A Non-Invasive Laboratory Panel as a Diagnostic and Prognostic Biomarker for Thrombotic Microangiopathy: Development and Application in a Chinese Cohort Study

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Abstract

Background

Thrombotic microangiopathy (TMA) in the kidney is a histopathologic lesion that occurs in a number of clinical settings and is often associated with poor renal prognosis. The standard test for the diagnosis of TMA is the renal biopsy; noninvasive parameters such as potential biomarkers have not been developed.

Methods

We analyzed routine parameters in a cohort of 220 patients with suspected TMA and developed a diagnostic laboratory panel by logistic regression. The levels of candidate markers were validated using an independent cohort (n = 46), a cohort of systemic lupus erythematosus (SLE) (n = 157) and an expanded cohort (n = 113), as well as 9 patients with repeat biopsies.

Results

Of the 220 patients in the derivation cohort, 51 patients with biopsy-proven TMA presented with a worse renal prognosis than those with no TMA (P = 0.002). Platelet and L-lactate dehydrogenase (LDH) levels showed an acceptable diagnostic value of TMA (AUC = 0.739 and 0.756, respectively). A panel of 4 variables - creatinine, platelets, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats 13) activity and LDH - can effectively discriminate patients with TMA (AUC = 0.800). In the validation cohort, the platelet and LDH levels and the 4-variable panel signature robustly distinguished patients with TMA. The discrimination effects of these three markers were confirmed in patients with SLE. Moreover, LDH levels and the 4-variable panel signature also showed discrimination values in an expanded set. Among patients undergoing repeat biopsy, increased LDH levels and panel signatures were associated with TMA status when paired evaluations were performed. Importantly, only the 4-variable panel was an independent prognostic marker for renal outcome (hazard ratio = 3.549; P<0.001).

Conclusions

The noninvasive laboratory diagnostic panel is better for the early detection and prognosis of TMA compared with a single parameter, and may provide a promising biomarker for clinical application.

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Most cited references 24

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Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression.

Shawn M. Arellano, Marina I Salvadori, Nick Barrowman … (2003)

The long-term renal prognosis of patients with diarrhea-associated hemolytic uremic syndrome (HUS) remains controversial. To quantify the long-term renal prognosis of patients with diarrhea-associated HUS and to identify reasons for different estimates provided in the literature. We searched MEDLINE and Experta Medica (EMBASE) bibliographic databases and conference proceedings, and we contacted experts until February 2003. We also searched the Institute for Scientific Information index and reference lists of all studies that fulfilled our eligibility criteria. The search strategy included the terms hemolytic-uremic syndrome, purpura, thrombotic thrombocytopenic, Escherichia coli O157, longitudinal studies, kidney diseases, hypertension, and proteinuria Any study that followed up 10 or more patients with primary diarrhea-associated HUS for at least 1 year for renal sequelae. Two authors independently abstracted data on study and patient characteristics, renal measures, outcomes, and prognostic features. Disagreements were resolved by a third author or by consensus. Forty-nine studies of 3476 patients with a mean follow-up of 4.4 years (range, 1-22 years at last follow-up) from 18 countries, 1950 to 2001, were summarized. At the time of recruitment, patients were aged 1 month to 18 years. In the different studies, death or permanent end-stage renal disease (ESRD) ranged from 0% to 30%, with a pooled incidence of 12% (95% confidence interval [CI], 10%-15%). A glomerular filtration rate lower than 80 mL/min per 1.73 m2, hypertension, or proteinuria was extremely variable and ranged from 0% to 64%, with a pooled incidence of 25% (95% CI, 20%-30%). A higher severity of acute illness was strongly associated with worse long-term prognosis. Studies with a higher proportion of patients with central nervous system symptoms (coma, seizures, or stroke) had a higher proportion of patients who died or developed permanent ESRD at follow-up (explaining 44% of the between-study variability, P =.01). Studies with a greater proportion of patients lost to follow-up also described a worse prognosis (P =.001) because these patients were typically healthier than those followed up. One or more years after diarrhea-associated HUS, patients with a predicted creatinine clearance higher than 80 mL/min per 1.73 m2, no overt proteinuria, and no hypertension appeared to have an excellent prognosis. Death or ESRD occurs in about 12% of patients with diarrhea-associated HUS, and 25% of survivors demonstrate long-term renal sequelae. Patients lost to follow-up contribute to worse estimates in some studies. The severity of acute illness, particularly central nervous system symptoms and the need for initial dialysis, is strongly associated with a worse long-term prognosis.

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Author and article information

Contributors

Nancy Lan Guo: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 5 November 2014

Volume: 9

Issue: 11

Electronic Location Identifier: e111992

Affiliations

[1 ]National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, P. R. China

[2 ]Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, P. R. China

West Virginia University, United States of America

Author notes

* E-mail: chenhuimei@ 123456nju.edu.cn (HC); liuzhihong@ 123456nju.edu.cn (ZL)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: TZ HC ZL. Performed the experiments: TZ HC DC CZ SL CZ. Analyzed the data: TZ HC ZL. Contributed reagents/materials/analysis tools: DC SL HZ. Contributed to the writing of the manuscript: TZ HC ZL.

Article

Publisher ID: PONE-D-14-23322

DOI: 10.1371/journal.pone.0111992

PMC ID: 4221199

PubMed ID: 25372665

SO-VID: 606ecf44-d993-4e95-b269-5d0048e9b83c

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 10 June 2014

Date accepted : 3 October 2014

Page count

Pages: 8

Funding

This work was supported in part by National Basic Research Program of China 973 Program No.2012CB517600 (No.2012CB517606) (to Z.L.)( http://www.973.gov.cn/AreaMana.aspx), National Natural Science Foundation (NSF) Grant 81370788 (to H.C.) ( http://www.nsfc.gov.cn/), The National Key Technology R&D Program (2011BAI10B04) (to Z.L.) ( http://kjzc.jhgl.org/) and Six Talent Peaks Project of Jiangsu Province (2012-WSN-071) (to H.C.) ( http://archives.nuist.edu.cn/rcgf/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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A Non-Invasive Laboratory Panel as a Diagnostic and Prognostic Biomarker for Thrombotic Microangiopathy: Development and Application in a Chinese Cohort Study

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Methods

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Most cited references 24

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

Thrombotic microangiopathies.

Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression.

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