Article In Brief
New findings suggest that chronic renal dysfunction and dipstick-positive proteinuria may be independent risk factors for the development of Parkinson's disease in older adults.
A large-scale Asian study found that chronic renal dysfunction and dipstick-positive proteinuria may serve as independent risk factors for the development of Parkinson's disease (PD) in older adults.
The study, supported by the National Research Foundation of Korea, was published online April 25 in Movement Disorders.
Combing through a nationwide South Korean database, the researchers from various colleges of medicine in Seoul reviewed the records of 3.5 million individuals aged 65 or older. The patients, who had undergone health checkups through the National Health Insurance Service of South Korea between 2009 and 2012, were followed until 2015.
“Notably, to the best of our knowledge, the current study was the first to study the impact of proteinuria on PD development and found that dipstick-positive proteinuria is associated with an increased risk of the incidence of PD,” the authors wrote. “Furthermore, the coexistence of CKD [chronic kidney disease] and dipstick-positive proteinuria was observed to affect PD development most strongly.”
Recent epidemiologic studies have suggested that chronic diseases such as diabetes mellitus, hypertension, and depression may elevate the risk of PD. However, as the researchers indicated, there is limited epidemiological evidence regarding a possible relationship between PD and chronic renal dysfunction.
“Chronic kidney disease is known to be more prevalent in the older population, and this age group may be more vulnerable to metabolic and hormonal disturbances related to renal dysfunction,” the authors wrote. “In addition, urinary protein is a strong marker for impaired kidney function and renal damage.”
Study Design, Findings
This study relied on the whole-population database provided by the National Health Insurance Service of South Korea. Launched in 2000 under the supervision of the Ministry of Health and Welfare, the universal health coverage insures 97 percent of Korean residents (about 50 million people). This database lists enrollees' sociodemographic information, use of outpatient and inpatient services, and pharmacy dispensing claims.
Standardized health exams, which are recommended at least biannually, include height, weight, and blood pressure measurements, laboratory tests evaluating parameters such as hemoglobin, glucose, cholesterol, liver enzymes, and creatinine, and a urine analysis.
The researchers used self-reported questionnaires to collect data regarding medical history and health-related behaviors such as smoking status, alcohol consumption, and physical activity.
From this database, they selected individuals aged 65 years and older who had undergone health checkups at least once from January 1, 2009 to December 31, 2012. They excluded individuals with any missing data and those who were diagnosed with Parkinson's within the four years before enrollment.
Ultimately, the study consisted of 3,580,435 subjects (1,602,945 men and 1,977,490 women). They were followed until death or December 31, 2015, whichever transpired first.
Of the more than 3.5 million individuals, 30,813 (86 percent) developed PD after a mean follow-up of 5.2 ± 1.3 years. Low glomerular filtration rate and a high degree of proteinuria on a dipstick were associated with higher risk of developing PD, the authors found. Co-existence of chronic kidney disease and proteinuria resulted in an increased hazard ratio of 1.33 (95% confidence interval, 1.23-1.45) for PD occurrence.
The investigators performed various adjustments for age, sex, body-mass index, smoking status, alcohol consumption, physical activity, income, hypertension, diabetes mellitus, and dyslipidemia. They found that “the incidence of PD persisted” after accounting for potential confounding variables.
Neurologists who were interviewed by Neurology Today reviewed the findings with interest but also expressed caution over generalizing them to other populations.
The study draws attention to the possible association between chronic kidney disease and PD, but it does not mean that all patients with Parkinson's require extensive assessment of their renal function, said Joseph Jankovic, MD, FAAN, professor of neurology and director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine.
In evaluating more than 10,000 patients with Parkinson's over the course of four decades, Dr. Jankovic said he has not observed patients with this disease are more likely to have renal dysfunction in comparison to other patients with movement disorders.
“Although I have not systematically studied this possible link, I wonder if there could be some explanation for the findings by the South Korean investigators,” he said. “One of the challenges of ‘big data’ analysis is that the accuracy of the diagnosis cannot be verified.”
Despite the fact that the individuals included in this study had undergone annual health checkups, it is unclear how many of the patients had their diagnosis of Parkinson's confirmed by neurologists and, more specifically, by subspecialists in PD, Dr. Jankovic said.
It is possible that some patients did not have Parkinson's, but rather, had vascular parkinsonism, known to be associated with hypertension, diabetes, and, indirectly, with renal disease. Also, he said, some of the patients were probably treated with amantadine, which may cause renal dysfunction.
Although the hazard ratio was quite low, the authors concluded that “chronic renal dysfunction and dipstick-positive proteinuria may be independent risk factors for the development of PD in older adults.” Individuals with CKD were two years older on average than those without kidney disease. They also had slightly, but significantly, higher frequency of potential risk factors for CKD, such as high blood pressure and glucose, which may be independent of PD, Dr. Jankovic said.
John Fang, MD, associate professor of neurology in the movement disorders division at Vanderbilt University Medical Center, concurred that “although these types of studies allow large numbers of patient records to be examined, there are significant issues of quality because neither the diagnosis of PD nor of other potentially confounding diseases is consistently or reliably validated.”
In addition, Dr. Fang noted, the population being studied may not reflect the general population, as an incentive was offered to individuals with the diagnosis of PD, potentially leading to increased recruiting of PD subjects or to misdiagnosis of PD, in order to encourage participation. Since 2006, the authors noted, “the South Korean government has implemented a registration program for copayment reduction of up to 10 percent for rare intractable diseases including PD.”
“The higher incidence of stroke history in the chronic renal dysfunction patients also raises the risk of patients with vascular parkinsonism being included in the PD population, which would skew the results toward a higher rate in this group,” said Dr. Fang, who is also a staff physician in the Neurology Service at VA Tennessee Valley Healthcare System.
“Thus, the results of the study must be interpreted cautiously,” he said. A better trial design would begin with a random sample of patients without PD or chronic renal dysfunction. Investigators would follow these patients prospectively for several years, delving into the incidence of PD over time. Brain MRI scans should be performed to exclude cerebrovascular disease, and all patients should be examined by experienced movement disorders specialists to confirm the diagnosis of PD, Dr. Fang said.
Harsh Gupta, MD, assistant professor of neurology at the University of Kansas Medical Center, pointed out several limitations of the study aside from the extraction of information from a whole-population database, which leads to selection bias. There is a possibility that some patients were misdiagnosed with Parkinson's disease, while others had Parkinson's but it was undetected.
Dr. Gupta also noted that the presence of protein in the urine can occur because of several factors other than kidney disease that were not accounted for in the study.
“According to this study, the presence of protein in the urine or chronic kidney disease only serves as a risk factor for PD,” he said. “This finding cannot serve as a biomarker (indicative of a pathological process) for PD. It is unlikely to have any impact on the early detection of PD.”
The study also lacks information about prognosis even with early detection. “More studies are required to see if prevention or control of chronic kidney disease helps in reducing the incidence of PD,” Dr. Gupta said.
Perhaps individuals with known renal dysfunction may be told that they have a heightened risk of developing PD. However, any benefit of such a warning remains unclear, said Amie L. Hiller, MD, assistant professor of neurology at Oregon Health & Science University School of Medicine.
Dr. Hiller added that she is “not sure how helpful this would be in the ‘real world,’ as rates of diagnosis were not that much higher and the vast majority of persons with dysfunction were not being diagnosed with Parkinson's.”
With the study involving participants in South Korea, Dr. Hiller questioned if it would be applicable to other populations. “We know genetics play a role in Parkinson's disease development, and it would be important to try to replicate findings in other ethnic groups or look at the interplay with genetics,” she said.
Even with the limited implications of this research for practicing neurologists, “it's important to continue to look for clues as to what may be contributing to the development of Parkinson's disease,” said Allison Willis, MD, MS, associate professor in the departments of neurology and epidemiology in the Perelman School of Medicine at the University of Pennsylvania.
“This is more crucial than ever because most of our initial thoughts about what things cause or contribute to Parkinson's disease have not allowed us to find neuroprotective or neuropreventive strategies,” Dr. Willis said, while adding that there is “definitely room to think more broadly.”
Numerous trials of many different compounds have not yielded ways to detect this heterogeneous disorder in early stages. “Our failure to find neuroprotective treatments suggests that there's a lot more to learn,” she said.
Drs. Jankovic, Fang, Gupta, Hiller, and Willis reported no disclosures relevant to the study.