Diabetic kidney disease (DKD), previously encountered predominantly in adult patients, is rapidly gaining center stage as a childhood morbidity and one that pediatric nephrologists are likely to encounter with increasing frequency. This is in large part due to the obesity epidemic and the consequent rise in type 2 diabetes in children and adolescents, as well as the more aggressive diabetes phenotype in today’s youth with more rapid β-cell decline and faster development and progression of diabetes-related complications along with lower responsiveness to the treatments used in adults. DKD, an end-organ complication of diabetes, is at the very least a marker of, and more likely a predisposing factor for, the development of adverse cardiovascular outcomes and premature mortality in children with diabetes. On an optimistic note, several new therapeutic approaches are now available for the management of diabetes in adults, such as GLP1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors, that have also been shown to have a favorable impact on cardiorenal outcomes. Also promising is the success of very low-energy diets in inducing remission of diabetes in adults. However, the addition of these pharmacological and dietary approaches to the management toolbox of diabetes and DKD in children and adolescents awaits thorough assessment of their safety and efficacy in this population. This review outlines the scope of diabetes and DKD, and new developments that may favorably impact the management of children and young adults with diabetes and DKD.

Objective: Acute kidney injury is common in surgical and critically ill patients. This study examined if pretreatment with a TLR4 agonist attenuated ischemia reperfusion-induced AKI (IRI-AKI). Design: A blinded, randomized controlled study in mice pretreated with PHAD, a synthetic TLR4 agonist. Two cohorts of male BALB/c mice received intraperitoneal vehicle or PHAD (10, 20, or 40 µg); or intravenous vehicle or PHAD (2, 20, or 200 µg) at 48 and 24 hours prior to unilateral renal pedicle clamping and simultaneous contralateral nephrectomy. A separate cohort of mice received vehicle or 200 µg of PHAD followed by bilateral IRI-AKI. Mice were monitored for 3 days post-reperfusion and euthanized for analysis. Methods and Results: Kidney function was assessed by BUN and serum creatinine measurements. Kidney tubular injury was assessed by semi-quantitative analysis of tubular morphology on PAS-stained kidney sections, and kidney mRNA quantification of injury (N-Gal, Kim-1 and HO-1) and inflammation (IL-6, IL-1b and TNF-α) using qRT-PCR technique. Immunohistochemistry was used to quantify Kim-1 and F4/80 protein to assess kidney injury and macrophages, respectively. PHAD pretreatment yielded dose-dependent kidney function preservation during unilateral IRI-AKI. Histological injury and N-Gal mRNA were lower, and IL-1b mRNA was higher in 200 µg 3D 6-Acyl PHAD treated mice. Similar pretreatment protection was noted at 200 mg PHAD after bilateral IRI-AKI, with significantly reduced Kim-1 immunostaining in the outer medulla of mice treated with PHAD after bilateral IRI-AKI. Conclusions: PHAD pretreatment leads to dose-dependent protection from renal injury after unilateral and bilateral IRI-AKI in mice.

Aims/Hypothesis: Diabetic kidney disease (DKD) remains a significant cause of morbidity and mortality in people with diabetes. Though animal models have taught us much about the molecular mechanisms of DKD, translating these findings to human disease requires greater knowledge of the molecular changes caused by diabetes in human kidneys. Establishing this knowledge base requires building carefully curated, reliable, and complete repositories of human kidney tissue, as well as tissue proteomics platforms capable of simultaneous, spatially resolved examination of multiple proteins. Methods: We used the multiplexed immunofluorescence platform CO-Detection by indexing (CODEX) to image and analyze the expression of 21 proteins in 23 tissue sections from 12 individuals with diabetes and healthy kidneys (DM, 5 individuals), DKD classes IIA, and IIB (2 individuals per class), IIA-B intermediate (2 individuals), and III (one individual). Results: Analysis of the 21-plex immunofluorescence images revealed 18 cellular clusters, corresponding to 10 known kidney compartments and cell types, including proximal tubules, distal nephron, podocytes, glomerular endothelial and peritubular capillaries, blood vessels, including endothelial cells and vascular smooth muscle cells, macrophages, cells of the myeloid lineage, broad CD45+ inflammatory cells and the basement membrane. DKD progression was associated with co-localized increase in collagen IV deposition and infiltration of inflammatory cells, as well as loss of native proteins of each nephron segment at variable rates. Compartment-specific cellular changes corroborated this general theme, with compartment-specific variations. Cell type frequency and cell-to-cell adjacency highlighted (statistically) significant increase in inflammatory cells and their adjacency to tubular and aSMA+ cells in DKD kidneys. Finally, DKD progression was marked by substantial regional variability within single tissue sections, as well as variability across patients within the same DKD class. The sizable intra-personal variability in DKD severity impacts pathologic classifications, and the attendant clinical decisions, which are usually based on small tissue biopsies. Conclusions/Interpretations: High-plex immunofluorescence images revealed changes in protein expression corresponding to differences in cellular phenotypic composition and microenvironment structure with DKD progression. This initial dataset demonstrates the combined power of curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools in revealing pathophysiology of human DKD.