Alfred Kim, MD, PhD

Alfred Kim MD PhD

Assistant Professor of Medicine; Assistant Professor, Pathology/Immunology Co-Director Lupus Clinic at Washington University

Clinical interests

  1. Systemic lupus erythematosus (SLE) including therapeutic clinical trials testing the newest treatments for lupus. Lupus Clinic co-directed with Dr. Deepali Sen
  2. Autoimmune kidney diseases

Research interests

B cells and glomerular injury

Awards

  • 2007 Resident of the Year (Washington University School of Medicine)
  • 2010 Distinguished Fellow Award (American College of Rheumatology)
  • 2011 Scientist Development Award (American College of Rheumatology/Rheumatology Research Foundation)
  • 2014 Investigator Award (American College of Rheumatology/Rheumatology Research Foundation)

Figure 1

Figure 1 (above). Scanning electron micrograph of a mouse glomerulus. The glomerulus is a specialized capillary loop, which filters blood to generate urine. Seen above is the glomerulus from the urinary space. Podocyte foot processes, primary and secondary processes, and cell body wrap around the glomerular capillary. The foot processes lose their interdigitating structure in proteinuric conditions (foot process effacement, see figure 2 below). Image obtained by Alfred Kim.

Figure 2

Figure 2 (above). Foot process effacement is the loss of normal foot process morphology. The left column show normal foot processes by transmission electron microscopy on top and scanning electron microscopy on the bottom. The right column shows diffuse foot process effacement from CD2AP-deficient mice generated by Dr. Andrey Shaw’s group (Shih et al. Science, 286:312, 1999). Note the complete loss of normal foot process morphology in the effaced samples. Effacement is seen in virtually all patients with heavy proteinuria (nephrosis). SEM Images obtained from Alfred Kim.

B cell depletion therapies are highly efficacious in several autoimmune diseases, but the mechanism of how B cells depletion mediates reduction in disease activity remains unclear. Many hypothesized that as B cells are depleted, autoantibodies should also disappear, but autoantibody-producing plasma cells are not eliminated with current B cell depletion therapies such as rituximab. This strongly suggests that antibody-independent effector functions of B cells such as cytokine secretion or antigen presentation to T cells may play critical roles in autoimmune tissue injury and failure.

One class of diseases where B cell depletion surprising demonstrated efficacy is nephrotic syndromes, a heterogenous group of kidney diseases (i.e. minimal change disease, primary focal segmental glomerulosclerosis) characterized by massive protein loss in the urine (proteinuria) and foot process effacement of the podocyte within the glomerular filtration unit. Rituximab efficacy is surprising in these conditions, as no B cells have been found in diseased kidneys at the time of biopsy nor is there any antibody or complement deposition in the glomeruli (a finding characteristic of immune-complex mediated glomerulonephritis). Autoantibodies are also absent in these conditions.

We hypothesized that B cells contribute to tissue injury through antibody-independent effector functions such as cytokine secretion. We have previously found that B cell-derived cytokines, particularly IL-4, alters actin cytoskeletal dynamics in podocytes which led to foot process abnormalities in vitro. Using a novel murine model of B cell induced proteinuria that we developed, we found that B cell-derived IL-4 is glomerulotoxic in vivo, leading to proteinuria and foot process effacement. Using this model, we found that IL-4 signaling was active within glomeruli (using phosphorylated STAT6 as a surrogate readout). Furthermore, using intravital two-photon microscopy (in collaboration with Dr. Mark Miller, Infectious Diseases), we observed that B cells arrested their trafficking within the glomerulus when cognate antigen was present. This strongly suggested the B cells become activated intraglomerularly and secrete cytokines such as IL-4 that subsequently drive glomerular pathology. Finally, if IL-4 signaling was blocked using JAK inhibitors, IL-4 mediated proteinuria was also abrogated.

Finally, using renal biopsy samples from patients with minimal change disease (in collaboration with Dr. Sanjay Jain of the O’Brien Center in the Renal Division at Washington University, the NEPTUNE cohort and Dr. Jeffrey Hodgin at the University of Michigan, and Dr. Ania Koziell at King’s College/Evelina Children’s Hospital in London, UK), we found that ~20% of untreated minimal change disease patients possessed activated glomerular STAT6. This implies that IL-4 may be playing a causative role in podocyte injury and proteinuria in this subset of patients. Furthermore, this suggests that blocking IL-4 in these patients will be efficacious and spare these patients from having to take long courses of glucocorticoids that have well-established significant side effects.

Current projects in the lab related to this topic include:
a) Laser-capture micro dissecting glomeruli from renal biopsy specimens obtained from patients with untreated nephrotic syndromes and other immune-mediated kidney diseases (i.e. lupus nephritis) to identify the cytokines acting on injured glomeruli. This has the potential to identify pathologic cytokines driving glomerular injury in a large spectrum of patients with nephrotic syndromes.
b) Determining how toll-like receptor (TLR) agonists can drive B cells to induce glomerular injury and proteinuria. As B cells can be nonspecifically activated by pathogen-associated molecular patterns (PAMPs) such as CpG motifs, this may be an alternative and more physiologically relevant mechanism for B cell-mediated glomerular damage.
c) Initiating a clinical trial to test IL-4 blockade in minimal change disease patients with activated glomerular STAT6.

2) CLARITY imaging of the mouse and human kidney using two-photon microscopy

3

Figure 3 above. Two-photon microscopy of mouse kidney cleared by CLARITY. In red are the glomeruli (stained with anti-podocin antibody), green is collagen and blue represents tubules. This approach will enable us to image the kidney with unprecented depth and resolution. Image courtesy of Matthew Cheung (under-graduate at SLU), Bernd Zinselmeyer and Alfred Kim.

Recent advances in tissue processing and imaging has enabled investigators to observe cellular processes within organs at with unprecedented detail. In collaboration with Dr. Bernd Zinselmeyer (Pathology and Immunology), we are utilizing multiple tissue clearing approaches (including CLARITY) coupled with two-photon microscopy to observe immune cell architecture with the kidney in a variety of model diseases.

3) Genetics of autoimmunity
In collaboration with Elisha Roberson, PhD, (Rheumatology), we are whole exome sequencing families with multiple members affected with autoimmune disease to identify rare genetic coding variants that may play causal roles in these families. Using CRISPR/Cas gene editing approaches, we will test the functional role of these variants in primary human immune cells in vitro and generate mice to evaluate for the presence of autoimmune disease.

4) Utility of iC3b as a diagnostic and disease activity monitoring tool in SLE
There is a significant unmet need to identify better markers for disease activity and diagnosis in SLE. In collaboration with Kypha Inc., we are performing a prospective study in our lupus clinic evaluating whether the complement protein iC3b associates with SLE disease activity and whether it can be used as a new diagnostic tool for SLE.

5) Biobanking patients with SLE
We see a high volume of patients in our lupus clinic, all of whom undergo SLEDAI-2K Responder Index-50 phenotyping. In conjunction with the Rheumatic Diseases Core Center (Principle Investigator: Dr. Wayne Yokoyama), we are currently banking peripheral blood lymphocytes, plasma/serum, spit (for genomic DNA extraction), and when possible, renal, synovial, and skin biopsy specimens for translational studies by WUSM investigators.

Kim Lab