Correlation of Serum Lead Levels with Inflammation, Nutritional Status, and Clinical Complications in Hemodialysis Patients

Abstract

The aim of this study was to determine blood lead level (BLL) in hemodialysis (HD) patients and their relation with high-sensitivity C-reactive protein (hsCRP) and albumin which are inflammatory and nutritional biomarkers, respectively, and clinical complications. A total of 93 patients, who were dialyzed at least for 3 months, were included in the study. Blood samples were collected before HD and BLL was measured and categorized as three equal groups: low normal (BLL < 8 μg/dL), middle normal (BLL = 8–10.6 μg/dL), and high normal (BLL > 10.6 μg/dL). All patients had normal BLL, 9.7 ± 3.4 g/dL. Patients with abnormal hsCRP level (>3 mg/L) had higher BLL than other patients (16.4 ± 0.8 vs. 11.5 ± 2.7 mg/L, p = 0.003). Patients with BLL > 10.6 μg/dL had significantly lower hemoglobin, ferritin, iron, and albumin levels and higher hsCRP and intact parathyroid hormone (iPTH) levels than the patients with BLL < 8 μg/dL. In addition, BLL revealed a significant positive correlation with duration of dialysis. We concluded that BLL associated to inflammation, malnutritional status, iron-deficiency condition, and high iPTH level in HD patients.

• lead
• hemodialysis patients
• hsCRP
• albumin
• ferritin

INTRODUCTION

Excessive blood lead level (BLL) could affect hematopoiesis and bone formation as well as the nervous and cardiovascular systems, and lead to hypertension, renal insufficiency, impaired cognitive function, abdominal pain, and peripheral neuropathy in general population.^{1– 12} In hemodialysis (HD) patients, BLL was increased when compared with subjects with normal renal function^13–16 and was related to increased risk for all-cause mortality, especially cardiovascular risk, in these patients.¹⁷

In addition, investigators found that mortality caused by cardiovascular diseases has a direct relation with high levels of high-sensitivity C-reactive protein (hsCRP).¹⁸ Serum hsCRP has a crucial role in immunomodulatory responses and assumed as hallmark of inflammation.^19,20 Moreover, previous studies showed that high level of C-reactive protein (CRP) is associated with decrease in plasma levels of albumin in HD patients.²¹ Lin et al. ²² found that BLL may contribute to inflammation (hsCRP level > 3 mg/dL) and malnutrition status (serum albumin level < 3.6 g/dL) in HD patients with diabetes and may be related to increased mortality in this population.

As lead mainly accumulate in red blood cells (RBCs), and patients with renal failure have a certain degree of anemia, correction for hemoglobin (Hb) should be considered to allow correct interpretation and comparison of literature data in this particular population.²³ Although previous studies suggested that BLL associated with Hb level, blood pressure (BP), and intact parathyroid hormone (iPTH) levels in HD patients,^15,16,24 the related variables were not adjusted and these results are questionable.

However, most mentioned associations were not investigated based on corrected BLL in all patients on maintenance HD. Therefore, in this study, we evaluated the concentration of BLL, which was corrected for Hb, and its relationship with serum level of hsCRP, albumin, and clinical complications in HD patients.

MATERIALS AND METHODS

This cross-sectional study was carried out on 102 patients suffering from chronic renal failure who were hemodialyzed at least for 3 months in two dialysis centers in Tehran. On the basis of examination and history, patients with age less than 18 years and suffered from inflammatory diseases, rheumatologic diseases, active infectious diseases, malignancy, a history of occupational exposure to heavy metals or metal intoxication, and those living in metal-contaminated areas were excluded from the study. The study included 93 patients, finally. All participants signed informed written consent.

All patients were hemodialyzed by the same apparatus and all samples were sent to an accredited laboratory. Demographic information, including age, gender, weight, height, and clinical examination, was collected by means of a questionnaire. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. BP at baseline was measured with the patient in a sitting position before HD. Patients’ blood samples were taken before the start of HD. The serum levels of hsCRP and ferritin were assessed by high-sensitive ELISA and electrochemiluminescence methods, respectively. Albumin and uric acid levels were assessed with colorimetric methods. All other markers were measured in standard laboratory procedures using an automatic analyzer. The Daugirdas formula (Kt/V) was used for determining the adequacy of dialysis. Serum calcium levels were corrected by serum albumin levels: Corrected calcium levels (mg/dL) = serum calcium levels + 0.8 × [4.0 – serum albumin (mg/dL)].

BLL was measured by lead analyzer using voltammeter method. BLL was corrected with Hb to prevent possible bias: Corrected BLL = initial lead level × 14/initial Hb level (g/dL) in males and initial lead level × 12/initial Hb level (g/dL) in females. Then, BLL was categorized into three equal groups: low normal (BLL < 8 μg/dL), middle normal (BLL = 8–10.6 μg/dL), and high normal (BLL > 10.6 μg/dL).

BLL association with patients’ characterizations, inflammation (hsCRP > 3 μg/mL), and malnutrition (albumin < 3.5 g/dL) states were investigated. SPSS 11.0 (SPSS Inc., Chicago, IL, USA) software was used for statistical analysis. Student’s t-test and the Mann–Whitney U-test were used for independent, normally and non-normally distributed, continuous variables, respectively. One-way analysis of variance was used when the grouping variable had more than two levels. Nominal variables were analyzed by means of chi-square test. Correlation between variables was evaluated by Pearson’s correlation analysis. Significance was defined at the level of p < 0.05.

RESULTS

The study included 93 patients (49 males and 44 females). The mean age was 56.4 ± 14.6 years. Mean of dialysis period in patients was 82 ± 67.7 months. Etiologies of renal failure were hypertension (n = 34, 36.6%), diabetes (n = 19, 20.4%), hypertension and diabetes (n = 13, 14.0%), polycystic kidney (n = 5, 5.4%), glomerulonephritis (n = 3, 3.2%), others (n = 14, 15.1%), and unknown (n = 5, 5.4%). Etiology and BLL had no significant correlation.

All patients had normal BLL, 9.7 ± 3.4 g/dL (range 4.5–18.7 g/dL). Table 1 lists the patients’ characteristics for the three BLL groups. The high normal BLL group had significantly lower RBC, Hb, mean corpuscular volume (MCV), ferritin, iron, total iron-binding capacity (TIBC), and albumin levels and higher hsCRP and iPTH levels than the low normal BLL group. Patients with abnormal hsCRP level (>3 mg/L), as an inflammation state, had higher BLL than other patients (16.4 ± 0.8 vs. 11.5 ± 2.7 mg/L, p = 0.003). There were no significant differences between BLL of patients with state of malnutrition (albumin < 3.5 g/dL) and other patients (1.1 ± 1.4 vs. 1.0 ± 0.6 g/dL, p = 0.894). However, serum level of hsCRP had negative correlation with serum albumin level (r = −0.366, p = 0.028).

Table 1. Baseline characteristics of renal failure patients on maintenance HD in three BLLs groups.

	Total	Low BLL group (<8 μg/dL) (n = 31)	Middle BLL group (8–10.6 μg/dL) (n = 31)	High BLL group (>10.6 μg/dL) (n = 31)	p-Value
Male sex	49 (52.7)	16 (51.6)	14 (45.2)	19 (61.3)	0.441
Age (y)	56.4 ± 14.6	59.7 ± 14.4	55.0 ± 15.8	54.4 ± 13.3	0.302
HD duration (month)	82.0 ± 67.7	71.5 ± 61.2	78.0 ± 67.9	96.1 ± 73.0	0.343
BMI (kg/m^2)	24.8 ± 4.7	23.7 ± 4.3	25.2 ± 4.9	25.6 ± 4.8	0.244
Systolic BP (mmHg)	139.9 ± 25.4	137.0 ± 23.8	142.8 ± 26.1	139.8 ± 26.7	0.679
Diastolic BP (mmHg)	85.7 ± 11.3	83.2 ± 14.5	87.0 ± 9.8	86.9 ± 8.9	0.329
RBC (×10 12/L)	3.8 ± 0.5	4.1 ± 0.4^a	3.7 ± 0.6	3.5 ± 0.5^a	0.010
Hb (g/dL)	10.7 ± 1.6	11.2 ± 1.4^b	10.9 ± 1.6	10.1 ± 1.6^b	0.022
MCV (fl)	91.6 ± 5.7	93.6 ± 6.5^c	91.8 ± 5.1	89.3 ± 5.5^c	0.041
Hematocrit (%)	31.9 ± 4.5	32.6 ± 5.4	32.8 ± 3.7	31.1 ± 4.6	0.406
Ca (mg/dL)	9.8 ± 1.0	9.6 ± 1.0	9.8 ± 1.0	10.1 ± 0.9	0.112
Phosphate (mg/dL)	7.2 ± 9.7	9.3 ± 16.8	6.0 ± 0.2	6.5 ± 1.2	0.357
Parathyroid hormone (pg/mL)	580.9 ± 720.7	334.4 ± 404.9^d	547.6 ± 682.4	860.6 ± 904.7^d	0.014
Iron (mg/L)	91.9 ± 77.3	114.1 ± 92.1^e	99.9 ± 86.9	60.5 ± 23.4^e	0.018
TIBC (mg/L)	297.8 ± 83.5	335.2 ± 76.9^f	288.9 ± 84.2	267.9 ± 76.9^f	0.004
Ferritin (μg/L)	716.5 ± 655.2	1006.6 ± 640.1^g	697.2 ± 758.4	445.9 ± 410.6^g	0.003
Uric acid	7.7 ± 1.6	7.5 ± 1.2	7.7 ± 1.7	7.9 ± 1.8	0.679
Albumin (g/dL)	4.3 ± 0.6	4.5 ± 0.7^h	4.2 ± 0.6	4.0 ± 0.5^h	0.004
hsCRP (mg/L)	1.1 ± 0.8	0.6 ± 0.4^i	1.0 ± 0.6	1.7 ± 1.4^i	0.017
Kt/V	1.4 ± 0.3	1.5 ± 0.4	1.4 ± 0.3	1.4 ± 0.3	0.619

Notes: BMI, body mass index; Hb, hemoglobin; HD, hemodialysis; hsCRP, high-sensitive C-reactive protein; MCV, mean corpuscular volume; RBC, red blood cell; TIBC, total iron-binding capacity.

^{a, b, c, d, e, f, g, h, i}p < 0.05.

*, n (%).

Table 2. Correlation of BLLs with patient characteristics and biochemical parameters in renal failure patients.

	BLLs, r
Age (y)	−0.150
HD duration (month)	0.254
BMI (kg/m^2)	0.263
Systolic BP (mmHg)	0.077
Diastolic BP (mmHg)	0.190
RBC (×10 12/L)	−0.451
Hb (g/dL)	−0.265
MCV (fl)	−0.375**
Hematocrit (%)	−0.078
Ca (mg/dL)	0.211
Phosphate (mg/dL)	0.038
Parathyroid hormone (pg/mL)	0.337**
Iron	−0.238
TIBC	−0.169
Ferritin (μg/L)	−0.424**
Uric acid	0.096
Albumin (g/dL)	−0.325**
hsCRP (mg/L)	0.283
Kt/V	−0.055

Notes: BMI, body mass index; Hb, hemoglobin; HD, hemodialysis; hsCRP, high-sensitive C-reactive protein; MCV, mean corpuscular volume; RBC, red blood cell; TIBC, total iron-binding capacity.

*p < 0.05.

**p < 0.01.

As shown in Table 2, the correlation study of elevated BLL revealed a significant positive correlation with duration of dialysis, hsCRP, and iPTH levels. Blood lead also showed a negative correlation with RBC, Hb, MCV, ferritin, iron, TIBC, and albumin levels.

Impaired cognitive function was found in 38 (40.9%) patients, abdominal pain in 24 (25.8%) patients, and peripheral neuropathy in 40 (43.0%) patients. There was no significant correlation between mentioned complications and BLL.

DISCUSSION

This study demonstrated that HD patients with high normal BLL had significantly higher hsCRP and iPTH levels and lower albumin, ferritin, iron, and Hb levels than patients with low normal BLL. In addition, patients with abnormal hsCRP level (>3 mg/L) had significantly higher BLL than other patients.

Although the mean BLL in the HD patients was in normal range (9.7 ± 3.4 g/dL), it was higher than that observed in the general population in Iran (3.5 ± 2.1 g/dL),²⁵ and was in agreement with those of previous studies performed in patients on maintenance HD.^{15,16,22,24,26} Since, there was positive correlation between BLL and duration of dialysis in this study, the elevated BLL in HD patients may be related to the problem in removing lead during HD.²² Therefore, environmental exposure to lead, even at low levels, may increase the BLL in these patients.

We found positive correlation between hsCRP, as an inflammatory marker, and BLL. In addition, HD patients with abnormal hsCRP (>3 mg/L) had higher BLL than other patients. Our results confirmed Lin et al.²² study on HD patients with diabetes. Although Khan et al.²⁷ reported that serum CRP levels were fourfold increased in the lead-exposed occupational workers compared with control group, a few studies are available on role of lead in causing inflammatory damage in human. Previous studies suggested that lead exposure may promote oxidative stress,^28–30 and overproduction of reactive oxygen species has been implicated in increased long-term complications, including accelerated inflammation and cardiovascular-cause mortality in HD patients.^{17,22,31–33} In consistent with Lin et al.,²² patients with greater BLL had lower levels of albumin, as nutritional marker, and there was negative correlation between hsCRP and albumin level. Hence, it seems that lead induced inflammation and other effects may influence the nutritional status of HD patients.²² However, further study is needed to confirm these results.

The study results showed that BLL was negatively correlated with serum ferritin, RBC, iron, Hb, and MCV in HD patients. Similar findings were seen in previous reports in the general population^34,35 and in HD patients.¹⁷ Lead could concern the hematological system by several mechanisms. For instance, chronic lead exposure causes damage to erythrocytes by lipid peroxidation;³⁶ lead may interfere with iron absorption in the gastrointestinal tract¹⁷ and impair Hb synthesis.³ In addition, the HD patients with high BLL had significantly greater iPTH level than those with low BLL, which may be associated to hyperparathyroidism-related osteitis fibrosa. Lin-Tan et al.³⁷ reported a correlation between BLL and bone lead contents. High iPTH level may cause lead stored in bone being released into the bloodstream and resulting in increased BLLs,²⁴ whereas the possibility of BLL influencing iPTH level cannot also be excluded.

Although previous studies on general population reported that lead toxicity may present nonspecific symptoms including impaired cognitive function, abdominal pain, and peripheral neuropathy,^{1–4,10–12,38,39} we found no significant correlation between these complications and BLL in HD patients, may be due to small sample size, as limitations of this study.

We concluded that blood lead can involve in occurring anemia, inflammation, and malnutrition in HD patients. Therefore, we suggest evaluating BLL for these patients. In addition, future studies are needed to determine the impact of changing modality of dialysis, membrane of device and water, etc. on BLL.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.