1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drugor chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation)

Classification and diagnosis of diabetes

Type 2 diabetic kidney disease (DKD) is the most common cause of CKD and ESRD worldwide, and carries with it enormous human and societal costs. The goal of this review is to provide an update on the diagnosis and management of DKD based on a comprehensive review of the medical literature. Topics addressed include the evolving presentation of DKD, clinical differentiation of DKD from non-DKD, a state-of-the-art evaluation of current treatment strategies, and promising emerging treatments. It is expected that the review will help clinicians to diagnose and manage patients with DKD.

Diagnosis and Management of Type 2 Diabetic Kidney Disease

Loss of normal kidney function affects more than 10% of the population and contributes to morbidity and mortality. Kidney diseases are currently treated with immunosuppressive agents, antihypertensives and diuretics with partial but limited success. Most kidney disease is characterized by breakdown of the glomerular filtration barrier (GFB). Specialized podocyte cells maintain the GFB, and structure-function experiments and studies of intercellular communication between the podocytes and other GFB cells, combined with advances from genetics and genomics, have laid the groundwork for a new generation of therapies that directly intervene at the GFB. These include inhibitors of apolipoprotein L1 (APOL1), short transient receptor potential channels (TRPCs), soluble fms-like tyrosine kinase 1 (sFLT1; also known as soluble vascular endothelial growth factor receptor 1), roundabout homologue 2 (ROBO2), endothelin receptor A, soluble urokinase plasminogen activator surface receptor (suPAR) and substrate intermediates for coenzyme Q10 (CoQ10). These molecular targets converge on two key components of GFB biology: mitochondrial function and the actin-myosin contractile machinery. This Review discusses therapies and developments focused on maintaining GFB integrity, and the emerging questions in this evolving field.

The glomerular filtration barrier: a structural target for novel kidney therapies

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

Background and aims Recently, the albuminocentric view of diabetic kidney disease (DKD) in type 2 diabetes (T2DM) has been changing. Therefore, the relationship between diabetic retinopathy (DR) and chronic kidney disease (CKD) has to be addressed according to this new clinical presentation of DKD. The aim of this study was to evaluate, in a real-world setting, the correlation DR–DKD in T2DM. Methods and results A total of 2068 type 2 diabetic patients enrolled in a multicenter cross-sectional study were investigated. Albuminuric subjects were largely prevalent among subjects with DR (p = 0.019). In the whole study population, no difference in albumin excretion rate (AER) was observed between presence/absence of DR; instead, AER was significantly higher among patients with glomerular filtration rate (eGFR)  Conclusion In T2DM with DKD, the AER seems to be related to the presence of DR. This association is confirmed above all in those with more severe DR.

Relationship between albuminuric CKD and diabetic retinopathy in a real-world setting of type 2 diabetes: Findings from No blind study.

Background: The patients with Type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) are prone to develop diabetic nephropathy (DN). In this study, we aimed to clarify the relationship betwe...

Diabetic retinopathy may predict the renal outcomes of patients with diabetic nephropathy

Background and objectives Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. Design, setting, participants, & measurements Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency Results HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein–protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. Conclusions The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

Aims Although abnormal thyroid hormone metabolism is common in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), the relationship between thyroid hormones and DN is unclear and has been ignored during clinical practice. This study aimed to investigate the relationship between thyroid hormones and clinicopathologic changes in biopsy-proven DN patients. Methods Clinical and pathological data for 146 biopsy-proven DN patients were collected. The patients were divided into four groups: euthyroid group, high-thyroid stimulating hormone (TSH) group (SCH), low-free triiodothyronine (FT3) group (with normal levels of TSH and FT4), and high-TSH + low-FT3 group (with normal levels of FT4). The clinicopathologic features among the four groups were investigated. We evaluated the risks of abnormal thyroid hormone levels on DN by logistic regression with multivariable adjustments for other risk factors. We also performed quarterback and eight-point analyses of TSH and FT3 levels to determine their influences on DN. Results The overt proteinuria (>5 g/24 h) (P = 0.008) and severity of glomerular lesions (P = 0.011) differed between euthyroid group and high-TSH group significantly. Moreover, the levels of estimated glomerular filtration rate (P =0.019), serum creatinine (P =0.014), and severity of glomerular lesions (P =0.003) differed between the euthyroid group and low-FT3 group significantly. There were also significant differences between high-TSH, low-FT3 and high-TSH + low-FT3 patients, respectively. Respective correlations between high-TSH, low-FT3 and renal clinicopathologic changes were found to be significant according to logistic regression analyses. Quarterback and eight-point analyses indicated that patients with TSH levels of 4.54-5.67 mU/L had the most severe renal clinicopathologic changes, and the severity of renal changes decreased with increased FT3 levels. Conclusions Diabetic nephropathy patients with high-TSH and/or low-FT3 had more severe proteinuria, renal insufficiency, and glomerular lesions, suggesting that regulating thyroid hormones might have a renoprotective effect.

Thyroid hormones and diabetic nephropathy: An essential relationship to recognize

Background The performance of various equations for estimated glomerular filtration rate (eGFR) in patients with diabetes remains controversial. We aimed to evaluate the performance of equations for eGFR in Chinese patients with diabetic nephropathy (DN). Methods This is a retrospective study included in 308 patients with type 2 diabetes and biopsy-proven DN who were followed up at least one year. eGFR was calculated using chronic kidney disease epidemiology (CKD-EPI) equations based on serum creatinine (eGFRCKD-EPI-Cr), cystatin C (eGFRCKD-EPI-CysC), and joint equations (eGFRCKD-EPI-Cr-CysC), respectively. End-stage kidney disease was defined by initiation of renal replacement therapy. The eGFR concordance between equations was assessed by Bland-Altman plots. Log-rank and multivariable logistic regression were employed to evaluate the performance of equations. Results Overall, the proportion of patients with eGFR 60 mL/min/1.73m2. Compared with eGFRCKD-EPI-Cr, 39% of patients were reclassified (reclassified group) from CKD 1-2 stages to CKD 3-5 stages by eGFRCKD-EPI-CysC and they presented significantly longer diabetic duration, heavier proteinuria, advanced pathological lesions, and poorer kidney outcomes. Multivariable logistic regression indicated cystatin C was independently associated with advanced glomerular classifications. Conclusion eGFR equations incorporating cystatin C are superior to eGFR based on creatinine alone for detecting kidney injury in the early stage. The independent association between cystatin C and glomerular classifications might contribute to it.

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Geer Teng

Papers

Diabetic retinopathy may predict the renal outcomes of patients with diabetic nephropathy

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

Thyroid hormones and diabetic nephropathy: An essential relationship to recognize

Comparison of Performance of Equations for Estimated Glomerular Filtration Rate in Chinese Patients with Biopsy-Proven Diabetic Nephropathy.