Correlation of hypercalcemia with kidney stone formation and calcium-regulating hormone changes in patients with acute pancreatitis

Abstract

BACKGROUND

Acute pancreatitis (AP) is a severe inflammatory condition of the pancreas that leads to significant morbidity and metabolic disturbances. Hypercalcemia, or elevated serum calcium levels, is a concerning complication that may contribute to kidney stone formation and exacerbate renal issues. Calcium homeostasis is regulated by hormones, such as parathyroid hormone (PTH), calcitonin, and vitamin D, which can be altered in AP. Understanding the interplay among hypercalcemia, kidney stones, and hormonal changes is crucial for improving management strategies and clinical outcomes in patients with AP.

AIM

To investigate the relationship between hypercalcemia and kidney stone formation in patients with AP, along with changes in calcium-regulating hormone levels.

METHODS

This study was conducted in 200 patients diagnosed with AP at Ningbo Urology and Nephrology Hospital. The participants underwent regular monitoring of serum calcium levels and kidney stone formation using imaging. Additionally, blood samples were analyzed to measure the levels of calcium-regulating hormones, including PTH, calcitonin, and vitamin D, at baseline and during the course of the disease.

RESULTS

Of the 185 patients who completed the study, 31 (16.8%) developed kidney stones during the 7-day follow-up period. Hypercalcemia occurred in 53 patients (28.6%), with a peak incidence on day 3. Among hypercalcemic patients, 41.5% developed kidney stones compared to 6.8% in normocalcemic patients (odds ratio = 9.67, 95% confidence interval: 4.12-22.68, P < 0.001). A significant positive correlation was found between hypercalcemia and kidney stone formation (P < 0.001). Elevated PTH levels were noted in 60% of the patients with hypercalcemia, indicating a strong association between increased PTH levels, hypercalcemia, and kidney stone formation.

CONCLUSION

This study highlights the complex interplay between AP, calcium metabolism, and renal complications, providing insights that may guide future therapeutic strategies.

Key Words: Acute pancreatitis; Hypercalcemia; Kidney stones; Calcium-regulating hormones; Parathyroid hormone; Metabolic disturbance

Core Tip: This study aimed to examine the relationship between hypercalcemia and kidney stone formation in patients with acute pancreatitis. Of the 200 patients, 35% developed kidney stones, with a significant correlation between hypercalcemia and stone formation (P < 0.001). Notably, elevated parathyroid hormone levels were observed in 60% of patients with hypercalcemia, underscoring the complex interactions between calcium metabolism and renal complications in acute pancreatitis. Understanding these relationships is essential for enhancing management strategies and improving clinical outcomes.

INTRODUCTION

Acute pancreatitis (AP) is a sudden inflammatory condition of the pancreas that can range from a mild self-limiting disease to severe and potentially fatal illness. AP is characterized by the activation of pancreatic enzymes within the gland, leading to auto-digestion and inflammation[1]. While the primary focus of AP management is often on pancreatic complications, metabolic disturbances, particularly those involving calcium homeostasis, can significantly affect patient outcomes.

Hypercalcemia, an elevated level of calcium in the blood, has been observed in a subset of patients with AP[2]. The exact mechanisms underlying this association are not fully understood; however, they are thought to involve a complex interplay among inflammatory mediators, hormonal changes, and altered calcium metabolism. Hypercalcemia can lead to various complications, including neurological symptoms, cardiac arrhythmias, and renal problems[3].

One potential consequence of hypercalcemia, which is of particular interest in the context of AP, is an increased risk of kidney stone formation. Kidney stones or nephrolithiasis are solid concretions formed within the kidneys and are often composed of calcium-based compounds. The formation of kidney stones can lead to significant morbidity, including severe pain, urinary tract infections, and potential kidney damage[4]. The relationship among AP, hypercalcemia, and kidney stone formation is complex and multifaceted, warranting further investigation to elucidate the underlying mechanisms and potential clinical implications.

Calcium homeostasis in the body is primarily controlled by three hormones: Parathyroid hormone (PTH), calcitonin, and vitamin D. These hormones work in concert to maintain serum calcium levels within a narrow physiological range. PTHs increase serum calcium levels by promoting bone resorption, increasing calcium reabsorption in the kidneys, and enhancing vitamin D activation. In contrast, calcitonin lowers serum calcium levels by inhibiting bone resorption and promoting calcium excretion. Vitamin D, particularly its active form 1,25-dihydroxyvitamin D3, increases calcium absorption in the intestine and promotes bone mineralization[5].

In AP, the delicate balance of these calcium-regulating hormones (CRHs) may be disrupted. Inflammation and tissue damage affect the production, secretion, and activity of these hormones, leading to alterations in calcium homeostasis. Understanding these changes and their relationship with hypercalcemia and kidney stone formation in patients with AP is crucial for developing targeted therapeutic strategies and improving patient outcomes. The inflammatory process in AP leads to the release of various cytokines and mediators, which may directly or indirectly affect the calcium metabolism. For instance, elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in AP have been shown to influence bone resorption and calcium homeostasis[6]. In addition, extensive tissue damage in severe AP can result in the release of intracellular calcium stores, potentially contributing to systemic hypercalcemia[7].

Despite its potential clinical significance, there is a paucity of comprehensive studies examining the relationships among hypercalcemia, kidney stone formation, and CRH levels in patients with AP. This knowledge gap presents an opportunity for research that could significantly affect the management of patients with AP and potentially reduce the incidence of renal complications. This study aimed to address this knowledge gap by investigating the correlation between hypercalcemia and kidney stone formation in patients with AP and examining changes in CRH levels throughout the course of the disease. By elucidating these relationships, we hope to provide a more comprehensive understanding of metabolic disturbances in AP and pave the way for improved patient care and outcomes.

MATERIALS AND METHODS

Study design and participants

This study was conducted at Ningbo Urology and Nephrology Hospital in China from January 2020 to January 2022. The study protocol was approved by the Institutional Ethics Committee of Ningbo Urology and Nephrology hospital and written informed consent was obtained from all participants or their legal representatives. Two hundred patients diagnosed with AP were enrolled in this study. The diagnosis of AP was based on the revised Atlanta classification[1], which requires at least two of the following three features: (1) Abdominal pain characteristic of AP; (2) Serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal; and (3) Characteristic findings of AP on contrast-enhanced computed tomography (CECT) or, less commonly, magnetic resonance imaging or transabdominal ultrasonography. The exclusion criteria were as follows: (1) Age < 18 years; (2) Chronic pancreatitis; (3) Pancreatic cancer; (4) Preexisting kidney stones; (5) Primary hyperparathyroidism; (6) Malignancy-associated hypercalcemia; (7) Vitamin D intoxication; (8) Chronic kidney disease stage 3 or higher; and (9) Pregnancy. These criteria were carefully selected to minimize the confounding factors that could independently affect calcium metabolism or kidney stone formation.

Data collection

Demographic data, medical history, and clinical characteristics of the patients were recorded upon admission. The etiology of AP was determined based on clinical, laboratory, and imaging findings. Common etiologies include gallstone-related, alcohol-induced, hypertriglyceridemia-associated, and idiopathic AP. AP severity was assessed using the revised Atlanta classification[1] and the Acute Physiology and Chronic Health Evaluation II score[8]. The Acute Physiology and Chronic Health Evaluation II scoring system consists of three major dimensions: (1) An acute physiology score based on 12 physiological variables; (2) Age points; and (3) Chronic health points for patients with severe organ system insufficiency or an immunocompromised status. The total score ranged from 0 to 71, with higher scores indicating greater disease severity.

The patients were closely monitored throughout their hospital stay, with particular attention paid to the development of local and systemic complications of AP. Local complications, such as peripancreatic fluid collection and pancreatic necrosis, were documented based on imaging studies. Systemic complications, including organ failure (respiratory, cardiovascular, or renal), were assessed daily using standardized criteria. According to the revised Atlanta classification, the severity of AP was stratified as follows: Mild AP, no organ failure, and no local or systemic complications. Moderately severe AP: Transient organ failure (resolving within 48 hours) and/or local or systemic complications without persistent organ failure. Severe AP: Persistent organ failure (> 48 hours) involving one or more organs (cardiovascular, respiratory, or renal systems).

Laboratory measurements

Blood samples were collected on admission (day 0) and on days 1, 3, 5, and 7 of hospitalization. The following parameters were measured: (1) Serum total calcium and ionized calcium; (2) Serum phosphate; (3) Serum albumin; (4) PTH; (5) Calcitonin; (6) 25-hydroxyvitamin D; (7) 1,25-dihydroxyvitamin D; (8) Serum creatinine; and (9) Serum amylase and lipase. Serum total calcium levels were adjusted for albumin using the following formula: Corrected calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 × [4.0 - serum albumin (g/dL)]. Hypercalcemia was defined as a corrected serum calcium level > 10.5 mg/dL or an ionized calcium level > 5.6 mg/dL. All laboratory measurements were performed using standardized techniques in the central laboratory of the hospital. PTH levels were measured using a chemiluminescent immunoassay, and vitamin D metabolites were quantified using liquid chromatography-tandem mass spectrometry. Calcitonin levels were determined by using a highly sensitive immunoradiometric assay.

Imaging studies

All patients underwent abdominal CECT upon admission and on day 7 or earlier, if clinically indicated. CECT was performed using a standardized pancreatic protocol that included both arterial- and venous-phase imaging. The scans were evaluated by experienced radiologists who were blinded to the patients’ clinical and laboratory data. The extent of pancreatic inflammation, presence of necrosis, and development of local complications were assessed and documented.

Renal ultrasonography was performed on admission and on days 3 and 7 to assess the presence of kidney stones. Trained sonographers conducted the ultrasound examinations, which were interpreted by radiologists blinded to the patients’ clinical and laboratory data. Kidney stones were defined as echogenic foci of > 2 mm in size with posterior acoustic shadowing. The size, number, and location of the detected stones were recorded. Additional imaging studies, such as magnetic resonance cholangiopancreatography or endoscopic ultrasound, were performed as needed for clinical management, particularly in cases where the etiology of AP was unclear or complications were suspected.

Statistical analysis

All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, United States). Continuous variables were expressed as mean ± SD or median with interquartile range, depending on the distribution of data. Categorical variables are expressed as n (%). The correlation between hypercalcemia and kidney stone formation was assessed using the χ² test and logistic regression analysis. Changes in CRH levels over time were analyzed using repeated-measures analysis ANOVA or Friedman’s test, as appropriate. Multivariate logistic regression analysis was performed to identify the independent predictors of kidney stone formation, including hypercalcemia, CRH levels, and other relevant clinical and laboratory parameters. A P value < 0.05 was considered statistically significant for all analyses.

RESULTS

Patient characteristics

Of the 200 patients enrolled in the study, 185 completed the full 7-day follow-up period and were included in the final analysis. Fifteen patients were excluded because of early discharge (n = 8), transfer to other facilities (n = 4), or withdrawal of consent (n = 3). The baseline characteristics of the study population are shown in Table 1.

Table 1 Baseline characteristics of study participants, n (%)/median (interquartile range).

Characteristic	Value
Age (years), mean ± SD	52.3 ± 15.7
Sex
Male	112 (60.5)
Female	73 (39.5)
Etiology of AP
Gallstone	98 (53.0)
Alcohol	52 (28.1)
Hypertriglyceridemia	18 (9.7)
Idiopathic	12 (6.5)
Other	5 (2.7)
Severity of AP (revised Atlanta classification)
Mild	119 (64.3)
Moderately severe	48 (25.9)
Severe	18 (9.8)
APACHE II score at admission	8 (5-12)
Serum amylase (U/L)	875 (450-1680)
Serum lipase (U/L)	1250 (680-2450)

AP: Acute pancreatitis; APACHE II: Acute Physiology and Chronic Health Evaluation II.

Incidence of hypercalcemia and kidney stone formation

Over the course of the study period, 53 patients (28.6%) developed hypercalcemia. The incidence of hypercalcemia was the highest on day 3 (22.7%) and gradually decreased thereafter. Kidney stone formation was observed in 31 (16.8%) patients during the 7-day follow-up period.

Correlation between hypercalcemia and kidney stone formation

A significant positive correlation was found between the occurrence of hypercalcemia and kidney stone formation (χ² = 28.5, P < 0.001). Among the patients who developed hypercalcemia, 22 (41.5%) had kidney stones, compared to only nine (6.8%) without hypercalcemia. The odds ratio (OR) for kidney stone formation in patients with hypercalcemia was 9.67 [95% confidence interval (CI): 4.12-22.68, P < 0.001].

Changes in CRH levels

Significant changes were observed in the levels of the CRHs during the course of the study (Table 2). PTH levels showed the most pronounced changes, with a peak on day 3, followed by a gradual decline. Calcitonin levels followed a similar pattern, whereas changes in vitamin D metabolites were less pronounced, but still significant.

Table 2 Changes in calcium-regulating hormone levels, mean ± SD.

Hormone	Day 0	Day 1	Day 3	Day 5	Day 7	P value1
PTH (pg/mL)	38.5 ± 15.2	52.7 ± 22.3	68.9 ± 30.1	59.4 ± 25.8	47.2 ± 18.6	< 0.001
Calcitonin (pg/mL)	5.2 ± 2.1	7.8 ± 3.5	9.1 ± 4.2	7.5 ± 3.3	6.1 ± 2.5	< 0.001
25(OH)D (ng/mL)	22.7 ± 8.9	21.5 ± 8.3	19.8 ± 7.6	20.3 ± 7.9	21.9 ± 8.5	0.032
1,25(OH)2D (pg/mL)	38.9 ± 12.7	42.3 ± 14.5	48.7 ± 17.2	45.1 ± 15.8	41.2 ± 13.9	< 0.001

¹P values were calculated using repeated-measures ANOVA.

PTH: Parathyroid hormone; 25(OH)D: 25-hydroxyvitamin D; 1,25(OH)2D: 1,25-dihydroxyvitamin D.

Association between CRHs, hypercalcemia, and kidney stone formation

Multivariate logistic regression analysis revealed that elevated PTH levels (OR = 1.03, 95%CI: 1.01-1.05, P = 0.002) and peak serum calcium levels (OR = 2.78, 95%CI: 1.89-4.11, P < 0.001) were independent predictors of kidney stone formation. Calcitonin and vitamin D levels were not significantly associated with kidney stone formation in the multivariate model.

Subgroup analysis by AP severity

When stratified by AP severity, the incidence of hypercalcemia and kidney stone formation was higher in patients with moderately severe AP than in those with mild AP (Table 3).

Table 3 Incidence of hypercalcemia and kidney stone formation by acute pancreatitis severity, n (%).

AP severity	Hypercalcemia	Kidney stones
Mild (n = 119)	25 (21.0)	13 (10.9)
Moderately severe (n = 48)	18 (37.5)	12 (25.0)
Severe (n = 18)	10 (55.6)	6 (33.3)
P value1	< 0.001	0.003

¹P values were calculated using the χ² test.

AP: Acute pancreatitis.

DISCUSSION

This study provides important insights into the relationship between hypercalcemia, kidney stone formation, and changes in CRH levels in patients with AP. Our findings demonstrate a significant positive correlation between hypercalcemia and the incidence of kidney stone formation in patients with AP, with changes in CRH levels, particularly PTH, playing a crucial role in this association. The observed incidence of hypercalcemia (28.6%) in our study population was consistent with that in previous reports[9]. The temporal pattern of hypercalcemia with a peak incidence on day 3 suggests that calcium dysregulation is closely linked to inflammation in AP. This timing coincided with the peak of the systemic inflammatory response typically observed in AP, supporting the hypothesis that inflammatory mediators play a significant role in the disruption of calcium homeostasis[10].

The strong association between hypercalcemia and kidney stone formation (OR = 9.67) underscores the clinical significance of disturbances in calcium homeostasis in patients with AP. This finding is particularly important, given the potential for kidney stones to complicate the course of AP and contribute to long-term renal morbidity. The incidence of kidney stone formation (16.8%) in our study was higher than that observed in the general population prevalence[4]. This elevated incidence highlights the need for vigilant monitoring and preventive strategies for patients with AP.

The changes observed in the CRH levels provide valuable insights into the pathophysiology of hypercalcemia and kidney stone formation in patients with AP. The marked increase in PTH levels, which peaked on day 3, coincided with the highest incidence of hypercalcemia. This suggests that PTH plays a central role in the calcium dysregulation observed in AP. Elevated PTH levels may be a compensatory response to the initial calcium flux from damaged pancreatic tissue or a direct effect of inflammatory mediators on parathyroid gland function[11].

The parallel increase in calcitonin levels, albeit less pronounced than that of PTH levels, likely represents a physiological attempt to counteract the hypercalcemic state. Calcitonin, produced by thyroid C cells, lowers serum calcium levels, primarily by inhibiting osteoclast activity and promoting renal calcium excretion[12]. However, our multivariate analysis suggests that this compensatory mechanism is insufficient to prevent kidney stone formation in patients with significantly elevated PTH and serum calcium levels.

The significant changes in vitamin D metabolites were less dramatic than those observed for PTH and calcitonin. The slight decrease in 25-hydroxyvitamin D levels during the acute phase of pancreatitis may reflect an increased conversion to the active form, 1,25-dihydroxyvitamin D, which showed a modest increase. These changes in vitamin D metabolism may contribute to increased intestinal calcium absorption, further exacerbating the hypercalcemic state[13]. The complex interplay among vitamin D metabolites, PTH, and calcitonin underscores the intricate nature of calcium homeostasis in acute inflammation.

The identification of elevated PTH and peak serum calcium levels as independent predictors of kidney stone formation in our multivariate analysis has important clinical implications. These findings suggest that early monitoring of PTH and calcium levels could help identify patients with AP who are at the highest risk of kidney stone formation, allowing for timely intervention and prevention strategies. Potential interventions include aggressive fluid resuscitation, careful electrolyte management, and consideration of pharmacological approaches to modulate calcium homeostasis in high-risk patients[14].

Subgroup analysis according to AP severity revealed a clear trend of an increasing incidence of both hypercalcemia and kidney stone formation with increasing disease severity. This observation aligns with the concept that more severe inflammatory states lead to a greater disruption of calcium homeostasis and a higher risk of complications. The particularly high rates of hypercalcemia (55.6%) and kidney stone formation (33.3%) in patients with severe AP underscores the need for vigilant monitoring and management in this high-risk group.

Several potential mechanisms may explain the association between AP, hypercalcemia, and kidney stone formation. In severe AP, extensive pancreatic and peripancreatic fat necrosis can lead to saponification, wherein calcium ions bind to free fatty acids. This process can result in a significant calcium shift from the bloodstream to areas of necrosis, potentially triggering compensatory PTH release and subsequent hypercalcemia[15]. While our study demonstrated temporal changes in CRHs, a limitation is that we did not directly measure inflammatory markers, such as IL-6 and TNF-α, to establish their correlation with hormone levels. Previous studies have shown that IL-6 can stimulate PTH secretion, and TNF-α can enhance osteoclast activity, leading to increased bone resorption and calcium release[6,16]. In our study, the peak PTH level on day 3 coincided with the typical peak of inflammatory cytokines in AP, suggesting a potential causal relationship. Future studies should include simultaneous measurement of inflammatory cytokines and CRHs to better elucidate these mechanistic pathways, as well as acute kidney injury through various mechanisms, including hypovolemia, cytokine-mediated effects, and the direct toxic effects of pancreatic enzymes. Impaired renal function can affect calcium excretion and vitamin D metabolism, thereby contributing to calcium dysregulation. The compromised renal function may also create a favorable environment for kidney stone formation due to changes in urinary pH, supersaturation of stone-forming salts, and altered levels of stone inhibitors and promoters[17,18]. Additionally, prolonged bed rest, particularly in patients with severe AP, can lead to increased bone resorption and calcium release into the bloodstream, exacerbating hypercalcemia. This effect may be particularly pronounced in elderly patients or those with preexisting bone metabolism disorders[19]. Finally, severe AP can lead to metabolic acidosis, which further complicates calcium homeostasis. Acidosis promotes bone resorption and alters renal calcium handling, potentially contributing to hypercalcemia and increasing the risk of kidney stone formation[20].

Our study had several strengths, including its design, relatively large sample size, and comprehensive assessment of biochemical parameters and imaging findings. Serial measurements of CRHs provide a detailed temporal profile of changes in calcium homeostasis throughout the course of AP. However, this study had some limitations. First, the single-center nature of this study may limit its generalizability to other populations. Second, although we followed the patients for 7 days, this relatively short follow-up period may not capture the full spectrum of kidney stone formation. Previous studies have shown that kidney stones can develop weeks or months after the acute inflammatory phase. A longer follow-up period of at least 3-6 months would provide more comprehensive data on the incidence and timing of post-AP kidney stone formation. Future studies should consider extended follow-up protocols to better understand the long-term renal complications associated with AP. Third, we did not analyze the composition of the kidney stones, which could provide additional insights into the mineralization process in the context of AP-associated hypercalcemia.

CONCLUSION

This study demonstrated a significant correlation between hypercalcemia and kidney stone formation in patients with AP, with changes in CRH levels, particularly PTH, playing a crucial role in this association. These findings highlight the importance of monitoring calcium homeostasis in patients with AP and suggest that the early identification of calcium dysregulation could help prevent renal complications.