African Americans - Hypertensive with CKD
Chronic Kidney Disease (CKD), the progressive loss of kidney function, disproportionally impacts African Americans. Due in large part to higher rates of diabetes and hypertension (high blood pressure), African Americans are three to four times more likely to suffer from CKD than Caucasians. One of the most serious consequences of untreated CKD is end stage renal disease (ESRD), where the kidneys have ceased to function and the individual requires continuous on-going dialysis or kidney transplantation. Kidney disease is reaching epidemic proportions in the United States. It is estimated that more than 7 million African Americans are afflicted with this potentially devastating condition.
According to the National Kidney Foundation, hypertension is the second leading cause of kidney failure among African Americans. The prevalence of hypertension in African Americans in the United States is among the highest in the world and the onset of hypertension in African Americans generally occurs at an earlier age than Caucasians. Contributing to this condition is the tendency for African Americans to be particularly sensitive to high salt diets, referred to “salt sensitive”. Research studies have shown that greater than 70% of hypertensive African Americans are salt sensitive. The exact cause of salt sensitivity is not fully understood, but hereditary genetic factors relating to sodium excretion and vascular tone are believed to play a key role.
In 2010, two variant, or mutated, alleles of the APOL1 gene on chromosome 22 were found to be associated with non-diabetic kidney disease in African Americans. It is estimated that over 50% of African Americans possess one risk allele and approximately 11-13% possess both. Compared to non-carriers of the mutated APOL1 gene, individuals possessing both alleles have a 2-fold greater risk of their chronic kidney disease progressing to ESRD. This risk increases to 7-fold among hypertensive individuals having both alleles.
Current treatment options for non-diabetic hypertensive African Americans with CKD are focused on managing their hypertension. These treatment approaches include diet and lifestyle changes, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta blockers, diuretics and calcium channel blockers. However, these treatments, at best, only slow the progression of kidney disease. Therefore, the lack of any direct treatment for this patient population represents a significant unmet medical need.
DM199 is a recombinant, or synthetic, form of the KLK1 protein also known as a serine protease. KLK1, a naturally occurring protein produced by the body, is a critical protein used by the body to maintain healthy, stable blood flow. The action of KLK1 as an agent to lower blood pressure was first recognized more than 100 years ago. In the century since its discovery, scientists have learned that KLK1 plays an essential role in maintaining kidney health and normal function. Furthermore, low levels of KLK1 have been associated with the progression of CKD. Research studies have also shown that African Americans tend to exhibit lower levels of naturally occurring KLK1 protein than Caucasians.
DM199 was created as a protein replacement therapy. In the case of non-diabetic, hypertensive African Americans with CKD, we believe that DM199 represents a potential shift in the treatment paradigm. We believe that DM199 may potentially act on the following inter-related mechanisms in the kidney to promote better overall function, stable blood flow and ultimately may potentially protect the kidney from further damage.
- Increasing renal blood flow and filtration by dilating the renal arteries and reducing pressure;
- Reducing inflammation, oxidative stress and fibrosis;
- Reducing kidney injury and levels of proteinuria; and
- Restoration of the body’s ability to regulate sodium and potassium.
As a serine protease, DM199’s mechanism of action is believed to modulate many different biological functions in the kidney. DM199 is believed to release bradykinin-mediated nitric oxide and prostaglandins (PGE2 and PGI2-cAMP) in the kidney. Nitric oxide and prostaglandins are believed to work synergistically to improve renal blood flow in a healthy or physiological manner. These signaling molecules dilate the renal arteries (afferent & efferent arterioles) to improve blood flow at lower pressures and are believed to reduce inflammation, oxidative stress and fibrosis. DM199 may also play a key role in restoring the body’s ability to naturally regulate salt retention by modulating the function of the epithelial sodium channel (ENaC).
DiaMedica is currently sponsoring a 30 patient, Phase 2 trial of DM199 in Non-Diabetic Hypertensive African Americans. This proof-of-concept trial will be conducted at approximately 5 sites in the United States. Under the current protocol, patients will receive DM199 as a subcutaneous injection twice per week for three months. The study is designed to evaluate changes in eGFR (blood flow through the kidney) and protein albuminuria (renal filtration ability). DiaMedica also intends to identify subjects with the APOL1 risk allele(s) in order to assess its impact on response to DM199 therapy.
To learn more about this study, or if you are interested in participating, please visit clinicaltrials.gov.