Pursuing Progress in Pediatric Chronic Kidney Disease
The incidence of childhood chronic kidney disease (CKD) has been increasing steadily over the last 20 years and is conservatively estimated to exceed 200,000 children in the United States. CKD has no cure and inevitably progresses to end-stage kidney disease (ESKD), which requires dialysis or kidney transplantation.
“Chronic kidney disease is an umbrella term for any progressive disease of the kidney associated with a decline of the kidney function,” says Oleh M. Akchurin, MD, PhD, a pediatric nephrologist at NewYork-Presbyterian Komansky Children’s Hospital and Assistant Professor of Pediatrics at Weill Cornell Medicine. “Gradually, a child will lose kidney function and sooner or later arrive at end-stage kidney disease. At this stage, the only treatment option available to save the child’s life is kidney replacement therapy.”
“The etiologies of chronic kidney disease in children are very different from adults,” notes Dr. Akchurin. “In adults, diabetes and hypertension are the likely causes, while more than 50 percent of children develop CKD as the result of congenital anomalies of the kidney and urinary tract. Glomerular disorders are the second major cause.”
Dr. Akchurin’s clinical and research expertise includes issues related to growth, nutrition, and inflammatory and metabolic changes in children with chronic kidney disease. He has conducted research in each of these areas, integrating studies at the basic and translational science levels with analysis of patient data to better understand the multiple complications affecting children with CKD. Dr. Akchurin is particularly interested in both iron metabolism and iron therapy in CKD.
Key to his research has been the availability of data and tissue samples, which he began accumulating some eight years ago from pediatric patients with a diagnosis of chronic kidney disease seen at NewYork-Presbyterian Komansky. The growing biorepository of these samples has informed several published studies by Dr. Akchurin and his Weill Cornell Medicine colleagues.
“Intriguing connections between iron and various aspects of CKD pathophysiology open promising opportunities for the optimization of care via carefully selecting those modalities of iron therapy that not only improve anemia, but also have favorable effects on other CKD complications,” says Dr. Akchurin, whose research in this area has included studying the contribution of Interleukin-6 to the development of anemia in children with CKD and how iron may be implicated in the pathophysiology of many CKD manifestations and complications.
“The kidney is also involved very heavily in mineral and bone metabolism through various mechanisms, including vitamin D that is activated in the kidney,” adds Dr. Akchurin. “However, many questions about mineral and bone complications in CKD remain unclear. For example, we do not know to what extent inflammation is involved as some of the bone lesions we see in CKD are also present in children with other chronic inflammatory diseases, such as juvenile arthritis and lupus. CKD is also characterized by chronic low-grade inflammation, albeit different from the inflammation found in rheumatologic diseases. Therefore, we wanted to clarify whether inflammation plays a role in mineral and bone disease and growth problems in our children with CKD.”
For this research, Dr. Akchurin and his team accessed samples from their biorepository from which they had previously developed a panel of 10 inflammatory markers as well as several markers of bone metabolism within their patient cohort. “We analyzed how these markers are related and found that one cytokine – tumor necrosis factor alpha [TNF-α] – was very closely associated with many bone biomarker parameters and therefore bone disease, and negatively correlated with height z-score, so shorter children had higher serum levels of TNF-α. This was not known before.”
A Novel Approach to Predicting CKD Progression
In May 2021, Dr. Akchurin received a Hartwell Individual Biomedical Research Award from The Hartwell Foundation to further support his investigations to improve understanding of the cellular and molecular mechanisms of CKD with a goal to:
- Identify new therapeutic targets that will enable novel personalized approaches focused on protecting the kidney and mitigating kidney fibrosis, thus delaying the initiation of dialysis or kidney transplantation
- Set the stage for testing engineered myeloid cells as a novel therapy in children through preclinical studies on adoptive transfer of engineered macrophages
- Facilitate the early detection of unwanted effects of medications and reduce the pill burden currently encountered by children with CKD
“Currently we do not have biomarkers that will reliably inform us on the early changes in the kidneys during CKD,” says Dr. Akchurin. “Until a patient loses more than half of their functioning kidney tissue, their currently available blood tests are still normal. That is the problem.”
Multiple complications can contribute to poor quality of life in children with CKD, including anemia, alterations in iron metabolism, hypertension, bone disorders, and other systemic conditions. This presents a catch-22 to clinicians: Most available therapies target CKD complications and are not delaying disease progression; furthermore, effects of these medications that control CKD complications on the kidney function are frequently unclear. “Unfortunately, each of these complications requires its own separate treatment so it is not uncommon that children may have to take up to 15 pills a day,” adds Dr. Akchurin. “As we are already overboard with treatments for these patients, we have to be very smart about introducing new treatments.”
Importantly, these complication-controlling treatments also may trigger kidney fibrosis. “For example, our experiments in mice showed that certain oral iron preparations were unexpectedly found to accelerate kidney fibrosis,” notes Dr. Akchurin. “Patients can receive kidney transplants to replace damaged kidneys, but there are currently no therapies to reverse renal fibrosis. What we can do is try to slow down disease progression by individualizing the selection of these treatments to minimize their adverse effects and maximize their beneficial effects. However, currently available laboratory tests for kidney function are not sensitive to the timely progression of kidney fibrosis and only signal very advanced kidney damage. Kidney biopsy can provide direct assessment of the disease but it is invasive and cannot be used to track disease progression. Risks of kidney biopsy include bleeding and potential loss of the kidney.”
With the Hartwell grant, Dr. Akchurin is tackling this impediment to timely care by investigating the potential of immunophenotyping peripheral blood monocytes for detecting the progression of CKD earlier on in the disease course. His goal is to determine the immunophenotype of circulating monocytes in comparison to healthy children without CKD and identify monocyte characteristics correlating with key clinical parameters. “We are interested in monocytes primarily because they are precursors of kidney macrophages, which, in the setting of kidney fibrosis, underlies chronic kidney disease,” explains Dr. Akchurin. “The monocytes invade the injured kidney tissue and accelerate the development of fibrosis, although some of these cells may be protective.”
“We know that fibrotic transformation of the kidney is when gradually functioning kidney tissue is being replaced by scar tissue, but understanding the drivers behind this very complex process is far from being complete despite decades of research,” adds Dr. Akchurin. “This has been particularly understudied in the context of pediatric CKD.”
Dr. Akchurin’s preliminary data suggest that macrophages may become protective against renal fibrosis after they take up iron. Using cutting-edge single-cell transcriptomic approaches, Dr. Akchurin seeks to identify monocyte signatures that are unique to children with CKD and therefore may enable the development of a liquid biopsy, which would only require a blood draw to sample the circulating monocytes. “Our patients, unfortunately, need to undergo frequent blood draws. But during a routine venipuncture, we can obtain this potentially very valuable source of information that can give us an insight into what’s going on in the kidney.”
“There are very few studies where people have analyzed peripheral blood mononuclear cells in adults with CKD using single cell RNA sequencing and none that involve children. If we can use peripheral blood mononuclear cells population as an additional way of evaluating fibrosis and as a potentially new way of assessing disease progression, this may pave the way for personalization of treatment for children, as well as provide prognostic biomarkers that can guide the selection of existing treatments.”
Furthermore, according to Dr. Akchurin, in the future monocytes can be used therapeutically after enhancing their beneficial features. This engineering process can range from exposing the cells to certain growth factors or medications, including iron, followed by the adoptive transfer of engineered myeloid cells back to the patient’s body to treat the fibrosis.
“If we can use peripheral blood mononuclear cells population as an additional way of evaluating fibrosis and as a potentially new way of assessing disease progression, this may pave the way for personalization of treatment for children, as well as provide prognostic biomarkers that can guide the selection of existing treatments.” — Dr. Oleh Akchurin
Collective Power of Two Children’s Hospitals Mobilizes Progress in Pediatric Nephrology
More recently, the Pediatric Nephrology Divisions at both NewYork-Presbyterian Komansky Children’s Hospital and NewYork-Presbyterian Morgan Stanley Children’s Hospital have begun working closely together leveraging the collective expertise and resources of both hospitals. This collaboration has provided an opportunity to expand the biorepository initiated by Dr. Akchurin and to strengthen investigations in research.
“This allowed us to further increase the patient sample size and subsequently the power of our analysis for future studies,” notes Dr. Akchurin. “We are currently collaborating on a project with Dr. Fangming Lin, Chief of Pediatric Nephrology and a physician scientist at NewYork-Presbyterian Morgan Stanley, that leverages the patient population served not only by Columbia and Weill Cornell Medicine but also by the campuses of NewYork-Presbyterian throughout the New York metropolitan area. This will provide us with useful data that allows us to answer several research questions important to optimizing the therapies we currently have and ultimately slow down progression of CKD in children.”
Tumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease. Meza K, Biswas S, Zhu YS, Gajjar A, Perelstein E, Kumar J, Akchurin O. Pediatric Nephrology. 2021 Jun;36(6):1579-1587.
Erythropoiesis-independent effects on iron in chronic kidney disease. Patino E, Akchurin O. Pediatric Nephrology. 2022 Apr;37(4):777-788.
Carbonyl iron and iron dextran therapies cause adverse effects on bone health in juveniles with chronic kidney disease. Patino E, Doty SB, Bhatia D, Meza K, Zhu YS, Rivella S, Choi ME, Akchurin O. Kidney International. 2020 Nov;98(5):1210-1224.
Interleukin-6 Contributes to the Development of Anemia in Juvenile CKD. Akchurin O, Patino E, Dalal V, Meza K, Bhatia D, Brovender S, Zhu YS, Cunningham-Rundles S, Perelstein E, Kumar J, Rivella S, Choi ME. Kidney International Reports. 2018 Dec 19;4(3):470-483.
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