Abstract
Aim
This study compared prevalence and characteristics of headaches between pediatric patients with chronic kidney disease and pediatric patients with transplanted kidneys and identify factors associated with headaches in the entire cohort.
Methods
We interviewed 87 children and adolescents with either chronic kidney disease or transplanted kidney, regarding the prevalence of headaches and their characteristics. We reviewed hospital charts for medical history and blood test.
Results
Twenty-two patients (25.3%) reported experiencing headaches, of them 15 (68%) had migraine. The prevalence was greater among those with chronic kidney disease than among those after kidney transplant: 36.6% vs 15.2%, P = .03. Headache, mostly migraine, was associated with lower glomerular filtration and higher phosphate level.
Conclusions
In a pediatric population, headaches were less prevalent among patients after kidney transplantation than among patients with chronic kidney disease. The lower headache rate after kidney transplantation may be related to improvement in homeostasis and electrolyte balance.
Introduction
Headaches have been described in children treated with hemodialysis, and to a lesser extent in children with chronic kidney disease. 1 Abnormal levels of magnesium and urea, and also abnormal hemodynamic parameters such as elevated blood pressure, are among the factors proposed to be associated with headaches in hemodialysis adult patients. 2
Chronic kidney and end-stage renal diseases are global health problems whose prevalences have increased over recent decades. 3 Kidney transplantation is the optimal treatment for end-stage renal disease, and increases survival. 4 However, according to the KDIGO (Kidney Disease: Improving Global Outcomes), 5 renal transplant recipients should be considered as having chronic kidney diseases regardless of their glomerular filtration rate. Although graft survival has improved over the last few decades, posttransplantation complications continue to present a growing challenge. 5
A meta-analysis of adult kidney transplant patients aged 25-65 years reported headaches as the fourth most common neurologic symptom. 6 Headaches were found to be related to drug toxicity of immune suppression drugs (such as tacrolimus and steroids), 6 with a low prevalence of 8.3%. 6 Headaches were also found to be related to infections, and secondary to renal allograft function deterioration.7,8
The aim of this study was to evaluate the prevalence and character of headaches among pediatric patients with chronic kidney disease, compared to patients after kidney transplantation. In addition, we investigated associations of headaches with factors relating to kidney function deterioration and disturbances in homeostasis.
Methods
Patients and Setting
The cohort comprised children, adolescents, and young adults aged 3-21 years who attended routine visits from November 2019 until August 2020 at the Nephrology Institute of Schneider Children's Medical Center of Israel, a tertiary, university-affiliated, pediatric medical center. The patients had various stages of kidney disease or had functioning renal grafts (kidney transplant). Patients with renal graft rejection were excluded from the study. Patients on peritoneal or hemodialysis were not included in the study.
Clinical Protocol and Headache Diagnosis and Ethics
The study participants, with their parents, or only the parents of very young children, were interviewed by one of the authors (EE) in the Pediatric Nephrology Institute. The information accessed included the number of headaches experienced per month, the nature of the headache attacks, the duration and related symptoms such as vomiting, photophobia, phonophobia, abdominal pain, and dizziness. Headache type was diagnosed based on the International Headache Society (ICHD-3) criteria. 9 Accordingly, for very young children with limited verbal communication, headache symptoms were determined by the children's complaints and the parents’ impressions of the children's behavior (applying the criteria of the ICHD-3).
We did not use a standard instrument for the collection of data. Rather, the interviewer asked questions according to a questionnaire that we established for the purpose of this study. The interviewer provided explanations and asked additional questions as needed.
The medical files were reviewed to access information regarding chronic kidney disease and its duration, organic comorbidities, medications taken, and blood tests.
The study was approved by the research ethics board of Rabin Medical Center (approval no. RMC 060719). Parents of all the patients, and patients who were older than 16 years, gave their assent before participation in the study.
Laboratory Investigations and Blood Pressure Measurements
Blood samples are routinely taken during visits to the Nephrology Institute for patients with chronic kidney disease, and for patients with transplanted kidneys, before patients meet with the pediatric nephrologist. Blood samples are taken while fasting before the patient's breakfast. The following blood tests were evaluated in our study: blood count, pH, bicarbonate, sodium, potassium, urea, alkaline phosphatase, magnesium, calcium, phosphate, iron, iron saturation transferrin, total transferrin saturation, and parathyroid hormone.
Blood pressure is measured routinely with an electronic blood pressure measurement instrument at the pediatric nephrology clinic, at every visit before patients meet with the nephrologist.
Definitions
Chronic kidney disease grades 1-5 were defined according to estimated glomerular filtration rate, 10 Estimated glomerular filtration rate was calculated according to the Schwartz formula for patients up to age 17 years and according to the Modification of Diet in Renal Disease Study equation for patients older than 17 years.11,12
In our center, renal failure is treated by the pediatric nephrologist with respect to blood pressure imbalance, electrolytes and PH imbalance, endocrine imbalance, and anemia, aimed to restore normal homeostasis. Patients are followed by a pediatric nephrology dietician according to their age, calorie demand chronic renal disease grade, and homeostasis imbalance.
Statistical Analysis
We performed 2 analyses of the data as follows. First, we compared between patients with chronic kidney disease and patients with transplanted kidneys, demographic and clinical parameters, headache prevalence and character, and blood tests. Second, we compared between patients with and without headaches, in the total cohort, clinical parameters relevant to chronic kidney disease and kidney transplantation. The data were analyzed using BMPD software. 13 A sample size calculation prior to conducting the study showed that 40 patients with chronic kidney disease and 40 patients with kidney transplantation would be required to yield a statistically significant result with a power of 85%. This computation assumes that the difference in proportions of headaches is 0.30 (specifically, 0.45 vs 0.15). Continuous variables were calculated as means and standard deviations. Because the sample size was relatively small, and because some parameters did not have a Gaussian distribution, the nonparametric Mann-Whitney U test was used to compare between groups. Discrete variables were calculated as numbers, and percentages were compared between groups using Pearson chi-square or Fisher exact test, as applicable. A P value of ≤.05 was considered significant. For the stepwise logistic regression, we included the variables found to be significant at P ≤.1 on univariate analysis. We also included age and gender. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined. The effect size for continuous variables was calculated with Cohen d.
Results
Characteristics of the Study Group
A total of 87 patients (30 females and 57 males) were enrolled in the study, mean age of 12.4 ± 4.9 years, range 3-21 years. The detailed renal diagnoses of the patients in the cohort are shown in Table 1.
A Comparison of the Clinical and Demographic Characteristics, and the Laboratory Results of Patients With Chronic Kidney Disease and Transplanted Kidneys.a
Data are presented as means ± standard deviations or as means ± standard deviations (median) or as number of patients (percentages) and positive parameters for the specific group.
Not related to kidney disease.
Normal ranges of laboratory values are presented in parentheses.
Altogether, 22 (25.3%) patients reported having headaches. Of them, 15 (68%) had migraine, 8 of them migraine with aura. Seven patients (32%) had tension-type headaches. The mean frequency of headaches per month was 4.08 ± 8.49, and the mean duration of headache attacks was 8.63 ± 16.05. Patients reported having the following symptoms during headaches: photophobia, 12 (54.5%); phonophobia, 15 (68.2%); nausea, 8 (36.4%); vomiting 5 (22.7%); abdominal pain, 4 (18.2%); dizziness, 8 (36.4%); and worsening during physical activity, 7 (31.8%).
Forty-one patients had chronic kidney disease and 46 were with transplanted kidneys. Table 1 compares demographic and clinical characteristics and blood test parameters between the 2 groups.
The proportion of patients reporting having headaches was significantly greater in the chronic kidney disease than in the kidney transplant group (36.6% vs 15.2%, P = .03, OR 3.21, 95% CI 1.04-10.54). Nine (60%) of the 15 patients with chronic kidney disease and headaches had migraine headache, 4 of these were migraine with aura. The remaining had tension type headache. Headaches were located in the frontal region in 8, in the temporal region in 4, in the occipital region in 2, and in the entire head in 1 patient. Regarding headache character, 8 patients had pressing pain, 1 had pulsating/throbbing pain, 2 stabbing pain, and 4 could not describe the headache character. Six (86%) of 7 patients with transplanted kidneys and headaches had migraine headaches (85.7%); 4 of these were migraine with aura. One had a tension-type headache. Four of the transplant kidney patients had headaches in the frontal region, 1 in the temporal region, 1 in the occipital region, and 1 patient had a headache in the entire head. Two patients described pressing pain, 3 pulsating/throbbing pain, and 2 could not define the character of their headache.
All 46 patients with transplanted kidneys received tacrolimus, with regular drug-level monitoring. Seven of them reported headaches, none of them had toxic levels of tacrolimus. All 46 patients with transplanted kidneys were treated with mycophenolate mofetil, for which headache is not one of its reported side effects.
The single patient treated with nifedipine, a medication that has been reported to be associated with headaches, did not report having headaches.
Comparing Patients With and Without Headaches
Compared to patients without headaches, among those with headaches, the mean glomerular filtration rate was lower (52.05 ± 31.81 vs 67.36 ± 26.8 mL/min/1.73 m2, P = .02, Cohen d 0.52), the distribution of chronic kidney disease grade indicated greater severity (P < .01), and the mean phosphate level was higher (4.84 ± 0.81 vs 4.39 ± 0.81 mg/dL, P = .01, Cohen d 0.61) (Table 2). Comparing these patient groups, the mean level of urea was higher, though without statistical significance (71.54 ± 50.11 vs 50.8 ± 29.02 mEq/L, P = .07, Cohen d 0.5), and magnesium was higher with borderline significance (1.95 ± 0.27 vs 2.09 ± 0.34 mg/dL, P = .05, Cohen d 0.49).
Demographic Clinical and Laboratory Parameters of Patients with and Without Headache. a
Data are presented as means ± standard deviations or as means ± standard deviations (median) or as number of patients (percentages) and positive parameters for the specific group.
Not related to kidney disease.
Normal ranges of laboratory values are presented in parentheses.
Stepwise Logistic Regression Analysis
Table 3 presents the results of the logistic regression analysis. Three variables were found to be significantly associated with having headaches: older age, higher phosphate level, and having chronic kidney disease vs having a transplanted kidney.
Stepwise Logistic Regression Factors Associated with Having a Headache.a
Area under the curve = 0.813.
Missing Data and Exclusion of Patients From the Analysis
Ninety-one patients and/or their parents who attended the chronic kidney disease and kidney transplantation clinic during the study were contacted to participate in the study; of them, 87 were interviewed according to the regulations of our hospital Helsinki committee (Figure 1). Of the 49 patients with transplanted kidneys, 2 refused to participate in the study and 1 was excluded because of graft rejection with deterioration of kidney function.
Data for some parameters were missing in a minority of patients. No significant differences were observed in missing data between those with and without headaches: pH in 4 vs 10 (P > .99), bicarbonate in 4 vs 10 (P > .99), magnesium in 1 vs 1 (P = .89), transferrin saturation in 1 vs 1 (P = .88), and parathyroid hormone in 4 vs 19 (P = .47).
Discussion
The main finding of this study is the significantly higher (by 2-fold) prevalence of headaches among pediatric patients with chronic renal disease compared to patients with transplanted kidneys. Headaches in our cohort were associated with lower glomerular filtration rate, higher chronic kidney disease grade (also reflecting the lower glomerular filtration rate), higher phosphate level, and a nonsignificant higher urea level.
The present study reported headache in 36.6% of patients with chronic renal disease and 15.2% of kidney transplant recipients. Higher rate of recurrent headache of 2.7% in a selected population of 17-year-old Israeli adolescent recruiting office. Information regarding their headaches obtained from family physicians. 14 The difference from our study may be also related to different methodologies.
Neurologic complications are very common in adult patients with chronic kidney disease, and patients with end-stage kidney disease generally have more than 1 complication. 15 These involve the central, peripheral, and autonomic nervous systems. 15
The prevalence and character of headaches in end-stage kidney disease was not investigated in a pediatric and adolescent population except in our earlier study. 1
Notably, the prevalence of headaches among pediatric patients with transplanted kidneys was not previously reported. Our finding in a pediatric population, of a lower prevalence of headaches in kidney transplant recipients compared to patients with chronic kidney disease, corroborates the findings of Viticchi et al. 16 In their interview study, 67% of transplant kidney recipients reported improvement or complete resolution of symptoms. The authors hypothesized that a possible reason for the resolution of headaches was that renal transplantation restores hemodynamic stability, hormonal balance, and homeostasis, with positive consequences on brain-kidney crosstalk and on neurologic symptoms, including reduced headache.
Maggioni et al 17 reported occurrence of headache after kidney transplantation in adults at rates higher than those reported for the general population.
A higher chronic kidney disease grade and lower glomerular filtration rate are known to be associated with a higher level of urea. Accumulation of urea can be related to headache because of similar mechanisms that have been proposed for the relation between chronic renal failure and neurologic complications. 15
Uremia and Headache
We report a higher grade of urea and headache in our patients with chronic renal failure than among those with transplanted kidneys. This finding may be related to the pathogenesis of a higher rate of headaches among patients with chronic kidney disease compared to those with transplanted kidneys.
A number of mechanisms that have been proposed for headache occurrence may be related to the toxigenic effect of uremia. For one, uremia in chronic kidney disease is related to neuroinflammation. The accumulation of uremic toxins results in neurotoxicity, neuroinflammation, and increasing levels of cytokines and interleukins, C-reactive protein, fibrinogen, and interleukin-6. 15 Renal insufficiency compared to chronic renal disease was associated with higher levels of inflammatory markers such as C-reactive protein, fibrinogen, and interleukin-6. 18 The values of all these parameters declined after renal transplantation. 19 Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release such as CGRP and interleukins. 20 This contributes to pain conditions such as headache and migraine, 21 even in the absence of triggers to migraine attacks. 20 Renal clearance of CGRP was reduced by half in sheep, following a bilateral nephrectomy. 22 We hypothesize that higher levels of CGRP may be related to migraine among our patients with chronic renal failure compared with transplant recipients.
A second possible mechanism in migraines involves blood-brain barrier dysfunction. 23 Blood-brain barrier injury was also proposed as a causative toxigenic factor in uremia and renal failure 15 and becomes more permeable in kidney failure.
Another possible mechanism in the toxigenic effect of uremia is endothelial dysfunction. Accordingly due to multiple uremic toxins, migraine is associated with systemic and cerebral endothelial dysfunction. The degree of these changes was strongly associated with the severity of migraine. 24
Phosphate and Headache
We report a higher mean phosphate level in patients with than without headache. However, among those with headaches, in all patients the levels were in the normal range owing to effective treatment by phosphate binders.
The onset of chronic kidney mineral disorder is considered to be caused by an abnormality in mineral metabolism hormone dysregulation, osteodystrophy, and appearance of cardiovascular complications. 25 FGF-23 regulates phosphate metabolism by excreting excess phosphate through the kidney. It is elevated in individuals with chronic kidney disease because of decreased renal mass. 25 In addition, FGF23 formation is upregulated by the proinflammatory transcription factor nuclear factor kappa B (NFκB), which eventually results in inflammation.
The elevated phosphate levels in patients with headaches compared to those without may be related to a higher inflammation level. This may be correlated to neurogenic inflammation, the progression of which provokes neurogenic pain that manifest as a headache. 21
Factors That Were Not Associated With Headaches
We did not find an association of headaches with the mean number of medications taken that may cause headaches. Among the medications used to treat chronic kidney disease, hydralazine, nifedipine, and nimodipine are most commonly reported to cause headaches. 9 These drugs were not used by our patients, except for nifedipine, which was used by 1 patient who did not have headaches. Because medicines are usually taken together, we could not identify any of the headaches as a “headache attributed to the occasional use of a non-headache medication,” an ICHDIII (8.1.19) criterion. 9 Immunosuppressive intoxication (such as tacrolimus) has been reported as causing headaches in persons with chronic renal failure. 15 None of our patients with transplanted kidneys had tacrolimus intoxication. All our patients with transplanted kidneys were treated with mycophenolate mofetil, but we did not find any studies that reported headaches as a side effect of this drug.
Elevated blood pressure was not found to be significantly associated with headaches in our cohort. Headache is only caused by hypertension during a hypertensive crisis. 9 Only 1 (4.5%) of our 22 patients with headaches had elevated blood pressure, but not hypertensive crisis.
We found a significantly higher mean magnesium level among patients with chronic kidney disease than among patients with transplanted kidneys. Although the literature shows that headaches are mostly associated with hypomagnesemia, magnesium is used to treat migraines. 26 Magnesium deficiencies are known to promote cortical spreading depression, alter nociceptive processing, and release neurotransmitters; these are all major elements of migraine development. 26 Because none of our patients had hypomagnesemia, we assume that the higher magnesium levels were not the cause of their headaches and were related to decreased renal function.
Patients with chronic renal disease who underwent a kidney transplantation demonstrated improvement in kidney function, electrolyte balance, and homeostasis. We assume that the lower rate of headache is related to improvements in all the disturbances together.
Study Limitations
Adolescents and young adults with chronic kidney disease have been reported to have low quality of life 27 and anxiety. 28 Children with transplanted kidneys have been reported to have anxiety regarding their future. 29 Emotional stress is related to headaches in children and adolescents. We did not interview patients regarding emotional factors and quality of life because our patients were interviewed during their relatively short visits to the pediatric nephrology clinic. All our patients with chronic renal failure and with transplanted kidneys are followed by psychologists, yet this information is confidential. Notably, a comparative study 30 did not show a difference in emotional repercussion among pediatric patients, between kidney transplant recipients and those with end-stage chronic kidney disease.
As our treatment of each patient with chronic disease is personally tailored, according to the homeostasis imbalance, it is not possible to analyze the possible effect of such management on the prevalence of headaches among the children who did not receive transplants. Another limitation is that the study was conducted in a single center, limiting the generalizability of the findings.
Conclusions
In our tertiary pediatric center, headache prevalence was significantly lower among pediatric and adolescent patients with transplanted kidneys than among patients with chronic kidney disease. The association of headache with higher chronic kidney disease stage, lower glomerular filtration rate, higher phosphate blood level, and higher though not statistically significant urea level reflected the severity of the deterioration in kidney function. The better values for kidney function, homeostasis, and electrolyte balance after kidney transplantation may explain the lower headache rate in patients with transplanted kidneys.
A flowchart of the pediatric patients with chronic kidney disease versus transplant kidney with and without headache who were included in the study.
Footnotes
Author Contributions
EE, MD and TEM: contributed to conception and design, contributed to acquisition, analysis, and interpretation, drafted manuscript, critically revised manuscript, agreed to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
The study was approved by the research ethics board of Rabin Medical Center (Approval no. RMC 060719). Parents of all the patients, and patients who were older than 16 years, gave their assent before participation in the study of Authors contribution: all authors contributed to the conception and design, drafted the manuscript, critically revised the manuscript and agreed to be acceptable for all aspects of work ensuring integrity and accuracy.
