Chronic Kidney Disease

Overview

DM199 offers a novel approach for the treatment Chronic Kidney Disease (CKD). CKD is a widespread health problem that generates significant economic burden throughout the world. The increasing incidence of CKD results in over 30 million Americans1 and 120 million Chinese2 suffering from this debilitating and potentially life-threatening condition. Primary causes of CKD are diabetes (Type 1 and Type 2) and hypertension. Over 40% of all diabetics will eventually develop CKD3 making it one of the more common risks for diabetics. Clinically, CKD is characterized by persistent protein in the urine (proteinuria) and a progressive loss of the kidney’s normal ability to filter out waste products. This loss of kidney function increases the risk for hypertension and life-threatening heart disease. 

Currently, there is no cure for CKD and treatment involves managing the inevitable disease process.  Blood pressure medications, such as angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) are often prescribed to control hypertension, and hopefully, slow the progression of CKD.  Nevertheless, many patients continue to show declining kidney function, and approximately 20% will progress to end stage renal disease despite receiving the standard of care, where dialysis or a kidney transplant are needed.

DM199 for Chronic Kidney Disease


More effective treatments are clearly needed to address the growing problem of CKD. DM199 is a recombinant form of human tissue kallikrein (KLK1), a protein which plays a vital role in normal kidney function. KLK1 releases bradykinin (BK) to activate the BK receptor system, triggering mechanisms that mitigate or repair damage to the kidney. Additionally, BK and the BK receptors are critical for healthy kidney integrity. It is becoming increasingly clear that patients with moderate to severe CKD have abnormally low levels of KLK1, and it is hypothesized that this KLK1 deficit contributes to disease progression. DM199 has been shown to replenish endogenous KLK1 and fully activate the BK system that protects the kidney from damage. In fact, DM199 treatment in an animal model of Type 1 Diabetes delayed the onset of the disease, attenuated the degree of insulitis and improved pancreatic beta cell mass in a dose-dependent manner by increasing T regulatory cells (Tregs). By providing additional KLK1, DM199 has the following beneficial actions:

  • Improves blood flow to the kidney by dilating blood vessels (vasodilation).
  • Promotes formation of new blood vessels (angiogenesis).
  • Supports the structural integrity of the kidney by reducing scar tissue formation (fibrosis), oxidative stress, and inflammation.
  • Activates mechanisms that upregulates Tregs, improve insulin sensitization, glucose uptake, glycogen synthesis, and lower blood pressure.

DM199 treatment directly replenishes KLK1 levels, normalizing kidney function. Current treatment options, especially ACEi drugs, only partially restore kidney function and are associated with high-risk side effects. ACEi drugs block the renin-angiotensin system (RAS) and increase BK by preventing the breakdown processes that normally target the effects of BK to the kidney. While this increase benefits the kidney, ACEi drugs generate excessive BK where is it not needed, potentially leading to related side effects such as cough and angioedema. DM199 treatment allows KLK1 to follow its normal physiological processes and release BK when and where it is needed, avoiding these side effects. Importantly, successful treatment with ACEi in kidney disease requires a fully functional KLK1 system, potentially making ACEi drugs less effective in patients with a pre-existing KLK1 deficit. Furthermore, blockage of the RAS by ACEi drugs can result in dangerous increase in potassium (hyperkalemia), leading to serious cardiac complications. These issues have not been seen with DM199 treatment.

A porcine form of the KLK1 protein has been approved in Asia and DiaMedica estimates that over 100,000 patients with CKD are treated each year. Numerous clinical papers have been published highlighting the positive effects of porcine KLK1 treatment alone or combined with valsartan (an ARB) in patient with CKD.  Clinical studies range from one to six months of KLK1 treatment and demonstrate a time-dependent improvement in kidney disease based on urinary protein excretion rate and other physiological markers that are reflective of kidney health. 

DiaMedica is preparing for an upcoming clinical trial in patients with moderate CKD.

 

For additional information, please see these published papers:

Liu et al. 2017. The kallikrein-kinin system in diabetic kidney diseaseCurr Opin Nephrol Hypertens 26(5): 351-357. 

Liu et al. 2016. Exogenous kallikrein protects against diabetic nephropathyKidney International 90: 1023-1036.

Maneva-Radicheva et al. 2014. Autoimmune diabetes is suppressed by treatment with recombinant human tissue kallikrein-1PLOS One 9(9): e107213

Kayashima et al. 2012. Kinins-the kallikrein-kinin system and oxidative stressCurr Opin Nephrol Hypertens 21(1): 92-96

Madeddu et al. 2007. Mechanisms of disease: the tissue kallikrein-kinin system in hypertension and vascular remodelingNat Clin Pract Nephrol 3(4): 208-21

Chao et al. 2006. The tissue kallikrein system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reductionBiol. Chem 387: 665-675. 

Naicker et al. 1999. Tissue kallikrein and kinins in renal diseaseImmunopharmacology 44: 183-192.

 

Notes:

  1. National Kidney Foundation. About Chronic Kidney Disease. 2017.
  2. Zhang, L., et al. Prevalence of Chronic Kidney Disease in China: A Cross-Sectional Survey. Lancet. 2012 Mar 3; 379(9818):815-22.
  3. Reutens, AT. Epidemiology of Diabetic Kidney Disease. The Medical Clinics of North America. 2013 Jan; 97(1):1-18.