Trajectory of extracellular fluid volume over time and subsequent risks of end-stage kidney disease and mortality in chronic kidney disease: a prospective cohort study.

BACKGROUND: Extracellular fluid volume (ECF) is independently associated with chronic kidney disease (CKD) progression and mortality in patients with CKD, but the prognostic value of the trajectory of ECF over time beyond that of baseline value is unknown. OBJECTIVES: To characterize ECF trajectory and evaluate its association with the risks of end-stage kidney disease (ESKD) and mortality. METHODS: From the prospective tricentric NephroTest cohort, we included 1588 patients with baseline measured glomerular filtration rate (mGFR) ≥15 mL min-1 /1.73 m2 and ECF measurement. ECF and GFR were measured repeatedly using the distribution volume and clearance of 51 Cr-EDTA, respectively. ESKD and mortality were traced through record linkage with the national registries. Adjusted shared random-effect joint models were used to analyse the association between the trajectory of ECF over time and the two competing outcomes. RESULTS: Patients were mean age 58.7 years, 66.7% men, mean mGFR of 43.6 ± 18.6 mL min-1 /1.73 m2 and mean ECF of 16.1 ± 3.6 L. Over a median follow-up of 5.3 [IQR: 3.0;7.4] years, ECF increased by 136 [95%CI 106;167] mL per year on average, whilst diuretic prescription and 24-hour urinary sodium excretion remained stable. ESKD occurred in 324 (20.4%) patients, and 185 (11.6%) patients died before ESKD. A higher current value of ECF was associated with increased hazards of ESKD (adjusted hazard ratio [aHR]: 1.12 [95%CI 1.06;1.18]; P < 0.001 per 1 L increase in ECF), and death before ESKD (aHR: 1.10 [95%CI 1.04;1.17]; P = 0.002). CONCLUSIONS: The current value of ECF was associated with the risks of ESKD and mortality, independent of multiple potential confounders, including kidney function decline. This highlights the need for a close monitoring and adjustment of treatment to avoid fluid overload in CKD patients.

Health-related behaviours in a remote Indigenous population with Type 2 diabetes: a Central Australian primary care survey in the Telehealth Eye and Associated Medical Services Network [TEAMSnet] project.

AIM: There is a wealth of data concerning the health behaviours of Indigenous Australians, but the health behaviours of Indigenous Australians with diabetes are not systematically documented. At the clinical level, understanding a person's health behaviours can help identify and address barriers to diabetes care and promote good clinical outcomes. METHODS: We used a novel survey tool to systematically collect health behaviour data on Smoking, Nutrition, Alcohol consumption, Physical activity and Emotional well-being (SNAPE) from Indigenous Australians with Type 2 diabetes in a remote primary care setting in Alice Springs. RESULTS: At least one of the five surveys in the SNAPE tool was completed by 210 participants: 30% male, mean age 52.6 years (range 22.9 - 87.4). Fifty per cent of men and 23% of women were current smokers (P < 0.001). None of the participants reported an adequate intake of vegetables. Only 9.6% reported an adequate fruit intake. Some 49% of men and 32% of women consumed alcohol in the past year (P = 0.022), and 46% of drinkers were considered high-risk or likely-dependent drinkers. On average, participants walked 10 min or more at a time 6.0 days a week and spent 4.8 h sitting on a weekday. Mean adapted Patient Health Questionnaire 9 score was 4.61, with 34% of participants having mild depressive symptoms and 11% having moderate-severe depressive symptoms. CONCLUSIONS: Our SNAPE survey tool results present a high-risk, disadvantaged Indigenous population with Type 2 diabetes. More resources will be needed to sustainably implement interventions with the goal of improving health behaviours and subsequent long-term health.

Diabetic retinopathy in a remote Indigenous primary healthcare population: a Central Australian diabetic retinopathy screening study in the Telehealth Eye and Associated Medical Services Network project.

AIM: To determine diabetic retinopathy prevalence and severity among remote Indigenous Australians. METHODS: A cross-sectional diabetic retinopathy screening study of Indigenous adults with Type 2 diabetes was conducted by locally trained non-ophthalmic retinal imagers in a remote Aboriginal community-controlled primary healthcare clinic in Central Australia and certified non-ophthalmic graders in a retinal grading centre in Melbourne, Australia. The main outcome measure was prevalence of any diabetic retinopathy and sight-threatening diabetic retinopathy. RESULTS: Among 301 participants (33% male), gradable image rates were 78.7% (n = 237) for diabetic retinopathy and 83.1% (n = 250) for diabetic macular oedema, and 77.7% (n = 234) were gradable for both diabetic retinopathy and diabetic macular oedema. For the gradable subset, the median (range) age was 48 (19-86) years and known diabetes duration 9.0 (0-24) years. The prevalence of diabetic retinopathy was 47% (n = 110) and for diabetic macular oedema it was 14.4% (n = 36). In the fully gradable imaging studies, sight-threatening diabetic retinopathy prevalence was 16.2% (n = 38): 14.1% (n = 33) for clinically significant macular oedema, 1.3% (n = 3) for proliferative diabetic retinopathy and 0.9% (n = 2) for both. Sight-threatening diabetic retinopathy had been treated in 78% of detected cases. CONCLUSIONS: A novel telemedicine diabetic retinopathy screening service detected a higher prevalence of 'any' diabetic retinopathy and sight-threatening diabetic retinopathy in a remote primary care setting than reported in earlier surveys among Indigenous and non-Indigenous populations. Whether the observed high prevalence of diabetic retinopathy was attributable to greater detection, increasing diabetic retinopathy prevalence, local factors, or a combination of these requires further investigation and, potentially, specific primary care guidelines for diabetic retinopathy management in remote Australia. Clinical Trials registration number: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN 12616000370404.

TB preventive therapy preferences among children and adolescents.

BACKGROUND: TB preventive therapy (TPT) is critical for ending TB, yet implementation remains poor. With new global guidelines expanding TPT eligibility and regimens, we aimed to understand TPT preferences among children, adolescents and caregivers.METHODS: We undertook a discrete choice experiment among 131 children, 170 adolescents and 173 caregivers, and conducted 17 in-depth interviews in 25 clinics in Cape Town, South Africa. The design included attributes for location, waiting time, treatment duration, dosing frequency, formulation/size, side effects, packaging and taste. Mixed-effects logistic regression models were used for analysis.RESULTS: Among children and caregivers, the number and size of pills, taste and side effects were important drivers of preferences. Among adolescents and caregivers, clinic waiting times and side effects were significant drivers of preferences. Adolescents expressed concerns about being stigmatised, and preferred services from local clinics to services delivered in the community. Dosing frequency and treatment duration were only significant drivers of choice among adolescents, and only if linked to fewer clinic visits.CONCLUSIONS: Introducing shorter TPT regimens in isolation without consideration of preferences and health services may not have the desired effect on uptake and completion. Developing TPT delivery models and formulations that align with preferences must be prioritised.

French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

French practical guidelines for the diagnosis and management of AA amyloidosis.

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.

COVID-19 and tuberculosis in South Africa: A dangerous combination.

There has been much speculation during the past week about the catastrophe that awaits once coronavirus disease 2019 (COVID-19) establishes itself in the poorest communities of South Africa (SA) and, importantly, in informal settlements. Evidence to date suggests that COVID-19 is efficiently passed from infected individuals via large droplets and hard-surface fomites.

When prevention is dangerous: perceptions of isoniazid preventive therapy in KwaZulu-Natal, South Africa.

SETTING: In 2011, the South African government began to offer isoniazid preventive therapy (IPT) through the public health system to presumptively treat latent tuberculous infection (LTBI) among people living with human immunodeficiency virus. OBJECTIVE: To describe IPT perceptions and experiences in three Zulu communities in KwaZulu-Natal Province, South Africa. DESIGN: Using a combination of community-based research and ethnographic methods, we undertook 17 individual and group interviews between October 2014 and May 2015. Interviews transcripts were analysed using qualitative content analysis and validated with grass-roots community advisors. RESULTS: Participants reported multiple ways in which IPT was perceived as dangerous: when costs related to pill collection or consumption were unsustainable, or when daily pill consumption resulted in stigma or was seen to introduce excess dirt or toxins, 'ukungcola', in the body. Theories on dirt are evoked to describe how IPT was perceived as 'matter out of place' when given to people who believed themselves to be healthy, suggesting that under the current TB aetiological model in Zulu culture, 'prevention as tablet' may not fit. CONCLUSION: Implementing IPT without understanding the realities of community stakeholders can unintentionally undermine TB control efforts by worsening the situation for people who already encounter numerous daily problems.

Nitric oxide inhibition induces early activation of type I collagen gene in renal resistance vessels and glomeruli in transgenic mice. Role of endothelin.

Hypertension is often associated with the development of nephroangio- and glomerulo-sclerosis. This pathophysiological process is due to increased extracellular matrix protein, particularly type I collagen, accumulation. This study investigated whether nitric oxide (NO) synthesis is involved in the mechanism(s) regulating activation of the collagen I gene in afferent arterioles and glomeruli. Experiments were performed on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter [procolalpha2(I)]. Measurements of luciferase activity provide highly sensitive estimates of collagen I gene activation. NO synthesis was inhibited by NG-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg per day) for a period of up to 14 wk. Systolic blood pressure was increased after 6 wk of treatment (117+/-2 versus 129+/-2 mmHg, P < 0.01) and reached a plateau after 10 wk (around 160 mmHg). Luciferase activity was increased in freshly isolated afferent arterioles and glomeruli as early as week 4 of L-NAME treatment (150 and 200% of baseline, P < 0.01, respectively). The activation of procolalpha2(I) became more pronounced with time, and at 14 wk increased four- and tenfold compared with controls in afferent arterioles and glomeruli, respectively (P < 0.001). In contrast, luciferase activity remained unchanged in aorta and heart up to 8 wk and was increased thereafter. Increased histochemical staining for extracellular matrix deposition, and particularly of collagen I, was detected in afferent arterioles and glomeruli after 10 wk of L-NAME treatment. This fibrogenic process was accompanied by an increased urinary excretion rate of endothelin. In separate experiments, the stimulatory effect of L-NAME on collagen I gene activation was abolished when animals were treated with bosentan, an endothelin receptor antagonist. Similarly, bosentan reduced the increased extracellular matrix deposition in afferent arterioles and glomeruli during NO inhibition. Interestingly, bosentan had no effect on the L-NAME- induced increase of systolic pressure. These data indicate that NO inhibition induces an early activation of the collagen I gene in afferent arterioles and glomeruli. This activation in the kidney precedes the increase in blood pressure and the procolalpha2(I) activation in heart and aorta, suggesting a specific renal effect of NO blockade on collagen I gene expression that is independent of increased blood pressure and, at least partly, mediated through stimulation of the endothelin receptor. Use of procolalpha2(I) transgenic mice provides a novel and efficient model to study the pathophysiological mechanism(s) regulating renal fibrosis.

[Renal hemodynamics and development of renal fibrotic lesions during hypertension]. / Dissociation entre l'hémodynamique rénale et les lésions histologiques rénales induites par l'hypertension artérielle.

Hypertension is frequently associated with the development of renal fibrosis leading to chronic renal failure. The objective of the present study was to evaluate the role of blood pressure and renal hemodynamics on the development of renal lesions during hypertension. To this end, rats were treated with a NO synthase inhibitor, L-NAME, for 4 weeks. At this time point, systolic blood pressure reached 170 mmHg, renal blood flow dropped to 3.3 +/- 0.7 ml/min and kidneys displayed glomerular and tubulo-interstitial lesions as evidenced by histological analysis. Thereafter, L-NAME treatment was combined with an AT1 receptor antagonist, losartan (30 mg/kg/d), for an additional period of 4 weeks. Treatment with losartan for 4 additional weeks did not significantly modify hypertension (168 mmHg) either the degree of tubulo-interstitial lesions; in contrast, a significant regression of ischemic and sclerotic glomerular lesions was observed. In parallel, renal blood flow was significantly improved by losartan (5.2 +/- 0.8 ml/min). In addition a negative correlation was observed between renal blood flow and index of glomerulosclerosis (r = -0.82), whereas tubulo-intarstitial damage was positively correlated to systemic pressure (r = 0.93). In conclusion, inhibition of the local effects of angiotensin II alleviates the fall of renal blood flow consecutive to NO deficiency and reduces the morphological and functional lesions of glomeruli, independently of the changes in blood pressure. In contrast, tubulo-interstitial lesions are not correlated with the levels of renal blood flow and do not regress with the blockade of AT1 receptors when rats remain hypertensive.

Angiotensin II activates collagen type I gene in the renal vasculature of transgenic mice during inhibition of nitric oxide synthesis: evidence for an endothelin-mediated mechanism.

BACKGROUND: Hypertension is frequently associated with renal vascular fibrosis. The purpose of this study was to investigate whether angiotensin II (Ang II) is involved in this fibrogenic process. METHODS AND RESULTS: Experiments were performed on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Hypertension was induced by chronic inhibition of NO synthesis (N(G)-nitro-L-arginine methyl ester, L-NAME). Procolalpha(2)(I) activity started to increase in the renal vasculature after 4 weeks of L-NAME treatment (P<0.01) and at 14 weeks reached 3- and 8-fold increases over control in afferent arterioles and glomeruli, respectively (P<0.001). Losartan, an AT(1) receptor antagonist, given simultaneously with L-NAME prevented the increase of procolalpha(2)(I) levels and attenuated the development of renal vascular fibrosis without normalizing systolic pressure increase. Because we found previously that endothelin mediated renal vascular fibrosis in the L-NAME model, the interaction between Ang II, endothelin, and procolalpha(2)(I) was investigated in ex vivo and short-term in vivo experiments. In both conditions, the Ang II-induced activation of procolalpha(2)(I) in renal cortex was blocked by an endothelin receptor antagonist. CONCLUSIONS: During chronic inhibition of NO, the collagen I gene becomes activated, leading to the development of renal vascular fibrosis. Ang II is a major player in this fibrogenic process, and its effect on collagen I gene is independent of systemic hemodynamics and is at least partly mediated by the profibrogenic action of endothelin.

Diagnostic accuracy of the Xpert® MTB/RIF assay for extra-pulmonary tuberculosis: a meta-analysis.

BACKGROUND: Xpert(®) MTB/RIF is a commercially available nucleic acid amplification test developed for the diagnosis of pulmonary tuberculosis (PTB). OBJECTIVE: To determine the diagnostic accuracy of Xpert for the detection of extra-pulmonary tuberculosis (EPTB). METHODS: We searched MEDLINE, EMBASE and Global Health databases from January 2010 to 15 August 2014 for studies of diagnostic performance in which Xpert was examined against culture for patients with clinically suspected EPTB. Bivariate random effects models were used to provide pooled estimates of diagnostic accuracy. RESULTS: Thirty-six studies were identified, with a pooled sensitivity and specificity of respectively 77% (95%CI 66-85) and 97% (95%CI 94-98). Substantial variations existed between study estimates of sensitivity (I(2) = 99%) and specificity (I(2) = 96%). Among site-specific estimates for lymph, pleural fluid, cerebrospinal fluid, gastro-intestinal and urinary samples, the pooled sensitivity was lower in pleural fluid (37%, 95%CI 26-50, meta-regression P < 0.001) and higher in lymph node samples (87%, 95%CI 75-95, meta-regression P = 0.03). CONCLUSION: Xpert has high specificity but limited sensitivity for the detection of EPTB. Although positive Xpert test results may be useful in rapidly identifying EPTB cases, negative test results provide less certainty for ruling out disease.

MPO-ANCA necrotizing glomerulonephritis related to rheumatoid arthritis.

Two patients with rheumatoid arthritis (RA) developed necrotizing crescentic glomerulonephritis with high titers of anti-myeloperoxidase antibodies (MPO) in the absence of overt extrarenal vasculitis. We therefore suggest that in some patients with RA, MPO-ANCA necrotizing glomerulonephritis (GN) may occur as a kidney-limited form of rheumatoid vasculitis, and that RA should be added to the list of diseases potentially associated with necrotizing GN with anti-MPO antibodies. These observations also point out the importance of repeatedly evaluating titers of anti-MPO antibodies in the course of RA, especially if renal impairment or abnormal urinary sediment are present.

A study of "broken appointment" patients in a children's hospital dental clinic.

Part I of this study investigated possible variables determining "High Risk No Show" behavior on the part of patients in a dental clinic. Only "source of payment" seemed important; namely, that Medicaid patients were statistically more likely to be "High Risk No Show" patients (P less than .001). Race was associated but was found to be confounded with Medicaid. In an attempt to investigate the reasons for the Medicaid group being "High Risk No Show" patients, Part II of the study compared three distinct groups of patients at the Children's Hospital Medical Center Clinic. These included the self-paying group and the Medicaid group of the original sample of 90 in addition to the Union plan group (patients receiving free third-party payment care as an employee benefit). It was shown that both groups with third-party coverage were associated with "High Risk No Show" behavior. The type of "No Show" behavior, however, was different for the two groups. Union plan patients tended to cancel appointments or at least notify in advance of inability to keep an appointment. Medicaid patients, conversely, were just as likely to fail appointments and not file advance notice of inability to keep an appointment.

A deep model of the incidence of dental caries on proximal surfaces.

As a component of an analysis of the benefits of alternative frequencies of bitewing radiographs to detect dental caries, the authors developed and validated a model to generate an individual's probability distribution for new carious lesions in a year. The model postulates two sources of variability in caries incidence--differences in individuals' underlying caries susceptibilities and a random component. The model is used to examine the nature of caries risk over time. The large random fluctuations in an individual's caries susceptibility from year to year, combined with the random nature of caries attack, makes it difficult to predict future caries experience from the individual's caries experience in the recent past. By modeling the process giving rise to observed incidence data rather than focusing directly on the observed data, i.e., by developing a deep rather than a surface model, the authors have elucidated underlying disease dynamics and provided a basis for generalizing from the particular data used to develop the model.

A longitudinal analysis from bite-wing radiographs of the rate of progression of approximal carious lesions through human dental enamel.

Four to ten years of serial bite-wing radiographs from over 700 children from five groups, three in Sweden and two in the U.S., were interpreted. By analysing changes in the depth of unfilled lesions over time, the mean time and probability distribution for the time a lesion remains in both the outer half and inner half of the enamel were estimated. The procedure incorporated information on filled lesions and non-progressing lesions and thus minimized bias that results in overestimation of the progression rate. In primary teeth, in both the U.S. and Swedish groups, it took on average 12 months for a lesion to progress through the outer half of the enamel and on average 10-12 months for a lesion to progress through the inner half. In newly-erupted first permanent molars, it took 21-23 months for a lesion to progress through the outer half of the enamel and between 19 (U.S. data) and 28 months (Swedish data) for progression through the inner half. In older adolescents in the two Swedish groups, progression was slower: 38-41 months through the outer-half and 47-56 months through the inner-half. In older U.S. adolescents, progression appeared to be more rapid: 16 months through the outer half of the enamel and 27 months through the inner half. The duration of time a lesion remains in different halves of the enamel could be approximated by a piecewise exponential or exponential probability distribution, which exhibits extreme variability. Assuming duration in each half of the enamel follows an exponential distribution with a mean of 2 yr, about 10 per cent of new lesions will progress through the enamel in one year and 25 per cent in two years. However, over 40 per cent of the lesions will not have progressed in 4 yr. There were no consistent differences in the rate of progression by sex, between upper and lower dentitions, for premolars versus molars, or between high and low-risk individuals.

A longitudinal study of multiple approaches to dental health education.

An evaluation was made of the separate effects on oral hygiene of token reward treatments, discovery (project) learning, and plaque staining feedback demonstrations with children in the first through fifth grades. Both short- and long-term effects were assessed in an open classroom setting. Twenty classrooms were non-randomly assigned to treatment and control groups. Plaque scores were recorded according to the Podshadley Patient Hygiene Performance Index (PHP) at time T0, before initiation of any of the educational interventions; and again at times T1, T2, and T3; 7 days, 74 days and 255 days, respectively, following cessation of the educational interventions. The combination of dental health interventions at this school had short-range effects at every grade level, and those effects persisted for 9 months among the third and fourth graders. It was not possible to identify which of the various treatments produced the observed differences, although the project learning method was generally less effective. A linear regression analysis was used to evaluate the shifts in oral hygiene behavior, a method not previously used in studies of this type.

Use of the Kaplan-Meier estimate to reduce biases in estimating the rate of caries progression.

An important determinant of how often to perform dental radiography is how rapidly dental caries progress. Estimates of the rate of progression of dental caries have been biased by the elimination of filled lesions and non-progressing lesions (i.e. censored data) from the analysis. We illustrate the use of the Kaplan-Meier estimate to incorporate information from these cases and demonstrate the effect of using this information on estimates of the rate of progression of approximal caries.

Study design to reduce biases in estimating the percentage of carious lesions that do not progress within a time period.

Much of the available information on the rate of caries progression comes from studies in which two examinations have been done and the percentage of lesions that do not progress from a carious state between the examinations recorded. Extrapolation from this type of study is subject to two offsetting biases. On the one hand, slow progressing lesions that have been in a state for a long time before the first examination may progress between examinations. When these are counted as lesions that progress within the time period between the two examinations, there will be an underestimation of non-progressing lesions. On the other hand, slow progressing lesions will be over-represented in the sample of lesions detected at the first examination. This will result in an overestimation of non-progressing lesions. We suggest a three examination protocol to minimize these biases.