Anemia of Chronic kidney Disease

Anemia is a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule. (1) Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. (1)

:Pathogenesis of Anemia of CKD

In anemia of CKD, anemia can be a result of any of the mechanisms:

The main cause of anemia of CKD is a result of a decreased production of red blood cells by the bone marrow. This defect is explained by the inability of the kidneys to secrete the hormone erythropoietin. This hormone is a necessary stimulus for normal bone marrow to produce red blood cells. The kidneys are responsible for approximately 90% of erythropoietin production in an individual; in those with chronic kidney disease, there is primary deficiency of erythropoietin production.[2]

The accumulation of uremic toxins: it 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. Platelets 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. Blood loss and red blood cell destruction also frequently contribute to the anemia in patients with renal failure; Very slow loss of blood can also cause anemia by depleting the bodys 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 marrows capacity to compensate is diminished.

Dysregulation of Iron Homeostasis:

A hallmark of anemia of CKD is the development of disturbances of iron homeostasis, with increased uptake and retention of iron within cells of the reticuloendothelial system. This leads to a diversion of iron from the circulation into storage sites of the reticuloendothelial system, subsequent limitation of the availability of iron for erythroid progenitor cells, and iron-restricted erythropoiesis.

Hepcidin, an endogenous antimicrobial peptide secreted by the liver, has been identified as controlling the level of plasma iron by regulating the intestinal absorption of dietary iron, as well as the release of iron from macrophages and the transfer of iron stored in the hepatocytes. Increase in hepcidin level in the course of inflammatory disease may be a significant mediator of the accompanying anemia. Hepcidin may be involved in the diversion of iron traffic through decreased duodenal absorption of iron and the blocking of iron release from macrophages that occurs in anemia of chronic disease. [ 3, 4,5]

Another proposed mechanism for anemia of CKD deals with cytokines, such as interleukins (IL-1 and IL-6), and tumor necrosis factor (TNF-alpha), which are believed to cause the destruction of RBC precursors, decrease the number of erythropoietin receptors on progenitor cells and Impaired Proliferation of Erythroid progenitor Cells. [6,7] In mice that are injected with the cytokines interleukin-1 and tumor necrosis factor (TNF-), both hypoferremia and anemia develop. This combination of conditions has been linked to cytokine-inducible synthesis of ferritin, the major protein associated with iron storage. [8] The role of hemodialysis:

Dialysis itself may also contribute to the anemia. Iron deficiency can result from unavoidable dialyzed blood loss, clotted dialysis membrane. Haemolysis may occur if there are problems with the dialysis (temperature problems, contamination with aluminum, fluoride, copper, chlorine). Folate, a water soluble vitamin necessary for normal RBCs production, is dialyzable. Generally, dialysis patients are given oral supplementation with folic acid to keep up with its loss through dialysis. [8]

Clinical picture:
Symptoms and Signs of anemia: The onset of anemia in CKD is gradual. Generalized weakness, malaise, easy fatigability, dizziness, Syncope. Decreased exercise tolerance Palpitations Inability to concentrate Loss of appetite

Skin: Pallor

Neurovascular: Decreased cognitive ability Eyes : Pale conjunctivae Cardiovascular: Orthostatic hypotension, tachyarrhythmias Pulmonary: Tachypnea underlying chronic kidney disease

Diagnosis
Laboratory Evaluation: [9, 10] The following 4 important laboratory tests are vital in the evaluation of anemia of chronic kidney disease: Hemoglobin and Hematocrit.

RBC indices Peripheral blood smear Reticulocyte count Bone marrow biopsy (optional in most cases)

Laboratory tests that may help eliminate other common causes of anemia include the following: Iron status: serum iron, ferritin, total iron-binding capacity (TIBC), iron saturation. Serum vitamin B12 and folic acid. Serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT). Serum creatinine. Electrophoretic studies of serum and urine. A test for occult blood in stool.

Renal imaging: Abdominal ultrasound, in which the size of the kidneys is measured, is commonly performed. Kidneys with CKD are usually smaller (< 9 cm) than normal kidneys.

Management:
Management plan:
i. ii.

Management of anemia in patients with chronic kidney disease Treatment of the underlying disease is the therapeutic approach of choice for anemia of chronic kidney disease.

Management of anemia:
The treatment of the anemia of chronic renal failure has changed dramatically in recent years; the principal treatment was transfusion of red blood cells. 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. In anemic patients with chronic renal failure, treatment with erythropoietin reduced the need for blood transfusions. It is important to monitor the iron status of treated patients, as iron deficient patients will not respond appropriately to administration of erythropoietin.

Erythropoietic Agents:
The preferred initial form of therapy for anemia of CKD is the use of Erythropoiesis stimulating agents (ESAs) to reduce the need for blood transfusions. There are presently two formulations of ESAs, epoetin Alfa (ProCrit) and darbepoetin (Aranesp). They differ in their receptor-binding affinity, and serum half-life, thus allowing for alternative dosing and scheduling strategies.83 Epoetin can exert additional biologic effects, including interference with the signal-transduction cascade of cytokines. For example, the long-term administration of epoetin has been reported to decrease levels of TNF- in patient with chronic kidney disease; reportedly, those who responded well to epoetin therapy had lower levels of interleukin-10, interleukin-12, interferon-, and TNF- than did those with a poor response. Combined treatment with epoetin and iron not only increased hemoglobin levels but also resulted in a reduction of disease activity. For monitoring the response to Erythropoietic agents, hemoglobin levels should be determined after four weeks of therapy and at intervals of two to four weeks thereafter. If the hemoglobin level increases by less than 1 g per deciliter, the iron status should be reevaluated and iron supplementation considered. The dose of the Erythropoietic agent should be adjusted once the hemoglobin concentration reaches 12 g per deciliter. If no response is achieved after eight weeks of optimal dosage in the

absence of iron deficiency, a patient is considered non responsive to Erythropoietic agents. [11] It is important to monitor the iron status of treated patients, as iron deficient patients will not respond appropriately to administration of erythropoietin. [11,12] Blood Transfusion: Blood transfusions are widely used as a rapid and effective therapeutic intervention. It is important not to recommend long-term blood transfusion therapy in patients with chronic kidney disease because of the risks associated with long-term transfusion, such as iron overload and sensitization to HLA antigens that may occur in patients before renal transplantation. [12] Iron Therapy: Iron supplementation should be considered for patients who are unresponsive to therapy with Erythropoietic agents because of functional iron deficiency. Parenteral iron has been demonstrated to enhance rates of response to therapy with Erythropoietic agents in patients undergoing dialysis. Before the initiation of therapy with an Erythropoietic agent, iron deficiency should be ruled out. Iron therapy may confer benefit. By inhibiting the formation of TNF-, iron therapy may reduce disease activity in end-stage renal disease.[13] Management of the original disease: The goal of therapy is to slow down the progression of CKD. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the progression of CKD to stage 5.[13][14] Replacement of erythropoietin and calcitriol, two hormones processed by the kidney, is often necessary in patients with advanced CKD. Extra calcium and vitamin D. Phosphate binders are also used to control the serum phosphate levels, which are usually elevated in advanced CKD. When one reaches stage 5 CKD, renal replacement therapy is required, in the form of either dialysis or a transplant. [14][15]

References:
1. Kausz AT, Obrador GT, Pereira BJ. Anemia in patients with chronic renal insufficiency. Am J Kidney Dis. 2000;36:S39-S51.

2. Besarab A, Levin A. Defining a renal anemia management period. Am J Kidney Dis. 2000;36(6 suppl 3):S13-23. 3. Deicher R, Horl WH. New insights into the regulation of iron homeostasis. Eur J Clin Invest. 2006;36(5):301-9. 4. Roy CN, Mak HH, Akpan I. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. 2007;109(9):4038-44. 5. Zaritsky J, Young B, Wang HJ, Westerman M, Olbina G, Nemeth E, et al. Hepcidin--a potential novel biomarker for iron

status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(6):1051-6. 6. Wang CQ, Udupa KB, Lipschitz DA. Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development. J Cell Physiol 1995;162:134-138 7. Taniguchi S, Dai CH, Price JO, Krantz SB. Interferon gamma downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-I receptors in human erythroid colonyforming cells. Blood 1997;90:2244-2252
8. Besarab A, Soman S; Anemia management in chronic heart failure: lessons learnt from chronic kidney disease. Kidney Blood Press Res. 2005;28(5-6):363-71. Epub 2006 Mar 7.; Kidney Blood Press Res. 2005;28(5-6):363-71. 9. Locatelli F, Aljama P, Barany P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19(suppl 2):147.

10.National Kidney Foundation. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis 2001; 37(suppl 1):182238.
11. Alvarez-Hernandez X, Liceaga J, McKay IC, Brock JH. Induction

of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab Invest 1989;61:319-322 12. 62NKF-K/DOQI Clinical Practice Guidelines for anemia of chronic kidney disease: update 2000. Am J Kidney Dis 2001;37:Suppl 1:S182-S238[Erratum, Am J Kidney Dis 2001;38:442. 13. Weiss G, Meusburger E, Radacher G, Garimorth K, Neyer U, Mayer G. Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin. Kidney Int 2003;64:572-578 14. ^ Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G (1998). "Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN followup trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy". Lancet 352 (9136): 12526. doi:10.1016/S0140-6736(98)04433-X. PMID 9788454. 15. ^ Ruggenenti P, Perna A, Gherardi G et al. (July 1999). "Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria". Lancet 354 (9176): 35964. doi:10.1016/S0140-6736(98)10363-X. PMID 10437863.