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Tubulointerstitial Fibrosis of Living Donor Kidneys Associates with Urinary Monocyte Chemoattractant Protein 1.

ABSTRACT: BACKGROUND:Non-invasive biomarkers that detect occult pathology in patients with normal glomerular filtration rate (GFR) and normal urine albumin excretion may help identify patients at risk for chronic kidney diseases. METHODS:Two promising biomarkers of interstitial fibrosis, urinary monocyte chemoattractant protein 1 (MCP-1) and collagen IV, were assayed among 634 living kidney donors from 2005 to 2011, who had both a frozen pre-donation spot urine sample and a core needle biopsy of their donated kidney at transplantation ('time zero biopsy'). The association of urine MCP-1 and collagen IV with kidney function (GFR and urine albumin excretion), kidney volume on computed tomographic imaging and histological findings was assessed. RESULTS:The mean ± SD age was 45 ± 12 years, 24-hour urine albumin was 4 ± 7 mg and measured GFR (mGFR) was 102 ± 18 ml/min/1.73 m2. The median (25th-75th percentile) urine level of MCP-1 was 146 (54-258) pg/ml and of collagen IV was 2.0 (1.0-3.5) µg/l. Higher urine MCP-1 associated with higher 24-hour urine albumin excretion; higher urine collagen IV associated with male gender. On kidney biopsy, any interstitial fibrosis was present in 22% and fibrosis >5% in 4% of donors. The mean MCP-1/Cr ratio was 1.49 pg/mg for 0% fibrosis, 1.80 pg/mg for 1-5% fibrosis, 2.33 pg/mg for 6-10% fibrosis and 4.33 pg/mg for >10% fibrosis. After adjustment for age, sex, mGFR and 24-hour urine albumin, higher urine MCP-1 but not collagen IV associated with interstitial fibrosis and tubular atrophy. CONCLUSION:Urine MCP-1 may detect early tubulointerstitial fibrosis in adults with normal kidney function.

SUBMITTER: Wang X

PROVIDER: S-EPMC4936940 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Tubulointerstitial Fibrosis of Living Donor Kidneys Associates with Urinary Monocyte Chemoattractant Protein 1.

Wang Xiangling X Lieske John C JC Alexander Mariam P MP Jayachandran Muthuvel M Denic Aleksandar A Mathew Jerry J Lerman Lilach O LO Kremers Walter K WK Larson Joseph J JJ Rule Andrew D AD

American journal of nephrology 20160610 6

<h4>Background</h4>Non-invasive biomarkers that detect occult pathology in patients with normal glomerular filtration rate (GFR) and normal urine albumin excretion may help identify patients at risk for chronic kidney diseases.<h4>Methods</h4>Two promising biomarkers of interstitial fibrosis, urinary monocyte chemoattractant protein 1 (MCP-1) and collagen IV, were assayed among 634 living kidney donors from 2005 to 2011, who had both a frozen pre-donation spot urine sample and a core needle biop ...[more]

PMID: 27288357

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Project description:In the present article we describe the gas-phase dissociation behavior of the dimeric form of monocyte chemoattractant protein-1 (MCP-1) using quadrupole-traveling wave ion mobility-time of flight mass spectrometry (q-TWIMS-TOF MS) (Waters Synapt™). Through investigation of the 9(+) charge state of the dimer, we were able to monitor dissociation product ion (monomer) formation as a function of activation energy. Using ion mobility, we were able to observe precursor ion structural changes occurring throughout the activation process. Arrival time distributions (ATDs) for the 5(+) monomeric MCP-1 product ions, derived from the gas-phase dissociation of the 9(+) dimer, were then compared with ATDs obtained for the 5(+) MCP-1 monomer isolated directly from solution. The results show that the dissociated monomer is as compact as the monomer arising from solution, regardless of the trap collision energy (CE) used in the dissociation. The solution-derived monomer, when collisionally activated, also resists significant unfolding within measure. Finally, we compared the collisional activation data for the MCP-1 dimer with an MCP-1 dimer non-covalently bound to a single molecule of the semi-synthetic glycosaminoglycan (GAG) analog Arixtra™; the latter a therapeutic anti-thrombin III-activating pentasaccharide. We observed that while dimeric MCP-1 dissociated at relatively low trap CEs, the Arixtra-bound dimer required much higher energies, which also induced covalent bond cleavage in the bound Arixtra molecule. Both the free and Arixtra-bound dimers became less compact and exhibited longer arrival times with increasing trap CEs, albeit the Arixtra-bound complex at slightly higher energies. That both dimers shifted to longer arrival times with increasing activation energy, while the dissociated MCP-1 monomers remained compact, suggests that the longer arrival times of the Arixtra-free and Arixtra-bound dimers may represent a partial breach of non-covalent interactions between the associated MCP-1 monomers, rather than extensive unfolding of individual subunits. The fact that Arixtra preferentially binds MCP-1 dimers and prevents dimer dissociation at comparable activation energies to the Arixtra-free dimer, may suggest that the drug interacts across the two monomers, thereby inhibiting their dissociation.

Dataset Information

Tubulointerstitial Fibrosis of Living Donor Kidneys Associates with Urinary Monocyte Chemoattractant Protein 1.

Publications

Tubulointerstitial Fibrosis of Living Donor Kidneys Associates with Urinary Monocyte Chemoattractant Protein 1.

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