| Abstract|| |
A retrospective study was conducted over seven years and it aimed to find out various causes of anemia among patients with chronic kidney disease (CKD). The study included nondialysis-dependent adult CKD patients who underwent anemia evaluation. A total of 584 patients were studied. Three hundred and twenty-one (55%) patients were male and 263 (45%) were female. The mean age of the patients was 55.5 ± 14 years. One hundred and seventy-eight (30.5%) had a diabetic CKD and 406 (69.5%) had a nondiabetic CKD. Seventy-two (12.3%) patients were in CKD Stage 3, 193 (33%) patients in CKD Stage 4, and 319 (54.6%) patients in CKD Stage 5. The mean hemoglobin was 9.2 ± 2.2 g/dL. There was a progressive fall in hemoglobin with increasing severity of CKD and in CKD Stage 3, 4, and 5 the mean hemoglobin was 10 ± 2.2, 9.4 ± 2.1, and 8.4 ± 1.9 g/dL, respectively (P = 0.001). Most (47.4%) patients had moderate anemia followed by anemia of mild (31.4%) and severe (21.4%) degrees. Three hundred and seven (52.6%) patients had percent transferrin saturation (TSAT) <20% (functional iron deficiency). One hundred and sixty-two (27.7%) patients had serum ferritin <100 ng/mL (absolute iron deficiency); 334 (57.2%) patients had serum ferritin 100–500 ng/mL, but in 175 (52.4%) of them, TSAT was <20%; 88 (15.1%) patients had serum ferritin >500 ng/mL (58 (65.6%) were C-reactive protein (CRP) + and 55 (62.5%) had TSAT <20%). Overall, 392 (67.1%) patients had functional or absolute iron deficiency. One-third of the patients had elevated CRP levels. The anemia was macrocytic in 20.4% suggesting deficiency of folic acid and/or Vitamin B12. A high proportion (74.6%) of patients with normocytic anemia had iron deficiency. In the majority of nondialysis-dependent CKD patients, the etiology of anemia may be multifactorial; therefore, the treatment should be determined by documented causes of anemia.
|How to cite this article:|
Vikrant S. Etiological spectrum of anemia in non-dialysis-dependent chronic kidney disease: A single-center study from India. Saudi J Kidney Dis Transpl 2019;30:932-42
|How to cite this URL:|
Vikrant S. Etiological spectrum of anemia in non-dialysis-dependent chronic kidney disease: A single-center study from India. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Jun 6];30:932-42. Available from: http://www.sjkdt.org/text.asp?2019/30/4/932/265471
| Introduction|| |
Anemia is one of the most distinctive features and visible manifestations of chronic kidney disease (CKD). The primary cause of anemia is a deficient production of erythropoietin (EPO) and may occur as early as Stage 3
CKD. Other causes include functional or absolute iron deficiency, blood loss (either occult or overt), the presence of uremic inhibitors, a reduced half-life of circulating blood cells, deficiencies of folate and/or Vitamin B12, inflammation or some combination of these and a deficiency of EPO.,
Anemia is a common condition among pre-end-stage renal disease (pre-ESRD) or pre-dialysis patients with CKD. Data from clinical studies have demonstrated that anemia may be present in as many as two-thirds of such patients. Anemia in the presence of CKD can lead to an increased risk of many adverse outcomes, including mortality, a progression of kidney disease, coronary heart disease, stroke, hospitalization, and decreases in quality of life.,, Anemia’s association with these adverse outcomes indicates that effective treatment of anemia in pre-ESRD CKD patients is of great importance and that substantial efforts should be made to ensure that these patients receive appropriate therapy to correct anemia.
Anemia in CKD poses a diagnostic and management challenge. That is especially important in developing countries due to economic implications of a higher dose of EPO and a higher prevalence of nutritional anemia in the general population. CKD is a significant public health problem in India, but the exact prevalence, morbidity, and mortality of CKD are not well studied. There is a lack of published data on anemia and its etiological spectrum among CKD. We undertook this study to find out various causes of anemia in CKD.
| Materials and Methods|| |
This was a retrospective study done over seven years (January 2010-December 2016) at Indira Gandhi Medical College, Shimla, India. The study included adult nondialysis-dependent CKD (ND-CKD) patients [estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2] who underwent anemia evaluation. The investigations of anemia included complete blood count (CBC), iron studies- serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum ferritin levels, serum C-reactive protein (CRP) levels, bone marrow aspiration (BMA), and other diagnostic tests (only in treatment-resistant cases). CBC was done by Cell Counter ACT5 differential using automated coulter volume conductivity, and light scatters impedance principle. Serum iron and TIBC was estimated by spectrophotometry on BN Prospec II, Dade Behring automated nephelometry analyzer. TSAT was calculated as the percentage of serum iron from TIBC. Serum ferritin levels were estimated by chemiluminescence immuno-assay on Advia Centaur, Bayer - a fully automated chemiluminescence immunoassay analyzer. CRP was assessed using a high-sensitivity latex immunoturbidometric method (Giesse Diagnostics).
We defined cases of Stages 3 to 5 CKD by the eGFR, taking into account the requirement of three-months chronicity for the formal diagnosis. The eGFR was calculated from serum creatinine levels using the abbreviated Modification of Diet in Renal Disease equation. Anemia was defined as hemoglobin concentration <13.0 g/dL in males and <12.0 g/dL in females. Iron status was also calculated using the following criteria: adequate iron status = serum ferritin ≥100 ng/mL + TSAT ≥20%; functional iron deficiency = serum ferritin 100 ng/mL + TSAT <20%; absolute iron deficiency = serum ferritin <100 ng/mL. Inflammation was considered to be present when the CRP level was >5 mg/L.
Patients with any previous iron or erythro-poiesis-stimulating agent therapy, current infectious conditions, cancer, blood transfusions, and active bleeding within the preceding three months, hemolytic anemia, were excluded. The Institutional Ethical Committee approved the study.
| Statistical Analysis|| |
Standard descriptive statistics were calculated for all study variables. Continuous data are expressed as means ± SD, and the means of the two study groups were compared using an unpaired t-test. Nominal data are expressed as frequencies or proportions, and the Chi- square test and Fisher’s exact test were used to compare the differences in frequency between the two study groups. For nonnormal data, a Mann–Whitney U-test was performed. A P <0.05 was considered as statistically significant. All statistics were carried out using the Statistical Package for the Social Sciences (SPSS) version 18.0 (SPSS Inc., Chicago, IL, USA).
| Results|| |
A total of 584 patients out of 2723 CKD patients who completed the anemia evaluation during the study period were analyzed. [Table 1] shows the demographic and clinical characteristic of the study patients. Three hundred and twenty-one (55%) patients were male and 263 (45%) were female. Mean age of the patients was 55.5 ± 14 years. One hundred and seventy-eight (30.5%) had a diabetic CKD and 406 (69.5%) had a nondiabetic CKD. The mean serum creatinine was 5.2 ± 3.6 mg/dL, and the mean GFR was 16.7 ± 12.5 mL/min/1.73 m2. Seventy-two (12.3%) patients were CKD Stage 3, 193 (33%) patients CKD Stage 4, and 319 (54.6%) patients CKD Stage 5. The mean hemoglobin was 9.2 ± 2.2 g/dL. There was a progressive fall in hemoglobin with increasing severity of CKD, and in CKD Stage 3, 4, and 5 the mean hemoglobin was 10 ± 2.2, 9.4 ± 2.1, and 8.4 ± 1.9 g/dL, respectively (P = 0.001) [Table 2]. Mean plot of hemoglobin by CKD stage is shown in [Figure 1]. The linear regression analysis revealed significant positive correlation between the hemoglobin level with GFR (r = 0.298, P = 0.001) [Figure 2].
|Table 1: Demographic and clinical characteristics of the study patients (n=584).|
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|Table 2: Hemoglobin and severity of anemia in various CKD stages (n=584).|
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|Figure 2: Scatter plot of mean hemoglobin according to the glomerular filtration rate.|
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Most (47.4%) patients had moderate anemia followed by anemia of mild (31.4%) and severe (21.4%) degrees [Figure 3]. The majority of patients had mild anemia in CKD Stage 3, whereas in CKD Stage 4 and 5, moderate anemia was the most common. The frequency of severe anemia rose with increasing CKD stage reaching 28% in CKD Stage 5 [Figure 4] and [Table 2].
|Figure 4: Distribution of anemia severity among chronic kidney disease stages.|
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Three hundred and seven (52.6%) patients had TSAT percent <20% (functional iron deficiency) [Table 3]. One hundred and sixty- two (27.7%) patients had serum ferritin <100 ng/mL (absolute iron deficiency); 334 (57.2%) patients had serum ferritin 100–500 ng/mL, but in 175 (52.4%) of them, TSAT was <20%; 88 (15.1%) patients had serum ferritin >500 ng/mL (58 (65.6%) were CRP + 55 (62.5%) had TSAT <20%). Overall, 392 (67.1%) patients had functional or absolute iron deficiency. About one-third of patients had elevated CRP levels. The frequency of patients with of a raised CRP levels increased with increasing serum ferritin levels, and two-thirds had an elevated CRP among patients with serum ferritin of >500 ng/mL (P = 0.001).
The anemia was normocytic in 65.4%, micro- cytic in 14.2%, and macrocytic in 20.4%. Red blood cell (RBC) indices were normocytic normochromic in 227 (38.9%); normocytic hypochromic in 155 (26.5%); microcytic hypochromic in 83 (14.2%); macrocytic hypochromic in 63 (10.8%) and macrocytic normochromic in 56 (9.6%) [Table 4]. RBC indices were hypochromic in 301 (51.5%) patients indicating iron deficiency and macrocytic in 119 (20.4%) patients showing a deficiency of folic acid or Vitamin B12. Even in patients with normocytic normochromic anemia, 130 (57.3%) out of 227 had functional or absolute iron deficiency. BMA done in 25 patients showed megaloblastic anemia (1 diagnosed pernicious anemia, bone marrow biopsy revealed MDS/refractory anemia in 3 patients).
There was no significant difference in hemoglobin level, RBC indices, iron status, and proportion of positive CRP between diabetic and nondiabetic CKD patients [Table 5]. However, the age, male gender, and the GFR were significantly higher in diabetic CKD. There was a significant increase in the proportion of CRP positive patients with increasing serum ferritin levels among both groups of CKD patients.
| Discussion|| |
Anemia is a common and serious complication of CKD that presents during the early phase of the disease and worsens as the kidney function deteriorates., In our study, there was a progressive fall in hemoglobin level with increasing severity of CKD and a significant positive correlation between the hemoglobin level with GFR was observed (r = 0.298, P = 0.001). Several large-scale population studies suggest that the incidence of anemia is <10% in CKD Stages 1 and 2, 20–40% in Stage 3, 50–60% in Stage 4, and >70% in ESRD (Stage 5) patients., These figures clearly show that anemia develops early in the course of CKD and increases in frequency while the glome- rular filtration rate further declines. The principal cause of anemia in CKD is a reduced the ability of the failing kidneys to produce EPO. Iron deficiency, Vitamin B12, and folate deficiency and inflammation are additional etiolo-gical factors that may contribute to anemia in CKD.
Over two-thirds (67.1%) of the patients in the current study had functional or absolute iron deficiency. Imbalance of the iron homeostasis plays a central role in the development of anemia of CKD and is a significant contributor toward resistance to treatment with erythro-poiesis-stimulating agents. Iron deficiency occurs in the vast majority of patients with CKD. The causes of iron deficiency in these patients are multifactorial. Primary factors that contribute to iron deficiency in CKD patients are reduced intake and impaired intestinal absorption of dietary iron, blood losses, chronic inflammation and/or increased iron requirements during therapy with erythropoiesis- stimulating agents (ESAs).
Iron deficiency is rampant in anemic ND-CKD patients. Depending on the CKD stage, the prevalence of low iron indices such as TSAT levels <20% and ferritin levels <100 ng/mL has been reported in 20%–70%.,,,, Moreover, iron deficiency is the most common cause of hyporesponsiveness to ESAs.,,, Anemia is iron-responsive in 30%–50% of patients with ND-CKD. Because an erythro- poietic response is seen in half of the patients and even one-third of those with iron-replete stores responded, whereas peripheral indices had only a moderate utility in predicting response, the therapeutic trial to intravenous iron seems to be a useful tool in the management of anemia in nondialysis patients with CKD.
Normocytic anemia is the most common form of anemia in patients with CKD. About 80.5% of patients with CKD and hemoglobin ≥11 g/dL have normocytic anemia and two- thirds (67.6%) where hemoglobin ≥9 g/dL. As the hemoglobin falls, so the proportion of people with microcytic anemia rises to 20%– 25%. The proportion of macrocytic anemia only slightly rises to 6%–7% as hemoglobin falls in CKD. Iron stores may be depleted (ferritin <100 ng/mL) in over >60% of people with normocytic anemia. RBC indices revealed normocytic anemia in about two- thirds of our patients. However, a high proportion (74.6%) of them had iron deficiency indicated by hypochromia or TSAT <20% and or ferritin <100 ng/mL. Over a half of the patients had hypochromia suggestive of iron-deficient erythropoiesis.
Over one-fifth of patients had macrocytosis suggestive of deficiency of folate or VitaminB12.
Folate and Vitamin B12 deficiency is uncommon but is essential causes of treatable anemia, generally associated with macrocytic RBC indices. Limited data indicate a prevalence of Vitamin B12 and folate deficiency in ≤10% of hemodialysis patients; the prevalence in CKD patients is not known. Nonetheless, since these deficiencies are easily correctable, and in the case of Vitamin B12 may indicate other underlying disease processes, assessment of folate and Vitamin B12 levels are generally considered standard components of anemia evaluation, especially in the presence of macrocytosis. Folate deficiency is best detected in most patients with serum folate level testing; RBC folate levels can be measured when serum folate levels are equivocal or when there is concern that recent dietary intake may obscure underlying folate deficiency using serum levels alone. The red cell indices, particularly of the classical parameter “mean cell volume” indicating macrocytosis or red blood cell distribution width may be an inexpensive, sensitive test to detect Vitamin B12 or folate deficiency in iron-replete patients. Although the assessment of folate and Vitamin B12 levels was not made, our study results suggest that the macrocytosis is a cheap and straightforward indicator of folate and Vitamin B12 deficiency in ND-CKD in developing countries.
Inflammation has an important role in the pathogenesis of the anemia of CKD. Epide-miologic data indicate a correlation between anemia and inflammation, especially with CRP. Initial observations indicated that CRP levels predicted EPO resistance, which may be related to functional iron deficiency, postulated to be the result of an inflammatory block. The high (60%–74%) prevalence of inflammation indicated by a raised CRP level is not unusual in patients with anemia and advanced CKD. Inflammation was present in a significant number (35.1%) of patients in our study.
Increased levels of inflammatory cytokines such as interleukin-6 enhance production and secretion of hepcidin, a hepatic protein that inhibits intestinal iron absorption and impairs iron transport from the reticuloendothelial system to bone marrow. Furthermore, EPO, which generally enhances iron transport from macrophages to the bloodstream, is impaired, thereby exacerbating relative iron deficiency. Modulation of iron metabolism appears to be the critical pathway by which inflammation drives anemia. Anemia of inflammation is characterized by decreased iron and iron-binding capacity, increased ferritin and an abundance of iron in the bone marrow. This picture represents a state of iron sequestration in reticuloendothelial cells and suggests that the plasma iron levels are inadequate to support erythropoiesis. Serum ferritin level, which increases as iron stores increase, may also be increased by inflammation, malnutrition, and infection despite limited or absent storage iron. During inflammatory states and malnutrition, TSAT may decrease.
A high proportion (72.3%) of our patients had an adequate iron store as shown by a normal or raised ferritin, but the majority (54.5%) of them had TSAT <20% (functional iron deficiency) and 41.7% of had inflammation as evidenced by a raised CRP levels. Commonly used iron indices, such as serum ferritin and TSAT, have limited utility in patients with CKD. Both dialysis and non-dialysis patients may have normal to high serum ferritin levels and little or no iron available for erythropoiesis. Inflammation can result in increased serum ferritin level and low TSAT and restrict the ability to mobilize iron stores. Management of anemia in patients with CKD requires recognizing that not only decreased EPO production but also decreased iron availability can lead to anemia.
Most (47.4%) patients had moderate anemia followed by anemia of mild (31.4%) and severe (21.4%) degrees. The majority of patients had mild anemia in CKD Stage 3, whereas in CKD Stage 4 and 5, moderate anemia was the most common. The frequency of severe anemia rose with increasing CKD stage reaching 28% in CKD Stage 5. A multicenter study from Italy among 755 non-dialysis CKD Stage 3b, 5 patients revealed a high prevalence of anemia at baseline which was severe in 44% and mild in 18% of patients. A study from Iran, the severity of anemia was reported as mild in 45% and moderate in 55% among pre-dialysis CKD. The most frequent morphologic features were normochromic-normocytic (80%), hypochromic-microcytic (15%) and macrocytic (5%). A study from Malaysia reports that the severity of anemia was mild in 47.7% of the patients, moderate in 32.2%, and severe in 20% among pre-dialysis patients. Based on the morphological classification of anemia, 76.9% of our patients had normochromic-normocytic anemia, whereas 21.8% and 1.3% had hypochromic- microcytic anemia and macrocytic anemia, respectively.
Diabetic status affects the prevalence of anemia in patients with CKD. Anemia occurs at an early CKD stage in diabetic patients. Anemia is more common in diabetic patients with CKD Stage 3–4 than in nondiabetic patients with similar renal function., In the Kidney Early Evaluation Program 2.0, the prevalence of anemia in diabetic patients was greater than in patients without diabetes at each level of GFR: 8.7% versus 6.9% in Stage 2 (P = NS), 7.5% versus 5.0% in Stage 3 (P = 0.015), 22.2% versus 7.9% in Stage 4 (P <0.001) and 52.4 versus 50% in Stage 5 (P = 0.88). There was no significant difference in hemoglobin level, RBC indices, iron status, and proportion of positive CRP between diabetic and nondiabetic CKD in our patients. However, the GFR was significantly higher in diabetic CKD patients.
Anemia is associated with adverse outcomes in CKD. Therefore, the determination of exact etiology is vital to guide effective treatment to correct anemia. Our study is probably the first study of anemia and its etiological spectrum among ND-CKD from India. The strength of this study lies in large sample size, single- center study, relevance to clinical practice on a disorder on which data are relatively limited, especially in developing countries. There are certain limitations in this study. First, it was a retrospective study, in which treatment and its efficacy results could not be studied. Second, the exact prevalence of anemia across CKD stages was not studied. Majority of the patients were late CKD stage; therefore, it may not represent the etiology of anemia across the spectrum of CKD stages. Finally, the assessment of folate and Vitamin B12 levels was not made. The results presented herein are generally consistent with what has been reported in previous studies from developed countries. However, in comparison, we found a higher prevalence of deficiency of nutritional factors, namely iron, folic acid, and Vitamin B12 which are common etiologies of nutritional anemia among the general population in developing countries.
In conclusion, anemia among ND-CKD is mostly normocytic and moderate in severity. Management of anemia in patients with CKD requires recognizing that not only decreased EPO production but also decreased iron availability, can lead to anemia. Iron deficiency is a leading cause of anemia among ND-CKD. The use of iron in combination with the ESA is required for optimal management of the anemia of CKD. Management of iron status in patients with CKD involves excluding iron deficiency, providing adequate iron stores to allow patients to maintain target hemoglobin levels efficiently, and avoiding iron overload. In addition, other factors such as folate and Vitamin B12 deficiency, and inflammation can contribute to the development of anemia. In the majority of ND-CKD patients, the etiology of anemia may be multifactorial; therefore, the treatment should be determined by documented causes of anemia. Thus, physicians managing ND-CKD patients should conduct a full anemia workup to determine its etiology and guide appropriate treatment decisions.
Conflict of interest: None declared.
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Department of Nephrology, Indira Gandhi Medical College, Shimla - 171 001, Himachal Pradesh
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]