Renal Outcomes in Patients with Type 1 Diabetes and Macroalbuminuria

Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss. We examined the long-term renal outcomes of persons with type 1 diabetes who developed incident macroalbuminuria during the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. One hundred fifty-nine participants developed incident macroalbuminuria and were subsequently followed for a median duration of 9 years (maximum of 25 years). At the time of macroalbuminuria diagnosis, mean (SD) age was 37 (9) years, mean (SD) duration of diabetes was 17 (5) years, median AER was 524 mg/d, and mean (SD) eGFR was 108 (20) ml/min per 1.73 m². Ten years after macroalbuminuria diagnosis, the cumulative incidence of a sustained reduction in AER to <300 mg/d was 52%, mostly but not entirely under treatment with renin-angiotensin system inhibitors. The cumulative incidence of impaired GFR (sustained eGFR<60 ml/min per 1.73 m²) 10 years after macroalbuminuria diagnosis was 32%, including 16% who developed ESRD. Lower hemoglobin A1c and BP and regression to AER<300 mg/d were associated with reduced risk of developing impaired GFR. In conclusion, people with type 1 diabetes who develop macroalbuminuria are at high risk of progressive kidney disease. However, through at least 10 years of follow-up, AER could often be controlled, and GFR frequently remained in the normal range.Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss.¹ In early published type 1 diabetes cohorts, macroalbuminuria was associated with a 15-year cumulative incidence of ESRD as high as 75%.^2,3 However, contemporary long-term renal outcomes of macroalbuminuria have not been fully characterized.The Diabetes Control and Complications Trial (DCCT) and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, present a valuable opportunity to examine macroalbuminuria and its long-term clinical outcomes. In DCCT/EDIC, the onset of macroalbuminuria can be defined with confidence using frequent longitudinal measurements of AER, participants have been followed for up to 25 years after the diagnosis of macroalbuminuria, and outcomes were meticulously recorded using standardized methods. Previous work in this cohort has shown that most cases of impaired GFR are preceded by macroalbuminuria,⁴ which is associated with a 50-fold higher risk of developing impaired GFR (eGFR<60 ml/min per 1.73 m²).⁵ Here, we extend these studies by comprehensively evaluating the long-term renal outcomes of incident macroalbuminuria in the DCCT/EDIC cohort and examining the risk factors for its progression to impaired GFR.     

A strategy to implement and support pre-hospital emergency medical systems in developing,resource-constrained areas of South Africa

Resource-constrained countries are in extreme need of pre-hospital emergency care systems. However, current popular strategies to provide pre-hospital emergency care are inappropriate for and beyond the means of a resource-constrained country, and so new ones are needed—ones that can both function in an under-developed area's particular context and be done with the area's limited resources. In this study, we used a two-location pilot and consensus approach to develop a strategy to implement and support pre-hospital emergency care in one such developing, resource-constrained area: the Western Cape province of South Africa. Local community members are trained to be emergency first aid responders who can provide immediate, on-scene care until a Transporter can take the patient to the hospital. Management of the system is done through local Community Based Organizations, which can adapt the model to their communities as needed to ensure local appropriateness and feasibility. Within a community, the system is implemented in a graduated manner based on available resources, and is designed to not rely on the whole system being implemented first to provide partial function. The University of Cape Town's Division of Emergency Medicine and the Western Cape's provincial METRO EMS intend to follow this model, along with sharing it with other South African provinces.     

Microwave coagulation therapy and drug injection to treat splenic injury

Background

The present study compares the efficacy of 915- and 2450-MHz contrast-enhanced ultrasound (CEUS)–guided percutaneous microwave coagulation with that of CEUS-guided thrombin injection for the treatment of trauma-induced spleen hemorrhage.

Materials and methods

In a canine splenic artery hemorrhage model with two levels of arterial diameter (A, <1 mm and B, between 1 and 2 mm), hemostatic therapy was performed using 915- and 2450-MHz microwaves and drug injection. Therapy efficacy was measured by comparing bleeding rate, hemostatic time, bleeding index, bleeding volume, and pathology.

Results

The most efficient technique was CEUS-guided 915-MHz percutaneous microwave coagulation therapy in terms of action time and total blood loss. The success rate of the 915-MHz microwave group was higher than that of the 2450-MHz microwave and the drug injection groups (except A level, P < 0.05). Hemostatic time, bleeding index, and bleeding volume were significantly less in the 915-MHz microwave group than those in the 2450-MHz microwave and drug injection groups (P < 0.05). Obvious degeneration and necrosis of parenchyma and large intravascular thrombosis were observed in the cavity of larger vessels in the 915-MHz microwave group, but pathologic changes of light injury could be seen in the other groups.

Conclusions

The present study provides evidence that microwave coagulation therapy is more efficient than thrombin injection for the treatment of splenic hemorrhage. Furthermore, treatment with 915-MHz microwaves stops bleeding more rapidly and generates a wider cauterization zone than does treatment with 2450-MHz microwaves.     

The interaction between Toll-like receptor 4 signaling pathway and hypoxia-inducible factor 1α in lung ischemia–reperfusion injury

Background

Lung ischemia–reperfusion injury (LIRI) is the life-threatening complication occurring after lung transplantation. Toll-like receptor 4 (TLR4) signaling pathway and hypoxia-inducible factor-1α (HIF-1α) are intimately involved in the development and progression of various inflammatory and hypoxia diseases; however, the relationship of them in LIRI in vivo is still far from clear.

Materials and methods

Forty-five Sprague–Dawley rats were randomly distributed in nine groups: (1) Sham group, (2) LIRI group, (3) LIRI + saline control group, (4) LIRI + dimethyl Sulfoxide control group, (5) LIRI + lipopolysaccharide group, (6) LIRI + TAK-242 group (TAK-242 is a TLR4 inhibitor, ethyl (6R)-6- [N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate), (7) LIRI + thioredoxin group (thioredoxin is an apoptosis signal–regulating kinase 1 (ASK1) inhibitor), (8) LIRI + SB203580 group (SB203580 is a p38 inhibitor), and (9) LIRI + chetomin group (chetomin is a HIF-1α inhibitor). The interaction between TLR4 signaling pathway (including TLR4, myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), ASK1, and p38) and HIF-1α and the role of TLR4-dependent HIF-1α were analyzed.

Results

In LIRI, HIF-1α accumulation was induced in a TLR4-dependent fashion, and MyD88, but not TRIF, and activation of ASK1 and p38 were found to be critical for TLR4-mediated HIF-1α accumulation. HIF-1α protein played a critical role in TLR4-mediated lung injury of LIRI (including inflammation, cell apoptosis, and lung damage). HIF-1α protein upregulated TLR4 expression of LIRI in a positive feedback manner.

Conclusions

We identify that the TLR4-HIF-1 loop may be existed in LIRI. Therefore, we suggest that the interaction between them may represent a novel therapeutic target for the development of novel target-based therapies of LIRI.