Disrupted tubular parathyroid hormone/parathyroid hormone receptor signaling and damaged tubular cell viability possibly trigger postsurgical kidney injury in patients with advanced hyperparathyroidism
Disrupted tubular parathyroid hormone/parathyroid hormone receptor signaling and damaged tubular cell viability possibly trigger postsurgical kidney injury in patients with advanced hyperparathyroidism
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DOI：
10.1093/ckj/sfy136
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发表时间：
2019-01
影响因子：
4.6
通讯作者：
Tetsuhiko Sato;Y. Kikkawa;Suguru Yamamoto;Yusuke Tanaka;J. Kazama;Y. Tominaga;T. Ichimori;M. Okada;T. Hiramitsu;M. Fukagawa
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文献类型：
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作者：
Tetsuhiko Sato;Y. Kikkawa;Suguru Yamamoto;Yusuke Tanaka;J. Kazama;Y. Tominaga;T. Ichimori;M. Okada;T. Hiramitsu;M. Fukagawa
摘要背景甲状旁腺切除术(PTX)可减轻晚期甲状旁腺功能亢进症(甲状旁腺功能亢进症)的临床表现，包括高钙血症和低磷血症，被认为是预防肾脏钙超载的最好方法。然而，手术后甲状旁腺激素(PTH)降低与围手术期肾小管细胞活性之间的关系知之甚少。PTX术后肾功能仍是肾移植后原发性甲状旁腺功能亢进症(PHPT)和三级甲状旁腺功能亢进症(TPT)的关键问题。方法作为一项临床研究，我们检查了2015-2017年间在我中心接受PTX治疗的52例患者(其中45例为PHPT，7例为TPT)的数据，以确定PTX后的肾损害。他们的临床数据，包括尿肝型脂肪酸结合蛋白(L-FABP)，急性肾损伤的管状生物标志物，从患者图表中获得。PTX定义AKI后第2天血清肌酐水平的绝对变化为0.3 mg/dL(26.5微克/L)。PTX后进行补钙剂量调整，使血钙严格维持在正常范围的下半部。为了模拟PTX术后的肾脏状态，制作了一种独特的甲状旁腺切除大鼠模型：13周龄大鼠接受了甲状旁腺切除术(TPTX)和/或5/6肾大部切除术(NX)。TPTX大鼠使用皮下植入的渗透压小泵持续输注生理水平的1-34PTH。免疫荧光分析是用针对PTH受体(PTHR)的多克隆抗体进行的，PTHR可能是肾脏损伤的关键调节因子Klotho。结果患者估计的肾小球滤过率(62.5±22.0对59.4±21.9mL/min/1.73m2，NS)无临床相关性变化；血钙(2.7±0.18对2.2±0.16 mmol/L，P 9.8µg/g肌酐)对PTX相关性急性肾损伤的预测准确率为100%。TPTX组大鼠肾脏PTHR表达较低。甲状旁腺素输注(+PTH)可恢复TPTX大鼠肾小管PTHR的表达。给予TPTX、+PTH和5/6NX的大鼠PTHR表达较未给予5/6NX的大鼠明显减少。5/6 NX部分取消+PTH驱动的肾小管PTHR上调。肾小管Klotho在正常大鼠肾脏中有少量表达，而在5/6 NX大鼠肾脏中有增强的斑片状小管表达。这种Klotho和表达定位模式在TPTX中被完全取消，表明PTH间接调控了Klotho表达模式。TPTX+PTH可恢复肾小管上皮细胞Klotho的表达，甚至引发Klotho的弥漫性表达。5/6NX使肾小管存活细胞减少，最终下调肾小管Klotho的表达和定位。结论尽管甲状旁腺功能亢进症患者在PTX后总体上有望保持良好的肾功能，但原有的肾小管损伤是PTX后AKI的潜在危险因素。肾小管细胞生物标记物水平升高的患者可能会遭受PTX后的肾脏损害，即使PTX后仔细调整了补钙。我们独特的实验大鼠模型表明，钝化的肾小管PTH/PTHR信号可能通过Klotho连锁途径损害肾小管细胞活性并恶化肾功能。
Abstract Background Parathyroidectomy (PTX) that alleviates clinical manifestations of advanced hyperparathyroidism, including hypercalcemia and hypophosphatemia, is considered the best protection from calcium overload in the kidney. However, little is known about the relationship between postsurgical robust parathyroid hormone (PTH) reduction and perisurgical renal tubular cell viability. Post-PTX kidney function is still a crucial issue for primary hyperparathyroidism (PHPT) and tertiary hyperparathyroidism after kidney transplantation (THPT). Methods As a clinical study, we examined data from 52 consecutive patients (45 with PHPT, 7 with THPT) who underwent PTX in our center between 2015 and 2017 to identify post-PTX kidney injury. Their clinical data, including urinary liver-type fatty acid-binding protein (L-FABP), a tubular biomarker for acute kidney injury (AKI), were obtained from patient charts. An absolute change in serum creatinine level of 0.3 mg/dL (26.5 µmol/L) on Day 2 after PTX defines AKI. Post-PTX calcium supplement dose adjustment was performed to strictly maintain serum calcium at the lower half of the normal range. To mimic post-PTX-related kidney status, a unique parathyroidectomized rat model was produced as follows: 13-week-old rats underwent thyroparathyroidectomy (TPTX) and/or 5/6 subtotal nephrectomy (NX). Indicated TPTX rats were given continuous infusion of a physiological level of 1-34 PTH using a subcutaneously implanted osmotic minipump. Immunofluorescence analyses were performed by polyclonal antibodies against PTH receptor (PTHR) and a possible key modulator of kidney injury, Klotho. Results Patients’ estimated glomerular filtration rate (eGFR) did not have any clinically relevant change (62.5 ± 22.0 versus 59.4 ± 21.9 mL/min/1.73 m2, NS), whereas serum calcium (2.7 ± 0.18 versus 2.2 ± 0.16 mmol/L, P 9.8 µg/g creatinine had 100% accuracy in predicting post-PTX-related AKI. Rat kidney PTHR expression was lower in TPTX. PTH infusion (+PTH) restored tubular PTHR expression in rats that underwent TPTX. Rats with TPTX, +PTH and 5/6 NX had decreased PTHR expression compared with those without 5/6 NX. 5/6 NX partially cancelled tubular PTHR upregulation driven by +PTH. Tubular Klotho was modestly expressed in normal rat kidneys, whereas enhanced patchy tubular expression was identified in 5/6 NX rat kidneys. This Klotho and expression and localization pattern was absolutely canceled in TPTX, suggesting that PTH indirectly modulated the Klotho expression pattern. TPTX +PTH recovered tubular Klotho expression and even triggered diffusely abundant Klotho expression. 5/6 NX decreased viable tubular cells and eventually downregulated tubular Klotho expression and localization. Conclusions Preexisting tubular damage is a potential risk factor for AKI after PTX although, overall patients with hyperparathyroidism are expected to keep favorable kidney function after PTX. Patients with elevated tubular cell biomarker levels may suffer post-PTX kidney impairment even though calcium supplement is meticulously adjusted after PTX. Our unique experimental rat model suggests that blunted tubular PTH/PTHR signaling may damage tubular cell viability and deteriorate kidney function through a Klotho-linked pathway.