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The cumulative incidence of End Stage Renal Disease (ESRD) according to index of protection of three proteins, Index=0/3 indicates no protection whereas Index=3/3 indicates full protection. CREDIT Copyright Joslin Diabetes Center

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Elevated levels of three specific circulating proteins are associated with protection against kidney failure in diabetes, according to research from the Joslin Diabetes Center that will be published 30th June in Science Translational Medicine.

“As well as acting as biomarkers for advancing kidney disease risk in diabetes, the proteins may also serve as the basis for future therapies against progression to the most serious types of kidney disease,” said Andrzej S. Krolewski MD, PhD, senior author on the publication, senior investigator at Joslin Diabetes Center and professor of medicine at Harvard Medical School. This would likely include the delay and prevention of end stage renal disease (ESRD), which is the most serious and advanced stage of diabetic kidney disease.

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The study marks a move towards looking for markers associated with protection against, rather than increased individual risk, for the rapid progression of diabetic kidney disease. This should more directly derive potential targets for slowing progression since it is based on the thinking that individuals with slow progression will have protective factors of some sort.

“Our research became possible only recently,” said Dr. Krolewski. “We were able to search for these markers thanks to the development of high-throughput proteomic platforms. More importantly, the availability of biobank specimens that we established many years ago in the Joslin Kidney Study was critical.”

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According to the report, the researchers profiled levels of just over 1000 proteins in the plasma samples that were taken at baseline in the original study. All of them had diabetes and moderately impaired kidney function. They used two cohorts of individuals with either type 1 or type 2 diabetes that were followed for between 7 and 15 years.

The main aim was to identify proteins that were elevated in individuals with slow or minimal decline in kidney function over the follow-up period. Notably they did validate the initial findings in a further cohort of individuals with type 1 diabetes.

Working through potential candidate proteins, they found three proteins that appeared to offer protection against progressive decline. These were fibroblast growth factor 20 (FGF20), angiopoietin-1 (ANGPT1) and tumor necrosis factor ligand superfamily member 12 (TNFSF12).

In each case elevated circulating levels reduced odds of progressive kidney decline and progression towards ESRD. The combined effect of having elevated levels of all three proteins translated to very low risk for ESRD.

“The protective effects of these proteins seem to be independent, which suggests that there are multiple mechanisms involved. They may be causally related to the disease process or represent as-yet unidentified pathways involved in progressive renal decline,” said first author Zaipul Md Dom PhD, a research fellow in the Dr. Krolewski’s laboratory

The authors go further to look at the current biological knowledge relating to the individual proteins and kidney disease, identifying a number of potential mechanisms that might explain their protective effects. According to Dr. Krolewski these are potential new routes for research that they will follow.

Dr Kevin Duffin, co-author on the publication, and chief operating officer at Eli Lilly, Diabetes and Diabetic Complications said: “Our study identified specific circulating proteins that were depleted in diabetes patients with kidney disease who progressed to ESRD. These results suggest a personalized medicine approach might be possible for treating patients with low levels of the protective proteins. We think that administering protein therapeutic mimetics or treatments that enhance circulating levels of these depleted proteins might be the future.” 

Dr. Krolewski added: “We have already started to develop protocols on how to measure concentrations of the protective proteins in clinical settings. We hope that these proteins can then be used to identify patients at risk of progression to ESRD, who can then be treated with new therapies.”

Mass spectrometer analysis of blood serum in diabetic patients. 1) SH-Albumin (unmodified), 2) Cys-Albumin (cysteine adduct (oxidized albumin), 3) Glu-Albumin (sugar adduct), 4) Cys-Glu-Albumin (simultaneous cysteine and sugar adduct), 5) Glu-Glu-Albumin (two sugar adducts) CREDIT Associate Professor Hiroshi Watanabe

A research group from Kumamoto University, Japan has discovered that cysteinylated albumin (oxidized albumin) in serum can be used as an early diagnostic marker for diabetic kidney disease. Compared with urinary albumin, serum oxidized albumin not only reflects renal pathology at an earlier stage, but can also predict the progression of renal pathology by its degree of elevation. The researchers believe that it can be used as a new diagnostic marker for early diagnosis of diabetic kidney disease.

Diabetic kidney disease is one of three major complications of diabetes. Its prognosis is difficult to improve as it progresses so diagnosing it as early as possible and providing appropriate therapeutic intervention is important. Albumin is the most abundant protein in blood serum and urine, and urinary albumin (albuminuria) is used to diagnose diabetic kidney disease. Albumin maintains osmotic pressure in serum and functions as a carrier of fatty acids and drugs. It is also frequently used as an early marker for diabetic nephropathy because albuminuria increases as kidneys begin failing. However, it is now clear that there are many cases of negative albuminuria in diabetic kidney diseases, especially those derived from type 2 diabetes. Thus, there is a need to develop new early diagnostic markers for these complex and diverse conditions.

In this study, the research group evaluated the association between pathological renal progression and post-translational modifiers of serum albumin in 257 type 2 diabetic patients. Serum albumin has a half-life of about 20 days and is known to undergo various chemical modifications (post-translational modifications) depending on the environment in the body. Researchers measured five post-translational modifications using a mass spectrometer and found that the level of cysteinylated albumin (oxidized albumin), an oxidized modification of albumin with one molecule of cysteine added, increased with the progression of diabetic kidney disease. This indicated that oxidized albumin can be used as a diagnostic marker for renal pathology. They also found that oxidized albumin may reflect earlier renal pathology compared to urinary albumin. Furthermore, patients with high levels of oxidized albumin showed faster progression of renal disease after two years, indicating that oxidized albumin can also be used to predict renal disease progression.

“Our study has shown that oxidized albumin may reflect early renal pathology even better than urinary albumin, which is the current gold standard,” said Associate Professor Hiroshi Watanabe, who led this study. “In particular, since kidney disease derived from type 2 diabetic patients includes many cases of negative albuminuria, we expect serum oxidized albumin can be used as a new diagnostic marker for diabetic kidney disease.”