This present study demonstrated that lower baseline PTH levels were associated with a greater risk of peritonitis. The overall incidence rate of peritonitis was nearly 1.6-fold greater in PD patients with low PTH levels than in the comparison cohort. In addition, low PTH levels were significantly associated with older age, high serum calcium levels and low alkaline phosphatase levels. To the best of our knowledge, we report for the first time that low PTH levels can be a potential predictor of peritonitis in PD patients.
In this cohort of PD patients over a 7-year follow-up, the prevalence of low PTH (<150pg/mL) levels was 28.9%, which was similar to that reported from the Dialysis Outcomes and Practice Patterns Study (DOPPS) that was undertaken in the United States in which 29% patients had PTH levels of <100pg/mL [18], and the United Kingdom Renal Registry (UKRR) study in which 32% of the patients had PTH levels of <150pg/mL [19]. In dialysis patients, low PTH levels play a vital role in influencing immunologic dysfunction for infectious diseases. PD patients have high infection rate due to the continuous peritoneal exposure to peritoneal dialysate and PD catheter [20]. In a recent study, Hong et al [9] suggested that low PTH levels were risk factors of infection-related mortality in a cohort of 1771 incident dialysis patients, including 511 PD patients. Our study expanded the previous findings of the associations of PTH levels with infection-related diseases in PD patients. This study focused on the incidence of PD-related peritonitis, which was the most common and fatal infection-related implication of PD. A recent cohort study covering 1321 PD patients demonstrated that peritonitis was independently associated with near 2-fold increased risk of all-cause mortality and near 4-fold increased risk of infection-related mortality [21]. The results of the present study suggested that PD patients with lowest PTH levels had the highest incidence rates of peritonitis, and patients with highest PTH levels had the lowest incidence rates of peritonitis, which were in accordance with the associations of infectious mortality in the previous study.
The pathophysiologic mechanisms, how low PTH levels increase the susceptibility of peritonitis incidence in PD patients, are not still well explained. However, some explanations can be proposed.
On the one hand, the impairment of the immune system in PD patients leads to an increased incidence of infections, and PTH plays an important role in the long-term immunodeficient and inflammation state, which is the main contributor to the peritonitis episodes [22]. Previous studies in vitro and in vivo verified that PTH can stimulate the proliferation of T lymphocytes, due to its ability to augment the movement of calcium into its target cells and enhance the production of interleukin-2 [23]. Conversely, inflammation can induce the inhibition of the hormone through proinflammatory cytokines, including interleukin-1 and interleukin-6 [24,25]. Inactivation of PTH will abolish its effects on T cells. Ozdemir et al [26] observed that low PTH levels were associated with an inadequate suppression of inflammation through impairing humoral and cellular immune response [27]. Low PTH levels have been demonstrated to be a predictor of chronic inflammation in CKD patients, especially with maintenance dialysis. A study of 748 dialysis patients implicated that PTH<150pg/mL was associated with elevated inflammatory markers, including tumor necrosis factor α and C-reactive protein, which were traditional evaluated parameters for peritonitis [8]. In this study, C-reactive protein levels in low-PTH group were highest among three groups, though without statistical significance. Meanwhile, low PTH levels were associated with advanced age, likely to be diabetic in this study, which can reflect clinical susceptibility to infection.
Vitamin D deficiency, a common metabolic disturbance among PD patients [28], has been found to be independently predictive of increased risk of peritonitis in PD patients [29], due to its contribution to microinflammation and a defective immune system. Some previous studies also demonstrated that oral active vitamin D therapy was associated with a reduced risk of peritonitis through the improvement of the bactericidal response. Kerschbaum et al [30] found that a 57% risk of peritonitis could be decreased by treatment with oral active vitamin D at a multivariate analysis from 726 PD patients. This study just collected the vitamin D therapy at the initiation of PD, but not the adjustment of vitamin D therapy during the PD duration. Therefore, there is no similar finding above in this study. The association between the variation of PTH levels, vitamin D therapy and peritonitis episodes need more studies searched.
On the other hand, low PTH levels can reflect a poor nutritional state, which will decline immunity and resistance to pathogens. Low immunity provides survival environment for conditional bacteria, inducing the episodes of peritonitis. As previous studies, we observed that patients with low PTH levels (<150pg/mL) had worse nutritional status including advanced age, diabetes mellitus, low serum creatinine, and phosphorus levels [31]. Inflammatory cytokines will increase due to immunodeficient status, and suppress PTH secretion further in a vicious circle. Fukagawa et al [6] demonstrated that low PTH levels reflected a state of malnutrition in dialysis patients. Dukkipati et al [8] advanced that low PTH levels might be a facet of the MICS, which per se was associated with chronic inflammation. In the foregoing study, patients with PTH<150pg/mL had higher malnutrition-inflammation score, a constellation of markers of malnutrition and inflammation, and the inflammation-induced suppression of PTH can be overcome by treatment of MICS. PD-related peritonitis may be the consequence of MICS. Meanwhile, low PTH levels were a predictor of protein-energy wasting, which also shared similar risk factors of inflammation in PD patients [4].
In addition, the interaction of microbiome with renal function is known as the gut-kidney axis. Uremic toxins originated by gut microbiota also affect the composition of gut microbiota and involve in inflammation state in dialysis patients [32]. Su et al [33] demonstrated that intestinal symptoms were associated with increased risk for enteric peritonitis episodes. Mirzaeian et al [34] assessed the effect of synbiotics in dialysis patients, which could improve intestinal environment and decrease intestinal concentration of nitrogenous metabolites. They identified that synbiotic therapy reduced inflammation and renal insufficiency, along with a parallel increase of PTH levels. In this study, we found that the predominant causative organism of peritonitis patients with low PTH levels was Gram-negative organism, especially Esherichia coli. It means that PD patients with low PTH levels may be especially vulnerable to peritonitis of enteric origin. We speculated the association of low PTH and impaired gut environment. Low PTH levels usually imply diet restriction in dialysis patients, aggravating the intestinal flora imbalance. As a result, increased bacterial translocation from the intestinal lumen into the peritoneal cavity provokes peritonitis of enteric origin [35]. To clarify this mechanism, further studies are needed.
The strengths of our study include its examination of a relatively large cohort of incident PD patients. And, we demonstrated the relationship between PTH and incidence of peritonitis in PD patients.
However, several limitations of our study should be discussed. First, the present findings were observational in nature, which precluded conclusions concerning causality. Second, the study population was restricted to patients in a single PD center of southwest China, which might limit the generalizability of the results to other ethnic groups. Third, we did not assess other biochemical markers related to CKD-MBD, such as fibroblast growth factor-23, vitamin D metabolities. Forth, we did lack the information of the prognosis of peritonitis episodes. Fifth, we lacked the information of the non-PD associated infections and responding antibiotic therapies during our observation period.