Institute of Physiology, University of Zurich, Zurich, Switzerland.
National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland.
Nephrol Dial Transplant. 2021 Sep 27;36(10):1806-1820. doi: 10.1093/ndt/gfab210.
Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with a higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy are associated with altered expression of proteins involved in renal acid-base metabolism.
We retrospectively collected kidney biopsies from 22 patients. Of these patients, nine had no acidosis, nine had metabolic acidosis [plasma bicarbonate (HCO3- <22 mmol/L) and four had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid-base handling.
We found that the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule (PT) amino acid and lipid metabolism and energy homoeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 potassium channel, an important regulator of PT HCO3- metabolism and transport, acyl-CoA dehydrogenase short/branched chain and serine hydroxymethyltransferase 1, genes involved in beta oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the PT NBCe1 HCO3- transporter in kidneys from acidotic patients who recovered with alkali therapy. In addition, the HCO3- exchanger pendrin was affected by acidosis and alkali therapy.
Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid-base transport proteins mostly from PT were also affected by acidosis and alkali therapy, suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients.
代谢性酸中毒在肾移植患者中很常见，与移植物功能丧失的风险增加和加速有关。迄今为止，尚不清楚这些患者的碱治疗是否能改善肾功能，以及酸中毒及其治疗是否与参与肾酸碱代谢的蛋白质表达改变有关。
我们回顾性地收集了 22 例患者的肾活检标本。其中 9 例无酸中毒，9 例代谢性酸中毒[血浆碳酸氢盐（HCO3-<22mmol/L），4 例酸中毒并接受碱治疗。我们进行了转录组分析和参与肾酸碱处理的蛋白质的免疫组织化学。
我们发现，非酸中毒和酸中毒患者的肾脏之间有 40 个转录本的表达明显改变。这些基因主要涉及近端肾小管（PT）的氨基酸和脂质代谢以及能量稳态。三种转录本通过碱治疗完全恢复：Kir4.2 钾通道，PT HCO3-代谢和转运的重要调节剂，酰基辅酶 A 脱氢酶短/支链和丝氨酸羟甲基转移酶 1，参与β氧化和蛋氨酸代谢的基因。免疫组织化学显示，酸中毒患者的 PT NBCe1 HCO3-转运体染色减少，这些患者在接受碱治疗后恢复。此外，HCO3-交换蛋白 pendrin 受酸中毒和碱治疗的影响。
肾移植受者的代谢性酸中毒与肾脏转录组的改变有关，这些改变部分可通过碱治疗恢复。酸碱转运蛋白主要来自 PT 也受到酸中毒和碱治疗的影响，这表明关键因子的下调可能导致这些患者发生代谢性酸中毒。
