To the best of our knowledge, our study is the first study to investigate the zinc level in whole blood in peritoneal dialysis patients in central area in China. Among studied patients, the average level of zinc in whole blood in PD patients is lower than that of healthy control were observed. Based on our findings, patients on chronic stable peritoneal dialysis with low level zinc in whole blood are prone to have decreased peritoneal dialysis efficiency as there is a negative correlation between zinc level and tKt/V. Furthermore, zinc concentration was negatively correlated with C-reactive protein, which is essential marker of inflammation. The ROC curve analysis showed that zinc level could be a diagnostic value as a biomarker with proper sensitivity and specificity. Our clinic study suggested that low zinc level in whole blood were associated with high risk of decreased peritoneal dialysis efficiency.
Although there is only 1% of total zinc existing in circulation, approximately 80% of the zinc is distributed in erythrocytes and 20% in serum. Most of previous studies evaluated the zinc level in either serum or plasma in CKD patients [18, 19], there is limited data revealing the statue of zinc in whole blood. Given ESKD patients prone to develop anemia, it is of great importance to reflect the accurate and true zinc homeostasis using samples from whole blood rather than in plasma or serum. Our present project first time uncovered the overall distribution and homeostasis of zinc in patients on PD. The result demonstrated that the zinc concentration in whole blood were significantly lower compared to the healthy population from the same region in where people having the diet habit in common, indicating that low level of zinc concentration in whole blood is prevalent among peritoneal patients in central area of China. Furthermore, previously published data revealed that there was no significant correlation between serum zinc and hemoglobin in hemodialysis patients, however, our study identified that there was a positive association between hemoglobin and zinc concentration in whole blood, implying that the hemoglobin level has an impact on zinc hemostasis in ESKD patient and suggesting that in future there should be more attentions on measuring zinc level in whole blood to evaluate the zinc status in this special population.
Several studies has already demonstrated that ESKD patients are prone to develop zinc deficiency due to various factors, including decreased food intake, uremic toxicity, increased loss through urine [19, 22–24]. One of the most essential factors which impact the zinc intake is diet habit. Seafood such as oyster and scallops were reported to known as food containing abundant zinc and are the main resource of zinc intake of human. The patients observed in our study inhabit the center part of China and seldom consume seafood mentioned above, which can partly explain the shortage of zinc intake. Furthermore, due to approximately 60–80% of serum zinc is bound to albumin, the amount of zinc might decrease not only because of the protein restriction and decreased absorption of zinc from the intestinal tract in ESKD patients, but also albumin being excreted via PD effluent fluid and protein urea. Our data are in accordance with previous studies suggesting that the zinc concentration in whole blood is significantly corelated with albumin level in PD patients . Furthermore, our study identified inverse negative correlation between zinc level and the albumin concentration in the PD effluent, indicating that the more albumin lost in the PD effluent the lower zinc concentration is. Moreover, there is significant negative correlation between zinc level and anuria, indicating that the less protein loss from urine the higher zinc concentration in whole blood. A similar relationship was also observed in the study in which Zn bound to albumin and globulin in spent CAPD fluid. Damianaki et.al reported that CKD patients had higher 24h urinary zinc excretion than non-CKD participants and impaired tubular activity account for zinc deficiency. However, some studies did not show the significant correlation between zinc loss and lower serum zinc levels. From clues mentioned above, our study further provided more evidences on the opinion that the losses of protein through peritoneal effluent and urea have impact on the zinc level in whole blood in patients on PD.
In recent decades emerging evidences demonstrated that there is a crosstalk between zinc and free fatty acid (FFA) including total cholesterol, LDL-Cholesterol and triglycerides[29, 30] and albumin mediate this crosstalk. This is due to the fact that binding site of zinc ion (Site A) and FFAs (FA2) both lie at the interface between domains I and domians II. Briefly speaking, Zn-Site A is only available in FFA-free albumin, but is disrupted when an FFA molecule occupies site FA2. Numerous intriguing interaction with regard to FFA-Zn crosstalk have been observed for energy metabolism and metabolic diseases[33, 34]. A statistically significant inverse correlation was found between zinc in whole blood and triglycerides but no significant relationships were found with LDL and total cholesterol. Nevertheless, the results of our study demonstrated that the total cholesterol positively correlated with tKt/V in PD patients. However, the mechanism underlying the crosstalk between FFA and zinc with regard to chronic kidney disease is unclear, implying more studies related should be conducted in future.
Inflammation is one of the major risk factors that contributes to the pathological process of PD ultrafiltration failure[35, 36]. Zinc plays an important role in regulating inflammation. Voelkl, Jet al demonstrated that zinc finger protein-TNFAIP3 is a suppressor of the NF-κB transcription factor pathway by inhibiting phosphorylation and degradation of IκB. Furthermore, another study reported that TNFAIP3 overexpression inhibits LPS induced NF-κB activation, TRAF6 and CD40 expression in rat peritoneal mesothelial cells. Some clinic investigations also showed that zinc supplements ameliorates TNFα,IL-1beta and Hs-CRP in hemodialysis patients. However, in those studies, no significant correlation was found of serum zinc levels with peritoneal dialysis adequacy[9, 40]. In this study we found that zinc levels in whole blood are significantly different between patients with high tKt/V patients and those with low tKt/V patients. Moreover, a moderate inverse association was found between zinc level in whole blood and C-reaction protein (CRP), indicating zinc deficiency is related with inflammation in long-term peritoneal dialysis patients and may result in chronic fibrosis of peritoneal membrane tissue. In addition, given the result of ROC analysis that compared with other risk factors such as albumin and cholesterol, zinc level in whole blood is the more proper biomarker to indicate the efficacy of peritoneal dialysis with higher specificity and sensitivity.
Several limitations in our study should be acknowledged. First of all, we could not evaluate the zinc intake from diet. Three-days dietary recall questionnaires were designed and supposed to evaluate nutrient intake among the PD patients, however, due to the Chinese diet habit of dining together, it is difficult to calculate the weight of food and then evaluate the zinc intake. In further more studies are required to access the zinc intake in patients and for developing strategies to improve nutrition status. Secondly, although our study measured the total amounts of albumin in PD effluent, the amount of zinc in PD effluent and urine were not measured due to the limited technique, therefore further investigations are required to access the loss of zinc particularly in PD patients and the association of the zinc loss via PD effluent and tKt/V is needed to be clarified. Last but not the least, our study could not observe the efficacy of zinc supplementation. A plethora of studies suggested that deficiency of the micronutrient zinc is also associated with CVD risk and overall mortality in CKD patients[12, 41]. Random clinical trials in multiple centers should be performed to further confirm the preliminary efficacy of zinc supplementation in patients on long-term dialysis with zinc deficiency.