We found that hemodialysis patients appear to have lower levels of zinc and selenium than people in the general population. Zinc deficiency is a leading cause of disease in developing countries , and is associated with delayed wound healing , and immune deficiency characterized by impaired cell proliferation, abnormal T-cell function, defective phagocytosis, and abnormal cytokine expression [150, 151], all of which might contribute to the excess risk of infection observed in hemodialysis patients [152–157]. Zinc deficiency may also cause or contribute to a number of relatively non-specific conditions commonly observed in hemodialysis patients, including anorexia , dysgeusia , and impaired cognitive function .
Although the biological significance of low blood selenium concentrations is less clear, severe selenium deficiency leads to sudden death and cardiomyopathy in the general population [6, 7, 161]. Lower levels of serum selenium without severe deficiency have been associated with hypertension , heart failure [163, 164], and coronary disease  in the general population, and with cardiomyopathy among dialysis patients [1, 166, 167]. Finally, mild selenium deficiency appears to increase susceptibility to oxidant stress [168, 169], which may be relevant to hemodialysis patients in whom oxidative stress is markedly increased [170–172].
In addition to the lower levels of selenium and zinc, hemodialysis patients seem to have higher average levels of certain trace elements compared with healthy controls. It was not possible to compare absolute levels of trace elements across studies (given the different techniques and specimens), and therefore we could not estimate the proportion of hemodialysis patients who have trace element levels in the toxic range. However, for many of the elements, the SMD for the differences between hemodialysis patients and controls exceeded 0.8 SD, which is considered to be a large between-group effect by authorities .
For most of the trace elements studied, the biological significance of higher blood levels is unclear. However, excessive levels of lead or arsenic in blood and other tissues are known to be potentially harmful. For example, minor elevations in whole blood lead levels are associated with impaired cognitive function [173, 174], impaired hemoglobin synthesis, and hypertension [175, 176]. Cerebrovascular disease and renal insufficiency [177–179] also appear to be more frequent at higher levels of blood lead, perhaps mediated by higher blood pressure. Thus, higher blood levels of lead may increase the risk of cardiovascular disease, although the mechanism remains unclear. Similarly, inorganic arsenic causes tissue damage by multiple mechanisms including oxidative injury [180, 181], inhibition of DNA repair , and chromosomal damage (deletion, aneuploidy ), and higher levels of arsenic are associated with increased risk of peripheral vascular disease [184, 185]. Animal studies suggest that low selenium status may predispose to arsenic toxicity , and underweight or malnourished humans may also be at increased risk , suggesting that hemodialysis patients may be at higher than average risk of arsenic toxicity.
Implications of the findings
Although the concentration of some trace elements in hemodialysis source water is monitored annually in accordance with federal regulation , blood or body levels of these substances are rarely (if ever) measured in hemodialysis patients. The potential for the accumulation of trace elements to cause harm in hemodialysis patients is exemplified by aluminum. Aluminum toxicity led to serious toxicity (anemia, disabling encephalopathy, neuropathy and severe symptomatic bone disease) in dialysis patients prior to the recognition that aluminum in dialysate and oral medications was responsible [189–193]. It is difficult to overstate the importance of this discovery for nephrology practice, which led to the elimination of aluminum-related toxicity (and substantial improvements in patient outcomes) within a few years. Today, clinically obvious toxicity due to accumulation of aluminum is exceedingly rare in hemodialysis patients, and the existing regulation  has been remarkably effective at reducing the risk of acute toxicity from excess trace elements such as fluorine [194–196]. However, the possibility that other trace elements may accumulate in patients with kidney failure and cause unrecognized chronic toxicity has received surprisingly little attention.
Oral trace element supplements are readily available, and oral zinc and selenium preparations have been shown to increase blood levels of these elements in dialysis patients [197–200]. However, few data describe the impact of trace element supplementation on clinical outcomes in hemodialysis patients, despite the fact that correction of zinc deficiency is beneficial in the general population [5, 201–204], including significantly reducing the risk of infection and all-cause death [205–211]. Data examining the relation between trace element status and clinical outcomes in hemodialysis patients are similarly scarce. One relatively small (N = 265) study published in the Lithuanian language shows a significant association between lower plasma zinc levels and the risk of infection . Our data suggest that future studies should investigate the link between zinc or selenium status and clinical outcomes in dialysis patients, in whom the risk of infection is dramatically elevated compared with people with normal kidney function [152–157].
The available literature has several potentially important limitations. First, study quality was moderate to poor, and many of the studies were relatively small. Second, the available data include multiple different analytical techniques, study populations, control groups, and specimen types (whole blood, serum, plasma). Perhaps for this reason, there was substantial between-study heterogeneity in the results, meaning that the extent to which trace element levels are higher or lower in hemodialysis patients cannot be estimated with certainty. We were unable to identify statistical sources of this heterogeneity, perhaps because we only had access to study-level (rather than patient-level) data. Despite the heterogeneity, for several of the elements studied, the great majority of studies found differences between hemodialysis patients and controls. Since the same technique and specimen types were used for both patients and controls, it is unlikely that these differences are spurious. However, it remains possible that important differences exist for other substances known or suspected to influence health. Third, studies generally did not report data on dietary intake of trace elements and thus we cannot assess whether reduced consumption of foods containing zinc and selenium was responsible for the lower levels of these elements among hemodialysis patients. Fourth, although we found large differences between the blood levels of certain trace elements in hemodialysis patients and those in control participants, the clinical significance of this finding remains to be confirmed. Fifth, although we studied blood levels of trace elements, it is possible that bone or other compartments may better reflect trace element body status, especially for heavy metals such as lead . Sixth, although simultaneous derangement of multiple trace elements (for example, low selenium and excess arsenic) may have synergistic toxicity , the nature of the available data precluded us from determining how frequently this occurs in hemodialysis patients. Finally, although all systematic reviews have potential limitations, we conducted and reported this analysis according to published guidelines aimed at reducing bias . Nonetheless, as with all systematic reviews, the strength of our conclusions is influenced by the quality of the studies on which they are based.