Two NIH Grants Awarded to Nephrology to Seek Cause of CKDu

In several discrete parts of the world, agricultural workers are at risk of contracting a deadly disease of their kidneys: chronic kidney disease of unknown origin (CKDu).  The critical letter in that acronym is U. Because the cause of the disease is a mystery, there is little to do for the workers who develop it except hydrate them and treat their symptoms, including kidney failure. In poor countries, that is a tall order.

After having been recognized for over 20 years, the disease has reached epidemic levels among sugar cane workers in Central America, specifically Guatemala and Nicaragua, farm workers in India, and rice farmers in Sri Lanka. Several Stanford faculty members have studied CKDu in recent years and are now the recipients of two grants from the National Institutes of Health (NIH) to discover the cause of the disease.  

Putting the Grants Together

Two NIH institutes, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and The National Institute of Environmental Health Sciences (NIEHS), have co-sponsored a U01 grant to methodically study the disease in India and Central America and find its cause. This is the first time these two institutes have sponsored a U01 grant together. Vivek Bhalla, MD, associate professor of nephrology, is co-principal investigator of this grant’s renal science core.                                         

A second grant, an R01, has been awarded to Shuchi Anand, MD, MS, assistant professor of nephrology, to continue a cross-regional collaboration in Sri Lanka that is studying agricultural workers who have acquired CKDu.

According to Bhalla, the NIDDK/NIEHS U01 grant “is the first time that NIH has put its might behind this disease and our ability to form a consortium to study it from a very basic, mechanistic point of view.”

The U01 has three parts. First is a scientific data coordinating center. Second are field epidemiology sites in each country where local scientists recruit and study patients over time, collect samples, and maintain communications with patients. Third is a renal science core, of which Bhalla is co-PI with David Friedman, MD, from Harvard University, and Sushrut Waikar, MD, from Boston University. Their leadership provides expertise in genetics (Friedman), biomarkers (Waikar), and renal physiology (Bhalla).

Year 1 of this grant will focus on creating a centralized protocol for all sites. Once that is agreed upon, sites and then patients can begin enrolling. Years 2 and 3 will be spent doing experiments on samples collected from patients at the sites. In years 4 and 5 the investigators will begin analyzing and then reporting their findings.

A Plan of Attack

What is known about CKDu is that it is a slowly progressive disease, unlike the typical chronic kidney disease prevalent in developed countries, and that it is a disease of the tubules, unlike the glomerular disease more commonly found in wealthier countries. Most important among the things not known about it is its cause. Bhalla lists some of the causes consortium members are considering: “Is it a toxin? An infection? Heat stress from global warming and climate change? These farm workers are constantly out in the heat, constantly dehydrated. Is it maybe a combination of some toxin in the environment and an infection and the heat? Is it heavy metal? We don’t know. So we need to dig deeper, and that’s our charge.”

Bhalla’s overall feeling about this grant is that it is “an exciting, challenging, tremendous opportunity to solve a problem in resource-poor settings where this diagnosis has been an epidemic. We will make substantial progress with the resources that the NIH has provided.”

Anand’s grant, she says, “is focused on a specific hot spot in Sri Lanka. Many of the aims of my grant overlap the NIH consortium, but we have an independent approach to sampling the population and we will be managing the biospecimens and environmental specimens independently as well. At the same time, because we will be bringing in additional data from a region where the U01 is not collecting, we will potentially function as a site for that grant.”

Although Anand’s grant started its 5-year course in January 2021, she had a head start due to several prior trips to Sri Lanka; as a result, “I have a very well-functioning team there who have been fantastic at keeping in pretty constant communication with me,” she says.

At the same time, she was not without advice and interest at home: “I had a great group supporting me at Stanford: Vivek Bhalla; our pathologist Neeraja Kambham, MD; Andrew Fire, PhD; as well as our amazing statistician, Maria Montez-Rath, PhD. We would all congregate in a small office with Dr. Fire, talk through the issues, talk through the challenges, think about potential internal resources, and just keep a focus and not forget that this was something that we really wanted to tackle, a true scientific passion.”

Kambham is part of both grants. Her involvement with the Sri Lanka study began, she says, “when Shuchi approached me to help her analyze samples from kidney biopsies from Sri Lanka. The disease was similar to what we were just hearing about a nephropathy from Central America.”

Her examination of the biopsy samples was complicated by the very small amount of tissue she received, but she set about looking at more than 70 elements in the samples, “more to exclude some of the heavy metals known to cause kidney disease, such as cadmium or arsenic or lead. We are also working on identifying pathogens in the tissue. So far we haven’t found any pathogens.”

The grant gives Bhalla the opportunity “to translate my bench research and expertise to the bedside. It’s a tremendous, exciting, challenging opportunity.”

Bhalla points to the involvement of several other Stanford personnel. Nephrology fellow Pablo Garcia, MD, a transplant nephrologist-in-training, has been a mentee of both Anand and Bhalla, and has contacts and collaborators in Guatemala with whom he will be working. Michael Angelo, MD, PhD (assistant professor of pathology) serves as a pathologist, and Garry Nolan, PhD (professor of pathology), as an advisor.