TOTAL DOSE INFUSION IRON DEXTRAN THERAPY IN PREDIALYSIS CHRONIC RENAL FAILURE PATIENTS

Abstract

Background: Intravenous iron therapy is now the standard modality of iron supplementation in hemodialysis patients, but its role in predialysis chronic renal failure patients is less well established. The efficacy and safety of intravenous iron dextran as a total dose infusion in predialysis chronic renal failure patients, not receiving erythropoietin was assessed in this study. Methods: Fifty-six predialysis chronic renal failure patients with anemia, not receiving erythropoietin were included in the study, after obtaining informed consent. Hemoglobin, serum creatinine, creatinine clearance rate and serum ferritin were assessed in all the patients at baseline. Iron dextran in a dose of 1 g dissolved in 500 mL normal saline was administered to all patients as a total dose infusion over 6 h after a prior test dose. Patients were kept in hospital under observation for at least 24 h. All the parameters were repeated in all the patients at 12 weeks and in 21 patients at 1 year. Results: The mean hemoglobin (g/dL) in the patients at baseline and at 12 weeks was 8.28 ± 0.57 and 9.22 ± 0.44 respectively (p<0.001). The mean serum ferritin (ng/mL) increased from 29.73 ± 9.38 at baseline to 218.43 ± 15.66 at 12 weeks (p< 0.00001). The mean ferritin value in the 21 patients at 1 year was 136.5 ± 23.4 (p<0.01). There were no major adverse events and only minor side effects were observed in 4.9% patients. Conclusion: Iron dextran as a total dose infusion corrects anemia in predialysis patients and is an effective method to replenish iron stores. The effect on serum ferritin are evident even at 1 year after the total dose infusion.

INTRODUCTION

Anemia contributes significantly to the morbidity and mortality associated with chronic renal failure (CRF). Correction of anemia, even partially, has conclusively been shown to improve the quality of life, reduce morbidity, regress left ventricular hypertrophy and decrease the associated cardiovascular risk and mortality if CRF patients.[[1]], [[2]], [[3]] A deficient production of erythropoietin (EPO), the glycoprotein that stimulates erythropoieses in the marrow, by the failing kidneys is the major factor responsible for anemia of CRF. The replacement of EPO in CRF patients to ameliorate anemia has been the most significant development in the management of CRF patients in the last century. In spite of this, many patients do not respond adequately to EPO—termed as hyporesponsiveness to EPO. Aluminium toxicity, folate deficiency, chronic inflammatory condition, hypothyroidism, hyperparathyroidism, reduced red cell survival, hemoglobinopathies and most importantly iron deficiency contribute to EPO hyporesponsiveness.

It is now the standard recommended protocol to replenish iron as intravenous (iv) iron therapy for all CRF patients on hemodialysis. There is a large body of evidence in support of iv iron therapy in hemodialysis patients irrespective of their iron stores or whether or not they receive EPO.[[4]], [[5]], [[6]], [[7]] The role of iv iron therapy in predialysis CRF patients is less defined. Oral iron supplementation is still considered effective in predialysis patients and this population comprises the major, still-varied, indication of oral iron therapy in CRF. However, recent studies have demonstrated that predialysis CRF patients may fail to maintain adequate iron stores or oral iron therapy[[8]], [[9]] thus prompting the need for iv iron replenishment.

The present study was conducted to assess the efficacy and safety of iv iron dextran preparation administered as a total dose infusion (TDI) in iron deficiency in predialysis CRF patients.

PATIENTS AND METHODS

Predialysis CRF patients attending the Nephrology Outpatient Clinic at our centre were considered for inclusion in the study. Patients with known hypersensitivity and those refused informed consent were excluded. A baseline hemoglobin (Hb), serum creatinine, creatinine clearance rate (C_Cr) and serum ferritin was assessed in all patients. The study group finally comprised of 56 anemic predialysis patients with baseline serum ferritin<100 ng/mL.

All 56 patients were first administered a standard test dose of 25 mg iv iron dextran preparation (MFERON) diluted in 100 mL normal saline infused over 60 min with monitoring for any possible adverse reactions. Subsequently, iron dextran was administered as a TDI of 1.0 gm dissolved in 500 mL normal saline over 6 h with careful monitoring of pulse, BP and a close watch for any possible adverse events. Patients were discharged the next day. The laboratory parameters were re-evaluated 12 weeks after the TDI in all patients and in as many patients as possible at the end of 1 year.

The data collected was analyzed statistically using the MS EXCEL software and the significance of changes in Hb and ferritin at 12 weeks over baseline was assessed using the paired student ‘t’ test with statistical significance assumed at a p value<0.05.

RESULTS

Of the 56 patients, 34 were male and 22 were females, with mean age 42.3 ± 8.6 years (range 18–62 years). The etiology of renal failure was as follows: diabetes mellitus n = 24, chronic glomerulonephritis n = 16, autosomal polycystic kidney n = 6, obstructive uropathy n = 4, hypertension n = 3 and 1 each systemic lupus erythematosus, membranous glomerulonephritis and focal segmental glomerulosclerosis. The mean C_Cr of the patients was 20.4 ± 6.8 mL/min. None of the patients was receiving EPO and all patients were receiving oral iron supplements for at least 3 months prior to the study.

The mean Hb and serum ferritin in the patients pre and post TDI are summarized in Table 1. As is evident, the mean Hb improved significantly (p<0.001) over baseline values as also did serum ferritin (p<0.00001). It was possible to assess Hb and S. ferritin in only 21 of 56 patients at 1 year over baseline. After 1 year, though both Hb and S. ferritin had dropped from the 12-week values, S. ferritin levels were still significantly greater than the baseline values (p<0.010. There were no statistically significant changes in the mean C_Cr and systemic and diastolic BP in the population at 12 weeks over baseline.

Table 1. Hemoglobin and S. Ferritin in the Study Group Pre and Post TDI

Time	Parameter
	Hb (g/dL)	S. Ferritin (ng/mL)
Baseline (n = 56)	8.28 ± 0.57	29.73 ± 9.38
12 weeks (n = 56)	9.22 ± 0.44 (p<0.001)	218.43 ± 15.66 (p < 0.0001)
1 year (n = 21)	8.75 ± 0.32	136.5 ± 23.4 (p<0.01)

The adverse event profile of the patients is summarized in Table 2. There were no major/life threatening adverse reaction observed in any patient given iron dextran as TDI.

Table 2. Adverse Events with Iron Dextran TDI

No Major Adverse Event	(%)
Flushing, nausea, vomiting	3.5
Arthralgias, myalgias	1.8
Fever chills, headache	1.8
Dyspnea, bronchospasm	1.8

DISCUSSION

The genesis of iron deficiency in CRF is multifactorial. To begin with, absorption of iron from gut is definitely suppressed.[[10]], [[11]] Also, there is a reduction in overall food intake due to nausea, anorexia and a decrease consumption of meat products (rich in iron) in order to reduce protein intake—all this leads to a decrease in the iron available for absorption. Further, the calcium containing phosphate-binders and antacids that are routinely prescribed to these patients have an inhibitory effect and reduce the iron available for absorption. Repeated blood sampling for laboratory investigation, blood losses during hemodialysis and occult gastrointestinal blood losses compound the problem.

The National Kidney Foundation-Dialysis Outcomes Quality initiative (NKF-DOQI) guidelines on the management of anemia in CRF patients have identified S. ferritin and percent transferrin saturation (TSAT) as the 2 investigations to assess and monitor iron status in CRF patients.[[12]] Based on these guidelines, iron deficiency is said to be present when S. ferritin is <100 ng/ml and/or TSAT ≤ 20%, and appropriate iron therapy is to be instituted in all these iron deficient patients.

The main drawback of oral iron replenishment is that it is heavily dependent on absorption of iron from the gut and it's inability to meet the increased iron demands during enhanced erythropoiesis for e.g., on EPO therapy. The body iron stores get progressively depleted and target Hb is not achieved.[[13]] Though initially oral iron therapy may suffice for predialysis patients, due to the reasons cited earlier, oral iron therapy is unable to sustain body stores and iv iron replacement may become necessary.

In the present study, 56 predialysis patients with iron-deficiency as defined by NKF-DOQI guidelines were administered iv iron dextran as a TDI. It is important to re-emphasize that the patients were receiving EPO (they could not afford it) and all of them were on oral iron supplements of 200 mg ferrous sulfate (containing 60 mg elemental iron) t.i.d. for at least 3 months prior to inclusion in the study. In spite of these, the mean S. ferritin in the patient at baseline was markedly low—29.73 ± 9.38 ng/mL. This demonstrates that iron deficiency is quite prevalent in predialysis patients. An important cause for this, in addition to the factors described earlier, could be the relatively high prevalence of iron deficiency to the tune of 60–70% in young adult females and males in the general population of India.[[14]]

With TDI, both Hb, and ferritin improved significantly in the study population over baseline though target Hb of 11 g/dL was not attained in any patient. Similar significant improvements in Hb and ferritin have been demonstrated in the few scarce studies that have been done on TDI in predialysis population.[[15]], [[16]] However in the study by Dawdah et al.,[[16]] only 14 patients were selected to receive 500 mg iron dextran as TDI in 2 consecutive weeks. The other study by Bhowmick et al.[[16]] consisted of only 11 patients, of whom only 6 were reassessed with ferritin evaluation at 1 month. The present study is the largest single study in the world of iv iron dextran as a TDI is 56 predialysis CRF patients of whom 21 were reassessed at 1 year and it clearly establishes the beneficial effect of this therapy.

The major concern on iron-dextran TDI is the occurrence of possible fatal adverse events associated with it. In this study, all the patients tolerated the TDI well and no major life-threatening hypersensitivity reaction was recorded. Only minor, self-limiting side effects were observed in a few patients as discussed in Table 2. Thus although the possibility of fatal adverse events always exists, if due precautions are taken especially administering a closely monitored test dose prior to the TDI, the incidence of these can be minimized. Alternatively, other preparations of iv iron is iron saccharate/sucrose or iron gluconate which have negligible risk for these events can be used.

Another determent to TDI with iron is the possibility of development of iron-overload (s. ferritin ≥ 800 ng/mL and/or TSAT ≥ 50%) with its attendant dangers of organ damage and increased risk of infection. In this study, none of the patients had any evidence of iron overload at 12 weeks. However, ferritin levels could not be estimated at 2 weeks after TDI when the levels are documented to be higher.[[15]] It is unlikely though that this population with such low iron stores would develop iron-overload within 2 weeks of a 1 gm TDI still, one should be aware of this possibility.

In resource poor—countries such as India, one of the major factor to be considered before any therapy is the costs involved. One week's treatment with EPO costs about Rs. 2000/- and this treatment essentially being for life long is not affordable by most patients as most of them have no access to any reimbursement schemes. The cost of 1 g iv iron dextran is about Rs. 80/- only. Further, this is a one-time therapy and is beneficial in sustaining iron stores for at least 1 year as shown in this study.

Hence this study demonstrates that contrary to prevailing belief iron deficiency is quite prominent in predialysis CRF patients. This is especially true in patients in countries where iron deficiency is widespread in the general population. Iron dextran as a TDI is a safe, well tolerated and effective therapy to correct iron deficiency and improve hematologic parameters for relatively sustained periods of time. Though target hematological parameters may not be achieved, iv iron dextran TDI may delay the need to start EPO in predialysis patients.

ACKNOWLEDGMENT

This study was conducted as part of the research under the Senior Research Associate Scientists Pool Scheme of the Council of Scientific and Industrial Research (CSIR-HRDG), India and the authors graciously acknowledge CSIR for this.