Tighter glucose and blood pressure control found to decrease incidence.
Chronic kidney disease (CKD) is characterized by the inability to normally excrete certain metabolites from the body due to inadequate renal function. In the United States, approximately 20 million (~10%) people suffer from chronic kidney disease to different extents. Diabetes along with high blood pressure are the leading risk factors for chronic kidney disease development. The macrovascular and microvascular complications from these diseases explain some of the physiological manifestations. For instance, reduced blood flow to the kidney results in impaired kidney function, which impairs glomerular filtration leading to accumulation of protein and other metabolites in the body. Build up from these metabolites (i.e. urea) results in various long-term health complications. Recently, urea has been linked to the development of diabetes through pancreatic beta cell destruction. Urea is associated with impaired cellular functions and increases oxidative functions in the peripheral tissues, which can ultimately impede glucose uptake by adipocytes and muscle tissue.
In a recent study by Vincent Poitout et al., CKD was associated with improper insulin secretion in mice models due to glucose intolerant patterns seen in models who were fed glucose (p<0.001). This discovery was the result of a hypothesis postulated by these researchers, where they explain that reactive oxygen species have a role in glucose-stimulated insulin secretion by acting as secondary messengers. However, the continuous stimulation by reactive oxygen species (ROS) can lead to pancreatic beta cell destruction and apoptosis.
Therefore, if urea accumulates in chronic kidney disease and increases oxidative stress, then what is the direct action on pancreatic beta cells? Ex vivo analysis of insulin secretion in CKD mice models showed reduced secretory function without changes in insulin content within secretory vesicles in pancreatic beta cells (p<0.05). Which confirms that insulin secretion is compromised in CKD. Furthermore, the effect of urea on the development of diabetes was observed in mice models exposed to 20 mmol/l of urea or higher, where insulin concentrations decreased. Consequently, a 1.5-fold increase was observed in reactive oxygen species (p< 0.05). This finding highlights the impact urea levels have on normal insulin secretion and the oxidative effect that affect pancreatic beta cell secretory functions.
The findings from the study explores how defective insulin secretion affects glucose regulation through oxidative stress. Similarly, the levels of urea in CKD were linked directly to altered cellular functions and apoptosis. This is why authors suggest that treatment with antioxidants is a potential therapeutic approach in reducing metabolic complications seen with chronic kidney disease. This discovery can be related to the proper management and incidence of chronic kidney disease; whose prevalence seems to not change significantly.
A recent study by Maryam Afkarian and colleagues showed that the prevalence of CKD and albuminuria has not changed significantly from 1988-2014. These findings are sustained by the high rates of medications used to control comorbidities leading to CKD (e.g. diabetes, hypertension, hyperlipidemia). The properties of antidiabetic medications, antihypertensive medications, and lipid-lowering drugs provide proper control to sustain proper hemodynamic function. The use of statins, for example, provides an antioxidant effect that can prevent damage to vasculature. The use of antihypertensive medications helps to increase renal blood flow, which ultimately benefits glomerular filtration. However, regardless of the observed trend on CKD and albuminuria, the glomerular filtration rate keeps declining. This decline warrants newer therapies that target these effects and prevent the onset of CKD.
In conclusion, the effects of diabetes on chronic kidney disease has been well-established. However, this new observed pattern in CKD mice models conveys that the opposite relationship is possible; chronic kidney disease can lead to diabetes. Therefore, if those disease states leading to chronic kidney disease are controlled, then the incidence of CKD keeps decreasing. Thus, highlighting the benefits of disease state management and optimizing therapy to prevent end-organ damage and/or complications.
- Increased levels of urea can lead to insulin resistance and glucose intolerance through pancreatic beta cell dysfunction.
- Chronic kidney disease (CKD) progression can be delayed by providing therapies that deter the effects of reactive oxygen species.
- Tighter glucose control and blood pressure control has proven to decrease the incidence of chronic kidney disease.
Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy
Afkarian, Maryam, Leila R. Zelnick, Yoshio N. Hall, Patrick J. Heagerty, Katherine Tuttle, Noel S. Weiss, and Ian H. De Boer. “Clinical Manifestations of Kidney Disease Among US Adults With Diabetes, 1988-2014.” Jama 316.6 (2016): 602. Web.
Koppe, Laetitia, Elsa Nyam, Kevin Vivot, Jocelyn E. Manning Fox, Xiao-Qing Dai, Bich N. Nguyen, Dominique Trudel, Camille Attané, Valentine S. Moullé, Patrick E. Macdonald, Julien Ghislain, and Vincent Poitout. “Urea Impairs β Cell Glycolysis and Insulin Secretion in Chronic Kidney Disease.” Journal of Clinical Investigation (2016): n. pag. Web.
Vassalotti, Joseph A., Robert Centor, Barbara J. Turner, Raquel C. Greer, Michael Choi, and Thomas D. Sequist. “Practical Approach to Detection and Management of Chronic Kidney Disease for the Primary Care Clinician.” The American Journal of Medicine 129.2 (2016): n. pag. Web.