Disease-modifying therapies for rare CKD
The need for new solutions
The majority of glomerular proteinuric diseases are classified as rare. For decades, people diagnosed with these rare proteinuric forms of CKD have faced the prospect of steadily declining kidney function and ultimately end-stage kidney disease — the complete failure of filtration capacity.
Even with treatment, many patients with focal segmental glomerular sclerosis (FSGS) and membranous nephropathy (MN) will progress to kidney failure in about a decade, and it is estimated that one-third of those with immunoglobulin A nephropathy (IgAN) reach end-stage disease within 20 years of diagnosis. In Alport Syndrome (AS), an X-linked genetic disease, the risk of progression to ESKD among men is 100%.
FSGS
Focal segmental glomerular sclerosis
~40k
US patients1
Progress to ESKD3
~50%
IgAN
Immunoglobulin A nephropathy
~110k
US patients2
Progress to ESKD3
~30%
MN
Membranous nephropathy
~57k
US patients4
Progress to ESKD5
~10-20%
AS
Alport Syndrome
~60k
US patients6
Men with x-linked disease progress to ESKD7
~100%
Percentages represent prevalence of each respective disease
Sources: (1) NephCure (https://nephcure.org/get-involved/advocacy/nephcure-policy-priorities); (2) Lerma, Edgar V., et al., Kidney medicine 5.9 (2023): 100693; (3) Cheung C.K., et al., J. Clin. Med. 2021, 10, 2493; (4) Moroni G and Ponticelli C (2020) Secondary Membranous Nephropathy. A Narrative Review. Front. Med. 7:611317. doi: 10.3389/fmed.2020.611317; (5) Couser WG., “Primary Membranous Nephropathy.” Clinical Journal of the American Society of Nephrology: CJASN, 12(6), 2017; (6) Warady, Bradley A., et al., Kidney medicine 2.5 (2020): 639-649
Current treatments
In proteinuric kidney diseases, damage to the filtration barrier leads to leakage of protein into the urine (proteinuria). The presence and degree of proteinuria influence risk for progression to ESKD. Existing treatment options primarily are either immunomodulators, which reduce the autoimmune drivers in some forms of CKD, or hemodynamic modulators, which reduce the pressure within the glomerulus, thereby decreasing the physical forces impinging on the blood filtration structures. But neither directly address the cellular stress responses that promote proteinuria — the leakage of blood proteins into urine that occurs as the kidney filtration barrier breaks down.
Advances in the understanding of CKD have led to increased focus on proteinuria as a measure of damage to the kidney’s filtration structures. The level of proteinuria is a prognostic factor in assessing the risk for progression to ESKD. Guidelines set by the international nonprofit Kidney Disease: Improving Global Outcomes (KDIGO) recommend supportive care and disease-specific strategies to lower proteinuria in an effort to preserve kidney function. KDIGO guidelines for proteinuria reduction in glomerular disease vary among the different causes of CKD. Durably achieving these targets often requires treatment with a combination of drugs, carefully balancing different mechanisms of action and side effects to achieve the desired result. Yet even with the diversity of treatments available today, a large fraction of patients are not well controlled.
In this treatment environment, highly effective disease-modifying drugs with superior side effect profiles are essential to help patients and their physicians meet treatment targets and avoid ESKD. Walden’s programs are designed to achieve this and offer a new approach to proteinuric CKD
Learn more about the common biological thread that underpins many rare chronic kidney diseases.
Pipeline
Scientific Publications
suPAR
Independent data showing mechanism of suPAR damage to cells
Kim EY and Dryer SE., Role of Formyl Peptide Receptors and β-Arrestin-1 in suPAR Signal Transduction in Mouse Podocytes: Interactions with αVβ3-Integrin, Cells 13, 172 (2024)
Mendelian Randomization demonstrates that suPAR causes renal disease
Hindy G, Tyrrell DJ, Vasbinder A, et al., Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis. J Clin Invest. Dec 15;132(24):e158788 (2022). See Figure S12 in supplementary data for association between suPAR, eGFR, and CKD
Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis (FSGS)
Wei C, El Hindi S, Li J, et al., Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17, 952–960 (2011)
Association of suPAR levels with incident CKD and accelerated decline in eGRF
Hayek SS, Sever S, Ko YA, et al., Soluble urokinase receptor and chronic kidney disease. NEJM 373, 1916-1925 (2015)
suPAR fragment is toxic to islet cells and impacts late onset type 1 diabetes
Ke Z, Mukherjee K, Wei C, et al., The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease. Sci Transl Med. Sep 20;15(174):eabq6492 (2023)
What is the role of suPAR in evolution
Wei C, Datta PK, Siegerist F, et al., suPAR mediates viral response proteinuria by rapidly changing podocyte function. Nat Commun 14, 4414 (2023)
Dynamin
Key publication showing drugging of dynamin will have multiple beneficial outcomes on CKD from stimulating dynamin pathway
Schiffer M, Teng B, Gu C, et al., Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat Med 21(6):601–609 (2015)
Simultaneous activator treatment in two different kidney specific cells leads to improvements in crosslinking that preserves renal function
Mukherjee K, Gu C, Collins A, et al., Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury. Nat Commun 13, 2422 (2022)
Role of dynamin in foot process formation and maintenance
Soda K, Balkin DM, Ferguson SM, et al., Role of dynamin, synaptojanin, and endophilin in podocyte foot processes. J Clin Invest. 122(12):4401–4411 (2012)
CD2AP is gatekeeper of podocyte TGF-β1 response. Genetic lesions in CD2AP leads to renal failure
Yaddanapudi S, Altintas MM, Kistler AD, et al., CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest 121(10):3965-3980 (2011)