Predicting the protein composition of human urine in normal and pathological states: Quantitative description based on Dent1 disease (CLCN5 mutation)
Predicting the protein composition of human urine in normal and pathological states: Quantitative description based on Dent1 disease (CLCN5 mutation)
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DOI：
10.1113/jp280740
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发表时间：
2020-11-24
影响因子：
5.5
通讯作者：
Norden, Anthony G. W.
中科院分区：
文献类型：
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作者：
Edwards, Aurelie;Christensen, Erik I.;Norden, Anthony G. W.
要点尿中血浆蛋白的存在很难定量解释。它可能是肾小球滤过受损或近端小管(PT)重吸收受损，或两者兼而有之。Dent1病(CLCN5突变)使PT蛋白重吸收丧失，肾小球功能保持不变。利用Dent1病患者和正常人的尿蛋白测量，我们设计了一个数学模型，该模型结合了两个具有不同动力学特征的PT转运过程。这个模型预测了白蛋白、α(1)-微球蛋白(α(1)-m)、β(2)-微球蛋白(β(2)-m)和视黄醇结合蛋白4(RBP4)的尿液浓度。我们的结果表明，尿β(2)-m和RBP4的排泄量与白蛋白和α(1)-m的不同，它们对肾小球滤过率、肾小球蛋白泄漏、通过内吞和PT水重吸收的肾小管蛋白摄取。模型定量地预测了超滤和肾小球渗漏如何相互作用以促进蛋白尿。我们的模型将有助于更好地理解和解释肾脏疾病中的尿蛋白测量。为了阐明肾小球滤过和肾小管摄取对尿蛋白排泄的相对贡献，我们利用Michaelis-Menten动力学和取自人类牙本质1病(CLCN5功能丧失突变)的摩尔尿蛋白测量，建立了人类近端小管(PT)蛋白重吸收的数学模型。β(2)-微球蛋白(β(2)-m)和视黄醇结合蛋白4(RbP4)通常以“非常高”的摄取动力学和尿排出分数0.025%被重吸收，而白蛋白和α(1)-微球蛋白(α(1)-m)通过“高”摄取动力学和高50倍的尿排出分数(1.15%)被重吸收。我们的模型正确地预测了马兜铃酸肾病患者尿β(2)-m、RBP4和α(1)-m的含量，并预测了单侧肾切除后尿β(2)-m排泄量的增加和单肾单位肾小球滤过率(SNGFR)的增加。我们探索了改变的内吞、水重吸收、SNGFR和肾小球蛋白过滤如何影响排泄。我们的结果有助于解释为什么β(2)-m和RBP4是比白蛋白或α(1)-m更敏感的PT功能障碍标志物，并提示Fanconi综合征患者PT钠和水重吸收减少可能导致蛋白尿。白蛋白排泄量从正常到微量白蛋白尿的转变，增加了5倍，相当于白蛋白肾小球滤过率增加了3.5倍，支持使用微量白蛋白尿筛查来检测糖尿病患者的肾小球渗漏。在大量白蛋白尿中，小的白蛋白通透性变化会导致大的排泄变化。然而，SNGFR的变化可以改变蛋白排泄，而高滤过和肾小球渗漏可以结合起来增加蛋白尿。我们的模型对人体尿液的蛋白质组成在正常和病理生理状态下的运输过程提供了有效的定量描述。
Key pointsThe presence of plasma proteins in urine is difficult to interpret quantitatively. It may be a result of impaired glomerular filtration or impaired proximal tubule (PT) reabsorption, or both.Dent1 disease (CLCN5 mutation) abolishes PT protein reabsorption leaving glomerular function intact. Using urine protein measurements from patients with Dent1 disease and normal individuals, we devised a mathematical model that incorporates two PT transport processes with distinct kinetics. This model predicts albumin, alpha(1)-microglobulin (alpha(1)-m), beta(2)-microglobulin (beta(2)-m) and retinol-binding protein 4 (RBP4) urine concentrations.Our results indicate that the urinary excretion of beta(2)-m and RBP4 differs from that of albumin and alpha(1)-m in their sensitivity to changes in the glomerular filtration rate, glomerular protein leak, tubular protein uptake via endocytosis and PT water reabsorption.The model predicts quantitatively how hyperfiltration and glomerular leak interact to promote albuminuria.Our model should contribute to improved understanding and interpretation of urine protein measurements in renal disease.To clarify the relative contributions of glomerular filtration and tubular uptake to urinary protein excretion, we developed a mathematical model of protein reabsorption in the human proximal tubule (PT) using Michaelis-Menten kinetics and molar urinary protein measurements taken from human Dent1 disease (CLCN5 loss-of-function mutation). beta(2)-Microglobulin (beta(2)-m) and retinol-binding protein 4 (RBP4) are normally reabsorbed with 'very high' efficiency uptake kinetics and fractional urinary excretion of 0.025%, whereas albumin and alpha(1)-microglobulin (alpha(1)-m) are reabsorbed by 'high' efficiency uptake kinetics and 50-fold higher fractional urinary excretion of 1.15%. Our model correctly predicts the urinary beta(2)-m, RBP4 and alpha(1)-m content in aristolochic acid nephropathy, and elevated beta(2)-m excretion with increased single nephron glomerular filtration rate (SNGFR) following unilateral-nephrectomy. We explored how altered endocytic uptake, water reabsorption, SNGFR and glomerular protein filtration affect excretion. Our results help to explain why beta(2)-m and RBP4 are more sensitive markers of PT dysfunction than albumin or alpha(1)-m, and suggest that reduced PT sodium and water reabsorption in Fanconi syndrome may contribute to proteinuria. Transition of albumin excretion from normal to microalbuminuria, a 5-fold increase, corresponds to a 3.5-fold elevation in albumin glomerular filtration, supporting the use of microalbuminuria screening to detect glomerular leak in diabetes. In macroalbuminuria, small albumin permeability changes produce large changes in excretion. However, changes in SNGFR can alter protein excretion, and hyperfiltration with glomerular leak can combine to increase albuminuria. Our model provides a validated quantitative description of the transport processes underlying the protein composition of human urine in normal and pathophysiological states.