(From the October 2015 issue of Research Now)
The most common pediatric cause of nephrotic syndrome, a disorder that leads to kidney damage and loss of too much protein in the urine (proteinuria), is minimal change disease, also known as minimal change nephrotic syndrome. The initial acute phase of minimal change nephrotic syndrome (MCNS) is difficult to control – by the time patients with proteinuria and edema are seeing a doctor, glomerular injury has already occurred. Once the initial phase passes, however, there may be an opportunity to prevent some further injury to the glomeruli, the tiny units within the kidney where blood is cleared.
Recent research published in Clinical & Experimental Immunology demonstrates that the initial acute phase actually leads to the attraction of monocyte-derived macrophages into the kidneys, which exacerbates the disease. Macrophages, which reside in every tissue of the body, are large, specialized cells of the immune system that form in response to infection or accumulating damaged or dead cells.
“A few weeks after the first episode, there is a second wave of inflammatory cells that can damage the kidneys,” says Santiago Partida-Sánchez, PhD, principal investigator in the Center for Microbial Pathogenesis at The Research Institute at Nationwide Children’s Hospital and senior author of the study. “You could stop those cells if you knew how they were being recruited.”
To find out, both Wistar and T-cell deficient nude rats were injected with the antibiotic puromycin aminonucleoside (PAN) to induce nephrotic syndrome (NS). PAN-NS in rats is a model of human MCNS.
In Wistar rats, researchers found strong evidence for a chain of events that results in greater damage to the kidneys after the first phase of PAN-NS. T helper type 1 lymphocytes release the cytokine IFN-y, and glomerular cells secrete glomerular tumor necrosis factor alpha (TNF-α). IFN-y and TNF-α, are small proteins important in cell signaling. They work synergistically to stimulate the release of the cytokine CXCL10 by glomerular podocytes, kidney cells that wrap around the capillaries of the glomerulus.
CXCL10 is a potent chemoattractant, or chemical agent, that directs the movement of activated macrophages from the blood into the kidneys in response to this stimulus. Those macrophages then aggravate PAN-NS, potentially leading to progressive glomerular disease and end-stage renal failure, the last stage of chronic kidney disease when the kidneys can no longer support the body’s needs.
In T-cell deficient nude rats, however, concentrations of IFN-y were nearly the same as in control animals without induced PAN-NS. The nude rats also had minimal macrophage infiltration, as did Wistar rats whose macrophages had been depleted after the first development of proteinuria. Overall, both macrophage depletion and the absence of mature T cells partially prevented injury to glomerular podocytes – an injury that leads to massive proteinuria in PAN-NS.
These findings point to possible clinical applications, says Dr. Partida-Sánchez, who is also an associate professor of Pediatrics at The Ohio State University College of Medicine. Antibodies can block chemokine receptors or chemokines such as CXCL10 that recruit the activated monocyte-derived macrophages.
“We have to explore more pathways,” explains Dr. Partida-Sánchez. “Each axis of chemokine and chemokine receptor involved in attracting monocytes to the kidney may contribute differently to aggravate renal injury.”
Petrovic-Djergovic D, Popovic M, Chittiprol S, Cortado H, Ransom RF, Partida-Sánchez S. CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis. Clinical and Experimental Immunology. 2015 May;180(2):305-15.