**1. Introduction**

160 Chronic Kidney Disease

van Ampting, JM, Penne, EL, Beek, FJ, Koomans, HA, Boer, WH, Beutler, JJ. (2003)

Zhang, Y, Ge, JB, Qian, JY, Ye, ZB. Prevalence and risk factors of atherosclerotic renal artery

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Prevalence of atherosclerotic renal artery stenosis in patients starting dialysis. *Nephrol Dial Transplant*, Vol. 18, No.6, (May 2011), pp.1147-1151, ISSN 0931-0509 White, CJ. (2010). Optimizing outcomes for renal artery intervention. *Circ Cardiovasc Interv*,

stenosis in 1,200 chinese patients undergoing coronary angiography. *Nephron Clin* 

Anemia is one of the leading causes of morbidity in chronic renal failure.**1** Chronic kidney disease (CKD) associated anemia is largely due to reduced erythropoietin (EPO) release and, to a lesser degree, to shortened red cell survival.**2** To overcome EPO deficiency in this population, the development and administration of erythropoiesis-stimulating agents (ESAs) such as recombinant human EPO and darbepoetin alfa (DPO) has resulted in substantial health benefits, including improved quality of life, reduced blood transfusion requirements, decreased left ventricular mass, diminished sleep disturbance and enhanced exercise capacity.**1-7** Unfortunately in recent clinical trials, a proportion of patients exhibited complications such as fatal or nonfatal stroke, access thrombosis, increase in thrombotic events and exacerbation of malignancy associated with overly aggressive correction of anemia. **8-10** It is not established whether these complications are related to higher dose of EPO, underlying EPO resistance factors (i.e. inflammation) or achieving higher hematocrit (HCT). A multifactorial combination of predisposing circumstances is possible. A number of pharmacologic agents have been evaluated as adjuvant to ESAs therapy. These agents include iron, L-carnitine, ascorbic acid, androgens, statins, pentoxifylline and Nacetylcysteine. In this review article we will focus on the agents that have been used in conjunction with EPO to correct anemia in patient with chronic kidney disease and endstage renal disease in an effort to reduce the dose requirement of EPO.

#### **2. Iron**

Iron is one of the most integral components of hematopoiesis in the anemia of kidney disease. "Trapped" iron storage or decreased availability of iron is the most common factor for the resistance to the effect of ESAs. Absolute iron deficiency is likely to be present in patients with CKD when**:** the percent transferrin saturation (plasma iron divided by total iron binding capacity x 100) falls below 20; the serum ferritin concentration is less than 100 ng/mL among advance CKD("predialysis") and peritoneal dialysis patients and less than

Pharmacologic Adjuvants to Reduce Erythropoietin Therapy Dose

in Anemia of Chronic Kidney Disease and End Stage Renal Disease 163

g/dL with oral iron. Among patients who were receiving ESAs, Hb increased 1.16±1.49 g/dL with ferumoxytol vs. 0.19±1.14 g/dL with oral iron. The increase in Hb at day 35, the primary efficacy end point, was 0.82+/-1.24 g/dL with ferumoxytol and 0.16+/-1.02 g/dL with oral iron (P<0.0001).**17** The authors concluded that a regimen of two doses of 510 mg of intravenous ferumoxytol administered rapidly within 5±3 days was well tolerated and had the intended therapeutic effect. The side effects associated with IV iron in the abovementioned studies were headache, myalgia, and hypotension (particularly in thin, older women<65 kg). Intravenous iron sucrose has shown better tolerability. Oral iron has more

GI associated side effects including constipation, diarrhea, nausea and vomiting.**13-17**

with better maintenance of iron stores and lower dosage requirements of EPO.**<sup>18</sup>**

necessary because of the downward trend in iron stores.**<sup>19</sup>**

Wingard et.al. conducted a prospective study on 46 EPO treated hemodialysis patients and randomized them into four different oral iron preparations. These four preparations included Chromagen (ferrous fumarate from Savage Laboratories), Feosol (ferrous sulphate from Smith Kline Beecham), Niferex (polysaccharide, Central Pharmaceutical) or Tabron (ferrous fumarate; Parke-Davis). All patients were prescribed approx 200 mg of elemental iron daily with at least 100 mg of ascorbic acid for six months. The study concluded that with emphasis on compliance, oral iron supplementation at the dose used for this study was able to maintain adequate iron status in the short term (less than 6 months) without the need for IV iron dextran. However, IV iron dextran eventually (after 6 months) would be

Ferumoxytol was studied in a randomized, open-label, controlled, multicenter Phase 3 trial by Provenzano et.al. to evaluate the safety and efficacy of IV ferumoxytol compared with oral iron.**20** Anemic patients on HD and on a stable ESA regimen received either two injections of 510 mg of ferumoxytol within 7 days (n = 114) or 200 mg elemental oral iron

therapy or intravenous iron therapy can be given in CKD patients.

**4. Anemia in end stage renal disease** 

As a result of these studies the K/DOQI guidelines have recommended that either oral iron

Among hemodialysis patients, studies show that transferrin saturation and serum ferritin levels usually continue to fall and anemia fails to correct despite ongoing oral iron therapy. MacDougall et.al. studied 37 iron-replete hemodialysis patients beginning EPO therapy randomized into three groups with different iron supplementation: Group1, IV iron dextran 5 ml (equivalent to 250 mg of elemental iron) every 2 weeks; Group 2, oral ferrous sulfate 200 mg tid; Group 3, no iron. Subjects were treated with 25 U/kg of EPO thrice weekly subcutaneously. After a period of 16 weeks, the Hb response in the group receiving IV iron (7.3+/-0.8 to 11.9+/-1.2 g/dL) was significantly greater than that for the other two groups (7.2 +/-1.1 to 10.2 +/-1.4 g/dL and 7.3+/-0.8 to 9.9+/-1.6 g/dL for Groups 2 and 3, respectively; p < 0.005 for both groups vs. Group 1 at 16 weeks). Serum ferritin levels remained constant in those receiving IV iron (345 +/-273 to 359+/-140 mcg/L) in contrast to the other two groups in which ferritin levels fell significantly (309+/-218 to 116+/- 87 mcg/L and 458+/-206 to 131+/- 121 mcg/L for Groups 2 and 3, respectively; p < 0.0005 for Group 1 vs. Group 2, and p < 0.005 for Group 1 vs. Group 3 at 16 weeks). Dosage requirements of EPO were also less in Group1.These results suggested that even in ironreplete patients, those supplemented with IV iron have an enhanced Hb response to EPO

200 ng/mL among home hemodialysis patients.**<sup>11</sup>** However, functional iron deficiency is associated with transferrin saturation (TSAT) ≤20 percent and elevated ferritin levels (between approximately 200 to 800 ng/mL) or higher. An elevated ferritin level in this condition is likely secondary to the acute phase reaction of underlying inflammation. The 2006 K/DOQI guidelines recommend goals of iron therapy during administration of ESAs**.** For predialysis and peritoneal dialysis patients: TSAT >20 percent or content of hemoglobin (Hb) in reticulocytes >29 percent and serum ferritin concentration >100 ng/mL. For patients undergoing hemodialysis: transferrin saturation >20 percent or content of Hb in reticulocytes >29 percent and serum ferritin concentration >200 ng/mL.**<sup>12</sup>**

A number of clinical trials have compared which route of iron administration Intravenous (IV) vs Oral (PO) is superior in treating anemia of CKD. 13-22

First we will discuss this issue in the Chronic Kidney Disease (CKD) population.
