Serum Calcium Levels and Prognosis of Cerebral Hemorrhage in Hemodialysis Patients

Worldwide, stroke is a major cause of death and the leading cause of disability among patients on hemodialysis; the incidence of stroke in patients on hemodialysis is several times higher than in the general population. Compared with cerebral infarction, cerebral hemorrhage has a greater impact on patient prognosis.

Risk factors for cerebral hemorrhage in hemodialysis patients have been identified, including male sex, absence of antihypertensive drugs, predialysis hypertension, and high blood hemoglobin. Other risk factors include chronic kidney disease­-mineral bone disorder, high serum phosphate level, and high intact parathyroid hormone (iPTH).

Previous studies have found an association between high calcium concentration and cardiovascular diseases and poor prognoses in patients on hemodialysis. Recommendations from the Kidney Disease Improving Global Guidelines for avoiding hypercalcemia in patients on hemodialysis have changed in light of those study results; however, the treatment range of serum calcium has been left unchanged. Conversely, some studies not restricted to patients with end-stage renal disease have found that a low serum calcium level worsens prognoses and enlarges the hematoma volume in acute cerebral hemorrhage.

Mineaki Kitamura, MD, PhD, and colleagues recently conducted a retrospective cross-sectional case-control study designed to assess the contradicting data on whether serum calcium levels in patients on hemodialysis with cerebral hemorrhage affect patients’ prognosis or onset. The researchers sought to examine the association between serum calcium and cerebral hemorrhage in patients on hemodialysis. Outcomes of interest included in-hospital death, volume of hematoma, and onset of cerebral hemorrhage. Study results were reported online in BMC Nephrology [doi.org/10.1186/s12822-019-1400-4].

The study included 99 hemodialysis patients with cerebral hemorrhage who were admitted to Nagasaki University Hospital (Japan) between 2007 and 2017 and three hemodialysis patients who developed cerebral hemorrhage while in the hospital (66 men and 33 women). Average age of the cohort was 64.8 years and median dialysis vintage was 87 months. Median date of the onset of cerebral hemorrhage was May 21, 2012. Severe outcomes occurred in 66 patients (67%): 32 died and 34 were severely disabled. There were significant differences between patients who died and those who survived in the Glasgow Coma Scale, National Institutes of Health Stroke Scale, intraventricular hemorrhage, and volume of hematoma.

In comparisons of patients who died and patients who survived following cerebral hemorrhage, there were significant differences in the past histories of ischemic heart disease and heart valve repair or replacement, use of antiplatelet drugs and warfarin, and corrected serum calcium levels. In multivariate logistic analysis, there was an independent association between corrected serum calcium, antiplatelet use, and heart valve repair or replacement and the severity of cerebral hemorrhage. Corrected serum calcium had the greatest effect on cerebral hemorrhage (P<.001).

To make comparisons to clarify the correlations for the onset of cerebral hemorrhage, the study included a control group of 339 patients on hemodialysis at the Nagasaki Renal Center between July 1, 2011, and June 30, 2012.  There were significant differences between the two groups in dialyzing time, blood pressure pre-hemodialysis, proportion of online hemodiafiltration, erythropoiesis-stimulating agent (ESA) doses, ferritin levels, blood urea nitrogen levels, corrected serum calcium levels, serum phosphate levels, and iPTH.

The univariate logistic regression model was applied to those factors as well as to the predetermined traditional risk factors; multivariable logistic regression analysis was subsequently performed. Model 1 included risk factors for traditional cerebral hemorrhage and model 2 was created by stepwise methods. In both models, the largest association with cerebral hemorrhage was systolic blood pressure pre-hemodialysis; other significant parameters for cerebral hemorrhage were corrected serum calcium and iPTH.

Multiple regression analysis was performed to determine the predictors and identify the relationship between the corrected serum calcium level and hematoma volume. Model 1 included predetermined factors and model 2 included use of antiplatelet drugs in addition to the factors included in model 1. The analyses indicated a significant correlation between the size of the hematoma and the corrected serum calcium level and with antiplatelet use. There was no significant correlation between systolic blood pressure pre-hemodialysis and hematoma volume.

Patients with cerebral hemorrhage were divided into four groups, according to serum calcium levels: Q1 (corrected serum calcium ≤8.8 mg/dL; Q2 (8.9-9.5 mg/dL); Q3 (9.6-10.1 mg/dL); and Q4 (≥10.2 mg/dL) and the severity of ADL (activities of daily living; modified Rankin Scale [mRS]). The proportion of patients with severe cerebral hemorrhage who were mRS 5 (severe disabled, bed ridden) and mRS 6 (in-hospital death) were: Q1, 57%; Q2, 63%; Q3, 67%; and Q4, 83%. There was a significant association between severity of ADL (mRS) at discharge and high calcium levels.

Study limitations cited by the authors included the retrospective design and the single location that may limit the generalizability of the findings. In addition, the numbers of patients and outcomes were not sufficient to adjust for confounding factors.

In conclusion, the researchers said, “To prevent the onset and progression of cerebral hemorrhage, serum calcium levels in hemodialysis patients should be monitored. Further examinations of the direct relationship between high serum calcium concentrations and cerebral hemorrhage in hemodialysis patients are warranted.”

Takeaway Points

  1. Researchers in Japan conducted a retrospective cross-sectional case-control study to examine the association between serum calcium and cerebral hemorrhage in patients on hemodialysis; outcomes of interest were in-hospital death, volume of hematoma, and onset of cerebral hemorrhage.
  2. There were significant associations between corrected serum calcium level and antiplatelet drug use and patient prognosis. Both factors were also significantly associated with hematoma volume.
  3. The corrected serum calcium level was associated with the onset of cerebral hemorrhage; pre-dialysis systolic blood pressure was also association with the onset of cerebral hemorrhage.