NIDDK Director Griffin P. Rodgers Honored for Sickle Cell Research

Griffin P. Rodgers, MD, MACP, director of the National Institute of Diabetes and Digestive and Kidney Diseases, was named a 2015 finalist for the Samuel J. Heyman Service to America Medals, recognizing his dedication to progress in the treatment of sickle cell disease (SCD). Known as the “Sammies,” the Heyman awards recognize federal employees for their “noteworthy and inspiring accomplishments.” That description certainly applies to Rodgers, a hematologist who has served as NIDDK director since 2007.

The honor reflects Rodgers’ career achievements in research on treatments for SCD. Beginning in the mid-1980s, he led studies demonstrating the effectiveness of hydroxyurea treatment for SCD. Since then, hydroxyurea—the only drug approved by the Food and Drug Administration to treat SCD—has become a mainstay therapy for sickle cell disease, reducing the rate of painful sickle cell crises and other complications.

Over the past decade, Rodgers has collaborated on new work on a reduced-toxicity stem cell transplant procedure that offers the hope of cure for many adult patients with SCD. Shortly after he was named a “Sammies” finalist, we talked to Rodgers about this exciting new curative therapy, as well as emerging evidence on genetic factors contributing to kidney disease in African Americans.

Non-myeloablative HSCT—emerging treatment for adult SCD

In addition to his duties as NIDDK Director, Rodgers has set aside time to continue his research on SCD—particularly new approaches to hematopoietic stem cell transplantation (HSCT). In children with SCD, HSCT from a matched sibling donor after myeloablative preparation is potentially curative. So far, hundreds of HSCT procedures have been performed in children with SCD at a handful of centers worldwide.

But for adults with SCD, transplantation hasn’t been an option. “One of the problems with doing the full myeloablative transplants in adults with SCD is [that] their organs have been damaged over the years as a result of the sickling process,” said Rodgers. “It puts them at very high risk of not actually being able to get through the conditioning regimen necessary for a full transplant.”

Last year, Rodgers and coauthors at the National Institutes of Health published a paper reporting an effective HSCT approach for adults with severe SCD. Their protocol used a non-myeloablative approach to conditioning, consisting of low-dose radiation along with small doses of chemotherapy. That regimen was designed to “provide some room in the bone marrow—not completely eradicating the entire marrow, which is the case with myeloablative transplants,” Rodgers said.

HLA-matched sibling blood stem cells were then infused, with the goal of achieving a state of “hematopoietic chimerism” in the recipient. “What we hope to correct is just the red cell defect, which is the genetic condition. So their red blood cell production ultimately will be donor origin, whereas their white cells and their platelets are all of recipient origin. And that’s what’s meant by a stable mixed chimerism—they’re half of one, and half of the other.”

The study included 30 patients with severe SCD or β-thalassemia major, ranging from 16 to 65 years of age. In 26 patients, HSCT reversed the disease, producing long-term stable donor engraftment without acute or chronic graft-versus-host disease. Fifteen patients of the 26 were able to discontinue immunosuppressive therapy.

After engraftment, hemoglobin levels normalized and hemolysis resolved, while brain imaging findings stabilized. Estimated pulmonary pressure decreased, and several patients were able to undergo phlebotomy to reduce excess iron in the liver. Four of the study participants had sickle nephropathy; none had further declines in renal function during follow-up.

Successful HSCT reduced hospitalizations from an average of 3.23 hospitalizations per year per patient before transplantation, to 0.63 during the first year after transplantation, and down to 0.11 percent in the third year. For patients taking long-term narcotics, morphine-equivalent doses decreased significantly. Since last year’s report, the NIH group has performed 12 additional successful HSCT procedures, for a total of 36 treated patients.

Other transplant centers have achieved similar outcomes, including successful outcomes in 15 of 16 patients at the University of Illinois Hospital & Health Sciences System in Chicago, according to Santosh Saraf, MD, assistant professor, internal medicine and oncology/hematology at the University of Illinois College of Medicine.

“We presented our data at the last bone marrow transplant meeting, and there were a lot of transplanters who were excited to see that this was validated, and the toxicity and outcomes were so good,” said Saraf. “We know of at least two or three other centers that decided that they were going to start opening this program as well.”

Saraf said he thinks the prospect for more widespread implementation in the coming years is “pretty good,” adding, “Having such a high cure rate with such low toxicity is kind of that perfect sweet spot of treatment.”

As in children, the need for HLA-matched sibling marrow is a key limiting factor. In Rodgers’ team’s experience screening adults for the study, “We find that somewhere in the neighborhood of one in four or one in five patients are likely to have a sibling match that could be used in this manner.” NIH and other transplant centers are also working on half-matched transplants, which could allow more patients to be transplanted.

The ultimate goal is to develop a more widely applicable approach. “The final end point is to take the patient’s own bone marrow, correct the mutation—or substitute something that would compensate for the mutation—and then give the bone marrow back to the patient,” said Rodgers. “And of course, in that case everyone will be potentially eligible. The problem is, even with the great advances that we currently have in gene editing technology, it still isn’t practical at the moment. But there are a number of groups, including our own laboratory, that are working on just this.”

Who gets sickle cell nephropathy—and why?

Nephrologists are familiar with nephropathy as a complication of SCD—kidney failure occurs in 5 to 18 percent of SCD patients. Rodgers said the kidneys are very sensitive to the effects of sickled red cells under certain situations, either when oxygen tension is low, or in hyperosmolar environments, when the cells give up their water. Over time, this repetitive sickling, vascular occlusion, and tissue damage eventually leads to sickle cell nephropathy.

And yet, most patients with SCD don’t develop renal failure. “There are obviously compensatory mechanisms that exist that allow this process to reverse,” said Rodgers.

So why do some patients develop sickle cell nephropathy while others do not? A growing body of evidence implicates genetic factors affecting resistance to parasitic diseases, according to Rodgers. “The mutation for sickle cell disease was thought to have arisen at some point in the old world, in Africa, thousands and thousands of years ago. This abnormality would cause their hemoglobin to polymerize, or aggregate, in affected individuals. And it’s this aggregation that causes the cells to sickle.

“As it turns out, the malaria parasite requires hemoglobin in order to undergo its life cycle, and it can’t ingest this aggregated hemoglobin very well.” Individuals with normal blood would be more vulnerable to malaria, while those with two copies of the sickle cell gene would die later of SCD.

But those who were heterozygous would be more likely to survive malaria, leading to a high frequency of the mutated gene in the population. Such a protective effect might explain why the sickle cell gene became highly prevalent in Africa and parts of the Mediterranean.

Sickle cell trait—one copy of the sickle cell gene—is generally a benign condition. But Rodgers noted a few areas of concern for nephrologists. “The two things that can encourage sickling of the red cells are a lack of oxygen or passing through a region that’s quite hyperosmolar. And the renal papilla is one part of the human body, probably the most distinct part, in which those conditions are met.

“So patients with sickle cell trait tend to have impairment in urine concentrating ability—which is due to so-called renal papillary necrosis. And oftentimes when they undergo this necrosis or damage to the renal papilla, that’s heralded by blood in the urine, known clinically as hematuria.”

Some reports suggest that African Americans with sickle cell trait may be at increased risk of kidney disease. One recent study of more than 2200 patients with chronic kidney disease (CKD) found that 19.2 percent of those who had sickle cell trait also had CKD, whereas 13.5 percent of those without sickle trait had CKD. Although the result was statistically significant, the effect size was modest, Rodgers said.

Sickle cell, APOL1, and kidney disease

Meanwhile, an emerging body of evidence implicates a different genetic factor, apolipoprotein L1 (APOL1), as playing a role in kidney disease progression in those with SCD. An APOL1 gene variant is far more common among African Americans than other groups—noteworthy since most people with sickle cell disease are also of African descent. It appears that those who have these APOL1 variants are protected against one of two forms of another type of parasitic disease: African sleeping sickness, or trypanosomiasis. “If it turns out that you have APOL1 kidney risk variants, and you also have sickle cell disease, this is what probably explains why certain patients go on to have kidney failure and others don’t,” Rodgers said. Approximately 13 percent of African Americans, or more than 5 million individuals, have two APOL1 risk variants, placing them at increased risk for kidney disease. This is a prime opportunity for precision medicine—one day developing effective medications that can treat APOL1 kidney disease.

“Recent research has suggested that sickle trait confers a small increased risk for CKD, much smaller than the effect of APOL1,” Rodgers said.

APOL1 is “really a remarkable story,” Rodgers added. “Understanding how it is that APOL1 perturbs either podocyte function or other cellular functions inside the kidney and leads to damage and ultimately to progression to end stage kidney disease is an area of intense investigation.”

Rodgers sees an opportunity to develop new classes of drugs that might be effective not only for those with two APOL1 gene variants, but also for those at risk of diabetic nephropathy—the most common cause of kidney disease and renal failure in the United States.

Meanwhile, increasing compliance with proper hydroxyurea dosing to improve SCD outcomes is an area of ongoing investigation. For example, a recent analysis looked at 383 patients with SCD who were seen at the NIH. While 66 percent of study participants were taking hydroxyurea, only 44 percent of those taking the drug were taking doses high enough to fall within the recommended range. The analysis was published in PLOS One in November (1). Rodgers was a co-author, as well as other researchers at NIDDK and the NIH’s National Heart, Lung and Blood Institute.

Participants taking recommended doses of hydroxyurea were 64 percent less likely to die from SCD, compared to those not taking hydroxyurea—a survival benefit not seen in patients taking lower doses. “This analysis suggests that many patients who take hydroxyurea should gradually increase their dose levels as tolerated, based upon the desired effect and side effects,” according to an NIH media advisory.

Hydroxyurea may also help protect kidney function in patients with SCD, according to a recent report in the Journal of the American Society of Nephrology (2). In that study, 58 adults with SCD had significant improvement in their urinary albumin/creatinine ratios six months after starting hydroxyurea therapy.

Rodgers didn’t win this year’s “Sammies” in the field of science and the environment—that honor went to Jacob Moss, a senior advisor from the Environmental Protection Agency, for his work on more efficient cook stoves and cleaner-burning fuels to reduce indoor pollution in developing countries.

But the NIDDK director’s dedication to scientific research and discovery has benefited countless patients and families affected by SCD. “Hydroxyurea elevated the quality of life and outcomes for our patients, and stem cell transplant is another level of elevation that will help cure patients with SCD,” Saraf said. “I think both have been very important strides for the care of our patients, with the hope of a new approach to cure in the future.”

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References

1. 

Fitzhugh CD, et al. Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia. PLoS ONE 2015; 10:11 e0141706. doi:10.1371/journal.pone.0141706

2. 

Pablo Bartolucci, et al. Six Months of Hydroxyurea Reduces Albuminuria in Patients with Sickle Cell Disease. JASN, November 2015 DOI: 10.1681/ASN.2014111126