(From the September 2015 Issue of PediatricsOnline)
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.
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.
“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 work synergistically to stimulate the release of the cytokine CXCL10 by glomerular podocytes.
CXCL10 is a potent chemoattractant that directs activated macrophages from the blood into the kidneys. Those macrophages then aggravate PAN-NS, potentially leading to progressive glomerular disease and end-stage renal failure.
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.