XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22759

Diagnosis, management, and treatment of hepatitis C: An update

Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.

TGF-β: the master regulator of fibrosis

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

Inflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease from other causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IκB/NF-κB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IκB/NF-κB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-κB activation, tubular CCL-2 expression, and interstitial macrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathway may promote tubulointerstitial inflammation in diabetic nephropathy.

Toll-Like Receptor 4 Promotes Tubular Inflammation in Diabetic Nephropathy

As of 22 February 2020, more than 77662 cases of confirmed COVID-19 have been documented globally with over 2360 deaths. Common presentations of confirmed cases include fever, fatigue, dry cough, upper airway congestion, sputum production, shortness of breath, myalgia/arthralgia with lymphopenia, prolonged prothrombin time, elevated C-reactive protein, and elevated lactate dehydrogenase. The reported severe/critical case ratio is approximately 7-10% and median time to intensive care admission is 9.5-10.5 days with mortality of around 1-2% varied geographically. Similar to outbreaks of other newly identified virus, there is no proven regimen from conventional medicine and most reports managed the patients with lopinavir/ritonavir, ribavirin, beta-interferon, glucocorticoid and supportive treatment with remdesivir undergoing clinical trial. In China, Chinese medicine is proposed as a treatment option by national and provincial guidelines with substantial utilization. We reviewed the latest national and provincial clinical guidelines, retrospective cohort studies, and case series regarding the treatment of COVID-19 by add-on Chinese medicine. We have also reviewed the clinical evidence generated from SARS and H1N1 management with hypothesized mechanisms and latest in silico findings to identify candidate Chinese medicines for the consideration of possible trials and management. Given the paucity of strongly evidence-based regimens, the available data suggest that Chinese medicine could be considered as an adjunctive therapeutic option in the management of COVID-19.

COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease.

Renal tubulointerstitial injury is characterized by inflammatory cell infiltrate; however, the stimuli for leukocyte recruitment are not fully understood. IL-8 is a potent chemokine produced by proximal tubular epithelial cells (PTECs). Whether nephrotic proteins stimulate tubular IL-8 expression remains unknown. Acute exposure of human PTECs to albumin induced IL-8 gene and protein expression time- and dose-dependently. Apical albumin predominantly stimulated basolateral IL-8 secretion. Electrophoretic mobility shift assay demonstrated nuclear translocation of NF-κB, and the p65/p50 subunits were activated. NF-κB activation and IL-8 secretion were attenuated by the NF-κB inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H2O2 stimulated NF-κB translocation and IL-8 secretion. Albumin-induced ROS generation, NF-κB activation, and IL-8 secretion were endocytosis- and PKC-dependent as these downstream events were abrogated by the PI3K inhibitors LY294002 and wortmannin, and the PKC inhibitors GF109203X and staurosporin, respectively. In vivo, IL-8 mRNA expression was localized by in situ hybridization to the proximal tubules in nephrotic kidney tissues. The intensity of IL-8 immunostaining was higher in nephrotic than non-nephrotic subjects. In conclusion, albumin is a strong stimulus for tubular IL-8 expression, which occurs via NF-κB–dependent pathways through PKC activation and ROS generation.

/pdf/albumin-stimulates-interleukin-8-expression-in-proximal-38s1mz6ojk.pdf

Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo

Increasing evidence suggests that renal inflammation contributes to the pathogenesis and progression of diabetic kidney disease (DKD) and that anti-inflammatory therapies might have renoprotective effects in DKD. Immune cells and resident renal cells that activate innate immunity have critical roles in triggering and sustaining inflammation in this setting. Evidence from clinical and experimental studies suggests that several innate immune pathways have potential roles in the pathogenesis and progression of DKD. Toll-like receptors detect endogenous danger-associated molecular patterns generated during diabetes and induce a sterile tubulointerstitial inflammatory response via the NF-κB signalling pathway. The NLRP3 inflammasome links sensing of metabolic stress in the diabetic kidney to activation of pro-inflammatory cascades via the induction of IL-1β and IL-18. The kallikrein–kinin system promotes inflammatory processes via the generation of bradykinins and the activation of bradykinin receptors, and activation of protease-activated receptors on kidney cells by coagulation enzymes contributes to renal inflammation and fibrosis in DKD. In addition, hyperglycaemia leads to protein glycation and activation of the complement cascade via recognition of glycated proteins by mannan-binding lectin and/or dysfunction of glycated complement regulatory proteins. Data from preclinical studies suggest that targeting these innate immune pathways could lead to novel therapies for DKD. Increasing evidence suggests that inflammation contributes to the development and progression of diabetic kidney disease (DKD). Here, the authors discuss the mechanisms by which innate immune pathways might contribute to DKD as well as the therapeutic potential of targeting these pathways.

Sydney C.W. Tang

Papers

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

Toll-Like Receptor 4 Promotes Tubular Inflammation in Diabetic Nephropathy

COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease.

Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo

Innate immunity in diabetic kidney disease.