As is well known, four ALP isozymes are expressed in humans: tissue-nonspecific ALP, intestinal ALP(IALP), placental ALP and germ cell ALP. Serum ALP mainly includes bone specific ALP and hepatogenic ALP, with an activity ratio of approximately 1:1, comprising more than 90% of the total. The remaining circulating ALP activity, 1–10%, is attributed mostly to IALP, which appear frequently in dialysis patients. It should be kept in mind for nephrologists and with the increases in the detectability of the intestinal type, we can explore serum ALP more accurately. Osteogenic ALP (BALP) is a glycoprotein secreted by osteoblasts. The serum BALP level can reflect the activity of osteoblasts, and its main physiological function is to promote the occurrence of calcification in the body, including bone and cartilage calcification, as well as soft tissues calcification such as blood vessels, tendons, and ligaments. Elevated serum ALP caused by hepatogenic diseases is often accompanied by other liver enzyme abnormalities. In the absence of liver disease, the increase in serum total ALP levels is mainly caused by an increase in BALP. In this situation serum total ALP can be used as a prognostic indicator for a range of illnesses. In the last two decades, many studies have revealed that serum total ALP level are associated with cardiovascular events and all-cause mortality, whether in the general population, non-dialysis CKD population, hemodialysis population, or peritoneal dialysis population8,9,10,11. Therefore, researchers pay more attention to serum total ALP and even explored it as a target for drug therapy recently12. In addition, in CKD patients, serum ALP raising also indicates renal osteodystrophy occurrence, and can be used to diagnose the type of renal bone disease, especially combined with serum iPTH, to predict the risk of fracture and mortality. So nephrology doctors pay more and more attention to serum ALP levels and make a large number of researches about it13,14. But most of these studies were based on cross-sectional serum ALP values, and it is unclear whether serum ALP changes gradually over time or not and what the pattern of change trend is. Our study investigated serum ALP change trend over time by utilizing repeated measurement data and the influencing factors of serum ALP in peritoneal dialysis patients.
This study observed the change trend of serum ALP over time, and the results indicated that during the 30-month follow-up period, the serum ALP values measured every 3 months gradually increased with time, but were non-linear, and the increase rate decelerated in the later stage. The variations of serum ALP over time was statistically significant. This suggested that if someone want to study the clinical significance of serum ALP in peritoneal dialysis patients, especially cross-sectional studies or prognostic studies that rely on cross-sectional values, Attention needed to be paid to the dialysis stage where the measurement point was located. Previous studies have showed that serum ALP rose with increasing dialysis vintage15. So we thought the increase of serum ALP values over time may be partially attributed to the accumulation of dialysis vintage, that is, as dialysis duration prolongs, CKD-MBD gradually progresses and soft tissue calcification also occurs. In addition, because more than two-thirds of the selected patients in our study were newly enrolled in peritoneal dialysis, the change trend also reflects the development trend of CKD-MBD, which was faster in the early stage and slower in the later stage. After adjusting for the variable of time, we found no significant difference in serum ALP levels between male and female patients, and the change trend over time between them had no difference. This finding was inconsistent with previous research conducted in general populations which revealed that serum ALP levels increase more rapidly among women over 40 years old16. However, in patients with diabetes nephropathy as the primary disease, serum ALP concentration increased faster over time than those without diabetes nephropathy. And there were no significant differences in terms of age, gender ratio, dialysis duration, or dialysis adequacy between the diabetes nephropathy group and the non-diabetes nephropathy group (shown in supplement 1). It is plausible that patients with diabetes nephropathy are more prone to CKD-MBD, particularly ectopic calcification, which is linked to the micro-inflammatory state and insulin resistance common in diabetic patients. Recent investigations have also demonstrated that serum ALP levels are associated with the development of diabetes in the general population, and high ALP levels serve as independent risk factors for poor prognosis in diabetes nephropathy17. Therefore, serum ALP should be closely monitored in diabetic patients undergoing peritoneal dialysis.
Then we explored the factors that may have impact on serum ALP levels utilizing longitudinal measurement data and GEE analysis. Our findings revealed that dialysis vintage emerged as an independent risk factor for an increase in serum ALP levels. As the duration of dialysis prolonged, the concentration of serum ALP rose, which was consistent with previous studies18. Other factors that may affect serum ALP level, such as age, gender, total Kt/V, creatinine, albumin, etc., were also included in the equation, and the results shown that a positive correlation between blood hemoglobin and serum ALP. Previous studies have hinted that higher serum ALP level may indicate better nutritional state among non-CKD patients with higher hemoglobin levels19. Another study observed a positive correlation between serum ALP and serum albumin among peritoneal dialysis patients with residual kidney function20. These findings suggested that serum ALP levels could serve as an indicator of nutritional status in specific peritoneal dialysis populations at particular time points. Notably, two-thirds of our study participants were newly initiated on peritoneal dialysis, suggesting that serum ALP levels in this subgroup may be linked to nutritional status. Specifically, individuals with higher ALP levels exhibited higher hemoglobin levels. However, our study also indicated that serum corrected calcium, blood phosphorus, iPTH, and blood 25 (OH) D all were not predictive factors for serum ALP levels in peritoneal dialysis patients. Researchers had made great effort to clarify the association between the above indicators in previous cross-sectional and prognostic studies, but the results were controversial. Some studies found that the group with elevated serum ALP had lower levels of serum phosphorus and calcium4,6, while others found that the group with higher serum ALP has higher levels of blood calcium21 or a higher incidence of hyperphosphatemia15. These inconsistent findings may attribute to the varying serum calcium and phosphorus levels and diverse therapeutic drugs in different clinical studies. Past most studies suggested a positive correlation between serum ALP and iPTH4,6,15,18, while others had the opposite conclusions21. In our study, we did not find that serum iPTH levels had impact on serum ALP concentrations, which may be attributed to the fact that most patients in our cohort were newly initiated on dialysis, typically having low serum iPTH levels, and only a minority received calcium mimetic agents to reduce iPTH. In addition, the study revealed that serum 25 (OH) D was not a predictive factor for serum ALP levels. In this study, serum 25 (OH) concentrations were generally low and did not exhibit significant temporal variations. Several researches have similarly found that the serum 25 (OH) D levels were low in the high ALP group, which may be due to inflammatory status19.In summary, the interplay between CKD-MBD indicators is complex and the studies findings about the relationship were inconsistent due to different dialysis stages and clinical interventions. Our study primarily focused on newly entered peritoneal dialysis patients, with diabetes nephropathy as the primary diagnosis. Their serum calcium and phosphorus levels were mostly managed to recommended ranges, serum iPTH and 25(OH)D concentrations were predominantly low, and most total Kt/V were up to recommended standards. On above conditions, the serum ALP values increased over the dialysis duration, though the trend was not linear, being more rapid in the early stage and slower in late stage during the 30-month follow-up. Dialysis duration emerged as an independent influencing factor, positively correlated with serum ALP.
Next, we investigated the impact of serum ALP on calcium and phosphorus metabolism. Our findings revealed that in clinical real world where drugs and treatment were often utilized to maintain serum calcium, phosphorus and the whole parathyroid gland levels up to recommended values, after accounting for other confounding factors, the serum ALP level exhibited no significant influence on the serum adjusted calcium, phosphorus and iPTH concentrations. This underscored the intricate nature of mineral and bone metabolism abnormalities in peritoneal dialysis patients, along with the independence of serum ALP as a biomarker. Serum ALP levels not only reflect calcium and phosphorus metabolism, but also nutrition condition, inflammation status, and cardiovascular complications.
The novelty of this study lies in utilizing repeated measurement data derived from long-term follow-up in peritoneal dialysis patients to examine the change patterns of serum ALP over time and the factors influencing its levels, which have been scarcely in previous research. The clinical significance of the study lies in the longitudinal observation of serum ALP in peritoneal dialysis patients, producing more comprehensive characteristics of this biomarker and serving as a reference for future therapeutic interventions. However, it is noteworthy that the study was limited by the relatively small sample size and potential heterogeneity among participants, comprising both newly initiated and long-term maintenance dialysis patients. As such, more subjects and a stratified design are needed for further research.
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- Source: https://www.nature.com/articles/s41598-024-63721-5