Role of the adaptive immune system in diabetic kidney disease.

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end-stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro-inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon-γ and tumor necrosis factor-α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

Performance of 4 Creatinine-based Equations in Assessing Glomerular Filtration Rate in Adults with Diabetes.

AIMS: To evaluate diagnostic performance of glomerular filtration rate (GFR) estimated by modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI), full age spectrum (FAS), and revised Lund-Malmö (r-LM) equations in adults with diabetes. METHODS: Individuals were included in this cross-sectional study if they had at least 1 measurement of technetium-99m diethylenetriamine-pentaacetic acid (99mTc-DTPA) GFR (mGFR) and serum creatinine (1487 patients with 2703 measures). GFR calculated by estimation equations was compared with mGFR. Diagnostic performance was assessed using concordance correlation coefficient (CCC), bias, precision, accuracy, reduced major axis regression (RMAR), and Bland-Altman plot. Analysis was repeated in subgroups based on sex, diabetes type, Hemoglobin A1C, and GFR level. RESULTS: Of all patients, 1189 (86%) had type 2 diabetes. Mean mGFR, MDRD, CKD-EPI, FAS, and revised Lund-Malmö eGFR were 66, 72, 74, 71, and 67 mL/min/1.73m2, respectively. Overall, the r-LM had the highest CCC (0.83), lowest bias (-1.4 mL/min/1.73 m2), highest precision (16.2 mL/min/1.73 m2), and highest accuracy (P10 = 39%). The RMAR (slope, intercept) in r-LM, FAS, MDRD, and CKD-EPI was 1.18, -13.35; 0.97, -2.9; 1, -6.4, and 1.04, -11.3, respectively. The Bland-Altman plot showed that r-LM had the lowest mean difference and the narrowest 95% limit of agreement (-1.0, 54.1 mL/min/1.73 m2), while mean difference was more than 5-fold higher in FAS, MDRD, and CKD-EPI (-5.2, -6.3, and -8.2, respectively). CONCLUSIONS: In adults with diabetes the revised Lund-Malmö performs better than MDRD, CKD-EPI, and FAS in calculating point estimates of GFR.

Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy.

CONTEXT: The thrombotic effects of estradiol therapy in transgender women are unclear. Global coagulation assays (GCA) may be better measures of hemostatic function compared with standard coagulation tests. OBJECTIVE: To assess the GCA profiles of transgender women in comparison to cisgender controls and to compare how GCA differ between routes of estradiol therapy in transgender women. DESIGN: Cross-sectional case-control study. SETTING: General community. PARTICIPANTS: Transgender women, cisgender male and cisgender female controls. MAIN OUTCOME MEASURES: Citrated blood samples were analyzed for (i) whole blood thromboelastography (TEG®5000), (ii) platelet-poor plasma thrombin generation (calibrated automated thrombogram); and (iii) platelet-poor plasma fibrin generation (overall hemostatic potential assay). Mean difference (95% confidence intervals) between groups are presented. RESULTS: Twenty-six transgender women (16 oral estradiol, 10 transdermal estradiol) were compared with 98 cisgender women and 55 cisgender men. There were no differences in serum estradiol concentration (P = 0.929) and duration of therapy (P = 0.496) between formulations. Transgender women demonstrated hypercoagulable parameters on both thromboelastography (maximum amplitude + 6.94 mm (3.55, 10.33); P < 0.001) and thrombin generation (endogenous thrombin potential + 192.62 nM.min (38.33, 326.91); P = 0.009; peak thrombin + 38.10 nM (2.27, 73.94); P = 0.034) but had increased overall fibrinolytic potential (+4.89% (0.52, 9.25); P = 0.024) compared with cisgender men. No significant changes were observed relative to cisgender women. Route of estradiol delivery or duration of use did not influence the GCA parameters. CONCLUSION: Transgender women on estradiol therapy demonstrated hypercoagulable GCA parameters compared with cisgender men with a shift towards cisgender female parameters. Route of estradiol delivery did not influence the GCA parameters.

Hypocalcaemia following denosumab in prostate cancer: A clinical review.

OBJECTIVES: Denosumab is often used in men with advanced prostate cancer to prevent skeletal-related events, but can be associated with severe hypocalcaemia. Our objective was to review the pathophysiology, identify risk factors and provide recommendations for prevention and management of denosumab-associated hypocalcaemia. DESIGN: We reviewed the literature regarding denosumab-associated severe hypocalcaemia, defined as necessitating hospitalization for intravenous calcium treatment, in the context of prostate cancer. PATIENTS: Men with prostate cancer with severe denosumab-associated hypocalcemia. RESULTS: We identified 20 men with prostate cancer with severe denosumab-associated hypocalcemia, including the present case. Median age (range) was 70 years (45-86). All had skeletal metastases and presented with symptomatic hypocalcemia 16 days (4-35) after the initial (n = 18) or second (n = 2) denosumab treatment, with a serum total calcium of 1.36 mmol/L (1.13-1.91). The key risk factor was presence of active osteoblastic metastases, evidenced by elevated serum alkaline phosphatase, 838 U/L (58-2620) and supportive imaging. Other risk factors reported in some men included vitamin D deficiency (<50 nmol/L), 25-OH vitamin D 44 nmol/L (22-81), renal impairment, serum creatinine 103 µmol/L (62-1131) and hypomagnesaemia, 0.82 mmol/L (0.29-1.20). Men received intravenous calcium infusions for 16 days (1-90), and median total intravenous elemental calcium requirements were 3.17 g (0.47-26.65). CONCLUSIONS: Denosumab treatment in men with metastatic prostate cancer can be associated with life-threatening hypocalcaemia requiring prolonged hospitalization for intravenous calcium treatment. Modifiable risk factors should be corrected before denosumab administration. In men with active osteoblastic metastases, consideration should be given to delay denosumab treatment until underlying disease activity is controlled, and/or be administered with close monitoring and proactive treatment with calcium and calcitriol.

Diagnostic performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at estimating glomerular filtration rate in adults with diabetes mellitus: a systematic review and meta-analysis protocol.

INTRODUCTION: Timely detection leading to the implementation of reno-protective measures reduces the progression of diabetic kidney disease. Estimated glomerular filtration rate (eGFR) is a major surrogate of kidney function. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation is a tool to estimate GFR. This protocol outlines a systematic-review, assessing the diagnostic accuracy of the CKD-EPI equation in adults with diabetes. METHODS AND ANALYSIS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials and grey literature will be searched for publications in English, Farsi, Dutch and Chinese from 2009 (when CKD-EPI was first introduced) to January 2019. Bridging searches will be conducted to capture literature published from January 2019 until final review publication. The inclusion criteria will be (1) study participants with diabetes; (2) age ≥18 years; (3) creatinine-based CKD-EPI eGFR as index test; (4) measured GFR using the clearance/plasma disappearance of inulin, iohexol, iothalamate, diethylenetriamine-pentaacetic acid (DTPA) or chromium labelled ethylenediaminetetraacetic acid (Cr-EDTA) as reference test; (5) report of the diagnostic accuracy of the index test. Exclusion criteria will be participants with renal transplant, chronic use of corticosteroids, chronic inflammatory diseases, pregnancy, non-diabetes related kidney disease, thalassaemia, heart failure, pregnancy and potential kidney donors as well as critically ill patients. Screening, eligibility check, risk of bias assessment and data extraction will be carried out by two independent reviewers. Any discrepancies will be discussed, and third-party opinion will be sought. The risk of bias will be assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A quantitative synthesis of the aggregated-data will be used if the included studies are homogenous. ETHICS AND DISSEMINATION: No ethics approval is required. The outcome will be published in a peer-reviewed journal. The results will help researchers and clinicians evaluate the diagnostic accuracy of the creatinine-based CKD-EPI eGFR in adults with diabetes. PROSPERO REGISTRATION NUMBER: CRD42018108776.

Three Dimensional Glomerular Reconstruction: A Novel Approach to Evaluate Renal Microanatomy in Diabetic Kidney Disease.

Mesangial metrics reflect glomerular filtration surface area in diabetes. The point-sampled intercept (PSI) method is the conventional method to calculate these parameters. However, this is time consuming and subject to underestimation. We introduce a novel three-dimensional (3D) reconstruction method applicable to light microscopy to measure mesangial metrics. Transmission electron microscopy (TEM), PSI and our new 3D imaging methods were used to quantify mesangial metrics from 22 patients with type 2 diabetes, normo-, micro- and macroalbuminuria and an estimated glomerular filtration rate of <60 mL/min/1.73 m2. Repeated-measures ANOVA test was used to test the equality of the measurement means from the three methods and the degree of inter method variability. Repeated-measures and post-estimation ANOVA tests together with correlation coefficient measurements were used to compare the methods with TEM as reference. There was a statistically significant difference in mesangial volume measurements (F(2, 16) = 15.53, p = 0.0002). The PSI method underestimated measurements compared to TEM and 3D methods by 30% (p = 0.001) and 15%, respectively (p < 0.001). 3D and TEM measurements did not differ significantly. 3D reconstruction is a reliable and time efficient method for calculating mesangial metrics. It may prove to be a useful tool in clinical and experimental diabetic kidney disease.

The Presence of Diabetes and Higher HbA1c Are Independently Associated With Adverse Outcomes After Surgery.

OBJECTIVE: Limited studies have examined the association between diabetes and HbA1c with postoperative outcomes. We investigated the association of diabetes, defined categorically, and the association of HbA1c as a continuous measure, with postoperative outcomes. RESEARCH DESIGN AND METHODS: In this prospective, observational study, we measured the HbA1c of surgical inpatients age ≥54 years at a tertiary hospital between May 2013 and January 2016. Patients were diagnosed with diabetes if they had preexisting diabetes or an HbA1c ≥6.5% (48 mmol/mol) or with prediabetes if they had an HbA1c between 5.7 and 6.4% (39 and 48 mmol/mol). Patients with an HbA1c <5.7% (39 mmol/mol) were categorized as having normoglycemia. Baseline demographic and clinical data were obtained from hospital records, and patients were followed for 6 months. Random-effects logistic and negative binomial regression models were used for analysis, treating surgical units as random effects. We undertook classification and regression tree (CART) analysis to design a 6-month mortality risk model. RESULTS: Of 7,565 inpatients, 30% had diabetes, and 37% had prediabetes. After adjusting for age, Charlson comorbidity index (excluding diabetes and age), estimated glomerular filtration rate, and length of surgery, diabetes was associated with increased 6-month mortality (adjusted odds ratio [aOR] 1.29 [95% CI 1.05-1.58]; P = 0.014), major complications (1.32 [1.14-1.52]; P < 0.001), intensive care unit (ICU) admission (1.50 [1.28-1.75]; P < 0.001), mechanical ventilation (1.67 [1.32-2.10]; P < 0.001), and hospital length of stay (LOS) (adjusted incidence rate ratio [aIRR] 1.08 [95% CI 1.04-1.12]; P < 0.001). Each percentage increase in HbA1c was associated with increased major complications (aOR 1.07 [1.01-1.14]; P = 0.030), ICU admission (aOR 1.14 [1.07-1.21]; P < 0.001), and hospital LOS (aIRR 1.05 [1.03-1.06]; P < 0.001). CART analysis confirmed a higher risk of 6-month mortality with diabetes in conjunction with other risk factors. CONCLUSIONS: Almost one-third of surgical inpatients age ≥54 years had diabetes. Diabetes and higher HbA1c were independently associated with a higher risk of adverse outcomes after surgery.

Higher maternal serum prolactin levels are associated with reduced glucose tolerance during pregnancy.

It is unknown if high prolactin levels during pregnancy contribute to the development of gestational diabetes. We hypothesized that higher prolactin levels are associated with reduced glucose tolerance, as determined by higher 2-h glucose level from an oral glucose tolerance test in pregnancy. The 75-g oral glucose tolerance test was carried out at 28 weeks of gestation in 69 participants. A multiple regression analysis was used to determine the relationship between serum prolactin and 2-h glucose levels. Multivariable regression analysis showed an independent and significant relationship between third trimester prolactin and 2-h glucose levels post oral glucose tolerance test. Higher prolactin levels were associated with higher glucose levels independent of age, body mass index, gravidity and parity. Higher prolactin levels associated with reduced glucose tolerance in the third trimester of pregnancy suggests the possible independent role of prolactin in the pathogenesis of gestational diabetes.

The arrector pili muscle, the bridge between the follicular stem cell niche and the interfollicular epidermis.

Proximally, the arrector pili muscle (APM) attaches to the follicular stem cell niche in the bulge, but its distal properties are comparatively unclear. In this work, a novel method employing an F-actin probe, phalloidin, was employed to visualize the APM anatomy. Phalloidin staining of the APM was validated by comparison with conventional antibodies/stains and by generating three-dimensional reconstructions. The proximal attachment of the APM to the bulge in 8 patients with androgenic alopecia was studied using Masson's trichrome stain. Phalloidin visualized extensive branching of the APM. The distal end of the human APM exhibits a unique "C"-shaped structure connecting to the dermal-epidermal junction. The proximal APM attachment was observed to be lost or extremely miniaturized in androgenic alopecia. The unique shape, location, and attachment sites of the APM suggest a significant role for this muscle in maintaining follicular integrity. Proximally, the APM encircles the follicular unit and only attaches to the primary hair follicle in the bulge; this attachment is lost in irreversible hair loss. The APM exhibits an arborized morphology as it ascends toward the epidermis, and anchors to the basement membrane.

Concomitant extraspinal hyperostosis and osteoporosis in a patient with congenital ichthyosis.

Ichthyosiform dermatosis is a term referred to a group of disorders that have as their basis a disorder of keratinization (1). These conditions which are present at birth result in a generalized dry, scaly skin without any inflammation. There are several types of ichthyosis based on their clinical presentation and mode of inheritance. The most common types are: ichthyosis vulgaris, X-linked recessive ichthyosis, epidermolytic hyperkeratosis (bullous), lamellar ichthyosis and non-bullous ichthyosiform erythroderma. Lamellar ichthyosis, which is inherited in an autosomal recessive pattern, shows genetic heterogeneity with the most severe type being due to mutations in the transglutaminase-1 gene. This condition presents with skin changes at birth and cases are referred to as collodion babies. Initially, the stratum corneum is smooth and appears as though it is covered with cellophane. This layer is discarded a few days after birth, leaving a generalized inflamed and scaly appearance. The skin is tight at this stage and may cause ectropion, and difficulties in feeding and temperature regulation. Lamellar ichthyosis is characterized by plate-like scales that last for life and can significantly impact the patient's quality of life (2). We report here a case of multiple extraspinal hyperostoses concomitant with marked osteoporosis and vitamin D deficiency in a patient taking acitretin for 20 years due to severe congenital lamellar ichthyosis.

Androgenetic alopecia: new insights into the pathogenesis and mechanism of hair loss.

The hair follicle is a complete mini-organ that lends itself as a model for investigation of a variety of complex biological phenomena, including stem cell biology, organ regeneration and cloning.  The arrector pili muscle inserts into the hair follicle at the level of the bulge- the epithelial stem cell niche.  The arrector pili muscle has been previously thought to be merely a bystander and not to have an active role in hair disease. Computer generated 3D reconstructions of the arrector pili muscle have helped explain why women with androgenetic alopecia (AGA) experience diffuse hair loss rather than the patterned baldness seen in men.  Loss of attachment between the bulge stem cell population and the arrector pili muscle also explains why miniaturization is irreversible in AGA but not alopecia areata. A new model for the progression of AGA is presented.

Beyond goosebumps: does the arrector pili muscle have a role in hair loss?

The arrector pili muscle (APM) consists of a small band of smooth muscle that connects the hair follicle to the connective tissue of the basement membrane. The APM mediates thermoregulation by contracting to increase air-trapping, but was thought to be vestigial in humans. The APM attaches proximally to the hair follicle at the bulge, a known stem cell niche. Recent studies have been directed toward this muscle's possible role in maintaining the follicular integrity and stability. This review summarizes APM anatomy and physiology and then discusses the relationship between the follicular unit and the APM. The potential role of the APM in hair loss disorders is also described, and a model explaining APM changes in hair loss is proposed.