Proteomics Identifies CKD Predictors

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Swedish study shows how protein profiling with a multiplex assay can enhance kidney disease research.
Swedish study shows how protein profiling with a multiplex assay can enhance kidney disease research.

Multiplex proteomics may offer promise as a way to discover novel aspects of kidney disease pathology, according to researchers.

In a study, this technique enabled Axel C. Carlsson, PhD, of the Karolinska Institutet in Stockholm, Sweden, and colleagues to identify circulating proteins associated with declining renal function. These proteins are involved in phosphate homeostasis, angiogenesis, extracellular matrix remodeling, endothelial dysfunction, and apoptosis.

The investigators assessed proteomic profiling of 80 proteins using a multiplex assay in a study involving participants in 2 studies: the Prospective Investigation of the Vasculature in Uppsala Seniors study (PIVUS, 687 patients, mean age 70 years, 51% women) and the Uppsala Longitudinal Study of Adult Men (ULSAM, 360 men, mean age 78 years). The researchers used the PIVUS study as the discovery cohort and the ULSAM study for replication. The investigators had 5-year follow-up data on estimated glomerular filtration rate (eGFR). The multiplex assay was designed primarily for assessing plasma proteins involved in cardiovascular disease (CVD) and inflammation.

In the discovery cohort, 28 plasma proteins were significantly associated with eGFR decline per year, Dr Carlsson and his colleagues reported online ahead of print in the Clinical Journal of the American Society of Nephrology. Twenty of these proteins were significantly associated with eGFR decline per year in the replication cohort after adjusting for age, sex, cardiovascular risk factors, medications, and urinary albumin-to-creatinine ratio.

Among the subset of patients free of chronic kidney disease (CKD) at baseline, CKD developed during follow-up in 231 of 660 participants in the PIVUS study and 206 of 319 patients in the ULSAM study. Eleven of the 20 proteins consistently predicted incident CKD in subgroup analyses in those with an eGFR above 60 mL/min/1.73 m2 at baseline in both cohorts.

“The vast number of proteins independently associated with decline in kidney function show CKD to be a multifactorial and highly complex disease, involving an impaired phosphate homeostasis, inflammation, apoptosis, increased extracellular matrix remodeling, a disturbed angiogenesis, and endothelial dysfunction,” the authors concluded. “The strongest association was found for TRAIL-R2 [TNF-related apoptosis-inducing ligand receptor 2], a protein that has not been associated with eGFR decline previously.”

The authors stated that impaired phosphate homeostasis “appeared to be a particularly important common pathway for the proteins associated with kidney function decline because half of the proteins were involved in this pathway, according to the functional analysis of our findings,” Dr Carlsson's group wrote.

In an accompanying editorial, Stein Hallan, MD, of the Norwegian University of Science and Technology in Trondheim, Norway, observed that “proteomics is expected to give important contributions to clinical nephrology in the coming years.”

Proteomics, he noted, could facilitate the drug development process. “In total, proteomics, accompanied by other omics, could contribute to more streamlined inclusion and exclusion criteria, smaller sample size requirements, and improved efficiency of clinical trials.”

References

Carlsson AC, Ingelsson E, Sundström J et al. Use of proteomics to investigate kidney function decline over 5 years. Clin J Am Soc Nephrol 2017; published online ahead of print. doi: 10.2215/CJN.08780816.

Hallan SI. The possibilities to improve kidney health with proteomics. Clin J Am Soc Nephrol 2017; published online ahead of print. doi: 10.2215/CJN.06200617.

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