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Observational Study
. 2020 Oct 20;21(1):441.
doi: 10.1186/s12882-020-02096-x.

Urinary nitrate concentration as a marker for kidney transplant rejection

Amy Riddell  1 , John Kirkwood  2 , Miranda Smallwood  3 , Paul Winyard  3 , Beatrice Knight  2 , Lidia Romanczuk  2 , Angela Shore  3 , Mark Gilchrist  3
Affiliations
Observational Study

Urinary nitrate concentration as a marker for kidney transplant rejection

Amy Riddell et al. BMC Nephrol. .

Abstract

Background: Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection at an earlier time point than current practice, or to inform earlier decision making to biopsy, could be transformative. It has previously been shown that urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice.

Methods: We conducted a prospective observational study, recruiting renal transplant participants over an 18-month period. We made no alterations to the patients' clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance. We assessed the urinary nitrate to creatinine ratio (uNCR) between patient groups: routine attendances, biopsy proven rejection, biopsy proven no rejection and other call backs. uNCR was examined over time for those with biopsy proven transplant rejection. These four groups were compared using an ANOVA test.

Results: A total of 2656 samples were collected. uNCR during biopsy proven rejection, n = 15 (median 49 μmol/mmol, IQR 23-61) was not significantly different from that of routine samples, n = 164 (median 55 μmol/mmol, IQR 37-82) (p = 0.55), or biopsy proven no rejection, n = 12 (median 39 μmol/mmol, IQR 21-89) (P = 0.77). Overall uNCR was highly variable with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. The total taking Tacrolimus was 204 patients, with no statistical difference between the uNCR of all those on Tacrolimus, against those not, p = 0.18.

Conclusion: The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.

Keywords: Biomarker; Kidney; Nitrate; Rejection; Transplant.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Nitrate: creatinine ratio for each group; Routine, Rejection, Non-Rejection and Other Call-backs. Showing the median, IQR, maximum and minimum values for each patient group. Minimum for ‘Non rejection’ and ‘Other call-backs were 0.73 and 0.26 respectively (μmol/mmol). ANOVA test showed no significant difference between any groups, p = 0.98
Fig. 2
Fig. 2
Graph showing the time courses of uNCR values (μmol/mmol) of all samples from 15 biopsy-proven rejection patients. formula image 1st month post transplant formula image Biopsy proven rejection. formula image Months 2-3 post tranmsplant formula image 1 month post confirmed rejection
See this image and copyright information in PMC

References

    1. Parajuli S, Aziz F, Garg N, Panzer SE, Joachim E, Muth B, Mohamed M, et al. Histopathological characteristics and causes of kidney graft failure in the current era of immunosuppression. World J Transplant. 2019;9(6):123–133. doi: 10.5500/wjt.v9.i6.123. - DOI - PMC - PubMed
    1. Nankivell B, Agrawal N, Sharma A, Taverniti A, P’Ng C, Shingde M, Wong G, Chapman J. The clinical and pathological significance of borderline T cell-mediated rejection. Am J Transplant. 2019;19(5):1452–1463. doi: 10.1111/ajt.15197. - DOI - PubMed
    1. Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, Nankivell BJ, Halloran PF, et al. The Banff 2017 kidney meeting report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next generation clinical trials. Am J Transplant. 2018;18(2):293–307. doi: 10.1111/ajt.14625. - DOI - PMC - PubMed
    1. Smith SD, Wheeler MA, Zhang R, Weiss ED, Lorber MI, Sessa WC, Weiss RM. Nitric oxide synthase induction with renal transplant rejection or infection. Kidney Int. 1996;50:2088–2093. doi: 10.1038/ki.1996.533. - DOI - PubMed
    1. Smith SD, Wheeler MA, Lorber MI, Weiss RM. Temporal changes of cytokines and nitric oxide products in urine from renal transplant patients. Kidney Int. 2000;58:829–837. - PubMed

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