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Recent advances in diabetic kidney disease
BMC Medicine ( IF 9.3 ) Pub Date : 2021-08-17 , DOI: 10.1186/s12916-021-02050-0
Mohamad Hanouneh 1, 2 , Justin B Echouffo Tcheugui 1, 3, 4 , Bernard G Jaar 1, 2, 3, 4
Affiliation  

Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in the USA and worldwide. An estimated 422 million adults are living with diabetes globally, and up to 40% of them may develop CKD during their lifetime [1]. Diabetic kidney disease (DKD) does not reflect a specific pathological phenotype. In fact, it can be diagnosed clinically based on the presence of persistent albuminuria, sustained reduction in the estimated glomerular filtration rate (eGFR), or both in patients with diabetes [2]. DKD is usually identified after five years of the diagnosis of type 1 diabetes, while it can be recognized at the time of diagnosis of type 2 diabetes. The presence of proliferative diabetic retinopathy typically correlates with ongoing DKD in patients with albuminuria. Even though a kidney biopsy can confirm the diagnosis of DKD, this procedure is usually considered when an alternative diagnosis suspected.

Albuminuria has more recently been classified into moderate (30 to 300 mg/g) or severe (> 300 mg/g). Nonetheless, any degree of albuminuria has been associated with an increased risk for CKD progression, end-stage kidney disease (ESKD), adverse cardiovascular disease outcomes, and mortality in patients with diabetes [3]. A reduced eGFR in diabetic patients has been observed in the absence of albuminuria; however, the progression of DKD appears to be slower in these individuals [3]. Furthermore, the combined presence of albuminuria and lower eGFR independently increases the risks for cardiovascular events and mortality in individuals with diabetes [3]. The Kidney Disease: Improving Global Outcomes (KDIGO) and the American Diabetes Association (ADA) guidelines recommend that all diabetic patients undergo annual screening by checking serum creatinine-based eGFR and urine tests to evaluate for albuminuria [2].

Individuals with type 2 diabetes may develop DKD before a clear diagnosis of diabetes is established. This has the consequence of delaying the diagnosis and appropriate treatment of DKD. More recently, we have witnessed significant progress in the treatment options for slowing DKD, but no real advance in reversing DKD. To date, available therapies are targeting DKD progression. Furthermore, not all DKD patients are eligible for these therapies because of variable side effects such as hyperkalemia, acute kidney injury (AKI), and extent of the DKD. Indeed, because of safety concerns, many of these newer medications are not approved for patients with eGFR below 30 mL/min/1.73 m2.

Hyperaminoacidemia, glomerular hyperfiltration and hyperperfusion, and hyperglycemia are the major metabolic abnormalities that affect the kidneys and are associated with inflammation and eventually fibrosis in diabetic patients [4]. The classic sequence of events in the natural history of DKD is driven by hyperglycemia in conjunction with hypertension and is characterized by glomerular hyperfiltration progressing to albuminuria, and then leading to a decline in kidney function. One mechanistic hypothesis suggests that a decrease in distal delivery of sodium chloride to the macula densa results from an increased proximal tubular reabsorption of glucose via sodium–glucose cotransporter 2 leading to a decrease in tubulo-glomerular feedback. This results in dilation of the afferent arteriole and increased glomerular perfusion [5]. On the other hand, increased production of angiotensin II leads to vasoconstriction in the efferent arteriole. The net effect is an elevated intraglomerular pressure leading to glomerular hyperfiltration [5]. Additionally, systemic hypertension and obesity can also contribute to glomerular hyperfiltration via glomerular enlargement [4].

A number of other factors can play a significant role in the pathogenesis of DKD. These include, for example, oxidative stress. Activation of advanced glycation end-products (AGE) receptors, which are represented on multiple cell types in the kidneys, induces the production of numerous cytokines. Hyperglycemia causes increased formation of AGE and activates protein kinase C, resulting in decreased production of endothelial nitric oxide synthase and increased levels of the endothelin 1, Angiopoietins 2, and vascular endothelial growth factor. Furthermore, hyperglycemia, angiotensin II, and AGE can activate macrophages, which are rich in cytokines and tumor necrosis factor. The net effect of these different pathways leads to endothelial instability, increased vascular proliferation, renal hypertrophy, podocyte injury, tubular epithelial cell injury, and increased cytokine production [6].

The structural changes of DKD start with thickening of the glomerular basement membrane followed by mesangial matrix expansion and foot process effacement [7]. Segmental mesangiolysis and Kimmelstiel–Wilson nodules are signs of DKD progression [8]. Interstitial fibrosis and global sclerosis develop in later DKD stages.

Intensive glycemic control is critical in the prevention of DKD in the early course of the disease. However, a number of studies have shown that intensive glucose control may not reduce the risk of CKD progression or cardiovascular mortality in advanced stages of DKD [9]. The KDIGO guidelines recommend a target HbA1c ranging from < 6.5 to < 8.0%, with the choice of an exact target guided by the extent of hypoglycemia risk in each patient [10].

For glycemic control, current guidelines suggest using both metformin and sodium-glucose cotransporter 2 inhibitors for patients with DKD and GFR > 30 ml/min per 1.73 m2 [10]. Glucagon-like peptide-1 receptor agonists can be added to manage hyperglycemia if needed [10]. Uncontrolled hypertension can worsen DKD and increase the risk of progression to ESKD. The KDIGO guidelines recommend using an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) to maintain blood pressure below 130/80 mmHg in all patients with CKD and albuminuria regardless of their diabetic status. Prior studies showed that ACEis and ARBs offer kidney protection by lowering proteinuria and slowing the rate of CKD progression [10]. Combination regimens with ACEis and ARBs are not recommended due to an increased risk of acute kidney injury and hyperkalemia.

Regarding the non-pharmacological therapies, KDIGO guidelines recommend the implementation of lifestyle modification among DKD patients, including low sodium intake (< 2 g/day), maintaining a protein intake of 0.8 g/kg/day for patients who are not on dialysis, and moderate-intensity physical activity for a cumulative duration of at least 150 min per week as tolerated [10].

Not applicable.

CKD:

Chronic kidney disease

eGFR:

Estimated glomerular filtration rate

DKD:

Diabetic kidney disease

ESKD:

End-stage kidney disease

KDIGO:

Kidney Disease: Improving Global Outcomes

ADA:

American Diabetes Association

AKI:

Acute kidney injury

AGE:

Advanced glycation end-products

ACEi:

Angiotensin-converting enzyme inhibitor

ARB:

Angiotensin receptor blocker

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Dr. Echouffo Tcheugui was supported by the National Heart, Lung, and Blood Institute (NHLBI) Grant K23HL153774.

Affiliations

  1. Department of Medicine, Johns Hopkins University School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21239, USA

    Mohamad Hanouneh, Justin B. Echouffo Tcheugui & Bernard G. Jaar

  2. Nephrology Center of Maryland, Baltimore, MD, USA

    Mohamad Hanouneh & Bernard G. Jaar

  3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Justin B. Echouffo Tcheugui & Bernard G. Jaar

  4. Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD, USA

    Justin B. Echouffo Tcheugui & Bernard G. Jaar

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Correspondence to Bernard G. Jaar.

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Hanouneh, M., Echouffo Tcheugui, J.B. & Jaar, B.G. Recent advances in diabetic kidney disease. BMC Med 19, 180 (2021). https://doi.org/10.1186/s12916-021-02050-0

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中文翻译：
糖尿病肾病研究进展

在美国和全世界，糖尿病是慢性肾病 (CKD) 的主要原因。全球估计有 4.22 亿成年人患有糖尿病，其中多达 40% 的人可能在其一生中发展为 CKD [1]。糖尿病肾病 (DKD) 并不反映特定的病理表型。事实上，临床上可以根据糖尿病患者是否存在持续性蛋白尿、估计肾小球滤过率 (eGFR) 持续降低或两者兼而有之来进行诊断 [2]。DKD 通常在 1 型糖尿病诊断 5 年后被识别，而在 2 型糖尿病诊断时可以识别。增殖性糖尿病视网膜病变的存在通常与白蛋白尿患者的持续 DKD 相关。尽管肾活检可以确诊 DKD，

Albuminuria has more recently been classified into moderate (30 to 300 mg/g) or severe (> 300 mg/g). Nonetheless, any degree of albuminuria has been associated with an increased risk for CKD progression, end-stage kidney disease (ESKD), adverse cardiovascular disease outcomes, and mortality in patients with diabetes [3]. A reduced eGFR in diabetic patients has been observed in the absence of albuminuria; however, the progression of DKD appears to be slower in these individuals [3]. Furthermore, the combined presence of albuminuria and lower eGFR independently increases the risks for cardiovascular events and mortality in individuals with diabetes [3]. The Kidney Disease: Improving Global Outcomes (KDIGO) and the American Diabetes Association (ADA) guidelines recommend that all diabetic patients undergo annual screening by checking serum creatinine-based eGFR and urine tests to evaluate for albuminuria [2].

2 型糖尿病患者可能会在明确诊断糖尿病之前发展为 DKD。这会导致延迟 DKD 的诊断和适当治疗。最近，我们见证了减缓 DKD 治疗方案的重大进展，但在逆转 DKD 方面没有真正的进展。迄今为止，可用的疗法针对 DKD 进展。此外，由于高钾血症、急性肾损伤 (AKI) 和 DKD 程度等多种副作用，并非所有 DKD 患者都适合接受这些治疗。事实上，出于安全考虑，许多这些较新的药物未被批准用于 eGFR 低于 30 mL/min/1.73 m 2 的患者。

高氨基酸血症、肾小球高滤过和高灌注以及高血糖是影响肾脏的主要代谢异常，并与糖尿病患者的炎症和最终纤维化有关 [4]。DKD 自然病程中的经典事件序列是由高血糖和高血压驱动的，其特征是肾小球高滤过进展为蛋白尿，然后导致肾功能下降。一种机制假设表明，通过钠 - 葡萄糖协同转运蛋白 2 增加近端肾小管对葡萄糖的重吸收，导致肾小管 - 肾小球反馈减少，导致向致密黄斑远端输送氯化钠减少。这导致传入小动脉扩张和肾小球灌注增加 [5]。另一方面，血管紧张素II的产生增加导致传出小动脉的血管收缩。净效应是升高的肾小球内压力导致肾小球高滤过 [5]。此外，全身性高血压和肥胖也可通过肾小球增大导致肾小球高滤过 [4]。

许多其他因素可以在 DKD 的发病机制中发挥重要作用。例如，这些包括氧化应激。晚期糖基化终末产物 (AGE) 受体（代表肾脏中的多种细胞类型）的激活会诱导产生多种细胞因子。高血糖会导致 AGE 形成增加并激活蛋白激酶 C，导致内皮一氧化氮合酶的产生减少，内皮素 1、血管生成素 2 和血管内皮生长因子的水平增加。此外，高血糖、血管紧张素II和AGE可以激活富含细胞因子和肿瘤坏死因子的巨噬细胞。这些不同途径的净效应导致内皮不稳定、血管增殖增加、肾肥大、足细胞损伤、肾小管上皮细胞损伤、

DKD 的结构变化始于肾小球基底膜增厚，然后是系膜基质扩张和足突消失 [7]。节段性系膜溶解和 Kimmelstiel-Wilson 结节是 DKD 进展的迹象 [8]。间质纤维化和全球硬化在后期 DKD 阶段发展。

强化血糖控制对于在疾病早期预防 DKD 至关重要。然而，许多研究表明，强化血糖控制可能不会降低 DKD 晚期 CKD 进展或心血管死亡率的风险 [9]。KDIGO 指南推荐的目标 HbA1c 范围为 < 6.5% 至 < 8.0%，并根据每位患者的低血糖风险程度选择准确的目标 [10]。

对于血糖控制，当前指南建议对 DKD 和 GFR > 30 ml/min/1.73 m 2 的患者使用二甲双胍和钠-葡萄糖协同转运蛋白 2 抑制剂[10]。如果需要，可以添加胰高血糖素样肽 1 受体激动剂来控制高血糖 [10]。不受控制的高血压会使 DKD 恶化并增加进展为 ESKD 的风险。KDIGO 指南推荐使用血管紧张素转换酶抑制剂 (ACEi) 或血管紧张素受体阻滞剂 (ARB) 将所有 CKD 和蛋白尿患者的血压维持在 130/80 mmHg 以下，无论其糖尿病状态如何。先前的研究表明，ACEis 和 ARB 通过降低蛋白尿和减缓 CKD 进展速度来提供肾脏保护 [10]。由于急性肾损伤和高钾血症的风险增加，不推荐使用 ACEI 和 ARB 的联合方案。

在非药物治疗方面，KDIGO 指南建议对 DKD 患者进行生活方式改变，包括低钠摄入（< 2 g/天），对未进行透析的患者保持 0.8 g/kg/天的蛋白质摄入量，每周至少 150 分钟的累积持续时间进行中等强度的身体活动 [10]。

不适用。

CKD：

慢性肾病

eGFR：

估计肾小球滤过率

丹麦克朗：

糖尿病肾病

ESKD：

终末期肾病

KDIGO：

肾脏疾病：改善全球结果

艾达：

美国糖尿病协会

阿基：

急性肾损伤

年龄：

高级糖基化终产物

ACE：

血管紧张素转换酶抑制剂

ARB：

血管紧张素受体阻滞剂

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Echouffo Tcheugui 博士得到了国家心肺血液研究所 (NHLBI) Grant K23HL153774 的支持。

隶属关系

  1. 医学系，约翰霍普金斯大学医学院，5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21239, USA

    Mohamad Hanouneh、Justin B. Echouffo Tcheugui 和 Bernard G. Jaar

  2. 美国马里兰州巴尔的摩市马里兰州肾脏病中心

    Mohamad Hanouneh 和 Bernard G. Jaar

  3. 美国马里兰州巴尔的摩市约翰霍普金斯大学彭博公共卫生学院流行病学系

    Justin B. Echouffo Tcheugui 和 Bernard G. Jaar

  4. 韦尔奇预防、流行病学和临床研究中心，美国马里兰州巴尔的摩

    Justin B. Echouffo Tcheugui 和 Bernard G. Jaar

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Hanouneh, M., Echouffo Tcheugui, JB & Jaar, BG 糖尿病肾病的最新进展。BMC Med 19, 180 (2021)。https://doi.org/10.1186/s12916-021-02050-0

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  • DOI : https://doi.org/10.1186/s12916-021-02050-0
更新日期：2021-08-17
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