Iron deficiency in children with early chronic kidney disease
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- Baracco, R., Saadeh, S., Valentini, R. et al. Pediatr Nephrol (2011) 26: 2077. doi:10.1007/s00467-011-1946-2
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Iron deficiency (ID) contributes to the development of anemia in patients with chronic kidney disease (CKD). The frequency of ID in children with early CKD has not previously been reported. This was a retrospective chart review of children with CKD stages 2 and 3 followed at the CKD clinic of Children’s Hospital of Michigan. ID was defined as low ferritin and transferrin saturation <20%. Patients on iron supplements were considered as iron-deficient cases. There were 50 patients included in the study (72% male) with a mean age of 10.31 (±5.21). The mean glomerular filtration rate (GFR) was 55.4 ml/min/1.73 m2 (±14.61). ID was present in 42% of patients, out of whom almost half (42.9%) presented with anemia. Females had a higher frequency of ID (64.3%). The frequency of ID with anemia increased from 4.3% to 29.6%, (p = 0.03) in stage 2 to stage 3 CKD, respectively. The frequency of ID without anemia also increased with progression of CKD from stage 2 to stage 3, however, the difference was not statistically significant. ID is frequent in patients with early CKD. Monitoring of iron tests and treatment of ID is important in this population of patients.
KeywordsIron deficiencyAnemiaChronic kidney diseaseFerritinTransferrin saturation
Anemia has been associated with increased mortality and increased risk of hospitalization in children with chronic kidney disease (CKD) . Apart from the complications of anemia, iron deficiency (ID) by itself is associated with lower cognitive performance  and long-lasting developmental limitations .
Patients with advanced CKD mostly have a normocytic and normochromic anemia because of deficiency of erythropoietin. This deficiency develops when the glomerular filtration rate (GFR) drops below 35–43 ml/min.1.73 m2 . ID is also an important cause for anemia in CKD . This is secondary to poor nutritional intake and a chronic state of inflammation that impairs iron utilization .
Little is known about the prevalence of ID with and without anemia in children with early CKD. The main objective of this study was to determine the frequency of ID in children with and without anemia with CKD stages 2 and 3.
This was a retrospective study of patients seen in the CKD clinic at Children’s Hospital of Michigan. Approval was obtained from the Wayne State University Institutional Review Board.
Included in the study were patients aged 1 to 18 years with CKD stages 2 and 3. Excluded from the study were patients who had a GFR less than 30 or required dialysis on initial presentation, known history of bleeding, history of anemia or ID prior to developing CKD or during CKD stage 1, were receiving erythropoietin stimulating agents (ESA), had nephrotic range proteinuria with hypoalbuminemia, had a primary disease known to cause anemia (e.g., vasculitis), and those with incomplete data required for analysis. Staging of CKD was defined as per the kidney disease outcomes quality initiative (KDOQI) guidelines .
Serum creatinine was measured by the Jaffe method. GFR was calculated using the Schwartz formula: (height in centimeters × K)/serum creatinine, where K values are assigned according to the age of the patient .
The charts of patients included were reviewed and the following information was extracted: age, gender, cause of CKD, current medications, and height for calculation of GFR. The three lowest consecutive hemoglobin levels the patient had while in CKD stage 2 or 3 were identified and other tests of interest that were done at the same time were noted, which included serum creatinine and GFR, ferritin level and transferrin saturation (Tsat).
Low hemoglobin level according to the patients’ age and gender .
Tsat <20% and a low ferritin level. Ferritin levels were measured by the Immulite 2000 instrument (Diagnostic Products Corporation, Los Angeles, CA) and were considered to be low according to our laboratory’s cut-off values, which were provided by the manufacturer: patients 15 days to 7 months old <57 ng/ml, patients 7 months to 13 years old <11 ng/ml, and patients 13 years old and above <25 ng/ml. Patients on iron supplementation were considered to be iron-deficient.
Iron deficiency anemia (IDA)
Presence of both anemia and ID.
Causes of CKD were divided into three groups: glomerular (focal segmental glomerulosclerosis, Alport’s disease, membranous glomerulonephritis, membranoproliferative glomerulonephritis); tubulo-interstitial (obstructive uropathy, renal dysplasia/hypoplasia, polycystic kidney disease, multicystic dysplastic kidney disease, interstitial nephritis, reflux nephropathy), and "other" causes of CKD.
SPSS® version 18.0 was used for analysis. The frequencies of anemia and ID were calculated by gender, stages and causes of CKD, and for the total patients. Chi-square test was used to compare proportions where appropriate. The mean age and mean GFR were also calculated.
Of a total of 99 charts reviewed, 49 were excluded: 17 patients had presented with a lower GFR or had been on dialysis in the past, 15 had incomplete data, 12 had nephrotic range proteinuria with hypoalbuminemia, three had a history of anemia prior to stage 2 CKD, one had gross hematuria, and one had systemic lupus erythematosus.
Of the 50 patients included in the study, 36 (72%) patients were male and 14 (28%) were female; 23 (46%) had stage 2 CKD and 27 (54%) had stage 3 CKD; 36 (72%) patients had tubulo-interstitial renal disease, 11 (22%) had glomerular disease, and three (6%) had other causes of CKD. The mean age was 10.31 years (±5.21). The mean GFR was 55.4 ml/min/1.73 m2 (±14.61).
Females had a higher frequency of ID with and without anemia (64.3%) than males (33.3%) (p = 0.06). ID was present in 47.2% of patients with tubulo-interstitial disease and 27.3% of patients with glomerular disease.
The percentage of patients with ID and IDA by stages of CKD is shown in Fig. 1b. The frequency of ID without anemia increased from 21.7% to 25.9% from stage 2 to stage 3. Similarly, the frequency of IDA increased from 4.3% to 29.6% from stage 2 to stage 3 CKD (p = 0.03).
Twelve (57.1%) of the patients with iron deficiency and six (20.7%) of the patients without iron deficiency were on one or more of the following medications: sevelamer, calcium acetate, calcium carbonate, ranitidine, proton-pump inhibitors and/or sodium bicarbonate.
The reported prevalence of anemia in children with CKD stage 2 is 21–30% and in stage 3, 39–65% [1, 9]. Our observations were similar; 36% of our patients with early CKD had anemia. Multiple factors contribute to anemia in CKD. The predominant cause is decreased production of erythropoietin. Additional factors include shortened lifespan of erythrocytes, and the possible existence of an inhibitory substance that suppresses erythroid precursor cells in the bone marrow .
Iron deficiency is an important contributor to anemia in patients with CKD . Hepcidin, a peptide hormone synthesized in the liver, appears to be involved in iron metabolism. It has been shown to inhibit duodenal iron absorption, and in inflammation state the hepcidin gene is over-expressed, which could explain iron sequestration and decreased intestinal iron absorption . High levels of hepcidin have been found in patients with renal failure, this may be secondary to impaired renal excretion and/or to the inflammatory state of CKD . According to these findings, high levels of hepcidin and impaired iron absorption could be expected with progressive CKD.
Appetite is decreased in patients with CKD; consequently, the intake of iron-containing foods may be decreased. Medications frequently used in CKD such as bicarbonate, antacids and calcium-based phosphorus binders decrease iron absorption . Almost 60% of our iron-deficient patients were on at least one of these medications, suggesting that this may be a factor contributing to iron deficiency. A chronic state of inflammation is also described in CKD, where ferritin levels are elevated and there is inefficient utilization of iron stores .
The frequency of ID in children with early CKD has not been reported in the literature. In adults, a study that reported National Health and Nutritional Examination Survey data found that most patients with CKD had low levels of ferritin and Tsat, 58.8% of men and 72.8% of women. Although this study used higher cut-off ferritin levels (<100 ng/ml), it showed that ID is very prevalent in patients with CKD regardless of the presence of anemia . We also found more ID in females (64.3 vs. 33.3%). This could be secondary to menstrual losses, which are not replaced by adequate nutrition. However, females in our study only accounted for 28% of the patients. This is likely because of the high frequency of obstructive uropathy in our patient population.
Our study shows that almost half of patients with early CKD have ID without anemia. In the initial stage of ID, iron stores are depleted before anemia develops; as the negative iron balance continues, hemoglobin levels begin to drop . KDOQI guidelines’ recommendations for the evaluation and treatment of ID are directed at anemic patients. Target levels of ferritin and Tsat are provided for patients on ESA. There are no guidelines as to when to begin evaluation for ID, how frequently to monitor iron studies, and if treatment of ID in the absence of anemia is recommended in children with early CKD. We found a significant increase in the frequency of ID from CKD stage 2 to stage 3, suggesting that work-up for ID should be done in early CKD so that this problem can be identified and treated before IDA develops. This is important to decrease the burden of these problems in more advanced CKD and to improve the quality of life of children with CKD.
In patients with advanced CKD, serum ferritin and Tsat are used to evaluate iron status. Ferritin is the primary storage protein for iron, and ID results in a decrease in serum ferritin. However, it is also an acute-phase reactant, and the serum level may be elevated with systemic inflammation, in which case the serum ferritin levels do not reflect actual iron stores . We used Tsat <20% and ferritin cut-off values according to our laboratory normal ranges as is used at our institution to define ID in otherwise healthy children and in children with early CKD. Since patients with CKD may have high levels of ferritin secondary to inflammation, the cut-off values that we used may have missed children that had normal or high ferritin levels, but were in fact iron-deficient. We considered children who were receiving iron supplements as iron deficient because these patients were started on these supplements when their Tsat and ferritin levels became low during their follow-up in the CKD clinic.
Although our study is limited by the retrospective design, the small number of patients, and the exclusion of almost half of the patients that were eligible for the study, it is the first to describe the occurrence of ID in children with early CKD. Another important limitation is the fact that we did not include any markers of inflammation which, as stated above, can affect the ferritin level and iron utilization. We conclude that ID is common in children with early CKD, and almost half of such patients have anemia. IDA increases with advancing CKD. Early identification and treatment of ID in early CKD is recommended. Future studies are needed to develop guidelines for the evaluation and management of ID in children with early CKD.