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A New Clinical Utility for Tubular Markers to Identify Kidney Responders to Saxagliptin Treatment in Adults With Diabetic Nephropathy

Published:August 02, 2021DOI:https://doi.org/10.1016/j.jcjd.2021.07.004

      Abstract

      Objectives

      In recent clinical studies, saxagliptin exhibited nephroprotective potential by lowering albuminuria. In this study, we aimed to determine whether these kidney effects of saxagliptin were mediated by changes in markers of kidney tubular damage, including urinary neutrophil gelatinase-associated protein (uNGAL) and liver-type fatty acid–binding protein (uL-FABP).

      Methods

      Our study included 80 patients with type 2 diabetes, hypertension and mild to moderate diabetic kidney disease (DKD) with prevalent albuminuria. Patients were either randomly assigned to saxagliptin as add-on therapy or remained unchanged on their stable antidiabetic therapy as a control arm.

      Results

      Saxagliptin significantly reduced uNGAL with a median change of −25.4% (interquartile range [IQR], −35.6% to −12.2%) compared with the control group (median change, −0.91%; IQR, −12% to 11.88%; p<0.001) after 3 months. Similarly, patients given saxagliptin had a highly significant reduction in uL-FABP (median change, −24.4%; IQR, −30.5% to −15.1%) compared with controls (median change, −3.8%; IQR −10% to 12.5%; p<0.001). Median estimated glomerular filtration rate (eGFR) values after 3 months in the saxagliptin arm were significantly higher (76.5 mL/min per 1.73 m2; IQR, 70 to 92.75 mL/min per 1.73 m2) in the low-risk uNGAL group compared with controls (59.8 mL/min per 1.73 m2; IQR, 51 to 76.2 mL/min per 1.73 m2; p=0.002). Also, higher—although not significantly—posttreatment eGFR levels were observed in patients with low risk of uL-FABP (73 mL/min per 1.73 m2; IQR, 58 to 91.3 mL/min per 1.73 m2) compared with controls (57.3 mL/min per 1.73 m2; IQR, 49.5 to 72.6 mL/min per 1.73 m2; p=0.06). No significant increase was observed in high-risk patients for either marker when compared with controls.

      Conclusions

      The albuminuria-lowering effect of saxagliptin may be due to inhibition of kidney tubular damage. Use of tubular markers may be a promising approach to identifying kidney responders to gliptins.

      Résumé

      Objectifs

      Des études cliniques récentes ont démontré que la saxagliptine présente un potentiel néphroprotecteur grâce à la diminution de l’albuminurie. Le but de la présente étude était de déterminer si les effets de la saxagliptine sur les paramètres rénaux étaient influencés par les changements dans les marqueurs des lésions tubulaires rénales, notamment les concentrations urinaires de la protéine associée à la gélatinase des neutrophiles (uNGAL, de l’anglais urinary neutrophil gelatinase-associated protein) et des protéines de liaison aux acides gras de type hépatique (uL-FABP, de l’anglais liver-type fatty acid–binding protein).

      Méthodes

      Notre étude regroupait 80 patients atteints du diabète de type 2, d’hypertension et de néphropathie diabétique (NPD) légère à modérée marquée par la prédominance de l’albuminurie. Les patients étaient répartis de façon aléatoire, soit au groupe qui recevait la saxagliptine en traitement complémentaire, soit au groupe témoin qui maintenait leur traitement antidiabétique.

      Résultats

      Le groupe qui recevait la saxagliptine a montré une réduction significative des uNGAL, soit un changement médian de −25,4 % (écart interquartile [ÉIQ] de −35,6 % à −12,2 %), par rapport au groupe témoin (changement médian de −0,91 %, ÉIQ de −12 % à 11,88 %, p < 0,001) après 3 mois. De la même façon, les patients qui recevaient la saxagliptine ont montré une réduction significative des uL-FABP (changement médian de −24,4 %, ÉIQ de −30,5 % à −15,1 %) par rapport aux témoins (changement médian de −3,8 %, ÉIQ de −10 % à 12,5 %, p < 0,001). Les valeurs médianes du débit de filtration glomérulaire estimé (DFGe) après 3 mois dans le bras qui recevait la saxagliptine étaient significativement plus élevées (76,5 mL/min/1,73 m2, ÉIQ de 70 à 92,75 mL/min/1,73 m2) dans le groupe qui présentait un faible risque d’uNGAL que dans le groupe témoin (59,8 mL/min/1,73 m2, ÉIQ de 51 à 76,2 mL/min/1,73 m2, p = 0,002). Après le traitement, nous avons également observé des concentrations du DFGe élevées, bien qu’elles n’étaient pas significatives, chez les patients qui présentaient un faible risque d’uL-FABP (73 mL/min/1,73 m2, ÉIQ de 58 à 91,3 mL/min/1,73 m2) par rapport aux témoins (57,3 mL/min/1,73 m2, ÉIQ de 49,5 à 72,6 mL/min/1,73 m2, p = 0,06). Ni les patients exposés à un risque élevé ni les témoins n’ont montré une augmentation significative de l’un de ces marqueurs.

      Conclusions

      L’effet de la saxagliptine sur la diminution de l’albuminurie peut être attribuable à l’inhibition des lésions tubulaires rénales. L’utilisation des marqueurs tubulaires constitue une approche prometteuse pour trouver les répondeurs rénaux aux gliptines.

      Keywords

      Mots clés

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