Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital.

Methods

Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B).

Results

Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of −11.2 (−17.6, −9.2) mL/min/1.73 m² after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m² and a yearly median (IQR) eGFR slope of −1.6 (−3.1, −0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B.

Conclusion

DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function.

中文翻译：

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二肽基肽酶 4 抑制剂相关的肾脏疾病

背景

二肽基肽酶 4 (DPP-4) 抑制剂广泛用于治疗 2 型糖尿病 (T2D)。降低血糖预计也能减少糖尿病肾病的进展。我们遇到过一位 2 型糖尿病患者，他使用 DPP-4 抑制剂实现了良好的血糖控制，但肾功能迅速恶化。因此，我们对在我院治疗的类似患者进行了回顾性研究。

方法

从 2018 年 1 月至 2022 年 12 月在虎之门医院接受自体肾活检的 56 名经活检证实的糖尿病肾病患者中，我们选择了 22 名在肾活检时已接受 DPP-4 抑制剂至少 9 个月的患者。在这些患者中，我们评估了 16 名根据 Tervaert 病理分类诊断为 IIa 级糖尿病肾病的患者。16 名患者的年度估计肾小球滤过率 (eGFR) 斜率按斜率从最高到最低排列。肾活检显示，10 名 eGFR 斜率较大的患者存在血栓性微血管病 (TMA) 样病变，其特征为肾小球内皮细胞增殖和 GBM 重复（A 组），而其余 6 名患者没有 TMA 样病变（B 组）。

结果

DPP-后，A 组的中位 eGFR 为 18.2 (16.2, 26.2)，年中位 (IQR) eGFR 斜率为 -11.2 (-17.6, -9.2) mL/min/1.73 m ² 4 次给药，而 B 组的中位 (IQR) eGFR 为 31.5 (21.9, 34.8) mL/min/1.73 m ²，年中位 (IQR) eGFR 斜率为 -1.6 (-3.1, -0.3)。A 组的肾功能下降速度明显快于 B 组，A 组的蛋白尿也高于 B 组（中位 [IQR]，3.4 [2.6, 4.4] g/天 vs 0.8 [0.4, 1.3] g/天， 分别）。A 组中有 5 名患者在随访期间进展为透析，但 B 组中没有患者这样做。A 组中位 (IQR) 血红蛋白 A1c 为 6.2 % (6.0 %, 6.6 %)，B 组为 5.8 % (5.7 %, 6.6 %)。

结论

DPP-4抑制剂促进血管内皮再生，但当这种作用发生在肾小球时，肾小球内皮细胞增殖导致TMA样病变，可能导致蛋白尿增加和肾功能迅速下降。