COMMENTARY

What Causes Focal Segmental Glomerulosclerosis?

Lynda Szczech, MD

Disclosures

December 29, 2016

Bone Marrow-Derived Immature Myeloid Cells Are a Main Source of Circulating suPAR Contributing to Proteinuric Kidney Disease

Hahm E, Wei C, Fernandez I, et al
Nat Med. 2016 Dec 12. [Epub ahead of print]

Remember when we first learned that many gastric ulcers were actually caused by bacteria? One of those "so that makes sense now" moments? Nephrology is having one of those moments.

Did you ever wonder why kidney diseases that didn't appear to be inflammatory when you biopsied and looked at them under the microscope responded clinically to immunosuppressives? Another piece of the puzzle has been found and added, at least for focal segmental glomerulosclerosis (FSGS).

FSGS is a common glomerular disease in the United States, particularly among African American persons. It has been associated with genetic variants at the APOL1 gene locus as part of a two-hit hypothesis, most notably in HIV infection.[1] In HIV infection, a patient can achieve partial success in HIV-associated nephropathy with steroids,[2] but far more success with the use of antiretrovirals.[3] In FSGS not associated with HIV, treatment with steroids and other immunosuppressives are the mainstay of treatment.

What link between the more common FSGS and HIV-associated nephropathy allows them to share a potential response to immunosuppressives? Have we been looking too closely at the kidney?

The authors of this paper expand their view of the body to find the "what" and the "from where" to add to the "how," giving us a bottom line that the kidney truly is responding to heightened level of a circulating factor that originates elsewhere in the body, and results in the familiar biopsy and clinical course of FSGS seen at the kidney. Even if you have never read a basic science paper before, read on. A fascinating story is unfolding that will really help our patients in decades to come.

uPAR and suPAR: How Are They Linked to Kidney Disease?

The main characters of this story are uPAR (urokinase-type plasminogen activator receptor) and suPAR (soluble urokinase-type plasminogen activator receptor). uPAR, a receptor that binds plasminogen, is common throughout the body and plays a role in cellular destruction and degradation after plasminogen binds. suPAR is the soluble form of this receptor that correlates with activation of the immune system and is more elevated in very active and severe forms of disease.

The work preceding that of Hahm and colleagues provides the "how." As previously reported, suPAR binds to podocyte membranes, leading to foot process effacement and glomerular barrier disruption that ultimately produces the proteinuria and the clinical scenario we see when FSGS is identified on biopsy. Much attention has focused on suPAR, in that prior studies have identified that high levels of suPAR are associated with states of poorer kidney function and can predict progression of disease.

How Does One Tease Apart a Single Receptor and Figure Out Its Location?

The Koch postulates are commonly pointed to in identifying the microbial cause of a disease. Among the postulates are that the organism is not present in a person without disease, and that when you introduce the organism into a person, he or she gets the disease. So, as one reads about and follows the components of the experiments in Hahm and colleagues' experiments, this approach should be kept in mind.

There are multiple components of this paper that serve to change one variable at a time, introducing and pulling back different potential contributors of the pathway of suPAR production to kidney disease, and ultimately providing firm evidence for the "what" and "from where" in the story behind suPAR and FSGS. The key components are summarized here.

Hahm and colleagues started with mice that were unable to make uPAR and irradiated them to destroy their bone marrow. Some of these mice were transplanted with bone marrow from other mice that couldn't make uPAR, and some were transplanted with normal mouse bone marrow.

All transplanted mice received a dose of lipopolysaccharide (LPS), which induces proteinuria in mice. In response to the LPS challenge, the mice that got the deficient bone marrow didn't develop proteinuria, whereas the mice that got the "uPAR-capable" bone marrow did. So having uPAR in the body is necessary.

Next, they took normal mice and irradiated them before giving them the LPS challenge. Irradiated mice had a blunted suPAR response to the LPS challenge, with diminished proteinuria. Mice that were reconstituted with normal bone marrow had a greater response to LPS and proteinuria. So the source of the cell producing the suPAR appears to be bone marrow.

The investigators then turned their attention to characterizing myeloid cells in the bone marrow and in peripheral blood after LPS administration. Cells from the bone marrow exhibited elevated levels of uPAR on their membranes, whereas this was not the case in peripheral blood cells. Within the bone marrow, they observed that LPS stimulation increased the proportion of less mature myeloid cells (demonstrating greater expression of Gr-1 antigens).

To find out whether damage to these cell populations could affect the disease course, the investigators tested the effect of bone marrow irradiation and transplantation on animals with proteinuria. They found that this interrupted the disease course of proteinuria, substantially ameliorating it.

To reinforce the potential role of suPAR, the investigators then created a mouse that constitutively expressed suPAR in adipose tissue. Without the need for LPS stimulation, these mice developed proteinuria and podocyte foot process effacement.

To reinforce that the source of the suPAR was immature cells in the bone marrow, the investigators isolated low Gr-1 myeloid cells adoptively transferred into a normal mouse, finding that proteinuria was induced. This role of immature myeloid cells was subsequently further strengthened in models where removal of these cells lowered proteinuria.

Finally, investigators created an immunodeficient mouse and engrafted it with human hematopoietic cells. They then provided peripheral blood mononuclear cells from individuals with recurrent FSGS or healthy individuals into the mice. Mice receiving the whole cells from individuals with the kidney disease developed proteinuria and had, as expected, high levels of suPAR in both blood and urine. Furthermore, the histology of the kidneys was similar to that in human FSGS. The investigators performed studies supporting that this was not related to graft vs host disease.

A Change in Dogma?

This is a complicated paper that tests and retests the role and source of suPAR in a mouse model of human glomerular disease. The consistency of the results is striking, and although they are not definitive for unraveling why immunosuppressives are the key therapeutic choice in human FSGS, they clearly pull back the curtain and contribute toward our ability to eventually apply them in the diagnosis and therapy of humans.

One of the key phrases written by the authors is that "this may reflect a dogma shift away from the kidney to a different source of the cascade that results in diseases such as FSGS." This is the primary message to me as a clinician. The poor kidney is the innocent bystander. Things are beginning to make more sense.

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