Diabetic Kidney Disease with a focus on Renal Hyperfiltration

Abstract

Currently, it is not known if the process of renal hyperfiltration is adaptive as a compensatory effect akin to pregnancy or is maladaptive and can result in non-reversible renal damage and the development of diabetic kidney disease. The overall aim of my study was to investigate renal hyperfiltration in diabetes, by comparing this to renal hyperfiltration in pregnancy, assessing renal biomarkers and utilizing functional magnetic resonance imaging.

Estimated glomerular filtration rate based on The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was used as the main surrogate measurement of renal function in this thesis. Where possible, measured glomerular filtration rate using renal Diethylenetriamine Penta-acetic Acid (DTPA) and plasma inulin clearance were employed. The threshold of renal hyperfiltration in this thesis is set at an estimated or measured glomerular filtration of >120ml/min/1.73m2. Candidate inflammatory and oxidative stress serum and urinary renal biomarkers were selected based on current evidence in diabetic kidney disease. 3-Tesla magnetic resonance imaging was used to acquire images on renal tract, with data providing information on renal hypoxia and microstructural changes.

The main findings from assessing women with type 1 and type 2 diabetes during pregnancy were that women with type 1 diabetes may have an attenuated ability to hyperfiltrate in pregnancy, which is possibly related to pre-existing impaired renal function. However, in general, women with type 1 and type 2 diabetes, including those with mild to moderate diabetic kidney disease are not at risk of accelerated renal function decline from pregnancy. Both type 1 and type 2 diabetes carry a similar high risk for poorer maternal and fetal outcomes compared to healthy pregnancies. For these outcomes, a lower estimated glomerular filtration rate was associated with pre-term birth and neonatal intensive care admission independent from albuminuria. Understanding how pregnancies in type 1 and type 2 diabetes can affect maternal renal function; and on the other hand, how maternal renal function can affect pregnancy outcomes are important in guiding clinicians to provide optimal care this high-risk antenatal cohort.

Secondly, with regards to functional magnetic resonance imaging, we demonstrated that there is no evidence that renal hypoxia or micro-structural changes occur in those with renal hyperfiltration and type 1 diabetes. Magnetic resonance imaging parameters also do not reflect level of renal function determined with a direct measurement of glomerular filtration rate, nor do they strongly correlate with selected inflammatory and oxidative stress markers in type 1 diabetes.

Finally, we did not observe any difference in the concentration of renal biomarkers in those who were hyperfiltering, compared to those who were not hyperfiltering in type1 diabetes. Elevation of renal biomarkers during peak hyperfiltration in the second trimester of pregnancy were comparable in women with and without diabetes. Our findings of a lack in rise of inflammatory and oxidative stress biomarkers do not support the hypothesis that inflammation is present in renal hyperfiltration in diabetes.

In conclusion, findings from this thesis suggest that hyperfiltration in diabetes may not necessarily reflect a maladaptive stage of diabetic kidney disease. Due to the exploratory nature of the studies, along with the limitation of estimated glomerular filtration rate, future work involving larger cohort of participants and measured glomerular filtration rate may provide more in-depth understanding of renal hyperfiltration in diabetes. Understanding the significance of renal hyperfiltration is important, particularly as this process occurs in the early stages of diabetes and would be an avenue of targeted therapy to prevent not only the progression, but development of diabetic kidney disease.