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

162 Chronic Kidney Disease

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

A number of clinical trials have compared which route of iron administration Intravenous

In a prospective trial by Stoves et.al, PO vs IV route of iron administration was studied. Forty five anemic patients with CKD, not on dialysis, were randomized to receive oral (ferrous sulfate 200 mg tid) or intravenous (300 mg iron sucrose monthly) iron therapy. EPO was started at the same time and the dose adjusted according to a pre-established protocol. After an average follow up of 5.2 months, there were no significant differences in Hb response and EPO dose between the two groups.**13** A prospective study by Charytan et. al. in 96 CKD anemic patients on EPO compared the efficacy of IV iron (5 doses of 200 mg iron sucrose weekly) to oral iron (ferrous sulfate 325 mg tid). They found an increase in Hb and ferritin following IV iron, whereas the oral iron group demonstrated an increase in Hb without increase in iron stores.**14** Both of the above studies failed to show IV iron superior to PO in either selected group of CKD patients. Van Wyck et.al. conducted a larger study of 182 non dialysis-dependent CKD (stages 3 to 5) patients to compare oral iron vs. IV iron. That randomized, controlled, multicenter trial tested IV iron as sucrose 1 g in divided doses over 14 days vs oral ferrous sulfate 325 mg three times a day for 56 days. Inclusion criteria for the group were Hb ≤11 g/dL, TSAT ≤25%, and ferritin ≤300ng/mL. EPO/DPO dose was not changed for eight weeks prior to or during the study. The proportion of patients achieving the primary outcome (Hb increase ≥1 g/dL) was greater in the IV iron treatment group than in the oral iron treatment group (44.3% vs. 28.0%, P = 0.0344), as was the mean increase in Hb by day 42 (0.7 vs. 0.4 g/dL, P = 0.0298).**<sup>15</sup>** Agarwal and colleagues conducted a randomized, multicenter, controlled trial in 75 adult, anemic, iron-deficient, non-dialysis CKD patients not receiving ESAs. The patients were randomly assigned to receive either IV ferric gluconate 250 mg weekly for 4 weeks or oral ferrous sulfate 325 mg three times a day for 42 days. Both oral and IV iron similarly increased Hb in anemic CKD patients not

A new IV iron preparation, ferumoxytol has been approved in the United States. It appears to be safe and effective when given as a rapid infusion of up to 510 mg in patients with CKD and patients on dialysis. A Phase III trial randomly assigned 304 patients with CKD in a 3:1 ratio to two 510-mg doses of intravenous ferumoxytol within 5 ± 3 days or 200 mg of elemental oral iron daily for 21 days. Among patients who were not receiving ESAs, Hb increased 0.62 ± 1.02 g/dL with ferumoxytol vs. 0.13±0.93

reticulocytes >29 percent and serum ferritin concentration >200 ng/mL.**<sup>12</sup>**

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

(IV) vs Oral (PO) is superior in treating anemia of CKD. 13-22

**3. Anemia in chronic kidney disease** 

receiving ESAs.**16** 

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 with better maintenance of iron stores and lower dosage requirements of EPO.**<sup>18</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 necessary because of the downward trend in iron stores.**<sup>19</sup>**

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

Pharmacologic Adjuvants to Reduce Erythropoietin Therapy Dose

in non-responders (N = 19).**<sup>25</sup>**

**7. Pentoxifylline** 

in Anemia of Chronic Kidney Disease and End Stage Renal Disease 165

significant rise in serum iron and TSAT and a fall in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68+/-37 vs. 124 +/-64 mcg/dL, TSAT 27+/-10 vs. 48+/-19%, E-ZPP 123+/-44 vs. 70+/-13 micromol/mol heme, and serum ferritin 816+/-435 vs. 587+/-323 mcg/L, p<0.05). Compared with responders, mean values of Hb, EPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and

A single PO study by Benz et. al. was conducted in 21 EPO resistant anemic hemodialysis patients with ferritin levels greater than 350 ng/mL had received oral daily ascorbic acid at a dose of 500 mg/day and were retrospectively studied. Hemoglobin, HCT, EPO dose, ferritin, and transferrin saturation were recorded at baseline and after three months of treatment. EPO dose/HCT was calculated. Serum oxalate levels were also measured. In this study, daily oral ascorbic therapy decreased ferritin levels and EPO dose requirements while raising Hb and HCT level. Hb increased 9% from 11.4 to 12.2 gm/dl (*p =* 0.05), HCT increased 10% from 33.3 to 36.7% (*p =* 0.05), and EPO dose requirement decreased 33% from 26,229 to 17,559 U/week (*p =* 0.03). Ferritin levels decreased 21% from 873 to 691 ng/mL (*p =*  0.004) Patients with oxalate levels >27 micromol/L were instructed to stop ascorbic acid treatment, and mean levels decreased from 107 to 19 micromol/L (*p =* 0.01) over a mean time of 71 days. This beneficial profile of the effects of ascorbic acid therapy is consistent

The primary concern for using Vitamin C in dialysis patients is secondary oxalosis because of the impairment in renal excretion and inadequate removal by dialysis procedures.**27-28** Tarng et.al. showed that oxalate levels increase modestly after 8 weeks of IV Vitamin C but information on longer courses of treatment is limited.**25** Canavese prospectively studied the dose of Vitamin C and effect on oxalate levels in 30 dialysis patients. Eighteen patients were administered intravenous ascorbate during 18 months (250 mg/wk, subsequently increased to 500 mg), and 12 patients were taken as reference untreated cases. The study found that plasma oxalate levels progressively increased as the dose of IV Vitamin C was increased from 250 to 500 mg/week. After six months at a dose of 500 mg per week, 7 of 18 patients (40 percent) attained plasma oxalate levels that exceeded the range that would be associated

The 2006 K/DOQI guidelines for anemia in CKD stated that there was insufficient evidence to recommend Vitamin C as an adjuvant to EPO therapy.**30** However, several of the clinical

Pentoxifylline (PTX) is a methyl xanthine derivative, which is approved for use in peripheral vascular disease and may also have anti-inflammatory effects according to studies. Benbernou et. al. studied pentoxifyline and examined its regulatory effect on T helper (TH1-and TH2) cell-derived cytokines in human whole blood and peripheral blood mononuclear cells stimulated with phytohemagglutinin and phorbol myristate acetate. The results showed that PTX at the appropriate concentrations (5 x 10**(-4)**M ) could induce selective suppression of interleukin (IL) -2 and interferon (INF) -gamma, whereas at high concentrations this drug could act as a suppressive agent of both TH1- and TH2-derived cytokines.**<sup>31</sup>** Bienvenu showed similar results that PTX possesses a much broader spectrum

with improvement of EPO resistance and cost savings in this population.**<sup>26</sup>**

with calcium oxalate super saturation at usual calcium concentrations**.29**

studies were published subsequent to the development of those guidelines.

daily for 21 days (n = 116). Ferumoxytol resulted in a mean increase in Hb of 1.02+/-1.13 g/dL at day 35 compared with 0.46+/-1.06 g/dL with oral iron (p = 0.0002). There was a greater mean increase in TSAT with ferumoxytol compared with oral iron at day 35 (p < 0.0001).
