Galectin-3 and Risk of Late Graft Failure in Kidney Transplant Recipients: A 10-year Prospective Cohort Study

Camilo G Sotomayor, Charlotte A Te Velde-Keyzer, Arjan Diepstra, Marco van Londen, Robert A Pol, Adrian Post, Rijk O B Gans, Ilja M Nolte, Riemer H J A Slart, Martin H de Borst, Stefan P Berger, Ramón Rodrigo, Gerjan J Navis, Rudolf A de Boer, Stephan J L Bakker, Camilo G Sotomayor, Charlotte A Te Velde-Keyzer, Arjan Diepstra, Marco van Londen, Robert A Pol, Adrian Post, Rijk O B Gans, Ilja M Nolte, Riemer H J A Slart, Martin H de Borst, Stefan P Berger, Ramón Rodrigo, Gerjan J Navis, Rudolf A de Boer, Stephan J L Bakker

Abstract

Background: Galectin-3 may play a causal role in kidney inflammation and fibrosis, which may also be involved in the development of kidney graft failure. With novel galectin-3-targeted pharmacological therapies increasingly coming available, we aimed to investigate whether galectin-3 is associated with risk of late graft failure in kidney transplant recipients (KTR).

Methods: We studied adult KTR who participated in TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study, recruited in a university setting (2001-2003). Follow-up was performed for a median of 9.5 (interquartile range, 6.2-10.2) years. Overall and stratified (Pinteraction < 0.05) multivariable-adjusted Cox proportional-hazards regression analyses were performed to study the association of galectin-3 with risk of graft failure (restart of dialysis or retransplantation).

Results: Among 561 KTR (age 52 ± 12 y; 54% males), baseline median galectin-3 was 21.1 (interquartile range, 17.0-27.2) ng/mL. During follow-up, 72 KTR developed graft failure (13, 18, and 44 events over increasing tertiles of galectin-3). Independent of adjustment for donor, recipient, and transplant characteristics, galectin-3-associated with increased risk of graft failure (hazard ratios [HR] per 1 SD change, 2.12; 95% confidence interval [CI], 1.63-2.75; P < 0.001), particularly among KTR with systolic blood pressure ≥140 mmHg (HR, 2.29; 95% CI, 1.80-2.92; P < 0.001; Pinteraction = 0.01) or smoking history (HR, 2.56; 95% CI, 1.95-3.37; P < 0.001; Pinteraction = 0.03). Similarly, patients in the highest tertile of galectin-3 were consistently at increased risk of graft failure.

Conclusions: Serum galectin-3 levels are elevated in KTR, and independently associated with increased risk of late graft failure. Whether galectin-3-targeted therapies may represent novel opportunities to decrease the long-standing high burden of late graft failure in stable KTR warrants further studies.

Trial registration: ClinicalTrials.gov NCT03272854 NCT03272785.

Conflict of interest statement

The authors declare no conflicts of interest.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Graphical abstract
Graphical abstract
FIGURE 1.
FIGURE 1.
Association of standardized circulating galectin-3 with risk of kidney graft failure. Data were fitted by Cox proportional-hazards regression using mean galectin-3 (21.1 ng/mL) as reference value. The black line represents the hazard ratio and the grey area represents the 95% confidence interval.
FIGURE 2.
FIGURE 2.
Stratified prospective analyses of the association of galectin-3 with risk of kidney graft failure. Pinteraction was calculated by fitting models which contain both main effects (as continuous variable for systolic blood pressure, and as dichotomized variable for smoking status) and their cross-product term. Hazard ratios (95% CI) are calculate per 1 SD increment in circulating galectin-3. CI, confidence intervals.
FIGURE 3.
FIGURE 3.
Representative histopathological sample of immunohistochemical expression of galectin-3 showing positive staining mainly in flattened/cuboidal tubular epithelial cells that directly surround atrophic areas in the renal cortex (magnification ×50 [A], and ×400 [B]).

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