ABSTRACT

Background Patients with kidney failure undergoing maintenance hemodialysis suffer high rates of major adverse cardiovascular events(MACE) that are not accurately predicted by traditional cardiovascular risk models. There is an urgent need to identify novel, modifiable cardiovascular risk factors for these patients.

Methods We analyzed associations of 6287 circulating proteins with MACE among 1048 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort(CRIC) (14-year follow-up) with validation in the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease study(PACE) (7-year follow-up). In both cohorts, proteins were measured shortly after dialysis initiation and one year later. We compared protein-based risk models derived by elastic net regression to the Pooled Cohort Equations(PCE) optimized for these cohorts(Refit PCE), and to an Expanded Refit PCE that included Troponin T and N-terminal pro-B-type natriuretic peptide.

Results In CRIC, 149 proteins were associated with MACE at false discovery rate<0.05. Among 22 proteins significant at Bonferroni p<8×10-6, proteins that validated in PACE included Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), Complement component C7, R-spondin 4, Tenascin, Fibulin-3 and Fibulin-5. Complement pathways were prominent in network analyses. SVEP1 surpassed other markers by statistical significance, with CRIC HR per log2 1.8 (p=2.1×10-12) and HR per annual doubling 1.6 (p=6.8×10-6). For 2-year MACE, AUC(95%CI) for SVEP1 alone was 0.72(0.59, 0.84) in CRIC, and 0.73(0.63, 0.81) in PACE. SVEP1 surpassed the Expanded Refit PCE in CRIC (0.61 (0.48, 0.73)) (p=0.038). In the pooled CRIC + PACE cohort, SVEP1 AUC(95%CI) (0.79(0.70, 0.88)) surpassed Refit PCE (0.61(0.51, 0.72)) (p=0.004).

Conclusions SVEP1, a 390 kDa protein unlikely to be renally cleared, surpassed over 6000 other proteins and by itself outperformed traditional clinical risk models in predicting MACE in two populations of patients undergoing maintenance hemodialysis. Future studies should provide mechanistic insights behind these findings.

Key Points:

Patients with kidney failure undergoing hemodialysis have 20-fold higher cardiovascular mortality compared to the general population, and conventional risk factors have low prognostic utility for these patients.

By applying large-scale circulating proteomics in two independent hemodialysis cohorts, we have discovered >20 novel proteins that predict major adverse cardiovascular events(MACE).

Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1) surpassed >6000 individual proteins and clinical factors for predicting MACE.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

NHLBI R01HL153499 (PIs: R. Dubin, P. Ganz) The PACE study was supported by NIDDK R01DK072367 (PI: R.S. Parekh).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of University of Texas Southwestern Medical Center gave ethical approval for this work.

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Yes

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Data Availability

The CRIC data included in these analyses will be available to approved requestors in the future in the NIDDK Central Repository and at dbGaP. Prior to the availability of data in the repositories, requests can be made to the CRIC Study group by contacting the CRIC Scientific and Data Coordinating Center at cri-projmgmtlists.upenn.edu. Appropriate regulatory and scientific approvals are required. The data are not publicly available due to individual-level informed consent restrictions.

Non-standard Abbreviations and AcronymsMADmedian absolute deviationSVEP1Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1ANMLAdaptive Normalization by Maximum LikelihoodIGFBPInsulin growth factor binding proteins