Chronic kidney disease (CKD) affects about 10% of the adult population worldwide¹ and 14% of the adult population of the United States.² CKD is diagnosed by either of two criteria being present for 3 months or longer: measured renal function using the recently updated race free Chronic Kidney Disease Epidemiology (CKD-EPI) 2021 formula with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² and/or albuminuria with urine albumin/ creatinine ratio(UACR) >30 mg/g.³ Analysis of data from the US National Health and Nutrition Examination Survey through 2012 showed evidence of CKD based on eGFR and/or UACR in approximately 40% of persons with type 2 diabetes (T2D) and in approximately 60% of those with T2D age ≥65,^{4, 5} and the reported CKD prevalence among persons with T2D globally is approximately 50%.⁶ Both eGFR and UACR are important as risk markers for atherosclerotic cardiovascular disease, heart failure, and mortality.⁷ CKD must also be taken into account in drug dosing for medications with predominantly renal excretion, recognizing that glomerular filtration is only one part of the mechanism of drug elimination by the kidneys, which also involves tubular secretion and tubular reabsorption.⁸ Renal function measurement in clinical practice is typically accomplished by assessing estimated glomerular function or eGFR ml/min/1.73 m² using serum creatinine (eGFR_creat).

The eGFR_creat shows day-to-day variability of 4%–10% in healthy individuals and of 5%–15% in people with CKD.^{9, 10} Both high and low creatinine generation have major impact on the accuracy of eGFR_creat. A high protein diet, including one with protein supplements, and drugs reducing tubular creatinine excretion, such as trimethoprim, H2 blockers, fenofibrate, and ritonavir and other HIV drugs, lead to falsely higher eGFR_creat. On the other hand, low creatine levels from a vegetarian diet, limb amputation, and states of sarcopenia including malnutrition, cirrhosis, and malignancies will be associated with an incorrectly lower eGFR_creat.¹¹

Cystatin C has been known for over 60 years¹² and the Food and Drug Administration approved a cystatin C assay in 2001 for use in estimating the GFR. Cystatin C, a member of a family of inhibitors of thiol proteinases, is generated by all nucleated cells. It is a low molecular weight protein that is filtered by the renal glomeruli and completely reabsorbed and metabolized in the proximal tubule with none excreted in the urine.¹³ It is not affected by race or muscle mass, although levels are increased by obesity, inflammation, and thyroid disease and by steroid therapy, chemotherapy, and smoking.^{11, 14} These features make cystatin C an attractive alternative and addition to creatinine in the estimation of GFR (eGFR_{Cystatin C}). A systematic review of use of eGFR_Creat vs eGFR_{Cystatin C} as kidney biomarkers showed the latter to be as accurate and, in most studies, superior for determination of drug dosing.¹⁵

For these reasons in 2012 Kidney Disease: Improving Global Outcomes recommended the use of cystatin C as an alternative and addition to eGFR_creat in confirming the diagnosis of CKD. Discrepancies between cystatin C and creatinine eGFR were greatest for eGFR Stage 3 (30–60 mL/min) in a general population.¹⁶

The accepted gold standard for eGFR measurement is the measurement of iothalamate plasma clearance after a bolus injection. A study of persons with T2D with preserved renal function using an alternate research method for eGFR measurements, plasma inulin clearance, noted that eGFR_creat underestimated measured GFR by 46%, suggesting the importance of developing alternative approaches.¹⁷ In a population of persons with type 1 diabetes and a wide range of GFR levels, eGFR estimated from cystatin C levels was more reliable than that estimated from creatinine.¹⁸ Furthermore, a study of changes in serum cystatin C over time showed that persons with T2D with higher baseline cystatin C levels and greater rate of increase in these levels have increased risk of subsequent CKD development.¹⁹

In a phase 3 trial in 4745 T2D patients treated with dapagliflozin with eGFR_creat between 30 and 60 mL/min (Stage 3 CKD), the use of eGFR_Cystatin reclassified 66% of patients as having eGFR >60 mL/ min.²⁰ The use of eGFR_Cystatin improved the categorization of CKD and risk estimation for all-cause mortality and ESKD in a meta-analysis of 11 population studies with 90 750 participants using both cystatin C and creatinine eGFR, showing in particular that, for CKD stage3a (eGFR_creat 45–59 mL/min), 42% were reclassified using eGFR_Cystatin as having an eGFR >60 mL/min.¹⁶ In a pooled population of 4050 persons from 12 trials, a new eGFR equation with combined use of creatinine and cystatin C performed best in assessing renal function.²¹ Importantly, when eGFR_Creat vs eGFR_{Cystatin C} are highly discordant, the new eGFR equation leads to greater accuracy in characterizing a given individual.²²

Additionally, with significant weight loss, as occurs following bariatric surgery and with incretin-based diabetes treatment approaches, approximately 25% of lost weight is due to loss of skeletal muscle.²³ The use of eGFR_creat in this setting might overestimate renal function – although this has not been directly investigated. Although the cost of measurement of cystatin C is somewhat greater than that of measurement of creatinine,²² given the importance for persons with diabetes of accurately arriving at the correct renal function and classification of CKD and its cardiovascular risk, use of cystatin C along with creatinine in estimating eGFR appears appropriate.

慢性肾病 (CKD) 影响着全球约 10% 的成年人口¹和 14% 的美国成年人口。² CKD 通过存在 3 个月或更长时间的两个标准之一进行诊断：使用最近更新的无种族慢性肾脏病流行病学 (CKD-EPI) 2021 公式测量肾功能，估计肾小球滤过率 (eGFR) <60 mL/ min/1.73 m ²和/或蛋白尿，尿白蛋白/肌酐比值 (UACR) >30 mg/g。³对 2012 年美国国家健康和营养检查调查数据的分析显示，基于 eGFR 和/或 UACR 的 CKD 证据显示，约 40% 的 2 型糖尿病 (T2D) 患者以及约 60% 的 T2D 年龄≥ 65,4,5 ^，据报道，全球 T2D 患者中 CKD 患病率约为 50%。⁶ eGFR 和 UACR 都是动脉粥样硬化性心血管疾病、心力衰竭和死亡率的重要风险标志物。⁷对于主要通过肾脏排泄的药物，在给药时还必须考虑 CKD，认识到肾小球滤过只是肾脏药物消除机制的一部分，该机制还涉及肾小管分泌和肾小管重吸收。⁸临床实践中的肾功能测量通常是通过使用血清肌酐 (eGFR _{creat ) 评估估计肾小球功能或 eGFR ml/min/1.73 m} ²来完成。

eGFR_{的创建结果}显示，健康个体的每日变异性为 4%–10%，慢性肾病患者的每日变异性为 5%–15%。^{9, 10}_{高肌酐生成和低肌酐生成对 eGFR creat}的准确性都有重大影响。高蛋白饮食（包括补充蛋白质的饮食）和减少肾小管肌酐排泄的药物（如甲氧苄啶、H2 阻滞剂、非诺贝特、利托那韦和其他 HIV 药物）会导致 eGFR 值错误_升高。另一方面，素食、截肢和肌肉减少症（包括营养不良、肝硬化和恶性肿瘤）导致的低肌酸水平将与错误的较低 eGFR 肌酸_相关。¹¹

半胱氨酸蛋白酶抑制剂 C 已为人所知 60 多年¹²，美国食品和药物管理局于 2001 年批准了半胱氨酸蛋白酶抑制剂 C 测定法用于估算 GFR。胱抑素 C 是硫醇蛋白酶抑制剂家族的成员，由所有有核细胞产生。它是一种低分子量蛋白质，经肾小球过滤，在近曲小管中完全重吸收和代谢，不随尿液排出。¹³尽管肥胖、炎症、甲状腺疾病以及类固醇治疗、化疗和吸烟会导致水平升高，但它不受种族或肌肉质量的影响。^{11, 14}这些特征使半胱氨酸蛋白酶抑制剂 C 成为 GFR 估算中肌酐的有吸引力的替代品和补充（eGFR_{半胱氨酸蛋白酶抑制剂 C}）。对使用 eGFR _Creat与 eGFR _{Cystatin C}作为肾脏生物标志物的系统评价表明，后者同样准确，并且在大多数研究中更适合确定药物剂量。¹⁵

由于这些原因，2012 年《肾脏疾病：改善全球成果》建议使用胱抑素 C 作为 eGFR _{creat 的}替代品和补充来确认 CKD 的诊断。一般人群中，胱抑素 C 和肌酐 eGFR 之间的差异在 eGFR 3 期（30-60 mL/min）时最大。¹⁶

eGFR 测量公认的金标准是推注后碘酞酸盐血浆清除率的测量。一项对肾功能保留的 T2D 患者进行的研究，使用 eGFR 测量的替代研究方法（血浆菊粉清除率）进行研究，发现 eGFR低估_了测量的 GFR 46%，这表明开发替代方法的重要性。¹⁷在 1 型糖尿病患者和各种 GFR 水平的人群中，根据胱抑素 C 水平估算的 eGFR 比根据肌酐估算的 eGFR 更可靠。¹⁸此外，一项关于血清胱抑素 C 随时间变化的研究表明，基线胱抑素 C 水平较高且这些水平增加率较高的 2 型糖尿病患者随后发生 CKD 的风险增加。¹⁹

在一项 3 期试验中，4745 名接受达格列净治疗且 eGFR_产生介于 30 至 60 mL/min 之间的 T2D 患者（第 3 期 CKD）中，使用 eGFR_胱抑素将 66% 的患者重新分类为 eGFR >60 mL/min。²⁰在一项对 11 项人群研究进行的荟萃分析中，使用胱抑素 C 和肌酐_eGFR改进了 CKD 的分类以及全因死亡率和 ESKD 的风险评估，其中 90 750 名参与者同时使用了胱抑素 C 和肌酐 eGFR，特别表明，对于 CKD 3a 期（eGFR_创建45–59 mL/min），使用 eGFR_胱抑素将 42% 的患者重新分类为 eGFR >60 mL/min。¹⁶在来自 12 项试验的 4050 名受试者的汇总人群中，联合使用肌酐和胱抑素 C 的新 eGFR 方程在评估肾功能方面表现最佳。²¹重要的是，当 eGFR _Creat与 eGFR _{Cystatin C}高度不一致时，新的 eGFR 方程可以更准确地表征特定个体。²²

此外，随着减肥手术和基于肠促胰素的糖尿病治疗方法发生的显着体重减轻，大约 25% 的体重减轻是由于骨骼肌的损失。²³在这种情况下使用 eGFR _creat可能会高估肾功能——尽管尚未对此进行直接研究。尽管测量胱抑素 C 的成本略高于测量肌酐的成本²² ，但考虑到准确获得正确的肾功能和 CKD 分类及其心血管风险对糖尿病患者的重要性，将胱抑素 C 与肌酐一起使用估计 eGFR 似乎是合适的。