Kidney Tubular Damage and Dysfunction Identify a Novel Axis of Chronic Kidney Disease (CKD)

Chronic kidney disease (CKD) is common and can lead to kidney failure requiring dialysis, and it is also a strong risk factor for cardiovascular disease and death. The kidneys filter 180 l/d through the glomerulus membrane, and equally important is the subsequent reabsorption of 179 l of pre-urine by the renal tubule system to preserve glucose, proteins and other important building blocks. The clinical diagnosis of CKD is currently based on glomerulus function alone, but the degree of tubular damage is, however, a better prognostic factor. The problem is that this information can currently only be obtained using a kidney biopsy, which is potentially dangerous. Our goal is to develop a kidney tubule health panel (KTHP) that will reflect the underlying pathological process and easily inform the doctor. This will give better information about the disease process and help diagnostics and risk assessment. The project is a collaboration between Norwegian and American researchers and started in July 2020. Briefly, KTHP will be developed in the USA based on patients from the SPRINT study, a large study on intensive versus standard blood pressure treatment. The panel will then be validated in Norway using samples from the HUNT study, which represent a general population. Information about the association between the biomarkers and the disease processes will also be studied using blood, urine and kidney tissue collected from Norwegian CKD patients. The tubular system needs large amounts of energy, and lack of oxygen is probably an important factor in the development of chronic kidney disease. We will therefore also study how exercise affects kidney function. The first Norwegian task was to establish the kidney biobank. This sub-goal has now been completed, and approx. 600 patients, which is a relatively large biobank also in an international context, from 8 different hospitals have been included. Together with the University of Bergen, we now accurately measure how much fibrosis (scarring changes) there is in the kidney biopsies we have collected using modern color techniques and image recognition programs ("artificial intelligence"). The results will probably be available in the first half of 2024. Fibrosis is the result of many different disease processes in the kidneys and is considered one of the most important targets for future disease development. As of today, fibrosis is graded visually on a rough scale (0-4). In collaboration with Department of Biotechnology and Food Science at NTNU (Gløshaugen), we have established an analysis method (LCMS) to measure 13 different markers of the kidneys' ability to actively pump toxins, medicines and other substances from the blood into the urine (tubular secretion). We have recently completed the analysis of blood and urine samples from 1,700 participants in the Norwegian HUNT-3 study to study the association between tubular kidney function and various future events. At HUNT Biobank Levanger, we have established a new platform for analysis of protein-based biomarkers (Meso Scale Discovery). We have analyzed a broad panel of 16 different well-established markers of kidney cell damage, inflammation, repair, and renal tubule function (capacity for reabsorption) from the same 1,700 people. We will then analyze the blood and urine samples from the kidney biopsied CKD patients we have included in the biobank using the same methods. In total, we have very large and comprehensive data material, and publication of the results will start in 2024. Our American partners have published data from the American LIFE study showing that elderly sedentary people (70-89 years old) participating in a structured exercise program over two years with moderate intensity (gait training, strength and balance) have 20% lower risk of rapid kidney function decline. We have measured kidney function in the Norwegian Generation 100 study to test whether older people (70-76 years) achieve better kidney health by participating in high-intensity interval training over 5 years compared to moderate continuous training. The results are submitted for publication. Data from the SPRINT study shows that blood pressure patients with reduced renal tubule secretion capacity have an increased risk of "unfortunate" events over the next 3 years: increased risk of acute kidney damage, disturbances in salt balance, low blood pressure, falls, and fainting. We believe that these secretion markers describe a new and important aspect of kidney function, namely the ability to maintain a stable and favorable internal environment in the body. The research group has also published data showing that protein biomarkers in urine predict the risk of future acute kidney injury and deterioration of kidney function. Patients with increased markers for tubule damage, repair, and fibrosis had an approximately 20% increased risk of future kidney damage. We will now begin work on validating these results in a general population (HUNT).

The prevalence of chronic kidney disease (CKD) is very high (10-14%), increases strongly with age, and is asymptomatic until 85% of kidney function has been irreversibly lost. Patients with kidney failure have seriously reduced quality of life and a mortality risk similar to metastatic breast or colon cancer. Clinicians rely upon serum creatinine to monitor kidney health, primarily a marker of glomerular filtration (GFR). However, the tubulus-interstitial compartment make up 90% of the kidney, and the kidney tubules are responsible for a myriad of functions (toxin secretion, nutrient reabsorption, acid/base control, and immune defense). Currently, clinicians cannot evaluate tubule health except in rare instances when kidney biopsies are obtained. A rising s-creatinine is often seen during treatment of hypertension, heart failure and CKD, but recent studies indicate that this reflects hemodynamic accommodation rather than kidney injury. Thus, many individuals are not receiving optimal care due to concern for kidney damage. To that end, we will evaluate a wide range of markers to capture the biological functions of kidney tubules. We will include patients from BP trials, the general population, and biopsy-verified cases, and monitor outcomes like incident CKD, GFR decline, acute kidney injury, CV morbidity and mortality, and histological changes. Then, we will choose tubule markers that maximize prognostic performance while minimizing the required number of measurements; this will be the Kidney Tubule Health Panel (KTHP). Finally, we will evaluate SPRINT participants who experience serum creatinine elevations during follow-up with the KTHP. We believe that the KTHP will differentiate benign, hemodynamic accommodations from the more concerning cases of intrinsic kidney damage. If successful, we will advance the KTHP as a novel and useful clinical tool to maximize adherence to life-saving therapies, moving beyond kidney measures that focus exclusively on the glomerulus.