes, cell rigidity, and splenic hemolysis in hemodialyzed uremic patients. Ann Intern Med 82:460, 1975.

Eaton JW, Kolpin CF, Swofford HS, et al: Chlorinated urban water: A cause of dialysis-induced hemolytic anemia. Science 181:463, 1973.

Orringer EP, Mattern WDL: Formaldehyde-induced hemolysis in chronic hemodialysis. N Engl J Med 294:416, 1976.

Rao DS, Shih M, Mohini R: Effect of serum PTH and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 328:171, 1993.

Okmai M, Telfer N, Ansani A, et al: Erythrocyte survival in chronic renal failure: Role of secondary hyperparathyroidism. J Clin Invest 76:1695, 1985.

Brain MC: The haemolytic-uremic syndrome. Semin Hematol 6:162, 1969.

Capelli JP, Wesson LG, Erslev AJ: Malignant hypertension and red cell fragmentation syndrome. Ann Intern Med 64:128, 1966.

Kaplan BS, Drummond KN: The hemolytic-uremic syndrome is a syndrome. N Engl J Med 298:964, 1978.

Gasser C, Gautier E, Steck A, et al: Hämolytisch-urämische Syndrome: Bilaterale Nierenrindennekrosen bei akuten erworbenen hämolytischen Anämien. Schweiz Med Wochenschr 85:906, 1955.

Lieberman E, Heuser E, Donnell GN, et al: Hemolytic-uremic syndrome: Clinical and pathological considerations. N Engl J Med 275:277, 1966.

Mitra D, Jaffe EA, Weksler B, Hajjar KA, Soderland C, Laurence J: Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood 89:1224, 1997.

Moake JL: Haemolytic-uraemic syndrome. Basic science. Lancet 343:393, 1994.

Miller RP, Denny WF: Hemolytic anemia during acute renal failure: Observations on plasma erythropoietin levels. South Med J 61:29, 1968.

Furlan M, Robles R, Galbusera M, et al: Von Willebrand factor–cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 339:1578–1584, 1998.

Tsai HM, Lian EC: Antibodies to von Willebrand factor–cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 339:1585, 1998.

Castaldi PA, Gorman DJ: Disordered platelet function in renal disease, in Hemostasis and Thrombosis, edited by RW Colman, J Hirsch, VJ Marder, EW Salzman, p 750. Lippincott, Philadelphia, 1987.

Stewart JH: Platelet numbers and life span in acute and chronic renal failure. Thromb Diath Haemorrh 17:532, 1967.

Horowitz HJ, Stein JM, Cohen BD, White JM: Further studies on the platelet inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding. Am J Med 49:336, 1970.

Fisher JW: Mechanism of the anemia of chronic renal failure. Nephron 25:106, 1980.

Bozzini CE, Devoto FCH, Tomio JM: Decreased responsiveness of hematopoietic tissue to erythropoietin in acutely uremic rats. J Lab Clin Med 68:411, 1966.

Radtke HW, Rege AB, La Mouche MB, et al: Identification of spermine as an inhibitor of erythropoiesis in patients with chronic renal failure. J Clin Invest 67:1623, 1981.

Caro J, Erslev AJ: Uremic inhibitors of erythropoiesis. Semin Nephrol 5:128, 1985.

Massry SG: Is parathyroid hormone a uremic toxin? Nephron 19:125, 1977.

Eschbach JW, Haley NR, Egrie JC, Adamson JW: A comparison of the responses to rHEpo in normal and uremic subjects. Kidney Int 42:407, 1992.

Erslev AJ, Besarab A: Erythropoietin in the pathogenesis and treatment of the anemia of chronic renal disease. Kidney Int 51:622, 1997.

Eschbach JW, Cook JD, Schribner BH, Finch CA: Iron balance in hemodialysis patients. Ann Intern Med 87:710, 1977.

Wills MR, Savory J: Aluminum poisoning: Dialysis encephalopathy, osteomalacia, and anaemia. Lancet 1:29, 1983.

Rifkind D, Kravetz HM, Knight V, Schade AL: Urinary excretion of iron binding protein in the nephrotic syndrome. N Engl J Med 265:115, 1961.

Hampers CL, Streiff R, Nathan DK, et al: Megaloblastic hematopoiesis in uremia and in patients on long-term hemodialysis. N Engl J Med 276:551, 1967.

Jacobson LO, Goldwasser E, Fried W, Plazak L: Role of the kidney in erythropoiesis. Nature 179:633, 1957.

Gordon AS, Cooper GW, Zanjani E: The kidney and erythropoiesis. Semin Hematol 4:337, 1967.

Erslev AJ: In vitro production of erythropoietin by kidneys perfused with a serum-free solution. Blood 44:77, 1974.

Bondurant MC, Koury M: Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol 6:2731, 1986.

Beru N, McDonald J, Lacombe C, Goldwasser E: Expression of the erythropoietin gene. Mol Cell Biol 6:2571, 1986.

Schuster SJ, Wilson J, Erslev AJ, Caro J: Physiologic regulation and tissue localization of renal erythropoietin mRNA. Blood 70:316, 1987.

Lacombe C, DaSilva J-L, Bruneval P, et al: Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest 81:620, 1988.

Koury ST, Bondurant MC, Koury MJ: Localization of erythropoietin-synthesizing cells in murine kidneys by in situ hybridization. Blood 71:524, 1988.

Maxwell PH, Ferguson DJP, Nicholls LG, et al: Sites of erythropoietin production. Kidney Int 51:393, 1997.

Maxwell PH, Ratcliffe PJ: The erythropoietin-producing cells. Exp Nephrol 4:309, 1996.

Maxwell PH, Ferguson DJ, Nicholls LG, et al: The interstitial response to renal injury: Fibroblast-like cells show phenotypic changes and have reduced potential for erythropoietin gene expression. Kidney Int 52:715, 1997.

Schuster SJ, Badiavas E, Costa-Giomi P, et al: Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood 73:13, 1989.

Erslev AJ, Caro J, Kansu E, Silver R: Renal and extrarenal erythropoietin production in anemic rats. Br J Haematol 45:65, 1980.

Caro J, Brown S, Miller O, et al: Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med 93:449, 1979.

Fried W: The liver is a source of extrarenal erythropoietin production. Blood 40:671, 1972.

Koury JT, Bondurant MC, Koury MJ, Semenza GL: Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77:2497, 1991.

Schuster SJ, Koury S, Borher M, et al: Cellular sites of extrarenal and renal erythropoietin production in anemic rats. Br J Haematol 81:153, 1992.

Maxwell PH, Ferguson DJ, Osmond MK, et al: Expression of a homologously recombined erythropoietin-SV40 T antigen fusion gene in mouse liver: Evidence for erythropoietin production by Ito cells. Blood 84:1823, 1994.

Köchling J, Curtis PT, Madan A: Regulation of human erythropoietin gene induction by upstream flanking sequences in transgenic mice. Br J Haematol 103:960, 1998.

Dagher FJ, Ramos E, Erslev AJ, et al: Are the native kidneys responsible for erythrocytosis in renal allorecipients? Transplantation 28:496, 1979.

Walle AJ, Wong GY, Clemons GK, et al: Erythropoietin-hematocrit feedback circuit in the anemia of end-stage renal disease. Kidney Int 31:1205, 1987.

Eckardt K-U, Druecke T, Leski M, Kurtz A: Unutilized reserves: The production capacity for erythropoietin appears to be conserved in chronic renal disease. Contrib Nephrol 88:18, 1991.

Schwartz SO, Motto SA: The diagnostic significance of “burr” red blood cells. Am J Med Sci 218:563, 1949.

Brecher G, Bessis M: Present status of spiculed red cells and their relationship to the discocyte-echinocyte transformation: A critical review. Blood 40:333, 1972.

Weed R: The red membrane in hemolytic disorders: Plenary papers. XII Congr Int Soc Hematol, p 81, 1968.

Goldblum SE, Reed WP: Host defenses and immunologic alterations associated with chronic hemodialysis. Ann Intern Med 93:597, 1980.

Craddock PR, Fehr J, Brigham KL, et al: Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 296:769, 1977.

Pasternack A, Wahlberg P: Bone marrow in acute renal failure. Acta Med Scand 181:505, 1967.

Callen JR, Limarzi LR: Blood and bone marrow studies in renal disease. Am J Clin Pathol 20:3, 1950.

Eschbach JW, Funk D, Adamson JW, et al: Erythropoiesis in patients with renal failure undergoing chronic dialysis. N Engl J Med 276:653, 1967.

Zappacosta AR, Caro J, Erslev A: The normalization of hematocrit in end-stage renal disease patients on continuous ambulatory peritonal dialysis: The role of erythropoietin. Am J Med 72:53, 1982.

Eschbach JW, Adamson JW: Improvement in the anemia of chronic renal failure with fluoxymesterone. Ann Intern Med 78:527, 1973.

Neff MS, Goldberg J, Slifkin RF, et al: A comparison of androgens for anemia in patients on hemodialysis. N Engl J Med 304:871, 1981.

Winearls CG, Oliver DO, Pippard MJ, et al: Effect of human erythropoietin derived from recombinant DNA on the anemia of patients maintained by chronic haemodialysis. Lancet 2:1175, 1986.

Eschbach JW, Egrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Engl J Med 316:73, 1987.

Recny MA, Scoble HA, Kim Y: Structural characterization of natural human urinary and recombinant DNA-derived erythropoietin. J Biol Chem 262:17156, 1987.

Tsuda E, Kawanishi G, Ueda M, et al: The role of carbohydrate in recombinant human erythropoietin. Eur J Biochem 188:405, 1990.

NKF-DOA: Anemia work group: Guidelines. Am J Kid Dis 30:8196, 1997.

Besarab A, Flaharty KK, Erslev A, et al: Clinical pharmacology and economics of recombinant human erythropoietin in end stage renal disease: The case for subcutaneous administration. J Am Soc Nephrol 2:1405, 1992.

Watson A, Gimenez L, Cotton J, et al: Treatment of anemia of chronic renal failure with subcutaneous rHEpo. Am J Med 89:432, 1990.

Flaharty KK, Caro J, Erslev A, et al: Pharmacokinetics and erythropoietic response to human recombinant erythropoietin in healthy men. Clin Pharmacol Ther 47:557, 1990.

Spivak J, Cotes M: Pharmacokinetics of erythropoietin, in Erythropoietin: Molecular, Cellular, and Clinical Biology, edited by AJ Erslev, JW Adamson, JW Eschbach, CG Winearls, p 62. The Johns Hopkins University Press, Baltimore, 1992.

Newmayer H, Brockmoller J, Fritscka E, et al: Pharmacokinetics of rHEpo after sc administration and in long-term IV treatment in patients on hemodialysis. Contrib Nephrol 76:131, 1989.

Kaufman JS, Reda DJ, Fye CL, et al: Subcutaneous compared with intravenous epoietin in patients receiving hemodialysis. N Engl J Med 339:578, 1998.

Eschbach J, Adamson J: Guidelines for rHEpo therapy. Am J Kidney Dis 14(suppl 1):2, 1989.

Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoietin. N Engl J Med 389:584, 1998.

Cazzola M: How and when to use erythropoietin. Curr Opin Hematol 5:103, 1998.

Koene R, Frenken LA: Renal function of pre-dialysis patients during treatment with rHEpo. Contrib Nephrol 80:192, 1991.

Kuriyama H, Tomonari H, Yoshida H, et al: Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in non-diabetic patients. Nephron 77:176, 1997.

Sunder-Plassmann G, Horl WH: Erythropoietin and iron. Clin Nephrol 47:141, 1997.

Drueke T: Modulating factors in the hemopoietic response to erythropoietin. Am J Kidney Dis 18(suppl 1):87, 1991.

Rosenlof K, Fyhrquist F, Tenfunen R: Erythropoietin, aluminum and anemia in patients on hemodialysis. Lancet 335:247, 1990.

Casati S, Passerini P, Campise MR, et al: Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis. Br Med J 295:1017, 1987.

Eschbach J: The anemia of chronic renal failure: Pathophysiology and the effects of rHEpo. Kidney Int 25:134, 1989.

Buccianti G, Colombi L, Battistel V: Use of recombinant human erythropoietin (rh-EPO) in the treatment of anemia in hemodialysis patients: A multicenter Italian experience. Haematologica 78:111, 1993.

Laupacis A: Changes in quality of life and functional capacity in hemodialysis patients treated with recombinant human erythropoietin. Semin Nephrol 10:11, 1990.

Bahlmann J, Schoter KH, Scigalla P, et al: Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: A controlled study. Contrib Nephrol 88:90, 1991.

Moia M, Vizotto L, Cattaneo M, et al: Improvement in the haemostatic defect of uraemia after treatment with recombinant human erythropoietin. Lancet 2:1227, 1987.

Schaefer R, Kokot F, Heidland A: Improvement of rHEpo on sexual function on hemodialyzed patients. Contrib Nephrol 76:273, 1989.

Silberberg J, Racine N, Barre P, Sniderman AD: Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin. Can J Cardiol 6:1, 1990.

Evans RW, Rader B, Manninen DL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. JAMA 263:825, 1990.

Adamson JW, Eschbach JW: Erythropoietin for end-stage renal disease (editorial) N Engl J Med 339:625, 1998.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



  1. Execelent details my friend, como ganar dinero con encuestas I just didn’t know what you published, fantastic share. ganar dinero con encuestas

  2. Ola! Medtextfree,
    Along the same lines,, Well, my mom says I probably have anemia. And I’m not going to lie, I’m scared to death. I know I don’t just have a minor case of it either. Which scares me even more. I’ve already warned my friends, so they don’t freak out. We’re all prepared for the worst. But just wondering, what if this worst in our book is just a small chapter in god’s? HELP?!
    All the Best

  3. Apple now has Rhapsody as an app, which is a great start, but it is currently hampered by the inability to store locally on your iPod, and has a dismal 64kbps bit rate. If this changes, then it will somewhat negate this advantage for the Zune, but the 10 songs per month will still be a big plus in Zune Pass’ favor.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s

%d bloggers like this: