Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets

Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease around the globe and is one of the main complications in patients with type 1 and 2 diabetes. The standard treatment for DKD is drugs controlling hyperglycemia and high blood pressure. Renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition have yielded promising results in DKD, but many diabetic patients on such treatments nevertheless continue to develop DKD, leading to kidney failure and cardiovascular comorbidities. New therapeutic options are urgently required. We review here the promising therapeutic avenues based on insights into the mechanisms of DKD that have recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonist, endothelin receptor A inhibition, anti-inflammatory agents, autophagy activators and epigenetic remodelling. The involvement of several molecular mechanisms in DKD pathogenesis, together with the genetic and epigenetic variability of this condition, makes it difficult to target this heterogeneous patient population with a single drug. Personalized medicine, taking into account the genetic and mechanistic variability, may therefore improve renal and cardiovascular protection in diabetic patients with DKD.     

Relationship between high‐normal albuminuria and arterial stiffness in Chinese population

High‐normal albuminuria is related to the morbidity and mortality of cardiovascular disease. Arterial stiffness has been regarded as a predictor of cardiovascular disease. However, the relationship between high‐normal albuminuria and arterial stiffness is uncertain in Chinese population. A total of 1343 Chinese participants (aged 58.9 ± 12.1 years, 63.53% male) were included in this study. High‐normal albuminuria was defined as urinary albumin‐to‐creatinine ratio (UACR) above the median within normal albuminuria. Based on the level of UACR, all participants were divided into low‐normal albuminuria group (UACR < 6.36 mg/g, n = 580), high‐normal albuminuria group (6.36 mg/g ≤ UACR < 30 mg/g, n = 581), microalbuminuria (30 mg/g ≤ UACR < 300 mg/g, n = 162), and macroalbuminuria (UACR ≥ 300 mg/g, n = 20). Arterial stiffness was assessed by measuring carotid‐femoral pulse wave velocity (cfPWV). With the increment of UACR, the level of cfPWV was increased gradually (P < .001). Stepwise multiple regression analysis showed that systolic blood pressure, age, serum creatinine, heart rate, logarithmic (LG)‐transformed UACR, and fasting plasma glucose were independently associated with cfPWV in all subjects (P < .001). LG‐UACR was found to be related to cfPWV in high‐normal albuminuria and macroalbuminuria subjects. After further stratification in the high‐normal albuminuria subjects, their relation remained in male, elderly over 65 years old, or normotensives. In summary, UACR is associated with arterial stiffness in subjects with proteinuria excretion in high normal level. High‐normal albuminuria might be an early indicator of arterial stiffness, especially in male, elderly, or normotensives in Chinese population. Furthermore, age and blood pressure are still observed to be the most important risk factor of arterial stiffness.     

左旋氨氯地平对血压控制不良患者微量白蛋白尿逆转作用的研究

目的观察不同联合治疗方案对高血压伴微量白蛋白尿(MAU)患者血压控制及白蛋白尿的逆转作用。方法选择使用血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体拮抗剂后,血压仍>140/90 mm Hg(1 mm Hg=0.133 kPa)且MAU阳性的高血压患者94例,随机分为左旋氨氯地平组52例(2.5～5 mg/d)、氢氯噻嗪组42例(1 2.5～25 mg/d),干预12周。观察不同治疗方案对血压控制以及MAU的逆转作用。结果左旋氨氯地平组和氢氯噻嗪组干预1 2周后,血压达标分别为35例和27例(67.3%vs 64.3%,P>0.05)。MAU转阴率分别为53.8%和1 9.0%(P<0.01);血压<140/90 mm Hg同时MAU下降≥30%的比例分别为80.8%和64.3%(P<0.05)。结论肾素-血管紧张素阻滞剂联合钙拮抗剂或利尿剂(氢氯噻嗪)的治疗方案在血压降低以及达标率方面无显著差异。联合钙拮抗剂在降低MAU方面明显优于联合利尿剂方案。     

Cystatin C and albuminuria as predictors of long‐term allograft outcomes in kidney transplant recipients

Although cystatin C (Cys) and albuminuria (Alb) are predictors of end‐stage renal disease in the general population, there are limited data about the performance of these markers alone or combined with respect to the prediction of the kidney transplant outcome. We assessed the ability of one‐yr creatinine (Cr), MDRD equation, Cys, Hoek equation, Alb, the logarithm of albuminuria (LogAlb), and two products of these variables for predicting death‐censored graft loss (DCGL) in 127 kidney transplant recipients. Mean follow‐up time was 5.6 ± 1.7 yr. During this time, 18 patients developed DCGL. The area under the receiver operating characteristic curve for DCGL ranged from 71.1% to 85.4%, with Cys*LogAlb being the best predictor. Cys‐based variables and variables combining LogAlb and renal function estimates have better discrimination ability than Cr‐based variables alone. After multivariate analysis, quartiles of all one‐yr variables (except of Cr and MDRD) were independent predictors for DCGL. Predictors combining Alb and a Cr‐ or Cys‐based estimate of renal function performed better than those markers alone to predict DCGL. Cys‐based predictors performed better than Cr‐based predictors. Using a double‐marker in kidney transplantation, it is possible to identify the highest risk group in which to prioritize specialty care.     

Novel avenues for drug discovery in diabetic kidney disease

Introduction: Diabetic kidney disease (DKD) has emerged as major cause of morbidity and mortality. After progressing to renal failure, over 70% of DKD patients are dead with five years. New treatments to slow this progression are desperately needed.

Areas covered: This review highlights the current treatment options for people with DKD with a particular focus on angiotensin pathway blockade and the potential use of sodium glucose linked transporter 2 (SGLT2) inhibitors. These treatments are associated with an initial decrease in glomerular filtration rate (GFR) and albuminuria; there is also attention on renal hyperfiltration as therapeutic target. Both clinical and preclinical testing are facilitated by leveraging albuminuria reduction as a dynamic biomarker of drug effect linked to renal failure. It is critical to ensure that animal models exhibit both albuminuria and progressive loss of renal function so drug effects can be established in both.

Expert opinion: New pathways and potential drug targets are emerging from gene expression profiling of human kidney biopsies and genome wide association studies. By harmonizing animal experimentation endpoints with clinical outcomes, focusing on disease pathophysiology and incorporating novel gene expression and biomarker changes, therapeutics can be advanced into clinical testing with greater confidence.     

Soluble TNF Receptors and Kidney Dysfunction in the Elderly

The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=−0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.     

Brain structural changes and their correlation with vascular disease in type 2 diabetes mellitus patients： a voxel-based morphometric study

Voxel-based morphometry has been used in the study of alterations in brain structure in type 1 diabetes mellitus patients. These changes are associated with clinical indices. The age at onset, pathogenesis, and treatment of type 1 diabetes mellitus are different from those for type 2 diabetes mellitus. Thus, type 1 and type 2 diabetes mellitus may have different impacts on brain structure. Only a few studies of the alterations in brain structure in type 2 diabetes mellitus patients using voxel-based morphometry have been conducted, with inconsistent results. We detected subtle changes in the brain structure of 23 cases of type 2 diabetes mellitus, and demonstrated that there was no significant difference between the total volume of gray and white matter of the brain of type 2 diabetes mellitus patients and that in controls. Regional atrophy of gray matter mainly occurred in the right temporal and left occipital cortex, while regional atrophy of white matter involved the right temporal lobe and the right cerebellar hemisphere. The ankle-brachial index in patients with type 2 diabetes mellitus strongly correlated with the volume of brain regions in the default mode network. The ankle-brachial index, followed by the level of glycosylated hemoglobin, most strongly correlated with the volume of gray matter in the right temporal lobe. These data suggest that voxel-based morphometry could detect small structural changes in patients with type 2 diabetes mellitus. Early macrovascular atherosclerosis may play a crucial role in subtle brain atro- phy in type 2 diabetes mellitus patients, with chronic hyperglycemia playing a lesser role.     

Low-grade albuminuria is associated with peripheral artery disease in Chinese diabetic patients

Background

Increasing studies have suggested that albuminuria might be an important risk factor for peripheral artery disease (PAD). However, studies focusing on the association between low-grade albuminuria and PAD are limited. It would be of great interest to elucidate the association between low-grade albuminuria and PAD in diabetic subjects.

Methods

A cross-sectional study was conducted in 1386 diabetic subjects (age ≥ 40 years) with normal urinary albumin levels from Shanghai, China. A first voided early morning spot urine sample was obtained for urinary albumin and creatinine measurements. Subjects were divided into three groups according to sex-specific cutoff points of urinary albumin–creatinine ratio (UACR) tertiles. Subjects in the upper tertile of UACR were classified as having low-grade albuminuria. PAD was defined by ankle–brachial index (ABI) <0.9 or >1.4.

Results

Overall, 106 (7.7%) of the study population had PAD. The prevalence of PAD in tertile 3 of UACR was higher than the prevalence in tertile 2 and tertile 1 (10.2%, 6.4% and 6.4%, respectively; P < 0.05). A fully adjusted logistic regression analysis revealed that compared with subjects in tertile 1 of normal UACR, those in tertile 3 had 1.7-fold increased risk for the presence of PAD.

Conclusions

In diabetic patients, high normal UACR level, which is below the current cutoff point of microalbuminuria, was associated with the increased prevalence of PAD. It suggested that low-grade albuminuria might be an early marker for the detection of PAD in diabetic patients.     

New approaches to the treatment of nephropathy in diabetes

Introduction: In individuals with diabetes, the presence and severity of kidney disease adversely affects their well-being, significantly contributes to burden of morbidity and increases their risk of a premature death. The efficiency of current management strategies for the treatment of diabetic nephropathy, even in optimal combination, is partial, at best. There remains an unmet need for additional renoprotective interventions in patients with diabetes.

Areas covered: This review presents a comprehensive summary of some of the ‘new contenders’ for the treatment of diabetic nephropathy that have been tested or are being tested in randomised clinical trials in patients with diabetes with a predefined renal endpoint, but are not currently indicated for renoprotective therapy. Many of these drugs have been in clinical use for other indications, or initially developed for other purposes.

Expert opinion: Although substantial progress has been made towards understanding the pathogenesis of diabetic nephropathy, at present there are no new drugs that provide the solutions we want for our patients. Even when used in combination with standard medical care, current data indicate that renal complications are at best only modestly reduced, at the expense of additional pill burden and exposure to off-target effects. Given the ever-growing burden of diabetic kidney disease, there is a substantial opportunity for better and more targeted (‘smarter’) therapeutic interventions in this context.